Patent Publication Number: US-9416139-B2

Title: Spiro ring compound as hepatitis C virus (HCV) inhibitor and uses thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This is a U.S. national stage application of the International Patent Application No. PCT/CN2013/001463, filed Nov. 28, 2013, which claims priorities to Chinese Patent Application No. 201210495665.5, filed Nov. 29, 2012, and No. 201310116312.4, filed Apr. 4, 2013, all of which are incorporated herein by reference in their entirety. 
     FIELD OF THE INVENTION 
     The present invention is in the field of medicine. The invention relates to compounds for treating Hepatitis C virus (HCV) infection, compositions comprising such compounds, the uses and the methods thereof. In particular, the invention relates to spiro ring compounds used as NS5A protein inhibitors. More specially, the invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), pharmaceutical compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein. 
     BACKGROUND OF THE INVENTION 
     HCV is a major human pathogen, infecting an estimated 170 million persons worldwide roughly five times the number infected by human immunodeficiency virus type I. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality. 
     Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40% of patients. Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. The treatment has side effects in many patients, so they do not durably respond to treatment. Thus, new and effective methods of treating HCV infection are urgently needed. 
     HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5′ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame (ORF). 
     Considerable heterogeneity is found within nucleotide and encoded amino acid sequence throughout the HCV genome. At least seven major genotypes have been characterized, and more than 50 subtypes have been described. 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, follows E1 and E2. Additionally, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a function role in the HCV lifecycle (see, for example, Lindenbach et al.,  Nature,  2005, 436, 933-938). 
     The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy. 
     The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease within the N-terminal region of NS3 (also referred herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV. 
     Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. In particular, compounds which are effective to inhibit the function of the NS5A protein are desired. The HCV NS5A protein is described, for example, in Tan et al.,  Virology.  2001, 284, 1-12; and in Park et al.,  J. Biol. Chem.,  2003, 278, 30711-30718. 
     SUMMARY OF THE INVENTION 
     Provided herein are novel spiro ring compounds and methods of their use in treating HCV infection. Specifically, it has been found that the spiro ring compounds disclosed herein, and compositions thereof, are effective as inhibitors of HCV infection, especially the non-structural 5A (NS5A) protein of HCV. 
     In one aspect, provided herein are compounds having Formula (I) as shown below: 
                         
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
 
A is a single bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, or —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                               
A′ is
 
                                           
wherein each X 1  and X 2  is independently O, S, NR 6 , or CR 7 R 7a ;
 
X 4  is (CR 7 R 7a ) n , —Y 1 ═Y 2 —, O, S or NR 6 ;
 
W is a carbocyclyl or heterocyclyl ring;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
Z is (CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b ;
 
each c and d is independently 1 or 2;
 
each a, b, n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2;
 
each of Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each of X and X′ is independently N or CR 7 ;
 
each of Y and Y′ is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent group derived from α-amino acid or an optically isomer thereof, or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12  or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ;
 
each Q 4  and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O) 2 —;
 
each t is independently 0, 1, 2, 3 or 4;
 
each k is independently 0, 1 or 2;
 
each of R 1 , R 2 , R 3  and R 4  is independently H, deuterium, alkyl, heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; or R 1  and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle; or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle;
 
each R 5  is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)- alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalky, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)- alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;
 
each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl;
 
each R 12  is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;
 
or R 11  and R 12  are optionally joined to form a 4-7 membered ring; and
 
and each R 13  and R 13a  is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —NR 11 —(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12 , —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 , NR 6 , CR 7 R 7a , CR 7 , —(CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b —, —(CH 2 ) a —O—(CH 2 ) b —, R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r —, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13a R 13 N-alkyl, R 13 S(═O)-alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, α-amino acid, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle, C 5-12  spiro heterobicycle, alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino and aryloxy is optionally substituted with one or more substituents independently selected from hydroxy, deuterium, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 — or carboxyl-substituted alkoxy.
 
     In some embodiments, W is a C 3-8  carbocyclyl or C 2-10  heterocyclyl ring. 
     In some embodiments, 
                                                                               
wherein each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each X 6  is independently CR 7 R 7a , O, S or NR 6 ;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl; and
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, 
                                                                                                 
wherein each Y 1  and Y 2  is independently N or CH;
 
each X 6  is independently CR 7 R 7a , O, S, or NR 6 ;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro or C 1-6  alkylamino;
 
R 6  is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocycyl-C 1-6 -alkyl, C 3-8  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, wherein A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, or —(CR 8 R 8a ), —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is 
                                                                                                 
A′ is
 
                                           
wherein each X 1  and X 2  is independently O, S, NR 6  or CR 7 R 7a ;
 
Q 4  is —C(═O)—, —S(═O)— or —S(═O) 2 —;
 
each e is independently 0, 1, 2, 3 or 4;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
Z is —(CH 2 ) a —, —CH═CH—, —N═CH, (CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b —;
 
each c and d is independently 1 or 2;
 
each a b n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-8  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
R 6  is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N—C 1-6 -alkyl, R 13 S(═O)—C 1-6 -alkyl, R 13 R 13a N—C(═O)—C 1-6 -alkyl, R 13a R 13 N—C 1-6 -alkoxy, R 13 S(═O)—C 1-6 -alkoxy, R 13 R 13a N—C(═O)—C 1-6 -alkoxy, C 6-10  aryl, C 1-9  heteroaryl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, mercapto, nitro, C 6-10  aryl-C 1-6 -alkyl, C 6-10  arylamino, C 1-9  heteroarylamino or C 6-10  aryloxy;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring; and
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl.
 
     In some embodiments, A is a single bond, —CH 2 —, —(CH 2 ) 2 —, —CH═CH—, —CH═CH—CH 2 —, —N(R 5 )—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R 5 )—, —OC(═O)N(R 5 )—, —OC(═O)O—, —N(R 5 )C(═O)N(R 5 )—, —(R 5 )N—S(═O) 2 —, —S(═O) 2 —, —OS(═O) 2 —, —(R 5 )N—S(═O)—, —S(═O)—, —OS(═O)—, or A is 
                                                                                                 
A′ is
 
                                           
wherein, X 1  is O or S;
 
Y 1  is N or CH;
 
each e is independently 0, 1, 2 or 3;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-8  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 6  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, mercapto or nitro; and
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, wherein each of R 1 , R 2 , R 3  and R 4  is independently H, C 1-8  alkyl, C 1-8  heteroalkyl, C 6-10  aryl-C 1-6 -alkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 1-9  heteroaryl or C 6-10  aryl; or R 1  and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle; or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle. 
     In other embodiments, R 1  and R 2 , together with X—CH they are attached to, or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle. 
     In other embodiments, R 1 , R 2  and Y—X—CH together form one of the following monovalent groups: 
                         
wherein each R 15  is independently H, deuterium, oxo(═O), F, Cl, Br, I, cyano, hydroxy, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 6-10  arylamino, C 6-10  aryloxy, C 1-9  heteroaryl, C 1-9  heteroaryloxy, C 1-9  heteroaryl-C 1-3 -alkyl or C 2-10  heterocyclyl;
 
each R 6  is independently H, deuterium, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  hydroxyalkyl, C 1-3  aminoalkyl, C 1-3  alkoxy-C 1-3 -alkyl, C 1-3  alkylamino-C 1-3 -alkyl, C 1-3  alkylthio-C 1-3 -alkyl, C 6-10  aryl-C 1-3 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each n 1  and n 2  is independently 1, 2, 3 or 4.
 
     In other embodiments, R 3 , R 4  and Y′—X′—CH together form one of the following monovalent groups: 
                         
wherein each R 15  is independently H, deuterium, oxo(═O), F, Cl, Br, I, cyano, hydroxy, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 6-10  arylamino, C 6-10  aryloxy, C 1-9  heteroaryl, C 1-9  heteroaryloxy, C 1-9  heteroaryl-C 1-3 -alkyl or C 2-10  heterocyclyl;
 
each R 6  is independently H, deuterium, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  hydroxyalkyl, C 1-3  aminoalkyl, C 1-3  alkoxy-C 1-3 -alkyl, C 1-3  alkylamino-C 1-3 -alkyl, C 1-3  alkylthio-C 1-3 -alkyl, C 6-10  aryl-C 1-3 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each n 1  and n 2  is independently 1, 2, 3 or 4.
 
     In some embodiments, the compound may have formula (II): 
                         
wherein,
 
                                           
wherein each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a )—, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ), —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                                                 
A′ is
 
                                           
X 1  is O, S, NR 6 , or CR 7 R 7a ;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — aminosulfonyl;
 
each R 5a  and R 6a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  aliphatic, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 1-9  heteroaryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  aliphatic, C 2-6  heteroalkyl, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2; and
 
each of Y 4  and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CHR 5a —, —CR 5a R 6a —, —CH 2 S(═O) r , or —CH 2 N(R 6 )—.
 
     In some embodiments, the compound may have formula (II′): 
                         
wherein
 
                                                             
wherein each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each X 6  is independently CH 2 , O, S or NR 6 ;
 
A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p , —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p , —(CR 8 R 8a ) n —S(═O) r O—(CR 8 R 8a )—, (CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p , —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                                                 
A′ is
 
                                           
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 5a  and R 6a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  aliphatic, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 1-9  heteroaryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  aliphatic, C 2-6  heteroalkyl, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2; and
 
each of Y 4  and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CR 5a R 6a —, CHR 5a —, —CH 2 S(═O) r , or —CH 2 N(R 6 )—.
 
     In other embodiments, the compound may have formula (III): 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (IV): 
                         
Wherein each of Q 2  and Q 3  is independently O, S, C(═O), NR 6 , or CH 2 .
 
     In other embodiments, the compound may have formula (V): 
                         
wherein e is 1, 2, 3 or 4.
 
     In other embodiments, the compound may have formula (III′): 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (IV′): 
                         
wherein each of Q 2  and Q 3  is independently O, S, C(═O), NR 6 , or CH 2 .
 
     In other embodiments, the compound may have formula (V′): 
                         
wherein e is 1, 2, 3 or 4.
 
     In some embodiments, each of Y and Y′ is independently a monovalent group derived from an α-amino acid which is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, I, hydroxy or cyano. 
     In other embodiments, the α-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophane, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline. 
     In other embodiments, the α-amino acid is in the D configuration. 
     In other embodiments, the α-amino acid is in the L configuration. 
     In some embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12  or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ]k-C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —C(═O)—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—C(═O)—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —C(═O)—O—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—C(═O)—O—R 13 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—R 12  wherein R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring. 
     In other embodiments, each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl; 
     each R 12  is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl;
 
or R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each t is independently 0, 1, 2, 3 or 4; and
 
each k is independently 0, 1 or 2.
 
     In other embodiments, each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl; 
     each R 12  is independently —C(═O)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl; 
     or R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring; and 
     each R 13  and R 13a  is independently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl. 
     In other embodiments, the compound may have formula (VI): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl; wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In other embodiments, the compound may have formula (VII): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-3  hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9  heteroaryl;
 
wherein each of C 1-3  hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl and C 1-9  heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (VIII): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl;
 
each n 2  is independently 1, 2, 3 or 4; and
 
wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (IX): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl;
 
each n 1  is independently 1, 2, 3 or 4; and
 
wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (X): 
                         
wherein R 5a  is H, deuterium, methyl, ethyl, F, Cl, Br or I;
 
each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl or tert-butyl;
 
each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy,
 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, methoxy, ethoxy, benzyl, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
wherein
 
                                           
wherein Bn is benzyl;
 
A is
 
                                                             
A′ is
 
                                           
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (XI): 
                         
wherein, each R 5a  is independently H, deuterium, C 1-4  alkyl, F, Cl, Br or I;
 
i is 1, 2, 3 or 4;
 
each of Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each of e and f is independently 0, 1, 2, 3 or 4;
 
Q 4  is —C(═O)—, —S(═O)— or —S(═O) 2 ;
 
X 1  is O, NR 6  or CR 7 R 7a ;
 
each of Y 1  and Y 2  is independently N or CR 7 ;
 
each R 6 , R 7  and R 7a  is independently H, deuterium, C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
each of R 14  and R 14a  is independently H, deuterium, C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
each of R 16  and R 16a  is independently hydroxy, C 1-4  alkoxy, C 6-10  aryloxy, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
wherein each of C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl and C 6-10  aryloxy is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
A is
 
                                                             
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In other embodiments, each R 5a  is independently H, deuterium, methyl, ethyl, F, Cl, Br or I; 
     each R 7  is independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; 
     each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl or tert-butyl; 
     each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy, 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (X′): 
                         
wherein R 5a  is independently H, deuterium, methyl, ethyl, F, Cl, Br or I;
 
each of Q 1  and Q 2  is independently CH 2 , C(═O), CF 2 , O, NR 6  or S;
 
X 6  is O, S, NH or CH 2 ;
 
R 6  is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
 
each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isobutyl, isopropyl or tert-butyl;
 
each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy,
 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
A is
 
                                                             
A′ is
 
                                           
wherein
 
                                           
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In another aspect, the present disclosure provides a pharmaceutical composition comprising any one of the above compounds. 
     In some embodiments, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 
     In certain embodiments, the pharmaceutical composition disclosed herein further comprises an anti-HCV agent. 
     In other embodiments, the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine-5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof. 
     In other embodiments, the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof. 
     In other embodiments, the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor. 
     In some embodiments, the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function. 
     In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress. 
     In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. 
     In another aspect, use of the compound or the pharmaceutical composition in inhibiting at least one of HCV replication process and HCV viral protein function is provided. 
     In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress. 
     In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. 
     In another aspect, use of the compound or the pharmaceutical composition disclosed herein for preventing, managing, treating or lessening the severity of HCV infection and a HCV disorder in a patient is provided, which comprises administering a therapeutically effective amount of the (a) compound or pharmaceutical composition disclosed herein to the patient. 
     In another aspect, the compound or the pharmaceutical composition disclosed herein for use in inhibiting at least one of HCV replication process and HCV viral protein function is provided. In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. 
     In another aspect, the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient is provided. 
     In another aspect, a method of inhibiting at least one of HCV replication process and HCV viral protein function is provided. In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. 
     In another aspect, a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient is provided, which comprises administering a therapeutically effective amount of the (a) compound or pharmaceutical composition disclosed herein to the patient. 
     In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (II′), (III′), (IV′), (V′) or (X′). 
     The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Definitions and General Terminology 
     Reference will now be made in detail to certain embodiments disclosed herein, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope disclosed herein as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice disclosed herein. Described herein is in no way limited to the methods and materials. In the event that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. 
     As used herein, the following definitions shall be applied unless otherwise indicated. For purposes disclosed herein, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the  Handbook of Chemistry and Physics,  75th Ed. 1994. Additionally, general principles of organic chemistry are described in Sorrell et al., “ Organic Chemistry ”, University Science Books, Sausalito: 1999, and Smith et al., “ March&#39;s Advanced Organic Chemistry ”, John Wiley &amp; Sons, New York: 2007, all of which are incorporated herein by reference in their entireties. 
     As described herein, compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”. In general, the term “substituted” whether preceded by the term “optionally” or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Wherein the substituents described herein include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (═O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     The term “aliphatic” or “aliphatic group” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. In some embodiments, the aliphatic group contains 1-10 carbon atoms. In other embodiments, the aliphatic group contains 1-8 carbon atoms. In still other embodiments, the aliphatic group contains 1-6 carbon atoms, and in yet other embodiments, the aliphatic group contains 1-4 carbon atoms. In other embodiments, the aliphatic group contains 1-3 carbon atoms. Some non-limiting examples of the aliphatic group include linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups, as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like. 
     The term “haloaliphatic” refers to an aliphatic group substituted with one or more of the same or different halogen atoms (i.e., F, Cl, Br or I), wherein the aliphatic group is as defined herein. Some non-limiting examples of the haloaliphatic group include trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl, and the like. 
     The term “hydroxyaliphatic” refers to an aliphatic group substituted with one or more hydroxy groups, wherein the aliphatic group is as defined herein. Some non-limiting examples of the hydroxyaliphatic group include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like. 
     The term “aminoaliphatic” refers to an aliphatic group substituted with one or more amino groups, wherein the aliphatic group is as defined herein. Some non-limiting examples of the aminoaliphatic group include aminomethyl, 2-aminoethyl, 2-amino isopropyl, and the like. 
     The term “alkyl” refers to a saturated linear or branched chain monovalent hydrocarbon radical of one to twenty carbon atoms, or one to ten carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms, or one to three carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. The examples of the alkyl group include, but are not limited to, methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl, —CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (—CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (—C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (—CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (—CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (—CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (—CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (—CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (—C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (—CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (—CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (—C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (—CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (—C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (—CH(CH 3 )C(CH 3 ) 3 ), 1-heptyl, 1-octyl, and the like. The prefix “alk-” refers to inclusive of both straight chain and branched saturated carbon chain. The term “alkylene” refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylidene, isopropylidene, and the like. 
     The term “alkenyl” refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i.e., a carbon-carbon, sp 2  double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Some non-limiting examples of the alkenyl group include ethenyl or vinyl (—CH═CH 2 ), allyl (—CH 2 CH═CH 2 ), and the like. 
     The term “alkynyl” refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Some non-limiting examples of the alkenyl group include ethynyl (—C≡CH), 2-propynyl or propargyl (—CH 2 C≡CH), and the like. 
     The term “hydroxy-substituted alkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined herein. Some non-limiting examples of the hydroxy-substituted alkyl group include hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like. 
     The term “haloalkyl” refers to an alkyl group substituted with one or more of the same or different halogen atoms (i.e., F, Cl, Br or I), wherein the alkyl group is as defined herein. Some non-limiting examples of the haloalkyl group include trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl, and the like. 
     The term “hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined herein. Some non-limiting examples of the hydroxyalkyl group include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like. 
     The term “aminoalkyl” refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined herein. Some non-limiting examples of the aminoalkyl group include aminomethyl, 2-aminoethyl, 2-amino isopropyl, and the like. 
     The term “alkylene” refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. The alkylene group is optionally substituted with one or more substituents. The substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy. Some non-limiting examples of the alkylene group include methylene (—CH 2 —), ethylidene (—CH 2 —CH 2 —, CH 3 —CH═), isopropylidene, (—CH 2 —CH(CH 3 )—), 2-methoxy-1,1-propylidene, 2-hydroxy-1,1-propylidene, 2-methyl-2-hydroxy-1,1-propylidene, and the like. 
     The term “alkenylene” refers to an unsaturated divalent hydrocarbon group derived from a straight or branched chain alkene by the removal of two hydrogen atoms. The alkenylene group is optionally substituted with one or more substituents. The substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy. Some non-limiting examples of the alkenylene group include ethenylene (—CH═CH—), isopropenylene (—C(CH 3 )═CH—), 3-methoxy-1,1-propenylidene, 2-methyl-1,1-butenylidene, and the like. 
     The term “carbocyclylene” or “cycloalkylene” refers to a saturated divalent hydrocarbon ring derived from a monocyclic ring having 3 to 12 carbon atoms or a bicyclic ring having 7 to 12 carbon atoms by the removal of two hydrogen atoms, wherein the carbocyclyl group or the cycloalkyl group is as defined herein. Some non-limiting examples of the carbocyclylene group include cyclopropylidene, cyclobutylene, cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene, and the like. 
     The term “heterocyclylene” refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has two points of attachment to the rest of the molecule, wherein the heterocyclyl group is as defined herein. Some non-limiting examples of the heterocyclylene group include piperidin-1,4-ylene, piperazin-1,4-ylene, tetrahydrofuran-2,4-ylene, tetrahydrofuran-3,4-ylene, azetidin-1,3-ylene, pyrrolidin-1,3-ylene, and the like. 
     The term “heterocyclylalkylene” refers to a divalent group derived from a heterocyclylalkyl by the removal of two hydrogen atoms, wherein the heterocyclylalkyl group is as defined herein. Some non-limiting examples of the heterocyclylalkylene group include morpholin-4-methylmethylene, piperidin-N-methylmethylene, and the like. 
     The term “haloalkylene” refers to haloalkyl system having two connection points connected to the rest of the molecule, wherein the alkylene group is as defined herein. Some non-limiting examples of the haloalkylene group include difluoromethylene (—CF 2 —). 
     The term “arylene” refers to aryl system having two connection points connected to the rest of the molecule, wherein the aryl radical is as defined herein. Some non-limiting examples of the arylene group include phenylene, p-fluorophenylene, and the like. 
     The term “aralkylene” refers to aralkyl system having two connection points connected to the rest of the molecule, wherein the aralkyl radical is as defined herein. Some non-limiting examples of the aralkylene group include benzylene, phenylethylene, and the like. 
     The term “heteroarylene” refers to heteroaryl system having two connection points connected to the rest of the molecule, wherein the heteroaryl radical is as defined herein. Some non-limiting examples of the heteroarylene group include pyridylene, pyrrylene, thiazolylene, imidazolylene, and the like. 
     The term “heteroarylalkylene” refers to heteroarylalkyl system having two connection points connected to the rest of the molecule, wherein the heteroarylalkyl group is as defined herein. Some non-limiting examples of the heteroarylalkylene group include pyridin-2-ethylene, thiazol-2-methylene, imidazol-2-ethylene, pyrimidin-2-methylene, and the like. 
     The term “fused bicyclylene” refers to fused bicyclyl system having two connection points connected to the rest of the molecule, wherein the fused bicyclyl group is as defined herein. Some non-limiting examples of the fused bicyclylene group include bicyclo[3.1.0]hexane-3,6-ylene. 
     The term “fused heterobicyclylene” refers to fused heterobicyclyl system having two connection points connected to the rest of the molecule, wherein the fused heterobicyclyl group is as defined herein. Some non-limiting examples of the fused heterobicyclylene group include 3-azabicyclo[3.1.0]hexane-3,6-ylene. 
     The term “fused bicyclylalkylene” refers to fused bicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused bicyclylalkyl group is as defined herein. 
     The term “fused heterobicyclylalkylene” refers to fused heterobicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused heterobicyclylalkyl group is as defined herein. 
     The term “spiro bicyclylene” refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein the spiro bicyclyl group is as defined herein. Some non-limiting examples of the spiro bicyclylene group include 5-spiro[2,4]heptane-5,7-ylene, spiro[4,4]nonane-2,7-ylene, and the like. 
     The term “spiro heterobicyclylene” refers to spiro heterobicyclyl system having two connection points connected to the rest of the molecule, wherein the spiro heterobicyclyl group is as defined herein. Some non-limiting examples of the spiro heterobicyclylene group include 5-azaspiro[2,4]heptane-5,7-ylene, 2-azaspiro[4,4]nonane-2,7-ylene, and the like. 
     The term “spiro bicyclylalkylene” refers to spiro bicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the spiro bicyclylalkyl group is as defined herein. 
     The term “spiro heterobicyclylalkylene” refers to spiro heterobicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the spiro heterobicyclylalkyl group is as defined herein. 
     The term “heteroalkyl” refers to alkyl chain inserted with one or more heteroatoms, wherein the alkyl and heteroatom are as defined herein. Unless otherwise specified, the heteroalkyl group contains 1-10 carbon atoms. In other embodiments, the heteroalkyl group contains 1-8 carbon atoms. In still other embodiments, the heteroalkyl group contains 1-6 carbon atoms, and in yet other embodiments, the heteroalkyl group contains 1-4 carbon atoms. In other embodiments, the heteroalkyl group contains 1-3 carbon atoms. Some non-limiting examples of the spiro bicyclylene group include CH 3 OCH 2 —, CH 3 CH 2 OCH 2 —, CH 3 SCH 2 —, (CH 3 ) 2 NCH 2 —, (CH 3 ) 2 CH 2 OCH 2 —, CH 3 OCH 2 CH 2 —, CH 3 CH 2 OCH 2 CH 2 —, and the like. 
     The term “cycloaliphatic”, “carbocycle”, “carbocyclyl” or “cycloalkyl” refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring exclusive of heteroatoms, having 3 to 12 carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system. Some non-limiting examples of the cycloaliphatic group include cycloalkyl, cycloalkenyl and cycloalkynyl. Further examples of the cycloaliphatic group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The term “cycloaliphatic”, “carbocycle”, “carbocyclyl” or “cycloalkyl” may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     The term “cycloalkyloxy” or “carbocyclyloxy” refers to an optionally substituted cycloalkyl or carbocyclyl radical, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like. 
     The term “cycloalkylamino” refers to an amino group substituted with one or two optionally substituted cycloalkyl radicals, wherein the cycloalkyl group is as defined herein. Some non-limiting examples of the cycloalkylamino group include cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, and the like. 
     The term “carbocyclyloxyalkoxy” refers to an alkoxy group substituted with one or more carbocyclyloxy groups, wherein the alkoxy group and carbocyclyloxy group are as defined herein. Some non-limiting examples of the carbocyclyloxyalkoxy group include cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl-3-oxyethoxy, and the like. 
     The term “cycloalkyloxyaliphatic” refers to an aliphatic group substituted with one or more optionally substituted cycloalkyloxy groups, wherein the aliphatic group and cycloalkyloxy group are as defined herein. Some non-limiting examples of the cycloalkyloxyaliphatic group include cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, halocyclopropyloxyethyl, and the like. 
     The term “cycloalkylaminoaliphatic” refers to an aliphatic group substituted with one or more optionally substituted cycloalkylamino groups, wherein the aliphatic group and cycloalkylamino group are as defined herein. Some non-limiting examples of the cycloalkylaminoaliphatic group include cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl, and the like. 
     The term “cycloalkylaliphatic” refers to an aliphatic group substituted with one or more cycloalkyl groups, wherein the cycloalkyl group and aliphatic group are as defined herein. Some non-limiting examples of the cycloalkylaliphatic group include cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like. 
     The term “cycloalkylalkoxy” (“carbocyclylalkoxy”) refers to an alkoxy group substituted with one or more cycloalkyl (carbocyclyl) groups, wherein the cycloalkyl (carbocyclyl) group and alkoxy group are as defined herein. Some non-limiting examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like. 
     The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” as used interchangeably herein refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but not aromatic having a single point of attachment to the rest of the molecule. One or more ring atoms are optionally substituted independently with one or more substituents described herein. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” group is a monocycle having 3 to 7 ring members (e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , PO or PO 2 , with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , PO or PO 2 ). 
     The heterocyclyl may be a carbon radical or heteroatom radical. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring or heterocyclic ring. Some non-limiting examples of the heterocyclic ring include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl (oxiranyl), azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolan-2-yl, 1,3-dioxopenyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinyl, 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphine-4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-diludine-1 (2H)-yl)ethanone-4-yl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, azabicyclo[2,2,2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-c]pyrimidin-6-yl, 4,5,6,7-teterhydro-isoxazole[4,3-c]pyridin-5-yl, 3H-indoxyl-2-oxo-5-azabicyclo[2,2,1]heptan-5-yl, 2-oxo-5-azabicyclo[2,2,2]octan-5-yl, quinolizinyl and N-pyridyl urea. Some non-limiting examples of a heterocyclic ring include 1,1-dioxo-thiomorpholinyl and heterocyclic group wherein 2 carbon atoms on the ring are substituted with oxo (═O) moieties are pyrimidindionyl. The heterocyclic group herein may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═O), hydroxy, amino, halo, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     The term “heterocyclylalkyl” refers to heterocyclic-substituted alkyl radical. The term “heterocyclylalkoxy” refers to heterocyclic-substituted alkoxy radical wherein oxygen atom serves as the attaching point to the rest of the molecule. The term “heterocyclylalkylamino” refers to heterocyclic-substituted alkylamino radical wherein nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkyl, alkoxy and alkylamino group are as defined herein. Some non-limiting examples of the heterocyclylalkyl group include pyrrol-2-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, and the like. 
     The term “heterocyclylaliphatic” refers to heterocyclic-substituted aliphatic group, wherein the heterocyclic group and aliphatic group are as defined herein. Some non-limiting examples of the heterocyclylaliphatic group include pyrrol-2-ylmethyl, piperidin-2-ylethyl, piperazin-2-ylethyl, piperidin-2-ylmethyl, and the like. 
     The term “heterocyclyloxy” refers to optionally substituted heterocyclyl radical, as defined herein, connected to an oxygen atom, and the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the heterocyclyloxy group include pyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy, and the like. 
     The term “heterocyclylamino” refers to an amino group substituted with one or two heterocyclyl groups, wherein nitrogen atom serves as the attaching point to the rest of the molecule and the heterocyclyl group is as defined herein. Some non-limiting examples of the heterocyclylamino group include pyrrol-2-ylamino, pyrrol-3-ylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperazin-2-ylamino, dipyrrol-2-ylamino, and the like. 
     The term “heterocyclyloxyalkoxy” refers to an alkoxy radical substituted with one or more heterocyclyloxy groups, wherein the alkoxy group and heterocyclyloxy group are as defined herein. Some non-limiting examples of the heterocyclyloxyalkoxy group include pyrrol-2-yloxymethoxy, pyrrol-3-yloxyethoxy, piperidin-2-yloxyethoxy, piperidin-3-yloxyethoxy, piperazin-2-yloxymethoxy, piperidin-4-yloxyethoxy, and the like. 
     The term “heterocyclyloxyaliphatic” refers to an aliphatic group substituted with one or more heterocyclyloxy groups, wherein the aliphatic group and heterocyclyloxy group are as defined herein. Some non-limiting examples of the heterocyclyloxyaliphatic group include pyrrol-2-yloxymethyl, piperazin-3-yloxyethyl, piperazin-2-yloxyethyl, morpholin-2-yloxymethyl, piperidin-2-yloxyethyl, and the like. 
     The term “heterocyclylaminoaliphatic” refers to an aliphatic group substituted with one or more heterocyclylamino groups, wherein the aliphatic group and heterocyclylamino group are as defined herein. Some non-limiting examples of the heterocyclylaminoaliphatic group include pyrrol-2-ylaminomethyl, piperazin-3-lyaminoethyl, piperazin-2-lyaminoethyl, piperidin-2-lyaminoethyl, morpholin-2-lyaminomethyl, and the like. 
     The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl). 
     The term “halogen” or “halo” refers to F, Cl, Br or I. 
     The term “unsaturated” as used herein, refers to a moiety having one or more units of unsaturation. 
     The term “alkoxy” refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen atom. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy defined above may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxy, amino, halo, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like. 
     The term “hydroxy-substituted alkoxy” or “hydroxyalkoxy” refers to an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group is as defined above. Some non-limiting examples of the hydroxyalkoxy group include hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, and the like. 
     The term “aminoalkoxy” refers to an alkoxy group substituted with one or more amino groups, wherein the alkoxy group is as defined above. Some non-limiting examples of the aminoalkoxy group include aminomethoxy, 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, and the like. 
     The term “azidoalkoxy” refers to an alkoxy group substituted with one or more azido groups, wherein the alkoxy group is as defined above. Some non-limiting examples of the azidoalkoxy group include 2-azidoethoxy, 3-azidopropoxy, 2-azidopropoxy, and the like. 
     The term “alkoxyalkoxy” refers to an alkoxy group substituted with one or more alkoxy groups, wherein the alkoxy group is as defined above. Some non-limiting examples of the alkoxyalkoxy group include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, and the like. 
     The term “alkoxyaliphatic” refers to an aliphatic group substituted with one or more alkoxy groups, wherein the aliphatic group and alkoxy group are as defined herein. Some non-limiting examples of the alkoxyaliphatic group include methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl, and the like. 
     The term “alkylaminoaliphatic” refers to an aliphatic group substituted with one or more alkylamino groups, wherein the aliphatic group and alkylamino group are as defined herein. Some non-limiting examples of the alkylaminoaliphatic group include dimethylaminoethyl, methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like. 
     The term “alkylthioaliphatic” refers to an aliphatic group substituted with one or more alkylthio groups, wherein the aliphatic group and alkylthio group are as defined herein. Some non-limiting examples of the alkylthioaliphatic group include methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl, and the like. 
     The term “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to an alkyl group, alkenyl group or alkoxy group substituted with one or more halogen atoms. Some non-limiting examples of the haloalkyl group include trifluoromethyl, 2-chloro-ethenyl, trifluoromethoxy, and the like. 
     The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “arylalkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term “aryl” may be used interchangeably with the term “aryl ring”. Some non-limiting examples of the aryl ring include phenyl, naphthyl and anthryl. The aryl may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     The term “arylaliphatic” refers to an aliphatic group substituted with one or more optionally substituted aryl groups, wherein the aliphatic group and the aryl group are as defined herein. Some non-limiting examples of the arylaliphatic group include phenylethyl, benzyl, (p-tolyl)ethyl, styryl, and the like. 
     The term “aryloxy” refers to optionally substituted aryl radicals, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Wherein the aryl radical is as defined herein. Some non-limiting examples of the aryloxy group include phenyloxy, methylphenyloxy, ethylphenyloxy, and the like. 
     The term “arylamino” refers to an amino group substituted with one or two optionally substituted aryl groups, wherein the aryl group is as defined herein. Some non-limiting examples of the arylamino group include phenylamino, (p-fluorophenyl)amino, diphenylamino, ditolylamino, (di-p-tolyl)amino, and the like. 
     The term “aryloxyalkoxy” refers to an alkoxy group substituted with one or more optionally substituted aryloxy groups, wherein the alkoxy group and the aryloxy group are as defined herein. Some non-limiting examples of the aryloxyalkoxy group include phenyloxymethoxy, phenyloxyethoxy, phenyloxypropoxy, and the like. 
     The term “aryloxyaliphatic” refers to an aliphatic group substituted with one or more optionally substituted aryloxy groups, wherein the aryloxy group and the aliphatic group are as defined herein. Some non-limiting examples of the aryloxyaliphatic group include phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, and the like. 
     The term “arylaminoaliphatic” refers to an aliphatic group substituted with one or more optionally substituted arylamino groups, wherein the arylamino group and the aliphatic group are as defined herein. Some non-limiting examples of the arylaminoaliphatic group include phenylaminomethyl, phenylaminoethyl, tolylaminoethyl, phenylaminopropyl, phenylaminoallyl, and the like. 
     The term “arylalkoxy” refers to an alkoxy group substituted with one or more optionally substituted aryl groups, wherein the aryl group and the alkoxy group are as defined herein. Some non-limiting examples of the arylalkoxy group include phenylmethoxy, phenylethoxy, (p-tolyl)methoxy, phenylpropoxy, and the like. 
     The term “arylalkylamino” refers to an alkylamino group substituted with one or more optionally substituted aryl groups, wherein the aryl group and the alkylamino group are as defined herein. Some non-limiting examples of the aryloxyalkoxy group include phenylmethylamino, phenylethylamino, phenylpropylamino, (p-tolyl)methylamino, and the like. 
     The term “heteroaryl” used alone or as part of a larger moiety as in “heteroarylalkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or “heteroaromatic compound”. The heteroaryl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     Some non-limiting examples of the suitable heteroaryl ring include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) or isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl). 
     The term “heteroaryloxy” refers to an optionally substituted heteroaryl radical, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the heteroaryloxy group include pyrid-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy, and the like. 
     The term “heteroaryloxyaliphatic” refers to an aliphatic group substituted with one or more optionally substituted heteroaryloxy groups, wherein the aliphatic group and the heteroaryloxy group are as defined herein. Some non-limiting examples of the heteroaryloxyaliphatic group include pyrid-2-yloxyethyl, thiazol-2-yloxymethyl, imidazol-2-yloxyethyl, pyrimidin-2-yloxypropyl, and the like. 
     The term “sulfonyl”, whether used alone or linked to other terms such as “alkylsulfonyl”, respectively refers to divalent radicals —SO 2 —. 
     The term “alkylsulfonyl”, refers to a sulfonyl radical substituted with an alkyl radical, forming an alkylsulfonyl (—SO 2 -alkyl, such as —SO 2 CH 3 ). 
     The term “sulfamyl”, “aminosulfonyl” or “sulfonamidyl” refers to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (—SO 2 NH 2 ). 
     The term “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, refers to —CO 2 H. 
     The term “carbonyl”, whether used alone or with other terms, such as “aminocarbonyl” or “carbonyloxy”, refers to —(C═O)—. 
     The term “carboxyalkoxy” refers to an alkoxy group substituted with one or more carboxy groups, wherein the alkoxy group and the carboxy group are as defined herein. Some non-limiting examples include carboxymethoxy, carboxyethoxy, and the like. 
     The term “aralkyl” or “arylalkyl” refers to aryl-substituted alkyl radicals. In some embodiments, the aralkyl radical includes “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. In other embodiments, the aralkyl radical includes “phenylalkylenyl” attached to alkyl portions having one to three carbon atoms. Some non-limiting examples of such radical include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl can be additionally substituted with halo, alkyl, alkoxy, haloalkyl or haloalkoxy. 
     The term “alkylthio” refers to radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. In some embodiments, the alkylthio radical includes lower alkylthio radicals having one to three carbon atoms. Some non-limiting examples of “alkylthio” include methylthio (CH 3 S—). 
     The term “haloalkylthio” refers to radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. In some embodiments, the haloalkylthio radical includes lower haloalkylthio radicals having one to three carbon atoms. Some non-limiting examples of “haloalkylthio” include trifluoromethylthio. 
     The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”, wherein amino groups are independently substituted with one alkyl radical or with two alkyl radicals, respectively. In some embodiments, the alkylamino radical includes lower alkylamino radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. In other embodiments, the alkylamino radical includes lower alkylamino radicals having one to three carbon atoms. Some non-limiting examples of the suitable alkylamino radical include mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like. 
     The term “alkylaminohaloalkoxy” refers to a haloalkoxy group substituted with one or more alkylamino groups, wherein the haloalkoxy group and the alkylamino group are as defined herein. Some non-limiting examples of the alkylaminohaloalkoxy group include methylaminodifluoromethoxy, ethylaminotrifluoromethoxy, and the like. 
     The term “heteroarylamino” refers to amino groups substituted with one or two heteroaryl radicals, wherein the heteroaryl radical is as defined herein. Some non-limiting examples of the heteroarylamino include N-thienylamino. In some embodiments, the “heteroarylamino” radical may be further substituted on the heteroaryl ring portion of the radical. 
     The term “heteroarylaliphatic” refers to aliphatic groups substituted with one or more heteroaryl radicals, wherein the heteroaryl group and the aliphatic group are as defined herein. Some non-limiting examples of the heteroarylaliphatic group include thiophen-2-ylpropenyl, pyridin-4-ylethyl, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like. 
     The term “heteroarylalkyl” refers to alkyl groups substituted with one or more heteroaryl radicals, wherein the heteroaryl group and the alkyl group are as defined herein. Some non-limiting examples of the heteroarylalkyl group include imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like. 
     The term “heteroarylalkylamino” refers to nitrogen-containing heteroarylalkyl radicals attached through a nitrogen atom to other radicals, wherein the heteroarylalkyl radical is as defined herein. Some non-limiting examples of the heteroarylalkylamino group include pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, and the like. 
     The term “aminoalkyl” refers to a linear or branched alkyl radical having one to ten carbon atoms, substituted with one or more amino radicals. In some embodiments, the aminoalkyl radical includes “lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Some non-limiting examples of such radical include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. 
     The term “alkylaminoalkyl” refers to alkyl radicals substituted with alkylamino radicals. In some embodiments, the alkylaminoalkyl radical includes “lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. In other embodiments, the alkylaminoalkyl radical includes lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Some non-limiting examples of the suitable alkylaminoalkyl radical may be mono and dialkyl substituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, and the like. 
     The term “carboxyalkyl” refers to a linear or branched alkyl radical having one to ten carbon atoms substituted with one or more carboxy radicals. Some non-limiting examples of such radical include carboxymethyl, carboxypropyl, and the like. 
     The term “aryloxy” refers to optionally substituted aryl radicals, as defined above, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of such radical include phenoxy. 
     The term “heteroarylalkoxy” refers to oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals, wherein the heteroarylalkyl radical is as defined herein. Some non-limiting examples of such radical include pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like. 
     The term “cycloalkylalkyl” refers to cycloalkyl-substituted alkyl radicals. Some non-limiting examples of such radical include cyclohexylmethyl. The cycloalkyl in the radicals may be additionally substituted with deuterium, halo, alkyl, alkoxy or hydroxy. 
     The term “fused bicyclic”, “fused cyclic”, “fused bicyclyl” or “fused cyclyl” refers to unsaturated or saturated fused cyclic system and bridged ring system that is not aromatic. For example, as depicted below (Formula (a1)), ring A1 and ring A2 share a bond that is a alkyl or heteroalkyl chain, wherein j is 0, 1, 2, 3 or 4. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). Each cyclic ring in a fused bicyclyl can be either a carbocyclic or a heteroalicyclic. Some non-limiting examples of the fused bicyclic ring system or bridged ring system include hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene. The fused bicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     
       
         
         
             
             
         
       
     
     The term “fused heterobicyclyl” refers to unsaturated or saturated fused cyclic system and bridged ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). And at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members, e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , PO or PO 2 . Some non-limiting examples of the fused heterobicyclic ring system include hexahydro-furo[3,2-b]furan, 6-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.1.0]heptane, 3-azabicyclo[3.1.0]heptane, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, and the like. The fused heterobicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     The term “spirocyclyl”, “spirocyclic”, “spiro bicyclyl” or “spiro bicyclic” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, ring A and ring B share a carbon atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl”. Each cyclic ring in the spirocyclyl or spiro bicyclyl can be either a carbocyclic or a heteroalicyclic. Some non-limiting examples of such radical include 2,7-diazaspiro[4.4]non-2-yl, 7-oxo-2-azaspiro[4.5]dec-2-yl, 4-azaspiro[2.4]hept-5-yl, 4-oxaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]hept-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl, 7-hydroxy-5-azaspiro[2.4]hept-5-yl, and the like. The spirocyclyl or spiro bicyclyl may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     
       
         
         
             
             
         
       
     
     The term “spiro bicyclylene” refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein the spiro bicyclyl radical is as defined herein. 
     The terms “spiro heterobicyclyl” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted above, ring A and ring B share a carbon atom between the two saturated ring system, which terms as a “spirocyclyl”. And at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members, e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , PO or PO 2 . Some non-limiting examples of such radical include 4-azaspiro[2,4]hept-5-yl, 4-oxaspiro[2,4]hept-5-yl, 5-azaspiro[2,4]hept-5-yl, 7-hydroxy-5-azaspiro[2,4]hept-5-yl, 5-azaspiro[2,4]hept-6-yl, 1,4-dioxo-7-azaspiro[4,4]non-8-yl, and the like. The spiro heterobicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 —, carboxyalkoxy, and the like. 
     As described herein, the group derived from α-amino acid refers to an α-amino acid radical derived from an α-amino acid by the removal of one hydroxy from the carboxy group, which is attached to X or X′, and the group derived from α-amino acid is optionally substituted with one or more substituents, wherein the substituent is deuterium, F, Cl, Br, I, hydroxy or cyano. For example, 
     
       
         
         
             
             
         
       
     
     As described herein, a bond drawn from a substituent to the center of one ring within a ring system (as shown in Formula (a)) represents substitution of the substituent (R 5a ) f  at any substitutable position on the rings (W1, W2, and W). For example, Formula (a) represents possible substitution in any of the positions on the ring W1, W2, and W. 
     
       
         
         
             
             
         
       
     
     As described herein, two attaching points either E or E′, within a ring system (as shown in Formula (b)), attach to the rest of the molecule, e.g., E and E′ may be used interchangeably with each other. 
     
       
         
         
             
             
         
       
     
     As described herein, a dot line drawn together with a bond within a ring system (as shown in Formula (c)) represents either a double bond or a single bond. For example, structure of Formula (c) represents any structures selected from Formula (d). 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric or geometric (or conformational) mixtures of the present compounds are within the scope disclosed herein. 
     Furthermore, what need to be explained is that the phrase “each . . . is independently” is used interchangeably with the phrase “each (of) . . . and . . . is independently”, unless otherwise stated. It should be broadly understood that the specific options expressed by the same symbol are independently of each other in different radicals; or the specific options expressed by the same symbol are independently of each other in same radicals. For example, R 9  of the structure formulas “—U—(CR 9 R 9a ) t —R 12 ” and “—[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ”, whose specific options are independently of each other; meanwhile, multiple R 9  of the structure formula “—[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ”, whose specific options are independently of each other. 
     The term “prodrug” refers to a compound that is transformed in vivo into a compound of formula (I). Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue. Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form. Other prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound. A thorough discussion of prodrugs is provided in Higuchi et al.,  Pro - drugs as Novel Delivery Systems , Vol. 14, A.C.S. Symposium Series; Roche, et al. ed.,  Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications,  Nat. Rev. Drug Discovery,  2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates,  J. Med. Chem.,  2008, 51, 2328-2345, all of which are incorporated herein by reference. 
     Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. 
     A “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. The metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including compounds produced by a process comprising contacting a compound disclosed herein with a mammal for a period of time sufficient to yield a metabolic product thereof. 
     Stereochemical definitions and conventions used herein generally follow Parker et al., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al., “ Stereochemistry of Organic Compounds ”, John Wiley &amp; Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity. 
     The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. 
     A “pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein. The pharmaceutically acceptable salt is well known in the art. For example, Berge et al., describe the pharmaceutically acceptable salt in detail in  J. Pharmacol Sci,  1977, 66: 1-19, which is incorporated herein by reference. Some non-limiting examples of the pharmaceutically salt include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4  alkyl) 4  salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8  sulfonate or aryl sulfonate. 
     A “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of the solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. 
     The term “protecting group” or “Pg” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Some non-limiting examples of the suitable amino-protecting group include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Some non-limiting examples of the suitable hydroxy-protecting group include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Some non-limiting examples of the common carboxy-protecting group include —CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see Greene et al.,  Protective Groups in Organic Synthesis , John Wiley &amp; Sons, New York, 1991 and Kocienski et al.,  Protecting Groups , Thieme, Stuttgart, 2005. 
     It should be noted that the term of “inhibiting HCV viral protein” should be broadly understood, which comprises inhibiting the expression level of HCV viral protein, inhibiting activity level of HCV viral protein, viral assembly and egress level. The expression level of HCV protein includes but not limited to translation level of the viral protein, posttranslational modification level of the viral protein, replication level of genetic material in offsprings and so on. 
     Description of Compounds of the Invention 
     Disclosed herein are spiro ring compounds and pharmaceutical formulations thereof, which are useful in inhibiting HCV infection, especially inhibiting the activity of the non-structural 5A (“NS5A”) protein. 
     In one aspect, provided herein are compounds having Formula (I) as shown below: 
                         
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
 
A is a single bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a )—, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, or —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                                                 
A′ is
 
                                           
wherein each X 1  and X 2  is independently O, S, NR 6 , or CR 7 R 7a ;
 
X 4  is (CR 7 R 7a ) n , —Y 1 ═Y 2 —, O, S or NR 6 ;
 
W is a carbocyclyl or heterocyclyl ring;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
Z is —(CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b ;
 
each c and d is independently 1 or 2;
 
each a, b, n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2;
 
each of Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each of X and X′ is independently N or CR 7 ;
 
each of Y and Y′ is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent group derived from α-amino acid or an optically isomer thereof, or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12  or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ;
 
each Q 4  and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O) 2 —;
 
each t is independently 0, 1, 2, 3 or 4;
 
each k is independently 0, 1 or 2;
 
each of R 1 , R 2 , R 3  and R 4  is independently H, deuterium, alkyl, heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; or R 1  and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle; or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle;
 
each R 5  is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)- alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalky, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)- alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;
 
each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl;
 
each R 12  is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;
 
or R 11  and R 12  are optionally joined to form a 4-7 membered ring; and
 
and each R 13  and R 13a  is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —NR 11 —(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12 , —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 CR 9a ) t ] k —U—(CR 9 CR 9a ) t —O—(CR 9 R 9a ) t —R 12 , NR 6 , CR 7 R 7a , CR 7 , —(CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b —, —(CH 2 ) a —O—(CH 2 ) b —, R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r —, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13a R 13 N-alkyl, R 13 S(═O)-alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, α-amino acid, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle, C 5-12  spiro heterobicycle, alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino and aryloxy is optionally substituted with one or more substituents independently selected from hydroxy, deuterium, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 — or carboxyl-substituted alkoxy.
 
     In some embodiments, W is a C 3-8  carbocyclyl or C 2-10  heterocyclyl ring. 
     In some embodiments, 
                                                                               
wherein each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each X 6  is independently CR 7 R 7a , O, S or NR 6 ;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocycyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocycyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl; and
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a  together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, 
                                                                                                                   
wherein each Y 1  and Y 2  is independently N or CH;
 
each X 6  is independently CR 7 R 7a , O, S, or NR 6 ;
 
each R 5a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro or C 1-6  alkylamino;
 
R 6  is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-8  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, wherein A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p — or —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is 
                                                                                                 
A′ is
 
                                           
wherein each X 1  and X 2  is independently O, S, NR 6  or CR 7 R 7a ;
 
Q 4  is —C(═O)—, —S(═O)— or —S(═O) 2 —;
 
each e is independently 0, 1, 2, 3 or 4;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
Z is —(CH 2 ) a , —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b —;
 
each c and d is independently 1 or 2;
 
each a b n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-8  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
R 6  is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N—C 1-6 -alkyl, R 13 S(═O)—C 1-6 -alkyl, R 13 R 13a N—C(═O)—C 1-6 -alkyl, R 13a R 13 N—C 1-6 -alkoxy, R 13 S(═O)—C 1-6 -alkoxy, R 13 R 13a N—C(═O)—C 1-6 -alkoxy, C 6-10  aryl, C 1-9  heteroaryl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, mercapto, nitro, C 6-10  aryl-C 1-6 -alkyl, C 6-10  arylamino, C 1-9  heteroarylamino or C 6-10  aryloxy;
 
each R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 6-10  aryloxy-C 1-6 -alkyl, C 2-10  heterocyclyloxy-C 1-6 -alkyl, C 3-10  cycloalkyloxy-C 1-6 -alkyl, C 6-10  arylamino-C 1-6 -alkyl, C 2-10  heterocyclylamino-C 1-6 -alkyl, C 3-10  cycloalkylamino-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring; and
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl.
 
     In some embodiments, A is a single bond, —CH 2 —, —(CH 2 ) 2 —, —CH═CH—, —CH═CH—CH 2 —, —N(R 5 )—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R 5 )—, —OC(═O)N(R 5 )—, —OC(═O)O—, —N(R 5 )C(═O)N(R 5 )—, —(R 5 )N—S(═O) 2 —, —S(═O) 2 —, —OS(═O) 2 —, —(R 5 )N—S(═O)—, —S(═O)—, —OS(═O)—, or A is 
                                                                                                 
A′ is
 
                                           
wherein, X 1  is O or S;
 
Y 1  is N or CH;
 
each e is independently 0, 1, 2 or 3;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-8  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 6  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  aminoalkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 1-6  alkylthio-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl;
 
each R 6a  is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, mercapto or nitro; and
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring.
 
     In some embodiments, wherein each of R 1 , R 2 , R 3  and R 4  is independently H, C 1-8  alkyl, C 1-8  heteroalkyl, C 6-10  aryl-C 1-6 -alkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 1-9  heteroaryl or C 6-10  aryl; or R 1  and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle; or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle. 
     In other embodiments, R 1  and R 2 , together with X—CH they are attached to, or R 3  and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle, C 5-12  fused bicycle, C 5-12  fused heterobicycle, C 5-12  spiro bicycle or C 5-12  spiro heterobicycle. 
     In other embodiments, R 1 , R 2  and Y—X—CH together form one of the following monovalent groups: 
                         
wherein each R 15  is independently H, deuterium, oxo(═O), F, Cl, Br, I, cyano, hydroxy, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 6-10  arylamino, C 6-10  aryloxy, C 1-9  heteroaryl, C 1-9  heteroaryloxy, C 1-9  heteroaryl-C 1-3 -alkyl or C 2-10  heterocyclyl;
 
each R 6  is independently H, deuterium, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  hydroxyalkyl, C 1-3  aminoalkyl, C 1-3  alkoxy-C 1-3 -alkyl, C 1-3  alkylamino-C 1-3 -alkyl, C 1-3  alkylthio-C 1-3 -alkyl, C 6-10  aryl-C 1-3 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each n 1  and n 2  is independently 1, 2, 3 or 4.
 
     In other embodiments, R 3 , R 4  and Y′—X′—CH together form one of the following monovalent groups: 
                         
wherein each R 15  is independently H, deuterium, oxo(═O), F, Cl, Br, I, cyano, hydroxy, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 6-10  arylamino, C 6-10  aryloxy, C 1-9  heteroaryl, C 1-9  heteroaryloxy, C 1-9  heteroaryl-C 1-3 -alkyl or C 2-10  heterocyclyl;
 
each R 6  is independently H, deuterium, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  hydroxyalkyl, C 1-3  aminoalkyl, C 1-3  alkoxy-C 1-3 -alkyl, C 1-3  alkylamino-C 1-3 -alkyl, C 1-3  alkylthio-C 1-3 -alkyl, C 6-10  aryl-C 1-3 -alkyl, C 1-9  heteroaryl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; and
 
each n 1  and n 2  is independently 1, 2, 3 or 4.
 
     In some embodiments, the compound may have formula (II): 
                         
wherein,
 
                                           
wherein each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each Y 1  and Y 2  is independently N or CR 7 ;
 
A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p , —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) r —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                                                 
A′ is
 
                                           
X 1  is O, S, NR 6  or CR 7 R 7a ;
 
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 5a  and R 6a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 C(═O) R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 , R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  aliphatic, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 1-9  heteroaryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  aliphatic, C 2-6  heteroalkyl, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2; and
 
each of Y 4  and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CHR 5a —, —CR 5a R 6a , —CH 2 S(═O) r , or —CH 2 N(R 6 )—.
 
     In some embodiments, the compound may have formula (II′): 
                         
wherein
 
                                                             
wherein each Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;
 
each e and f is independently 0, 1, 2, 3 or 4;
 
each X 3  and X 5  is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;
 
each X 6  is independently CH 2 , O, S or NR 6 ;
 
A is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 3-8  cycloalkylene, C 2-10  heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is
 
                                                                                                                   
A′ is
 
                                           
each R 5  is independently H, deuterium, hydroxy, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 5a  and R 6a  is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6  alkylacyl, C 1-6  alkylacyloxy, C 1-6  alkoxyacyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfinyloxy, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy;
 
each R 6  is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6  aliphatic, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 1-9  heteroaryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each of R 7  and R 7a  is independently H, deuterium, F, Cl, Br, I, C 1-6  aliphatic, C 2-6  heteroalkyl, C 1-6  alkoxy-C 1-6 -aliphatic, C 1-6  alkylamino-C 1-6 -aliphatic, C 6-10  aryl-C 1-6 -aliphatic, C 2-10  heterocyclyl-C 1-6 -aliphatic, C 3-10  cycloalkyl-C 1-6 -aliphatic, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-10  carbocyclyl;
 
each R 8  and R 8a  is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  alkoxy, C 1-6  alkyl-OC(═O)—, C 1-6  alkyl-C(═O)—, carbamoyl, C 1-6  alkyl-OS(═O) r —, C 1-6  alkyl-S(═O) r O—, C 1-6  alkyl-S(═O) r — or aminosulfonyl;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each n and p is independently 0, 1, 2 or 3;
 
each r is independently 0, 1 or 2; and
 
each of Y 4  and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CR 5a R 6a —, CHR 5a —, —CH 2 S(═O) r , or —CH 2 N(R 6 )—.
 
     In other embodiments, the compound may have formula (III): 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (IV): 
                         
Wherein each of Q 2  and Q 3  is independently O, S, C(═O), NR 6 , or CH 2 .
 
     In other embodiments, the compound may have formula (V): 
                         
wherein e is 1, 2, 3 or 4.
 
     In other embodiments, the compound may have formula (III′): 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (IV′): 
                         
wherein each of Q 2  and Q 3  is independently O, S, C(═O), NR 6 , or CH 2 .
 
     In other embodiments, the compound may have formula (V′): 
                         
wherein e is 1, 2, 3 or 4.
 
     In some embodiments, each of Y and Y′ is independently a monovalent group derived from an α-amino acid which is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, I, hydroxy or cyano. 
     In other embodiments, the α-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophane, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline. 
     In other embodiments, the α-amino acid is in the D configuration. 
     In other embodiments, the α-amino acid is in the L configuration. 
     In some embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12  or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 ) t —C(═O)—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —C(═O)—O—R 13 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 ) t —C(═O)—O—R 13 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 . 
     In other embodiments, each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—R 12 , wherein R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring. 
     In other embodiments, each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl, C 6-10  aryl-C 1-6 -alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl; 
     each R 12  is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl;
 
or R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring;
 
each R 13  and R 13a  is independently H, deuterium, C 1-6  alkyl, C 2-6  heteroalkyl, C 3-10  cycloalkyl, C 2-10  heterocyclyl, C 6-10  aryl, C 1-9  heteroaryl or C 6-10  aryl-C 1-6 -alkyl; with the proviso that where R 13  and R 13a  are bonded to the same nitrogen atom, R 13  and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;
 
each t is independently 0, 1, 2, 3 or 4; and
 
each k is independently 0, 1 or 2.
 
     In other embodiments, each R 9 , R 9a , R 10  and R 11  is independently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl; 
     each R 12  is independently —C(═O)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl; 
     or R 11  and R 12 , together with the atom they are attached to, form a 4-7 membered ring; and 
     each R 13  and R 13a  is independently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl. 
     In other embodiments, the compound may have formula (VI): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl; wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In other embodiments, the compound may have formula (VII): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-3  hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9  heteroaryl;
 
wherein each of C 1-3  hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl and C 1-9  heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (VIII): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl;
 
each n 2  is independently 1, 2, 3 or 4; and
 
wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (IX): 
                         
wherein each of R 14  and R 14a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl;
 
each n 1  is independently 1, 2, 3 or 4; and
 
wherein each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 2-6  heteroalkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl and C 3-8  cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (X): 
                         
wherein R 5a  is H, deuterium, methyl, ethyl, F, Cl, Br or I;
 
each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl or tert-butyl;
 
each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy,
 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, methoxy, ethoxy, benzyl, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
wherein
 
                                           
wherein Bn is benzyl;
 
A is
 
                                                                               
A′ is
 
                                           
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In other embodiments, the compound may have formula (XI): 
                         
wherein, each R 5a  is independently H, deuterium, C 1-4  alkyl, F, Cl, Br or I;
 
i is 1, 2, 3 or 4;
 
each of Q 1  and Q 2  is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;
 
each of e and f is independently 0, 1, 2, 3 or 4;
 
Q 4  is —C(═O)—, —S(═O)— or —S(═O) 2 ;
 
X 1  is O, NR 6  or CR 7 R 7a ;
 
each of Y 1  and Y 2  is independently N or CR 7 ;
 
each R 6 , R 7  and R 7a  is independently H, deuterium, C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
each of R 14  and R 14a  is independently H, deuterium, C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
each of R 16  and R 16a  is independently hydroxy, C 1-4  alkoxy, C 6-10  aryloxy, C 2-10  heterocyclyl or C 3-8  cycloalkyl;
 
wherein each of C 1-4  alkyl, C 6-10  aryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl and C 6-10  aryloxy is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
A is
 
                                                                               
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In other embodiments, each R 5a  is independently H, deuterium, methyl, ethyl, F, C, Br or I; 
     each R is independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; 
     each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl or tert-butyl; 
     each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy, 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.
 
     In some embodiments, the compound may have formula (X′): 
                         
wherein R 5a  is independently H, deuterium, methyl, ethyl, F, Cl, Br or I;
 
each of Q 1  and Q 2  is independently CH 2 , C(═O), CF 2 , O, NR 6  or S;
 
X 6  is O, S, NH or CH 2 ;
 
R 6  is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
 
each of R 14  and R 14a  is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isobutyl, isopropyl or tert-butyl;
 
each of R 16  and R 16a  is independently hydroxy, methoxy, ethoxy, phenoxy,
 
                         
or tert-butoxy;
 
wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;
 
A is
 
                                                                               
A′ is
 
                                           
wherein
 
                                           
wherein R 1 , R 2  and N—CH together form one of the following divalent groups:
 
                         
wherein R 3 , R 4  and N—CH together form one of the following divalent groups:
 
     
       
         
         
             
             
         
       
     
     In some embodiments, non-limiting examples of compounds disclosed herein, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, are shown in the following: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Provided herein includes the use of a compound disclosed herein (In present disclosure, “a compound disclosed herein” comprises a compound of formula (I), a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate and a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for the treatment either acutely or chronically of HCV infection in a patient, including those described herein. Also provided herein is the use of the compound in the manufacture of an anti-HCV medicament. Provided herein is the use of the compound disclosed herein, in the manufacture of a medicament to attenuate, prevent, manage or treat HCV-mediated disease, especially HCV&#39;s NS5A protein. Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent. 
     In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable” refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a Formulation and/or the mammal being treated therewith. Persons skilled in the art can choose the “pharmaceutically acceptable” substance or composition specifically according to other components and the object being treated with (such as man). 
     The compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of formula (I) and/or for separating enantiomers of compounds of formula (I). 
     If the compound disclosed herein is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like. 
     If the compound disclosed herein is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Some non-limiting examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like. 
     Composition, Formulations and Administration of Compounds of the Invention 
     The pharmaceutical composition disclosed herein comprises any one of the compounds in the present disclosure. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. And the pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially it is effective as inhibitor of the non-structural 5A (NS5A) protein of HCV. 
     The pharmaceutical composition disclosed herein further comprises an additional anti-HCV agent. The anti-HCV agent refers to any known agents for anti-HCV and they are different from the compounds disclosed herein. For example, the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine-5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof. The interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof. The pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor. In some embodiments, the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function. In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress. In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. 
     When it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as pharmaceutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (I) or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term “therapeutically effective amount” refers to the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., a reduction in viral load). When applied to individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carrier(s), diluents(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to recipient thereof. In accordance with another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term “pharmaceutically acceptable” refers to those compounds, materials, composition and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. 
     Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (“mg/kg”) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects. 
     When the compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection is preferred. 
     Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solution or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions. 
     For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present. 
     Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. 
     Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose, β-lactose, corn sweetener, natural gum and synthetic resin such as Arabic gum, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluents or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadiamucilage or solution of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulation, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. 
     Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added. 
     Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like. 
     The compounds of formula (I), and pharmaceutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. 
     The compounds of formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carrier to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly(s-caprolactone), polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. 
     Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in  Pharmaceutical Research,  1986, 3(6), 318. 
     Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch. 
     Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas. 
     Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient. 
     Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators. 
     Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations. 
     Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. 
     It should be understood that in addition to ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. 
     Use of the Compounds and Compositions of the Invention 
     Provided herein is use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting at least one of HCV replication process and HCV viral protein function. In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress. In some embodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. And any one of the compounds or the pharmaceutical compositions disclosed herein can be used for treating HCV infection or a HCV disorder, especially it is effective as inhibitor of the non-structural 5A (NS5A) protein of HCV. 
     Also provided herein is a method, which comprises the compound or the pharmaceutical composition disclosed herein, further comprising administering to the patient additional anti-HCV agents (combination therapy), wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine-5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof; and the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, or interferon γ. 
     The treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional anti-HCV agent, wherein the additional anti-HCV drug is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form. The additional anti-HCV agent may be administered at the same time as a compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months. 
     In certain embodiments disclosed herein, an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders. The compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above. 
     General Synthetic Procedures 
     Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for formula (I), above, except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention. 
     Persons skilled in the art will recognize that the chemical reactions described herein may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein. 
     In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory. 
     Anhydrous THF, dioxane, toluene and ether were obtained by refluxing the solvent with sodium. Anhydrous CH 2 Cl 2  and CHCl 3  were obtained by refluxing the solvent with CaH 2 . EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4  prior to use. 
     The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. 
     Column chromatography was conducted using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.  1 H NMR spectra were obtained as CDCl 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone solutions (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). 
     Low-resolution mass spectral (MS) data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30° C.), a G1329A autosampler and a G1315B DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer. 
     Low-resolution mass spectral (MS) data were also determined on an Agilent 6120 series LC-MS spectrometer equipped with G1311A Quaternary pump, a G1316A TCC (Temperature Control of Column, maintained at 30° C.), a G1329A autosampler and a G1315D DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer. 
     Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1×30 mm, 5 μm column. Injection volume was decided by the sample concentration. The flow rate was 0.6 mL/min. The HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient condition is shown in Table 1: 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 A (CH 3 CN, 
                 B (H 2 O, 
               
               
                 Time (min) 
                 0.1% HCOOH) 
                 0.1% HCOOH) 
               
               
                   
               
             
            
               
                 0-3 
                 5-100 
                 95-0 
               
               
                 3-6 
                 100 
                  0 
               
               
                     6-6.1 
                 100-5   
                  0-95 
               
               
                 6.1-8     
                  5 
                 95 
               
               
                   
               
            
           
         
       
     
     Purities of compounds were also assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1×30 mm, 4 micron, 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 O). Column was operated at 40° C. 
     The following abbreviations are used throughout the specification: 
     HOAc acetic acid 
     MeCN, CH 3 CN acetonitrile 
     NH 3  ammonia 
     NH 4 Cl ammonium chloride 
     BBr 3  boron tribromide 
     BSA bovine serum albumin 
     Br 2  bromine 
     BOC, Boc tert-butyloxycarbonyl 
     Cbz benzylcarboxy 
     Cs 2 CO 3  cesium carbonate 
     CHCl 3  chloroform 
     CDCl 3  chloroform deuterated 
     CDI 1,1′-Carbonyldiimidazole 
     Cu copper 
     CuI copper (I) iodide 
     Et 2 O diethyl ether 
     DMF dimethylformamide 
     DMAP 4-dimethylaminopyridine 
     DMSO dimethylsulfoxide 
     EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
     Dppa diphenylphosphoryl azide 
     EtOAc, EA ethyl acetate 
     Fmoc fluorenylmethyloxycarbonyl 
     HBr hydrobromic acid 
     HCl hydrochloric acid 
     HOAt, HOAT 1-hydroxy-7-azabenzotriazole 
     HOBT 1-hydroxybenzotriazole hydrate 
     H 2  hydrogen 
     H 2 O 2  hydrogen peroxide 
     Fe iron 
     LDA lithium diisopropylamide 
     MCPBA meta-chloroperbenzoic acid 
     MgSO 4  magnesium sulfate 
     MeOH, CH 3 OH methanol 
     MeI methyl iodide 
     CH 2 Cl 2 , DCM methylene chloride 
     NMP N-methylpyrrolidinone 
     mL, m milliliter 
     N 2  nitrogen 
     Pd/C palladium on carbon 
     PE petroleum ether (60-90° C.) 
     PBS phosphate buffered saline 
     POCl 3  phosphorous oxychloride 
     Pd(PPh 3 ) 4  palladium tetrakis triphenylphosphine 
     Pd(dppf)Cl 2  1,1-bis(diphenylphosphino)ferrocene palladium chloride 
     K 2 CO 3  potassium carbonate 
     KOH potassium hydroxide 
     RT, rt room temperature 
     Rt retention time 
     NaHCO 3  sodium bicarbonate 
     NaBH 4  sodium borohydride 
     NaBH 3 CN sodium cyanoborohydride 
     NaOtBu sodium tert-butoxide 
     NaOH sodium hydroxide 
     NaClO 2  sodium chlorite 
     NaCl sodium chloride 
     NaH 2 PO 4  sodium dihydric phosphate 
     NaH sodium hydride 
     NaI sodium iodide 
     Na 2 SO 4  sodium sulfate 
     TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate 
     THF tetrahydrofuran 
     Et 3 N, TEA triethylamine 
     TFA trifluoroacetic acid 
     P(t-bu) 3  tri(tert-butyl)phosphine 
     NBS N-bromosuccinimide 
     TBAI tetrabutylammonium iodide 
     H 2 O water 
     TEAF formic acid triethylamine complex 5:2 
     PPA polyphosphoric acid 
     Tf 2 O Trifluoromethanesulfonic anhydride 
     HCl.EA a solution of HCl in ethyl acetate 
     DIPEA N,N-diisopropylethylamine 
     DME 1,2-dimethoxyethane 
     HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 
     NIS N-iodosuccinimide 
     TFAA trifluoroaceticanhydride 
     SEMCl2-(Trimethylsilyl)ethoxymethyl chloride 
     Dess-Martin (Dess-Martin periodinane) 
     (1,1,1-Triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one 
     p-TSA(TsOH) p-toluenesulfonic acid 
     TMSA Trimethyl silyl acetylene 
     Meldrum&#39;s acid 2,2-Dimethyl-1,3-dioxane-4,6-dione 
     BAST Bis(2-methoxyethyl)aminosulphurtrifluoride Deoxo-fluor 
     SbCl 3  antimony trichloride 
     SmCl 3  samarium chloride 
     LiHMDS lithium hexamethyldisilazide 
     TMSCl trimethyl chlorosilane 
     PhNTf 2  N,N-Bis(trifluoromethylsulfonyl)aniline 
     TBDMSOTf tert-butyldimethylsilyl triflate 
     Et 2 NSF 3  diethylaminosulfur trifluoride 
     MTBE methyl tert-butyl ether 
     LiN(SiMe 3 ) 2  Lithium bis(trimethylsilyl)amide 
     PPh 3 MeBr Methyltriphenylphosphonium bromide 
     Lawesson&#39;s Reagent 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide 
     TEBAC benzyltriethylammonium chloride 
     I 2  iodine 
     DAST Diethylaminosulfur trifluoride 
     IPA isopropanol 
     TCCA trichloroisocyanuric acid 
     TEMPO 2,2,6,6-tetramethylpiperidinooxy 
     IMPDH Inosine monophosphate dehydrogenase 
     IRES Internal ribosome entry site 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 22 can be prepared by the process illustrated in Scheme 1. Wherein each X 5  is F, Cl, Br or I and each of Y 2 , w, R 5a , f, Y 4 ′, Y 1 , Y 4 , R 6a , R 14 , R 14a , R 16  and R 16a  is as defined herein. Pg is a amino-protecting group such as Boc, Fmoc or Cbz. Compound 1 can undergo cyclization to give compound 2 in the presence of a base. Compound 2 can react with a reductant to give compound 3. Compound 3 can be transformed to compound 4 by reacting with NIS. The methyl group in compound 4 can then be removed in the presence of boron tribromide to provide compound 5. Compound 5 can react with trifluoromethanesulfonic anhydride to afford compound 6 in the presence of a base catalyst. Condensation of compound 7 with compound 8 can give compound 9. Then compound 9 can undergo cyclization to give compound 10 at elevated temperature in the presence of ammonium acetate. The protecting group Pg in compound 10 can be removed to provide compound 11. Compound 11 can then condense with a amino acid to afford compound 12. Compound 12 can react with bis(pinacolato)diboron in the presence of a Pd catalyst to afford compound 13. Coupling reaction of compound 13 with compound 6 in the presence of a Pd catalyst can give compound 14. Compound 15 can be converted to compound 16 by base catalysis. Compound 16 can be converted to compound 17 in the presence of CDI and ammonium hydroxide. Condensation of compound 17 with compound 18 can give compound 19. Compound 19 can be cyclized in the presence of a base to form compound 20. Reaction of compound 20 with bis(pinacolato)diboron can afford compound 21 in the presence of a Pd catalyst. Coupling reaction of compound 21 with compound 14 in the presence of a Pd catalyst can give compound 22. 
     
       
         
         
             
             
         
       
     
     Compound 30 can be prepared by the process illustrated in Scheme 2. Wherein each X 5  is F, Cl, Br or I and each of Y 2 , w, R 5a , f, Y 4 ′, Y 1 , Y 4 , R 6a , R 14 , R 14a , R 16  and R 16a  is as defined herein. Pg is a amino-protecting group such as Boc, Fmoc or Cbz. Compound 23 can be converted to compound 24 by reacting with ethyl potassium malonate in the presence of CDI/MgCl 2 . Reaction of compound 24 with compound 25 can afford compound 26 by acid catalysis. The protecting group Pg in compound 26 can be removed to provide compound 27. Compound 27 can then be condensed with a amino acid to afford compound 28. Compound 28 can further react with bis(pinacolato)diboron in the presence of a Pd catalyst to afford compound 29. Coupling reaction of compound 29 with compound 14 in the presence of a Pd catalyst can give compound 30. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 43 can be prepared by the process illustrated in Scheme 3. Wherein each X 5  is F, Cl, Br or I and each of Y 2 , w, R 5a , f, Y 4 ′, Y 1 , Y 4 , R 6a , R 9 , R 9a , R 14 , R 14a , R 16  and R 16a  is as defined herein. Pg is a amino-protecting group such as Boc, Fmoc or Cbz. Compound 31 can be converted to compound 32 by reacting with diethyl malonate by base catalysis. Compound 32 can be converted to compound 33 in the presence of LiCl and water. Compound 33 can give compound 34 in the presence of a base by alkylation. Compound 34 can afford compound 35 by base catalysis. Compound 35 can be converted to compound 36 in the presence of a base and DPPA. Condensation of compound 36 with compound 23 can give compound 37. Compound 37 can react with a reductant to give compound 38. Then compound 38 can undergo cyclization to give compound 39 in the presence of acetic acid. The protecting group Pg in compound 39 can be removed to provide compound 40. Compound 40 can then be condensed with an amino acid to afford compound 41. Compound 41 can further react with bis(pinacolato)diboron in the presence of a Pd catalyst to afford compound 42. Coupling reaction of compound 42 with compound 14 in the presence of a Pd catalyst can give compound 43. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 53 can be synthesized through the procedure depicted in Scheme 4. Wherein each X 5  is independently F, Cl, Br or I and each of w, Y 4 ′, Y 4 , Y 1 , Y 2 , R 5a , R 6a , f, R 14 , R 14a , R 16  and R 16a  is as defined herein, and Pg is an amino-protecting group such as Boc, Fmoc or Cbz. Compound 44 can be transformed to compound 45 by reacting with sodium sulfite. Compound 45 can be converted to compound 46 in the presence of thionyl chloride and ammonium hydroxide. Reduction of compound 46 with a reducing agent such as HI can afford compound 47. Reaction of compound 47 with compound 48 can form compound 49 in the presence of a base. The protecting group Pg in compound 49 can be removed to afford compound 50. Compound 50 can then be condensed with an amino acid to provide compound 51. Reaction of compound 51 with bis(pinacolato)diboron can afford compound 52 by Pd catalysis. Coupling reaction of compound 52 with compound 14 in the presence of a Pd catalyst can give compound 53. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 64 can be prepared by the process illustrated in Scheme 5. Wherein each of Y 4 , Y 4 ′, w, R 5a , f, Y 2 , R 14 , R 14a , R 16  and R 16a  is as defined herein, and Pg is an amino-protecting group such as Boc, Fmoc or Cbz. Compound 7 can react with a reductant such as diborane to give compound 54. Compound 54 can be oxidized to give compound 55 with an oxidant such as Dess-Matin agent. Compound 55 can be cyclized in the presence of ammonium hydroxide and glyoxal to form compound 56. Compound 56 can be transformed to diiodo compound 57 by reacting with NIS. One of the iodine atoms of the diiodo compound 57 can then be removed in the presence of sodium sulfite to provide compound 58. The protecting group Pg in compound 58 can be removed to provide compound 59. Compound 59 can further condense with an amino acid to afford compound 60. Reaction of compound 60 with TMSA can afford compound 61 by Pd catalysis. Compound 61 can give compound 62 by removing TMS in the presence of a base. Coupling reaction of compound 62 with compound 63 in the presence of a Pd catalyst can give compound 64. 
     
       
         
         
             
             
         
       
     
     Compound 70 can be synthesized through the procedure depicted in Scheme 6. Wherein each X 5  is independently F, Cl, Br or I and each of w, Y 4 ′, Y 4 , Y 1 , R 5a , R 6a , f, R 14 , R 14a , R 16  and R 16a  is as defined herein, and Pg is an amino-protecting group such as Boc, Fmoc or Cbz. Compound 65 can be transformed to compound 67 by reacting with compound 66 in the presence of an acid. Compound 67 can further react with compound 13 in the presence of a Pd catalyst to afford compound 68. Coupling reaction of compound 68 with compound 69 in the presence of a Pd catalyst can give compound 70. 
     
       
         
         
             
             
         
       
     
     Compound 73 can be prepared by the process illustrated in Scheme 7. Wherein each of Y 4 , Y 4 ′, Y 2 , w, R 5a , f, R 14 , R 14a , R 16  and R 16a  is as defined herein. Reaction of compound 63 with bis(pinacolato)diboron can afford compound 71 by Pd catalysis. Coupling reaction of compound 71 with compound 72 in the presence of a Pd catalyst can give compound 73. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 79 can be prepared by the process illustrated in Scheme 8. Wherein each of Y 4 , Y 4 ′, X 2 , Y 2 , w, R 5a , R 14 , R 14a , R 16  and R 16a  is as defined herein. Coupling reaction of compound 63 with compound 74 in the presence of a Pd catalyst can give compound 75. Compound 75 can react with trifluoromethanesulfonic anhydride to afford compound 76 by base catalysis. Reaction of compound 76 with bis(pinacolato)diboron can afford compound 77 by a Pd catalysis. Coupling reaction of compound 77 with compound 78 in the presence of a Pd catalyst can give compound 79. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compound 89 can be synthesized through the procedure depicted in Scheme 9. Wherein each X is independently F, Cl, Br or I and each of Y 4 , Y 4 ′, Y 2 , Y 1 , w, R 5a , R 6a , f, R 14 , R 14a , R 16  and R 16a  is as defined herein. Brominating compound 80 with NBS can give compound 81. Compound 81 can be converted to compound 82 by reacting with diethyl malonate by base catalysis. Compound 82 can be converted to compound 83 in the presence of NaCl. Compound 84 can be formed via compound 83 by hydrolysis in base system. Compound 84 can react with acetyl chloride to afford compound 85 in the presence of aluminium chloride. Compound 85 can undergo cyclization to give compound 86 in the presence of a base. Compound 86 can react with a reductant to give compound 87. Coupling reaction of compound 87 with compound 13 can afford compound 88 by Pd catalysis. Coupling reaction of compound 88 with compound 52 in the presence of a Pd catalyst can give compound 89. 
     EXAMPLES 
     Example 1 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 1-2 
     A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride (25.0 g, 432 mmol) was stirred at 150° C. until the solid was melted, and then compound 1-1 (20.0 g, 135 mmol) was added slowly. At the end of the addition, the mixture was stirred at 200° C. for 1.0 hr. After the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mL), then filtered to get a gray solid which was purified by beating in methanol to give the title compound 1-2 (19.0 g, 95%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 149.5 [M+H] + ; and 
     1HNMR (400 MHz, CDCl 3 ) δ (ppm): 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J=4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H). 
     Step 2) The Preparation of Compound 1-3 
     To a mixture of compound 1-2 (5.0 g, 33.7 mmol) and K 2 CO 3  (23.4 g, 168.5 mmol) in acetone (50.0 mL) was added iodomethane (3.15 mL, 50.55 mmol). At the end of the addition, the mixture was stirred at 60° C. for 5.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL) and water (150 mL), and then filtered through a celite pad. The aqueous layer was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as a yellow solid (2.5 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 163.5 [M+H] + ; and 
       1 HNMR (400 MHz, CDCl 3 ) δ (ppm): 7.51-7.48 (m, 1H), 7.30-7.26 (m, 1H), 6.91-6.87 (m, 1H), 3.90 (s, 3H), 3.08-3.05 (m, 2H), 2.70-2.67 (m, 2H). 
     Step 3) The Preparation of Compound 1-4 
     To a suspension of potassium tert-butanolate (3.5 g, 31.19 mmol) in toluene (40.0 mL) was added a solution of 4-methoxy-1-indanone (2.0 g, 12.34 mmol) and 1,4-dibromobutane (3.2 g, 14.96 mmol) in toluene (20.0 mL) dropwise at 0° C. At the end of the addition, the mixture was stirred at 90° C. for 5.0 hrs. After the reaction was completed, the mixture was quenched with ice-water (100 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=3/1) to give the title compound 1-4 as yellow slurry (2.0 g, 75%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 217.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.36-7.31 (m, 2H), 7.03-7.01 (m, 1H), 3.89 (s, 3H), 2.94 (s, 2H), 2.01-1.90 (m, 4H), 1.81-1.76 (m, 2H), 1.62-1.56 (m, 2H). 
     Step 4) The Preparation of Compound 1-5 
     To a suspension of compound 1-4 (2.0 g, 9.25 mmol) and triethylsilane (7.4 mL, 46.33 mmol) was added TFA (20.0 mL, 26.93 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 24 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=15/1) to give the title compound 1-5 as colorless oil (1.59 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 203.14 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.13-7.10 (m, 1H), 6.81-6.80 (m, 1H), 6.67-6.65 (m, 1H), 3.83 (s, 1H), 2.85 (s, 2H), 2.80 (s, 2H), 1.72-1.57 (m, 8H). 
     Step 5) The Preparation of Compound 1-6 
     To a mixture of compound 1-5 (14.1 g, 69.8 mmol) and NIS (17.2 g, 76.8 mmol) in MeCN (200 mL) was added CF 3 COOH (0.5 mL, 6.98 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at 45° C. overnight. After the reaction was completed, the mixture was concentrated in vacuo, then 100 mL of water was added, and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated sodium sulfite aqueous solution (50 mL×2) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=20/1) to give the title compound (19.7 g, 86%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 329.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.45 (d, 1H), 6.43 (d, 1H), 3.77 (s, 3H), 2.90 (s, 2H), 2.81 (s, 2H), 1.73-1.69 (m, 4H), 1.63-1.59 (m, 4H). 
     Step 6) The Preparation of Compound 1-7 
     To a solution of compound 1-6 (19.6 g, 59.7 mmol) in DCM (15.0 mL) was added boron tribromide (74.7 g, 298.8 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was quenched with ice-water (100 mL). The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=20/1) to give the title compound (17.25 g, 92%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 315.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.36 (d, 1H), 6.41 (d, 1H), 4.91 (s, 1H), 2.89 (s, 2H), 2.82 (s, 2H), 1.73-1.69 (m, 4H), 1.67-1.63 (m, 4H). 
     Step 7) The Preparation of Compound 1-8 
     To a solution of compound 1-7 (5.0 g, 15.92 mmol) in DCM (50.0 mL) was added pyridine (6.5 mL, 79.62 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (8.0 mL, 47.77 mmol) was added, and then the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice-water (100 mL). The aqueous layer was extracted with DCM (60 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as yellow oil (5.98 g, 84.2%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.57 (d, 1H), 6.79 (d, 1H), 3.07 (s, 2H), 2.88 (s, 2H), 1.75-1.72 (m, 4H), 1.65-1.63 (m, 4H). 
     Step 8) The Preparation of Compound 1-10 
     A mixture of compound 1-9 (25.0 g, 125.6 mmol), NBS (24.5 g, 138.2 mmol) and p-TSA (3.4 g, 20.9 mmol) was stirred at 100° C. under N 2  for 2.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with DCM (200 mL). The resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=15/1) to give the title compound (25.0 g, 72%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 276.8 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.93 (d, 1H), 7.78 (d, 1H), 4.93 (s, 2H). 
     Step 9) The Preparation of Compound 1-11 
     To a solution of compound 1-10 (30 g, 107.9 mmol) and compound 1-10-2 (25.6 g, 118.7 mmol) in DCM (250 mL) was added DIPEA (21.4 mL, 129.5 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the reaction was quenched with ice water (100 mL), and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (40 g, 91%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 412.7 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H). 
     Step 10) The Preparation of Compound 1-12 
     A suspension of compound 1-11 (15.0 g, 36.4 mmol) and ammonium acetate (42.0 g, 54.6 mmol) in xylene (150 mL) was stirred at 120° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt and the reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (12.1 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 392.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H). 
     Step 11) The Preparation of Compound 1-13 
     To a solution of compound 1-12 (10.0 g, 25.5 mmol) in EtOAc (50.0 mL) was added a solution of HCl in EtOAc (60.0 mL, 4 M) dropwise, and the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo and EtOAc (30 mL) was added. The resulting mixture was stirred and pulped, and then filtered to give the title compound as a pale yellow solid (8.0 g, 86.2%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 292.6 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H), 7.21-7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m, 1H), 3.49-3.39 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H). 
     Step 12) The Preparation of Compound 1-14 
     To a solution of compound 1-13 (7.03 g, 19.26 mmol), compound 1-13-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was added DIPEA (21 mL, 127 mmol) dropwise at 0° C., and the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, 100 mL of water was added to the mixture, and the aqueous layer was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a solid (7.6 g, 88%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 450.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.22 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H). 
     Step 13) The Preparation of Compound 1-15 
     To a mixture of compound 1-14 (5.0 g, 11.13 mmol), compound 1-14-2 (4.3 g, 16.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.91 g, 1.11 mmol) and KOAc (3.3 g, 33.4 mmol) was added DMF (50.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (200 mL). The resulting mixture was filtered through a celite pad. The filtrate was washed with water (100 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (3.95 g, 71.4%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.22 (m, 1H), 2.21-1.95 (m, 5H), 1.45-1.32 (m, 12H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H). 
     Step 14) The Preparation of Compound 1-16 
     To a mixture of compound 1-8 (3.56 g, 7.98 mmol), compound 1-15 (3.3 g, 6.65 mmol), Pd(PPh 3 ) 4  (768 mg, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and H 2 O (10.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, DME was removed. The residue was dissolved in EtOAc (150 mL), and washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a beige solid (3.66 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.84-7.82 (m, 1H), 7.69-7.66 (m, 2H), 7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 5.41-5.39 (m, 1H), 5.29-5.27 (m, 1H), 4.34-4.30 (m, 1H), 3.75-3.70 (m, 1H), 3.69 (s, 3H), 3.64-3.62 (m, 1H), 3.20-3.01 (m, 1H), 2.99 (s, 2H), 2.95 (s, 2H), 2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.78-1.52 (m, 8H), 0.88-0.86 (m, 6H). 
     Step 15) The Preparation of Compound 1-18 
     To a solution of compound 1-17 (2.1 g, 9.17 mmol) in THF (20.0 mL) was added a aqueous solution of NaOH (2.1 g, 20.0 mL). At the end of the addition, the mixture was stirred at 60° C. overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (50 mL) and extracted with water (50 mL×3). The combined aqueous phase was adjusted to pH 4 with hydrochloric acid (1M) and the solid was precipitated. The resulting mixture was filtered to give the title compound as a yellow solid (1.4 g, 72%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 217 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.59 (d, 1H, J=8.0 Hz), 6.96 (d, 1H, J=1.6 Hz), 6.64 (dd, 1H, J=8.0 Hz, 2.0 Hz). 
     Step 16) The Preparation of Compound 1-19 
     To a mixture of compound 1-18 (1.51 g, 7.00 mmol) in dry THF (5.0 mL) was added CDI (0.83 g, 5.12 mmol). At the end of the addition, the mixture was stirred at rt for 2.0 hrs. And then NH 3 .H 2 O (20 mL) was added dropwise at 0° C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 217 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J=2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J=8.0 Hz, 2.0 Hz). 
     Step 17) The Preparation of Compound 1-20 
     To a suspension of compound 1-19 (1.5 g, 7.00 mmol), compound 1-19-2 (2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) via syringe dropwise at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as colorless slurry (0.66 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.33 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.57 (d, 1H, J=8.0 Hz), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 1H), 3.89-3.86 (m, 2H), 3.68 (s, 3H), 2.24-2.15 (m, 2H), 2.09-2.00 (m, 2H), 1.09 (d, 3H, J=6.0 Hz), 0.97 (d, 3H, J=6.0 Hz). 
     Step 18) The Preparation of Compound 1-21 
     To a solution of compound 1-20 (0.6 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed. The residue was dissolved in EtOAc (50 mL), and then washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.55 g, 96%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 452.33 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.31 (s, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.53 (dd, 1H, J=8.0 Hz, 2.0 Hz), 5.78 (d, 1H, J=8.0 Hz), 5.10 (dd, 1H, J=8.0 Hz, 2.0 Hz), 4.33 (t, 1H, J=8.0 Hz), 4.14-4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.66 (s, 3H), 2.53-2.51 (m, 1H), 2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.04-1.79 (m, 2H), 0.93 (d, 1H, J=2.0 Hz). 
     Step 19) The Preparation of Compound 1-22 
     A suspension of compound 1-21 (0.2 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.04 g, 0.049 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 80° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (0.16 g, 70%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 499.26 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.08 (s, 1H), 8.22 (d, 1H, J=8.0 Hz), 8.11 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 5.71 (d, 1H, J=8.0 Hz), 5.17 (d, 1H, J=6.0 Hz), 4.35 (t, 1H, J=8.0 Hz), 4.15-4.10 (m, 1H), 3.88-3.86 (m, 1H), 3.67 (s, 3H), 2.71-2.67 (m, 1H), 2.34-2.32 (m, 1H), 2.09-1.99 (m, 2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H). 
     Step 20) The Preparation of Compound 1-23 
     A mixture of compound 1-22 (0.12 g, 0.23 mmol), compound 1-16 (0.12 g, 0.16 mmol), Pd(PPh 3 ) 4  (30 mg, 0.03 mmol) and K 2 CO 3  (60 mg, 0.44 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 4.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (74.7 mg, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 911.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.21 (s, 1H), 10.46 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.54-7.51 (m, 2H), 7.46 (s, 2H), 7.37-7.33 (m, 2H), 5.70-5.60 (m, 2H), 5.31-5.30 (m, 1H), 5.21-5.20 (m, 1H), 4.55-4.35 (m, 2H), 3.95-3.86 (m, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 2.98 (s, 4H), 2.69-2.57 (m, 2H), 2.35-2.01 (m, 8H), 2.09-1.99 (m, 2H), 0.92-0.84 (m, 12H). 
     Example 2 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 2-2 
     MgCl 2  (1.53 g, 16.4 mmol) was added in one portion to a solution of ethyl potassium malonate (3.55 g, 20.85 mmol) in THF (25.0 mL). The reaction mixture was stirred for 7.0 hrs at 70° C. and then at 30° C. overnight. A solution of compound 2-1 (4.0 g, 16.06 mmol) in THF (10.0 mL) was slowly added to a mixture of CDI (3.12 g, 19.25 mmol) in THF (15.0 mL), which was stirred at 30° C. for 2.0 hrs. The solution was added to the mixed system of ethyl potassium malonate described above. At the end of the addition, the mixture was stirred overnight at 30° C. After the reaction was completed, the mixture was cooled to 20° C. and neutralized with diluted HCl (4 M). The solution was concentrated in vacuo and the product was dissolved in EtOAc (50 mL), washed with 5% aqueous sodium bicarbonate and brine and, then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (4.6 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 320.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.19-7.18 (m, 5H), 5.13-5.12 (m, 2H), 4.23, 4.21, 4.19, 4.18 (s, s, s, s, 2H), 4.03-3.97 (m, 1H), 3.59, 3.58 (s, s, 2H), 3.50-3.43 (m, 1H), 3.32-3.23 (m, 1H), 2.08-1.93 (m, 2H), 1.82-1.70 (m, 2H), 1.29-1.25 (t, 3H, J=8.0 Hz). 
     Step 2) The Preparation of Compound 2-3 
     To a solution of compound 2-2 (1.0 g, 3.13 mmol) and acetic acid glacial (0.17 mL, 3.13 mmol) in toluene (10.0 mL) was added 4-bromoaniline (0.4 g, 2.35 mmol) dropwise at rt. At the end of the addition, the mixture was refluxed for 6.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in Dowtherm A (5.0 mL) and then stirred at 235° C. for 1.5 hrs. After the reaction was completed, the mixture was cooled to rt, and ether (8.0 mL) followed by heptane (5.0 mL) was added. An oily residue precipitated and the solvent was decanted. The residue was purified by silica gel column chromatography (DCM/EtOAc (v/v)=1/1) to give the title compound (0.15 g, 11%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 428.9 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd, 1H), 7.45, 7.43 (dd, dd, 1H), 7.28-7.22 (m, 5H), 6.58 (t, 1H), 5.14-5.13 (m, 2H), 4.98-4.94 (m, 1H), 3.64-3.57 (m, 1H), 3.43-3.36 (m, 1H), 2.26-2.17 (m, 1H), 2.09-1.83 (m, 3H). 
     Step 3) The Preparation of Compound 2-4 
     To a solution of compound 2-3 (2.13 g, 5.0 mmol) in EtOAc (40.0 mL) was added Pd/C (0.2 g). The mixture was stirred at 40° C. under 10 atm of H 2  gas for 5.0 hrs. After the reaction was completed, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (1.25 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 293.5 [M+H] + . 
     Step 4) The Preparation of Compound 2-5 
     To a solution of compound 2-4 (2.92 g, 10.0 mmol), compound 1-13-2 (1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) was added DIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (100 mL). The resulting mixture was washed with aqueous NH 4 Cl and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (2.69 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 450.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd, 1H), 7.45, 7.43 (dd, dd, 1H), 6.64 (m, 1H), 5.32, 5.29 (dd, dd, 1H), 5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.49 (m, 1H), 3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 5) The Preparation of Compound 2-6 
     To a mixture of compound 2-5 (0.45 g, 0.91 mmol), compound 1-14-2 (0.46 g, 1.82 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (71.0 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) was added DMF (5.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (60 mL), and then filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.38 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 498.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.48-8.47 (m, 1H), 8.00, 7.99 (dd, dd, 1H), 7.47, 7.45 (dd, dd, 1H), 6.76 (m, 1H), 5.32, 5.29 (dd, dd, 1H), 5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 1.23, 1.20 (m, m, 12H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 6) The Preparation of Compound 2-7 
     A mixture of compound 2-6 (0.30 g, 0.61 mmol), compound 1-16 (0.42 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.3 mg, 0.03 mmol) and K 2 CO 3  (0.25 g, 1.83 mmol) in the mixed solvent of DME/H 2 O (v/v=5/1, 6.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (0.31 g, 56%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 455.8 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.05 (m, 1H), 7.72-7.71 (m, 1H), 7.70-7.69 (m, 1H), 7.62 (dd, 1H), 7.60-7.56 (m, 4H), 7.52-7.49 (m, 2H), 7.00-6.99 (m, 1H), 5.32, 5.29 (dd, dd, 2H), 5.23-5.19 (m, 1H), 5.18-5.13 (m, 1H), 4.41-4.36 (m, 1H), 4.27-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H), 2.93-2.88 (m, 4H), 2.30-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 3 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 3-2 
     NaH (60%, 3.13 g, 78 mmol) was added to DMSO (100 mL) followed by dropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end of the addition, the mixture was stirred at 100° C. for 40 mins. The mixture was cooled to rt, then compound 3-1 (10 g, 35.60 mmol) was added, and the mixture was stirred for 30 mins at rt, then heated to 100° C. for 1.0 hr. After the reaction was completed, the reaction was quenched with aqueous saturated NH 4 Cl solution (50 mL), and then EtOAc (150 mL) was added to the mixture. The combined organic layer were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (11.0 g, 86%), which was used for the next step. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.36-8.35 (m, 1H), 7.73, 7.70 (dd, dd, 1H), 7.60, 7.58 (t, t, 1H), 5.24-5.23 (m, 1H), 4.32-4.26 (m, 4H), 1.29-1.25 (t, 6H, J=8.0 Hz). 
     Step 2) The Preparation of Compound 3-3 
     To a solution of compound 3-2 (11.0 g, 0.64 mmol) in DMSO (100 mL) was added LiCl (3.0 g, 70 mmol) and water (0.64 g, 35.6 mmol) slowly at rt. At the end of the addition, the mixture was stirred at 100° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with 200 mL of EtOAc, washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=50/1) to give the title compound as a solid (8.0 g, 91%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 287.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.32 (m, 1H), 7.77, 7.75 (m, m, 1H), 7.22, 7.20 (m, m, 1H), 4.50 (m, 2H), 4.42-4.36 (m, 2H), 1.42-1.38 (t, 3H, J=8.0 Hz). 
     Step 3) The Preparation of Compound 3-4 
     NaH (60%, 3.75 g, 93 mmol) was added to a stirred suspension of compound 3-3 (8.0 g, 27.8 mmol) in DMF (90.0 mL) at rt. After 15 mins, CH 3 I (22.2 g, 156 mmol) was added. At the end of the addition, the reaction mixture was stirred at rt overnight. After the reaction was completed, the mixture was poured into a mixture of ice water (200 mL) and EtOAc (200 mL). The organic layer was washed with water (200 mL×3) and brine (50 mL), dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=200/1) to give the title compound as a solid (7.0 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.11-8.10 (m, 1H), 7.58 (m, 2H), 4.08-3.94 (m, 2H), 1.62 (s, 6H), 1.08-1.04 (t, 3H, J=8.0 Hz). 
     Step 4) The Preparation of Compound 3-5 
     To a solution of compound 3-4 (7.0 g, 22.1 mmol) in MeOH (80.0 mL) and THF (40.0 mL) was added KOH (2 M, 80 mL, 160 mmol). At the end of the addition, the mixture was stirred at 80° C. for 5.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was diluted with water (50 mL), and washed with MTBE (50 mL). The aqueous layer was acidified to pH 2 by addition of HCl (6 M) and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (5.0 g, 79%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.15 (m, 1H), 7.65, 7.62 (d, d, 1H), 7.59, 7.57 (d, d, 1H), 1.64 (s, 6H). 
     Step 5) The Preparation of Compound 3-6 
     Compound 3-5 (8.8 g, 30.5 mmol) was dissolved in DCM (200 mL) under N 2 . After addition of triethylamine (4.01 g, 39.6 mmol), the mixture was stirred at rt for 15 mins. Diphenylphosphoryl azide (11 g, 40.0 mmol) was added and the reaction mixture was stirred at rt for 3.0 hrs. After removal of the volatiles in vacuo, the obtained residue was diluted with toluene (200 mL) and the mixture was refluxed for 2.0 hrs. The mixture was cooled to rt and HCl (6 M, 100 mL) was added. The resulting solution was refluxed for 3.0 hrs. The crude mixture was concentrated in vacuo, diluted with ice water (100 mL) and basified with aq. NaOH (5 M), then extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (7.1 g, 89%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.90-7.89 (m, 1H), 7.57, 7.54 (d, d, 1H), 7.46, 7.44 (d, d, 1H), 1.84 (brs, 2H), 1.58 (s, 6H). 
     Step 6) The Preparation of Compound 3-7 
     To a solution of compound 1-10-2 (6.42 g, 29.8 mmol) in DCM (150 mL) were added HATU (20.6 g, 54.2 mmol) and triethylamine (8.22 g, 81.4 mmol) dropwise at rt in turn, then the mixture was stirred at rt for 15 mins. Compound 3-6 (7.1 g, 27.4 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was diluted with 150 mL of water. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (8.97 g, 72%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 456.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.08-8.07 (m, 1H), 7.65 (m, 2H), 6.40 (m, 1H), 4.19-4.15 (m, 1H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.72 (m, 2H), 1.68 (d, 6H), 1.40 (s, 9H). 
     Step 7) The Preparation of Compound 3-8 
     To a solution of compound 3-7 (8.9 g, 19.5 mmol) in MeOH (50.0 mL) was added Pt/C (1.0 g). The mixture was stirred at rt under 20 atm of H 2  gas overnight. After the reaction was completed, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (8.29 g, 100%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.07, 7.05 (dd, dd, 1H), 7.04, 7.02 (dd, dd, 1H), 6.77 (q, 1H), 6.40 (m, 1H), 4.11-4.07 (m, 1H), 3.98 (brs, 2H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.73 (m, 2H), 1.69 (d, 6H), 1.40 (s, 9H). 
     Step 8) The Preparation of Compound 3-9 
     A solution of compound 3-8 (8.29 g, 19.5 mmol) in acetic acid glacial (100 mL) was stirred at 50° C. for 1.0 hr. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=7/1) to give the title compound (1.5 g, 19%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 408.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H), 7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.14 (brs, 1H), 4.81-4.77 (m, 1H), 3.52-3.46 (m, 1H), 3.41-3.34 (m, 1H), 2.52-2.45 (m, 1H), 2.18-2.09 (m, 1H), 1.95-1.86 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.42 (s, 9H). 
     Step 9) The Preparation of Compound 3-10 
     To a solution of compound 3-9 (1.5 g, 3.68 mmol) in EtOAc (15.0 mL) was added a solution of HCl in EtOAc (10.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated. The residue was washed with EtOAc (10 mL) and filtered to give the title compound as a pale yellow solid (1.02 g, 90%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 308.5 [M+H] + . 
     Step 10) The Preparation of Compound 3-11 
     To a solution of compound 3-10 (3.07 g, 10.0 mmol), compound 1-13-2 (1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) was added DIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, 50 mL of DCM was added to the mixture. The resulting mixture were washed with aq. NH 4 Cl and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a solid (3.94 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 465.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H), 7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.65-4.61 (m, 1H), 4.32-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 11) The Preparation of Compound 3-12 
     To a mixture of compound 3-11 (0.42 g, 0.91 mmol), compound 1-14-2 (0.46 g, 1.82 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (71.0 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) was added DMF (5.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (60 mL). The resulting mixture was filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.37 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 513.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.67, 7.65 (d, d, 1H), 7.48-7.47 (m, 1H), 7.26, 7.24 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.65-4.61 (m, 1H), 4.33-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.25-1.24 (q, 6H), 1.22-1.21 (q, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 13) The Preparation of Compound 3-13 
     To a mixture of compound 3-12 (0.31 g, 0.61 mmol), compound 1-16 (0.42 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.26 mg, 0.03 mmol) and K 2 CO 3  (0.25 g, 1.83 mmol) were added DME (5.0 mL) and H 2 O (1.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50.0 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound (0.34 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H), 7.52-7.47 (m, 4H), 7.40-7.38 (dd, dd, 1H), 7.37-7.35 (d, d, 1H), 7.19, 7.17 (d, d, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 4.65-4.61 (m, 1H), 4.41-4.28 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88 (m, 2H), 2.40-2.32 (m, 1H), 2.30-1.92 (m, 7H), 1.90-1.82 (m, 1H), 1.80-1.71 (m, 1H), 1.69-1.51 (m, 12H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 4 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 4-2 
     To a solution of compound 4-1 (5.0 g, 69 mmol) in THF (50.0 mL) was added compound 4-1-2 (8.34 g, 69 mmol) and Ti(OEt) 4  (20.0 mL). At the end of the addition, the mixture was stirred at 50° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt and quenched with 200 mL of water. The resulting mixture was filtered and the filtrate was extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as a solid (5.55 g, 46%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.39 (s, 4H), 1.31 (s, 9H). 
     Step 2) The Preparation of Compound 4-3 
     To a solution of compound 4-2-2 (3.0 g, 9.18 mmol) in THF (20.0 mL) was added n-BuLi (4.4 mL, 2.5 M) dropwise via syringe at −78° C. under N 2 . At the end of the addition, the mixture was stirred at −78° C. for 15 mins. Compound 4-2 (1.92 g, 11 mmol) was added to the mixture. The reaction was stirred at −78° C. for 30 mins and then stirred at r.t for another 5.0 hrs. After the reaction was completed, the mixture was poured into ice water (50 mL). The resulting mixture layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound (1.3 g, 38%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 378.7 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.14-8.13 (m, 1H), 7.69, 7.67 (d, d, 1H), 7.43, 7.41 (d, d, 1H), 4.45 (brs, 1H), 4.36, 4.35 (brs, brs, 2H), 4.15, 4.13 (brs, brs, 2H), 1.21 (s, 9H). 
     Step 3) The Preparation of Compound 4-4 
     To a solution of compound 4-3 (1.3 g, 3.45 mmol) in MeOH (10.0 mL) was added a solution of HCl in 1,4-dioxane (10.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 30 mins, and then the mixture was concentrated in vacuo. The residue was dissolved in DCM (10 mL), then compound 1-10-2 (0.84 g, 3.94 mmol), HATU (1.49 g, 3.94 mmol) and triethylamine (0.66 g, 6.56 mmol) were added to the mixture in turn. At the end of the addition, the reaction was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with water (20 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (20 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the compound (a) (1.27 g). To a solution of compound (a) (1.0 g, 2.1 mmol) in mixed solvent of MeOH and water (20 mL, v/v=1/1) were added Fe (0.35 g, 6.3 mmol) and NH 4 Cl (0.55 g, 10.5 mmol) in turn. At the end of the addition, the mixture was refluxed for 3.0 hrs. After the reaction was cooled to rt, the mixture was concentrated in vacuo, and then 10 mL of water was added. The resulting mixture was extracted with DCM (10 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and stirred at 80° C. for 30 mins. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.96 g, 66%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 422 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.40, 7.37 (d, d, 1H), 7.19 (q, 1H), 6.91, 6.88 (d, d, 1H), 5.14 (brs, 1H), 4.82-4.78 (m, 1H), 4.45-4.39 (m, 2H), 4.23-4.18 (m, 2H), 3.62-3.55 (m, 1H), 3.44-3.36 (m, 1H), 2.24-2.16 (m, 1H), 2.11-2.01 (m, 1H), 2.00-1.91 (m, 1H), 1.89-1.79 (m, 1H), 1.43 (s, 9H). 
     Step 4) The Preparation of Compound 4-5 
     To a solution of compound 4-4 (0.49 g, 1.16 mmol) in EtOAc (5.0 mL) was added a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated. The residue was washed with EtOAc (10.0 mL) and filtered to give the title compound as a pale yellow solid (0.36 g, 95%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 322.5 [M+H] + . 
     Step 5) The Preparation of Compound 4-6 
     To a solution of compound 4-5 (1.6 g, 5.0 mmol), compound 1-13-2 (0.97 g, 5.5 mmol) and EDCI (1.05 g, 5.5 mmol) in DCM (15.0 mL) was added DIPEA (3.3 mL, 19.95 mmol) dropwise at 0° C., and the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (50 mL). The resulting mixture was washed with aq NH 4 Cl and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (1.91 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 479.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.40, 7.37 (d, d, 1H), 7.19 (q, 1H), 6.91, 6.88 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.89-4.85 (m, 1H), 4.45-4.39 (m, 2H), 4.33-4.28 (m, 1H), 4.23-4.18 (m, 2H), 3.63 (s, 3H), 3.62-3.56 (m, 1H), 3.26-3.18 (m, 1H), 2.34-2.27 (m, 1H), 2.10-2.01 (m, 1H), 1.99-1.83 (m, 2H), 1.81-1.71 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 6) The Preparation of Compound 4-7 
     To a mixture of compound 4-6 (2.39 g, 5.0 mmol), compound 1-14-2 (1.52 g, 6.0 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.41 g, 0.5 mmol) and KOAc (1.23 g, 12.5 mmol) was added DMF (10.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (150 mL). The resulting mixture was filtered through a celite pad. The filtrate was washed with water (60 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (2.1 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 527.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.73, 7.71 (d, d, 1H), 7.36, 7.34 (d, d, 1H), 7.21 (m, 1H), 5.32, 5.30 (d, d, 1H), 5.14 (brs, 1H), 4.89-4.85 (m, 1H), 4.44-4.39 (m, 2H), 4.33-4.28 (m, 1H), 4.23-4.18 (m, 2H), 3.63 (s, 3H), 3.62-3.56 (m, 1H), 3.26-3.18 (m, 1H), 2.34-2.27 (m, 1H), 2.10-2.01 (m, 1H), 1.99-1.83 (m, 2H), 1.81-1.71 (m, 1H), 1.25-1.24 (m, 6H), 1.22-1.21 (m, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) 3H). 
     Step 7) The Preparation of Compound 4-8 
     To a mixture of compound 4-7 (0.32 g, 0.61 mmol), compound 1-16 (0.42 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.3 mg, 0.03 mmol) and K 2 CO 3  (025 g, 1.83 mmol) were added DME (5.0 mL) and H 2 O (1.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a beige solid (0.34 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H), 7.52-7.48 (m, 3H), 7.41-7.38 (m, 2H), 7.37, 7.35 (dd, dd, 1H), 7.29, 7.27 (dd, dd, 1H), 5.32, 5.30 (d, d, 2H), 5.23-5.19 (m, 1H), 4.89-4.85 (m, 1H), 4.41-4.36 (m, 1H), 4.31-4.28 (m, 3H), 4.15-4.09 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.62-3.56 (m, 1H), 3.26-3.18 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88 (m, 2H), 2.34-1.33 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 5 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 5-2 
     To a solution of compound 5-1 (5.0 g, 22.7 mmol) in EtOH (60.0 mL) was added a suspension of Na 2 SO 3  (7.16 g, 56.8 mmol) in EtOH (100 mL) and water (125 mL) dropwise. At the end of the addition, the suspension was stirred at 70° C. for 15 hrs. After the reaction was completed, the mixture was cooled to rt, and the reaction was acidified with HCl (2 M) to pH 2, and then concentrated in vacuo. The residue was dissolved under reflux in brine (100 mL). Subsequently, water (10.0 mL) was added and the solution was cooled in an ice bath. The precipitate was collected by filtration, resulting in compound 5-2 (5.70 g, 89%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 282.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.75 (br, 1H), 8.31 (m, 1H), 8.07 (m, 2H). 
     Step 2) The Preparation of Compound 5-3 
     To a solution of compound 5-2 (3.0 g, 10.6 mmol) in toluene (50.0 mL) and DMF (1 drop) was added thionyl chloride (5.0 mL). At the end of the addition, the reaction was refluxed for 4.0 hrs. After the reaction was completed, the mixture was cooled and concentrated in vacuo. The residue was dissolved in toluene (4.0 mL), and then to the resulting mixture was added a mixture of concentrated aqueous ammonium hydroxide solution (1.0 mL) and THF (10.0 mL) at −10° C. After stirring for 2.0 hrs, the reaction was acidified with hydrochloric acid (6 M) to pH 4. The organic layer was separated and then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. PE (15.0 mL) was added to the resulting slurry and the product was collected by vacuum filtration to afford compound 5-3 (2.12 g, 71.4%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 281.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.18, 8.17 (d, d, 1H), 8.03, 8.00 (d, d, 1H), 7.84, 7.81 (d, d, 1H), 5.47 (br, 2H). 
     Step 3) The Preparation of Compound 5-4 
     A suspension of compound 5-3 (2.12 g, 7.5 mmol) in HI (25.0 mL, 57% aq.) was stirred at 90° C. for 4.0 hrs. After cooling to rt, the dark purple mixture was diluted with EtOAc (50 mL) and washed successively with saturated aq. Na 2 S 2 O 3 , saturated aq NaHCO 3  and brine. The colorless organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude product was purified by high-performance liquid chromatography (eluent: CH 3 CN/H 2 O from 22/78 to 52/48 with 0.01% NH 3 .H 2 O as buffer), resulting in compound 5-4 (1.86 g, 98%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 251.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.62-7.60 (m, 1H), 7.18-7.15 (m, 2H), 4.85 (brs, 4H). 
     Step 4) The Preparation of Compound 5-5 
     To a solution of compound 5-4 (1.86 g, 7.4 mmol) in acetone (20.0 mL) was added triethylamine (4.05 mL, 29.6 mmol) dropwise. Compound 5-4-2 (1.28 g, 4.8 mmol) was added to the reaction at 0° C. After stirring for 5.0 hrs, the mixture was diluted with water (10 mL) and acidified with hydrochloric acid (2 M) to pH 4. The resulting precipitate was collected by filtration and then transferred to another flask. A solution of K 2 CO 3  (1.5 g, 10.87 mmol) in water (10 mL) was added and then the mixture was refluxed for 2.0 hrs. The reaction was acidified with hydrochloric acid (2 M) to pH 4. The precipitate was filtered off and washed with water. The crude product was purified by high-performance liquid chromatography (eluent: CH 3 CN/H 2 O from 35/65 to 65/35 with 0.75% CF 3 COOH as buffer), resulting in compound 5-5 (1.00 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 464.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m, 1H), 7.43, 7.41 (d, d, 1H), 7.28-7.22 (m, 5H), 6.30 (brs, 1H), 5.14-5.13 (m, 2H), 4.86-4.80 (m, 1H), 3.68-3.62 (m, 1H), 3.50-3.43 (m, 1H), 2.22-1.98 (m, 4H). 
     Step 5) The Preparation of Compound 5-6 
     To a solution of compound 5-5 (3.73 g, 8.03 mmol) in EtOAc (40.0 mL) was added a catalytic amount of Pd/C (0.35 g), then the mixture was stirred at 40° C. under 10 atm of H 2  gas for 5.0 hrs. After the reaction was completed, the mixture was filtered, the filtrate was concentrated in vacuo to give the title compound 5-6 (2.27 g, 86%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 330.5 [M+H] + . 
     Step 6) The Preparation of Compound 5-7 
     To a suspension of compound 5-6 (3.29 g, 10.0 mmol), compound 1-13-2 (1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) was added DIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (50 mL). The resulting mixture was washed successively with water (30 mL×3), saturated aq. NH 4 Cl and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (2.43 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 487.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m, 1H), 7.43, 7.41 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H), 5.08-5.04 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.38-2.31 (m, 1H), 2.10-1.97 (m, 2H), 1.91-1.71 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 7) The Preparation of Compound 5-8 
     A mixture of compound 5-7 (0.44 g, 0.91 mmol), compound 1-14-2 (0.46 g, 1.82 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (71.0 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After cooling to rt, the mixture was diluted with EtOAc (50.0 mL) and filtered through a celite pad. The filtration was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (0.43 g, 88%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 535.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.02 (t, 1H), 7.80, 7.78 (d, d, 1H), 7.46, 7.44 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H), 5.08-5.04 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.38-2.31 (m, 1H), 2.10-1.97 (m, 2H), 1.91-1.71 (m, 2H), 1.32, 1.29 (m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 8) The Preparation of Compound 5-9 
     To a mixture of compound 5-8 (0.33 g, 0.61 mmol), compound 1-16 (0.42 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.26 mg, 0.03 mmol) and K 2 CO 3  (0.25 g, 1.83 mmol) were added DME (5.0 mL) and H 2 O (1.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (0.38 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 474.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.27 (brs, 2H), 7.89 (q, 1H), 7.75, 7.73 (d, d, 1H), 7.60-7.57 (m, 4H), 7.52-7.48 (m, 3H), 7.47, 7.45 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 5.08-5.04 (m, 1H), 4.41-4.37 (m, 1H), 4.31-4.26 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 6H), 3.60-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.97-2.94 (m, 2H), 2.92-2.89 (m, 2H), 2.38-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.91, 0.89 (m, m, 6H). 
     Example 6 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 6-1 
     To a mixture of compound 1-22 (0.64 g, 1.28 mmol), compound 1-8 (0.27 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.26 mg, 0.03 mmol) and K 2 CO 3  (0.25 g, 1.83 mmol) were added DME (5.0 mL) and H 2 O (1.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (0.33 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 457.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.90 (m, 3H), 7.83, 7.81 (d, d, 1H), 7.59, 7.57 (d, d, 1H), 7.55-7.50 (m, 2H), 6.72-6.71 (m, 1H), 6.08-6.05 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.21-5.15 (m, 1H), 5.10-5.05 (m, 1H), 4.30-4.25 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.91-2.87 (m, 2H), 2.50-2.27 (m, 3H), 2.15-2.02 (m, 5H), 1.93-1.73 (m, 2H), 1.69-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 6H), 0.93, 0.91 (m, m, 6H). 
     Example 7 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 7-1 
     To a mixture of compound 1-22 (0.30 g, 0.61 mmol), compound 1-8 (0.27 g, 0.61 mmol), Pd(PPh 3 ) 4  (35.3 mg, 0.03 mmol) and K 2 CO 3  (0.25 g, 1.83 mmol) were added DME (5.0 mL) and H 2 O (1.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.34 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 691.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.90-7.89 (m, 1H), 7.71, 7.69 (d, d, 1H), 7.64, 7.62 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.29, 7.27 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.21-5.15 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s, 3H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 2.91-2.87 (m, 2H), 2.85-2.81 (m, 2H), 2.50-2.42 (m, 1H), 2.37-2.27 (m, 1H), 2.11-1.98 (m, 2H), 1.93-1.83 (m, 1H), 1.74-1.42 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 2) The Preparation of Compound 7-2 
     To a solution of compound 1-10-2 (10.0 g, 46.6 mmol) in THF (100 mL) was added diborane (100 mL, 1M in THF) via syringe at 0° C. under N 2 . At the end of the addition, the mixture was stirred at 0° C. for 3.0 hrs. After the reaction was completed, the mixture was quenched with MeOH (80 mL), and the resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-2 as colorless oil (7.04 g, 75.2%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 3.99-3.87 (br, 1H), 3.68-3.51 (m, 2H), 3.48-3.39 (m, 1H), 3.34-3.25 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.71 (m, 2H), 1.45 (s, 9H). 
     Step 3) The Preparation of Compound 7-3 
     To a solution of compound 7-2 (7.0 g, 34.8 mmol) in DCM (250 mL) was added Dess-Martin periodinane (20.7 g, 48.8 mmol) portionwise at 0° C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, 250 mL of water was added to the mixture, and the resulting mixture was filtered. After the layers were partitioned, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-3 as colorless oil (3.5 g, 50.7%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.46 (d, 1H, J=2.8 Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 1.91-1.84 (m, 2H), 2.01-1.93 (m, 2H), 1.43 (s, 9H). 
     Step 4) The Preparation of Compound 7-4 
     To a solution of compound 7-3 (3.5 g, 17.6 mmol) and ammonia (13 mL) in MeOH (30.0 mL) was added glyoxal (8 mL, 40% in H 2 O) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-4 as a white solid (2.0 g, 47.6%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 238.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.96 (s, 1H), 4.94 (dd, 1H, J=7.68, 2.40 Hz), 3.38 (t, 2H, J=6.24 Hz), 2.17-2.03 (m, 2H), 1.99-1.91 (m, 2H), 1.48 (s, 9H). 
     Step 5) The Preparation of Compound 7-5 
     To a solution of compound 7-4 (2.0 g, 8.4 mmol) in DCM (60.0 mL) was added N-iodosuccinimide (3.8 g, 16.8 mmol) at 0° C. portionwise, and the mixture was stirred at 0° C. for 1.5 hrs. After the reaction was completed, the mixture was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-5 as a white solid (2.6 g, 63.1%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 490.0 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.89 (dd, 1H, J=7.64, 2.52 Hz), 3.36 (t, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H). 
     Step 6) The Preparation of Compound 7-6 
     To a suspension of compound 7-5 (1.6 g, 3.27 mmol) in mixed solvent of ethanol and water (50.0 mL, v/v=3/7) was added Na 2 SO 3  (3.7 g, 29 mmol), and the mixture was refluxed for 17 hrs. After the reaction was completed, ethanol was removed in vacuo, and 20 mL of water was added to the mixture. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-6 as a white solid (1.0 g, 84%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 364.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.04 (d, 1H, J=1.84 Hz), 4.89 (dd, 1H, J=7.72 Hz, 2.56 Hz), 3.36 (t, 2H), 2.18-2.03 (m, 2H), 1.97-1.82 (m, 2H), 1.47 (s, 9H). 
     Step 7) The Preparation of Compound 7-7 
     To a solution of compound 7-6 (1.50 g, 4.1 mmol) in EtOAc (10.0 mL) was added a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered, and the filter cake (1.2 g) was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 264.1 [M+H] + . 
     Step 8) The Preparation of Compound 7-8 
     A suspension of compound 7-7 (1.2 g, 3.6 mmol), compound 1-13-2 (0.69 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) in DCM (20.0 mL) was stirred at 0° C. for 5 mins, then DIPEA (2.38 mL, 14.4 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with saturated NH 4 Cl aqueous solution, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/EtOH (v/v)=50/1) to give the title compound as a pale yellow solid (1.31 g, 86.8%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 421.1[M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.35 (s, 1H), 5.32, 5.29 (brs, brs, 1H), 5.20-5.15 (m, 1H), 4.41-4.37 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 2.28-2.17 (m, 3H), 2.11-1.96 (m, 2H), 0.97-0.95 (m, 3H), 0.91-0.89 (m, 3H). 
     Step 9) The Preparation of Compound 7-9 
     To a mixture of compound 7-8 (0.58 g, 1.38 mmol), CuI (78 mg, 0.41 mmol), tetrabutylammonium iodide (1.53 g, 4.14 mmol) and PdCl 2 (PPh 3 ) 2  (98 mg, 0.14 mmol) in DMF (5.0 mL) was added Et 3 N (2.0 mL) via syringe under N 2 . The mixture was stirred at rt for 10 mins, then trimethylsilylacetylene (0.98 mL, 6.89 mmol) was added. The resulting mixture was stirred at 70° C. overnight. After the reaction was completed, the mixture was filtered through a celite pad. The filtrate was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound (0.3 g, 55.8%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 391.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.27 (s, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.24 (m, 1H), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.65 (m, 1H), 3.63 (s, 3H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.32 (m, 9H). 
     Step 10) The Preparation of Compound 7-10 
     A solution of compound 7-9 (0.34 g, 0.87 mmol) and K 2 CO 3  (0.60 g, 4.35 mmol) in mixed solvent of MeOH (2.0 mL) and THF (2.0 mL) was stirred at rt for 6.0 hrs. After the reaction was completed, the mixture was concentrated. The residue was diluted with water (10 mL) and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (0.23 g, 82.6%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 319.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.27 (s, 1H), 5.35-5.31 (m, 1.5H), 5.30-5.29 (d, 0.5H, J=4.0 Hz), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.66 (m, 1H), 3.63 (s, 3H), 3.36 (s, 1H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 11) The Preparation of Compound 7-11 
     To a mixture of compound 7-1 (0.27 g, 0.39 mmol), compound 7-10 (0.14 g, 0.43 mmol), CuI (33 mg, 0.172 mmol), PdCl 2 (PPh 3 ) 2  (14.1 mg, 0.02 mmol) and PPh 3  (0.23 g, 0.86 mmol) were added anhydrous DMF (10.0 mL) and Et 3 N (5.0 mL) in turn via syringe under N 2 . At the end of the addition, the mixture was stirred at rt for 10 mins and stirred at 90° C. for another 5.0 hrs. After the reaction was completed, the mixture was filtrated through a celited pad. The filtrated was diluted with water (20 mL) and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=60/1) to give the title compound (0.2 g, 58.7%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 859.5 [M+H] + ; and 
       1 H NMR (400 MHz, CD 3 OD) δ (ppm): 8.02-8.01 (m, 1H), 7.64, 7.62 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.48 (s, 1H), 7.47, 7.45 (dd, dd, 1H), 7.30, 7.28 (dd, dd, 1H), 5.51-5.47 (m, 1H), 5.32, 5.30 (d, d, 2H), 5.21-5.15 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.66 (m, 1H), 3.63 (s, 6H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.15-3.11 (m, 2H), 2.81-2.78 (m, 2H), 2.50-2.42 (m, 1H), 2.31-1.83 (m, 9H), 1.73-1.52 (m, 6H), 1.48-1.37 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 8 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 8-1 
     To a solution of formic acid (3.7 mL) was added triethylamine (5.4 mL) at 0° C., followed by 2,5-dimethoxybenzaldehyde (2.0 g, 12 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12 mmol). At the end of the addition, the mixture was stirred at 100° C. for 2.0 hrs. After the reaction was completed, 20 mL of ice water was added to the mixture, and the resulting mixture was adjusted to pH 1 with hydrochloric acid (2 M) and extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound 8-1 as a white solid (0.21 g, 83%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 211.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.78-6.70 (m, 6H), 3.78 (s, 3H), 3.75 (s, 3H), 2.91 (t, 2H, J=7.8 Hz), 2.65 (t, 2H, J=7.8 Hz). 
     Step 2) The Preparation of Compound 8-2 
     A mixture of compound 8-1 (4.68 g, 22.3 mmol) and PPA (50.87 g, 24.8 mL) was stirred at 80° C. for 4.0 hrs. After the reaction was completed, 250 mL of ice water was added to the mixture, and the resulting mixture was extracted with EtOAc (100 mL×5). The combined organic layers were washed with NaHCO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound 8-2 as a pale yellow solid (3.0 g, 70.0%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 193.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.98 (d, 1H, J=8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 3.90 (s, 3H), 3.85 (s, 3H), 3.00-2.97 (m, 2H), 2.68-2.65 (m, 2H). 
     Step 3) The Preparation of Compound 8-3 
     To a suspension of potassium tert-butanolate (1.17 g, 10.41 mmol) in toluene (10.0 mL) was added a solution of compound 8-2 (0.80 g, 4.16 mmol) and 1,5-dibromopentane (0.62 mL, 4.58 mmol) in toluene (20.0 mL) via syringe at 0° C. under N 2 . At the end of the addition, the mixture was stirred at 110° C. for 2.5 hrs. After the reaction was completed, the mixture was quenched with ice-water (50 mL). The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a pale yellow solid (0.63 g, 58%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 261.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.98 (d, 1H, J=8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 3.89 (s, 3H), 3.86 (s, 3H), 2.88 (s, 2H), 1.82-1.68 (m, 5H), 1.51-1.26 (m, 5H). 
     Step 4) The Preparation of Compound 8-4 
     To a suspension of compound 8-3 (0.99 g, 3.8 mmol) and triethylsilane (3.7 mL, 23 mmol) was added TFA (8.0 mL) via syringe at 0° C. under N 2 . At the end of the addition, the mixture was stirred at 40° C. for 7.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with saturated Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound (0.81 g, 87%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 247.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.61 (s, 2H), 3.79 (s, 6H), 2.74 (s, 4H), 1.58-1.40 (m, 10H). 
     Step 5) The Preparation of Compound 8-5 
     To a solution of compound 8-4 (0.78 g, 3.17 mmol) in DCM (20.0 mL) was added boron tribromide (1.20 mL, 12.67 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (0.7 g, 100%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 219.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.49 (s, 2H), 5.07-4.53 (br, 2H), 2.68 (s, 4H), 1.59-1.37 (m, 10H). 
     Step 6) The Preparation of Compound 8-6 
     To a solution of compound 8-5 (0.69 g, 3.16 mmol) in DCM (20.0 mL) was added pyridine (2.03 mL, 25.29 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (3.19 mL, 19.97 mmol) was added, and then the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (20 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=6/1) to give the title compound as colorless oil (1.11 g, 73%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.13 (s, 2H), 2.92 (s, 4H), 1.59-1.41 (m, 10H). 
     Step 7) The Preparation of Compound 8-7 
     To a mixture of compound 8-6 (3.84 g, 7.98 mmol), compound 1-15 (3.3 g, 6.65 mmol), Pd(PPh 3 ) 4  (0.77 g, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and H 2 O (10.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL). The resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (3.5 g, 75%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H), 7.25, 7.23 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 2.82-2.78 (m, 2H), 2.72-2.69 (m, 2H), 2.30-1.92 (m, 5H), 1.77-1.65 (m, 4H), 1.57-1.49 (m, 4H), 1.29-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 8) The Preparation of Compound 8-9 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 8-8 (2.99 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) via syringe at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as colorless slurry (0.84 g, 25%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 483.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.54, 7.52 (dd, dd, 1H), 7.51, 7.48 (m, m, 1H), 6.39 (s, 2H), 5.57-5.56, 5.55-5.54 (d, d, 1H, J=4.0 Hz), 4.50-4.45 (m, 1H), 4.32-4.28 (m, 1H), 3.64 (s, 3H), 3.57-3.50 (m, 1H), 3.44-3.36 (m, 1H), 2.17-2.03 (m, 2H), 1.96-1.86 (m, 1H), 1.84-1.65 (m, 2H), 1.42-1.31 (m, 1H), 1.12-0.99 (m, 1H), 0.90-0.83 (m, 6H). 
     Step 9) The Preparation of Compound 8-10 
     To a solution of compound 8-9 (0.62 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed. The residue was dissolved in EtOAc (50 mL), and then washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.56 g, 95%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 465.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.74 (m, 2H), 7.72, 7.70 (d, d, 1H), 5.39, 5.36 (d, d, 1H), 5.02-4.97 (m, 1H), 4.34-4.30 (m, 1H), 3.63 (s, 3H), 3.51-3.43 (m, 1H), 3.41-3.34 (m, 1H), 2.24-2.15 (m, 1H), 2.12-1.98 (m, 3H), 1.94-1.84 (m, 1H), 1.61-1.51 (m, 1H), 1.25-1.12 (m, 1H), 1.00-0.98 (m, 3H), 0.92-0.88 (m, 3H). 
     Step 10) The Preparation of Compound 8-11 
     A suspension of compound 8-10 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.049 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 80° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (182 mg, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 513.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.80 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.39, 5.36 (d, d, 1H), 5.03-4.97 (m, 1H), 4.34-4.30 (m, 1H), 3.63 (s, 3H), 3.51-3.43 (m, 1H), 3.41-3.34 (m, 1H), 2.24-2.15 (m, 1H), 2.12-1.98 (m, 3H), 1.96-1.83 (m, 1H), 1.61-1.51 (m, 1H), 1.32 (q, 6H), 1.29 (q, 6H), 1.25-1.12 (m, 1H), 1.00-0.98 (m, 3H), 0.92-0.88 (m, 3H). 
     Step 11) The Preparation of Compound 8-12 
     A mixture of compound 8-11 (0.12 g, 0.23 mmol), compound 8-7 (0.12 g, 0.16 mmol), Pd(PPh 3 ) 4  (30 mg, 0.03 mmol) and K 2 CO 3  (60 mg, 0.44 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 4.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (76.9 mg, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 469.5 [M+H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.05 (m, 1H), 7.72-7.71, 7.70-7.69 (d, d, 1H, J=4.0 Hz), 7.62-7.57 (m, 5H), 7.52-7.49 (m, 2H), 7.43, 7.41 (dd, dd, 1H), 7.00-6.99 (m, 1H), 5.99-5.98, 5.97-5.96 (d, d, 1H, J=4.0 Hz), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 5.15-5.09 (m, 1H), 4.41-4.36 (m, 1H), 4.32-4.27 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 3.55-3.49 (m, 1H), 3.17-3.09 (m, 1H), 2.85-2.81 (m, 4H), 2.30-1.76 (m, 10H), 1.73-1.60 (m, 4H), 1.56-1.48 (m, 4H), 1.46-1.37 (m, 1H), 1.29-1.21 (m, 2H), 1.17-1.05 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.87, 0.85 (m, m, 3H), 0.84-0.83 (m, 3H). 
     Example 9 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 9-2 
     To a solution of compound 9-1 (11.0 g, 44.84 mmol) in DCM (200 mL) was added Et 2 NSF 3  (8.85 mL, 67.3 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 2.0 hrs and then at rt for another 19 hrs. After the reaction was completed, the reaction was quenched with NH 4 Cl aqueous solution (100 mL). The aqueous layer was extracted with DCM (100 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as a pale yellow liquid (7.76 g, 70%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 248.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.26, 5.13 (d, d, 1H), 4.55-4.41 (m, 1H), 3.88-3.74 (m, 1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 2.52-2.44 (m, 1H), 2.40-2.32 (m, 1H), 1.42-1.47 (d, 9H, J=20 Hz). 
     Step 2) The Preparation of Compound 9-3 
     To a solution of compound 9-2 (5.83 g, 23.58 mmol) in THF (30.0 mL) was added LiOH aqueous solution (1.98 g, 30.0 mL) at 0° C., and the mixture was stirred at rt for 2.0 hrs and then adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL×3). The combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (5.3 g, 96%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 234.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J=16 Hz). 
     Step 3) The Preparation of Compound 9-4 
     To a solution of compound 9-3 (5.0 g, 21.45 mmol) and compound 1-10 (4.93 g, 17.87 mmol) in DCM (100 mL) was added TEA (4.34 g, 42.9 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the reaction was quenched with water (50 mL), and the resulting mixture was extracted with DCM (60 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound (3.74 g, 52.2%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 403.3 [M+H] + . 
     Step 4) The Preparation of Compound 9-5 
     A mixture of compound 9-4 (4.5 g, 11.19 mmol) and ammonium acetate (12.5 g, 162 mmol) in toluene (50.0 mL) was refluxed at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 50 mL of water was added. The resulting mixture was extracted with EtOAc (80 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound (4.21 g, 92%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 411.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.56-7.51 (m, 2H), 7.47-7.45 (m, 2H), 7.22 (s, 1H), 5.38-5.29 (m, 1H), 5.25-5.17 (m, 1H), 4.13-4.07, 3.62-3.39 (m, m, 1H), 3.68-3.58 (m, 1H), 2.68-2.38 (m, 2H), 1.38 (s, 9H). 
     Step 5) The Preparation of Compound 9-6 
     A mixture of compound 9-5 (2.0 g, 4.87 mmol), compound 1-14-2 (1.26 g, 4.97 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (70 mg, 0.10 mmol) and KOAc (1.19 g, 12.2 mmol) in DMF (20 mL) was stirred at 90° C. under N 2  for 2.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL) and filtered through a celite pad. Water (30 mL) was added to the filtrate, and the resulting mixture was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (1.43 g, 64%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 458.4 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.81-7.79 (m, 2H), 7.65-7.60 (m, 2H), 7.28 (s, 1H), 5.39-5.26 (m, 1H), 5.20-5.12 (m, 1H), 4.07-3.99, 3.59-3.41 (m, 1H), 3.69-3.62 (m, 1H), 2.62-2.51 (m, 2H), 1.34 (s, 12H), 1.28 (s, 9H). 
     Step 6) The Preparation of Compound 9-7 
     To a solution of compound 9-6 (4.57 g, 10 mmol) in EtOAc (20.0 mL) was added a solution of HCl in EtOAc (20 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo, and EtOAc (30 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a pale yellow solid (3.04 g, 85%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 358.6 [M+H] + . 
     Step 7) The Preparation of Compound 9-8 
     A suspension of compound 9-7 (6.88 g, 19.26 mmol), compound 1-13-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was stirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with water (100 mL). The aqueous layer was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a solid (6.44 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 515.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H), 7.26 (s, 1H), 5.56, 5.55 (d, d, 1H), 5.32-5.24 (m, 0.5H), 5.19-5.11 (m, 0.5H), 4.91-4.87 (m, 1H), 4.30-4.25 (m, 1H), 4.13-4.01 (m, 1H), 3.75-3.69 (m, 1H), 3.66 (s, 3H), 2.93-2.77 (m, 1H), 2.29-2.15 (m, 2H), 1.35 (q, 6H), 1.32 (q, 6H), 1.02, 1.00 (m, m, 3H), 0.95, 0.91 (m, m, 6H). 
     Step 8) The Preparation of Compound 9-9 
     To a mixture of compound 8-4 (3.85 g, 7.98 mmol), compound 9-8 (3.42 g, 6.65 mmol), Pd(PPh 3 ) 4  (0.77 g, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and pure water (10.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), and then washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a beige solid (3.83 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71-7.66 (m, 4H), 7.41 (s, 1H), 7.25, 7.23 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.56, 5.55 (d, d, 1H), 5.32-5.24 (m, 0.5H), 5.19-5.11 (m, 0.5H), 4.91-4.87 (m, 1H), 4.30-4.25 (m, 1H), 4.13-4.01 (m, 1H), 3.75-3.67 (m, 1H), 3.66 (s, 3H), 2.93-2.84 (m, 1H), 2.82-2.77 (m, 2H), 2.72-2.69 (m, 2H), 2.29-2.15 (m, 2H), 1.77-1.65 (m, 4H), 1.57-1.49 (m, 4H), 1.29-1.21 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.92 (m, m, 6H). 
     Step 9) The Preparation of Compound 9-10 
     To a solution of compound 9-3 (5.94 g, 25.5 mmol) in EtOAc (30.0 mL) was added a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo, and EtOAc (30 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a pale yellow solid (3.05 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 134.5 [M+H] + . 
     Step 10) The Preparation of Compound 9-11 
     A suspension of compound 9-10 (2.56 g, 19.26 mmol), compound 1-13-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was stirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (200 mL), washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a solid (4.47 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 291.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.32-5.24 (m, 1.5H), 5.19-5.11 (m, 0.5H), 4.73-4.68 (m, 1H), 4.41-4.36 (m, 1H), 3.94-3.81 (m, 1H), 3.63 (s, 3H), 3.61-3.49 (m, 1H), 2.78-2.62 (m, 1H), 2.29-2.08 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 11) The Preparation of Compound 9-12 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 9-11 (3.04 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.85 g, 25%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 487.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H), 6.39 (s, 2H), 5.56-5.55 (d, d, 1H), 5.29-5.20 (m, 0.5H), 5.16-5.08 (m, 0.5H), 4.41-4.35 (m, 1H), 4.31-4.27 (m, 1H), 3.88-3.76 (m, 1H), 3.66 (s, 3H), 3.57-3.44 (m, 1H), 2.87-2.72 (m, 1H), 2.37-2.10 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 12) The Preparation of Compound 9-13 
     To a solution of compound 9-12 (0.62 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed. The residue was dissolved in EtOAc (50 mL), washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.54 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 469.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78 (m, 1H), 7.77, 7.74 (d, d, 1H), 7.72, 7.70 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.33-5.26 (m, 1.5H), 4.99-4.93 (m, 1H), 4.34-4.29 (m, 1H), 3.93-3.81 (m, 1H), 3.63 (s, 3H), 3.57-3.44 (m, 1H), 2.89-2.72 (m, 1H), 2.32-2.17 (m, 1H), 2.06-1.94 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 13) The Preparation of Compound 9-14 
     A suspension of compound 9-13 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.19 g, 82.9%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 517.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.79-7.78 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.34-5.26 (m, 1.5H), 5.00-4.93 (m, 1H), 4.34-4.29 (m, 1H), 3.93-3.81 (m, 1H), 3.63 (s, 3H), 3.57-3.44 (m, 1H), 2.89-2.72 (m, 1H), 2.32-2.17 (m, 1H), 2.06-1.94 (m, 1H), 1.32, 1.29 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 14) The Preparation of Compound 9-15 
     A mixture of compound 9-14 (0.12 g, 0.23 mmol), compound 9-9 (0.17 g, 0.23 mmol), Pd(PPh 3 ) 4  (30 mg, 0.03 mmol) and K 2 CO 3  (60 mg, 0.44 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 4.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (99.4 mg, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 481.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.74-7.67 (m, 4H), 7.52, 7.50 (d, d, 1H), 7.49, 7.47 (d, d, 1H), 7.43-7.40 (m, 2H), 5.56, 5.55 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.34-5.24 (m, 2H), 5.19-5.07 (m, 1.5H), 4.91-4.87 (m, 1H), 4.34-4.25 (m, 2H), 4.13-4.01 (m, 1H), 3.93-3.81 (m, 1H), 3.75-3.68 (m, 1H), 3.66 (s, 3H), 3.63 (s, 3H), 3.57-3.44 (m, 1H), 2.93-2.68 (m, 6H), 2.29-2.15 (m, 3H), 2.06-1.96 (m, 1H), 1.72-1.60 (m, 4H), 1.55-1.48 (m, 4H), 1.29-1.21 (m, 2H), 1.02-0.89 (m, 12H). 
     Example 10 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 10-2 
     To a solution of compound 10-1 (10 g, 77.5 mmol) in MeOH (50.0 mL) was added thionyl chloride (5.5 mL, 75.8 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at 0° C. for 1.0 hr and then at rt for another 2.0 hrs. After the reaction was completed, NaHCO 3  aqueous solution (50 mL) was added to the mixture, and the solvent MeOH was removed. To the residue was added water (30 mL), and the resulting mixture was extracted with CH 2 Cl 2  (35 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as colorless liquid (7.5 g, 67.6%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 144.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.38 (br, 1H), 4.20-4.16 (m, 1H), 3.67 (s, 3H), 2.39-2.23 (m, 3H), 2.14-2.07 (m, 1H). 
     Step 2) The Preparation of Compound 10-3 
     To a solution of compound 10-2 (6.45 g, 45.06 mmol) in MeCN (30.0 mL) was added DMAP (0.55 g, 4.5 mmol) at 0° C., followed by di-tert-butyl dicarbonate (10.82 g, 49.56 mmol) dropwise, and the mixture was stirred at 0° C. for 30 mins and then at rt for another 2.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as colorless liquid (5.0 g, 45.6%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 144.2 [M−Boc] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.60-4.57 (m, 1H), 3.75 (s, 3H), 2.65-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.96 (m, 1H), 1.45 (s, 9H). 
     Step 3) The Preparation of Compound 10-4 
     To a solution of compound 10-3 (3.74 g, 15.4 mmol) in toluene (50.0 mL) was added lithium triethylborohydride dropwise (1.79 g, 16.9 mmol) at −78° C. After the mixture was stirred at −78° C. for 70 mins, DIPEA (3.2 mL, 19.4 mmol), DMAP (0.19 g, 1.54 mmol) and TFAA (3.0 mL, 40.4 mmol) were added in turn, and then the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as yellow liquid (2.26 g, 64.8%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 128.2 [M−Boc] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.65-6.52 (br, 1H), 4.96-4.91 (br, 1H), 4.68-4.57 (m, 1H), 3.76 (s, 3H), 3.12-3.00 (m, 1H), 2.71-2.61 (m, 1H), 1.49-1.44 (br, 9H). 
     Step 4) The Preparation of Compound 10-5 
     To a solution of diethylzinc (0.49 g, 3.94 mmol) in toluene (6.0 mL) was added chloroiodomethane (1.39 g, 7.9 mmol) at 0° C. After the mixture was stirred at 0° C. for 45 mins, a solution of compound 10-4 (0.3 g, 1.32 mmol) in toluene (4.0 mL) was added, and then the mixture was stirred at 0° C. for 18 hrs. After the reaction was completed, the mixture was quenched with saturated NH 4 Cl aqueous solution (15 mL). The resulting mixture was extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as yellow liquid (0.19 g, 59.7%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 142.2 [M−Boc] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.64-4.51 (m, 1H), 3.70 (s, 3H), 3.56-3.45 (m, 1H), 2.64-2.54 (m, 1H), 2.05-2.01 (m, 1H), 1.50, 1.41 (s, s, 9H), 0.75-0.65 (m, 3H). 
     Step 5) The Preparation of Compound 10-6 
     To a solution of compound 10-5 (1.02 g, 4.23 mmol) in THF (20.0 mL) was added lithium hydroxide monohydrate aqueous solution (0.89 g, 21.2 mmol, 10 mL) at 0° C., and the mixture was stirred at 40° C. for 12 hrs. After the reaction was completed, THF was removed and 10 mL of water was added to the mixture. The resulting mixture was extracted with EtOAc (25 mL×3), and then the aqueous phase was adjusted to pH 1 with hydrochloric acid (10%) and extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (0.84 g, 87%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, neg.ion) m/z: 226.2 [M−H] − ; and 
       1 H NMR (400 MHz, CD 3 OD) δ (ppm): 4.53-4.46 (m, 1H), 3.48-3.42 (m, 1H), 2.70-2.57 (m, 1H), 2.05-2.01 (m, 1H), 1.60-1.54 (m, 1H), 1.48, 1.41 (s, s, 9H), 0.89-0.80 (m, 1H), 0.73-0.66 (m, 1H). 
     Step 6) The Preparation of Compound 10-7 
     To a solution of compound 10-6 (5.79 g, 25.5 mmol) in EtOAc (30.0 mL) was added a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo, and EtOAc (30 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a pale yellow solid (2.92 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 128.5 [M+H] + . 
     Step 7) The Preparation of Compound 10-8 
     A suspension of compound 10-7 (2.45 g, 19.26 mmol), compound 1-13-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was stirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (100 mL), washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a solid (4.38 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 285.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.56, 5.55 (d, d, 1H), 4.40-4.37 (m, 1H), 4.05-4.01 (m, 1H), 3.66 (s, 3H), 3.33-3.27 (m, 1H), 2.29-2.15 (m, 2H), 1.91-1.85 (m, 1H), 1.48-1.40 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.94-0.88 (m, 4H), 0.49-0.45 (m, 1H). 
     Step 8) The Preparation of Compound 10-9 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 10-8 (2.97 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.67 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 481.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.42-4.38 (m, 1H), 4.09-4.05 (m, 1H), 3.66 (s, 3H), 3.41-3.35 (m, 1H), 2.45-2.38 (m, 1H), 2.21-2.09 (m, 1H), 2.08-2.03 (m, 1H), 1.45-1.37 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.88-0.83 (m, 1H), 0.43-0.40 (m, 1H). 
     Step 9) The Preparation of Compound 10-10 
     A solution of compound 10-9 (0.61 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then the residue was dissolved in EtOAc (50 mL). The combined organic phase were washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.50 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.79 (m, 1H), 7.77-7.74 (d, d, 1H), 7.72, 7.70 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 4.84-4.80 (m, 1H), 4.35-4.31 (m, 1H), 3.63 (s, 3H), 3.30-3.23 (m, 1H), 2.46-2.38 (m, 1H), 2.07-1.94 (m, 2H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H). 
     Step 10) The Preparation of Compound 10-11 
     A suspension of compound 10-10 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and anhydrous KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.19 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 511.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13-8.11 (d, d, 1H), 7.80-7.79 (m, 1H), 7.47-7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 4.85-4.81 (m, 1H), 4.35-4.31 (m, 1H), 3.63 (s, 3H), 3.30-3.23 (m, 1H), 2.46-2.38 (m, 1H), 2.07-1.94 (m, 2H), 1.49-1.42 (m, 1H), 1.32, 1.29 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H). 
     Step 11) The Preparation of Compound 10-12 
     To a solution of compound 8-2 (2.75 g, 14.34 mmol) and compound 10-0 (5.23 g, 21.51 mmol) in DMF (15.0 mL) was added NaH (60%, 1.43 g, 35.85 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at 50° C. for 18 hrs. After the reaction was completed, the mixture was cooled to rt and quenched with water (100 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound (0.79 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 276.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.84, 6.82 (m, m, 1H), 6.77, 6.75 (m, m, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.81-2.79 (m, 2H), 2.73-2.65 (m, 2H), 2.51-2.39 (m, 2H), 2.35-2.34 (m, 3H), 1.84-1.74 (m, 4H). 
     Step 12) The Preparation of Compound 10-13 
     To a suspension of compound 10-12 (1.05 g, 3.8 mmol) and triethylsilane (3.7 mL, 23 mmol) was added TFA (8.0 mL) dropwise at 0° C. under N 2 . At the end of the addition, the mixture was stirred at 40° C. for 7.0 hrs. After the reaction was completed, the solvent TFA was removed, and then the residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound (0.84 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 262.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.62-6.61 (m, 2H), 3.77 (s, 6H), 2.77-2.69 (m, 6H), 2.56-2.45 (m, 2H), 2.30-2.29 (m, 3H), 1.89-1.79 (m, 4H). 
     Step 13) The Preparation of Compound 10-14 
     To a solution of compound 10-13 (1.12 g, 4.3 mmol) in glacial acetic acid (40.0 mL) was added hydrogen bromide (9.6 mL, 85 mmol) dropwise. At the end of the addition, the mixture was refluxed for 12 hrs. After the reaction was completed, the mixture was quenched with saturated NaHCO 3  aqueous solution (50 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.45 g, 45%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.45 (m, 2H), 4.97 (brs, 2H), 2.81-2.69 (m, 6H), 2.60-2.48 (m, 2H), 2.30-2.29 (m, 3H), 1.91-1.81 (m, 4H). 
     Step 14) The Preparation of Compound 10-15 
     To a solution of compound 10-14 (0.35 g, 1.5 mmol) in DCM (20.0 mL) was added trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) dropwise at 0° C. Triethylamine (2.4 mL, 17.27 mmol) was then added slowly, and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was quenched with ice water (20 mL). The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (0.56 g, 75%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.28 (m, 2H), 2.79-2.69 (m, 6H), 2.56-2.44 (m, 2H), 2.30-2.29 (m, 3H), 2.04-1.92 (m, 4H). 
     Step 15) The Preparation of Compound 10-16 
     To a mixture of compound 10-15 (3.31 g, 6.65 mmol), compound 1-15 (3.3 g, 6.65 mmol), Pd(PPh 3 ) 4  (0.77 g, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and H 2 O (10.0 mL) via syringe. The mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL). The resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a beige solid (3.1 g, 65%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H), 7.25, 7.22 (d, d, 1H), 7.02, 7.00 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 2.83-2.81 (m, 2H), 2.77-2.69 (m, 4H), 2.56-2.44 (m, 2H), 2.30-2.29 (m, 3H), 2.26-1.96 (m, 9H), 0.97, 0.95 (m, m, 3H), 0.90-0.89 (m, m, 3H). 
     Step 16) The Preparation of Compound 10-17 
     A mixture of compound 10-16 (0.16 g, 0.23 mmol), compound 10-11 (0.12 g, 0.23 mmol), Pd(PPh 3 ) 4  (30 mg, 0.03 mmol) and K 2 CO 3  (60 mg, 0.44 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 4.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (98.48 mg, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 476.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.92-7.87 (m, 2H), 7.60-7.56 (m, 5H), 7.52-7.49 (m, 2H), 6.72-6.71 (m, 1H), 5.32, 5.30 (m, m, 2H), 5.23-5.19 (m, 1H), 4.83-4.80 (m, 1H), 4.41-4.31 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 6H), 3.30-3.23 (m, 1H), 3.02-2.98 (m, 2H), 2.89-2.85 (m, 2H), 2.76-2.68 (m, 2H), 2.55-2.38 (m, 3H), 2.30-2.29 (m, 3H), 2.27-1.85 (m, 11H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H). 
     Example 11 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 11-2 
     To a solution of N,N,N′,N′-tetramethylethylenediamine (40.0 mL) in hexane (100 mL) were added 1,2-dimethoxybenzene (40.0 g, 0.29 mol) and n-BuLi (1.6 M in hexane, 200 mL, 0.32 mol) dropwise in turn. At the end of the addition, the mixture was stirred at rt for 28 hrs. After cooling to −78° C., ClSiMe 3  (45.0 mL) was added dropwise to the mixture. At the end of the addition, the reaction was stirred at rt. After the reaction was completed, the mixture was quenched with water (100 mL). The aqueous layer was extracted with hexane (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/DCM (v/v)=10/1) to give the title compound as colorless oil (51.5 g, 85%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.06-7.02 (m, 1H), 6.97-6.93 (m, 2H), 3.86 (s, 6H), 0.28 (s, 9H). 
     Step 2) the preparation of compound 11-3 To a solution of compound 11-2 (69.34 g, 0.33 mol) in N,N,N′,N′-tetramethylethylenediamine (60.0 mL) was added n-BuLi (1.6 M in hexane, 250 mL, 0.40 mol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 25 hrs. After cooling to −78° C., ClSiMe 3  (60.0 mL) was added dropwise to the mixture. At the end of the addition, the reaction was stirred at rt. After the reaction was completed, the mixture was quenched with ice water (150 mL). The aqueous layer was extracted with hexane (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/DCM (v/v)=10/1) to give the title compound as colorless oil (82.86 g, 89%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.11 (s, 2H), 3.83 (s, 6H), 0.29 (s, 18H). 
     Step 3) The Preparation of Compound 11-4 
     To a solution of compound 11-3 (19.2 g, 68.1 mmol) in DCM (100 mL) was added a solution of ICl (23.1 g, 0.14 mol) in DCM (100 mL) dropwise at 0° C. At the end of addition, the mixture was stirred at rt for 30 mins. After the reaction was completed, the mixture was quenched with saturated sodium thiosulfate aqueous solution (100 mL). The organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/DCM (v/v)=10/1) to give the title compound as a pale yellow solid (21.5 g, 81%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.24 (s, 2H), 3.87 (s, 6H). 
     Step 4) The Preparation of Compound 11-5 
     To a solution of compound 11-4 (1.80 g, 4.62 mmol) in DCM (20.0 mL) was added boron tribromide (2.0 mL, 21.2 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as a white solid (1.5 g, 90%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.00 (s, 2H), 5.66 (s, 2H). 
     Step 5) The Preparation of Compound 11-6 
     A solution of compound 11-5 (0.36 g, 1.0 mmol), cyclopentanone (0.25 g, 3.0 mmol) and p-toluenesulfonic acid (19 mg, 0.1 mmol) in hexane (20.0 mL) was refluxed for 5.0 hrs. After the reaction was completed, the mixture was quenched with water (25 mL). The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/DCM (v/v)=1/1) to give the title compound (0.20 g, 46%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.84 (s, 1H), 2.17 (m, 4H), 1.87 (m, 4H). 
     Step 6) The Preparation of Compound 11-7 
     A mixture of compound 11-6 (4.28 g, 10 mmol), compound 1-15 (4.96 g, 10 mmol), Pd(PPh 3 ) 4  (1.16 g, 1.0 mmol) and K 2 CO 3  (3.45 g, 25 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 40.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) to give the title compound as a pale yellow solid (3.35 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 671.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.74, 7.71 (s, s, 1H), 7.60-7.56 (m, 3H), 7.38-7.34 (m, 2H), 6.84, 6.82 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 2.30-1.77 (m, 13H), 0.97, 0.95 (m, m, 3H), 0.90-0.89 (m, m, 3H). 
     Step 7) The Preparation of Compound 11-8 
     A mixture of compound 11-7 (3.35 g, 5.0 mmol), compound 10-11 (2.55 g, 5.0 mmol), Pd(PPh 3 ) 4  (0.58 g, 0.5 mmol) and K 2 CO 3  (1.73 g, 12.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 40.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (250 mL), and washed with water (100 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (2.08 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 464.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77 (m, 1H), 7.60-7.57 (m, 3H), 7.54-7.51 (m, 2H), 7.43-7.40 (m, 2H), 7.36-7.32 (m, 2H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 4.97-4.94 (m, 1H), 4.41-4.31 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.30-3.23 (m, 1H), 2.45-2.38 (m, 1H), 2.30-1.74 (m, 15H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H). 
     Example 12 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 12-1 
     To a solution of compound 8-2 (1.31 g, 6.82 mmol), compound 12-0 (1.64 g, 7.15 mmol) and TEBAC (0.3 g, 1.36 mmol) in DMSO (30.0 mL) was added sodium hydroxide aqueous solution (50%, 2.0 mL) at 0° C. At the end of the addition, the mixture was stirred at 50° C. for 2.0 hrs. After the reaction was completed, 50 mL of water was added to the mixture, and the resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as yellow oil (1.07 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 263.5 [M+H] + ; and 
       1 H NMR (400 MHz, d 6 -DMSO) δ (ppm): 6.84, 6.82 (m, m, 1H), 6.77, 6.75 (m, m, 1H), 3.97-3.90 (m, 2H), 3.84 (d, 3H), 3.81 (d, 3H), 3.70-3.62 (m, 2H), 2.83-2.81 (m, 2H), 2.01-1.93 (m, 2H), 1.80-1.71 (m, 2H). 
     Step 2) The Preparation of Compound 12-2 
     To a suspension of compound 12-1 (1.0 g, 3.8 mmol) and triethylsilane (3.7 mL, 23 mmol) was added TFA (8.0 mL) dropwise at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 7.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as pale yellow oil (0.80 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 249.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.67-6.66 (m, 2H), 3.77 (d, 6H), 3.71-3.66 (m, 4H), 2.77-2.74 (m, 4H), 1.76-1.70 (m, 4H). 
     Step 3) The Preparation of Compound 12-3 
     To a solution of compound 12-2 (0.69 g, 2.77 mmol) in DCM (20.0 mL) was added boron tribromide (0.36 mL, 3.88 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (20 mL). The aqueous layer was extracted with DCM (25 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=12/1) to give the title compound as colorless liquid (0.61 g, 100%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 221.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.45 (m, 2H), 4.97 (brs, 2H), 3.74-3.70 (m, 4H), 2.75-2.72 (m, 4H), 1.79-1.72 (m, 4H). 
     Step 4) The Preparation of Compound 12-4 
     To a solution of compound 12-3 (1.70 g, 7.7 mmol) in DCM (50.0 mL) was added pyridine (3.1 mL, 38.6 mmol) dropwise at 0° C. under N 2 . After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (3.9 mL, 23.1 mmol) was added, and then the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (60 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound as pale yellow oil (3.17 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 485.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.28 (m, 2H), 3.71-3.66 (m, 4H), 2.78-2.76 (m, 4H), 1.90-1.84 (m, 4H). 
     Step 5) The Preparation of Compound 12-6 
     To a solution of compound 12-5 (6.86 g, 27.97 mmol) in DCM (70.0 mL) was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions at 0° C. At the end of the addition, the mixture was stirred at rt for 7.0 hrs. After the mixture was completed, the reaction was quenched with Na 2 S 2 O 3  aqueous solution (100 mL), and the mixture was filtered through a celite pad. The filtrate was extracted with DCM (100 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=6/1) to give the title compound as pale yellow liquid (5.78 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 244.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.49-4.45 (m, 1H), 4.05, 4.00 (m, m, 1H), 3.88, 3.84 (m, m, 1H), 3.79 (s, 3H), 3.19-3.12 (m, 1H), 2.72-2.65 (m, 1H), 1.43 (s, 9H). 
     Step 6) The Preparation of Compound 12-7 
     To a solution of compound 12-6 (5.81 g, 23.9 mmol) in DCM (70.0 mL) was added Et 2 NF 3  (4.85 mL, 35.9 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 2.0 hrs and then at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH 4 Cl aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 266.25 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.68-4.63 (m, 1H), 4.01-3.87 (m, 1H), 3.78 (s, 3H), 3.75-3.63 (m, 1H), 2.84-2.66 (m, 1H), 2.51-2.31 (m, 1H), 1.43 (d, 9H, J=16 Hz). 
     Step 7) The Preparation of Compound 12-8 
     To a solution of compound 12-7 (5.0 g, 18.86 mmol) in THF (40.0 mL) was added LiOH aqueous solution (1.5 g, 20 mL) at 0° C., and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (4.45 g, 94%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 252.23 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.60 (brs, 1H), 4.94-4.72, 4.60-4.57 (m, m, 1H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J=16 Hz). 
     Step 8) The Preparation of Compound 12-9 
     To a solution of compound 1-10 (2.41 g, 8.66 mmol) and compound 12-8 (2.17 g, 8.66 mmol) in DCM (30 mL) was added TEA (2.5 mL, 17.32 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), and the resulting mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (3.6 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 421.25 [M+H] + . 
     Step 9) The Preparation of Compound 12-10 
     A mixture of compound 12-9 (3.6 g, 8.6 mmol) and ammonium acetate (7.0 g, 86 mmol) in toluene (30.0 mL) was refluxed at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 60 mL of water was added. The resulting mixture was extracted with EtOAc (80 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=6/1) to give the title compound (1.47 g, 40%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 429.27 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.54-7.52 (m, 2H), 7.48-7.46 (m, 2H), 7.26-7.25 (m, 1H), 5.19-5.18 (m, 1H), 3.70-3.52 (m, 2H), 2.78-2.65 (m, 2H), 1.48 (s, 9H). 
     Step 10) The Preparation of Compound 12-11 
     A mixture of compound 12-10 (1.4 g, 3.27 mmol), compound 1-14-2 (0.92 g, 3.6 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.13 g, 1.16 mmol) and KOAc (0.81 g, 8.17 mmol) in DME (25.0 mL) was stirred at 90° C. under N 2  for 2.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (100 mL) and filtered through a celite pad. The filtrate was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (1.5 g, 96%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 476.34 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.54-7.52 (m, 2H), 7.48-7.46 (m, 2H), 7.26-7.25 (m, 1H), 5.19-5.18 (m, 1H), 3.70-3.52 (m, 2H), 2.78-2.65 (m, 2H), 1.48 (s, 9H), 1.35 (s, 12H). 
     Step 11) The Preparation of Compound 12-12 
     To a solution of compound 12-11 (5.75 g, 12.1 mmol) in EtOAc (40.0 mL) was added a solution of HCl in EtOAc (20.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo, and EtOAc (50 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a white solid (3.41 g, 75%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 376.1 [M+H] + . 
     Step 12) The Preparation of Compound 12-13 
     A suspension of compound 12-12 (0.98 g, 2.6 mmol), compound 1-13-2 (0.6 g, 2.86 mmol) and EDCI (0.55 g, 2.86 mmol) in DCM (15.0 mL) was stirred at 0° C., then DIPEA (1.72 mL, 10.4 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a white solid (0.80 g, 58%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H), 7.29 (s, 1H), 5.56, 5.55 (d, d, 1H), 5.10-5.05 (m, 1H), 4.32-4.28 (m, 1H), 3.94-3.81 (m, 1H), 3.66 (s, 3H), 2.90-2.72 (m, 1H), 2.50-2.31 (m, 1H), 2.28-2.16 (m, 1H), 1.35, 1.32 (m, m, 12H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 13) The Preparation of Compound 12-14 
     To a mixture of compound 12-13 (0.43 g, 0.81 mmol), compound 12-4 (0.39 g, 0.81 mmol), Pd(PPh 3 ) 4  (47 mg, 0.04 mmol) and K 2 CO 3  (0.29 g, 2.04 mmol) were added DME (8.0 mL) and pure water (2.0 mL) via syringe. The mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was diluted with EtOAc (30 mL). The resulting mixture was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOHc (v/v)=100/1) to give the title compound as a white solid (0.33 g, 55%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 741.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71-7.66 (m, 4H), 7.43 (s, 1H), 7.25, 7.22 (d, d, 1H), 7.02, 7.00 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.10-5.05 (m, 1H), 4.32-4.28 (m, 1H), 4.21-4.07 (m, 1H), 3.94-3.81 (m, 1H), 3.70-3.65 (m, 7H), 2.91-2.72 (m, 5H), 2.50-2.30 (m, 1H), 2.28-2.16 (m, 1H), 1.85-1.79 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.94, 0.91 (m, m, 3H). 
     Step 14) The Preparation of Compound 12-15 
     To a solution of compound 12-8 (6.4 g, 25.5 mmol) in EtOAc (30.0 mL) was added a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo, and EtOAc (60.0 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a pale yellow solid (3.47 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 152.5 [M+H] + . 
     Step 15) The Preparation of Compound 12-16 
     A suspension of compound 12-15 (2.91 g, 19.26 mmol), compound 1-13-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was stirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (200 mL), washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a solid (3.86 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 309.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.56, 5.55 (d, d, 1H), 4.91-4.86 (m, 1H), 4.25-4.21 (m, 1H), 4.06-3.93 (m, 1H), 3.82-3.68 (m, 1H), 3.66 (s, 3H), 2.75-2.57 (m, 1H), 2.44-2.11 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 16) The Preparation of Compound 12-17 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 12-16 (3.23 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL) and washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.71 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 505.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.57-4.52 (m, 1H), 4.32-4.28 (m, 1H), 3.96-3.83 (m, 1H), 3.76-3.67 (m, 1H), 3.66 (s, 3H), 2.92-2.74 (m, 1H), 2.63-2.43 (m, 1H), 2.20-2.08 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 17) The Preparation of Compound 12-18 
     A solution of compound 12-17 (0.65 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then the residue was dissolved in EtOAc (50 mL). The combined organic phase were washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.53 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 487.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.70 (m, 3H), 5.32, 5.29 (d, d, 1H), 5.24-5.18 (m, 1H), 4.36-4.31 (m, 1H), 4.01-3.88 (m, 1H), 3.76-3.66 (m, 1H), 3.63 (s, 3H), 2.96-2.78 (m, 1H), 2.64-2.43 (m, 1H), 2.05-1.93 (m, 1H), 0.97-0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 18) The Preparation of Compound 12-19 
     A suspension of compound 12-18 (0.22 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.049 mmol) and KOAc (0.11 g, 1.12 mmol) in DME (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.19 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 535.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.77 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.25-5.20 (m, 1H), 4.36-4.31 (m, 1H), 4.01-3.88 (m, 1H), 3.76-3.66 (m, 1H), 3.63 (s, 3H), 2.96-2.78 (m, 1H), 2.64-2.43 (m, 1H), 2.05-1.93 (m, 1H), 1.32-1.29 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 19) The Preparation of Compound 12-20 
     A mixture of compound 12-19 (0.53 g, 1.0 mmol), compound 12-14 (0.74 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (0.40 g, 40%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 500.5 [M+2H]2; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.74-7.67 (m, 4H), 7.50-7.49, 7.48-7.47 (dd, dd, 1H), 7.46, 7.44 (d, d, 1H), 7.43 (s, 1H), 7.42, 7.41 (dd, dd, 1H), 5.56, 5.55 (d, d, 1H), 5.35-5.29 (m, 2H), 5.10-5.05 (m, 1H), 4.36-4.28 (m, 2H), 4.21-4.07 (m, 1H), 4.00-3.72 (m, 3H), 3.69-3.65 (m, 7H), 3.63 (s, 3H), 2.94-2.72 (m, 6H), 2.62-2.16 (m, 3H), 2.05-1.93 (m, 1H), 1.80-1.74 (m, 4H), 1.02-0.89 (m, 12H). 
     Example 13 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 13-1 
     A mixture of compound 1-10 (4.0 g, 10.23 mol), compound 1-14-2 (2.86 g, 11.25 mmol), Pd(dppf)Cl 2 .CH 2 C 2  (0.42 g, 0.51 mmol) and KOAc (2.51 g, 25.57 mmol) in DMF (40.0 mL) was stirred at EtOAc (250 mL) and filtered through a celite pad. The filtrate was washed with water (120 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (3.6 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.35 (m, 4H), 7.10 (s, 1H), 4.93 (t, 1H, J=8.2 Hz), 3.88-3.66 (m, 2H), 2.90 (t, 1H, J=8.0 Hz), 2.50-2.47 (m, 2H), 2.27-2.25 (m, 1H), 1.48 (s, 9H), 1.26 (s, 12H). 
     Step 2) The Preparation of Compound 13-2 
     To a mixture of compound 13-1 (2.92 g, 6.65 mmol), compound 1-8 (2.97 g, 6.65 mmol), Pd(PPh 3 ) 4  (0.77 g, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and H 2 O (10.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the solvent DME was removed. The residue was dissolved in EtOAc (150 mL). The resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a pale yellow solid (2.52 g, 60%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H), 7.24-7.23, 7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 4.97-4.93 (m, 1H), 3.64-3.58 (m, 1H), 3.31-3.23 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.47-2.38 (m, 1H), 2.29-2.16 (m, 1H), 2.10-1.97 (m, 2H), 1.74-1.43 (m, 8H), 1.41 (s, 9H). 
     Step 3) The Preparation of Compound 13-3 
     To a solution of compound 5-4-2 (22.0 g, crude product) in dry THF (250 mL), compound 1-19 (7.6 g, 35.5 mmol) and NaOH (1 M, 85.0 mmol) were added in turn. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with NaOH aqueous solution (1 M, 15 mL) and brine, dried over Na 2 SO 4  and concentrated in vacuo to give the title compound (17.0 g, 100%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 446.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.06 (br, 1H), 7.75 (d, 1H), 7.35, 7.33 (d, d, 1H), 7.28-7.22 (m, 5H), 6.69, 6.67 (d, d, 1H), 5.68 (brs, 2H), 5.14-5.13 (m, 2H), 4.29-4.25 (m, 1H), 3.66-3.60 (m, 1H), 3.45-3.37 (m, 1H), 2.39-2.32 (m, 1H), 2.09-2.00 (m, 1H), 1.96-1.77 (m, 2H). 
     Step 4) The Preparation of Compound 13-4 
     A solution of compound 13-3 (17.0 g, 38.1 mmol) and KOH (34.0 mL, 10% aq) in EtOH (200 mL) was stirred at 80° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to 0° C. and neutralized to pH 7 by carefully adding concentrated HCl. The resulting precipitate was collected by filtration and washed with EtOAc/hexane (v/v=5/1) to give the title compound 13-4 (12.6 g, 77.0%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 428.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.02, 8.01 (d, d, 1H), 7.65, 7.62 (d, d, 1H), 7.28-7.22 (m, 5H), 7.20, 7.18 (d, d, 1H), 5.14-5.13 (m, 2H), 5.00-4.95 (m, 1H), 3.64-3.57 (m, 1H), 3.44-3.37 (m, 1H), 2.49-2.41 (m, 1H), 2.36-2.26 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.81 (m, 1H). 
     Step 5) The Preparation of Compound 13-5 
     To a solution of compound 13-4 (3.43 g, 8.03 mmol) in EtOAc (40.0 mL) was added a catalytic amount of Pd/C (0.35 g), and then the mixture was stirred at 40° C. under 10 atm of H 2  gas for 5.0 hrs. After the reaction was completed, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound 13-5 (2.02 g, 86%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 294.5 [M+H] + . 
     Step 6) The Preparation of Compound 13-6 
     To a solution of compound 13-5 (1.32 g, 4.5 mmol) in MeCN (30.0 mL) was added DMAP (55.03 mg, 0.45 mmol) at 0° C., followed by di-tert-butyl dicarbonate (1.1 g, 4.96 mmol) dropwise, and the mixture was stirred at 0° C. for 30 mins and then at rt for another 2.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as colorless liquid (0.88 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 394.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.02-8.01 (dd, 1H), 7.65, 7.62 (d, d, 1H), 7.20, 7.18 (d, d, 1H), 5.01-4.96 (m, 1H), 3.64-3.57 (m, 1H), 3.46-3.39 (m, 1H), 2.51-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.04-1.95 (m, 1H), 1.93-1.83 (m, 1H), 1.43 (s, 9H). 
     Step 7) The Preparation of Compound 13-7 
     A mixture of compound 13-6 (0.36 g, 0.91 mmol), compound 1-14-2 (0.46 g, 1.82 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (71.0 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) in DMF (10.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (60 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (0.34 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 442.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.60-8.59 (m, 1H), 7.78, 7.76 (d, d, 1H), 7.63, 7.61 (d, d, 1H), 5.01-4.96 (m, 1H), 3.64-3.57 (m, 1H), 3.46-3.39 (m, 1H), 2.51-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.04-1.95 (m, 1H), 1.93-1.83 (m, 1H), 1.43 (s, 9H), 1.23, 1.20 (m, m, 12H). 
     Step 8) The Preparation of Compound 13-8 
     To a mixture of compound 13-7 (1.16 g, 2.62 mmol), compound 13-2 (1.65 g, 2.62 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.10 mmol) and K 2 CO 3  (0.90 g, 5.24 mmol) were added DME (12.0 mL) and H 2 O (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a white solid (1.36 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 797.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.92, 7.90 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.01-4.92 (m, 2H), 3.65-3.57 (m, 2H), 3.46-3.39 (m, 1H), 3.31-3.23 (m, 1H), 2.93-2.88 (m, 4H), 2.51-2.16 (m, 4H), 2.10-1.83 (m, 4H), 1.70-1.49 (m, 6H), 1.43 (s, 9H), 1.41 (s, 9H), 1.39-1.35 (m, 2H). 
     Step 9) The Preparation of Compound 13-9 
     To a solution of compound 13-8 (3.98 g, 5.0 mmol) in EtOAc (40.0 mL) was added a solution of HCl in EtOAc (15 mL, 4 M) dropwise, and the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo, and EtOAc (50 mL) was added. The resulting mixture was stirred and pulped, and then filtered to give the title compound as a white solid (2.60 g, 70%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 597.5 [M+H] + . 
     Step 10) The Preparation of Compound 13-10 
     To a suspension of compound 13-9 (1.93 g, 2.6 mmol), compound 13-9-2 (597.94 mg, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6 mmol) in DCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (1.27 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 491.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 7.35-7.27 (m, 6H), 7.19-7.14 (m, 4H), 5.91, 5.89 (s, 2H), 5.35-5.34, 5.33-5.32 (m, m, 1H), 5.22-5.21, 5.20 (m, m, 1H), 5.18-5.13 (m, 1H), 5.09-5.04 (m, 1H), 3.91-3.84 (m, 1H), 3.75-3.67 (m, 1H), 3.64 (s, 6H), 3.57-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.93-2.88 (m, 4H), 2.51-1.85 (m, 8H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H). 
     Example 14 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 14-2 
     To a suspension of compound 13-9 (1.55 g, 2.6 mmol), compound 14-1 (0.42 g, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6 mmol) in DCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (1.11 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 855.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.44, 5.42 (m, m, 2H), 5.12-5.05 (m, 2H), 4.64-4.47 (m, 2H), 3.88-3.81 (m, 1H), 3.72-3.66 (m, 1H), 3.64 (s, 6H), 3.63-3.60 (m, 1H), 3.30-3.22 (m, 1H), 2.93-2.88 (m, 4H), 2.53-2.44 (m, 1H), 2.34-1.74 (m, 7H), 1.70-1.49 (m, 6H), 1.46-1.37 (m, 2H), 1.36, 1.34 (d, d, 3H), 1.30, 1.29 (d, d, 3H). 
     Example 15 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 15-2 
     To a suspension of compound 13-9 (1.93 g, 2.6 mmol), compound 15-1 (0.62 g, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6 mmol) in DCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (1.16 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 496.27 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.21, 5.19 (d, d, 2H), 5.09-5.01 (m, 2H), 4.47-4.41 (m, 1H), 4.35-4.29 (m, 1H), 3.86-3.80 (m, 1H), 3.70-3.65 (m, 1H), 3.63 (s, 6H), 3.59-3.53 (m, 1H), 3.20-3.12 (m, 1H), 2.93-2.88 (m, 4H), 2.43-1.06 (m, 38H). 
     Example 16 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 16-1 
     To a solution of L(−)-pipecolinic acid (10.0 g, 77.4 mmol) in MeOH (50 mL) was added thionyl chloride (8.5 mL, 117.2 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at 0° C. for 1.0 hr and then at 70° C. for another 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (11.0 g, 79.1%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 144.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.02 (br, 1H), 4.00 (br, 1H), 3.85 (s, 3H), 3.63 (br, 1H), 3.15 (br, 1H), 2.28 (m, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.63 (br, 1H). 
     Step 2) The Preparation of Compound 16-2 
     To a solution of compound 16-1 (1.0 g, 5.57 mmol), compound 1-13-2 (1.47 g, 8.38 mmol) and EDCI (2.14 g, 11.17 mmol) in DCM (40.0 mL) was added DIPEA (5.0 mL, 30.25 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, 40 mL of water was added to the mixture, and the resulting mixture was extracted with CH 2 Cl 2  (35 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as colorless liquid (1.337 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 301.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H), 4.31-4.26 (m, 1H), 3.70 (s, 3H), 3.67-3.64 (m, 1H), 3.63 (s, 3H), 3.11-3.02 (m, 1H), 2.23-2.14 (m, 1H), 2.13-2.05 (m, 2H), 1.20-1.02 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 3) The Preparation of Compound 16-3 
     To a solution of compound 16-2 (1.41 g, 4.7 mmol) in THF (40.0 mL) was added LiOH aqueous solution (0.99 g, 23.5 mmol, 20 mL) at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 12 hrs. After the reaction was completed, the solvent THF was removed. The residue was added water (50 mL), and then extracted with EtOAc (40 mL×3). The aqueous layer was adjusted to pH 1 with diluted hydrochloric acid (10%) and extracted with EtOAc (35 mL×3). The combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (1.24 g, 92%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 287.5 [M+H] + . 
     Step 4) The Preparation of Compound 16-4 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 16-3 (2.99 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.84 g, 25%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 483.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.54, 7.52 (dd, dd, 1H), 7.50, 7.48 (m, m, 1H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.35-4.26 (m, 2H), 3.88-3.81 (m, 1H), 3.66 (s, 3H), 3.15-3.06 (m, 1H), 2.25-2.13 (m, 2H), 1.91-1.79 (m, 1H), 1.54-1.35 (m, 2H), 1.16-1.04 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 5) The Preparation of Compound 16-5 
     A solution of compound 16-4 (0.62 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then dissolved in EtOAc (50 mL). The resulting mixture was washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.50 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 465.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.70 (m, 3H), 5.46-5.40 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.28-4.23 (m, 1H), 3.63 (s, 3H), 3.34-3.26 (m, 1H), 3.09-3.00 (m, 1H), 2.09-1.99 (m, 2H), 1.96-1.88 (m, 1H), 1.60-1.45 (m, 2H), 1.12-0.98 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 6) The Preparation of Compound 16-6 
     A suspension of compound 16-5 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (20 mL). The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a yellow solid (0.18 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 513.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.80, 7.79 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.49-5.43 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.28-4.23 (m, 1H), 3.63 (s, 3H), 3.34-3.26 (m, 1H), 3.09-3.00 (m, 1H), 2.09-1.99 (m, 1H), 1.97-1.88 (m, 2H), 1.60-1.45 (m, 2H), 1.32, 1.29 (m, m, 12H), 1.11-0.98 (m, 2H), 0.97, 0.95 (m, m, 6H). 
     Step 7) The Preparation of Compound 16-7 
     To a solution of compound 1-10 (3.0 g, 10.79 mmol) and compound 16-3 (3.4 g, 11.87 mmol) in MeCN (30.0 mL) was added DIPEA (2.14 mL, 12.95 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the reaction was quenched with ice water (50 mL), and the resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as a white solid (4.68 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 483.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.28 (s, 2H), 5.07-5.01 (m, 1H), 4.33-4.29 (m, 1H), 3.72-3.66 (m, 1H), 3.63 (s, 3H), 3.13-3.04 (m, 1H), 2.23-2.14 (m, 1H), 2.13-2.04 (m, 2H), 1.20-1.00 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 8) The Preparation of Compound 16-8 
     A mixture of compound 16-7 (1.76 g, 3.64 mmol) and ammonium acetate (4.2 g, 5.46 mmol) in xylene (30.0 mL) was refluxed at 120° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 50 mL of water was added. The resulting mixture was extracted with EtOAc (50 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a yellow solid (1.43 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.58 (s, 1H), 7.45-7.41 (m, 2H), 7.29-7.26 (m, 2H), 5.32, 5.29 (d, d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35 (m, 1H), 3.77-3.69 (m, 1H), 3.63 (s, 3H), 2.86-2.76 (m, 1H), 2.25-2.13 (m, 1H), 2.02-1.93 (m, 1H), 1.82-1.70 (m, 1H), 1.67-1.49 (m, 2H), 1.21-1.00 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 9) The Preparation of Compound 16-9 
     A mixture of compound 16-8 (4.73 g, 10.23 mmol), compound 1-14-2 (2.86 g, 11.25 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.42 g, 0.51 mmol) and KOAc (2.51 g, 25.57 mmol) in DMF (40.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (200 mL) and filtered through a celite pad. The filtrate was washed with water (120 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a pale yellow solid (4.18 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 511.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64-7.57 (m, 4H), 7.19 (s, 1H), 5.32, 5.29 (d, d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35 (m, 1H), 3.77-3.69 (m, 1H), 3.63 (s, 3H), 2.86-2.76 (m, 1H), 2.25-2.13 (m, 1H), 2.02-1.93 (m, 1H), 1.82-1.69 (m, 1H), 1.67-1.49 (m, 2H), 1.35, 1.32 (m, m, 12H), 1.21-0.99 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 10) The Preparation of Compound 16-10 
     To a mixture of compound 16-9 (413.34 mg, 0.81 mmol), compound 1-8 (361.24 mg, 0.81 mmol), Pd(PPh 3 ) 4  (47 mg, 0.04 mmol) and K 2 CO 3  (290 mg, 2.04 mmol) were added DME (8.0 mL) and H 2 O (2.0 mL) via syringe. The mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (30 mL). The resulting mixture was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a white solid (0.34 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 703.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H), 7.24-7.23, 7.22-7.21 (d, d, 1H), 7.03, 7.00 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35 (m, 1H), 3.77-3.69 (m, 1H), 3.63 (s, 3H), 2.89-2.76 (m, 5H), 2.25-2.13 (m, 1H), 2.02-1.93 (m, 1H), 1.82-1.42 (m, 11H), 1.21-1.00 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 11) The Preparation of Compound 16-11 
     A mixture of compound 16-10 (0.70 g, 1.0 mmol), compound 16-6 (0.51 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (0.47 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.3 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.53-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.18-5.13 (m, 1H), 4.78-4.72 (m, 1H), 4.39-4.35 (m, 1H), 4.28-4.24 (m, 1H), 3.77-3.69 (m, 1H), 3.63 (s, 6H), 3.34-3.26 (m, 1H), 3.09-3.00 (m, 1H), 2.93-2.89 (m, 4H), 2.86-2.76 (m, 1H), 2.25-1.35 (m, 18H), 1.21-0.99 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.91, 0.89 (m, m, 6H). 
     Example 17 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 17-2 
     To a solution of compound 17-1 (3.75 g, 13.1 mmol) and compound 1-10 (3.63 g, 13.1 mmol) in DCM (40.0 mL) was added Et 3 N (2.73 mL, 19.65 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), and the resulting mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (5.35 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 455.5 [M+H] + . 
     Step 2) The Preparation of Compound 17-3 
     A mixture of compound 17-2 (3.72 g, 8.2 mmol) and ammonium acetate (5.1 g, 66 mmol) in toluene (34 mL) was refluxed at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 50 mL of water was added. The resulting mixture was extracted with EtOAc (80 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound (3.22 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.63-7.60 (m, 2H), 7.49-7.45 (m, 2H), 7.24 (s, 1H), 6.08, 6.05 (d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m, 1H), 3.92-3.85 (m, 1H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.37-2.14 (m, 3H), 1.71-1.63 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.94-0.90 (m, 6H). 
     Step 3) The Preparation of Compound 17-4 
     A mixture of compound 17-3 (3.19 g, 6.9 mmol), compound 1-14-2 (1.93 g, 7.6 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.28 g, 0.34 mmol) and KOAc (1.7 g, 17.25 mmol) in DME (30.0 mL) was stirred at 90° C. under N 2  for 2.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (200 mL) and filtered through a celite pad. The filtrate was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a pale yellow solid (3.10 g, 88%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 511.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H), 7.46 (s, 1H), 6.08, 6.05 (d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m, 1H), 3.92-3.85 (m, 1H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.37-2.14 (m, 3H), 1.71-1.63 (m, 1H), 1.35, 1.32 (m, m, 12H), 1.02, 1.00 (m, m, 3H), 0.94-0.90 (m, 6H). 
     Step 4) The Preparation of Compound 17-5 
     To a mixture of compound 17-4 (3.93 g, 7.7 mmol), compound 1-8 (3.43 g, 7.7 mmol), Pd(PPh 3 ) 4  (0.45 g, 0.38 mmol) and K 2 CO 3  (2.1 g, 15.4 mmol) were added DME (32.0 mL) and H 2 O (8.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (200 mL). The resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (3.79 g, 70%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 703.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71-7.66 (m, 4H), 7.32 (s, 1H), 7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 6.07, 6.05 (d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m, 1H), 3.92-3.85 (m, 1H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.37-2.14 (m, 3H), 1.74-1.42 (m, 9H), 1.02, 1.00 (m, m, 3H), 0.94-0.90 (m, 6H). 
     Step 5) The Preparation of Compound 17-6 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 17-1 (2.99 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL) and washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.84 g, 25%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 483.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.36-4.27 (m, 2H), 3.66 (s, 3H), 3.65-3.61 (m, 1H), 3.43-3.37 (m, 1H), 2.39-2.31 (m, 1H), 2.20-2.02 (m, 2H), 1.89-1.79 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93-0.91 (m, 3H), 0.89-0.86 (m, 3H). 
     Step 6) The Preparation of Compound 17-7 
     A solution of compound 17-6 (0.62 g, 1.28 mmol) in THF (10 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then the residue was dissolved in EtOAc (50 mL). The combined organic phase were washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.50 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 465.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78 (q, 1H), 7.76, 7.74 (d, d, 1H), 7.72, 7.70 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.04 (m, 1H), 4.30-4.25 (m, 1H), 3.72-3.65 (m, 1H), 3.63 (s, 3H), 3.47-3.37 (m, 1H), 2.40-2.20 (m, 2H), 2.05-1.92 (m, 1H), 1.80-1.71 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.96-0.86 (m, 6H). 
     Step 7) The Preparation of Compound 17-8 
     A suspension of compound 17-7 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DME (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (20 mL). The resulting mixture was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.18 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 513.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.79-7.78 (q, 1H), 7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.04 (m, 1H), 4.30-4.25 (m, 1H), 3.72-3.65 (m, 1H), 3.63 (s, 3H), 3.47-3.37 (m, 1H), 2.40-2.20 (m, 2H), 2.05-1.92 (m, 1H), 1.80-1.71 (m, 1H), 1.32, 1.29 (q, q, 12H), 0.97, 0.95 (m, m, 3H), 0.96-0.86 (m, 6H). 
     Step 8) The Preparation of Compound 17-9 
     A mixture of compound 17-5 (0.70 g, 1.0 mmol), compound 17-8 (0.51 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (0.42 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.3 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.34-5.29 (m, 3H), 5.07-5.02 (m, 1H), 4.42-4.37 (m, 1H), 4.30-4.25 (m, 1H), 3.92-3.85 (m, 1H), 3.72-3.67 (m, 1H), 3.63 (s, 6H), 3.61-3.54 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.88 (m, 4H), 2.38-2.11 (m, 5H), 2.05-1.94 (m, 1H), 1.78-1.49 (m, 8H), 1.45-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.93-0.86 (m, 12H). 
     Example 18 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 18-2 
     To a solution of compound 18-1 (1.34 g, 4.6 mmol) in THF (10.0 mL) was added LiOH aqueous solution (2.1 g, 50 mmol, 8.0 mL) at 0° C., and then the mixture was stirred at rt overnight. After the reaction was completed, the solvent THF was removed. The residue was diluted with water (50 mL) and extracted with EtOAc (20 mL×3). The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (10%) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to give the title compound as colorless slurry (1.08 g, 85%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.26 (m, 5H), 5.13-5.12 (m, 2H), 4.37-4.34 (m, 1H), 3.30-3.26 (m, 1H), 3.24-3.17 (m, 1H), 2.14-2.09 (m, 1H), 1.76-1.71 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 2) The Preparation of Compound 18-3 
     To a solution of compound 18-2 (3.63 g, 13.1 mmol) and compound 1-10 (3.63 g, 13.1 mmol) in DCM (40.0 mL) was added TEA (2.73 mL, 19.65 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the reaction was quenched with water (50 mL), and the resulting mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (4.96 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 446.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.42-7.38 (m, 2H), 7.32-7.24 (m, 5H), 7.18-7.15 (m, 2H), 5.17-5.08 (m, 4H), 4.37-4.34 (m, 1H), 3.30-3.22 (m, 1H), 3.20-3.14 (m, 1H), 2.14-2.13, 2.11-2.09 (m, m, 1H), 1.72-1.71, 1.69-1.67 (m, m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 3) The Preparation of Compound 18-4 
     A mixture of compound 18-3 (3.66 g, 8.2 mmol) and ammonium acetate (5.1 g, 66 mmol) in toluene (30.0 mL) was refluxed at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 50 mL of water was added. The resulting mixture was extracted with EtOAc (80 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound (3.16 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 455.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.63-7.60 (m, 2H), 7.49-7.45 (m, 2H), 7.31-7.24 (m, 6H), 5.25 (m, 2H), 5.10-5.05 (m, 1H), 3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 2.17-2.11 (m, 1H), 1.80-1.73 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 4) The Preparation of Compound 18-5 
     A mixture of compound 18-4 (3.14 g, 6.9 mmol), compound 1-14-2 (1.93 g, 7.6 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.28 g, 0.34 mmol) and KOAc (1.7 g, 17.25 mmol) in DME (30.0 mL) was stirred at 90° C. under N 2  for 2.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (200 mL) and filtered through a celite pad. The filtrate was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (3.04 g, 88%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 502.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H), 7.32-7.24 (m, 5H), 7.23 (s, 1H), 5.25 (m, 2H), 5.10-5.05 (m, 1H), 3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 2.17-2.11 (m, 1H), 1.80-1.73 (m, 1H), 1.35, 1.32 (m, m, 12H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 5) The Preparation of Compound 18-6 
     To a mixture of compound 18-5 (3.86 g, 7.7 mmol), compound 1-8 (3.43 g, 7.7 mmol), Pd(PPh 3 ) 4  (0.45 g, 0.38 mmol) and K 2 CO 3  (2.1 g, 15.4 mmol) were added DME (32.0 mL) and pure water (8.0 mL) via syringe. The mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), and then washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a pale yellow solid (3.74 g, 70%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 694.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71-7.66 (m, 4H), 7.39 (s, 1H), 7.32-7.25 (m, 5H), 7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (d, d, 1H), 5.25 (m, 2H), 5.10-5.05 (m, 1H), 3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 2.90-2.86 (m, 2H), 2.84-2.82 (m, 2H), 2.17-2.11 (m, 1H), 1.79-1.74 (m, 1H), 1.73-1.42 (m, 8H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 6) The Preparation of Compound 18-8 
     To a solution of compound 18-7 (10.48 g, 35.5 mmol) in dry THF (250 mL), compound 1-19 (7.6 g, 35.5 mmol) and NaOH (1 M, 85.0 mmol) were added in turn. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with NaOH aqueous solution (1M, 15 mL) and brine, dried over Na 2 SO 4  and concentrated in vacuo to give the title compound (18.1 g, 100%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 474.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.11-9.10 (m, 1H), 7.89-7.88 (m, 1H), 7.54-7.49 (m, 2H), 7.32-7.24 (m, 5H), 6.39 (s, 2H), 5.14-5.13 (m, 2H), 4.55-4.51 (m, 1H), 3.28-3.21 (m, 1H), 3.19-3.12 (m, 1H), 2.33-2.27 (m, 1H), 1.96-1.90 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 7) The Preparation of Compound 18-9 
     A solution of compound 18-8 (18.07 g, 38.1 mmol) and KOH (34.0 mL, 10% aq) in EtOH (200 mL) was stirred at 80° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to 0° C. and neutralized to pH 7 by carefully adding concentrated HCl. The resulting precipitate was collected by filtration and washed with EtOAc/hexane (v/v=5/1) to give the title compound 18-9 (13.38 g, 77.0%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 456.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.02-8.01 (dd, 1H), 7.65, 7.62 (d, d, 1H), 7.32-7.24 (m, 5H), 7.20-7.18 (d, d, 1H), 5.17-5.09 (m, 3H), 3.28-3.21 (m, 1H), 3.18-3.12 (m, 1H), 2.43-2.38 (m, 1H), 2.01-1.95 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 8) The Preparation of Compound 18-10 
     A mixture of compound 18-9 (0.2 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (60 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.18 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 504.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.60-8.59 (dd, 1H), 7.78, 7.76 (d, d, 1H), 7.62, 7.60 (d, d, 1H), 7.32-7.24 (m, 5H), 5.17-5.09 (m, 3H), 3.28-3.21 (m, 1H), 3.18-3.12 (m, 1H), 2.43-2.38 (m, 1H), 2.01-1.95 (m, 1H), 1.24, 1.20 (q, q, 12H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 9) The Preparation of Compound 18-11 
     To a mixture of compound 18-10 (0.50 g, 1.0 mmol), compound 18-6 (0.69 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) were added DME (6.0 mL) and H 2 O (2.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a pale yellow solid (0.41 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 461.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.97, 7.95 (d, d, 1H), 7.94-7.93 (m, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H), 7.47-7.44 (m, 2H), 7.32-7.24 (m, 10H), 5.25 (m, 2H), 5.17-5.07 (m, 4H), 3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 3.27-3.21 (m, 1H), 3.18-3.12 (m, 1H), 2.93-2.88 (m, 4H), 2.43-2.38 (m, 1H), 2.17-2.11 (m, 1H), 2.01-1.95 (m, 1H), 1.80-1.73 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H). 
     Step 10) The Preparation of Compound 18-12 
     To a solution of compound 18-11 (1.84 g, 2.0 mmol) in EtOAc (10.0 mL) was added a catalytic amount of Pd/C (0.2 g), then the mixture was stirred at 40° C. under 10 atm of H 2  gas for 5.0 hrs. After the reaction was completed, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound 18-12 (1.20 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 653.4 [M+H] + . 
     Step 11) The Preparation of Compound 18-13 
     To a suspension of compound 18-12 (0.19 g, 0.29 mmol), compound 1-13-2 (0.11 g, 0.65 mmol), EDCI (120 mg, 0.65 mmol) and HOAT (80 mg, 0.59 mmol) in DCM (5.0 mL) was added DIPEA (0.49 mL, 2.97 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (0.18 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 485.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H), 7.47-7.44 (m, 2H), 5.32-5.26 (m, 3H), 5.21-5.16 (m, 1H), 4.40-4.36 (m, 1H), 4.28-4.24 (m, 1H), 3.63 (s, 6H), 3.57-3.50 (m, 1H), 3.46-3.39 (m, 1H), 3.36-3.29 (m, 1H), 3.27-3.20 (m, 1H), 2.93-2.88 (m, 4H), 2.38-2.33 (m, 1H), 2.28-2.22 (m, 1H), 2.20-2.08 (m, 1H), 2.03-1.91 (m, 2H), 1.88-1.81 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.01-0.99 (m, 6H), 0.97-0.95 (m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.84 (m, 6H). 
     Example 19 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 11) The Preparation of Compound 19-2 
     To a suspension of compound 18-12 (0.51 g, 0.78 mmol), compound 19-1 (0.39 g, 1.64 mmol), EDCI (315 mg, 1.64 mmol) and HOAT (0.21 g, 1.56 mmol) in DCM (7.0 mL) was added DIPEA (1.09 mL, 6.26 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to give the title compound as a white solid (0.51 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 546.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) ((ppm): 7.94 (m, 1H), 7.88, 7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H), 7.47-7.44 (m, 2H), 7.36-7.30 (m, 4H), 7.24-7.19 (m, 2H), 7.13-7.10 (m, 4H), 5.48, 5.46 (d, d, 2H), 5.31-5.25 (m, 1H), 5.21-5.16 (m, 1H), 4.47-4.42 (m, 1H), 4.35-4.31 (m, 1H), 3.57-3.50 (m, 1H), 3.46-3.39 (m, 1H), 3.36-3.29 (m, 1H), 3.27-3.20 (m, 1H), 2.93-2.88 (m, 4H), 2.38-2.33 (m, 1H), 2.28-2.21 (m, 1H), 2.20-2.10 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.93 (m, 1H), 1.88-1.81 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.01-0.99 (m, 6H), 0.97-0.95 (m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.84 (m, 6H). 
     Example 20 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 20-1 
     A mixture of compound 7-1 (2.29 g, 3.32 mmol), compound 1-14-2 (1.68 g, 6.63 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.54 g, 0.66 mmol) and KOAc (0.98 g, 9.96 mmol) in DME (15.0 mL) was stirred at 90° C. under N 2  for 3 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL) and filtered through a celite pad. The filtrate was washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a white solid (1.79 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 669.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94 (q, 1H), 7.84, 7.82 (d, d, 1H), 7.78, 7.76 (dd, dd, 1H), 7.52-7.50 (d, d, 1H), 7.45, 7.42 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.21-5.15 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s, 1H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.02-2.98 (m, 2H), 2.78-2.75 (m, 2H), 2.50-2.42 (m, 1H), 2.37-2.27 (m, 1H), 2.11-1.98 (m, 2H), 1.93-1.83 (m, 1H), 1.72-1.52 (m, 4H), 1.51-1.40 (m, 2H), 1.32, 1.29 (m, m, 12H), 1.28-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 2) The Preparation of Compound 20-2 
     To a mixture of compound 20-1 (2.30 g, 3.44 mmol), compound 20-1-2 (1.79 g, 3.78 mmol), Pd(PPh 3 ) 4  (0.40 g, 0.34 mmol) and K 2 CO 3  (1.19 g, 8.62 mmol) were added DME (12.0 mL) and H 2 O (4.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL). The resulting mixture was was washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=25/1) to give the title compound as a pale yellow solid (1.98 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 888.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.96 (m, 1H), 7.94-7.93 (q, 1H), 7.83, 7.81 (d, d, 1H), 7.59-7.53 (m, 5H), 7.52, 7.50 (d, d, 1H), 7.46, 7.44 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.17-5.11 (m, 1H), 4.31-4.22 (m, 3H), 3.63 (s, 6H), 3.61-3.55 (m, 1H), 3.52-3.45 (m, 1H), 3.44-3.36 (m, 1H), 3.34-3.27 (m, 1H), 2.93-2.88 (m, 4H), 2.41-2.32 (m, 1H), 2.20-1.49 (m, 15H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 21 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 21-2 
     To a suspension of PPh 3 MeBr (5.05 g, 14.2 mmol) in THF (50.0 mL) was added potassium tert-butanolate (14.9 mL, 14.9 mmol, 1.0 M in THF) dropwise at −20° C. At the end of the addition, the mixture was warmed to −5° C. and stirred for 30 mins, and then compound 21-1 (1.72 g, 7.07 mmol) was added. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was quenched with ice water (50 mL), and THF was removed. The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound (1.07 g, 62.9%) as pale yellow oil. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 242.12 [M+H] + ; and 
       1 H NMR (400 Mhz, DMSO-d 6 ) δ (ppm): 5.01 (d, 2H, J=10.8 Hz), 4.36 (t, 1H, J=11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q, 1H, J=14.6 Hz), 2.57-2.50 (m, 1H), 1.38 (s, 9H). 
     Step 2) The Preparation of Compound 21-3 
     To a solution of diethylzinc (2.30 g, 18.60 mmol) in toluene (30.0 mL) was added chloroiodomethane (6.57 g, 37.24 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 45 mins. The solution of compound 21-2 (1.5 g, 6.22 mmol) in toluene (15.0 mL) was then added. At the end of the addition, the mixture was stirred at 0° C. for 18 hrs. After the reaction was completed, the reaction was quenched with saturated NH 4 Cl aqueous solution (20 mL) and the aqueous layer was extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as white liquid (0.58 g, 36.5%) as white oil. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 156.2 [M−Boc] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.47-4.33 (m, 1H), 3.71 (s, 3H), 3.37-3.29 (m, 2H), 2.25-2.17 (m, 1H), 1.86-1.75 (m, 1H), 1.44, 1.40 (s, s, 9H), 0.62-0.50 (m, 4H). 
     Step 3) The Preparation of Compound 21-4 
     To a solution of compound 21-3 (0.69 g, 2.7 mmol) in EtOAc (6.0 mL) was added a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give the title compound (0.5 g, 96.5%) as colorless oil. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 156.2 [M+H] + ; and 
       1 H NMR (400 MHz, CD 3 OD) δ (ppm): 4.66-4.62 (m, 1H), 4.45-4.44 (m, 1H), 3.86 (s, 3H), 3.61-3.60 (m, 1H), 2.39-2.34 (m, 1H), 2.19-2.14 (m, 1H), 1.49-1.46 (m, 1H), 1.19-1.16 (m, 1H), 0.88-0.87 (m, 1H), 0.81-0.79 (m, 1H). 
     Step 4) The Preparation of Compound 21-5 
     A suspension of compound 21-4 (0.53 g, 2.77 mmol), compound 1-13-2 (0.73 g, 4.16 mmol) and EDCI (1.06 g, 5.55 mmol) in DCM (10.0 mL) was stirred at 0° C., and then DIPEA (2.4 mL, 14.52 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (20 mL), washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.61 g, 70.2%) as white liquid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 313.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.44-5.42 (br, 1H), 4.71-4.68 (m, 1H), 4.29-4.20 (m, 1H), 3.73 (s, 3H), 3.72-3.69 (m, 1H), 3.67 (s, 3H), 3.59-3.54 (m, 1H), 2.20-2.15 (m, 1H), 2.06-2.01 (m, 1H), 1.95-1.90 (m, 1H), 1.05-0.93 (m, 6H), 0.66-0.61 (m, 4H). 
     Step 5) The Preparation of Compound 21-6 
     To a solution of compound 21-5 (0.20 g, 0.64 mmol) in THF (5.0 mL) was added lithium hydroxide monohydrate aqueous solution (0.13 g, 3.20 mmol, 5.0 mL) at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 12 hrs. After the reaction was completed, the solvent THF was removed and 10 mL of water was added. The resulting mixture was extracted with EtOAc (25 mL×3), and the aqueous layer was adjusted to pH 1 with hydrochloric acid (10%), and then extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (0.16 g, 82.8%) as a white solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 299.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.06 (br, 1H), 5.76 (br, 1H), 4.73-4.69 (m, 1H), 4.23-4.18 (m, 1H), 3.79 (d, 1H, J=9.7 Hz), 3.66 (s, 3H), 3.49 (d, 1H, J=9.7 Hz), 2.26-2.18 (m, 1H), 2.07-1.93 (m, 2H), 1.00-0.94 (m, 6H), 0.68-0.64 (m, 4H). 
     Step 6) The Preparation of Compound 21-7 
     A solution of compound 1-10 (0.31 g, 1.11 mmol), compound 21-6 (0.30 g, 1.00 mmol) in MeCN (10.0 mL) was stirred at 0° C. under N 2 , and then DIPEA (0.21 mL, 1.27 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, 20 mL of water was added and MeCN was removed. The resulting mixture was dissolved in EtOAc (30 mL), washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.33 g, 66.7%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 495.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H), 5.32, 5.29 (br, br, 1H), 5.31 (s, 2H), 4.72-4.70 (m, 1H), 4.35-4.30 (m, 1H), 3.67 (s, 3H), 3.61-3.59 (m, 1H), 3.55-3.49 (m, 1H), 2.20-2.07 (m, 2H), 1.83-1.76 (m, 1H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H). 
     Step 7) The Preparation of Compound 21-8 
     To a solution of compound 21-7 (0.33 g 0.67 mmol) in xylene (10.0 mL) was added NH 4 OAc (1.04 g, 13.43 mmol), and the mixture was stirred at 120° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and 20 mL of water was added. The resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (0.19 g, 58.9%) as a yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 475.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.58 (s, 1H), 7.45-7.41 (m, 2H), 7.29-7.26 (m, 2H), 5.46, 5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.41-4.37 (m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.97 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H). 
     Step 8) The Preparation of Compound 21-9 
     To a mixture of compound 21-8 (0.19 g, 0.40 mmol), compound 1-14-2 (0.15 g, 0.59 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (33 mg, 0.04 mmol) and KOAc (0.12 g, 1.19 mmol) was added DMF (10.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and 50 mL of water was added. The resulting mixture was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (0.17 g, 80%) as a beige solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 523.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64-7.57 (m, 4H), 7.21 (s, 1H), 5.46, 5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.42-4.37 (m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.97 (m, 1H), 1.35 (m, 6H), 1.32 (m, 6H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H). 
     Step 9) The Preparation of Compound 21-10 
     To a mixture of compound 1-8 (3.43 g, 7.7 mmol), compound 21-9 (4.02 g, 7.7 mmol), Pd(PPh 3 ) 4  (0.45 g, 0.38 mmol) and K 2 CO 3  (2.1 g, 15.4 mmol) were added DME (32.0 mL) and water (8.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (200 mL). The combined organic layer was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (3.58 g, 65%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 715.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H), 7.24, 7.22 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H), 4.41-4.37 (m, 1H), 3.72-3.66 (m, 1H), 3.63 (s, 3H), 3.50-3.44 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.97 (m, 1H), 1.74-1.42 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H). 
     Step 10) The Preparation of Compound 21-11 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 21-6 (3.12 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL) and washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.69 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 495.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.46-4.36 (m, 2H), 3.66 (s, 3H), 3.39-3.33 (m, 1H), 3.31-3.25 (m, 1H), 2.53-2.46 (m, 1H), 2.22-2.10 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.49-0.36 (m, 4H). 
     Step 11) The Preparation of Compound 21-12 
     A solution of compound 21-11 (0.63 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then the residue was dissolved in EtOAc (30 mL). The combined organic phase were washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.52 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 477.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.70 (m, 3H), 5.32, 5.29 (d, d, 1H), 5.08-5.04 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s, 3H), 3.45-3.39 (m, 1H), 3.29-3.23 (m, 1H), 2.53-2.46 (m, 1H), 2.21-2.13 (m, 1H), 2.06-1.94 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.47-0.34 (m, 4H). 
     Step 12) The Preparation of Compound 21-13 
     A suspension of compound 21-12 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (20 mL). The resulting mixture was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.19 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 525.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.77 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.11-5.06 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s, 3H), 3.45-3.39 (m, 1H), 3.29-3.23 (m, 1H), 2.53-2.46 (m, 1H), 2.21-2.13 (m, 1H), 2.06-1.94 (m, 1H), 1.32, 1.29 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.47-0.34 (m, 4H). 
     Step 13) The Preparation of Compound 21-14 
     A mixture of compound 21-10 (0.71 g, 1.0 mmol), compound 21-13 (0.52 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (0.43 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 482.3 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.88-7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H), 7.47-7.44 (m, 2H), 5.32, 5.29 (d, d, 2H), 5.21-5.16 (m, 1H), 4.93-4.89 (m, 1H), 4.42-4.37 (m, 1H), 4.30-4.25 (m, 1H), 3.72-3.66 (m, 1H), 3.63 (s, 6H), 3.50-3.39 (m, 2H), 3.29-3.23 (m, 1H), 2.93-2.88 (m, 4H), 2.54-2.46 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 2H), 2.06-1.94 (m, 2H), 1.70-1.49 (m, 6H), 1.45-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.55-0.34 (m, 8H). 
     Example 22 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 22-1 
     To a solution of compound 10-6 (3.91 g, 17.22 mmol) and compound 1-10 (5.47 g, 19.81 mmol) in DCM (60.0 mL) was added DIPEA (3.4 mL, 20.67 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3 hrs. After the reaction was completed, the mixture was quenched with water (80 mL), and the resulting mixture was extracted with DCM (100 mL×3). The combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as a white solid (4.5 g, 61.73%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 424.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.53-5.09 (m, 2H), 4.78-4.67 (m, 1H), 3.59-3.46 (m, 1H), 2.69-2.62 (m, 1H), 2.43-2.40 (m, 1H), 1.42 (s, 9H), 1.00-0.96 (m, 1H), 0.76-0.69 (m, 2H). 
     Step 2) The Preparation of Compound 22-2 
     A mixture of compound 22-1 (4.5 g, 10.64 mmol) and acetamide (16.4 g, 212.73 mmol) in toluene (50.0 mL) was stirred at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and 50 mL of water was added. The resulting mixture was extracted with EtOAc (100 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound (2.14 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 404.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.62-7.52 (br, 2H), 7.49-7.46 (d, 2H, J=12 Hz), 7.21 (s, 1H), 5.27-5.24 (d, 1H, J=10.0 Hz), 3.31-3.27 (m, 1H), 1.71-1.67 (m, 2H), 1.52 (s, 9H), 0.89-0.86 (m, 1H), 0.69-0.64 (m, 2H). 
     Step 3) The Preparation of Compound 22-3 
     A mixture of compound 22-2 (2.1 g, 5.2 mmol), compound 1-14-2 (1.59 g, 6.25 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.43 g, 0.52 mmol) and KOAc (1.54 g, 15.63 mmol) in DMF (30.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL) and filtered through a celite pad. To the filtrate was added 150 mL of water, and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (2.27 g, 97%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 452.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.81-7.79 (d, 2H, J=8.04 Hz), 7.60 (br, 2H), 7.26 (s, 1H), 5.28-5.26 (d, 1H, J=8.0 Hz), 3.53 (br, 1H), 3.30-3.27 (br, 1H), 1.67-1.66 (m, 2H), 1.52 (s, 9H), 1.34 (s, 12H), 0.89-0.86 (m, 1H), 0.69-0.64 (m, 2H). 
     Step 4) The Preparation of Compound 22-4 
     To a solution of compound 22-3 (5.46 g, 12.1 mmol) in EtOAc (40.0 mL) was added a solution of HCl in EtOAc (20 mL, 4 M) dropwise. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo, and EtOAc (50 mL) was added. The mixture was stirred and pulped, then filtered to give the title compound as a white solid (4.11 g, 80%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 352.5 [M+H] + . 
     Step 5) The Preparation of Compound 22-5 
     A suspension of compound 22-4 (1.10 g, 2.6 mmol), compound 1-13-2 (0.6 g, 2.86 mmol) and EDCI (0.55 g, 2.86 mmol) in DCM (15.0 mL) was stirred at 0° C., then DIPEA (1.72 mL, 10.4 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with NH 4 Cl aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a white solid (0.77 g, 58%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64-7.57 (m, 4H), 7.29 (s, 1H), 5.32, 5.29 (d, d, 1H), 4.89-4.85 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.00-1.94 (m, 1H), 1.43-1.37 (m, 1H), 1.35, 1.32 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.94-0.89 (m, 4H), 0.50-0.46 (m, 1H). 
     Step 6) The Preparation of Compound 22-6 
     To a mixture of compound 22-5 (0.41 g, 0.81 mmol), compound 1-8 (0.36 g, 0.81 mmol), Pd(PPh 3 ) 4  (47 mg, 0.04 mmol) and K 2 CO 3  (0.29 g, 2.04 mmol) were added DME (8.0 mL) and pure water (2.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL). The resulting mixture was washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/EtOH (v/v)=100/1) to give the title compound as a white solid (0.31 g, 55%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 701.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.62 (s, 1H), 7.60-7.57 (m, 2H), 7.48-7.45 (m, 2H), 7.24-7.23, 7.22-7.21 (m, m, 1H), 7.03-7.02, 7.00 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H), 4.89-4.85 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.89-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.00-1.94 (m, 1H), 1.74-1.36 (m, 9H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.50-0.46 (m, 2H). 
     Step 7) The Preparation of Compound 22-7 
     A mixture of compound 22-6 (0.70 g, 1.0 mmol), compound 10-11 (0.51 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (40 mL), and washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a pale yellow solid (0.42 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 468.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (q, 1H), 7.88, 7.86 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.62 (s, 1H), 7.60-7.57 (m, 2H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.15-5.11 (m, 1H), 4.89-4.85 (m, 1H), 4.35-4.31 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s, 6H), 3.45-3.38 (m, 1H), 3.30-3.23 (m, 1H), 2.93-2.88 (m, 4H), 2.46-2.38 (m, 2H), 2.22-2.09 (m, 1H), 2.07-1.94 (m, 3H), 1.70-1.35 (m, 10H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.50-0.46 (m, 2H), 0.41-0.38 (m, 1H). 
     Example 23 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 23-2 
     To a solution of (R)-1-phenylethylamine (1.3 mL, 10.1 mmol) in toluene (15.0 mL) was added anhydrous Na 2 SO 4  (3.48 g, 24.5 mmol) at rt, followed by ethyl glyoxalate (1 mL, 10.1 mmol) dropwise, and the mixture was stirred at rt for 1 hr and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow liquid (1.9 g, 91.8%), which was used for the next step without further purification. 
     Step 2) The Preparation of Compound 23-3 
     To a solution of compound 23-2 (2.0 g, 9.7 mmol) in DMF (15.0 mL) was added TFA (0.75 mL, 10.1 mmol). After 2 mins, to the mixture were added freshly prepared 1,3-cyclopentadiene (1.29 g, 19.5 mmol) and two drops of water in turn. The reaction mixture was stirred for another 12 hrs, then the solvent DMF was removed and NaHCO 3  aqueous solution (20 mL, 10%) was added. The mixture was adjusted to pH 8 with Na 2 CO 3  and extracted with PE (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as pale yellow liquid (2.38 g, 90%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.35-7.17 (m, 5H), 6.42 (br, 1H), 6.28-6.26 (br, 1H), 4.34-4.30 (m, 2H), 3.82-3.78 (m, 2H), 3.04-3.02 (m, 1H), 2.90 (br, 1H), 2.20 (br, 1H), 2.13 (m, 1H), 1.41 (d, 3H, J=6.6 Hz), 0.95 (t, 3H, J=7.2 Hz). 
     Step 3) The Preparation of Compound 23-4 
     To a solution of compound 23-3 (2 g, 7.37 mmol) in ethanol (60.0 mL) was added Pd/C (0.20 g). The mixture was stirred at rt under 20 atm of H 2  gas for 24 hrs. After the reaction was completed, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound as yellow liquid (1.2 g, 96.2%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 170.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.21-4.15 (m, 2H), 3.55 (br, 1H), 3.33 (br, 1H), 2.63 (br, 1H), 2.32 (br, 1H), 1.64-1.60 (m, 2H), 1.53-1.47 (m, 2H), 1.42-1.36 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). 
     Step 4) The Preparation of Compound 23-5 
     To a solution of compound 23-4 (0.68 g, 4.02 mmol), compound 1-13-2 (1.06 g, 6.03 mmol) and EDCI (1.54 g, 8.05 mmol) in DCM (25.0 mL) was added DIPEA (2.1 mL, 12.7 mmol) dropwise at 0° C., and the mixture was stirred at rt overnight. After the reaction was completed, 30 mL of water was added to the mixture, and the resulting mixture was extracted with CH 2 Cl 2  (35 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (0.74 g, 56.4%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 327.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 5.44 (br, 1H), 4.40 (br, 1H), 4.33-4.30 (m, 1H), 4.19-4.14 (m, 2H), 4.02 (br, 1H), 3.66 (s, 3H), 2.74 (br, 1H), 2.04 (br, 1H), 1.91-1.88 (m, 2H), 1.80-1.74 (m, 2H), 1.56-1.54 (m, 1H), 1.43-1.38 (m, 1H), 1.26 (t, 3H, J=7.1 Hz), 1.07 (d, 3H, J=6.8 Hz), 0.97 (d, 3H, J=6.8 Hz). 
     Step 5) The Preparation of Compound 23-6 
     To a solution of compound 23-5 (0.74 g, 2.27 mmol) in THF (25.0 mL) was added lithium hydroxide monohydrate aqueous solution (0.48 g, 11.35 mmol, 10 mL) at 0° C., and the mixture was stirred at 40° C. for 12 hrs. After the reaction was completed, the solvent THF was removed and 20 mL of water was added to the mixture. The resulting mixture was washed with EtOAc (15 mL×3), and the aqueous phase was adjusted to pH 1 with hydrochloric acid (10%) and extracted with EtOAc (25 mL×3). The combined organic layers were washed by brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (0.55 g, 81.3%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 299.2 [M+H] + ; and 
       1 H NMR (400 MHz, CD 3 OD) δ (ppm): 4.52 (br, 1H), 4.20 (d, 1H, J=7.8 Hz), 3.93 (br, 1H), 3.63 (s, 3H), 2.73 (br, 1H), 2.01-1.98 (m, 4H), 1.85-1.75 (m, 2H), 1.54-1.46 (m, 2H), 1.05 (d, 3H, J=6.8 Hz), 0.98 (d, 3H, J=6.8 Hz). 
     Step 6) The Preparation of Compound 23-7 
     To a mixture of compound 1-10 (0.31 g, 1.11 mmol) and compound 23-6 (0.3 g, 1.01 mmol) in DCM (10.0 mL) was added DIPEA (0.20 mL, 1.21 mmol) dropwise under N 2  at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the residue was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (50 mL×3), and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a pale yellow solid (0.33 g, 66.7%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 495.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.75 (d, 2H, J=8.52 Hz), 7.68 (d, 2H, J=8.56 Hz), 5.45 (d, 1H, J=9.4 Hz), 5.24 (d, 1H, J=16.56 Hz), 4.59-4.55 (m, 1H), 3.67 (s, 3H), 3.57 (m, 1H), 2.73-2.65 (m, 2H), 2.27-2.19 (m, 1H), 2.04 (s, 1H), 1.84-1.77 (m, 2H), 1.49-1.46 (m, 1H), 1.27-1.24 (m, 1H), 1.08-1.07 (br, 1H), 1.05-1.03 (m, 1H), 0.91-0.89 (m, 6H). 
     Step 7) The Preparation of Compound 23-8 
     To a solution of compound 23-7 (0.33 g, 0.67 mmol) in toluene (8.0 mL) was added NH 4 OAc (1.04 g, 13.43 mmol), and the mixture was stirred at 110° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, 20 mL of water was added, and the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a yellow solid (0.19 g, 58.9%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 476.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.35 (s, 1H), 7.64-7.62 (d, 2H, J=8.52 Hz), 7.55-7.45 (d, 2H, J=1.84 Hz), 7.16 (s, 1H), 5.54-5.46 (br, 2H), 4.57-4.53 (m, 1H), 3.70 (s, 3H), 3.58 (m, 1H), 2.69 (m, 1H), 2.54-2.48 (m, 1H), 1.87-1.76 (m, 4H), 1.47-1.45 (m, 2H), 0.85-0.81 (m, 6H). 
     Step 8) The Preparation of Compound 23-9 
     To a mixture of compound 23-8 (0.19 g, 0.40 mmol), compound 1-14-2 (0.15 g, 0.59 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (33 mg, 0.04 mmol) and KOAc (0.12 g, 1.19 mmol) was added DMF (5.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, 20 mL of water was added, and the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (0.17 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 523.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.48 (s, 1H), 7.81-7.75 (m, 4H), 7.43-7.41 (d, 1H, J=8.0 Hz), 5.49-5.39 (m, 2H), 4.58-4.53 (m, 2H), 3.67 (s, 3H), 3.57 (m, 1H), 2.65 (m, 1H), 2.54-2.47 (m, 1H), 2.10-2.04 (m, 2H), 1.83-1.79 (m, 1H), 1.49-1.46 (m, 2H), 1.38 (s, 12H), 0.85-0.81 (m, 6H). 
     Step 9) The Preparation of Compound 23-10 
     To a mixture of compound 23-9 (0.42 g, 0.81 mmol), compound 1-8 (0.36 g, 0.81 mmol), Pd(PPh 3 ) 4  (47 mg, 0.04 mmol) and K 2 CO 3  (0.29 g, 2.04 mmol) were added DME (8.0 mL) and pure water (2.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL), and the resulting mixture was washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/EtOH (v/v)=100/1) to give the title compound as a white solid (0.35 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 715.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.61-7.57 (m, 2H), 7.48-7.45 (m, 2H), 7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.56, 5.55 (d, d, 1H), 5.06-5.02 (m, 1H), 4.80-4.75 (m, 1H), 4.21-4.17 (m, 1H), 3.66 (s, 3H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.55-2.50 (m, 1H), 2.26-2.14 (m, 1H), 2.08-2.00 (m, 1H), 1.83-1.78 (m, 1H), 1.74-1.37 (m, 13H), 1.02, 1.00 (m, m, 3H), 0.94, 0.92 (m, m, 3H). 
     Step 10) The Preparation of Compound 23-11 
     To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 23-6 (3.12 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N 2 . At the end of addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL) and washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as colorless slurry (0.69 g, 20%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 495.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.88 (m, 1H), 7.56, 7.53 (dd, dd, 1H), 7.51, 7.49 (m, m, 1H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.71-4.67 (m, 1H), 4.48-4.44 (m, 1H), 4.17-4.13 (m, 1H), 3.66 (s, 3H), 2.52-2.48 (m, 1H), 2.22-2.10 (m, 1H), 1.87-1.79 (m, 1H), 1.72-1.60 (m, 2H), 1.59-1.50 (m, 1H), 1.42-1.28 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 11) The Preparation of Compound 23-12 
     A solution of compound 23-11 (0.63 g, 1.28 mmol) in THF (10.0 mL) was added lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the end of the addition, the mixture was stirred at rt for 5.0 hrs. After the reaction was completed, the solvent THF was removed, and then the residue was dissolved in EtOAc (30 mL), washed with water and brine, dried over Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.52 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 477.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77-7.74 (m, 2H), 7.72, 7.70 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.96-4.92 (m, 1H), 4.66-4.62 (m, 1H), 4.34-4.29 (m, 1H), 3.63 (s, 3H), 2.53-2.49 (m, 1H), 2.07-1.94 (m, 2H), 1.86-1.77 (m, 1H), 1.73-1.59 (m, 3H), 1.22-1.15 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 12) The Preparation of Compound 23-13 
     A suspension of compound 23-12 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13 g, 0.51 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL) and filtered through a celite pad. The filtrate was washed with water (10 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid (0.19 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 525.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.14, 8.12 (d, d, 1H), 7.75-7.74 (m, 1H), 7.47, 7.45 (d, d, 1H), 5.32-5.29 (d, d, 1H), 4.99-4.95 (m, 1H), 4.66-4.62 (m, 1H), 4.34-4.29 (m, 1H), 3.63 (s, 3H), 2.53-2.49 (m, 1H), 2.07-1.94 (m, 2H), 1.86-1.77 (m, 1H), 1.73-1.59 (m, 3H), 1.32, 1.29 (m, m, 12H), 1.22-1.15 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 13) The Preparation of Compound 23-14 
     A mixture of compound 23-10 (0.71 g, 1.0 mmol), compound 21-13 (0.52 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid (0.43 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 482.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89, 7.87 (d, d, 1H), 7.86, 7.84 (dd, dd, 1H), 7.61-7.56 (m, 4H), 7.54-7.49 (m, 3H), 6.72-6.71 (dd, 1H), 6.08, 6.05 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.06-5.02 (m, 1H), 4.82-4.75 (m, 2H), 4.66-4.62 (m, 2H), 4.21-4.17 (m, 1H), 4.14-4.10 (m, 1H), 3.66, 3.65 (s, s, 6H), 3.06-3.03 (m, 2H), 2.92-2.88 (m, 2H), 2.55-2.49 (m, 2H), 2.26-2.14 (m, 1H), 2.11-1.98 (m, 3H), 1.86-1.77 (m, 2H), 1.73-1.49 (m, 14H), 1.47-1.35 (m, 2H), 1.22-1.15 (m, 1H), 1.02, 1.00 (m, m, 6H), 0.93, 0.91 (m, m, 6H). 
     Example 24 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 24-2 
     To a suspension of compound 24-1 (3.48 g, 18.6 mmol), compound 1-13-2 (3.26 g, 18.6 mmol) and EDCI (7.1 g, 37 mmol) in DCM (50.0 mL) was added DIPEA (12.3 mL, 74.4 mmol) at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as pale yellow oil (2.5 g, 39.1%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 Hz, CDCl 3 ) δ (ppm): 5.32, 5.29 (d, d, 1H), 4.95-4.91 (m, 1H), 4.33-4.29 (In, 1H), 4.01-4.00 (In, 4H), 3.80-3.78 (m, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.55-3.50 (m, 1H), 2.76-2.70 (m, 1H), 2.35-2.29 (m, 1H), 2.18-2.06 (In, 1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Step 2) The Preparation of Compound 24-3 
     To a solution of compound 24-2 (0.9 g, 2.6 mmol) in THF (5.0 mL) was added a solution of LiOH (0.12 g, 5.0 mmol) in water (5.0 mL). At the end of the addition, the mixture was stirred at 40° C. for 12 hrs. After the reaction was completed, THF was removed and water (20 mL) was added. The mixture was adjusted to pH 2 with diluted hydrochloric acid (1 M), and then extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (0.85 g, 99%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 Hz, CD 3 Cl) δ (ppm): 9.80 (s, 1H), 4.54 (d, 1H, J=7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H). 
     Step 3) The Preparation of Compound 24-4 
     To a mixture of compound 1-10 (1.65 g, 5.9 mmol) and compound 24-3 (1.78 g, 5.4 mmol) in MeCN (30.0 mL) was added DIPEA (1.1 mL, 6.7 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a pale yellow solid (2.76 g, 97.3%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.30 (s, 1H), 7.95 (d, 2H, J=8.27 Hz), 7.71 (d, 2H, J=8.25 Hz), 5.72-5.34 (m, 2H), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). 
     Step 4) The Preparation of Compound 24-5 
     A suspension of compound 24-4 (3.0 g, 5.7 mmol) and NH 4 OAc (4.4 g, 57.1 mmol) in toluene (20.0 mL) was stirred at 110° C. overnight. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL). The resulting mixture was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (2.6 g, 89.9%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.30 (s, 1H), 7.95 (d, 2H, J=8.27 Hz), 7.71 (d, 2H, J=8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). 
     Step 5) The Preparation of Compound 24-6 
     A suspension of compound 24-5 (1.68 g, 3.32 mmol), compound 1-14-2 (1.68 g, 6.63 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.54 g, 0.66 mmol) and KOAc (0.98 g, 9.96 mmol) in DME (20.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL) and filtered through a celite pad. The filtrate was washed with water and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=1/2) to give the title compound as a white solid (1.45 g, 79.2%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 555.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64-7.58 (m, 4H), 7.22 (s, 1H), 5.40-5.36 (m, 1H), 5.32, 5.29 (brs, brs, 1H), 4.42-4.38 (m, 1H), 3.98-3.96 (m, 2H), 3.94-3.92 (m, 2H), 3.71-3.69 (m, 1H), 3.67-3.66 (m, 1H), 3.63 (s, 3H), 2.83-2.78 (m, 1H), 2.45-2.39 (m, 1H), 2.23-2.11 (m, 1H), 1.35 (br, 6H), 1.32 (br, 6H), 0.97-0.95 (m, 3H), 0.91-0.89 (m, 3H). 
     Step 6) The Preparation of Compound 24-7 
     A mixture of compound 7-1 (0.69 g, 1.0 mmol), compound 24-6 (0.55 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=3/1, 8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a pale yellow solid (0.44 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 485.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (q, 1H), 7.83, 7.81 (d, d, 1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 2H), 7.52-7.49 (m, 3H), 7.46, 7.44 (dd, dd, 1H), 7.35 (s, 1H), 6.08, 6.06 (d, d, 2H), 5.40-5.36 (m, 1H), 5.21-5.16 (m, 1H), 4.35-4.25 (m, 2H), 3.99-3.92 (m, 4H), 3.71-3.69 (m, 1H), 3.67-3.66 (m, 1H), 3.65 (s, 6H), 3.60-3.54 (m, 1H), 3.23-3.17 (m, 1H), 2.93-2.88 (m, 4H), 2.83-2.77 (m, 1H), 2.45-2.36 (m, 3H), 2.28-2.16 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 1H), 1.70-1.49 (m, 6H), 1.45-1.35 (m, 2H), 1.02, 1.00 (m, m, 6H), 0.93, 0.91 (m, m, 6H). 
     Example 25 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 25-1 
     To a suspension of compound 1-3 (7.29 g, 45.0 mmol) and triethylsilane (20.98 g, 180 mmol) was added TFA (30.0 mL) dropwise at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 24 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=15/1) to give the title compound (5.2 g, 78%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 149.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.03-6.96 (m, 2H), 6.68-6.66 (m, 1H), 3.86 (s, 3H), 2.99-2.81 (m, 4H), 2.24-2.05 (m, 2H). 
     Step 2) The Preparation of Compound 25-2 
     To a solution of compound 25-1 (10.34 g, 69.8 mmol) and NIS (17.2 g, 76.8 mmol) in MeCN (200 mL) was added TFA (0.52 mL, 6.98 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the mixture was quenched with saturated NaHCO 3  aqueous solution (100 mL). The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound (16.44 g, 86%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 275.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.42, 7.40 (t, t, 1H), 6.41-6.40, 6.39-6.38 (m, m, 1H), 3.87 (s, 3H), 2.96-2.76 (m, 4H), 2.37-2.18 (m, 2H). 
     Step 3) The Preparation of Compound 25-3 
     To a solution of compound 25-2 (16.35 g, 59.7 mmol) in DCM (150 mL) was added boron tribromide (74.7 g, 298.8 mmol) dropwise at −78° C. At the end of the addition, the reaction mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (200 mL) and the organic phase was separated. The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=40/1) to give the title compound (14.28 g, 92%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 261.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.32, 7.30 (t, t, 1H), 6.32, 6.30 (t, t, 1H), 4.81 (br, 1H), 2.90-2.74 (m, 4H), 2.36-2.18 (m, 2H). 
     Step 4) The Preparation of Compound 25-4 
     A mixture of compound 25-3 (0.42 g, 1.62 mmol), compound 1-14-2 (0.42 g, 1.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (67 mg, 0.08 mmol) and KOAc (0.40 g, 4.05 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (0.30 g, 70%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 261.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94, 7.92 (t, t, 1H), 6.71, 6.69 (t, t, 1H), 4.81 (br, 1H), 2.97-2.92 (m, 2H), 2.87-2.70 (m, 2H), 2.29-2.10 (m, 2H), 1.32, 1.29 (m, m, 12H). 
     Step 5) The Preparation of Compound 25-5 
     A mixture of compound 25-4 (0.88 g, 3.40 mmol), compound 7-1 (2.35 g, 3.40 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) in the mixed solvent of DME/H 2 O (15 mL, v/v=4/1) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (80 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (1.03 g, 45%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 675.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.62, 7.59 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.38, 7.35 (dd, dd, 1H), 6.97, 6.94 (m, m, 1H), 6.65, 6.63 (t, t, 1H), 6.07, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.81 (brs, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.04-2.87 (m, 6H), 2.75-2.70 (m, 2H), 2.45-2.36 (m, 1H), 2.32-2.15 (m, 2H), 2.13-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 6) The Preparation of Compound 25-6 
     To a solution of compound 25-5 (6.74 g, 10.0 mmol) in DCM (20.0 mL) was added pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL, 40.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (6.45 g, 80%) as white oil. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.62, 7.59 (dd, dd, 1H), 7.52, 7.50 (d, d, 1H), 7.38, 7.35 (dd, dd, 1H), 7.15-7.14, 7.13-7.12 (t, t, 1H), 6.89, 6.86 (t, t, 1H), 6.08, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.06-2.87 (m, 6H), 2.75-2.70 (m, 2H), 2.45-2.19 (m, 3H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.50 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.94, 0.91 (m, m, 3H). 
     Step 7) The Preparation of Compound 25-7 
     A mixture of compound 25-6 (1.31 g, 1.62 mmol 1), compound 1-14-2 (0.42 g, 1.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (67 mg, 0.08 mmol) and KOAc (0.40 g, 4.05 mmol) in DMF (8.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (80 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound (0.89 g, 70%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 785.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.92, 7.90 (t, t, 1H), 7.83, 7.81 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.44, 7.42 (dd, dd, 1H), 7.38-7.33 (m, 2H), 6.08, 6.06 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.13-3.09 (m, 2H), 2.92-2.87 (m, 4H), 2.78-2.73 (m, 2H), 2.45-2.36 (m, 1H), 2.24-2.01 (m, 4H), 1.94-1.72 (m, 2H), 1.70-1.49 (m, 6H), 1.45-1.35 (m, 2H), 1.32-1.29 (m, m, 12H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 8) The Preparation of Compound 25-8 
     A mixture of compound 25-7 (2.67 g, 3.40 mmol), compound 7-8 (1.57 g, 3.74 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) in the mixed solvent of DME/H 2 O (15.0 mL, v/v=4/1) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL), and washed with water (50 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound (1.45 g, 45%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 476.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94-7.93 (m, 1H), 7.85 (s, 1H), 7.83, 7.81 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.43-7.40 (m, 2H), 7.38, 7.35 (d, d, 1H), 7.33, 7.31 (m, m, 1H), 5.32-5.28 (m, 3H), 5.21-5.16 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 2.92-2.76 (m, 8H), 2.44-2.37 (m, 1H), 2.31-1.73 (m, 11H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 26 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 26-2 
     A mixture of compound 26-1 (0.44 g, 1.62 mmol), compound 1-14-2 (0.42 g, 1.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (67.0 mg, 0.08 mmol) and KOAc (0.40 g, 4.05 mmol) in DMF (5.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=15/1) to give the title compound (0.31 g, 70%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 271.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.53-8.50 (m, 1H), 8.45-8.43 (m, 1H), 7.83, 7.81 (m, m, 1H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 1H), 7.06, 7.04 (br, br, 1H), 6.17 (br, 1H), 1.57 (m, 6H), 1.54 (m, 6H). 
     Step 2) The Preparation of Compound 26-3 
     A mixture of compound 26-2 (0.92 g, 3.4 mmol), compound 7-1 (2.35 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) in the mixed solvent of DME/H 2 O (15.0 mL, v/v=4/1) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (60 mL), and then washed with water (20.0 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (1.05 g, 45%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 685.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.25-8.24, 8.23-8.22 (m, m, 1H), 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.65, 7.62 (dd, dd, 1H), 7.52, 7.50 (d, d, 1H), 7.48-7.44 (m, 2H), 7.41-7.39 (m, m, 1H), 7.33, 7.31 (brs, brs, 1H), 7.22-7.17 (m, 1H), 7.04, 7.02 (m, m, 1H), 6.17 (brs, 1H), 6.08, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.45-2.36 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 3) The Preparation of Compound 26-4 
     To a solution of compound 26-3 (6.84 g, 10.0 mmol) in DCM (40.0 mL) was added pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL, 40.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound (6.94 g, 85%) as white oil. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ): δ (ppm): 8.38-8.37, 8.36-8.35 (m, m, 1H), 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.66, 7.64 (dd, dd, 1H), 7.63, 7.60 (m, m, 1H), 7.52-7.46 (m, 2H), 7.41-7.39 (m, m, 1H), 7.34, 7.31 (m, m, 1H), 7.26, 7.24, 7.22 (m, m, m, 1H), 7.17-7.15 (m, m, 1H), 6.07, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.45-2.36 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 4) The Preparation of Compound 26-5 
     A mixture of compound 26-4 (1.32 g, 1.62 mmol), compound 1-14-2 (0.42 g, 1.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (67 mg, 0.08 mmol) and KOAc (0.40 g, 4.05 mmol) in DMF (10.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (60 mL) and filtered through a celite pad. The filtrate was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound (0.9 g, 70%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 795.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.81, 8.79 (m, m, 1H), 8.17, 8.14 (m, m, 1H), 7.94-7.93 (q, 1H), 7.90, 7.87 (brs, brs, 1H), 7.83, 7.81 (d, d, 1H), 7.79-7.75 (m, 2H), 7.60-7.56 (m, 1H), 7.52, 7.50 (d, d, 1H), 7.48, 7.46 (dd, dd, 1H), 7.22-7.18 (m, 1H), 6.08, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.45-2.36 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.52 (m, 18H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 5) The Preparation of Compound 26-6 
     A mixture of compound 26-5 (2.70 g, 3.4 mmol), compound 7-8 (1.57 g, 3.74 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) in the mixed solvent of DME/H 2 O (15 mL, v/v=4/1) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (100 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound (1.31 g, 40%) as a pale yellow solid. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 481.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.02-8.01, 8.00-7.99 (m, m, 1H), 7.94-7.93 (q, 1H), 7.88, 7.86 (m, m, 1H), 7.83, 7.81 (d, d, 1H), 7.74 (s, 1H), 7.72, 7.70 (dd, dd, 1H), 7.63, 7.60 (m, m, 1H), 7.54-7.50 (m, 2H), 7.48, 7.46 (dd, dd, 1H), 7.43-7.38 (m, 1H), 7.10-7.06 (m, 1H), 5.36-5.31 (m, 1.5H), 5.29 (d, 0.5H), 5.21-5.16 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.44-2.37 (m, 1H), 2.30-1.73 (m, 9H), 1.69-1.49 (m, 6H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 27 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 27-2 
     A solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) in anhydrous DMF (6.0 mL) was slowly added dropwise in the dark to a solution of compound 27-1 (0.72 g, 6.0 mmol) in anhydrous DMF (6.0 mL) at −15° C. At the end of the addition, the mixture was stirred at room temperature for 1.0 hr and then at 60° C. for another 5.0 hrs. After the reaction was completed, the mixture was poured into 50 mL of ice water and 60.0 mL of ethyl ether. The organic layer was separated, washed several times with water to neutral pH, and dried with anhydrous Na 2 SO 4 . The solvent was evaporated to give an oily liquid (1.07 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 275.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.02 (d, 1H), 7.53, 7.51 (s, s, 1H), 7.34, 7.32 (d, d, 1H). 
     Step 2) The Preparation of Compound 27-3 
     A mixture of compound 27-2 (0.25 g, 0.91 mmol), compound 1-14-2 (0.53 g, 2.09 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (71 mg, 0.09 mmol) and KOAc (0.27 g, 2.73 mmol) in DMF (10.0 mL) was stirred at 90° C. under N 2  for 3.0 hrs. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL) and filtered through a celite pad. The filtration was washed with water (30 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/2) to give the title compound (0.27 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 372.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.53 (d, 1H), 8.53, 8.51 (d, d, 1H), 7.94, 7.92 (d, d, 1H), 1.56, 1.54 (m, m, 12H), 1.32, 1.29 (m, m, 12H). 
     Step 3) The Preparation of Compound 27-4 
     To a mixture of compound 27-3 (0.27 g, 0.72 mmol), compound 25-7 (0.30 g, 0.72 mmol), Pd(PPh 3 ) 4  (83 mg, 0.07 mmol) and K 2 CO 3  (0.30 g, 2.12 mmol) were added DME (4.0 mL) and water (1.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 10 mL of water, and the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.23 g, 60%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 538.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.37 (d, 1H), 7.66 (s, 1H), 7.54, 7.52 (d, d, 1H), 7.26, 7.24 (s, s, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 2.30-1.92 (m, 5H), 1.56, 1.53 (m, m, 12H), 0.97-0.89 (m, 6H). 
     Step 4) The Preparation of Compound 27-5 
     To a mixture of compound 27-4 (0.54 g, 1 mmol), compound 7-1 (0.69 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) were added DME (4.0 mL) and water (1.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 10 mL of water, and the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound (0.48 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 476.7 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.08 (dd, 1H), 7.94-7.93 (q, 1H), 7.83-7.79 (m, 2H), 7.63 (s, 1H), 7.60, 7.57 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.45, 7.43 (d, d, 1H), 7.38, 7.36 (dd, dd, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d, 2H), 5.25-5.16 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.44-2.37 (m, 1H), 2.30-1.73 (m, 9H), 1.67-1.50 (m, 6H), 1.46-1.35 (m, 2H), 0.97-0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 28 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 28-2 
     To a solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) and compound 28-1 (2.54 g, 10 mmol) in CCl 4  (20.0 mL) was added benzoyl peroxide (0.24 g, 1.0 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at room temperature for 15 mins and then refluxed for another 7.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (4.0 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 335.8 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.70 (t, 1H), 4.73 (d, 2H). 
     Step 2) The Preparation of Compound 28-3 
     NaH (60%, 3.13 g, 78 mmol) was added to DMF (100 mL) followed by dropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end of the addition, the mixture was heated to 100° C. for 40 mins, and then cooled to room temperature. Compound 28-2 (11.81 g, 35.60 mmol) was added. The mixture was stirred for 30 mins at room temperature, and then heated to 75° C. for another 1.0 hr. After the reaction was completed, the reaction was quenched with aqueous saturated NH 4 Cl solution (50 mL), and then EtOAc (150 mL) was added to the mixture. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (14.0 g), which was used for the next step. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.93 (m, 1H), 4.18-4.13 (q, 4H), 3.84-3.81 (m, 1H), 3.35, 3.33 (dd, dd, 2H), 1.23-1.19 (m, 6H). 
     Step 3) The Preparation of Compound 28-4 
     To a solution of compound 28-3 (14.0 g) in DMSO (100 mL) was added NaCl (4.10 g, 70 mmol) and water (0.64 g, 35.6 mmol) dropwise at rt. At the end of the addition, the mixture was stirred at 100° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with 200 mL of EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (9.0 g). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.88 (t, 1H), 4.11-4.06 (q, 2H), 3.05, 3.03, 3.01 (m, m, m, 2H), 2.69-2.65 (m, 2H), 1.24-1.20 (m, 3H). 
     Step 4) The Preparation of Compound 28-5 
     To a solution of compound 28-4 (3.42 g, 10 mmol) in MeOH (20.0 mL) was added NaOH aqueous solution (800 mg, 20 mL) at 0° C., and the mixture was stirred at rt for 3.0 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent MeOH was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (2.82 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 315.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.94 (brs, 1H), 6.93 (t, 1H), 3.05, 3.03, 3.01 (m, m, m, 2H), 2.79, 2.77, 2.75 (d, d, d, 2H). 
     Step 5) The Preparation of Compound 28-6 
     To a solution of compound 28-5 (3.14 g, 10 mmol) in dry DCM (40.0 mL) and DMF (0.05 mL) was added oxalyl chloride (0.93 mL, 11 mmol) dropwise at −10° C. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was used for the next step without further purification. 
     To a suspension of aluminium chloride (1.73 g, 13 mmol) in DCM (30.0 mL) was added the above solution dropwise at −15° C. At the end of addition, the mixture was stirred at −15° C. for 2.0 hrs. After the reaction was completed, the mixture was poured into ice water (100 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with water and saturated Na 2 CO 3  aqueous solution, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as a pale yellow solid (2.37 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 296.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 2.96-2.93 (m, 2H), 2.81-2.78 (m, 2H). 
     Step 6) The Preparation of Compound 28-7 
     To a solution of compound 28-6 (2.96 g, 10 mmol), 1,4-dibromobutane (1.31 mL, 11 mmol) and TEBAC (0.46 g, 2.0 mmol) in DMSO (30.0 mL) was added sodium hydroxide aqueous solution (1.6 g, 40 mmol, 1.6 mL) dropwise at −5° C. At the end of the addition, the mixture was stirred at 60° C. for 8.0 hrs. After the reaction was completed, the mixture was poured into ice water (100 mL) and filtered. The filter cake was dissolved in EtOAc (50 mL). The solution was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (2.63 g, 75%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 351.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 2.65-2.63 (m, 2H), 1.94-1.64 (m, 6H), 1.25-1.15 (m, 2H). 
     Step 7) The Preparation of Compound 28-8 
     To a suspension of compound 28-7 (3.5 g, 10 mmol), NH 4 F (1.11 g, 30 mmol) and triethylsilane (4.79 mL, 30 mmol) was added TFA (9.0 mL, 120 mmol) dropwise at −5.0° C. At the end of the addition, the mixture was stirred at 50° C. for 15 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (2.87 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 337.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 2.81-2.79 (m, 4H), 1.77-1.46 (m, 6H), 1.34-1.24 (m, 2H). 
     Step 8) The Preparation of Compound 28-9 
     A mixture of compound 28-8 (0.34 g, 1.0 mmol), compound 1-15 (0.50 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=4/1, 5.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (0.41 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 626.6 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.67-7.64 (m, 2H), 7.59 (s, 1H), 7.51-7.48 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 2.84-2.81 (m, 2H), 2.75-2.72 (m, 2H), 2.30-1.92 (m, 5H), 1.75-1.54 (m, 4H), 1.53-1.43 (m, 2H), 1.31-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 9) The Preparation of Compound 28-10 
     A mixture of compound 28-9 (0.63 g, 1.0 mmol), compound 1-22 (0.50 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=4/1, 5.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound (0.41 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 459.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.24-8.23 (m, 1H), 7.77, 7.74 (d, d, 1H), 7.66-7.62 (m, 2H), 7.59 (s, 1H), 7.50-7.45 (m, 3H), 5.32, 5.29 (d, d, 2H), 5.23-5.16 (m, 2H), 4.41-4.37 (m, 1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.66 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 2.82-2.75 (m, 4H), 2.44-2.37 (m, 1H), 2.30-1.39 (m, 15H), 1.29-1.18 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 29 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 29-2 
     To a solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) and compound 29-1 (2.51 g, 10 mmol) in CCl 4  (20.0 mL) was added benzoyl peroxide (0.24 g, 1.0 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at room temperature for 15 mins and then refluxed for another 7.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), and then washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (4.0 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 330.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.18-8.17 (m, 1H), 7.79 (m, 1H), 4.66-4.65 (m, 2H). 
     Step 2) The Preparation of Compound 29-3 
     NaH (60%, 3.13 g, 78 mmol) was added to DMF (100 mL) followed by dropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end of the addition, the mixture was heated to 100° C. for 40 mins and then cooled to room temperature. Compound 29-2 (11.74 g, 35.60 mmol) was added. The mixture was stirred for 30 mins at room temperature, and then heated to 75° C. for 1.0 hr. After the reaction was completed, the mixture was quenched with aqueous saturated NH 4 Cl solution (50 mL), and then EtOAc (150 mL) was added to the mixture. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo to give the title compound (13.0 g), which was used for the next step. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.14 (m, 1H), 7.75 (m, 1H), 4.18-4.13 (q, 4H), 3.83-3.80 (m, 1H), 3.55-3.54, 3.53-3.52 (m, m, 2H), 1.23-1.19 (t, 6H). 
     Step 3) The Preparation of Compound 29-4 
     To a solution of compound 29-3 (13.0 g) in DMSO (100 mL) were added NaCl (4.10 g, 70 mmol) and water (0.64 g, 35.6 mmol) dropwise at rt. At the end of the addition, the mixture was stirred at 100° C. for 3.0 hrs. After the reaction was completed, the mixture was cooled to rt and diluted with 200 mL of EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (8.5 g). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.08-8.07 (m, 1H), 7.75 (m, 1H), 4.08-4.03 (q, 2H), 2.98-2.97, 2.96, 2.94 (m, m, m, 2H), 2.75, 2.74, 2.72 (d, d, d, 2H), 1.22-1.19 (t, 3H). 
     Step 4) The Preparation of Compound 29-5 
     To a solution of compound 29-4 (3.37 g, 10 mmol) in MeOH (20.0 mL) was added NaOH aqueous solution (800 mg, 20 mL) at 0° C., and the mixture was stirred at rt for 3.0 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent MeOH was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to give the title compound as a white solid (2.78 g, 90%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 309.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.32 (brs, 1H), 8.08-8.07 (m, 1H), 7.78 (m, 1H), 3.02-3.01, 3.00-2.99, 2.98-2.97 (m, m, m, 2H), 2.88, 2.86, 2.84 (d, d, d, 2H). 
     Step 5) The Preparation of Compound 29-6 
     To a solution of compound 29-5 (3.09 g, 10 mmol) in dry DCM (40.0 mL) and DMF (0.05 mL) was added oxalyl chloride (0.93 mL, 11 mmol) dropwise at −10° C. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was used for the next step without further purification. 
     To a suspension of aluminium chloride (1.73 g, 13 mmol) in DCM (30.0 mL) was added the above solution (3.27 g, 10 mmol) dropwise at −15° C. At the end of the addition, the mixture was stirred at −15° C. for 2.0 hrs. After the reaction was completed, the mixture was poured into ice-water (100 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with water and saturated Na 2 CO 3  aqueous solution, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as a pale yellow solid (2.33 g, 80%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 292.5 [M+H] + ; 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.38 (s, 1H), 3.22-3.20 (m, 2H), 2.80-2.78 (m, 2H). 
     Step 6) The Preparation of Compound 29-7 
     To a solution of compound 29-6 (2.91 g, 10 mmol), 1,4-dibromobutane (1.31 mL, 11 mmol) and TEBAC (0.46 g, 2.0 mmol) in DMSO (30.0 mL) was added sodium hydroxide aqueous solution (1.6 g, 40 mmol, 1.6 mL) dropwise at −5° C. At the end of the addition, the mixture was stirred at 60° C. for 8.0 hrs. After the reaction was completed, the mixture was poured into ice water (100 mL) and filtered. The filter cake was dissolved in EtOAc (50 mL). The solution was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (2.59 g, 75%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 346.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.38 (s, 1H), 3.07-3.06 (q, 2H), 2.03-1.91 (m, 2H), 1.82-1.62 (m, 4H), 1.34-1.24 (m, 2H). 
     Step 7) The Preparation of Compound 29-8 
     To a suspension of compound 29-7 (3.45 g, 10 mmol), NH 4 F (1.11 g, 30 mmol) and triethylsilane (4.79 mL, 30 mmol) was added TFA (9.0 mL, 120 mmol) dropwise at −5.0° C. At the end of the addition, the mixture was stirred at 50° C. for 15 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (2.81 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 332.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.08 (dd, 1H), 3.23-3.20 (m, 2H), 3.04-3.01 (m, 2H), 1.77-1.45 (m, 8H). 
     Step 8) The Preparation of Compound 29-9 
     A mixture of compound 29-8 (0.33 g, 1.0 mmol), compound 1-15 (0.50 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=4/1, 5.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (0.40 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 621.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (dd, 1H), 7.92-7.89 (m, 2H), 7.75-7.72 (m, 2H), 7.59 (s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.25-3.22 (m, 2H), 2.82-2.79 (m, 2H), 2.30-1.92 (m, 5H), 1.74-1.53 (m, 6H), 1.52-1.42 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 9) The Preparation of Compound 29-10 
     A mixture of compound 29-9 (0.62 g, 1.0 mmol), compound 5-8 (0.53 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in the mixed solvent of DME/H 2 O (v/v=4/1, 5.0 mL) was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine. The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound (0.43 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 475.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (dd, 1H), 8.27 (brs, 2H), 7.91-7.88 (m, 2H), 7.82 (q, 1H), 7.78, 7.76 (d, d, 1H), 7.75-7.72 (m, 2H), 7.59 (s, 1H), 7.53, 7.51 (d, d, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 5.08-5.04 (m, 1H), 4.41-4.36 (m, 1H), 4.31-4.26 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 6H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 1H), 3.06-3.03 (m, 2H), 2.85-2.82 (m, 2H), 2.38-1.39 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 30 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 30-2 
     To a solution of compound 1-10-2 (23.0 g, 107 mmol) and compound HATU (48.82 g, 128.4 mmol) in THF (250 mL) was added DIPEA (19.5 mL, 118 mmol) at 0° C. After stirring at 0° C. for 0.5 hr, to the solution was added compound 30-1 (22.25 g, 119 mmol) portionwise, and then the reaction mixture was stirred at rt for 4.0 hrs. After the reaction was completed, the reaction was quenched with water (100 mL). The solvent THF was removed, and the resulting mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 mL). The solution was stirred at 40° C. overnight, and HOAc was removed. The resulting mixture was dissolved in EtOAc (400 mL), washed with Na 2 CO 3  aq (150 mL×3), dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (31.74 g, 81%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 367.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H). 
     Step 2) The Preparation of Compound 30-3 
     To a solution of compound 30-2 (10.0 g, 27.39 mmol) in EtOAc (50.0 mL) was added a solution of HCl in EtOAc (60.0 mL, 4 M) dropwise at 0° C., and the mixture was stirred at rt. After the reaction was completed, the mixture was filtered, and the filter cake was washed with EtOAc to give the title compound as a pale yellow solid (8.0 g, 86.49%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 267.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.01 (s, 1H), 7.76-7.70 (m, 2H), 5.27-5.25 (m, 1H), 3.31-3.30 (m, 2H), 2.77-2.74 (m, 1H), 2.54-2.52 (m, 1H), 2.40-2.37 (m, 1H), 2.30-2.10 (m, 1H). 
     Step 3) The Preparation of Compound 30-4 
     To a solution of compound 30-3 (6.0 g, 18.8 mmol), compound 1-13-2 (4.9 g, 28.2 mmol) and EDCI (5.4 g, 28.2 mmol) in DCM (100 mL) was added DIPEA (18.6 mL, 112.8 mmol) dropwise at 0° C., and the mixture was stirred at rt. After the reaction was completed, 100 mL of water was added to the mixture, and the resulting mixture was extracted with DCM (150 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a solid (6.74 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 423.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.59-7.51 (m, 1H), 7.34-7.21 (m, 2H), 5.42-5.38 (m, 2H), 4.34-4.30 (m, 1H), 3.87-3.76 (m, 1H), 3.70 (s, 3H), 3.66-3.62 (m, 1H), 3.04-2.98 (m, 1H), 2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 0.88-0.84 (m, 6H). 
     Step 4) The Preparation of Compound 30-5 
     To a mixture of compound 30-4 (3.0 g, 7.1 mmol), compound 1-14-2 (2.72 g, 10.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.65 g, 0.8 mmol) and KOAc (2.09 g, 21.3 mmol) was added DMF (30.0 mL) via syringe under N 2 , and the mixture was stirred at 90° C. After the reaction was completed, the mixture was cooled to rt, followed by adding 60 mL of water, and the resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (2.1 g, 62.9%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 471.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.87-7.80 (m, 1H), 7.71-7.66 (m, 2H), 5.47-5.42 (m, 2H), 4.34-4.30 (m, 1H), 3.86-3.84 (m, 1H), 3.70 (s, 3H), 3.64-3.62 (m, 1H), 3.04-2.98 (m, 1H), 2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.35 (s, 12H), 0.88-0.84 (m, 6H). 
     Step 5) The Preparation of Compound 30-6 
     A mixture of compound 25-7 (0.88 g, 3.40 mmol), compound 29-8 (1.12 g, 3.40 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) in the mixed solvent of DME/H 2 O (15 mL, v/v=4/1) was stirred at 90° C. under N 2  for 4.0 hrs. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL). The resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound (0.59 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 385.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.44-8.43 (dd, 1H), 7.23, 7.21 (t, t, 1H), 6.59, 6.57 (t, t, 1H), 4.81 (brs, 1H), 3.23-3.20 (m, 2H), 3.07-2.90 (m, 2H), 2.86-2.82 (m, 2H), 2.81-2.76 (m, 2H), 2.32-2.13 (m, 2H), 1.71-1.42 (m, 8H). 
     Step 6) The Preparation of Compound 30-7 
     To a solution of compound 30-6 (3.84 g, 10.0 mmol) in DCM (20.0 mL) was added pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL, 40.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice-water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound (4.13 g, 80%) as white oil. The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.44-8.43 (dd, 1H), 7.14, 7.12 (t, t, 1H), 7.10, 7.08 (t, t, 1H), 3.23-3.20 (m, 2H), 3.09-2.92 (m, 2H), 2.86-2.82 (m, 2H), 2.78-2.73 (m, 2H), 2.41-2.22 (m, 2H), 1.74-1.42 (m, 8H). 
     Step 7) The Preparation of Compound 30-8 
     To a mixture of compound 30-7 (1.76 g, 3.40 mmol), compound 7-8 (1.43 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, 100 mL of EtOAc was added, and the resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (1.01 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 661.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.43 (s, 1H), 7.85 (s, 1H), 7.59, 7.57 (t, t, 1H), 7.30, 7.28 (t, t, 1H), 5.32-5.28 (m, 2H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 3H), 3.23-3.20 (m, 2H), 2.93-2.88 (m, 2H), 2.86-2.83 (m, 2H), 2.79-2.75 (m, 2H), 2.35-1.92 (m, 7H), 1.74-1.40 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 8) The Preparation of Compound 30-9 
     To a mixture of compound 30-8 (2.25 g, 3.40 mmol), compound 30-5 (1.60 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 100 mL of EtOAc, and the resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (1.41 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.57 (s, 1H), 7.85 (s, 1H), 7.76, 7.73 (d, d, 1H), 7.62 (dd, 1H), 7.58, 7.56 (t, t, 1H), 7.53, 7.51 (d, d, 1H), 7.30, 7.28 (t, t, 1H), 5.32-5.28 (m, 3H), 5.25-5.20 (m, 1H), 4.41-4.35 (m, 2H), 3.85-3.77 (m, 2H), 3.69-3.65 (m, 2H), 3.63 (s, 6H), 2.94-2.86 (m, 6H), 2.79-2.75 (m, 2H), 2.37-1.88 (m, 12H), 1.71-1.50 (m, 6H), 1.49-1.39 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 31 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 31-1 
     To a mixture of compound 26-2 (0.92 g, 3.40 mmol), compound 29-8 (1.12 g, 3.40 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 80 mL of EtOAc, and the resulting mixture was washed with water (20 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as a pale yellow solid (0.67 g, 50%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 395.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.66-8.65 (dd, 1H), 8.35, 8.34 (m, m, 1H), 7.64-7.59 (m, 1H), 7.54, 7.52 (brs, brs, 1H), 7.41-7.37 (m, 1H), 7.30-7.27 (m, 1H), 7.12, 7.10 (brs, brs, 1H), 6.17 (brs, 1H), 3.31-3.28 (m, 2H), 2.86-2.83 (m, 2H), 1.73-1.42 (m, 8H). 
     Step 2) The Preparation of Compound 31-2 
     To a solute ion of compound 31-1 (3.94 g, 10.0 mmol) in DCM (20.0 mL) was added pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL, 40.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as white oil (4.20 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.66-8.65 (dd, 1H), 8.49, 8.47 (m, m, 1H), 7.97, 7.95 (brs, brs, 1H), 7.79-7.74 (m, 1H), 7.46-7.41 (m, 1H), 7.36, 7.34 (brs, brs, 1H), 7.32-7.29 (m, 1H), 3.31-3.28 (m, 2H), 2.86-2.83 (m, 2H), 1.74-1.42 (m, 8H). 
     Step 3) The Preparation of Compound 31-3 
     To a mixture of compound 31-2 (1.79 g, 3.40 mmol), compound 7-8 (1.43 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 100 mL of EtOAc, and the resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (1.03 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 671.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.65 (s, 1H), 8.07-8.04 (m, 1H), 7.88-7.85 (m, 1H), 7.78, 7.76 (brs, brs, 1H), 7.74 (s, 1H), 7.59-7.48 (m, 3H), 5.36-5.29 (m, 2H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.31-3.28 (m, 2H), 2.86-2.83 (m, 2H), 2.30-1.92 (m, 5H), 1.74-1.42 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 4) The Preparation of Compound 31-4 
     To a mixture of compound 31-3 (2.28 g, 3.40 mmol), compound 30-5 (1.60 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 100 mL of EtOAc, and the resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (1.43 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 468 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.52 (s, 1H), 8.07-8.04 (m, 1H), 7.88-7.85 (m, 1H), 7.82-7.81, 7.80-7.79 (brs, brs, 1H), 7.76-7.73 (m, 2H), 7.62-7.61 (dd, 1H), 7.59-7.58, 7.57-7.56 (m, m, 1H), 7.55-7.48 (m, 3H), 5.36-5.29 (m, 3H), 5.25-5.20 (m, 1H), 4.41-4.35 (m, 2H), 3.85-3.77 (m, 2H), 3.69-3.65 (m, 2H), 3.63 (s, 3H), 3.00-2.97 (m, 2H), 2.89-2.86 (m, 2H), 2.37-1.87 (m, 10H), 1.74-1.39 (m, 8H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 32 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 32-1 
     To a mixture of compound 28-8 (1.14 g, 3.40 mmol), compound 27-4 (1.83 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 100 mL of EtOAc, and the resulting mixture was washed with water (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound (1.02 g, 45%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 667.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.65 (d, 1H), 7.77, 7.75 (d, d, 1H), 7.63 (s, 1H), 7.60, 7.58 (s, s, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 2.30-1.92 (m, 5H), 1.75-1.43 (m, 6H), 1.32-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Step 2) The Preparation of Compound 32-2 
     To a mixture of compound 32-1 (2.27 g, 3.40 mmol), compound 30-5 (1.60 g, 3.4 mmol), Pd(PPh 3 ) 4  (0.20 g, 0.17 mmol) and K 2 CO 3  (1.41 g, 10.22 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixture was stirred at 90° C. under N 2  for 4.0 hrs. After the reaction was completed, the mixture was cooled to rt, followed by adding 100 mL of EtOAc, and the resulting mixture was washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (1.27 g, 40%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 466 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.68 (d, 1H), 7.81-7.77 (m, 2H), 7.67-7.66 (q, 1H), 7.63 (s, 1H), 7.52, 7.50 (s, s, 1H), 7.18, 7.16 (d, d, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d, 1H), 5.25-5.20 (m, 1H), 4.41-4.35 (m, 2H), 3.85-3.77 (m, 2H), 3.69-3.66 (m, 2H), 3.63 (s, 6H), 3.06-3.03 (m, 2H), 2.94-2.91 (m, 2H), 2.37-1.87 (m, 10H), 1.73-1.52 (m, 4H), 1.50-1.39 (m, 2H), 1.28-1.18 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 6H). 
     Example 33 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1) The Preparation of Compound 33-2 
     The mixture of compound 33-1 (25 g, 125.6 mmol), NBS (24.5 g, 138.2 mmol) and p-TSA (3.4 g, 20.9 mmol) was stirred at 100° C. for 2.0 hrs under N 2 . After the reaction was completed, the mixture was cooled to rt, and 200 mL of DCM was added. The organic layer were washed with water (50 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound (25 g, 71%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 279.9 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.95 (d, 1H, J=1.12 Hz), 8.14-8.11 (m, 1H), 7.68-7.66 (m, 1H), 4.41 (s, 2H). 
     Step 2) The Preparation of Compound 33-3 
     To a solution of compound 33-2 (5.0 g, 17.9 mmol) and compound 1-19-2 (5.36 g, 19.7 mmol) in MeCN (100 mL) was added DIPEA (3.3 mL, 19.7 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was quenched with ice water (50 mL), and the resulting mixture was extracted with EtOAc (60 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound (8.0 g, 96%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.88 (s, 1H), 8.04 (d, 1H, J=3.88 Hz), 7.65 (d, 1H, J=4.16 Hz), 5.61-5.59 (m, 1H), 5.48 (d, 1H, J=8.32 Hz), 5.23 (d, 1H, J=8.3 Hz), 4.67 (t, 1H, J=5.72 Hz), 4.31 (t, 1H, J=7.52 Hz), 3.86-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.66 (s, 3H), 2.34-2.15 (m, 4H), 1.01 (t, 3H), 0.94-0.93 (m, 3H), 0.88-0.85 (m, 1H). 
     Step 3) The Preparation of Compound 33-4 
     A mixture of compound 33-3 (2.0 g, 4.25 mmol) and ammonium acetate (4.9 g, 83 mmol) in xylene (50.0 mL) was refluxed at 130° C. for 5.0 hrs. After the reaction was completed, the mixture was cooled to rt, and quenched with 50 mL of water. The resulting mixture was extracted with EtOAc (50 mL×3), and the combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound (1.39 g, 73%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 450.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.70 (s, 1H), 7.93 (d, 1H, J=6.92 Hz), 7.45 (d, 1H, J=8.28 Hz), 5.41 (d, 1H, J=4.6 Hz), 5.24-5.22 (m, 1H), 4.32 (m, 1H), 3.85-3.83 (m, 1H), 3.67 (s, 3H), 3.63-3.62 (m, 3H), 3.05-3.03 (m, 1H), 2.31-1.93 (m, 4H), 1.04-1.03 (m, 1H), 0.88 (s, 3H), 0.86 (s, 3H). 
     Step 4) The Preparation of Compound 33-6 
     To a solution of formic acid (3.7 mL) was added triethylamine (5.4 mL) at 0° C., followed by compound 33-5 (1.85 g, 12 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12 mmol). At the end of the addition, the mixture was stirred at 100° C. for 2.0 hrs. After the reaction was completed, 20 mL of ice water was added to the mixture, and the resulting mixture was adjusted to pH 1 with hydrochloric acid (2 M) and extracted with EtOAc (25 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a white solid (2.02 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 199.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 9.60 (brs, 1H), 7.13-7.09 (m, 1H), 6.82-6.81, 6.79-6.77 (m, m, 1H), 6.76-6.71 (m, 1H), 3.79 (d, 3H), 2.90-2.85 (m, 2H), 2.62, 2.60, 2.58 (d, d, d, 2H). 
     Step 5) The Preparation of Compound 33-7 
     A mixture of compound 33-6 (4.42 g, 22.3 mmol) and PPA (50.87 g, 24.8 mL) was stirred at 80° C. for 4.0 hrs. After the reaction was completed, 250 mL of ice water was added to the mixture, and the resulting mixture was extracted with EtOAc (100 mL×5). The combined organic layers were washed with NaHCO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a pale yellow solid (2.81 g, 70%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 181.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.87-6.83 (m, 1H), 6.81-6.76 (m, 1H), 3.96 (d, 3H), 3.11-3.06 (m, 2H), 2.64-2.60 (m, 2H). 
     Step 6) The Preparation of Compound 33-8 
     To a suspension of potassium tert-butanolate (1.17 g, 10.41 mmol) in toluene (10.0 mL) was added a solution of compound 33-7 (0.75 g, 4.16 mmol) and 1,4-dibromobutane (0.55 mL, 4.58 mmol) in toluene (20.0 mL) via syringe under N 2  at 0° C. At the end of the addition, the mixture was stirred at 110° C. for 2.5 hrs. After the reaction was completed, the mixture was quenched with water (50 mL). The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a pale yellow solid (0.63 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 235.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.82-6.81, 6.79 (m, m, 1H), 6.78, 6.75 (m, m, 1H), 3.92 (s, 3H), 2.97-2.95 (m, 2H), 2.24-2.12 (m, 2H), 1.78-1.58 (m, 4H), 1.56-1.45 (m, 2H). 
     Step 7) The Preparation of Compound 33-9 
     To a suspension of compound 33-8 (0.89 g, 3.8 mmol) and triethylsilane (3.7 mL, 23 mmol) was added TFA (8.0 mL) via syringe under N 2  at 0° C. At the end of the addition, the mixture was stirred at 40° C. for 7.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with saturated Na 2 CO 3  aqueous solution and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow oil (0.73 g, 87%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 221.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.68-6.60 (m, 2H), 3.81 (d, 3H), 2.87-2.84 (m, 2H), 2.77-2.73 (m, 2H), 1.72-1.51 (m, 6H), 1.44-1.33 (m, 2H). 
     Step 8) The Preparation of Compound 33-10 
     A mixture of compound 33-9 (15.37 g, 69.8 mmol) and NIS (17.2 g, 76.8 mmol) in MeCN (200 mL) was added CF 3 COOH (0.5 mL, 6.98 mmol) dropwise at 0° C. At the end of the addition, the mixture was stirred at 45° C. overnight. After the reaction was completed, the mixture was neutralized with saturated NaHCO 3  aqueous solution. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=20/1) to give the title compound (20.54 g, 85%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 347.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.55-6.54, 6.51-6.50 (m, m, 1H), 3.85 (s, 3H), 2.86-2.83 (m, 2H), 2.82-2.78 (m, 2H), 1.72-1.53 (m, 6H), 1.41-1.31 (m, 2H). 
     Step 9) The Preparation of Compound 33-11 
     To a solution of compound 33-10 (1.10 g, 3.17 mmol) in DCM (20.0 mL) was added boron tribromide (1.20 mL, 12.67 mmol) dropwise at −78° C. At the end of the addition, the mixture was stirred at −78° C. for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was quenched with ice-water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as pale yellow oil (1.0 g, 95%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 333.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.57, 6.54 (dd, dd, 1H), 5.48 (brs, 1H), 2.83-2.80 (m, 2H), 2.79-2.76 (m, 2H), 1.76-1.56 (m, 6H), 1.47-1.37 (m, 2H). 
     Step 10) The Preparation of Compound 33-12 
     To a solution of compound 33-11 (1.05 g, 3.16 mmol) in DCM (20.0 mL) was added pyridine (2.03 mL, 25.29 mmol) dropwise at 0° C. After the mixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (3.19 mL, 19.97 mmol) was added, and then the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was quenched with ice-water (50 mL). The aqueous layer was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v)=6/1) to give the title compound as colorless oil (1.17 g, 80%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.14-7.13, 7.11-7.10 (dd, dd, 1H), 2.84-2.78 (m, 4H), 1.76-1.55 (m, 6H), 1.52-1.41 (m, 2H). 
     Step 11) The Preparation of Compound 33-13 
     To a mixture of compound 33-12 (3.09 g, 6.65 mmol), compound 1-22 (3.31 g, 6.65 mmol), Pd(PPh 3 ) 4  (0.77 g, 0.79 mmol) and K 2 CO 3  (2.77 g, 19.9 mmol) were added DME (50.0 mL) and water (10.0 mL) via syringe under N 2 . The mixture was stirred at 90° C. for 3.0 hrs. After the reaction was completed, the solvent DME was removed. The residue was dissolved in EtOAc (150 mL) and the solution was washed with water (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a beige solid (3.54 g, 75%). The compound was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.05, 8.02 (d, d, 1H), 7.49, 7.47 (q, q, 1H), 7.34, 7.31 (d, d, 1H), 6.51-6.50 (m, 1H), 6.07, 6.05 (d, d, 1H), 5.10-5.05 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 2.91-2.88 (m, 2H), 2.80-2.77 (m, 2H), 2.46-2.39 (m, 1H), 2.15-2.00 (m, 2H), 1.93-1.43 (m, 10H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 12) The Preparation of Compound 33-14 
     A mixture of compound 33-13 (5.03 g, 7.1 mmol), compound 1-14-2 (2.72 g, 10.7 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2  (0.65 g, 0.8 mmol) and KOAc (2.09 g, 21.3 mmol) in DMF (30.0 mL) was stirred at 90° C. under N 2 . After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (200 mL) and filtered through a celite pad. The filtrate was washed with water (60 mL×3) and brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a beige solid (3.17 g, 65%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 687.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.04, 8.02 (d, d, 1H), 7.54, 7.52 (q, q, 1H), 7.44-7.43, 7.42-7.41 (dd, dd, 1H), 6.64-6.63 (m, 1H), 6.08, 6.05 (d, d, 1H), 5.10-5.05 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.00-2.97 (m, 2H), 2.85-2.81 (m, 2H), 2.46-2.39 (m, 1H), 2.15-2.02 (m, 2H), 1.93-1.73 (m, 2H), 1.72-1.42 (m, 6H), 1.32, 1.29 (m, m, 12H), 1.28-1.21 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H). 
     Step 13) The Preparation of Compound 33-15 
     A suspension of compound 33-14 (0.69 g, 1.0 mmol), compound 33-4 (0.45 g, 1.0 mmol), Pd(PPh 3 ) 4  (0.12 g, 0.1 mmol) and K 2 CO 3  (0.35 g, 2.5 mmol) in mixed solvent of DME and H 2 O (6 mL, v/v=5/1) was stirred at 90° C. under N 2  for 3.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with brine, dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a beige solid (0.70 g, 75%). The compound was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 466.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.82-8.81 (dd, 1H), 8.04, 8.02 (d, d, 1H), 7.74, 7.72 (d, d, 1H), 7.67 (m, 1.5H), 7.65 (d, 0.5H), 7.53, 7.51 (q, q, 1H), 7.26, 7.24 (d, d, 1H), 6.63-6.62 (m, 1H), 6.08, 6.06 (d, d, 1H), 5.38-5.33 (m, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.05 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.26 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 2.99-2.96 (m, 2H), 2.89-2.86 (m, 2H), 2.46-2.39 (m, 1H), 2.30-1.73 (m, 10H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Example 34 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compounds of Example 34 disclosed herein can be synthesized through the procedure depicted in Example 1: 
     Compound 34-2 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 412.7 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 77.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H). 
     Compound 34-3 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 392.2 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H), 7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d, 9H). 
     Compound 34-4 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 292.6 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H), 7.21-7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m, 1H), 3.49-3.39 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H). 
     Compound 34-5 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 450.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H). 
     Compound 34-6 was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H), 2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.45-1.32 (m, 12H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H). 
     Compound 34-7 was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.84-7.82 (m, 1H), 7.69-7.66 (m, 2H), 7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 5.41-5.39 (m, 1H), 5.29-5.27 (m, 1H), 4.34-4.30 (m, 1H), 3.75-3.70 (m, 1H), 3.69 (s, 3H), 3.64-3.62 (m, 1H), 3.20-3.01 (m, 1H), 2.99 (s, 2H), 2.95 (s, 2H), 2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.78-1.52 (m, 8H), 0.88-0.86 (m, 6H). 
     Compound 34-9 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 470.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.57 (d, 1H, J=8.0 Hz), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 1H), 3.89-3.86 (m, 2H), 3.68 (s, 3H), 2.24-2.15 (m, 2H), 2.09-2.00 (m, 2H), 1.09 (d, 3H, J=6.0 Hz), 0.97 (d, 3H, J=6.0 Hz). 
     Compound 34-10 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 452.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.31 (s, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.53 (dd, 1H, J=8.0 Hz, 2.0 Hz), 5.78 (d, 1H, J=8.0 Hz), 5.10 (dd, 1H, J=8.0 Hz, 2.0 Hz), 4.33 (t, 1H, J=8.0 Hz), 4.14-4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.66 (s, 3H), 2.53-2.51 (m, 1H), 2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.04-1.79 (m, 2H), 0.93 (d, 1H, J=2.0 Hz). 
     Compound 34-11 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 499.3 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.08 (s, 1H), 8.22 (d, 1H, J=8.0 Hz), 8.11 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 5.71 (d, 1H, J=8.0 Hz), 5.17 (d, 1H, J=6.0 Hz), 4.35 (t, 1H, J=8.0 Hz), 4.15-4.10 (m, 1H), 3.88-3.86 (m, 1H), 3.67 (s, 3H), 2.71-2.67 (m, 1H), 2.34-2.32 (m, 1H), 2.09-1.99 (m, 2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H). 
     Compound 34-12 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 911.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 11.21 (s, 1H), 10.46 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.54-7.51 (m, 2H), 7.46 (s, 2H), 7.37-7.33 (m, 2H), 5.70-5.60 (m, 2H), 5.31-5.30 (m, 1H), 5.21-5.20 (m, 1H), 4.55-4.35 (m, 2H), 3.95-3.86 (m, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 2.98 (s, 4H), 2.69-2.57 (m, 2H), 2.35-2.01 (m, 8H), 2.09-1.99 (m, 2H), 0.92-0.84 (m, 12H). 
     Example 35 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
     
     Compounds of Example 35 disclosed herein can be synthesized through the procedure depicted in Example 2: 
     Compound 35-2 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 320.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.19-7.18 (m, 5H), 5.13-5.12 (m, 2H), 4.23, 4.21, 4.19, 4.18 (s, s, s, s, 2H), 4.03-3.97 (m, 1H), 3.59, 3.58 (s, s, 2H), 3.50-3.43 (m, 1H), 3.32-3.23 (m, 1H), 2.08-1.93 (m, 2H), 1.82-1.70 (m, 2H), 1.29-1.25 (t, 3H, J=8.0 Hz). 
     Compound 35-3 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 428.9 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd, 1H), 7.45, 7.43 (dd, dd, 1H), 7.28-7.22 (m, 5H), 6.58 (t, 1H), 5.14-5.13 (m, 2H), 4.98-4.94 (m, 1H), 3.64-3.57 (m, 1H), 3.43-3.36 (m, 1H), 2.26-2.17 (m, 1H), 2.09-1.83 (m, 3H). 
     Compound 35-4 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 293.5 [M+H] + . 
     Compound 35-5 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 450.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd, 1H), 7.45, 7.43 (dd, dd, 1H), 6.64 (m, 1H), 5.32, 5.29 (dd, dd, 1H), 5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.49 (m, 1H), 3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Compound 35-6 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 498.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.48-8.47 (m, 1H), 8.00, 7.99 (dd, dd, 1H), 7.47, 7.45 (dd, dd, 1H), 6.76 (m, 1H), 5.32, 5.29 (dd, dd, 1H), 5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 1.23, 1.20 (m, m, 12H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H). 
     Compound 35-7 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 455.8 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.05 (m, 1H), 7.72-7.71 (m, 1H), 7.70-7.69 (m, 1H), 7.62 (dd, 1H), 7.60-7.56 (m, 4H), 7.52-7.49 (m, 2H), 7.00-6.99 (m, 1H), 5.32, 5.29 (dd, dd, 2H), 5.23-5.19 (m, 1H), 5.18-5.13 (m, 1H), 4.41-4.36 (m, 1H), 4.27-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H), 2.93-2.88 (m, 4H), 2.30-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Example 36 
                         
Synthetic Route:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Compounds of Example 36 disclosed herein can be synthesized through the procedure depicted in Example 3: 
     Compound 36-1 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 456.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.08-8.07 (m, 1H), 7.65 (m, 2H), 6.40 (m, 1H), 4.19-4.15 (m, 1H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.72 (m, 2H), 1.68 (d, 6H), 1.40 (s, 9H). 
     Compound 36-2 was characterized by the following spectroscopic data: 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.07, 7.05 (dd, dd, 1H), 7.04, 7.02 (dd, dd, 1H), 6.77 (q, 1H), 6.40 (m, 1H), 4.11-4.07 (m, 1H), 3.98 (brs, 2H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.73 (m, 2H), 1.69 (d, 6H), 1.40 (s, 9H). 
     Compound 36-3 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 408.1 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H), 7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.14 (brs, 1H), 4.81-4.77 (m, 1H), 3.52-3.46 (m, 1H), 3.41-3.34 (m, 1H), 2.52-2.45 (m, 1H), 2.18-2.09 (m, 1H), 1.95-1.86 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.42 (s, 9H). 
     Compound 36-4 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 308.5 [M+H] + . 
     Compound 36-5 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 465.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H), 7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.65-4.61 (m, 1H), 4.32-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Compound 36-6 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 513.5 [M+H] + ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.67, 7.65 (d, d, 1H), 7.48-7.47 (m, 1H), 7.26, 7.24 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.65-4.61 (m, 1H), 4.33-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.25-1.24 (q, 6H), 1.22-1.21 (q, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H). 
     Compound 36-7 was characterized by the following spectroscopic data: 
     MS (ESI, pos.ion) m/z: 463.5 [M+2H] 2+ ; and 
       1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H), 7.52-7.47 (m, 4H), 7.40-7.38 (dd, dd, 1H), 7.37-7.35 (d, d, 1H), 7.19, 7.17 (d, d, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 4.65-4.61 (m, 1H), 4.41-4.28 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88 (m, 2H), 2.40-2.32 (m, 1H), 2.30-1.92 (m, 7H), 1.90-1.82 (m, 1H), 1.80-1.71 (m, 1H), 1.69-1.51 (m, 12H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H). 
     Biological Activity 
     HCV Replicon System was utilized as an evaluation model in the present disclosure for verifying the effects of the compounds disclosed herein on HCV. An HCV Replicon assay was first described in  Science,  1999, 285 (5424), 110-3. HCV Replicon System is one of the most important tools for research on HCV RNA replication, pathogenicity and persistent of virus, for example, 5′-NCR minimum areas is necessary for HCV RNA replication that was proved by using replicon, and HCV Replicon System was utilized successfully as an evaluation model of antiviral drugs. To determine the potential anti-HCV effects of the test compounds, luciferase assay and antibiotic Neomycin resistance gene were tested according to the method described in  Science.  1999 Jul. 2; 285 (5424), 110-3 and  J. Virol.  2003 March; 77 (5), 3007-19. 
     In a word, the compounds disclosed herein were tested by using human hepatic carcinoma cell line which is transfected stably HCV GT1a, GT1b or GT2a replicon respectively, and resistant cells Y93H, L31F, P32L or I302V and wild-type cells HCV 1b. HCV Replicon System disclosed herein containing Neomycin resistance gene and Luciferase Reporter Gene, the level of HCV replication in host cells is characterized by the expression level of the NEO gene expression level or Luciferase Reporter Gene, and the effects of the compounds herein inhibit HCV replication can be evaluated. In this article, a real-time quantitative polymerase chain reaction (qPCR) method was used to detect NEO gene expression level, and chemiluminescence method was used to test Luciferase Reporter Gene expression level. 
     Operating Procedure: 
     1. Test Method for Measuring EC 50  of the Compounds Base on Luciferase Assay. 
     The Huh-7 cells transfected with HCV replicons system were seeded into 96-well plates (8,000 cells in 125 μL/well) respectively; each test compound was diluted to desired concentration using 5-fold serial dilutions protocol, 10 doses in duplicate, and added to wells with POD™ 810 Plate Assembler. The plates were incubated in a CO 2  incubator for 72 hours; after that, 40 μL of Luciferase assay substrate (Promega Bright-Glo) was added to each well, and detected by a chemiluminescence detection system (Topcount Microplate Scintillation and Luminescence Counter) 5 minutes later; the EC 50  (half-maximal effective concentration, concentration for 50% of maximal effect) values of test compounds were analyzed by GraphPad Prism software, respectively. In this paper, experiments were repeated twice and set the holes without compounds as negative control. 
     2. Test Method for Measuring EC 50  of the Compounds by Detecting Antibiotic G418 Resistance Gene NEO Gene. 
     The Huh-7 cells transfected with HCV replicons system were seeded into 96-well plates (8,000 cells in 125 μL/well) respectively; each test compound was diluted to desired concentration using 5-fold serial dilutions protocol, 10 doses in duplicate, and added to each well with POD™ 810 Plate Assembler; the cells were incubated in a CO 2  incubator for 72 hours; and detected the expression level of the NEO gene expression with real-time qualitative PCR later; The EC 50  (half-maximal effective concentration, concentration for 50% of maximal effect) values of test compounds were analyzed by GraphPad Prism software, respectively. In this paper, experiments were repeated twice and set the holes without compounds as negative control. 
     3. Results 
     The test compounds of the present disclosure can be effective against the HCV 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a genotypes according to the experiment data, and EC 50  ranges of the test compounds against HCV 1b are 1 pM-99 nM; Table 2 shows the EC 50  values of representative compounds of the present disclosure against the HCV 1a and HCV 1b genotypes. 
     
       
         
           
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Example 
                 1a (nM) 
                 1b (nM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 0.760 
                 0.042 
               
               
                 2 
                 1.276 
                 0.087 
               
               
                 3 
                 0.537 
                 0.040 
               
               
                 4 
                 0.089 
                 0.016 
               
               
                 5 
                 0.078 
                 0.023 
               
               
                 6 
                 0.109 
                 0.077 
               
               
                 7 
                 0.210 
                 0.103 
               
               
                 8 
                 0.982 
                 0.065 
               
               
                 9 
                 0.439 
                 0.072 
               
               
                 10 
                 1.275 
                 0.438 
               
               
                 11 
                 0.068 
                 0.032 
               
               
                 12 
                 0.380 
                 0.049 
               
               
                 13 
                 2.067 
                 0.273 
               
               
                 14 
                 0.884 
                 0.013 
               
               
                 15 
                 0.206 
                 0.142 
               
               
                 16 
                 0.089 
                 0.036 
               
               
                 17 
                 0.023 
                 0.006 
               
               
                 18 
                 0.326 
                 0.065 
               
               
                 19 
                 4.769 
                 0.436 
               
               
                 20 
                 3.672 
                 0.685 
               
               
                 21 
                 0.080 
                 0.029 
               
               
                 22 
                 0.561 
                 0.072 
               
               
                 23 
                 0.310 
                 0.047 
               
               
                 24 
                 0.475 
                 0.099 
               
               
                 25 
                 0.829 
                 0.103 
               
               
                 26 
                 0.727 
                 0.216 
               
               
                 27 
                 1.529 
                 0.323 
               
               
                 28 
                 1.104 
                 0.763 
               
               
                 29 
                 0.061 
                 0.009 
               
               
                 30 
                 0.336 
                 0.052 
               
               
                 31 
                 5.873 
                 0.539 
               
               
                 32 
                 10.285 
                 0.446 
               
               
                 33 
                 0.078 
                 0.022 
               
               
                 34 
                 0.641 
                 0.055 
               
               
                 35 
                 10.552 
                 0.103 
               
               
                 36 
                 0.438 
                 0.062 
               
               
                   
               
            
           
         
       
     
     According to the experimental results of wild-type HCV 1b and resistance cells Y93H, L31F, P32L, I302V, and the simulation results of molecular modeling and docking show that compounds disclosed herein play an excellent anti-HCV role, which suggest a novel anti-HCV mechanism by interfering with HCV NS5A protein. 
     It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 
     The compounds of the present disclosure may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment the compounds of the present disclosure inhibit HCV replicon and in another embodiment the compounds of the present disclosure inhibit NS5A. The compounds of the present disclosure may inhibit multiple genotypes of HCV. 
     Reference throughout this specification to “an embodiment,” “some embodiments,” “one embodiment”, “another example,” “an example,” “a specific example,” or “some examples,” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments,” “in one embodiment”, “in an embodiment”, “in another example,” “in an example,” “in a specific example,” or “in some examples,” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. 
     Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.