TW201238961A - Analogues for the treatment or prevention of flavivirus infections - Google Patents

Abstract

Compounds represented by formula I or pharmaceutically acceptable salts thereof, wherein A, B, B', X, Y, R1, R2, R2', R3, R3', R4, R4', R5, R5', m, n, or p are as defined herein, are useful for treating flaviviridae viral infections.

Description

201238961 VI. INSTRUCTIONS: This application claims the benefit of 35 U.S.C. § 119(4) of the United States, Shen Qing Case No. 61/3 16,988, dated March 24, 2000, which is incorporated herein by reference in its entirety. The present invention relates to novel compounds and methods of using the novel compounds to treat or prevent flavivirus infection. Hepatitis is a disease that exists worldwide. It is generally viral in nature, but there are other known causes. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans in the mother's year are affected by hepatitis, and more than one is infected with hepatitis C virus ("HCV"). HCV is a positive-stranded rna virus belonging to the Flaviviridae (corpse) and is closely related to the prion virus (pestivinis) including hog cholera virus and bovine viral thirst-quenching virus (BVDV). The HCV is replicated by making a complementary negative strand RNA template. Due to the lack of an efficient culture replication system for viruses, HCV particles were isolated from mixed human plasma and shown by electron microscopy to have a diameter of about 5 〇 6 〇 nm. The HCV genome is a 9,600 bp single-stranded sense RNA that encodes a polymeric protein of 3009-3030 amino acids that is cleaved into mature viral proteins during translation and translation (core, El, E2, p7, NS2). NS3, NS4A, NS4B, NS5A, NS5B). The salt-synthesis glycoproteins El and E2 are embedded in the disease 201238961 w* toxic lipid envelope and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form a nuclear sheath. Non-structural proteins termed NS2 to NS5 include proteins with viral replication and protein processing involved in protein processing, including polymerases, proteases, and helicases. The main source of HCV contamination is blood. The magnitude of HCV infection as a health problem is illustrated by the incidence in the high-risk group. For example, in Western countries, 60/〇 to 90% of hemophiliacs and more than 8% of intravenous drug abusers have long been sputum HCV. For intravenous drug abusers: the incidence varies between approximately 28% and 7G%, depending on the study population. Recently, the proportion of new HCV infections caused by infusion has been significantly reduced due to advances in diagnostic tools for screening blood donors. The combination of polyethylidene s-interferon plus ribavirin is a chronic Hcv infection treatment option. This treatment does not provide a sustained viral response (svr) in most patients with the most common genotypes (h and 1匕). In addition, significant =: compliance with pre-therapy and may be required to be reduced in some patients: therefore, antiviral agents. There is a great need to develop a method for treating or preventing a flavivirus infection. The present invention provides a compound of formula (I): 201238961

Or a pharmaceutically acceptable salt thereof, wherein each A is independently C6.M aryl, 4-12 membered heterocyclic ring, c3-1()cycloalkyl or 5-12 membered heteroaryl; B and B' are each independently not Exist, being a C 6 alkyl group, a C 2 6 alkenyl group or a C 2 6 alkynyl group; C and C′ are each independently a 4-7 membered heterocyclic ring;

Ri is i, -ORa, -NRaRb, _c( = 0)0Ra, -C(0)NRaRb, _C( = 0) OH, -C(=0)Ra, -C(=NORc)Ra, _c( =NRc)NRaRb, -NRdC( = 0) NRaRb, -NRbC( = 0)Ra, -NRdC(=NRc)NRaRb, -NRbC(=0)0Ra, -0C( = 0)NRaRb, -〇C( = 〇)Ra, _〇C( = 〇)〇Ra, hydroxy, nitro, azide, cyano, -S(O)0.3Ra, _S〇2NRaRb, -NRbS〇2Ra, -NRbS〇2 NRaRb, - P(= 〇)〇Ra〇Rb, unsubstituted or substituted by R10 for one or more times, C 6·6 alkyl, unsubstituted or substituted by Ri 一 one or more C 2 6 alkenyl, un. Substituting or substituting RW for one or more C24 alkynyl groups, or the presence of any two & together with the atoms to which they are attached may form an unsubstituted or r11 substituted one or more 5-7 cycloalkyl groups Or a 5-7 member heterocyclic ring which is unsubstituted or substituted one or more times by Ru;

Ra-Rd are each independently Η, C丨.丨2 alkyl, (: 2丨2 alkenyl, (: 2 heptaynyl, C6-12 aryl, C7_16 aralkyl, 5.12-membered heteroaryl) 6_18 member heteroarylalkyl, 201238961 3-12 member heterocyclic ring or 4-18 member heterocyclic ring-alkyl group; R2' is dentate, CM alkyl group, Cm halogenated alkyl group, -((:Η2)〗-6〇 Η, -NRbC (=〇)Ra, C6.12 aryl or 5·12 membered heteroaryl; each R2 is independently _, Cm 〇 alkyl, Ci 6 dentate alkyl, _(CH2)i 6 〇H-ORa. -C(=〇)〇Ra,_NRaRb. -NRbC(=0)Ra. -C(0)NRaRb , -S(0)〇-3Ra, c6·丨2 aryl, 5_12 member Ring or 5-12 membered heteroaryl; r3 and r3' are each independently H, c] 6 alkyl...(CH2)16〇H, c2 6 alkenyl or c2_6 alkynyl; R4 and R4i are each independently _, _NRaRb, _c(〇)NRaRb, _(CH2)1 < OH, Cu alkyl, cN6 halogenated alkyl, hydroxy, c6 14 aryl or Ci 6 alkoxy; wherein the presence of two R4 may be combined with The attached atoms together form an unsubstituted or substituted one or more Cm alkenyl groups, unsubstituted or substituted by the ''R', one or more times 3 _ 7 cycloalkyl or unsubstituted or via r 12 Substituted or eve-human 4-7 beta heterocycle; The presence of two ft 4' may be combined with the atoms to which they are attached to form an unsubstituted or substituted 1 1 or more, 1 6 alkenyl, unsubstituted or substituted by R 11 one or more times. 3-7 alkylcycloalkyl or 4-7 membered heterocyclic ring which is unsubstituted or substituted one or more times by R12; X and Y are each independently OU;

^ 1 or II °Hs-HO - I ' - \ 6 NIR OL, 〆〆* , ·* ·" bOA where the asterisk (*) indicates the point of attachment to the ring c or c, the nitrogen; R5 and R51 are independent The earth is unsubstituted or substituted by one or more of the Ci-u, unsubstituted or substituted by r1g for one or more c2i2. 201238961 unsubstituted or R, substituted or Multiple CM alkynyl groups, unsubstituted or substituted by R—or multiple aryl groups, unsubstituted or substituted hydrazine or multiple aralkyl groups, unsubstituted or substituted by Rll—or multiple times 5-12 membered heteroaryl, unsubstituted or substituted by R" substituted one or more members, heteroarylalkyl, unsubstituted or substituted by Ri2, one or more, heterocyclic or unsubstituted or Substituting one or more 4] 8 membered heterocyclic-alkyl groups; R6 is hydrazine, Cu alkyl or halogenated Cl 6 alkyl; m and η are each independently 〇, 1, 2, 3 or 4; Is 0, 1, 2, 3 or 4; q is 0, 1 or 2; u is 0 or 1; s is 0, 1, 2, 3 or 4; R is halogen, -ORa, sideoxy (oxo) , _NRaRb, =NO-Rc, -C( = 0) 〇Ra, -C(0)NRaRb, -C(=0)0H, -C(=0)Ra ' -C(=NORc)Ra, -C (=NRc)NRaRb, -NR dC(=0)NRaRb, -NRbC(=〇)Ra, -NRdC (=NRc)NRaRb, -NRbC(=0)0Ra, -0C(=0)NRaRb, -0C(=0)Ra, -OC( =0) 〇Ra, hydroxy, nitro, azido, cyano, 4(0)0.31^, -S〇2 NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P( = 0)0Ra0Rb; R" is _ , _ORa, -NRaRb, _C( = 0)0Ra, -C(0)NRaRb, -C(=0) OH, -C( = 0)Ra, -C(=NORc)Ra, -C(=NRc) NRaRb, -NRdC( = 0) NRaRb> -NRbC( = 0)Ra' -NRdC(=NRc)NRaRb ' -NRbC( = 0)0Ra > -〇C( = 0)NRaRb, -0C( = 0) Ra, -0C(=0)0Ra, hydroxy, nitro, azido, cyano, -S(0) 〇-3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02 NRaRb or -P(=0)0Ra0Rb, Cm2 Alkyl, C2_12 alkenyl, C2-12 alkynyl, 201238961 C6-12 aryl, C7-16 aryl, 5-12 membered heteroaryl, 6-18 member heteroaryl, 3-12 member heterocyclic Or a 4-18 membered heterocyclo-alkyl group; and R12 is halogen, -ORa, pendant oxy, -NRaRb, =NO-Rc, -C(= 〇)〇Ra, -C(0)NRaRb, -C( = 〇)〇H, -C( = 0)Ra, -C(=NORc)Ra, -C(=NRc) NRaRb, -NRdC(=〇)NRaRb, -NRbC( = 0)Ra, -NRdC(= NRc)NRa Rb, -NRbC(=0)0Ra, _〇c(=0)NRaRb, -0C(=0)Ra, -〇c(=〇) Ra, hydroxy, nitro, azido, cyano, -S(0)Q.3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P(=〇)〇Ra〇Rb, Cm2 alkyl, C2-12 Alkenyl, Cn2 alkynyl, c6_丨2 aryl, C7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic ring . In another aspect, a method of treating or preventing a Flaviviridae viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound, composition or combination of the invention. In another aspect, a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient is provided. In another aspect, the invention provides a combination of the invention comprising: ::- or a plurality of other agents selected from the group consisting of viral serine egg (5) toxic polymerase inhibitor, viral helicase inhibitor, Free a = agent: cardiac, antibacterial, therapeutic vaccine, liver protective agent. Antisense agent, HCV NS2/3 protease such as magic * ^ r. t, . Inhibitor and internal ribosome into 2 Inhibitor of point (nuernalribosomeentry _ AS r , , RES). In another grief, the use of the human of the present invention for the treatment or prevention of human flavivirus: ^ I or ^ 毋村病 t infection is provided. 201238961 Compositions or combination-infected pharmaceuticals, in an aspect-by-side manner, for use in the manufacture of a compound of the invention for the manufacture or prevention of a Flaviviridae virus in humans. In a specific example, the compounds of the invention comprise independent The compounds of the following specific examples exist in situ or in combination. According to another specific example, the compound of the invention is represented by the formula (Π):

Each of these variables is as defined herein. According to another embodiment, the compound of the invention is represented by the formula (ΙΙΙΑ), (IIIB), (IV) or (V):

201238961

Each of these variables is as defined herein. According to another embodiment, A is phenyl, thiophene, thieno[3,2-b]thiophene. Bis pyridine, pyrimidine, naphthyl, benzo[1,3]dioxole, benzo. Sitting or three saliva. According to another embodiment, A is phenyl, thiophene, thieno[3,2-b]thiophene, naphthyl, benzo[1,3]dioxol or benzoxazole. According to another embodiment, A is phenyl, thiophene, pyridine, pyrimidine or tris. 201238961. According to another specific example, A is phenyl or thieno[3,2-b]thiophene. According to another specific example, A is phenyl. Or thiophene. According to another specific example, A is 'S' according to another specific example, A is

S According to another specific example, A is

According to another specific example, A is

According to another specific example, A is a key. According to another embodiment, B and B' are each independently C2.6 alkynyl or Cw alkyl. According to another embodiment, B and B' are each independently -(C=C)- or -(CH2)2-. According to another specific example, B and B• are each -(CH2)2-. According to another embodiment, B and B' are each -(OC)-. 12 201238961

According to another specific example, m or η is 2. According to another specific example, m or η is 1. According to another specific example, m and η are 1. According to another specific example, one of m or η is 1 and the other of m or η is 0. According to another embodiment, m and η are each independently 0 or 1, with the constraint that at least one of m and η is one. 13 201238961 According to another specific example, p is 2 β According to another specific example, ρ is 1. According to another embodiment, X and Υ are each 0 〇. According to another specific example, X and Υ are each a nitrogen in which the bond to ring c or c is indicated by a asterisk (*) 4 vote. According to another embodiment, R4 and Rule 4, each independently H, halogen, CM alkyl, hydroxy, phenyl or Ci4 alkoxy. According to another embodiment, R4 and R4 are each independently hydrazine, halogen, methyl, ethyl, tert-butoxy or hydroxy. According to another specific example, R4 and R4 are each Η. According to another embodiment, R4 and R4 are each a fluoro group. According to another embodiment, R4 and each are methyl. According to another embodiment, at least one of R4 and R4 is a fluorenyl group. According to another specific example, R3 and r3 are each Η. According to another specific example, R1 is Η, _, -ORa ' -NRaRb, -C(=0)0Ra, -C(0)NRaRb, _C(=0)0H, _NRbC(=0)Ra, .hydroxyl , nitro, cyano '-S(0) 〇-3Ra, Cl 6 alkyl, C 2 6 alkenyl, c 2-6 alkynyl or Ci. 6 halogenated alkyl. According to another embodiment, R is halogen, Cm alkyl, hydroxy 'cyano or Cw alkoxy. 14 201238961 According to another embodiment, R # is a gas group, a chaotic group, a thiol group, a hydroxyl group, a chaotic group or a decyloxy group. According to another specific example, Ri is a fluorenyl group. According to another specific example, R is Ηβ according to another specific example, m2, each independently being 1; '(c!2) 1-3〇H^OR--c^ 〇h'c6_12 aryl or 5_12 member a heterotetracycline group, wherein each of Ra-Rd is independently Η, C, -丨2 alkyl, C6 12 aryl, > 7-丨6-square alkyl, 5-12 hexaaryl, 6-18 member Heterocyclyl, 3-12 member, j, hetero or 4-18 member heterocyclic-alkyl. According to another specific example 1 and R2 are each independently H, _, CK6, and - (CHdwOH, ~

Ra'-C(=0)〇Ra,.c(〇)NRaRb,_c(=〇) ◦ Η The base or 5-6 member heterogeneous Α, 烧基,. 612 aryl, c a — Rd are each independently H, Cl·12. Soil 7.16 octaalkyl, 5-12 membered heteroaryl, 6-18 membered heteroaryl, 3-12 membered heterocyclic ring or 4, membered heterocyclic ring alkyl. According to another specific example, according to another specific example, according to another specific example, R10 is substituted one or more times. According to another specific example, hydrazine, each is a methyl group. 'R2 and r2' are each an iodine group. 'The ruler 2 and R2' are each η. 'h is a hydrazine or a CV3 alkyl group. R.sup.5 and R.sup.5 are each independently unsubstituted or calcined, unsubstituted or substituted by Rio with a C2-8 alkenyl group, de-substituted or substituted by R10 one or more times. Block base, unsubstituted or substituted, substituted by R-quot; or more... phenyl, unsubstituted or human Gw aralkyl, unsubstituted or Rll. taken one or more times | + betaryl, unsubstituted or substituted by Ri 一 1 or more 15 201238961 6.8-membered heteroaralkyl, unsubstituted or Rl heterocyclic or unsubstituted or ~- or more 2 to 3-6 base. According to another specific example, the core and I, each R10 is substituted by a compound which is unsubstituted or Ci- 6 alkyl, which has not been taken more than seven times. Tuhe! Substituting or substituting R10 for one or 2·6 alkenyl, unsubstituted or substituting RlG for a group: unsubstituted or ~- or multiple phenyl::: = substituted by R1丨 multiple times left unleft Substituted or poly- owed to the methyl group, unsubstituted or substituted by R" substituted- or-membered, unsubstituted or substituted by Rll—or multiple times Or by r12 or unsubstituted ..., ... two Ge " the next 5-6 members of the heterocyclic ring - or a number of 6 · 7 members of the heterocyclic ring - appearance base" AS Xi - human C -6 alkyl, not Substituting or replacing one or more C 2-6 alkenyl groups with R 〇 or unsubstituted or one alkynyl group via R 10 . 4 - Human c2-6 According to another specific example, RjR5. are each independently a CU12 alkyl group which is unsubstituted or substituted one or more times by R. According to another embodiment, ^ and Rs are each independently methyl, ethyl, propyl, isopropyl, butyl, second butyl, tert-butyl, pentyl, 2-methylbutane 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl (CH2)-, which in each case is unsubstituted or substituted a number of times by r1q. According to another embodiment, Rs and Rs are each independently methyl, ethyl, propyl, isopropyl, butyl, t-butyl, t-butyl, decyl, 2-carbyl 201238961' Butane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl (CH2)-. According to another embodiment, R5 and R5 are each independently isopropyl which is unsubstituted or substituted one or more times by R. According to another embodiment, R5 and each independently are one or more isopropyl groups which are unsubstituted or substituted with -OCH3. According to another embodiment, R5 and Rs are each isopropyl. According to another embodiment, Rs and Rs are each a hydrazine or a tert-butyl group. According to another embodiment, I and R are each independently phenyl which is unsubstituted or substituted one or more times by R11. According to another embodiment, RS and R are each independently unsubstituted or substituted with one or more benzyl groups via R. According to another embodiment, R10 is halogen, -〇Ra, pendant oxy, _NRaRb, =N〇.Rc, -C(= 〇)〇Ra . -C(0)NRaRb ^ -C( = 0)〇H ^ -C(=0)Ra . -C(-NORe)Ra, _c(=NRc)NRaRb, -NRdC(=0)NRaRb, -NRbC( = 〇)

Ra, -NRdC(=NRc)NRaRb, -NRbC(=0)〇Ra, _〇C(=0)NRaRb, _〇C( = 〇)Ra, _〇C( = 〇)〇Ra, hydroxyl, nitrate Alkyl, azido, cyano, _s(〇)h Ra, -S02NRaRb, -NRbS02Ra or -NRbS02NRaRb, wherein Ra_Rd are each independently Η, Cm2 alkyl, C2, 12 alkenyl, c2_12 alkynyl, C6-12 Aryl', C7_16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl. According to another embodiment, R10 is _NRaRb, _NRdC ( = 〇)NRaRb, -NRbC(=〇)Ra, _NRdC(=NRc)NRaRb, _NRbC(=0)0Ra, -NRbS〇2

Ra or -NRbS〇2NRaRb, wherein Ra_Rd are each independently H, Ci丨2 alkyl, 17 201238961 c2.12 dilute, c2.12 fast radical, C6_12 aryl 'c7_16 aralkyl, 5-12 heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl. According to another specific example, R10 is _NRaRb, _NRdC(=〇)NRaRb, -NRbC(=〇)Ra, -NRbC(=0)〇Ra 4_NRbS〇2Ra, wherein Ra, Rb and Rd are each independently H, Cm2 alkyl, alkenyl, C2_l2 alkynyl, C6 i2 aryl, (: 7.16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 According to another embodiment, R10 is _NRaRb or _NRdC(= 〇)NRaRb, wherein Ra and Rb are each independently Η, C丨·丨2 alkyl, C 2 丨 2 alkenyl , C 2 - 2 alkynyl, C 6 - 12 aryl, (: 7 - 16 aralkyl, 5 - 12 membered heteroaryl, 6 - 18 membered heteroaryl, 3 - 12 membered heterocyclic or 4 - 18 membered heterocyclic - alkyl. Another specific example 'R10 is _NRdC(=:〇)NRaRb, wherein Ra and Rb are each independently Η, C丨-丨2 alkyl, (: 2·12 alkenyl, c2 u alkynyl, c6 12 aryl a C7,6 aralkyl group, a 5-12 membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. According to another specific example, r 〇 is halogen, -〇Ra, pendant oxy, -C(-0)0Ra, -C(0)NRaRb, -C(=〇)〇H, -C(=0)Ra, -0C(= 0)NRa, -0C(=0)Ha ' -〇c( = 〇)〇Ra 'hydroxy , cyano, wherein Ra_Rb are each independently Η, (:di)alkyl, c2•丨2 alkenyl, C2 i2 alkynyl, &arylaryl, 匸7-16 aralkyl, 5-12 member Heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl. According to another embodiment, Ri is halogen, 〇Ra, pendant oxy, _c(= 〇) 〇Ra, -C(0)NRaRb, _(:( = 〇)〇Η, _〇c( = 〇)NRaRb, hydroxy or cyano, wherein Ra-Rb are each independently H, Ci i2 alkyl, C2 I2 alkenyl, C2 i2 201238961 * fast radical, tartary buckwheat, ρ ^ -2 cubic earth C7.16 aralkyl, 5-12 member heteroaryl, 6-18 member heteroaryl 3-12 member heterocyclic ring or 418 member heterocyclic ring According to another embodiment, R1 is halogen, C.6 alkoxy, hydroxy or NH2. According to another embodiment, R1 is a hydroxyl group, a hydroxyl group or nh2. According to another specific example, R10 is Halogen. According to another specific example, R11 is a element, _〇Ra, _NRaRb, _C(= 〇) 〇Ra ' -C(〇)NRaRb . -C(=〇)〇H ^ -C( = 〇)Ra > -C(=NORc)Ra ^ C( NRc)NRaRb > -NRdC(=〇)NRaRb . -NRbC( = 0)Ra ^ -NRdC (-NRc)NRaRb, -NRbC(=〇)〇Ra. -〇C(= 〇)NRaRb > -0C(=0)Ra > -〇c(=o)ORa, hydroxy, nitro, azido, cyano, _s(〇)g 3Ra, _s〇2 NRaRb, -NRbS02Ra or _NRbS〇2NRaRb, Ci i2 alkyl, &-丨2 alkenyl, c2-12 alkynyl, c6-12 aryl, 〇7_16 aralkyl, 5-12 membered heteroaryl, 618 • heteroarylalkyl, a 3-12 member heterocyclic ring or a 4-18 member heterocyclic ring-alkyl group, wherein each of Ra_Rd is independently fluorene, Cuu alkyl, au alkenyl, & 丨 2 alkynyl, C 6 丨 2 aryl, 〇 7-16 aralkyl Base, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic-alkyl group. According to another specific example, Rn is a element, _〇Ra, _NRaRb, _c(= 〇) 〇Ra, -C(0)NRaRb, -C(=0)0H, -C(=0)Ra, -NRdC ( = 〇)NRaRb, -NRbC(-0)Ra' -NRbC(=0)0Ra' -0C(=0)NRaRb > -〇C(=0)Ra ' -OC( = 〇)〇Ra, hydroxyl , cyano, _s〇2NRaRb, -NRbS02Ra, Ci.6 alkyl, C2_6 alkenyl, c2.6 alkynyl, phenyl, c7-8 aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroarylene a 5- to 6-membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, wherein each of Ra, Rb and Rd is independently fluorene, Cm2 alkyl, C2-12 alkenyl, C2-12 19 201238961 fluorenyl, c6 -12 aryl, (: 7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered oxalate, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic ring-alkyl group. Another specific example 'R" is!| prime, · 〇Κίΐ, _NRaRb, _c(〇)NRa

Rb, _C( = 〇)〇H, _C( = 〇)Ra' _NRdC( = 〇)NRaRb, _NRbC( = 〇)Ra, -NRbC( = 〇)ORa,_0C(=0)NRaRb, hydroxy, cyano , Ci 6 alkyl, C 2-6 alkenyl, c 2 - 6 alkynyl, phenyl, c 7-8 aralkyl, 5-6 heteroaryl, 6-8 membered heteroaryl, 5-6 heterocyclic or 6-8 heterocyclic -alkyl, wherein Ra, Rb and Rd are each independently η, Cm2 alkyl, c2-12 alkenyl, C2_u alkynyl, fluorenyl-12 aryl, fluorene: 7-16 aralkyl, 5-12 membered heteroaryl, 6 An -18 membered heteroaralkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. According to another embodiment, R11 is halogen, 〇Ra, _NRaRb, hydroxy, aryl or C,.6 alkyl, wherein Ra_Rb are each independently η, (: 丨heptadecene 'c2-12 dilute' C2 12 alkynyl, C612 aryl, C716 aralkyl, 512 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic-alkyl group according to another specific example 'R11 is halogen, hydroxy, cyano or NH2. According to another embodiment, R11 is halogen. According to another embodiment, R12 is halogen, 〇Ra, pendant oxy, _NRaRb, =N〇-RC, -C (=0) 0Ra, -C(0)NRaRb, -C( = 0)0H, -C( = 0)Ra, -C(=N〇Rc)Ra. -C(=NRc)NRaRb> -NRdC( = 0)NRaRb^ -NRbC( = 0) Ra, -NRdC(=NRc)NRaRb, -NRbC( = 0)0Ra, -0C( = 0)NRaRb, -OC( = 〇)Ra, _〇c(= 〇)〇Ra'hydroxy, nitro 'azido, cyano, _s(〇)〇3 Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb, (^.12 alkyl, C2-12 alkenyl, C2-12 Fast radical, Ce-12 aryl, C7.i6 aryl, 5-12 membered heteroaryl '6-18 membered heteroaralkyl, 3-12 membered heterocyclic or 4-18 alicyclic-alkyl, 20 201238961 * wherein Ra-Rd are each independently Η, Cm2 alkyl, c2_12 olefin , c2-12 alkynyl [6-123⁄4• group, <37-16 arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroaryl, 3-12 membered heterocyclic ring or 4-18 member Heterocyclic-alkyl. According to another embodiment, R12 is halogen, _〇Ra, pendant oxy, _NRaRb, -C(=〇)〇Ra, -C(0)NRaRb, -C(=〇)〇H , -C(=0)Ra, _NRdC( = 〇) NRaRb, -NRbC(=〇)Ra, -NRbC(=〇)〇Ra, -〇C(=〇)NRaRb, _〇c (=〇)Ra , -oc(=〇)〇Ra, hydroxy, cyano, _s〇2NRaRb, _NRbS〇2Ra, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, stupyl, C7-8 aralkyl a 5-6 membered heteroaryl group, a 6-8 membered heteroarylalkyl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic ring-alkyl group, wherein each of Ra, Rb and Rd is independently hydrazine, Cu alkyl group, c2_12 Alkenyl, C2-12 alkynyl, c6-fluorene 2 aryl, C7_16 arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered hetero Cyclo-alkyl.

According to another specific example, R12 is dentate, _0Ra, pendant oxy, _NRaRb, C(〇)NRaRb, -C(=0)0H, _c(= 〇)Ra, _cities=〇), _NRbC ( = 0)Ra,:NRbC(=〇)〇Ra ...〇c(=〇)NRaRb, hydroxy, cyano, ^6 alkyl, c2-6 alkenyl, c2_6 alkynyl, phenyl, c7 8 aralkyl a 5-, 6-membered heteroaryl group, a 6-8 membered heteroaralkyl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, wherein each of Ra, Rb and Rd is independently h, Ci-12 alkyl , C 2 12 alkenyl, C 2 12 alkynyl, C6.12 aryl, 匚7_16 aralkyl, 5-12 membered heteroaryl '618 heteroaryl, 3-12 heterocyclic or 4-18 heterocyclic _ alkyl. According to another embodiment, R12 is a peptidic, -〇Ra, pendant oxy, -NRaRb, L-cyano or C!-6 alkyl, wherein each of Ra-Rb is independently η, C!-12 alkane a base c2"2 alkenyl, 〇2.12 alkynyl, c6-12 aryl, C7 i6 aralkyl, 5-12 heteroaryl, 6-18 membered heteroaryl, 3-12 heterocycle or 4 18-member heterocycle _ 21 201238961 Burning base. According to another embodiment, R12 is a halogen. According to another specific example, Ra-Rd are each independently hydrazine, Cw alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, c7.8 aralkyl, 5-6 membered heteroaryl, 6 -8 membered heteroaralkyl, 5-6 membered heterocyclic or 6-8 membered heterocyclo-alkyl. According to another embodiment, Ra and Rc are each independently Η, alkyl, (: 2-6 alkenyl, (: 2-6 alkynyl, phenyl, (: 7.8 aralkyl, 5-6 membered heteroaryl) a 6-8 membered heteroaralkyl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, and each of Rb and Rd is independently a hydrazine or a C1 alkyl group. According to another specific example, Ra and Re Each independently is hydrazine, (^.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5 a 6-membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, and each of Rb& Rd is independently hydrazine or an alkyl group. According to another specific example, each of Ra-Rd is independently hydrazine or Cw alkyl. A specific example 'The compound of the present invention is represented by the formula (IV): According to another specific example 'R8 and R8, each independently is _NRaRb, -NRbC(= 〇)Ra or _NRbC(=〇)〇Ra, wherein Ra_Rb is each independently η, Cu alkyl, phenyl, alum, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 membered heterocyclic or 6-8 membered heterocyclic-alkyl. In one embodiment, Rs and R8 are each independently -NRaRb or NRbC(-〇)〇Ra, wherein Ra_Rb are each independently H, a 6 alkyl, phenyl, Methyl, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 membered heterocyclic or 6-8 membered heterocyclo-alkyl. According to another embodiment, Rs and Rsi are each independently _NRbC(=〇) 22 201238961 〇Ra, wherein Ra-Rb are each independently H'Cw alkyl, phenyl, phenyl fluorenyl, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 member Ring or 6-8 membered heterocyclic ring - according to another embodiment, R8 and R8 in formula (IV) are each independently • NRbC(=〇)〇Ra' wherein Ra_Rb is independently H, Ci 6 alkane Base, phenyl, tetrahydrofuran or phenylhydrazine. According to another embodiment, the sizing 8 and r8 in the formula (IV) are each independently -NRbC(= 〇) 〇Ra ' wherein Ra is Cw alkyl and Rb is According to another specific example, Rs and r8 in the formula (IV) are each independently -NRbC(=0)0Ra, wherein Ra is a Cl_6 alkyl group and Rb is η. According to another specific example, R8 and R8 in the formula (IV) are each independently _NRbC(= 〇)〇Ra ' wherein Ra is a methyl group and Rb is H. According to another specific example, the core and R/ are each independently a Ci 8 alkane Base, cw alkenyl, c2-8 alkynyl, phenyl, benzoinyl, 5-6 heteroaryl, 6 7 hetero An alkyl group, a 3-6 membered heterocyclic ring or a 4-7 membered heterocyclic-alkyl group; according to another embodiment, R7 and R?, each independently are phenyl" according to another specific example, and R7, each independently It is a C 6 alkyl group. According to another embodiment, R? and R? are each independently fluorenyl, ethyl, propyl, isopropyl, butyl, second butyl, tert-butyl, pentyl, 2-methylbutyl Alkane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. According to another specific example, and R/ is each isopropyl. According to another embodiment, the compound of the present invention is represented by the formula (V). According to another specific example, when the valence is allowed, β, B, Ra_R (

Ri R11 and R12 mesogen, R2·, R3, R3i, R4, R4, Rl0 23 201238961 alkenyl, alkynyl, alkoxy, aryl A, — arylalkyl, heteroaryl, heteroaralkyl Base, hetero- or hetero-alkyl-alkyl each NR R~ independently unsubstituted or dentate, -ORa.' _NRa.Rb,, c(=〇)〇Ra, ' _Cm, 'TD n Its preparation has been) NRa.Rb·, 'C(=〇)〇H, hydroxy, nitro, azido or cyano substituted—or multiple H, C “12 alkyl. Each independently is based on another specific Examples, when the valence allows, in the olefins I R2 R3 : R3, R4, R', R1, R11 and R*2, alkyl, carbaryl, heteroaryl, heteroarylalkyl, hetero % or heterocyclo-alkyl are each independently substituted or substituted once with halogen. According to another specific example, when the valence allows, at B, B, R_Rd,

Rl, R2, W, Rn', H4', R'Rl^Rl,, ^*, yl: alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, hetero-W or The heterocyclic-alkyl groups are each independently unsubstituted or substituted once by the I group. According to the invention, the compounds are selected from the group consisting of compounds as defined by the formula: wherein A is a C6-14 aryl group, a 5-12 membered heteroaryl group or a bond; and B and B' are each independently -(c^c )- or _(ch2)2_ ; R1 is Η, 齿, -0Ra, _c(=〇)〇Ra, _c(〇)NRaRb, _C(=〇)〇H,·ΝΚ)3(::( = 0) ι, hydroxy, nitro, cyano, _s (〇). 3Ra, CK6 alkyl, c2_6 alkenyl, C2.6 alkynyl or Ci-6 halogenated alkyl; l and RV are each independently H, Mercapto or iodine; City and 11 are each independently 〇, ι or 2; Ρ is 0, 1 or 2; and R3' is η; 24 201238961 ^ and RV are each independently η, halogen, CN6 alkyl, Hydroxy, phenyl or Cm alkoxy; X and Y are 0

R5 and R5' are each independently a C!_12 alkyl group which is unsubstituted or substituted one or more times by R10. According to the invention, the compounds are selected from the group consisting of compounds as defined by the formula: wherein A is a C6_14 aryl group, a 5-12 membered heteroaryl group or a bond; and B and B' are each independently -(C=C)- Or -(CH2)2-; h is Η or 曱.; R2 and R/ are each independently Η, methyl or iodine; m and η are each independently 0, 1 or 2; ρ is 0, 1 Or 2; R3 and R3' are Η; 114 and RV are each independently oxime, halogen, Cm alkyl, hydroxy, phenyl or C, .4 alkoxy; X and Y are 0

R5 and R5' are each independently unsubstituted or substituted one or more times by R1Q. According to the invention, the compounds are selected from the compounds defined by the formulae, wherein: 25 201238961 A is phenyl, thiophene, thieno[3,2_b]thiophene, pyridine, pyrimidine, naphthyl, benzo[1,3] Dioxole, benzoxazole or triazole; B and B' are each independently -(CsC)- or -(CH2)2_. I is hydrazine or methyl; R2 and R2' are each independently Η, methyl or fluorenyl; m and η are each independently 〇, ι or 2; Ρ is 〇, 1 or 2; 尺 3 and R3 are Η; h and R4' are each independently 卤素, halogen, Ci 6 alkyl, hydroxy, stupid or q alkoxy; X and γ are 〇J,

And V I and R5, each independently a C alkyl group which is unsubstituted or substituted one or more times by RlQ. According to the invention, the compounds are selected from the group consisting of the compounds defined by the formulae, wherein: A is a strepyl, thiophene, thieno[3,2-b]thiophene, naphthyl, benzodioxole or benzindene Oxazole; B and each independently _(CsC)_4_(ch2)2_; R1 is Η ' _ 素, _〇Ra, _NRaRb, _c(=〇)〇Ra c(〇)NRaRb 4(=0)01^ , -NRbC (=0)Ra, hydroxy, nitro, cyano, _s(〇)〇3Ra, alkyl, c2-6 alkenyl' c2:6 alkynyl or Cw functional alkyl; l and R2, each Independently H, thiol or iodine; towels and η are each independently 0,1*2; 26 201238961 P is 〇, 1 or 2; R3 and R3 are Η; hydroxy, phenyl or Cw R4 and RV Each is independently Η, a a a factor, Cy alkyl alkoxy; X and γ are each 0 7 R> 5 and R5 are each independently unbranched decathene/shallow group; substituted or via ruler 1. Substituting one or more Cl-12 R7&W are each independently unsubstituted or substituted by W- or multiple times of c" alkyl, unsubstituted or branched by R1Q - ... 〇 10, , or a C2-8 alkenyl group, unsubstituted or substituted by the left R, one or more ρ ^ w 2-8 alkynyl groups, unsubstituted or substituted by Rn, substituted or substituted one or more The next benzyl, unsubstituted or substituted by R11 - 5-6 membered heteroaryl groups, 1 or more, unsubstituted or substituted by R11, one or more - 6~7 beta heteroarylenes a 4-7 member heterocyclic-alkyl group which is unsubstituted or substituted by R for one or more times. 3 __ 6 Chang Miscellaneous, 1 member heterozygous or unsubstituted or substituted with R 1 2 one or more times. And r8 and r8, each independently _NRaRb, ·Ν¥(=〇)νιιλ, _NRbC(4)

Ra, -NRdC(=NRe)NRaRb, tearing bC(,(10)a,·division also wind S02NRaRb 'where Ra_Rd are each independently H, & η alkyl, a η dilute, c 2-12 alkynyl, c6 丨2 aryl, C7_i6 aralkyl, 5-i2 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 418 membered heterocyclic-alkyl. In some specific examples, the compounds of the invention are presented in In Table 1 a. In some embodiments, the variables used herein are as defined in the specific examples shown in Table A. 27 201238961 In some embodiments, the compounds of the invention are presented in Table 1B. In some embodiments, the variables used herein are as defined in the specific embodiment shown in Table 1B. In a specific embodiment of the compound of the present invention, Ri is halogen, 〇Ra, -NRaRb, -C( = 〇)〇Ra, -C(0)NRaRb, _c( = 〇)〇H, _c( = 〇)Ra, -C(=NORe)Ra, _c(=NRe)NRaRb, -NRdC(= 0) NRaRb, -NRbC(=〇) Ra, -NRdC(=NRc)NRaRb, -NRbC( = 0)〇Ra, -〇C(=〇)NRaRb, -〇C( = 0)Ra,_0C( = 0) 0Ra, hydroxy, nitro, azido, cyano, _s(〇).3

Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb ' -P(=〇)〇Ra 〇Rb, unsubstituted or via r1. Substituting one or more Ci6 alkyl groups, C2·6 alkenyl groups which have not been substituted or substituted one or more times by R, unsubstituted or one or more C2_6 alkynyl groups substituted by Ri. In a specific example of the compound of the present invention, when the valence herein allows, 'in B, B, Ra-Rd, Rl, R2, r2, r3, R3, R4, R4, R10'R11 and In R12, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclo-alkyl are each independently unsubstituted or substituted by One or more times: halogen, _〇Ra, 'sideoxy, -NRa, Rb,, =n〇-Rc,, -C(=0)0Ra., -C(0)NRa.Rb. ' -C ( = 〇)〇H, -C(=0)Ra,, _c(=NORc.)Ra', -C(=NRe.)NRa.Rb., -NRd.C(=0) NRa,Rb,, -NRb.C(=0)Ra., -NRd,C(=NRc,)NRa, Rbt, -NRb, C( = 0) 〇Ra', -0C( = 0)NRa.Rb,, -OC( = 〇)Ra,,·〇(:(=〇)〇Κ3, hydroxy, nitro, azido, cyano, -S(0)〇_3Ra., _s〇2NRa, Rb,, -NRb, S02Ra.; wherein Ra.-Rd, each independently is a ruthenium, Cu12. In a specific example of the compound of the present invention, p is 〇, 1 or 2. 28 201238961 In a specific example of the compound of the present invention P is 0 or 1. In a specific example of the compound of the present invention, ρ is 〇. One of the compounds of the present invention In one embodiment, hydrazine is 2. In a specific example of the compound of the present invention, r4 and R4 are hydrazine. In a specific embodiment of the compound of the present invention, R1 is halogen, Ci-3 alkyl, hydroxy, cyanide Or a Cm alkano group. In a specific embodiment of the compound of the present invention, Ri is a gas group, a fluorine group, a thiol group, a hydroxyl group, a cyano group or a methoxy group. In a specific example of the compound of the present invention, R In a specific example of the compound of the present invention, R10 is halogen, 〇Ra, pendant oxy, -C(=0)〇Ra, _c(0)NRaRb, -C(=0)0H, -C( = 0)Ra, -〇C(=0)NRaRb, -〇c(=〇)Ra, -〇C(=0)ORa, hydroxy, cyano, wherein Ra-Rb are each independently Η, Cm2 alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.12 aryl, 匚7-16 aryl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 member Ring or 4-18 membered heterocyclo-alkyl. In a specific embodiment of the compound of the present invention, R11 is halogen, 〇Ra, -NRaRb, -C(=0)Ra, _c(0)NRaRb, - C( = 0)0H, -C( = 0)Ra, -C(=NORc)Ra . --C(=NRc)NRaRb ' -NRdC(=0)NRaRb > -NRbC ( = 0)Ra,- NRdC(=NRc)NRaRb, -NRbC( = 0 )0Ra, -〇C( = 0)NRa

Rb, -〇C(=0)Ra,_0C(=0)0Ra, hydroxy, nitro, azido, cyano, -S(O)0-3Ra, -S02NRaRb, -NRbS02Ra or -NRbS02NRaRb, C, .12 alkyl-based C2-12 dilute group, C2-12 fast group, C6-12 aryl group, C7-I6 aryl group, .5_12 member heteroaryl group, 6-18 member heteroarylalkyl group, 3-12 member miscellaneous Ring or 4-18 membered heterocyclic ring - alkyl 'wherein Ra-Rd are each independently Η, Cm 2 alkyl, C 2-12 alkenyl, 29 201238961 C 2-12 alkynyl, C 6-12 aryl, C 7-16 aryl Alkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl. In a specific embodiment of the compound of the present invention, Rii is halogen, 〇Ra, -NRaRb, -C(=〇)〇Ra, -C(0)NRaRb, _c(= 〇)〇H, -C( = 〇)Ra, -NRdC(=〇)NRaRb, -NRbC(=0)Ra, -NRbC( = 0)0Ra, -〇c( = 〇) NRaRb, -〇C( = 〇)Ra, -〇C( =0) ORa, hydroxy, cyano, -S〇2NRaRb, -NRbS02Ra, CN6 alkyl, C2.6 alkenyl, C2_6 alkynyl, phenyl, c7.8 ^•院基' 5-6 member heteroaryl a 6-8 membered heteroaryl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, wherein each of Ra, Rb and Rd is independently a decyl group, a C2-12 dilute group, and a C2-12 alkynyl group. , C6_12 aryl, C7.16 aralkyl, 5-12 membered heteroaryl '6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclo-alkyl group. In a specific embodiment of the compound of the present invention, Rii is halogen, 〇Ra, _NRaRb, -C(0)NRaRb, -C(=〇)〇H, -C(=0)Ra, -NRdC(=〇 )NRa Rb, -NRbC( = 0)Ra, -NRbC( = 0)0Ra, -〇C( = 0)NRaRb, hydroxy, cyano, cN6 alkyl, c2_6 alkenyl 'C2-6 alkynyl, phenyl , C7 8 aralkyl, 5- 6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 membered heterocyclic ring or 6-8 membered heterocyclic ring - alkyl group wherein Ra, Rb and Rd are each independently Η, Cl_12 Alkyl, c2-12 alkenyl, c2_12 alkynyl, c6:12 aryl, C7 16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 Heterocyclic-alkyl. In a specific embodiment of the compound of the present invention, R! 1 is halogen, 〇Ra, _NRaRb, hydroxy, cyano, Ci 6 alkyl, wherein Ra_Rb are each independently H, Cm2 alkyl, c2-12 alkenyl , c2.12 alkynyl, c6_12 aryl, C7 16 aralkyl, heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered. 30 201238961 'In a specific example of the compound of the present invention, R12 is halogen, 〇Ra, oxy, -NRaRb, =NO-Rc, -C(=0)ORa, -C(0)NRaRb, - C(=C〇OH, -C(=0)Ra, -C(=NORc)Ra, -C(=NRc)NRaRb, -NRdC(=〇) NRaRb, -NRbC(=0)Ra, -NRdC( =NRc)NRaRb, -NRbC( = 0)0Ra, -〇C( = 〇)NRaRb, -〇C( = 〇)Ra, -OC(=0)ORa, hydroxy, nitro, azide, cyano , -S(0)〇_3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb, Cm2 alkyl, C2-12 alkenyl, C2-12 alkynyl, c6.12^, 07_16 aryl, 5_i2 a 6-18 member heteroaromatic group, a 3-12 member heterocyclic ring or a 4-1 8 member heterocyclic ring-alkyl group, wherein each of Ra-Rd is independently H, a substituent, a C2-12 alkenyl group, a C2-12 alkyne a C6-12 aryl group, a C7-16 aralkyl group, a 5-12 membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic ring-alkyl group. In one specific example, R12 is halogen, _0Ra, pendant oxy, -NRaRb, -C(= 〇)〇Ra, -C(0)NRaRb, -C(=0)0H, ~C(=0)Ra -NRdC(=〇)NRaRb ^ -NRbC( = 〇)Ra > -NRbC( = 〇) 〇Ra, -0C(=0)NRaRb,_0C(=0)Ra, _〇c( = 〇)〇Ra, hydroxy, cyano, -S02NRaRb, -NRbS〇2Ra, Cm alkyl, C2-6 alkenyl, c2.6 block, phenyl, C7-8 aralkyl, 5-6 heteroaryl, 6-8 member heteroaryl, 5-6 member heterocyclic or 6-8 member heterocyclic-alkyl, wherein Ra' Rb and core are each independently Η, Cm 2 alkyl, C 2-12 alkenyl, c 2 . 12 alkynyl, c6_12 aryl, & 16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 312 membered heterocyclic or octacyclic heterocyclic-alkyl. In the compounds of the invention In a specific example, Rl2 is halogen, _〇Ra,

Sideoxy, -NRaRb, -C(〇)NRaRb, -C(=0)〇H, -C( = 〇)Ra, _NRdC 31 201238961 (= 0)NRaRb, -NRbC(=0)Ra, -NRbC ( = 0) 0Ra, -0C ( = 0) NRaRb, thiol, nitrogen, Cl.6 alkyl, c2 6 alkenyl, c2 6 alkynyl, phenyl, c7 8 aromatic, 5-6 Aryl, 6-8 membered heteroaralkyl, 5-6 membered heterocyclic ring or 6-8 membered heterocyclic ring-alkyl group wherein Ra, 1 and Rd are each independently H, Cl 12 alkyl, C 2 · 丨 2 dilute, (: 2 -丨2 alkynyl, CV丨2 aryl, C7_10 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocycloalkyl. In the compounds of the invention - In a specific example, Ri2 is halogen, _〇Ra, pendant oxy, -NRaRb, hydroxy, cyano, Ci δ alkyl, wherein Ra_Rb are each independently Η, C丨-丨2 alkyl, c2.i2 olefin a group, a C2丨2 alkynyl group, a c6u aryl group, a C7-16 aralkyl group, a 5-12 membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 312 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. In a specific example of the compound of the present invention, wherein, when the valence is allowed, 'in B, B', Ra-Rd, R1, R2, R2, R3, R3, R, R4, R1, R11 and R12 , alkyl 'saturated, The base 'alkoxy, aryl, aralkyl, heteroaryl, heteroaryl|, heterocyclic or heterocyclic-institutional groups are independently unsubstituted or _, -ORa, -NRa, Rb, , C( = 〇)〇Ra., _c(〇)NRa &, _c(〇H, hydroxy, deterministic, azido, cyano substituted one or more times; each of which is independently Η, C丨-丨2 alkyl. d In the specific example of the compound of the present invention, wherein, in B, B, Ra-Rd, Rl, R p , _ ^, the number of turns allows 4 to R2, R2, R3, R3', R4, r 1(), and a wide range of alkyl, alkenyl, alkoxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclic-alkyl groups, each independently Not: substituted once by halogen. Also substituted or in the specific example of the compound of the present invention, wherein when the valence allows 32 201238961, in B, B|, Ra-Rd, Rl, R2, R2, R3, R3,, R4, R4, Ri., f and R12, an alkyl group, a dilute group, a block group, an alkoxy group, an aryl group, an aromatic group, a heteroaryl group, a heterocyclic 7 group, a heterocyclic ring or a heterocyclic ring. · 6 bases are unsubstituted or substituted once by a fluorine group. In a specific example, the compound of the present invention The substance is represented by a compound of the formula (νι) or a pharmaceutically acceptable salt thereof:

(R4)n where

Ra-Rd are each independently Η, C丨_丨2 alkyl, C 2 丨 2 alkenyl, C 2 丨 2 alkynyl, 匸 6-12 aryl, (: 7-16 aralkyl, 5-12 member hetero An aryl group, a 6-18 membered heteroaralkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic ring-alkyl group;

Ri is || prime, -ORa, -NRaRb, _C(=〇)〇Ra, _c(〇)NRaRb, cdi) 〇H ^ -C(=0)Ra ^ .C(=N0Rc)Ra , - C(=NRc)NRaRb > -NRdC(=〇) NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRaRb, -NRbC( = 〇)〇Ra, -0C(=0)NRaRb,- 〇C(=〇)Ra, _〇c(=〇)〇Ra, thiol, nitro, azide, cyano, -S(0)〇.3Ra, _S〇2NRaRb, _NRbS〇2Ra, S〇 2NHaRb, -P(=〇)〇Ra〇Rb, unsubstituted or substituted for one or more times by R10, Cu alkyl, unsubstituted or substituted by R1〇 one or more q 6 alkenyl, unsubstituted Or one or more Cw alkynyl groups substituted by R1Q, or any two R, may be present together with the atoms to which they are attached to form unsubstituted or 33 201238961 substituted 5 or 7 cycloalkyl groups by R11 or a 5-7 member heterocyclic ring which is unsubstituted or substituted one or more times by Ri2; R2' is halogen, C丨·decylalkyl, Cl 6 halogenated alkyl, gas CH2h 6〇H, _NRb C (= 0) Ra, C6-12 aryl or 5-12 membered heteroaryl; each R2 is independently halogen, CU10 alkyl, C丨-6 halogenated alkyl, -(CHA.eOH, -ORa, _c(=〇)〇 Ra, _NRaRb, -C(0)NRaRb, -S(O)0.3Ra, q 12 fang , 512 5_12 membered heterocyclic or heteroaryl group; R4 and R4 'are each independently CU6 alkyl; X and Y are each independently person

(T

II '•S—or a bond; 0 where the asterisk (*) indicates the point of attachment to the nitrogen of the pyrrolidine ring; I and I' are each independently Η, unsubstituted or substituted by RlG—or multiple times C, -18 alkyl, unsubstituted or substituted with r1g for one or more alkenyl groups, t substituted or substituted with R1° - or multiple % alkynyl groups, unsubstituted, ! R substituted - or multiple times of aryl, unsubstituted or substituted hydrazine or multiple aryl groups 'unsubstituted or substituted by R11 - or multiples of two: heteroaryl, unsubstituted Or substituted by hydrazine - or multiple times of 6 to 18 members of the heteroatomyl group, unsubstituted or taken or unsubstituted by Ri2 or by a heterocyclic ring of ~ or :: each independently of °, 1 or 2' The condition is... straight 34 201238961 ._ · One less is 1; p is 0, 1, 2, 3 or 4; q is 1 or 2; u is 0 or 1; s is 0, 1, 2, 3 Or 4; R10 is -, -ORa, pendant oxy, -NRaRb, =NO-Rc, -C( = 0)0Ra, -C(0)NRaRb, -C( = 0)0H, -C( = 0) Ra, -C(=NORc)Ra, -C(=NRc) NRaRb, -NRdC( = 0)NRaRb, -NRbC( = 0)Ra, -NRdC(=NRc)NRa Rb, -NRbC( = 0 0Ra, -0C( = 0)NRaRb, -0C( = 0)Ra, -0C(=0) 〇Ra, thiol, triazole, azido, cyano, -S(0)〇.3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P( = 0)ORa〇Rb; R11 is il, -ORa, -NRaRb, -C(=0)0Ra, -C(0)NRaRb, -C(=0 OH, -C( = 0)Ra, -C(=NORc)Ra, -C(=NRc)NRaRb, -NRdC(=0) NRaRb, -NRbC( = 0)Ra, -NRdC(=NRc)NRaRb , -NRbC(=0)0Ra -0C( = 0)NRaRb, -0C( = 0)Ra, -0C(=0)0Ra, hydroxy, nitro, azide, cyano, -S(〇V3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02 NRaRb or -P(=0)ORaORb, C, i2 alkyl, 〇2·ΐ2, C2-12 alkynyl, 〇6-12 aryl, (7-7 aralkyl, 5-12 membered heteroaryl) a 6-18 membered heteroaralkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group; and R12 is halogen, -ORa, pendant oxy, -NRaRb, =NO-Rc, -C( = 0) 0Ra, -C(0)NRaRb, -C( = 0)0H, -C( = 0)Ra, -C(=NORe)Ra, -C(=NRc) NRaRb, -NRdC( = 0) NRaRb, -NRbC( = 0)Ra, -NRdC(=NRc) NRaRb, -NRbC(=0)0Ra, -0C(=0)NRaRb, -0C(=0)Ra, -0C(=0) 〇Ra , hydroxy, nitro, azido, cyano, -S(0)G.3Ra, -S02NRaRb, 35 201238961 -NRbS02Ra, -NRbS02NRaRb or -P( = 0)0Ra0Rb, Cm2 alkyl, C2-丨2ene Base, C2-12 alkynyl, C6-丨2 aryl, C7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 member Heterocyclic-alkyl. In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein K is halo, unsubstituted or substituted by R1() one or more Cw alkyl groups, -C(=0)0Ra, - C(0)NRaRb, hydroxy, cyano or Cu alkoxy. In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein at least one of R4 and R4' is a fluorenyl group. In one embodiment, the compound of the present invention is represented by a compound of formula (VI) wherein R4 and R4' are indenyl. In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein one of m and η is 1 and the other is 0. In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein m and η are 1. In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein X and oxime are Ο

In one embodiment, the compound of the invention is represented by a compound of formula (VI) wherein q is 2. In one embodiment, the compound of the invention is represented by a compound of formula (VIA) or a pharmaceutically acceptable salt thereof: 36 201238961

MR/each are independently unsubstituted or passed through r1. Substituting a alkyl, unsubstituted or R1 or --human 〇丨8 or substituted by R1Q - or more owing or planting C2·8 counties, un-acquired C2-8 alkyne a phenyl group which has not been substituted seven or more times, is unsubstituted or substituted by R", substituted, or substituted or substituted; or multiple times: a substituted or via Rl , 6- to 6-membered heteroaralkyl, or: 3, 6 members who have not been replaced by R12 one or more times to ', 'sit substitution or beta or unsubstituted or via Rl2 One or more 4-7 membered heterocyclic-alkyl groups; and R8 and R8 are each independently _NR, -NRdC(=0)NRaRb, _NRbC (=0)Ra > -NRdC(=NRc) NRaRb, -NRbC(=0)0Ra. -NRbS〇2Ra 戒-NRbS02NRaRb, wherein Ra_Rd are each independently H, alkyl, a c2-12 alkenyl, c2.12 alkynyl, C6-12 aryl, C7 i6 Aralkyl, 5_i2 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 418 membered heterocyclic-alkyl group. In one embodiment, the compound of the invention is represented by a compound of formula (VIB) as a pharmaceutically acceptable salt thereof: 37 201238961

R7 and R/ are each independently unsubstituted or R1. Substituting C, unsubstituted or heart. Substituting one or more CM alkenyl groups, non-disubstituted or via R1. Substituting one or more C2.8 blocks, unsubstituted or R, substituted or multiple phenyl, unsubstituted or substituted by Rll for one benzyl, unsubstituted or via R" Substituted- or multiple times of 5-6 membered heteroaryl' unsubstituted or substituted by Rii one or more times 6-7 members, unsubstituted or substituted by R12 one or more 3-6 member heterocycles or not Substituted or substituted by Riz for one or more 4-7 membered heterocyclic-alkyl groups; and r8 and r8, each independently _NRaRb, _NRdC(=〇)NRaRb, _NRbC(==0) Ra, -NRdC( =NRc)NRaRb, _NRbC(=0)0Ra, -NRbS02Ra or -NiU S〇2NRaRb 'where Ra_Rd are each independently h, c _12 alkyl, C2_i2 alkenyl, C2-12 alkynyl, c6.|2fang A C7-16 aryl group, a 5-12 membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. In one embodiment, the compound of the invention is represented by a compound of formula (VIIA) or a pharmaceutically acceptable salt thereof: 38 201238961

Each P' is independently 〇, 1 or 2; R? and W are each independently unsubstituted or substituted by r1G - or more than burned: substituted or substituted by hydrazine - or multiple times c times, without: R $-- or multiple times of h-block, unsubstituted or substituted by one or more phenyl 'unsubstituted or substituted by Rll- or multiple benzyl, unsubstituted or via Rn Substituting - 5_6 (tetra) aryl, unsubstituted or substituted by R11 - a 矣-a - r. σ ΐ2 ' ^ _ 6_7 bet heteroaralkyl, unsubstituted or substituted by R12 - or a plurality of 3-6 heterocycles or unsubstituted or substituted by one or more of 4 to 4 heterocycles _ Alkyl; and R8 and R8, each independently -NRaRb, _NRdC(=〇)NRaRb, _NRbCb0) Ra, -NRdC(=NRc)NRaRb, _NRbC(=〇)〇Ra, _NRbS〇2Ra or NRb S02NRaRb Wherein Ra_Rd are each independently H, ^ i2 alkyl, cmalkenyl, c2-12 alkynyl, c6-12 aryl, c7-16 aralkyl, 5-12 heteroaryl, 6-18 membered heteroaryl, 3_12 member heterocyclic or 4-18 member heterocycloalkyl. In a specific example, the compound of the present invention is represented by a compound of the formula (ViiB) or a pharmaceutically acceptable salt thereof: 39 201238961

=T is independently unsubstituted or via Ri. Substituting one or more times ~ deuterated or substituted by Rl ° - or multiple times CW is not taken & one or more of alkynyl, unsubstituted or substituted by Rn one or more phenyl, Unsubstituted or substituted by R-quot; or multiple times of benzyl, substituted by unsubstituted ❹RH—or multiple 5-6 membered heteroaryl, unsubstituted or substituted one or more times by R" a 7-membered heteroaralkyl group, unsubstituted or substituted by R12 - or a plurality of 3·6 M heterocyclic rings or a 4-7 membered heterocyclic alkyl group which is unsubstituted or substituted one or more times by r12; R8 and R8 are each independently -NRaRb, _NRdc(= 〇)NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRaRb, -NRbC(=0)〇Ra, -NRbS02Ra or -NRb S02NRaRb, wherein Ra-Rd are each independently h, Cm2 alkyl, c2.12 alkenyl, C2-12 alkynyl, C6-12 aryl, c7_16 aralkyl '5-12 member heteroaryl, 6-18 member heteroaryl Hyun base, 3-12 member heterocyclic ring or 4-18 member heterocyclic ring-alkyl group. In a specific example, 'the compound of the invention is represented by a compound of formula (VIA), (VIB), (VIIA) or (VIIB), wherein R8 and r8 are each independently -NRaRb, -NRbC(=0)Ra , -NRbC(=0)0Ra, wherein Ra_Rb are each independently H 'Cm alkyl, phenyl, phenyl fluorenyl, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 member Ring or 6-8 membered heterocyclo-alkyl. 201238961 • In a specific example, the compound of the present invention is represented by a compound of the formula (VIA), (VIB), (VIIA) or (νΠΒ), wherein s and u are hydrazine. In a specific embodiment, the present invention < compound is represented by a compound of formula (VIA), (VIB), (VIIA) or (VIIB), wherein R8 and RV in formula (IV) are each independently -NRbC (= 〇) 〇Ra, wherein Ra_Rb are each independently η, Ci-6 alkyl, phenyl, tetrahydrofuran or benzyl. In a specific example, 'the compound of the invention is represented by a compound of formula (VIA), (VIB), (VIIA) or (VIIB), wherein r7 and r7, each independently unsubstituted or substituted by R11 one or more The second phenyl. In a specific embodiment, the compound of the invention is represented by a compound of formula (VIA), (VIB), (VIIA) or (VIIB), wherein &7 and &, are each independently unsubstituted or substituted by RW One or more Ci 6 alkyl groups. In a specific example, 'the compound of the invention is represented by a compound of the formula (Via), (viB), (VIIA) or (VIIB), wherein each, independently, is fluorenyl, ethyl, propyl, isopropyl , methoxyisopropyl butyl, butyl, second butyl, pentyl, 2-methylbutane, 3-decylbutane, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl. In a specific example, 'the compound of the invention is represented by a compound of formula (VIA), (viB), (VIIA) or (VIIB), wherein R7 and Rs or, and Rs, together with the carbon to which they are attached, are each independently The location is: 201238961

ο

Or the use of a compound of the present invention for the treatment of a compound of the human c-hepatitis virus infection, which further comprises administering at least one other agent. The use of a compound of the present invention, wherein the at least one other agent is selected from the group consisting of a viral serine protease inhibitor 'viral polymerase inhibitory virus helicase helicase inhibitor, an immunomodulator, an antioxidant, and an antibacterial Qi 1 /α treatment Live vaccines, hepatoprotective agents, antisense agents, inhibitors of HCV NS2/3 protease, and inhibitors of internal ribosome entry sites (IREs). Use of a compound of the invention, wherein the at least one additional agent is selected from the group consisting of ribavirin and interferon-[alpha]. The use of the compounds of the invention for the manufacture of pharmaceuticals. A pharmaceutical formulation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient. Use of a compound of the invention for the treatment of a hepatitis C virus infection in a human of a compound of the invention, further comprising administering at least one other agent. The use of the compound of the present invention, wherein the other agent is selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral helicase inhibitor, an immunomodulator, an antioxidant, and an antibacterial agent. Vaccines, hepatoprotectants, antisense agents, inhibitors of Hcv NS2/3 protease, and inhibitors of internal ribosome entry sites (IRES). 42 201238961 The use of a compound of the invention, wherein the at least one additional agent is selected from the group consisting of viral sputum and interferon-Q; The use of the compounds of the invention for the manufacture of pharmaceuticals. A pharmaceutical formulation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient. In a specific embodiment, the invention provides a method of treating or preventing a viral infection of a HCV disease comprising administering a biological sample to a compound in need thereof or treating or inhibiting the amount of the compound disclosed herein. In one specific example of the method, it is genotype 1. In another example, 'HCV is genotype la, genotype ib, or a combination thereof. According to one aspect of the invention, the compound of the invention is selected from Table 1A.

43 201238961

And its pharmaceutically acceptable salts. According to one aspect of the invention, the compound of the invention is selected from Table 1B. 44 201238961

45 201238961

46 201238961

47 201238961

48 201238961 Compound No. h3c , 0 h:3c / h3c h3c...

49 201238961

H3c - ο

H3C

50 201238961 Compound No. CH,

51 201238961 Compound number ch3 , /\ ch3 , / H3C 0' η A:: Ν ' /· CH3 /Λ ....0 l 彳l-丄/.Λη h3c N ·_,,, n ”,—— j,广" 0 -/ CH3 / , \ H3c b \/ H3Cf h3c 35

52 201238961 Compound No. ch3

53 201238961 Compound No. ° c H3 H3 c . 'oh3c i — o H3 丨c 1’ /·-· N, c H5 / N.. s i o

H3 C 43 i \

H3C ό H3

o.3C H oH3c \v i- o s

N H3 c. H3 —丨,c

HN

•N -V-. s \xsv

• N

o • NH N.

H3C 1

3 CHP 44 h3c -''-ο H3 c Ό c H3 oH3c .Λ

H3 CH i — of i s

Av,,.. //· H3 c

N $

, N

'NH N! o

HN

3 CHP 45 h3c ό H3 c

Cl 3 H H3 ck

54 201238961 Compound number CH3 0 t 〇夕, h3c h3c K „ /^>· '·~Λ >-ch3 ~Ar,.'VL'f V,VNH fk \ ! \=--: \--/ , '二' 〇—/ /-- h3c , 0 H3C 47 h3c ch3 Λ . r-~—\ l ! ;...... 'n /;~Λ /'; Factory / ΓΗ h3c ! m ί ij % 乂丨尸3 h3c -- ° i HN. , 0 Λ NH T"°"< 〇x 〇CH3 H3C 48

55 201238961

56 201238961

In a particular embodiment, the invention is one or more of the pharmaceutically acceptable salts of Table 1A. In one embodiment, the invention is a pharmaceutically acceptable salt of one or more of Tables 1B. In a specific embodiment, the invention provides a compound of the invention as described herein for use in the treatment or prevention of a flavivirus infection in a host. In one embodiment, the invention provides a pharmaceutical composition comprising at least one of the compounds of the invention described herein and at least one pharmaceutically acceptable carrier or excipient. In one embodiment, the invention provides a pharmaceutical composition viral infection comprising at least one of the compounds of the invention described herein and at least one pharmaceutically acceptable carrier 57 201238961 or excipient. For use in the treatment or prevention of a host's flavivirus, in a specific embodiment, the invention provides a medical article comprising at least one of the compounds of the invention described herein, and further comprises administering at least one selected from the group consisting of Other tinctures: Leze · Viral serine protease inhibitor, viral polymerase inhibitor, virus solution, still known as enzyme inhibitor, immunomodulator, antioxidant, antibacterial agent, treatment J / α Inhibition of sputum vaccine, liver protective agent, antisense agent, HCV NS.2/3 protease! Inhibitors of knowledge and internal ribosome entry sites (IRES). In another embodiment, a combination comprising at least one of the compounds of the invention described herein and one or more other pharmaceutical agents is provided. In another embodiment, a combination comprising at least one compound of the invention described herein and one or more additional agents selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a virus Anti-helical enzyme inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease, and inhibitors of internal ribosome entry sites (IRES) . 11 In a combined embodiment, the compound and other agents are administered sequentially. In another combination of embodiments, the compound and other agents are administered simultaneously. Combinations of the above are preferably presented in the form of a pharmaceutical formulation and, accordingly, a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention. Other agents for use in compositions and combinations include, for example, ribavirin, amantadine, melibep〇dib, levovirin, eu 58 201238961, viramidine, and histamine dihydrochloride (maxamine).

As used herein, the term "viral serine protease inhibitor" means an agent that is effective to inhibit the function of a mammalian viral serine protease, including HCV serine protease. Inhibitors of HCV serine protease include, for example, the compounds described in the following patents: WO 99/07733 (Boehringer Ingelheim) > WO 99/07734 (Boehringer Ingelheim), 00/09558 (Boehringer Ingelheim), WO 00 /09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006039488 (Vertex), WO 2005077969 (Vertex), WO 2005035525 (Vertex) ^ WO 2005028502 (Vertex) > WO 2005007681 (Vertex) > WO 2004092162 (Vertex) 'WO 2004092161 (Vertex), w〇2003035060 (Vertex), WO 03/087092 (Vertex), WO 02/1 8369 (Vertex) or W098/17679 (Vertex). In a specific embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention as described herein, and further comprising one or more additional agents selected from the group consisting of viral serine protease inhibitors, viruses Polymerase inhibitors 'viral helicase inhibitors, immunomodulator antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease, and internal ribosome entry sites ( Inhibitor of IRES). In another embodiment, a combination therapy comprising at least one compound of the invention described herein in combination with one or more other agents selected from the group consisting of a viral serine protease inhibitor, a viral polymerase 59 201238961 Formulations, viral helicase inhibitors, immunomodulators, antioxidants, antibacterials, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease and internal ribosome entry sites (IRES) Inhibitors. Other agents for the compositions and combinations include, for example, viruses. Gui, amantadine, metopibrin, levovirin 'viramididine and histamine dihydrochloride. In a combined embodiment, the compound and other agents are administered sequentially. In another combination of embodiments, the compound and other agents are administered simultaneously. The combinations mentioned above are intended to be presented in the form of a pharmaceutical formulation and, accordingly, a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention. As used herein, the term "viral serine protease inhibitor" means an agent that is effective to inhibit the function of a mammalian viral serine protease, including HCV serine protease. Inhibitors of HCV serine protease include, for example, the compounds described in the following patents: WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim) > WO 00/09558 (Boehringer Ingelheim) > WO 00/09543 (Boehringer Ingelheim) 'WO 00/59929 ( Boehringer Ingelheim ), WO 02/060926 (BMS ), WO 2006039488 (Vertex ), WO 2005077969 (Vertex ), WO 2005035525 (Vertex ) ' WO 2005028502 ( Vertex ), WO 2005007681 (Vertex), WO 2004092162 (Vertex), WO 2004092161 (Vertex), WO 2003035060 (Vertex) > WO 03/087092 (Vertex), WO 02/18369 (Vertex) or W098/17679 (Vertex). Specific examples of viral serine protease inhibitors include Teira Pavia•60 201238961 (Telaprevir) (VX-950, Vertex), VX-500 (Vertex), TMC435350 (Tibotec/Medivir), MK-7009 (Merck), ITMN-191 (R7227, IntefMune/Roche) and Boceprevir (SCH503034, Schering) As used herein, the term "viral polymerase inhibitor" means a viral polymerase that effectively inhibits mammals (including An agent that functions as an HCV polymerase. Inhibitors of HCV polymerase include non-nucleosides, such as those described in the following patents: WO 03/010140 (Boehringer Ingelheim) 'WO 03/026587 (Bristol Myers Squibb); WO 02/100846 A1 > WO 02/ 100851 A2, WO 01/85 172 Al (GSK), WO 02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck), WO 01/47883 (Japan Tobacco), WO 03 /000254 (Japan Tobacco) and EP 1 256 628 A2 (Agouron) o In addition, other inhibitors of HCV polymerase also include nucleoside analogs, such as those described in the following patents: WO 01/90121 A2 (Idenix ), WO, 02/069903 A2 (Biocryst Pharmaceuticals) and WO 02/057287 A2 (Merck/Isis) and WO 02/057425 A2 (Merck/Isis) Specific examples of HCV polymerase inhibitors include VCH-759 (ViroChem) Pharma ), VCH-916 (ViroChem Pharma ), VCH-222 ( ViroChem Pharma), R1626 ( Roche ) ' R7128 (Roche/Pharmasset ), PF-868554 ( Pfizer ), MK-0608

(Merck/Isis), MK-3281 (Merck), A-837093 (Abbott), GS 61 201238961 9190 (Gilead), ana598 (Anadys), HCV-796 (Viropharma) and GSK625433 (GlaxoSmithKline), R1479 (Roche), MK-0608 (Merck), R1656 (Roche-Phdrmasset) and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include jtk-002/003 and JTK-109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190 (Gilead), and PF-868, 554 (Pfizer). The term "viral helicase inhibitor" as used herein means an agent that effectively inhibits the function of a mammalian viral helicase, including a Flaviviridae helicase. As used herein, "immunomodulatory agent" means an agent that is effective to enhance or potentiate the immune system response of a mammal. Immunomodulators include, for example, type I interferons (such as alpha interferon, cardiac interferon, delta interferon and omega interferon, tau interferon, interferon and asialo interferon), type II Interferons (such as gamma-interferon) and pegylated interferons. Specific examples of immunomodulatory agents as used herein include IL-29 (PEG-interferon λ, ZymoGenetics), injectable or oral Belerofon (Nautilus Biotech), ornithine interferon a (Amarillo) Biosciences), BLX-883 (Locteron, Biolex Therapeutics/Octoplus), Omega Interferon (Intarcia Therapeutics), Polyferon (Viragen), Albumin Interferon (Albuferon) (Human Genome Sciences ), complex interferon (Infergen, Three Rivers Pharmaceuticals), Medusa Interferon (Flaml Technologies), NOV-205 (Novelos Therapeutics), Oglufanide disodium 62 201238961 (Implicit Bioscience), SCV-07 (SciClone), Zadaxin® (thy.malfasin, SciClone/Sigma-Tau) 'AB68 (XTL bio) and Civacir (NABI). As used herein, the term "viral polymerase inhibitor" means an agent that effectively inhibits the function of a mammalian viral polymerase, including HCV polymerase. Inhibitors of HCV polymerase include non-nucleosides, such as those described in the following patents: WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb); WO 02/100846 Ab WO 02/10085 1 A2, WO 01 /85172 AI (GSK) 'WO 02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck), WO 01/478 83 (Japan Tobacco), WO 03 /000254 (Japan Tobacco) and EP 1 256 628 A2 (Agouron). In addition, other inhibitors of HCV polymerase also include nucleoside analogs, such as those described in the following patents. Compounds: WO 01/90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals), and WO 02 /057287 A2 (Merck/Isis) and WO 02/057425 A2 (Merck/lsis). Specific examples of nucleoside inhibitors of HCV polymerase include R1626/R1479 (Roche), R7128 (Roche), MK-0608 (Merck), R1656 (Roche-Pharmasset), and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include JTK-002/003 and JfK-109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190 (Gilead), and PF-868, 554 (Pfizer). As used herein, the term "viral helicase inhibitor" means 63 201238961 an agent that effectively inhibits the function of a mammalian viral helicase, including a Flaviviridae helicase. As used herein, "immunomodulatory agent" means an agent that is effective to enhance or potentiate the immune system response of a mammal. Immunomodulators include, for example, type I interferons (such as interferon 'cardiac interferon, interferon- and cardiointerferon' X-interferon, interferon and asialo interferon), type π interferon ( Such as gamma-interferon) and pegylated interferon. Exemplary immunomodulatory agents include, but are not limited to, thalidomide; IL-2; hematopoietic; IMPDH inhibitors, such as meperabine (Vertex Pharmaceuticals); interferons, including natural interferons (such as Fu Ren (0MNIFER0N, Viragen) and SUMIFERON (Sumitomo) 'which is a blend of natural interferon), natural interferon a (ALFERON, Hemispherx Biopharma), interferon α n 1 from lymphoblastoid cells ( Wellferon, Glaxo Wellcome), oral ο; interferon, peg_interferon, peg_ interferon o: 2a (PEGase, Peche), recombinant interferon 〇; 2a (ROFERON) 'Roche', inhaled interferon a2b (AERX, Aradigm), Peg-interferon 〇; 2b (albumin interferon (Human Genome)

Sciences/Novartis), PEGINTRON, Schering), recombinant interferon a 2b (INTRON A, Schering), polyethylated interferon a2b (Schering, Vivenen) (VIRAFERONPEG 'Schering )), interferon / 3-la (REBIF 'Serono and Pfizer), complex interferon 〇; (dry chujin, Valeant Pharmaceutical), interferon (Atemu 64 201238961 * ( ACTIMMUNE) 'Intermune'), non-pegylated interferon alpha, alpha interferon and its analogues; and synthetic thymosin alpha 1 (ZADAXIN 'Sc.iClone Pharmaceuticals). As used herein, the term "type I interferon" means an interferon selected from the group consisting of interferons that bind to a type 1 receptor. This interferon includes type I interferons produced naturally and synthetically. Examples of type I interferons include interferon, cardiac interferon, delta interferon and Ω-interferon, r-interferon, complex interferon, and asialo interferon. As used herein, the term "π" Type interferon" means an interferon selected from the group consisting of interferons that bind to a type II receptor. Examples of type II interferons include gamma interferon. Antisense agents include, for example, ISIS-14803. Specific examples of inhibitors of the HCV NS3 protease include BIlN-2061 (Boehringer Ingelheim), SCH-6 and SCH-503034/Schering-Plough, VX-950/Vertex and itmn b (InterMune), GS9132 (Gilead), TMC-435350 (Tibotec/ Medivir), ITMN-191 (InterMune), MK-7009 (Merck). Inhibitors of the internal ribosome entry site (IRES) include ISIS-14803 (ISIS Pharmaceuticals) and their compounds (PTC therapeutics) as described in WO 200601983. In one embodiment, the other agent is interferon alpha, ribavirin, silybum marianum, interleukin-12, amantadine, ribonuclease, thymosin, N-acetoxysemisylamine or cyclosporin. (cyCi〇Sp0rin). In one embodiment, the other agent is interferon alpha or ribavirin, lactis, interleukin-1, amantadine, ribonuclease, thymosin, Ν _ 乙 乙 65 201238961 cysteine or cyclosporine Prime. In one embodiment, the other agent is interferon alpha 1A, interferon alpha 1 Β, interferon alpha; 2 Α or interferon q: 2B. Interferons can be obtained in PEGylated and non-PEGylated forms. Pegylated interferons include PEGASYStm and pegintr〇ntm. The recommended dose of PEGASYSTM monotherapy for chronic hepatitis C is to subcutaneously deliver 18 〇 mg (丨〇 mL vial or 〇 5 mL pre-filled syringe) subcutaneously to the abdomen or thighs once a week for 48 weeks. When used in combination with ribavirin for chronic hepatitis C, the recommended dose of PEGASYSTM is 1 80 mg (1. 〇 mL vial or 〇 5 mL pre-filled syringe) once a week. The recommended dose for PEG_lntr〇nTM therapy is i 〇mg/kg per week, administered subcutaneously for one year. This dose should be administered on the same day of the week. When administered in combination with ribavirin, the recommended dose of PEG-lntron is 1.5 μg/kg per week. Ribavirin is typically administered orally, and carbazole is currently available in the form of a lozenge. A typical standard dose of a viral azole tablet (e.g., about 2 mg of a tablet) is from about 800 mg to about 1200 mg. For example, for an individual weighing less than 75 kg, about 1 mg of ribavirin is administered. A dose of about 12 mg of viral sputum agent is administered to an individual having a body weight greater than or equal to 75 kg. However, the methods or combinations of the invention are not limited herein to any particular dosage form or therapy. Typically, ribavirin can be administered according to the dosage regimen described in its commercial label. In one embodiment, the other agents are interferon alpha 1A, interferon alpha 66 201238961 .1B, interferon alpha 2 (rhamycin), peg-interferon alpha 2 (珮格西施), interferon alpha 2Β (Gan Leeng) Or PEG-interferon α 2Β (Pegylene). In one embodiment, the other agent is a combination of standard or pegylated interferon alpha (Rasmin, Sigma, Schneider, PegIntron) and ribavirin. In a specific embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention described herein, one or more other agents selected from the group consisting of at least one pharmaceutically acceptable carrier or Agents. Non-nucleotide HCV polymerase inhibitors (eg HCV-796), nucleoside HCV polymerase inhibitors (eg R7128, R1626/R1479), HCV NS3 protease inhibitors (eg VX-950/Terrapa and ΙΤΜΝ_191) ), interferon and virus σ sit. Combinations of the above-mentioned combinations are preferably presented in the form of a pharmaceutical formulation and, accordingly, a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier - thus constitutes another aspect of the invention. The individual components used in the methods of the invention or combinations of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In another embodiment, the composition or combination of the invention further comprises at least one compound of the invention described herein; one or more additional agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (eg, HCV-796) ), nucleoside HCV polymerase inhibitors (eg, Rm8, R1626/R1479) and HCV NS3 protease inhibitors (eg, νχ_95〇/Tiraipiv and ΙΤΜΝ-191); and interferon and/or viral saliva. In one embodiment, the other agents are interferon alpha 1 Α, interferon alpha 67 201238961 1B, interferon alpha 2 Α or interferon, and viral spitting as appropriate. In a specific embodiment, the invention provides a method of treating or preventing a HCV viral infection comprising administering to the host a combination therapeutically effective amount of at least a compound of the invention and/or a plurality selected from the group Other agents of the following: non-(IV) Hcv polymerase inhibitors (eg, HCV-796), nuclear HCV polymerase inhibitors (eg, Km R1626/R1479), HCV NS3 protease inhibitors (eg, νχ_95〇/Terapet and ΙΤΜΝ -191) '• Interferon and ribavirin. Compounds and other agents are administered in the <combination specific examples'. In another embodiment of the combination, the compound and other agents are administered simultaneously. In one embodiment, S is a method for inhibiting or reducing hcv viral polymerase activity of a host, comprising administering to the host a combination of a therapeutically effective amount of at least one compound of the invention and one or more other selected from the group consisting of Agents. Non-nucleoside HCV polymerase inhibitors (eg, HCV 796) and nucleoside HCV polymerase inhibitors (eg, R7128, R1626/Ri479), interferons, and viral alpha sit. In one embodiment, the invention provides a combination of at least one use of a compound of the invention and the use of one or more other agents selected from the group consisting of a non-nucleoside HCV polymerase inhibitor (eg, HCV_796), a nucleoside hCV polymerase Inhibitors (eg, r7128, R1626/R1479), HCV NS3 protease inhibitors (eg, VX-950/Terrapavir and ITMN_丨9丨), interferons, and ribavirins, which are used in the manufacture of therapeutic or prophylactic hosts HCV-infected pharmaceuticals. When a compound of the invention as described herein is used in combination with at least one second therapeutic agent having activity against the same virus, the dose of each compound may be the same as or different from the dose when the compound is used alone. The appropriate dosage will be readily understood by those skilled in the art. The amount of the compound of the invention described herein administered is in combination with other agents (non-nucleoside HCV polymerase inhibitors (e.g., HCV_796), nucleoside hcv polymerase inhibitors (e.g., R7128, R1626/R1479), HCV NS3 protease inhibition. The ratio of the amount of agent (e.g., VX-950/Terrapavir and itmN-191), interferon or virus (sit) will vary depending on the choice of compound and other agents. In one embodiment, the other agent is selected from the group consisting of Α-831 (AZD0530, Arrow Therapeutics acquired by AstraZeneca), TLR9 agonist: IMO-2125 (Idera Pharmaceuticals), PYN17 (Phynova), Vafiximab (Vavituximab) Tarvacin, Peregrine, DEBIO-025 (DEBIO), NIM-811 (Norartis), SCY635 (Scynexis), PF-03491390 (IDN-6556, Pfizer), Suvus (formerly known as BIVN- 40 1, Virostat, Bioenvision ), MX-3 253 (Celgosivir, Migenix), Viramidine (Taribavirin, Valeant Pharmaceuticals), HepacondaX Giaconda), TT033 (Benitec/Tacere Bio/Pfizer), SIRNA-034 (Sirna Therapeutics acquired by Merck) and EHC-18 (Enzo Biochem), AQH-1095 (Achillion/Gilead), JKB-022 (Jenkin.) ' CTS-1027 (Conatus), MitoQ (mitoquinone, Antipodean Pharmaceuticals), Alinia (Nalonia 69 201238961 (nitazoxanide), Romark Laboratories) and Baviximab (Bavituximab) (Peregrine Phar m).

In one embodiment, the other agent is selected from the group consisting of CSL123 (Chiron/CSL) 'IC41 (Intercell Novartis ) ' GI 5005 (Globeimmune ), TG4040 (Transgene ) ' Chronvac C (Tripep/Inovio ), GNI-103 ( GE Nimmune ), A therapeutic vaccine of HCV/MF59 (Chiron/Novartis), PeviPR〇TM (Pevion biotect). Recommended dose of PEGASYStm monotherapy for chronic hepatitis C. 18 〇 mg (1.0 mL vial or mL pre-filled syringe) is administered subcutaneously in the abdomen or thigh, once a week for 48 weeks. In one embodiment, the viral serine protease inhibitor is a flavivirus ketamine inhibitor. In one embodiment, the viral polymerase inhibitor is a Flaviviridae polymerase inhibitor. In a specific example, the viral helicase inhibitor is a Flaviviridae helicase inhibitor. In other specific examples: : C =,, 糸 蛋白 protein inhibitor is a serine protease inhibitor; disease: polymerase inhibitor is HCV polymerase inhibitor; 'Solution 4 repase inhibitor is HCV helicase Inhibitor. In a specific embodiment, the invention provides a method of treating or preventing a host comprising administering to the host a compound of formula (I), (II), (III) or (IV). 70 201238961 In a specific example, the viral infection is selected from the group consisting of a flavivirus infection. In one embodiment, the flavivirus infection is hepatitis C virus (HCV), (BVDV) 'H virus, dengue encephalitis virus or yellow fever virus. In a specific case of infection (HCV). Flaviviridae Virus Sense (IV) Hepatitis C Virus In a specific example, the host is a human. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; At least one other agent is administered. In a particular embodiment, the invention provides a method of treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of the invention described herein, and further comprising administering At least one other agent selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral helicase inhibitor, an immunomodulator, an antioxidant, an antibacterial agent, a therapeutic vaccine, a hepatoprotectant, Antisense agents, inhibitors of HCV NS2/3 protease, and inhibitors of internal ribosome entry sites (IRES). Combinations of the above, and combinations thereof, which are used in the form of a pharmaceutical formulation and thus comprise a combination as defined above and a pharmaceutically acceptable carrier, thus constitute a further aspect of the invention. The individual components used in the methods of the invention or combinations of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. 71 201238961 In a specific example, the invention provides the use of a compound of the invention as described herein for the treatment or prevention of a Flaviviridae viral infection in a host. In a specific embodiment, the invention provides a compound of the invention described herein and further comprises the use of at least one other agent selected from the group consisting of a diseased serine protease inhibitor, a viral polymerase inhibitor, a viral solution. A helicase inhibitor, an immunomodulator, an antioxidant, an antibacterial agent, a therapeutic vaccine, a hepatoprotectant, an antisense agent, an inhibitor of HCV NS2/3 protease, and an inhibitor of an internal ribosome entry site (IRES); It is used to treat or prevent a Flaviviridae virus infection in a host. In one embodiment, the invention provides the use of a compound of the invention as described herein for the manufacture of a medicament. In one embodiment, the invention provides the use of the invention described herein for the manufacture of a medicament for the treatment or prevention of a Flaviviridae viral infection in a host. In a specific example, the invention provides a compound of the invention as described herein and further comprises at least one other agent selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral helicase. Inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease, and inhibitors of internal ribosome entry sites (IRES); For the manufacture of a medicament for treating or preventing a Flaviviridae virus infection in a host. In a specific example, the invention provides a method of treating or preventing a JJCV infection, which comprises contacting a biological sample or administering to a patient in need thereof an amount of a compound disclosed herein effective to treat or prevent the infection. 72 201238961 In one embodiment of the method, HCV is genotype 1. In another embodiment, the HCV is genotype 1 &amp; genotype "or a combination thereof. - Unless otherwise specified, the structures described herein are also intended to include all isomeric forms of the structure (eg, enantiomers, Diastereomeric and geometric (form) forms; for example, the R and s configurations of each asymmetric center and (8) the double bond (4) and the (Z) and (8) configuration isomers. Thus, the compounds of the invention Mono-stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the invention. Single optical isomers or enantiomers may be employed in the art. Well known methods are available: such as chiral HPLC, enzymatic resolution and chiral auxiliaries. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. In one embodiment, 97% and at least 99% are free of phase. The compound of the invention is at least 95%, at least one-stereoisomer of the stereoisomer. In another embodiment, the compound of the invention is present to 95. % does not contain a single stereoisomer of the corresponding stereoisomer The form of the body. In another embodiment, the compound of the invention is in the form of at least 97% free of the stereoisomer of the corresponding stereoisomer. In another embodiment, the compound of the invention is at least 99% excluding the form of a single stereoisomer of the corresponding stereoisomer. Also provided are pharmaceutically acceptable salts of the compounds of the invention. The term pharmaceutically acceptable salts of compounds is meant to be derived from a pharmaceutically acceptable Accepted inorganic acid 73 201238961 and their salts of organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid. , glycolic acid, lactic acid, salicylic acid, succinic acid, p-benzoic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, decane sulfonic acid, citric acid, benzoic acid, malonic acid, naphthalene-2- Sulfonic acid and sulfonic acid. Other acids which are not pharmaceutically acceptable by themselves, such as oxalic acid, may be used as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts. Salt from amino acid E.g. L- "leucine, L- lysine). Salts derived from appropriate bases include alkali metal (e.g., sodium, bell, potassium) and alkaline earth metal (e.g., calcium, magnesium) salts. The compounds mentioned below which include the compounds and their pharmaceutically acceptable salts are mentioned below. For pharmaceutically acceptable salts, see also Berge et al.

Pharmaceutical Salts, J. of Phar. Sci., Vol. 66, j. January 1977, List of commercially available salts approved by Fda listed in Table I on pages 1-19, the disclosure of which is incorporated by reference. The way is incorporated in this article. Those skilled in the art will appreciate that the compounds of the present invention may exist in different polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize in a variety of different crystalline or "polymorphic" species. The polymorph is a solid crystalline phase of the compound. The compound molecule has at least two different configurations or polymorphic forms under a solid bear. The polymorphic form of any given compound is defined by the same chemical formula or composition and its chemical structure is different from the crystal structure of two different compounds. It will be further understood by those skilled in the art that the compound of the present invention can be opened by a general practitioner who can be used in the medicinal treatment or prevention during the process of the 2012 201261 crystallization process. It is limited to the presence of different/valency compositions, such as hydrates. A solvate of a compound is also known when the solvent molecule of the gentleman is incorporated into the crystal lattice structure of the compound molecule. In addition to the compounds of this invention, the derivatives or prodrugs and esters of the compounds of the invention may be employed in the compositions for the conditions identified herein. Unless defined otherwise, technical and scientific terms have the same meaning as commonly understood in the art to which this invention belongs. All of the publications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflicts, this manual (including definitions) rights. In addition, the materials, methods, and examples are illustrative only. For the purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handb〇〇k. of Chemistry and Physics, 苐 75 version). In addition, the general principles of organic chemistry are described in "〇rganic Chemistry", Th〇mas Sorrell, University Science Books, Sausalito: 1999 and

March s Advanced Organic Chemistry, 5th Ed., Smith, M.B. and March, J. ed., John Wiley &amp; Sons, New York: 2001, the entire contents of which are incorporated herein by reference. In each of the formulas and formulas, the curve is transected in the formula (I) and bonded to a line such as B, B', Ri, R4 or R4'.

This means that when the valence allows, the group may be bonded to any carbon of the ring or, if applicable, a hetero atom such as N. The term "alkyl group" means a straight chain, a branched chain or a ring portion. The terms "dense base" and "fast radical" refer to a straight, branched or cyclic hydrocarbon moiety having one or more double or parametric bonds in the chain. Examples of alkyl, alkenyl and alkynyl groups include, but are not limited to, methyl, ethyl, propyl 'isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, iso Pentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, ethynyl, vinyl 'propenyl, isopropenyl, butenyl, isobutenyl, hexenyl , butyl dipentyl, pentenyl, pentadienyl, hexenyl, heptenyl, heptadienyl, heptadienyl, alkenyl, propenyl, butynyl, pentynyl, hexyl Alkynyl, cyclopropyl, cyclobutyl, cyclohexenyl, cyclohexadienyl and cyclohexyl. The term alkyl, alkenyl and alkynyl also includes combinations of straight chain and branched chain groups such as % propyl fluorenyl, cyclohexyl ethyl and the like. The term banyl also includes a C.1 dilute group in which one carbon atom is attached to the remainder of the molecule via a double bond. In the specified case, "alkyl" and "alkenyl" and "block" may be optionally substituted, such as in the case of one or more hydrogen atoms substituted by a halogen (e.g., an alkyl halide). Examples of _alkyl include, but are not limited to, trifluorodecyl, difluorodecyl, fluoroindenyl, trichloroindenyl, dichloroindenyl, fluorenyl, trifluoroethyl 76 201238961, difluoroethyl , fluoroethyl, tri-gas ethyl, dichloroethyl, gas ethyl, gas fluoride methyl, difluoro gas sulfhydryl, di-fluoroethyl. In addition to halogen, the 'alkyl, alkenyl or alkynyl group may, where specified, be substituted, for example, by the following: halogen, -ORa, pendant oxy, -NRaRb, =N〇_Rc, _c(=〇)〇Ra , _c(〇) NRaRb, -C( = 0)OH, -C( = 〇)Ra, _c(=NORc)Ra, -C(=NRc)NRa

Rb ' -NRdC( = 0)NRaRb χ -NRbC(=〇)Ra ^ -NRdC(=NRc)NRaRb &gt; -NRbC(=0)0Ra, -〇C(=〇)NRaRb, _〇c(=〇 Ra, _〇c( = 〇)〇Ra, hydroxy, nitro, azido, cyano, ·s(〇)()_3Ra, _s〇2NRaRb, _NRb S02Ra, -NRbS02NRaRb or _P(=〇) 〇Ra〇Rb, wherein Ra_Rd are each independently H, (: 丨...alkyl, c2_]2 alkenyl, Cm alkynyl, c6i2 aryl, c7|6 aralkyl, 5-12 membered heteroaryl, 6_18 a heteroarylalkyl group, a 312 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. The terms "cycloalkyl" and "cycloalkenyl" mean a cycloalkylalkyl or alkenyl group, respectively, and are intended to include a single ring (eg, Cyclopropyl, cyclobutyl, cyclohexyl), spiro (eg spiro[2.3]hexyl), fused (eg bicyclo[4 4 fluorene] fluorenyl) and bridged (eg bicyclo [2.2.1] heptyl) hydrocarbon The terms "alkoxy", "alkenyloxy" and "alkynyloxy" mean an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to an adjacent atom via an oxygen atom. Examples include (but not Limited to) methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, third Butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy. Similar to alkyl, alkenyl and Alkynyl, in the specified case, the '13 oxy, alkenyloxy and alkynyloxy groups may be substituted, for example, by the following: halogen, -ORa, pendant oxy, _NRaRb, =N〇_Rc, _c(= 〇)〇Ra , 77 201238961 -C(0)NRaRb, -C(=0)0H, -C( = 0)Ra, -C(=NORc)Ra, -C(=NRc)NRaRb, -NRdC(=0)NRaRb, -NRbC( = 0)Ra , -NRdC(=NRc)NRa Rb, -NRbC( = 0)0Ra, -0C( = 0)NRaRb, -0C( = 0)Ra, -0C( = 0) ORa, hydroxyl , nitro, azido, cyano, -S(0)〇.3Ra, -S〇2NRaRb, -NRbS〇2Ra, _NRbS〇2NRaRb or -P(=0)0Ra0Rb, wherein Ra-Rd are each independently H, C!-12 alkyl, C2,12 dilute, C2-12 fast radical, C6-12 aryl, C7-I6 aryl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group. The term "aryl" means a carbocyclic moiety containing at least one benzene-like ring (ie, may be monocyclic or polycyclic) and is specified In case it may be replaced by one or more Substituted. Examples include, but are not limited to, phenyl, tolyl, monodecylphenyl, aminophenyl, anilino, naphthyl, anthracenyl, phenanthryl or biphenyl. In the specified case, the aryl group may be optionally substituted by, for example, halogen, -ORa, -NRaRb, -C(=0)0Ra, -C(0)NRaRb, -C(=0)0H, -C(=〇 Ra, -C(=NORc)Ra, __C(=NRc)NRaRb, -NRdC(=0)NRaRb, -NRbC (=0)Ra, -NRdC(=NRc)NRaRb, -NRbC( = 〇)〇Ra , -〇C( = 〇)NRa

Rb, -0C(=0)Ra, -〇c(=〇)〇Ra, hydroxyl, nitro, azido, cyano, -S(0)〇.3Ra, -S〇2NRaRb, -NRbS02Ra, - NRbS02NRaRb or -P( = 〇) 〇Ra〇Rb 'C丨-12 alkyl, c2-12 alkenyl, C2•丨2 alkynyl, C6 η aryl, C7-16 aralkyl, 5_i2 member heteroaryl a 6-18 membered heteroaralkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group, wherein each of Ra_Rd is independently η, q η alkyl, c 2-12 alkenyl ' C 2 12 alkynyl , C6 12 aryl, Q aralkyl, 512 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl. 78 201238961 The term "aralkyl" means an aryl group attached to an adjacent atom via an alkyl, alkenyl or alkynyl group. Similar to the aryl group, the aralkyl group may also be substituted as the case may be. Examples include, but are not limited to, benzyl, diphenylmethyl, triphenylmethyl, phenethyl '3-phenylpropyl' 2-propoxypropyl, 4-phenylbutyl and naphthylfluorenyl. In the specified case, the 'aralkyl group may be substituted one or more times, for example, by -, -, Ra, -NRaRb, -C(=〇)〇Ra, -C(0)NRaRb, -C( = 0 OH' -C(=〇)Ra&gt;-C(=NORc)Ra&gt; --C(=NRc)NRaRb ' -NRdC( = 0) NRaRb, -NRbC(=0)Ra, -NRdC(=NRc) NRaRb, -NRbC( = 0)0Ra, _OC( = 〇)NRaRb, -〇C( = 0)Ra, -〇c(=0)〇Ra, hydroxy, nitro, 4 nitrogen, cyano, -S (0) Ra.3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02 NRaRb or -P(=〇)〇Ra〇Rb, c] i2 alkyl, C2 η alkenyl, C2 丨2 alkynyl, 〇6-丨2 Aryl, (7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl, wherein Ra_Rd are each independently H, Cm2 alkyl, C2.12 alkenyl, c2.12 alkynyl, c6_12 aryl, (:7.16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring Or a 4 to 18 membered heterocyclic-alkyl group. The term "heterocyclic ring" means a non-aromatic, saturated or partially saturated cyclic moiety wherein the cyclic moiety is heterozygous at least one selected from the group consisting of oxygen (sulfonium) and sulfur (s) sU. (N), heteroatom heterocycles may be monocyclic or polycyclic. Examples include (but not a) azetyl, butane, dioxolanyl 'morpholinyl, N-morpholinyl, oxacyclic phenyl morphyl, piperididyl/piperidinyl, cyclopentane &amp; , 衣 pentadiene and hired arable, cyclopentadienyl furanyl 'four ^ Fu Nanji, 嗟 琳 琳 、, 嗤 嗤 基 、, 派 派. Nanji, Azide, Nitrogen, Ni (4) 'Base, diazepine group, oxiranyl Uxyranyl), 79 201238961 morphine, beta piroxicam and thiobathyl, thioindole, β ratio β sit π-based, monodecyl And an imidazolidinyl group. In the specified case, the heterocyclic group may be substituted one or more times by, for example, the following: a pheromone, _〇Ra 'sideoxy', :NO-Rc, -C(=0)Ra, -C(0)NRaRb, -C( = 〇)〇H, -C(=〇)Ra, -C(=NORc)Ra&gt; .C(=NRc)NRaRb^NRdC( = 〇)NRaRb^NRbc(= 0)

Ra &gt; -NRdC(=NRc)NRaRb &gt; -NRbC(=0)0Ra &gt; -OC( = 〇)NRaRb . •OC( = 〇)Ra, -〇c( = 〇)〇Ra, hydroxyl, nitrate Base, azido, cyano, _s(〇)〇

Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or _P(=〇)〇Ra 0Rb, Cm2 alkyl, C2-12 alkenyl, c2 12 alkynyl, c6·丨2 aryl, q 芳 aralkyl, 5 a 12-membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group, wherein each of Ra_Rd is independently H, Cii2 alkyl, 2-12 alkenyl, anthracene 2_12 alkynyl, (: 6_12 aryl, (: 7-16 aryl, 5- 12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclic-alkyl). "Alkyl" means that a heterocyclic group is bonded to an adjacent atom via an alkyl group, an alkenyl group or an alkynyl group. For example, in the 18-member heterocyclic ring group, 4 represents a ring atom present in the heterocyclic moiety. The total number of carbon atoms present in the alkyl group, the dilute group or the fast group. For example, the 7-membered heterocyclic ring-hospital group covers the following groups (* indicates a point of attachment):

In this case, the heterocyclic-alkyl group may be substituted by, for example, the following -ORa, pendant oxy, -NRaRb, =N0_Rc, _c(=〇)〇Ra, sedative halogen, in the finger or multiple times: 201238961 -C (0)NRaRb' -C(=〇)〇H' -C(=〇)Ra,_C(=NORc)Ras -C(=NRc) NRaRb, -NRdC(=〇)NRaRb, -NRbcb0)Ra , _NRdC NRjNRa Rb' -NRbC(-0)0Ra . -0C(=0)NRaRb &gt; -〇C(=0)Ra , .〇C(=〇) ORa, hydroxyl, nitro, azide, Cyano, _s(〇)Q 3Ra, -NRbS〇2Ra, -NRbS〇2NRaRb or -P(=〇)〇Ra〇Rb, Ci i2 alkyl, C2-12.alkenyl, C2-12 alkynyl, c6 -12 aryl, c7j6 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 418 membered heterocycloalkyl, wherein each of Ra-Rd is independently H, Cl 丨2 alkyl, C 2 丨 a alkenyl, q 2 alkynyl, CVu aryl, aralkyl, 5 · 12 membered heteroaryl, heteroarylalkyl, 3-12 heterocyclic or 4-18 hetero Ring_alkyl. The term "heteroaryl" means an aromatic cyclic moiety, wherein the cyclic moiety: ! at least one hetero atom selected from the group consisting of oxygen (oxime), sulfur (1) or nitrogen (8). Aromatic: a ring or a polycyclic ring wherein at least one ring of the polycyclic ring system is: face % and at least one material (not necessarily the same ring) contains a heterogene: ΓΓ is limited to a phenanthrenyl decyl group, a heterologous sinyl group, Different glutinous rice saliva, hire two. Sit on base, hire. Sitrate, morphine, thaphthyl 1 than bite base... than sulphate, phenyl... succinyl ' oxazolyl, triazolyl, thiazolyl, thiazide, sputum saponin Earthworm soil, thiadibenzyl 2, hydrazine, cyclin, mercaptopurine, porphinyl, thienothiazolyl, oxazolopyrazolyl.比 并 吨 咯 吨 吨 吨 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻Benzo(4), benzofluorenyl, benzoyl, dioxin, benzoin, benzof and chirality 81 201238961 imidazopyrylene, sulfhydryl, pyrazolopyrimidinyl, imidazolium Pyridyl, benzimidazolyl, oxazolyl, benzoxaxathilyl, benzodiazepine alpha, benzodithiol (benz〇dithi〇iyi)'吲哚Plough, porphyrin, isoindolyl, furopyrimidinyl, furanoacridinyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridinyl, benzothiophene Benzyl, benzothiaphthyl, quinazolinyl, alpha naphthyridyl, quinolinyl, isoquinolinyl, benzopipetanyl, pyridomorphinyl 'alpha keene, benzo Dimorphine. In the specified case, the heteroaryl group may be substituted one or more times by, for example, dentate, -ORa, -NRaRb ' _c(=0)0Ra, -C(0)NRaRb, -C( = 0)0H, -C(=0)Ra, -C(=N〇Rc)Ra ' -_C(=NRc)NRaRb, -NRdC( = 〇)NRaRb, -NRbC(=〇)Ra, _NRdC(=NRe)NRaRb, - NRbC( = 〇) 〇Ra ' _〇c( = 〇)NRaRb, _〇c( = 〇)Ra, -〇C( = 〇)〇Ra, hydroxy, nitro, azide, cyano, -s (〇)() 3Ra, _s〇2NRaRb, •NRbS02Ra, -NRbS〇2NRaRb or _p(=〇)〇Ra〇Rb, Ci i2 alkyl, c2·丨2 dilute 'C2.12 alkynyl, C612fang a group, a c716 aralkyl group, a 5-12 membered heteroaryl group, a 6-18 membered heteroarylalkyl group, a 3-12 membered heterocyclic ring or a 4-18 membered heterocyclic-alkyl group, wherein each of Ra-Rd is independently Η, Cbu Alkyl, C2-12 alkenyl, c2.12 alkynyl, C6.12 aryl, c7 16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring Or a 4-18 member heterocyclic-alkyl group. The term "heteroaralkyl" denotes an optionally substituted heteroaryl group attached to an adjacent atom via an alkyl group, a dilute group or an alkynyl group. In the specified case, the heteroarylalkyl group may optionally be substituted one or more times, for example :il, -ORa, -NRaRb, 'C(=0)〇Ra , -C(0)NRaRb ' -C(=0)0H &gt; -C(=〇)Ra ^ -C(=N〇Rc )Ra , -C(=NRc)NRaRb . -NRdC(=0)NRaRb ^ 82 201238961

C2-12 alkynyl, c6-12 aryl, c7l6 aralkyl, 5-12 membered heteroaryl, 618 member heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic ring-alkyl group, wherein Ra_Rd C2-12 Alkenyl, C2-12 alkynyl, (36.12 aryl each independently H, (^.12 alkyl, yl, C7_16 aralkyl, 5-12 heteroaryl, 6-18 heteroaryl, 3-12 heterocycle or 4-18 membered heterocyclo-alkyl. It is understood that, for example, in the 6-membered 8-membered heteroaralkyl moiety, 6-18 members represent a ring atom present in the heterocyclic moiety and an alkyl, alkenyl or alkynyl group. The total number of carbon atoms. For example, a 7-member heteroaryl group covers the following groups (* indicates a point of attachment)··

The "halogen atom or halogen group" is specifically a fluorine atom, a gas atom, a bromine atom or a broken atom. The term "sideoxy" means =0. A dash ("-") between two letters or symbols is not used to refer to the connection point of the currency substitution base. For example, -CONRdRe is linked via a carbon of guanamine. A dotted line ("...") is used to indicate the point of attachment of the group. For example, in the following depiction, A is linked via carbon at positions 1 and 4: 83 201238961 Ο - When a sulfur atom is present, the sulfur atom may have a different degree of oxidation, i.e., s, SO or S 〇 2 . All such degrees of oxidation are within the scope of the invention. The term "individually" means that the substituents may be the same or different definitions. In general, the term "substituted", whether or not preceded by the term "optionally", refers to the replacement of a group of carbon radicals on a carbon or nitrogen atom in a given structure with a specified substituent. Specific substituents are described in the above definitions and in the description of the following compounds and examples. Unless otherwise indicated, the optionally substituted group may have a substituent at each substitutable position of the group, and the more than one or more positions in the volume (4) of the predetermined structure may be selected from one or more selected groups. When substituted with a substituent, the substituent may be the same or different at each position. For example, 'the wording' is unsubstituted or substituted by R10 one or more times. When the group is substituted by more than one R 1 nm nm , , , , , , , , , , , , , , , , , , = ". Ring substituents (such as heterocycles) may be bonded to another - (such as ring =) ' to form a spiro' bicyclic system, for example, two rings share - a common one, as will be recognized by those skilled in the art, the present invention It is intended to form a combination of compounds which are stable or chemically achievable, and which are used in the text, and the compounds of W:: such as the best recycled and purified materials are allowed to be prepared, detected and More or less unchanging, one or more purposes or chemically feasible:: In some specific examples, stable, compounded "do not be in water or other chemical reactions Sexual conditions 84 201238961 A compound which does not substantially change 4 when kept at 40 ° C or lower for at least one week. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups together with the atoms to which they are attached may form a ring. Η In some embodiments, the compound represented by , also includes the case where the R group replaces the ruthenium on the nitrogen atom. In addition, unless otherwise specified, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopes. The compounds of the invention in which a plurality of hydrogen atoms are replaced by HI or _ or a plurality of carbon atoms, a C or a C-enriched carbon, are within the scope of the invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or antiviral compounds with improved therapeutic profiles. Surgery: "Host" Ge "Patient" means a human male or female, such as a child, a teenager or an adult. 1. The amount of the compound of the present invention required for the treatment will vary not only with the particular compound, but also with the age and condition of the disease, the age of the disease, and the condition. It is determined by the Japanese veterinarian or the veterinarian. Lack of worry and will eventually be treated by the attending physician ", and, generally, sputum, suitable for the weight of the pound is about 0.1 ms $ 幼 7 川 肘 肘 在 在 在 母 母 母 母 母 , , , , , , , , , , , , , , , , , , , , , , , , , , , , Within the range of mg, bite in the range of Example 1. 4 For example, the amount of sputum per kilogram of body weight on the mother's day: |: administered in a single or two doses or at intervals, for example, twice a day, three times a day (,, Dosage for four-person or more than four times. 85 201238961. The substance should be administered in a unit dosage form; for example, containing 1 〇 mg to 1500 mg per unit dosage form, preferably 20 mg to 1000 mg, most preferably 50 mg Up to 700 mg of active ingredient. Preferably, the active ingredient is administered such that the peak plasma/agronomy of the active compound is from about 1 μΜ to about 75 —, about 2 _ to palpebral, about 3 _ to about 3 〇 μΜ. This concentration can be achieved, for example, by intravenous injection of 0.1 〇/〇 to 5% of the active ingredient solution, as appropriate in physiological saline, or by oral administration of a bolus containing from about (10) to about the active ingredient. The blood content can be provided by continuous delivery to provide approximately Q qi per hour to approximately $ 』mg/kg of the active ingredient or by infusion solution containing between about 0.4 mg/kg and about 15 active ingredient. The compound of the present invention or its pharmaceutically acceptable salt is the same as the virus with the needle. The active second therapeutic agent is used in combination with a daily dose, and the dose of each compound may be the same as or different from the dose when the compound is only used. Suitable dosages will be readily apparent to those skilled in the art. It is possible that when used in therapy, the present invention The compound is administered in the form of a chemical material, but preferably the active ingredient is provided in the form of a pharmaceutical composition. Thus, the present invention further provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof. And one or more pharmaceutically acceptable carriers, and thus other therapeutic and/or prophylactic ingredients, as the case may be. The elixirs must be compatible with the other ingredients of the formulation and The recipient is harmless in the sense that it is "acceptable". The pharmaceutical composition includes those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, transvaginal or non- The composition of the intestine (including intramuscular, cutaneous 86 201238961 and intravenous), or such compositions suitable for administration by inhalation or insufflation. Where appropriate, the formulation should be a separate agent S The unit form is provided and can be prepared by any method well known in the art of pharmacy. All methods include bringing the active compound into association with a liquid carrier or a fine carrier or both, and then, if necessary, shaping the product into The step of the desired formulation. ^ σ, the pharmaceutical preparation of the oral administration should be provided in the form of individual units containing a predetermined amount of live! knives, such as capsules, cachets or keys; Provided in the form of granules; provided as a solution, suspension or emulsion. The tongue: the fraction can also be provided in the form of a bolus, tincture or paste. The key and capsule for the oral medicine may contain a conventional excipient such as a binder, a filler, a lubricant, a disintegrant or a wetting agent. Tablets can be coated according to the techniques in the art. The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, a solution, an emulsion, a sugar (d), or a dry product in the form of a suitable or other suitable vehicle. These liquids are powerful, such as suspending agents, emulsifiers, non-aqueous media states (which may include edible oils) or preservatives. • The compound of the present invention can also be formulated with *, .* u F, sputum (eg, by ', for example, rapid injection or continuous infusion) and can be &amp; 之 amp, pre-filled syringe, small volume loss The main additive is added with a preservative unit dosage form... The county ocean tour in a multi-dose container - for example in an oily or aqueous medium: / octa, gluten or emulsion and may contain, for example, a suspending agent , 稃 &quot; and / or dispersant formulation. Alternatively, the activity is "stable", the sterile solid or the sputum is obtained from the self-drying by means of a sterile separation, and is prepared by using a suitable vehicle (eg sterility) prior to use of 87 201238961. Constructed without pyrogens. For topical administration to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions or transdermal patches. These transdermal patches may incorporate penetration enhancers such as agarwood Alcohol, carvacrol, thymol, citral, menthol and aniseed brain. Ointments and creams may be formulated, for example, with an aqueous or oily base, with the addition of suitable thickening and/or gelling agents. The lotion may be formulated with an aqueous or oily base, and will generally contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents or coloring agents. Compositions suitable for topical administration in the mouth include buccal inclusions An ingot comprising an active ingredient in a flavoring base, typically a sucrose and a gum arabic or tragacanth; a tablet comprising an active ingredient in an inert matrix such as gelatin and glycerin or sucrose and gum arabic And a mouthwash comprising the active ingredient in a suitable liquid carrier. A pharmaceutical composition suitable for rectal administration wherein the carrier is a solid is provided, for example, in the form of a unit dosage suppository. Suitable carriers include cocoa butter and the like Other materials commonly used in the art, and suppositories are preferably formed by mixing the active compound with a softening or melting carrier, followed by cooling and shaping in a mold. Compositions suitable for vaginal administration may contain such items in addition to the active ingredient. It is known in the art to provide such carriers in the form of pessaries, tampons, creams, gels, pastes, foams or sprays. For intranasal administration, the compounds of the invention may be liquid sprayed or dispersible. The powder may be used in the form of a powder or in the form of a drop. The drops may be formulated with an aqueous or non-aqueous base which may also contain a plurality of dispersing agents, solubilizers, and a liquid spray. The liquid spray is preferably delivered from a pressurized pack. 88 201238961 For administration by inhalation, Soil to be on ^ The compound of the present invention should be self-contained A 51, atomizer or pressurized packaging or complex immortal * man buried in the eight he passed the appropriate structure of the aerosol spray The pressurized package may contain a propellant suitable for the entanglement member, such as dichlorodifluoromethane, chlorofluoromethane-gas tetragas, &amp;Μ#❹&amp; in the case of aerosol,曰&amp; body The amount of premature position can be determined by supplying the valve to deliver the measured amount. Suppressing &lt;or for the administration of the compound of the present invention by inhalation or insufflation, it is known that the form of the dry powder composition, such as a compound A powder mixture with a suitable powder base such as a sugar or a starch. The powder composition may be provided, for example, in a capsule or cartridge or in a unit dosage form such as gelatin or a foamed packet (the powder may be administered therefrom). &quot; The following general procedures and examples are provided to illustrate various specific examples of the invention and are not to be considered as limiting. Those skilled in the art will appreciate that other compounds of this month can be obtained by substituting the reactants and/or operating conditions generally or specifically described in the following examples. In the above and following examples, all temperatures are uncorrected in degrees Celsius; and unless otherwise indicated, all parts and percentages are by weight using the following abbreviations as follows: aq c〇nc e&gt;cm aqueous/aqueous solution Dioxane 89 201238961 DIPEA Diisopropylethylamine DMF Dimercaptoguanamine DMSO Dimethyl sulphate EtOAc Ethyl acetate HATU Hexafluoroic acid 0-(7-azalyl)-v, ν, ν' , ν·- four 曱 base! Urine 莫 molar concentration MeOH methanol MTBE methyl tert-butyl ether n-BuLi n-butyl lithium

PdCl2dppf Pd(PPh3)2Cl2 RT TEA THF Digas (1,1·-bis(diphenylphosphino)-ferrocene) palladium (II) anti-digas bis(triphenylphosphine) (Π) room The warm triethylamine tetrahydrofuran compound of the present invention can be prepared according to the specification using procedures generally known to those skilled in the art. These compounds can be analyzed by known methods including, but not limited to, LCMS (liquid chromatography mass spectrometry) HpLCh-effect liquid chromatography) and NMR (nuclear magnetic resonance). The particular strips shown below are to be understood as merely examples and are not intended to limit the invention that can be used in the preparation of the present invention. The present invention also includes those skilled in the art. The conditions of the compound. Unless otherwise extended, it will be represented by hooliganism. General Procedures: All variables of L&quot; are as defined herein. 90 201238961 Mass spectrometry samples were analyzed on a MicroMass Quattro Micro or MicroMass LCZ mass spectrometer operating in electrospray ionization in a single MS mode. The sample was introduced into the mass spectrometer using chromatography. The mobile phase for all mass spectrometry consists of 10 mM pH 7 ammonium acetate and a 1:1 acetonitrile-methanol mixture. Method A: Column gradient conditions were 5 〇/0-1 〇〇〇/0 acetonitrile-methanol on a ACE 5 C8 3.0 x 75 mm column over a 3 - 5 minute gradient and 4.8 minutes. The flow rate was 1.2 ml/min. Method B: Column gradient was 5%-1 〇〇% acetonitrile-methanol' on a ACE5C8 4.6 χ 1 50 mm column over a 10 minute gradient time and a 12 minute column time. The flow rate is 1.$ ml/min. As used herein, the term "Rt (minutes) (Rt(min))" refers to the LCMS residence time in minutes associated with a compound. Unless otherwise indicated, the LCMS method used to obtain the reported residence time is as detailed above. If Rt (minutes) &lt; 5 is known, use Method A. If Rt (minutes) &gt; 5 minutes, use Method B ° to record 1 H-NMR spectra at 400 MHz using a Bruker DPX 400 or Varian instrument. . Reverse phase HPLC purification was performed under standard conditions using a Phenomenex Gemini C18 column, 21.2 mm IDx2 50 mm '5 μηι, 110 A. The elution was carried out at a flow rate of 5. 〇 ml/min using a 20% to 90% linear gradient (ch/n aqueous solution or CHsCN aqueous solution containing 〇〇2% Hci). EXAMPLES Reverse phase Ηριχ purification was carried out under standard conditions using a Phenomenex Geminicl8 column, 21 2 mm ID x 250 mm, 5 drops, 110 A. The elution was carried out at a flow rate of 5.0 ml/min using a 20% to 90% linear gradient (c^cn aqueous solution or 91 201238961 CHsCN aqueous solution containing 〇〇2% hci). Example 1: ((S)_l-{(2S,4S)-2-[5-(4'-{2-[(2S,4S)-l-((S)-2-methoxycarbonylamino) -3-mercapto-butenyl)-4-methyl-pyrrolidine_2_ylbu-1H_imidazole_4•pyridin-4-yl)-1Η-benzosin-2-yl]-4 -Methyl-«»Bihabitajib 2-methyl-propyl)-methyl-carbamic acid methyl ester (Compound 7)

Step I: 2-Bromo-l-[4-(4-bromophenyl)phenyl]ethanone to 1-[4-(4-bromophenyl)phenyl]ethanone (5 g, 18.17 mmol) Bromine (983 / x L, 19 mmol) was added to a solution of CH2C12 (40 mL). The resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with a methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, water, brine, and evaporated The crude solid was triturated with diethyl ether to give 2--[4-(4-&lt;&quot;&gt;&gt; Step II: 92 201238961 • (2S,4S)-4-methyl 0-pyridin-12-didecanoic acid 2-(2-(4'-bromobiphenyl·4_yl)_2_ side oxyethyl) Add 1 - tert-butyl ester to a solution of (2S,4S)-1-2,2,2-butoxymethyl-4-methylpyramine-2-carboxylic acid (437 mg, 1.905 mmol) in acetonitrile (6 mL) _Bromo444 (4-Molyphenyl)phenyl]ethanone (693 mg, 1.732 mmol) and j) IPEA (0 332 mL, 1.905 mmol). The reaction mixture was stirred at room temperature for 4 h and diluted with EtOAc EtOAc EtOAc. The organic layer was concentrated to dryness (m.p.) (m.) Pyridyl-bito-n-nonanoic acid 2-(2-(4'-indibiphenyl-4-yl)-2-oxoethyl)1 _ tertidine. (870 mg, 1.732 mmol) 〇Step III : (2S, 4S)-2-[4-(4'-,; odor-biphenyl-4-yl)-1H-dm0-yl-2-yl]-4-fluorenyl-. Thirteen butyl phthalate-1-yl phthalate to (2S,4S)-4-mercaptopyrrolidine-1,2-didecanoic acid 2-(2-(4·-bromobiphenyl-4-yl) Acetate (2.. 670 g, 34.64 mmol) was added to a solution of 2-acetoxyethyl)1-tertiary g (870 mg, 1.732 mmol) in a solution (8.7 mL). The reaction mixture was stirred at 1 ° C for 1 hour, then cooled to room temperature and diluted with water (8.7 mL). The layers were separated and EtOAc (EtOAc)EtOAc. The residue was purified by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc 1Η-Imidazol-2-yl]-4-methyl-pyrrolidine_1-carboxylic acid tert-butyl ester (727 mg, 87% overall, from step II). 93 201238961 'H NMR (300 MHz, CDC13) δ 10.72 (s, 1H), 7.81 (s, 1H), 7.50 (dd, 6H), 7.26 (s, 1H), 4.93 (s, 1H), 3.77 (s , 1H), 2.86 (s, 1H), 2.60 (d, 2H), 2.26 (d, 1H), 1.48 (s, 9H), 1.11 (d, 3H). LC/MS: m/z = 481.97 (M + H + ). Step IV: (2S,4S)-4-mercapto-2-{4-[4'-(4,4,5,5-tetramethyl-[1,3,2]dioxosole-2 -yl)-biphenyl-4-yl]-1Η- °m n sit-.2-yl}-. Ratio of 0 to each α-1,3-decanoic acid third butyl g is intended to be 80° (: (28,43)-2-[4-(4,-bromo-biphenyl-4-yl) under nitrogen atmosphere) -1Η-M.. 2-yl]-4-mercapto-pyrrolidinic acid tert-butyl ester (725 mg, 1.503 mmol), 4,4,5,5-tetradecyl-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaboron yttrium-2-yl)-1,3,2-dioxaborium alpha (1.145 g, 4.509 mmol), Pd (DPPF) (Cl) 2. CH2Cl2 (122.7 mg, 0.1503 mmol) and a solution of KOAc (737.5 mg, 7.515 mmol) in DMF (7.3 mL·), for 1 hour, then cooled to room temperature and passed through a bed of diatomaceous earth Filtration. The mixture was diluted with EtOAc (EtOAc (EtOAc) (EtOAc) Purification by silica gel flash column chromatography (6% to 50% EtOAc in hexane) to give (2S,4S)_4_meryl-2-{4-[4·-(4,4,5,5 -tetradecyl-[ι,3,2]dioxaboron-ind- 2-yl)-biphenyl-4-yl]-1 oxime-salt-2-ylpyrrolidinyl]-carboxylic acid tert-butyl ester ( 53〇mg, 67%) NMR (300 MHz, CDC13) δ 10.75 (br s, 1H), 8.00 -7.49 (m, 8H), 7.30 ( s, 1H), 4.98 (t, 1H), 3.88 - , 3.71 (m5 1H), 2.90 (t, 1H), 2.77 - 2.42 (m, 2H), 2.29 (d, 1H), 1.56 (d, 9H) , 94 201238961 1.38 (s,12H),.1.15 (d,3H) 〇Step V: 2S,4S)-2-{4-[4'-(2-{(2S,4S)-l-[(S ) 2 - (曱 羰 oxycarbonyl-indolyl-amino)-3 -methyl-butanyl]-4-methyl-pyrrolidine_2_ kib iH-benzimidazole _5_ yl)-biphenyl- 4-yl]-1H-imidazol-2-yl}, 4-methylpyridinium_ι_carboxylic acid tert-butyl ester to (2S,4S)-4-mercapto-2-{4-[4'- (4,4,5,5-tetradecyl_[1,3,2]dioxygen phenanthrene-2-yl)-linked stupid-4-yl]-1Η-Ρ米嗤-2-yl} -° ratio ρ 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1:^ Benzomidino-2-yl)-4-methyl-pyrrolidine-i-carbonyl]-2-mercapto-propyl]-N-methyl-amino phthalic acid vinegar (198.6 mg, 0 , 3985 mmol), Pd(DPPF) (C1)2.CH2C12 (32.54 mg' 0.03 985 mmol) in 2-propanol (2.1 mL)

LC/MS: .m/z 774.55 (M+H+).

Step VI u~-zm_[(2S,4SM_methyl_2_(5 is more than each bit-2-) _ih- 咪 ___ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -[2-((2S,4S)-4--4-yl}-lH-benzoimidine 95 201238961 oxazol-2-yl)-pyrrolidine-1-carbonyl]-propyl-p-aminocarbazate Acid salt to (28,43)-2-{4-[4,-(2-{(23,43) small [(exo 2_(methoxyh)-indolyl-amino)-3-methyl-醯醯基]-4-mercapto-pyrrolidine_2·kib 1H_benzimidazol-5-yl)-biphenyl-4-yl]-1H-imidazol-2-yl-4-methyl-pyrrolidine_ Add a 4 M HCl solution (0.632 mL ' 2.526 mmol) to a solution of 第三 曱 第三 第三 第三 ( (115 mg ' 0.1486 mmol) in methanol. Mix the reaction mixture for 1 hour at room temperature and concentrate to dryness. The title product was used as such in the next step.

Step VII ((S)-l-{(2S,4S)-2-[5-(4'-{2-[(2S,4S)-l-((S)-2-methoxycarbonylamino)- 3-mercapto-butanyl)-4-methyl-&lt;»pyridin-2-yl]-anthracene-β-methane-4-yl}- phenyl-4-yl)-1Η-benzimidazole- 2-yl]-4-mercapto-pyrrolidin-1-carbonyl}-2-mercapto-propyl)-fluorenyl-amino decanoate thiol under nitrogen atmosphere to thiol in ice bath {(S)-2-mercapto-l-[(2S,4S)-4-methyl,2-(5-{4'-[2-((2S,4S)-4-mercapto-indole ratio) Rrrolidin-2-yl)-1Η-imidazol-4-yl]-biphenyl-4-yl}-1Η-benzoimidazol-2-yl)-pyrrolidin-1-carbonyl]-propyl}-amino HATU ( 28.3 mg, 0.0744 mmol) and DIPEA (0.037 mL, 0.212 mmol) were added sequentially to a solution of decyl decanoate hydrochloride (50.2 mg, 0.707 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 17 h and diluted with aq. The mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by preparative HPLC to give ((3)-1-{(23,43)-2-[5-(4,-{2-[(2S,4S)-l-((S)- 2-methoxycarbonylamino-3-mercapto-butenyl)-4- 96 201238961 Methyl-pyrrolidin-2-yl]-1 Η-imidazol-4-ylbuphenyl-4-yl)-1H- Benzimidazol-2-yl]-4-indolyl-pyrrolidine-1-carbonyl-2-mercapto-propyl)-indolyl-amino decanoic acid methyl ester (29.1 mg, 47%). !H NMR (400 MHz, dmso-d6) δ 8.13 (s, 1Η), 7.86 (m, 11H), 7.25 (d, 1H, J = 7.9 Hz), 5.14 (m, 1H), 5.06 (m, 1H) ), 4.38 (m, 1H), 4.08 (m, 3H), 3.66 (m, 3H), 3.51 (s, 3H), 3.35 (m, 2H), 2.72 (m, 3H), 2.45 (m, 4H) , 1.95 (m, 4H), 1.11 (m, 6H), 0.79 (d, 3H, J = 6.7 Hz), 0.73 (m, 9H). LC/MS: m/z = 83 1.67 (M + H + ) 〇 Example 2: N-[(lS)-l-[(2S,4S)-2-[4-[4-[4-[2 -[(2S,4S)-l-[(2S)-2-[methoxycarbonyl(methyl)aminopurin-3-mercapto-butenyl]-4-methyl-pyrrolidin-2-yl b 1H- Benzimidazol-5-yl]phenyl 1 phenyl]-1 Η-imidazol-2-yl]-4-methyl-carzolidine-1-carbonyl b-2-methyl-propyl hydrazide-fluorenyl- Methyl carbazate (.Compound 6):

(2S)-2-[Methoxycarbonyl(indenyl)amino]-3-mercapto-butyric acid (12.8 mg, 0.06765 mmol) and mercapto (S) were cooled in an ice bath under a nitrogen atmosphere. 3-methyl-l-((2S,4S)-4-methyl-2-(6-(4'-(2-((2S,4S)-4-indolyl)pyridine-2- -1Η-imidazole-5-yl)-[1,Γ-biphenyl]-4-yl)-1Η-benzo[d]imidazol-2-ylpyrrolidin-1-yl)-1- side HATU ( 28.3 mg, 0.0744 mmol) and DIPEA (0.035) were added sequentially to a solution of methyl butylbutan-2-yl)carbamate hydrochloride (48.1 mg, 0.0677 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 19 h and diluted with aq. EtOAc EtOAc (EtOAc (EtOAc) Dehydrated with NajSO4, filtered and concentrated to dryness. The residue was purified by reverse phase preparative HPLC to give N-[(lS)-l-[(2S,4S)-2-[4-[4-[4- [2-[(2S,4S) -l-[(2S)-2-[oximeoxycarbonyl(indenyl)amino]]]]]]]]]]]]] -1H-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]-4-indolyl-pyrrolidine-1-carbonyl] -2-Methyl-propyl]-N-decyl-amino ruthenate 曱S (24.4 mg '.41%). 'Η NMR (400 MHz, dmso-d6) δ 7.84 (m, 12H), 5.06 (m, 2H), 4.45 (t, 2H), 4.28 (m, 1H), 4.14 (m, 1H), 4.07 (m, 1H), 3.64 (s, 6H), 3.36 (m, 2H), 2.73 (m, 6H), 2.43 (m, 4H), 1.96 (m, 2H), 1.87 (m, 2H), 1.11 (m, 6H), 0.74 (m, 12H) 〇.LC/MS: m/z = 845.57 (M+H+). Example 3: ((S)-l-((2S,4S)-2-(4_(4,-(2-((2S,4S)-l-((S)-) 2-((Methoxycyclo)amino)-3-methylbutanyl)-4-methyl "Bilobit-2-yl)-3 Η-benzopyrene d] sinyl)-[1, 1'-Biphenyl 4-(Miso-indole-2-yl)-4-methyl*pyrobityl)-3-mercapto-1-yloxybutan-2-yl)(methyl)amine Methyl formate (compound 201238961

Step i: (2S,4S)-2-[4-(4,-{2-[(2S,4S)-l-((S)-2-methoxycarbonylamino-3-indolyl-butanyl) -4-Methyl ratio ° bit-2-yl]-1H-benzomidine-5-yl}-biphenyl-4-yl)-1Η-imidazol-2-yl]-4-indolyl- Pyrrolidine-1-decanoic acid tert-butyl vinegar to (2S,4S)-4-mercapto-2-{4-[4,-(4,4,5,5-tetradecyl-[1,3, 2] Diboronium-2-yl)-biphenyl-4-yl]-1H-imidazol-2-ylpyrrolidine-1-carboxylic acid terpene vinegar (138 mg, 0.2606 mmol), ((S )-l-((2S,4S)-2-(5-峨-1H-benzo[d]imidazol-2-yl)-4-indolylpyrrolidin-1-yl)-3-indolyl-1 -Phenyloxybutan-2-yl)amine decanoic acid formazan (126.2 mg, 0.2606 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (21.3 mg, 0.02606 mmol) in 2-propanol (1.4 mL) A 1 M NaHCO 3 aqueous solution (1.3 mL, 1.3 mmol) was added to the suspension. The reaction mixture was heated at 80 ° C for 19 hours, cooled to room temperature and extracted with a hot air (2×10 mL). The organic layer was filtered through aq. The residue was purified by silica gel flash column chromatography (5% to 100 EtOAc / EtOAc hexane) to afford (2s, 4S)-2-[4-(4'-{2-[(2S, 4S)-l-((S)-2-methoxylaminoamino-3 methyl-butanyl)_4_mercapto-indolyl-2-yl]-1Η-stupidazole-5-yl Biphenyl_4_yl)_1Η_imidazole_2_ 99 201238961 base]_4_mercapto-pyrrolidine-1-decanoic acid tert-butyl ester (75 mg ' 38%)» HPLC :

Waters symmetry shield RP18 3.5 jum 4.6 mmx50 mm 'Solvent A: 0.01% TFA in acetonitrile, solvent B: 0.01% TFA in water' gradient: 15:85 A:B to 90:10 A:B, after 10 minutes, RT= 4.87 minutes. Step II: {(S)-2-Mercapto-l-[(2S,4S)-4-methyl-2-(5-{4,-[2-((2S,4S)-4-methyl) -pyrrolidin-2-yl)-1Η-imidazol-4-yl]-biphenyl-4-yl}-1Η-benzoimidazol-2-yl)-pyrrolidin-1 -carbonyl]-propyl} -Methyl carbazate hydrochloride (2S,4S)-2-[4-(4,-{2-[(2S,4S)-l-((S)-2-indoleoxycarbonylamino- 3-methyl-butanyl)-4-methyl-pyrrolidine-2-yl]-1H-benzimidazole _5-yl}-biphenyl-4-yl)-1Η-imidazol-2-yl]-4 - tert-butyl pyrrolidine-1-decanoate (75 mg '0.0987 mmol) was stirred with 4 M HCl in dioxane (4 mL, 16 mmol). The reaction mixture was stirred at room temperature for 5 hours and concentrated to dryness. The product {(S)-2-methylindolyl-2(5{4,-[2_((2S,4S)-4-indolyl-1pyrrolidin-2-yl)-1Η-imidazole_4_ The base]_biphenyl_4_ ester hydrochloride was used in the next step as it is. }}-1Η·benzimidazole-2_yl)_° ratio biting-W carbon-based]-propyl}-aminocarboxylic acid Step A:

{(s)_2 methyl-1_((SS-l-)-((2S,4S)-2-(4-(&lt;-yl)-3-methylbutanyl) cooled in an ice bath in an ice bath )_4-basic HU'-biphenyl]-4-yl)-3-methyl-1_sideoxy τ under nitrogen atmosphere 100 201238961 [(2S,4S)-4-methyl-2-( 5-{4'-[2-((2S,4S)-4-indolyl-pyrrolidinyl-2-yl)-1Η- °米峻-4 -yl]-biphenyl-4 -yl} -1 η - Stupid and oligo ο -2 -yl)-β ratio ° ° -1 -carbonyl]-propyl-amino decanoate hydrochloride (68 7 mg, 0.0987 mmol) and (2S)-2- Addition of HATU ( 41.25 mg ' 0.1085 mmol) and DIPEA in a solution of [methoxybenzyl (methyl)amino]_3_methyl-butyric acid (18.67 mg ' 0.09867 mmol) in DMF (2 mL·) (3 8.26 mg, 51.56 pL '0.2960 mmol). The mixture was stirred at room temperature for 5 h and diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) Dehydrated by Na2SO4, filtered and concentrated to dryness. Purified residue by flash chromatography (〇0/. to 1 〇% sterol CH2C12 solution) and further by reverse phase preparative HPLC Purified 'get (( S)-l-((2S,4S)-2-(4-(4'-(2-((2S,4S)-l-((S)-2-((methoxy)))) -3-methylbutyryl)-4-methyl-11 ratio. 17 17 _2-yl)-3H-benzo[d]°m-sodium-6-yl)-[1,1·-biphenyl ]-4 -yl)-iH-mimi. sit--2·yl)-4-fluorenyl ° ratio. deuterated-1-yl)-3-mercapto-1-yloxybutan-2-yl)曱 ) 胺 3 3 3 (3 6 mg, 41 % ) NMR (400 MHz, dmso-d6) δ 8.13 (s, iH) 7 88 (m 11H), 7.25 (d, 1H, J = 8.3 Hz), 5.14 (m, 1H), 5 〇 8 (m, iH), 4.37 (m, 1H), 4·13 (m, 2H), 3.64 (s, 3H), 3.51 (s, 3H), 3 4 〇 (m, 3H), 2.72 (s, 3H), 2.48 (m, 4H), 1.93 (m, 4H), ln (m, 6H), 0.76 (m, 12H). LC/MS: m/ z = 831.61 (M+H+) 0 Example 4: ((S)-l-{(2S,4S)-2-[5-(4'-{2_[(2S,4S)-l-((S _2 曱 曱 羰 羰 101 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2·yl]_4_methyl-pyrrolidine 4 —carbonyl}·2—methyl-propyl)-carbamic acid methyl ester (compound 5):

Step I : (2S,4S)-2-(6-(4,-(2-((2S,4S) -1 -(T-butoxy))- 4-methyl ° ratio 0 pyridine-2- -1Η-imidazole-...yl)-^,;!,-biphenyl]-4-yl)-3H-benzo[d]imidazol-2-yl)-4-indolylpyrrolidine_丨_曱Preparation of (2S,4S)-2-(5-iodo-1 oxime-benzimidazole) in isopropanol (31.2mL) /NaHC03 (23.4 mL, 1ΜΗ2〇 solution, 23.40 mni〇l) 2-yl)-4-methylpyridine _ 1 -decyl citrate (2.0 g, 4.68 1 mmol ), (2S,4S)_4-mercapto-2-[4-[4-[ 4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)phenyl]phenyl]_1H•imidazole-2·yl]pyrrolidine_丨· T-butyl formate (2.478 g, 4.681 mmol) and [3-(2-dicyclohexylphosphinoalkyl)-2,4-dioxaxy-phenyl]sulfonyloxy sodium (VPHOS) (183.7 mg, 0.3745 mmol) of the solution' was then degassed for 15 minutes under a stream of n2. After the addition of palladium acetophenoxide (21.02 mg '0.09362 mmol), the solution was heated to 1 ° C for 8 hours under reflux condenser. The puncture mixture was allowed to cool to room 102 201238961 and then diluted with EtOAc (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×1 () mL). The combined organic phases were dehydrated by NazSCU and filtered. The crude residue was purified by a ruthenium dioxide column (50-100% EtO Ac/hexane) to give (2S,4S)-2-(6-(4'-(2-((2S,4S))) -(t-butoxycarbonylmethyl is.pyrrolidin-2-yl)-1Η-imidazol-4-yl)-[ι,ι,_biphenyl]-4-yl)-3H-stupid -2-yl)-4-methylpyrrolidine-1-decanoic acid tert-butyl ester (2.55 g), Rf = 〇3 (EtOAc). 4 NMR (300 MHz, acetone _d6) ό 11.40 (s, 1H ), 11.09 (s 1H), 8.00 - 7.41 (m, 12H), 5.05 (s, 1H), 4.90 (s, 1H), 3.86 (s 2H), 2.99 (d, 2H), 2.39 (ddt, 5H) , 1.90 - 1.75 (m, 1H), i.45 (s 9H), 1.29 _ 1.16 (m, 9H), l.ii (d, 6H). LC/MS: m/z = 703.62 (M+H+) Step 11: 2_((2S,4S)-4-meryl 0 to n each mouth:-2-yl)-6-(4,-(2-((2S,4S)-4-yl). [rhodin-2-yl)-iH-imidazole_4_ylbiphenyl]_4_yl)_3H_stupid [d] in a 100 mL flask, (23,43)_2_(6_(41_(2_(( (23,43)_1(2nd butoxyxopyridinylpyrrolidin-2-yl)-1H-imidazol-4-yl)-[i5l,_Lian]_4_yl)_3H-benzo[d] Imidazolium-2-yl)-4-methyl"pyrrolidine-1-decanoic acid tributylhydrazine (2.55 g ' 3.628 mmol) Solution to CH2C12 (10 mL). Allow the solution to cool to (TC and add HC1 (18 14 mL, 2 〇M, % 28 ° and then forcefully drop the reaction at room temperature to mix 3 〇 * ώ ώ concentrated bath Then, it was dried under high vacuum. The yellow salt (2.353 g) was used for the next reaction without further purification. 103 201238961

Step III ((S)-l-{(2S,4S)-2-[5-(4'-{2-[(2S,4S)-l-((S)-2-methoxycarbonylamino)- 3-mercapto-butyl-based 4-pyridyl-°tt each bite-2_yl]-ΐΗ-β-sodium-4-yl}-biphenyl-4-yl)-1Η-benzox ° sit-2-yl]-4-methyl-indole 〇 〇 - l -l-carbocarbyl 2-mercapto-propyl)-carbamic acid methyl ester in a 100 mL round bottom flask, 2 -((2S,4S)-4-mercaptopyrrolidin-2-yl)-6-(4'-(2-((2S,4S)-4-mercapto]u ratio b) _1H-Min. Sodium-4-yl)-[1,1'-biphenyl]-4-yl)-3H-benzo[d]pyrene ( 2.353 g, 3.628 mmol), (2S)-2- (曱Oxycarbonylamino)·3_decyl-butyric acid (1.589 g, 9.070 mmol) and HATU ( 4.966 g, 13.06 mmol) were combined in DMF ( 25.95 mL), then cooled to 0 ° C. DIPEA (4.889 g, 6.319 mL, 3 6.28 mmol) was added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated and EtOAc (EtOAc) The organics were washed with a saturated aqueous solution of NaHC03 (20 mL) and water (20 mL). The aqueous layer was re-extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude residue was purified by EtOAc (EtOAc (EtOAc:EtOAc) ,43)-2-[5-(4,-{2-[(2S,4S)-l-((S)-2-nonyloxycarbonylamino-3-3-indolyl-butanyl)-4-fluorenyl) -n-r-pyridin-2-yl]-1Η-imidazol-4-yl}-biphenyl-4-yl)-1Η-benzimidazol-2-yl]-4-indenyl ]]·_2-mercapto-propyl)-amino ruthenate 曱 旨 (905 mg, 30%). 'H NMR (400 MHz, dmso-d6) δ 12.29 (m, 1H), 12.02 (m, 1H), 7.73 (m, 12H), 7.23 (m, 2H), 5.02 (m, 1H), 4.91 (m , 1H), 104 201238961 4.10 (m, 4H), 3.51 (br. s, 6H), 3.28 (m, 2H), 3.15 (d, 2H), 2.38 (m, 4H), 1.81 (m, 4H), 1.09 (m, 6H), 0.80 (m, 12H). LC/MS: m/z = 816.99 (M+H+). Example 4 (alternative route) ((8)_1-{(28,48)-2-[5-(4,-{2-[(28,48)-1-((8)-2-methoxy) Carbonylamino-3 -mercapto-butenyl)_4_methyl-0 piroxime_2_yl]-1H-imidol-4-yl}-biphenyl-4-yl)-1Η-benzimidazole _ 2_Kib 4_mercapto-pyrrolidine_1-carbonyl-2-methyl-propyl)-carbamic acid methyl ester (Compound 5):

In a microwave vial, to N-[(lS)-l-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-indolyl-pyrrolidin-1_ Methyl carbonyl]_2-mercapto-propyl]methyl carbamate (52.40 mg, 0.1082 mmol), ((S)-l-((2S,4S)-2-(4-iodo-1H-imidazol-2-) Ethyl)-4-mercaptopurine-i-yl)_3_methyl-1-oxobutan-2-yl) decyl carbamate (47 mg, 0.1082 mmol), [1,1,- a suspension of biphenyl]-4,4,-diyldiboronic acid (26.17 mg '0.1082 mmol), Pd(DPPF)(Cl) 2 .Ci^Ch (4.418 mg, 0.005410 mmol) and 1 mL of 2-propanol 1 M NaHC03 aqueous solution (541.0, 0.5410 mmol) was added. The reaction mixture was stirred at room temperature for 3 minutes and heated by microwave to i5 〇t: for 1 〇 8 hours. The reaction mixture was concentrated to dryness. The residue was purified by silica gel flash column chromatography (Ο% 105 201238961 to 10% decyl alcohol in CHzCl2) and purified by reverse phase preparative HPLC to give ((8)-1-(( 28,43)-2^5-(4, [(2S,4S)-l-((S)-2-indoleoxycarbonylamino-3-indolyl-butanyl)_4_fluorenyl-〇pyrrolidine -2-yl]-1H.imidazol-4-yl}-biphenyl-4-yl)_1H-benzoimin_2·.yl]-4-mercapto-pyrrolidine-1-carbonyl}-2- Mercapto-propyl carbamic acid oxime <12 mg, 25%) LC/MS: m/z = 817.62 (M+H+). Example 5: ((S)-l-{(S)-2 -[5-(4'-{2-[(S)-l-((S)-2-methoxycarbonylamino-3-3-methyl-butanylpyridyl-2-yl]-3H-benzimidazole _5-yl}-biphenyl_4-yl)_1H_imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid A (Compound 4):

Step I: (S)-4-(4,-Mo-[1,1-biphenyl]-4-yl)-2-(.bile-2-yl)-1 Η-β rice saliva at room temperature Search: Mix (S)_2-(4-(4'_--[1,Γ-biphenyl]-4-yl)-1Η-β- oxazol-2-yl). A suspension of beclozol-1-carboxylic acid tert-butyl ester (505 mg 'I.078 mmo1) in Hci (4M diphthene solution, 5.4 mL '21.6 mmol) 2 106 201238961 • hour and diluted with ether (2 mL). The suspension was cooled in an ice bath and the product was collected by passing through to obtain (S) - 4 - ( 4'-au-[1,1 '-biphenyl]_ 4 - Hua·)- 2 - (deuterium ratio) Succinct-2-yl)-1 Η-imidazole hydrochloride (436 mg, 99%). Step II: ((3)-1-((8)-2-(4-(4,-Bromo-[1,1,-biphenyl]-4-yl)-111-imidazol-2-yl)indole The pyridyl-1-yl)-3-methyl-1-oxobutan-2-yl) decanoic acid decanoate is (8)_4-(4'-&gt; [1,1' - do stupid] -4 · - base)_2_ (. than 0 each mouth = 2-base) -1 Η - ° m. Add (2S)-2-(methoxycarbonylamino)-3-indolylbutyric acid (201.5 mg, 1.150 mmol) &gt; in a solution of hydrochloride (423 mg, 1.045 mmol) in DMF (5 mL) DIPEA (405.2 mg &gt; 546.1, 3.135 mmol) and HATH (596.2 mg, 1.568 mmol). The reaction mixture was stirred at room temperature for 2 hr and diluted with saturated aqueous NaHCI (1 mL). The reaction mixture was extracted with EtOAc (5×1 mL) and evaporated and evaporated. The residue was purified by silica gel flash chromatography (2% to 20% methanol in CHjCl2) to afford ((S)-l-((S)-2,(4-(4'_bromo-[1, 1'_ 联笨]_4_ base)_1H imidazolyl).Byrrolidin-1-yl)-3-indol-1-yloxybut-2-yl)amino decanoate (々a mg, 84%). Step III: ((8) small {(SH-PH'-AUS) small ((8)_2_ f oxocarbylaminomethylbutanyl)-t 唆-2-yl] benzophenone. Sitting _5_ base} Benzene_4_基^ 口米峻_2·基]4 洛 bite-W carbon-based M_methyl.propyl)-aminocarbamic acid methyl vinegar to ((8)-W(8)-2-(4-(4,_ Mo,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Mg, 0.1896 mmol ), ((S)-3 -methyl-1-oxo-l-((S)-2-(6-(4,4,5,5-tetramethyl-1,3) ,2-dioxaboronium-2-yl)-311-benzo[(1]imidazol-2-yl)pyrrolidin-1-yl)butan-2-yl)amino decanoate and hydrazine Add 1 M NaHCO03 (0.284 mL, 0.569 mmol) to a suspension of acetonitrile (2 mL) in EtOAc (2 mL). The reaction mixture was heated to EtOAc (3 mL), EtOAc (EtOAc)EtOAc. Chromatography by gel column chromatography (2% to 20% sterol CH2C12 solution) The residue was further purified by reverse phase preparative HPLC to give ((S)-l-{(S)-2-[5-(4'-{2-[(S)-l-((S) -2-oxooxycarbonylamino-3-mercapto-butenyl)-pyrrolidin-2-yl]-3H-benzimidazol-5-yl}-biplex-4-yl)-1Η-imidazole -2-yl]-pyrrolidine-1-carbonylindolyl-propyl)-amino decanoate (30 mg, 19%). *H NMR (400 MHz, dmso-d6) δ 8.13 (s, 1H ), 7.89 (m, 11H), 7.32 (m, 2H), 5.25 (m, 1H), 5.15 (m, 1H), 4.11 (q, 2H, J = 8.2 Hz), 3.93 (m, 2H), 3.85 (m, 2H), 3.52 (s, 6H), 2.42 (m, 2H), 2.16 (m, 4H), 2.04 (m, 4H), 0.82 (d, 6H, J = 6.8 Hz), 0.76 (d, 6H, J = 6.8 Hz) 〇 Example 6: N-[(lS)-l-[(2S,4S)-2-[5-[4-[4-[2-[(2S,4S)-l -[(2S)-2-(methoxycarbonylamino)-3-methyl-butanyl-4-yl-pyrrolidine-2-yl]_1H-benzimidazol-5-yl]phenyl 1phenyl 4-methyl-1H-imidazol-2-yl]-4-methyl-pyrrole 108 201238961 pyridine-1-carbonyl]-2-mercapto-propyl]methylamino decanoate (compound 15) :

Procedure and for ((S)-l-{(2S,4S)-2-[5-(4'-{2-[(2S,4S)-l-((S)-2-methoxycarbonylamino) -3-fluorenyl-butanyl)-4-mercapto-.pyrrolidin-2-yl]-lH-imidazol-4-yl}-biphenyl-4-yl)-1Η-benzoimidazole-2-yl The same is described for the oxime ester of 4-mercapto-pyrrolidine-1-carbonyl}-2-mercapto-propyl)-carbamic acid (Example 4). ]H NMR (400 MHz, CD3OD) δ 7.97 - 7.70 (m, 11Η), 7.69 -7.62 (m5 2H), 5.35 (m,lH), 5.13 (m, 1H), 4.35 (m, 2H), 4.10 ( m, 2H), 3.64 (s, 6H), 3.45 (m,.2H), 2.67-2.40 (m, 4H), 2.40 (s, 3H), 2.05-1.80 (m, 4H), 1.37 (m, 6H) ), 0.95 (m 6H), 0.78 (m, 6H). LC/MS: m/z =495 1.21. (M + H + ). Intermediate: (28,48)-2-(5-(4,-Bromo-[1,1,-biphenyl]-4-yl)-4-indolyl-111-imidazol-2-yl)-4 -methylpyrrolidine-1-carboxylic acid tert-butyl ester:

To (2S,4S)-2-(5-iodo-4-indolyl-1H-imidazol-2-yl)-4-indenylpyrrolidine-1-butyric acid tert-butyl (289 mg, 0.7387 mmol) Add [4_(4-bromophenyl)phenyl] succinic acid (346.7 mg ' 1.252 mmol), K3PO4 (199.3 mg, 0.9389 mmol) in 6 mL of 5:1 曱109 201238961 benzene: decyl alcohol solution. Pd(PPh3)4 (71 _85 mg, 0.06218 mmol). The reaction mixture was heated at 75 ° C for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated to dryness. The residual residue was dissolved in methylene chloride and purified by a flash chromatography (〇_1 0〇/sterol/二气甲院) to obtain (2S,4S)-2- (5-(4,-Bromo-[1,1,-biphenyl]·4-yl)_4-indenyl·1H-imidazol-2-yl)-4-indolylpyrrolidine-1-decanoic acid Butyl ester (160 mg, 0.322 mmol) 0 LC-MS: m/z = 495·········· [4-[2-[(2S)-l-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanyl) II-yl]-1H-benzoimidine_5 -yl]phenyl]-1H-flavored-2-yl]&quot;Bilo biting-1-hexyl]-2-methyl-propyl]carbamic acid methyl ester (Compound 3):

2HCI Step I: (2S)-2-[4-[4-[2-[(2S)Small [(2S)-2-(indolyl))]]]吼 啶 -2- -2- 基 基 基 基 坐 坐 坐 坐 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 (25 mL) meso (2S)_2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]- 111-0 m sal-2-yl] pyrrolidine_1-decanoic acid tert-butyl ester (169 mg, 0.3847 mmol) (refer to w〇2008/021923), ((S)-l-((S)-2 -(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-indolyl-1-oxobutan-2-yl)amino decanoate ( 180.9 mg, 0.3847 mmol) and a solution of Pd(dppf)Cl2-CH2Cl2 (47.13 mg, 0.05771 mmol) in acetonitrile (4 mL). The resulting suspension was heated in an oil bath at 100 ° C for 16 hours, concentrated, diluted with water and CH.sub.2 C.sub.2. The residue was purified using MeOH-EtOAc (EtOAc:EtOAc (EtOAc:EtOAc) 4-[2-[(2S)-l-[(2S)-2-(methoxycarbonylamino)-3-indolyl-butanyl]pyridin-2-yl]-1H-benzimidazole-5 -yl] stupid]-1H-imidazol-2-yl]. Bis-butyl pyridin-1-carboxylic acid (101 mg, 0.1491 mmol, 3 8.75%) ° LC/MS: m/z = 65 ό.55 (Μ + Η +). Step II: 4-(4-(2-((8)-1-((8)-2-((methoxycarbonyl)))))))) 1Η-stupid [d]imidazole _5_yl)phenylpyrrolidine_丨_镔_2_ base)-1Η-imi嗤-3-rust gasification_ to (2S)_2-[4-[4- [2-[(2S)-l-[(2S)-2-(oximeoxycarbonylamino)-3-111 201238961 methyl-butanyl] °bilu. Ding-2-yl]-1 Η-benzo[methane-5-yl]phenyl]·ιΗ-imidazol-2-yl]pyrrolidine-1-decanoic acid tert-butyl ester (1 mg, A solution of HCl (0.15 mmol) in EtOAc (1················ 4-(4-(2-((S)-l-((S)-2-((曱-oxycarbonyl)amino)-3-indolyl)-indolyl)-pyridin-2-yl)-1Η-benzene And [d]imidazol-5-yl)phenyl)-2-((S)-e ratio slightly.-1-lan-2-yl)-1Η-imiline-3-mineral (1〇〇 Mg, 0.15 29 mmo b 100.3%). LC-MS <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Step III: N-[(lS)-l-[(2S)-2-[4-[4-[2-[(2S)-l-[(2S)-2-(indolylamino)) -3-decyl-butanyl]pyridin-2-yl]-1H-benzimidazol-5-yl]pyridyl-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2- Methyl propyl-propyl]carbamate to cold (0-4 ° C) and stirred 4-(4-(2-((S)-l-((S)-2-)) Oxycarbonyl)amino)-3-methylbutanyl).Byrrolidin-2-yl)-1Η-benzo[d]. Sodium-5-yl)phenyl)-2-((S)-吼Ralidine-1-rust-2-yl)-1Η-imidazole-3-rust gas (98.09 mg, 0.15 mmol) and (2S)-2-(methoxycarbonylamino)_3_indolyl_butyric acid (28.91) Mg ' 0.1650 mmol) HATU (85.55 mg, 0.2250 mm 〇l) and DIPEA (116.3 mg, 156.7 pL, 0.9000 mmol) were added sequentially to a light suspension in DMF (1_5 mL). The mixture was slowly warmed to room temperature, stirred overnight, then diluted with water (5 m·L) and extracted with ethyl acetate (3×6 mL). The combined extracts were washed with a saturated aqueous solution of bicarbonate, brine 112 2012. The residue was purified using EtOAc-EtOAc (EtOAc:EtOAc (EtOAc:EtOAc) -2-[4-[4-[2-[(2S)-l-[(2S)-2-(oximeoxycarbonylamino)-3-indolyl]butanyl]pyridin-2-yl]- 1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-reyl]-2-mercapto-propyl]amino decyl decanoate (45 8 mg , 0.06007 mmol, 37.45%). The product was re-purified by reverse phase HPLC to give N-[(lS)-l-[(2S)-2-[4-[4-[2-[(2S)-l-[ 2S)-2-(indolylcarbonylamino)-3-indolyl-butenyl]pyrrolidinyl-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl p Ethrolidine-1-carbonylindolyl-propyl]carbazate (29.6 mg). .H NMR (400 MHz, CD3OD) δ 7.87 - 7.20 (m, 10Η), 5.27 (dd, 1H), 5.17 (dd, 1H), 4.3- 4.2 (m, 2H), 4.12 - 3.8 (m, 5H ), 3.65 (s, 6H), 3.55-3.45 (m, 1H), 2.51 - 1.92 (m, 10H), l.〇2 -0.80 (double peak., 12H). LC/MS: m/z = 713.6 (M + H+). Example 8 N-[(lS)-l-[(2S,5S)-2-[4-[4-[4-[2-[(2S,5S)-l-[2-(methoxycarbonylamine) ))-3-mercapto-butenyl]-5-methyl-pyrrolidinium-2-yl]_1H-benzimidazole _5_yl]phenyl]phenyl]-1H-imidazole_2-yl]-5- Methylpyrrolidinecarbonyldi-2-methyl-propyl]carbamic acid methyl ester (Compound 13): 113 201238961

Step i: (23,58)-2-(4-(4-(4-1:24(28,53)-1-(2-(methoxycarbonylamino).3_methyl-butyl) -5 - mercapto-anthracene bite-2-yl]-1Η - stupid and taste. sit _5_yl]phenyl] stupid]-1Η-miw-2-yl]-5-mercapto- 0 ratio '.1 -1 -carboxylic acid third butyl vinegar ' to (2S,5S)-2-mercapto-5-[4-[4-[4-(4,4,5,5-tetradecyl- 1,3,2-dioxaboron-2-yl)phenyl]phenyl]-1Η-imidazol-2-yl]pyrrolidine-1-decanoic acid Third T^ (180 mg '0.34 mmol), N -[(lS)-l-[(2S,5S)-2-(5-i^-iH- benzoimidazol-2-yl)-5-indolyl-pyrrolidine-1-carbonyl]-2-indole Addition of a mixture of propyl-propyl]amino phthalic acid vinegar (164.7 mg, 0.34 mmol), Pd(dppf)(Cl)2.CH2Cl2 (27.77 mg '0.034 mmol) in 2-propanol (2 ml) Aq. NaHH3 (1 mL, EtOAc, EtOAc, EtOAc (EtOAc) The residue was purified by flash column chromatography (1% to 30% MeOH in EtOAc) 2-[(2S, 5S)_1_[2-(methoxycarbonylamino) -3-mercapto-butenyl]-5-mercaptopyridinyl-2-yl-2-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]-5-fluorenyl 0. Determined __ tert-butyl citrate (97 mg, 37.5%) LC/MS: m/z = 760.5 (M+H+) 114 201238961 Step II: N-[2-methyl_i_ [(2S,5S)_2_ Methyl_5_[4_[4_[4 [2[(2S,5s) 曱 。.Byrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]benzene (j_1H-benzimidazole_2-yl]pyrrolidine-1-carbonyl]propyl]-carbamic acid methyl ester soil toward (2S,5S)-2-[4-[4-[4-[2 -[(2S,5S)-l-[2-(Methoxymethylamino)-3-indolyl-butanyl]_5_indolyl-pyrrolidinyl-2-yl]_1H_benzimidazolyl]benzene a group of phenyl]-1H-imidazol-2-yl] Qiao·methyl-pyrrolidine-丨-carboxylic acid terpene vinegar (97mg, 〇.12mmol) Me〇H(imi) solution card (638. From '4M two hired burning solution 'Ummoi). The reaction mixture was allowed to accumulate at room temperature for 3 hours, and the mixture was concentrated and dehydrated to obtain N-[2-methyl small [(2) 2 曱 5 5 ^ [ [(2S, 5S) )-5-曱基》Bilo bite_2_其]ιττ ΜΗ-imidazole-5-yl]phenyl]phenyl]-1Η-benzopyr-2-yl] 〇比洛嘴,, , The thiol]-propyl]-amino decanoate was used in the next ~~ step without further purification. Step III: N-[(lS)-l-[(2S,5S)-2-[4-[4-[4,h Γ, ^ methoxycarbonylamino)-3-methyl-butanyl]-5 -Methyl-〇tb 匕 各 each pyridine-2-yl]-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl ymethyl-indolyl-1- Methyl carbonyl]_2-mercapto-propyl]carbamic acid methyl ester at 〇 ° C to N-[2-methyl-K "(8) c c., K2S, 5S)-2-methyl_5_[4_[4 -[4_[2_[(2S,5S)-5-decylpyrrolidin-2-ylindole, ΜΗ-imidazol-5-yl]phenyl]phenyl]-1 oxime-benzimidazol-2-yl] Pyrrole. 1 - mercapto] propyl] amino decanoate (88 mg, 〇 · 126 mmol), (2S)-2 rm 匕 methoxycarbonylamino)_3_mercapto-butyric acid

Us 201238961 (22 mg ' 0.126 mmol ) and 2,4,6-trimethyl "Bit (5〇·11 μb 0.38 mmol) in a mixture of DMF (3.5 ml) added hatU ( 52.8 mg, 0.14 mmol ). The reaction mixture was stirred at rt for 5 h then diluted with EtOAc EtOAc. The organic phase was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) N_[(is)- l-[(2S,5S)-2-[4-[4-[4-[2-[(2S,5S)-l-[2-(曱 oxycarbonylamino))]) -butyryl]-5-methyl-~pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-mi-[sodium-2-yl]-5- Methyl ratio slightly bite _1_carbonyl]_2-methyl-propyl]carbazate carbazate (22 mg, 19.9%). *H NMR (400 MHz, CD3OD): δ [ppm] 7.95-7.71 (m* 11H), 7.33-7.26 (m, 1H), 5.21 (m, 1H), 5.12 (m, 1H), 4.13-4.07 ( m, 2H), 3.62 (s, 6H), 2.5 (m, 2H), 2.3-2.25 (m, 4H), 2.01-1.96 (m, 4H), 1.54 (m, 6H), 1.24-1.2 (m, 2H), 0.97 (m, 6H), 0.85 (m, 6H). LC/MS: m/z = 817.5 (M + H + ). Intermediate: N-[(lS)_l-[(2S,5S)-2-(5-Moth-1H-benzo-salt-sodium-2-yl)-5-methyl-mouth Methyl -2-methyl-propyl] methic acid methyl vinegar: 116 201238961

Step i: (2S,5S)-l-[(2S)-2-(methoxycarbonylamino)_3_methyl-butanyl]_5_mercapto_D ratio 0 each bite-2-formic acid S For the cold (0-4C) and stirred (2S,5S)_5_decylpyrrolidinium-pyridin-2-carboxylic acid ethyl acetate (7 g '24.4 mmol) («/· CAem· 2006,49, 3520-3535), (2S)-2-(methoxycarbonylamino)_3_mercaptobutyric acid (45 g, 25.6 mmol) and HATU (9.7 g, 25 6 mm〇1) are called! DIPEA (12.7 mL, 73.3 mmol) was added to the solution in (66 mi). The resulting mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with sodium bicarbonate, brine, dried (Na.sub.2) and concentrated. The residue was purified by ethyl acetate-hexane (3:7 to 4:6) eluting to afford (2S,5S)-l_[ (2S)-2-(Hydroxycarbonylamino)_3_indolyl-butanyl]-5-fluorenyl-pyrrolidine-2-carboxylic acid ethyl ester (5 6 g, 73 〇/〇). LC/MS: m/z = 314.9 (M + H +) ° Step II: (23,5 5)-1-[(23)-2-(methoxycarbonylamino)_3_indolyl-butanyl]_5_ Methyl 0 is slightly more. Ding-2 -formic acid 117 201238961 to cold and stirred (2S,5S)-K[(2S)-2-(methoxycarbonylamino)-3-methyl-butanyl]-5-fluorenyl- To a solution of pyrrolidine-2, ethyl formate (56 g, 17 8 mmol) in ethanol (18 ml) was added a solution of lithium hydroxide monohydrate (17 8 mL '1.7 M, 30.3 mmol). The reaction mixture was stirred at room temperature for $hour. The concentrated reaction mixture was diluted with water and washed with diethyl ether. The aqueous solution was acidified with a 1 N H C1 aqueous solution and extracted with CH.sub.2. The combined extracts were washed with brine <RTI ID=0.0>(</RTI> </RTI> <RTI ID=0.0>(2 </RTI> </RTI> <RTIgt; Base-butenyl]_5_methyl-. Than each bite tannic acid (5 g, 94%). LC/MS: m/z = 286.8 (M + H + ). Step III: N-[(lS)-l-[(2S,5S)-2-(5-A-1H-Benzamidino-2-yl)-5-indenyl ratio 0 bite-1 - Prison ]]-2-methyl-propyl]carbamic acid hydrazine is intended to be cold (0-4 ° C) and stirred 4-iodobenzene-1,2-diamine (1.3 g, 5.3 mmol) and (28,53)-1-[(23)-2-(oximeoxycarbonylamino)_3_indolyl-butanyl]-5-fluorenyl-0 ratio slightly bite-2-carboxylic acid (1.52 g, 4.99 mmol) HATU (2.321 g, 6.103 mmol) and 2,4,6-diindolyl 0 ratio were added sequentially to the solution in DMF (23.8 ml). (l.〇52ml' 7.964 mmol). The reaction mixture was stirred at room temperature overnight and diluted with water &lt The combined extracts were washed with water, aq. The resulting residue which was dissolved in acetic acid (28 ml) was heated at 60 ° C for 8 hr. The acetic acid was removed and the residue was neutralized with saturated NaHC EtOAc (EtOAc) (EtOAc). The aqueous solution was extracted with ethyl acetate. The organic extract was combined with NaHCO3 aqueous solution and brine, and then dried (NajO4) and concentrated. Purification of the concentrate by flash chromatography on Shixia gum using ethyl acetate-hexan (1:1 7 ··3) as an eluent to provide &gt;^-[(18)-1-[( 23,5 3)-2-(5-iodo-111-benzimidazol-2-yl)-5-methyl-pyrrolidine-1-carbonylindole]-2-methyl-propyl]carbamate Vinegar (2.3 g, 2.28 mmol, 92%). 4 NMR (400 MHz, CD3OD, 2:1 of the rotamer), for the main rotamer, δ 8.0 - 7.2 (m, 3H), 5.13 (dd, 1H), 4.78 - 4.70 (m, 1H), 4.2 - 4.1 (m, 1H), 3.64 (s, 3H), 2.8 _ 1.8 (m, 5H), 1.49 (d, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.80 (d , J = 6.8 Hz, 3H). Select the peak of the minor rotamer. 5 48 (m, 1H), 3.58 (s, 3H), 1.205 (d, 3H), 0.99 (t, 6H) 〇 LC/MS: m/z = 484.9 (M+H+). Intermediate: (2S,5S)-2-methyl-5-[4_[4-[4-(4,4,5,5-tetramethyl-1,3,2-digas shed east _2 -yl)phenyl]phenyl]-1H-flavored salicyl-+2-yl]"Biluo bite_i_decanoic acid third D.

Step I: (2S, 5S)-5-fluorenyl. Bilobidine-1,2-didecanoic acid 2_[2_[4_(4-bromophenyl)phenyl]-2-yloxy-ethyl]-1 -t-butyl ester 119 201238961 to 2-bromo- 1-[4-(4-Bromophenyl)phenyl]ethanone (735 3 mg, 2 111111〇1), (23,53)-b-butoxycarbonyl-5-methyl-pyrrolidine_2 DIPEA (3 80 /iL ' 2.18 mmol ) was added to a mixture (suspension) of acetic acid (5 mg, 2. 18 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 3 hr then diluted with EtOAc EtOAc. The organic phase was washed with brine, dried over Na 2 S s 4 and then concentrated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut Birodine·1,2-didecanoic acid 2-[2-[4-(4-indolyl)phenyl]-2-oxo-ethyl]-1-tert-butyl ester (〇·8 g, 76.7%). Step II: (2S,5S)-2-[4-[4-(4-Molyphenyl)phenyl]. Sodium-2-yl]-5-nonylpyrrolidine-1 -decyl citrate to 2-(2-) containing (2S,5S)-5-decylpyrrolidinium ι,2-didecanoic acid [4-(4-Bromophenyl)indolyl]_2_sideoxy-ethyl]1_t-butyl ester (62 mg, 1.23 mmol) of benzene (5.8 ml) was added with ammonium acetate (L9 g) , 24.7 mmol). At 100. The reaction mixture was heated overnight overnight and then diluted with Et EtOAc and HA. The organic phase was washed with brine and dried over NajO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc 1H-imidazol-2-yl]-5-mercaptopyrrolidine-1-decanoic acid tert-butyl ester (43 mg, 72_2%). LC/MS: m/z = 483.9 (M+H+) 〇 Step III: (2S,5S)-2-mercapto-5·[4-[4-[4-(4,4,5,5-four Mercapto-1,3,2-di-boron-boron-dong 120 201238961 -2-yl)phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl vinegar (2S, 5S)-2-[4-[4-(4-Bromophenyl)phenyl]-1H-mito-2-yl]-5-indolyl-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg , 0.37 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)-l , 3,2-dioxane sulphate (2 84 mg, l.llmmol) and Pd(DPPF)(Cl)2.CH2Cl2 (30.47 mg, 0.03731 mmol) in a mixture of DMF (1.800 ml) 1 83 · 1 mg, 1.866 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, dried over Na 2 EtOAc, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) elute [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborium Q-t-yl)phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidine -1 - tert-butyl formate (1 80 mg, 91%). LC/MS: m/z = 530.1 (M + H + ) 〇 Example 9 N-[(lS)-l-[(2S,4S)-2-[4-[4-[2-[2.- [(2S,4S)-l-[(2S)-2-.(曱-oxylamino)-3-methyl-butyl-indenyl]-4-methyl-β-Bilo bite_2_yl iH-stupid imidazolium-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidyl]-2-methyl-propyl]aminocarboxylic acid A g (compound 9): 121 201238961

Step i: (23,43)-2-[4-[4-[2-[2-[(23,43)-1-tert-butoxycarbonyl-4-indenyl]. Specific ratio of each bit-2-yl]_1 benzopyrimidin-5-yl]ethynyl]phenyl bortyrimidazole-2-phenyl]-4-methyl-pyrrolidine _ 1 -decyl citrate To (2S,4S)-2-(5-Moth-1H-Benzam0-Spin-2-yl)-4-methyl-α ratio 0-but-1-butyric acid tert-butyl ester (68.5 mg (23,43)-2-[4-(4-ethynylphenyl)-111-imidyl-2-yl]-4-methylpyridine was added sequentially to a solution of 0.16 mmol) in DMF (3 mL) T-butyl pyridine-1-decanoate (47 mg, 0.13 mm 〇1), Pd(DPPF)(Cl)2.CH2Cl2 (5.4 mg, 0.0067 mmol). The mixture was thoroughly degassed under vacuum and TEA (37 μί, 0.27 mmol) and Cul (1.2 mg, 0.0067 mmol) were sequentially added thereto. It was then searched at room temperature under nitrogen; the reaction mixture was stirred overnight. After the solvent was removed, the crude material was purified by flash chromatography using EtOAc, EtOAc (EtOAc:EtOAc) 2S, 4S)-l - 3 -butoxymethyl-4-indolyl-0 - each. _2 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sitrate _2_yl]-4-methyl-indolyl-1-decanoic acid tert-butyl ester (56 mg, 64%). LC/MS: m/z = 651.41 (M+H+). 122 201238961 Step II: 2-[(2S,4S)-4-indenyl. Bilobidine_2_yl]_5_[2_[4[2[(2S,4S) 4 decylfluoren-2-yl]-1H-imidazole-4-yl]phenyl]ethynyl]_1H_benzo Imidazole hydrochloride to (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-l-t-butoxy-yl-4-methylpyrrolidine-2- (μιH-benzimidazole _5-yl]ethynyl]phenyl]_1H-imidazol-2-yl]-4-methyl-. To a solution of the tert-butyl carbamate (56 mg, 〇 86 mm 〇 1) in methanol (2 mL) was added 4 Μ HC 1 / 2 hexane (430 μί, 1.72 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum to give 2-[(2S,4S)-4-methylpyrrolidine-2-yl]-5_[2_[4-[2_[(2S,4s)_4_methyl) Pyridin-2-yl]-1 η-imidazole_4_yl]phenyl]ethynyl]·丨H_benzoimylidene hydrochloride. The crude material was used directly in the next step. Step III: N_[(lS)-l-[(2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-l-[(2S)-2-(曱) Oxycarbonylamino)-3-mercapto-butenyl]_4•decylpyrrole_2_yl]_1H benzimidazol-5-yl]ethynyl]phenyl]_丨H imidazole_2_yl]_4曱 _ _ pyrrolidine _ 1 _ carbonyl]-2 -methyl-propyl] carbamic acid carbaryl ester to 2_[(2S, 4S)-4-fluorenyl. Bilobidine_2_yl p5_[2_[4_[2[(2S, 4S)-4-methyloxaridin-2-yl]μ1Η_imidazole-4-yl]phenyl]ethynylbenzimidazole hydrochloride (25 mg, 〇〇42 mmol) in DMF (3 mL) solution (2S)-2-(methoxycarbonylamino)_3_methyl-butyric acid (17 6 mg, 0.10 mmol), HATU (39,8 mg, 0.10 mm〇l) and DIPEA (73, 0.42 mmol). The mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, the residue of 123 201238961 was purified by 矽_7% Me〇H/CH 2 Cl 2 by silica gel flash column chromatography, and the main extract was further purified by reverse phase preparative hplc. N-[(lS)-l-[(2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-l-[(2S)-2-(methoxycarbonyl) Amino)-3 -mercapto-butenyl]-4-methylpyrrolidin-2-yl]-1H-benzoimidazole-5-yl]ethynyl]phenyl]-1Η-imidazol-2-yl] Methyl 4-mercapto-indolyl-l-carbonyl]-2-methyl-propyl]carbamate (19 mg, 58.9%). .H NMR (CD3OD, 400 MHz): 7.33-7.66 (m, 8H), 5.03-5.11 (m, 2H), 4.20 (m, 4H), 3.62 (s, 6H), 3.41 (m, 2H), 2.46 (m, 4H), 1.96 (m, 4H), 1.20 (m, 6H), 0.84 (m, 12H). LC/MS: m/z = 651.41 (M+H+). Intermediate: (2S,4S)-2-[4-(4-ethynylphenyl)-1Η-imidazol-2-yl-4-methyl-pyrrolidinic acid tert-butyl ester:

Step I: (2S,4S)-4-methyl-2-[4-[4-(2-tridecyldecylethynyl)phenyl]_1H_imidazol-2-yl]pyrrolidin-1 -decanoic acid a third butyl ester to (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-indenylpyrrolidine tributyl acrylate (150 mg, 0.3976 mmol) and Pd(DPPF)(Cl)2_CH2Cl2 was added sequentially to a solution of [4-(2-trimethylsulfanylethynyl)phenyl]-decanoic acid (130 mg, 0.6 mmol) in isopropanol (3 mL). (16 mg, 0.02 124 201238961 'mmo1) and 2 M NaHC03 (600 pL, 1.2 mmol). The mixture was heated to 85 ° C overnight in a sealed tube. After the reaction, the solvent was removed under reduced pressure and the mixture was stirred. Column chromatography, using 0-5% decyl alcohol / CH2C12 to purify the residue to give (2S,4S)-4-methyl-2-[4-[4-(2-trimethyldecyl ethynyl)benzene -1H-imidazol-2-yl]pyrrolidine-1-furic acid tert-butyl ester (168 mg, 95%) 〇LC/MS: m/z = 423.98 (M+H+). Step II: ( 2S,4S)-2-[4-(4-ethynylphenyl)_1H-imidazol-2-yl]-4-methyl-pyrrolidine•1-tert-butyl tributyl ester to (2S,4S)- 4-. Mercapto-2-[4-[4-(2-tridecyldecylalkylethynyl)phenyl]-1H-. K2C03 (37.2 mg, 0.27 rrnno 1 ) was added to a solution of 2-butyrrolidine-1-decanoic acid tert-butyl ester (57 mg, 0.1346 mmol) in MeOH (2 mL). After removal of the solvent under reduced pressure, the residue was purified eluted with EtOAc EtOAc EtOAc EtOAc EtOAc -1Η-imidazol-2-yl]-4-methyl-pyrrolidin-1 -carboxylic acid tert-butyl ester (47 mg, 99%). H NMR (CD3OD, 400 MHz): 7.33-7.66 (m, 5H) , 4.79 (m 1H), 3.79 (m, 1H), 3.46 (s, 1H), 3.14 (m, 1H)S 2.29-2.46 (m, 2H), 1.70 (m, 1H), 1.09-1.40 (m, 12H). Example 10: N-[(lS)-l-[(2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-l-[(2S)) -2-[曱Oxycarbonyl-(methyl)aminophenyl 3-methyl-butanyl 4_mercapto-Bilo bite_2_ 125 201238961 base]-1H-benzimidazole_5_yl]ethynyl i Phenyl 1H_imidazole_2 keb 4•methyl-pyrrolidine-1-carbonyl]_2_methyl-propyl]_N_methyl-carbamic acid methyl ester (Compound 10):

To 2-[(2S,4S)-4-mercaptopyrrolidinyl-2-yl]-5-[2-[4-[2-[(2S,4S)-4-indolyl)pyrrolidyl]- 1H-isoxazol-4-yl]phenyl]ethynyl]-1H-stuppy. Add (2S)-2-[methoxycarbonyl(indenyl)amino]_3·methyl-butyric acid (24.3 mg ') in a solution of hydrochloride (32 mg, 0.053 mmol) in DMF (3 mL). 0.13 mmol), HATU (51 mg, 0.13 mmol) and DIPEA (93 ML, 0.5 3 mmol). The mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with 0-7% MeOH/CH.sub.2Cl.sub. lS)-l-[(2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-l-[(2S)-2_[曱Oxycarbonylcarbonyl) 3-methyl-butanyl]-4-mercapto-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]- 4-曱基•. Methylpyrrolidine-1-carbonyl]-2-mercapto-propyl]-N-indolyl-carbamic acid methyl ester (20 mg, 45.4%). 'H NMR (CD3OD, 400 MHz): 7.33-7.66 (m, 8H), 4.91- 5 〇9 (m, 2Η), 4.20-4.57 (m, 4H), 3.62 (s, 6H), 3.41 (m, 2H), 2-83 (m, 6H), 1.84-2,60 (m, 8H)} 1.20 (m, 6H), 0.84 (m, 12H) 〇LC/MS: m/z = 793.38 (M+H + ) ° 126 201238961 Example 11: N-[(lS)-l-[(2S,4S)-2-[4]2-[4-[2_[(2S,4S)_l-[(2S)- 2-(methoxycarbonylamino)-3-methyl-butanyl]_4_methyl-pyrrolidine_2-yl b 1H_stupid imidazole-5-yl]phenyl]ethynyl]·1H_imidazole_ 2_yl]_4_methylpyrrolidinylcarbonyl]-2-methyl-propyl]methyl carbamate (Compound 12):

Step I: (2S,4S)-4-methyl-2-[5-[4-(2-trimethyldecylethynyl)phenyl]_1Η·benzimidazol-2-yl]pyrrolidinecarboxylic acid Tributyl ester will be ethynyl-dimethyl-stone (34 44 ^g, 49,55 juL '0.3506 mmol)' (2S'4S)-2-[5-(4-bromophenyl, ^heart benzene And imidazolium-zinc-methylmethyl group was dissolved in anhydrous DMF (2 mL·) than tributyl ketone-1-butyrate (8 ,, 0.1753 mmol), 〇.〇1 753 mmo1). At 70 ° C at

Pd(DPPF)(Cl)2.CH2Cl2 (14.32 (35.48 mg '48.87, 〇·35〇6 mg, 0.01753 mmol), TEA mmol) and Cul (3.339 mg, stirred under N2 overnight. Remove under reduced pressure After the solvent, the residue was purified by silica gel SP1 25M flash column I chromatography using MeOH/cm 2 ( 〇 5%) to afford US, 4S)-. 4-mercapto-2-[5-[4 -(2-tridecylfluorenylethyl 127 201238961 alkynyl)phenyl]-1H-benzoimidazol-2-yl]pyrrolidine-1-furic acid tert-butyl ester (40 mg). LC/MS: m/z = 474.15 (M+H+) ° Step II: (2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-l-3rd Oxycarbonyl-4-indenyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]ethynyl]-1H-imidazol-2-yl]-4-indolyl-pyrrolidine- The fully degassed (2S,4S)-2-(4-iodo-1H-°m2-pyridin-2-yl)-4-indole at 70 ° C under N2 at 70 ° C Base - 〇 比 slightly. Ding-1-carboxylic acid tert-butylate (38.21 mg, 0.1013 mmol), (2S,4S)-4-mercapto-2-[5-[4-(2-tridecyldecylalkylethynyl)phenyl] -1H-benzimidazol-2-yl]pyrrolidine-1-furic acid tert-butyl ester (40 mg « 0.08444 mmol) &gt; Pd(DPPF)(Cl)2.CH2Cl2 ( 6.896 mg &gt; 0.008444 mmol), A solution of Cul ( 3.217 mg, 0.01 689 mmol) &lt;RTI ID=0.0&gt;&gt; After removing the solvent under reduced pressure, the residue was purified by silica gel flash chromatography using EtOAc (EtOAc) (EtOAc) (EtOAc) (2s 4S)-1-tert-butoxycarbonyl_4_fluorenyl-pyrrolidinyl-2-yl]_1H benzoimidazole·5_yl]phenyl]ethynyl]-lH-imidazole·2_yl]_4_ Mercapto-pyrrolidine-decanoic acid third vinegar (34 mg, 61.8% yield). LC/MS: m/z = 651 42 (^η + ): Step III: 2-[(2S,4S)-4-methyl-n-pyrrolidine-2-yl]5_[4 [2 [2_[(23) ,48)^methylpyrrolidin-2-yl]-1H-imidinyl]ethynyl]phenyl]_丨η stupid imidazole 128 201238961 The third butoxycarbonyl _4_ 曱 base each bite -2 -yl]-m-benzopyrimidin-5-yl]phenyl]ethynyl]_1 astringent. Sodium 2-ylindole-mercapto-pyrrolidine q•carboxylic acid tert-butyl ester (28 mg, 〇〇43〇2 mm〇1) was dissolved in methanol (2 mL) and then hci (i〇7.6 A was added thereto) , 4M, 0.4302 mmol). Mix the mixture overnight at room temperature. The solvent was removed under vacuum to give 2-[(2S,4S)-4-methylpyrrolidine-2-yl]_5_[4_[2-[2-[(2S,4S)-4-mercaptopyrrole Pyridin-2-yl]-1H-imidazole-4-yl]ethynyl]phenyl]-1H-benzimidazole, which was used as it is in the next step. Step IV: N-[(lS)-l-[(2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-l-[(2S)-2-) Oxygen

Ik-aminoamino)-3-indolyl-butyl-aryl]-4-mercapto-indenyl] each bite_2_yl]_ih-benzo. Mizozol-5-yl]phenyl]ethynyl]_ιη_imidazole_2_yl]_4_mercaptopurine carbonyl]-2-methyl-propyl]carbamic acid formazan is intended for room temperature (2S)-2-(methoxycarbonylamino)_3_methyl-butyric acid (19 〇9 mg ' 0.1090 mmol ), 2-[(2S,4S)-4-mercaptopyrrolidin-2-yl ]-5-[4-[2- [2-[(2S,4S)-4-indenyl). Biloxidin-2-yl]-1H-imidazol-4-yl]ethynyl]phenyl]-1H-benzimidazole (26 mg, 0.04359 mmol), HATU (41.45 mg, 0.1090 mmol) and DIPEA (56.34 mg) , 75.93 ML, 0.4359 mmol) The solution in DMF (2 mL) was stirred overnight. After removal of the solvent, the crude material was purified using EtOAc EtOAc EtOAc. Further purifying the main extract by reverse phase preparative HPLC to obtain a white solid ί 曱 曱 胺 胺 -3- -3- -3- -3- ] ] ] ] ] ] ] ] 苯 苯 苯 苯 苯Imidazol-5-yl]phenyl]ethynyl]_1Η_imidazole_2_yl]_4_methyl_D ratio biting 129 201238961 -1-carbonyl]-2-mercaptopropyl] carbamic acid methyl ester (18 mg, 53% yield). NMR NMR (CD3OD, 400 MHz): 7.51-7.66 (m, 8H), 4.92. 5.15 (m, 2H), 4.20 (m, 4H), 3.62 (s, 6H), 3.41 (m, 2H), 2.46 ( m, 4H), 1.96 (m, 4H), 1.20 (m, 6H), 0.84 (m, 12H) 〇LC/MS: m/z = 765.53 (M+H+). Example 12: 1\-[(18)-1-[(28,48)-2-[4-[5-[2-[(28,48)-1-[(28)-2-) Oxidylamino)-3-methyl-butanyl]-4-methyl-pyrrolidinyl-2-yl]-1H-benzo-saltyl]thieno[3,2-b]thiophen-2-yl -1H-imidazol-2-yl]-4-methyl-pyridin-1-carbonyl]-2-methyl-propyl]methyl carbamate (Compound 16):

N-[(lS)-l-[(2S,4S)-2-(4-Iodom. sit-2-yl)-4-methyl-α ratio to degassing (vacuum/blowing) π定-1-Rexyl]-2-mercapto-propyl]carbazylcarbamate (153.5 mg, 0.3347 mmol), N-[(lS)-l-[(2S,4S)-2-(5 -Iodo-1 oxime-benzimidazol-2-yl)-4-indolylpyrrolidine-1-carbonyl]-2-mercapto-propyl]carbamic acid methyl ester (162.1 mg, 0.3347 mmol), 4 ,4,5,5-tetradecyl-2-[5-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)thieno[3, 2-b]thiophen-2-yl]-1,3,2-dioxaborondong (125 mg, 0.3188 mmol) and K2C〇3 (220.3 mg, 1.594 mmol) in degassed isopropanol (3.750 130) [3-(2-Dicyclohexylphosphinoalkyl)-2,4-didecyloxy-phenyl]sulfonic acid sodium (VPHOS) was added to the mixture of 201238961 mL) and H20 (1.250 mL). (13.07 mg, 0.02550 mmol) and Pd(OAc) 2 ( 1.431 mg, 0.006376 mmol). After degassing twice, the reaction mixture was heated at 90 ° C for 16 hours, then diluted with ethyl acetate (30 mL). The aqueous solution was discarded, and the organic solution was washed with water and brine, dried (Na 2 SO 4 ) and concentrated. The residue was purified by chromatography on silica gel eluting with EtOAc to EtOAc EtOAc (EtOAc:EtOAc) The desired compound was isolated by reverse phase preparative HPLC to give N-[(lS)-l-[(2S,4S)-2-[4-[5-[2-[(2S,4S) )-l-[(2S)-2-(methoxycarbonylamino)-3-indolyl-butanyl]-4-mercaptobipyridine-2-yl]-1H-benzimidazol-5-yl]嚷-[3,2-b]°cephen-2-yl]-1Η-imi嗤-2-yl]-4-mercaptopyrrolidine D-1,4-methyl-1-methyl-propion Methylamino decanoate (34.4 mg). *H NMR (400 MHz, CD3OD) δ 7.8 - 7.2 (m, 6Η), 5.14 (dd, 1H)S 5.02 (dd, 1H), 4.29 (t, 1H), 4.25 - 4.18 (m, 3H), 3.64 (s, 3H), 3.49 - 3.36 (m, 2H), 2.66 - 2.26 (m, 4 H), 2.09 - 1.80 (m, 4H), 1.21 (d, 3H), 1.19 (d, 3H), 0.95 - 0.89 (m, 6H), 0.87 (d, 3H), 0.835 (d, 3 H). LC/MS: m/z = 803.34 (M+H+). Intermediate: (2S)-2-(4-(4'-bromo-[1,1,-biphenyl-4-yl)_1H-imidazol-2-yl)pyrrolidine small tert-butyl formate: 131 201238961

Step i: (2S, 4S) -4-methyl 〇 〇 each bite -1,2_di-f-acid 2_(2_(4, 联 苯 心)-2_ ethoxyethyl) 1 - third Butyl ester to 2-bromo-l-[4-(4-bromophenyl)phenyl]ethyl (759, 丨 897 mmol) and (2S)-1-tert-butoxycarbonyl. Bilo. Add 〇ιρΕΑ (29〇 8 mg, 392 #, 2.25 mm〇1) to a solution of 2-1 carboxylic acid (484 3 °, 2.25 mmol) in acetonitrile (7.5 mL). The reaction mixture was stirred at room temperature for 2 hours and washed with brine (3×5 mL). The organic layer was concentrated to dryness. The residue was diluted with toluene (5 mL) and evaporated to dryness. 2-(2-(4,-bromobiphenyl-4-yl)-.2_ethyloxyethyl tert-butyl phthalate (855 mg, 93%) was used in the next step. Step II: (2S)_2_(4_(4'-moly-[1,!'-biphenyl]_4_yl)·1Η_isoxazole_2_pyrrolidine citrate tartrate to 2S , 4S)-4-methyl. Specific bite · 1 &gt; 2_ dicarboxylic acid 2_(2_(4, 联 苯_心基)-2- oxoethyl) 1-tert-butyl ester ( 855 mg Add ammonium acetate (2 699 g, 35 〇2 _〇1) to a solution of toluene (8 mL) in i 751 _〇1). Heat the reaction mixture at 100 C for 24 hours, cool to room temperature, and use water (^ 〇mL) diluted. The layers were separated and the aqueous layer was extracted with Et EtOAc (1 mL) and the combined organic layer was dehydrated with Nasser, filtered and concentrated to dryness. 矽 鱼 132 132 201238961 • 骤 column chromatography (6%) The residue was purified to 80% EtOAc in hexanes to afford (2S)-2-(4-(4'-bromo-[1,1--biphenyl]-4-yl)-1H-imidazole-2 Base Triacyl 1 - decanoic acid tert-butyl ester (5 11 mg, 62%). Intermediate 4,4,5,5-tetramethyl-2-[5-(4,4,5,5-tetra Methyl-1,3,2-dioxaboronic acid _2 base) porphin [3,2-b] sultin-2-yl]-1,3,2-dioxypyridinium π:

i U. /U At a temperature of -78 ° C, a solution of thieno[3,2_b]thiophene (丨5 g with 〇1) in THF (25.5 mL) was added dropwise to a solution of 8.9 (1.888). mL, 2.5 M, 22.47 mm 〇 1), mix for 2 minutes, replace the cooling bath with an ice bath and search for 50 minutes. The resulting thick suspension was quenched with 2_isopropoxy[4,4,5,5tetradecyl-1,3,2-dioxane D East (4.181 g, 4.584 mL, 22.47 mmol). Capturing the θ pain ^ The reaction mixture was kept overnight, followed by a saturated aqueous NH4C1 solution. After extracting with CH2Cl2 (2×10 mL), the combined extracts were washed with brine and dehydrated (Na2S〇4)e. The organic solution was diluted with about 20' of ethyl acetate, and concentrated slowly on the 旌 chain 任 任 任 直至 直至 直至 直至Except CH2CI2. Mistakes collected by the ff · 曰 / / / 3⁄4 I* should be collected white fine crystals. Washing with heptane

The body was cut and examined under high vacuum, and P was passed to 4,4,5,5-tetramethyl-2-[5-(4,4,5,5-tetramethyl) which was a semi-white solid. 2 q soil-,3,2-dioxaboron oxime _2_yl)thieno[3,2_b thiophen-2-yl]-1,3,2-dioxaboronic asper [2.57g, 6.554mmol, 6 1.2 5%). H NMR (400 MHz rnm n ^

Zj CDC13)S7.75 (s,2H)5 1.343 (s,12H) 〇 133 201238961 Intermediate (2S)-2-(methoxycarbonylamino)_3-methyl-butyric acid:

H^^COOH

L-Proline (140 g, 1.1 95 mol) was added to a stirred 1 NaOH solution (1.183 L, 1.183 mol). After complete dissolution, sodium carbonate (65.8 g, 621.4 mmol) and methyl decanoate (122 g '99.75 mL, 1.291 mol) were sequentially added over 40 minutes under 〇C. The reaction mixture was stirred at room temperature for 3.5 hours, then washed with diethyl ether (3×200 ml). The aqueous layer was cooled to 0 C and acidified to pH 1-2. The white solid formed by hydrazine on Buchner was washed with cold water and dehydrated to give the title compound (2j </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Intermediate (2S)-2-indole methoxycarbonyl (methyl)amino] _3·methyl-butyric acid:

(2S)-3-Mercapto-2-mercaptoamino-butyric acid (5 g, 38.12 mmol) was added to a stirred sodium hydroxide solution (76.2 mL, 1 Μ, 76.24 mm 〇1). After complete dissolution, sodium carbonate (2.1 g, 19.82 mmol) and methyl decanoate (3.18 mL, 41.17 mm 〇〇) were sequentially added at 〇 ° C for 40 minutes. The reaction mixture was stirred at room temperature 134 201238961 ' After an hour, it was washed with diethyl ether (2x7S, .mL). The aqueous layer was cooled to 〇 ° C, acidified to pH 1-2 and taken with CH2C1 and then taken up. The organic phase was dehydrated with MgSCU, filtered and concentrated to dryness. The title compound (2S)-2-[methoxycarbonyl(methyl)amino][3]methyl-butyric acid (5 12 g, 71%) is obtained as an oil. Intermediate iodine-1H-imidazole _ 2_yl)_4_methyl-〇pyrrolidine-1-carbonyl]-2-methyl-propyl]amino decanoate:

Step I: (2S)-i-t-butoxycarbonyl-4-methyl-pyridinium-2-indole acid purifies (2S)-1-tert-butoxycarbonyl-4_indenyl group under &amp; A solution of _0 bromididine-2-carboxylic acid (25 g, 11 mmol) in decyl alcohol or ethanol (25 mL) was then added <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; The solution was again purged with vacuum and H2 and the process was repeated twice. The reaction mixture was then stirred under an atmosphere of hydrogen 135 201238961 for 20 hours. The reaction mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated to dryness to afford (2 s) _ _ 2 butyloxycarbonyl-4-methyl-pyrrolidine 2 - decanoic acid as a white solid ( 24 9 g, 98.70 / 〇) (a cis / trans mixture of about 80 / 20 ratio). Step II: (2S)-2-(transmethylmethyl)-4-methyl ratio η each bite _ι_ decanoic acid third butyl is aimed at 〇°C down (2S)-1-third butoxide A solution of 1 M boron pit in THF (243.6 mL, 243.6 mmol) was added to a solution of carbonyl <RTI ID=0.0># </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NH4C1 (50 mL) was then carefully added (drip), then h20 (100 mL). The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel flash chromatography ( EtOAc EtOAc EtOAc EtOAc Tributyl ester (23.5 g, 94%). Step III: (2S)-2-mercapto-4-indenyl abbreviated-i_carboxylic acid tert-butyl vinegar. DMSO (90.69 mL, 1.28 mol) was added to a solution of ethylene dioxide (319.4 mL, 2 Μ, 63 8.8 mmol) in CH2C12 ( 460 mL) over 30 min, maintaining an internal temperature of -60 °C. Next, (2S)-2-(hydroxyindenyl)-4-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester (55 g, 25 5.5 mmol) of CH2C12 (460) was added at -78 °C over 50 min. mL) solution. The reaction mixture was stirred for 20 min then DIPEA ( 445 mL, 2.55 mol). The reaction mixture was stirred at 136 201238961 • -78 ° C for 2 hours and allowed to warm to room temperature over 2 hours. To this mixture A was slowly added i N HC1 (800 mL). After the charcoal is removed, the organic phase is separated, dried over Na2SO4, filtered and concentrated to dry. The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc EtOAc _丨_T-butyl formate (48 5 g, 227.4 mmol, 85%) (77/23 cis/trans mixture). Step IV: (2S)-2-(lH-imidazol-2-yl)-4-indenylpyrylene-1-carboxylic acid tert-butyl to a stirred (2S)-2-mercapto-4- To a solution of decyl-pyrrolidine hydrazine-tert-butyl formate (45 g, 211 mmol) in MeOH (90 mL) EtOAc (EtOAc) Glyoxal (85.6 g, 67.7 mL, 40 〇/〇w/v, 466 7 mmol) was added in portions (exothermic reaction). The reaction mixture was stirred at room temperature overnight, diluted with h.sub.2 (30.sup.11.11) and extracted with (:112 (:12 &lt;&lt;&gt;&gt;&lt; The combined organic layers were washed with EtOAc EtOAc (EtOAc m. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut elut elut elut -methyl-pyrrolidine-1-carboxylic acid main butyl ester (33.67 2, Ο 63.5%). 4 NMR (400 MHz, dmso-d6, a mixture of cis and trans isomers and their rotamers) 511.71 (8, 1 printed, 6.85 (8, 211), 4.86-4.58 (m, 2 Η), 3.75-3.5 (m, 2 Η), 3.03 - 2.82 (m, 2 Η), 2 36 137 201238961 2 25 (m , 1 H), 2.25 - 2.U (m, 1 H), 1.6-1.45 (m, 1 H), 1.39. (S, minor isomer of the minor isomer), ! 37 (s , the minor isomer of the major isomer, K15 (the main rotation of the s' minor isomer) Isomer), 1.09 (the main rotamer of the s' major isomer) 〇〇5 (d, minor isomer) 0.99 (d, major isomer) Step V: (2S, 4S) -2-(4,5-diindole-1H-0 to "if?, / n氺 _2_yl)-4-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester at 5 ° C Add to the stirred solution of (2S) 2-(1H imidazo-2-yl)-4-methylpyrrolic acid tert-butyl ester (36.6 g, 145.6 mmol) in CH2Cl2 (366.0 mL) over 15 min. Iopyrrolidine 2,5-dione (68.80 g '305.8 mmol). After 1 hour, add 1% sodium thiosulfate solution (800 ml). After stirring for 1 minute, the organic phase was separated and washed with water. Na2S〇4 dehydrated 'filtered and evaporated to dryness. The crude material was purified by silica gel column chromatography (% to 50% EtOAc in hexane) to afford (2S, 4s) 1H-Mic. Sodium-2-yl)-4-merylpyrrolidine tert-butyl citrate (52.3 g, 65.7%)) NMR (400 MHz, dmso-cl6, 2.5 of rotamer: 1 mixed compound), the peak of the main rotamer, δ 12.70 (s, 1 H), 4.57 (dd, 1 H), 3.62 - 3.52 (m, 1 Η), 2.95 (t, 1 H) 2.35 - 2.0 (m, 2 H), 1.50 (dd, 1 H), 1.10 (s, 9 H), 1.01 (d, 3 H). (2S,4R)-2-(4,5-Diiodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-furic acid tert-butyl ester (10.5 g, 13%) ). 4 NMR (400 MHz, dmso-d6, rotamer i.2:1 mixed 138 201238961), peak of the main rotamer, δ 12 65 (br s, 丨Η), 4 69 (Μ, H), 3.69 - 3.50 (m, 1 H), 2.82 (t, 1 H), 2.45-2.3 (m, 1 H), 1.91 1.68 (m, 2 H), 1.15 (s, 9 H), 0.97 (d, 6.6 Hz, 3 H). Select the peak of the minor rotamer: 4 77 (d), i 38 (s). Step 乂1: (23,48)-2-(4-Broken-111-.mazole-2-yl)_4_methyl-0-byridine_1-carboxylic acid tert-butyl ester LiCl in THF solution (3 9 mL, 〇5 M solution, i 99 ugly (1) added to (2S,4S)-2-(4,5-diiodo-1H-imidazolyl)_4_fluorenyl _o-pyrrolidine 1 _ A夂Second butyl ester (1 g, 1.99 mmol). After stirring at room temperature, the reaction mixture was cooled to _2 〇〇c and a solution of hydrazine-based magnesium in THF was added dropwise (946.7 /xL). ' 2.1 Μ, 1.99 mmol). After stirring for 2 minutes at -2 (after 20 minutes of TC), add a solution of vaporized isopropyl magnesium in thf (3.2 mL, 1 ·24 Μ '3 _97 mmol). Slow the reaction mixture. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to EtOAc and saturated nh 4 s water / s. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 4-iodo-1H-imidazol-2-yl)-4-mercapto-pyrrolidine-i-decanoic acid tert-butyl ester 636 mg, 83%) 4 NMR (400 MHz, dmso-d6, 2:1 mixture of rotamers), peak of major rotamer, δ 12.15 (s, 1 H), 7.19 (s, 1) H), 4.65 - 4.57 (m,1 Η), 3.65 - 3.55 (m,1 Η), 2.95 (t,1 Η), 2·4-2.1 (m,2 H), 1.52 (dd,1 H) , 1.10 (s, 9 H), 1.00 (d, 3 139 201238961) Select the peak of the isomer, 0.29 (s), 7.15 (s), 1.36 (s). Step VII: in the form of the hydrochloride Sodium 4-bromo-2-[(2S,4S)-4-mercaptopyrrolidinyl-2-yl]-1H- (2S,4s)_2-(4-iodo-1H- at 0 C Imidazol-2-yl)-4-indenylpyrrolidine-1-carboxylic acid flurethane-dibutyl ester (1.6 g, 4.242 mmol) in MeOH (16 mL):, plus 4 M HC1 in the second hospital solution (niL The reaction mixture was scrambled overnight at room temperature and evaporated to dryness to give 4- iodine 2 as a yellow solid. [(2S,4S)-4-methylpyrroles. Saliva (j 37 g, 92 5%) H NMR (400 MHz, dmso-d6) δ 9.98 (br s, 1 Η), 9.17 (br s, 1 H), 7.46 (s, 1 H), 4.8- (4.6, m) , 3 H). Step VIII: 1^-[(18)-1-[(23,43)-2-(4-峨-111-Imidazot-2-yl)_4-methyl-pyrrolidine-1-carbonyl]-2- Methyl-propyl]carbazinate. Add HATU (1.4 g, 3.68 mmol) to a solution of (2S)-2-(indolylamino)-3-mercaptobutyric acid (6445 mg ' 3.68 mmol) in DMF (25 mL). DIPEA (2.5 mL ' 14.57 mmol) in the form of the hydrochloride salt of 4-iodo-2-[(2S,4S)-4-mercaptopyrrolidine-2-yl]. Sit (1.28 g ' 3.64 mmol). The reaction mixture was stirred at room temperature for 2 hrs then diluted with EtOAc &EtOAc. The organic phase was separated, washed with h.sub.2, and then filtered and evaporated from Na.sub.2. By Shi Xijiao sudden tube j main, . _ analysis (〇% to 1〇〇〇/„

The residue was purified to give a white solid: N-[(lS)-l-[(2S,4S)-2-(4-iodo-1H-imidazol-2-yl) 4 methyl -. Specific absorption of α-carbonyl-1-carbonyl]-2-mercapto-propyl]carbamic acid decyl ester (1 i &amp; 疋 • g, 87.3%) 〇!H NMR (400 MHz, dmso-d6) δ 12. 〇3 ( U, 1 H), 7.19 (d 1 H), 7.18 (s, 1 H), 4.83 (dd, 1 H), 4.16 - 3 , 1 2 H) 3 59 ( 3 H), 3.16 (t , 1 H), 2.38-2.08 (m, 2 Η) i ' · (S, '1 -72 (mi H)

1.72-1.61 (m, 1 H), 1.06 (d, 3 H), 0.76 (d. T H). , 3H), 〇.755 (m, 3 intermediate N-[(lS)_l-[(2S,4S)-2-(5-iodo-1H-imidazole-2_ 篡, -1-yl)-2 _Methyl-propyl]carbamic acid methyl vinegar:

Mold

Step I (2S)-4 -Methyl-2-(4-mercapto-1H-methane. Sodium-2-ylpyrene) is more stirred than the pyridin-1-decanoic acid tert-butylate 2S)-2-mercapto-4-indenyl ομμ Λ 比, pyrrolidine-1-decanoic acid tributyl hydrazine (282 mg, 1.322 mmol) Me〇H fs I 5,6 mL) solution To -20 ° C and bubbling with gaseous ammonia for 10 minutes. Add 1 'Sideoxypropanol (3 5 % w/w aqueous solution, 1.905 g, 9.254 mmol) and the girl, 'two hours to warm the reaction mixture to room temperature ^ then add the mixture to ", after 65 C The mixture was concentrated for 1 hour, 141 201238961. (〇〇/. to 20% MeOH in CH2C12) Purify the residue to give (2S)-4-methyl-2-(4-methyl-1H-imidazol-2-yl)pyrrolidine-1 -decanoic acid Third butyl ester (307 mg, 88%). Step II · (2S,4S)-2-(5-indole-4-methyl-1H-0m0-n-yl)-4-fluorenyl- More than 1» each. _1·carboxylic acid tert-butyl ester. At 5 C under tax (2S)-4-mercapto- 2- (4-methyl-1H-d m α sit - 2 · * Base) 0 Add N-iodobutanediimide (240 mg, lo i 3 mmol) to a solution of tributyl ketone 1-benzoate (307 mg, 1.013 mmol) in CH2C12 (15 mL). The reaction mixture was stirred for 1 hour and water (2 mL) was added. The organic layer was separated from NaeO4 and evaporated to dryness. Chromatography (12% to 100% EtOAc in hexanes) Base-pyrrolidine·dicarboxylic acid tert-butyl ester (246 mg, 62%). Intermediate (S)-2-(5-iodo-1H-benzimidazol-2-yl)-pyrrolidine-1-carboxylic acid Three Ding

X0 To a dry 1000 mL round bottom flask was added 4-A-stup-1 2 diamine (45 g), (S)-pyrrolidine-1,2-didecanoate 1-tributyl ester under nitrogen. 41.39 g) 142 201238961 and THF (450. Mix the reaction mixture until complete dissolution followed by cold P to 0 2 c DIPEA (5〇17 mi) was added dropwise to control the exotherm, followed by the addition of HATU (8G.38 g). The mixture was reacted for 3 hours in ice (4) and then subjected to HPLC to monitor the completion of the reaction. To this solution was added 500 ml of water and · ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate: two. The organic phase was combined and evaporated. Drop one 丨. Add 45 〇... acetic acid to the 相 phase and evaporate the mixture to 300 m. This procedure is repeated 3. times, the residue is about 47 〇, then the mixture is heated at 5 (TC) overnight. Add toluene (2 〇〇μ ) and evaporate at least the residue (repeated 6 times). Add 45 〇W B = ethyl ester to this solution. Wash the organic phase with saturated sodium carbonate 'dehydrated with sodium sulfate, filter the hair to dry. (2)_2_(5_iodine_1) was obtained as a beige powder using a 25% ethyl acetate/hexane mixture to purify the residue. 11_Stupid and succinyl-2-yl)-pyrrolidine-indole-carboxylic acid tert-butyl ester (67 g). 'H NMR (400 MHz, CD3OD): δ [ppm] 8.0-7.7 (bs, 1 H) (7.5, m) , 1 H), 2.2-1.8 (m, 3 H), i 4 (s, 3 H), 1.1 (s, 6 H) LC/MS: m/z = 413.95 (M + H+). Intermediate (2S , 4S)-2-(5-Moth-1H-stupid [d]-sodium-2-yl)-4-mercapto® piroxicamperic acid tert-butyl ester (1) and (2S,4R)-2 -(5-iodo-1H-benzo[d]imidazolium-2-yl), 4 methylpyrrolidine-1-decanoic acid tert-butyl ester (2): 143 201238961

Will (2SM-Tertioxetyl·4_methylpyridine each bite _2-pyrrolidine-2-carboxylic acid (880

Heat to 50 ° C overnight. The AcOH 10 mL AcOH was removed under vacuum under vacuum. After addition, the residue was purified by silica gel chromatography (0 - 50% ethyl acetate / hexane) to give the trans compound 2 (2S, 4R) -2-(5-峨-1H-iso-α-sial-2-yl)-4·_mercapto-u ratio p each bite_ι_ decanoate (260 mg, 15%). NMR (400 MHz, CD3OD) δ 7.85 (d, 1 Η), 7.49 (dt, 1H), 7.31 (d, 1H), 4.98 (m, 1H), 3.90 (m, 1H), 3.04 (dt, 1H), 2.48 (dd, 1H), 2.25 - 1.94 (m, 2H), 1.47 (d, 3H), 1.08 (s, 9H). Further elution gave cis compound 1 (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-indolyl-pyrrolidine-1-furic acid tert-butyl ester (1.38) g, 84%).屯NMR (400 MHz, CD3OD) δ 7.82 (d, 1H), 7.49 (m, 1H), 7.31 (d, 1H), 4.90 (m, 1H), 3.82 (m, 1H), 3.15 (t, 1H) , 2.55 (m, 1H), 2.36 (m, 1H), 1.40 (d, 3H), 1.08 (s, 9H). 5. Iodide-2-((2S,4S)-4-methylpyrrolidin-2-yl)-1Η-benzo[d]imidazole:

144 201238961 White jade mixed (2S,4S)_2-(5_峨-1H-benzopyrene) sit-2-yl)·4_mercapto-pyrrolidine-1_carboxylic acid tert-butyl ester (3.70 g To a solution of 8.659 mmol) of dichlorohydrin (34 mL·), TFA (17·22 mL, 223.5 mm 〇1) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, azeotroped twice with toluene and dried in vacuo. The residue was diluted with dioxane (200 mL) and washed with sat. NaH. The organic matter was evaporated to give 5-iodo-2_[(23,43)_4_decylpyrrolidinium-2-yl]-lH benzoimidine. Sit (2.32 g, 82%). (S)-l-((2S,4S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4-indolylpyrrole-1-yl)-3-methyl · ι_Sideoxybut-2-ylaminocarbamate:

5-Iodo-2-[(2S,4S)-4-indolylpyrrolidin-2-yl]-1Η-stupidimidazole (2.29 g, 7.00 mmol) and (2S)-2- at room temperature HATU (3.46 g, 9.1 mmol) and DIPE.A (2.4 mL, 14.0 mmol) were added to &lt;RTI ID=0.0&gt;0&gt; The reaction mixture was stirred overnight at room/JSL. Water (350 mL) was added to the reaction mixture under rapid mixing, followed by a white solid. The solid was filtered off with suction and dried under vacuum to give <RTI ID=0.0>#</RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Pyridylcarbonyl]_2-methyl-propyl]amino decanoate (2.73 g, 81%) 〇145 201238961 'H NMR (400 MHz, CD3OD) δ 7.83 (d, 1H), 7.49 (dd, 1H ), 7.29 (d, 1H), 5.09 (dd, 1H), 4.31 - 4.15 (m, 2H), 3.59 (s, 6H), 2.54 (m, 1H), 2.43 (m, 1H), 2.00-1.90 ( m, 2H), 1.18 (d, 3H), 0.95 (d, 3H), 0.82 (d, 3H). LC/MS: m/z = 485.0 (M + H +) ° (S)-l-((2S,4R)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4 -Methyl-quot; than bite-l-l-yl)-3-methyl-1 - pendant oxybutyl-2-ylamino decanoic acid.

lH NMR (400 MHz, CD3OD) δ 7.84 (d, 1 Η), 7.48 (dd, 1H), 7.30 (d, 1H), 5.29 (dd, 1H), 4.24 - 4.15 (m, 1H), 4.01 (dt, (H, 1H) (d, 3H), 0.88 (d, 3H). LC/MS: m/z = 485.0 (M + H + ) ° Intermediate {(S)-l-[(S)-2-(5-iodo-1H-benzimidazol-2-yl)-pyrrolidine Methyl-1-carbonyl]-2-mercapto-propyl}-carbamic acid:

146 201238961 Step i: (S)-5-iodo-2-(pyrrolidin-2-yl)_m_benzo[d]imidazole-trifluoroacetate. Stirring (S)-2-(5-iodo-1H-benzimidazole-2-yl)-pyrrole at a temperature of 〇°C to bite the tributyl methacrylate (20 g, 48. mmol) in CH2C12 TFA (200.mL) was added to the mixture in (200 mL). The reaction mixture was stirred at room temperature for 2 hr and concentrated in vacuo. The residue was dissolved in aq. EtOAc (aq.) (EtOAc) -1Η-stupid [d]imidazole-trifluoroacetate (ug) H NMR (400 MHz, CDC13): δ [ppm] 8.40 (br s, 2H), 7.82 (s, 1H), 7.45 (d, 1H), 7.26 (d, 1H), 4.66 (t, 1H), 3.10 (m, 2H), 2.30 (m, ih), 2.18 (m, 1H), 1.90 (m, 2H). Step II: (( S)-l-((S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)"*byrrolidine-丨_yl)·3_methyl-1 -oxyl Butyl-2-yl)amino decanoate to (S)-2-indoleoxycarbonylamino-3-indolinyl-butyric acid (68 mg, 〇39 mm〇1) and (S)-5-moth -2-(^ is slightly biti-2-yl)-iH-benzo[d]mi. Sodium-trifluoroacetate (100 mg, 0.32 mmol) in a mixture of anhydrous DMF (2 mL·) Add a. DIPEA (0.25 mL, 1.43 mmol), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc, Dehydrated with sodium sulfate and concentrated in vacuo. Glue flash column chromatography (to 丨〇0/〇

The residue was purified by EtOAc / EtOAc (EtOAc (EtOAc)MeOH) Mercapto side oxybutan-2-yl)amine 147 201238961 methyl carbamic acid (150 mg). 'H NMR (400 MHz, dmso-d6) 12.25 (d, 1H), 7.8 (d, 1H), 7.45-7.33 (m, 1H), 7.33-7.15 (m, 2), 5.1-5.2 (m, 1H ), 3.9-3.7 (m5 2H), 3.5 (s, 3H), 2.25-2.05 (m, 2H), 2.05-1.8 (m, 3H), 0.8 (m, 7H) LC/MS: m/z = 470.90 (M + H + ). HPLC (Method C): tR = 7.78 min. Intermediate ((8)-3-methyl-1-oxo-l-((8)-2-(5-(4,4,5,5-tetramethyl-1,3,2-di) Boronium-2-yl)-1Η-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-yl)methyl carbamate:

((S)-l-((S)-2-(5-A-1H-benzo[d]1^.sup-2-yl)) η is more than b each α-1-yl)-3- Methyl decyl-1-oxobutan-2-yl)carbamate (2.23 g, 4.74 mmol), 4,4,4,4,5,5,5,5,8-methyl -2,2,; (1,3,2-dioxaboron (3.61g&gt; 14.22mmol), PdCl2dppf (193 mg) and acetic acid clock (1.53 g: 15.64 mmol) were added to anhydrous DMF (40 mL) The mixture was purged twice with nitrogen and stirred overnight at 85 &lt;=c. After removing the solvent under reduced pressure, the residue was purified by flash chromatography (methanol/Cf^ci2, 〇% to 5%). '(S)-3-Methyl-1-oxo-l-((S)-2-(5-(4,4,5,5-tetramethyl'丨,3,2- Dioxonium-2-yl)-1Η-benzo[d]imidazol-2-yl)pyrrolidine]· 148 201238961 yl)but-2-yl)amino decanoic acid 'a g (1.5 g) • h NMR (400 MHz, CDCi3): δ [ppm] 7.60-7.95 (m, 3H), 5.82 (m, 1H), 5.42 (m, 1H), 4.29 (m, 1H), 3.63-3.75 (m , 6H), 3.04 (m, 1H), 1.91-2.40 (m, 5H), 1.26-1.34 (m, 12H), 0.79-1.03 (m, 6H). LC/MS: m/z 471.19 (M + H + ) = compounds 1-3, 11, 14, 15 and 17-57 according to The procedures outlined in Examples 1-12 were prepared using the appropriate intermediate starting materials to prepare the compounds 丨_3, 11, 14, 4, and 17-57 as disclosed in Tables 1A and 1B. Example 13 Use ELISA and subgenomic replicon la cell line activity assays The drug potency was determined using a cell line W11·8 containing the subgenomic HCV replicon of genotype la. The NS5A protein content of the cell line after 4 days of drug treatment was used in this cell line. Indirect measurement of RNA replication in the presence of different drug concentrations shows that the content of NS5A protein is sufficiently correlated with the amount of HCV RNA in the replicon cell line. The cells divide twice a week to keep the confluence below 85% of the surface area of the flask. Medium for cell passage from sputum/fetal calf serum and 100 UI/mL penicillin, 1 〇〇 gg/mL streptomycin, 2 mM glutamic acid, 1 mM sodium pyruvate, non-essential amine The base acid (1 x ) and 6 〇〇 G418 final concentration of DMEM composition. Monolayer W11 8 cells were trypsinized and cells counted. Dilute the cells with 50,000 cells per ml in complete DMEM without G41, then apply approximately 5,000 live cells (1〇〇0) 149 201238961 to white opaque 96 7丨; ^丹^ is the outer hole puzzle In each well of the titration plate.纟 Still 5% in the C02 incubator,], n± + After the β 2·4 hour period from the eye, the various concentrations were added to make the music resuspended in DMSO at the concentration of the raw material of (7). The drug is then serially diluted at twice the final concentration in the same medium. Next, a volume ((10) from) each drug dilution is added to each well containing the cells. A control compound was used as an internal standard for each plate assay. Sixteen wells were used as a drug-free control group (〇% inhibition). Eight wells of Shaw were used as a background control group containing: 2 _ (final concentration) control drug. 〇〇% inhibition), the drug showed about 1 GG% inhibition of NS5A expression and was non-toxic to cells. The value from the 100% suppression well was averaged and used as the f-field value. In addition, the cells were incubated for 4 days in a redundant (3) "intercooling oven" under the pit. After 4 days of incubation, the medium was removed and the wells were washed once with 15 PBS at room temperature for five minutes. Then 15 μ per well was used. The cells were fixed in a cold (2 〇t) fixative (5 〇% methanol/50% acetone mixture) for five minutes. Then the cells were washed twice with 15 〇pBs (phosphate buffered saline) per well, and 15 〇L was added. After blocking the Lok solution, the cells were incubated for 1 hour at 3 71 to block the non-specific sites. The blocking solution was removed and the cells were washed twice with 150 PBS per well and 150 PBSTS solution per well (PBS/0.1). % Triton Χ-1〇〇/〇·〇2% SDS) Wash the strip once. Then add 50/xL mouse anti-NS5A antibody diluted in blocking solution with 1 / 丨, 〇〇〇 in each well ( Santa Cruz, Cat. No. sc-52417), and incubated overnight at 4° C. On the next day, the medium was removed and the plates were washed five times with 1 50 /xL PBS per well and incubated for five minutes at room temperature. Add 50 μί per well to the peroxidase-conjugated donkey anti-mouse antibody (jackson immunore) with blocking solution at 1/1 〇, 〇〇〇 Search, catalog number 150 201238961 715-036 -150 ) and incubate for 3 hours at room temperature on an oscillator (5 rpm). Wash the plate four times with 150 PBSTS per well and wash the knees with 15 μl PBS - Next, a substrate solution (1〇〇SuperSignal ELISA PiC0 Chemiluminescent Substrate, Fisher, Cat. No. 37069) was added to each well and the plate was incubated for 6 minutes, then read on the Anaiyst RT plate. The illuminating reading (relative light unit) on the extractor. Calculate the percent inhibition (in duplicate) at each drug concentration tested. Then follow the self-dose response curve using nonlinear regression analysis and GraphPad Prism software 2. GraphPad Software, Inc., San Diego, CA, USA) Determines the concentration (ic50) required to reduce viral replication by 50%.Example 14 Cell-based luciferase reporter gene HCV ( lb ) RNA replication assay Cell culture such as Krieger, N; Lohmann, V; Bartenschlager, R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J. Kko/. 2001, 75, 4614-4624 roughly described as 'from Huh-7 liver cancer Obtained based replicon cell line Huh-5.2, maintained in culture. These Huh-5.2 cells contain a highly adaptable cell culture replicon I389luc-ubi-neo/NS3-3'/5.1 construct with an integrated copy of the firefly luciferase gene in addition to the neomycin gene (Krieger , N; Lohmann, V; Bartenschlager, R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations, j. 2001, 75, 4614-4624). This cell line allows measurement of HCV RNA replication and translation by measuring luciferase activity. Previously 151 201238961 showed that luciferase activity closely followed the replicon RNA content in these cells (Krieger, N; Lohmann, V; Bartenschlager, R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. /. Fi.ro/. 2001, 75, 4614-4624). The Huh-ET lineage has the same characteristics as described for the Huh-5.2 cell line, except that the et cells are more robust and contain an adaptive mutation of the HCV NS4B gene rather than NS5A. Both cell lines were maintained in culture at a subconfluent content (&lt;85%) because the amount of replicon RNA was highest in actively proliferating cells. The medium used for cell passage is supplemented with 1% fetal calf serum and 1% penicillin/streptomycin, i% branic acid, 1% sodium pyruvate, 1% non-essential amino acid and 18〇^g /ml G418 Final concentration of DMEM (Gibco BRL Laboratories, Mississauga, ON'Canada). The cells were incubated at 37 t: in a 5% (: 〇 2 atmosphere and subculture twice a week to maintain subconfluence. About 3000 live Huh-ET cells (1 〇〇μΐ) were applied to white opaque 96-well microtiter titration In each well of the plate, the cell culture medium used for the assay is the same as above except that it does not contain G418 and does not contain phenol red. After incubation for 3-4 hours at 37 ° C in a 5% c-shirt, Compounds of various concentrations (1 〇〇Μ) were added and the cells were further incubated for 4 days at 37 C in a 5% C〇2 incubator. Subsequently, the medium was removed and 95 luciferase buffer (with fluorescein added) A photo-accepting buffer cleaner) to solubilize the cells. Incubate the cell lysate at room temperature and prevent direct light for at least 1 minute. Use a luminometer (leak with M1CroBeta Tnlux, Perkin Elmer' ma,usa) to the plate Reading luciferase counts. HCV la and 11} are the two most prevalent Hcv genotypes and most difficult to deal with. 152 201238961. It has been shown in the past that there are problems with good viables for both genotypes. a compound of the present invention, especially having a compound having 4, a base group The foregoing examples can be successfully repeated for the use of the reactants and/or operating conditions of the present invention in conjunction with the lb&amp; From the above description, those skilled in the art can readily determine the essential characteristics of the present invention and make various changes and modifications to the various uses and conditions without departing from the invention &lt;RTIgt; Agent 5 reaction curve, each compound used 11 concentrations to determine the 50 / 〇 inhibitory concentration (ic50) used for sputum suppression, in duplicate. Using a nonlinear curve to fit the data points, and from the resulting curve, Use Graphpad

Prism 敕 salt 9 λ ur·, ζ·υ (GraphPad Software, San Diego, CA, USA) interpolates IC5Q. Table 2 shows the compounds representing the invention. 153 201238961 Table 2 No. M + 1 (View RT (minutes) 'h-nmr EC50 lb 〇M) 1 ++ 2 ++ 3 713.6 6.9 +++ 4 789.6 7.81 +++ 5 817.7 8.41 +++ 6 845.06 9.23 +++ 7 831.67 '8.77 8 831.61 8.72 +++ 9 765.5 8.11 +++ 10 793.38 9.04 +++ 11 831.85 2.5 +++ 12 765.53 7.91 +++ 13 817.5 8.62 +++ 14 823.68 2.56 H NMR ( 300.0 MHz, acetone)d 11.45 - 11.13 (m, 2H), 7.98 - 7.21 (m, 8H), 6.28 - 6.19 (m, 2H), 5.36 - 5.22 (m, 1H), 5.18 - 5.12 (m, 1H) , 3.60 (s, 3H), 3.24 (s, 3H), 2.83 (s, 2H), 1.17 (m, 14H) and 1_00 - 0.80 (m, 18H) ppm +++ 15 831.46 • 8.26 +++ 16 803.34 8.16 17 845.58 8.94 +++ 18 817.62 8.43 +++ 19 817.32 8.18 +++ 20 791.37 7.7 +++ 21 833.68 7.89 22 831.9 2.65 H NMR (300.0 MHz, acetone) d 11 _04 (s,1H), 8.20 - 7.29 (m, 12H), 6.28 (d, J = 8.6 Hz, 2H), 5.35 - 5.29 (m, 1H), 5.17 - 5.12 (m, 1H), 4.32 - 4.20 (m, 3H), 4.01 (s, 3H), 3.69 (s, 1H), 3.61 (s, 6H), 3.44 (t, J = 10.2 Hz, 1H), 3.28 - 3.19 (m, 1H), 2.66 - 2.57 (m, 1H), 2.51 - 2.38 (m, 3H), 2. 07 - 1.83 (m, 4H), 1.40 (m, 3H), 1.22 - 1_15 (m, 6H) and 0.96 - 0.66 (m, 9H) ppm 23 845.6 [11 +-H- 24 829.66 [11 +++ 25 879.78 [1], 880.1 [21 +++ 26 879.72 [11 +++ 27 823.47『11 +++ 28 831.9『11 +++ 29 789.35 (1) +++ 30 861.3 (1) +++ 31 845.49 [11 ++ + 32 835.5 m +++ 154 201238961 No. M + 1 (fine RT (minutes) ^-NMR EC50 lb (μΜ_) 33 797.43 Γ11 +++ 34 792.5 [1], 792.58 (2) +++ 35 831.65 [Π + ++ 36 689.4Γ11 37 489.05 [1], 489.17 Γ21 38 831.37 [11 +++ 39 835.6 m. +++ 40 815.51 [11 +++ 41 797.44 [11 +-H- 42 781.47 [I] ++ 43 803.57 ΓΠ +++ 44 827.49 [11 +++ 45 827.42 m +++ 46 817.01 m +Ή- 47 817.84"11 +++ 48 817.51 rn +++ 49 503.29 [1], 503.29"21 50 703.65 Π1 51 660.7 [1], 660.66 [2], 660.62 [31 +-H- 52 821.7 [1], 821.8 (2) +++ 53 760.75 Γ11 54 817.74 rn +++ 55 916.78 [11 +++ 56 916.65 [11 ++ + 57 660.58 ΓΠ /χΜ · + + + &lt;= 0.005 &lt; ++ &lt;= 5.0 &lt; + 3 shows comparative data of exemplary compounds of formula (I). As shown in the table, a compound having a substituent at the 4-position of the pyrrolidine ring (i.e., R4 and R, a compound of the present invention which is a fluorenyl group). The data shows IC50 values for subgenomic replicon la and lb cell lines. 155 201238961 Table 3 Structure ICso (pM) (la) IC5〇 (pM) (lb) 1 5 . Wide H, C — ( .N —{ HH—J -9 . . , , P~&lt;1, 4.1 5 2 18 H, h, 'A y'”&lt;;Λ:.0:.;3 o ! ':〇&quot;··· '· - , / , ..,." &lt;〇·,,[· 1 I o HjC CH3 HjC〆CH3 8.5 8.5 3 13 MJC ' O CH , 36 2.6 4 4 140 13 [Simple description of the diagram] No [Main component symbol description] No 156

Claims (1)

201238961 VII. Patent application scope: k—Formula (IIIA) compound (FV) Or a pharmaceutically acceptable salt thereof, wherein each A is independently C6_14 aryl, 4-12 membered heterocyclic ring, C3-10 cycloalkyl or .5-12 membered heteroaryl; B and B' are each independently Abs exist, Cl 6 alkyl, c2_6 alkenyl or c2_6 alkynyl; Ri is il, -〇Ra, -NRaRb, -C( = 0)0Ra, -C(0)NRaRb, -c(=0) OH, -C(=0)Ra, -C(=NORc)Ra, _c(=NRc)NRaRb, -NRdC(=0)NRaRb&gt;-NRbC(=0)Ra&gt; -NRdC(=NRc)NRaRb' - NRbC(=〇)ORa &gt; -〇C(=0)NRaRb, -OC(=0)Ra, _〇c(=〇)〇Ra, hydroxyl, nitro, nitrogen-rich, cyano, -S( 〇)3Ra, -S〇2NRaRb, -NRbS02Ra, -NRbS02 NRaRb, -P( = 〇)〇RaORb, unsubstituted or substituted one or more Ci-6 alkyl, unsubstituted or R Substituting one or more c26 dilute, unsubstituted or substituted C or 6 C 2-6 alkynyl groups via R, or the presence of any two R i may form unsubstituted together with the atoms to which they are attached Or a 5-7 cycloalkyl group substituted one or more times by Ryl or a 5-7 membered heterocyclic ring which is unsubstituted or substituted one or more times by Rlz; each of Ra-Rd is independently H, Cl-12 alkyl, C2_12 alkenyl, C2-12 alkynyl, 157 201238961 C6-12 aryl, C7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclic-alkyl; RV is Halogen, Cwo, ketone, (^.6 haloalkyl), -(CHJuOH, -NRbC(=0)Ra, C6-i2 aryl or 5-12 membered heteroaryl; each R2 is independently il, C丨·1〇 alkyl, Cl 6 halogenated alkyl, —(CH 2 ), .6OH ' -0Ra ' -C(=〇)〇Ra , -NRaRb ' -NRbC( = 〇)Ra ' -C(0)NRaRb , -S(O)0-3Ra, c6 12 aryl, 5_i2 member heterocyclic ring or 5-12 member heteroaryl; R3 and R3, each independently Η ' (: 丨-6 alkyl, -(cHJmOH, C2. 6 alkenyl or C2_6 alkynyl; R4 and R4' are each independently CN6 alkyl; X and Y are each independently 0 II on -•S-·- or a bond; 0 V/ υ Λ-. Λ- The asterisk (*) indicates the point of attachment to D to the nitrogen of the π-ring; R5 and R5, each independently A Η, unsubstituted or substituted by R10, one or more times of Cl18, unsubstituted or R, G substituted - or multiple times of rare, unsubstituted or substituted by RIQ, one or more, substituted by R11 - or multiples of two: : 2; 2 alkynyl, unsubstituted or unaltered Or replace one or the second with R丨丨a aryl group, unsubstituted or substituted by Rl&gt; 5-12 membered heteroaryl, unsubstituted or subtly substituted 〜/heteroaralkyl, unsubstituted or substituted by r12 J \ n or ϋΙ2 Or a plurality of 3-12 member heterocyclic substitutions or hydrazine substitutions one or more times... heterocyclic-alkyl groups; 158 201238961 R6 is hydrazine, Cw alkyl or halogenated Cu alkyl; m and η are each independently 0, 1, 2, 3 or 4 and m and η together are 1, 2, 3 or 4; ρ is 0, 1, 2, 3. or 4; q is 0, 1 or 2; u is 0 or 1; s Is 0, 1, 2, 3 or 4; R10 is _, -〇Ra, pendant oxy, -NRaRb, =NO-Rc, -C( = 0)0Ra, -C(0)NRaRb, -C( =0) 0H, -C(=0)Ra, -C(=NORc)Ra, -C(=NRc) NRaRb, -NRdC( = 0)NRaRb, -NRbC( = 0)Ra, -NRdC(=NRc )NRa Rb, -NRbC( = 0)0Ra, -0C( = 0)NRaRb, -0C( = 0)Ra, -0C( = 0) 〇Ra, hydroxy, nitro, azide, cyano, - S(0)〇_3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P(=0)0Ra0Rb; R11 is halogen, -ORa, -NRaRb, -C(=0)0Ra, -C(0)NRaRb, -C( = 0) OH, -C( = 0)Ra, -C(=NORc)Ra, -C(=NRc)NRaRb, -NRdC(=0) NRaRb, -NRbC(=0)Ra, -NRdC (=NRc)NRaRb, -NRb C( = 0)0Ra, -0C( = 0)NRaRb, -0C(=0)Ra, -0C( = 0)0Ra, hydroxy, nitro, azide, cyano, -S(0)〇- 3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02 NRaRb or -P(=0)〇Ra〇Rb, C1-12 alkyl, C2-1.2, C2-12, C6-12 aryl, C7-16 Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclo-alkyl; and R12 is halo, -ORa, pendant oxy, -NRaRb, =NO-Rc, -C( = 0)0Ra, -C(0)NRaRb, -C( = 0)0H, -C(=0)Ra, -C(=NORc)Ra, -C( =NRc) NRaRb, -NRdC(=0)NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRa 159 201238961 Rb, -NRbC(=0)0Ra, -〇C(=0)NRaRb, - 0C(=0)Ra, -〇C( = 0) 〇Ra, hydroxy, nitro, azido, cyano, -S(0)〇-3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P( = 〇) 〇Ra〇Rb, Cm2 alkyl, C2-12 alkenyl, C2_12 alkynyl, c6-i2 aryl, C7_16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 member heterocyclic ring or 4-18 member heterocyclic-alkyl group. 2. A compound according to claim 1 wherein each A is independently cyclopropyl, cyclohexyl, imidazolidinyl, piperidinyl, piperidinyl, phenyl, naphthyl, thienylfuranyl, pyrrole Base, pyrazolyl, imidazolyl, thiazolyl, thiadiazolylzolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrenyl quinoneyl fluorenyl, oxazolyl, benzimidazolyl, Benzozozolyl, benzodiazepine, benzo(tetra)yl, benzene Ml, hydrogen benzodithiophenefuranyl, thienothiophenyl, thienofluorenyl, quinolinyl Employing Linke, 啥 (4), base or trisal; and its ten sites are replaced by (R,)p. 3. For the scope of patent application, item 2. „ σ 物 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Independence 4. The compound of claim 3, for example, is selected from the group consisting of: 160 201238961 Tl + t2 = p . 5. For the compound of claim 4, wherein A is: 6. For the compound of claim 2, wherein each A is independently a leucoyl group, a brittle base. The thiophene group, the fluorenyl group, and the ratio η base. ratio. Sitting base, ° meters. Full base, alpha thiol, exposure. Sitting base, α plug two spit base, ° ratio α. Fixed base. ratio. Stationary, lyophilic D-based, alpha-biphthyl, thaphthyl, benzoxanthene, benzodiazepine, benzothiazolyl, benzothiadiazolyl, dihydrobenzodiazepine A thiophene, a thiophenanyl group, a 11-phenanthyl- 11-mercapto group, a salino group or a tri-α-based group. 7. For the application of the compound of Article 6 of the patent scope, each of which is independently selected from the group consisting of: 161 201238961 (Ri)P 162 201238961 (Rl)t2 (Rl&gt;2 and t1 + t2 = p 〇8. The compound of claim 1, wherein each A is independently 5-12 wherein the hetero atom is selected from the group consisting of oxygen and sulfur. A heteroaryl group; wherein each A is independently substituted with (R,)p. 9. A compound according to any one of claims 1 to 8, wherein B and B' are independently absent, are CU6 alkyl Or a C2_6 alkynyl group. 10. A compound according to claim 9 wherein B and B1 are independently absent, and are -(CH2)2- or -(OC)-. 163 201238961 11. Compound of item 0, wherein B and independently are absent or -(OC)-. 12. Combination of any one of claims 1 or 8 to 11 Β—物, where (ROp / q chooses the group consisting of the following 164 201238961 (R〇p (Ri)ti (Ri)t2 (Ri)n (Ri)n 165 201238961 166 201238961 167 201238961 168 201238961 169 201238961 Ti + -N N- V|V (Rl)p t2 = p. 1 3. If you apply for the combination of the 12th patent scope, and ...B. B—(Ri)p / q Choose from the group consisting of: 170 201238961 (R〇p (Ri)P -Q- (Ri)p ' (Ri)p &lt;R〇p (Rt)p (Ri)p (Rt)p and (Rl)p and t 1 + t2 = p 0 14. The compound of claim 13 wherein B- (Ri)p 7 q Choose the group consisting of: c. (RO·, (Ri)m and ; and 171 201238961 T1 + t2 = p 〇 172 201238961 18. The compound of claim 15 wherein T1 + t2 = p . 19. A compound according to any one of claims 1 to 13 which is halogen, unsubstituted or substituted by R1G one or more times (3,-4 alkyl, -C(=0)0Ra, -C(0)NRaRb, hydroxy, decyl or Cu alkoxy. 20. A compound according to claim 19, wherein R is a gas group, a fluoro group, a bromo group, a decyl group, an ethyl group, a propyl group , butyl, -CH2OH, difluorodecyl, trifluoromethyl, -C(=0)ORa, hydroxy, cyano or decyloxy. 21. As claimed in any one of claims 1 to 20. A compound, wherein R2' is fluorenyl, trifluoromethyl, iodo, CH2OH or NHC(0)CH3. 22. A compound according to claim 21, wherein u is 0. 23. The compound of any one of the above-mentioned items, wherein each R2 is independently a fluoro group or a fluorenyl group. 24. A compound according to claim 23, wherein s is 0. 25. A compound according to any one of the preceding claims, wherein R3 and R3' are anthracene or fluorenyl. 26. A compound according to claim 25, wherein R4 and R4' are methyl. 173 201238961 27. The compound of any of the 26 items in paragraph 1.a, one of the political parties... is the other and the other is the 〇., 28. If the patent application is π 90, . ^ ^ the compound of the compound 'where m And 11 is 1〇29. If the X and Y in the first application of the patent scope are the compound of any of the 28 items, the compound of the second and the second of the range 1 to 29, the second: each Independently substituted with one or more G-8 alkyl groups which are unsubstituted or substituted by r1, unsubstituted or substituted by Rl() or substituted by C with one or more of two C2-8 thin groups, not R1丨Substitution of human C2-8 alkynyl' unsubstituted or via c:; phenyl, unsubstituted or substituted by R11 one or more '8-membered alkyl, unsubstituted or via Rll Aryl, unsubstituted or ruled &quot;substituted-...Eight eve...6 杂 未经 未经 未经 未经 未经 未经 未经 未经 未经 未经 未经 〜 〜 〜 〜 〜 〜 〜 〜 〜 一 〜 〜 〜 〜 〜 〜 〜 〜 〜 〜 〜 〜 〜 Heterocyclic or unsubstituted or substituted or multiple 4-8 membered heterocyclic ring. 31. A compound according to claim 3, wherein ... 5, which is unsubstituted or substituted by R. One or more Gs are substituted or passed through Ri. Substituting one or more groups, not R, 0 for one or singular a C 2 · 6 alkenyl, unsubstituted or by human C "block, unsubstituted or substituted one or more substituted one or more times Benzene, phenyl, unsubstituted or substituted by one or more of 5-6 membered heteroaryl, unsubstituted or substituted ~ or 6-7 membered heteroaralkyl, unsubstituted or R12 厂/ eve - human 5-6 member heterocyclic or unsubstituted or substituted by R12 one or more - human 6-7 member heterocyclic-alkyl. 174 201238961 32. The compound of claim 3, wherein r5 and r5 are each independently unsubstituted or substituted by riq one or more Ci 6 alkyl groups, unsubstituted or substituted by R1Q one or more The second c2 6 alkenyl group, unsubstituted or substituted with R10 one or more C2 6 alkynyl groups. 33. The compound of claim 32, wherein R5, each independently is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, t-butyl, pentyl , 2-mercaptobutane, 3-mercaptobutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl (CH2)-, which is unsubstituted or substituted one or more times by R1〇 . 34. The compound of claim 2, wherein r5 and each are independently unsubstituted or substituted one or more phenyl groups by Rll. 35. A compound according to claim 31, wherein each of the compounds is independently unsubstituted or substituted with one or more phenyl fluorenyl groups. The compound of any one of claims 1 to 35, wherein R10 is halogen, -〇Ra, pendant oxy, _NRaRb, =N〇_Rc, _c(=〇)〇Ra, -C( 0)NRaRb. -C( = 〇)〇H^ -C( = 0)Ra^ -C(=NORc)Ra, -C(=NRc) NRaRb, -NRdC( = 〇)NRaRb, -NRbC(=0 Ra, -NRdC(=NRc)NRa Rb, -NRbC( = 0)〇Ra,_0C(=0)NRaRb, _〇c(=〇)Ra, 〇c Bu(7) 〇Ra, hydroxyl, nitro, stack Nitrogen, cyano, _S(〇){)_3Ra, _s〇2NRaRb, _NRbS02Ra or ΝΚΐ)8〇2ΝΚΛ, wherein Ra_Rd are each independently H 1-12 alkyl, c 2-12 alkenyl, c 2 12 alkynyl , C612 aryl, C7M aralkyl, 5-7 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic alkyl group. 37. The compound of claim 36, wherein R10 is 175 201238961 -NRaRb, -NRdC(=0)NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRa Rb, -NRbC( = 0) 0Ra, -NRbS02Ra or -NRbS02NRaRb. 38. The compound of claim 36, wherein R10 is -NRaRb, -NRdC(=〇)NRaRb, -NRbC(=0)Ra, -NRbC(=0)0Ra or -NRbS02Ra. The compound of any one of claims 1 to 38, wherein each of Ra-Rd is independently Η, (: 丨.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl a C7.8 aralkyl group, a 5-6 membered heteroaryl group, a 6-8 membered heteroarylalkyl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic ring-alkyl group: 40. The compound of claim 39, Its center and heart are each independently H, C丨.6 alkyl, (: 2·6 alkenyl, C 2 6 alkynyl, phenyl, C 7 8 aralkyl, 5-6 membered heteroaryl, 6-8 member An aralkyl group, a 5-6 membered heterocyclic ring or a 6-8 membered heterocyclic-alkyl group, and the heart and Rd are each independently a hydrazine or a Cl-3 alkyl group. 41. A compound according to claim 39, wherein Ra-Rd Each of which is independently a hydrazine or a C..3 alkyl group. The compound of any one of claims 1 to 41, wherein the compound is of formula (IV): Or a pharmaceutically acceptable salt thereof, wherein 176 201238961 R7 and R/ are each independently unsubstituted alkyl, unsubstituted or substituted by a ruler (7), and R!G substituted one or more times of Cl f or Substituted by R10 - 戋多 &amp; or multiple 〇 2·8 alkenyl, unsubstituted one or more stupid, z C2·8 alkynyl, unsubstituted or taken by R11 and not Substituted or substituted by a base, unsubstituted or by size, substituted by one or the next, or replaced by R&quot; or more than 5: 6 heteroaryl, without R12 - Or many times 3_6 members? (10), unsubstituted or one or more 4-7 membered heterocyclic-alkyl groups; substituted Rs and each independently _NRaRb, -NRdC(=〇)NRaRb, _NRbC(=0)Ra^-NRdC( =NRc)NRaRb, -NRbC(=0)0Ra^-NRbS02Ra or -NRbS02NRaRb, wherein Ra_Rd are each independently H, 丨2 alkyl, c2-12 alkenyl, c2-12 alkynyl, C6_12 aryl, C716 aralkyl 5i2 member heteroaryl, 6-18 member heteroarylalkyl group, 3-12 member heterocyclic ring or 4-18 member heterocyclic ring-alkyl group. 4 3. Shikou by Xuanzang. Correction fsi·^^ ^ „ person.. B-- for 177 201238961 44. The compound of claim 42 wherein r8 and R8 are each independently -NRaRb, _NRbC(= 〇)Ra, _NRbC(= 〇)〇Ra, wherein Ra-Rb are each independently H ' Ci Μ Alkyl, phenyl, benzyl, heteroaryl, 6-8 membered heteroaryl, 5-6 heterocyclic or 6-8 heterocyclic-alkyl. 〜w~ 丹甲式<IV) wherein ^ and R8 are each independently _NRbC(tetra))0Ra, wherein Ra_Rb are each independently H, C丨_6 alkyl, stupid, tetrahydrofuran or stupid methyl. 46. In the case of claims 42 to 45, R7 and R/ are each independently unsubstituted or substituted by one of the compounds of the formula, substituted one or more times. 47. A compound of 178 201238961 is unsubstituted-substituted- or ... 48. As claimed in the scope of the invention, where the MR/ each independently is a compound of the five-item of the term "is isopropyl, butyl" , second butyl, V ethyl, propyl, isopropyl, methoxy 3-methylbutane, cyclopropyl, cyclohexane; 'yl, pentyl, 2-methylbutane, 4Q, * ^ * Earth, pentyl or cyclohexyl. 49. For example, the scope of the patent, where ... or ... 8, together with its compound of 4 = 任-term, is: 〇 eight Eight. ◦ or ° 50. As claimed in the patent application, wherein the compound is a compound of any one of formula (v): to 5,049, Or a pharmaceutically acceptable salt thereof. 51. - Compound of formula (VI) 179 201238961 Or a pharmaceutically acceptable salt thereof, wherein each of Ra-Rd is independently Η, C丨-12 alkyl, C2.12 alkenyl, C2-12 alkynyl, C6-i2 aryl, C7-16 aralkyl , 5-12 membered heteroaryl, heteroarylalkyl, 3-12 membered heterocyclic or 4-18 membered heterocyclic-alkyl; Ri is dentate, -ORa, -NRaRb' _c(=0)0Ra, - C(0)NRaRb' -C(=0) OH, -C( = 〇)Ra, -C(=NORc)Ra, -C(=NRc)NRaRb, -NRdC(=0) NRaRb, -NRbC( = 〇)Ra, _NRdC(=NRc)NRaRb, -NRbC(=〇)〇Ra, -0C(=0)NRaRb, -〇c( = 〇)Ra,_0C(=0)0Ra, hydroxyl, nitro, stack Nitrogen, cyano, -S(〇V3Ra' -S〇2NRaRb, -NRbS02Ra, -NRbS02 NRaRb, -P( = 〇)〇Ra〇Rb, unsubstituted or substituted one or more times by R1〇, -6 alkyl, unsubstituted or substituted by C1 one or more C26 alkenyl, 'unsubstituted or substituted by R10 one or more C2.6 alkynyl, or any two Ri may be present together with And the attached atoms together form a 5-7 cycloalkyl group which is unsubstituted or substituted one or more times or a 5-7 member heterocyclic ring which is unsubstituted or substituted one or more times by ri2; RV is halogen, C丨-nonylalkyl, Cl 6 halogenated alkyl, -(chJuOH, - NRbC (= 0)Ra, C6-12 aryl or 5-12 member heteroaryl; each r2 is independently halogen, Ci i 〇 alkyl, Ci 6 halogenated alkyl, -(Ch2)i 6 OH' -ORa&gt; - C(=〇)〇Ra. _NRaR^ -NRbC( = 0)Ra' -C(0)NRaRb ^ -S(0)〇-3Ra, C6.12 aryl, 5-12 heterocyclic or 5-1212 heteroaryl 180 201238961 R4 and RV are each independently CN6 alkyl; X and Y are each independently The asterisk (*) indicates the same. a point of attachment of the nitrogen of the bromopyridine ring; Rs and Rs' are each independently Η, unsubstituted or substituted by R1〇- or a a-C-丨s alkyl group, unsubstituted or substituted by a ruler or , 10 ~ second eve - human c2.12 alkenyl, unsubstituted or via Ri. Substituting one or more of the unsubstituted or R&quot; substituted or multiple C6.14 aryl groups, unsubstituted or substituted by Rii one or more C^6 aryl groups, not 5- or 2-membered heteroaryl, substituted or substituted by Ri 1 , or substituted 6 to 18 heteroaryl, unsubstituted or via Ri2 is substituted by one or eve 3 or unsubstituted or substituted by R12 one or more times, 4 2 membered hydrazine and 4-18 benzene heterocyclic _ alkyl; Κ·6 is H, Ci_6 炫 or tooth. m and n are each independently 〇, 丨 or 2, and one of the restriction strips is 1; T i P is 0, 1, 2, 3 or 4; q is 1 or 2; u is 0 or 1; s is 0, 1, 2, 3 or 4; R10 is _, -ORa, pendant oxy, -NRaRb, =Νη β Ν. -Rc, -C( = 0)0Ra, -C(〇)NRaRb&gt; -C( = 0)0H^C(=0)Ra,.C(=N v 1NURc)Ra&gt;-C(=NRc) NRaRb , -NRdC( = 0)NRaRb, -NRbC(=〇, R, U)Ra, -NRdC(=NRc) 181 201238961 NRaRb ' -NRbC( = 0)0Ra, -0C( = 0)NRaRb, -0C( =0)Ra ' -0C( = 0)0Ra, hydroxy, nitro, azido, cyano, -S(0)〇.3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P(=0)0Ra0Rb ; R11 is _, -ORa, -NRaRb, -C(=0)0Ra, -C(0)NRaRb, -C(=0) OH, -C( = 0)Ra, -C(=NORc)Ra , -C(=NRc)NRaRb, -NRdC( = 0) NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRaRb, -NRbC( = 0)0Ra, -OC(=〇)NRaRb,- 〇C(=0)Ra, -〇C(=0)ORa, hydroxy, nitro, azido'cyano, -S(O)0.3Ra, -S02NRaRb, -NRbS02Ra, -NRbS02 NRaRb or -P( -0) 〇Ra〇Rb'.卜12 alkyl, C2-12 dilute, C2-12 fast radical, c6-12 aryl, C7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 Heterocyclic or 4-18 membered heterocyclo-alkyl; and R is _, 〇 〇 Ra, pendant oxy, -NRaRb, =NO-Rc, -C(=0)0Ra ' -C(0)NRaRb , -C( = 〇)〇H, -C( = 0)Ra, -C(=NORe)Ra, -C(=NRc) NRaRb, -NRdC( = 〇)NRaRb, -NRbC(=0)Ra, -NRdC(=NRc)NRa Rb ' -NRbC( = 0)〇Ra &gt; -〇C(=0)NRaRb ' -0C(=0)Ra ^ -〇C(=0) 0Ra, hydroxy, nitro, Azido, cyano, 3Ra, _s〇2NRaRb, -NRbS02Ra, -NRbS02NRaRb or -P(=0)0Ra0Rb, (^-12 alkyl, c2-12 alkenyl, c2-12 alkynyl, c612 aryl, (: 7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 4-18 membered heterocyclic ring-alkyl group. 52. The compound of claim 51, wherein Ri is halogen, unsubstituted or substituted with one or more Ci-4 alkyl, _c(=〇)Ra, -C(〇)NRaRb, hydroxy, cyano or djalkoxy. Patent application No. 51 or 52 of the compound, where p is 0 〇 182 201238961 : 54. If the patent application scope A compound of 52, wherein at least one of R4 and R4. is a methyl group. 55. A compound according to claim 52, wherein R4 and R4' are fluorenyl groups. 56. A compound according to any one of the items 55, wherein one of m and η is 1 and the other is 0. 57. The compound according to any one of claims 5 to 55, wherein m and η The compound of any one of claims 51 to 55, wherein X and Υ are Ο The compound of any one of claims 5 to 55, wherein q is 2. The compound of any one of claims 5 to 59, wherein the compound is of the formula (VIA): Or a pharmaceutically acceptable salt thereof, wherein each p' is independently 0, 1 or 2; R7 and R7' are each independently unsubstituted or substituted by R1Q one or more times of Cu 183 201238961 alkyl, not Substituted or rig substituted one or more C2 8 alkenyl groups, unsubstituted or substituted by R1q one or more C 2 ·8 alkynyl groups, unsubstituted or substituted 1 or more phenyl groups, not Substituted or substituted by Rn one or more benzyl, unsubstituted or substituted by Rn one or more 5-6 membered heteroaryl, unsubstituted or substituted by R11 one or more 6-7 heteroaryl a 3-6 membered heterocyclic ring substituted with one or more substituents substituted by R1, or a 4-7 membered heterocyclic-alkyl group substituted one or more times by Ru; and R8 and R8, each independently The ground is _NRaRb, ·ΝΚ{ΐ(;;(=0)Ν1&amp;, NRbC(=〇) Ra, -NRdC(= NRc)NRaRb, _NRbC( = 〇)〇Ra, _NRbS〇2Ra or _NRbS〇2NRaRb Wherein Hd is independently H, CU12 alkyl, C2 i2 alkenyl, a. 丨 2 alkynyl, Ce 丨 2 aryl, aralkyl, 5 ΐ 2 member heteroaryl, 6-18 member heteroaryl aralkyl Base, 3_12 member heterocyclic ring or 418 member heterocyclic ring-alkyl group. 61. Patent application 6〇 silk items 51 to any one of the compound, wherein the compound is of formula (VIB): W C substituted or substituted by R 丨 0 for one or more C alkyl groups, unsubstituted or substituted with 1-8 D10 by Rio for one or more C 2-8 alkenyl ' unsubstituted or substituted with R Or multiple times r. 2 - 8 fast radical, unsubstituted or taken by R 1 1 184 201238961 one or more phenyl 'unsubstituted or substituted by Rll - or multiple times of methyl, not Substituting one or more of 5_6 贞 aryl, substituted by R&quot; substituted by one or more. 6_7 member heteroarylalkyl, unsubstituted to 'to replace or eve 3_6 a heterocyclic ring or a 4-7 membered heterocyclic-alkyl group which is unsubstituted or substituted one or more times by r 12; and R8 and r8| are each independently _NRaRb, _NRdC(=0)NRaRb, _NRbC(=〇 Ra, -NRdC (=NRe)NRaRb, catching (7) team, picking or solitary S02NRaRb, the towel Ra_Rd is independently H, Cm2 burning base, ^ i2 women's base Cm block 棊匸 6-丨 2 ^ • a group, a C7_le aryl group, a 5-membered heteroaryl group, a 6-18 member heteroaryl group, a 3-12 member heterocyclic ring or a 4-membered heterocyclic group. 62. A compound according to any one of clauses 51 to 6 of the patent application, wherein the compound of the formula is (VIIA): Or a pharmaceutically acceptable salt thereof, wherein each P' is independently hydrazine, 1 or 2; and R7 and R/ are each independently unsubstituted or substituted by R?, or multiple times, Unsubstituted or via Rl. Substituted—or multiple times C2 8 dilute, not taken 8 or 厶R $- or multiple C 2 8 alkynyl, unsubstituted or substituted by one or more Substituting or replacing one or more of the ones or more of the benzene 185 201238961 base, unsubstituted or substituted by R11 one or more 5-6 membered heteroaryl, substituted or substituted by R11 one or more 6-7 members An aralkyl group, an unsubstituted Ge group R12 substituted one or more 3-6 membered heterocyclic rings or an unsubstituted or RU substituted one or more 4-7 membered heterocyclic-alkyl groups; and a size 8 and r8' Independently _NRaRb, _NRdC(=〇)NRaRb, _NRbC 〇) Ra, -NRdC(=NRc)NRaRb, _NRbC(=0)0Ra, _NRbS〇2Ra or -NRbS02NRaRb, where Ra_Rd are each independently H, eh&quot ; alkyl, alkenyl, 丨 2 alkynyl, Ce u aryl, C 7 u aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-12 membered heterocyclic ring or 418 membered heterocyclic ring base. The compound of any one of claims 51 to 62, wherein the compound is of the formula (VIIB): Or a pharmaceutically acceptable salt thereof, wherein R7' is each independently unsubstituted or R1. Substituting one or more times =:=substitution or substitution by R1°- or multiple times of one of the dilute groups... Substituting or, R, replacing one or more L2_8 alkynyl groups, unsubstituted or one or more times via R1 Substituted phenyl, de-M, substituted or substituted by R&quot; substituted by one or more substituents, unsubstituted or substituted by Rll or 5-6, or substituted by R丨丨—式夕 A A shellfish ^ 一 一 - - - - - - - - 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 186 12 substituted one or more 4-7 membered heterocyclic-alkyl groups; and R8 and R8, each independently -NRaRb, -NRdC(=0)NRaRb, -NRbC(=〇) Ra, -NRdC(=NRc )NRaRb, -NRbC(=〇)〇Ra, -NRbS02Ra or ·ΝΚι> S02NRaRb 'wherein Ra_Rd are each independently η, (:丨(1)alkyl, C2_12 alkenyl, C2-12 alkynyl, c6-12 aryl , C7-16 aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaryl, 3-12 membered heterocyclic or 4-18 membered heterocyclic-alkyl group. ό 4 · as claimed in the patent scope The compound of any one of 6 to 6, wherein R8 and R8 are each independently _NRaRb, -NRbC(=0)Ra, -NRbC (=C〇〇Ra ' wherein Ra-Rb is independently Η, Cu alkyl, phenyl, phenyl fluorenyl, 5-6 membered heteroaryl, 6-8 membered heteroarylalkyl, 5-6 membered heterocyclic or 6-8 member A compound according to any one of claims 6 to 63, wherein the uldent 8 and Rsi in the formula (IV) are each independently _NRbC(=〇)〇Ra, wherein Ra-Rb is each independently h, c]-6 hexyl, phenyl, tetrahydrofuran or benzyl. 66. A compound according to any one of claims 6 to 65, wherein R? and The RV is independently a compound which is unsubstituted or substituted with Ri 1 or a plurality of times. 67. A compound according to any one of claims 6 to 65, wherein R? and RV are each independently A compound of any one of claims 6 to 65, wherein R? and R/ are each independently a fluorenyl group. , ethyl, propyl, isopropyl, oxime 187 201238961 isopropyl butyl, second butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, ring Propyl, cyclobutyl, cyclopentyl or cyclohexyl. A compound of any one of 65 to patent 6〇 range, or wherein R and R ?, Rs, and Rs, together with the carbon and the like which are attached together are each independently of?: The compound of any one of claims 6 to 69, wherein s and u are hydrazine. 71. A compound selected from the group iB or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 71 for use in the treatment or prevention of hepatitis C virus infection in humans. 73. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 72 and at least one pharmaceutically acceptable carrier or excipient. 74. Treatment or prevention A method of infecting a hCV virus, comprising a compound according to any one of claims 1 to 7 wherein the biological sample is contacted or administered to a patient in need thereof in an amount effective to treat or prevent the infection. 75. The method of claim 74, wherein the HCV is genotype 1 〇 76. The method of claim 74, wherein the HCV is genotype la, genotype ib, or a combination thereof. 188