BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL

COMPOSITIONS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefits of Chinese Patent Application Serial Nos. 201310061368.4, filed with the State Intellectual Property Office of P. R. China on February 27, 2013 ; and 2013 10117146.X, filed with the State Intellectual Property Office of P. R. China on April 4, 2013, the entire content of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present disclosure relates to a field of medicine, and more particularly to compounds for treating Hepatitis C virus (HCV) infection, compositions comprising such compounds, use of the compounds and the compositions thereof, and methods thereof.

BACKGROUND OF THE INVENTION

[0003] HCV is a major human pathogen, infecting an estimated 170 million persons worldwide — roughly five times the number infected by human immunodeficiency virus type 1. 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.

[0004] 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.

[0005] 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).

[0006] 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 El 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).

[0007] 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.

[0008] 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.

[0009] 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

[0010] Provided herein are novel bridged ring compounds and methods of their use to treat HCV infection. Specifically, it has been found that the fused ring compounds disclosed herein, and compositions thereof, are effective as inhibitors of HCV infection, especially the HCV NS5A protein.

[001 1] In one aspect, provided herein are compounds having Formula (I):

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

each of A and A' is independently a bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ⁸ V, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=0)-(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(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - or -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

wherein each X ¹ , X ¹ and X ² is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ; is a carbocyclylene or heterocyclylene group;

W ₂ is a fused bicyclylene or fused heterobicyclylene group;

each X, X', Y ¹ , Y ² , 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 -0-(CH ₂ ) _b -;

each a, b, n and p is independently 0, 1, 2 or 3;

each c and d is independently 1 or 2;

each r is independently 0, 1 or 2;

each of f, f and e is independently 0, 1, 2, 3 or 4;

each of Y and Y' is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent group derived from an a-amino acid or an optically isomer thereof -[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 ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² ;

each U is independently -C(=0)-, -C(=S)-, -S(=0)- or -S(=0) 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 heterocyclylene or carbocyclylene, C ₅ _i ₂ fused bicyclylene, C ₅ _i ₂ fused heterobicyclylene, C ₅ _i ₂ spiro bicyclylene or Cs_i ₂ spiro heterobicyclylene; or R ³ and R ⁴ , together with X'-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C ₅ _i ₂ fused bicyclylene, C ₅ _i ₂ fused heterobicyclylene, C ₅ _i ₂ spiro bicyclylene or C ₅ _i ₂ spiro heterobicyclylene;

each R ⁵ is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=0)-, alkyl-C(=0)-, carbamoyl, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r - or aminosulfonyl;

each R ^a and R ^a is independently H, deuterium, oxo (=0), hydroxy, amino, F, CI, Br, I, cyano, R ^lja R ^1J N_

-C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-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 ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) 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 ^a is independently H, deuterium, hydroxy, amino, F, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-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, CI, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, 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, CI, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=0)-, alkyl-C(=0)-, carbamoyl, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r - or amino sulfonyl;

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(=0)R ¹³ , -C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;

11 12

or R and R ^{^ '} are optionally joined to form a 4-7 membered ring; 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 or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group,

wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR 8 R 8a ) _n -0-(CR 8 R 8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ⁸ V, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=S)-(CR ⁸ R ^8a ) _p -, -[U-(CR ⁹ R ^9a ) _r NR ¹⁰ -(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r NR ¹¹ -(CR ⁹ R ^9a ) _r 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 -0-(CH ₂ ) _b -, R ^13a R ¹³ N-, -C(=0)R ¹³ , -C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, alkyl-OC(=0)-, alkyl-C(=0)-, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r -, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a-amino acid, C ₅ _i ₂ fused bicycle, C ₅ _i ₂ fused heterobicycle, C ₅ _i ₂ spiro bicycle, C ₅ _i ₂ 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 or aryloxy is optionally substituted with one or more substituents independently selected from deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(=0), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0) ₂ and carboxy alkoxy.

[0012] In some embodiments, is a C3_g carbocyclylene or C ₂ _io heterocyclylene group; and

W ₂ is a C ₅ _i ₂ fused bicyclylene or C ₅ _i ₂ fused heterobicyclylene group.

[0013] In some embodiments, is

wherein each X ³ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each X ⁴ and X ⁵ is independently O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each Y ¹ , Y ² , Y ¹ and Y ^2' is independently N or CR ⁷ ;

each Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CR ⁷ R ^7a );;

3 7

each Q is independently N or CR ;

each f, f , e and i independently 0, 1, 2, 3 or 4;

each R ^a and R ^a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^lja R ^1J N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, d_ ₆ alkylacyl, d_ ₆ alkylacyloxy, d_ ₆ alkoxyacyl, Ci_6 alkylsulfonyl, Ci_6 alkoxysulfonyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyloxy, Ci_6 alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, Ce-w aryl, -CF ₃ , -OCF ₃ , mercapto, nitro, Ci_6 alkylamino, C3 0 cycloalkyl or C ₆ _io aryloxy;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, Ci_ ₆ aminoalkyl, Ci_ ₆ alkoxy-Ci_ ₆ -alkyl, Ci_ ₆ alkylamino-Ci_ ₆ -alkyl, Ci_ ₆ alkylthio-Ci_ ₆ -alkyl, C ₆ _io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl, C340 cycloalkyl-Ci_6-alkyl, C6-10 aryloxy-Ci_6-alkyl, C ₂ _io heterocyclyloxy-Ci_6-alkyl, C340 cycloalkyloxy-Ci_6-alkyl, C6-10 arylamino-Ci_6-alkyl, C ₂ o heterocyclylamino-Ci_ ₆ -alkyl, C340 cycloalkylamino-Ci_ ₆ -alkyl, C ₆ 4o aryl, Ci_ ₉ heteroaryl, C2 0 heterocyclyl or C340 carbocyclyl;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, Ci_6 alkyl, C ₂ _6 heteroalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_ ₆ aminoalkyl, Ci_ ₆ alkoxy-Ci_ ₆ -alkyl, Ci_ ₆ alkylamino-Ci_ ₆ -alkyl, Ci_ ₆ alkylthio-Ci_ ₆ -alkyl, C ₆ 4o aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ 4o heterocyclyl-Ci_6-alkyl, C340 cycloalkyl-Ci_6-alkyl, C64o aryloxy-Ci_6-alkyl, C ₂ 4o heterocyclyloxy-Ci_6-alkyl, C340 cycloalkyloxy-Ci_6-alkyl, C64o arylamino-Ci_6-alkyl, C ₂ 4o heterocyclylamino-Ci_ ₆ -alkyl, C340 cycloalkylamino-Ci_ ₆ -alkyl, C ₆ 4o aryl, Ci_ ₉ heteroaryl, C ₂ 4 ₀ heterocyclyl or C340 carbocyclyl; and

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C ₂ _6 heteroalkyl, C340 cycloalkyl, C ₂ 4o heterocyclyl, C640 aryl, Ci_g heteroaryl or C640 aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group.

 wherein each Y ¹ , Y ² , Y ¹ and Y ² is independently N or CH;

each f is independently 0, 1, 2, 3 or 4;

each R ^5a and R ^5a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^13a R ¹³ N- -C(=0)NR ¹³ R , -OC(=0)NR ¹³ R , -OC(=0)OR , -N(R ¹³ )C(=0)NR ¹³ R , -N(R ¹³ )C(=0)OR , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, Ci_ ₆ alkylacyl, Ci_ ₆ alkylacyloxy, Ci_ ₆ alkoxyacyl, Ci_ ₆ alkylsulfonyl, Ci_ ₆ alkoxysulfonyl, Ci_ ₆ alkylsulfinyl, Ci_ ₆ alkylsulfonyloxy, Ci_ ₆ alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, Ce-io aryl, -CF ₃ , -OCF3, mercapto, nitro or Ci_6 alkylamino;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, d_ ₆ alkyl, C« haloalkyl, d_ ₆ hydroxyalkyl, d-6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, d-6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, Ce-io aryl-Ci_6-alkyl, d-9 heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

each R ¹³ and R ^13a is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C ₃ _i ₀ cycloalkyl, C ₂ _i ₀ heterocyclyl, Ce-io ^ar Ci_9 heteroaryl or Ce-io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group.

[0015] In some embodiments, each of A and A' is independently a bond, Ci_6 alkylene, C ₂ _6 alkenylene, C3_g cycloalkylene, C ₂ . ₁₀ heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(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(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - or -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

wherein each X ¹ , X ¹ and X ² is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

t is 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 -0-(CH ₂ ) _b -;

each a, b, n and p is independently 0, 1, 2 or 3;

each c and d is independently 1 or 2;

each r is independently 0, 1 or 2;

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ _6 heteroalkyl, _g cycloalkyl, C ₂ _io heterocyclyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkyl-OC(=0)-, Ci_ ₆ alkyl-C(=0)-, carbamoyl, Ci_6 alkyl-OS(=0) _r -, Ci_6 alkyl-S(=0) _r O-, Ci_6 alkyl-S(=0) _r - or aminosulfonyl;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, d_ ₆ alkyl, d_ ₆ haloalkyl, d_ ₆ hydroxyalkyl, Ci_6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, Ci_6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl, C3 0 cycloalkyl-Ci_6-alkyl, C6-10 aryloxy-Ci_ ₆ -alkyl, C ₂ _i ₀ heterocyclyloxy-Ci_ ₆ -alkyl, C3 0 cycloalkyloxy-Ci_ ₆ -alkyl, C ₆ _io arylamino-Ci_ ₆ -alkyl, C ₂ _io heterocyclylamino-Ci_6-alkyl, C3_io cycloalkylamino-Ci_6-alkyl, C6-10 aryl, heteroaryl, C ₂ _io heterocyclyl or C3_io carbocyclyl;

each R ^6a is independently H, deuterium, hydroxy, amino, F, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-Ci_ ₆ alkyl, R ¹³ S(=0)-Ci_ ₆ alkyl, R ¹³ R ^13a N-C(=0)-d_ ₆ alkyl, R ^13a R ¹³ N-d_ ₆ alkoxy, R ¹³ S(=0)-d_ ₆ alkoxy, R ¹³ R ^13a N-C(=0)-d_ ₆ alkoxy, Ce-io aiyl, Ci_9 heteroaryl, Ci_6 alkoxy, Ci_6 alkylamino, Ci_6 alkyl, Ci_6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-10 heterocyclyl, C3_g cycloalkyl, mercapto, nitro, Ce-io aryl-Ci_6-alkyl, Ce-io arylamino, Ci_g heteroarylamino or Ce-io aryloxy;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, Ci_6 alkyl, C2-6 heteroalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, Ci_6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, Ce-io aryl-Ci_ ₆ -alkyl, C ₂ _io heterocyclyl-Ci_ ₆ -alkyl, C ₃ _i ₀ cycloalkyl-Ci_ ₆ -alkyl, C ₆ _io aryloxy-Ci_ ₆ -alkyl, C ₂ _io heterocyclyloxy-Ci_6-alkyl, C3_io cycloalkyloxy-Ci_6-alkyl, Ce-io arylamino-Ci_6-alkyl, C2-10 heterocyclylamino-Ci_6-alkyl, C3_io cycloalkylamino-Ci_6-alkyl, Ce-io aryl, Ci_g heteroaryl, C2-10 heterocyclyl or C ₃ _8 carbocyclyl;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C2-6 heteroalkyl, C3_io cycloalkyl, C2-10 heterocyclyl, Ce-io ^ar Ci_9 heteroaryl or Ce-io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group; and

each R ⁸ and R ^8a is independently H, deuterium, hydroxy, cyano, nitro, F, CI, Br, I, Ci_ ₆ alkyl, C ₂ _6 heteroalkyl, C3 0 cycloalkyl, C2-10 heterocyclyl, Ce-io aryl, heteroaryl, Ce-io aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_ ₆ alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or amino sulfonyl.

[0016] In some embodiments, each of A and A' is independently a bond, -CH ₂ -, -(CH ₂ )2-, -CH=CH-,

-CH=CH-CH ₂ -, -N(R ⁵ )-, -C(=0)-, -C(=S)-, -C(=0)-0-, -C(=0)N(R ⁵ )-, -OC(=0)N(R ⁵ )-, -OC(=0)0-, -N(R ⁵ )C(=0)N(R ⁵ )-, -(R ⁵ )N-S(=0) ₂ -, -S(=0) ₂ -, -OS(=0) ₂ -, -(R ⁵ )N-S(=0)-, -S(=0)- or -OS(=0)-, or each of A and A' is independently selected from

wherein X ¹ is O or S;

Y ¹ is N or CH;

t is 0, 1, 2 or 3;

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ -6 heteroalkyl, C3_g cycloalkyl, C ₂ -10 heterocyclyl, C6-10 aryl, Ci_g heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_6 alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl;

each R ⁶ is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, Ci_6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, C6-10 aryl-Ci_6-alkyl, Ci_g heteroaryl, C6-10 aryl, C ₂ _io heterocyclyl or C ₃ _ ₈ carbocyclyl;

each R ^a is independently H, deuterium, hydroxy, amino, F, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, Ci_ ₆ alkoxy, Ci_6 alkylamino, Ci_6 alkyl, Ci_6 haloalkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, mercapto or nitro; and

each of R ¹³ and R ^13a is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _6 heteroalkyl, C ₃ _i ₀ cycloalkyl, C ₂ _io heterocyclyl, C6-10 ^r l, Ci_9 heteroaryl or C6-10 aryl-Ci_6-alkyl; with the proviso that where R ¹³ and R ^13a are bonded to the same nitrogen atom, R and R ^a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicycyl group or fused bicyclyl group.

[0017] In some embodiments, each of R ¹ , R ² , R ³ and R ⁴ is independently H, deuterium, Ci_g alkyl, Ci_g

1 2 heteroalkyl, Ce-io aryl-Ci_6-alkyl, C ₃ _io cycloalkyl, C ₂ -10 heterocyclyl, Ci_g heteroaryl or C6-10 aryl; or R and R , together with X-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C _{5 2} fused bicyclylene, C _{5 2} fused heterobicyclylene, C ₅ _i ₂ spiro bicyclylene or C _{5 2} spiro heterobicyclylene; or R ³ and R ⁴ , together with X'-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C _{5 2} fused bicyclylene, C ₅₄₂ fused heterobicyclylene, C ₅₄₂ spiro bicyclylene or C ₅₄₂ spiro heterobicyclylene .

[0018] 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 heterocyclylene, C ₅₄₂ fused bicyclylene, C ₅₄₂ fused heterobicyclylene, C ₅₄₂ spiro bicyclylene or C ₅₄₂ spiro heterobicyclylene.

[0019] 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(=0), F, CI, Br, I, cyano, hydroxy, Ci_ ₃ alkyl, Ci_ ₃ haloalkyl, Ci_3 alkoxy, Ci_3 alkylamino, Ci_3 alkylthio, Ce-io arylamino, Ce-io aryloxy, heteroaryl, heteroaryloxy, Ci_g heteroaryl-Ci_3-alkyl or C ₂₄₀ heterocyclyl;

each R ⁶ is independently H, deuterium, Ci_ ₃ alkyl, Ci_ ₃ haloalkyl, Ci_ ₃ hydroxyalkyl, Ci_ ₃ aminoalkyl, Ci_ ₃ alkoxy-Ci_3-alkyl, Ci_3 alkylamino-Ci_3-alkyl, Ci_3 alkylthio-Ci_3-alkyl, Ce-io aryl-Ci_3-alkyl, heteroaryl, Ce-io aryl, C ₂₄₀ heterocyclyl or C ₃ _g carbocyclyl; and

each n _! and n ₂ is independently 1, 2, 3 or 4.

[0020] In other embodiments, R ³ , R ⁴ and Y' -X'-CH together form one of the following monovalent groups:

wherein each R is independently H, deuterium, oxo(=0), F, CI, Br, I, cyano, hydroxy, Ci_3 alkyl, Ci_3 haloalkyl, Ci_3 alkoxy, Ci_3 alkylamino, Ci_3 alkylthio, Ce-io arylamino, Ce-io aryloxy, Ci_9 heteroaryl, Ci_9 heteroaryloxy, Ci_ ₉ heteroaryl-Ci_ ₃ -alkyl or C ₂ _io heterocyclyl;

each R ⁶ is independently H, deuterium, Ci_3 alkyl, Ci_3 haloalkyl, Ci_3 hydroxyalkyl, Ci_3 aminoalkyl, Ci_3 alkoxy-Ci_3-alkyl, Ci_3 alkylamino-Ci_3-alkyl, Ci_3 alkylthio-Ci_3-alkyl, Ce-io aryl-Ci_3-alkyl, Ci_9 heteroaryl, Ce-io aryl, C ₂ _io heterocyclyl or C ₃ _ ₈ carbocyclyl; and

each ni and n ₂ is independently 1, 2, 3 or 4.

[0021] In some embodiments, the compound having formula (II):

wherein is

wherein each Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ );; each Q is independently N or CH;

each X ³ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each X ¹ is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

each e, i, f and f is independently 0, 1, 2, 3 or 4; each X ⁴ and X ⁵ is independently O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each Y^ Y ² , Y ¹ and Y ² is independently N or CR ⁷ ;

each of A and A' is independently a bond, Ci_ ₆ alkylene, C ₂ _6 alkenylene, C ₃ _ ₈ cycloalkylene, C ₂ _io heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(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(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_io cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, Ci_g heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_6 alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl;

each R ^5a , R ^5a and R ^6a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, d_ ₆ alkylacyl, d_ ₆ alkylacyloxy, d_ ₆ alkoxyacyl, Ci_6 alkylsulfonyl, Ci_6 alkoxysulfonyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyloxy, Ci_6 alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, C6-10 aryl, -CF ₃ , -OCF ₃ , mercapto, nitro, Ci_6 alkylamino, C3 0 cycloalkyl or C ₆ _io aryloxy;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, Ci_ ₆ aliphatic, Ci_ ₆ alkoxy-Ci_ ₆ -aliphatic, Ci_6 alkylamino-Ci_6-aliphatic, C -w aryl-Ci_6-aliphatic, Ci_g heteroaryl-Ci_6-aliphatic, C ₂ _io heterocyclyl-Ci_6-aliphatic, C340 cycloalkyl-Ci_6-aliphatic, C6-10 aryl, heteroaryl, C ₂ _io heterocyclyl or C3_io carbocyclyl;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, C _ ₆ aliphatic, C ₂ _ ₆ heteroalkyl, C _ ₆ alkoxy-Ci_6-aliphatic, Ci_6 alkylamino-Ci_6-aliphatic, C6-10 aryl-Ci_6-aliphatic, C ₂ _io heterocyclyl-Ci_6-aliphatic, C340 cycloalkyl-Ci_6-aliphatic, C6-10 aryl, heteroaryl, C ₂ o heterocyclyl or C340 carbocyclyl;

each R ⁸ and R ^8a is independently H, deuterium, hydroxy, cyano, nitro, F, CI, Br, I, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C340 cycloalkyl, C2 0 heterocyclyl, C64o aryl, heteroaryl, C64o aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_ ₆ alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C ₂ _6 heteroalkyl, C340 cycloalkyl, C ₂ 4o heterocyclyl, C64o aryl, Ci_9 heteroaryl or C64o aryl-Ci_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, or a substituted or unsubstituted spiro bicyclic group or fused bicyclic group;

each n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2;

t is 0, 1, 2, 3 or 4; and

each of Y ₄ and Y ₄ ' is independently a bond, O, S, -(CH ₂ ) _n -, -CH=CH-, -S(=0) _r -, -CH ₂ 0-, -CH ₂ S-, -CF ₂ -, -CHR ^5a , -CR ^5a R ^6a , -CH ₂ S(=0) _r or -CH ₂ N(R ⁶ )-.

[0022] In other embodiments, the compound having formula (III): wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently NR ⁶ , O, S, C(=0) or (CR ⁷ R ^7a ) _; ; each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ; and each of i and e is independently 0, 1, 2, 3 or 4.

[0023] In other embodiments, the compound having formula (IV):

wherein each of Q ¹ , Q ² and Q ⁴ is independently O, S, C(=0), NR ⁶ or (CH ₂ )i;

X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ; and

each i and e is independently 0, 1, 2, 3 or 4.

[0024] In other embodiments, the compound having formula (V):

wherein each of Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or (CH ₂ )i;

each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ; and each of i and e is independently 0, 1, 2, 3 or 4.

[0025] In other embodiments, the compound having formula (VI):

(VI), wherein Q ⁴ is O, S, C(=0), NR ⁶ or (CH ₂ ) _; ; X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ; and

each i and e is independently 0, 1, 2, 3 or 4.

[0026] In some embodiments, each of Y and Y' is independently a monovalent group derived from an a-amino acid.

[0027] In other embodiments, the a-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, Ν,Ν-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline.

[0028] In other embodiments, the a-amino acid is in the D configuration.

[0029] In other embodiments, the a-amino acid is in the L configuration.

[0030] In some embodiments, each of Y and Y' is independently -[U-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r 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 .

[0031] In other embodiments, each of Y is independently -[U-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0032] In other embodiments, wherein each of is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _r U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _t -R ¹² .

[0033] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0034] In other embodiments, each of Y and Y' is independently

-[C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0035] 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 .

[0036] In other embodiments, each of Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0037] In other embodiments, each of Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _r C(=O)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0038] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[0039] In other embodiments, of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=0)-R ¹

[0040] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ^u )-C(=0)-R ¹³ .

[0041] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _t -C(=0)-0-R ¹³ .

[0042] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ^u )-C(=0)-0-R ¹³ .

[0043] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -R ¹² . [0044] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r R ¹² .

[0045] 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 .

[0046] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _r U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[0047] In other embodiments, each of Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _r C(=O)-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[0048] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[0049] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _t -0-(CR ⁹ R ^9a ) _t -R ¹² .

[0050] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _t -N(R ^u )-R ¹² , and wherein

11 12

R and R , together with the atom they are attached to, form a 4-7 membered ring.

[0051] In other embodiments, each R ⁹ , R ^9a , R ¹⁰ and R ¹¹ is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C3 0 cycloalkyl, C ₂ -10 heterocyclyl, Ce-io aryl, Ci_9 heteroaryl, Ce-io aryl-Ci_6-alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_g heteroaryl-Ci_6-alkyl, C ₂ -10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl;

each R ¹² is independently R ^13a R ¹³ N-, -C(=0)R ¹³ , -C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C _3- io cycloalkyl, C ₂ _io heterocyclyl, C ₆ _io ^ryl, Ci_ ₉ heteroaryl or C ₆ _io aryl-Ci_ ₆ -alkyl;

11 12

or R and R , together with the atom they are attached to, form a 4-7 membered ring;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_io cycloalkyl, C ₂ _io heterocyclyl, Ce-io ^ar yl _> Ci-9 heteroaryl or Ce-io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group;

each t is independently 0, 1, 2, 3 or 4; and

each k is independently 0, 1 or 2.

[0052] 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(=0)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;

11 12

or R and R , 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.

[0053] In other embodiments, the compound having formula (VII):

wherein each of R and R ^a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io ary Ci_g heteroaryl, C2-10 heterocyclyl, C ₃ _8 cycloalkyl, Ce-io aryl-Ci_6-alkyl, Ci_g heteroaryl-Ci_ ₆ -alkyl, C ₂ _io heterocyclyl-Ci_ ₆ -alkyl or C ₃ _ ₈ cycloalkyl-Ci_ ₆ -alkyl; and

wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io aryl, Ci_g heteroaryl, C2-10 heterocyclyl, C ₃ _g cycloalkyl, Ce-io aryl-Ci_6-alkyl, Ci_g heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl and C ₃ _8 cycloalkyl-Ci_ ₆ -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[0054] In other embodiments, the compound having formula (VIII):

wherein each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_ ₃ hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or Ci_9 heteroaryl; and

wherein each of the Ci_ ₃ hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl and Ci_g heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[0055] In some embodiments, the compound having formula (IX):

wherein each of Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ )i;

i is 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, C ₂ _6 heteroalkyl, Ce-w aryl, heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

each n ₂ is independently 1, 2, 3 or 4,

wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, C6-10 aryl, heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl and C ₃ _8 cycloalkyl-Ci_ ₆ -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[0056] In some embodim nts, the compound having formula (X):

wherein each of Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ );;

i is independently 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C ₂ _io heterocyclyl, C ₃ _ ₈ cycloalkyl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₉ heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

each ni is independently 1, 2, 3 or 4,

wherein each of the Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, C ₂ _6 heteroalkyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl and C3_8 cycloalkyl-Ci_6-alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[0057] In some embodiments, the compound having formula (XI):

(xi),

wherein each R ^5a and R ^5a is independently H, deuterium, oxo(=0), benzyl, Ci_4 alkyl, F, CI, Br or I;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_4 alkyl, Ce-io aryl, C2-10 heterocyclyl or C3_g cycloalkyl;

each of R ¹⁶ and R ^16a is independently hydroxy, Ci_4 alkoxy, Ce-io aryloxy, C2-10 heterocyclyl or C3_g cycloalkyl;

wherein each of benzyl, C _w alkyl, C ₆ _io aryl, C ₂ _io heterocyclyl, Ci_ ₄ alkoxy, C ₃ _ ₈ cycloalkyl and C ₆ _io aryloxy is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;



 -CH together form one of the following divalent groups:

[0058] In other embodiments, each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I;

each of R ¹⁴ and R ^14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl or tert-butyl; and each of R ¹⁶ and R ^16a is independently hydroxy, methoxyl, ethyoxyl, phenoxy, ^— / or tert-butoxy, wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[0059] In some embodim

wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or CH ₂ ;

each of e, f and f is independently 0, 1, 2, 3 or 4;

each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I;

each of Y 1 , Y 2 , Y 1 ' and Y 2' is independently N or CR 7 ;

each R ⁶ , R ⁷ and R ^7a 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 or tert-butyl; ί ^/ ~\

16 16a *~ ^{N 0}

each of R and R ^a is independently hydroxy, methoxyl, ethyoxyl, phenoxy, ^— ' or tert-butoxy; wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;

each of A and A' is independently

1 , R 2 and N-CH together form one of the following divalent groups:

wherein R , R and N-CH together form one of the following divalent groups:

wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or CH ₂ ;

X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each R ⁶ , R ⁷ and R ^7a is independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;

each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I;

each of Y 1 , Y 2 , Y 1 ' and Y 2' is independently N or CR 7 ;

each of i, e, f and f is independently 0, 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl or tert-butyl; each of R and R ^a is independently hydroxy, methoxyl, ethyoxyl, phenoxy, or tert-butoxy; wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;

each of A and A' is independently

1 , R 2 and N-CH together form one of the following divalent groups:

-CH together form one of the following divalent groups:

[0061] In another aspect, the present disclosure provides a pharmaceutical composition comprising any one of the above compounds. [0062] In some embodiments, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0063] In certain embodiments, the pharmaceutical composition disclosed herein further comprises an anti-HCV agent.

[0064] 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, ribavirin, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, ABT-450, danoprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA-975, ABT-267, EDP-239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032), sovaprevir (ACH- 1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX- 136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PSI-7977), INX-189, IDX- 184, IDX- 102, R-1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof.

[0065] In other embodiments, the interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, interferon γ or a combination thereof.

[0066] In other embodiments, the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor.

[0067] In some embodiments, the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function.

[0068] In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.

[0069] In some embodiments, the HCV viral protein is or comprises a metalloproteinase, non- structural protein 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,

[0070] 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.

[0071] In some embodiments, the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.

[0072] In some embodiments, the HCV viral protein is or comprises a metalloproteinase, non- structural protein 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,

[0073] 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.

[0074] 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 or comprises a metalloproteinase, non- structural protein 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.

[0075] 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.

[0076] 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 or comprises a metalloproteinase, non- structural protein 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.

[0077] 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.

[0078] 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), (XII) or (ΧΙΓ).

[0079] 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

[0080] Reference will now be maded 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. [0081] 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, 75 ^th 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's Advanced Organic Chemistry", John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference in their entireties.

[0082] 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, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=0), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxyalkoxy, etc.

[0083] 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, the aliphatic group contains 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, etc.

[0084] The term "haloaliphatic" refers to an aliphatic group substituted with one or more of the same or different halogen atoms (i.e., F, CI, 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, etc.

[0085] 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, etc.

[0086] 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, etc. [0087] 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 below. The examples of the alkyl group include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), «-propyl (w-Pr, -CH ₂ CH ₂ CH ₃ ), /-propyl (z ^' -Pr, -CH(CH ₃ ) ₂ ), «-butyl («-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), /-butyl (/-Bu, -CH ₂ CH(CH ₃ ) ₂ ), s-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), /-butyl (/-Bu, -C(CH ₃ ) ₃ ), «-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-l-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), «-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 , «-heptyl, «-octyl, etc. 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, ethylene, isopropylene, etc.

[0088] 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 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 ), etc.

[0089] 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 alkynyl group include ethynyl (-C≡CH), propynyl (propargyl, -CH ₂ C≡CH), etc.

[0090] 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, hydroxy ethyl, 1,2-dihydroxy ethyl, etc.

[0091] The term "haloalkyl" refers to an alkyl group substituted with one or more of the same or different halogen atoms, wherein the alkyl group is as defined herein. Some non-limiting examples of the haloalkyl group include trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl, etc.

[0092] 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, hydro xymethyl, etc.

[0093] 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, etc.

[0094] 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 -), ethylene (-CH ₂ -CH ₂ -), isopropylidene (-CH ₂ -CH(CH ₃ )-), ethylidene, 2-methoxy-l,l-propylidene, 2-hydroxy-l,l-propylidene, 2 -methyl -2 -hydroxy- 1 , 1 -propylidene, etc.

[0095] The term "alkenylene" refers to an unsaturated divalent hydrocarbon group derived from a straight or branched- chain unsaturated hydrocarbon 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-l,l-propenylidene, 2-methyl-l,l-butenylidene, etc.

[0096] 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 cycloalkylene group include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, 1-cyclopent-l-enylene, l-cyclopent-2-enylene, etc.

[0097] The term "heterocyclylene" refers to a non-aromatic 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 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-l,4-ylene, piperazin-l,4-ylene, tetrahydrofuran-2,4-ylene, tetrahydrofuran-3,4-ylene, azetidin-l,3-ylene, pyrrolidin-l,3-ylene, etc.

[0098] 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 mo holin-4-methylmethylene, piperidin-N-methylmethylene, piperazin-4-ethyl-l-yl, piperidin-4-ethyl-l-yl, pyrrolidon-2-methyl-l-yl, etc.

[0099] The term "haloalkylene" refers to haloalkyl system having two points connected to the rest of the molecule, wherein the haloalkyl group is as defined herein. Some non-limiting examples of the haloalkylene group include difluoromethylene (-CF ₂ -), etc.

[00100] 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, 7-fluorophenylene, etc.

[00101] 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, etc.

[00102] 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, etc.

[00103] 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 pyridine-2-ethylene, thiazole-2-methylene, imidazole-2-ethylene, pyrimidine-2 -methylene, etc.

[00104] The term "fused bicyclyl ene" 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.

[00105] 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.

[00106] 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.

[00107] 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.

[00108] The term "spiro bicyclylene" refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein the fused 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, etc.

[00109] The term "spiro heterobicyclylene" refers to spiro heterobicyclyl system having two connection points connected to the rest of the molecule, wherein the fused 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, etc.

[001 10] The term "spiro bicyclylalkylene" refers to spiro bicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused spiro bicyclylalkyl group is as defined herein.

[001 1 1] The term "spiro heterobicyclylalkylene" refers to spiro heterobicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused spiro heterobicyclylalkyl group is as defined herein.

[001 12] The term "heteroalkyl" refers to hydrocarbon chain inserted with one or more heteroatoms. Unless otherwise specified, heteroalkyl groups contain 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 heteroalkyl 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 -, etc.

[001 13] 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-l-enyl, l-cyclopentyl-2-enyl, l-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-l-enyl, l-cyclohexyl-2-enyl, l-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The term "cycloaliphatic", "carbocycle", "carbocyclyl", or "cycloalkyl" may be substituted or unsubstituted, wherein the substitutent may be, but is not limited to, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

[001 14] 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, etc.

[001 15] The term "cycloalkylamino" refers to an amino group substituted with one or two 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, etc.

[001 16] 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, cyclopropyloxy ethoxy, cyclopentyloxy ethoxy, cyclohexyloxyethoxy, cyclohexenyl-3-oxyethoxy, etc.

[001 17] The term "cycloalkyloxyaliphatic" refers to an aliphatic group substituted with one or more 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, etc.

[001 18] The term "cycloalkylaminoaliphatic" refers to an aliphatic group substituted with one or more 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, etc.

[00119] 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, etc.

[00120] The term "cycloalkylalkoxy" or "carbocyclylalkoxy" refers to an alkoxy group substituted with one or more cycloalkyl groups or carbocyclyl groups, wherein the carbocyclyl group, cycloalkyl group and alkoxy group are as defined herein. Some non-limiting examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, etc.

[00121] 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 S0 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 S0 ₂ , PO or P0 ₂ ).

[00122] 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- l-yl, 1,2,3,6-tetrahydropyridine- l-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolidin- l-yl, 2-pyrrolinyl, 3-pyrrolinyl, 2 /-indolinyl, 2 /-pyranyl, 4 /-pyranyl, dioxolan-2-yl, 1 ,3-dioxopenyl, pyrazolinyl, dithianyl, ditholanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-dithiazinyl, l,l-dioxo-2-yl, 4-hydroxy-l ,4-azaphosphine-4-oxide- l-yl,

2-hydroxy- 1 -(piperazin- 1 -yl)ethanone-4-yl, 2-hydroxy- 1 -(5 ,6-dihydro- 1 ,2,4- triazin- 1 (4 /)-yl)ethanone-4-yl, 5,6-dihydro-4 /- 1 ,2,4-oxadiazine-4-yl, 2-hydroxy- l -(5,6-diludine- l (2//)-yl)ethanone-4-yl, 3-azabicyclo[3, l ,0]hexyl, 3-azabicyclo[4, l ,0]heptyl, azabicyclo [2,2,2]hexyl, 2-methyl-5,6,7,8-tetrahydro- [ l ,2,4]triazole[ l ,5-c] pyrimidine-6-yl, 4,5,6,7-teterhydro-isoxazolo[4,3-c] pyrimidine-5-yl, 3//-indoxyl-2-oxo-5-azabicyclo[2,2, l ]heptane-5-yl, 2-oxo-5-azabicyclo[2,2,2]octane-5-yl, quinolizinyl and N-pyridyl urea. Some non-limiting examples of the heterocyclic ring include 1, 1-dioxo-thiomorpholinyl and heterocyclic group wherein 2 carbon atoms on the ring are substituted with oxo (=0) moieties are pyrimidindionyl. The heterocyclic groups herein may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=0), hydroxy, amino, halo, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0)2-, carboxy alkoxy, etc.

[00123] 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, etc.

[00124] The term "heterocyclylaliphatic" refers to heterocyclic-substituted aliphatic group, wherein the heterocyclic radical 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, etc.

[00125] 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, etc.

[00126] The term "heterocyclylamino" refers to an amino group substituted with one or two heterocyclyl groups, wherein 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, etc.

[00127] The term "heterocyclyloxyalkoxy" refers to an alkoxy radical substituted with one or more heterocyclyloxy groups, wherein the alkoxy radical 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, etc.

[00128] 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-yloxy ethyl, piperazin-2-yloxyethyl, morpholin-2-yloxymethyl, piperidin-2-yloxyethyl, etc.

[00129] 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, mo holin-2-lyaminomethyl, etc.

[00130] 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-2 /-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[00131] The term "halogen" refers to F, CI, Br or I.

[00132] The term "unsaturated" as used herein, refers to a moiety having one or more units of unsaturation.

[00133] The term "alkoxy" refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") atom. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy defined above may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxy, amino, halo, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[00134] 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, etc.

[00135] 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, etc.

[00136] 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, etc.

[00137] 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, etc.

[00138] 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, etc.

[00139] 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, etc.

[00140] 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, etc.

[00141] 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, etc.

[00142] 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, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy- substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0)2-, carboxy alkoxy, etc.

[00143] The term "arylaliphatic" refers to an aliphatic group substituted with one or more 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, etc.

[00144] 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, etc.

[00145] The term "arylamino" refers to an amino group substituted with one or two 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-/?-tolyl)amino, etc.

[00146] The term "aryloxyalkoxy" refers to an alkoxy group substituted with one or more 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, etc.

[00147] The term "aryloxyaliphatic" refers to an aliphatic group substituted with one or more 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, etc.

[00148] The term "arylaminoaliphatic" refers to an aliphatic group substituted with one or more 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, etc.

[00149] The term "arylalkoxy" refers to an alkoxy group substituted with one or more 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, etc.

[00150] The term "arylalkylamino" refers to an alkylamino group substituted with one or more aryl groups, wherein the aryl group and the alkylamino group are as defined herein. Some non-limiting examples of the arylalkylamino group include phenylmethylamino, phenylethylamino, phenylpropylamino, (p-tolyl)methylamino, etc.

[00151] 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, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

[00152] Some non-limiting examples of the suitable heteroaryl ring include the following monocyclic groups: 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, pyrimidine-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, l,3,4-thiadiazol-2-yl, pyrazinyl, pyrazine-2-yl, and 1,3,5-triazinyl; and the following bicyclic groups: benzimidazolyl, benzofuryl, benzothiophenyl, benzo[c?]thiazol-2-yl, imidazo[ l ,5-a]pyridin-6-yl, indolyl {e.g. , 2-indolyl), purinyl, quinolinyl {e.g., 2-quinolinyl, 3-quinolinyl, and 4-quinolinyl), and isoquinolinyl {e.g., 1-isoquinolinyl, 3-isoquinolinyl, and 4-isoquinolinyl).

[00153] 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, etc.

[00154] The term "heteroaryloxyaliphatic" refers to an aliphatic group substituted with one or more heteroaryloxy groups, wherein the aliphatic group and the heteroaryloxy group are as defined herein. Some non-limiting examples of the heteroaryloxy group include pyrid-2-yloxyethyl, thiazol-2-yloxymethyl, imidazol-2-yloxyethyl, pyrimidin-2-yloxypropyl, etc.

[00155] The term "sulfonyl", whether used alone or linked to other terms such as "alkylsulfonyl", refers to respectively divalent radicals -SO ₂ -.

[00156] The term "alkylsulfonyl" refers to a sulfonyl radical substituted with an alkyl radical forming an alkylsulfonyl (-S0 ₂ CH ₃ ).

[00157] The term "sulfamyl", "aminosulfonyl" or "sulfonamidyl" refers to a sulfonyl radical substituted with an amine radical forming a sulfonamide (-SO ₂ NH ₂ ).

[00158] The term "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", refers to -CO ₂ H.

[00159] The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl" or "carbonyloxy", refers to -(C=0)-.

[00160] 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 of the carboxyalkoxy group include carboxymethoxy, carboxyethoxy, etc.

[00161] 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 is "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.

[00162] 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 other embodiments, the alkylthio radical includes lower alkylthio radicals having one to three carbon atoms. Some non-limiting examples of the "alkylthio" include methylthio (CH ₃ S-).

[00163] The term "haloalkylthio" refers to radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. In other embodiments, the haloalkylthio radical includes lower haloalkylthio radicals having one to three carbon atoms. Some non-limiting examples of the "haloalkylthio" include trifluoromethylthio .

[00164] 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 other 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 still 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, NN-diethylamino, etc. [00165] 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, etc.

[00166] 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 group include N-thienylamino. In other embodiments, the "heteroarylamino" radical include substituted on the heteroaryl ring portion of the radical.

[00167] The term "heteroarylaliphatic" refers to aliphatic groups substituted with one or more heteroaryl radicals, wherein the heteroaryl radical 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-methyl, furan-2-ethyl, indole-3 -methyl, etc.

[00168] The term "heteroarylalkyl" refers to alkyl groups substituted with one or more heteroaryl radicals, wherein the heteroaryl radical and the alkyl group are as defined herein. Some non-limiting examples of the heteroarylalkyl group include imidazol-2 -methyl, furan-2-ethyl, indol-3 -methyl, etc.

[00169] The term "heteroarylalkylamino" refers to nitrogen-containing heteroarylalkyl radicals attached through a nitrogen atom to other radicals, wherein the heteroarylalkyl radicals is as defined herein. Some non-limiting examples of the heteroarylalkylamino radical include pyridin-2-methylamino, thiazol-2-ethylamino, imidazol-2-ethylamino, pyrimidin-2-propylamino, pyrimidin-2-methylamino, etc.

[00170] 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.

[00171] 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 include mono and dialkyl substituted, such as N-methylaminomethyl, NN-dimethyl-aminoethyl, NN-diethylaminomethyl, etc.

[00172] 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, etc.

[00173] 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.

[00174] 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, etc.

[00175] 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 halo, alkyl, alkoxy or hydroxy.

[00176] The term "fused bicyclic", "fused cyclic", "fused bicyclyl" or "fused cyclyl" refer to unsaturated or saturated fused cyclic system and bridged ring system that is not aromatic. For example, as depicted below (Formula (al)), ring Al 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-Z>]furan, 2,3,3a,4,7,7a-hexahydro- l /-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 l,2,3,4,4a,5,8,8iz-octahydro- naphthalene. The fused bicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (=0), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substitut alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

(al)

[00177] 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 fused heterobicyclic ring system include hexahydro-furo[3,2-Z>]furan, 6-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.1.0]heptane, 3-azabicyclo[3.1.0]heptane, 2-azabicyclo[2.2.1]heptane, etc. The fused heterobicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, deuterium, oxo (=0), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

[00178] 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 (Formula (a2)), 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-diaza-spiro[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, etc. The spirocyclyl or spiro bicyclyl may be substituted or unsubstituted, wherein the substituents include, but are not limited to, oxo (=0), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

(a2)

[00179] The term "spiro bicyclylene" refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein spiro bicyclyl radical is as defined herein.

[00180] 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 S0 ₂ , PO or P0 ₂ . Some non-limiting examples of the spiro heterobicyclyl group 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, l,4-dioxo-7-azaspiro [4,4]non-8-yl, etc. The spiro heterobicyclyl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, oxo (=0), hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0) ₂ -, carboxy alkoxy, etc.

[00181] As described herein, the group derived from an a-amino acid refers to an a-amino acid radical derived from an a-amino acid by the removal of one hydroxy in carboxy, which attached to X or X', and the group derived from a-amino acid is optionally substituted with one or more substituents. In some embodiments, the substituent is deuterium, F, CI, Br, I, hydroxy, cyano alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or heterocycylcarbonyl. For example:

[00182] As described herein, a bond drawn from a substituent to the center of one ring within a ring system (as shown below (a)) represents substitution of the substituent (R ^5a ) _f at any substitutable position on the rings (W, Wi and W ₂ ) to which it is attached. For example, Formula (a) represents possible substitution in any of the positions on the Wi, W ₂ , and W ring.

(a)

[00183] 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.

(b)

[00184] As described herein, a dotted 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 in Formula (c) represents any structures selected from Formula (d).

v ₅ ^

I! I

^V 3

(c)

(d)

[00185] 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.

[00186] 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 (C1-C24) 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 T. 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.

[00187] 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.

[00188] A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. The metabolites 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, etc, 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.

[00189] 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 Eli el et al., "Stereochemistry of Organic Compounds", John Wiley & 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, diaster eomers, 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 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 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.

[00190] 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.

[00191] A "pharmaceutically acceptable salt" refers to organic or inorganic salts of a compound disclosed herein. The pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts 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, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, sodium malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (Ci_4 alkyl) ₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. 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, Ci_g sulfonate or aryl sulfonate.

[00192] 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 solvent that form the solvate 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.

[00193] 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 suitable amino-protecting groups 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 suitable hydroxy-protecting groups 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 common carboxy-protecting group include -CH ₂ CH ₂ S0 ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxymethyl, 2-(/?-toluenesulfonyl)ethyl, 2-(/7-nitrophenylsulfonyl)ethyl, 2-(diphenyl phosphino)-ethyl, nitroethyl, etc. For a general description of protecting groups and their use, see Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al, Protecting Groups, Thieme, Stuttgart, 2005.

[00194] 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

[00195] Provided herein are bridged ring compounds, and pharmaceutical formulations thereof, that are useful in inhibiting HCV infection, especially inhibiting the activity of the non-structural 5A ("NS5A") protein [00196] In one aspect, provided herein are compounds having Formula (I):

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

each of A and A' is independently a bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ⁸ V, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -C(=0)-(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(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - or -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

wherein each X ¹ , X ¹ and X ² is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ; is a carbocyclylene or heterocyclylene group;

W ₂ is a fused bicyclylene or fused heterobicyclylene group;

each X, X', Y ¹ , Y ² , 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 -0-(CH ₂ ) _b -;

each a, b, n and p is independently 0, 1, 2 or 3;

each c and d is independently 1 or 2;

each r is independently 0, 1 or 2;

each of f, f and e is independently 0, 1, 2, 3 or 4;

each of Y and Y' is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent group derived from an a-amino acid or an optically isomer thereof -[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 ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² ;

each U is independently -C(=0)-, -C(=S)-, -S(=0)- or -S(=0) 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 heterocyclylene or carbocyclylene, C ₅ _i ₂ fused bicyclylene, C ₅ _i ₂ fused heterobicyclylene, C ₅ _i ₂ spiro bicyclylene or Cs_i ₂ spiro heterobicyclylene; or R ³ and R ⁴ , together with X'-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C ₅ _i ₂ fused bicyclylene, C ₅ _i ₂ fused heterobicyclylene, C ₅ _i ₂ spiro bicyclylene or C ₅ _i ₂ spiro heterobicyclylene;

each R ⁵ is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=0)-, alkyl-C(=0)-, carbamoyl, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r - or aminosulfonyl;

each R ^a and R ^a is independently H, deuterium, oxo (=0), hydroxy, amino, F, CI, Br, I, cyano, R ^lja R ^1J N_ -C(=0)NR ¹³ R , -OC(=0)NR ¹³ R , -OC(=0)OR , -N(R ¹³ )C(=0)NR ¹³ R , -N(R ¹³ )C(=0)OR , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-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, alkylsulflnyloxy, heterocyclylalkylamino or aryloxy;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) 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, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-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, alkylsulflnyloxy, heterocyclylalkylamino or aryloxy;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, 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, CI, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(=0)-, alkyl-C(=0)-, carbamoyl, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r - or amino sulfonyl;

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(=0)R ¹³ , -C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;

11 12

or R and R" ^' are optionally joined to form a 4-7 membered ring; 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 or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group,

wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(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 R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r 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 -0-(CH ₂ ) _b -, R ^13a R ¹³ N-, -C(=0)R ¹³ ,-C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, alkyl-OC(=0)-, alkyl-C(=0)-, alkyl-OS(=0) _r -, alkyl-S(=0) _r O-, alkyl-S(=0) _r -, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ^13a R ¹³ N-alkyl, R ¹³ S(=0)-alkyl, R ¹³ R ^13a N-C(=0)-alkyl, R ^13a R ¹³ N-alkoxy, R ¹³ S(=0)-alkoxy, R ¹³ R ^13a N-C(=0)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a-amino acid, C ₅ _i ₂ fused bicycle, C ₅ _i ₂ fused heterobicycle, C ₅ _i ₂ spiro bicycle, C ₅ _i ₂ 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 deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(=0), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0) ₂ -, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0) ₂ and carboxy alkoxy.

[00197] In some embodiments, is a C ₃ _ ₈ carbocyclylene or C ₂ _i ₀ heterocyclylene group; and

W ₂ is a C ₅ _i ₂ fused bicyclylene or C ₅ _i ₂ fused heterobicyclylene group.

56

wherein each X ³ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each X ⁴ and X ⁵ is independently O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each Y ¹ , Y ² , Y ¹ and Y ^2' is independently N or CR ⁷ ;

each Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CR ⁷ R ^7a );;

3 7

each Q is independently N or CR ;

each f, f , e and i independently 0, 1, 2, 3 or 4;

each R ^a and R ^a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^lja R ^1J N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, d_ ₆ alkylacyl, d_ ₆ alkylacyloxy, d_ ₆ alkoxyacyl, Ci_6 alkylsulfonyl, Ci_6 alkoxysulfonyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyloxy, Ci_6 alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, Ce-w aryl, -CF ₃ , -OCF ₃ , mercapto, nitro, Ci_6 alkylamino, C3 0 cycloalkyl or C ₆ _io aryloxy;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, Ci_ ₆ aminoalkyl, Ci_ ₆ alkoxy-Ci_ ₆ -alkyl, Ci_ ₆ alkylamino-Ci_ ₆ -alkyl, Ci_ ₆ alkylthio-Ci_ ₆ -alkyl, C ₆ _io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl, C340 cycloalkyl-Ci_6-alkyl, C6-10 aryloxy-Ci_6-alkyl, C ₂ _io heterocyclyloxy-Ci_6-alkyl, C340 cycloalkyloxy-Ci_6-alkyl, C6-10 arylamino-Ci_6-alkyl, C ₂ o heterocyclylamino-Ci_ ₆ -alkyl, C340 cycloalkylamino-Ci_ ₆ -alkyl, C ₆ 4o aryl, Ci_ ₉ heteroaryl, C2 0 heterocyclyl or C340 carbocyclyl;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, Ci_6 alkyl, C ₂ _6 heteroalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_ ₆ aminoalkyl, Ci_ ₆ alkoxy-Ci_ ₆ -alkyl, Ci_ ₆ alkylamino-Ci_ ₆ -alkyl, Ci_ ₆ alkylthio-Ci_ ₆ -alkyl, C ₆ 4o aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ 4o heterocyclyl-Ci_6-alkyl, C340 cycloalkyl-Ci_6-alkyl, C64o aryloxy-Ci_6-alkyl, C ₂ 4o heterocyclyloxy-Ci_6-alkyl, C340 cycloalkyloxy-Ci_6-alkyl, C64o arylamino-Ci_6-alkyl, C ₂ 4o heterocyclylamino-Ci_ ₆ -alkyl, C340 cycloalkylamino-Ci_ ₆ -alkyl, C ₆ 4o aryl, Ci_ ₉ heteroaryl, C ₂ 4 ₀ heterocyclyl or C340 carbocyclyl; and each R and R ^a is independently H, deuterium, Ci_6 alkyl, C ₂ -6 heteroalkyl, C3_io cycloalkyl, C ₂ -10 heterocyclyl, C6-10 ^r l, Ci_9 heteroaryl or C6-10 aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group.

[00199] In some embodiments, is



1 2 1 ' 2'

wherein each Y , Y , Y and Y is independently N or CH;

each f is independently 0, 1, 2, 3 or 4;

each R ^5a and R ^5a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, Ci_ ₆ alkylacyl, Ci_ ₆ alkylacyloxy, Ci_ ₆ alkoxyacyl, Ci_ ₆ alkylsulfonyl, Ci_ ₆ alkoxysulfonyl, Ci_ ₆ alkylsulfinyl, Ci_ ₆ alkylsulfonyloxy, Ci_ ₆ alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, Ce-w aryl, -CF ₃ , -OCF ₃ , mercapto, nitro or Ci_6 alkylamino;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, d_ ₆ alkyl, C« haloalkyl, d_ ₆ hydroxyalkyl, Ci_6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, Ci_6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl or _g cycloalkyl-Ci_6-alkyl; and

each R ¹³ and R ^13a is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C ₃ _i ₀ cycloalkyl, C ₂ _i ₀ heterocyclyl, C -io ^r l, Ci_9 heteroaryl or C -io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group.

[00200] In some embodiments, each of A and A' is independently a bond, Ci_6 alkylene, C ₂ _6 alkenylene, _g cycloalkylene, C ₂ . ₁₀ heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(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(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p - or -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

,

wherein each X ¹ , X ¹ and X ² is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

t is 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 -0-(CH ₂ ) _b -;

each a, b, n and p is independently 0, 1, 2 or 3;

each c and d is independently 1 or 2;

each r is independently 0, 1 or 2;

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_g cycloalkyl, C ₂ _io heterocyclyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkyl-OC(=0)-, Ci_ ₆ alkyl-C(=0)-, carbamoyl, Ci_6 alkyl-OS(=0) _r -, Ci_6 alkyl-S(=0) _r O-, Ci_6 alkyl-S(=0) _r - or aminosulfonyl;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, d_ ₆ alkyl, C« haloalkyl, d_ ₆ hydroxyalkyl, d-6 aminoalkyl, d-6 alkoxy-Ci_6-alkyl, d-6 alkylamino-Ci_6-alkyl, d-6 alkylthio-Ci_6-alkyl, Ce-w aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C ₂ _io heterocyclyl-Ci_6-alkyl, C3 0 cycloalkyl-Ci_6-alkyl, C6-10 aryloxy-Ci_6-alkyl, C2-10 heterocyclyloxy-Ci_6-alkyl, C3 0 cycloalkyloxy-Ci_6-alkyl, C6-10 arylamino-Ci_6-alkyl, C2-10 heterocyclylamino-Ci_6-alkyl, C3_io cycloalkylamino-Ci_6-alkyl, C6-10 aryl, Ci_g heteroaryl, C2-10 heterocyclyl or C ₃ _i ₀ carbocyclyl;

each R ^a is independently H, deuterium, hydroxy, amino, F, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ^13a R ¹³ N-d_ ₆ alkyl, R ¹³ S(=0)-d_ ₆ alkyl, R ¹³ R ^13a N-C(=0)-Ci_ ₆ alkyl, R ^13a R ¹³ N-Ci_ ₆ alkoxy, R ¹³ S(=0)-Ci_ ₆ alkoxy, R ¹³ R ^13a N-C(=0)-Ci_ ₆ alkoxy, C ₆ _i ₀ aryl, Ci_9 heteroaryl, Ci_6 alkoxy, Ci_6 alkylamino, Ci_6 alkyl, Ci_6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-10 heterocyclyl, C ₃ _ ₈ cycloalkyl, mercapto, nitro, C ₆ _io aryl-Ci_ ₆ -alkyl, C ₆ _io arylamino, Ci_ ₉ heteroarylamino or C ₆ _io aryloxy;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, Ci_6 alkyl, C2-6 heteroalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_ ₆ aminoalkyl, Ci_ ₆ alkoxy-Ci_ ₆ -alkyl, Ci_ ₆ alkylamino-Ci_ ₆ -alkyl, Ci_ ₆ alkylthio-Ci_ ₆ -alkyl, C ₆ _io aryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl, C3_io cycloalkyl-Ci_6-alkyl, C6-10 aryloxy-Ci_6.alkyl, C2-10 heterocyclyloxy-Ci_6-alkyl, C3_io cycloalkyloxy-Ci_6-alkyl, C6-10 arylamino-Ci_6-alkyl, C2-10 heterocyclylamino-Ci_ ₆ -alkyl, C ₃ _i ₀ cycloalkylamino-Ci_ ₆ -alkyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C ₂ _io heterocyclyl or C3_8 carbocyclyl;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C2-6 heteroalkyl, C3_io cycloalkyl, C2-10 heterocyclyl, d-io aryl, Ci_g heteroaryl or d-io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group; and

8 8a

each R and R is independently H, deuterium, h droxy, cyano, nitro, F, CI, Br, I, Ci_6 alkyl, C2-6 heteroalkyl, C340 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, d_ ₆ alkyl-C(=0)-, carbamoyl, d_ ₆ alkyl-OS(=0) _r -, d_ ₆ alkyl-S(=0) _r O-, d_ ₆ alkyl-S(=0) _r - or amino sulfonyl.

[00201] In some embodiments, each of A and A' is independently a bond, -CH ₂ -, -(CH ₂ )2-, -CH=CH-, -CH=CH-CH ₂ -, -N(R ⁵ )-, -C(=0)-, -C(=S)-, -C(=0)-0-, -C(=0)N(R ⁵ )-, -OC(=0)N(R ⁵ )-, -OC(=0)0-, -N(R ⁵ )C(=0)N(R ⁵ )-, -(R ⁵ )N-S(=0) ₂ -, -S(=0) ₂ -, -OS(=0) ₂ -, -(R ⁵ )N-S(=0)-, -S(=0)- or -OS(=0)-, or each of A and A' is independently selected from

,

wherein X ¹ is O or S;

Y ¹ is N or CH;

t is 0, 1, 2 or 3;

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ -6 heteroalkyl, C3_g cycloalkyl, C ₂ -10 heterocyclyl, C6-10 aryl, Ci_g heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_6 alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl; each R ⁶ is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 aminoalkyl, Ci_6 alkoxy-Ci_6-alkyl, Ci_6 alkylamino-Ci_6-alkyl, Ci_6 alkylthio-Ci_6-alkyl, Ce-io aryl-Ci_6-alkyl, Ci_g heteroaryl, Ce-io aryl, C ₂ _io heterocyclyl or C ₃ _ ₈ carbocyclyl;

each R ^a is independently H, deuterium, hydroxy, amino, F, CI, Br, I, cyano, oxo(=0), R ^13a R ¹³ N-, Ci_ ₆ alkoxy, Ci_6 alkylamino, Ci_6 alkyl, Ci_6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, mercapto or nitro; and

each of R ¹³ and R ^13a is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _6 heteroalkyl, C ₃ _i ₀ cycloalkyl, C ₂ _io heterocyclyl, C6-10 ^r l, Ci_9 heteroaryl or C6-10 aryl-Ci_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, or a substituted or unsubstituted spiro bicycyl group or fused bicyclyl group.

[00202] In some embodiments, each of R ¹ , R ² , R ³ and R ⁴ is independently H, deuterium, Ci_g alkyl, Ci_g heteroalkyl, C ₆ _io aryl-Ci_ ₆ -alkyl, C ₃ _i ₀ cycloalkyl, C ₂ _io heterocyclyl, Ci_ ₉ heteroaryl or C ₆ _io aryl; or R ¹ and R ² , together with X-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C5 2 fused bicyclylene, C5 2 fused heterobicyclylene, C ₅ _i2 spiro bicyclylene or C5 2 spiro heterobicyclylene; or R ³ and R ⁴ , together with X'-CH they are attached to, optionally form a 3-8 membered heterocyclylene or carbocyclylene, C542 fused bicyclylene, C542 fused heterobicyclylene, C542 spiro bicyclylene or C542 spiro heterobicyclylene .

[00203] 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 heterocyclylene, C542 fused bicyclylene, C542 fused heterobicyclylene, C542 spiro bicyclylene or C542 spiro heterobicyclylene.

wherein each R ¹⁵ is independently H, deuterium, oxo(=0), F, CI, Br, I, cyano, hydroxy, Ci_ ₃ alkyl, Ci_ ₃ haloalkyl, Ci_ ₃ alkoxy, Ci_ ₃ alkylamino, Ci_ ₃ alkylthio, C6 o arylamino, C64o aryloxy, Ci_9 heteroaryl, Ci_9 heteroaryloxy, Ci_ ₉ heteroaryl-Ci_ ₃ -alkyl or C240 heterocyclyl;

each R ⁶ is independently H, deuterium, Ci_ ₃ alkyl, Ci_ ₃ haloalkyl, Ci_ ₃ hydroxyalkyl, Ci_ ₃ aminoalkyl, Ci_ ₃ alkoxy-Ci_ ₃ -alkyl, Ci_ ₃ alkylamino-Ci_ ₃ -alkyl, Ci_ ₃ alkylthio-Ci_ ₃ -alkyl, C64o aryl-Ci_ ₃ -alkyl, Ci_9 heteroaryl, C64o aryl, C2-10 heterocyclyl or C3_g carbocyclyl; and

each ni and n ₂ is independently 1, 2, 3 or 4.

[00205] In other embodiments, R ³ , R ⁴ and Y'-X'-CH together form one of the following monovalent groups

wherein each R is independently H, deuterium, oxo(=0), F, CI, Br, I, cyano, hydroxy, Ci_3 alkyl, Ci_3 haloalkyl, Ci_3 alkoxy, Ci_3 alkylamino, Ci_3 alkylthio, Ce-io arylamino, Ce-io aryloxy, heteroaryl, heteroaryloxy, heteroaryl-Ci_ ₃ -alkyl or C ₂ _io heterocyclyl;

each R ⁶ is independently H, deuterium, Ci_3 alkyl, Ci_3 haloalkyl, Ci_3 hydroxyalkyl, Ci_3 aminoalkyl, Ci_3 alkoxy-Ci_3-alkyl, Ci_3 alkylamino-Ci_3-alkyl, Ci_3 alkylthio-Ci_3-alkyl, Ce-io aryl-Ci_3-alkyl, heteroaryl, Ce-io aryl, C ₂ _io heterocyclyl or C ₃ _ ₈ carbocyclyl; and

each ni and n ₂ is independently 1, 2, 3 or 4.

[00206] In some embodiments, the compound having formula (II):

wherein

66

wherein each Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ )i;

each Q is independently N or CH;

each X ³ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each X ¹ is independently O, S, NR ⁶ or CR ⁷ R ^7a ;

each e, i, f and f is independently 0, 1, 2, 3 or 4;

each X ⁴ and X ⁵ is independently O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each Y^ Y ² , Y ¹ and Y ² is independently N or CR ⁷ ;

each of A and A' is independently a bond, Ci_6 alkylene, C ₂ -6 alkenylene, C3_g cycloalkylene, C ₂ -10 heterocycloalkylene, -(CR ⁸ R ^8a ) _n -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-(CR ⁸ R ^8a ) _p -,

-(CR ⁸ R ^8a ) _n -S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-C(=0)-N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -N(R ⁵ )-S(=0) _r -N(R ⁵ )-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -S(=0) _r -0-(CR ⁸ R ^8a ) _p -, -(CR ⁸ R ^8a ) _n -C(=0)-(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(=0)-0-(CR ⁸ R ^8a ) _p -, or each of A and A' is independently

each R ⁵ is independently H, deuterium, hydroxy, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_io cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, Ci_g heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_6 alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl;

each R ^5a , R ^5a and R ^6a is independently H, deuterium, oxo(=0), hydroxy, amino, F, CI, Br, I, cyano, R ^13a R ¹³ N-, -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, d_ ₆ alkylacyl, d_ ₆ alkylacyloxy, d_ ₆ alkoxyacyl, Ci_6 alkylsulfonyl, Ci_6 alkoxysulfonyl, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyloxy, Ci_6 alkylsulfinyloxy, Ci_6 alkoxy, Ci_6 alkyl, C6-10 aryl, -CF ₃ , -OCF ₃ , mercapto, nitro, Ci_6 alkylamino, C3 0 cycloalkyl or C ₆ _io aryloxy;

each R ⁶ is independently H, deuterium, R ¹³ R ^13a NC(=0)-, R ¹³ OC(=0)-, R ¹³ C(=0)-, R ¹³ R ^13a NS(=0)-, R ¹³ OS(=0)-, R ¹³ S(=0)-, R ¹³ R ^13a NS(=0) ₂ -, R ¹³ OS(=0) ₂ -, R ¹³ S(=0) ₂ -, Ci_ ₆ aliphatic, Ci_ ₆ alkoxy-Ci_ ₆ -aliphatic, Ci_6 alkylamino-Ci_6-aliphatic, C -w aryl-Ci_6-aliphatic, Ci_g heteroaryl-Ci_6-aliphatic, C ₂ _io heterocyclyl-Ci_6-aliphatic, C340 cycloalkyl-Ci_6-aliphatic, C6-10 aryl, heteroaryl, C ₂ _io heterocyclyl or C3_io carbocyclyl;

each R ⁷ and R ^7a is independently H, deuterium, F, CI, Br, I, C _ ₆ aliphatic, C ₂ _ ₆ heteroalkyl, C _ ₆ alkoxy-Ci_6-aliphatic, Ci_6 alkylamino-Ci_6-aliphatic, C6-10 aryl-Ci_6-aliphatic, C ₂ _io heterocyclyl-Ci_6-aliphatic, C340 cycloalkyl-Ci_6-aliphatic, C6-10 aryl, heteroaryl, C ₂ o heterocyclyl or C340 carbocyclyl;

each R ⁸ and R ^8a is independently H, deuterium, hydroxy, cyano, nitro, F, CI, Br, I, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C340 cycloalkyl, C ₂ 4o heterocyclyl, C64o aryl, heteroaryl, C64o aryl-Ci_6-alkyl, Ci_6 alkoxy, Ci_6 alkyl-OC(=0)-, Ci_ ₆ alkyl-C(=0)-, carbamoyl, Ci_ ₆ alkyl-OS(=0) _r -, Ci_ ₆ alkyl-S(=0) _r O-, Ci_ ₆ alkyl-S(=0) _r - or aminosulfonyl;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_io cycloalkyl, C2-10 heterocyclyl, C io aryl, Ci_g heteroaryl or C _io aryl-Ci_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, or a substituted or unsubstituted spiro bicyclic group or fused bicyclic group;

each n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2;

t is 0, 1, 2, 3 or 4; and

each of Y ₄ and Y ₄ ' is independently a bond, O, S, -(CH ₂ ) _n -, -CH=CH-, -S(=0) _r -, -CH ₂ 0-, -CH ₂ S-, -CF ₂ -, -CHR ^5a , -CR ^5a R ^6a , -CH ₂ S(=0) _r or -CH ₂ N(R ⁶ )-.

[00207] In other embodiments, the compound having formula (III):

wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently NR ⁶ , O, S, C(=0) or (CR ⁷ R ^7a ) _; ;

each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e and

each of i and e is independently 0, 1, 2, 3 or 4.

[00208] In other embodiments, the compound having formula (IV):

(IV),

wherein each of Q ¹ , Q ² and Q ⁴ is independently O, S, C(=0), NR ⁶ or (CH ₂ ) _; ;

X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ; and

each i and e is independently 0, 1, 2, 3 or 4.

[00209] In other embodiments, the compound having formula (V):

wherein each of Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or (CH ₂ )i;

each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ; and

each of i and e is independently 0, 1, 2, 3 or 4.

[00210] In other embodiments, the compound having formula (VI):

(VI), wherein Q ⁴ is O, S, C(=0), NR ⁶ or (CH ₂ ) _; ;

X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ; and

each i and e is independently 0, 1, 2, 3 or 4.

[00211] In some embodiments, each of Y and Y' is independently a monovalent group derived from an a-amino acid.

[00212] In other embodiments, the a-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, Ν,Ν-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline.

[00213] In other embodiments, the a-amino acid is in the D configuration.

[00214] In other embodiments, the a-amino acid is in the L configuration.

[00215] In some embodiments, each of Y and Y' is independently -[U-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² , -U-(CR ⁹ R ^9a ) _t -R ¹² or

-[U-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[00216] In other embodiments, each of Y and Y' is independently -[U-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00217] In other embodiments, wherein 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 ^u )-(CR ⁹ R ^9a ) _t -R ¹² .

[00218] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00219] In other embodiments, each of Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -U-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00220] 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 .

[00221] In other embodiments, each of Y and Y' is independently -[C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _t ] _k -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00222] In other embodiments, each of Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _r C(=O)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00223] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a ) _r R ¹² .

[00224] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a )t-C(=0)-R ¹³ .

[00225] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ^u )-C(=0)-R ¹³ .

[00226] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ¹¹ )-(CR ⁹ R ^9a )t-C(=0)-0-R ¹³ .

[00227] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r N(R ^u )-C(=0)-0-R ¹³ .

[00228] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -R ¹² .

[00229] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _r R ¹² .

[00230] 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 .

[0023 1] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _t -N(R ¹⁰ )-(CR ⁹ R ^9a ) _r U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[00232] In other embodiments, each of Y and Y' is independently -C(=O)-(CR ⁹ R ^9a ) _r N(R ¹⁰ )-(CR ⁹ R ^9a ) _r C(=O)-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[00233] In other embodiments, each of Y and Y' is independently -U-(CR ⁹ R ^9a ) _r O-(CR ⁹ R ^9a ) _r R ¹² .

[00234] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _t -0-(CR ⁹ R ^9a ) _t -R ¹² .

[00235] In other embodiments, each of Y and Y' is independently -C(=0)-(CR ⁹ R ^9a ) _t -N(R ^u )-R ¹² , and wherein

11 12

R and R , together with the atom they are attached to, form a 4-7 membered ring.

[00236] In other embodiments, each R ⁹ , R ^9a , R ¹⁰ and R ¹¹ is independently H, deuterium, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C3 0 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, Ci_9 heteroaryl, C6-10 aryl-Ci_6-alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_g heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl;

each R ¹² is independently R ^13a R ¹³ N-, -C(=0)R ¹³ , -C(=S)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , -OC(=0)NR ¹³ R ^13a , -OC(=0)OR ¹³ , -N(R ¹³ )C(=0)NR ¹³ R ^13a , -N(R ¹³ )C(=0)OR ^13a , -N(R ¹³ )C(=0)-R ^13a , R ¹³ R ^13a N-S(=0) ₂ -, R ¹³ S(=0) ₂ -, R ¹³ S(=0) ₂ N(R ^13a )-, R ¹³ OS(=0) ₂ -, Ci_ ₆ alkyl, C ₂ _ ₆ heteroalkyl, C _3- io cycloalkyl, C ₂ _io heterocyclyl, C ₆ _io aryl _> Ci_ ₉ heteroaryl or C ₆ _io aryl-Ci_ ₆ -alkyl;

11 12

or R and R , together with the atom they are attached to, form a 4-7 membered ring;

each R ¹³ and R ^13a is independently H, deuterium, Ci_6 alkyl, C ₂ _6 heteroalkyl, C3_io cycloalkyl, C ₂ _io heterocyclyl, C^o aryl, Ci_g heteroaryl or C io aryl-Ci_6-alkyl; with the proviso that where R ¹³ and R ^13a are bonded to the same nitrogen atom, R and R ^a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicyclyl group or fused bicyclyl group;

each t is independently 0, 1, 2, 3 or 4; and

each k is independently 0, 1 or 2.

[00237] 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(=0)R ¹³ , -C(=0)-0-R ¹³ , -C(=0)NR ¹³ R ^13a , methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;

11 12

or R and R , 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.

[00238] In other embodiments, the compound having formula (VII):

(VII), wherein each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl,

C ₂ _6 heteroalkyl, C ₆ _io ary Ci_ ₉ heteroaryl, C ₂ _io heterocyclyl, C ₃ _ ₈ cycloalkyl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₉ heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, C6-10 aryl, Ci_ ₉ heteroaryl,

C ₂ _io heterocyclyl, C ₃ _ ₈ cycloalkyl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₉ heteroaryl-Ci_ ₆ -alkyl, C ₂ _io heterocyclyl-Ci_ ₆ -alkyl and C3_8 cycloalkyl-Ci_6-alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[00239] In other embodiments, the compound having formula (VIII):

wherein each of R and R ^a is independently H, deuterium, Ci_3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or Ci_ ₉ heteroaryl; and

wherein each of the Ci_3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl and Ci_ ₉ heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[00240] In some embodiments, the compound having formula (IX):

(IX), wherein each of Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ );;

i is 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, C ₆ _io aryl _> Ci_ ₉ heteroaryl, C ₂ _io heterocyclyl, C ₃ _ ₈ cycloalkyl, C ₆ _io aryl-Ci_ ₆ -alkyl, Ci_ ₉ heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

each n ₂ is independently 1, 2, 3 or 4,

wherein each of the Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, C ₂ _6 heteroalkyl, C ₆ _io aryl, Ci_ ₉ heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, Ci_ ₉ heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl and C3_8 cycloalkyl-Ci_6-alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[00241] In some embodiments, the compound having formula (X):

wherein each of Q ¹ and Q ² is independently a bond, NR ⁶ , O, S, C(=0) or (CH ₂ )i;

i is independently 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ hydroxyalkyl, C ₂ _6 heteroalkyl, Ce-w aryl, heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and

each n! is independently 1, 2, 3 or 4,

wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, C6-10 aryl, heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, C6-10 aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl and C ₃ _8 cycloalkyl-Ci_ ₆ -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[00242] In some embodiments, the compound having formula (XI):

(xi), wherein each R ^5a and R ^5a is independently H, deuterium, oxo(=0), benzyl, C _w alkyl, F, CI, Br or I;

each of R ¹⁴ and R ^14a is independently H, deuterium, Ci_4 alkyl, C6-10 aryl, C2-10 heterocyclyl or C ₃ _g cycloalkyl;

each of R ¹⁶ and R ^16a is independently hydroxy, Ci_ ₄ alkoxy, C ₆ _io aryloxy, C ₂ _io heterocyclyl or C ₃ _ ₈ cycloalkyl;

wherein each of benzyl, Ci_4 alkyl, C6-10 aryl, C2-10 heterocyclyl, Ci_4 alkoxy, C3_g cycloalkyl and C6-10 aryloxy is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;

wherein R ¹ , R ² and N-CH together fonn one of the following divalent groups:

4 and N-CH together form one of the following divalent groups:

[00243] In other embodiments, each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I;

each of R ¹⁴ and R ^14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl or Zerf-butyl; and each of R ¹⁶ and R ^16a is independently hydroxy, methoxyl, ethyoxyl, phenoxy, — ^/ or tert-butoxy; wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tei t-bxAoxy and teri-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano.

[00244] In some embodiments, the compound having formula (XII):

wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or CH ₂ ;

each of e, f and f is independently 0, 1, 2, 3 or 4;

each of X ³ and X ⁵ is independently O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I;

each of Y 1 , Y 2 , Y 1' and Y 2' is independently N or CR 7 ;

each R ⁶ , R ⁷ and R ^7a 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 or tert-butyl;

16 16a

each of R and R is independently hydroxy, methoxyl, ethyoxyl, phenoxy, ^— / or tert-butoxy; wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;

each of A and A' is independently

wherein R ³ , R ⁴ and N-CH together fonn one of the following divalent groups:

wherein each of Q ¹ , Q ² , Q ⁴ and Q ⁵ is independently O, S, C(=0), NR ⁶ or CH ₂ ;

X ³ is O, S, NR ⁶ , C(=0) or (CR ⁷ R ^7a ) _e ;

X ⁴ is O, S, NR ⁶ , C(=0) or CR ⁷ R ^7a ;

each R ⁶ , R ⁷ and R ^7a is independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl; each R ^5a and R ^5a is independently H, deuterium, methyl, ethyl, oxo(=0), benzyl, F, CI, Br or I; each of Y 1 , Y 2 , Y 1' and Y 2' is independently N or CR 7 ;

each of i, e, f and f is independently 0, 1, 2, 3 or 4;

each of R ¹⁴ and R ^14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl or tert-butyl;

16 16a

each of R and R is independently hydroxy, methoxyl, ethyoxyl, phenoxy, ^— / or tert-butoxy; wherein each of methyl, ethyl, phenyl, benzyl, cyclohexyl, 1-methyl-propyl, isopropyl, isobutyl, methoxyl, ethyoxyl, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, CI, Br, hydroxy and cyano;

each of A and A' is independently

wherein R 1 , R 2 and N-CH together form one of the following divalent groups:

[00246] 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:

82

[00247] 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. Provided herein is 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 disorders through inhibition of HCV, especially HCV'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.

[00248] 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.The skills in the art could choose "pharmaceutically acceptable" substance or composition base on the other ingredients and the objects for treatment such as human.

[00249] 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).

[00250] 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, etc. 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 7-toluenesulfonic acid or ethanesulfonic acid, etc.

[00251] 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, etc. Some non-limiting examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, 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, etc.

COMPOSITION, FORMULATIONS AND ADMINISTRATION OF COMPOUNDS OF THE

INVENTION

[00252] The pharmaceutical composition disclosed herein comprises any one of the compounds. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. The pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially, it is great for inhibiting HCV NS5A protein.

[00253] The pharmaceutical composition disclosed herein further comprises anti-HCV agents. The anti-HCV agent may be any other known anti-HCV agent except the compound described herein, such as interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, an interfering RNA, an anti-sense RNA, imiquimod, an inosine-5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, virazole, bavituximab, Civacir™, boceprevir, telaprevir, erlotinib, daclatasvir, ABT-450, danoprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA-975, ABT-267, EDP-239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032), sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PSI-7977), ΓΝΧ-189, IDX-184, IDX-102, R-1479, ΓΝΧ-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof. The interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, 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 non- structural protein or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication. [00254] 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," as used herein, 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," as used herein, 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 complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[00255] 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.

[00256] 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 and 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 of administration by injection is preferred.

[00257] Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules of 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.

[00258] 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, etc. 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, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.

[00259] Capsules are maded 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.

[00260] 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 acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, etc. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, etc. 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 aliginate, gelating, 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, acadia mucilage, 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.

[00261] 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 additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, etc can also be added.

[00262] 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 of embedding particulate material in polymers, wax, or the like.

[00263] 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 phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

[00264] 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(8-caprolactone), polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

[00265] 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 Pharmacol. Res., 1986, 3(6), 318.

[00266] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.

[00267] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

[00268] 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.

[00269] 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.

[00270] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[00271] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, 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.

[00272] 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.

USES OF THE COMPOUNDS AND COMPOSITIONS OF THE INVENTION

[00273] 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 non-structural protein 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.

[00274] Also provided herein is a method, which comprises administering 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 an interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, an interfering RNA, an anti-sense RNA, imiquimod, an inosine-5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ribavirin, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, ABT-450, danoprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA-975, ABT-267, EDP-239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, simeprevir (TMC-435), vaniprevir (MK-7009), faldaprevir (BI-201335), ciluprevir, asunaprevir (BMS-650032), sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX-102, R-1479, ΓΝΧ-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof. Wherein the interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, interferon γ or a combination thereof.

[00275] 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.

[00276] 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, etc. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above.

GENERAL SYNTHETIC PROCEDURES

[00277] 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.

[00278] Persons skilled in the art will recognize that the chemical reactions described 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.

[00279] 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.

[00280] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing the solvent with calcium hydride, ethyl acetate, petroleum ether, hexane, NN-dimethylacetamide and N,N-dimethylformamide were treated with anhydrous sodium sulfate prior to use.

[00281] 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.

[00282] Column chromatography was conducted using a silica gel column. Silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory. ^l li NMR spectra were recorded with a Bruker 400 MHz spectrometer at ambient temperature. ¾ NMR spectra were obtained as CDCI ₃ , i¾-DMSO, CD ₃ OD or i/ 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), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[00283] 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.

[00284] 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.

[00285] Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1 x 30 mm, 5 μιη 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 :

Tab. 1

Time (min) A (CH ₃ CN, 0.1% HCOOH) B (H ₂ Q, 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

[00286] Purities of compounds were 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 mi corn, 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 0). Column was operated at 40°C.

[00287] The following abbreviations are used throughout the specification:

HOAc acetic acid

MeCN, CH ₃ CN acetonitrile

NH ₃ ammonia

NH ₄ C 1 ammonium chloride

BBr ₃ boron tribromide

BSA bovine serum albumin

Br ₂ bromine

BOC, Boc tert-butyloxycarbonyl

Cs ₂ C0 ₃ cesium carbonate

CHC1 ₃ chloroform

CDC 1 ₃ chloroform deuterated

Cu copper

Cul copper (I) iodide

Et ₂ 0 diethyl ether

DMF dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethylsulfoxide

EDC, EDCI l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Dppa diphenylphosphoryl azide

EtOAc ethyl acetate

EA ethyl acetate

g gram

HBr hydrobromic acid

HC1 hydrochloric acid

HI hydroiodic acid

HOAt, HO AT 1 -hydro xy-7-azabenzotriazole

HOBT 1 -hydro xybenzotriazole hydrate

H ₂ hydrogen H ₂ O ₂ hydrogen peroxide

Fe iron

LDA lithium diisopropylamide

MCPBA meta-chloroperbenzoic acid

MgS0 ₄ magnesium sulfate

MeOH, CH ₃ OH methanol

Mel methyl iodide

CH ₂ C1 ₂ , DCM methylene chloride

NMP TV-methylpyrrolidinone

mL, ml milliliter

min minute

N ₂ nitrogen

Pd/C palladium on activated carbon

PE petroleum ether (60-90 °C)

PBS phosphate buffered saline

POC I ₃ phosphorous oxychloride

Pd(PPh ₃ ) ₄ palladium tetrakis triphenylphosphine

Pd(dppf)Cl ₂ l,l-Z«s(diphenylphosphino)ferrocene palladium chloride

K ₂ CO ₃ potassium carbonate

KOH potassium hydroxide

T, rt room temperature

Rt retention time

NaHCC>3 sodium bicarbonate

NaBH ₄ sodium borohydride

NaBH ₃ CN sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOH sodium hydroxide

NaC10 ₂ sodium chlorite

NaCl sodium chloride

NaH ₂ P0 ₄ sodium dihydric phosphate

NaH sodium hydride

Nal sodium iodide

Na ₂ S0 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 irz ^' (teri-butyl)phosphine

NBS N-bromosuccinimide

TBAI tetrabutylammonium iodide

H ₂ O water

TEAF formic acid triethylamine complex 5:2

PPA polyphosphoric acid

Tf ₂ 0 trifluoromethanesulfonic anhydride

HC1.EA a solution of HQ in ethyl acetate

DIPEA N,N-diisopropylethylamine

DME 1 ,2-dimethoxyethane

HATU 2-(7-aza- l /-benzotriazole- l -yl)- l , l,3,3-tetramethyluronium hexafluorophosphate

NIS N-iodosuccinimide

TFAA trifluoroaceticanhydride

SEMC1 2-(Trimethylsilyl)ethoxymethyl chloride

Dess-Martin(Dess-Martin periodinane) (1 , 1, 1 -Triacetoxy)- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 ( l /)-one

TsOH 7-toluenesulfonic acid

TMSA trimethyl silyl acetylene

Meldrum's acid 2,2-dimethyl- l,3-dioxane-4,6-dione

BAST ZHs(2-methoxyethyl)aminosulphurtrifluoride Deoxo-fluor

SbCl ₃ antimony trichloride

SmCb samarium chloride

LiHMDS lithium hexamethyldisilazide

TMSC1 trimethyl chlorosilane

PhNTf ₂ N,N-ZHs(trifluoromethylsulfonyl)aniline

TBDMSOTf trifluoromethanesulfonic acid tert-butyldimethylsilyl ester

Et ₂ NSF ₃ diethylaminosulfur trifluoride

MTBE methyl tert-butyl ether

LiN(SiMe ₃ ) ₂ lithium Z«s(trimethylsilyl)amide

PPh ₃ MeBr methyltriphenylphosphonium bromide

Lawesson's Reagent 2,4-Z) 5(4-methoxyphenyl)- l,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

[00288] Compound 17 can be prepared by a general synthetic procedure illustrated in Scheme 1, wherein each of X ⁷ and X ⁸ is independently F, CI, Br, I or OTf; each R ^5a , R ^5a' , f, f, Y ¹ , Y ² , Y ^{1 '} , Y ^2' , X ³ , X ⁵ , e, Y ₄ , R ¹⁴ and R ¹⁶ is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz, and so on. Compound 1 can be reduced to afford compound 2 in the presence of Pd/C under H ₂ . By the reaction of halogenation, compound 2 can be converted to compound 3. Compound 3 can be converted to compound 4 by demethylation. Compound 4 can react with ZHs(pinacolato)diboron to afford compound 5 by Pd catalysis. Coupling reaction of compound 5 with compound 4' in the presence of a Pd catalyst can give compound 6. Compound 6 can react with trifluoromethanesulfonic anhydride to afford compound 7 by a base catalyzed reaction. Compound 7 can react with ZHs(pinacolato)diboron to afford compound 8 by Pd catalysis. Reduction of compound 9 in the presence of borane-tetrahydrofuran can give compound 10. Then compound 10 can be oxidized in the presence of Dess-Martin Periodinane to give compound 11. Compound 12 can be obtained via cyclization reaction of compound 11 with ammonium hydroxide and glyoxal. Compound 12 can react with NIS to afford compound 13. One iodine atom of compound 13 can be removed in the presence of sodium sulfite to provide compound 14. Compound 14 can be coupled with compound 8 in the presence of a Pd catalyst to afford compound 15. The protecting group Pg of compound 15 can be removed to afford compound 16. Compound 16 can be condensed with compound 16-1 to provide compound 17.

[00289] Compound 35 can be prepared by a general synthetic procedure illustrated in Scheme 2, wherein each of A ¹ , A ² and A ³ is independently N or CR ⁷ ; X ⁷ is F, CI, Br, I or OTf; each R ^5a , R ^5a' , f, f, Y ¹ , Y ² , Y ^2' , Y ^3' , e, w, Yzt, R ¹⁴ , R ¹⁶ , Y4', R ^14a and R ^16a is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz, and so on. By the reaction of halogenation, compound 18 can be converted to compound 19. The methyl group of compound 19 can be removed to afford compound 20. Compound 20 can react with trifluoromethanesulfonic anhydride to afford compound 21 under alkaline condition. Compound 21 can be coupled with compound 5 in the presence of a Pd catalyst to afford compound 22. The protecting group Pg of compound 14 can be removed to afford compound 23. Compound 23 can be condensed with compound 16-1 to provide compound 24. Compound 24 can be treated with ZHs(pinacolato)diboron to afford compound 25 by Pd catalysis. The condensation of compound 26 with compound 9-1 can afford a mixture of compound 27 and compound 28. The mixture is heated in acetic acid resulting in cyclization to give compound 29. The protecting group Pg of compound 29 can be removed to afford compound 30. Compound 30 can be condensed with compound 16-2 to provide compound 31. Compound 31 can be treated with ZHs(pinacolato)diboron to afford compound 32 by Pd catalysis. Coupling reaction of compound 22 with compound 25 in the presence of a Pd catalyst can give compound 33. Compound 33 can react with trifluoromethanesulfonic anhydride to afford compound 34 by a base catalyzed reaction. Compound 34 can react with compound 32 in the presence of a Pd catalyst to give compound 35.

Scheme 3

[00290] Compound 44 can be prepared by a general synthetic procedure illustrated in Scheme 3, wherein X ⁷ is F, CI, Br, I or OTf; each R ^5a , R ^5a' , f, f, Y ¹ , Y ² , Y ^1' , Y ^2' , X ³ , X ⁵ , e, Y ₄ , Y ₄ ', R ^& , R ^14a and R ^16a is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz, and so on. Compound 7 can be coupled with compound 36 to afford compound 37 by Pd catalysis. Condensation reaction of compound 9-1 with compound 38 can obtain compound 39 in the presence of a base. Cyclization of compound 39 can give compound 40 in ammonium acetate under heating condition. Compound 40 can be treated with ZHs(pinacolato)diboron to afford compound 41 by Pd catalysis. Coupling reaction of compound 41 with compound 7 in the presence of a Pd catalyst can give compound 42. Deprotection of compound 42 can obtain compound 43 which can further react with compound 16-2 to obtain compound 44.

Scheme 4

[00291] Compound 48 can be prepared by a general synthetic procedure illustrated in Scheme 4, wherein each R , R , f, f , Y , Y Y , Y , X X e, Y ₄ , Y ₄ ', R and R is as defined herein. Coupling reaction of compound 7 with compound 25 in the presence of a Pd catalyst can give compound 45. Compound 24-1 can react with TMSA to afford compound 46 by a Pd catalyzed reaction. TMS group of compound 46 can be removed under alkaline condition to obtain compound 47. Compound 47 can react with compound 45 in the presence of a Pd catalyst to give compound 48.

[00292] Compound 53 can be prepared by a general synthetic procedure illustrated in Scheme 5, wherein each R , R , f, f , Y , Y Y , Y X ³ , X e, Y ₄ , Y ₄ ', R , R , R and R ^{10i 1} is as defined herein; and Pg is an amino-protecting group such as Boc, Fmoc or Cbz, and so on. Deprotection of compound 49 can obtain compound 50 which can further react with compound 16-2 to obtain compound 51. Compound 51 can be treated with ZH ^' s(pinacolato)diboron to afford compound 52 by Pd catalysis. Coupling reaction of compound 52 with compound 45 in the presence of a Pd catalyst can give compound 53.

[00293] Compound 61 can be prepared by a general synthetic procedure illustrated in Scheme 6, wherein X ⁷ is F, CI, Br, I or OTf; each R ^5a , R ^5a' , f, f, Y ¹ , Y ² , Y ^{1 '} , Y ^2' , Y ³ , X ⁵ , e, Y ₄ , Y ₄ ',R ¹⁴ , R ¹⁶ , Y ₄ ', R ^14a and R ^16a is as defined herein. Compound 54 can be converted to compound 55 in the presence of a base, and then compound 55 can be treated with CDI under ammonium hydroxide condition to give compound 56. Condensation reaction of compound 56 with compound 57 can afford compound 58. Cyclization of compound 58 in the presence of a base can obtain compound 59. Compound 59 can be treated with ZHs(pinacolato)diboron to afford compound 60 by Pd catalysis. Coupling reaction of compound 60 with compound 45 in the presence of a Pd catalyst can give compound 61.

Scheme 7

[00294] Compound 71 can be prepared by a general synthetic procedure illustrated in Scheme 7, wherein X ⁷ is F, CI, Br, I or OTf; each R ^5a , R ^5a' , f, f, Y ¹ , Y ² , Y ^{1 '} , Y ^2' , X ³ , X ⁵ , e, Y ₄ , Y ₄ ', R ¹⁴ , R ¹⁶ , R ^14a and R ^16a is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz, and so on. Compound 62 can be converted to compound 63 in the presence of sodium sulfite, and then compound 63 can be treated with thionyl chloride and ammonium hydroxide in turn to obtain compound 64. Compound 64 can be converted to compound 65 in the presence of HI. Compound 65 can react with compound 66 under alkaline condition to obtain compound 67. Deprotection of compound 67 can obtain compound 68. Compound 68 can be condensed with an amino acid to afford compound 69. Compound 69 can be treated with ZH ^' s(pinacolato)diboron to afford compound 70 by Pd catalysis. Coupling reaction of compound 70 with compound 45 in the presence of a Pd catalyst can give compound 71.

Scheme 8

[00295] Compound 77 can be prepared by a general synthetic procedure illustrated in Scheme 8, wherein X ⁷ is F, CI, Br, I or OTf; each Y R , Y ₄ , R ^14a and R ³ is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz, and so on. Condensation of compound 9 with compound 72 can afford compound 73, and then cyclization of compound 73 in ammonium acetate under heating condition can give compound 74. Deprotection of compound 74 can obtain compound 75. Compound 75 can be condensed with compound 16-2 to afford compound 76. Compound 76 can be treated with ZHs(pinacolato)diboron to afford compound 77 by Pd catalysis.

EXAMPLE

Example 1

Synthetic routes

Step 1) the preparation of compound 1-2

[00296] To a solution of «-butyllithium (5.0 mL, 7.93 mmol, 1.6 M in «-hexane) in freshly distilled THF (20 mL) at -70 °C were added a solution of compound 1-1 (1.0 g, 7.93 mmol) in THF (10 mL) and a solution of I ₂ (2.32 g, 9.12 mmol) in THF (15 mL) dropwise respectively. At the end of the addition, the mixture was stirred for 20 mins and allowed to warm up to -60 °C and then an aqueous solution of sodium thiosulfate (3.0 mL, 10%) was added to the mixture. After the reaction was completed, the mixture was quenched by adding an aqueous ammonium chloride solution (10 mL) slowly. The THF was removed in vacuo and the aqueous phase was extracted with «-hexane (50 mL x 3). The combined organic layers were washed with an aqueous sodium thiosulfate solution (10%) and water, dried over anhydrous Na ₂ S0 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 oil (1.6 g, 80%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 MHz, CDCI ₃ ): δ 6.79, 6.77, 6.75 (d, dd, d, 1H), 6.63, 6.62, 6.60, 6.58 (s, d, d, s, 1H), 6.53-6.52, 6.51-6.50 (m, m, 1H) ppm.

Step 2) the preparation of compound 1-3

[00297] To a mixture of Mg (0.15 g, 6.35 mmol) were added a solution of compound 1-2 (1.6 g, 6.35 mmol) in THF (20 mL) and freshly prepared cyclopentadiene (0.71 g, 10.8 mmol) dropwise respectively under N ₂ . At the end of the addition, the mixture was refluxed for 5 hours. After the reaction was completed, the mixture was quenched with a saturated aqueous ammonium chloride solution (50 mL). The aqueous phase was extracted with ether (50 mL x 3). The combined organic layers were washed with an aqueous sodium thiosulfate solution (10%), water and then a saturated aqueous ammonium chloride solution. The washed organic phase was dried over anhydrous Na ₂ S0 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 as oil (0.75 g, 69%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.10-7.09, 7.08-7.07 (m, m, 1H), 6.97, 6.95, 6.93 (s, d, s, 1H), 6.76, 6.74 (m, m, 1H), 6.72-6.66 (m, 2H), 4.31-4.27 (m, 1H), 3.84-3.81 (m, 1H), 3.80 (s, 3H), 2.29-2.25, 2.22-2.18 (m, m, 2H) ppm.

Step 3) the preparation of compound 1-4

[00298] A suspension of compound 1-3 (0.75 g, 4.36 mmol) and Pd/C (75 mg) in methanol (10 mL) was stirred at 50 °C under H ₂ for 4 hours. After the reaction was completed, the methanol was removed in vacuo and 20 mL of water was added to the residue. The resulting mixture was extracted with DCM (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 as a yellow solid (0.64 g, 85%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.17, 7.15, 7.13 (s, d, s, 1H), 6.74-6.73, 6.72-6.71 (m, m, 1H), 6.58-6.57, 6.56-6.55 (m, m, 1H), 3.88 (s, 3H), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H) ppm.

Step 4) the preparation of compound 1-5

[00299] A suspension of compound 1-4 (0.65 g, 3.7 mmol) and NIS (0.92 g, 4.07 mmol) in acetonitrile (10 mL) was stirred at 50 °C overnight. After the reaction was completed, the acetonitrile was removed in vacuo and 20 mL of water was added to the residue. The resulting mixture was extracted with DCM (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless liquid (0.83 g, 75%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 301.1 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.46, 7.44 (s, s, 1H), 6.38, 6.36 (m, m, 1H), 3.87 (s, 3H), 3.69-3.66 (m, 1H), 3.45-3.42 (m, 1H), 1.99-1.90 (m, 2H), 1.87-1.83 (m, 1H), 1.64-1.60 (m, 1H), 1.26-1.16 (m, 2H) ppm.

Step 5) the preparation of compound 1-6

[00300] To a solution of compound 1-5 (0.83 g, 2.77 mmol) in DCM (20 mL) at -78 °C was added BBr ₃ (0.36 mL, 3.88 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the mixture was poured into ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>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 oil (0.79 g, 100%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 287.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.39, 7.37 (s, s, 1H), 6.31, 6.28 (s, s, 1H), 5.77 (brs, 1H), 3.52-3.46 (m, 2H), 2.05-1.99 (m, 1H), 1.96-1.90 (m, 1H), 1.88-1.84 (m, 1H), 1.65-1.61 (m, 1H), 1.32-1.26 (m, 1H), 1.23-1.17 (m, lH) ppm.

Step 6) the preparation of compound 1-7

[00301] To a mixture of compound 1-6 (0.5 g, 1.75 mmol), compound 1-6-2 (0.49 g, 1.92 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (72 mg, 0.087 mmol) and anhydrous potassium acetate (0.43 g, 4.37 mmol) was added anhydrous DMF (5.0 mL) under N ₂ via syringe and the resulting mixture was stirred at 90 °C for 2 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.48 g, 69.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 397.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 8.00, 7.98 (s, s, 1H), 6.94, 6.92 (s, s, 1H), 5.77 (brs, 1H), 3.58-3.55 (m, 1H), 3.49-3.46 (m, 1H), 1.99-1.93 (m, 1H), 1.82-1.76 (m, 2H), 1.59-1.55 (m, 1H), 1.32 (q, 6H), 1.29 (q, 6H), 1.26-1.20 (m, 1H), 1.09-1.03 (m, lH) ppm.

Step 7) the preparation of compound 1-8

[00302] To a mixture of compound 1-7 (0.45 g, 1.14 mmol), compound 1-6 (0.36 g, 1.25 mmol), potassium carbonate (0.39 g, 2.84 mmol) and Pd(PPh ₃ ) ₄ (65.7 mg, 0.057mmol) were added DME (8.0 mL) and water (2.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the mixture was allowed to cool to rt, diluted with EtOAc (50 mL), washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 a white solid (0.29 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 319.3 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.10, 7.08 (s, s, 2H), 6.55, 6.53 (s, s, 2H), 5.77 (brs, 2H), 3.59-3.54 (m, 2H), 3.47-3.43 (m, 2H), 1.99-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.59-1.55 (m, 2H), 1.26-1.19 (m, 4H) ppm.

Step 8) the preparation of compound 1-9

[00303] A solution of triethylamine (0.57 mL, 4.09 mmol) and compound 1-8 (0.26 g, 0.82 mmol) in DCM (10 mL) was stirred at 0 °C for 10 mins and to the solution was added trifluoromethanesulfonic anhydride (0.39 mL, 2.29 mmol) dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the mixture was quenched with ice water (25 mL) and the aqueous layer was extracted with DCM (25 mL x 3). The combined organic phases were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless oil (0.43 g, 90%). The compound was characterized by the following spectroscopic data: *H NMR (400 MHz, CDC1 ₃ ): δ 7.10, 7.08 (s, s, 1H), 6.55, 6.53 (s, s, 1H), 5.77 (brs, 2H), 3.59-3.54 (m, 2H), 3.47-3.43 (m, 2H), 1.99-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.59-1.55 (m, 2H), 1.26-1.19 (m, 4H) ppm.

Step 9) the preparation of compound 1-10

[00304] To a mixture of compound 1-9 (0.4 g, 0.69 mmol), compound 1-6-2 (0.37 g, 1.44 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (28 mg, 0.034 mmol) and potassium acetate (0.17 g, 1.72 mmol) was added anhydrous DMF (5.0 mL) under N ₂ via syringe and the resulting mixture was stirred at 90 °C for 3 hours. 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 (25 mL x 3) and a saturated aqueous solution of NaCl respectively, dried over anhydrous Na ₂ S0 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 white solid (0.26 g, 70%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.61, 7.59 (s, s, 2H), 7.44, 7.42 (s, s, 2H), 3.76-3.73 (m, 2H), 3.69-3.66 (m, 2H), 1.96-1.90 (m, 2H), 1.80-1.74 (m, 4H), 1.57-1.53 (m, 2H), 1.32, 1.29 (q, q, 24H), 1.23-1.17 (m, 2H), 1.07-1.01 (m, 2H) ppm.

Step 10) the preparation of compound 1-12

[00305] To a solution of compound 1-11 (10.0 g, 46.6 mmol) in THF (100 mL) at 0 °C was added borane (100 mL, 1 M in THF) dropwise slowly under N ₂ . At the end of the addition, the mixture was stirred for 3 hours at 0 °C. After the reaction was completed, the mixture was quenched with methanol (80 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as colorless oil (7.0 g, 75.2%). The compound was characterized by the following spectroscopic data: ^! H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 11) the preparation of compound 1-13

[00306] To a solution of compound 1-12 (7.0 g, 34.8 mmol) in DCM (250 mL) at 0 °C was added Dess-Martin periodinane (20.7 g, 48.8 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was diluted with water (250 mL) and filtered. The filtrate was partitioned. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 as colorless oil (3.5 g, 50.7%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 9.46 (d, 1H, J = 2.8 Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 2.01-1.93 (m, 2H), 1.91-1.84 (m, 2H), 1.43 (s, 9H) ppm.

Step 12) the preparation of compound 1-14

[00307] To a solution of compound 1-13 (3.5 g, 17.6 mmol) and ammonium hydroxide (13 mL) in methanol (30 mL) at 0 °C was added aqueous glyoxal solution (40 %, 8 mL) dropwise. At the end of the addition, the mixture was stirred 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 as a white solid (1.99 g, 47.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 238.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 6.96 (s, 1H), 4.94 (dd, 1H, J= 7.68 Hz, 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) ppm.

Step 13) the preparation of compound 1-15

[00308] To a solution of compound 1-14 (2.0 g, 8.4 mmol) in DCM (60 mL) at 0 °C was added N-iodosuccinimide (3.8 g, 16.8 mmol) in portions, and the mixture was stirred for 1.5 hours at 0 °C. After the reaction was completed, the mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (2.6 g, 63.1%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 490.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 4.89 (dd, 1H, J= 7.64 Hz, 2.52 Hz), 3.36 (t, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H) ppm.

Step 14) the preparation of compound 1-16

[00309] To a suspension of compound 1-15 (1.6 g, 3.27 mmol) in a mixed solvent (50 mL, ethanol and water, v/v=3/7) was added sodium sulfite (3.7 g, 29 mmol) and the mixture was refluxed for 17 hours. After the reaction was completed, the ethanol was removed in vacuo and 50 mL of water added to the residue. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (1.0 g, 84%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 364.1 [M+H] ⁺ ; and ¹ H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 15) the preparation of compound 1-17

[00310] To a mixture of compound 1-10 (0.24 g, 0.45 mmol), compound 1-16 (0.34 g, 0.94 mmol), anhydrous potassium carbonate (0.15 g, 1.12 mmol) and Pd(PPli ₃ )4 (25.8 mg, 0.023 mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (20 mL), washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.25 g, 75%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 379.4 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.05-5.00 (m, 2H), 3.77-3.73 (m, 4H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H), 2.47-2.38 (m, 2H), 2.28-2.17 (m, 2H), 2.10-1.97 (m, 6H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.41 (s, 18H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

Step 16) the preparation of compound 1-18

[00311] To a solution of compound 1-17 (0.24 g, 0.317 mmol) in DCM (5.0 mL) was added a solution of HC1 in EtOAc (4.0 mL, 4M) dropwise slowly and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc (10 mL) and filtered to afford a white solid (214 mg, 96%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 557 [M+H] ⁺ .

Step 17) the preparation of compound 1-19

[00312] To a solution of compound 1-18 (0.2 g, 0.29 mmol), compound 1-18-2 (115 mg, 0.60 mmol) and EDCI (0.27 g, 1.42 mmol) in DCM (5.0 mL) at 0 °C was added DIPEA (0.76 mL, 4.27 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 3 hour. The reaction mixture was diluted with DCM (20 mL), washed with ammonium chloride aqueous solution and saturated aqueous solution of NaCl respectively, dried over anhydrous Na ₂ S0 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 as a white solid (173 mg, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 436.5 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.56, 5.55 (d, d, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 2H), 4.41-4.37 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.73 (m, 4H), 3.66 (s, 6H), 3.65-3.61 (m, 2H), 2.30-2.16 (m, 6H), 2.13-1.89 (m, 8H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (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) ppm.

Example 2

Synthetic route

Step 1) the preparation of compound 2-1

[00313] To a solution of compound 1-16 (1.50 g, 4.13 mmol) in EtOAc (10 mL) was added a solution of HQ in EtOAc (5 mL, 4 M) dropwise. After the addition was completed, the mixture was stirred overnight. The mixture was filtered to give the title compound as a solid (1.2 g, 86.5%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 264 A [M+H] ⁺ .

Step 2) the preparation of compound 2-2

[00314] A suspension of compound 2-1 (1.2 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) in DCM (20 mL) was stirred at 0 °C for 5 mins and then to the suspension was added DIPEA (2.38 mL, 14.4 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was diluted with DCM (40 mL). The organic layer was washed with a saturated ammonium chloride aqueous solution, dried over anhydrous Na ₂ S0 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 foam (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 ^! H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 3) the preparation of compound 2-3

[00315] To a solution of compound 2-3-0 (30 g, 107.9 mmol) and compound 1-11 (25.5 g, 118.7 mmol) in DCM (250 mL) at 0 °C was added DIPEA (21.4 mL, 129.5 mmol) dropwise slowly At the end of addition and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was quenched with ice water (100 mL), the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (40.36 g, 91%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 412.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 2-4

[00316] A suspension of compound 2-3 (15 g, 36.4 mmol) and ammonium acetate (42 g, 54.6 mmol) in toluene (150 mL) was stirred at 110 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and quenched with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (12.1 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 392.3 [M+H] ⁺ ; ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 5) the preparation of compound 2-5

[00317] To a solution of compound 2-4 (10 g, 25.5 mmol) in EtOAc (50 mL) was added a solution of HQ in EtOAc (60 mL, 4 M) and the mixture was stirred at rt for 8 hours. After the mixture was completed, the mixture was concentrated, the residue was triturated with EtOAc (30 mL). The resulting mixture was filtered to give the title compound as a yellow solid (8.0 g, 86.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 292.2 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 6) the preparation of compound 2-6

[00318] To a solution of compound 2-5 (7.01 g, 19.26 mmol), compound 1-18-2 (5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) at 0 °C was added DIPEA (21 mL, 127 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, water (100 mL) was added to the mixture and the resulting mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 7) the preparation of compound 2-7

[00319] To a mixture of compound 2-6 (4.99 g, 11.13 mmol), compound 1-6-2 (4.24 g, 16.7 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.91 g, 1.11 mmol) and KOAc (3.30 g, 33.4 mmol) was added DMF (50 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc and filtered through a Celite Pad. The filtrate was washed with water (100 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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: ^l H NMR (400 MHz, CDC1 ₃ ): δ 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), 3.5-3.81 (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), 1.32-1.45 (m, 12H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H) ppm.

Step 8) the preparation of compound 2-8

[00320] To a mixture of compound 1-9 (0.58 g, 1.0 mmol), compound 2-7 (0.5 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (10 mL) and pure water (2 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (15 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 yellow foam (0.52 g, 65%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 2H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.45-3.42 (m, 1H), 2.30-2.15 (m, 3H), 2.13-1.90 (m, 6H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 9) the preparation of compound 2-9

[00321] To a mixture of compound 2-8 (0.8 g, 1.0 mmol), compound 1-6-2 (0.28 g, 1.1 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (81.7 mg, 0.1 mmol) and KOAc (0.25 g, 2.5 mmol) was added DMF (3.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (30 mL) and filtered through a Celite Pad. The filtrate was washed with water (20 mL x 3) and saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.48 g, 62%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 781.8 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 4H), 7.58, 7.56 (s, s, 1H), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.37 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.75-3.71 (m, 2H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 2.30-2.15 (m, 3H), 2.13-1.90 (m, 6H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 10) the preparation of compound 2-10 [00322] To a mixture of compound 2-9 (0.78 g, 1.0 mmol), compound 2-2 (0.43 g, 1.02 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added EtOH (10 mL) and pure water (2 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 yellow foam (0.52 g, 55%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 474.6 [M+2H] ²⁺ ; and ^! H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 4.34-4.30 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.71 (m, 3H), 3.69-3.66 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.30-2.16 (m, 6H), 2.13-1.89 (m, 8H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 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) ppm.

Example 3

Synthetic route

Step 1) the preparation of compound 3-1

[00323] To a mixture of compound 2-2 (4.2 g, 10 mmol), compound 1-6-2 (2.59 g, 10.2 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.82 g, 1.0 mmol) and KOAc (2.45 g, 25 mmol) was added DMF (20 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 (100 mL x 3) and saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (2.73 g, 65%). The compound was characterized by the following spectroscopic data: ^l n NMR (400 MHz, CDC1 ₃ ): δ 7.64 (s, 1H), 5.55-5.51 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.41-4.37 (m, 1H), 3.78-3.72 (m, 1H), 3.63 (s, 3H), 3.61-3.54 (m, 1H), 2.25-1.87 (m, 5H), 1.39, 1.36 (q, q, 12H), 0.97, 0.95 (m, m,

3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 2) the preparation of compound 3-3

[00324] A mixture of alchlor (90 g, 676 mmol) and sodium chloride (25 g, 432 mmol) was stirred at 150 °C until melted and then compound 3-2 (20 g, 135 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at 200 °C for 1 hour. After the reaction was completed, the mixture was cooled to rt and poured into ice water (500 mL). The resulting mixture was filtered. The filter cake was triturated with methanol and filtered to afford the title compound as a gray solid (19 g, 95 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 149.5 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 3) the preparation of compound 3-4

[00325] To a suspension of compound 3-3 (5.0 g, 33.7 mmol) and K ₂ CO ₃ (23.4 g, 168.5 mmol) in acetone (50 mL) was added methyl iodide (3.15 mL, 50.55 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at 60 °C for 5 hours. After the reaction was completed, the mixture was concentrated in vacuo. To the residue were added water (150 mL) and EtOAc (150 mL). The resulting mixture was filtered through a Celite Pad and the filtrate was partitioned. The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (2.46 g, 45%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 163.5 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 3-5

[00326] To a suspension of compound 3-4 (20.0 g, 123.3 mmol) in methanol (250 mL) at 0 °C was added NaB¾ (2.8 g, 74.0 mmol) in portions and the mixture was stirred at rt for 1 hour. After the reaction was completed, the methanol was removed in vacuo and the residue was dissolved in EtOAc (400 mL). The resulting mixture was washed with water (100 mL x 2) and a saturated aqueous solution of NaCl (100 mL), dried over anhydrous Na ₂ S0 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 pale yellow solid (17.6 g, 87%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 165.5 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDCI ₃ ): δ 7.13-7.09 (m, 1H), 7.08-7.05 (m, 1H), 6.75-6.72 (m, 1H), 5.29-5.25 (m, 1H), 3.84 (d, 3H), 3.70 (brs, 1H), 2.84-2.80 (m, 2H), 2.49-2.40 (m, 1H), 1.96-1.88 (m, 1H) ppm.

Step 5) the preparation of compound 3-6

[00327] To a solution of compound 3-5 (2.0 g, 12.2 mmol) in THF (20 mL) at 0 °C was added p-TSA (1.0 g, 6.1 mmol) and the mixture was refluxed for 3 hours. After the reaction was completed, the THF was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with water (50 mL x 2) and a saturated aqueous solution of NaCl (100 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless liquid (1.23 g, 69%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 147.1 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.29 (t, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 1A Hz), 6.90-6.86 (m, 1H), 6.77 (d, 1H, J= 8.0 Hz), 6.61-6.57 (m, 1H), 3.92 (s, 3H), 3.39 (s, 2H) ppm.

Step 6) the preparation of compound 3-7

[00328] To a solution of compound 3-6 (5.0 g, 34.2 mmol) in anhydrous ethylether (35 mL) was added activated zinc powder (2.5 g, 37.6 mmol). The mixture was stirred for 10 mins and then a solution of trichloro-acetic chloride (4.0 mL, 35.9 mmol) and phosphorus oxychloride (3.3 mL, 35.9 mmol) in ethylether (35 mL) was added dropwise slowly. At the end of the addition, the mixture was refluxed overnight. After the reaction was completed, the mixture was filtered. To the filtrate was added 50 mL of water and the resulting mixture was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a pale solid (6.5 g, 74%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 257.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.28 (t, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.6 Hz), 6.79 (d, 1H, J = 8.0 Hz), 4.53-4.45 (m, 2H), 3.82 (s, 3H), 3.36 (d, 1H, J= 17.2 Hz), 3.09-3.00 (m, 1H) ppm.

Step 7) the preparation of compound 3-8

[00329] To a solution of compound 3-7 (6.45 g, 25.2 mmol) in methanol (80 mL) were added zinc powder (8.2 g, 126 mmol) and ammonium chloride (6.7 g, 126 mmol) and the mixture was stirred at 45 °C under N ₂ overnight. After the reaction was completed, the mixture was filtered through a Celite Pad and the filtrate was concentrated in vacuo. To the residue was added 50 mL of water and the resulting mixture was extracted with EtOAc (60 mLx3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 60/1) to give the title compound as colorless oil (3.69 g, 78%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 189.1 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.22 (t, 1H, J= 7.8 Hz), 6.89 (d, 1H, J= 7.6 Hz), 6.71 (d, 1H, J= 8.0 Hz), 4.11-3.99 (m, 2H), 3.82 (s, 3H), 3.63-3.52 (m, 1H), 3.27 (d, 1H, J= 17.2 Hz), 3.03-2.93 (m, 1H), 2.92-2.84 (m, 1H) ppm. Step 8) the preparation of compound 3-9

[00330] To a solution of compound 3-8 (2.3 g, 12.2 mmol) in 2,2'-(ethylenedioxy)diethanol (30 mL) were added KOH (2.1 g, 36.7 mmol) and hydrazine hydrate (4.8 mL, 97.8 mmol). The mixture was stirred at 130 °C for 20 mins and then stirred at 200 °C to remove water by Dean-Stark trap. After the reaction was completed, the mixture was cooled to rt and 100 mL of water was added. The resulting mixture was extracted with PE (150 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless liquid (1.42 g, 67%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 175.1 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.19 (t, 1H, J = 7.7 Hz), 6.84 (d, 1H, J = 7.5 Hz), 6.71 (d, 1H, J = 8.0 Hz), 3.84 (s, 3H), 3.78-3.70 (m, 1H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.80-2.70 (m, 1H), 2.60-2.46 (m, 1H), 2.30-2.17 (m, 1H), 1.86-1.70 (m, 2H) ppm.

Step 9) the preparation of compound 3-10

[00331] To a solution of compound 3-9 (9.92 g, 57.0 mmol) in THF (80 mL) and acetonitrile (40 mL)was added NIS (14.2 g, 63.0 mmol). The mixture was stirred for 10 mins and then a catalytic amount of trifluoroacetic acid was added dropwise. The resulting mixture was stirred at rt for 5 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and to the residue was added EtOAc (200 mL). The mixture was washed with saturated sodium sulfite (50 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless liquid (12.8 g, 75%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 301.1 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.52 (d, 1H, J = 8.4 Hz), 6.49 (d, 1H, J = 8.4 Hz), 3.81 (s, 3H), 3.70-3.62 (m, 1H), 3.17-3.08 (m, 1H), 3.08-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.60-2.48 (m, 1H), 2.32-2.20 (m, 1H), 1.94-1.84 (m, 1H), 1.82-1.68 (m, lH) ppm.

Step 10) the preparation of compound 3-11

[00332] To a solution of compound 3-10 (2.16 g, 7.2 mmol) in DCM (20 mL) at -78 °C was added BBr ₃ (2.7 mL, 28.8 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and further stirred at rt for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water (100 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (1.85 g, 90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 287.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 1.43 (d, 1H, J = 8.3 Hz), 6.46 (d, 1H, J = 8.3 Hz), 5.05 (s, 1H), 3.70-3.62 (m, 1H), 3.17-3.08 (m, 1H), 3.08-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.60-2.48 (m, 1H), 2.32-2.20 (m, 1H), 1.94-1.84 (m, 1H), 1.82-1.68 (m, lH) ppm.

Step 11) the preparation of compound 3-12

[00333] To a solution of compound 3-11 (1.55 g, 5.4 mmol) in DCM (20 mL) at 0 °C was added pyridine (1.1 mL, 13.5 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (1.4 mL, 8.1 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless liquid (2.21 g, 98%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 419.0 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.64 (d, 1H, J= 8.5 Hz), 6.86 (d, 1H, J= 8.5 Hz), 3.76-3.67 (m, 1H), 3.30-3.14 (m, 2H), 3.12-3.00 (m, 1H), 2.65-2.50 (m, 1H), 2.35-2.23 (m, 1H), 1.94-1.84 (m, 1H), 1.83-1.72 (m, 1H) ppm. Step 12) the preparation of compound 3-13

[00334] To a mixture of compound 1-7 (0.27 g, 0.96 mmol), compound 3-12 (0.40 g, 0.96 mmol), Pd(PPh ₃ ) ₄ (55.5 mg, 0.048 mmol) and potassium carbonate (0.33 g, 2.4 mmol) were added DME (8 mL) and pure water (2 mL) via syringe under N2 and the mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the mixture was diluted with EtOAc (50 mL), washed with saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.19 g, 45%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.26, 7.24 (s, s, IH), 7.07 (m, 2H), 6.75, 6.72 (s, s, IH), 5.77 (brs, IH), 4.03-3.96 (m, IH), 3.58-3.54 (m, IH), 3.50-3.46 (m, IH), 3.08-2.97 (m, IH), 2.81, 2.79, 2.76, 2.74 (m, m, m, m, IH), 2.56-2.46 (m, IH), 2.43, 2.41, 2.39, 2.37 (m, m, m, m, IH), 2.18-2.02 (m, 2H), 1.99-1.92 (m, 2H), 1.82-1.78 (m, IH), 1.61-1.52 (m, 2H), 1.26-1.19 (m, 2H) ppm.

Step 13) the preparation of compound 3-14

[00335] To a mixture of compound 3-13 (0.45 g, 1.0 mmol), compound 3-1 (0.43 g, 1.02 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.3 g, 51%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 595.7 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDCI ₃ ): δ 7.59 (s, IH), 7.39, 7.37 (s, s, IH), 7.38, 7.36 (t, t, IH), 7.22, 7.20 (s, s, IH), 6.75, 6.72 (s, s, IH), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.85-3.78 (m, IH), 3.69-3.65 (m, IH), 3.63 (s, 3H), 3.58-3.54 (m, IH), 3.50-3.46 (m, IH), 3.24-3.12 (m, IH), 2.70-2.57 (m, 2H), 2.30-1.92 (m, 10H), 1.82-1.78 (m, IH), 1.66-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 14) the preparation of compound 3-15

[00336] To a solution of compound 3-14 (0.3 g, 0.5 mmol) in DCM (5 mL) was added pyridine (0.16 mL, 2.0 mmol) dropwise at 0 °C. After the mixture was stirred at this temperature for 10 mins, Tf ₂ 0 (0.17 mL, 1.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (0.35 g, 96.4%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.59 (s, IH), 7.38, 7.35 (t, t, IH), 7.26, 7.24 (s, s, IH), 7.22, 7.21 (s, s, IH), 7.20, 7.19 (s, s, IH), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.88-3.78 (m, 2H), 3.69-3.64 (m, IH), 3.63 (s, 3H), 3.47-3.44 (m, IH), 3.24-3.12 (m, IH), 2.70-2.57 (m, 2H), 2.30-1.92 (m, 10H), 1.82-1.78 (m, IH), 1.66-1.55 (m, 2H), 1.30-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm. Step 15) the preparation of compound 3-16

[00337] To a solution of compound 1-11 (23 g, 107 mmol) and HATU (48.82 g, 128.4 mmol) in THF (250 mL) at 0 °C was added DIPEA (19.5 mL, 118 mmol). The mixture was stirred at this temperature for 0.5 hour and then compound 3-16-0 (22.1 g, 119 mmol) was added in portions. After the reaction was completed, the reaction was quenched with water (100 mL) and the THF was removed in vacuo. The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (400 mL). The solution was washed with sodium carbonate aqueous solution (150 mL x 3), dried over anhydrous Na ₂ S0 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 oil (31.6 g, 81%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion ) mlz: 367.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 16) the preparation of compound 3-17

[00338] To a mixture of compound 3-16 (4.11 g, 11.27 mmol), compound 1-6-2 (4.29 g, 16.9 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.65 mg, 0.8 mmol) and KOAc (2.76 g, 28.17 mmol) was added DMF (30 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 x 3) and saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (3.02 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 414.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.45-7.43 (m, 1H), 7.32-7.30 (m, 1H), 5.12-5.10 (m, 1H), 3.45-3.43 (m, 2H), 2.95-2.94 (m, 1H), 2.25-2.22 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H) ppm.

Step 17) the preparation of compound 3-18

[00339] To a solution of compound 3-17 (0.58 g, 1.4 mmol) in EtOAc (5.0 mL) was added a solution of HC1 in EtOAc (5 mL, 4 M) and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated and the residue was triturated with EtOAc (10 mL). The resulting mixture was filtered to give the title compound as a pale yellow solid (0.49 g, 91%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 314.2 [M+H] ⁺ .

Step 18) the preparation of compound 3-19

[00340] To a suspension of compound 3-18 (1.0 g, 2.6 mmol), compound 3-18-2 (0.59 g, 3.1 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.35 g, 2.6 mmol) in DCM (15 mL) at 0 °C was added DIPEA (1.72 mL, 10.4 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (40 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (1.17 g, 93%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 485.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 10.62 (brs, 1H), 8.22 (m, 1H),

7.73- 7.65 (m, 2H), 5.72 (d, 1H, J = 8.0 Hz), 5.43 (d, 1H, J = 8.0 Hz), 4.35-4.31 (m, 1H), 3.95-3.88 (m, 1H), 3.78-3.75 (m, 1H), 3.69-3.67 (m, 4H), 3.08-3.04 (m, 1H), 2.43-2.37 (m, 1H), 2.25-2.15 (m, 2H), 1.91 (s, 1H),

1.74- 1.72 (m, 1H), 1.52-1.50 (m, 1H), 1.35 (s, 12H), 1.24 (t, 2H, J = 8.0 Hz), 1.12-1.10 (m, 1H), 0.93-0.88 (m, 1H) ppm.

Step 19) the preparation of compound 3-20

[00341] To a mixture of compound 3-19 (0.48 g, 1.0 mmol), compound 3-15 (0.53 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.42 g, 45%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 468.6 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.59 (s, 1H), 7.48, 7.46 (s, s, 1H), 7.41, 7.40 (t, t, 1H), 7.23, 7.21 (d, d, 1H), 7.20, 7.19 (s, s, 1H), 5.39, 5.36 (d, d, 1H), 5.32-5.28 (m, 2H), 5.13-5.09 (m, 1H), 4.46-4.30 (m, 3H), 3.93-3.90 (m, 1H), 3.85-3.76 (m, 3H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.24-3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.42-2.34 (m, 1H), 2.30-1.86 (m, 14H), 1.84-1.80 (m, 1H), 1.66-1.49 (m, 3H), 1.27-1.10 (m, 3H), 0.98-0.95 (m, 6H), 0.92-0.89 (m, 6H) ppm.

Example 4

Synthetic route

Step 1) the preparation of compound 4-2

[00342] To a solution of compound 4-1 (10 g, 77.5 mmol) in MeOH (50 mL) at 0 °C was added thionyl chloride (5.5 mL, 75.8 mmol) dropwise. The mixture was stirred at this temperature for 1 hour and then stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with aqueous NaHCC>3 solution (50 mL). The methanol was removed in vacuo and the residue was extracted with DCM (35 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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) mlz: 144.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 2) the preparation of compound 4-3

[00343] To a solution of compound 4-2 (6.45 g, 45.06 mmol) in MeCN (30 mL) at 0 °C was added DMAP (0.55 g, 4.5 mmol). The mixture was stirred for 10 mins and then di-tert-butyl dicarbonate (10.82 g, 49.56 mmol) was added dropwise. At the end of the addition, the mixture was stirred at this temperature for 30 mins and then stirred at rt for 2 hour. 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) mlz: 144.2 [M-BOC] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 3) the preparation of compound 4-4

[00344] To a solution of compound 4-3 (3.74 g, 15.4 mmol) in toluene (50 mL) at -78 °C was added a solution of lithium triethylborohydride (1.79 g, 16.9 mmol, 1M in THF) dropwise. The mixture was stirred at this temperature for 70 mins and then DIPEA (3.2 mL, 19.4 mmol), DMAP (0.19 g, 1.54 mmol) and TFAA (3 mL, 40.4 mmol) were added in turn. The resulting mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of ammonium chloride (15 mL) and the aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 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 (2.26 g, 64.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 128.2 [M-BOC] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 4-5

[00345] To a solution of diethylzinc (0.49 g, 3.94 mmol) in toluene (6 mL) was added chloroiodomethane (1.40 g, 7.9 mmol) at 0 °C. The mixture was stirred for 45 mins and a solution of compound 4-4 (0.3 g, 1.32 mmol) in toluene (4 mL) was added dropwise. The reaction mixture was stirred at this temperature for 18 hours. After the reaction was completed, the mixture was quenched with a saturated aqueous solution of NH ₄ C1 (15 mL) and the aqueous layer was extracted with EtOAc (25 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 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 solid (0.19 g, 59.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 142.2 [M-BOC] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 5) the preparation of compound 4-6

[00346] To a solution of compound 4-5 (1.02 g, 4.23 mmol) in THF (20 mL) at 0 °C was added a solution of Lithium hydroxide hydrate (0.89 g, 21.2 mmol) in water (10 mL) dropwise. At the end of the addition, the mixture was stirred at 40 °C for 12 hours. After the reaction was completed, the THF was removed in vacuo and 10 mL of water was added. The resulting mixture was extracted with EtOAc (25 mL x 3). The aqueous layers were then acidified with aqueous HC1 (10 %) till pH = 1 and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a white solid (0.84 g, 87.5%). The compound was characterized by the following spectroscopic data: MS (ESI, neg.ion) mlz: 226.2 [M-H] ^~ ; and ^l U NMR (400 MHz, CD ₃ OD): δ 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) ppm.

Step 6) the preparation of compound 4-7

[00347] To a solution of compound 4-6 (2.43 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (25 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. The mixture was stirred at this temperature for 0.5 hour and compound 3-16-0 (2.21 g, 11.9 mmol) was added in portions. Then the mixture was stirred at rt for 4 hours. After the reaction was completed, the reaction was quenched with water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The resulting solution was washed with an aqueous solution of sodium carbonate (50 mL x 3), dried over anhydrous Na ₂ S0 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 (2.02 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 378.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.67 (dd, 1H), 7.22, 7.20 (d, d, 1H), 7.19, 7.17 (d, d, 1H), 5.03-5.00 (m, 1H), 3.31-3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.12-2.07 (m, 1H), 1.53-1.48 (m, 1H), 1.46 (s, 9H), 1.42-1.38 (m, 1H), 1.00-0.97 (m, 1H) ppm.

Step 7) the preparation of compound 4-8

[00348] To a solution of compound 4-7 (1.03 g, 2.74 mmol) in EtOAc (5.0 mL) was added a solution of HQ in EtOAc (6.0 mL, 4 M) at 0 °C and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated and the residue was triturated with EtOAc (10 mL). The resulting mixture was filtered to give the title compound as a pale yellow solid (0.82 g, 85.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 278.2 [M+H] ⁺ .

Step 8) the preparation of compound 4-9

[00349] To a suspension of compound 4-8 (0.66 g, 1.88 mmol), compound 1-18-2 (0.49 g, 2.82 mmol) and EDCI (0.54 g, 2.82 mmol) in DCM (10 mL) was added DIPEA (1.86 mL, 11.28 mmol) dropwise slowly at 0 °C and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (50 mL). The resulting mixture was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.69 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 435.3 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.67 (dd, 1H), 7.22, 7.20 (d, d, 1H), 7.19, 7.17 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.13-4.08 (m, 1H), 3.63 (s, 3H), 3.42-3.36 (m, 1H), 2.62-2.55 (m,lH), 2.21-2.09 (m, 2H), 1.53-1.45 (m, 1H), 0.97-0.89 (m, 7H), 0.50-0.46 (m, 1H) ppm.

Step 9) the preparation of compound 4-10

[00350] To a mixture of compound 4-9 (3.08 g, 7.1 mmol), compound 1-6-2 (2.72 g, 10.7 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.57 g, 0.7 mmol) and KOAc (2.09 g, 21.3 mmol) was added DMF (30 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (2.22 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 483.5 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.82 (dd, 1H), 7.65, 7.63 (d, d, 1H), 7.45, 7.42 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.13-4.08 (m, 1H), 3.63 (s, 3H), 3.42-3.36 (m, 1H), 2.62-2.55 (m, 1H), 2.22-2.09 (m, 2H), 1.53-1.45 (m, 1H), 1.32, 1.29 (m, 12H), 0.97-0.89 (m, 7H), 0.50-0.46 (m, 1H) ppm.

Step 10) the preparation of compound 4-11

[00351] To a mixture of compound 4-10 (0.24 g, 0.5 mmol), compound 1-9 (0.29 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were added DME (6 mL) and pure water (2 mL) via syringe under N2 and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL). The mixture was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.28 g, 71%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDCI ₃ ): δ 7.62, 7.60 (d, d, 1H), 7.53-7.49 (m, 2H), 7.41, 7.38 (s, s, 1H), 7.32 (m, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.14-5.10 (m, 1H), 4.13-4.08 (m, 1H), 3.79-3.74 (m, 2H), 3.73-3.71 (m, 1H), 3.63 (s, 3H), 3.45-3.36 (m, 2H), 2.62-2.55 (m, 1H), 2.22-2.11 (m, 2H), 2.03-1.90 (m, 4H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.53-1.45 (m, 1H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.95-0.91 (m, 1H), 0.90, 0.88 (m, m, 3H), 0.50-0.46 (m, 1H) ppm.

Step 11) the preparation of compound 4-12

[00352] To a mixture of compound 4-11 (0.39 g, 0.5 mmol), compound 3-1 (0.21 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and potassium carbonate (0.17 g, 1.25 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.15 g, 32%). The compound was

2+ 1

characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 467.6 [M+2H] ; and H NMR (400 MHz, CDCI ₃ ): δ 7.81 (s, 1H), 7.62, 7.59 (d, d, 1H), 7.53, 7.51 (d, d, 1H), 7.50, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.32 (m, 1H), 7.26, 7.24 (s, s, 1H), 5.32, 5.30 (m, m, 2H), 5.29-5.25 (m, 1H), 5.14-5.10 (m, 1H), 4.41-4.36 (m, 1H), 4.13-4.08 (m, 1H), 3.85-3.73 (m, 5H), 3.68-3.65 (m, 1H), 3.63 (s, 6H), 3.42-3.36 (m, 1H), 2.62-2.55 (m, 1H), 2.30-1.89 (m, 11H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.53-1.45 (m, 1H), 1.30-1.16 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.94-0.91 (m, 1H), 0.90, 0.88 (m, m, 6H), 0.50-0.46 (m, 1H) ppm.

Example 5

Synthetic

Step 1) the preparation of compound 5-1

[00353] To a solution of 1,4-benzoquinone (10.0 g, 92.5 mmol) in DCM (90 mL) was added 1,3-cyclohexadiene (11.12 g, 138.8 mmol) dropwise at -10 °C. The mixture was stirred at this temperature for 1 hour and then stirred at rt for 48 hours. After the reaction was completed, the solvent was removed in vacuo and to the residue was added «-hexane (500 mL). After the mixture was stirred for a while and filtered, the filtrated was dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a pale yellow solid (12.5 g, 71.8%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 189.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 6.59 (s, 2H), 6.47 (s, 2H), 3.42 (s, 2H), 3.20-3.18 (m, 2H), 1.52-1.39 (m, 4H) ppm.

Step 2) the preparation of compound 5-2

[00354] A solution of compound 5-1 (5.0 g, 26.6 mmol) and sodium acetate (6.54 g, 79.7 mmol) in methanol (100 mL) was stirred at 50 °C for 4 hours under N ₂ . After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as a white solid (4.56 g, 91.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 189.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 6.43-6.39 (m, 2H), 6.28 (s, 2H), 3.65 (s, 2H), 3.45 -3.41 (m, 2H), 2.48-2.44 (m, 2H), 2.09-2.01 (m, 2H) ppm.

Step 3) the preparation of compound 5-3

[00355] A suspension of compound 5-2 (4.0 g, 21.3 mmol) and Pd/C (0.4 g) in methanol (50 mL) was stirred at rt for 1.5 hours under ¾ at atmospheric pressure. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by re-crystallization to give the title compound as a white solid (3.06 g, 75.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 191.1 [M+H] ⁺ ; and *H NMR (400 MHz, d ₆ -DMSO): δ 7.18 (s, 2H), 6.21 (s, 2H), 3.47-3.44 (m, 2H), 1.61-1.54 (m, 4H), 1.42-1.38 (m, 4H) ppm.

Step 4) the preparation of compound 5-4

[00356] To a solution of compound 5-3 (3.61 g, 19.0 mmol) in DCM (20 mL) at 0 °C was added pyridine (9.0 g, 114 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (21.0 g, 76.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v) = 10/1) to give the title compound as colorless oil (8.4 g, 97.3%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.15 (s, 2H), 3.69-3.67 (m, 2H), 1.75-1.71 (m, 4H), 1.36-1.32 (m, 4H) ppm.

Step 5) the preparation of compound 5-5

[00357] A suspension of compound 5-4 (7.99 g, 17.6 mmol), compound 1-7 (5.15 g, 18.0 mmol), Pd(PPh ₃ ) ₄ (1.02 g, 0.88 mmol) and potassium carbonate (9.73 g, 70.4 mmol) in a mixed solvent of DME and H ₂ 0 (80 mL, v/v = 3/1) was stirred at 90 °C for 3 hours under N ₂ . After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (250 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v) = 8/1) to give the title compound as a white solid (4.08 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 465.5 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.14, 7.12 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 7.04, 7.02 (s, s, 1H), 6.58, 6.56 (s, s, 1H), 5.77 (brs, 1H), 3.59-3.54 (m, 1H), 3.45-3.40 (m, 1H), 3.23-3.13 (m, 1H), 2.78-2.69 (m, 1H), 1.99-1.78 (m, 5H), 1.62-1.49 (m, 5H), 1.30-1.19 (m, 4H) ppm.

Step 6) the preparation of compound 5-6

[00358] To a solution of compound 5-5 (1.76 g, 3.8 mmol) in DCM (10 mL) at 0 °C was added pyridine (1.22 mL, 15.2 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (21.0 g, 76.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (1.81 g, 80%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.14, 7.12 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.06, 7.04 (s, s, 1H), 7.00, 6.98 (s, s, 1H), 3.74-3.71 (m, 1H), 3.41-3.38 (m, 1H), 3.23-3.13 (m, 1H), 2.78-2.69 (m, 1H), 2.03-1.78 (m, 5H), 1.62-1.49 (m, 5H), 1.30-1.19 (m, 4H) ppm.

Step 7) the preparation of compound 5-7

[00359] To a mixture of compound 5-6 (1.19 g, 2.0 mmol), compound 1-6-2 (1.07 g, 4.2 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (82 mg, 0.1 mmol) and KOAc (0.49 g, 5 mmol) was added DMF (10 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. 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 (50 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (0.44 g, 40%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.68, 7.65 (s, s, IH), 7.62, 7.60 (s, s, IH), 7.42, 7.40 (s, s, IH), 7.38, 7.36 (s, s, IH), 3.70-3.67 (m, 2H), 3.20-3.03 (m, 2H), 1.96-1.90 (m, IH), 1.80-1.74 (m, 2H), 1.69-1.58 (m, 2H), 1.57-1.53 (m, IH), 1.46-1.33 (m, 4H), 1.32, 1.29 (q, q, 24H), 1.23-1.17 (m, IH), 1.14-1.01 (m, 3H) ppm.

Step 8) the preparation of compound 5-9

[00360] To a solution of compound 5-8 (6.86 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 7 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of sodium thiosulfate (100 mL) and filtered through a Celite Pad. The filtrate was extracted with DCM (100 mL x 3) and the organic layers were washed, dried over anhydrous Na ₂ S0 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%).

Step 9) the preparation of compound 5-10

[00361] To a solution of compound 5-9 (5.81 g, 23.9 mmol) in DCM (70 mL) at -78 °C was added Et ₂ NSF ₃ (4.85 mL, 35.9 mmol) dropwise slowly. At the end of the addition, the mixture was stirred for 2 hours at -78 °C and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of NH ₄ CI (50 mL) and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>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) mlz: 266.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.

Step 10) the preparation of compound 5-11

[00362] To a solution of compound 5-10 (5.0 g, 18.86 mmol) in THF (40 mL) at 0 °C was added an aqueous solution of lithium hydroxide (1.5 g, 20 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1 M) till pH = 5 and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1 M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>4 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.

Step 11) the preparation of compound 5-12

[00363] To a solution of compound 5-11 (2.37 g, 9.43 mmol) in THF (30 mL) at 0 °C was added borane (14.2 mL, 1 M in THF) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction was quenched with methanol (4 mL), and concentrated in vacuo. The residue was dissolved in DCM (100 mL). The solution was washed with water (40 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as colorless slurry (1.79 g, 80%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 MHz, CDC1 ₃ ): δ 4.43-4.27 (m, 1H), 3.59-3.34 (m, 2H), 3.60-3.46 (m, 2H), 2.48-2.18 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.

Step 12) the preparation of compound 5-14

[00364] To a solution of compound 5-12 (1.8 g, 7.59 mmol) in DCM (20 mL) were added TCCA (1.77 g, 7.59 mmol) and a solution of TEMPO in DCM (0.12 g, 0.76 mmol, 5.0 mL) in turn at 0 °C. At the end of the addition, the mixture was stirred at this temperature for 1 hour and then stirred at rt for 1 hour. After the reaction was completed, the mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium sulfite (40 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved in a solution of NH ₃ in methanol (20 mL, 7 M). The solution was stirred at 0 °C for 0.5 hour and then stirred at rt for 1 hour and then to the mixture was added glyoxal (2.0 mL, 40%) dropwise at 0 °C. At the end of the addition, the resulting mixture was stirred at rt for 24 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (150 mL). The solution was washed with water (50 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 60/1) to give the title compound as colorless oil (1.04 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 274.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.00 (s, 2H), 5.83-5.80 (m, 1H), 4.05-3.79 (m, 1H), 3.74-3.52 (m, 1H), 3.11-2.33 (m, 2H), 1.51 (s, 9H) ppm.

Step 13) the preparation of compound 5-15

[00365] To a solution of compound 5-14 (0.93 g, 3.4 mmol) in DCM (30 mL) was added NIS (1.7 g, 7.5 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of sodium sulfite (50 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a yellow solid (1.07 g, 60%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 526.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDCI ₃ ): δ 5.13-5.08 (m, 1H), 3.91-3.87 (m, 1H), 3.58-3.46 (m, 2H), 2.74-2.72 (m, 1H), 1.51 (s, 9H) ppm.

Step 14) the preparation of compound 5-16

[00366] To a solution of compound 5-15 (1.03 g, 1.96 mmol) in ethanol (10 mL) were added sodium sulfite (2.47 g, 19.6 mmol) and water (10 mL) and the mixture was stirred at 90 °C for 30 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (80 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as a white solid (0.26 g, 33%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 400.2 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.08 (s, 1H), 5.33-4.95 (m, 1H), 3.91-3.87 (m, 1H), 3.78-3.36 (m, 2H), 2.96-2.55 (m, 1H), 1.49 (s, 9H) ppm.

Step 15) the preparation of compound 5-17

[00367] To a solution of compound 5-16 (0.80 g, 2.0 mmol) in EtOAc (4.0 mL) was added a solution of HQ in EtOAc (5.0 mL, 4M) dropwise slowly and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered to afford a solid (0.33 g, 90%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 399.1 [M+H] ⁺ .

Step 16) the preparation of compound 5-18

[00368] A suspension of compound 5-17 (1.34 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) in DCM (10.0 mL) was stirred at 0 °C for 5 mins and then DIPEA (2.38 mL, 14.4 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hour. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL). The resulting mixture was washed with an aqueous ammonium chloride solution, dried over anhydrous Na ₂ S0 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 (1.41g, 86%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 457.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.42 (s, 1H), 5.56, 5.55 (d, d, 1H), 5.11-5.06 (m, 1H), 4.32-4.28 (m, 1H), 4.21-4.19, 4.17-4.15, 4.13-4.11, 4.09-4.07 (m, m, m, m, 1H), 3.94-3.93, 3.91-3.89, 3.87-3.84, 3.82-3.81 (m, m, m, m, 1H), 3.66 (s, 3H), 2.93-2.75 (m, 1H), 2.54-2.34 (m, 1H), 2.28-2.16 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H) ppm.

Step 17) the preparation of compound 5-19

[00369] To a mixture of compound 5-18 (0.23 g, 0.5 mmol), compound 5-7 (0.28 g, 0.5 mmol), anhydrous potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.19 g, 40%). The

2+ compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) mlz: 479.5 [M+2H] ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.99 (s, 1H), 7.60 (s, 1H), 7.39, 7.36 (s, s, 1H), 7.32, 7.30 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.81, 6.79 (s, s, 1H), 5.32, 5.29 (d, d, 2H), 5.20-5.15 (m, 2H), 4.48-4.43 (m, 2H), 4.21-4.19, 4.17-4.15, 4.13-4.11, 4.09-4.07 (m, m, m, m, 2H), 3.94-3.93, 3.91-3.89, 3.87-3.84, 3.82-3.81 (m, m, m, m, 2H), 3.77-3.74 (m, 1H), 3.70-3.67 (m, 1H), 3.63 (s, 6H), 3.48-3.38 (m, 2H), 2.92-2.74 (m, 2H), 2.52-2.31 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.97 (m, 1H), 1.95-1.89 (m, 1H), 1.87-1.83 (m, 1H), 1.71-1.50 (m, 5H), 1.38-1.16 (m, 6H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 6

Synthetic route:

Step 1) the preparation of compound 6-1

[00370] To a mixture of compound 1-9 (0.58 g, 1.0 mmol), compound 3-17 (0.41 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N2 and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 foam (0.32 g, 45%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 MHz, CDCI ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.51, 7.49 (s, s, 1H), 7.41, 7.38 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.04-4.99 (m, 1H), 3.82-3.71 (m, 4H), 3.64-3.57 (m, 1H), 3.45-3.42 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 1H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.53 (s, 9H), 1.30-1.17 (m, 4H) ppm.

Step 2) the preparation of compound 6-2

[00371] To a mixture of compound 6-1 (0.72 g, 1.0 mmol), compound 1-6-2 (0.28 g, 1.1 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (82 mg, 0.1 mmol) and KOAc (0.25 g, 2.5 mmol) was added DMF (5 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (30 mL) and filtered through a Celite Pad. The filtrate was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.35 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 698.7 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.55, 7.53 (s, s, 1H), 7.50-7.48 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 5.04-4.99 (m, 1H), 3.82-3.73 (m, 4H), 3.69-3.66 (m, 1H), 3.64-3.57 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 1H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 5H), 1.84-1.74 (m, 2H), 1.61-1.55 (m, 2H), 1.53 (s, 9H), 1.32, 1.29 (q, q, 12H), 1.26-1.17 (m, 3H), 1.07-1.01 (m, 1H) ppm.

Step 3) the preparation of compound 6-3

[00372] To a mixture of compound 6-2 (0.70 g, 1.0 mmol), compound 1-16 (0.37 g, 1.02 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) were added EtOH (5.0 mL) and pure water (1.0 mL) via syringe under N2 and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow foam (0.36 g, 45%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 808.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.51, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 5.05-4.99 (m, 2H), 3.82-3.73 (m, 5H), 3.64-3.57 (m, 2H), 3.31-3.24 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.35 (m, 2H), 2.29-2.15 (m, 2H), 2.10-1.89 (m, 7H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.53 (s, 19H), 1.30-1.16 (m, 4H) ppm.

Step 4) the preparation of compound 6-4

[00373] To a solution of compound 6-3 (0.24 g, 0.3 mmol) in EtOAc (3.0 mL) was added a solution of HQ in EtOAc (2.0 mL, 4 M) at 0 °C and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated. The residue was triturated with EtOAc (5 mL) and the resulting mixture was filtered to give the title compound as a white solid (216 mg, 96%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 607.8 [M+H] ⁺ .

Step 5) the preparation of compound 6-5

[00374] To a solution of compound 6-4 (0.15 g, 0.2 mmol), compound 6-4-2 (88 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HO AT (41 mg, 0.3 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.26 mL, 1.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (109 mg, 55%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 495.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.51, 7.49 (s, s, 1H), 7.48, 7.46 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.35-7.29 (m, 6H), 7.26, 7.24 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 7.19-7.15 (m, 4H), 5.91-5.89 (d, d, 2H), 5.35-5.34, 5.33-5.32 (m, m, 2H), 5.19-5.14 (m, 2H), 3.91-3.84 (m, 2H), 3.79-3.66 (m, 6H), 3.64 (s, 6H), 2.42-2.08 (m, 6H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H) ppm.

Example 7

Synthetic route:

Step 1) the preparation of compound 7-1

[00375] To a mixture of compound 1-16 (0.55 g, 1.5 mmol), compound 1-6-2 (0.42 g, 1.65 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.12 g, 0.15 mmol) and KOAc (0.37 g, 3.75 mmol) was added DMF (3 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 (15 mL x 3) and saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 beige solid (0.38 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 364.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.66 (s, 1H), 5.20-5.16 (m, 1H), 3.59-3.53 (m, 1H), 3.28-3.21 (m, 1H), 2.38-2.30 (m, 1H), 2.27-2.12 (m, 2H), 2.07-1.98 (m, 1H), 1.53 (s, 9H), 1.39, 1.36 (q, q, 12H) ppm.

Step 2) the preparation of compound 7-2

[00376] To a solution of LDA (7.4 mL, 1.1 eq) in THF (15 mL) were added furan (15 mL) and l-bromo-2,5-dimethoxybenzene (2.16 g, 10 mmol) in turn at -78 °C. The mixture was stirred at this temperature for 30 mins and quenched with water and then the mixture was allowed to warm up to rt and extracted with ethyl ether (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Hex/EtOAc (v/v) = 1/1) to give the title compound as a white solid (2.1 g, 86%). The compound was characterized by the following spectroscopic data: ¾ NMR (400MHz, CDC1 ₃ ) δ 7.06 (2H, s), 6.97 (2H, s), 6.54 (2H, s), 5.92 (2H, s), 3.78 (6H, s) ppm.

Step 3) the preparation of compound 7-3

[00377] To a solution of compound 7-2 (2.5 g) in EtOAc (150 mL) was added Pd/C (0.6 g) and the mixture was stirred under ¾ at rt overnight. Then the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound 7-3 (2.38, 92%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 1.36-1.41 (m, 2H), 2.01-2.06 (m, 2H), 3.79 (s, 6H), 5.56-5.58 (m, 2H), 6.63 (s, 2H). Step 4) the preparation of compound 7-4

[00378] To a solution of compound 7-3 (2.06 g, 10 mmol) in DCM (50 mL) at -78 °C was added BBr ₃ (7.7 mL, 80 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and further stirred at rt for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (1.6 g, 90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 179.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 6.55 (s, 2H), 6.51 (br, 2H), 5.51-5.45 (m, 2H), 1.78-1.65 (m, 2H), 1.00-0.87 (m, 2H) ppm.

Step 5) the preparation of compound 7-5

[00379] To a solution of compound 7-4 (1.78 g, 10 mmol) in DCM (20 mL) at 0 °C was added pyridine (4.8 mL, 60 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (6.73 mL, 40 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction mixture was quenched with ice water (25 mL) and the aqueous layer was extracted with DCM (30 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (3.98 g, 90%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.36 (s, 2H), 5.53-5.47 (m, 2H), 1.69-1.56 (m, 2H), 0.91-0.78 (m, 2H) ppm.

Step 6) the preparation of compound 7-6

[00380] To a mixture of compound 1-7 (0.29 g, 1.0 mmol), compound 7-5 (0.44 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) were added DME (4.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (20 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.23 g, 50%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 MHz, CDCI ₃ ): δ 7.24, 7.22 (s, s, 1H), 7.19, 7.17 (s, s, 1H), 7.11, 7.09 (s, s, 1H), 6.58, 6.56 (s, s, 1H), 5.77 (brs, 1H), 5.70-5.63 (m, 1H), 5.42-5.36 (m, 1H), 3.58-3.55 (m, 1H), 3.51-3.48 (m, 1H), 2.02-1.92 (m, 2H),

I.85-1.81 (m, 1H), 1.77-1.65 (m, 2H), 1.62-1.58 (m, 1H), 1.29-1.19 (m, 2H), 0.99-0.87 (m, 2H) ppm.

Step 7) the preparation of compound 7-7

[00381] To a mixture of compound 7-6 (0.23 g, 0.5 mmol), compound 7-1 (0.18 g, 0.5 mmol), anhydrous potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) were added EtOH (4.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.16 g, 60%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.88 (s, 1H), 7.45, 7.43 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.20, 7.17 (s, s, 1H), 6.58, 6.56 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.07-5.00 (m, 1H), 3.64-3.55 (m, 2H), 3.51-3.48 (m, 1H), 3.31-3.24 (m, 1H), 2.47-2.38 (m, 1H), 2.29-2.17 (m, 1H), 2.10-1.92 (m, 4H), 1.86-1.78 (m, 2H), 1.75-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.41 (s, 9H), 1.29-1.19 (m, 2H), 1.08-1.00 (m, 1H), 0.98-0.89 (m, 1H) ppm.

Step 8) the preparation of compound 7-8

[00382] To a solution of compound 7-7 (1.03 g, 1.9 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.9 g,

I I.4 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (2.1 g, 7.6 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (1.02 g, 80%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.88 (s, 1H), 7.45, 7.43 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.13, 7.11 (s, s, 1H), 7.08, 7.06 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.07-5.00 (m, 1H), 3.64-3.58 (m, 1H), 3.56-3.53 (m, 1H), 3.49-3.46 (m, 1H), 3.31-3.24 (m, 1H), 2.47-2.38 (m, 1H), 2.29-2.17 (m, 1H), 2.10-1.92 (m, 4H), 1.86-1.78 (m, 2H), 1.75-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.41 (s, 9H), 1.33-1.27 (m, 1H), 1.25-1.19 (m, 1H), 1.08-1.00 (m, 1H), 0.98-0.89 (m, 1H) ppm.

Step 9) the preparation of compound 7-10

[00383] A mixture of compound 7-9 (5.91 g, 29 mmol), NBS (5.76 g, 32 mmol) and p-TSA (1.0 g, 5.2 mmol) was stirred at 100 °C for 0.5 hour. After the reaction was completed, the mixture was cooled to rt and dissolved in DCM (100 mL). The solution was washed with water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v) = 5/1) to give the title compound as yellow slurry (5.72 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 285.1 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.55 (d, 1H, J= 4.0 Hz), 7.14 (d, 1H, J= 4.0 Hz), 4.29 (s, 2H) ppm.

Step 10) the preparation of compound 7-11

[00384] To a solution of compound 7-10 (5.58 g, 19.8 mmol) and compound 1-11 (4.7 g, 21.8 mmol) in DCM (100 mL) was added DIPEA (3.62 mL, 21.9 mmol) dropwise slowly at 0 °C. At the end of the addition, the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was quenched with water (50 mL), the DCM was removed in vacuo and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (5.78 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 418.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.49 (d, 1H, J = 4.0 Hz), 7.13 (t, 1H, J = 4.0 Hz), 5.23-5.02 (m, 2H), 4.48-4.37 (m, 1H), 3.60-3.38 (m, 2H), 2.29-2.26 (m, 2H), 2.11-1.92 (m, 2H), 1.44 (s, 9H) ppm.

Step 11) the preparation of compound 7-12

[00385] A suspension of compound 7-11 (7.92 g, 19 mmol) and NH ₄ OAc (22.2 g, 288 mmol) in xylene (100 mL) was stirred at 140 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and 100 mL of water was added. The aqueous layer was then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (6.94 g, 92%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 398.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 10.51 (br, 1H), 7.07 (s, 1H), 6.94 (s, 2H), 4.91-4.90 (m, 1H), 3.39 (s, 2H), 2.98 (s, 1H), 2.12 (s, 2H), 1.95 (s, 1H), 1.48 (s, 9H) ppm.

Step 12) the preparation of compound 7-13

[00386] To a mixture of compound 7-12 (1.0 g, 2.5 mmol), compound 1-6-2 (0.96 g, 3.8 mmol), Pd(dppf)Cl ₂ -CH ₂ Ci2 (0.11 g, 0.13 mmol) and KOAc (0.74 g, 7.5 mmol) was added DMF (12 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. 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 (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.89 g, 80%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 10.51 (br, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 4.94-4.93 (m, 1H), 3.39 (s, 2H), 2.99 (s, 1H), 2.12-1.94 (m, 4H), 1.49 (s, 9H), 1.34 (s, 12H), 1.24 (m, 8H) ppm.

Step 13) the preparation of compound 7-14

[00387] To a mixture of compound 7-13 (0.45 g, 1.0 mmol), compound 7-8 (0.67 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.38 g, 45.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 842.1 [M+H] ⁺ ; and ^l n NMPv (400 MHz, CDC1 ₃ ): δ 7.88 (s, 1H), 7.53, 7.51 (s, s, 1H), 7.50, 7.48 (s, s, 1H), 7.47 (s, 1H), 7.40, 7.38 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.14, 7.13 (d, d, 1H), 7.01, 7.00 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.16-5.11 (m, 1H), 5.05-5.01 (m, 1H), 3.92-3.90 (m, 1H), 3.83-3.81 (m, 1H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H), 2.48-2.38 (m, 2H), 2.29-2.16 (m, 2H), 2.12-1.95 (m, 6H), 1.90-1.78 (m, 2H), 1.75-1.63 (m, 2H), 1.53 (s, 9H), 1.41 (s, 9H), 1.30-1.22 (m, 2H), 1.08-1.00 (m, 1H), 0.98-0.89 (m, lH) ppm.

Step 14) the preparation of compound 7-15

[00388] To a solution of compound 7-14 (0.25 g, 0.3 mmol) in EtOAc (3.0 mL) was added a solution of HC1 in EtOAc (2.0 mL, 4 M) at 0 °C and the mixture was stirred at rt for 8 hours. After the mixture was completed, the mixture was concentrated. The residue was triturated with EtOAc (5 mL) and the resulting mixture was filtered to give the title compound as a white solid (224 mg, 95%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 641.3 [M+H] ⁺ .

Step 15) the preparation of compound 7-16

[00389] To a solution of compound 7-15 (0.16 g, 0.2 mmol), compound 7-15-2 (90 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HO AT (41 mg, 0.3 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.26 mL, 1.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (93 mg, 55%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 518.7 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.79 (s, 1H), 7.53, 7.51 (s, s, 1H), 7.50, 7.48 (s, s, 1H), 7.41 (s, 1H), 7.40, 7.38 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.14, 7.13 (d, d, 1H), 7.01, 7.00 (s, s, 1H), 5.78-5.75 (m, 1H), 5.43-5.40 (m, 1H), 5.24-5.19 (m, 3H), 5.13-5.08 (m, 1H), 4.47-4.41 (m, 2H), 3.92-3.89 (m, 1H), 3.86-3.80 (m, 3H), 3.70-3.64 (m, 2H), 3.63 (s, 6H), 2.35-2.05 (m, 8H), 2.03-1.78 (m, 6H), 1.75-1.62 (m, 4H), 1.58-1.51 (m, 4H), 1.40-1.31 (m, 8H), 1.30-1.22 (m, 2H), 1.18-1.00 (m, 7H), 0.98-0.89 (m, lH) ppm. Example 8

Synthetic route:

Step 1) the preparation of compound 8-2

[00390] To a solution of compound 8-1 (1.54 g, 19 mmol) and compound 8-1-2 (1.36 g, 10 mmol) in freshly distilled THF (25 mL) was added «-butyllithium (6.7 mL, 1.6 M in «-hexane) dropwsie at -78 °C under N ₂ . At the end of the addition, the mixture was stirred at this temperature for 1 hour and allowed to warm up to rt for overnight stirring. After the reaction was completed, the reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with diethyl ether (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 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 pale yellow solid (1.09 g, 50.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 218.5 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDCI ₃ ): δ 6.93-6.91 (t, 1H, J= 4.0 Hz), 6.83 (m, 2H), 4.71-4.69 (m, 2H), 3.71 (s, 6H), 2.11 (s, 3H) ppm. Step 2) the preparation of compound 8-3 [00391] To a solution of compound 8-2 (1.74 g, 8.03 mmol) in anhydrous ethanol (40 mL) was added Pd/C (10%, 0.35 g) and the mixture was stirred under H ₂ (10 atm) at rt for 24 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to give the tile compound 8-3 as a white solid (1.51 g, 86%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion ) mlz: 220.3 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 6.60-6.24 (s, 2H), 4.28-4.26 (m, 2H), 3.70 (s, 6H), 2.11 (s, 3H), 1.26-1.11 (m, 4H) ppm.

Step 3) the preparation of compound 8-4

[00392] To a solution of compound 8-3 (2.19 g, 10 mmol) in DCM (50 mL) at -78 °C was added BBr ₃ (7.7 mL, 80 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and stirred at rt for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (1.72 g, 90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 192.5 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 6.42 (s, 2H), 5.77 (br, 2H), 4.24-4.22 (m, 2H), 2.15 (s, 3H), 1.31-1.18 (m, 4H) ppm. Step 4) the preparation of compound 8-5

[00393] To a solution of compound 8-4 (1.91 g, 10 mmol) in DCM (20 mL) at 0 °C was added pyridine (4.8 mL, 60 mmol) dropwise and the mixture was stirred at this temperature for 10 mins, and then Tf ₂ 0 (6.73 mL, 40 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (25 mL) and the aqueous layer was extracted with DCM (30 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (4.32 g, 95%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.29 (s, 2H),

4.39- 4.37 (m, 2H), 2.50 (s, 3H), 1.24-1.09 (m, 4H) ppm.

Step 5) the preparation of compound 8-6

[00394] A suspension of compound 8-5 (2.27 g, 5.0 mmol), compound 1-7 (1.43 g, 5.0 mmol), anhydrous potassium carbonate (1.73 g, 12.5 mmol) and Pd(PPli ₃ )4 (0.29 g, 0.25 mmol) in a mixed solvent of DME and pure water (24 mL, DME/H ₂ 0 (v/v = 3/1)) was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was allowed to cool to rt, and diluted with EtOAc (150 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 liquid (1.16 g, 50%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDCI ₃ ): δ 7.14, 7.12 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 6.98, 6.96 (s, s, 1H), 6.52, 6.50 (s, s, 1H), 5.77 (brs, 1H),

4.40- 4.37 (m, 1H), 4.04-4.01 (m, 1H), 3.58-3.55 (m, 1H), 3.52-3.50 (m, 1H), 2.25 (s, 3H), 2.01-1.92 (m, 2H), 1.84-1.80 (m, 1H), 1.61-1.52 (m, 2H), 1.31-1.16 (m, 4H), 0.98-0.89 (m, lH) ppm Step 6) the preparation of compound 8-7

[00395] A suspension of compound 8-6 (0.47 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) in a mixed solvent of DME and pure water (8 mL, DME/H ₂ 0 (v/v = 3/1)) was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (150 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.27 g, 45%). The compound was characterized by the following spectroscopic data: ¹ !! NMR (400 MHz, CDC1 ₃ ): δ 7.46, 7.44 (s, s, 1H), 7.40 (s, 1H), 7.36, 7.34 (s, s, 1H), 7.15, 7.13 (s, s, 1H), 6.52, 6.50 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24-4.18 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.52-3.50 (m, 1H), 2.40 (s, 3H), 2.30-2.15 (m, 3H), 2.13-2.03 (m, 1H), 2.01-1.92 (m, 3H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.57 (m, 1H), 1.31-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 7) the preparation of compound 8-8

[00396] To a solution of compound 8-7 (2.31 g, 3.8 mmol) in DCM (20 mL) was added pyridine (1.22 mL, 15.2 mmol) at 0 °C dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (1.3 mL, 7.6 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (2.25 g, 80%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.46, 7.44 (s, s, 1H), 7.40 (s, 1H), 7.36, 7.34 (s, s, 1H), 7.11, 7.09 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.16-5.12 (m, 1H), 4.41-4.36 (m, 1H), 4.24-4.18 (m, 2H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 3.49-3.47 (m, 1H), 2.40 (s, 3H), 2.30-2.15 (m, 3H), 2.13-1.92 (m, 4H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.57 (m, 1H), 1.32-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 8) the preparation of compound 8-9

[00397] To a solution of compound 2-2 (0.58 g, 1.38 mmol), PdCl ₂ (PPh ₃ ) ₂ (98 mg, 0.14 mmol), tetrabutylammonium iodide (1.53 g, 4.14 mmol) and Cul (78 mg, 0.41 mmol) in DMF (5 mL) was added triethylamine (2.0 mL) dropwise under N ₂ . After the mixture was stirred at rt for 10 mins, TMSA (0.98 mL, 6.89 mmol) was added dropwise and the resulting mixture was stirred at 70 °C overnight. After the reaction was completed, the reaction mixture was filtered through a Celite Pad. The filtrate was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>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 ¾ NMR (400 MHz, CDC1 ₃ ): δ 1.21 (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) ppm.

Step 9) the preparation of compound 8-10

[00398] A mixture of compound 8-9 (0.34 g, 0.87 mmol) and K ₂ C0 ₃ (0.60 g, 4.35 mmol) in MeOH (2 mL) and THF (2 mL) was stirred at rt for 6 hours. After the reaction was completed, the solvents were removed in vacuo and to the residue was added water (10 mL). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (0.23 g, 82.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 319.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 10) the preparation of compound 8-11

[00399] To a mixture of compound 8-10 (0.12 g, 0.39 mmol), compound 8-8 (0.29 g, 0.39 mmol), PdCl ₂ (PPh ₃ ) ₂ (14.1 mg, 0.02 mmol), Cul (33 mg, 0.172 mmol) and PPh ₃ (0.23 g, 0.86 mmol) were added DMF (10 mL) and triethylamine (5.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 10 hours. After the reaction was completed, the mixture was allowed to cool to rt and filtered through a Celite Pad. To the filtrate was added water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (106 mg, 30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 456.1 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.62 (s, 1H), 7.56, 7.54 (s, s, 1H), 7.46 (s, 1H), 7.45, 7.43, 7.41 (s, d, s, 2H), 7.29, 7.26 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.51-5.47 (m, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 1H), 4.41, 4.38, 4.36 (m, m, m, 1H), 4.34, 4.31, 4.30 (m, m, m, 1H), 4.24-4.18 (m, 2H), 4.11-4.08 (m, 1H), 3.89-3.78 (m, 2H), 3.73-3.67 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.58-3.55 (m, 1H), 2.37 (s, 3H), 2.32-1.90 (m, 12H), 1.82-1.68 (m, 3H), 1.59-1.55 (m, 1H), 1.34-1.17 (m, 4H), 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) ppm.

Example 9

Synthetic route:

[00400] To a suspension of compound 1-18 (0.18 g, 0.26 mmol), compound 9-1-0 (83.8 mg, 0.57 mmol), EDCI (0.11 g, 0.57 mmol) and HO AT (0.07 g, 0.52 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.5 mL, 2.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 pale yellow solid (0.13 g, 61.4%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 408.5 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 7.29, 7.26 (s, s, 1H), 6.07, 6.05 (d, d, 1H), 5.51-5.47 (m, 1H), 5.44, 5.42 (m, m, 2H), 5.15-5.11 (m, 2H), 4.64-4.57 (m, 2H), 3.88-3.82 (m, 2H), 3.77-3.74 (m, 4H), 3.72-3.65 (m, 2H), 3.64 (s, 6H), 2.34-2.06 (m, 6H), 2.04-1.89 (m, 6H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.36, 1.34 (d, d, 6H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

Example 10

Synthetic route:

Step 1) the preparation of compound 10-2

[00401] To a solution of compound 10-1 (1.12 g, 4.88 mmol) in THF (10 mL) at 0 °C was added borane (7.3 mL, 1 M in THF) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with methanol (4 mL) and concentrated in vacuo. The residue was dissolved in DCM (50 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (1.05 g, 100%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 216.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 4.02 (s, 1H), 3.99-3.87 (m, 1H), 3.75-3.68 (m, 1H), 3.66 (dd, 1H, J = 11.6 Hz, 2.0 Hz), 3.57 (dd, 1H, J= 11.6 Hz, 7.4 Hz), 2.76 (t, 1H, J= 10.5 Hz), 2.19-2.06 (m, 2H), 1.46 (s, 9H), 1.01 (d, 3H, J= 6.2 Hz) ppm.

Step 2) the preparation of compound 10-4

[00402] To a solution of compound 10-2 (1.0 g, 4.64 mmol) in DCM (12 mL) were added TCCA (1.08 g, 4.64 mmol) and a solution of TEMPO (64 mg, 0.46 mmol) in DCM (5.0 mL) in turn at 0 °C. At the end of the addition, the mixture was stirred at this temperature for 1 hour and then stirred at rt for 1 hour. After the reaction was completed, the mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium sulfite, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give compound 10-3 as colorless oil.

[00403] Compound 10-3 was dissolved in a solution of NH ₃ in methanol (10 mL, 7 M). The solution was stirred at 0 °C for 0.5 hour and further stirred at rt for 1 hour. Then to the mixture was added glyoxal (1.2 mL, 40%) at 0 °C. At the end of the addition, the mixture was stirred at rt for 24 hours. After the mixture completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (100 mL). The solution was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale yellow solid (0.51 g, 44%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 6.97 (s, 2H), 4.90 (t, 1H, J = 8.0 Hz), 3.76 (dd, 1H, J = 10 Hz, 7.2 Hz), 2.83 (t, 1H, J = 8.0 Hz), 2.64-2.33 (m, 2H), 2.32-2.12 (m, 1H), 1.47 (s, 9H), 1.09 (d, 3H, J= 6.4 Hz) ppm.

Step 3) the preparation of compound 10-5

[00404] To a solution of compound 10-4 (0.51 g, 2.03 mmol) in DCM (10 mL) was added NIS (1.0 g, 4.46 mmol) at 0 °C and the mixture was stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of sodium sulfite (30 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a yellow solid (0.92 g, 90%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 504.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 4.85 (t, 1H, J = 8.0 Hz), 3.75 (dd, 1H, J = 10 Hz, 7.2 Hz), 2.84 (t, 1H, J = 10 Hz), 2.52-2.29 (m, 2H), 2.21 (d, 1H, J = 6.6 Hz), 1.48 (s, 9H), 1.08 (d, 3H, J = 6.4 Hz) ppm.

Step 4) the preparation of compound 10-6

[00405] To a solution of compound 10-5 (0.91 g, 1.8 mmol) in ethanol (10 mL) were added sodium sulfite (2.0 g, 16 mmol) and water (10 mL) and the mixture was stirred at 90 °C for 30 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (50 mL). The solution was washed with water (20 mL x 2) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as a white solid (0.41 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 378.2 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.04 (s, 1H), 4.85 (t, 1H, J = 8.4 Hz), 3.75 (dd, 1H, J = 10.3 Hz, 7.3 Hz), 2.82 (t, 1H, J = 10.4 Hz), 2.58-2.36 (m, 2H), 2.29-2.11 (m, 1H), 1.08 (d, 3H, J= 6.4 Hz) ppm.

Step 5) the preparation of compound 10-7

[00406] To a mixture of compound 10-6 (0.63 g, 1.66 mmol), compound 1-6-2 (0.46 g, 1.82 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (68 mg, 0.083 mmol) and KOAc (0.41 g, 4.14 mmol) was added DMF (5.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 2 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (40 mL) and filtered through a Celite Pad. The filtrate was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.53 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 378.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 4.90-4.85 (m, 1H), 3.75-3.68 (m, 1H), 3.04-2.97 (m, 1H), 2.44-2.34 (m, 1H), 2.33-2.20 (m, 1H), 1.83-1.75 (m, 1H), 1.41 (s, 9H), 1.38, 1.36 (m, m, 12H), 0.96-0.93 (m, 3H) ppm.

Step 6) the preparation of compound 10-8

[00407] To a mixture of compound 10-7 (0.63 g, 1.66 mmol), compound 3-13 (0.75 g, 1.66 mmol), potassium carbonate (0.57 g, 4.14 mmol) and Pd(PPh ₃ ) ₄ (96 mg, 0.083 mmol) were added DME (5 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (30 mL). The resulting mixture was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl and dried over anhydrous Na ₂ SC>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 (0.5 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 552.7 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.67 (s, 1H), 7.39, 7.37 (s, s, 1H), 7.36, 7.34 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 6.75, 6.72 (s, s, 1H), 5.06-5.01 (m, 1H), 4.37-4.30 (m, 1H), 3.80-3.73 (m, 1H), 3.58-3.54 (m, 1H), 3.50-3.46 (m, 1H), 3.24-3.12 (m, 1H), 3.09-3.02 (m, 1H), 2.70-2.57 (m, 2H), 2.35-2.12 (m, 5H), 1.99-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.76-1.68 (m, 1H), 1.66-1.55 (m, 2H), 1.41 (s, 9H), 1.26-1.19 (m, 2H), 0.96-0.93 (m, 3H) ppm.

Step 7) the preparation of compound 10-9

[00408] To a solution of compound 10-8 (1.65 g, 3.0 mmol) in DCM (20 mL) was added pyridine (0.97 mL, 12 mmol) dropwise at 0 °C. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (1.0 mL, 6.0 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (1.74 g, 85%). The compound was characterized by the following spectroscopic data: ¹ !! NMR (400 MHz, CDC1 ₃ ): δ 7.67 (s, 1H), 7.38, 7.36 (t, t, 1H), 7.26, 7.24 (s, s, 1H), 7.22, 7.21 (s, s, 1H), 7.20, 7.19 (s, s, 1H), 5.06-5.01 (m, 1H), 4.37-4.30 (m, 1H), 3.88-3.85 (m, 1H), 3.80-3.73 (m, 1H), 3.47-3.44 (m, 1H), 3.24-3.12 (m, 1H), 3.09-3.02 (m, 1H), 2.70-2.57 (m, 2H), 2.35-2.13 (m, 5H), 2.03-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.76-1.68 (m, 1H), 1.66-1.55 (m, 2H), 1.41 (s, 9H), 1.30-1.19 (m, 2H), 0.96-0.93 (m, 3H) ppm.

Step 8) the preparation of compound 10-10

[00409] To a solution of compound 10-1 (2.45 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. The mixture was stirred at this temperature for 0.5 hour and compound 3-16-0 (2.21 g, 11.9 mmol) was added in portions. Then the mixture was stirred at rt for 4 hours. After the reaction was completed, the reaction was quenched with water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The resulting solution was washed with an aqueous solution of sodium carbonate (50 mL x 3), dried over anhydrous Na ₂ S0 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 (3.24 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 381.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.84 (d, 1H, J= 2.9 Hz), 7.44 (d, 1H, J= 15.0 Hz), 7.33 (dd, 1H, J= 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J= 16.9 Hz), 4.27 (dd, 1H, J= 24.8 Hz, 17.3 Hz), 3.14 (dd, 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 1.41 (s, 9H), 0.95 (d, 3H, J= 12.7 Hz) ppm.

Step 9) the preparation of compound 10-11

[00410] To a mixture of compound 10-10 (4.27 g, 11.27 mmol), compound 1-6-2 (4.29 g, 16.9 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.65 g, 0.8 mmol) and KOAc (2.76 g, 28.17 mmol) was added DME (30 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt and the DME was removed in vacuo. To the residue was added water (50 mL) and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 beige solid (2.89 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 428.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.82 (dd, 1H), 7.65,7.63 (d, d, 1H), 7.27, 7.25 (d, d, 1H), 5.07-5.02 (m, 1H), 3.85-3.78 (m, 1H), 3.14-3.07 (m, 1H), 2.51-2.42 (m, 1H), 2.30-2.16 (m, 1H), 1.86-1.78 (m, 1H), 1.41 (s, 9H), 1.32, 1.29 (m, m, 12H), 0.96-0.93 (m, 3H) ppm.

Step 10) the preparation of compound 10-12

[00411] To a mixture of compound 10-11 (0.25 g, 0.58 mmol), compound 10-9 (0.40 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (80 mg, 1.4 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The mixture was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.29 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 418.5 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.66 (s, 1H), 7.62, 7.60 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.48 (m, 1H), 7.47, 7.45 (s, s, 1H), 7.41, 7.39 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 5.14-5.09 (m, 1H), 5.06-5.01 (m, 1H), 4.37-4.29 (m, 1H), 3.93-3.90 (m, 1H), 3.85-3.73 (m, 3H), 3.23-3.02 (m, 3H), 2.70-2.57 (m, 2H), 2.51-2.42 (m, 1H), 2.35-2.12 (m, 6H), 2.00-1.90 (m, 2H), 1.86-1.78 (m, 2H), 1.76-1.68 (m, 1H), 1.66-1.56 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H), 1.27-1.17 (m, 2H), 0.96-0.93 (m, 6H) ppm.

Step 11) the preparation of compound 10-13

[00412] To a solution of compound 10-12 (0.25 g, 0.3 mmol) in EtOAc (4.0 mL) was added a solution of HC1 in EtOAc (3.0 mL, 4 M) at 0 °C and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated. The residue was triturated with EtOAc (5 mL) and the resulting mixture was filtered to give the title compound as a pale yellow solid (0.21 g, 90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 635.8 [M+H] ⁺ .

Step 12) the preparation of compound 10-14

[00413] To a solution of compound 10-13 (0.24 g, 0.31 mmol), compound 1-18-2 (0.12 g, 0.68 mmol), EDCI (0.13 g, 0.68 mmol) and HOAT (85 mg, 0.62 mmol) in DCM (5 mL) at 0 °C was added DIPEA (0.51 mL, 3.1 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.13 g, 44%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 475.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.69, 7.67 (s, s, 1H), 7.62, 7.59 (d, d, 1H), 7.58 (s, 1H), 7.52, 7.50 (d, d, 1H), 7.48 (m, 1H), 7.47, 7.45 (s, s, 1H), 7.41, 7.39 (t, t, 1H), 7.22, 7.20 (s, s, 1H), 5.32-5.26 (m, 3H), 5.17-5.13 (m, 1H), 4.41-4.29 (m, 3H), 3.93-3.84 (m, 3H), 3.79-3.76 (m, 1H), 3.63 (s, 6H), 3.61-3.54 (m, 2H), 3.23-3.13 (m, 1H), 2.70-2.58 (m, 2H), 2.57-2.47 (m, 1H), 2.38-2.09 (m, 8H), 2.00-1.90 (m, 2H), 1.84-1.75 (m, 2H), 1.73-1.56 (m, 3H), 1.27-1.17 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.93-0.89 (m, 12H) ppm.

Example 11

Synthetic route:

Step 1) the preparation of compound 11-1 [00414] To a solution of compound 5-8 (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. The mixture was stirred at this temperature for 2 hours and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with saturated aqueous NH ₄ C1 and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were wash a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (7.75 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 248.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDCI ₃ ): δ 5.26, 5.13 (ds, ds, 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) ppm.

Step 2) the preparation of compound 11-2

[00415] To a solution of compound 11-1 (5.83 g, 23.58 mmol) in THF (30 mL) at 0 °C was added an aqueous solution of lithium hydroxide (1.98 g, 30 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1M) till pH = 5, and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a white solid (5.27 g, 96%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 234.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 3) the preparation of compound 11-3

[00416] To a solution of compound 11-2 (1.3 g, 5.57 mmol) in THF (20 mL) at 0 °C was added borane (8.3 mL, 1 M in THF) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with methanol (4 mL) and concentrated in vacuo. The residue was dissolved in DCM (50 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as colorless oil (1.07 g, 88%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 220.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 5.19-5.06 (m, 1H), 4.12-4.04 (m, 1H), 3.99-3.79 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.46 (m, 2H), 2.25-2.00 (m, 2H), 1.44 (s, 9H) ppm.

Step 4) the preparation of compound 11-5

[00417] To a solution of compound 11-3 (1.15 g, 5.24 mmol) in DCM (20 mL) were added TCCA (1.22 g, 5.24 mmol) and a solution of TEMPO in DCM (82 mg, 0.52 mmol, 3 mL) in turn at 0 °C. At the end of the addition, the mixture was stirred at this temperature for 1 hour and stirred at rt for 1 hour. After the reaction was completed, the mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium sulfite, dried over anhydrous Na ₂ SC>4 and concentrated in vacuo. The residue was dissolved in a solution of NH ₃ in methanol (7 mL, 7 M). The solution was stirred at 0 °C for 0.5 hour and stirred at rt for 1 hour and then to the mixture was added glyoxal (1.1 mL, 40%) at 0 °C. At the end of the addition, the mixture was stirred at rt for 24 hours. After the reaction completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (50 mL). The solution was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale yellow solid (0.67 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 256.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 6.98 (s, 2H), 5.36-5.13 (m, 2H), 3.72-3.31 (m, 2H), 2.58-2.32 (m, 2H), 1.48 (s, 9H) ppm.

Step 5) the preparation of compound 11-6

[00418] To a solution of compound 11-5 (0.63 g, 2.47 mmol) in DCM (8 mL) was added NIS (1.23 g, 5.43 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with DCM (50 mL) and filtered. The filtrated was washed with a saturated aqueous solution of sodium sulfite (20 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a yellow solid (1.07 g, 85.6%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 508.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 5.34-5.08 (m, 2H), 3.72-3.28 (m, 2H), 2.58-2.33 (m, 2H), 1.48 (s, 9H) ppm.

Step 6) the preparation of compound 11-7

[00419] To a solution of compound 11-6 (1.07 g, 2.12 mmol) in ethanol (6 mL) were added sodium sulfite (2.14 g, 17 mmol) and water (6 mL) and the mixture was stirred at 90 °C for 30 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (40 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous NaCl solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (0.59 g, 73%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 382.2 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.04 (s, 1H), 5.35-5.09 (m, 2H), 3.98-3.63 (m, 1H), 3.58-3.29 (m, 1H), 2.55-2.34 (m, 2H), 1.48 (s, 9H) ppm.

Step 7) the preparation of compound 11-8

[00420] To a solution of compound 11-7 (0.76 g, 2.0 mmol) in EtOAc (4.0 mL) was added a solution of HC1 in EtOAc (5.0 mL, 4M) dropwise slowly and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered to afford a solid (0.32 g, 90%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 282.1 [M+H] ⁺ .

Step 8) the preparation of compound 11-9

[00421] A suspension of compound 11-8 (1.27 g, 3.6 mmol), compound 1-18-2 (0.68 g, 3.9 mmol) and EDCI (0.75 g, 3.9 mmol) in DCM (10.0 mL) was stirred at 0 °C for 5 mins and then DIPEA (2.38 mL, 14.4 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hour. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL). The resulting mixture was washed with an aqueous ammonium chloride solution, dried over anhydrous Na ₂ S0 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 (1.35g, 85.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 439.3 [M+H] ⁺ ; *H NMR (400 MHz, CDC1 ₃ ): δ 7.41 (s, 1H), 5.32, 5.30 (d, d, 1H), 5.19-5.18, 5.17-5.16, 5.15-5.14, 5.06-5.05, 5.04-5.03, 5.02-5.01 (m, m, m, m, m, m, 1H), 4.93-4.88 (m, 1H), 4.45-4.41 (m, 1H), 4.13-4.01 (m, 1H), 3.75-3.64 (m, 1H), 3.63 (s, 3H), 3.02-2.85 (m, 1H), 2.38-2.24 (m, 1H), 2.23-2.12 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 9) the preparation of compound 11-10

[00422] To a mixture of compound 11-9 (0.48 g, 1.1 mmol), compound 1-10 (0.27 g, 0.5 mmol), anhydrous potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous NaCl solution, dried over anhydrous Na ₂ S0 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 (0.18 g, 40%). The

2+ compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 454.5 [M+2H] ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.00 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.32, 5.30 (d, d, 2H), 5.19, 5.11 (m, m, 2H), 5.07-5.02 (m, 2H), 4.45-4.41 (m, 2H), 4.13-4.01 (m, 2H), 3.77-3.72 (m, 4H), 3.71-3.69, 3.68-3.67, 3.66-3.65 (m, m, m, 2H), 3.63 (s, 6H), 2.98-2.81 (m, 2H), 2.30-2.12 (m, 4H), 2.03-1.97 (m, 2H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 12

Synthetic route:

12-14-2

Step 1) the preparation of compound 12-2

[00423] To a solution of 1,4-benzoquinone (10.0 g, 92.5 mmol) in xylene (250 mL) was added compound 12-1 (24.4 g, 92.5 mmol) at rt. The mixture was stirred at this temperature for 1 hour and stirred at 100 °C for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo and to the residue was added «-hexane (500 mL). The resulting mixture was stirred and filtered. The filtrate was dried over anhydrous Na ₂ SC>4 and concentrated to afford a pale yellow solid (24.7 g, 71.8%) without further purification. The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 6.59 (d, J=7.6Hz, 2H), 3.66 (s, 3H), 3.57 (m, 5H) ppm ₀

Step 2) the preparation of compound 12-3

[00424] A solution of compound 12-2 (9.89 g, 26.6 mmol) and pyridine (6.30 g, 79.7 mmol) in methanol (100 mL) was stirred at 50 °C under N ₂ for 4 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as a white solid (9.02 g, 91.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 372.9[M+H] ⁺ ; H NMR (400 MHz, CDC1 ₃ ): δ 6.43-6.39 (d, J=7.3Hz, 2H), 5.67 (s, 2H), 3.64 (s, 6H), 3.52(s, 3H).

Step 3) the preparation of compound 12-4

[00425] To a mixture of compound 12-3 (9.00 g, 24.2 mmol) and K ₂ C0 ₃ (10.01 g, 72.6mmol) in DCM (100 mL) was added CH ₃ I (7.56g, 53.2mmol) at 0 °C dropwise. After the addition, the mixture was stirred at rt for 5 hours and then the mixture was filtered. The filtrated was concentrated and the residue was purified by silica gel column chromatography (DCM) to give the title compound as a white solid (8.8 g, 91.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 401.0 [M+H] ⁺ ; and H NMR (400 MHz, CDCI ₃ ): δ 6.43-6.39 (d, J=7.8Hz, 2H), 3.82 (s, 6H), 3.50(s, 3H), 3.66(s, 3H).

Step 4) the preparation of compound 12-5

[00426] A suspension of compound 12-4 (8.52g, 21.3 mmol) and Pd/C (0.8 g) in methanol (80 mL) was stirred under H ₂ at rt for 1.5 hours. After the stirring, the mixture was filtered and the filtrate was concentrated. The residue was purified by re-crystallization to afford the title compound as a white solid (6.47, 75.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 403.0 [M+H] ⁺ ; and ^l n NMR (400 MHz, CDC1 ₃ ): δ 6.43-6.39 (d, J=7.4Hz, 2H), 3.82 (s, 6H), 3.73(s, 3H), 3.53(s, 3H), 1.77(m, 2H), 2.50(m, 2H).

Step 5) the preparation of compound 12-6

[00427] To a solution of naphthalene (12.7 g, 96.6 mmol) in DME (50 mL) was added Na (1.83g, 80.5mmol) at 0 °C. The mixture was stirred at this temperature for 30 mins and then compound 12-5 (6.47 mL, 16.1 mmol) was added dropwise. The mixture was stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with ethanol (10 mL) and 100 mL of water was added. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: EA = 6: 1) to give the title compound as a white solid (3.87, 91%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 265.2 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): 6.43-6.39 (d, J=7.5Hz, 2H), 3.90(s, 6H ), 3.54 (dd, J=1.8, 1.8Hz, 2H), 3.29(s, 3H), 3.12(s,3H),2.24 (m, 2H), 1.43 (m, 2H). Step 6) the preparation of compound 12-7 [00428] To a solution of compound 12-6 (3.87g, 14.7mmol) in dioxane (30 mL) was added aqueous H ₂ SO ₄ (20 %, 100 mL) dropwise at 0 °C. At the end of the addition, the mixture was stirred at 50 °C for 11 hours. After the stirring, the mixture was cooled to rt, washed with satuated aqueous NaCl (30 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (Hexane/EtOAc (v/v) = 5/1) to give the title compound as a white solid (2.72 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 219.1 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDCI ₃ ): 6.43-6.39 (d, J=8.2Hz, 2H), 3.90(s, 6H ), 3.54 (dd, J=1.8, 1.8Hz, 2H), 2.24 (m, 2H), 1.43 (m, 2H).

Step 7) the preparation of compound 12-8

[00429] To a solution of compound 12-7 (1.48 g, 6.8 mmol) in DCM (20 mL) at -78 °C was added BBr ₃ (9.0 mL, 22.5 mmol, 2.5 M in DCM) dropwise and the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (1.19 g, 92%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 191.5 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 6.59 (s, 2H), 5.49 (br, 2H), 3.64-3.58 (m, 2H), 2.50-2.41 (m, 2H), 2.15-2.05 (m, 2H) ppm.

Step 8) the preparation of compound 12-9

[00430] To a solution of compound 12-8 (3.61 g, 19.0 mmol) in DCM (50 mL) at 0 °C was added pyridine (9.00 g, 114 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (21.0 g, 76 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (7.76 g, 90%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.36 (s, 2H), 3.61-3.55 (m, 2H), 2.56-2.47 (m, 2H), 2.20-2.12 (m, 2H) ppm.

Step 9) the preparation of compound 12-10

[00431] To a mixture of compound 1-7 (0.29 g, 1.0 mmol), compound 12-9 (0.45 g, 1.0 mmol), anhydrous potassium carbonate (0.35 g, 2.5 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (20 mL). The resulting mixture was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 liquid (0.23 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 465.5 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.08, 7.06 (s, s, 1H), 7.04, 7.02 (s, s, 1H), 7.01, 6.99 (s, s, 1H), 6.53, 6.51 (s, s, 1H), 5.77 (brs, 1H), 3.89-3.86 (m, 1H), 3.65-3.62 (m, 1H), 3.58-3.55 (m, 1H), 3.51-3.48 (m, 1H), 2.58-2.51 (m, 1H), 2.48-2.40 (m, 1H), 2.23-2.15 (m, 1H), 2.13-2.05 (m, 2H), 1.98-1.90 (m, 2H), 1.71-1.67 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, lH) ppm.

Step 10) the preparation of compound 12-11

[00432] To a mixture of compound 12-10 (0.23 g, 0.5 mmol), compound 7-1 (0.18 g, 0.5 mmol), anhydrous potassium carbonate (0.17 g, 1.25 mmol) and Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) were added EtOH (4.0 mL) and pure water (1.0 mL) via syringe under N2 and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.15 g, 54.3%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.89 (s, 1H), 7.32, 7.30 (s, s, 1H), 7.11, 7.09 (s, s, 1H), 6.97, 6.95 (s, s, 1H), 6.53, 6.51 (s, s, 1H), 5.05-5.01 (m, 1H), 3.95-3.91 (m, 2H), 3.64-3.55 (m, 2H), 3.51-3.48 (m, 1H), 3.31-3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.47-2.38 (m, 2H), 2.28-1.90 (m, 8H), 1.71-1.67 (m, 1H), 1.41 (s, 9H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, lH) ppm.

Step 11) the preparation of compound 12-12

[00433] To a solution of compound 12-11 (1.05 g, 1.9 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.9 g, 11.4 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (2.1 g, 7.6 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (1.15 g, 88.5%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.89 (s, 1H), 7.61, 7.59 (s, s, 1H), 7.34, 7.31 (s, s, 1H), 7.07, 7.04 (s, s, 1H), 6.97, 6.95 (s, s, 1H), 5.05-5.01 (m, 1H), 3.95-3.91 (m, 2H), 3.74-3.71 (m, 1H), 3.64-3.58 (m, 1H), 3.49-3.46 (m, 1H), 3.31-3.24 (m, 1H), 2.56-2.49 (m, 1H), 2.47-2.38 (m, 2H), 2.28-1.90 (m, 8H), 1.71-1.67 (m, 1H), 1.41 (s, 9H), 1.40-1.36 (m, 1H), 1.25-1.19 (m, lH) ppm.

Step 12) the preparation of compound 12-13

[00434] To a mixture of compound 12-12 (0.68 g, 1.0 mmol), compound 3-17 (0.41 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 pale yellow solid (0.45 g, 54.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 822.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.89 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.53, 7.50 (s, s, 1H), 7.43, 7.41 (s, s, 1H), 7.36, 7.34 (s, s, 1H), 7.23, 7.21 (d, d, 1H), 6.97, 6.95 (s, s, 1H), 5.05-4.99 (m, 2H), 3.95-3.91 (m, 2H), 3.82-3.76 (m, 3H), 3.64-3.57 (m, 2H), 3.31-3.24 (m, 1H), 2.62-2.49 (m, 2H), 2.47-2.36 (m, 3H), 2.28-1.92 (m, 10H), 1.73-1.69 (m, 1H), 1.41 (s, 18H), 1.35-1.29 (m, 1H), 1.27-1.21 (m, lH) ppm.

Step 13) the preparation of compound 12-14

[00435] To a solution of compound 12-13 (0.25 g, 0.3 mmol) in EtOAc (3.0 mL) was added a solution of HC1 in EtOAc (2.0 mL, 4 M) at 0 °C and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc (5 mL) and the resulting mixture was filtered to give the title compound as a pale yellow solid (0.2 g, 86.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 621.8 [M+H] ⁺ .

Step 14) the preparation of compound 12-14-2

[00436] To a solution of L- valine (1.17 g, 10 mmol) in an aqueous solution of NaOH (13 mL, 1 M) was added phenyl chloroformate (1.72 g, 11.0 mmol) at 0 °C dropwise and the mixture was stirred at 0 °C for 5 hours. After the stirring, the mixture was washed with EtOAc (20 mL x 3) and acidified with concentrated hydrochloric acid till pH = 2. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to afford the title compound as a white solid (1.8 g, 75.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 238.1 [M+H] ⁺ .

Step 15) the preparation of compound 12-15

[00437] To a solution of compound 12-14 (0.15 g, 0.2 mmol), compound 12-14-2 (100 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HO AT (41 mg, 0.3 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.26 mL, 1.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (0.15 g, 70.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 530.6 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.83 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.53, 7.50 (s, s, 1H), 7.43, 7.41 (s, s, 1H), 7.36-7.30 (m, 5H), 7.24-7.23, 7.22-7.21, 7.20-7.19 (m, m, m, 3H), 7.13-7.12, 7.11-7.10 (m, m, 4H), 6.97, 6.95 (s, s, 1H), 5.49, 5.46 (d, d, 2H), 5.29-5.20 (m, 2H), 4.48-4.42 (m, 2H), 3.95-3.91 (m, 2H), 3.85-3.76 (m, 4H), 3.69-3.60 (m, 2H), 2.56-1.87 (m, 17H), 1.73-1.69 (m, 1H), 1.35-1.29 (m, 1H), 1.27-1.21 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 13

Synthetic route:

Step 1) the preparation of compound 13-1

[00438] To a solution of compound 2-3-0 (3.63 g, 13.1 mmol) and compound 10-1 (3.0 g, 13.1 mmol) in DCM (40 mL) at 0 °C was added TEA (3.9 mL, 26.3 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound (3.27 g, 62.9%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 399.3 [M+H] ⁺ .

Step 2) the preparation of compound 13-2

[00439] A suspension of compound 13-1 (3.27 g, 8.2 mmol) and ammonium acetate (5.1 g, 66 mmol) in toluene (30 mL) was stirred at 110 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (2.85 g, 86%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 407.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.45 (m, 4H), 7.20 (s, 1H), 4.93 (t, 1H, J = 8.2 Hz), 3.88-3.66 (m, 1H), 2.90 (t, 1H, J= 8.0 Hz), 2.50-2.47 (m, 2H), 2.27-2.25 (m, 1H), 1.48 (s, 7H), 1.26 (s, 2H), 1.12 (d, 3H, J= 6.2 Hz) ppm.

Step 3) the preparation of compound 13-3

[00440] To a mixture of compound 13-2 (2.8 g, 6.9 mmol), compound 1-6-2 (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) was added DME (30 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 2 hours. 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 (20 mL x 3) and a saturated aqueous solutionof NaCl, dried over anhydrous Na ₂ S0 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 (2.76 g, 88.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 454.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.35 (m, 4H), 7.10 (s, 1H), 4.93 (t, 1H, J = 8.2 Hz), 3.88-3.66 (m, 1H), 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), 1.02 (d, 3H, J= 6.2 Hz) ppm.

Step 4) the preparation of compound 13-4

[00441] To a mixture of compound 13-3 (0.26 g, 0.58 mmol), compound 1-9 (0.34 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (0.08 g, 1.4 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL). The resulting mixture was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.3 g, 68%). The compound was characterized by the following spectroscopic data: ^ι ΐΙ NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 4.88-4.84 (m, 1H), 3.92-3.90 (m, 1H), 3.80-3.71 (m, 3H), 3.45-3.42 (m, 1H), 3.09-3.02 (m, 1H), 2.33-2.18 (m, 2H), 2.03-1.90 (m, 4H), 1.84-1.78 (m, 2H), 1.74-1.66 (m, 1H), 1.61-1.55 (m, 2H), 1.41 (s, 9H), 1.30-1.17 (m, 4H), 0.96-0.93 (m, 3H) ppm.

Step 5) the preparation of compound 13-5

[00442] To a mixture of compound 13-4 (0.44 g, 0.58 mmol), compound 10-7 (0.22 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (0.08 g, 1.4 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.3 g, 60.1%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 431.5 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 4.97-4.92 (m, 1H), 4.88-4.84 (m, 1H), 3.92-3.90 (m, 1H), 3.80-3.71 (m, 5H), 3.09-3.02 (m, 2H), 2.35-2.18 (m, 4H), 2.03-1.89 (m, 4H), 1.87-1.80 (m, 2H), 1.76-1.66 (m, 2H), 1.64-1.57 (m, 2H), 1.41 (s, 18H), 1.30-1.16 (m, 4H), 0.96-0.93 (m, 6H) ppm.

Step 6) the preparation of compound 13-6

[00443] To a solution of compound 13-5 (0.26 g, 0.3 mmol) in EtOAc (4.0 mL) was added a solution of HC1 in EtOAc (3.0 mL, 4 M) and the mixture was stirred at rt for 8 hours. After the mixture was completed, the mixture was concentrated. The residue was triturated with EtOAc (5 mL) and the resulting mixture was filtered to give the title compound as a pale yellow solid (0.2 g, 82.6%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 661.4 [M+H] ⁺ .

Step 7) the preparation of compound 13-7

[00444] To a solution of compound 13-6 (0.20 g, 0.31 mmol), compound 1-18-2 (0.12 g, 0.68 mmol), EDCI (0.13 g, 0.68 mmol) and HOAT (85 mg, 0.62 mmol) in DCM (20 mL) at 0 °C was added DIPEA (0.51 mL, 3.1 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (125 mg, 41%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 488.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.80 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 5.32, 5.29 (d, d, 2H), 5.15-5.10 (m, 1H), 5.07-5.02 (m, 1H), 4.42-4.37 (m, 2H), 3.92-3.85 (m, 3H), 3.77-3.71 (m, 3H), 3.63 (s, 6H), 3.61-3.55 (m, 2H), 2.38-2.09 (m, 6H), 2.03-1.89 (m, 4H), 1.87-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.30-1.16 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.93-0.89 (m, 12H) ppm.

Example 14

Synthetic route:

Step 1) the preparation of compound 14-2

[00445] To a suspension of PPh ₃ MeBr (5.05 g, 14.2 mmol) in THF (50 mL) was added a solution of potassium tert-butoxide (14.9 mL, 14.9 mmol, 1.0 M in THF) dropwise at -20 °C. At the end of the addition, the mixture was allowed to warm up to -5 °C and stirred for 30 mins and then compound 14-1 (1.72 g, 7.07 mmol) was added. The resulting mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (1.07 g, 62.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 242.2 [M+H] ⁺ ; and ^l li NMR (400 MHz, DMSO-i¾: δ 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) ppm.

Step 2) the preparation of compound 14-3

[00446] To a solution of diethylzinc (2.3 g, 18.6 mmol) in toluene (30 mL) was added chloroiodomethane (6.6 g, 37.24 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at this temperature for 45 mins and then a solution of compound 14-2 (1.5 g, 6.22 mmol) in toluene (15 mL) was added dropwise. The resulting mixture was continued to stir at 0 °C for 18 hours. After the reaction was completed, the reaction was quenched with saturated aqueous NH ₄ C1 (20 mL) and the aqueous layer was extracted with EtOAc (25 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 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 colorless liquid (0.58 g, 36.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 156.2 [M-BOC] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 4.33-4.47 (m, 1H), 3.71 (s, 3H), 3.29-3.37 (m, 2H), 2.17-2.25 (m, 1H), 1.75-1.86 (m, 1H), 1.44, 1.40 (s, s, 9H), 0.50-0.62 (m, 4H) ppm.

Step 3) the preparation of compound 14-4

[00447] To a solution of compound 14-3 (0.69 g, 2.7 mmol) in EtOAc (6.0 mL) was added a solution of HC1 in EtOAc (5.0 mL, 4 M) dropwise slowly and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated to afford colorless oil (0.5 g, 96.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 156.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CD ₃ OD): δ 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, 1Η),0.81-0.79 (m, 1H) ppm.

Step 4) the preparation of compound 14-5

[00448] A suspension of compound 14-4 (0.53 g, 2.77 mmol), compound 1-18-2 (0.73 g, 4.16 mmol) and EDCI (1.06 g, 5.55 mmol) in DCM (10.0 mL) was stirred at 0 °C for 5 mins and then DIPEA (2.4 mL, 14.52 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 3 hour. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous ammonium chloride solution and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.60 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 313.2 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 5) the preparation of compound 14-6

[00449] To a solution of compound 14-5 (0.2 g, 0.64 mmol) in THF (5 mL) at 0 °C was added an aqueous solution of lithium hydroxide (0.134 g, 3.2 mmol, 5 mL) dropwise. At the end of the addition, the mixture was stirred at 40 °C for 12 hours. After the reaction was completed, the THF was removed and 30 mL of water was added to the residue. The resulting mixture was extracted with EtOAc (10 mL x 3). The aqueous layer was acidified with aqueous HC1 (10%) till pH = 1 and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a white solid (0.16 g, 82.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 299.2 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 6) the preparation of compound 14-7

[00450] To a solution of compound 2-3-0 (0.31 g, 1.11 mmol) and compound 14-6 (0.3 g, 1.0 mmol) in MeCN (10 mL) at 0 °C was added DIPEA (0.21 mL, 1.27 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, to the reaction mixture was added water (10 mL) and the MeCN was removed. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with an aqueous solution of NH ₄ C1 and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.365 g, 66.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 495.3 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 7) the preparation of compound 14-8

[00451] A suspension of compound 14-7 (0.33 g, 0.67 mmol) and ammonium acetate (1.04 g, 13.43 mmol) in xylene (10 mL) was stirred at 120 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.19g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 475.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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), 3.67 (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) ppm.

Step 8) the preparation of compound 14-9

[00452] To a mixture of compound 14-8 (0.19 g, 0.4 mmol), compound 1-6-2 (0.15 g, 0.6 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 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.16 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 523.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm. Step 9) the preparation of compound 14-10

[00453] To a mixture of compound 1-9 (0.30 g, 0.52 mmol), compound 14-9 (0.27 g, 0.52 mmol), Pd(PPh ₃ ) ₄ (60.3mg, 0.052 mmol) and potassium carbonate (0.22 g, 1.57 mmol) were added DME (6 mL) and pure water (1.5 mL) via syringe under N2 and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (30 mL). The resulting mixture was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.22 g, 50.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 415.5 [M+2H] ²⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.57 (s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H), 4.42-4.41, 4.40-4.39, 4.38-4.37 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.74-3.66 (m, 3H), 3.63 (s, 3H), 3.50-3.42 (m, 2H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H) ppm.

Step 10) the preparation of compound 14-11

[00454] To a mixture of compound 14-10 (0.42 g, 0.5 mmol), compound 1-6-2 (0.17 g, 0.6 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (41 mg, 0.05 mmol) and KOAc (0.17 g, 1.25 mmol) was added DMF (5 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.21 g, 52%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.58, 7.57 (s, s, 1H), 7.56 (s, 1H), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m, 1H), 4.42-4.41, 4.40-4.39, 4.38-4.37 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.76-3.66 (m, 4H), 3.63 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 1H), 2.05-1.90 (m, 5H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.55-0.43 (m, 4H) ppm.

Step 11) the preparation of compound 14-12

[00455] To a solution of compound 14-6 (1.39 g, 4.66 mmol) in THF (20 mL) at 0 °C was added borane (10 mL, 1 M in THF) dropwise slowly under N ₂ . At the end of the addition, the mixture was stirred at this temperature for 3 hours. After the reaction was completed, the mixture was quenched with methanol (10 mL) 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 oil (0.86 g, 65%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 5.32, 5.29 (d, d, 1H), 4.98 (brs, 1H), 4.39-4.34 (m, 1H), 4.33-4.27 (m, 1H), 3.73-3.72, 3.70-3.69, 3.68-3.67, 3.66-3.65 (m, m, m, m, 2H), 3.63 (s, 3H), 3.25-3.18 (m, 1H), 3.10-3.03 (m, 1H), 2.15-2.03 (m, 1H), 1.90-1.82 (m, 1H), 1.47-1.38 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H),

0.50-0.37 (m, 4H) ppm.

Step 12) the preparation of compound 14-13

[00456] To a solution of compound 14-12 (0.99 g, 3.48 mmol) in DCM (15 mL) at 0 °C was added Dess-Martin periodinane (2.07 g, 4.88 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with water (20 mL) and filtered and the filtrate was partitioned. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 oil (0.49 g, 50%). The compound was characterized by the following spectroscopic data: *H NMR (400 MHz, CDC1 ₃ ): δ 9.61-9.60 (m, 1H), 5.32, 5.30 (d, d, 1H), 4.40-4.38 (m, 1H), 4.33, 4.31, 4.29 (m, m, m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 3.34-3.27 (m, 1H), 2.43-2.37 (m, 1H), 2.24-2.12 (m, 1H), 1.80-1.73 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H) ppm. Step 13) the preparation of compound 14-14

[00457] To a solution of compound 14-13 (0.5 g, 1.76 mmol) and ammonium hydroxide (2 mL) in methanol (5 mL) was added an aqueous glyoxal solution (40%, 1.0 mL) dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the reaction mixture was 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 (0.28 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 321.4 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 6.97 (s, 2H), 5.56, 5.55 (d, d, 1H), 5.20-5.16 (m, 1H), 4.33, 4.31, 4.29 (m, m, m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.52-3.46 (m, 1H), 2.46-2.38 (m, 1H), 2.28-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.55-0.42 (m, 4H) ppm. Step 14) the preparation of compound 14-15

[00458] To a solution of compound 14-14 (2.69 g, 8.4 mmol) in DCM (30 mL) was added NIS (3.8 g, 16.8 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (2.88 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 573.2 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 5.56, 5.55 (d, d, 1H), 5.22-5.18 (m, 1H), 4.45, 4.43, 4.42 (m, m, m, 1H), 3.80-3.73 (m, 1H), 3.66 (s, 3H), 3.51-3.45 (m, 1H), 2.51-2.43 (m, 1H), 2.28-2.11 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.56-0.43 (m, 4H) ppm.

Step 15) the preparation of compound 14-16

[00459] To a suspension of compound 14-15 (1.87 g, 3.27 mmol) in a mixed solvent of ethanol and water (50 mL, ethanol/water (v/v) = 3/7) was added sodium sulfite (3.7 g, 29 mmol) and the mixture was refluxed for 17 hours. After the reaction was completed, the ethanol was concentrated in vacuo and 50 mL of water was added to the residue. The resulting mixture was extracted with EtOAc (50 mL x 3). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a white solid (1.02 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 447.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.34 (s, 1H), 5.56, 5.55 (d, d, 1H), 4.89-4.85 (m, 1H), 4.43, 4.41, 4.39 (m, m, m, 1H), 3.77-3.71 (m, 1H), 3.66 (s, 3H), 3.54-3.48 (m, 1H), 2.48-2.40 (m, 1H), 2.28-2.16 (m, 1H), 2.14-2.06 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.55-0.42 (m, 4H) ppm. Step 16) the preparation of compound 14-17

[00460] To a mixture of compound 14-16 (0.32 g, 0.72 mmol), compound 14-11 (0.58 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.43 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 500.6 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.78 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.57 (s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (m, 3H), 6.13, 6.11 (s, s, 1H), 5.91, 5.89 (s, s, 1H), 5.49-5.43 (m, 2H), 5.21-5.17 (s, s, 1H), 5.32, 5.29 (d, d, 2H), 5.02-4.98 (m, 1H), 4.93-4.89 (m, 1H), 4.41, 4.39, 4.37 (m, m, m, 2H), 3.92-3.90 (m, 1H), 3.77-3.66 (m, 5H), 3.63 (s, 6H), 3.50-3.44 (m, 2H), 2.40-2.32 (m, 2H), 2.23-2.11 (m, 2H), 2.06-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 0.97-0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.55-0.42 (m, 8H) ppm.

Example 15

Synthetic route:

Step 1) the preparation of compound 15-1

[00461] To a solution of compound 2-3-0 (5.47 g, 19.81 mmol) and compound 4-6 (3.91 g, 17.22 mmol) in DCM (60 mL) at 0 °C was added DIPEA (3.4 mL, 20.67 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was quenched with ice water (50 mL) and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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, 61.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 425.3 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 2) the preparation of compound 15-2

[00462] A suspension of compound 15-1 (4.5 g, 10.64 mmol) and ammonium acetate (16.4 g, 212.73 mmol) in xylene (50 mL) was stirred at 120 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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) mlz: 404.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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), 0.64-0.69 (m, 2H) ppm.

Step 3) the preparation of compound 15-3

[00463] To a mixture of compound 15-2 (2.1 g, 5.2 mmol), compound 1-6-2 (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) was added DMF (20 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 (60 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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) mlz: 452.4 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 15-4

[00464] To a solution of compound 15-3 (0.9 g, 2 mmol) in EtOAc (10 mL) was added a solution of HQ in EtOAc (5.0 mL, 4M) dropwise slowly and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc (5 mL) and filtered to afford a solid (0.94g, 95%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 425.2 [M+H] ⁺ .

Step 5) the preparation of compound 15-5

[00465] To a suspension of compound 15-4 (0.37 g, 0.75 mmol), compound 1-18-2 (0.13 g, 0.75 mmol) and EDCI (0.3 g, 1.58 mmol) in DCM (5.0 mL) was added DIPEA (1.0 mL, 6.01 mmol) at 0 °C dropwise slowly and the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL). The resulting mixture was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous Na ₂ SC>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 (324 mg, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 509.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 8.96 (brs, 1H), 7.68-7.67 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.10 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.55-4.51 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.55 (m, 1H), 3.47-3.40 (m, 1H), 2.27-1.99 (m, 4H), 1.94-1.82 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm. Step 6) the preparation of compound 15-6

[00466] To a mixture of compound 15-5 (0.54 g, 1.07 mmol), compound 1-9 (0.62 g, 1.07 mmol), anhydrous potassium carbonate (0.37 g, 2.67 mmol) and Pd(PPh ₃ ) ₄ (0.12 g, 0.11 mmol) were added DME (5.0 mL) and pure water (1.0 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was allowed to cool to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.52 g, 60%). The compound was characterized by the following spectroscopic data: *H NMR (400 MHz, CDC1 ₃ ): δ 7.63 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 4.89-4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.74-3.71 (m, 2H), 3.63 (s, 3H), 3.45-3.38 (m, 2H), 2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.03-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.43-1.36 (m, 1H), 1.30-1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H), 0.91, 0.89 (m, m, 3H), 0.50-0.46 (m, 1H) ppm.

Step 7) the preparation of compound 15-7

[00467] To a mixture of compound 15-6 (0.33 g, 0.4 mmol), compound 1-6-2 (0.15 g, 0.6 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 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (30 mL) and filtered through a Celite Pad. The filtrate was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.25 g, 80.1%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 781.8 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 4H), 7.58, 7.56 (s, s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 4.89-4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.92-3.90 (m, 1H), 3.85-3.78 (m, 1H), 3.76-3.71 (m, 2H), 3.69-3.66 (m, 1H), 3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.46-2.39 (m, 1H), 2.21-2.09 (m, 1H), 2.00-1.90 (m, 4H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.43-1.36 (m, 1H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 2H), 1.07-1.01 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H), 0.90, 0.89 (m, m, 3H), 0.50-0.46 (m, 1H) ppm.

Step 8) the preparation of compound 15-8

[00468] To a solution of compound 4-6 (1.06 g, 4.66 mmol) in THF (10 mL) at 0 °C was added borane (10 mL, 1 M in THF) dropwise slowly under N ₂ . At the end of the addition, the mixture was stirred at this temperature for 3 hours. After the reaction was completed, the mixture was quenched with methanol (8 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as colorless oil (0.65 g, 65%). The compound was characterized by the following spectroscopic data: ^! H NMR (400 MHz, CDC1 ₃ ): δ 4.37 (brs, 1H), 3.94-3.78 (m, 3H), 2.93-2.86 (m, 1H), 2.11-2.03 (m, 1H), 1.83-1.77 (m, 1H), 1.46 (s, 9H), 1.41-1.33 (m, 1H), 1.09-1.03 (m, 1H), 0.65-0.62 (m, 1H) ppm.

Step 9) the preparation of compound 15-9

[00469] To a solution of compound 15-8 (0.74 g, 3.48 mmol) in DCM (10 mL) at 0 °C was added Dess-Martin periodinane (2.07 g, 4.88 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with water (20 mL) and filtered and the filtrate was partitioned. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 as colorless oil (0.5 g, 68%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 9.75-9.72 (m, 1H), 4.19-4.14 (m, 1H), 3.24-3.18 (m, 1H), 2.41-2.34 (m, 1H), 1.82-1.80, 1.78-1.86 (m, m, 1H), 1.45 (s, 9H), 1.41-1.34 (m, 1H), 1.26-1.21 (m, 1H), 0.83-0.80 (m, 1H) ppm.

Step 10) the preparation of compound 15-10

[00470] To a solution of compound 15-9 (0.37 g, 1.76 mmol) and ammonium hydroxide (2 mL) in methanol (5 mL) was added an aqueous glyoxal solution (40%, 1.0 mL) dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the reaction 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 as a white solid (0.35 g, 79.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 250.3 [M+H] ⁺ ; and 'H NMR (400 MHz, CDC1 ₃ ): δ 7.04 (s, 2H), 4.92-4.88 (m, 1H), 3.31-3.25 (m, 1H), 2.48-2.41 (m, 1H), 2.00-1.98, 1.96-1.94 (m, m, 1H), 1.45-1.43 (m, 1H), 1.42 (s, 9H), 1.41-1.39 (m, 1H), 1.02-0.95 (m, lH) ppm.

Step 11) the preparation of compound 15-11

[00471] To a solution of compound 15-10 (0.5 g, 2.0 mmol) in DCM (60 mL) was added NIS (0.9 g, 4.0 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (0.65 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 502.1 [M+H] ⁺ ; and ^ NMR (400 MHz, CDC1 ₃ ): δ 4.93-4.89 (m, 1H), 3.49-3.42 (m, 1H), 2.57-2.46 (m, 1H), 2.12-2.10, 2.09-2.07 (m, m, 1H), 1.45-1.43 (m, 1H), 1.42 (s, 9H), 1.41-1.39 (m, 1H), 1.02-0.95 (m, lH) ppm.

Step 12) the preparation of compound 15-12

[00472] To a solution of compound 15-11 (0.75 g, 1.5 mmol) in a mixed solvent of ethanol and water (12.5 mL, ethanol/water (v/v) = 3/7) was added sodium sulfite (1.7 g, 13.5 mmol) and the mixture was refluxed for 17 hours. After the reaction was completed, the ethanol was concentrated in vacuo and 50 mL of water was added to the residue. The resulting mixture was extracted with EtOAc (50 mL x 3). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as a white solid (0.45 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 376.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.41 (s, 1H), 4.71-4.68 (m, 1H), 3.34-3.28 (m, 1H), 2.50-2.43 (m, 1H), 2.05-2.03, 2.01-1.99 (m, m, 1H), 1.45-1.43 (m, 1H), 1.42 (s, 9H), 1.41-1.39 (m, 1H), 1.02-0.94 (m, lH) ppm.

Step 13) the preparation of compound 15-13

[00473] To a solution of compound 15-12 (0.75 g, 2.0 mmol) in EtOAc (4.0 mL) was added a solution of HQ in EtOAc (5.0 mL, 4 M) dropwise slowly and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered to afford a solid (0.65 g, 93.4%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 276 A [M+H] ⁺ .

Step 14) the preparation of compound 15-14

[00474] A suspension of compound 15-13 (0.63 g, 1.8 mmol), compound 1-18-2 (0.35 g, 1.98 mmol) and EDCI (0.38 g, 1.98 mmol) in DCM (20.0 mL) was stirred at 0 °C for 5 mins and then DIPEA (2.38 mL, 14.4 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hour. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous ammonium chloride solution, dried over anhydrous Na ₂ S0 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 (0.65 g, 83.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 433.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.38 (s, 1H), 5.32, 5.30 (d, d, 1H), 4.89-4.85 (m, 1H), 4.08, 4.06, 4.04 (m, m, m, 1H), 3.63 (s, 3H), 3.51-3.45 (m, 1H), 2.55-2.48 (m, 1H), 2.22-2.11 (m, 1H), 2.09-2.06, 2.05-2.03 (m, m, 1H), 1.49-1.41 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.94-0.92 (m, 1H), 0.90, 0.89 (m, m, 3H), 0.50-0.46 (m, 1H) ppm.

Step 15) the preparation of compound 15-15

[00475] To a mixture of compound 15-14 (0.31 g, 0.72 mmol), compound 15-7 (0.57 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.42 g, 60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 486.6 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.84 (s, 1H), 7.62 (s, 1H), 7.61-7.59 (m, 2H), 7.56-7.52 (m, 2H), 7.51-7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 5.32, 5.30 (d, d, 2H), 4.92-4.85 (m, 2H), 4.08, 4.06, 4.04 (m, m, m, 2H), 3.92-3.90 (m, 1H), 3.77-3.71 (m, 3H), 3.63 (s, 6H), 3.45-3.38 (m, 2H), 2.46-2.38 (m, 2H), 2.22-2.09 (m, 2H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.43-1.36 (m, 2H), 1.30-1.16 (m, 4H), 0.97, 0.95 (m, m, 6H), 0.94-0.92 (m, 2H), 0.91, 0.89 (m, m, 6H), 0.50-0.46 (m, 2H) ppm.

Example 16

Synthetic route:

Step 1) the preparation of compound 16-1

[00476] To a mixture of compound 15-3 (0.45 g, 1.0 mmol), compound 1-9 (0.58 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 a pale yellow solid (0.55 g, 72.6%). The compound was characterized by the following spectroscopic data: ^ι ΐΙ NMR (400 MHz, CDCI ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.47 (s, 1H), 7.42, 7.40 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 4.75-4.72 (m, 1H), 3.92-3.90 (m, 1H),

3.74- 3.71 (m, 2H), 3.45-3.42 (m, 1H), 3.29-3.23 (m, 1H), 2.42-2.35 (m, 1H), 2.03-1.90 (m, 5H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.43 (s, 9H), 1.41-1.34 (m, 2H), 1.30-1.17 (m, 4H), 1.02-0.95 (m, 1H) ppm.

Step 2) the preparation of compound 16-2

[00477] To a mixture of compound 16-1 (0.39 g, 0.52 mmol), compound 1-6-2 (0.15 g, 0.6 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (60 mg, 0.073mmol) and KOAc (0.13 g, 1.3 mmol) was added DMF (4 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (40 mL) and filtered through a Celite Pad. The filtrate was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.3 g, 78.4%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 736.8 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.58, 7.56 (s, s, 1H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.47 (s, 1H), 7.31, 7.29 (s, s, 1H),

4.75- 4.72 (m, 1H), 3.92-3.90 (m, 1H), 3.76-3.71 (m, 2H), 3.69-3.66 (m, 1H), 3.29-3.23 (m, 1H), 2.42-2.35 (m, 1H), 2.00-1.90 (m, 4H), 1.84-1.74 (m, 3H), 1.61-1.53 (m, 2H), 1.43 (s, 9H), 1.42-1.36 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.26-1.17 (m, 3H), 1.07-1.01 (m, 1H), 1.00-0.95 (m, 1H) ppm.

Step 3) the preparation of compound 16-3 [00478] To a mixture of compound 16-2 (0.74 g, 1.0 mmol), compound 15-12 (0.38 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL), the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.45 g, 50.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 429.5 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.95 (s, 1H), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.47 (s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 4.82-4.79 (m, 1H), 4.75-4.72 (m, 1H), 3.92-3.90 (m, 1H), 3.77-3.71 (m, 3H), 3.29-3.23 (m, 2H), 2.42-2.34 (m, 2H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.43 (s, 18H), 1.40-1.34 (m, 4H), 1.30-1.16 (m, 4H), 1.02-0.95 (m, 2H) ppm.

Step 4) the preparation of compound 16-4

[00479] To a solution of compound 16-3 (0.26 g, 0.3 mmol) in EtOAc (3.0 mL) was added a solution of HC1 in EtOAc (2.0 mL, 4 M) and the mixture was stirred at rt for 8 hours. After the mixture was completed, the mixture was concentrated. The residue was triturated with EtOAc (5 mL), and the resulting mixture was filtered to give the title compound as a white solid (0.2 g, 83%). The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) mlz: 657.8 [M+H] ⁺ .

Step 5) the preparation of compound 16-5

[00480] To a solution of compound 16-4 (0.16 g, 0.2 mmol), compound 3-18-2 (79.4 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HOAT (41 mg, 0.3 mmol) in DCM (3.0 mL) at 0 °C was added DIPEA (0.26 mL, 1.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (0.1 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 500.6 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.84 (s, 1H), 7.62 (s, 1H), 7.61-7.60, 7.59-7.58 (m, m, 2H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 6.51, 6.49 (s, s, 2H), 4.89-4.82 (m, 2H), 4.12, 4.10, 4.08 (m, m, m, 2H), 3.92-3.90 (m, 1H), 3.77-3.71 (m, 3H), 3.65 (s, 6H), 3.37-3.31 (m, 2H), 2.44-2.35 (m, 2H), 2.24-2.13 (m, 2H), 2.03-1.89 (m, 6H), 1.87-1.80 (m, 2H), 1.64-1.57 (m, 2H), 1.47-1.31 (m, 4H), 1.30-1.16 (m, 4H), 1.12-0.99 (m, 2H), 0.95, 0.94, 0.93, 0.91, 0.89 (m, m, m, m, m, 2H), 0.88-0.87, 0.86-0.85, 0.84, 0.82 (m, m, d, d, 12H), 0.51, 0.49, 0.48, 0.47 (m, m, m, m, 2H) ppm.

Example 17

Synthetic route:

Step 1) the preparation of compound 17-2

[00481] To a solution of (R)-l -phenyl ethylamine (1.3 mL, 10.1 mmol) in toluene (15 mL) were added anhydrous Na ₂ SC>4 (3.48 g, 24.5 mmol) and ethyl glyoxalate (1 mL, 10.1 mmol) dropwise in turn and the mixture was stirred at rt for 1 hour. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as yellow liquid (1.9 g, 91.8%) without further purification.

Step 2) the preparation of compound 17-3

[00482] To a solution of compound 17-2 (2.0 g, 9.7 mmol) in DMF (15 mL) was added TFA (0.75 mL, 10.1 mmol). The mixture was stirred for 10 mins and then freshly prepared 1,3-cyclopentadiene (1.29 g, 19.5 mmol) and two drops of water were added. The resulting mixture was stirred at rt for 12 hours. After the reaction was completed, the mixture was concentrated and an aqueous NaHC0 ₃ solution was added to the residue. The mixure was basified with Na ₂ CC>3 till pH = 8 and then the mixture was extracted with PE (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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, 90.0%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 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= 12 Hz ) ppm.

Step 3) the preparation of compound 17-4

[00483] To a solution of compound 17-3 (2.0 g, 7.37 mmol) in ethanol (60 mL) was added Pd/C (0.2 g) and the mixture was stirred at rt under ¾ (20 atm) for 24 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as yellow liquid (1.2 g, 96.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 170.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 17-5

[00484] To a solution of compound 17-4 (1.69 g, 10 mmol) in MeOH (20 mL) were added Et ₃ N (1.67 mL, 12 mmol) and B0C ₂ O (2.41 mL, 10.5 mmol) dropwise in turn 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 and the residue was dissolved in DCM (50 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC> ₄ and concentrated in vacuo to afford the title compound as colorless oil (2.37 g, 88%).

Step 5) the preparation of compound 17-6

[00485] To a solution of compound 17-5 (0.61 g, 2.27 mmol) in THF (25 mL) at 0 °C was added an aqueous solution of lithium hydroxide hydrate (0.48 g, 11.35 mmol, 10 mL) dropwise. At the end of the addition, the mixture was stirred at 40 °C for 12 hours. After the reaction was completed, the THF was removed in vacuo and 50 mL of water was added to the residue. The aqueous layer was washed with EtOAc (25 mL x 3) and acidified with aqueous HC1 (10%) till pH = 1 and the resulting mixture was extracted with EtOAc (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a white solid (0.44 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 242.3 [M+H] ⁺ .

Step 6) the preparation of compound 17-7

[00486] To a solution of compound 17-6 (1.34 g, 5.57 mmol) in THF (20 mL) at 0 °C was added borane (8.3 mL, 1 M in THF) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was quenched with methanol (4 mL) and concentrated in vacuo and the residue was dissolved in DCM (50 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as colorless oil (1.01 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 228.3 [M+H] ⁺ .

Step 7) the preparation of compound 17-9

[00487] To a solution of compound 17-7 (1.19 g, 5.24 mmol) in DCM (20 mL) were added TCCA (1.22 g, 5.24 mmol) and a solution of TEMPO in DCM (82 mg, 0.52 mmol, 3 mL) in turn at 0 °C. At the end of the addition, the mixture was stirred at this temperature for 1 hour and further stirred at rt for 1 hour. After the reaction was completed, the mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium sulfite (20 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved in a solution of NH ₃ in methanol (7 mL, 7 M). The solution was stirred at 0 °C for 0.5 hour and further stirred at rt for 1 hour. Then to the mixture was added glyoxal (1.1 mL, 40%) at 0 °C. At the end of the addition, the mixture was stirred at rt for 24 hours. After the stirring, the mixture was concentrated in vacuo and the residue was dissolved in DCM (60 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a pale yellow solid (0.59 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 264.3 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 6.99 (s, 2H), 4.88-4.85 (m, 1H), 4.49-4.44 (m, 1H), 2.57-2.53 (m, 1H), 2.04-1.96 (m, 1H), 1.89-1.84 (m, 1H), 1.74-1.62 (m, 2H), 1.59-1.46 (m, 2H), 1.44 (s, 9H) ppm.

Step 8) the preparation of compound 17-10

[00488] To a solution of compound 17-9 (0.65 g, 2.47 mmol) in DCM (8 mL) was added NIS (1.23 g, 5.43 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with DCM (30 mL) and filtered. The filtrated was washed with a saturated aqueous solution of sodium sulfite (20 mL x 3), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a yellow solid (1.27 g, 100%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 516.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 5.33-5.30 (m, 1H), 4.39-4.35 (m, 1H), 2.76-2.72 (m, 1H), 2.04-1.92 (m, 2H), 1.83-1.71 (m, 2H), 1.61-1.51 (m, 2H), 1.44 (s, 9H) ppm.

Step 9) the preparation of compound 17-11

[00489] To a solution of compound 17-10 (1.12 g, 2.12 mmol) in a mixed solvent of ethanol (6 mL) and water (6 mL) was added sodium sulfite (2.14 g, 17 mmol) and the mixture was stirred at 90 °C for 30 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved in DCM (80 mL). The solution was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (0.58 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 390.3 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDCI ₃ ): δ 7.36 (s, 1H), 4.81-4.78 (m, 1H), 4.47-4.43 (m, 1H), 2.65-2.61 (m, 1H), 2.04-1.96 (m, 1H),

I.93-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.59-1.48 (m, 2H), 1.44 (s, 9H) ppm.

Step 10) the preparation of compound 17-12

[00490] To a solution of compound 3-13 (0.86 g, 1.9 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.9 g,

I I.4 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (2.1 g, 7.6 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 liquid (0.94 g, 85%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.26, 7.24 (s, s, 1H), 7.17,

7.15 (s, s, 1H), 7.08, 7.06 (s, s, 1H), 7.03, 7.01 (t, t, 1H), 4.03, 4.01, 3.99, 3.97 (m, m, m, m, 1H), 3.88-3.85 (m, 1H), 3.47-3.44 (m, 1H), 3.08-2.97 (m, 1H), 2.81, 2.78, 2.76, 2.74 (m, m, m, m, 1H), 2.56-2.46 (m, 1H), 2.43, 2.41, 2.39, 2.37 (m, m, m, m, 1H), 2.18-2.04 (m, 2H), 2.03-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.61-1.52 (m, 2H), 1.30-1.19 (m, 2H) ppm.

Step 11) the preparation of compound 17-13

[00491] To a mixture of compound 17-12 (0.92 g, 1.58 mmol), compound 1-6-2 (0.92 g, 3.63 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (60 mg, 0.073 mmol) and potassium acetate (0.47 g, 4.7 mmol) was added anhydrous DMF (10.0 mL) under N ₂ via syringe and the resulting mixture was stirred at 90 °C for 3 hours. After the reaction completed, the mixture was cooled to rt, diluted with EtOAc (60 mL) and filtered through a Celite Pad. The filtrate was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl respectively, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.63 g, 7.1%). The compound was characterized by the following spectroscopic data: *H NMR (400 MHz, CDC1 ₃ ): δ 7.26, 7.24 (s, s, 1H), 7.17, 7.15 (s, s, 1H), 7.08, 7.06 (s, s, 1H), 7.03, 7.01 (t, t, 1H), 4.01 (m, 4H), 3.88-3.85 (m, 1H), 3.47-3.44 (m, 1H), 3.08-2.97 (m, 1H), 2.78, (m, 4H), 2.56-2.46 (m, 1H), 2.41(m, 4H), 2.18-2.04 (m, 2H), 2.03-1.92 (m, 2H), 1.82-1.78 (m, 1H), 1.61-1.52 (m, 2H), 1.30-1.19 (m,26H) ppm.

Step 12) the preparation of compound 17-14

[00492] To a mixture of compound 17-13 (0.58 g, 1.0 mmol), compound 17-11 (0.39 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.4 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 810.1 [M+H] ⁺ ; and H NMR (400 MHz, CDCI ₃ ): δ 7.75 (s, 1H), 7.60 (s, 1H), 7.51, 7.49 (s, s, 1H), 7.41, 7.39 (t, t, 1H), 7.24, 7.22 (s, s, 1H), 7.18,

7.16 (s, s, 1H), 4.85-4.81 (m, 1H), 4.79-4.76 (m, 1H), 4.50-4.46 (m, 2H), 4.37-4.30 (m, 1H), 3.78-3.74 (m, 1H), 3.24-3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.54-2.50 (m, 2H), 2.25-2.12 (m, 3H), 2.04-1.96 (m, 3H), 1.95-1.89 (m, 1H), 1.88-1.83 (m, 3H), 1.73-1.45 (m, 11H), 1.44 (s, 18H), 1.30-1.24 (m, 1H), 1.22-1.16 (m, lH) ppm.

Step 13) the preparation of compound 17-15

[00493] To a solution of compound 17-14 (0.24 g, 0.3 mmol) in EtOAc (3.0 mL) was added a solution of HC1 in EtOAc (2.0 mL, 4M) dropwise slowly and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc (5 mL) and filtered to afford a white solid (0.21 g, 94%). The compound was characterized by the following spectroscopic data: MS

(ESI, pos.ion) mlz: 609.8 [M+H] ⁺ .

Step 14) the preparation of compound 17-16

[00494] To a solution of compound 17-15 (0.15 g, 0.2 mmol), compound 1-18-2 (100 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) and HO AT (41 mg, 0.3 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.26 mL, 1.6 mmol) dropwise slowly and the mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL). The resulting mixture was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 as a white solid (0.12 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 462.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.89 (s, 1H), 7.61 (s, 1H), 7.44, 7.42 (s, s, 1H), 7.31, 7.29 (s, s, 1H), 7.28, 7.26 (s, s, 1H), 7.25, 7.23 (t, t, 1H), 5.32, 5.30 (d, d, 2H), 4.98-4.94 (m, 2H), 4.80-4.75 (m, 2H), 4.45, 4.43-4.42, 4.41 (m, m, m, 2H), 4.27-4.20 (m, 1H), 3.87-3.84 (m, 1H), 3.79-3.76 (m, 1H), 3.63 (s, 6H), 3.29, 3.26, 3.24, 3.22 (m, m, m, m, 1H), 3.21-3.12 (m, 1H), 2.83, 2.81, 2.79, 2.77 (m, m, m, m, 1H), 2.59-2.45 (m, 3H), 2.23-1.94 (m, 8H), 1.92-1.88 (m, 1H), 1.83-1.78 (m, 2H), 1.69-1.55 (m, 8H), 1.47-1.36 (m, 2H), 1.30-1.24 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm

Example 18

Synthetic route:

Step 1) the preparation of compound 18-1

[00495] To a solution of compound 3-18 (0.73 g, 1.88 mmol), compound 1-18-2 (0.4 g, 2.25 mmol) and EDCI (0.43 g, 2.25 mmol) in DCM (5 mL) at 0 °C was added DIPEA (1.24 mL, 7.52 mmol) dropwise slowly. The mixture was stirred at rt for 3 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (15 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.75 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 471.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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), 2.25-2.21 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.35 (s, 12H), 0.88-0.84 (m, 6H) ppm.

Step 2) the preparation of compound 18-2

[00496] To a mixture of compound 18-1 (0.27 g, 0.58 mmol), compound 3-13 (0.26 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (0.08 g, 1.4 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (40 mL). The resulting mixture was washed with water (20 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow solid (0.25 g, 68%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 645.8 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60 (m, d, 2H), 7.49 (t, 2H), 7.24, 7.22 (m, m, 1H), 7.08, 7.06 (s, s, 1H), 6.64, 6.62 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.24-5.20 (m, 1H), 4.39,

4.37, 4.35 (m, m, m, 1H), 4.12-4.05 (m, 1H), 3.84-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.56 (m, 1H), 2.54, 2.52, 2.50, 2.48 (m, m, m, m, 1H), 2.38-2.28 (m, 1H), 2.24-1.88 (m, 9H), 1.87-1.83 (m, 1H), 1.64-1.52 (m, 2H), 1.31-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 3) the preparation of compound 18-3

[00497] To a solution of compound 18-2 (1.22 g, 1.9 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.9 g, 11.4 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (2.1 g, 7.6 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 liquid (1.25 g, 85%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60 (m, d, 2H), 7.49 (t, 2H), 7.24, 7.22, 7.20 (m, m, s, 2H), 7.04, 7.02 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.24-5.20 (m, 1H), 4.40,

4.38, 4.36 (m, m, m, 1H), 4.12-4.05 (m, 1H), 3.84-3.76 (m, 2H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.56-3.53 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.39-2.28 (m, 1H), 2.24-1.88 (m, 9H), 1.87-1.83 (m, 1H), 1.64-1.52 (m, 2H), 1.35-1.29 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm. Step 4) the preparation of compound 18-4

[00498] To a mixture of compound 18-3 (0.60 g, 0.77 mmol), compound 1-6-2 (0.22 g, 0.85 mmol), Pd(dppf)Cl ₂ -CH ₂ Ci ₂ (30 mg, 0.036 mmol) and potassium acetate (0.13 g, 1.3 mmol) was added anhydrous DMF (8.0 mL) under N ₂ via syringe and the resulting mixture was stirred at 90 °C for 3 hours. After the reaction completed, the mixture was cooled to rt, diluted with EtOAc (70 mL) and filtered through a Celite Pad. The filtrate was washed with water (10 mL x 3) and saturated aqueous solution of NaCl respectively, dried over anhydrous Na ₂ S0 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 (0.48 g, 82.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 754.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.57 (m 2H), 7.39 (m, 2H), 7.22 (m, 2H), 7.04, 7.02 (s, s, 1H), 5.32, 5.29 (d, d, 1H), 5.24-5.20 (m, 1H), 4.38 (m, 1H), 4.12-4.05 (m, 1H), 3.84-3.76 (m, 2H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.56-3.53 (m, 1H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.39-2.28 (m, 1H), 2.24-1.88 (m, 9H), 1.87-1.83 (m, 1H), 1.64-1.52 (m, 2H), 1.35-1.29 (m, 1H), 1.25-1.19 (m, 13H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm

Step 5) the preparation of compound 18-5

[00499] To a mixture of compound 18-4 (0.44 g, 0.58 mmol), compound 2-2 (0.24 g, 0.58 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and potassium carbonate (80 mg, 1.4 mmol) were added EtOH (4 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.35 g, 65.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 461.6 [M+2H] ²⁺ ; and 'H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.62-7.61, 7.60 (m, d, 2H), 7.58, 7.56 (s, s, 1H), 7.50, 7.48 (t, t, 1H), 7.31, 7.29 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.23, 7.22 (m, m, 1H), 5.32, 5.30 (d, d, 2H), 5.28-5.20 (m, 2H), 4.41-4.35 (m, 2H), 4.12-4.05 (m, 1H), 3.87-3.76 (m, 4H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.12-3.01 (m, 1H), 2.67-2.48 (m, 2H), 2.37-1.88 (m, 16H), 1.69-1.65 (m, 1H), 1.62-1.52 (m, 1H), 1.30-1.21 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 19

Synthetic route:

Step 1) the preparation of compound 19-1

[00500] To a mixture of compound 1-10 (0.54 g, 1.0 mmol), compound 2-2 (0.42 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added EtOH (5 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and diluted with with EtOAc (20 mL). The resulting mixture was washed with water (10 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.5 g, 71%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDCI ₃ ): δ 7.81 (s, IH), 7.66, 7.64 (s, s, IH), 7.61, 7.59 (s, s, IH), 7.51, 7.49 (s, s, IH), 7.26, 7.24 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 4.41-4.37 (m, IH), 3.85-3.78 (m, IH), 3.77-3.73 (m, 3H), 3.69-3.65 (m, 2H), 3.63 (s, 3H), 2.30-1.89 (m, 8H), 1.87-1.83 (m, IH), 1.80-1.74 (m, 2H), 1.64-1.60 (m, IH), 1.57-1.53 (m, IH), 1.32, 1.29 (q, q, 12H), 1.28-1.24 (m, IH), 1.23-1.16 (m, 2H), 1.07-1.01 (m, IH), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 2) the preparation of compound 19-3

[00501] To a solution of compound 19-2 (2.0 g, 15.3 mmol) in MeOH (20 mL) was added thionyl chloride (3.4 mL, 46.9 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at 80 °C for 3.5 hours. After the reaction was completed, the mixture was concentrated in vacuo to afford the title compound as a white solid (2.76 g, 99.5%) without further purification. The compound was characterized by the following spectroscopic data: H NMR (400 Hz, CDC1 ₃ ): δ 3.68 (s, 3H), 3.58 (t, IH), 3.56 (s, IH), 3.32 (m, IH), 3.02 (m, IH), 2.77 (m, 1H), 2.52 (s, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm.

Step 3) the preparation of compound 19-4

[00502] To a mixture of benzyl chloroformate (3.7 mL, 26.3 mmol) and potassium carbonate (10.6 g, 76.7 mmol) in a mixed solvent of THF and H ₂ 0 (THF/H ₂ 0 (v/v) = 20 mL/10 mL) was added compound 19-3 (3.1 g, 17.1 mmol) in one portion with vigorous stirring. At the end of the addition, the mixuture was stirred at rt overnight. After the reaction was completed, the mixture was acidified with aqueous HC1 (1 M) till pH = 1 and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow oil (3 g, 62.8%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 Hz, CDCI ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J= 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm

Step 4) the preparation of compound 19-5

[00503] To a solution of compound 19-4 (1.0 g, 3.6 mmol) in DCM (20 mL) at 0 °C was added Dess-Martin periodinane (3.0 g, 7.1 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 1 hour. 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) = 5/1) to give the title compound as pale yellow oil (0.79 g, 79.5 %). The compound was characterized by the following spectroscopic data: ^l H NMR (400 Hz, CDCI ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm.

Step 5) the preparation of compound 19-6

[00504] To a solution of compound 19-5 (1.0 g, 3.6 mmol) in toluene (20 mL) were added ethylene glycol (0.8 mL, 15.7 mmol) and TsOH (0.14 g, 0.8 mmol) in turn. After the addition, the mixture was refluxed overnight. After the reaction was completed, the mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with a saturated aqueous NaHCC>3 solution and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.54 g, 46.7%). The compound was characterized by the following spectroscopic data: H NMR (400 Hz, CDC1 ₃ ): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm.

Step 6) the preparation of compound 19-7

[00505] To a solution of compound 19-6 (0.58 g, 1.8 mmol) in MeOH (10 mL) was added Pd/C (0.5 g) and the mixture was stirred under H ₂ at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (0.33 g, 98.9%) without further purification. The compound was characterized by the following spectroscopic data: ^l li NMR (400 Hz, CDCI ₃ ): δ 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm. Step 7) the preparation of compound 19-8

[00506] A suspension of compound 19-6 (3.48 g, 18.6 mmol), compound 1-18-2 (3.26 g, 18.6 mmol) and EDCI (7.1 g, 37 mmol) in DCM (50 mL) was stirred at 0 °C and DIPEA (7.1 g, 37 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for overnight. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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: *H NMR (400 Hz, CDC1 ₃ ): δ 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), 3.45 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H) ppm.

Step 8) the preparation of compound 19-9

[00507] To a solution of compound 19-8 (0.9 g, 2.6 mmol) in THF (5 mL) was added an aqueous solution of lithium hydroxide (0.12 g, 5.0 mmol, 5 mL) dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the mixture was acidified with aqueous HC1 (1M) till pH = 2 and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SC>4 and concentrated in vacuo to give the title compound as a white solid (0.85 g, 99%) without further purification. The compound was characterized by the following spectroscopic data: ^l li NMR (400 Hz, CDCI ₃ ): δ 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) ppm.

Step 9) the preparation of compound 19-10

[00508] To a solution of compound 19-9 (1.54 g, 4.66 mmol) in THF (10 mL) at 0 °C was added borane (10 mL, 1 M in THF) dropwise slowly under N ₂ . At the end of the addition, the mixture was stirred at this temperature for 3 hours. After the reaction was completed, the mixture was quenched with methanol (8 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as colorless oil (0.96 g, 65%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 5.32, 5.30 (d, d, 1H), 4.36, 4.34, 4.32, 4.30, 4.28 (m, m, m, m, m, 3H), 3.99-3.97 (m, 4H), 3.73-3.72, 3.71-3.69, 3.67-3.66 (m, m, m, 2H), 3.63 (s, 3H), 3.61-3.59, 3.57-3.55 (m, m, 1H), 3.40-3.38, 3.36-3.34 (m, m, 1H), 25.42-2.36 (m, 1H), 2.17-2.04 (m, 1H), 1.94-1.88 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 10) the preparation of compound 19-11

[00509] To a solution of compound 19-10 (1.1 g, 3.48 mmol) in DCM (10 mL) at 0 °C was added Dess-Martin periodinane (2.07 g, 4.88 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction was quenched with 20 mL of water and filtered and the filtrate was partitioned. The organic layer was washed with a saturated solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (0.71 g, 65%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 9.49-9.48 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.79-4.75 (m, 1H), 4.34, 4.32, 4.30 (m, m, m, 1H), 3.98-3.97 (m, 4H), 3.76-3.75, 3.73-3.71 (m, m, 1H), 3.63 (s, 3H), 3.40-3.38, 3.36-3.34 (m, m, 1H), 2.64-2.62, 2.61-2.59 (m, m, 1H), 2.22-2.10 (m, 1H), 2.00-1.93 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 11) the preparation of compound 19-12

[00510] To a solution of compound 19-11 (0.55 g, 1.76 mmol) and ammonium hydroxide (2 mL) in methanol (5 mL) was added an aqueous glyoxal solution (40%, 1.0 mL) dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the reaction 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 as a white solid (0.4 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 353.4 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 6.99 (s, 2H), 5.60-5.56 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.43, 4.41, 4.39 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.94-3.93 (m, 1H), 3.71-3.70, 3.67-3.66 (m, m, 1H), 3.63 (s, 3H), 2.77-2.71 (m, 1H), 2.36-2.30 (m, 1H), 2.24-2.11 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 12) the preparation of compound 19-13

[00511] To a solution of compound 19-12 (0.70 g, 2.0 mmol) in DCM (60 mL) was added NIS (0.9 g, 4.0 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (0.72 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 605.2 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 5.32, 5.29 (d, d, 1H), 5.29-5.26 (m, 1H), 4.40, 4.38, 4.36 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.93-3.92 (m, 1H), 3.70-3.69, 3.67-3.65 (m, m, 1H), 3.63 (s, 3H), 2.75-2.69 (m, 1H), 2.36-2.30 (m, 1H), 2.24-2.11 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 13) the preparation of compound 19-14

[00512] To a suspension of compound 19-13 (0.91 g, 1.5 mmol) in a mixed solvent of ethanol and water (12.5 mL, ethanol/water (v/v) = 3/7) was added sodium sulfite (1.7 g, 13.5 mmol) and the mixture was refluxed for 17 hours. After the reaction was completed, the mixture was concentrated in vacuo and 50 mL of water was added to the residue. The resulting mixture was extracted with EtOAc (50 mL x 3). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as a white solid (0.57 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 479.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.34 (s, 1H), 5.32, 5.29 (d, d, 1H), 5.25-5.21 (m, 1H), 4.42, 4.40, 4.38 (m, m, m, 1H), 3.98-3.96 (m, 4H), 3.93-3.92 (m, 1H), 3.70-3.69, 3.67-3.65 (m, m, 1H), 3.63 (s, 3H), 2.76-2.74, 2.73-2.70 (m, m, 1H), 2.38, 2.36-2.34, 2.32 (m, m, m, 1H), 2.24-2.11 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 14) the preparation of compound 19-15 [00513] To a mixture of compound 19-14 (0.35 g, 0.72 mmol), compound 19-1 (0.51 g, 0.72 mmol), Pd(PPh ₃ ) ₄ (83 mg, 0.07 mmol) and potassium carbonate (0.30 g, 2.12 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.35 g, 52.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 465.6 [M+2H] ²⁺ ; and ^! H NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 1H), 7.81 (s, 1H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.61-5.60, 5.59-5.58, 5.57 (m, m, m, 1H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 1H), 4.42-4.37 (m, 2H), 3.98-3.96, 3.94-3.92 (m, m, 5H), 3.85-3.78 (m, 1H), 3.77-3.73 (m, 4H), 3.71-3.69, 3.68-3.64 (m, m, 2H), 3.63 (s, 6H), 2.83-2.81, 2.80-2.77 (m, m, 1H), 2.46-2.39 (m, 1H), 2.30-1.89 (m, 10H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.91, 0.89 (m, m, 6H) ppm.

Example 20

Step 1) the preparation of compound 20-1

[00514] To a solution of compound 20-1 (1.72 g, 4.13 mmol) in EtOAc (10.0 mL) was added a solution of HC1 in EtOAc (5.0 mL, 4 M) dropwise slowly and the mixture was stirred at rt for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc (5.0 mL) and the resulting mixture was filtered to afford a solid (1.38 g, 86%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 317.5 [M+H] ⁺ .

Step 2) the preparation of compound 20-3 [00515] A suspension of compound 20-2 (1.4 g, 3.6 mmol), compound 1-18-2 (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 and then DIPEA (2.38 mL, 14.4 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction mixture was diluted with DCM (40 mL). The resulting mixture was washed with an aqueous ammonium chloride solution, dried over anhydrous Na ₂ S0 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 (1.45 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 474.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.96 (brs, 1H), 7.68-7.67 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.10 (m, 1H), 5.32, 5.29 (d, d, 1H), 4.55-4.51 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.55 (m, 1H), 3.47-3.40 (m, 1H), 2.27-1.99 (m, 4H), 1.94-1.82 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 3) the preparation of compound 20-4

[00516] To a mixture of compound 20-3 (0.76 g, 1.61 mmol), compound 1-6-2 (0.45 g, 1.77 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (66 mg, 0.081 mmol) and KOAc (0.4 g, 4.03 mmol) was added DMF (4 mL) via syringe under N ₂ and the mixture was stirred at 120 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt, diluted with EtOAc (40 mL) and filtered through a Celite Pad. The filtrate was washed with water (30 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (0.42 g, 55%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 474.3 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.96 (m, 1H), 7.94-7.93 (m, 1H), 7.65-7.64, 7.63-7.62 (m, m, 1H), 7.41-7.34 (m, 2H), 5.32, 5.30 (d, d, 1H), 4.71-4.66 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.55 (m, 1H), 3.48-3.40 (m, 1H), 2.27-1.99 (m, 4H), 1.94-1.82 (m, 1H), 1.32, 1.29 (q, q, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 4) the preparation of compound 20-5

[00517] To a mixture of compound 20-4 (99 mg, 0.21 mmol), compound 19-1 (0.15 g, 0.21 mmol), Pd(PPh ₃ ) ₄ (25 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) was added a mixed solvent of DME and pure water (4 mL, DME/H ₂ 0 (v/v = 3/1)) via syringe under N ₂ and the mixture was stirred at 90 °C for 5 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (20 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 pale yellow solid (87 mg, 44%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 463.1 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.90 (m, 1H), 8.00-7.99 (m, 1H), 7.81 (s, 1H), 7.52-7.51, 7.50-7.49 (m, m, 1H), 7.44, 7.42 (m, m, 1H), 7.41, 7.40 (s, s, 1H), 7.39, 7.37 (s, s, 1H), 7.33, 7.31 (s, s, 1H), 7.26, 7.24 (s, s, 1H), 7.22, 7.20, 7.18 (m, m, m, 1H), 5.56, 5.55 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 4.62-4.57 (m, 1H), 4.41, 4.39, 4.37 (m, m, m, 1H), 4.32, 4.30, 4.29 (m, m, m, 1H), 4.07-4.04 (m, 1H), 3.85-3.78 (m, 1H), 3.77-3.73 (m, 3H), 3.66 (s, 3H), 3.65-3.64 (m, 1H), 3.63 (s, 3H), 2.92-2.80 (m, 2H), 2.30-2.15 (m, 5H), 2.13-1.80 (m, 11H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 1.02, 1.01 (m, m, 3H), 0.97, 0.95 (m, m, 3H), 0.94, 0.92 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Example 21

Step 1) the preparation of compound 21-1

[00518] To a solution of 1,4-benzoquinone (10.0 g, 92.5 mmol) in DCM (100 mL) was added freshly prepared 1,3-cyclopentadiene (9.20 g, 138.8 mmol) at -10 °C dropwise. The mixture was stirred at this temperature for 1 hour and then stirred at rt for 0.5 hour. After the reaction was completed, the solvent was removed in vacuo and to the residue was added «-hexane (500 mL). After the mixture was stirred for a while and filtered, the filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (10.5 g, 65.2%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 175.1 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 6.57 (s, 2H), 6.68 (s, 2H), 3.55 (s, 2H), 3.22-3.21 (m, 2H), 1.56-1.42 (m, 2H) ppm.

Step 2) the preparation of compound 21-2

[00519] A solution of compound 21-1 (5.50 g, 31.6 mmol) and sodium acetate (7.77 g, 94.7 mmol) in methanol (100 mL) was stirred at 50 °C for 3 hours under N ₂ . After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as a white solid (5.10 g, 92.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 175.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 6.80-6.79 (m, 2H), 6.35 (s, 2H), 3.55 (s, 2H), 4.10-4.09 (m, 2H), 2.25-2.18 (m, 2H) ppm. Step 3) the preparation of compound 21-3

[00520] To a solution of compound 21-2 (3.31 g, 19.0 mmol) in DCM (100 mL) at 0 °C was added pyridine (9.0 g, 114 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (21.0 g, 76.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (50 mL) and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (40 mL x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (7.9 g, 95%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.34 (s, 2H), 6.64-6.61 (m, 2H), 4.12-4.08 (m, 2H), 1.89-1.85 (m, 1H), 1.82-1.78 (m, 1H) ppm.

Step 4) the preparation of compound 21-4

[00521] A suspension of compound 21-3 (0.44 g, 1.0 mmol), compound 1-7 (0.29 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) in a mixed solvent of DME (5.0 mL) and H ₂ 0 (1.0 mL) was stirred at 90 °C for 4 hours under N ₂ . 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/DCM (v/v) = 8/1) to give the title compound as pale yellow oil (0.25 g, 55.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 449.5 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.15, 7.13 (s, s, 1H), 7.10, 7.08 (s, s, 1H), 7.06, 7.04 (s, s, 1H), 6.95-6.91 (m, 1H), 6.63-6.60 (m, 1H), 6.57, 6.55 (s, s, 1H), 5.77 (brs, 1H), 4.40-4.36 (m, 1H), 3.93-3.90 (m, 1H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.31-2.27 (m, 1H), 2.23-2.20 (m, 1H), 2.07-2.01 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.34-1.28 (m, 1H), 1.25-1.19 (m, lH) ppm.

Step 5) the preparation of compound 21-5

[00522] A suspension of compound 21-4 (0.22 g, 0.5 mmol), compound 2-7 (0.25 g, 0.5 mmol), Pd(PPh ₃ ) ₄ (0.17 g, 1.25 mmol) and potassium carbonate (57.8 mg, 0.05 mmol) in a mixed solvent of DME (4 mL) and H ₂ 0 (1 mL) was stirred at 90 °C for 6 hours under N ₂ . After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 pale yellow solid (0.2 g, 59.8%). The compound was characterized by the following spectroscopic data: ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.63-7.62, 7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.41, 7.38 (s, s, 1H), 7.28, 7.25 (s, s, 1H), 7.17, 7.15 (s, s, 1H), 6.96-6.95 (m, 2H), 6.57, 6.55 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.33-2.15 (m, 5H), 2.13-1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.34-1.28 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 6) the preparation of compound 21-6 [00523] To a solution of compound 21-5 (0.67 g, 1.0 mmol) in DCM (5 mL) at 0 °C was added pyridine (0.3 mL, 4.0 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (0.34 mL, 2.0 mmol) was added dropwise. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (10 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 pale yellow liquid (0.65 g, 81.2%). The compound was characterized by the following spectroscopic data: ^l li NMR (400 MHz, CDCI ₃ ): δ 7.63-7 ^' .62, 7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.38, 7.35 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.09, 7.07 (s, s, 1H), 7.03, 7.01 (s, s, 1H), 6.96-6.95 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.51-3.48 (m, 1H), 2.33-2.15 (m, 5H), 2.13-1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 7) the preparation of compound 21-7

[00524] To a mixture of compound 21-6 (0.8 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (0.45 g, 47.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 473.6 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.63-7.62, 7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.46, 7.44 (d, d, 2H), 7.28, 7.25 (d, d, 2H), 6.96-6.95 (m, 2H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.37 (m, m, m, 3H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 3H), 3.78-3.73 (m, 1H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 2.33-2.15 (m, 8H), 2.13-2.03 (m, 2H), 2.02-1.91 (m, 5H), 1.72-1.68 (m, 1H), 1.30-1.24 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

Example 22

Synthetic route:

Step 1) the preparation of compound 22-2

[00525] To a solution of 1,4-benzoquinone (10.0 g, 92.5 mmol) in DCM (50 mL) was added compound 22-1 (11.12 g, 138.8 mmol) at -10 °C dropwise. The mixture was stirred at this temperature for 1 hour and then stirred at rt for 0.5 hour. After the reaction was completed, the solvent was removed in vacuo and to the residue was added «-hexane (500 mL). The mixture was stirred for a while and then filtered to give the title compound as a pale yellow solid (11.3 g, 65%) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 189.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 6.71 (d, 2H), 6.20-6.19 (m, 2H), 3.08-3.05 (m, 2H), 2.46-2.44 (m, 2H), 2.30-2.23 (m, 1H), 0.96-0.93 (m, 3H) ppm.

Step 2) the preparation of compound 22-3

[00526] A solution of compound 22-2 (5.94 g, 31.6 mmol) and sodium acetate (7.77 g, 94.7 mmol) in methanol (100 mL) was stirred at 50 °C for 3 hours under N ₂ . After the reaction was completed, the mixture was concentrated in vacuo to give the title compound as a white solid (5.5 g, 92.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 189.5 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 6.65-6.64 (m, 2H), 6.47 (s, 2H), 5.41 (br, 2H), 3.76-3.72 (m, 2H), 2.64-2.57 (m, 1H), 1.15-1.12 (m, 3H) ppm.

Step 3) the preparation of compound 22-4

[00527] A suspension of compound 22-3 (5.07 g, 27.0 mmol) and Pd/C (0.5 g) in methanol (50 mL) was stirred at rt for 1.5 hours under H ₂ at atmospheric pressure. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by re-crystallization to give the title compound as a white solid (3.59 g, 70%). The compound was characterized by the following spectroscopic data: ^! H NMR (400 MHz, CDC1 ₃ ): δ 6.40 (s, 2H), 5.77 (br, 2H), 3.10-3.08 (m, 2H), 2.42-2.34 (m, 1H), 2.08-2.04 (m, 2H), 1.34-1.30 (m, 2H), 0.90-0.87 (m, 3H) ppm.

Step 4) the preparation of compound 22-5

[00528] To a solution of compound 22-4 (3.61 g, 19.0 mmol) in DCM (90 mL) at 0 °C was added pyridine (9.0 g, 114 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (21.0 g, 76.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (50 mL) and the aqueous layer was diluted with DCM (50 mL). The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 as colorless oil (8.45 g, 98%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.27 (s, 2H), 3.22-3.19 (m, 2H), 2.17-2.10 (m, 1H), 2.03-1.99 (m, 2H), 1.29-1.25 (m, 2H), 1.03-1.01 (m, 3H) ppm.

Step 5) the preparation of compound 22-6

[00529] A suspension of compound 22-5 (0.45 g, 1.0 mmol), compound 1-7 (0.29 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) in a mixed solvent of DME (5 mL) and H ₂ 0 (1 mL) was stirred at 90 °C for 6 hours under N ₂ . After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless liquid (0.35 g, 75.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 465.5 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.11, 7.09 (s, s, 1H), 7.06, 7.05 (s, s, 1H), 7.04, 7.03 (s, s, 1H), 6.57, 6.55 (s, s, 1H), 5.77 (brs, 1H), 3.58-3.54 (m, 1H), 3.53-3.47 (m, 2H), 3.16-3.12 (m, 1H), 2.44-2.37 (m, 1H), 2.06-1.92 (m, 4H), 1.82-1.78 (m, 1H), 1.59-1.55 (m, 1H), 1.31-1.19 (m, 4H), 0.86, 0.84 (t, t, 3H) ppm.

Step 6) the preparation of compound 22-7

[00530] To a solution of compound 22-6 (1.86 g, 4.0 mmol) in DCM (5 mL) at 0 °C was added pyridine (1.29 mL, 16 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (1.35 mL, 8.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (20 mL) and the aqueous layer was extracted with DCM (20 mLx3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 oil (1.95 g, 81.7%). The compound was characterized by the following spectroscopic data: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.12, 7.10 (s, s, 1H), 7.07-7.02 (m, 3H), 3.88-3.85 (m, 1H), 3.51-3.47 (m, 2H), 3.16-3.12 (m, 1H), 2.44-2.37 (m, 1H), 2.06-1.92 (m, 4H), 1.82-1.78 (m, 1H), 1.59-1.55 (m, 1H), 1.31-1.19 (m, 4H), 0.86, 0.84 (t, t, 3H) ppm.

Step 7) the preparation of compound 22-8

[00531] To a mixture of compound 22-7 (0.6 g, 1.0 mmol), compound 3-1 (0.88 g, 2.1 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (0.35 g, 39.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 444.6 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.80 (s, 1H), 7.36, 7.35 (s, s, 1H), 7.34, 7.32 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.24, 7.23 (s, s, 1H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 2H), 4.41, 4.39, 4.37 (m, m, m, 2H), 3.85-3.78 (m, 3H), 3.77-3.74 (m, 1H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.52-3.49 (m, 1H), 3.17-3.13 (m, 1H), 2.40-2.33 (m, 1H), 2.30-1.89 (m, 14H), 1.87-1.83 (m, 1H), 1.64-1.60 (m, 1H), 1.35-1.24 (m, 3H), 1.22-1.16 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.87 (t, 3H) ppm.

Example 23

Synthetic route:

Step 1) the preparation of compound 23-1

[00532] To a solution of compound 12-4 (0.46 g, 1.0 mmol) in DCM (5 mL) at 0 °C was added pyridine (0.32 mL, 4.0 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (0.34 mL, 2.0 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (10 mL) and the aqueous layer was extracted with DCM (15 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 colorless oil (0.52 g, 87.2%). The compound was characterized by the following spectroscopic data: H NMR (400 MHz, CDC1 ₃ ): δ 7.65, 7.62 (s, s, 1H), 7.07, 7.05 (s, s, 1H), 7.04, 7.02 (s, s, 1H), 7.00, 6.98 (s, s, 1H), 3.89-3.86 (m, 1H), 3.74-3.71 (m, 1H), 3.65-3.62 (m, 1H), 3.49-3.46 (m, 1H), 2.58-2.51 (m, 1H), 2.48-2.40 (m, 1H), 2.23-2.17 (m, 1H), 2.16-2.05 (m, 2H), 1.98-1.90 (m, 2H), 1.71-1.67 (m, 1H), 1.42-1.36 (m, 1H), 1.25-1.19 (m, 1H) ppm.

Step 2) the preparation of compound 23-2

[00533] To a mixture of compound 23-1 (0.6 g, 1.0 mmol), compound 3-1 (0.88 g, 2.1 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (5 mL) and pure water (1 mL) flask via syringe under N ₂ and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.45 g, 50.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 443.5 [M+2H] ²⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.83 (s, IH), 7.81 (s, IH), 7.37, 7.36 (s, s, IH), 7.35, 7.34 (s, s, IH), 7.28, 7.26 (s, s, IH), 6.97, 6.95 (s, s, IH), 6.07, 6.05 (d, d, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, 2H), 4.41, 4.39, 4.37 (m, m, m, IH), 4.33, 4.31, 4.30 (m, m, m, IH), 3.95-3.91 (m, 2H), 3.85-3.74 (m, 4H), 3.69-3.65 (m, 2H), 3.64 (s, 3H), 3.63 (s, 3H), 2.56-2.49 (m, IH), 2.47-2.40 (m, IH), 2.30-1.92 (m, 15H), 1.76-1.72 (m, IH), 1.34-1.24 (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) ppm.

Example 24

Synthetic route:

Step 1) the preparation of compound 24-2

[00534] To a solution of compound 24-1 (2.1 g, 9.17 mmol) in THF (20 mL) was added an aqueous NaOH solution (2.1 g, 20 mL) and the mixture was stirred at 60 °C overnight. After the mixture was completed, the THF was removed in vacuo. The residue was dissolved in EtOAc (50 mL) and the solution was extracted with water (50 mL x 3). The combined aqueous layers were acidified with aqueous HC1 (1 M) till pH = 4 and solid precipitated out. The mixture was filtered to afford the title compound as a pale yellow solid (1.4 g, 72%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 7.59 (d, IH, J= 8.0 Hz), 6.96 (d, IH, J= 1.6 Hz), 6.64 (dd, IH, J= 8.0 Hz, 2.0 Hz) ppm.

Step 2) the preparation of compound 24-3

[00535] To a solution of compound 24-2 (1.51 g, 7.00 mmol) in anhydrous THF (5 mL) was added CDI (0.83 g, 5.12 mmol). After the mixture was stirred at rt for 2 hours, the mixure was cooled to 0 °C and ammonium hydroxide (20 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF was removed in vacuo and the rediue was dissolved in EtOAc (100 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to afford a pale yellow solid (1.2 g, 80 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 3) the preparation of compound 24-4

[00536] A suspension of compound 24-3 (1.5 g, 7.00 mmol), compound 24-3-2 (2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in a mixed solvent of DCM (15 mL) and THF (10 mL) was stirred at 0 °C and DIPEA (5.8 mL, 35 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 8 hours. After the reaction was completed, the reaction mixture was concentrated and the residue was dissolved in EtOAc (100 mL). The solution was washed with an aqueous ammonium chloride solution, dried over anhydrous Na ₂ S0 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 oil (0.66 g, 20%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 470.33 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 4) the preparation of compound 24-5

[00537] To a solution of compound 24-4 (0.6 g, 1.28 mmol) in THF (10 mL) was added an aqueous solution of lithium hydroxide (0.27 g, 6 mL) dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt for 5 hours. After the reaction was completed, the THF was removed in vacuo and the residue was added to 50 mL of EtOAc. The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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) mlz: 452.33 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm. Step 5) the preparation of compound 24-6

[00538] To a mixture of compound 24-5 (0.2 g, 0.44 mmol), compound 1-6-2 (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) was added DMF (5 mL) via syringe under N ₂ and the mixture was stirred at 80 °C for 3 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.16 g, 70%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 499.26 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 11. 08 (s, IH), 8.22 (d, IH, J = 8.0 Hz), 8.11 (s, IH), 7.83 (d, IH, J= 8.0 Hz), 5.71 (d, IH, J= 8.0 Hz), 5.17 (d, IH, J= 6.0 Hz), 4.35 (t, IH, J= 8.0 Hz), 4.15-4.10 (m, IH), 3.88-3.86 (m, IH), 3.67 (s, 3H), 2.71-2.67 (m, IH), 2.34-2.32 (m, IH), 2.09-1.99 (m, 2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H) ppm.

Step 6) the preparation of compound 24-7

[00539] To a mixture of compound 24-6 (0.12 g, 0.23 mmol), compound 19-1 (0.11 g, 0.16 mmol), Pd(PPh ₃ ) ₄ (30 mg, 0.03 mmol) and potassium carbonate (60 mg, 0.44 mmol) were added DME (3 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 3 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (98.7 mg, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 475.6 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.97-7.96 (m, IH), 7.81 (s, IH), 7.56 (d, 2H), 7.47, 7.45-7.44, 7.42 (d, m, d, 2H), 7.39, 7.37 (s, s, IH), 7.26, 7.24 (s, s, IH), 5.56, 5.55 (d, d, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 5.21-5.15 (m, IH), 4.41, 4.39, 4.37 (m, m, m, IH), 4.29, 4.27, 4.26 (m, m, m, IH), 4.03-4.01 (m, IH), 3.85-3.78 (m, IH), 3.77-3.73 (m, 3H), 3.68-3.67 (m, IH), 3.66 (s, 3H), 3.63 (s, 3H), 3.51-3.43, 3.42-3.34 (m, m, 2H), 2.50-2.42 (m, IH), 2.37-1.80 (m, 15H), 1.64-1.57 (m, 2H), 1.30-1.16 (m, 4H), 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) ppm.

Example 25

Synthetic route:

Step 1) the preparation of compound 25-2

[00540] To a solution of compound 25-1 (1.9 g, 10 mmol) in DCM (20 mL) was added a solution of m-CPBA (3.45 g, 20 mmol) dropwise at 0 °C and then the mixture was stirred at rt for 7 hours. After the reaction was completed, the mixture was diluted with DCM (20 mL), washed with saturated aqueous NaCl, dried over anhydrous Na ₂ S0 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 (1.6 g, 77%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 208.3 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): 38.29 (d, 1H), 7.11 (d, 1H), 3.43 (s, 3H), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H)ppm.

Step 2) the preparation of compound 25-3

[00541] To a solution of sodium methoxide (0.54 g, 10 mmol) in methanol (20 mL) was added compound 25-2 (1.6 g, 6.67 mmol). The mixture was refluxed for 10 hours and concentrated in vacuo and to the residue was added EtOAc (100 mL). The resulting mixture was washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SC>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 (1.1 g, 82.3%). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) mlz: 176.2 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 8.29 (d, 1H), 7.11 (d, 1H), 3.8 (s, 3H), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H)ppm.

Step 3) the preparation of compound 25-4

[00542] To a solution of compound 25-3 (1.3 g, 6.31 mmol) in DCM (20 mL) was added NBS (1.35 g, 7.6 mmol) in portions and then the mixture was stirred at rt for 5 hours. The reaction mixture was diluted with DCM (50 mL), washed with saturated aqueous NaCl, dried over anhydrous Na ₂ S0 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 as a white solid (1.4 g, 87.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 255.1 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.88 (d, 1H), 3.8 (s, 3H), 3.56-3.53 (m, 1H), 3.33-3.30 (m, 1H), 1.97-1.86 (m, 2H), 1.80-1.76 (m, 1H), 1.57-1.53 (m, 1H), 1.24-1.13 (m, 2H)ppm

Step 4) the preparation of compound 25-5

[00543] To a mixture of compound 1-7 (0.33 g, 1.14 mmol), compound 25-4 (0.32 g, 1.25 mmol), Pd(PPh ₃ ) ₄ (65.9 mg, 0.057mmol) and potassium carbonate (0.39 g, 2.84 mmol) were added DME (8 mL) and pure water (2 mL) via syringe under N2 and the mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (50 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 a white solid (0.27 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 334.4 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 8.29 (s, 1H), 7.11, 7.09 (s, s, 1H), 6.63, 6.61 (s, s, 1H), 5.77 (brs, 1H), 3.95 (s, 3H), 3.66-3.58 (m, 2H), 3.43-3.40 (m, 1H), 3.33-3.28 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.91 (m, 3H), 1.81-1.77 (m, 1H), 1.69-1.65 (m, 1H), 1.58-1.54 (m, 1H), 1.50-1.46 (m, 1H), 1.25-1.18 (m, 3H), 1.14-1.08 (m, 1H) ppm.

Step 5) the preparation of compound 25-6

[00544] To a solution of compound 25-5 (0.27 g, 0.8 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.26 mL, 3.2 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (0.27 mL, 1.6 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (25 mL) and the aqueous layer was extracted with DCM (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as colorless oil (0.34 g, 90.5%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.37 (s, 1H), 7.30, 7.28 (s, s, 1H), 7.18, 7.16 (s, s, 1H), 3.98-3.96 (m, 1H), 3.95 (s, 3H), 3.61-3.58 (m, 1H), 3.43-3.40 (m, 1H), 3.28-3.25 (m, 1H), 2.08-1.91 (m, 4H), 1.81-1.77 (m, 1H), 1.69-1.65 (m, 1H), 1.58-1.54 (m, 1H), 1.50-1.46 (m, 1H), 1.29-1.18 (m, 3H), 1.14-1.08 (m, 1H) ppm. Step 6) the preparation of compound 25-7

[00545] To a mixture of compound 25-6 (0.47 g, 1.0 mmol), compound 3-1 (0.42 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) were added DME (4 mL) and pure water (1 mL) via syringe under N2 and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was cooled to rt and diluted with EtOAc (30 mL). The resulting mixture was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.5 g, 82%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 610.8 [M+H] ⁺ ; and ^l li NMR (400 MHz, CDC1 ₃ ): δ 8.40 (s, IH), 7.81 (s, IH), 7.38, 7.36 (s, s, IH), 7.30, 7.28 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m, m, m, IH), 3.95 (s, 3H), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 2H), 3.63 (s, 3H), 3.61-3.58 (m, IH), 3.43-3.40 (m, IH), 2.30-2.15 (m, 3H), 2.13-1.88 (m, 6H), 1.86-1.82 (m, IH), 1.69-1.65 (m, IH), 1.63-1.59 (m, IH), 1.50-1.46 (m, IH), 1.30-1.15 (m, 3H), 1.14-1.08 (m, IH), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 7) the preparation of compound 25-8

[00546] To a solution of compound 25-7 (1.69 g, 2.77 mmol) in DCM (20 mL) at -78 °C was added BBr ₃ (0.36 mL, 3.88 mmol) dropwise and the mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (20 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 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 gray solid (1.55 g, 94%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 596.7 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 8.04 (s, IH), 7.81 (s, IH), 7.38, 7.36 (s, s, IH), 7.29, 7.26 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m, m, m, IH), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 2H), 3.63 (s, 3H), 3.62-3.60 (m, IH), 3.53-3.51 (m, IH), 2.30-2.15 (m, 3H), 2.13-1.88 (m, 6H), 1.86-1.82 (m, IH), 1.67-1.59 (m, 2H), 1.48-1.44 (m, IH), 1.30-1.24 (m, 2H), 1.21-1.09 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 8) the preparation of compound 25-9

[00547] To a solution of compound 25-8 (0.48 g, 0.8 mmol) in DCM (5 mL) at 0 °C was added pyridine (0.25 g, 3.2 mmol) dropwise. The mixture was stirred at this temperature for 10 mins and then Tf ₂ 0 (0.45 g, 1.6 mmol) was added. At the end of the addition, the mixture was stirred at rt for 1 hour. After the mixture was completed, the reaction was quenched with ice water (10 mL) and the aqueous layer was extracted with DCM (25 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 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 (0.52 g, 90%). The compound was characterized by the following spectroscopic data: ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.36 (s, IH), 7.81 (s, IH), 7.38, 7.36 (s, s, IH), 7.30, 7.28 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m, m, m, IH), 3.85-3.78 (m, 2H), 3.69-3.64 (m, 3H), 3.63 (s, 3H), 3.51-3.48 (m, IH), 2.30-2.15 (m, 3H), 2.13-1.88 (m, 6H), 1.86-1.82 (m, 1H), 1.66-1.59 (m, 2H), 1.47-1.44 (m, 1H), 1.34-1.24 (m, 2H), 1.21-1.09 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Step 9) the preparation of compound 25-11

[00548] To a solution of compound 25-10 (5.0 g, 22.7 mmol) in EtOH (60 mL) was added a mixture of Na ₂ S0 ₃ (7.16 g, 56.8 mmol) in EtOH (60 mL) and water (125 mL) dropwise. At the end of the addition, the mixture was stirred at 70 °C for 15 hours. After the reaction was completed, the mixture was cooled to rt, acidified with aqueous HC1 (2 M) till pH = 2 and then concentrated in vacuo and to the residue was added 100 mL a saturated aqueous solution of NaCl. The resulting mixture was refluxed until all the residue was dissolved and water (10 mL) was then added. The reaction mixture was cooled to 0 °C and solid precipitated out. When there was no more solid precipitate formed, the mixture was filtered to afford the title compound (5.70 g, 89%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 282.5 [M+H] ⁺ ; and ¹ !! NMR (400 MHz, CDC1 ₃ ): δ 8.75 (br, 1H), 8.31 (m, 1H), 8.07 (m, 2H) ppm.

Step 10) the preparation of compound 25-12

[00549] To a solution of compound 25-11 (3.0 g, 10.6 mmol) and DMF (one drop) in toluene (50 mL) was added thionyl chloride (5 mL) dropwise and the mixture was refluxed for 4 hours. After the reaction was completed, the mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in toluene (4 mL) and the solution was cooled to -10 °C. To the solution were added a saturated aqueous ammonium hydroxide solution (1 mL) and THF (10 mL) and the resulting mixture was stirred at this temperature for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (6 M) till pH = 4. The organic layer was dried over anhydrous Na ₂ SC>4 and concentrated in vacuo. A mixture of the residue and PE (15 mL) was stirred and then solid precipitated out. The mixture was filtered to afford compound 25-12 (9.0 g, 85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 281.5 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 11) the preparation of compound 25-13

[00550] A solution of compound 25-12 (2.12 g, 7.5 mmol) in aqueous HI (25 mL, 57% in water) was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to rt and the reaction mixture turned into purple-black. The mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with aqueous sodium thiosulfate, saturated aqueous NaHC(¾ and saturated aqueous NaCl respectively, then dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by prep-HPLC (CH ₃ CN/H ₂ 0 = 22/78-52/48, 0.01% ΝΗ ₃ Ή ₂ 0 buffer solution) to give the title compound (1.86 g). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 251.5 [M+H] ⁺ ; and ^! H NMR (400 MHz, CDCI ₃ ): δ 7.62-7.60 (m, 1H), 7.18-7.15 (m, 2H), 4.85 (brs, 4H) ppm.

Step 12) the preparation of compound 25-14

[00551] To a solution of compound 25-13 (1.86 g, 7.4 mmol) in acetone (20 mL) was added Et ₃ N (4.05 mL, 29.6 mmol) dropwise. The mixture was stirred at 0 °C and compound 25-10-2 (1.28 g, 4.8 mmol) was added. The resulting mixture was stirred at this temperature for 5 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and acidified with aqueous HC1 (2 M) till pH = 4. Solid precipitated out and was filtered. The filter cake was washed with water and purified by prep-HPLC (CH ₃ CN/H ₂ 0 = 35/65-65/35, 0.75% CF ₃ COOH buffer solution) to give the title compound (1.00 g, 45%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 464.5 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 13) the preparation of compound 25-15

[00552] To a solution of compound 25-14 (3.73 g, 8.03 mmol) in EtOAc (40 mL) was added Pd/C (0.35 g) and the mixture was stirred at 40 °C under H ₂ (10 atm) for 5 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrate in vacuo to afford compound 25-15 (2.27 g, 86%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 330.5 [M+H] ⁺ .

Step 14) the preparation of compound 25-16

[00553] A suspension of compound 25-15 (3.29 g, 10.0 mmol), compound 1-18-2 (1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) was stirred at 0 °C and then DIPEA (6.6 mL, 39.9 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 3 hour. After the reaction was completed, the reaction mixture was diluted with DCM (50 mL). The resulting mixture was washed with water (30 mL x 3), an aqueous ammonium chloride solution and a saturated aqueous solution of NaCl respectively, dried over anhydrous Na ₂ S0 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) mlz: 487.5 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDCI ₃ ): δ 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) ppm.

Step 15) the preparation of compound 25-17

[00554] To a mixture of compound 25-16 (0.44 g, 0.91 mmol), compound 1-6-2 (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 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 3 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SC>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 (0.43 g, 88%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 535.3 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

Step 16) the preparation of compound 25-18 [00555] To a mixture of compound 25-17 (0.33 g, 0.61 mmol), compound 25-6 (0.44 g, 0.61 mmol), Pd(PPh ₃ ) ₄ (35.26 mg, 0.03 mmol) and potassium carbonate (0.25 g, 1.83 mmol) were added DME (5 mL) and pure water (4 mL) via syringe under N ₂ and the mixture was stirred at 90 °C for 4 hours. 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 x 3) and a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (0.39 g, 65%).

2+

The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 494 A [M+2H] ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.63 (s, 1H), 8.26 (m, 1H), 8.15, 8.13 (d, d, 1H), 7.81 (s, 1H), 7.55, 7.53 (s, s, 1H), 7.39, 7.37 (d, d, 1H), 7.34, 7.32 (s, s, 1H), 5.56, 5.55 (d, d, 1H), 5.32, 5.30 (d, d, 1H), 5.29-5.25 (m, 1H), 5.08-5.02 (m, 1H), 4.41-4.40, 4.39-4.38, 4.37-4.36 (m, m, m, 1H), 4.27, 4.25, 4.23 (m, m, m, 1H), 3.85-3.78 (m, 4H), 3.66 (s, 3H), 3.65-3.64 (m, 1H), 3.63 (s, 3H), 3.52-3.49 (m, 1H), 3.47-3.39 (m, 1H), 3.38-3.30 (m, 1H), 2.30-2.15 (m, 3H), 2.13-1.81 (m, 13H), 1.68-1.62 (m, 2H), 1.31-1.20 (m, 3H), 1.13-1.07 (m, 1H), 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) ppm.

Example 26

Synthetic route:

Compounds disclosed herein can be prepared by an analogous procedure to that described in example 1.

[00556] Compound 26-2: 'H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00557] Compound 26-3 : ^! H NMR (400 MHz, CDCI ₃ ): δ 9.46 (d, 1H, J = 2.8 Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 2.01-1.93 (m, 2H), 1.91-1.84 (m, 2H), 1.43 (s, 9H) ppm.

[00558] Compound 26-4: MS (ESI, pos.ion) mlz: 238.2 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 6.96 (s, 1H), 4.94 (dd, 1H, J= 7.68 Hz, 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) ppm.

[00559] Compound 26-5: MS (ESI, pos.ion) mlz: 490.0 [M+H] ⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 4.89 (dd, 1H, J= 7.64 Hz, 2.52 Hz), 3.36 (t, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H) ppm.

[00560] Compound 26-6: MS (ESI, pos.ion) mlz: 364.1 [M+H] ⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00561] Compound 26-7: MS (ESI, pos.ion) mlz: 379.4 [M+2H] ²⁺ ; and ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.05-5.00 (m, 2H), 3.77-3.73 (m, 4H), 3.64-3.58 (m, 2H), 3.31-3.24 (m, 2H), 2.47-2.38 (m, 2H), 2.28-2.17 (m, 2H), 2.10-1.97 (m, 6H), 1.95-1.89 (m, 2H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.41 (s, 18H), 1.30-1.24 (m, 2H), 1.22-1.16 (m, 2H) ppm.

[00562] Compound 26-8: MS (ESI, pos.ion) mlz: 557 [M+H] ⁺ . Compound 26-9 : MS (ESI, pos.ion) mlz: 436.5 [M+2H] ²⁺ ; and H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 2H), 7.39, 7.37 (s, s, 2H), 7.26, 7.24 (s, s, 2H), 5.56, 5.55 (d, d, 1H), 5.46, 5.44 (d, d, 1H), 5.29-5.25 (m, 2H), 4.41-4.37 (m, 1H), 4.34-4.30 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.73 (m, 4H), 3.66 (s, 6H), 3.65-3.61 (m, 2H), 2.30-2.16 (m, 6H), 2.13-1.89 (m, 8H), 1.87-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.30-1.24 (m, 2H), 1.22-1.16 (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) ppm.

Example 27

Synthetic route:

Compounds disclosed herein can be prepared by an analogous procedure to that described in example 2.

[00563] Compound 27-1: MS (ESI, pos.ion) mlz: 264 A [M+H] ⁺ .

[00564] Compound 27-2: MS (ESI, pos. ion) m/z: 421.1 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00565] Compound 27-3: MS (ESI, pos.ion) mlz: 412.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00566] Compound 27-4: MS (ESI, pos.ion) mlz: 392.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00567] Compound 27-5: MS (ESI, pos.ion) mlz: 292.2 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00568] Compound 27-6: MS (ESI, pos.ion) m/z: 450.5 [M+H] ⁺ ; and ^l H NMR (400 MHz, CDC1 ₃ ): δ 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) ppm.

[00569] Compound 27-7: H NMR (400 MHz, CDC1 ₃ ): δ 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), 3.5-3.81 (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), 1.32-1.45 (m, 12H), 1.04-1.02 (m, 1H), 0.88-0.86 (d, 6H) ppm.

[00570] Compound 27-8: *H NMR (400 MHz, CDC1 ₃ ): δ 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.42, 7.40 (s, s, IH), 7.31, 7.29 (s, s, IH), 7.10, 7.08 (s, s, IH), 7.07, 7.05 (s, s, IH), 5.32, 5.29 (d, d, IH), 5.23-5.19 (m, IH), 4.41-4.37 (m, IH), 3.92-3.90 (m, IH), 3.85-3.78 (m, IH), 3.74-3.71 (m, 2H), 3.69-3.64 (m, IH), 3.63 (s, 3H), 3.45-3.42 (m, IH), 2.30-2.15 (m, 3H), 2.13- 1.90 (m, 6H), 1.84-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.30- 1.17 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00571] Compound 27-9: MS (ESI, pos.ion) mlz: 781.8 [M+H] ⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.66, 7.64 (s, s, IH), 7.62-7.61, 7.60-7.59 (m, m, 4H), 7.58, 7.56 (s, s, IH), 7.55-7.54, 7.53-7.52 (m, m, 2H), 7.31, 7.29 (s, s, IH), 5.32, 5.29 (d, d, IH), 5.23-5.19 (m, IH), 4.41-4.37 (m, IH), 3.92-3.90 (m, IH), 3.85-3.78 (m, IH), 3.75-3.71 (m, 2H), 3.69-3.64 (m, IH), 3.63 (s, 3H), 2.30-2.15 (m, 3H), 2.13- 1.90 (m, 6H), 1.84-1.74 (m, 3H), 1.61- 1.53 (m, 2H), 1.32, 1.29 (q, q, 12H), 1.27-1.17 (m, 3H), 1.07- 1.01 (m, IH), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00572] Compound 27-10: MS (ESI, pos.ion) mlz: 474.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, IH), 7.62-7.61, 7.60-7.59 (m, m, 3H), 7.56-7.55, 7.53-7.52 (m, m, 2H), 7.51, 7.48 (s, s, IH), 7.39, 7.37 (s, s, IH), 7.31, 7.29 (s, s, IH), 7.26, 7.24 (s, s, IH), 6.07, 6.05 (d, d, IH), 5.32, 5.30 (d, d, IH), 5.29-5.25 (m, IH), 5.23-5.19 (m, IH), 4.41-4.36 (m, IH), 4.34-4.30 (m, IH), 3.92-3.90 (m, IH), 3.85-3.78 (m, 2H), 3.77-3.71 (m, 3H), 3.69-3.66 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.30-2.16 (m, 6H), 2.13- 1.89 (m, 8H), 1.87-1.80 (m, 2H), 1.64- 1.57 (m, 2H), 1.30-1.16 (m, 4H), 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) ppm.

Example 28

Synthetic route:

Compounds disclosed herein can be prepared by an analogous procedure to that described in example 3.

[00573] Compound 28-1: *H NMR (400 MHz, CDC1 ₃ ): δ 7.64 (s, IH), 5.55-5.51 (m, IH), 5.32, 5.29 (d, d, IH), 4.41-4.37 (m, IH), 3.78-3.72 (m, IH), 3.63 (s, 3H), 3.61-3.54 (m, IH), 2.25- 1.87 (m, 5H), 1.39, 1.36 (q, q, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm ₀

[00574] Compound 28-2: MS (ESI, pos.ion) mlz: 595.7 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.59 (s, IH), 7.39, 7.37 (s, s, IH), 7.38, 7.36 (t, t, IH), 7.22, 7.20 (s, s, IH), 6.75, 6.72 (s, s, IH), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.85-3.78 (m, IH), 3.69-3.65 (m, IH), 3.63 (s, 3H), 3.58-3.54 (m, IH), 3.50-3.46 (m, IH), 3.24-3.12 (m, IH), 2.70-2.57 (m, 2H), 2.30-1.92 (m, 10H), 1.82- 1.78 (m, IH), 1.66-1.55 (m, 2H), 1.26- 1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00575] Compound 28-3 : *H NMR (400 MHz, CDC1 ₃ ): δ 7.59 (s, IH), 7.38, 7.35 (t, t, IH), 7.26, 7.24 (s, s, IH), 7.22, 7.21 (s, s, IH), 7.20, 7.19 (s, s, IH), 5.32-5.28 (m, 2H), 4.41-4.30 (m, 2H), 3.88-3.78 (m, 2H), 3.69-3.64 (m, IH), 3.63 (s, 3H), 3.47-3.44 (m, IH), 3.24-3.12 (m, IH), 2.70-2.57 (m, 2H), 2.30- 1.92 (m, 10H), 1.82-1.78 (m, IH), 1.66- 1.55 (m, 2H), 1.30-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00576] Compound 28-4:MS (ESI, pos.ion ) mlz: 367.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.68 (s, IH), 7.42-7.40 (m, IH), 7.30-7.28 (m, IH), 5.1 1-5.09 (m, IH), 3.45-3.43 (m, 2H), 2.94-2.93 (m, IH), 2.21-2.18 (m, 2H), 2.01-1.91 (m, IH), 1.49 (s, 9H) ppm.

[00577] Compound 28-5: MS (ESI, pos.ion) mlz: 414.3 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.69 (s, IH), 7.45-7.43 (m, IH), 7.32-7.30 (m, IH), 5.12-5.10 (m, IH), 3.45-3.43 (m, 2H), 2.95-2.94 (m, IH), 2.25-2.22 (m, 2H), 2.01-1.91 (m, IH), 1.49 (s, 9H), 1.35 (s, 12H) ppm.

[00578] Compound 28-6: MS (ESI, pos.ion) m/z: 314.2 [M+H] ⁺ .

[00579] Compound 28-7: MS (ESI, pos.ion) m/z: 485.4 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 10.62 (brs, IH), 8.22 (m, IH), 7.73-7.65 (m, 2H), 5.72 (d, IH, J = 8.0 Hz), 5.43 (d, IH, J = 8.0 Hz), 4.35-4.31 (m, IH), 3.95-3.88 (m, IH), 3.78-3.75 (m, IH), 3.69-3.67 (m, 4H), 3.08-3.04 (m, IH), 2.43-2.37 (m, IH), 2.25-2.15 (m, 2H), 1.91 (s, IH), 1.74-1.72 (m, IH), 1.52-1.50 (m, IH), 1.35 (s, 12H), 1.24 (t, 2H, J = 8.0 Hz), 1.12-1.10 (m, IH), 0.93-0.88 (m, IH) ppm.

[00580] Compound 28-8: MS (ESI, pos.ion) mlz: 468.6 [M+2H] ²⁺ ; and ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.69, 7.67 (s, s, IH), 7.62-7.61, 7.60-7.59 (m, m, 2H), 7.59 (s, IH), 7.48, 7.46 (s, s, IH), 7.41, 7.40 (t, t, IH), 7.23, 7.21 (d, d, IH), 7.20, 7.19 (s, s, IH), 5.39, 5.36 (d, d, IH), 5.32-5.28 (m, 2H), 5.13-5.09 (m, IH), 4.46-4.30 (m, 3H), 3.93-3.90 (m, IH), 3.85-3.76 (m, 3H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 3.24-3.12 (m, IH), 2.70-2.57 (m, 2H), 2.42-2.34 (m, IH), 2.30-1.86 (m, 14H), 1.84-1.80 (m, IH), 1.66-1.49 (m, 3H), 1.27-1.10 (m, 3H), 0.98-0.95 (m, 6H), 0.92-0.89 (m, 6H) ppm.

Example 29

Compounds disclosed herein can be prepared by an analogous procedure to that described in example 8.

[00581] Compound 29-1: ^l U NMR (400 MHz, CDC1 ₃ ): δ 7.46, 7.44 (s, s, IH), 7.40 (s, IH), 7.36, 7.34 (s, s, IH), 7.15, 7.13 (s, s, IH), 6.52, 6.50 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.16-5.12 (m, IH), 4.41-4.36 (m, IH), 4.24-4.18 (m, 2H), 3.85-3.78 (m, IH), 3.69-3.64 (m, IH), 3.63 (s, 3H), 3.58-3.55 (m, IH), 3.52-3.50 (m, IH), 2.40 (s, 3H), 2.30-2.15 (m, 3H), 2.13-2.03 (m, IH), 2.01-1.92 (m, 3H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, IH), 1.61-1.57 (m, IH), 1.31-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00582] Compound 29-2: *H NMR (400 MHz, CDC1 ₃ ): δ 7.46, 7.44 (s, s, IH), 7.40 (s, IH), 7.36, 7.34 (s, s, IH), 7.11, 7.09 (s, s, IH), 7.07, 7.05 (s, s, IH), 5.32, 5.30 (d, d, IH), 5.16-5.12 (m, IH), 4.41-4.36 (m, IH), 4.24-4.18 (m, 2H), 3.85-3.78 (m, IH), 3.74-3.71 (m, IH), 3.69-3.65 (m, IH), 3.63 (s, 3H), 3.49-3.47 (m, IH), 2.40 (s, 3H), 2.30-2.15 (m, 3H), 2.13-1.92 (m, 4H), 1.85-1.77 (m, 2H), 1.75-1.67 (m, IH), 1.61-1.57 (m, IH), 1.32-1.15 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00583] Compound 29-3: MS (ESI, pos. ion) m/z: 391.5 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.27 (s, IH), 5.32, 5.30 (d, d, IH), 5.29-5.24 (m, IH), 4.41-4.36 (m, IH), 3.89-3.83 (m, IH), 3.73-3.65 (m, IH), 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) ppm.

[00584] Compound 29-4: MS (ESI, pos. ion) m/z: 319.4 [M+H] ⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.27 (s, IH), 5.35-5.31 (m, 1.5H), 5.30-5.29 (d, 0.5H, J = 4.0 Hz), 4.41-4.36 (m, IH), 3.89-3.83 (m, IH), 3.73-3.66 (m, IH), 3.63 (s, 3H), 3.36 (s, IH), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

Compound 29-5: MS (ESI, pos. ion) m/z: 456.1 [M+2H] ²⁺ ;

[00585] *H NMR (400 MHz, CDC1 ₃ ): δ 7.62 (s, IH), 7.56, 7.54 (s, s, IH), 7.46 (s, IH), 7.45, 7.43, 7.41 (s, d, s, 2H), 7.29, 7.26 (s, s, IH), 6.07, 6.05 (d, d, IH), 5.51-5.47 (m, IH), 5.46, 5.44 (d, d, IH), 5.29-5.25 (m, IH), 4.41, 4.38, 4.36 (m, m, m, IH), 4.34, 4.31, 4.30 (m, m, m, IH), 4.24-4.18 (m, 2H), 4.11-4.08 (m, IH), 3.89-3.78 (m, 2H), 3.73-3.67 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.58-3.55 (m, IH), 2.37 (s, 3H), 2.32-1.90 (m, 12H), 1.82-1.68 (m, 3H), 1.59-1.55 (m, IH), 1.34-1.17 (m, 4H), 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) ppm.

Example 30

Compounds disclosed herein can be prepared by an analogous procedure to that described in example 21.

[00586] Compound 30-1: *H NMR (400 MHz, CDC1 ₃ ): δ 7.63-7.62, 7.61-7.60 (m, m, 2H), 7.59 (s, 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.41, 7.38 (s, s, 1H), 7.28, 7.25 (s, s, 1H), 7.17, 7.15 (s, s, 1H), 6.96-6.95 (m, 2H), 6.57, 6.55 (s, s, 1H), 5.32, 5.30 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H), 2.33-2.15 (m, 5H), 2.13-1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.34-1.28 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00587] Compound 30-2: ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.63-7.62, 7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.38, 7.35 (s, s, 1H), 7.27, 7.25 (s, s, 1H), 7.09, 7.07 (s, s, 1H), 7.03, 7.01 (s, s, 1H), 6.96-6.95 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.36 (m, m, m, 2H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 1H), 3.74-3.71 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 3H), 3.51-3.48 (m, 1H), 2.33-2.15 (m, 5H), 2.13-1.92 (m, 4H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.19 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H) ppm.

[00588] Compound 30-3: MS (ESI, pos.ion) mlz: 473.6 [M+2H] ²⁺ ; and *H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.63-7.62, 7.61-7.60 (m, m, 2H), 7.59 (s, 1H), 7.57-7.56, 7.55-7.54 (m, m, 2H), 7.46, 7.44 (d, d, 2H), 7.28, 7.25 (d, d, 2H), 6.96-6.95 (m, 2H), 5.32, 5.30 (d, d, 2H), 5.29-5.25 (m, 1H), 5.23-5.19 (m, 1H), 4.44-4.41, 4.39, 4.37 (m, m, m, 3H), 4.25-4.22 (m, 1H), 3.85-3.78 (m, 3H), 3.78-3.73 (m, 1H), 3.69-3.64 (m, 2H), 3.63 (s, 6H), 2.33-2.15 (m, 8H), 2.13-2.03 (m, 2H), 2.02-1.91 (m, 5H), 1.72-1.68 (m, 1H), 1.30-1.24 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H) ppm.

BIOLOGICAL ACTIVITY

[00589] 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 are 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. The above was validated by the inventor of the invention according to the method described in Science. 1999 Jul 2; 285 (5424), 110-3 and J Virol. 2003 Mar; 77 f5),3007-19.

[00590] In a word, the compounds disclosed herein were tested by using human hepatic carcinoma cell line which was transfected stably with HCV GTla, GTlb or GT2a replicon respectively, resistant cells Y93H, L31F, P32L or I302V and wild-type cells HCV lb. HCV Replicon System disclosed herein contains G418 resistance gene NEO 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 disclosed herein inhibiting 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 ₅ o of the compounds based on luciferase assay.

[00591] The Huh-7 cells transfected with HCV replicons system were seeded into 96-well plates (8,000 cells in 125 JJL I well) respectively. Each test compound was diluted to desired concentration using 5-fold serial dilution protocol, 10 doses in duplicate, and added to wells with POD™ 810 Plate Assembler. The plates were incubated in a CO2 incubator for 72 hours. After that, 40 μΐ. 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). After 5 minutes, the EC50 (half-maximal effective concentration, concentration for 50% of maximal effect) values of the test compounds were analyzed by GraphPad Prism software respectively. In this paper, experiments were repeated twice and negative control was prepared without adding the test compound.

2. Test method for measuring EC50 of the compounds by detecting antibiotic G418 resistance gene NEO gene.

[00592] The Huh-7 cells transfected with HCV replicons system were seeded into 96-well plates (8,000 cells in 125 JJL / well) respectively. Each test compound was diluted to desired concentration using 5-fold serial dilution protocol, 10 doses in duplicate, and added to each well with POD™ 810 Plate Assembler. The cells were incubated in a CO2 incubator for 72 hours and detected the expression level of the NEO gene expression with qualitative PCR later. The EC50 (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 negative control was prepared without adding the test compound.

3. Results

[00593] The test compounds of the present disclosure can be effective against the HCV la, lb, 2a, 2b, 3a, 3b, 4a, 5a and 6a genotypes according to the experimental data. EC ₅ o range of the test compounds against HCV lb is 1 pM-99 nM. Table 2 shows that the EC50 values of representative compounds of the present disclosure against the HCV la and HCV lb genotypes.

Table 2

[00594] The experimental results of HCV lb wild-type and Y93H, L31F, P32L and I302V resistance cells and the simulation results of molecular modeling and docking show that the present disclosure plays an excellent anti-HCV role which suggest a novel anti-HCV mechanism by interfering with HCV NS5A protein.

[00595] 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.

[00596] 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.

[00597] In the description of the invention, the reference term "one embodiment," "some embodiments," "example", "a specific example", or "some examples" and means in connection with the embodiment described in or example described in Example particular feature, structure, material, or characteristic be included in the present invention, at least one embodiment or example. In the present specification, the term of the above schematic representation is not necessarily referring to the same embodiment or example. Moreover, describe a particular feature, structure, material, or characteristics can be in any one or more embodiments or examples in combination in an appropriate manner.

[00598] Although embodiments of the present invention has been shown and described above, the above embodiments are illustrative embodiments that can be understood, and cannot be understood as a limit for the invention, the skills in the art without departing from the principles of the invention and purpose, can change modify, substitute, and vary these embodiments within the scope of the present invention.