TW201200517A - Novel inhibitors of hepatitis C virus replication - Google Patents

Abstract

The embodiments provide compounds of the general Formulae VI, VII, VIII, IX, X, XI, XII, XIII, XIV, and XV as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Description

201200517 VI. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The embodiments described herein relate to compounds, methods for their synthesis, compositions and methods for the therapeutic use of such compounds, such as for the treatment of hepatitis C virus ( HCV) infection. This application claims the following U.S. Provisional Application: No. 61/345,222, May 17, 2010; No. 61/345,553, May 17, 2010; June 14, 2010 No. 61/354, 671; No. 61/361,328, filed on July 2, 2010; No. 61/382,872, filed on September 14, 2010; No. 61/405,138, Application, January 20, 2010 </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; [Prior Art] Hepatitis C virus (HCV) infection is the most common chronic blood-borne φ infection in the United States. Although the number of new infections has declined, the burden of chronic infections is quite large. According to the Center for Disease Control, the estimated number of infected people in the United States is 3,900,000 (1.8%). In the United States, chronic liver disease is the tenth leading cause of death in adults, and causes approximately 25 deaths per year, or approximately 1% of all deaths. ^ Studies have shown that 40% of chronic liver disease is associated with HCV' is estimated to result annually 8,000-1 years old, the death of the case. End-stage liver disease associated with HCV is the most common indication for adult liver transplantation. Antiviral therapy for chronic hepatitis C has developed rapidly over the past decade, with significant improvements in therapeutic efficacy. However, even in combination therapy with PEGylated I56115.doc 201200517 IFN-α plus ribavirin, 40% to 50% of patients still have no treatment; they are non-responders or relapsers. These patients currently have no effective treatment alternatives. In particular, liver biopsies in patients with advanced fibrosis or cirrhosis are at significant risk of developing complications of advanced liver disease, including ascites, yellow marks, variceal hemorrhage, encephalopathy, and progressive liver failure, and The high prevalence of chronic HCV infection at a significantly increased risk of hepatocellular carcinoma has important public health implications for the future burden of chronic liver disease in the United States. According to data from the National Health and Nutrition Examination Survey (NHANES III), new HCV infections occurred between the late 1960s and early 1980s, especially among people between the ages of 20 and 40. The rate has increased dramatically. It is estimated that the number of people with long-term HCV infection (20 or more years) may be more than four times that of 1990, from 750,000 to more than 3,000,000. The proportion of people infected for 30 or 40 years will increase even more. Because the risk of HCV associated with HCV is related to the duration of infection, the risk of cirrhosis is increased for people over 20 years of infection, which will lead to morbidity and mortality associated with cirrhosis in patients infected between 1965 and 1985. The rate is substantially increased. HCV is a enveloped positive-strand RNA virus of the Flaviviridae family. The Xianxin single-stranded HCV RNA genome is a single open reading frame (ORF) of approximately 9500 nucleotides in length with a single larger polymeric protein encoding approximately 3000 amino acids. In infected cells, this polymeric protein is cleaved by cellular and viral proteases at multiple sites to produce a viral structure and a non-knotted protein (NS) protein. In the case of HCV, the mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A and NS.5B) were produced by two viral proteases. The NS2-NS3 junction of the first viral protease cleavage polymerized protein. The second viral protease is a serine protease (referred to herein as "NS3 protease") contained in the N-terminal region of NS3. The NS3 protease mediates all subsequent cleavage processes in the polymeric protein relative to the downstream site of the NS3 position (i.e., the site between the C-terminus of NS3 and the C-terminus of the polymeric protein). The NS3 protease exhibited activity in both cis (at the NS3-NS4 cleavage site) and trans (for the remaining NS4A-NS4B, NS4B-NS5A and NS5A-NS5B sites). The NS4A protein provides multiple functions as a cofactor for NS3 protease and may help with membrane localization of NS3 and other viral replicase components. Clearly, the formation of a complex between NS3 and NS4A may be necessary for NS3-mediated processing and enhances the efficiency of proteolysis at all sites identified by NS3. The NS3 protease also appears to display nucleoside triphosphatase and rna helicase activities. The NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. Furthermore, compounds which inhibit the action of NS5A in viral replication may be suitable for the treatment of HCV. SUMMARY OF THE INVENTION Some embodiments include a compound having the structure of Formula VI: R1\

VI 156115.doc 201200517 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of nitrogen, Rlac (=〇), and Rlac(=s)_; each R is independently selected from the group consisting of Group: _c(R2a)2NR3aR3b, alkoxyalkyl, C, _6 alkyl 〇C(= 〇)_, Ci 6 alkyl 〇C(= 〇)Ci 6 alkyl, c _6 alkyl ChCOCM Base, aryl, aryl (CH=CH)m_, arylalkyl fluorene-, arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl) (CH=CH) ni-, ( Cycloalkyl)alkyl, cycloalkylsulfonylheterocyclyl, heterocyclyl (CH=CH)m•, heterocyclyl alkoxy, heterocycloalkyl, heterocyclylalkyl, hydroxyalkyl , RcRdN, (ReRdN)(CH=CH)m_, (RRN)alkyl, (WN)c(=〇)_, as appropriate, Cw alkoxy substituted by up to _ base, and optionally up to 9 Halo-substituted alkyl; each independently selected, wherein ... and ... are each independently selected from the group consisting of nitrogen, decyloxy c(=o)-, Cl.6 alkyl, Ci.6 yard c(=〇) _, Ci 6-based sulfonyl, arylalkyl 0C (=0)-, arylalkyl, arylalkyl c (= 〇) _, aryl c (= o) -, aryl sulfonium Base, heterocyclylalkyl, Heterocyclylalkyl C(= 〇)_, heterocyclic group C(=0)_, (ReRfN)alkyl, (ReRfN)alkane c(=0)- and (ReRfN)C(=0)-, Wherein the arylalkyl, arylalkyl C(=0)-, heterocyclylalkyl and heterocyclylalkyl c(=〇)_2 alkyl moieties are each optionally substituted with an irRfN_ group; Arylalkyl, arylalkyl c(=o)-, aryl c(=0)_ and arylsulfonyl aryl moiety and heterocyclylalkyl, heterocyclylalkyl c(=o And the heterocyclyl moieties of the heterocyclyl group c(=0)_ are each optionally substituted with up to three substituents each independently selected from the group consisting of cyano, halo, nitro, optionally Up to 9 halo 1561l5.doc 201200517 substituted Cw alkoxy group and optionally up to 9 _ group substituted Ci 6 alkyl groups; ·6 each ReRfN system is independently selected, wherein ... and ... are independently selected From hydrogen, Ci-6 alkyl, aryl &amp; arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (RXRyN)alkyl and (RXRyN)c (=〇)_; Each RxRyN is independently selected, wherein each of ^ and ^ is independently selected from the group consisting of argon, and a thiol (=m, alkyl c(=0)-, aryl group An aryl group, a cycloalkyl group and a heterocyclic group; each R2a is independently selected from the group consisting of hydrogen, L-, aryl, aryl (CH2)n and heteroaryl (CIi2) n_; Is independently selected from the group consisting of hydrogen and optionally substituted C!-6 alkyl; each R is independently selected from the group consisting of optionally substituted C 6 alkyl, heteroaryl, _ ( CH2)nC(=0)NR4aR4b, -(CH2)nC(=〇)〇RSa and (CH2)nC(-〇)R a 'The heteroaryl group is optionally substituted by the following groups: cyano group, south group, a nitro group, a hydroxy group, a Cl_6 alkoxy group substituted by up to 9 dentate groups, and optionally a c丨·6 alkyl group substituted with up to 9 groups; each RRN is independently selected, wherein R4b is each independently selected from the group consisting of: ^, optionally substituted A 6 alkyl and aryl (CH 2 ) n -; each RSa is independently selected from the group consisting of: optionally substituted Cl. 6 alkyl and aryl (CH2)n-; each R is independently selected from the group consisting of optionally substituted Cu alkyl and aryl (CH2)n_; 156115.doc 201200517 L1 is selected from the group consisting of Group:

-C(=0)(CH2)m0C(=0)-, -C(CF3)2NR2c-r2c is selected from the group consisting of hydrogen, Cw alkyl, c2-6 alkenyl, C2-6 alkynyl , C3-7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, the alkyl optionally being ReRfN_, alkoxy or Ck alkane a group S-substituted; each X group is independently selected from the group consisting of NH, NC16 alkyl, anthracene (oxygen), and S (sulfur); each m is independently 1 or 2; each η is independently 〇, 1 Or 2; each R7 is independently selected from the group consisting of hydrogen, ci 6 alkyl 〇 c ( 〇), aryl alkyl 〇 c (= q), (RaRbN) c (= 〇) ·, The group is a group selected from the group consisting of: a group consisting of L2 and L3_L4; the group of L2 is selected from the group consisting of:

156115.doc 201200517

Each A line is independently selected from the group consisting of: cr3 &amp; n (nitrogen); each R3 is independently selected from the group consisting of hydrogen, Cl 6 alkoxy, 1-6 alkyl OCK 6 alkyl, (: 16 alkyl hydrazine (: (; = 〇), arylalkyl 〇 c (= 〇) _ a ^ 〇〇Η _ group, hydroxyl, RaRbN-, (RaRbN),

(RaRbN)C(=〇)• and, where appropriate, up to 9 _ groups and up to (10) radicals substituted c 1 · 6 alkyl; each RaRbN is independently via the following group: hydrogen, select 'where Ra and Rb is each independently selected from the group consisting of C2-6 and Ck6 alkyl;

Hydrogen 'cN6 alkoxy, arylalkyl oc(=〇). (RaRbN)alkyl, each R8 is independently selected from the group consisting of Ci-6 alkyl hydrazine Cb6 alkyl, Cw alkyl hydrazine c ( =〇)_, -COOH, a hydroxyl group, a hydroxyl group, RaRb^_ 156115.doc 201200517 (RaRbN)C(=〇)-, optionally up to 9 _ group substituted 匕6 alkyl groups and optionally up to 5 a hydroxy-substituted Cl6 alkyl group, or optionally a two-position R8 together as a pendant oxo (oxo); X is selected from the group consisting of hydrazine (oxygen), NR9 (nitrogen), and c(R8)2; And R9 is independently selected from the group consisting of hydrogen, aryl (CH2)n_,

Cj-6 alkyl hydrazine (CH2)n, Cu alkyl 〇 c (= 〇) _, d. 6 alkyl NHC (= 0) -, C 〗 6. alkyl c (=0) -, aryl c (=〇)_, aryl 〇c(=0)-, aryl NHC(=〇)_, arylalkyl〇c(=〇)-, (RaRbN)(CH2)n, (RaRbN)C( =0)- and optionally up to 9 halo-substituted Ci.6 alkyl groups, the aryl (CH2)n-, aryl C(=〇)-, aryl 〇c(=〇)· and aryl The radicals NHC(=〇)_ are each optionally substituted by up to 5 substituents each individually selected from the group consisting of: a dentate group, a hydroxyl group, a cyano group, a nitro group, optionally substituted with up to 9 functional groups. 6 alkyl and, as the case may be, up to 9 dentate substituted Cw alkoxy groups. In some embodiments, the compound of Formula VI has the structure:

156115.doc •12· 201200517

Some embodiments include a compound having the structure of Formula VII: 156115.doc 13· 201200517

Or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of argon, Rlac (=〇)_&amp;RlaC(=S)-; each "separately selected from the group consisting of Group: _c(R2a)2NR3aR3b, alkoxyalkyl, CU6 alkyl 〇C(=〇)-, cK6 alkyl 0(:(=0)(^-6 alkyl, C 〗 6 alkyl hydrazine :( = 0)(^.6 alkyl, aryl, aryl (CH2)n_, aryl (CHAO-, aryl (Ci^CHU-, arylalkyl〇, arylalkyl, aryl) 0 alkyl, cycloalkyl, (cycloalkyl)(CH=CH)m-, (cycloalkyl)alkyl, cyclohexylsulfonyl, heterocyclyl, heterocyclyl (CH=CH)m- , heterocyclic alkoxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, R«=RdN_, RcRdN(CH2)n-, (WNKCI^CHU-, (RcRdN) alkyl, ( RcRdN)C(=0)-, optionally a Cw alkoxy group substituted with up to 9 groups, and optionally up to 9 groups substituted (^_6 alkyl, the aryl and heteroaryl 156115.doc • 14 - 201200517 Each is substituted by the following groups: cyano, -yl, nitro, hydroxy, optionally up to 9 halo-substituted C1-6 alkoxy and optionally up to 9 halo Instead Cu alkyl;

Each ReRdN is independently selected wherein RC and Rd are each independently selected from the group consisting of hydrogen, alkoxy C(=0)_, Ci.6 alkyl, Ci 6 alkyl C(=0)- , Ci-6 alkylsulfonyl, arylalkyl 〇C(= 〇), arylalkyl, arylalkyl c(=o)-, aryl c(=0)-, arylsulfonate , heterocyclylalkyl, heterocyclylalkyl C(=0)-, heterocyclyl c(=〇)-, (ReRfN)alkyl, (ReRfN)alkyl c(=0)_ and (ReRfN c(=0)_, wherein the arylalkyl, arylalkyl C(=〇)-, heterocyclylalkyl and heterocyclylalkyl c(=〇)_2 alkyl moieties are each optionally a ReRfN_ group substituted; and wherein the arylalkyl group, the arylalkyl group C(=0)-, the aryl group of the aryl C(=0)- and arylsulfonyl group, and the heterocyclic alkyl group, The heterocyclyl moiety of the heterocyclylalkyl c(=0)- and heterocyclyl c(=0)_, respectively, are optionally substituted with up to three substituents each independently selected from the group consisting of: cyano, A dentate group, a nitro group, a CM alkoxy group substituted with up to 9 嗰 halo groups, and optionally a C 1 ·6 yard group substituted with up to 9 functional groups; each ReRfN system is independently selected, wherein Re&amp;Rf&amp; Independent Selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (RXRyN)alkyl and RxRyN)C(=〇).; Each RxRyN is independently selected, wherein RX&amp;Ry&amp; is independently selected from the group consisting of hydrogen, alkyl 00 (=0) _, (: 丨 6 alkyl, 〇: 16 alkyl C (=0)-, aryl, aryl, cycloalkyl and heterocyclic; 1561J5.doc • 15· 201200517 each C (R2a) 2 is independently selected, each R2a Is independently selected from the group consisting of hydrogen, optionally up to 9 halo substituted CM alkyl groups, aryl groups (CHA• and heteroaryl (CH2)n-, the aryl and heteroaryl groups each The situation is replaced by the following groups: cyano, dentate, nitro, hydroxy, optionally up to 9 halo-substituted Cl-6 alkoxy and, optionally, up to 9 halo or C(R2a)2 The substituted R6a group, each R3a is independently selected from the group consisting of hydrogen and optionally substituted cN6 alkyl; each R3b is independently selected from the group consisting of Cw alkyl optionally substituted Miscellaneous , _(CH2)nC(=〇)〇R5a and -(CH2)nC(=〇)R6a, which are optionally substituted by the following groups: cyano, dentate, nitro, hydroxy, optionally Ci 6 alkoxy substituted with up to 9 dentate groups and optionally up to 9 _ group substituted c -6 alkyl groups; each R 4 a R 4 b N group is independently selected, wherein R 4a and R 4b are each independently selected from the group consisting of Group: hydrogen, optionally substituted alkyl and aryl (CH2)n-; each RSa is independently selected from the group consisting of CiAC alkyl and aryl (CH2)n, optionally substituted Each R6a is independently selected from the group consisting of Ci-6 alkyl and aryl(CH2)n- which are optionally substituted; X1 is (C(R2)2)q, or χϊ is absent; Υ1 is It is selected from the group consisting of 0 (oxygen), S (sulfur), S(0), s〇2, NR2, and c(r2)2, and its 156115.doc -16-201200517 is limited to when Y1 is not present, Y1 is C ( R2)2; χ2 is (C(R2)2)q, or Χ2 is absent; Υ is selected from 0 (oxygen), s (sulfur), S(O), s〇2, NR2 and C(R2) 2 ' The limiting condition is that when X2 is absent, Y2 is C(R2)2; 々 each R2 is independently selected 'its is selected from the following :

&quot;&quot;Cl-6 methoxy, Cl-6 alkyl, aryl, halo, hydroxy, RaRbN_ and 2, up to 9 (tetra) substituted Cd groups, or 2 adjacent R as appropriate The carbon-up is a fused 3-member to 6-membered carbocyclic ring substituted by up to 2 c丨_6 yards as appropriate; each of the groups is independently selected from the group consisting of CR3 and N (nitrogen); each R3 The group is independently selected from the group consisting of hydrogen, Ci.6 oxy, Ci-6 alkyl OCw alkyl, Ci 6 alkyl 〇c (=〇), arylalkyl, a_Cb〇〇H, tooth a group, a hydroxyl group, a RaRbN-, a (RaRbN)alkyl group, (N)C(〇)_, optionally up to 9 halo groups and up to 5 hydroxy-substituted c 1 -6 alkyl groups; each L1 system is independently selected from The following group of groups:

0, -C(=0)(CH2)m〇C(=0)-, -c(CF3)2NR2c- and 丨人Λ The following group of components: hydrogen, Cl·6 alkyl, C2_6 alkenyl, 2&lt;;: selected from C2-6 fast radicals, ^3-7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl, and heterocyclic ketone groups, as appropriate 、 156115.doc -17· 201200517 oxy or Cm alkyl s_substituted; each χ 3 is independently selected from the group consisting of NH, nCi 6 alkyl, oxime (oxygen) and s (sulfur); The R7 is independently selected from the group consisting of hydrogen, Ci 6 alkyl 〇 C( 〇)-, ^ 烧 〇 〇 c( = 〇) _, _C 〇〇 H, (RaRbN)c (= 〇) _ a dialkyl decylalkyl 0 alkyl group and optionally up to 9 _ group substituted Cl 6 alkyl groups; each of the 14 series is independently selected, wherein each of the groups is independently selected from the group consisting of: hydrogen , C 2-6 alkenyl and C 丨 · 6 alkyl; each Z series is independently selected, wherein z is selected from the group consisting of: 〇 (oxygen) and CH 2 , or Z is absent; each m is independently 1 Or 2; each π is independently 〇, 1 or 2; each p is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; The site is 〇, 1, 2, 3 or 4; B1 is fused or replaced by saturated or unsaturated 3 to 7 Å or fused or replaced by saturated or unsaturated 3 to 7 Each of them is replaced by one or more R4; B2 is a fused or substituted saturated or unsaturated 3 to 7 member of an anthracene ring or a slightly saturated or substituted Unsaturated 3 to 7 heterocyclic rings, each of which is optionally substituted by one or more R 4 ; and each R 4 is independently selected from the group consisting of CN 6 alkoxy, cl 6 OCw alkyl, Cw Alkyl oc(=o)-, arylalkyl 0C(=0)-, _CC)C)H, 156115.doc -18 - 201200517 From base, Ci-6 _ pit base, trans group, RaRbN-, ( RaRbN), radiant, (RaRbN)C(=0)- and optionally up to 9 C i ·6 alkyl groups substituted by a base and up to 5 thio groups, or 2 偕R4 as the case Oxygen.

In some embodiments of Formula VII, the group:

Choose the following components

And each X4 is independently selected from the group consisting of: cr&gt;n (nitrogen); and each Y4 is independently selected from the group consisting of C(R4)2, NR4, hydrazine (oxygen), and s (sulfur). . In some embodiments of Formula VII, each z is absent. In some embodiments of Formula VI1, a saturated or unsaturated 3 to 7 membered carbon ring is optionally fused by one or more of 2 . In some of the red cases of formula VH, B2 is the fused saturation of _ or multiple r4 substitutions as appropriate or 156115.doc •19- •h«t 201200517 Unsaturated 3 to 7 carbon rings. In some embodiments of Formula VII, B1 is a fused saturated or unsaturated 3 to 7 membered heterocyclic ring, optionally substituted with one or more R4. In some embodiments of formula vii, b2 is a fused saturated or unsaturated 3 to 7 membered heterocyclic ring optionally substituted with one or more substituents. In some embodiments of Formula VII, the group:

Is selected from the following

156115.doc •20· 201200517 Γ〇3 In some embodiments of Formula VII, ... is selected from the group consisting of:

156115.doc •21- 201200517

In some embodiments, the compound of Formula VII has the structure of Formula Vila:

Vila, or a pharmaceutically acceptable salt thereof. 156115.doc -22- 201200517 In some embodiments, the compound of formula VII has the structure of formula V11b:

b I I V or a pharmaceutically acceptable salt thereof. In some embodiments of Formula V11b, each R1 is RlaC(=〇)-. In some embodiments of Formula V11b, each Rla is -CHR2aNHR3b. In some embodiments of Formula V11b, each is only "alkyl"; each 1131&gt; is -(:(=0)01^; and each R5 is a Ci_6 lei. In some embodiments, the compound of Formula V11b has The following structure: 156115.doc 23- 201200517 jv〇/ JV a &quot;^, /-NH οφ οΛ Vn\ h〇hnnV fVl •kArf 0C&gt; 0:^ ΛΓ , , jv〇/ CW jv〇/ NH c (人/=N\ hnnV hnn&gt; rrV-^ yO UL^ ιΓ^γΛ kX) y^&gt;· ^&quot;nh Anh Cb heart wide, A 丫,

156115.doc -24- 201200517

156115.doc -25- 201200517

156115.doc •26- 201200517

156115.doc -27- 201200517

156115.doc -28 - 201200517

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156115.doc -30- 201200517

156115.doc -31 · 201200517

156115.doc ·32· 201200517

156115.doc -33· 201200517

In some embodiments, the compound of Formula VII has the structure of Formula Vile:

Vile 156115.doc-34-201200517 or a pharmaceutically acceptable salt thereof, wherein: each of the groups is independently selected from the group consisting of cr4 and N (nitrogen); and each γ4 is independently selected from the group consisting of Group: c(r4)2, NR4 〇 (oxygen) and s(琉). In some embodiments the compound of formula VII has the structure of formula VIId: X, 1 &gt; 2

LW R2 R1 H-~n R2 乂 &gt; R2 Y2

Or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted with up to 9 halo-substituted C!-6 alkyl groups. In some embodiments, R6 is a fluorenyl group. Some embodiments include a compound having the structure of Formula VIII: yi R2

156115.doc -35.

VIII 201200517 or a pharmaceutically acceptable salt thereof, wherein: each R is independently selected from the group consisting of hydrogen, Rlac (=〇), and

RlaC(=s)-; Each R is independently selected from the group consisting of: _C(R2a)2NR3aR3b 'alkoxyalkyl, CU6 alkyl 〇c(=〇)_, Ci 6 alkyl 0C (=0 Ci6 alkyl, Cu alkyl cpCOC, ·6 alkyl, aryl, aryl (CH2)n_, aryl (CHAO-, aryl (CH=CH) m_, arylalkyl hydrazine, aryl alkane Alkyl aryl group, cycloalkyl group, (ring-based group) ((^=(: team, (cycloalkyl)), % cycloalkylalkyl, heterocyclic, heterocyclic (CH= CH) m_, heterocyclylalkoxy, heterocyclyl, heterocyclyl fluorenyl, hydroxyalkyl, R(:RdN_, RRN(CH2)n-, (RcRdN)(CH=CH)m_, (RCRdN)alkyl, (RRN)C(=〇)-, optionally up to 9 halo-substituted Cw alkoxy groups, and optionally up to 9 functional group-substituted Cl_6 alkyl groups, which are aryl and hetero The aryl groups are each optionally substituted by a cyano group, a cyano group, a nitro group, a hydroxy group, optionally up to 9 halo-substituted C1-6 alkoxy groups, and optionally up to 9 halo groups substituted by Ci-6. Alkyl; each ReRdN is independently selected, wherein Re and Rd are each independently selected from the group consisting of hydrogen, alkoxy C(=〇)-, CN6 alkyl, Cb6 alkyl C(=0)-, cumane Alkyl, arylalkyl 0C(=0)-, arylalkyl, arylalkyl c(=0)-, aryl C(=〇)-, aryl sulfhydryl, heterocyclic Hyun group, heterocyclic group C (= 0) _, heterocyclic group C (= 〇) _, (ReRfN) alkyl, (ReRfN) alkyl c (=0) - and (ReRfN) C (=0 )-, wherein the alkyl moiety of the arylalkyl group, the arylalkyl group C(=0)-, the heterocyclylalkyl group and the heterocyclylalkyl group c(=〇)- are each 156II5.doc -36-201200517 The case is substituted by a WN_ group; and wherein the arylalkyl group, the arylalkyl group c(=o)-, the # group c ('- and the arylsulfonyl group of the aryl moiety and the heterocyclic group) a heterocyclic group C (which and a heterocyclic group c), wherein each of the heterocyclic groups is optionally substituted by at least three substituents selected from the group consisting of τ, 'cyano, halo, and nitrate a Cw alkoxy group substituted with up to 9 halo groups and, if appropriate, a 6 alkyl group substituted with up to 9 dentate groups;

Each line is independently selected, wherein each of them is independently selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heteroalkyl, heterocycloalkyl a group, (RxRyN)alkyl and (RXRyN)c(=〇)_; each RxRyN is independently selected, wherein ... and ^ are each independently selected from hydrogen, Cw alkyl oc (=0) _, Ci 6 burned a group, a Ci 6 alkyl group c (= 〇), an aryl group, an arylalkyl group, a cycloalkyl group, and a heterocyclic group; each C(R2a) 2 system is independently selected, wherein each RZa system is independently selected from the following a group consisting of: hydrogen, optionally substituted by 9 groups of alkyl groups, aryl (CH2)n- and heteroaryl (CH2)n_, the aryl and heteroaryl groups are each optionally substituted by the following groups : cyano, dentate, nitro, hydroxy, optionally as defined above, substituted by up to 9 dentyl groups, and optionally up to 9 units of N6 or F(R2a)2, substituted by a V6 group. The radical R3a is independently selected from the group consisting of hydrogen and optionally substituted C丨·6 alkyl; each R is independently selected from the group consisting of: optionally substituted c丨-alkyl, Heteroaryl, -(CH2)nC(=0)NR4aR4b, - (CH2)nC(=0)0RSa 156J15.doc •37·201200517 and (CH2)nC(-〇)R, the heteroaryl group is optionally substituted by the following groups: cyano, halo, nitro, hydroxy, Optionally, up to 9 Ci-6 alkyl groups substituted with a base substituted c**6 alkoxy group and optionally up to 9 dentate groups; each R4aR4bNS is independently selected, wherein each of R4a and R4b is independently selected from the group consisting of a group consisting of: hydrogen, optionally substituted CM alkyl and aryl (CH2)n-; each RSa is independently selected from the group consisting of optionally substituted Cu alkyl and aryl (CH2)n - each R6a is independently selected from the group consisting of CiAC alkyl and aryl (CH2)n-, as appropriate;

X is (C(R2)2)q, \wr, or χι does not exist; Υ1 is selected from 0 (oxygen), S (sulfur), s(〇), s〇2, nr2, and C(R2)2, The constraint is that when X1 is not present, Y^C(R2)2; X2 is (C(R2)2)q

Or X2 is absent; Y2 is selected from the group consisting of 0 (oxygen), s (sulfur), s (0), S02, NR2, and C(R2)2, with the constraint that when X2 is absent, Υ2 is c(r2) 2; each R2 is independently selected, wherein R2 is selected from the group consisting of: hydrogen Cl.6 alkoxy, C -6 alkyl, aryl, halo, pyloryl, RaRbN· and optionally Up to 9 dentate-substituted Ci6 alkyl' or, as the case may be, 2 adjacent Rs together with the carbon to which they are attached, up to 2 (^-6 alkyl-substituted fused 3- to 6-membered carbocycles; 156115 .doc •38· 201200517 Each RaRbN line is independently selected by grazing mountain, 丄, wherein RlRb are each independently selected from the group consisting of hydrogen Α 虱 alkenyl and C 丨 · 6 alkyl; L is selected from The following group of groups:

Each X system is independently selected from the group consisting of: ΝΗ-, 〇 (oxygen), S (sulfur), and -CH2-; κψ^} Each A-system is independently selected from the group consisting of A 3 卜: CR3 And N (nitrogen); each R3 is independently selected from the group consisting of: r. nr consisting of hydrogen, c, -6 alkoxy,

Ci.6 alkyl-based OCk base, c-lu | 6 said base oc (=〇)-, aryl alkyl oc (=o)-, -COOH, halogen, surface

, RaRbmcr=.., base, RR N-, (WN) alkyl, ) (0)-, depending on the situation j; brother to the guest q phase + Gan% l. 目,, σ 丄 to the evening 9 halogen Substituted C丨_6 alkyl and, as the case may be, up to 5 c丨·6 alkyl groups substituted by a certain enthalpy; L6 is selected from the group consisting of:

The L7 is selected from the group consisting of:

156115.doc •39· 201200517

each. The lines are independently selected from the group consisting of -(CH=CH)-; each X4 line is independently selected from the group consisting of: cr4an (nitrogen); each Y4 line is independently selected from the group consisting of: C (R4) 2, NR4, hydrazine (oxygen) and S (sulfur); each R4 is independently selected from the group consisting of Ci6 alkoxy, Ci6 alkyl ocw alkyl, Cl-6 alkyl oc (=0) _ , arylalkyl 〇 c (= 〇), _c 〇〇 h, halo, Cu dentate, thiol, RaRbN-, (RaRbN) alkyl, (RaRbN) C (= 〇) -, as the case may be Up to 9 yl-substituted 1-6 alkyl groups and optionally up to 5 hydroxy-substituted Cl. 6 alkyl groups, or optionally 2 oximes R4, are pendant oxy groups; each m is independently 1 or 2 Each η is independently 〇, 1 or 2; each ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; and each r is independently 〇, 1, 2, 3 or 4,

The restriction is that L6-L4-L7 is not in some embodiments of Formula VIII. Each R1 is RlaC(=0)-. In some embodiments of the formula vm 156115.doc -40-201200517, each is only "-CHR2aNHR3b. In some embodiments of Formula VIII, each ruler is "匸" alkyl; each R3b is -C(=0) 0R5; and each R5 is a Cw alkyl group. In some embodiments of Formula VIII, the L6-:L4-L7 is selected from the group consisting of:

156115.doc •41- 201200517

In some embodiments of Formula VIII, each L6 is selected from the group consisting of

In some embodiments of Formula VIII, the compound is not selected from the group consisting of:

156115.doc •42- 201200517

In some embodiments, the compound of Formula VIII has the structure of Formula Villa:

156115.doc -43· S 201200517

R

Villa or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted with up to 9 halo-substituted Cw alkyl groups. In some embodiments, R6 is methyl. Some embodiments include a compound having the structure of Formula IX:

IX or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, RlaC(=0)-, and RlaC(=S)-; 156115.doc •44-201200517 each "" is independently selected from the group consisting of: _C(R2a)2NR3aR3b, alkoxyalkyl, Cw alkyl oc(=o)-, CN6 alkyl 〇c(=o)c.6 alkyl, CN6 Alkyl (:(=0)(:,-6-alkyl, aryl, aryl(CH2)n-, aryl(CH2)nO-, aryl(CH=CH)m-, arylalkyl〇 _, arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl (CH=cH)m -heterocyclylalkoxy, heterocyclyl-based, heterocyclic-based fluorenyl, via-based, RCRdN_, Φ RCRdN(CH2)n-, (RCRdN)(CH=CH)m·, (RcRdN An alkyl group, (ReRdN)C(=0)-, optionally a Ci 6 alkoxy group substituted with up to 9 groups, and optionally up to 9 _ group substituted 〇1_6 alkyl groups, the aryl group and the hetero group The aryl groups are each substituted by the following groups: cyano, yl, nitro, hydroxy, optionally up to 9 dentyl substituted Cl. 6 alkoxy and optionally up to 9 halo Cw alkyl; each ReRdN is independently selected, wherein Re and Rd are each independently selected from the group consisting of hydrogen, alkoxy c (=〇)...Ci 6 alkyl, Ci6 alkyl® C (〇 )-, CN6-based thiol, arylalkyl 〇c(=〇)_, arylalkyl, arylalkyl c(=〇)_, aryl c(=0)...arylsulfonate , heterocyclylalkyl, heterocyclylalkyl C(=〇)-, heterocyclyl C(=〇)_, (ReRfN)alkyl, (ReRfN)alkyl C(=0)- and (ReRfN c(=〇)_, wherein the alkyl moiety of the arylalkyl group, the arylalkyl group C(=〇)-, the heterocyclylalkyl group and the heterocyclylalkyl group c(=〇)_ are each optionally a ReRfN_ group substituted; and wherein the arylalkyl group, the arylalkyl group c(=0)-, the aryl group c(=0)_, and the aryl moiety of the arylsulfonyl group, and the heterocyclylalkyl group The heterocyclyl moiety of the 'heterocyclylalkyl c(=0)_&amp;heterocyclyl group c(=0)_, each optionally, up to three, each independently selected from the group consisting of 56115.d〇c-45· Substituents for the group of 201200517 are substituted: cyano, halo, nitro, optionally substituted by up to 9 halo. C. 6 alkoxy and optionally up to 9 functional groups substituted by C 1 ·6 Base ReRfN is independently selected from the group consisting of: hydrogen and c]-6 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterogeneously selected from the group consisting of: a cyclic group, a heterocyclylalkyl group, a (RxRyN)alkyl group, and (RxRyN)C(=〇)-; each RxRyN is independently selected, wherein only * and ^ are each independently selected from the group consisting of hydrogen, Cl_6 alkyl 0C (=0) _, Ci 6 alkyl, Ci 6 alkyl C (= 〇)-, aryl, arylalkyl, cycloalkyl and heterocyclic; each C (R2a) 2 is independent Selected as follows, wherein each R 2a is independently selected from the group consisting of hydrogen, optionally up to 9 halo substituted C16 alkyl, aryl (CH 2 ) n and heteroaryl (CH 2 ) n -, The aryl and heteroaryl groups are each optionally substituted by the following groups: cyano, halo, nitro, hydroxy, optionally up to 9 halo substituted C _ 6 alkoxy and optionally up to 9 halo

The Cw alkyl group substituted, or c(R2a)2, wherein each R3a is independently selected from the group consisting of hydrogen and optionally substituted CN6 alkyl; each R3b is independently selected from the group consisting of: The situation has been replaced

Ci-6 alkyl, heteroaryl, _(cH2)nC(=0)NR4aR4b, _(CH2)nC(=0)0R5a and -(CH2)nC(=〇)R", the heteroaryl optionally Substituted by the following groups: cyano, halo, nitro, hydroxy, optionally up to 9 halo substituted C丨6 alkoxy and optionally up to 9 dentate substituted Cl-6 alkyl; 156115. Doc • 46. 201200517 Each R "R, is independently selected, wherein R4a and R4b are each independently selected from the group consisting of hydrazine, optionally substituted carboalkyl and aryl (CH2)n-; Each Rsa is independently selected from the group consisting of cN6 alkyl and aryl (CH2)n_ substituted by up to 5 R2 groups; each R6a is independently selected from the group consisting of: C!·6 alkyl and aryl (cH2)n_;

Χ1 is (c(R2)2)q, Y Wr , or X1 is absent; Y1 is selected from the group consisting of 〇 (oxygen), S (sulfur), s(0), s〇2, NR2, and c(r2)2, The restriction condition is that when X1 is not present, Y^C(R2)2;

X2 is (C(R2)2)q, λ wr , or 2 is absent; Y2 is selected from 〇 (oxygen), S (sulfur), s(9), s〇2, NR2, and C (2, the constraints thereof In the absence of X2, γ2 is C(R2)2, and each R2 is independently selected, wherein r2 is selected from the group consisting of 虱, 氘, C丨.6 alkoxy, c丨· 6 alkyl, aryl, dentate, hydroxy, WN- and optionally substituted by up to 9 dentate C1. "Complete, or as the case 2, 2, and the carbon to which it is attached - as the case may be - or two separate, selected from 0 (oxygen), N (nitrogen) and 8 (sulfur) heteroatoms of slightly more than 3 members to 8 members of carbon % 'where the 3 to 8 members of the carbon ring Or a plurality of substituents selected from the group consisting of m, a trans group, a pendant oxy group, a m R compound C (=0), a R compound Ci 6 alkyl group, a heteroaryl aryl group, Ϊ56115.doc • 47- 201200517 Optionally, up to 9 halo-substituted Ci_6 alkyl groups and optionally up to 9 halo-substituted C 6·6 alkoxy groups, at least one of R 2 being deuterium or RZa, Rh, Rh, R 4b, RSa and Rfia, at least one of which is substituted cN0 alkyl substituted with at least one non-alkyl substituent or a substituted aryl group substituted with a non-alkyl substituent; each of the groups 4 is independently selected, wherein ... and ... are each independently selected from the group consisting of hydrogen, C2-6 alkenyl, and Cl-6 alkyl; The L1 line is independently selected from the group consisting of:

-(:(=0)((^2)^0(:(=0)-, -C(CF3)2NR2c- and

R2e is selected from the group consisting of hydrogen, Cl-6 alkyl, c2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl a base, a heterocyclic group, and a heterocyclic group alkyl group. The alkyl group is optionally substituted with ReRfN_, alkoxy or Cw alkyl S-;

Each X3 system is independently selected from the group consisting of NH, NC1-6 leumino, hydrazine (oxygen), and S (sulfur); each m is independently 1 or 2; each η is independently 0, 1, or 2; Each ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 0, 1, 2, 3 or 4; and each R7 is independently selected Free group consisting of: hydrogen, Cl_6 alkyl 156115.doc •48· 201200517 〇C( 0) 基基烧基〇C(=〇)-, -COOH, (RaRbN)C(=0)-, trioxane A C 1.6 alkyl group substituted with an alkylalkylalkyl group and optionally up to 9 dentities. In some embodiments of Formula IX, each R1 is RlaC(=〇). In some embodiments of Formula IX, each Rla is _CHR2aNHR3b. In some embodiments of the formula, each R2a4Cl_6 alkyl; each R3bg_c(= 〇)〇R5; and each ... is a Ci-6 alkyl group. In some embodiments of Formula IX, at least one Rla is each -C(R2a)2NR3aR3b and in the at least one Rla, at least one R2a is substituted C?-6 alkyl substituted with at least one non-alkyl substituent or Substituted aryl substituted with at least one non-alkyl group substituent. In some embodiments, at least one R1!^-C(R2a)2NR3aR3b, wherein R3»^_(CH2)nC(:=〇)〇Rsa and RSa is substituted with at least one non-alkyl substituent Substituted aryl substituted by c] 6 alkyl or substituted with at least one non-alkyl substituent. In some embodiments, at least one of R2a, R3a, R4a, R4I&gt;, R5a, and R6a is a C!·6 alkyl group substituted with up to 9 halogens or an aryl group substituted with up to 9 halogens. . In some embodiments of Formula IX, each R 2 is independently selected from the group consisting of hydrogen, C. 6 alkyloxy, aryl, halo, thio, thio, and optionally up to 9 A halogen group substituted C!·6 alkyl. In some embodiments of Formula IX, at least one of R2a, R3a, R4a, Rule 41) and R6a is an aryl group substituted with up to 9 halogen-substituted Ci_6 alkyl groups or up to 9 halogens. In some embodiments, the compound of Formula IX has the structure of Formula IXa: I561i5.doc • 49· 201200517

Or a pharmaceutically acceptable salt thereof, in R, R6, in J, R&lt;&gt;&gt;melon&quot;f&quot; is a Cw alkyl group substituted with up to 9 halo groups, as the case may be. In some embodiments, R6 is methyl. Some embodiments include a compound having the structure of Formula X:

Or a pharmaceutically acceptable salt thereof, wherein: hydrogen, RlaC(=0)-, and C(R2a)2NR3aR3b, each of which is independently selected from the group consisting of

RlaC(=s).; Each R is independently selected from the group consisting of 1561l5.doc •50·201200517 alkoxyalkyl, Cw alkyl 〇C(=〇)-, Cb6 alkyl 0(:(= 0) (^-6 alkyl, CN6 alkyl CpCOCu alkyl, aryl, aryl (CH2)n-, aryl (CH2)nO-, aryl (CH=CH)m-, arylalkyl hydrazine _, arylalkyl, aryl 0 alkyl, cycloalkyl, (cycloalkyl) (CH=CH) m_, (cycloalkyl)alkyl, cycloalkyl 0 alkyl, heterocyclic, heterocyclic , heterocyclylalkoxy, heterocyclylalkyl, heterocyclyl anthracenyl, hydroxyalkyl, ReRdN_,

RcRdN(CH2)n-, (RcRdN)(CH=CH)m-, (RcRdN)alkyl, (ReRdN)C(=0)-, optionally up to 9 halo-substituted c16 alkoxy groups and In the case of up to 9 dentate-substituted Cl6 alkyl groups, the aryl and heteroaryl groups are each optionally substituted by a cyano group, a functional group, a nitro group, a hydroxyl group, optionally substituted with up to 9 halo groups. C1-6 alkoxy and optionally up to 9 halo substituted C _ 6 alkyl; each ReRdN is independently selected wherein R«: and Rd are each independently selected from hydrogen, alkoxy C (= 〇)-, Cl_6 alkyl, Cl 6 alkyl c(=〇)_, Cl_6 alkylsulfonyl, arylalkyl 0C (=0)_, arylalkyl, arylalkyl c (=〇 ), aryl c(=o)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl C(=0)-, heterocyclyl C(=0)_, (ReRfN) , ()ReRfN)alkyl c(=0)- and (ReRfN)C(=0)-, wherein arylalkyl, arylalkyl C(=0)-, heterocyclylalkyl and heterocycle The alkyl moiety of the alkyl group (7)- is each optionally substituted with a ReRfN- group; and wherein the arylalkyl group, the arylalkyl group C(=0)-, the aryl group (:(:=〇)_ And an aryl moiety of an arylsulfonyl group, and The heterocyclic moiety of the cyclic ketone, heterocyclyl c(=0)-, and heterocyclyl c(=〇)-, each optionally, up to three substituents each independently selected from the group consisting of Substitution: cyano, halo, nitro, optionally up to 9 halo 156115.doc •51 - 201200517 Substituted C,·6 alkoxy and optionally up to 9 groups substituted by cl 6 alkyl Each ReRfN is independently selected, wherein Re and Rf are each independently selected from the group consisting of hydrogen, C!·6 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclic , heterocyclylalkyl, (WN)alkyl and (RxRyN)c(=o)-; each RxRyN is independently selected, wherein !^* and Ry are each independently selected from hydrogen, C]-6 alkyl hydrazine C(=0)·, C〗.6 alkyl, Ci-6 alkyl c(=o)-, aryl, arylalkyl, cycloalkyl and heterocyclic; each C(R2a)2 is independent The ground is selected wherein each R2a is independently selected from the group consisting of hydrogen, optionally substituted c-alkyl, aryl (CH2)n•, and heteroaryl (CH2)n-, the aryl group. And heteroaryl groups are each substituted by the following groups. Cyano group, dentate group, terminal group, surface group, as appropriate In the case of up to 9 halo-substituted c,6 alkoxy groups and optionally up to 9 halo groups.

Cw alkyl, or C(R2a)2, wherein each R3a is independently selected from the group consisting of hydrogen and optionally substituted CN6 alkyl; each R3b is independently selected from the group consisting of: Cw alkyl, heteroaryl, _(CH2)nC(=〇)NR4aR4b, _(CH2)nC(=〇)〇RSa and -(CH2)nC(=〇)R6«' the heteroaryl optionally Substituted by: cyano, dentate, nitro, hydroxy, Ci6 alkoxy substituted with up to 9 functional groups, and optionally up to 9 halo substituted c丨·6 alkyl; R4aR4bN is independently selected, wherein R4a and R4b are each independently selected from the group consisting of hydrogen, optionally substituted Cu alkyl, and aryl 156115.doc • 52· 201200517 (CH2)n-; each RSa Independently selected from the group consisting of: optionally substituted 匸1.6 alkyl and aryl ((:112) „-; each 63 series independently selected from the group consisting of: · optionally substituted Cl- 6 yard base and aryl (CH2)n_,

X1 is (C(R2)2)q, Y, or X1 does not exist;

Y1 is selected from the group consisting of 0 (oxygen), S (sulfur), s (〇), S〇2, NR2 and C(R2)2,4 with the constraint that when χΐ is absent, Y1 is C(R2)2; X2 Is not present in (C(R2)2)q, or X2; Y2 is selected from 0 (oxygen), S (sulfur), S(O), S〇2, NR2 and C(R2)2, with restrictions In the absence of X2, Y2 is c(r2)2; each R2 is independently selected, wherein R2 is selected from the group consisting of: hydrogen, C!6 oxime, aryl, halo, hydroxy , RaRbN_ and optionally up to 9 halo substituted c]_6 alkyl' or, as the case may be, 2 R2 together with, as the case may be, one or two, each independently selected from hydrazine (oxygen), A fused 3- to 8-membered carbocyclic ring of a hetero atom of N (nitrogen) and S (sulfur); wherein the 3 to 8 membered carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of: Base, hydroxy, pendant oxy, RXRyN, RXRyNC (=〇), RR NCw, aryl, aryl, optionally substituted by up to 9 dentate C. 6 alkyl and optionally up to 9 Substituted by a dentate group [decyloxy; each WN system, independently selected, wherein each is independently selected from 15 6115.doc -53- 201200517 A group consisting of nitrogen, C2-6, and Ci-6 alkyl; L8 is selected from the group consisting of:

The L9 is selected from the group consisting of:

The L1G line is selected from the group consisting of: 156115.doc -54· 201200517

Each χ3 series is independently selected from the group consisting of: NCi 6 alkyl, oxime (oxygen), and S (sulfur); each m is independently 1 or 2; each η is independently 〇, 1 or 2; Independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; and each r is independently 〇, 1, 2, 3 or 4, wherein Rh, RSa and R6a At least one of them is a substituted C丨.6 alkyl group.

In some embodiments of Formula X, each is 13 (: ( = 〇) _. In some embodiments of Formula ,, each Rh is -CHWhr3·». In some embodiments of Formula ,, each 1 ^ is (:1-6 alkyl; each r3»^_c(=〇)〇rS; and each rS 1 · 6 alkyl" In some embodiments of formula X, at least one Rla is _c(R2a)2NR3aR3b And in the at least one Rh', at least one R2a is a substituted alkyl group. In some embodiments of Formula X, at least one Rla is wherein R3, -(CH2)nC(=〇)OR5a and R5a are substituted Ci 6 yard base. At 156115.doc -55- 201200517

In some embodiments of Formula X, at least one of R2a, R3a, R4a, R4b, RSa, and R6a is an aryl group substituted with up to 9 halogen-substituted Cw alkyl groups or up to 9 dentate substitutions. In some embodiments of Formula X, each R2 is independently selected from the group consisting of hydrogen, C. 6 alkoxy, aryl, halo, thio, RaRbN-, and optionally up to 9 halo. Substituted Cw alkyl. In some embodiments of Formula X, at least one of R2a, R3a, R4a, R4b, and R6a is an aryl group substituted with up to 9 halogen-substituted C -6 alkyl groups or up to 9 elements. In some embodiments of Formula X, the L9 is selected from the group consisting of

R*

Group: R2 In some embodiments, the compound of formula X has the structure of formula Xa:

Xa or a pharmaceutically acceptable salt thereof wherein R6 is optionally substituted with up to 9 halo groups. In some embodiments, it is a methyl group. Some embodiments include compounds having the structure of Formula XI: Human R2 X1 丫 R2 N-/-L20-J2 〆R2 156115.doc -56-

XI 201200517 or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, Rlac(= 〇)_&amp;RlaC(=S)-; 厌" is selected from the group consisting of Group: alkoxyalkyl, CU6 alkyl 0C (=0)-, Cb6 alkyl 0 (: (=0) (^..6 alkyl, Cw thiol (: (=0) (^.6) Alkyl, aryl, aryl (CH2)n〇, aryl (CH=CH)m_, arylalkyl 0-, arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl) (CH=CH)m-, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclic, heterocyclic (CH=CH)m_, heterocyclylalkoxy, heterocyclylalkyl , heterocyclic fluorene, hydroxyalkyl, RcRdN-, ReRdN(CH2)n-, (ReRdN) (CH=CH)m-, (RcRdN)alkyl, (RcRdN)C(=0)-, visual In the case where more than 9 _ groups are substituted (^.6 alkoxy groups and, as the case may be, at most 9 substituents, C!_6 alkyl groups, the aryl and heteroaryl groups are each substituted by the following groups: cyanide a base, a dentate group, a nitro group, a hydroxyl group, optionally a Cu alkoxy group substituted with up to 9 functional groups, and optionally a Cl. 6 alkyl group substituted with up to 9 functional groups; Rc&Rdg is independently selected from Group of constituents: hydrogen, alkoxy C(=〇)-, C -6 alkyl, Cw alkyl C(=0)-, Cw alkylsulfonyl, arylalkyl 0C (=0)- , an arylalkyl group, an aryl group c(=〇)_, an aryl C(=0)-, an arylsulfonyl group, a heterocyclylalkyl group, a heterocyclylalkyl group c(=〇)_, Heterocyclyl C(=0)-, (ReRfN)alkyl, (ReRfN)alkyl c(=0)- and (ReRfN)C(=0)- 'wherein arylalkyl, arylalkyl c( =〇), the heterocyclic alkyl group and the alkyl group of the heterocyclylalkyl group C(=〇)• are each optionally substituted by a ReRfN- group; and wherein the aryl group, the aryl group c ( =〇)_, 芳156115.doc •57-201200517 base c(=o)- and arylsulfonyl aryl moiety 'and heterocyclylalkyl, heterocyclylalkyl C(=0)- and The heterocyclic group of the heterocyclic group c(=0)-, respectively, is optionally substituted with up to three substituents each independently selected from the group consisting of: cyano, halo, nitro, optionally up to 9 a halo-substituted C 6 alkoxy group and optionally a c -6 alkyl group substituted with up to 9 dentate groups; each of the ruthenium groups is independently selected, wherein R* and Rf are each independently selected from the group consisting of Group: hydrogen, Cl·6 alkane , aryl, arylalkyl, cycloalkyl, (cyclohexyl)alkyl, heterocyclyl, heterocyclyl, (RXRyN)alkyl and (RxRyN)C(=0)-; each RxRyN Independently selected, wherein RX and ... are each independently selected from the group consisting of hydrogen, CN6 alkyl 〇c(=〇)-, Cl 6 alkyl, Ci 6 alkyl c (==〇), aryl, arylalkane a group selected from the group consisting of hydrogen, optionally substituted c μalkyl, aryl (CH 2 ) n - and heteroaryl (CH 2 ) n —, aryl And the heteroaryl group, respectively, may be substituted by a group of ni-methyl groups, as appropriate, with up to 9 i-substituted alkoxy groups and optionally up to 9 halo groups. a substituted c丨 alkyl group, or (:(112»)2 is \/V; R is selected from the group consisting of hydrogen and optionally substituted c"alkyl; the heart is selected from the group consisting of : optionally substituted Cl.6 alkyl, heteroaryl, -(CH2)nC(=0)NR "R4b, _(CH2)nC(=〇)〇R5a(H2)nC(-〇)R , The heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of cyano, i-, nitro, thiol, 156115.doc-58·201200517, substituted by up to 9 halo Cw alkoxy and, optionally, up to 9 halo-substituted Ck alkyl groups; the ruler "and the ruler 41" are each independently selected from the group consisting of hydrogen, optionally substituted C -6 alkyl and aryl a group (CH2)n-; each RSa is independently selected from the group consisting of CiAC alkyl and aryl (CH2)n-, as appropriate;

Each R6a is independently selected from the group consisting of Ck6 alkyl and aryl (CH2)n-, as appropriate; X1 is (C(R2)2)q

Or X1 is absent; Y1 is selected from the group consisting of 0 (oxygen), S (sulfur), S(O), S02, NR2, and C(R2)2, with the constraint that when X1 is absent, γ1 is C(R2) 2 ;

Each R2 is independently selected, wherein r2 is selected from the group consisting of hydrogen, C!6 alkoxy, aryl, halo, hydroxy, RaRbN_ and, optionally, up to 9 halo substituted c 〖6 Burning base' or, as the case may be, two r2 together with the carbon to which it is attached, as the case optionally contains one or two heteroatoms each independently selected from the group consisting of helium (oxygen), helium (gas) and S (sulfur) heteroatoms. a 3- to 8-membered carbocyclic ring; wherein the 3 to 8 membered carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, pendant oxy, R*RyN, RxRyNC ( = 〇), r RyNc!·6 alkyl, heteroaryl, aryl, optionally up to 9 halo substituted C丨-6 alkyl and optionally up to 9 self-substituted.丨·6 alkoxy, or optionally 2 偕R2 together with the carbon to which they are attached is a carbonyl group, or 2 偕R, as the case may be, together with the carbon to which it is attached, optionally up to 2 a 6 alkyl groups 3 to 6 carbon rings; 156115.doc -59-201200517 Each RaRbN system is independently selected, wherein Ra&amp;Rb are each independently selected from the group consisting of: hydrogen, C2.6 alkenyl, and C. L20 is selected from the group consisting of QLQ2, Q3-Q4,

Q1 is selected from the group consisting of J5, J4-J5, jLjS-J10, jLjLj3

156115.doc -60- 201200517

Z1 is selected from the group consisting of C(R2)2; 〇(oxygen), S(sulfur NR and each 'system are independently selected from the group consisting of: cr3 and 戦广R each independently selected from the following 纟. , 成之群·虱, c!-6 alkoxy, i-6-based 〇Cl-6 alkyl, k-alkyl OC(tetra))-, arylalkyl OC (which, -Cb〇〇H, halo) , a radical, RH(RaRbN)alkyl'(RaR N)C (drinking_, optionally up to 9 radicals and up to 5 radicals substituted cK6 alkyl;

G1 is -CH2- or -CH2CH2-;

R2e is selected from the group consisting of hydrogen, Ci-6 alkyl 'c2 6 alkenyl, C2·6 alkynyl, C3_7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero a cyclic group and a heterocyclic group, which are optionally substituted by ReRfN... 156115.doc 201200517 oxy or Cw alkyl s-; J2 is aryl, heteroaryl, heterocyclic or polycyclic hydrocarbon, Each is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, RxRyN, RxRyNC (=0), WNCw alkyl, heteroaryl, aryl, optionally up to 9 And a Cw alkoxy group substituted with up to 9 halo groups, optionally substituted with one or more R14; each R14 is independently selected Free group consisting of hydroxyl groups, optionally up to 9 fluoro group-substituted Cw alkoxy groups, Cl6 alkyl hydrazine Ci6 alkyl groups, Ci_6 alkyl oc(=o)_, arylalkyl oc (=0) _, _c〇〇H, halo and optionally up to 9 halo-substituted C 6 alkyl groups; J is C2_4 alkyl, NH, 0 (oxygen), ΝΗ (: (〇)·, s (sulfur ), _(CH2)nX8(CH2)m_ or -X7=X7-; J4

And -C(CF3)2NRZC- or J5 is an aryl group, a heteroaryl group, a heterocyclic group or a polycyclic hydrocarbon, each of which is optionally substituted by one or more R3;

〇 (oxygen) and S (sulfur);

Each m is independently 1 or 2; 156115.doc 201200517 each η is independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2' 3 or 4; each R is independently selected from the group consisting of hydrogen, Ci-6 alkyl 〇C(=〇)_, arylalkyl 〇c (=〇)-, (RaRbN)C(=0)- and, as the case may be, up to 9 dentate-substituted Cl-6 alkyl groups; and R7 is selected from the group consisting of hydrogen, halo, (:6-alkane) Base 〇C(=〇)-, arylalkyl 〇c(=〇)-, -COOH, (RaRbN)C(=〇)_, trialkyl sulphate alkyl decyl group and, as the case may be, at most 9! I group substituted Cw alkyl. In some embodiments of Formula XI, the L2 lanthanide is selected from the group consisting of:

N 156115.doc -63- 201200517

B2 is an aliphatic ring including 0 (oxygen), S (sulfur) 4NH, or optionally a N (nitrogen) aromatic ring, and the aliphatic or aromatic ring in the definition of B2 is optionally subjected to one or more Rg Substituting; and each of the groups is independently selected from the group consisting of: ", hydroxy, optionally up to 9 fluoro group-substituted Ci_6 alkoxy groups, and optionally up to 9 dentate groups (:, .6 alkane) In some embodiments of Formula XI, Q is selected from the group consisting of: 156115.doc -64· 201200517

One or more Rg substitutions;

Each Rg is independently selected from the group consisting of halohydroxyl, optionally up to 9 fluoro-substituted Cw entertainment; oxy and optionally up to 9 halo substituted (^.6 alkyl. In some embodiments of Formula XI, Q3 is selected from the group consisting of:

156115.doc -65- 201200517

B2 is an aliphatic ring including 0 (oxygen), s (sulfur) or nh or an aromatic ring including N (nitrogen) as appropriate, and the aliphatic or aromatic ring in the definition of B2 is one or more depending on the situation. Rg is substituted; and each line is independently selected from the group consisting of: up to 9 fluoro group-substituted Ci.6 alkoxy groups, as appropriate, and optionally up to 9 dentate groups ( ^.6 alkyl. In some embodiments, the χι compound has the following structure:

156115.doc -66- 201200517

156115.doc -67- 201200517

156115.doc • 68 - 201200517

Or a pharmaceutically acceptable salt thereof. Some embodiments include a compound having the structure of Formula XII:

R

156115.doc •69·

XII 201200517 or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of argon, Rlac (= 〇)_&amp;

RlaC(=s)-; each 1^ is independently selected from the group consisting of: _c(R2a)2NR3aR3b, alkoxyalkyl, Cb6 alkyl oc(=o)-, Cl 6 alkyl 0C (=0 )Cl_6 alkyl, CN6 alkyl (:(=0)(:,-6-alkyl, aryl, aryl(CH2)n, aryl(CH2)n〇-, aryl (CH=CH)m• , arylalkyl hydrazine, arylalkyl, aryl 0 alkyl, cycloalkyl, (cycloalkyl) (CH=CH)m_, (cycloalkyl)alkyl, cycloalkylalkylalkyl, Heterocyclic group, heterocyclic group (CH=CH)m, heterocyclylalkoxy group, heterocyclylalkyl group, heterocyclic group 0 alkyl group, hydroxyalkyl group, ReRdN_, RRN(CH2)n-, (RCRdNXCi^ CH:^-, (RcRdN)alkyl, (ReRdN)C(=〇)-, as the case may be substituted with up to 9 functional groups of 6 alkoxy groups and optionally up to 9 _ groups substituted 〇16 alkane The aryl group and the heteroaryl group are each optionally substituted by a group: a cyano group, a benzyl group, a schiff base group, a thiol group, a phenanthrene group, a J group, and at most 9 halogen groups substituted by a Ci6 alkoxy group. In the case of up to 9 dentate-substituted CN6 alkyl groups; each RRN is independently selected, wherein... and each independently selected from the group consisting of f, alkoxy C(=〇)_, C -6 alkyl, Ci_6 Alkyl c ( a 6 alkyl 1 group, arylalkyl hydrazine C (which, fluorenyl aryl, aryl alkyl c (= 〇) _ aryl Ac ( 〇) _, aryl sulfonyl, heterocycloalkyl ,heterocyclylalkyl C(0)·,heterocyclyl C(=0)-, (ReRfN)alkyl, (ReRfN)alkyl c(=〇)-, and (ReRfN)c(=0)_, Wherein arylalkylarylalkyl 156115.doc 201200517 c(=o)-, heterocyclylalkyl and heterocyclylalkyl. The alkyl moiety of (=0)_ is optionally subjected to a ReRfN-group Substituted; and wherein the arylalkyl group, the arylalkyl group C(=0)-, the aryl group of the aryl C(=〇)- and the arylsulfonyl group, and the heterocyclic alkyl group, heterocycloalkane The heterocyclyl moieties of the group (:(=〇)_ and heterocyclyl C(=〇)- are each optionally substituted with up to three substituents each independently selected from the group consisting of a cyano group, a functional group, Nitro, depending on the situation, up to 9 halo groups

Substituted Cu alkoxy and, optionally, up to 9 dentate substituted 6 alkyl groups; each ReRfN is independently selected wherein Re and Rf are each independently selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkane , cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (WN)alkyl and (RXRyN)c(=〇)_; each RxRyN is independently selected, wherein RX And Ry are each independently selected from the group consisting of hydrogen, CN6 alkyl 〇c(=〇)·, Cu alkyl, c, -6 alkyl C(=〇)-, aryl, arylalkyl, cycloalkyl and hetero Each of the C(R2a)2 groups is independently selected, wherein each RZa is independently selected from the group consisting of hydrogen, optionally up to 9 halo-substituted Cm alkyl groups, aryl groups (CHA- and a heteroaryl group (CH2)n_, the aryl group and the heteroaryl group being optionally substituted by a cyano group, a cyano group, a schiff base group, a thiol group, a Ci6 oxy group substituted with up to 9 dentate groups, and optionally Up to 9 Nanxun as appropriate. Substituted by a C alkyl group, or C(R2a)2*; each R3a is independently selected from the group consisting of hydrogen and optionally substituted cN6 alkyl; each independently selected from the group consisting of Group··I56115.doc as required. •71· 201200517

Ci-6 alkyl, heteroaryl, _(cH2)nC(=0)NR4aR4b, _(CH2)nC(=0)0RSa and -(CH2)nC(=〇)R6a, the heteroaryl is optionally Substituting the following groups: cyano, a functional group, a nitro group, a hydroxy group, a Cl 6 alkoxy group substituted with up to 9 halo groups, and optionally a c 1-6 alkyl group substituted with up to 9 dentate groups; R4aR4bN is independently selected wherein only "and R4b are each independently selected from the group consisting of hydrogen, optionally substituted Ci 6 alkyl, and aryl (CH2)n-; each R5a is independently selected from the group consisting of a group consisting of: optionally substituted C!·6 alkyl and aryl (CH 2 ) n-; each R 6a is independently selected from the group consisting of CN6 alkyl and aryl (CH 2 ) as appropriate substituted N-; X is (C(R2)2)q, 'or χι does not exist; Υ1 is selected from 0 (oxygen), S (sulfur), S(O), S02, NR2 and C(R2)2, The constraint is that when X1 is not present, γΐ is C(R2)2; X2 is (C(R2)2)q

, or X2 is absent; Y2 is selected from the group consisting of 0 (oxygen), S (sulfur), s (0), S〇2, NR2, and C(R2)2, with the constraint that when X2 is absent, γ2 is C. (R2)2; each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, C!-6 alkoxy, C&quot; alkyl, aryl, halo', and RaRbN_ and Optionally, up to 9 halo-substituted C _ 6 alkyl groups, or optionally 2 adjacent R 2 together with the carbon to which they are attached, as the case may be up to 2 c 丨 6 alkyl substitutions 156115.doc -72- The fused 3-member to 6-membered carbocycle of 201200517; each RRN is independently selected 'wherein Ra&amp;Rb are each independently selected from the group consisting of hydrogen, C2.6 dilute, and Cl.6 alkyl; Independently selected from the group consisting of: cr3 and N (gas); : -(jVclVcjVcl5)^-,

- , , -c(=o)·, 〇 (oxygen),

〇C(R )2 H '-C(CF3)2NR2c- &gt;NH^-(CH=CH)-; J is aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl or polycyclic a hydrocarbon, each of which is optionally substituted with one or more R1S; each R&quot; is independently selected from the group consisting of a hydroxyl group, optionally a fluoro group substituted with a fluoro group, and an alkyl group ( 6 alkyl, alkyl 〇c(=〇)-, thiol-based group% (, _, _c〇()h, a functional group and, if appropriate, up to 9 halo-substituted Cl_6 alkyl groups; each R15 is independent The group is selected from the group consisting of a halogen group, a hydroxyl group, a Cw alkyl group OC^alkyl group, a Cl_6 alkyl group oc(=〇), an arylalkyl group (:(=〇)_, -COOH, R9, WN , RXRyNC (=〇), RXRyNCi 6 alkyl, heteroaryl, aryl, optionally substituted by up to 9 dentyl Ci6 alkyl, substituted by up to 5 hydroxy groups of C -6 alkyl, as appropriate Up to 9 halo-substituted Ci_6 alkoxy groups, Cl-6 functional groups, RaRl>N_, (RiiRbN) alkyl, (RaRbN)C(=〇)-, Ci 6 Hyun substituted with up to 5 radicals The substituents and the substituents are each replaced by one or more R&quot; or, as the case may be, 2 adjacent R15 The attached carbon together is a fused 3-member to 6-membered carbocyclic ring substituted with up to 2 ci 6 alkyl groups as appropriate, or 2 偕Rls as the case may be associated with the carbon to which 156115.doc •73· 201200517 is attached In the case of up to 2 Cl_6 alkyl substituted 3 to 6 carbon rings 'or 2 as appropriate, R 15 - as a pendant oxy group;

And -(CH=CH)-; R2c is selected from the group consisting of hydrogen, Cl-6 alkyl, C2-6 alkenyl, C: 2.6 alkynyl, C3.7 cycloalkyl, aryl, arylalkyl a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic group, which are optionally substituted with ReRfN, a methoxy or a Cw alkyl S-; the L6 is selected from the group consisting of:

The L7 is selected from the group consisting of:

156115.doc _ 74. 201200517

: CR4 and N (nitrogen), wherein: N (nitrogen) and CR8; group: C(R4)2, NR4, each x4 is independently selected from the group consisting of: if X4 is N (nitrogen)' then γ4 is not Each X6 is independently selected from the group consisting of Y series independently selected from the group consisting of hydrazine (oxygen) and S (sulfur); hydrazine (oxygen) and each Y9 system are independently selected from S (sulfur); The following composition group: -ΝΗ-, each X9 series is independently selected from the group consisting of CH and Ν (nitrogen), wherein if X9 is Ν (nitrogen), γ9 is not ΝΗ; . The lines are independently selected from the group consisting of: Ma and _ΝΗ·; each LU line is independently selected from the group consisting of underarms: (5) Guan and ΝΗ;

Each L12 is independently selected from the group consisting of: a code and each of the l13 are independently selected from the group consisting of mCH·CH -CH2CH2-, -(CH2)mNR4(CH2)n-, and _(CH2)m〇 (CH2)n_ each m is independently 1 or 2; each η is independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5 ; each independently is 〇, 1, 2, 3 or 4; each s is independently 〇 or 1; 156115.doc -75- 201200517 Each R3 is independently selected from the group consisting of hydrogen, Ci.6 Alkoxy group, Cl-6 alkyl group 0 (:!·6 alkyl group, C|-6 alkyl group 0C(= 0)_, arylalkyl group C(=〇)_, -COOH, _ group, hydroxyl group , RaRbN-, (RaRbN)alkyl, (RaRbN)C(=〇)-, optionally up to 9 dentate groups and up to 5 thio-substituted CN6 alkyl groups; each R4 system is independently selected from the group consisting of Group: hydrazine (hydrogen), C] · 6 alkoxy, C 〗 6. Alkyl OCm alkyl, Cw alkyl 〇 c (= 〇) -, arylalkyl 〇 C (= 〇) -, -COOH , halo, haloalkyl, mercapto, RaRbN-, (RaRbN)alkyl, (RaRbN)C(=〇)- and optionally up to 9 yl groups and up to 5 hydroxy substituted Ck alkyl groups, or Depending on the situation, 2 positions R4 together a pendant oxy group; R9 is selected from the group consisting of hydrogen and _C(= 〇)R9a; 1^ is selected from the group consisting of _NR9bR9c, _〇R9d, and optionally up to 9 functional groups substituted by Cw An alkyl group and optionally a substituted aryl group; R is selected from the group consisting of hydrogen, optionally up to 9 halo groups

Substituted C _ 6 alkyl and optionally substituted aryl; R is selected from the group consisting of: up to 9 halo substituted C 1.6 hospitals and optionally substituted Fangmei. R9d is selected from the group consisting of C1·6 alkyl and optionally substituted aromatic as appropriate. The L4 is selected from the group consisting of: L6-L4-L7 Not in some embodiments of Formula XII 156115.doc *76- 201200517

L2 is selected from the group consisting of -C(=0)-, -(CH2CH2)-, -(CH20)-, -(CH2S)-, -(CH=CH)., -(CH=N)- , -NH-, 〇 (oxygen), s (sulfur) and -CH2-; 156115.doc -77- 201200517 L3 is selected from the group consisting of S (sulfur) and -CH2-;

Ad 9 H , -(NR9)·, 0 (oxygen),

The Ls is selected from the group consisting of NH and -(CH=CH)-; A〆1

〇 (oxygen), a group of the following components: NH, 0 (oxygen) and each X3 system are independently selected from S (sulfur); each Xs is independently selected from the group consisting of S (sulfur) and -CH2-; -NH-, 0 (oxygen), each X6 system is independently selected from the group consisting of N (nitrogen) and CR«; each R8 is independently selected from the group consisting of: hydrogen, &amp; alkyl O f , Ci-6 alkyl 〇 c (=0) -, arylalkyl 0C (=0) _, dentate, (RRN) alkyl, (R RbN) c ( = 〇) _ and optionally up to 9 a functional group and up to 5 hydroxy-substituted Ci 6 alkyl groups; each B-series is independently selected 'where B is a fused, substituted, saturated or unsaturated 3 to 7 carbon ring or fused view Substituted saturated or unsaturated 3 to 7 membered heterocyclic rings, each of which is optionally substituted with one or more R 4 ; and each R 4 is independently selected from the group consisting of Ci 6 oxime, c "6 Hyun-based ocw alkyl, Cl_6 alkyl 0C (=0)-, arylalkyl 0 (: (= 〇) _, _c 〇〇 H, halo, c〗. 6 _ alkyl, hydroxyl, RaRbN-, (RaRbN)alkyl, (RaRbN)C(=〇)- and optionally up to 9 dentate groups and up to 5 hydroxy groups substituted by C -6·alkane Or, as the case may be, the two units R4 together are pendant oxy groups. 1561I5.doc • 78 - 201200517 In some embodiments, the compound of formula XII has the structure of formula XIIa R2 X1 - R2 R/ r6 l6-L4 l!, r2 R1 Y-N7 R2^ Y2 XIIa or a pharmaceutically acceptable salt thereof, wherein r6 is a C^6 alkyl group substituted with up to 9 halogen groups, as the case may be. In some embodiments, R6 is comparable. Examples include combinations of structures having the formula XIII

I L&lt;-L7

X or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of chlorine, Rlac (which and RlaC(=S)-; each R is independently selected from the group consisting of: _C(R2a)2NR3aR3b, alkoxyalkyl, Cl_6 alkyl oc(=〇)_, Ci 6 alkyl 〇c(=〇)Ci 6^, cl-6 alkyl c(=o)cl-6 Alkyl, aryl, aryl (CH2)n•, aryl (CHAO-, aryl (CH=CH) m·, arylalkyl fluorene, arylalkyl, aryl 0 alkyl, cycloalkyl (cycloalkyl)(CH=CH)m_, (cycloalkyl, 156115.doc •79· 201200517 cycloalkylalkyl, heterocyclyl, heterocyclyl (CH=CH)m_, heterocyclyl Alkoxy, heterocyclylalkyl, heterocycloalkylalkyl, hydroxyalkyl 'ReRdN_, RcRdN(CH2)n-, (ReRdN)(CH=CH)m_, (RcRdN)alkyl, (ReRdN)C (=0)-, optionally with up to 9 halo-substituted Gy alkoxy groups and, optionally, up to 9 dentate-substituted Cw alkyl groups, the aryl and heteroaryl groups being optionally substituted by the following groups : cyano, _ yl, nitro, hydroxy, optionally up to 9 halo substituted C 6 alkoxy and optionally up to 9 halo substituted C _ 6 Alkyl; each C(R2a)2 is independently selected, wherein each R2a is independently selected from the group consisting of hydrogen, optionally up to 9 halo substituted Ci 6 alkyl, aryl (CH2) N- and heteroaryl (CH2)n_, the aryl and heteroaryl are each optionally substituted by a cyano group, a dentyl group, a nitro group, a hydroxy group, and optionally up to 9 functional groups substituted by a c-alkyl group. Oxyl and optionally up to 9 halo). Substituted (: 丨.6 alkyl, or C(R2a)2g; each R3a is independently selected from the group consisting of hydrogen and optionally substituted CN6 alkyl; each R3b is independently selected from the group consisting of Cw alkyl optionally substituted, heteroaryl, -(CH2)nC(=0)NR4aR4b, ((:Η2)ηί:(= 〇) and -(CH2)nC(=〇)R6a 'The heteroaryl group is optionally substituted by the following groups: cyano, halo, nitro, hydroxy, optionally up to 9 halo Alkoxy and optionally up to 9 dentyl substituted Cw alkyl; each R4aR4bN is independently selected, wherein ya and ro are each independently selected from the group consisting of: hydrogen, optionally substituted C丨.6 appearance And aryl 156II5.doc -80 - 201200517 yl (CH2)n-; each RSa is independently selected from the group consisting of Cl.6 and aryl (CH2)n-, as appropriate; each R6a Independently selected from the group consisting of Ci-6 alkyl and aryl (Cii2) n_, as appropriate; each R10 is RH; each R is independently selected from the group consisting of H (hydrogen), alkane OxyalkylCi-6 alkyl 00: (=0) (^.6 alkyl, c!.6 alkyl cpcOCu alkyl, aryl (CH2)n_, arylalkyl, aryl aryl, Cycloalkyl, (cycloalkyl)alkyl, cycloalkylOalkyl, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, R RdN(CH 2 ) n-, (RcRdN)alkyl and Optionally, up to 9 halo-substituted C!.6 alkyl groups; each RRN is independently selected, wherein each of the ruthenium and ... is independently selected from the group consisting of hydrogen, alkoxy c(=〇)_, Cl.6 Alkyl, Ci 6 alkyl c(=〇)_, Ci 6 alkyl fluorenyl, arylalkyl hydrazine C(=〇)_, arylalkyl, arylalkyl C(=〇)_, Square group C(=〇)_, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl C(〇)-, heterocyclic C(=〇)_, (ReRfN)alkyl, (ReRfN )alkyl c(=0)- 0TRfN)c(=o)_ 'wherein the alkyl moiety of the arylalkyl group, the arylalkyl group c(=〇)-, the heterocyclylalkyl group and the heterocyclylalkyl group c(=〇)_ are each optionally Substituted by a ReRfN_ group; and wherein the arylalkyl group, the arylalkyl group c(=o)·, the aryl group c(=0)_, and the aryl moiety of the arylsulfonyl group, and the heterocycloalkylene The heterocyclyl moieties of the heterocyclylalkyl group (:(=0)_ and the heterocyclyl group c(=0)_ are each replaced by up to three substituents each independently selected from the group consisting of the following: .t, halo, nitro, optionally up to 9 halo 156115.doc 201200517 Substituted C1.6 alkoxy and optionally up to 9 halo substituted c, _6 alkyl, gReRfN independent Selected as follows, wherein "and each independently selected from hydrogen, C"-6 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl And (RNRy&gt;j)alkyl and (wN)c(=〇)_; each RxRyN is independently selected, wherein Rx and ... are each independently selected from hydrogen, CN6 alkyl 〇c(=〇)-, Ci .6 alkyl, c, -6 alkyl c(=o)-, aryl, arylalkyl, cycloalkyl and heterocyclic; Y1 is selected from 0 (oxygen) S (sulfur), s(0), S〇2, NR2 and C(R2)2; each A1 is independently selected from the group consisting of Cw alkenyl, [1.6 alkyl and (CH2)n-〇- (CH2)m-, each of which is optionally substituted by one or more R2;

Each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, Ci-6, O, C, alkyl, aryl, halo, ketone, Wj and = substituted by up to 9 dentations Ci 6 alkyl, or as the case may be; the neighboring R and the carbon to which it is attached are fused from 3 to 6 carbon rings, as the case may be, up to 2 Cm. The 偕R2 is connected to it: Carbon 1-4 is a group of 3 to 6 carbon rings, which are replaced by up to 2 Ci 0 alkyl groups as the case may be selected from the group consisting of: _(j2)s (lS)s_ (j2)s (l, _j2_ ^= one! J ==^^, ', -c( = 0)-, 〇(oxygen), 〇C(R )2. &gt;&lt; η , -C(CF3 2NR2c-^NHA-(CH=CH)-; _J is a aryl group, a heteroaryl group, a heterocyclic group, a cycloalkyl group, a cycloalkenyl group or a polyhydrocarbon', each of which is optionally substituted by one or more Rls; 156115 .doc •82- 201200517 Each R14 is independently selected from the group consisting of: a hydroxyl group, optionally up to 9 fluoro groups substituted by a Cl. 6 alkoxy group, a Ci6 alkyl group, an alkyl group, a Ci6 alkyl group. 0C(=0)-, arylalkyl〇c(=〇)_, -cooh, _ group and CN6 alkyl group substituted by up to 9 groups, as appropriate; each 15 series independent Selected from the group consisting of: halo, hydroxy, ci 6 alkyl hydrazine Ci-6 alkyl, Ci-6 alkyl 0C (=0) _, arylalkyl 〇 c (= 〇), _C00H, R9, RAW, RXRyNC(=〇), RXRyNCi 6 alkylheteroaryl, aryl, optionally up to 9 yl substituted Ci 6 alkyl, optionally up to 9 halo substituted Cl.e alkoxy, Ci6 Alkyl, RaRbN_, (RRN)alkyl, (RaRbN)C(=〇)-, and up to 5 hydroxy-substituted Q·6 alkyl groups, the substituent aryl and heteroaryl each being treated as appropriate Multiple R14 substitutions, or optionally 2 adjacent Ris together with the carbon to which they are attached, are fused 3 to 6 carbon rings, optionally substituted with 2 Cμ alkyl groups, or 2 偕R and The connected carbon together is up to 2 _6 depending on the situation.

The alkyl substituted 3 member to 6 membered carbocyclic ring or, as the case may be, the two aryl groups Rls together are pendant oxy groups; each RaRbN system is independently selected, of which only 3 and only "&gt; are each independently selected from the group consisting of Group: hydrogen, c26 alkenyl, and Ci 6 alkyl; each Ls is independently selected from the group consisting of: |一·=| \ = -= \,

, H, -C(CF3)2NR2c-, c(r)2, -C(R2)2〇-, _c(=〇)_, 〇(oxygen), nh and -(CH=CH)-; 156115. Doc •83· 201200517 L6 is selected from the group consisting of:

Take ..., -C(CF3)2NR2c-, L7 is selected from the group consisting of:

-C(CF3)2NR2c-, each A is independently selected from the group consisting of CR3 and N (nitrogen); each R3 is independently selected from the group consisting of hydrogen. _6 alkoxy, C, -6 alkyl 〇 Cl. 6 alkyl, Cl. 6 alkyl 〇 c (= 〇), arylalkyl hydrazine (: (= 〇) _, -COOH, dentate, hydroxyl , RaRbN, (RaRbN)alkyl, (RRN)C(-〇)-, optionally up to 9 halo groups and up to 5 hydroxy substituted C丨_6 alkyl groups; R is selected from the group consisting of: Gas, Ci 6 alkyl, 6-dish, C2·6 alkynyl, C3·7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloalkane Further, the alkyl group is optionally substituted with ReRfN_, alkoxy or Cm alkyl group; each X9 is independently selected from the group consisting of CH and N (nitrogen); each X10 is (C(R2)2) q; each Y1G line is independently selected from the group consisting of: _CH2_ and ·NH_; each Y line is independently selected from the group consisting of -〇(c(R2)2)n, 156115.doc-84 · 201200517 -S(C(R2)2)n- ' -S(0)(C(R2)2)n- &gt; -S02(C(R2)2)n- ' -NR2(C(R2)2)n And (C(R2)2)q; each m is independently 1 or 2; each n is independently 0, 1 or 2; each ρ is independently 1, 2, 3 or 4; each q is independently 1 , 2, 3, 4 or 5; each r is independently 0, 1, 2, 3 or 4;

Each s is independently 〇 or 1;

Q7 is selected from the group consisting of R1 / /R1 Υίϊ&gt; and office;

X2 is (c(r2)2)( , or X2 is absent; Υ2 is selected from 〇 (oxygen), S (sulfur), S (〇), S〇2, NR2 and C(R2)2; R9 is selected Free group consisting of hydrogen and _C(= 〇)R9a; 1193 is selected from the group consisting of _NR9bR9c, _〇R9d, optionally up to 9 _ groups substituted (^.6 alkyl and optionally) Substituted aryl; R 9 b is selected from the group consisting of: hydrogen, optionally up to 9 dentate substituted C 1 alkyl and optionally substituted aryl R 9 C selected from the group consisting of: As the case I, up to 9 substituted 匸··6 alkyl groups and optionally substituted aryl groups, and R9d are selected from the following composition: β, β,, Λ meaning group. Depending on the situation, up to 9 i Base substitution 156115.doc -85. 201200517 Cu alkyl and optionally substituted aryl. In some embodiments of Formula XIII, the compound is not selected from the group consisting of:

156115.doc -86 - 201200517

156115.doc -87 - 201200517

156115.doc •88- 201200517

156115.doc -89- 201200517 \

156115.doc -90- 201200517

L2 is selected from the group consisting of _c( = 〇)_, _(CH2CH2) _,

-(CH20)-, -(CH2S)-, -(CH=CH)-, -(CH=N)-, -NH-, oxime (oxygen), S (sulfur) and -CH2-; L3 is selected from Group of the following

, -(NR9)-, 0 (oxygen), S (sulfur) and -CH2-; It is selected from the group consisting of fresh NH and -(CH=CH)-;

, ο (oxygen), each χ 3 series are independently selected from S (sulfur); a group consisting of ΝΗ, 0 (oxygen) and 156115.doc -91 · 201200517 each x series is independently selected from C/TA, a group consisting of: -NH-, 0 (oxygen), S (sulfur) and -CH2-; each of the 68 series is independently selected from the group consisting of: and), each R is independently selected from the following consisting of Group: nitrogen, CM alkyl ο. Alkyl, C丨·6 alkyl 〇c(=〇)_, 、, arylalkyl oc(=o)-, halo, (RaRbN), (RaRbN)c, κ N)C(- 〇)_ and optionally up to 9 halo groups and up to 5 hydroxy-substituted c] 6-alkyl groups; each h is independently selected, wherein B is fused, optionally substituted or not A 7-membered carbocyclic ring or a fused, optionally substituted, saturated or unsaturated 3 to 7 membered heterocyclic ring', each of which is optionally substituted with one or more feet 4; and each R4 is independently selected from the group consisting of : q•oxy group, Ci6 alkyl 〇Ci.6 alkyl, Ci.6 alkyl 0C(=0)-, arylalkyl 0C(=0)_, _c〇〇H, halo, Ci- 6 li appearance group, mercapto group, RaRbN_, (RaRbN) alkyl group, (RaRbN) C (=0)- and optionally up to 9 halo groups and up to 5 hydroxyl groups substituted C!·6 alkyl ' or In the case of two niches R4 - it is a pendant oxy group. R6 R1 In some embodiments of Formula XIII, Q7 is R2 Υ2_Χ and R6 is a C 1-6 pit group substituted with up to 9 dentate groups, as appropriate. In some embodiments, R6 is a fluorenyl group. In some embodiments of Formula XIII, L4 is selected from the group consisting of: 〇 (oxygen), -〇C(R2)2-, Bu = ' 'NH &gt; -(CH=CH)- 'Y6 ' Υ6 - Υ6^ γ6.γ6_γ6 ; • C(CF3)2NR2c. , , 丨&quot;V, 156115.doc •92-201200517, heterogeneous composition Each of the Y6 systems is independently selected from the group consisting of aryl, heteroaryl And x, each of which is optionally substituted by a substituent selected from the group consisting of: R2, R3, R4 &amp;R8; each R2 is independently selected, wherein &quot; is selected from the group consisting of Group k k-oxyl, C -6 -6, aryl, dentate, thiol, RaRbN _ and optionally substituted by up to 9 (tetra) or, as the case may be, 2 adjacent R 2 and the carbon to which they are attached Depending on the situation, up to 2 cores to 6 bases can be substituted for 3 to 6 carbon rings, or 2 偕, wherever R2, together with the carbon to which they are attached, can be replaced by up to 2 Ci-6 alkyls. 3 to 6 carbon rings; each R3 is independently selected from the group consisting of: q-oxy group, A-based oCk alkyl group, Ci e-based 〇c (=〇), aryl-based 〇c ( =〇), dentate, thiol, irRbN_, (RaRbN) alkyl, ( RaRbN)c(=〇) and, as the case may be, up to 9 dentations and up to 5 thio-substituted Ci6 alkyl groups;

Each R4 is independently selected from the group consisting of: Ci• said oxy, Ci 6 alkyl 〇c丨·6 alkyl, Cl.6 alkyl 0C (=0)... aryl base 〇c (=〇 ), _c〇〇h, halo, Cb6 from alkyl, hydroxy, RaRbN_, (RaRbN)alkyl, (RRN)C(-〇)_ and optionally up to 9 halo and up to 5 hydroxy groups Cw alkyl, or optionally 2 oximes R4 together are pendant oxy; and each R8 is independently selected from the group consisting of Ci 6 alkyl 〇 Ci 6 alkyl, Cl-6 alkyl 〇 C (= 〇)·, arylalkyl 〇 c(=〇)_, halo, (RaRbN)alkyl, (RaRbN)c(=〇)_&amp; optionally substituted with up to 9 dentities and up to 5 hydroxy groups Ci 6 alkyl. In some embodiments, the hydrazine compound has the structure: 156115.doc •93· 201200517

Or a pharmaceutically acceptable salt thereof. Some embodiments include a compound having the structure of Formula XIV:

XIV

Or a pharmaceutically acceptable salt thereof, wherein:

Q7 is selected from the group consisting of J2 each X10 is (C(R2)2)q; each X11 line is independently selected from the group consisting of: (C(R2)2)q and 156115.doc-94-201200517

Each γ11 line is independently selected from the group consisting of _〇(c(R2)2)n_, S(C(R)2)n-, -S(0)(C(R2)2)n-,- S〇2(C(R2)2)n_, _NR2(c(R2)2)n- and (c(R2)2)q; each R1 is independently selected from the group consisting of hydrogen, Rlac (=0 And RlaC(=S)-; Lu's R series are independently selected from the group consisting of -C(R2a)2NR3aR3b, alkoxyalkyl, Cw alkyl 〇C(=〇)-, Cl 6 alkane Base 〇 c (= 〇) Ci 6 alkyl, Ck alkyl C (= 〇) Ci 6 alkyl, aryl, aryl, aryl (CH 2 ) n 〇 -, aryl (CH = CH) m, aromatic Alkyl hydrazine, arylalkyl, aryl 0 alkyl, cycloalkyl, (cycloalkyl) (CH=CH)m, (cycloalkyl)alkyl, ring-based, heterocyclic, Heterocyclic group (CH=CH)m_, heterocyclic alkoxy group, heterocyclylalkyl group, heterocyclic group 0 alkyl group, hydroxyalkyl group, ReRdN_, RcRdN(CH2)n-, (RCRdN) (CH=CH) M_, (RCRdN)alkyl, • (ReRdN)C(=0)-, optionally up to 9 dentate-substituted Cl-6 alkoxy groups and, optionally, up to 9 1 | group-substituted iCw alkyl groups, The aryl and heteroaryl groups are each optionally substituted by the following groups: cyano, decyl, nitro, hydroxy, optionally up to 9 a substituted Cl. 6 alkoxy group and optionally up to 9 halo substituted Cl. 6 alkyl groups; each ReRdN system is independently selected wherein RC&amp;Rd are each independently selected from hydrogen, alkoxy c ( =o)-, Cl_6 alkyl, Ci 6 alkyl c(=0)_, Ci 6 alkylsulfonyl, arylalkyl 〇C(=0)-, arylalkyl, arylalkyl c (=0)_, aryl C(=〇)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl 156115.doc •95- 201200517 C( = 〇)·, heterocyclic C ( = 〇)·, (ReRfN)alkyl, (ReRfN)alkyl c(=0)- and (ReRfN)C(=〇)·, wherein arylalkyl, arylalkyl c(=〇)- a heterocyclylalkyl group and a heterocyclylalkyl group c (=〇x alkyl moiety, each optionally substituted by a rRfN_ group; and wherein the arylalkyl group, the arylalkyl group c(=0)-, Heteroaryl group of aryl c(=0)_ and arylsulfonic acid and heterocyclic group of heterocyclylalkyl, heterocyclylalkyl c(=0)_ and heterocyclic group c(=0)_ Partially, as the case may be, up to three substituents each independently selected from the group consisting of cyano, dentyl, nitro, optionally up to 9 halo substituted Cw alkoxy and, where appropriate, More than 9 _ a substituted Cw alkyl group; each ReRfN is independently selected, wherein each of R and Rf is independently selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl , heterocyclyl, heterocyclylalkyl, (RXRyN)alkyl and (RXRyN)c(=〇)_; each RxRyN is independently selected, wherein ... and each are independently selected from hydrogen, Cu alkyl hydrazine c(=〇)_, (^.6 alkyl, c, 6 alkyl c(=〇)_, aryl, arylalkyl, cycloalkyl and heterocyclic; each C(R2a)2 is independent The ground is selected wherein each R 2a is independently selected from the group consisting of hydrogen, optionally up to 9 halo-substituted c丨·6 alkyl, aryl (CHA- and heteroaryl (CH 2 ) n • , the aryl and heteroaryl are each substituted by the following groups: cyano, dentate, nitro, hydroxy, optionally up to 9 halo substituted c 6 · alkoxy and optionally 9 halogens). Substituted C丨-6 alkyl, or C(R2a): ^\/V; each R3a is independently selected from the group consisting of hydrogen and, as appropriate, 156115.doc • 96·201200517 Cw alkane Each R3b is independently selected from the group consisting of Cu, aryl, heteroaryl, -(CH2)nC(=〇)NR4aR4b' _(CH2)nC(=0)0R5a and - (CH2)nC(=〇)R6a 'The heteroaryl group is optionally substituted with a cyano group, a halogen group, a nitro group, a hydroxyl group, and optionally up to 9 dentyl groups substituted by a Cl 6 alkoxy group and In the case of up to 9 halo-substituted ci -6 alkyl groups; each R4aR4bN is independently selected, wherein R4b is independently

The group consisting of hydrogen, optionally substituted Ci 6 alkyl and aryl (CH 2 ) n-; each RSaS is independently selected from the group consisting of, optionally substituted Ci-6 alkyl and aromatic The group (CH2)n-; each R6a is independently selected from the group consisting of CiAC alkyl and aryl (CH2)n_, as the case may be substituted; X is (C(R2)2)q, or Χΐ does not exist; Υ is selected from 〇 (oxygen), s (sulfur), S(O), S02, NR2, and C(R2)2, with the constraint that when X1 is absent, Y1 is C(R2)2 ; X2 is (C(R2)2)q

Or X2 is absent; γ2 is selected from the group consisting of 0 (oxygen), S (sulfur), S(0), s〇2, NR2, and c(r2)2, with the constraint that when X2 is absent, γ2 is C ( r2L; each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, cU6 alkoxy, Ci6 alkyl, aryl, yl, hydroxy, 156115.doc •97-201200517 and 2 a fused 3-member to 6-membered carbocyclic ring substituted with up to 9 dentate-substituted Ci6 alkyl groups, or optionally 2 adjacent Rs to the carbon to which they are attached, optionally with up to 2 Ci·alkyl groups; Each R RbN is independently selected, wherein each of the groups is independently selected from the group consisting of hydrogen, CM alkenyl, and alkyl; L4 is selected from the group consisting of: _(j2)s_(lS)s_ (j2) s_(lS)s_j2_, c(=o)·, 0(oxygen)\, 卜三二-OC(R2)2-, &lt; Η, _C(CF3)2Nr2c_, NH and ·(CH=CH J2 is an aryl group, a heteroaryl group, a heterocyclic group, a cycloalkyl group, a cycloalkenyl group or a polycyclic ring, each of which is optionally substituted by one or more R15; each R14 is independently selected from the group consisting of Group: hydroxyl group, optionally up to 9 fluoro group-substituted Cw alkoxy groups, Cl6 alkyl hydrazine Ci6 alkyl groups, Ci6 alkyl OC (=0) _, arylalkyl 0C (=0)-, -COOH, li group and optionally up to 9 _ group substituted 匚!. 6 alkyl; each R15 is independently selected Free group consisting of: halo, hydroxy, Cl_6 OCw alkyl, Cb6 alkyl 〇C(=〇)-, arylalkyl hydrazine (= 〇)-, -COOH, R9, WN, RxRyNC ( =〇), RXRyNCi 6 alkyl, heteroaryl, aryl, optionally up to 9 halo substituted Cw alkyl, up to 5 hydroxy substituted q. 6 alkyl, optionally up to 9 teeth Substituted C 丨 6 oxime, c 丨 6 hexyl, RaRbN-, (RaRbN) alkyl, (RaRbN) C (=0)-, and up to 5 hydroxy substituted cN6 alkyl, The substituent aryl and heteroaryl are each substituted by one or more, or 2 adjacent 1^15, as the case may be, together with the carbon to which they are attached, as the case may be up to 2 c _6 156115.doc -98- 201200517 Burning-based fused 3-member to 6-membered carbon ring, or 2 偕 position Η&quot; depending on the situation, the carbon to which it is connected is replaced by up to 2 Cl• bases, 3 to 6 Carbocyclic ring, or 2 偕Ris together as the side oxy group;

Each L line is independently selected from the group consisting of: |-, ~, a-v1kVa • C(R2) and -(CH=CH)-; C(CF3)2NR2· 2, -C(R2)2〇_ , _c (=0) _, 〇 (oxygen), nh each A is independently selected from the group consisting of 纟e + : CR3 and N (nitrogen); R2e is selected from the group consisting of:虱, C〗.6 Institute base, C2_6 dilute base, alkynyl group, C3-7 cycloalkyl-aryl, aryl-based, heteroaryl, heteroaryl-based hetero- &amp; base and heterocyclic base Further, the alkyl group is optionally substituted with ReRfN_, a polyoxyl group or a Cw alkyl group; and the L6 is selected from the group consisting of:

L7 is selected from the group consisting of: 156115.doc •99- 201200517

Each R is independently selected from the group consisting of hydrazine, c&quot;alkyl 〇c(=〇)·, arylalkyl oc(=0)·, (RaRbN)c(=〇), and optionally 9 self-substituted c16 alkyl groups; + each line is independently selected from the group consisting of CR4 &amp; N (nitrogen), wherein if X4 is N (nitrogen), then Y4 is not NH; each Y4 is independently selected Free group consisting of: C(R4)2, NR4, hydrazine (oxygen), and S (sulfur); each V system is independently selected from the group consisting of: ΝΗ_, 〇 (oxygen), and s (sulfur); CH and hydrazine (nitrogen), wherein each X9 system is independently selected from the group consisting of 156115.doc-100·201200517, if X9 is N (nitrogen)' then Y9 is not nh; each YU is selected from the group consisting of: _CH2_和鲁; 0 Each L11 is independently selected from the group consisting of: 丨人丨 and nh; each L12 is independently selected from the group consisting of: 偶和妈cH2_; each L13 is independently selected from the following Group consisting of: _cH2_, _n=ch_, -CH=CH-^-CH2CH2-^-(CH2)mN^(CH2)n^.(CH2)mO(CH2)n-; each m is independently 1 or 2 ;

Each η is independently 〇, 1 or 2; each ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2 3 or 4; each S is independently 〇 or 1; each R3 is independently selected from the group consisting of hydrogen, Ci6 alkoxy, Ci-6 alkyl OCw alkyl, Cw alkyl 〇C (=〇) _, arylalkyl 0C (=0) _, -COOH, halo, hydroxy, R «RbN_, (RaRbN) alkyl, (RaRbN) C (= 〇) -, as the case may be up to 9 from the base and More than 5 hydroxy-substituted C丨·6 alkyl groups; each R4 group is independently selected from the group consisting of hydrazine (hydrogen), C丨_6 alkoxy-Ci-6 alkyl-based OCu-based, Ci_6-alkyl oc (=o)·., arylalkyl group 0C(=0)_ ' _C00H 'halo group, Ci 6 haloalkyl group, hydroxyl group, RaRbN ·, (RaRbN) alkyl group, (RaRbN)c(=0)- and Optionally, up to 9 halo groups and up to 5 hydroxy-substituted Cl. 6 alkyl groups or, as the case may be, two oxime positions R4 together are pendant oxy groups; 156115.doc 201200517 R is selected from the group consisting of hydrogen and _C( = 〇)R9a ; Ruler "selected from the group consisting of: _NR9bR9c, _〇R9d, optionally up to 9 halo substituted Ck alkyl and optionally substituted Aryl; R9b is selected from the group consisting of hydrogen, optionally up to 9 dentate substituted Cw alkyl and optionally substituted aryl; R is selected from the group consisting of: up to 9 a C1 ·6 alkyl group and optionally substituted aryl group, and R" is selected from the group consisting of: up to 9 _ group substituted C! · 6 alkyl groups and optionally Substituted aryl. In some embodiments, the compound of formula xIV has the structure:

156115.doc •102- 201200517

156115.doc •103- 201200517

156115.doc •104- 201200517

156115.doc -105- 201200517

156115.doc •106· 201200517

156115.doc -107- 201200517

156115.doc •108- 201200517

156115.doc -109- 201200517

〇

156115.doc •110· 201200517

156115.doc 111 · 201200517

156115.doc •112- 201200517

156115.doc -113- 201200517

156115.doc 114- 201200517

156115.doc 115· 201200517

X&lt; R6 R1 y—n R2 乂 'X2 In some embodiments of Formula XIV, Q7 is R2 γ2 and R6 is a Cw alkyl group substituted with up to 9 halo groups, as appropriate. In some embodiments, R6 is methyl. In some embodiments of Formula XIV, L4 is selected from the group consisting of:

156115.doc -116- 201200517

L2 is selected from the group consisting of _c( = 〇), _(CH2CH2)

-(ch2o)_, -(ch2s)-, -(CH=CH)_, _(CH=N)·, _NH 〇(oxygen), s(sulfur) and -CH2-;

〇 (oxygen) L3 is selected from the group consisting of S (sulfur) and -CH2-; LS is selected from the group consisting of: NH and -(CH=CH)-; each X3 is independently selected from the following S (Sulfur); -(NR9)-, 0 (oxygen) ifyi if1, group of constituents: NH, 0 (oxygen) and each X-series are independently selected from the group consisting of the following "Japanese" &gt; -, 0 (oxygen), S (sulfur) and -CHy; groups of the following composition groups below each group 6 are independently selected from each of the 8 series independently selected from: hydrazine (nitrogen) and CR8;: hydrogen, Ci -6 House Foundation OCI.6 156115.doc •117- 201200517, element b, C丨·6 alkyl 〇c(=〇)-, arylalkyl 〇 (: (=〇)_, halo, (RRN Alkyl, (RaRbN)c (=〇) and optionally up to 9 halo and up to 5 hydroxy substituted Ci 6 alkyl; each B is independently selected, wherein B is fused as appropriate Substituted saturated or unsaturated 3 to 7 carbon rings or a slightly substituted, saturated or unsaturated 3 to 7 heterocyclic ring, each optionally substituted by one or more R 4 and each R 4 system Independently selected from the group consisting of: q-oxy, Cm-choline OCw alkyl, Cu alkyl 〇c (=〇 ·, arylalkyl 〇 c (= 〇), _c 〇〇 H, halo, CN6 i alkyl, hydroxy, RaRbN_, (RaRbN) alkyl, (RaRbN) C (=0) · and as the case may be Up to 9 _ groups and up to 5 hydroxy substituted C..6 alkyl groups, or optionally 2 oximes R4 together are pendant oxy groups. Some examples include compounds having the structure of formula XV:

Xv or a pharmaceutically acceptable salt thereof, wherein: Q7 is selected from the group consisting of

And 156115.doc •118* 201200517

Or x2 is absent; each Y2 is selected from the group consisting of hydrazine (oxygen), S (sulfur), s(0), S02, NR2, and C(R2)2, with the constraint that when X2 is absent, Y2 is C (R2) 2; each X10 is (C(R2)2)q;

Each X11 line is independently selected from

The group consisting of: (C(R2)2)q and each Y11 line are independently selected from the group consisting of: -(((((((((((((((((())))) S(0)(C(R2)2)n-^-S〇2(C(R2)2)n- . -NR2(C(R2)2)n- and (C(R2)2)q;

Each R12R13N is independently selected, wherein each is independently selected from hydrogen, -[(Y14)(C(R2)2)r(NR2)s(C(R2)2)rHY"(c(R2)2)r (NR2)s (C(R2)2)r]s-(Y14)s-R80 &gt; -[(Y14)(C(R2)2)r(NR2)s(C(R2)2)r]- Y14 (C(R2)2)rO(C(R2)2)r-(Y14)s-R8e, alkoxyalkyl, alkoxy C(=〇)-, Cw alkyl, C2.6 alkenyl , C2.6 alkynyl, (^7 cycloalkyl, Cl.6 alkyl C(=0)·, C3-7 cycloalkyl c(=0)-, CV6 alkylsulfonyl, arylalkyl 0C(=0)-, aryl, arylalkyl, arylalkyl c(=〇), aryl c(=0)-, arylsulfonyl, heterocyclic, heteroaryl, heteroaryl An alkyl group, a heterocyclic group, a heterocyclic group C(=0)-, a heterocyclic group c(=〇)_, a heteroaryl C(=0)-, a heteroaryl group C (= 0)-, (ReRfN) alkyl, (ReRfN) alkyl C (=0)- and (ReRfN) C (=0)-, 156115.doc -119-201200517 The alkoxyalkyl group, alkoxy C (=〇)-, c1-6 yard base, C3.7 cycloalkyl, Ci_6 alkyl c(=o)-, c3_7 cycloalkyl c(=0)_, Cl.6 alkylsulfonyl, aromatic Alkyl oc(=o)-, aryl, arylalkyl 'arylalkyl c(=o)-, aryl c(=o)-, aryl fluorenyl, heterocyclic, heteroaryl Base, hetero-based base, miscellaneous Alkyl group, heterocyclic group C(=〇)_, heterocyclic group C(=0)-, heteroaryl C(=0)-, heteroarylalkyl c(=〇)_ and ReRfN)alkyl and (ReRfN)alkyl c(=〇)·decylalkyl are each substituted by one or more Rlab; or R12R13N is a cyclic nitrogen atom which is substituted by one or more of the following depending on the case. Linked heterocyclic group: pendant oxy group, _[(Yi4)(c(R2)2)jNR2h (C(R2)2)r]-[Y14(C(R2)2)r(NR2)s(C( R2)2)r]s_(Y")s_R8〇, _[(γΐ4) (C(R )2)r(NR2)s(C(R2)2)r]-Y14(C(R2)2)r 〇(c(R2)2)r_(Y14)s_R8〇, alkoxyalkyl 'alkoxy C(=〇)-, cN6 alkyl, c2.6 alkenyl, c2-6 alkynyl, c3.7 Cycloalkyl, Cw alkyl c(=o)-, c3.7 cycloalkyl c(=0)_, Cl 6 alkylsulfonyl, arylalkyl 〇C(=〇)...aryl, aromatic Alkyl, arylalkyl c(=0)-, aryl c(=〇)-'arylsulfonyl, heterocyclic, heteroaryl, heteroarylalkyl, heterocyclylalkyl, Heterocyclylalkyl c(=0)_, heterocyclic ruthenyl c(=0)-, heteroaryl c(=0)...heteroarylalkyl c(=〇), (ReRfN)alkyl, ReRfN)alkyl c(=〇)- and (ReRfN)c(=〇)_, the alkoxyalkyl group, alkoxy group C(=〇)_, Ci6 alkyl group, C3_7 Alkyl, CN6 alkyl C(=0)_, c3-7 cycloalkyl c(=〇)_, 4 6 alkylsulfonyl-, arylalkyl 0C(=0)-, aryl, aromatic Alkyl, arylalkyl c( 〇)- 'aryl C(=〇)_, arylsulfonyl, heterocyclic, heteroaryl, heteroaryl, heterocyclic, heterocyclic Hyunyl C(=Q)·, heterocyclyl c(—〇)-, heteroaryl c(=0)_, heteroarylalkyl c(=0) and at 156115.doc •120· 201200517 (ReRfN The alkyl group and the alkyl group of (ReRfN)alkyl C(=〇)· are each substituted by one or more Rlabs; each of the scales 13|1 is independently selected from the group consisting of: _[(Y14) (C(R2)2)r (NR2)s(C(R2)2)r]-[Y14(C(R2)2)r(NR2)s(C(R2)2)r]s-(Y14) s-R80 ' -[(Y14)(C(R2)2)r(NR2)s(C(R2)2)r]-Y14(C(R2)2)rO(C(R2)2)r- ( Y14)s-R80, -C(R, 2NR3aR3b, alkoxyalkyl, ci 6 alkyl 0C(=0)-, Cu alkyl 0 (:(=0)(:!.6 alkyl, CN6 alkane Base: (=0) (^.6 alkyl, aryl, aryl (CH2)n-, aryl (CH2)n〇-, aryl (CH=CH)m-, arylalkyl 0- , arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl)(CH=CH)m-, (cycloalkyl)alkyl, cycloalkylsulfonyl, heterocyclyl, Heterocyclyl (CH=CH)m-, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyl fluorene, ruthenium, ReRdN·, ReRdN(CH2)n-, (RCRdNXCH^CH , -, (RcRdN)alkyl, (RcRdN)c(=〇)·, optionally up to 9 dentate-substituted Cw alkoxy groups, and optionally up to 9 halo-substituted C丨·6 alkyl groups The aryl and heteroaryl groups are each substituted as follows: cyano group, _ group, nitro group, hydroxyl group, optionally substituted with up to 9 dentate groups, C!·6 alkoxy groups and optionally up to 9 a dentate-substituted c16 alkyl group; each R80 is independently selected from the group consisting of hydrogen, alkoxyalkyl, C..6 alkyl, C3·7 cycloalkyl, aryl, arylalkyl, Heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl and (ReRfN)alkyl, the alkoxyalkyl, C!.6 alkyl, (:3· a 7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl group and an alkyl group in a (ReRfN)alkyl group Optionally substituted by one or more Rlae; each (4) is independently selected from the group consisting of: -C(R2 a) 2NR3aR3b, 156115.doc •121 - 201200517 alkoxyalkyl, Cu alkyl 0C (=0)-, Cw alkyl 0 (: (=0) (:, -6 alkyl, CN6 alkyl hydrazine: (=0)(^-6 alkyl, aryl, aryl(CH2)n-, aryl(CH2)n〇-, aryl (CH=CH)m·, arylalkyl〇-, aryl Alkyl, arylalkyl, cycloalkyl, (cycloalkyl XCHzCHh-, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl (CH=CH)m-, Heterocyclylalkoxy, heterocyclylalkyl, heterocyclylalkyl, hydroxy, WN_,

RcRdN(CH2)n-, (WnHCIKH:^-, (RcRdN)alkyl, (R RdN)C(=0)-, optionally up to 9 halo substituted c1-6 alkoxy groups and optionally Up to 9 functional groups substituted Cw alkyl groups, the aryl and heteroaryl groups are each substituted as follows: cyano group, functional group, G Schiff base, trans group, optionally up to 9 halo substituted Cm Alkoxy and optionally up to 9 dentate substituted (^.6 alkyl; each Y14 is independently selected from the group consisting of: _0 (=〇)-, -8 (=〇;)-, _C (=S)-, -S(=0)2-, -C(=0)0-, -C(=〇)NR2c-, -S(=〇)2NR2c_, -C(=〇)NR2eC(= 0)· and -C(CF3)2NR2c-; R1 is selected from the group consisting of: Rlaa, RlaC (= 〇), and RlaC(=S)-; each "series is independently selected from the group consisting of: _C (R2a)2NR3aR3b, alkoxyalkyl group, CN6 alkyl group 0C(=0)-, Cw alkyl group (:(=〇)〇〖_6 appearance base, CN6 yard base (:(=0)(1^- 6 alkyl, aryl, aryl (CH2) n-, aryl (CH2) n〇-, aryl (Ct^CHU-, arylalkyl hydrazine, aryl aryl, aryl decyl, Cycloalkyl, (cycloalkyl)(CH=CH)m-, (cycloalkyl)alkyl, cycloalkylsulfonyl, hetero Cyclo, heterocyclyl (CH=CH)m-, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, ReRdN_, 156115.doc -122· 201200517

RcRdN(CH2)n-, (RcRdN)(CH=CH)m-, (RcRdN)alkyl, (ReRdN)C(=0)-, optionally up to 9 functional groups substituted with Cl_6 alkoxy and In the case where at most 9 functional groups are substituted for the Cl-6 alkyl group, the aryl group and the heteroaryl group are each substituted by the following groups: nitrogen group, dentate group, exact group, transbasic group, and optionally up to 9 groups. a dentate-substituted (^_6 alkoxy group and, optionally, up to 9 halo-substituted Cu alkyl groups; a ruler--selected from the group consisting of: _C(R2a)2NR3aR3b, [(y14)(c(r2) 2乂φ(NR2)S(C(R2)2) is small [Y14(C(R2)2)r(NR2)s(C(R2)2)r]s-(Y14)s-R80 ' -[( Yl4)(C(R2)2)r(NR2)s(C(R2)2)r]-Y^(C(R2)2)r〇(C(R2)2)r-(y14)s-r8G , alkoxyalkyl, alkoxy c (= = 0) _, Ci 6 substituent, c 2 6 alkenyl, C 2 6 alkynyl, (: 3-7 cycloalkyl, Cw alkyl c (= o) - , c3_7 cycloalkyl c(=0)·, Ck alkylsulfonyl, arylalkyl oc(=〇)_, aryl, arylalkyl, arylalkyl c(=0)-, aromatic Group C(=C))_, arylsulfonyl, heterocyclic, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkyl C(=〇)- 'heterocyclyl (:(=0)_, heteroaryl c(=〇)_, heteroarylalkyl C (= 0) - (ReRfN)alkyl, (ReRfN)alkyl c(= 〇) and (ReRfN)C(=0)-, the alkoxyalkyl group, alkoxy C(=0)_, Ci6 alkyl group, C37 cycloalkyl, CV6 alkyl c(=0)-, c3.7 cycloalkyl c(=0)_, Ci6 alkylsulfonyl, arylalkyl oc(=o)-, aryl, aromatic Alkyl, arylalkyl C( 〇)-, aryl C(=0)-, arylsulfonyl, heterocyclic, heteroaryl, heteroarylalkyl, heterocyclylalkyl, hetero Cycloalkyl c(==0)_, heterocyclyl c(=〇)_, heteroaryl c(=o)-, heteroarylalkyl c(=0)_ and in (ReRfN)alkyl And the alkyl groups of (R«RfN)alkyl c(=〇)_ are each optionally substituted by - or more than Rlab; 156115.doc -123· 201200517 each 1() is RcRdN-; each R is independently Selected from the following groups: hydrazine (hydrogen), alkoxyalkyl Ci-6 alkyl OCpCOCu alkyl, Ci6 alkyl c (= 〇) Ci6 alkyl, aryl (CHA-, arylalkyl, aromatic Alkyl aryl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl,]TRdN(CH2)n-, ( ReRdN) alkyl and optionally up to 9 halo substituted (^.6 alkyl; SRcRdN is independently selected Alternatively, each of the scales and ^ is independently selected from the group consisting of hydrogen, alkoxy c(=o)-, Cw alkyl, Cl 6 alkyl c(=0)_, Ci 6 alkyl sulfhydryl, aryl aryl Base 〇(=〇)_, arylalkyl, arylalkyl c(=〇)_, aryl C(=〇)_, arylsulfonyl, heterocyclylalkyl 'heterocyclyl a group C(-O)-, a heterocyclic group C(=〇)-, (R*RfN)alkyl, (ReRfN)alkyl c(=0)- and (ReRfN)C(=0)-, wherein The alkyl moiety of the alkyl, arylalkyl C(=0)-, heterocyclylalkyl and heterocyclylalkyl c(=〇) groups are each optionally substituted with a ReRfN- group; and wherein the aryl group Alkyl, arylalkyl C(=0)-, aryl c(=〇)- and arylsulfonyl aryl moiety, and heterocyclylalkyl, heterocyclylalkyl c(=0) And the heterocyclyl moieties of the heterocyclyl group c(=0)_ are each optionally substituted with up to three substituents each independently selected from the group consisting of cyano, dentyl, nitro, optionally as appropriate 9 halo-substituted Ck alkoxy groups and optionally up to 9 halo-substituted Ci 6 alkyl groups; each ReRfN system is independently selected 'wherein and Rf are each independently selected from argon, Cw alkyl, aryl , arylalkyl, ring Alkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (WN)alkyl and (RxRyN)C(=〇)-; 156115.doc -124- 201200517 Each RxRyN is independently Selected, wherein RX&amp;Ry&amp; is independently selected from the group consisting of hydrogen, cN6 alkyl hydrazine C(=0)-, c "6 alkyl, Cl 6 alkyl c(=〇)_, aryl, arylalkyl, a cycloalkyl group and a heterocyclic group;

Each C(R2a)2 is independently selected, wherein each Rh is independently selected from the group consisting of hydrogen, optionally up to 9 functional groups, and 6 aryl groups, aryl groups (CHA- and Heteroaryl (CH2)n·, the aryl and heteroaryl are each substituted by the following: cyano, functional, schiffyl, thiol, as appropriate, up to 9 i-substituents (: -6 hexane The oxy group and optionally up to 9 groups are taken, all). Instead of Cu alkyl, or as the case C(R2a)2 is Y^y; each of the 3 series is independently selected from the &quot;J7 , the group consisting of the following: Hydrogen and optionally substituted C 1 · 6 yards; each R3b is independently selected from the group consisting of: k ^ ^ &gt; -(CH2)nC (=〇)NR^R4b . . . (CH2)nC(=0)〇R^(H2)nC( 〇)R, which is optionally substituted by the following groups: cyano group, dentate group, exact group, (d), optionally, a 9 (tetra)-substituted CM alkoxy group and optionally up to 9 _ group-substituted Cl 6 alkyl groups; optionally independently selected wherein R 4a and R 4b are each independently selected from the group consisting of: , c, .6 alkyl and aryl, as appropriate CH2)n-; optionally substituted, each of which is independently selected from the group consisting of: Cl-6 alkyl and aryl (Cfj2) n_; each Μ3 is independently selected from the group consisting of Group: Cl.6 alkyl and aryl(CH2)n_; 156115.doc -125- 201200517 Each A1 is independently selected from the group consisting of Gy alkenyl, Cl6 alkyl and -(CH2)n-〇 -(CH2)m-', each optionally substituted by one or more R2; each R2 is independently selected, wherein R2 is selected from the group consisting of: hydrogen, halo, hydroxy, (:, .6 alkane Oxy group, (: w alkyl group, c2_6 alkenyl group, c2_6 fast group, alkoxyalkyl group, C3_7 cyclodecyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, heterocyclic group, Heterocyclylalkyl, (ReRfN)alkyl, RaRbN-, the c!.6 alkyl group optionally has one or more functional groups, _〇R2b, -C(=0)〇R2b. -C(=0 NHR2b '-NHC(=NH)NHR2b &gt; -NHR2b, SR2b, imidazolyl, fluorenyl, _SCH3, phenyl and 4-hydroxyphenyl substituted, the Cw alkoxy, alkoxyalkyl, aryl , c2.6 alkenyl, c2-6 alkynyl, C3·7 cycloalkyl, arylalkyl, heterocyclic, heteroaryl , heteroarylalkyl, heterocyclylalkyl and alkyl in (ReRfN)alkyl, each optionally substituted by one or more R 4 ' or optionally 2 adjacent R 2 together with the carbon to which they are attached In the case of at most a 6-alkyl substituted fused 3-member to 6-membered carbocyclic ring; R2b is selected from the group consisting of argon, C -6 alkyl, C 2_6 alkenyl, C: 2 · 6 alkyne a group, a Cm cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroaryl group, a heterocyclic group and a heterocyclic alkyl group; each of which is 2. Is selected from the group consisting of hydrogen, c丨·6 alkyl, c2_6 dilute, CM alkynyl, CM cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle And a heterocyclylalkyl group, the alkyl group being optionally substituted by ReRfN_, alkoxy or CK6 alkyl s-; each RaRbN is independently selected, wherein Ra and Rb are each independently selected from the group consisting of: hydrogen , C2-6 alkenyl and Cl.6 alkyl; 156115.doc •126- 201200517 )s-(L5)s.(J2)s-(L5)s-J2-, -C( = 0)-,〇 (Oxygen) 'L is selected from the group consisting of: _(j2 ο

() 2, _C(CF3)2NR "·, NH and -(CH=CH)-; broadly and independently selected from the group consisting of aryl, heteroaryl, hetero-based, cycloalkyl, cycloolefin And polycyclic hydrocarbons, each of which is optionally substituted by one or more R1S;

Each R14 is independently selected from the group consisting of a hydroxyl group, optionally up to 9 gas-substituted CWoxy groups, a k-alkyl ruthenium Cl.6 alkyl group, a Cl.6 alkyl group oc(-o)-, a base group oc (=〇), _c〇〇h, a halogen group, and optionally a Ci6 alkyl group substituted with up to 9 halo groups; each R1S system is independently selected from the group consisting of: a base group, a base group, ~ alkyl OCw alkyl, C 丨 · 6 alkyl 〇 c (= 〇) _, aryl alkyl 〇 c (which, - COOH, Μ, wN, RXRyNC (= 〇), (tetra) 6 burning base Aryl, aryl, optionally up to 9 dentate substituted c]-6 alkyl, optionally up to 9 ytyl substituted 匕6 alkoxy, Ci 6 alkyl, RaRbN_, (RaRbN) alkane a group, (RaR«&gt;N)c(=〇) and a C.·6 alkyl group substituted with up to 5 hydroxy groups, the substituent aryl group and the heteroaryl group being each substituted by one or more R14, or Depending on the situation, two adjacent Ris together with the carbon to which they are attached may be up to two (^.6 alkyl-substituted fused 3-member to 6-membered carbocycles, or 2 偕R15 depending on the case) Carbon together is a 3-member to 6-member carbon ring that is replaced by up to 2 Cm alkyl groups, or 2 as appropriate The ris ris is a pendant oxy group; each L5 line is independently selected from the group consisting of: ^__Ξ__j 156115.doc •127· 201200517 -C(CF3)2NR2c-, 丨\丨, -c(r2)2, _c (r2)2〇_, and -(CH=CH)·;

C(=〇)-, 〇(oxygen), NH Each A is independently selected from the group consisting of L6 selected from the group consisting of CR3 and N (nitrogen);

The L7 is selected from the group consisting of:

Each X4 system is independently selected from the group consisting of: CR4 and hydrazine (nitrogen);

Each of the Υ4 lines is independently selected from the group consisting of: C(R4)2, nr' 〇 (oxygen) and s (sulfur); 156115.doc •128-201200517 Each X9 series is independently selected The following components are free: CH and N (nitrogen)·, each γ1. Is independently selected from the group consisting of: _cH2- and _νη·; each m is independently 1 or 2; each η is independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; Each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2, 3 or 4; φ each s is independently 〇 or 1; each R3 is independently selected from the group consisting of Group: hydrogen,. _6 alkoxy, CV6 alkyl 〇 Cl. 6 alkyl, Cl. 6 alkyl 〇 c 〇), arylalkyl 〇 c (= 〇) _, -COOH, self group, hydroxyl group, RaRbN, (RilRbN An alkyl group, (RRN)C(-O)-, optionally up to 9 halo groups and up to 5 hydroxy-substituted C 1 -6 alkyl groups; each R4 system is independently selected from the group consisting of: H ( Hydrogen), Cm alkoxy, Ci-6 alkyl OCI.6 alkyl, C!-6 alkyl 〇c(=〇)_, arylalkyl • 〇C(=0)_, -C00H, _ a group, Ci-6-alkyl, hydroxy, (R RbN)alkyl, (RaRbN)C(=〇)_, and optionally up to 9 halo and up to 5 hydroxy substituted C w alkyl, or Depending on the case, the two units R4 together are pendant oxy groups; R6 is selected from the group consisting of hydrogen, dentate, hydroxy, Ci6 alkoxy, Cw alkyl, C2_6 alkenyl, c2-6 alkynyl, alkoxy Alkyl, c3 7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclyl, (R), RaRbN, Cw The base-view condition is based on one or more _ groups, -OR2b, -C(=0)0R2b, 156115.doc-129. 201200517 -NHC(=NH)NHR2b, -NHR2b, SR2b, imiline, sulfhydryl , -S CH3, phenyl and 4-hydroxyphenyl substituted, and the Cl.6 alkoxy group, alkoxyalkyl group, aryl group, c:2·6 alkenyl group, C2_6 alkynyl group, c3_7 cycloalkyl group, aryl alkane a base, a heterocyclic group, a heteroaryl group, a heteroarylalkyl group, a heterocyclylalkyl group, and an alkyl group in the (ReRfN)alkyl group, each optionally substituted with one or more R 4 ; R 9 is selected from the group consisting of Group: hydrogen and _C(=〇)R9a ; only "selected from the group consisting of: _NR9bR9c, _〇R9d, optionally up to 9 _ group substituted c丨.6 alkyl and optionally substituted Aryl; R9b is selected from the group consisting of hydrogen, optionally up to 9 halo substituted C!·6 alkyl and optionally substituted aryl; RN is selected from the group consisting of: a C 1 alkyl group substituted with up to 9 functional groups and optionally substituted aryl groups, and R is selected from the group consisting of C1 substituents substituted with up to 9 dentate groups, as appropriate, and optionally substituted In some embodiments of Formula XV, l4 is selected from the group consisting of:

156115.doc •130· 201200517

B B

L2 is selected from the group consisting of -C(=0)-, -(CH2CH2)-, -(CH20)-, -(CH2S)-, -(CH=CH)-, -(CH=N)- , -NH-, ◦ (oxygen), s (sulfur) and -CH2-; 0 L3 is selected from the group consisting of ξ η , -(NR9)-, 0 (oxygen), S (sulfur) and -CH2 - L5 is selected from the group consisting of NH and -(CH=CH)-;

〇 (oxygen), each X3 system is independently selected from the group consisting of NH, 0 (oxygen), and S (sulfur); 156115.doc -131 - 201200517 Each Xs is independently selected from the group consisting of: NH_, 0 (oxygen), S (sulfur) and -CH2-; each X6 is independently selected from the group consisting of underarms: N (nitrogen) and CR8; and each B is independently selected, and the standing B is Slightly saturated or unsaturated 3 to 7 members of the 掂: tsa 乂 或 or fused, as appropriate, saturated or unsaturated 3 to 7 heterocyclic, Ganzi A 4 ^ their respective Replace with one or more R4 as appropriate. In some embodiments, R is a C 1-6 alkyl group substituted with up to 9 dentate groups as appropriate. In the embodiment of Formula XV, the B-6 is selected from the group consisting of:

The L7 is selected from the group consisting of:

-C(CF3)2NR2c-,

In some embodiments of Formula XV, the compound is not selected from the group consisting of: 156115.doc • 132· 201200517

Η

156115.doc -133- 201200517

156115.doc -134- 201200517

201200517

201200517

In some embodiments, the compound of formula xv has the following structure:

Or a pharmaceutically acceptable salt thereof. Some embodiments provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV. Some embodiments provide a method of treating an HCV infection in a subject, the method comprising administering to the individual an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV or comprising a pharmaceutically Acceptable excipients and pharmaceutical compositions of the compounds of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV. Some embodiments provide a method of treating an HCV infection in an individual comprising administering to the individual an effective amount of a compound of Formula VI, νπ, V][I1, IX, X, XI, XII, XIII, XIV or XV or comprising Pharmaceutical compositions of 156115.doc-137-201200517 excipients and compounds of formula VI, VII, VIII, IX, x, XI, oxime, XIII, XIV or XV are pharmaceutically acceptable. In some embodiments, the method further comprises identifying an individual afflicted with a hepatitis C infection. Some embodiments provide a method of treating liver fibrosis in a subject, the method comprising administering to the individual an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV or comprising a medicinal An acceptable excipient and a pharmaceutical composition of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV. In some embodiments, the method further comprises identifying an individual afflicted with a hepatitis C infection. Some embodiments provide a method of increasing liver function in an individual infected with a hepatitis C virus. The method comprises administering to the individual an effective amount of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV. Or a XV compound or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula νΙ, νπ, νιπ, IX, X, XI, XII, XIII, XIV or XV. In some embodiments, the method additionally comprises identifying an individual afflicted with a hepatitis C infection. [Embodiment] Definitions As used herein, common organic abbreviations are defined as follows:

Ac ethoxylated 〇 2 〇 acetic anhydride aq. Aqueous Bn Benzyl Bz phenyl fluorenyl 156115.doc -138- 201200517 BOC or Boc tert-butoxycarbonyl Bu n-butyl cat. Catalytic Cbz benzoquinone Carbonyl CDI 1,1'-carbonyldiimidazole Cy(c-C6Hn) Cyclohexyl °C Celsius temperature DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane Burning DCM Dichloromethane DIEA Diisopropylethylamine DMA Dimercaptoacetamide DME Dimethoxyethane DMF NW-Dimercaptoamine DMSO Dioxetane Et Ethyl EtOAc Ethyl acetate g g Hour HATU 2-(1//-7-azabenzotriazol-1-yl)- 1,1,3,3-tetramethyl-HOBT N-hydroxybenzotriazole iPr isopropyl LCMS liquid chromatography-mass spectrometry 156115.doc -139- 201200517 LDA diisopropylamino lithium mCPBA m-gas peroxybenzoic acid MeOH methanol MeCN acetonitrile mL ml MTBE methyl tert-butyl ether NH4〇Ac acetic acid Ammonium PG protecting group Pd/C 1 bar/activated carbon Ph phenyl ppt precipitation RCM ring closure metathesis rt room temperature sBuLi second butyl lithium TEA triethylamine TCDI Ι, Γ-thiocarbonyl dimethine Te Rt,t third TFA trifluoroacetic acid THF tetrahydro sulphur TLC thin layer chromatography TMEDA tetramethylethylenediamine PL microliters terms "individual (subject)", "host" and "patient" in this paper It is used interchangeably and refers to mammals, including but not limited to 156115.doc • 140- 201200517 Primates, including apes and humans. As used herein, the term "liver function" refers to normal liver functions including, but not limited to, synthetic functions including, but not limited to, serum proteins such as 'albumin, coagulation factors, alkaline phosphatase, aminotransfers. Synthesis of proteins (eg, alanine transaminase, aspartate transaminase, 5, ribozyme, guanidinium aminotransferase, etc.), synthesis of bilirubin, synthesis of cholesterol And bile acid synthesis; liver metabolism, including (but not limited to) carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; detoxification of exogenous drugs; hemodynamic function, including visceral and portal vein blood Kinetics; and similar functions. "As used herein, the term "sustained viral response" (svr; also known as continuous response) or "sustained response" refers to an individual's response to a treatment regimen for HCV infection based on serum $. In general, "sustained viral response" means at least about j months, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 after treatment has ceased. At the time of the month, no detectable HCV RNA was found in the patient's serum (eg, less than about 500' per milliliter of serum, or less than about 100 copies of the genome). "Measuring patients who have failed treatment" generally refers to those who have not responded to HC V prior therapy (called "non-responders") or who have responded to previous therapies but have not been treated (called "relapsers"). HCV infection, first month treatment: may include the treatment of IFN-a monotherapy or combination therapy, wherein combination therapy may include administration of IFN-a and an antiviral agent (such as ribavirin). 156115.doc 201200517 "As used herein, the term "treatment" and like terms mean obtaining a pharmacological and/or physiological effect. The effect may be therapeutic in terms of completely or partially preventing the disease or its symptoms, and the effect may be prophylactic and/or in terms of partially or completely curing the disease and/or attributable to the adverse effects of the disease. As used herein, "treatment"; any treatment of a disease in a mammal, especially a human, and includes: (4) prevention of the disease in an individual susceptible to the disease but not diagnosed with the disease; (b) Suppress the disease, also; stop its development; and (C) reduce the disease, even if the disease subsides. As used herein, the term "alkyl" refers to a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group (i.e., composed of carbon and hydrogen & does not contain a double bond or a bond). In some embodiments, an alkyl group can be substituted or unsubstituted. Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl 'iso-yl, tert-butyl, pentyl, hexyl, and the like, in some embodiments their respective Can be replaced as appropriate. As used herein, the term "heteroalkyl" refers to a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group containing one or more heteroatoms in the carbon backbone (ie, one or more carbon atoms through a hetero atom). Displacement of the alkyl group In some embodiments, the heteroalkyl group may be substituted or unsubstituted. Heteroalkyl groups include, but are not limited to, ethers, thioethers, and alkyl-amino-alkyl groups. By "halo" is meant fluoro, chloro, moth or moth. As used herein, the term "alkoxy" refers to a straight or branched alkyl group bonded to the parent molecule via a bond. In some embodiments, The alkoxy group may be substituted or unsubstituted. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, 156,115. .doc .142 - 201200517 Monobutoxy, tert-butoxy and the like. The term "dilute" as used herein refers to a monovalent straight chain of 2 to 20 carbon atoms containing at least one carbon-carbon double bond. Or a branched chain group including, but not limited to, 1-propenyl, 2-propenyl, 2-indenyl, iota-propenyl, fluorenyl-butenyl 2 - butenyl group and the like. In some embodiments, the alkenyl group may be substituted or unsubstituted. The term "alkynyl" as used herein means 2 to 20 carbon atoms containing at least one carbon-carbon bond. Monovalent straight or branched chain groups including, but not limited to, 1-propynyl '!-butanyl, 2-butynyl, and the like. In some embodiments, alkynyl may be substituted or Unsubstituted. The term "aryl" used in Fengwen is called 曰〇, called κ, 11 because of the attachment ring or a fused ring aromatic group. Examples of aryl include (but not Diphenyl, naphthyl, biphenyl, phenanthryl, copper tetraphenyl and the like. In some implementations, the secret can be substituted or unsubstituted.

The term "ring-based" as used herein, refers to a ring IT" system group having 3 to 2 carbon atoms, including but not limited to, cyclopropyl, cyclopentyl, substituted or unsubstituted. In the examples, the term "cycloalkenyl" as used in the ring-based system means having from 3 to 2. a carbon atom of a ruthenium, a long system group, which has a double bond in the ring to the apos; Examples of cycloolefins include, but are not limited to, cyclopropenyl, benzyl, cycloheptenyl, and the like. Substituted or unsubstituted in soil or cyclohexane. In two embodiments, a cycloalkenyl can be used herein as the term "polycyclic fluorenyl", a saturated aliphatic ring system radical having at least two rings fused in the presence or absence of a bridge 156115.doc • 143-201200517 head carbon. group. Examples of polycycloalkyl groups include, but are not limited to, bicyclo[4.40]fluorenyl, bicyclo[2 2...heptyl, adamantyl, norbornyl and the like. The term "polycyclic dilute radical" as used herein, refers to an aliphatic cyclic system radical having at least two rings fused in the presence or absence of a bridge carbon wherein at least one of the rings has a carbon-carbon double bond. Examples of polycyclic, total + ρ "deuterium" alkenyl groups include, but are not limited to, norbornene, 1,1,-bicyclopentenyl, and the like. The term "multi-ring gunpowder" as used herein is a system-based circle of carbon atoms. The polycyclic hydrocarbon can be 芸 ', non-slurry, or can contain less than the maximum number of I non-complexed double bonds. The polycyclic chelating group m includes, but is not limited to, a naphthyl group, a dihydronaphthyl group, a dentate group, and the like. The term "heterocyclic ring" or "in the context of a ring system radical having at least one non-hybridizing group J or a "heterocycloalkyl group", wherein ^^ is not a carbon atom, is also a heterocyclic ring. Wherein the - or more of the base moiety is a non-aromatic 阽 her heterocyclic ring" or "heterocyclic ring - a non-aromatic ring: its medium: ring "heterocyclic ring" or "heterocyclic group" part of the "heterocyclic ring" Or "heterocyclic m is in at least one heteroatom. At least one heterodimeric non-aromatic ring exists in the tricyclic ring, morphine, tetrahydrocough - examples include (but are not limited to) maidenyl, (d) Anthracene; anthracene ring, quinone 1 sulphate, the term as used herein: hetero = and its class: a group. One or more ring atoms 'soil' refers to an aromatic ring system group in which a plurality of Human production, horse carbon 'is also a hetero atom Γ not with the pan, :: thick .... In the loop of the ring system (not ... ring or in a ring. Miscellaneous or a hetero atom can only exist in the case of the base ^ I56J J5.doc

J includes (but is not limited to) benzothiazole-144 - 201200517 base, benzo-m-based, (d) partial, base, iso(tetra)yl, hydrazine. If Lin, base, η than aryl group ... oxalyl, aryl and its similar groups. In some embodiments, a heteroaryl group can be substituted or unsubstituted. The term "heteroatom" as used herein refers to, for example, oxygen 'sulfur and gas. The term "arylalkyl" as used herein, means that - or a plurality of aryl groups are attached to an alkyl group. Examples of arylalkyl groups include, but are not limited to, phenylhydrazine, phenethyl, phenylpropyl, phenylbutyl, and the like. In some embodiments, two

The group may be substituted or unsubstituted and may be substituted on or in the aryl U group moiety. The term "cycloalkyl (4)" as used herein means that - or a plurality of ring groups are attached to a pit base. Examples of cycloalkyl groups include, but are not limited to, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, and the like. In some embodiments the 'cycloalkyl aryl group can be substituted or unsubstituted. The term "heteroarylalkyl" as used herein means that one or more heteroaryl groups are attached to the alkyl group. Examples of heteroaryl alkyl groups include, but are not limited to. More than a bite-based methyl group &quot; fumonyl group [sinter phenethyl and its like. In some embodiments, the heteroarylalkyl group can be substituted or unsubstituted, and can be substituted on the hetero or the alkyl moiety or both. Soil 5 The term "heterocyclylalkyl" as used herein, refers to, or refers to, a plurality of heterocyclic groups attached to an alkyl group. Examples of heterocyclic alkyl groups include, but are not limited to, morphinylmethyl, morpholinylethyl, morpholinylpropyl, tetrahydropropylpropyl and the like. Methyl, each bite The term "aryloxy" as used herein means that the aryl group is covalently bonded to the parent molecule via a bond. 156115.doc -145-201200517 The term "alkylthio" as used herein, refers to a straight or branched alkyl group bonded to the parent molecule via an --S-- bond. Examples of alkylthio groups include, but are not limited to, mercaptothio, ethanethio, propanethio, isopropanethio, dibutylthio, n-butanethio, second butanethio, third Butanethio group and the like. The term "arylthio" as used herein means that the aryl group is covalently bonded to the parent molecule via the __s__ bond. The term "alkylamino" as used herein, refers to a nitrogen group attached to one or more alkyl groups. Thus, a monoalkylamine group refers to a nitrogen group to which an alkyl group is attached and a monoalkyl group refers to a nitrogen group to which two pendant groups are attached. The term "cyanoamino" as used herein, refers to a nitrogen group to which a nitrile group is attached. The term "amine methyl sulfonyl" as used herein refers to RNHCOO-. The terms "keto" and "carbonyl" as used herein mean c=〇. The term "carboxy" as used herein refers to -COOH.

The term "amine sulfonyl" as used herein refers to _s〇2NH2. The term "sulfonyl" as used herein refers to _s〇2_. The term "sulfinyl" as used herein refers to _s〇_. The term "thiol-based" as used herein refers to c=s. The term "thiol" as used herein refers to CSOH. The term "sulfonamide" as used herein means _s〇2NR, 2, each of which is: solidly selected from the group consisting of hydrazine (hydrogen), Cl_C6 alkyl, cycloalkyl, arylalkyl) 'as appropriate _C6 alkyl substitution. The term "ester" as used herein means _C00R, where R is 156115.doc • 146-201200517 C!-C6 alkyl, CrC7 bad base, aryl base and aryl, as appropriate (VC6 Alkyl Substitution. The term "C-guanamine" as used herein means _C(= 〇)NR.2, wherein each RI is individually selected from the group consisting of hydrazine (hydrogen), CrC6 alkyl, CrC7 cycloalkyl, aryl. An alkyl group and an aryl group, which are optionally substituted by a C1-C6 alkyl group. The term "N-decylamine" as used herein means _NR, C(=0)R', wherein each R. is individually selected from hydrazine. (hydrogen), alkyl, C3_C7 cycloalkyl, arylalkyl and aryl' are optionally substituted by CrCe alkyl. The term "N-urethane" as used herein means -NR, C ( = 〇) 〇r, wherein each R' is individually selected from the group consisting of H (hydrogen), Ci_C6 alkyl, C3_Cyt alkyl, arylalkyl and aryl, optionally substituted by a Cl_c6 alkyl group. "〇_Amino phthalate" means _〇c(=〇)nr, 2, wherein each R' is individually selected from the group consisting of H (hydrogen), Ci_C6 alkyl, C3_C7 cycloalkyl, arylalkyl and An aryl group which is optionally substituted by a Ci_c6 alkyl group. The term "urea" is used herein. Refers to -NR, C(=0)NR, 2, wherein each R, • is individually selected from H (hydrogen), amide, ~(:7cyclohexyl, arylalkyl and aryl, as appropriate C丨-c6 alkyl substituted. As used herein, 'a group means a substance having one or more unpaired electrons' such that a substance bearing the group can be covalently bonded to one or more other substances. Therefore, right too In the context of this document, a group is not necessarily a free radical. More specifically, a radical -h is not a specific part of the macromolecule. The term "group" can be combined with the term "portion" or "group" ( Group) is used interchangeably. As used herein, Λ-', a star-substituted group is derived from an unsubstituted parent 156115.doc-147·201200517 structure in which one or more hydrogen atoms have been exchanged for another atom. Or a group. When substituted, the substituents are individually and independently selected from one or more of the following groups: CVCe alkyl, CVCe: !# base, CVC6 alkynyl, c3-C7 cycloalkyl (optionally) Substituted by: nuclide, alkyl, alkoxy, carboxy, !|alkyl, CN, -S02-alkyl, -CF3 and -OCF3), hydrazine-bonded cycloalkyl Ci-C: 6 miscellaneous, C3-C1G heterocycloalkyl (eg tetrahydrocarbyl) (substituted as follows: halo, alkyl, alkoxy, carboxyl, CN, -S02-alkyl , -CF3 and -OCF3), aryl (substituted as follows: halo, alkyl, optionally substituted by CrC6 alkyl, arylalkyl, alkoxy, carboxyl, CN, -S〇 2-alkyl, -CF3 and -〇CF3), arylalkyl (substituted as follows: halo, alkyl, alkoxy, aryl, thiol, CN, -S〇2-alkyl, -CF3 and _OCF3), heteroaryl (substituted as follows: il group, alkyl group, alkoxy group, aryl group, aryl group, carboxyl group, CN, -S02-hospital group, -CF3 and -OCF3) , halogen (such as gas, desert, broken and fluorine), cyano, thiol, -CF3, C^-C6, oxy, aryloxy, sulfhydryl (sulfenyl), halogen (Ci-C6 ) an alkyl group, a Ci-C6 alkylthio group, an arylthio group, a mono- and di-(CVC6)alkylamino group, a quaternary ammonium salt, an amine group (C^Ce), an oxy group, a hydroxyl group (C^) -C: 6) alkylamino group, amine group (C^C: 6) alkylthio group, cyanoamino group, nitro group, amine carbenyl group, keto group (oxy group), carbonyl group Carboxyl, ethylenic, glycidinyl, fluorenyl, fluorenyl, sulfonyl, sulfonyl, sulfenyl, thiol, thiol, sulfonamide, SI, C - Amine amine, N-nitramine, N-amino phthalate, hydrazine-urethane and urea. Protecting groups which form protective derivatives of the above substituents are known to those skilled in the art and can be found, for example, in Greene and Wuts Proiecizve Growps h 156115.doc -148-201200517

John Wiley and Sons: New York, 1999 references. If the substituent is described as "optionally substituted", the substituent may be substituted with the above substituent.

Asymmetric carbon atoms may be present in the compound. All such isomers, including diastereomers and enantiomers, as well as mixtures thereof, are intended to be included within the scope of the compounds. In some cases, the compounds may exist in tautomeric forms. All tautomeric forms are intended to be included in this category. Similarly, when the compound contains an alkenyl group or an alkenyl group, the cis and trans isomeric forms of the compound may be present. A mixture of extramuscular and trans isomers of the lake and cis. Thus, reference to a compound herein includes all such isomeric forms, unless the context clearly dictates otherwise. Example t includes various forms including polymorphs, solvates, hydrates, conformers, salts, and prodrug derivatives. Polymorphs are compositions having the same chemical formula but having different structures. A solvate is a composition formed by solvation (a combination of a solvent molecule and a solute molecule or ion). A compound is a compound formed by incorporation of water. A conformational isomer is a structure which is a isomer. The configuration isomerized to a salt having the same structural formula but having a different configuration (conformational isomer) with respect to the spin bond can be prepared by a method known to the skilled artisan. For example, °. The salt can be made by reacting with a suitable base or acid complex. &amp; The formula from the dry T-Rita is a compound that undergoes peak chemical conversion (chemical conversion) before displaying the pharmacological effect. This may be considered as a specific second::: or a non-desired property of the parental molecule, and therefore, unless the context clearly indicates otherwise, 156115.doc -149-201200517 . As used herein, and particularly when referring to pharmaceutically acceptable salts of the compounds, including formulas w, VII, VIII, Ix, X, XI, χπ, xm, χιν, or as prepared and synthesized by the methods disclosed herein. In the case of a compound, "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of the compound, and preferably means an acid addition salt of the compound. With respect to the basic nitrogen-containing compound synthesized by the method of this example, a preferred example of a pharmaceutically acceptable salt is a pharmaceutically acceptable inorganic or organic acid (including but not limited to, hydrogen hydride, An acid addition salt of sulfuric acid, phosphoric acid, an aliphatic or aromatic carboxylic acid, or a % acid). Examples of pharmaceutically acceptable inorganic or organic acids as components of the addition salt include, but are not limited to, hydrochloric acid, hydrobromic acid, thionine, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, lemon Acid, ascorbic acid, bitter acid, formic acid, p-toluene or acid. Preferred examples of the acid-functional compound-acceptable salt synthesized by the method of this example include (but are limited to) a metal salt (sodium or potassium), an alkaline earth metal salt (calcium or magnesium). Or an ammonium salt derived from ammonia or a pharmaceutically acceptable organic amine such as Ci_C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine or cis-(hydroxymethyl)-aminomethane. Isotopes may be present in the compound. Each chemical represented in the structure of the compound may include any isotope of the element. For example, in the structure of a compound, it is expressly disclosed or understood that a hydrogen atom is present in the compound. At any position where a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen including, but not limited to, hydrogen-! (氕) and hydrogen-2 (氘). Therefore, unless the context otherwise explicitly refers to #, the compounds referred to herein cover all isotopic forms of 156115.doc •150·201200517. Unless otherwise stated, if a substituent is depicted as a di-group (ie, having two points of attachment to the rest of the molecule), it is understood that the substituents may be attached to any of the states, thus, for example, ' Substituents described as or Υ / include substituents that are oriented such that the oxime is attached to the leftmost junction of the molecule and A is attached to the rightmost junction of the molecule.

When a range of values is provided, it is understood that each of the median values between the upper and lower limits of the range and the upper and lower limits are encompassed in the examples. It should be understood that a particular group naming convention may include a single base (m〇n〇_ radical) or a di-radical (visual basis) depending on the context. For example, when a substituent needs to have two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. Substituents identified as building groups and requiring two points of attachment include diradicals such as _CH2_, _〇Ή2 (: ϋ2-, -CH2CH(CH3)CH2-, and the like; depicted as alkoxy and requiring two Substituents for the attachment points include diradicals such as _〇CH2_, -OCHKH2, and their like groups; and are depicted as aryl c(=0)- and require two consecutive sites to attack their red _ All of the technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains, unless otherwise defined. Equivalent to any method and material, but the preferred methods and materials are now described. All publications referred to herein are incorporated by reference in their entirety by reference to 156115.doc. 151 - 201200517 herein to disclose and describe such methods The singular forms "a" and "the" are used in the plural, unless the context clearly dictates otherwise. Indicator Thus, for example, reference to "a method" includes a plurality of such methods and reference to "a dose" includes reference to one or more doses and equivalents known to those skilled in the art, and the like. Embodiments provide a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV as defined above, and Formulas VI, VII, VIII, IX, X, XI, XII, XIII, Pharmaceutical compositions and formulations of any of the compounds of XIV or XV. As discussed below, the compounds of the invention are useful in the treatment of HCV infection and other disorders. In many embodiments, the compounds of the invention inhibit HCV viral replication. For example, Compounds of the invention inhibit HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40% compared to HCV viral replication in the absence of a compound. At least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% or more. The compounds of the invention can be assayed using methods known in the art, including in vitro viral replication assays. Whether to inhibit HCV disease Toxic replication. Compositions Embodiments of the invention additionally provide compositions comprising a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV, including 156115.doc .152-201200517 Pharmaceutical combination The pharmaceutical compositions of the present invention comprise a compound of the present invention; and a pharmaceutically acceptable excipient. A variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Acceptable excipients have been fully described in various publications including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th Edition, Lippincott, Williams, &amp;Wilkins; Pharmaceutical Lu Dosage Forms and Drug Delivery Systems (1999) HC Ansel et al., eds., 7th edition, Lippincott, Williams, &amp;Wilkins; and Handbook of Pharmaceutical Excipients (2000) AH Kibbe et al., 3rd edition, Amer. Pharmaceutical Assoc. Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are known in the art. "In addition, pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers Agents, tonicity modifiers, stabilizers, wetting agents and the like are known in the art. φ In some embodiments, a compound as described herein is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in intensity from about 5 mM to about 100 mM. In some embodiments, the aqueous buffer comprises an agent provided for the isotonic solution. Such agents include, but are not limited to, sodium vaporized; and sugars such as mannitol, dextrose, cane stalk, and the like. In some embodiments, the aqueous buffer additionally includes a nonionic surfactant such as polysorbate 20 or 80. Optionally, the formulation may additionally include a preservative. Suitable preservatives include, but are not limited to, phenylhydrin, phenol, chlorobutanol, gasified benzine 156115.doc-153-201200517 and the like. In many cases, the formulation is stored at about 4.匚. The formulation may also be lyophilized, in which case it will generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol and the like. The lyophilized formulation can even be stored for long periods of time at ambient temperature. Thus, administration of a compound as described herein can be accomplished in a variety of ways, including orally, buccally, rectally, parenterally, intraperitoneally, intradermally, subcutaneously, intramuscularly, transdermally, intratracheally, and the like. In some embodiments, the administration is by rapid injection, such as subcutaneous rapid injection, intramuscular rapid injection, and the like. The pharmaceutical compositions of the embodiments can be administered orally, parenterally or via an implantable reservoir. Oral administration or injection is preferred. The subcutaneous administration of the pharmaceutical compositions of the present invention is carried out using standard methods and devices, such as needles and syringes, hypodermic injection delivery systems, and the like. No. 4, 755, 173; The combination of a hypodermic injection device and a device for administering a pharmaceutical composition of the examples to a patient via a sputum is referred to herein as a "subcutaneous injection sputum delivery system." In many embodiments, subcutaneous administration is achieved by rapid delivery of needles and syringes. The compounds as described herein in a pharmaceutical dosage form may be administered in the form of their pharmaceutically acceptable salts, or they may be used alone or in combination with other pharmaceutically active compounds as appropriate. The following methods and excipients are illustrative only and are not intended to be limiting in any way. For oral formulations, the compounds as described herein may be used alone or in combination with suitable additives for the manufacture of lozenges, powders, granules or capsules, for example with conventional additives such as lactose, mannose, and 156115.doc • 154·201200517 Sugar alcohol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; and disintegrants such as corn starch, potato starch or methine cellulose; In combination with a lubricant such as talc or magnesium stearate; and if necessary with diluents, buffers, wetting agents, preservatives and flavoring agents. • a compound as described herein may be dissolved, suspended or emulsified in an aqueous or non-aqueous solvent such as vegetable oil or other similar oil, synthetic aliphatic acid glycerin, high carbon aliphatic acid or propylene glycol; Injectable formulations are formulated using a second additive such as a solubilizing agent, an isotonic agent, a suspending agent, an emulsifier, a stabilizer, and a preservative. Furthermore, the compounds as described herein can be formulated as a suppository by mixing with various bases such as emulsifiable bases or water-soluble bases. The compounds of the examples can be administered rectally via a suppository. Suppositories may include vehicles such as cocoa butter, carbowax, and polyethylene glycol which melt at body temperature but cure at room temperature. Unit dosage forms for oral or rectal administration such as syrups, elixirs and suspensions may be provided, wherein each dosage unit (eg, one teaspoon, spoon amount, lozenge or suppository) contains a predetermined amount of one Or a plurality of compositions of the compounds as described herein. Similarly, unit dosage forms for injection or intravenous administration may comprise a compound as described herein in the form of a solution in sterile water, physiological saline or otherwise pharmaceutically acceptable carrier. 156115.doc •155· 201200517 The term “unit dosage form” as used herein refers to a physical individual unit suitable for use as a single dose in humans and animal subjects, each unit containing a predetermined amount of the compound of the example (calculated to produce the desired effect) The amount is combined with a pharmaceutically acceptable diluent, carrier or vehicle. Novel Units of the Examples The specifications of the dosage forms depend on the particular compound employed and the effect to be achieved and the efficacy of each compound in the host. Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are known in the art. In addition, pharmaceutically acceptable adjuvant materials such as pH adjusting agents and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like are readily known in the art. Treatment of Hepatitis Virus Infections The methods and compositions described herein are generally applicable to the treatment of HCV infection. The invention provides a method for treating hepatitis C disease in an individual. Infection The method comprises administering to the individual an effective amount of a composition comprising a compound of the present invention. The preferred embodiment provides a method of treating liver fibrosis in an individual, the method 投3 administering to the individual an effective amount of a composition comprising a compound of the invention. The method of providing a method of providing liver function to an individual having a hepatitis C virus infection&apos; method comprises administering to the individual an effective amount of a composition comprising a compound of the invention. ^ Confirmation by reducing viral load, reducing seroconversion (in patients' sera), increasing the rate of sustained viral response to therapy, reducing bed morbidity, or morbidity or mortality or disease response Whether the method of the invention is effective in treating HCV infection. 156115.doc •156- 201200517 In general, an effective amount of a compound of formula VI, VII, VIII 'IX, X, XI, XII, XIII, XIV or XV and optionally one or more other antiviral agents is effective to reduce The amount of viral load or the amount of sustained viral response to the therapy. Whether the method of the present invention can be determined by measuring viral load or by measuring parameters associated with HCV infection including, but not limited to, liver fibrosis, elevated serum transaminase levels, and necroinflammatory activity of the liver Effective treatment of HCV infection. Instructions for liver fibrosis are discussed in detail below. In some embodiments, the methods involve administering an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV, optionally with an effective amount of one or more additional antiviral agents. combination. In some embodiments, an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and optionally one or more other antiviral agents is effective to reduce viral titer to An amount of undetectable amount, such as from about 1000 to about 5000' per milliliter of serum, from about 500 to about 1000, or from about 100 to about 500 genomic copies. In some embodiments, an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and optionally one or more other antiviral agents is effective to reduce viral load to a low level The amount of 100 genomic copies per ml of serum. In some embodiments, an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV, and optionally one or more other antiviral agents, is effective to achieve viral efficacy in the individual's serum. Price 1.5-log ' 2-log ' 2.5-log ' 3-log ' 3.5-log ' 4-log ' 4.5-log or 5-log reduction. 156115.doc • 157·201200517 In many embodiments, the compounds of formula VI, VII, νιπ, ΤΥν, χ, ΧΙ, XII, XIII, XIV or XV and, as appropriate, are effective for other antiviral agents The amount is effective to achieve a sustained viral response, such as at least about 1 month, at least about 2 months, at least about 3 j solid months, at least about 4 months, at least about 5 months, or at least about 6 after the therapy is known. Undetectable or substantially undetectable HCV RNA is found in the patient's serum during the month (eg, less than about 5 〇〇, less than about 4 〇〇, less than about 200, or less than about 1 基因 transcript copies per ml of serum) The amount. As described above, whether the method of the present invention is effective in treating Hcv infection can be determined by measuring parameters related to Hcv infection, such as liver fibrosis. Methods for determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the serum marker content of liver fibrosis is indicative of the extent of liver fibrosis. As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard assays. In general, it is believed that the ALT content of less than about 45 international units is normal. In some embodiments, an effective amount of one or more other antiviral agents of the formula νι, νπ, νιιι, ιχ, x, XI, ΧΙΙ, xm, χιν or χνκ, and optionally one or more other antiviral agents is effective to reduce the alt content to Less than about 45 per milliliter of serum. Comparing with the content of the marker in an untreated individual or a placebo-treated individual, the formula VI, VII, VIII, IX, x, XI, χπ, ΧΠΙ, 乂, or χν compound and optionally one or more other antibodies The therapeutically effective amount of the viral agent is an effective reduction of the serum content of the liver fibrosis marker by at least about 10 〇 / 〇, at least about 20%, at least about 25%, at least about 3%, at least about 156115.doc 201200517 35%, An amount of at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. Methods for measuring serum markers include immunological-based methods using antibodies specific for a particular serum marker, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like. In many embodiments, an effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and other antiviral agents is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and other antiviral agents is an incremental improvement over the therapeutic outcome. A combination dose effective for therapeutic or prophylactic treatment of HCV infection, which may be predicted or expected only by additive combinations of (1) and (ii): (i) when administered at the same dose as monotherapy Therapeutic or prophylactic benefit of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and (ii) therapeutic of other antiviral agents when administered at the same dose as monotherapy Or preventive benefits. In some embodiments, when used in combination therapy for a disease, a selected amount of a Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV4 conjugate and a selected amount of other antiviral agent are Effective, but when used in monotherapy of disease, a selected amount of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and/or a selected amount of other antiviral agent is less effective . Thus, the examples encompass (1) when used in combination therapy for disease, a selected amount of other antiviral agent enhances selected amounts of Formula VI, VII, 156115.doc-159·201200517 VIII, IX, X, XI, XII, A regimen of therapeutic benefit of a compound of XIII, XIV or XV, wherein a selected amount of other antiviral agent provides a negligible therapeutic benefit when used in monotherapy for a disease, and (2) when used in combination therapy for a disease, a selected amount A regimen of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV enhancing the therapeutic benefit of a selected amount of other antiviral agent, wherein selected amounts of formula VI, VII, VIII, IX, X, Compounds of XI, XII, XIII, XIV or XV provide negligible therapeutic benefit when used in monotherapy for disease, and (3) when used in combination therapy for disease, selected quantities of formulas VI, VII, VIII, IX, A therapeutic benefit is provided by a compound of formula X, XI, XII, XIII, XIV or XV and a selected amount of other antiviral agent, wherein a selected amount is of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV Each of the compounds and other antiviral agents are used in the disease Provide therapeutic benefit are negligible when the monotherapy. As used herein, it is to be understood that "a synergistically effective amount" of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and other antiviral agents and their grammatical equivalents include (1) above. (3) Any of the approaches encompassed by any of the above. Fibrosis This embodiment provides a method of treating liver fibrosis, including forms of liver fibrosis caused by or associated with HCV infection, and generally involves administration. The therapeutic amount is a compound of formula VI, VII, VIII, IX, X, XI, X11, XIII, XIV or XV and optionally one or more other antiviral agents. The effective amount of the compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and the dosage regimen are discussed below in the presence and absence of one or more other antiviral agents. 156115.doc -160- 201200517

Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV compounds and optionally, may be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether treatment with one or more other antiviral agents is effective in reducing liver fibrosis. Liver fibrosis was measured by analyzing liver biopsy samples. The analysis of liver biopsy involves the evaluation of two main components: necrotic inflammation as assessed by "grade" as a measure of severity and current disease activity, and fibrosis and substantial or vascular remodeling as assessed by the "stage" The damage is reflected in the progression of long-term disease. See, for example, Brunt (2000) Hepatol. 31:241-246 ’ and METAVIR (1994) Hepatology 20:15-20. Based on liver biopsy analysis, assign a score. There are many standardized scoring systems that provide a quantitative assessment of the extent and severity of fibrosis. These systems include METAVIR, KnodeU, Scheuer, Ludwig, and Ishak scoring systems. The METAVIR scoring system is based on analysis of various features of liver biopsy, including fibrosis (portal fibrosis, lobular center fibrosis, and cirrhosis). , necrosis (small and lobular necrosis, acidophilic retraction and balloon-like degeneration) 'inflammation (inflammation of portal vein, portal vein lymphoid aggregation and portal vein inflammation); bile duct changes; and ruler (10) palpitations index (neuropathic necrosis, leaflets Necrosis, portal vein inflammation, fibrosis, and scoring of overall disease activity). The stages in the METAVIR system are defined as follows: score ·· 〇, no fibrosis, servant.1, portal veins increase in star shape but no diaphragm formation; get/knife. 2 ' The iliac vein is enlarged and forms a very small number of diaphragms ; Score: 3, many septum but no cirrhosis; and score: 4, cirrhosis. 156115.doc -161 - 201200517

Knodell's scoring system, also known as hepatitis activity index (H邛

Activity Index), classifying samples based on scores of four types of tissue characteristics: peripheral and/or bridging necrosis of the portal vein; variability and local necrosis of π leaflets; III-inflammation of the portal vein, and Ιν·fibrosis. In the system of slave training, the ten knives are as follows. The score is .0, no fibrosis; score: 1, mild fibrosis (fibrous portal vein dilatation); score: 2, moderate fibrosis; score: 3, severe Fibrosis (bridge fibrosis); and score: 4, cirrhosis. Score Yu Gao' The liver tissue damage is more serious. Kn〇deU (1981) kiss 1:431 〇cheuei• scoring system, the score is as follows: score:, no fibrosis; score: Bu portal vein enlargement, fibrosis; score: 2, portal vein or portal vein - Portal vein septum, but the structure is complete; score: 3, fibrosis and structural distortion, but no obvious cirrhosis; score: possible or clear cirrhosis. Scheuer (1991) J. HepatoL 13:372.

The Ishak scoring system is described in Ishak (1995), Suppression of Money 696_ _. Stage 0, no fibrosis; stage i, some portal vein fibers = Zhang, with or without a short fiber septum, · Stage 2, most portal veins: fiber. Quasi/·sheng expansion' with or without short Fibrous septum · Stage 3, most of the portal vein area fibrous iliac crest, &quot;sheng expansion, occasional portal vein and portal vein (Ρ·Ρ) bridging; stage 4' iliac vein regional fibrosis with obvious bridging (ρ_ρ) And portal vein-center (P_C); stage 5, obvious bridging (ρ_ρ and / or μ), ^ see nodules (incomplete liver cirrhosis, stage 6, very likely or clear liver hard can also use Child-Pugh scoring system Measuring and evaluating the benefits of the anti-fibrous treatment J56115.doc -162- 201200517, the scoring system includes serum bilirubin content, serum albumin content, prothrombin time, presence and severity of ascites, and encephalopathy Multi-component system for the presence and severity of abnormalities. Based on the existence and severity of abnormalities in these parameters, patients can be classified as one of three types of clinical diseases with increased severity: A, B or C. In some embodiments, The therapeutically effective amount of VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV compounds and optionally one or more other antiviral agents is based on pre- and post-treatment liver biopsy to achieve fibrosis The amount by which one or more units are changed in a stage. In a particular embodiment, a therapeutically effective amount of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV, and optionally one or more Other antiviral agents reduce liver fibrosis by at least one unit in the METAVIR 'Knodell, Scheuer, Ludwig or Ishak scoring system. Equations VI, VII, VIII, IX, X can also be evaluated using a second or indirect index of liver function. The therapeutic efficacy of XI, XII, XIII, XIV or XV compounds. The semi-automated evaluation of the morphometric measurement of the degree of liver fibrosis based on the specific staining of collagen and/or serum markers of liver fibrosis may also be The measurement is an indication of the efficacy of the method of treatment of the invention. The second index of liver function includes, but is not limited to, serum transaminase content, prothrombin time, bilirubin, platelet count, portal pressure Albumin content and Child-Pugh score assessment. Compounds of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV compared to liver function indices in untreated or placebo treated individuals And optionally, one or more other antiviral agents are used 156115.doc -163-201200517 to effectively increase the liver function index by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least About 35%, at least about 4%, at least about 45%, at least about 50%, at least about 55%, at least about 6%, at least about 65%, at least about 70%, at least about 75%, or at least about 8 〇 % or higher. Those skilled in the art can readily measure these liver function indices using standard analytical methods&apos; many of which are commercially available and routinely used in clinical settings. Serum markers of liver fibrosis can also be measured as an indication of the efficacy of the methods of treatment of the present invention. Serum markers for liver fibrosis include, but are not limited to, hyaluronic acid, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and ilaminin ^ Other biochemical markers of liver fibrosis include (X-2 macroglobulin, hepatic globulin, gamma globulin, lipoprotein sputum and gamma glutamine thiol transpeptidase) with untreated individuals or A therapeutically effective amount of a marker in a placebo-treated individual compared to a compound of Formula VI, VII, VIII, IX, X, XI, χη, χΗΐ, 乂^ or XV and optionally one or more other antiviral agents To effectively reduce the gold content of the liver fibrosis marker by at least about 10%, at least about 20%, at least about 25°/〇, at least about 30%, at least about 35, at least about 40%, at least about 45% An amount of at least about 5%, at least about 55 Å, at least about 60%, at least about 65 Å, at least about 7%, at least about 75%, or at least about 80% or more. Standard analytical methods can be readily used to measure these liver fibrosis serum markers, many of which are privately analyzed The method is commercially available and routinely used in clinical settings. Methods for measuring serum markers include immunological methods using 156115.doc-164 - 201200517 specific for specific serum markers, φίΕΤ τ 〇Δ. , ^ ^ 铋 免疫 免疫 免疫 免疫 免疫 免疫 免疫 、 、 、 、 、 、 、 、 、 、 、 、 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Decompensation of the sequelae of sequelae of stagnation of the disease: or after the occurrence of liver fibrosis and as a result of it, see, but not limited to, ascites, variceal hemorrhage, portal hypertension, κ plague, Liver dysfunction, encephalopathy, hepatocellular carcinoma, tang to aqi Βΐ^ ΧΛ. And hepatic sputum transplantation with liver failure and with the liver

Guan Zhi's death. In combination with an untreated individual or a placebo-treated individual, a compound of formula, νπ, VI„, IX, χ, ΧΙ, ΧΙΙ, χ, χιν or χν, and depending on the condition - or a variety of other antiviral agents The therapeutically effective amount is such that the incidence of a condition associated with liver cirrhosis (eg, an individual's likelihood of developing a disease) is effectively reduced by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40°/〇, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 702⁄4, at least about 75%, or at least about 80% or more Highly skilled. Those skilled in the art can readily determine treatment with Formula VI, VII, VIII, IX, X, XI, XII, guanidine, XIV* XV compounds, and optionally one or more other antiviral agents. Whether it is effective in reducing the incidence of diseases associated with liver cirrhosis. The reduction of liver fibrosis can improve liver function. Therefore, the examples provide a method for improving liver function, generally involving administering a therapeutically effective amount of formula VI, VII, VIII, IX, X, XI, χπ, ΧΙΠ, XIV or XV compounds and Use one or more other antiviral agents as appropriate. Liver function includes (but is not limited to 156115.doc -165-201200517) such as serum proteins (eg, albumin, coagulation factors, alkaline phosphatase, aminotransferases) For example, protein synthesis of alanine transaminase, aspartate transaminase, 5'-nucleosidase, γ-glutamate thiol transpeptidase, synthesis of bilirubin, synthesis of cholesterol and Synthesis of bile acids; liver metabolism, including but not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; detoxification of exogenous drugs; hemodynamic function, including visceral and portal vein hemodynamics Learning; and similar functions. Whether liver function is improved can be easily determined by those skilled in the art using recognized liver function tests. Thus, such as albumin, alkaline phosphatase, alanine transaminase, aspartate The synthesis of liver function markers for transaminase, bilirubin and its analogs can be assessed by measuring the levels of these markers in serum using standard immunological and enzymatic assays. Venous hemodynamics can be measured by portal wedge pressure and/or impedance using standard methods. Metabolic function can be measured by measuring the amount of ammonia in the serum. It can be measured by standard immunology and enzymatic analysis. The content of these proteins is used to determine whether the whey protein normally secreted by the liver is in the normal range. The normal range of such serum proteins is known to those skilled in the art. The following are (4) Qualitative examples. The normality of alanine transaminase The content is about IU per ml of serum. The normal range of aspartate transaminase is about 5: about the unit per liter of serum. Standard assay is used to measure bilirubin. Normal bilirubin content is usually less than about 1.2. Mg/db uses standard assays to measure eight levels of serum albumin. Normal levels of serum albumin range from about 35 to about 55 g/L. Standard assays are used to measure prolongation of prothrombin time. Normal coagulation &amp; time is less than about 4 seconds longer than the control time. Transfer to the original 156H5.doc -166- 201200517

A therapeutically effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV, and optionally one or more other antiviral agents, is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80°/. Or a higher amount. For example, a therapeutically effective amount of a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and optionally one or more other antiviral agents is a serum marker of liver function The amount of increase is effective to reduce at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or higher or will The serum marker content of liver function is reduced to an amount within the normal range. The therapeutically effective amount of a compound of formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and optionally one or more other antiviral agents is also effective to reduce the amount of serum markers of liver function. Increasing at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about φ 80% or higher or labeling liver function serum The content of the substance is increased to the normal range. Dosage, Formulation, and Route of Administration In the methods of the invention, the active agent can be administered to the host using any convenient means capable of producing the desired therapeutic effect (eg, Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV) Or XV compound and optionally one or more other antiviral agents). Thus, the agents can be incorporated into a variety of formulations for therapeutic administration. More specifically, the agents of the examples can be formulated into pharmaceutical compositions 156115.doc • 167·201200517 by combination with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated as solid, semi-solid, Formulations in liquid or gaseous form, such as lozenges, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols. Other antiviral or anti-fibrotic agents, as discussed above, will be administered in some embodiments by administering a compound of Formula VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV and optionally Or a plurality of other antiviral agents for carrying out the method of the invention. In some embodiments, the method additionally comprises administering one or more interferon receptor agonists. In other embodiments the method additionally comprises administering pirfenidone or a pirfenidone analog. Other antiviral agents suitable for combination therapy include, but are not limited to, nucleotides and nucleoside analogs. Non-limiting examples include azidothymidine (ΑΖτ) (zidovudine) and its analogs and derivatives; 2,3,-dideoxyinosine (DDI) (dinoinosine 'didanosine) And its analogues and derivatives; 2,, 3, _ deoxycytidine (DDC) (dideoxycytidine) and its analogues and derivatives; 2', 3, dihydrogen 2' , 3,-di-deoxythymidine (D4T) (stavudine 'stavudine) and its analogues and derivatives; cabez (c〇mbivir); abacavir (abacavir); adanfudipine (adef〇vir dip〇xil); cidofovir; ribavirin; ribavirin analogs; and analogs thereof. In some embodiments, the method additionally comprises administering ribavirin. The ribavirin (Ι-β-D-ribofuranosyltriazole·3_f decylamine) purchased from ICN Pharmaceutical Inc., c〇sU Mesa, CaUf is described in 156115.doc •168- 201200517

Merck Index, Compound No. 8199, u. Its manufacture and formulation is described in U.S. Patent No. 4,211,771. Some embodiments also involve the use of derivatives of ribavirin (see, e.g., U.S. Patent No. 6,277,83). The azole can be administered orally in the form of a capsule or lozenge, or administered in the same or different administration form as the compound of the present invention and in the same or different routes. Of course, other types of administration of the two drugs are also contemplated, such as by nasal spray, percutaneous, intravenous, by suppository, by sustained release dosage form, and the like. only

Any form of administration will be effective in delivering the proper dosage without destroying the active ingredient. In some embodiments, the method additionally comprises administering ritonavir. Ritonavir (1〇_hydroxy-2-methyl-5-(1_mercaptoethyl) small [2_(1mercaptoethyl)4·thiazolyl]-3,6- from Abbott Laboratories Bis-oxy-8, U_bis(phenylmethyl)_2,4,7,12•tetraazatriazin-13-acid 5-oxazolylmethyl ester [5S_(9)*,8ΛΜ谢,, Inhibitors of human immunodeficiency virus proteases are also inhibitors of cytochrome ρ45〇3Α and ρ45〇2〇6 liver enzymes, which are often involved in the liver metabolism of therapeutic molecules in humans. In some embodiments, Including administration of a protease inhibitor. In some embodiments, the '13' method additionally comprises administering a secreted formulation. In some embodiments, the method additionally comprises administering a helicase inhibitor. In some embodiments, the method additionally Including the administration of a polymerase inhibitor. In some embodiments, 'administering other antiviral agents during the course of the treatment of the compound of the invention throughout the period of time of administration of other antiviral agents with the compounds of the invention Time period overlap, such as other disease resistance 156115.doc -169- 201200517 poison treatment can be treated in the compound of the present invention (d) before the start - and before the end of the treatment of the compound of the invention; other antiviral treatments may begin after the start of treatment of the compound of the invention and end after the treatment of the compound of the invention; other antiviral treatments may begin at the treatment of the compounds of the invention Thereafter, and before the end of treatment of the compound of the invention; or other antiviral treatment may begin prior to the initiation of treatment of the compound of the invention and after the end of treatment of the compound of the invention. Methods of Treatment Monotherapy The compounds described herein may be used in Hcv In short-term or long-term therapy of the disease, in many embodiments, a compound as described herein can last from about κ to about 7 days, or from about 1 week to about 2 weeks, or from about 2 weeks to about 3 weeks or from about 3 weeks to about 4 Week, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 Months to about 12 months, or at least one year, and can be administered over a longer period of time. Compounds as described herein can be taken 5 times a day, 4 times a day, 3 times a day, '2 times a day' per day 1 Times Times, 2 times a week, 3 times a week, once a week, once every other week, 3 times a month 'or monthly. In other examples' NS5 A inhibitor compound as a continuous infusion In the sufficiency of the application, the compounds described herein can be administered orally as described in the Examples. In combination with the above methods for treating HCV disease in a patient, the compounds as described herein can be administered per kilogram per day. A dose having a body weight of from about 1 mg to about 1 mg, administered to the patient in divided doses from 1 to 5 in the mother's day. In some embodiments, 156115.doc • 170·201200517 The compound as described herein may be administered daily. Each kilogram of patient weighs approximately 5 mg to approximately 75 mg and is administered daily in 5 divided doses. The amount of active ingredient which can be combined with the carrier materials to produce the dosage form will vary depending upon the mode of administration and the mode of administration. A typical pharmaceutical preparation may contain from about 5% to about 95% active ingredient (w/w in other embodiments, the pharmaceutical preparation may contain from about 20% to about 80% active ingredient. Those skilled in the art will readily understand the dosage. Depending on the particular compound, the severity of the condition, and the susceptibility of the individual to side effects, the preferred dosage of a particular compound as described herein can be readily determined by a variety of means by those skilled in the art. To measure the physiological potency of a particular interferon receptor agonist. In multiple embodiments, multiple doses of the NS5A inhibitor compound are administered. For example, the NS5A inhibitor compound is administered over a period of about i weeks, about 2 weeks to about 4 weeks, about two months to about two months, about two months to about two months, about four months to about six months, about six months to about eight months, About 8 months to about ^ Lu S, about 1 year to about 2 years or about 2 years to about 4 years, or a longer period of time once a month, twice a month, 3 times a month, every other week ^(10)), weekly owe (qw), twice a week (biw), 3 times a week (tiw), 4 times a week, 5 times a week, 6 times a week, every other day ^ ), daily sputum, 2* (qid) or 3 times a day (tid). Combination therapy with TNF-a antagonist and interferon Some examples provide Hcv infection in individuals with HCV infection A method comprising administering an effective amount of a compound as described herein, and an effective amount of a TNF-α antagonist and an effective amount of one or more of 156115.doc • 171 - 201200517. Suitable for treatment Individuals In certain embodiments, a particular regimen for treating a drug therapy in a HCV patient is selected based on certain disease parameters exhibited by the patient, such as the initial viral load in the patient, the genotype of the patient's HCV infection, Stages of liver tissue structure and/or liver fibrosis. Individuals of the above treatment regimen may be administered to individuals diagnosed with Hcv infection. Individuals with advanced or severe stage liver fibrosis (eg by Knodell) An individual who has no liver fibrosis or has early liver fibrosis (eg, scored by Kn〇deU, i or 2) is administered to any of the above treatment regimens. Previous to HCV infection Ineffective treatment of a body ( "treatment failure patients," including non-responders and relapsers) administering any of the above treatment regime of one. In many embodiments, it is particularly contemplated that individuals who are clinically diagnosed with Hcv-infected HCV are identified as having hcv RNA in their blood and/or having anti-HCV antibodies in their serum. Such individuals include anti-hCv ELISA-positive individuals, and individuals with positive recombinant immune dot analysis (RIBA). Such individuals may also (but need not) have elevated serum ALT levels. Individuals clinically diagnosed with HCV infection include untreated individuals (eg, individuals who have not previously received HCV, especially those who have not previously received IFN-a and/or ribavirin-based therapies) and individuals who have failed previous HCV treatment (" Treatment failed "patient". Treatment failure patients include non-responders (ie, previous HCV treatment (eg, previous IFN_a monotherapy, previous combination therapy with ribavirin or combination therapy with previously PEGylated IFN-a and ribavirin) did not appear 156115.doc -172· 201200517 Individuals with or substantially reduced HCV titers; and relapsed (ie, prior treatment of HCV (eg, receiving prior iFN-alpha monotherapy, previous IFN-α and ribavirin combination therapy or previous PEGylation) Combination therapy with IFN-a and ribavirin), individuals with reduced HCV titers and subsequent increases). In a particular embodiment of interest, the individual has an HCV titer of at least about 105, at least about 5 x 1 〇 5, or at least about 1 〇 6, or at least about 2 x 106 HCV genomic copies per milliliter of serum. Patients can be infected with any HCV genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (eg, 2a, 2b, 3a, etc.)), especially difficult to treat, such as type 1 HCV genotypes and especially HCV subtypes and quasi-species. Also concerned with HCV-positive individuals (as described above) that exhibit severe fibrosis or early cirrhosis (non-compensated, Class A Child's-Pugh or lower) or more advanced cirrhosis caused by chronic HCV infection (compensatory disorder, b or class C Child's-Pugh) and it is a viral phase prior to antiviral therapy with IFN-alpha based therapy or it may not be contraindicated or otherwise contraindicated by IFN-alpha based therapy. In a particular embodiment of interest, an HCV positive individual having stage 3 or stage 4 liver fibrosis according to the METAVIR scoring system is suitable for treatment as described herein. In other embodiments, the individual suitable for treatment by the methods of the embodiments is a patient with decompensated cirrhosis with clinical manifestations&apos; including patients with very advanced cirrhosis, including those awaiting liver transplantation. In other embodiments, an individual suitable for treatment by the methods described herein includes patients having a relatively mild degree of fibrosis, including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; Stage 1, 2 or 3) in the Ishak scoring system. 156115.doc • 173-201200517 Synthesis The compounds and methods of the present invention will be better understood in conjunction with the following synthetic schemes which illustrate methods by which the compounds of the invention can be prepared. The starting materials can be obtained from commercial sources or prepared by accepted literature methods known to those of ordinary skill in the art. Unless otherwise stated below, the variables are as defined above. Part I Preparation of compounds: Part I Example Ϊ : Preparation of general compounds

Process I-I

0H

SOCI,

CI

HNRJ2 l-lc

Ι-Ιβ Boc Pd(PPh3)4t NaHC03 〈 Ξ DME/H2〇

J2 RN

HCI/MeOH

J2 RN

N HATU, DIEA, DCM J2 RN &gt; =N \/A=\ /) y~\\ r - N A-A 101 The variables shown in the flow of Example I are defined according to the definition of Equation XI. -174· 156115.doc 201200517 Process I-Ia

General Procedure I_A To a solution of the general compound I-Ia (4·4 mm 〇l) in s〇Cl2 (1 mL) was added DMF (0.3 mL) and the reaction mixture was stirred under reflux overnight. After chilling to room temperature, the mixture was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. Process I_Ib ci

Mb HNRJ2 RM-j2

General Procedure I-B To a mixture of the general compound I-Ib (4.5 mmol), EtOAc (m.), EtOAc (EtOAc) The reaction mixture was stirred under reflux for two days. After cooling to temperature, the precipitated solid was collected by filtration. Washing the solid two 3, / general compound I_Ide with CHsCN to obtain 156115.doc -175· 201200517 Scheme I-Ie

General procedure IC under N2 protection to general compound I-id (1.0 mmol), general compound I-Ie (1.3 mm 〇G, NaHCO3 (0.17 g, 2.0 mmol) in DME/H20 (9 mL/3 mL) Pd(PPh3)4 (0.04 g, catalytic amount) was added to the mixture. The mixture was stirred for 5 hours under reflux, then cooled to room temperature. Then H2O (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3) The combined organic layers were washed with brine (12 mL &lt;2) and dried over anhydrous Na.sub.2.sub.4. filtered and concentrated. The residue was purified by column chromatography to give the general compound I-If. 5 g, yield 83%) » Process I_Id

General Procedure I-D A mixture of the general compound I_If (3 mmol) in EtOAc / MeOH (5 mL) The solvent was removed under reduced pressure to give the general compound I-Ig 156 156115.doc -176 - 201200517 Process I-Ie

General procedure I-E

To a mixture of the general compound I-Ig (0.32 mmol), EtOAc (EtOAc, EtOAc) The resulting mixture was stirred at room temperature for 1 hour. The mixture was then treated with water (10 mL) and EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the compound. Example VIII-XVI: Preparation of Compound 421

Process VIII-XVI

156115.doc -177- 201200517 Process Vlll-XVIa

4-gas-L-ct-phenylglycine

General Procedure VIII-BT Cool a solution of 4-fluoro-L-α-phenylglycine (1.7 g '10 mmol) in 1 mL of 1 N sodium hydroxide solution to 1 (TC. Add gas formic acid) Vinegar (0.94 g, 10 mmol) and 10 mL of 2 N NaOH solution. After stirring at room temperature for 16 hrs, the mixture was acidified with 1 N HCl aqueous solution until pH 2 s and ethyl acetate (100 mL &gt;&lt;3 The product was extracted. The combined extracts were dried with sodium sulfate, filtered and concentrated to afford compound VIII-XVIa (0.9 g, yield 39%) as a white solid.

廿 l-XVIlaa

General procedure VIII-BU to compound I-XVIIaa (1.0 g, 2.2 mmol), compound 156H5.doc-178·201200517 I-VIIIn (0.89 g, 2·2 mmol), K2C〇3 (0.62 g, 4.5 under N2) Methyl) Pd(dppf)Cl2 (〇.1 g, catalytic amount) was added to a mixture of oxalic acid/H2O (20 mL/1 mL). The reaction mixture was refluxed overnight under N2. After cooling to rt, EtOAcqqqqqqqqqq The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by silica gel column chromatography to afford compound VIII-XVIb (0.8 g, yield 57%). Process VIII-XVIc

General Procedure VIII-BV A mixture of compound VIII-XVIb (0.1 g, 0.16 mmol) in EtOAc / MeOH (4 <RTIgt; After concentration under reduced pressure, compound VIII-XVIc was used in the next step without further purification. 流程 Process Vlll-XVId

General Procedure VIII-BW 156115.doc -179-201200517 To Compound VIII-XVIc (0.1 g '0.24 mmol), Compound VIII-XVIa (0.11 g, 0.48 mmol), HATU (0.2 g, 0.52 mmol) in DCM (5 mL DIEA (0.18 g, 1.4 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (1 mL) and EtOAc (EtOAc EtOAc (EtOAc) 12 mg, yield 6%). *H NMR (300 MHz, CDC13): δ 7.82-7.64 (m, 2 Η), 7.61-7.49 (m, 6 Η), 7.43-7.30 (m, 4 Η), 7.29-7.04 (m, 3 Η) , 7.00-6.92 (m, 3 Η), 6.16 (d, J=6.0 Hz, 2 H), 5.50 (d, J=8.1 Hz, 2 H), 5.30 (br, 2 H), 3.74 (br, 2 H), 3.68 (s, 6 H), 3.32 (br, 2 H), 2.80 (br, 2 H), 2.25-1.88 (m, 8 H) ° MS (ESI) m/z (M+H) + 843.2 ° Example VIII-XVII: Preparation of Compound 422 Scheme νιπ-χνπ

General procedure VIII-BX • 180- 156115.doc 201200517

Add DIEA (0.17 g, 1.3) to a mixture of compound VIII-XVIIa (0.1 g '0.22 mmol), compound νΐΙΙ-Χνΐ3 (0.11 g, 0.48 mmol), HATU (0.19 g, 0.5 mmol) in DCM (5 mL) Mm). The resulting mixture was scrambled at room temperature for 2 hours. The mixture was then diluted with water (10 mL) and EtOAc (EtOAc) The combined organic layers were dried with Na2SO4 and evaporated. The crude product was purified by preparative EtOAc (EtOAc) 4 NMR (400 MHz, CDC13): δ 7.69-7.40 (m, 11 Η), 7.33-7.26 (m, 3 Η), 7.10-7.05 (m, 1 Η), 6.97-6.93 (m, 3 Η), 6.20 (d, 7=8.0 Hz, 2 Η), 5.54-5.45 (m, 4 Η), 3.73-3.64 (m, 8 Η), 3.35 (br, 1 H), 2.86 (br, 2 H), 2.31 -1.96 (m, 8 H). MS (ESI) m/z (M+H) + 867.3. Example VIII-XVIII: Preparation of Compound 423

CF3 Ο

PCl5, Et3N

Process VIII-XVIII

H2, Pd/C CH3OH nh2 F3CV^V〇h cf3 0 VIII-XVlIlc

Vlil-XVIlId

156I15.doc • 181 - 201200517 f3c

Process Vlll-XVIIIa

General Procedure VIII-BY A solution of 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoic acid (5.0 g, 24 mmol) in DCM (50 mL) PC15 (5 g, 24 mmol) was added portionwise, and then the mixture was stirred at room temperature for 3 hr. After concentrating under reduced pressure, EtOAc EtOAc m. In solution. The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added and EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Process Vlll-XVIIIb F3Vy cf3 ο VII|.XVIig

General procedure VIII-BZ Add (·5)-(·)-α-methylbenzylamine to a solution of compound VIII-XVIIIa (2.0 g, 6.7 mmol) in MeOH (10 mL) at -70 °C (0.82 g, 6.7 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour, followed by 156115.doc •182-201200517

Treatment with MeOH (10 mL) containing EtOAc (1_27 g, 7. 4 mmol). Subsequently, MeOH was evaporated to remove most of the MeOH, then Et20 was added until the hydrochloride salt began to solidify. The solid was collected by filtration then added to a mixture of Et.sub.2O (10 mL) and sat. NaHCO3 (10 mL). After the C02 (gas) precipitation was stopped, the mixture was extracted with Et20. The organic layer was separated and the Et20 solution was dried over Na.sub.2SO.sub.4 and filtered to remove solids. After filtration, the filtrate was treated with HCl gas for 25 min and solvent was evaporated to give Compound VIII-XVIIIb (0.7 g, yield 23%) as the hydrochloride salt. Process VIII-XVIIIc

General procedure VIII-CA

Pd/C (10%, 0.07 g) was added to a mixture of compound VIII-XVIIIb (0-7 g, 1.5 mmol) in EtOH (10 mL). The mixture was stirred at 50 psi H2 for 6 hours at room temperature. Subsequently, the solids were removed by filtration. After filtration, the filtrate was concentrated to give Compound VIII-XVnic (0.3 g, yield: 86%). </ RTI> Vlll-XVIIId nh2 f3c

VIII-XVIIIc

NaHC〇3 aqueous solution dioxane/h2o

CF$ OH Vlll-XVIIId 156115.doc -183· 201200517

General procedure VIII-CB to VIII-XVIIIc (0.1 g '0·4 mmol), NaHC〇3 (1.0 g, 11.9 mmol) in dioxin (2 mL) and H2 〇 (2 mL) at 〇 °C Methyl decanoate (0.04 g, 0.4 mmol) was added to the mixture. Subsequently, the reaction mixture was stirred at room temperature for 5 hours. The mixture was then extracted with EtO Ac. The residual aqueous layer was acidified with dilute HCl to pH = 2 and extracted with EtOAc. The combined organic layers were dried with EtOAc EtOAc (EtOAc) Process Vlll-XVIIIe nh2 f3c

VIII-XVIIIc ο 〇Λ〇

NaHC03 aqueous solution Dioxane/H20

General procedure VIII-CC is added to a mixture of compound VIII-XVIIIc (0.1 g, 0.4 mmol), NaHCO3 (1.0 g, 11.9 mmol) in dioxane (2 mL) and H20 (2 mL). Methyl decanoate (〇·〇4 g, 0.4 mmol). Subsequently, the reaction mixture was stirred at room temperature for 5 hours. The mixture was then extracted with EtOAc. The residual aqueous layer was acidified with dilute HCl to pH = 2 and extracted with EtOAc. The combined organic layers were dried with EtOAc (EtOAc)EtOAc. 156115.doc -184- 201200517 Process Vlll-XVIIIf VIII-XVIc

General procedure VIII-CC to compound VIII-XVIc (0.065 g, 0.2 mmol), compound

VIII-XVIIId (0.09 g, 0.3 mmol), DIEA (0.5 g, 3.9 mmol)

Add HATU (0.2 g, 0.5 mmol) to a solution in CH2C12 (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with H20 and extracted with EtOAc. The organic phase was separated, dried over Na 2 EtOAc and concentrated. The residue was purified by preparative HPLC to afford compound 423 ( 0.02 g, yield 13%). 4 NMR (400 MHz, CD3OD) 3 7.68-7.76 (m, 8H), 7.41 (s, 2H), 5.30 (d, J=7.6 Hz, 2H), 5.16-5.27 (m, 2H), 4.29-4.33 ( m, 2H), 3.86-3.89 (m, 2 H), 3.76 (s, 6 H), 2.07-2_34 (m, 10H). MS (ESI) m/z (MH+) Example VIII-XIX: Preparation of Compound 424

Process VIII_XIX

Separated by SFC

F CbzCI Cb2 Ναόίίϋ Η

156115.doc -185- 201200517

Process Vlll-XVIXa

O^/OH

F CbzCI ^ Qbz NaOH solution 〇 nu

Vlll-XIXa

General Procedure VIII-CD CbzCl (2.5 g, 14.7) was added dropwise to a solution of 3-fluoro-α-phenylglycine (1 g, 5.9 mmol) in 10 mL NaOH (2 M) at 0 °C. Methyl) and the mixture was stirred at room temperature for 3 hours. The mixture was then acidified with EtOAc (2 mL). After concentration under reduced pressure, the residue was purified mjjjjjjjjjj NMR (300 MHz, DMSO-d6): (5 13.01 (s, 1 Η), 8.18 (d, J=8.4 Hz, 1 H), 7.10-7.39 (m, 9 H), 5.22 (d, «7= 6.6 Hz, 1H), 5.04 (s, 2 H). The compound Vlll-XIXa was isolated by supercritical fluid chromatography (SFC) to give 500 mg of compound 3. Column: CHIRALPAK® AS, 250 x 4.6 mm ID, 5 μπι. Flow Vlll-XVIXb

F CbzCI ^ Cbz, aqueous NaOH solution

Separating Cbz by SFC,

VHUXIXb [aj= + 57.5 Vlll-XIXb* [aj= - 56.6 156115.doc -186 201200517

General Procedure VIII-CE CbzCl (2.5 g, 14.7) was added dropwise to a solution of 3-fluoro-α-phenylglycine (1 g, 5.9 mmol) in 10 mL NaOH (2 Μ) at 0 °C. Methyl) and the mixture was stirred at room temperature for 3 hours. The mixture was then acidified with EtOAc (2 mL). After concentration under reduced pressure, the residue was purified mjjjjjjjjjj 4 NMR (300 MHz, DMSO-A): (5 13.01 (s, 1 Η), 8.18 (d, J=8.4 Hz, 1 H), 7.10-7.39 (m, 9 H), 5.22 (d, */ =6·6 Hz, 1H), 5·04 (s, 2 H). Compound VIII-XIXa was isolated by supercritical fluid chromatography (SFC) to give 500 mg of compound XlXb. Column: CHIRALPAK® AS, 250x4 .6 mm ID, 5 μιη. Flow VIII_XVIXc

General Procedure VIII-CF To a mixture of compound XIXb (500 mg, 1.6 mmol) in HOAc (5 mL) was added HBr (5 mL, 40% HOAc solution). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give &lt;RTIgt;&lt;/RTI&gt;&gt;&lt;/RTI&gt; </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; 156115.doc •187· 201200517 Process VIII-XVIXd

General procedure VIII-CG To a solution of 3-fluoro-L-α-phenylglycine (VIII-XIXc, 270 mg, 1.6 mmol) in 5 mL of H2O, NaOH (256 mg, 6.4 mmol) The mixture was stirred at rt for 0.5 hr then EtOAc (EtOAc &lt The mixture was then extracted with EtOAc (20 mL). The aqueous phase was separated, dried with EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjjjj Fluorine-L-α-phenylglycine (VIII-XIXd, 240 mg, yield 66%). NMR (300 MHz, CD3OD): δ 7.01-7.40 (m, 4 Η), 5.25 (s, 1 Η), 3.64 (s, 3 H). Process Vlll-XVIXe

General procedure VIII-CH To a mixture of compound VIII-XVIc (113 mg, 0.27 mmol) in DMF (5 mL) was added DIPEA (104 mg &lt;RTI ID=0.0&gt;

HATU (205 mg, 0. 54 mmol) and compound VIII-XIXd (120 mg, 0.54 mmol). The mixture was stirred at room temperature for 2 hr then EtOAc (EtOAc) The residue was purified by preparative HPLC to afford compound 424 (50 mg, yield 22%). 1H NMR (300 MHz, CD3OD): δ 7.63-7.83 (m, 8H), 7.04-7.44 (m, 10H), 5.16-5.25 (m, 2H), 4.93-4.95 (m, 2H), 3.86-3.89 ( m, 2H), 3.58 (s, 6H), 3.53 (s, 2H), 2.17-2.33 (m, 5H), 1.62-2.14 (m, 3H). MS (El) m/z: (M+H) + 843.4. Part II Preparation of compounds: Part II Example IX-I: Preparation of compound 501

Process IX-I

IX-la

IX-lb

BnBr &gt; DMF, K2C03 Br2 HBr/HOAc, 10°C

501 Process IX-Ia

BnBr ^ DMF, K2C03

IX-lb 156115.doc -189- 201200517

General procedure IX-A gives a drop of 1-(4-( ° °qin-1-yl)phenyl)acetamidine (IX-Ia) (2 g ' 9.8 mmol), K2CO3 (2.02 g, 14.7) at room temperature A mixture of EtOAc (5 mL) EtOAc (EtOAc) The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and EtOAcqqqqqqqqqqqqq -Ib) (2.9 g, yield 99%). Process IX-Ib

IX-lb

General Procedure IX-B Add 1-(4-(4-phenylmethylpiperazin-1-yl) to a fraction of Βγ2 (0·59 g, 3.74 mmol) in HBr/HOAc (20 mL) Phenyl)ethanone (IX-Ib) (lg, 3.4 mmol). The mixture was stirred overnight at room temperature. The mixture was poured into 200 mL EtOAc. The precipitate was collected by hydrazine. The solid was dried under vacuum to give compound IX-Ic (1.2 g, 67%) as a pale yellow solid.

156115.doc -190 201200517

General procedure IX-C The compound ix-lc (0.146 g, 0.53 6 mmol), compound I-IIh (0.1 g, 0.268 mmol), THF (10 mL) and DIEA (0.104 g, 0.804 mmol) was stirred at 25 °C. The mixture was 72 hours. The solvent was removed, and the residue was purified mjjjjjjjjj MS (ESI) m/z (M + H) + 565.1. Example IX-II: Preparation of Compounds 502 and 503

Process IX-II

Process IX-IIa

General Procedure IX-D Compound 502 (10 mg, 19%) was prepared according to General procedure VII-V. MS (ESI) m/z (MH+) 156115.doc -191 - 201200517 Process IX-IIb

Vll-Vb

General procedure IX-E

Compound 503 (9 mg, yield 11%) was prepared according to General procedure VII-V. MS (ESI) m/z (M+Na) + 447.1. Example IX-III: Preparation of Compound 504

Process IX-III

IX-llla α

HCl/MeOH

IX·chuan b

Boc

[^^-COOH period 2 HCI &quot;L丨·丨~Br HATU, DIEA IX-lllc NH4OAc toluene—* 110 °c v person 0 VI-IIA HATU, DIHA, DMF

Process IX-IIIa

• 192- 156115.doc 201200517

General Procedure IX-F Stir 2-bromo-i-(4-bromophenyl)ethanone (IX_IIIa) (2〇g, 7.2 mmol) and hexamethylenetetramine (10·3 g, 72 mmol) at room temperature The mixture in chloroform (400 mL) was overnight. The precipitated solid was collected by filtration, washed with methylene chloride and dried in vacuo. The solid was then suspended in a mixture of concentrated HCl (80 mL) and methanol (300 mL). The suspension was stirred overnight at room temperature. The precipitated solid was collected by filtration, washed with decyl alcohol (50 mL) and dried in vacuo to give 18 g of 2-amino-i-(4-bromophenyl)ethanone hydrochloride (m.p. It can be used after purification. Process IX-IIIb

Br

IX-IIIb nh2 hci

COOH Boc l-lf ^ HATU, DIEA

General procedure IX-G will be HATU (38.2 g, o.ll mol), diisopropylethylamine (23 8 g, 〇 2 mmol) and iV-Boc-L-proline (I-lf) (i4. 4 g, 67.2 mmol) added to a suspension of 2-amino-1-(4-bromophenyl)ethanone hydrochloride (ix_IIIb) (16 g, 64 j mmol) in tetrahydrofuran (120 mL) . The resulting mixture was stirred for 4 hours and the solid was dissolved. The reaction mixture was quenched by the addition of a π% aqueous sodium chloride solution (5 Torr) and stirred for further 30 minutes. The layers were separated and the organic layer was combined with toluene (150 mL) and concentrated to a volume of 1 〇〇mL. The solution of character IX-IIIc was used in the next step. 156115.doc •193· 201200517 Process IX-IIIc

A stupid 110 °c

NH4OAC

General procedure IX-H The solution of compound IX-IIIc obtained in the previous experiment was treated with ammonium acetate (53.7 g, 672 mmol) and heated to 100-110 ° C for 25 hours. The mixture was allowed to cool to room temperature, filtered, concentrated, and the residue was purified by column chromatography (300 g EtOAc EtOAc EtOAc EtOAc Compound IX-IIId (15.0 g, yield 61% in two steps) was obtained. Process IX-IIId

General Procedure IX-I Compound IX-IIId (783 mg, 2 mmol) was added to HC 1 CH30H (40 mL, 4 EtOAc). The mixture was then stirred at room temperature for 2-3 hours. When the reaction was completed, the mixture was concentrated in vacuo to give Compound IX-IIIe (600 mg, yield about 100%). 156115.doc -194- , 0201200517 Process IX-IIIe

IX-IIIe

Break into VI-IIA HATU, DIEA, DMF IX-lllf

General procedure IX-J

Add HATU (470 mg, a mixture of compound IX-IIIe (300 mg, 1 mmol), compound VI-IIA (1 80 mg, 1 mmol) and DIPEA (400 mg, 3 mmol) in DMF (10 mL) 1.1 mmol). The resulting mixture was scrambled at room temperature. LCMS judged that the substance 6 was consumed. The mixture was diluted with EtOAc and brine (EtOAc) The residue was purified by silica gel chromatography to give Compound IX-IIIf (3 00 mg, yield 67%).

H2 -► 10% Pd/C,

EtOH IX-lllf 504

General Procedure IX-K Pd-C (10%, 5 mg) was added to a solution of Compound IX-IIIf (50 mg, 0.13 mmol) in EtOH (8 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at room temperature under H2 (45 psi) for 5 hours. TLC showed the reaction was complete. The Pd/C was then filtered off, the filtrate was concentrated under reduced pressure 156115.doc -195 - 201200517, and the residue was purified by preparative TLC (PE: EA = 5:1) to give 504 (10 mg, yield 21%) . MS (ESI) m/z (M+H) + 371. Example IX-IV: Preparation of Compound 505

Process IX-IV ~/〇 DMSO, NEta; Ethylene Brewing Boc IX-IVa

Boc IX-IVc

N32SO3 Et0H/H20

Pd(PPh3)4, Na2C03, toluene/H^O

IX-IVf B(OH)2

505 Process IX-IVa DMSO, NEt3

\

Boc IX-IVa

General Procedure IX-L A flask containing DMSO (3 5 mL, 0.5 mol) and CH 2 Cl 2 (200 mL) was stirred at -78 °C under nitrogen. A solution of CH2CI2 (2 Torr, 35 mL, 0.3 mol) was added dropwise and the mixture was stirred at -78 °C for 1 hour. A solution of Boc-prolinol (IX-IVa) (50 g, 0.25 mol) in CH2C12 (100 mL) was added dropwise and the mixture was stirred at -78 °C for 2 hr. Triethylamine (120 mL, 1 mol) was added to the mixture and the mixture was allowed to warm to room temperature. The reaction was poured into H20 and the organic phase was removed. The aqueous phase was extracted with CH2C12 (500 mL) and brine (100 mL). The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. ). 4 NMR (300 MHz, DMSO-A) δ: 9.36 (m, 1H), 4.00 (m, 1H), 3.32 (m, 2H), 1.70-1.88 (m, 4H), 1.38 (m, 9H). Process IX-IVb

Boc b〇c IX-IVb ιχ-ivc

General Procedure IX-M Glyoxal (13 g, 〇) was added dropwise to a solution of NH4〇H (200 mL) and B〇c_decamperaldehyde (IX_IVb) (45 g, 2.3 mol) in THF over 30 min. 23 m〇l). The mixture was searched for 36 hours at room temperature. The volatile component was removed in vacuo and the residue was purified by flash chromatography (EtOAc EtOAc) (7 g, yield 13%).嗞(3〇〇mhz, CDC13) δ: 6.93 (s, 2H), 4.89-4.93 1H)&gt; 3.33-3.43 (m5 2H), 2.90-2.91 (m, 1H), i.88-2.15 (m, 4H), 187 (s, 9 H). Process IX-IVc

Lx-, Vc IX-IVd

General procedure IX-N NBS (9 g, 51 mmol) was added to a solution of compound IX_IVc (6 g' 25 Curry 1) in thf ((10) 156115. After the addition, the mixture was allowed to warm to room temperature and stirred overnight. The solution was concentrated and the residue was purified tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj NMR (300 MHz, CDC13) a 4.82-4.88 (m, 1H), 3.36-3.38 (m, 2H), 2.78-2.83 (m, 1H) 1.93-2.01 (m, 3H), 1.43 (s, 9H). Process IX-IVd

Br N32S〇3 --1 , Br Et0H/H20

Boc IX-IVd General procedure IX-0 To a suspension of compound IX-IVd (7 g' 18 mmol) in EtOH/H2O (90 niL, 1/2) was added Na2S03 (22 g, 180 mmol). The compound was refluxed overnight. After filtration, the filtrate was concentrated and purified by methylene chloride chromatography (PE: EA = 10:1) to afford compound IX-lVe (4 g, yield 67%). 4 NMR (400 MHz, CDC13) δ: 10.58 (s, 1H), 6.85 (s, 1Η), 4.80-4.83 (m, 1H), 3.28-3.32 (m, 2H), 2.81-2.84 (m, 1H) , 1.86-2.05 (m, 3H), 1.32 (s, 9H).

General procedure IX-P Flow IX-IVe

To compound IX-IVe under nitrogen at room temperature (100 mg, 0.32 156115.doc _ 198· 201200517

Add Pd (PPh3) to a solution of compound IX-IVf (95.89 mg, 0·47 mmol) and Na2C〇3 (67.1 mg, 0.63 mmol) in toluene (10 mL) and water (1 mL) ) 4 (4 mg, 0.03 mmol). The resulting mixture was stirred overnight under reflux. Subsequently, TLC (PE: EA = 2: 1) indicates that the starting material is depleted. The terpene was removed under reduced pressure and the residue was diluted with EtOAc (20 mL). The organic layer was washed with brine, dried and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H NMR (300 MHz, CDC13) δ 12.0 (br, 1 Η), 8.09 (s, 1H), 7.81--7.67 (m, 3H), 7.48 (s, 1 H), 7.19-7.17 (m, 1 H ), 7.06-7.03 (m, 1H), 4.72-4.61 (br, 1H), 3.79 (s, 3H), 3.32 (br, 2H), 2.12 (br, 1H), 1.98-1.81 (m, 3H), 1.2 (br, 9H). MS (ESI) m/z (M+H). 394 ° EXAMPLE IX-V: Preparation Compound 506

Process IX-V

156115.doc -199- 201200517

Pd(dppf)CI2 KOAc 1,4-di-alkane

IX-Vb

General procedure IX-Q Add Pd(dppf)Cl2 (0.2 g) to compound IX-Va (2 g, 5.1 mmol), bis(pinacolyl)diboron and KOAc (1.0 g, 10.2 mmol) under N2 The mixture was mixed in 1,4-dioxalate (20 mL) and the mixture was refluxed overnight. The mixture was cooled, filtered and concentrated, and then purified, mjjjjjjj Process IX-Vb

General procedure IX-R Add Pd(PPh3)4 (0.03 g) to 4-bromobenzylamine (0.14 g, 0.75 mmol), K2CO3 (0.19 g, 1.4 mmol) and compound IX-Vb (0.3 g) under N2 , 0.68 mmol) in a mixture of CH3CN (3 mL). Subsequently, the mixture was refluxed for 3 hours. The mixture was allowed to cool to room temperature, filtered and concentrated to give </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Process IX-Vc

General procedure IX-S

iV-Boc-proline (I-If; 0.22 g, 1.0 mmol) was dissolved in CH2C12 (5 mL) eluted with HATU (0.35 g, 0.9 mmol), DIEA (0.2 mL, 1.4 mmol) and stirred 1 The compound [X-Vc (0.3 g, 0.7 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and concentrated in the air. The crude product was purified by silica gel column chromatography to yield Compound IX-Vd (0.25 g, yield 58%). Process IX-Vd

General procedure IX-T A solution of compound IX-Vd (0.25 g, 0.4 mmol) in EtOAc (4 EtOAc, 2 mL) was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure. The crude product IX-Ve was used in the next step without further purification. Process IX-Ve

156115.doc -201 - 201200517

General Procedure IX-U Compound VII-IIA (0.18 g, 1.0 mmol) was dissolved in CH.sub.2Cl.sub.2 (25 mL). Compound IX-Ve (0.2 g, 0.48 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was filtered and concentrated. The crude product was purified by silica gel chromatography to afford compound 506 (0.085 g, yield 26%). MS (ESI) m/z (495+). Part X Preparation of the compound: Part X Example X-I: Preparation of compound 601

Process X-I

156115.doc -202- 201200517 Process X-Ia

General procedure χ_Α

To a solution of the compound I-IIif (〇.6 g ' 1.95 mmol) in dioxo (10 mL) was added bis (pinacol) diboron (〇 54 g, 2.14 mmol), KOAc (〇. 38 g ' 3.90 mmol) and Pd(dppf)Cl 2 (0.05 g, catalytic amount) ° The mixture was purged with nitrogen for 5 minutes and heated to 90 ° C overnight. After cooling to room temperature, the mixture was diluted with H.sub.2 (20 mL). Purification by preparative TLC (EtOAc:EtOAc:EtOAc) MS (ESI) m/z (MH+) NMR (300 MHz, CDC13) δ 7.65 (m, 2 H), 3.21 (t, 2 H), 3.12 (t, 2 H), 2.60 (s, 3 H), 2.03 (m, 2 H), 1.35 ( s, 12 H). Process X-Ib

X-la

156115.doc -203 201200517

General Procedure XB To a solution of compound X-Ia (0.37 g, 1.30 mmol) in toluene / H20 (1 mL / 1 mL), Na2CO3 (0.28 g, 2·6 mmol) and compound I-IIIf (0.40 g) ' 1.30 mmol), the resulting mixture was purged with nitrogen, followed by the addition of Pd(PPh3)4 (10 mg 'catalytic amount). The reaction mixture was stirred overnight at 80 ° C under a nitrogen atmosphere. After the reaction was completed, the mixture was poured into water (50 mL). The residue was purified by EtOAc (EtOAc:EtOAc) 4 NMR (300 MHz, CDC13) δ 7.73 (d, J = 10.4 Hz, 2 H), 7.14 (d, J = \0.4 Hz, 2 H), 3.33 (t, 2 H), 2.67 (t, 2 H ), 2.63 (s, 6 H), 2.09-1.99 (m, 6 H) 〇Process X-Ic

General procedure X-C is a mixture of X-Ib (〇.2〇 g, 0.63 mm〇i) in h〇Ac (9 mL). The solution of Br2 (〇 2 g 'h26 min〇l) in h〇Ac (1 mL) was added dropwise and the mixture was stirred overnight at 3 ° C. Et 〇Ac (5 〇 mL) was added to the mixture and washed with a saturated aqueous solution of NaHC 〇 3 (3 χ 5 〇 mL). The organic layer was concentrated under reduced pressure to give compound He, which was used directly in the next step 156115.doc-204-201200517. MS (ESI) m/z (Μ+Η)+ 287·0. Process X-Id

General Procedure XD Add Cs2CO3 (0.27 g, 0·84 mmol) and compound I-IIh (0.23 g, 0.84 mmol) to a suspension of compound X-Ic (0.1 g, 0.21 mmol) in DMF (5 mL) in. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) andEtOAcEtOAc The combined organic layers were washed with water (5 mL×5), brine (5 mL×2), and the filtrate was concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc: MS (ESI) m/z (M+H)+ 476.8 ° Process X-Ie

General procedure X-E To a solution of the compound X-Id (0.08 g, 0.093 mmol) in anhydrous benzene (5 mL), EtOAc (0.072 g, 0.93 mmol). The mixture was stirred overnight under reflux. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 156115.doc - 205 - 201200517 mL &gt;&lt;3&gt;). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by EtOAcjjjjj: 1H NMR (400 MHz, CDC13)

δ 7.13 (m, 6 Η), 5.45 (d, /=8.8 Hz, 2 Η), 5.28 (d, J=5.6 Hz, 2 H), 4.33 (t, 2 H), 4.82 (m, 2 H) , 3.70-3.63 (m, 10 H), 3.12-3.09 (m, 6 H), 2.79-2.78 (m, 4 H), 2.35 (m, 2 H), 2.23-1.96 (m, 6H), 0.88 ( d, J = 3.6 Hz, 12 H). MS (ESI) m/z (MH+) Example X-II: Preparation of Compound 602

Process X-II

OH

N〇2 H2i Pd/C 2-nitrosuccinene

-OH CH3OH

BnBr

N^O

NaH, DMF NBS

X_llc X-Ild

/〇_^3 - ( ch3cn Ph X-llb

H^Pd/C -»

CH3OH

156115.doc -206- 201200517

Process X-IIa

OH

H2i Pd/C CH3〇H 2·nitroresorcinol

OH

2-amino streptophenol

General Procedure X-F Pd/C (10 g, 10%) was added to a mixture of 2-nitroresorcin (89.0 g, 0.57 mmol) in 1 L methanol. The mixture was placed under hydrogen using a hydrogen balloon and hydrogenated at room temperature for 4 hours. After removing the hydrogen gas, the catalyst was filtered off through celite, and the filtrate was concentrated to give crude 2-amino-resorcin (75.0 g, yield 99%). Process X-IIb

OH OH

2-amino streptophenol x-||a 156115.doc -207- 201200517

General Procedure X-G A mixture of 2-aminoresorcinol (31 g, 0.25 mol) and CH(OCH3)3 (56.00 g, 0.38 mol) was stirred at 130 ° C for 2 hours under nitrogen. The reaction was monitored by TLC. After the completion of the reaction, the mixture was concentrated in vacuo</RTI></RTI></RTI></RTI> MS (ESI) m/e (M+H)+ : 136 »

OH

X-lla process X-IIc

General procedure X-H Add NaH (6〇% mineral oil dispersion, 6 52) to a solution of the stirred compound x_IIa (2() g, 〇 14 mol) in DMF under argon at 〇 °c.

g, 0.16 mmol). The solution was stirred for 5 hours. Next, BnBr (29.00 g, 〇 1 a i, Q / + g 0. 丨 6 mol) was added dropwise under argon and the mixture was slowly warmed to room temperature and re-growth for 3 hours. Subsequently, add H2 〇 (60 mL) and use

The conjugate was extracted with EtOAc (60 mL x 3). The organic layer was separated, washed with brine, dried over Na. The residue was purified by EtOAc (EtOAc: EtOAc:EtOAc) 156115.doc -208- 201200517 Process X-IId

N^O NBS CH3CN

Br Ph X-llc N^o

(A

Ph X-llb

General Procedure X-I NBS (26.00 g, 0.14 mmol) was added to a solution of compound X-IIb (21.00 g, 0.13 mmol) in CH3CN (1000 mL). The reaction mixture was then stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford compound X-IIc (27 g, yield: 65%). MS (ESI) m/e (M+H)+: 305. Process X-IIe

Pd(dppf)CI2l KOAc dioxane

General Procedure XJ Compound X-IIc (6.00 g, 19.67 mmol), bis(pinadol) diboron (9.99 g, 39.33 mmol), KOAc (3.86 g, 39.38 mmol) and Pd (dppf) under argon. A mixture of Cl2 (719 mg, 0.98 mmol) in 100 mL of 1,4- dioxane was stirred under reflux for 4 hr. After concentrating, the residue was partitioned between H.sub.2 and DCM. EtOAc (EtOAc) EtOAc (EtOAc) The residue was purified by silica gel column chromatography to yield Compound X-IId (5.5 g, yield: 89%). Process X-IIf

General Procedure XK Compound X-IId (2.50 g, 7.12 mmol), Compound IX-IVe (2.24 g, 7.08 mmol), Na2C03 (1.51 mg, 14.24 mmol) and Pd(dppf)Cl2 (363) under argon The mixture of mg, 0.49 mmol) in 50 mL THF / H20 (v / v = 5: 1) was refluxed overnight. After concentration, the residue was partitioned between H20 and DCM. The combined organic layers were washed with brine, dried over Na~~~ The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) MS (ESI) m/z (M+H) + 461. Process X-IIg

General procedure X-L To a mixture of compound X-IIe (1.20 g, 2.60 mmol) in 20 mL of decyl alcohol was added Pd/C (120 mg, 10%). The mixture was placed under argon with argon balloon 156115.doc -210-201200517 and hydrogenated overnight at room temperature. After completion of the reaction and removal of hydrogen, the catalyst was filtered through celite, and the filtrate was concentrated to give crude product X-IIf (0.80 g, yield 86%). MS (ESI) m/z (M+H) + 371. Process X-IIh

Tf20 TEA, DCM, eight N -►

OTf

General Procedure XM Tf20 (334 mg, 1.18) was added dropwise to a solution of the stirred compound X-IIf (0.8 mg, 2.16 mmol) and Et3N (328 mg) in DCM under argon at -78 °C. Mm). After the addition, the solution was stirred for 0.5 hours, then slowly warmed to room temperature, and stirred for another 3 hours. H20 (5 mL) was then added and extracted with EtOAc (10 mL > &lt;3&gt;). The organic layer was separated, washed with brine, dried over Nazjz The residue was purified by silica gel column chromatography to yield Compound X-II g (240 mg, yield 52%). MS (ESI) m/z (M+H) + 503. Process X-Iii

General procedure XN Compound X-IIg (287 mg, 0.57 mmol), bis (frequency 156115.doc -211 - 201200517 alcohol radical) diboron (290 mg ' 1.14 mmol), KOAc (112 mg ' 1.14) under argon Methyl) and Pd(dppf)Cl2 (21 mg, 0.03 mmol) in l〇mL 1,4-di. The mixture in the mixture was refluxed for 4 hours. After concentration, the residue was partitioned between H.sub.2 and DCM. The organic layer was separated, washed with brine and dried over Naz. The residue was purified by silica gel column chromatography to yield Compounds Compound Compound Compound Compound Compound MS (ESI) m/z (M+H) + 481. Process X_IIj

General procedure X-0 Compound X-IIh (120 mg, 0.23 mmol), compound X-IIg (115 mg, 0.23 mmol), Na2C03 (51 mg, 0.06 mmol) and Pd(dppf)Cl2 (9) under argon The mixture of mg, 0.01 mmol) in 6 mL THF:H20 (v:v = 5:1) was refluxed overnight. After concentration, the residue was partitioned between h.sub.2 and EtOAc. EtOAc. The residue was purified by preparative HPLC to afford compound <RTI ID=0.0># </RTI> <RTI ID=0.0> MS (ESI) m/z (M+H) + 707. Process X-IIj

156115.doc -212 201200517 General Procedure χ-ρ Add compound X-IIi (30 mg, 0.04 mmol) to TFA/DCM solution (10 mL, 1/1). The reaction mixture was stirred at room temperature for 2 hours. When the reaction was completed, the mixture was concentrated under vacuum to give compound X-IIj (30 mg, yield 80%). MS (ESI) m/e (M+H)+: 507. Process X-IIk

General procedure X-Q

Add BOP (92) to a mixture of compound X-IIj (53 mg, 0.10 mmol), compound VII-IIA (37 mg, 0.21 mmol) and DIPEA (81 mg, 0.63 mmol) in DMF (3 mL) Mg, 0.21 mmol). The resulting mixture was stirred overnight at room temperature. After concentration under reduced pressure, the residue was purified mjjjjjjjj ^ NMR (400 MHz, CD3〇D): δ 8.61 (s, 2 Η), 8.18-8.04 (m, 4 Η), 7.82 (s, 2 Η), 5.28-5.25 (m, 2 Η), 4.30- 4.26 (m, 2 Η), 4.04-4.01 (m, 2 Η), 3.95-3.92 (m, 2 Η), 3.68 (s, 6 Η), 2.42-2.25 (m, 5 H), 2.13-2.06 ( m, 5 H), 1.03-0.87 (m, 12 Η). MS (ESI) m/e (M+H)+: 821.4. Example X-III: Preparation of Compound 603 156115.doc •213 - 201200517 OTf

Process X-III

l-XVIf

Process X-IIIa

OH

l-XVIe OTf

General Procedure XR Tf2O (0.19 mL, 1.14 mmol) was added to the stirred compound I-XVIe (200 mg, 1.04 mmol) and TEA (0.2 mL, 1.55 mmol) in DCM (10 mL) In the solution. The reaction mixture was stirred for 30 min then poured into ice water and extracted with DCM (50 mL &gt;&lt;3&gt; The combined organic layers were dried with EtOAc EtOAc (EtOAc) 156115.doc -214- 201200517 OTf

l-XVIf Process X-IIIb

General procedure X_ S Under stirring of N2, the compound I-XVIf (340 mg, 1.02 mmol), bis (pinacolyl) bis (387 mg, 1.52 mmol) and KOAc (203 mg, 2·04 mmol) Pd(dppf)Cl2 (85 mg) was added to a mixture of 1,4-bis"(10 mL). The mixture was stirred at 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and diluted with DCM (100 mL). The residue was recrystallized from MeOH to afford compound <RTI ID=0.0>#</RTI> </RTI> <RTIgt; MS (ESI) m/z (M+H) + 353.1. 1H NMR (400 MHz, CDC13) δ 9.19 (s, 2H), 8.28 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 2.85 (s, 6H) ° Process X-IIIc

General Procedure XT Bromine (Br2, 193 mg, 1.2 mmol) was added to the 156115.doc-215-201200517 compound X-IIIa (170 mg, 0.48 mmol) in AcOH (3 mL) at 90 °C. In the solution. The reaction mixture was stirred for 30 min then poured over EtOAc EtOAc EtOAc. The combined organic layers were dried with EtOAc EtOAc (EtOAc) Process X-IIId

General Procedure X-U To a stirred mixture of compound X-IIIb (150 mg, 0.29 mmol), DIEA (0.5 mL) in THF (5 mL), Compound I-IIh (160 mg, 0.59 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative TLC to afford compound X-IIIc (25 mg, yield 9%). MS (ESI) m/z (M+H) + 893. Process X-IIIe

156115.doc -216- 201200517 General Procedure x-v A mixture of compound X-IIIc (25 mg, 0.028 mmol) and NH4OAc (21 mg, 0.28 mmol) in benzene (5 mL) was stirred overnight. After the reaction was completed, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by preparative HPLC to afford 603 (5.2 g, MS (ESI) m/z (M + H/2) + 853.2. Example X-IV: Preparation of Compound 604

Process X-IV

Process X-IVa

SOCI2 - ϊ MeOH

l-IVa 156115.doc -217- 201200517 General procedure xw In a mixture of 2-methyl-L-proline (1.0 g, 7.8 mmol) in 20 mL of anhydrous methanol under nitrogen at 〇 ° C SOCl2 (2.8 g, 23.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure to give Compound I-IVa (1.4 g, yield 100%) as the hydrochloride salt. iH NMR (300 MHz, CD3OD): 3 3.86 (s, 3H), 3.42-3.46 (m5 2H), 2.36-2.45 (m, 1H), 2.00-2.19 (m, 3H), 1.68 (s, 3H). Process X-IVb

General Procedure xx To a solution of compound I-IVa (1.35 g, 7.7 mmol) in 30 mL DCM was added compound VI-IIa (1.5 g, 8.5 mmol), HATU (4.4 g, 11.6 mmol) and DIEA (3 g, 23 mmol). The resulting mixture was stirred overnight at room temperature. Subsequently, the mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na 2 EtOAc and concentrated. The residue was purified by column chromatography (EtOAc / EtOAc = EtOAc) to afford Compound I-IVb (1.5 g, yield: 65%). MS (ESI) m/z (M+H) + 301 〇 156115.doc -218· 201200517 Process X-IVc

General Procedure X-Y # A mixture of the compound I-IVb (1.5 g, 5 mmol) and NaOH (0, 6 g, 15 mmol) in MeOH (30 mL) and H20 (5 mL) was stirred for 2 hr. The residue was dissolved in MeOH (20 mL) EtOAc (EtOAc)EtOAc. The organic layer was washed with EtOAc (EtOAc m.) NMR (300 MHz, DMSO-J6): δ 12.20 (s, 1H), 7.24 (d, /=8.4 Hz, 1 H), 3.54-3.98 (m, 3H), 3.50 (s, 3H), 1.78-2.05 ♦ (m, 5H), 1.34 (s, 3H), 0.84·0·88 (m, 6H). Process X-IVd

General procedure XZ 156115.doc •219· 201200517 The compound x-lc (100 mg, 0.21 mmol), compound I-IVc (150 mg, 0.53 mmol) and Cs2C03 (137 mg, 0.42 mmol) were stirred at room temperature. The mixture in mL DMF was 2 hours. The mixture was then diluted with EtOAc (30 mL) and brine. The organic layer was separated, dried over anhydrous Na.sub. The residue was purified by preparative TLC (DCM / MeOH = 20 /l) to afford compound I-IVd (140 mg, yield 75%). MS (ESI) m/z (M+H) + 887. Process X-IVe

General procedure X-AA A mixture of compound I-IVd (140 mg, 0.16 mmol) and NH4 〇Ac (243 mg, 3.2 mmol) in 10 mL of xylene was stirred at 120 ° C for 5 hours. After cooling to rt, EtOAc (EtOAc) (EtOAc) The organic layer was separated, dried over anhydrous Na.sub. The residue was purified by preparative HPLC to afford compound 604 (35 mg, yield 26%). 4 NMR (300 MHz, MeOD): δ 7.49-7.54 (m, 2H), 7.05-7.10 (m, 4H), 4.18 (d, /=7.8 Hz, 2H), 4.00-4.06 (m, 2H), 3.86 -3.94 (m, 2H), 3.65 (s, 6H), 3.05-3.10 (m, 4H), 2.73-2.80 (m, 4H), 2.54-2.63 (m, 2H), 2.01-2.15 (m, 12H) , 1.87 (s, 6H), 0.87-0.96 (m, 12H). MS (ESI) /z (M+H) + 847.6. 156115.doc •220· 201200517 Example X-V: Preparation of Compound 605

Process X-V

Process X-Va

General procedure X-AB Spoil compounds X-Ic (100 mg, 0.21 mmol), compound I-IIh (57 mg, 0·21 mmol), DIEA (82 mg, 0.63 mmol) in DMF (5 mL) at room temperature The mixture in 2 hours. The mixture was diluted with EtOAc (30 mL) then washed with water and brine. The organic layer was dried over anhydrous Na.sub.s. The crude residue was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) w/z (M+H)+ 668. Process X-Vb

General procedure X-AC Stabilize compound X-Va (60 mg, 0.09 mmol), compound I-IVc (26 mg, 0.09 mmol) and Cs2C〇3 (58 mg, 0.18 mmol) in DMF (3 mL) The mixture was 2 hours. The mixture was diluted with EtOAc (30 mL) and washed with water and brine. The organic layer was separated, dried with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The rate is 38%). MS (ESI) m/z (M+H) + 874. Process X-Vc

General Procedure X-AD A mixture of compound X_Vb (30 mg, 0.03 mmol) and NH4 〇Ac (77 mg, 1.0 mmol) in diphenylbenzene (10 mL) was stirred overnight at 120 °C. After cooling to room temperature, remove the solvent under reduced pressure and use 156115.doc • 222-201200517

The residue was diluted with EtOAc (30 mL)EtOAc. The organic layer was separated, dried over anhydrous Na. The residue was purified by preparative HPLC to afford compound 605 (6.5 mg, yield 23%). !H NMR (300 MHz, CD3OD): δ 7.47-7.51 (m, 2Η), 7.05-7.11 (m, 4H), 5.17-5.21 (m, 1H), 4.19-4.23 (m, 2H), 3.87-4.02 (m, 4H), 3.64 (s, 6H), 3.04-3.12 (m, 4H), 2.73-2.76 (m, 4H), 2.58-2.61 (m, 1H), 2.20-2.35 (m, 3H), 2.02 -17 (m, • 10H), 1.86 (s, 3H), 0.86-0.95 (m, 12H). Part XII Preparation of the compound: Part XII Example XII-I: Preparation of substituted hexahydropyridazin-5(1H)-one intermediate

Process XII-I

(3S, 6S, 9S)-XII-lc (3S, 6R, 9R)-Xll-lc' Process XII-Ia

O^V^COOMe 156115.doc -223 - 201200517

General procedure XII-A Add ruthenium chloride (30 mL) to a stirred solution of L-pyroglutamic acid (15 g, 0.12 mol) in MeOH (120 mL) at 〇 ° C under nitrogen. , 0.16 mmol). After the addition, the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After concentration under reduced pressure, EtOAc (EtOAc) (EtOAc) The organic layer was separated, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Process XII_Ib

General procedure XII-B to L · 〇 〇 〇 〇 〇 〇 7.6 g, 0.12 mol)

To a mixture of Et3N (12.4 g, 0·12 mol), DMAP (15.0 g, 0.12 mol) in DCM (200 mL), DCM (100 mL) After the addition, the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo. The residue was purified by column chromatography (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 5:1) to give methyl phthalocyanate (1 〇 g, yield 33%). Process XII-Ic

156115.doc -224- 201200517

General procedure XII-C is added dropwise to a stirred solution of Boc-L-pyroglutamate (8.5 g, 34.4 mol) in anhydrous THF (150 mL) under nitrogen at -40 °C. Vinyl magnesium bromide (42 mL, 42 mmol). After the addition, the mixture was stirred for 3 hours. The mixture was then treated with EtOAc (MeOH) (EtOAc) The organic layer was separated and aqueous was extracted with diethyl ether (60 mL×3). The combined organic layers were washed with brine, dried EtOAc EtOAc The residue was purified by silica gel column chromatography (PE: EA = 4:1) to afford compound XII-Ia (9.3 g, yield 98%). Process XII-Id

O

MeOOC

Xll-la NHBoc (Ph)2=NCH2COOf-Bu -»

Cs2C03, THF

General Procedure XII-D To a solution of compound XII-Ia (9.3 g, 34.3 mmol) and N-(diphenylhydrazinyl)glycine tert-butyl ester (11.1 g, 37.6 mmol) in THF (200 mL) Cs2C03 (11.2 g, 34.5 mmol) was added. The reaction mixture was then stirred overnight under nitrogen at room temperature. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford compound XII-Ib (8.8 g, yield 45%). MS (ESI) m/e (M+H)+: 566. 156115.doc -225 - 201200517 XI lb Process XII-Ie 10% Pd/C -» EtOH/HOAc

(3S, 6S, 9S)-XII-lc

H

General Procedure XII-E Pd/C (1 g, 10%) was added to a solution of compound XII-Ib (8.8 g, 15.5 mmol) in 180 mL EtOH/HOAc (9/1). The mixture was hydrogenated overnight by hydrogen balloon at room temperature. Subsequently, the catalyst was filtered off through celite, and the filtrate was concentrated to give a crude product which was purified by preparative HPLC to give compound (3S,6S,9S)-XII-Ic and (3S,6R,9R)-XII-Ic '(total 3.7 g, total yield 57%). Example XII-II: Preparation of Compound 801

Process XII-II

156115.doc -226 - 201200517 Process ΧΙΙ-IIa

General procedure XII-F The compound (3S,6S,9S)-XII-Ic (2.0 g, 5.64 mmol) was stirred in 20 mL of TEA/Et3SiH (V/V=95/5) under nitrogen at room temperature. The mixture was 1 hour. The mixture was then concentrated in vacuo to afford crude compound <RTI ID=0.0># </RTI> </RTI> <RTIgt; Process Xll-IIb

General procedure XII-G methyl chlorodecanoate (1.0 g, 10.5 mmol) was added to a solution of the compound ΧΙΙ-IIa (2 g, 10.1 mmol) in dioxime: (20 mL), followed by 10% Aqueous Na2C03 (20 mL). The resulting mixture was stirred overnight at room temperature. The mixture is then concentrated in a vacuum. The residue was extracted with EtOAc (30 mL×3). The aqueous solution was acidified to pH~2 and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2zjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Flow ΧΠ-IIc

General procedure XII-H Add compound XII-IIb (650) to a solution of compound XII-IIc (480 mg, 1.26 mmol) and DIEA (328 mg, 2.54 mmol) in CH3CN under nitrogen at 〇 °C. Mg, 2.53 mmol). After the addition, the mixture was stirred for 0.5 hours, then slowly warmed to room temperature and stirred for additional 3 hours. After concentrating under reduced pressure, the residue was purified by preparative HPLC to afford compound XII-IId (130 mg, yield 7%). MS (ESI) m/z (M+H) + 747 ° Flow Xll-IId

General Procedure XII-I Compound XII-IId (130 mg, 0.17 156115.doc -228-201200517 mmol) and NH4〇Ac (322 mg, 4.18 mmol) in diphenylbenzene (l〇mL) were stirred under reflux in a sealed tube. The mixture in the middle of the night. After washing with water, the organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to afford compound 801 (22 mg, 17.9%). 4 NMR (400 MHz, CD3OD) 3 7.83-7.88 (m, 10H), 5.33 (d, /=8.8 Hz, 2H), 4.11-4.17 (m} 2 H), 3.80-3.87 (m, 2 H), 3.65 (s, 6 H), 2.57-2.60 (m, 2 H), 2.15-2.33 (m, 8 H) 1.80-2.14 (m, 6 H). MS (ESI) m/z (M+H) + 707.3. Example XII-III: Preparation of Compound 802

Process XII-III

NH2 Xll-llla

General Procedure XII-J Add BOP to a mixture of compound XII-IIIa (133 mg, 0.46 mmol), compound ΧΙΙ-IIb (240 mg, 0.94 mmol) and DIPEA (420 mg, 3.25 mmol) in DMF (3 mL) (415 mg, 0.94 mmol). The resulting mixture was stirred at room temperature for 1 hour. LC-MS indicated the disappearance of the compound ΧΙΙ-IIIa. The mixture was washed with water and then extracted with EtOAc. The residue was purified by preparative HPLC to afford compound 802 (20 mg, yield 6%). 4 NMR (400 MHz, CD3OD) δ 7.58 (d, J=8.4 Hz, 4 H), 7.51 (d, 156115.doc -229- 201200517 J=8.8 Hz, 4 H), 7.09 (s, 2 H), 4.55 (d, J=8.4 Hz, 2 H), 4.25-4.29 (m, 2 H), 3.78-3.85 (m, 2 H), 3.68 (s, 6 H), 2.21-2.28 (m, 4 H) , 2.10-2.17 (m, 4 H), 1.79-1.88 (m, 8H). MS (ESI) m/z (M+H)+: 687.3. Example XII-IV: Preparation of Compound 803

Process XII-IV

NH40AC is stupid, 120. (^

Process Xll-IVa

156115.doc -230- 201200517 General Procedure ΧΙΙ-Κ Compound XII-IIc (lg, 2.52 mmol) was dissolved in DMF (15 mL) at 〇 ° C, followed by the addition of compound I-IIh (687 mg, 2.52 mmol) And DIPEA (326 mg, 2.52 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes, and then stirred at room temperature for further 3 hours. Subsequently, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL &gt;&lt;3&gt; The combined organic layers were washed with brine, dried over sodium sulfate dried The residue was purified by preparative φ HPLC to afford compound XII-IVa (567 mg, yield 38%). MS (ESI) m/z (M+H) + 588. Process ΧΙΙ-IVb

General procedure ΧΠ-L The compound XII-IVa (307 mg, 0. 52 mmol) was dissolved in DMF (10 mL) and mixture was treated with compound XII_IIb (134 mg, 2.52 mmol) and DIPEA (67 mg '0.52 mmol) . The mixture was then stirred at room temperature for 3 hours. The mixture was then diluted with EtOAc (30 mL EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate The obtained residue was purified by preparative HPLC to afford compound XII-IVb (100 mg, yield 25%). MS (ESI) m/z 156115.doc -231 - 201200517 (M+H)+763 Process XII-IVc 0,

Xll-IVb NH4OAc dimethyl stupid, 120°ϊ

N

.NH

General Procedure XII-M A mixture of compound XII-IVb (100 mg, 0.13 mmol) and NH4OAc (242 mg, 3.14 mmol) in diphenylbenzene (10 mL) was stirred overnight at 120 °C. After cooling to room temperature, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained was purified by preparative HPLC to afford compound 803 (25 mg, yield 27%). 1H NMR (300 MHz, CD3OD) δ 7.84-7.86 (m, 10 Η), 5.34 (d, 7=8.7 Hz, 1 H), 5.22-5.27 (m, 1 H), 4.23 (d, J=6.9 Hz , 1 H), 4.00-4.11 (m, 2 H), 3.83-3.88 (m, 2 H), 3.65 (s, 3 H), 3.64 (s, 3 H), 2.27-2.57 (m, 3 H) , 2.04-2.25 (m, 10 H), 1.85-2.01 (m, 6 H). MS (ESI) m/z (MH+) Example XII-V: Preparation of Compound 804 156115.doc -232- 201200517

Process XII-V

Process XII-Va 八t1 ΒοοΗΝ^γΝ^ 0 〇^° NaHMDS' BocHN/^N, 4 THF 0 〇〆, ' /V λ, (3S, 6R, 9R)-XII-lc· (3S, 6R, 9S }-XH-Va

General procedure XII-N is carried out in a solution of the stirred compound -^, &lt;ίΛ,9/?)-ΧΙΙ-Ι(:' (1.00 g, 2.8 mmol) in THF at -78 °C under nitrogen. NaHMDS (2 THF THF solution, 2·8 mL, 5.6 mmol) was added. After stirring, the solution was stirred at -78 ° C for 3 hr. The reaction was quenched with water and extracted with EtOAc (30 mL &gt; The combined organic layers were washed with brine, dried over sodium sulfate and evaporatedlilulululululululululululululululululululululululululululululululululululululululululululululululululu (490 mg, yield 49%). MS (ESI) m/z (M+Na) + 377. Process XII-Vb

H BocHN

O

H2N

TFA/DCM -5 Et3SiH

N^c〇〇h XII-Vb

(3S, 6R, 9S)-XII-Va General procedure XII-O at 〇 °C under nitrogen (M,6i?,9S)-Xn-Va (490 mg, 1.38 mmol) in DCM TFA (4.65 mL) and Et3SiH (0.25 mL) were added to the solution in (10 mL). Subsequently, the reaction mixture was stirred at 0 ° C for 30 minutes, followed by stirring at room temperature for 3 hours. The solution was concentrated under reduced pressure to give Compound <RTI ID=0.0># </RTI> </RTI> <RTIgt; MS (ESI) m/z (M+H)+

199. Process XII-Vc h2n 々ο N^5^cooh

XII-Vb o c丨人0〆 -^ Na2COyJc solution

General procedure ΧΠ-Ρ Compound XII-Vb (270 mg, 1.36 mmol) was dissolved in dioxane (20 156115.doc • 234-201200517 mL) and 10% aqueous Na 2 C 〇 3 (20 mL). To the resulting solution was added decyl chloroformate (145 mg, 1.53 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated to remove most of the dioxane. The aqueous layer was acidified and extracted with EtOAc (20 mL & The combined organic layers were washed with EtOAc EtOAc EtOAc m.

Process XII-Vd

General Procedure XII-Q A solution of compound XII-IVa (270 mg, 0.46 mmol) in DMF (10 mL) was obtained from compound XII-Vc (117 mg, 0.46 mmol) and DIPEA (59 mg, 0.46 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with water (30 mL) and EtOAc (30 mLEtOAc). The combined organic layers were washed with brine, dried over sodium sulfate dried The obtained residue was purified by preparative HPLC to afford compound XII-Vd (240 mg, yield 68.5%). MS (ESI) m/z (M+H) + 763. 156115.doc -235 - 201200517

General Procedure XII-Q A mixture of compound xn_Vb (24 〇 mg, 0.31 mmol) and NH4OAc (580 mg, 7, 53 mmol) in xylene (1 〇 mL) was stirred overnight at 120 ° C in a sealed tube. The solvent was removed under reduced pressure and EtOAc (EtOAc)EtOAc. The organic layer was dried over sodium sulfate and removed under reduced pressure to give a residue. Purification of the residue by preparative HPLC gave compound 8 4 (30 mg, yield 13%). NMR (400 MHz, CD3OD) δ 7.84-7.94 (m, 1 〇Η) 5 35-5.39 (m, 1 Η), 5.25-5.29 (m, 1 Η), 4.25 (d, /=7.2 Hz, 1 Η ), 4.05-4.13 (m, 2 Η), 3.86-3.93 (m, 2 Η), 3.68 (s, 3 Η), 3.65 (d, 3 Η), 2.57-2.75 (m, 3 Η), 2.05- 2.35 (m, 1 〇Η), 1.62-1 81 (m, 6 Η). MS (ESI) m/z (Μ+Η) + 723.5. Example XII-VI: Preparation of Compound 805 156115.doc -236· 201200517

Process XII-VI

Process ΧΙΙ-VIa

General Procedure XII-R The flask was charged with compound XII-IIc (700 mg, 1.76 mmol), compound I-IVc (510 mg, 1.76 mmol), DIPEA (228 mg, 1.76 mmol) and DMF (10 mL). The resulting mixture was stirred at 0 ° C for 0.5 hour, 156115.doc - 237 - 201200517 and then stirred at room temperature for 3 hours. The mixture was then treated with water (30 mL) then EtOAc (30 mL &lt The combined organic layers were washed with brine, dried EtOAc EtOAc The residue was purified by preparative HPLC to afford compound XII-VIa (430 mg, yield 41%). MS (ESI) m/z (M+H) + 601.

Process ΧΙΙ-VIb

General Procedure χ π-s Stabilize compound XII-VIa (265 mg, 0.44 mmol), compound XII-IIb (113 mg, 0.44 mmol) and DIPEA (57 mg, 0.44 mmol) in DMF (10 mL) The mixture was 3 hours. Subsequently, water (30 mL) was added to the mixture, and the obtained aqueous mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried with EtOAc EtOAcjEtOAc The residue was purified by preparative HPLC to afford compound XII-VIb (140 mg, yield 42%). MS (ESI) m/z (M+H) + 777. Process XII-Vic

156115.doc •238 · 201200517 General procedure ΧΠ-τ Stir compound XII-VIb (140 mg, 0.19 mmol) and NH4OAc (345 mg, 4.48 mmol) in xylene (10 mL) at 120 ° C in a sealed tube. The mixture is overnight. After cooling to room temperature, the solvent was evaporated and evaporated. The organic layer was washed with EtOAcq. The residue was purified by preparative HPLC to afford compound 805 (60 mg, yield 44.

NMR (400 MHz, CD3OD): δ 7.83-7.86 (rn, 10 Η), 5.32 (d, 7=5.7 Hz, Η), 4.11-4.16 (m, 3 Η), 3.91-3.97 (m, 2 Η) , 3.65(s, 3 Η), 3.63 (s, 3 Η), 2.13-2.54 (m, 9 Η), 1.81-2.07 (m, 7 H), 0.92 (d, /=6.9 Hz, 3 H), 0.86 (d, /=6.9 Hz, 3 H). MS (ESI) m/z (M+H) + 737.5 〇 Example XII-VII: Preparation Compound 806

Process XII-VII Allyl Tributylstannane

CbzCl H 5*Bu DIEA.DCM· 0°C Xll-Vlld ^ 9-BBN, H2Q2> Factory ^bz liBu NaOH solution, TH^ H0 Xll-Vlle

Cb2 0, BU

Xll-Vlif

(COCI)2i DMSO -» TEA, DCM, &quot;60oC

Only Cbz OBu tBuOK, DCM, -70°C

Xll-Vllg

XlUVIlh I56115.doc -239- 201200517

Β〇〇2〇 -► DMAP, THF

Bocv Cbz COOMe Cbz °,B H2.Pd-C B〇c Bu —THF _

NaOH &quot;ΜθΟΗ* xii-vih xn-viij

Bocv

COOH

Xit&gt;Vllk H 〇*Bu

XII-VIIL

Process XII-Vila

General Procedure XII-U Boc20 (276 g, 1.26 mol) was added dropwise at 0 °C to L-pyroamine•240·156115.doc 201200517 Tert-butyl acid (108 g, 0.97 mol) and DMAP ( 10.8 g, 0.087 mol) in a solution of acetonitrile (2 L). Subsequently, the reaction mixture was allowed to warm to room temperature and stirred for 48 hours. After concentration, the mixture was diluted with EtOAc (250 mLEtOAc) The combined organic layers were dried with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc)

Process Xll-VIIb

General procedure XII-V Boc-L-tert-butyl glutamate (100 g, 0.35 mol) was dissolved in anhydrous THF (1 L). The resulting mixture was treated dropwise with LiEt3BH (1 M THF solution, 420 mL, 0.42 mol) at -70 ° C, and then the mixture was stirred for 3 hours. After quenching with aqueous aq. EtOAc (EtOAc) (EtOAc) The combined organics were washed with EtOAc EtOAc EtOAc m. Process XII-VIIc

Allyltributylstannane -» Me3SiOTf/DCM, -70 ° C

Xll-VIIb 156115.doc • 241 201200517 General procedure χπ-w Under stirring at -70 ° C to compound XII-VIIa (100 g, 0.35 mol) and allyltributyltin (128 mL, 0.42 mol) in anhydrous Me3SiOTf (75 mL, 0.42 mol) was added dropwise to the solution in CH2C12 (800 mL). The resulting mixture was stirred at -70 °C for 1 hour, then treated with a saturated aqueous solution of NH4Cl. The aqueous mixture was extracted with EtOAc (5 mL) &lt;3&gt;. The combined organic layers were washed with brine, dried over Na2zjz The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc) MS (ESI) m/e (M+H)+ : 312.2 » Process ΧΙΙ-VIId

General Procedure XII-X A solution of compound XII-VIIb (88 g, 0.28 mol) in HC 1 /dioxane (500 mL, 4 EtOAc) was stirred for 1 hr. After concentrating under reduced pressure, EtOAc EtOAc m. The combined organic layer was washed with EtOAc (EtOAc m.) VIId and compound 156115.doc •242- 201200517 ΧΙΙ-VIId' (cis/trans, about 2/1, cis XII-VI) [d', 17 g; trans ΧΙΙ-VIId, 8 g, total yield Rate 54%). Compound XII-VIId: 1H NMR (400 MHz, CDCl3): (5 5.75 - 5.84 (m5 1 Η), 5.01-5.11 (m, 2H), 3.72-3.76 (q, 1H), 3.26-3.30 (m, 1H) , 2.37 (brs, 1H), 2.16-2.24 (m, 3H), 1.76-1.90 (m, 2H), 1.40-1.50 (m, 10H). MS (ESI) m/z (M+H) + 212.2.

Compound XII-VIId,: 1H NMR (300 MHz, CDCl3): &lt;5 5.76- 5.85 (m, 1 H), 5.02-5.14 (m, 2H), 3.64-3.69 (m, 1H), 3.12-3.17 (m , 1H), 2.60 (brs, 1H), 2.24-2.32 (m, 2H), 2.12-2.04 (m, 1H), 1.81-1.90 (m, 2H), 1.46 (s, 9H), 1.31-1.49 (m , 1H). MS (ESI) m/z (M+H) +21.21. Process XII-Vile

&gt;'·

Xll-Vtld

CbzCI DIEA, DCM, 0°C

Xll-Vlle

General Procedure XII-Y Add Cbz-Cl (12 g) to a solution of compound XII-VIId (7.5 g, 35 mmol) and DIEA (18 g, 140 mmol) in DCM (200 mL). , 70 mmol). The resulting mixture was stirred at 0 ° C for 3 hours. Subsequently, water (50 mL) was added to the stirred mixture. The layers were partitioned and the organic layer was separated, dried mjjjjj The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc) 156115.doc -243 - 201200517 Process ΧΙΙ-VIIf 9~BBN, Η2〇ζ,

^bz 〇*Bu NaOH aqueous solution, H0 ^bz 〇«B

Xll-Vlle Xll-Vllf

General procedure XII-Z To a stirred solution of compound XII-VIIe (10 g, 29 mmol) in anhydrous THF (200 mL), 9-BBN (139 mL, 69 mmol, 0.5 M in THF). The resulting mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was cooled to 〇 ° C and water (200 mL) was added dropwise, followed by NaOH solution (3 Μ, 88 mL) and 30% H202 (26.5 mL). The resulting mixture was stirred at room temperature for 1 hour and then refluxed overnight. After cooling, the aqueous phase was extracted with EtOAc (EtOAc). The combined organic layers were washed with brine, dried over Na 2 EtOAc and evaporated The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS (ESI) m/z (M+Na) + 364.0. Process ΧΙΙ-VIIg

〇bz 〇lBu TEA, DCM, -60°C Xll-Vllf (COCI)2, DMSO OHC-^\,

General procedure XII-AA Ethylene dioxane (10 g, 79.2 mmol) was added dropwise to a solution of stirred DMSO (8.3 g, 106 mmol) in CH.sub.2 (12 mL). After 30 minutes, the mixture was treated dropwise with a solution of compound XII-VIIf (9.6 g, 26.4 mmol) in 156115.doc-244-201200517 CH2C12 (20 mL) and stirring was continued at -60 °C for 30 minutes. This temperature was maintained during the subsequent dropwise addition of TEA (13.2 g, 132 mmol). The resulting mixture was stirred at -60 ° C, and then allowed to warm to room temperature for an additional 1 hour. The mixture was treated with water (70 mL) and the layers were partitioned. The aqueous phase was extracted with CH2C12 (80 mL×3). The combined organic layers were washed with brine, dried over Na 2 EtOAc and evaporated The crude product was purified by silica gel column chromatography ( petroleum ether: EtOAc = 20:1) to afford compound XII-VIIg (7.5 g, yield 79%). MS (ESI) m/z (M+Na)+ 384.0 ° Process Xll-VIIh

CbzHN— \ I rvtp., COOMe Cbz υΰυ Xll-VIIh

General Procedure XII-AB The flask was charged with KOi-Bu (5.6 g, 49.9 mmol) and anhydrous CH2C12 (60 mL), and Cbz-α-phosphite carboxyglycine was used under nitrogen at -70 °C. The resulting mixture was treated with a solution of trimethyl ester (11 g, 33.2 mmol) in anhydrous C:H2C12 (10 mL). The mixture was stirred at this temperature for 30 minutes, then treated with a solution of compound XII-VIIg (6 g, 16.6 mmol) in anhydrous CH2 C12 (10 mL). After 5 hours, the mixture was warmed to room rt and then worked-up water (5 mL). The solvent was evaporated under reduced pressure and EtOAc EtOAc m. The combined organics were washed with brine, dried EtOAc sol The residue was purified by silica gel 156115.doc - 245 - 201200517 column chromatography ( petroleum ether: EtOAc = 20:1) to give compound XII-VIIh as a (Z)/(E) diastereomeric mixture. (6.5 g, yield 69 ° /.). MS (ESI) m/z (M+Na) + 589.1. Process ΧΠ-VIIi

CbzHN

Boc20 -► DMAP, THF

Boc,

Cbz 0, Bu Cbz COOMe

Xll-Vlli

General procedure XII-AC Compound XII-VIIh (6.5 g '11.5 mmol) was dissolved in anhydrous THF (80 mL), followed by Boc20 (25 g, 11.3 mmol) and a catalytic amount of DMAP (150 mg, 1.2 mmol) . The resulting mixture was stirred under nitrogen for 3 hours. Subsequently, the mixture was diluted with water (60 mL) and the obtained aqueous mixture was extracted with EtOAc (60 mL &gt;&lt;3&gt;). The combined organic layers were washed with brine, dried over Naz. The residue was purified by hydrazine column chromatography (peel ether: EtOAc = 15:1) to afford compound XII-VIIi (7 g, yield 92%). MS (ESI) m/z (M+Na) + 689.1. Process ΧΠ-VIIi

Boc,

Cbz COOMe boo

Ibz 0,Bu THF H

General Procedure XII-AD Hydrogenation of a compound containing a catalytic amount of P% Pd/C(lg) at H2 (50 psi) 156115.doc • 246· 201200517 XII-VIIi (7 g, 10 mmol) in THF (100 Solution in mL). After stirring at room temperature for 20 hours, the catalyst was removed by filtration through celite. The filtrate was concentrated to dryness <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ESI) m/z (M+H) + 401.1. Process ΧΙΙ-VIIi

Bocv

COOMe Xfl-Vllj

〇'Bu MeOH

General procedure XII-AE

A solution of compound XII-VIIj (3.8 g, 9.5 mmol) in MeOH (EtOAc) After stirring for 1.5 hours at room temperature, the mixture was acidified to pH 3 by treatment with aqueous HCl (1 N). The mixture was extracted with CH2C12 (100 mL×3). The combined organic layer was washed with EtOAc EtOAc m. MS (ESI) m/z (M+H) + 387.1. Process ΧΙΙ-VIIj

Xll.vilk XII-VIIL XII-VIIL*

General Procedure XII-AF The flask was charged with HATU (2.8 g, 7.4 mmol), I) IEA (2.5 g, 19.7 mmol) and DCM (400 mL). The resulting mixture was treated dropwise with a solution of 156115.doc-247-201200517 Compound XII-VIIk (0.9 g, 4.9 mmol) in DCM (20 mL) over 30 min. The resulting mixture was stirred at room temperature for 1.5 hours. Subsequently, the mixture was washed with water and the organic layer was dried over Na.sub. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 4 NMR (400 MHz, CDC13): 3 5.67 (brs, 1 Η), 4.43-4.47 (m, 1Η), 4.20-4.22 (m, 1H), 3.75 (brs, 1H), 2.25-1.57 (m, 10H ), 1.45 (brs 18H). MS (ESI) m/z (M+Na) + 39. Process ΧΙΙ-VIIk

General Procedure ΧΠ-AG A solution of compound XII-VIIL (470 mg, 1.28 mmol) in DCM (10 mL) was taken from TFA (4.23 mL) and TES (0.23 mL). The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give crude compound <RTI ID=0.0># </RTI> </ RTI> </ RTI> </ RTI> </ RTI> (345 mg, crude yield 100%) which was used in the next step without further purification. MS (ESI) m/z (M+H) +21.21.

Process XII-VIIL

156115.doc -248- 201200517 General procedure ΧΙΙ-ΑΗ Treatment of compound xn-VIIm (270 mg, 1.27) with aqueous NaOH (ΐ〇mL, 1 Μ solution) and methyl chloroformate (600 mg, 6.38 mmol) at room temperature Methyl) solution in THF (10 mL). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the mixture was acidified to pH 3 with an aqueous HCl solution (1 N). The resulting mixture was extracted with CH2C12 (30 mL×5). The combined organic layer was washed with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ESI) m/z (MH+) Process ΧΙΙ-VIIm

General procedure XII-AI

The flask was charged with compound XII-VIIn (80 mg, 0.3 mmol), compound XII-IVa (200 mg, 0.35 mmol) ' Cs2C03 (200 mg &gt; 0.6 mmol) and DMF (10 mL). Search at room temperature; the resulting mixture was mixed for 3 hours. Subsequently, the mixture was treated with water (10 mL), and the mixture was extracted with EtOAc: (30 mL). The combined organic layers were washed with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS (ESI) m/z (M+H)+ 777.4 » 156115.doc •249· 201200517 Process ΧΙΙ-VIIn

General Procedure XII_AJ A mixture of compound XII-VII(R) (100 mg, 0.13 mmol) and NH4OAc (100 mg, 1.3 mmol) in diphenylbenzene (10 mL) was stirred at 130 °C. After cooling to room temperature, the solvent was removed under reduced pressure to give a residue. The residue was dissolved in EtOAc (30 mL)EtOAc. The layers were partitioned and dried over Na 2 EtOAc. The residue was purified by preparative HPLC to afford compound 806 (10 mg, yield 10%). NMR (400 MHz, CD3OD): (5 7.64-7.81 (m, 8H), 7.32-7.38 (m, 2H), 5.34-5.38 (m, 1H), 5.16-5.19 (m, 1H), 4.32-4.38 ( m, 1H), 4.19-4.23 (m, 2H), 3.95-4.02 (m, 1H), 3.81-3.87 (m, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.30-2.41 ( m, 3H), 2.12-2.28 (m, 4H), 1.98-2.06 (m, 3H), 1.59-1.87 (m, 5H), 0.89-0.99 (m, 6H). MS (ESI) m/z (M +H) + 737.2. Example XII-VIII: Preparation of Compound 807:

Process XII-VIII

^OH

CbzCI T round ground ^ H 〇 * Bu DIEA, DCM, 0oC ^ |) tBu NaOH aqueous solution, THF ^ O'Bu

Xll-Vlld' Xll-Vllla Xil-Vlllb 156115.doc 250- 201200517

CbzHN 〇 P 0'Bu

(COCl)2, DMSO TEA, DCM, -60°C

CHO ibZ 〇,丨

ΚΟιΒυ ( DCM, -70°C

CbzHN*

Xll-Vllld Β〇〇2〇

DMAP, THF

Boc. Jf, v Cbz COOMe Cbz 〇ΐβυ

H2, Pd-C THF

Boc,

H *COOMe Xll-Vlllf

HATU, DIEA -^ Separate ns&gt;^l 〇«bu rlsTN ( Vis^o + W&quot;0 NH 0=&lt;t O'Bu NH 0=K OlBu Xll-Vlllh Xll-Vlllh' and 〆ry^° risr' i oh -O

Xll-Vlllg CS2CO3, DMF

〇 NaOH aqueous solution THF NH °=&lt;) UI-VIIIJ 丫 \ xylene, 130 ° C o Xll-Vlllk

Aqueous NaOH solution D〇〇h H —

b&gt;Bu TFA/TES.

NH °=&lt;. O^u X!l-VII!h XIMVa

NH4OAC 'γΧ n Process XII-Villa

CbzCI

6*Bu DIEA, DCM, 0°C

-251 - 156115.doc 201200517 General Procedure ΧΙΙ-ΑΚ Compound XII-VIId' (12.6 g, 59.63 mmol) was dissolved in DCM (150 mL) then DIEA (30.7 g, 178.9 mmol). The resulting solution was treated dropwise with Cbz-Cl (20.3 g, 119.3 mmol) at 0 °C. The resulting mixture was stirred at 0 ° C for 3 hours. After the addition of water (50 mL), EtOAc m. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Process Xll-VIIIb

General Procedure XII-AL Compound XII-VIIIa (30 g, 86.8 mmol) was dissolved in anhydrous THF (600 mL). The resulting solution was treated dropwise with 9-BBN solution (350 mL, 173.7 mmol, 0.5 M in THF). The resulting mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was cooled to 〇 ° C, water (300 mL) was added dropwise, followed by a solution of NaOH (3 N, 260 mL) and 30% H 2 〇 2 (40 mL). The resulting mixture was stirred at room temperature for further 1 hour and then refluxed overnight. After cooling, the aqueous layer was extracted with EtOAc (200 mL &gt;&lt;3&gt;). The combined organic layers were washed with brine, dried over Nazsss The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc MS (ESI) m/z 156115.doc - 252 - 201200517 (M+H) + 364.0. Process XII-VIIIc

General Procedure XII-AM Ethylene dioxane (31.2 g, 0.24 mmol) was added dropwise to a solution of stirred DMSO (25.8 g, 0.33 mmol) in CH2C12 (500 mL) at -60 °C. After 30 minutes, the resulting mixture was treated dropwise with a solution of compound XII- VIIIb (30 g, 82.5 mmol) in CH.sub.2Cl.sub.2 (5 mL) and stirring was continued at -60 °C for 3 Torr. Subsequently, the resulting mixture was treated dropwise with TEA (41.7 g, 0.42 mmol) at -60 °C. The resulting mixture was scrambled at -60 ° C, then allowed to warm to room temperature for an additional 1 hour. Subsequently, the mixture was treated with water (1 〇〇 mL) and the layers were dispensed. The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc MS (ESI) m/z (M+Na) + 384.0. Process ΧΙΙ-VIIId

CHO

K〇tBu, DCM, -70〇C

CbzHN

156115.doc -253 - 201200517

General Procedure XII-AN The flask was charged with KOi-Bu (9.3 g, 83 mmol) and anhydrous CH2C12 (150 mL), then Cbz-α-phosphite carboxylamine was added thereto at -70 ° C under nitrogen. A solution of trimethyl ester (18.3 g, 55.3 mmol) in dry CH2C12 (20 mL). The mixture was stirred at this temperature for 30 minutes, then treated with a solution of compound XII-VIIIc (10 g, 27.66 mmol) in anhydrous CH2 C12 (20 mL). After 5 hours, the mixture was allowed to warm to rt and was then taken with water (10 mL). Subsequently, the solvent was removed under reduced pressure and the residue was combined with water (200 mL). The aqueous mixture was extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine and dried over Na 2 EtOAc. The solid was removed by filtration and the filtrate was removed in vacuo to give a residue. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc:EtOAc . MS (ESI) m/z (M+Na) + 589.1. Process ΧΠ-VIIIe

General procedure ΧΠ-ΑΟ Compound XII-VIIId (11.5 g, 20.3 mmol) was dissolved in anhydrous THF (100 mL). Boc20 (44.2 g, 203 mmol) and a catalytic amount of DMAP (250 mg, 0.1 mmol) were added to the resulting solution. The resulting mixture was stirred under nitrogen for 3 hours. The mixture was then diluted with water (1 mL) and EtOAc (EtOAc &lt The combined organic layer was washed with brine, 156115.doc -254-201200517

The Na2SO4 was dried and concentrated under reduced pressure to give a residue. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc MS (ESI) m/z (M+Na) + 689.1.

Process ΧΙΙ-VIIIf

General procedure XII-AP

A solution of the compound XII-VIIIe (10 g, 15 mmol) in THF (100 mL) containing a catalytic amount of 15% Pd/C (1 g) was hydrogenated at H2 (50 psi). After stirring at room temperature for 20 hours, H2 was replaced with N2, and then the catalyst was removed by filtration through celite. The filtrate was concentrated to dryness <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ESI) m/z (M+H) + 401.1. Process ΧΙΙ-VIIIg B〇C,

COOMe XH-Vlllf

Aqueous NaOH solution Boc COOH XU-Vlllg

OxBu-^

MeOH

General Procedure ΧΠ-AQ A solution of compound XII-VIIIf (3.5 g, 8. 7 mmol) in MeOH (EtOAc) (EtOAc) After stirring 1.5 156 115.doc - 255 - 201200517 hours at room temperature, the mixture was acidified to pH 3 ' with aqueous HCl (1 N) and then aqueous layer was extracted with CH.sub.2 C.sub.2 (100 mL x 3). The combined organic layer was washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH MS (ESI) m/z (M+H) + 387.1. Process ΧΙΙ-VIIIh

Hl^COOH H BOC Xll-Vlllg

〇=&lt; 0*Bu Xll-VHIh

°=&lt; t O^u Xll-Vlllh'

General procedure ΧΠ-AR A solution of compound XII-VIIIg (3 g, 7.5 mmol) in DCM (20 mL) was added dropwise to a previously loaded HATU (4.3 g, 11.25 mmol), DIEA at room temperature over 30 min. (2.9 g, 22.5 mmol) in a DCM (700 mL) flask. The resulting mixture was stirred at room temperature for 1.5 hours. Subsequently, the mixture was washed with water and the layers were dispensed. The organic layer was dried (Na2SO4) and evaporated The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 1H NMR (400 MHz, CDC13): 3 5.86-5.88 (brs, 1 H), 4.41-4.45 (m, 1H), 4.10-4.16 (m, 1H), 3.70-3.78 (brs, 1H), 2.23-1.50 (m, 10H), 1.35-1.39 (brs 18H). MS (ESI) m/z (M+Na) + 39. •256- 156115.doc 201200517 Process ΧΙΙ-VIIIi

General Procedure ΧΠ-AS A solution of compound XII-VIIIh (500 mg, 1.3 mmol) in DCM (10 mL) was taken from TFA (4.2 mL) and TES (0.3 mL). The mixture was stirred at room temperature for 1 hr then concentrated under reduced pressure to afford compound <RTI ID=0.0># </RTI> </RTI> MS (ESI) m/z (M+H) +21.21. Process ΧΙΙ-VIIIj

* General procedure XII-AT Compound XII-VIIIi (280 mg, 1.3 mmol) was dissolved in THF (5 mL) and NaOH aqueous solution (5 mL, 1 M solution) and methyl phthalate ( The resulting mixture was treated with 63 8 mg, 6.8 mmol. The resulting mixture was stirred at room temperature for 2 hours, then the mixture was acidified to pH 3 with aqueous HCl (1 N) and extracted with CH2C12 (30 mL×5). The combined organic layer 156115.doc - 257 - 201200517 was washed with EtOAc (EtOAc m. Purification can be used in the next step. MS (ESI) m/z (M+H) + 270. Process ΧΙΙ-VIIIk

General Procedure ΧΠ-AU The flask was charged with compound XII-VIIIj (90 mg, 0.33 mmol), compound XII-IVa (234 mg, 0.4 mmol), Cs2C〇3 (434 mg, 1.33 mmol) and DMF (10 mL) . The resulting mixture was stirred at room temperature for 3 hours. Subsequently, water (1 〇 mL) was added, and the mixture was extracted with EtOAc (30 mL &gt;&lt;2). The combined organic layers were washed with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc MS (ESI) m/z (M+H)+ 777.4 » Process ΧΠ-VIIIm

General Procedure ΧΠ-AV 156115.doc -258- 201200517 Compound XII-VlIIk (120 mg, 0.15 mmol) and NH4〇Ac (120 mg, 1.5 mmol) in diphenylbenzene were stirred at 130 ° C in a sealed tube. After the mixture in mL) was cooled to room temperature, the solvent was removed under reduced pressure to give a residue. The residue was dissolved in DCM (30 mL)EtOAc The organic layer was separated, dried over Na 2 EtOAc and evaporated The residue was purified by preparative HPLC to afford compound 807 (15 mg, yield 13%). 4 NMR (400 MHz, CD3OD): (5 7.55-7.69 (m, 8H), 7.23 (s, 2H), 5.20 (d, /=7.2 Hz, 1H), 5.05-5.08 (m,1H), 4.20 ( d, / = 10.8 Hz, 1H), 4.12 (d, · 7 = 7.2 Hz, 1H), 3.87-3.91 (m, 2H), 3.75-3.80 (m, 1H), 3.50 (s, 6H), 2.21- 2.27 (m, 3H), 2.05-2.11 (m, 3H), 1.92-1.97 (m, 4H), 1.89-1.90 (m, 4H), 1.79-1.83 (m, 1H), 0.79-0.89 (m, 6H) MS (ESI) m/z (M+H) + 737.0. Part XVII HCV Replicon Detection Huh7 cells containing an HCV replicon incorporating a luciferase reporter gene at 37 ° C, 5% CO 2 Maintained with 10% heat-inactivated fetal bovine serum (FBS; Mediatech, Herndon, VA), 2 mM L-faceted tyrosine (Cambrex Bioscience, Walkersville, MD), 1% non-essential amino acid (Lonza, Walkersville, MD), 50 IU/mL penicillin (Mediatech, Herndon, VA), 50 mg/mL streptomycin (Mediatech, Herndon, VA) and 0.5 mg/mL G418 (Promega, Madison, WI) Duchen modified Eagle's medium (Dulbecco's modified Eagle's medium/DMEM; Mediatech, Herndon, VA). Cells were cultured at 156115.doc -259-201200517 every 1:2-3 days for 2-3 days. Huh7 cells containing subgenomic HCV replicons were collected, counted, and plated at 5000 cells per well in 100 mL standard maintenance medium (above) in Nunclon 96-well tissue culture plates (ThermoFisher, Rochester, NY) for 24 hours. And incubated under the above conditions. To start the assay, the medium was removed and replaced with 90 mL of maintenance medium lacking G418. The test compounds were serially diluted with dimethyl sulfoxide (DMSO) in two double replicates. Times to determine each EC5 〇. These compound solutions were diluted 10-fold with DMEM lacking serum and G418. 10 mL of medium containing these compound solutions was added to the double replicate tissue culture plates. The final volume is 1 〇 〇 pL with a DMSO concentration of 1%. The compound concentration was adjusted to appropriately determine the dose response curve. Typical dilution series range from a final concentration of 100 mM to 1.69 nM to a final concentration of 1 nM to 16.9 fM. The plates were incubated at 37 ° C for about 48 hours. Determine the EC50. Active example. After incubation, the medium was removed from one of the two double replicate plates and the Replica-Reporter Fluorescence was measured using the Bright-Glo Luciferase Assay Kit (Promega, Madison, WI) according to the manufacturer's instructions. Enzyme activity. A 4-parameter logistic function was fitted to the log-log plot of the logarithm of luciferase activity versus compound concentration using XLfit software (IDBS Inc., Guildford, UK) to Table 20:

Compound EC50 nM 421 C 422 C 156115.doc -260- 201200517

423 C 424 c 501 A 502 A 504 A 505 A 506 C 601 C 602 C 603 C 604 C 605 C 801 A 802 A 803 C 804 C 805 B 806 C 807 C

A indicates that EC5〇 is 100 nM and greater than 100 nM B indicates that EC5〇 is between 10 nM and 100 nM C indicates that EC5〇 is 10 nM and less than 10 nM 156115.doc 261 -

Claims (1)

201200517 VII. Patent application scope: 1 · A compound having the structure of formula VII, VII or a pharmaceutically acceptable salt thereof, wherein: each R is independently selected from the group consisting of hydrogen, Rlac (=〇)_, and RlaC(=S)-; each R is independently selected from the group consisting of Group: _C(R2a)2NR3aR3b, alkoxyalkyl, Cw alkyl 0C (=0)-, Ci-6 alkyl hydrazine (: (= 〇) (: 1_6 alkyl, C 〗 6 alkyl 0 (=0) (^.6 alkyl, aryl, aryl (CH2)n_, aryl (CH2)nO_, aryl (CH=CH) m•, arylalkyl〇, arylalkyl, Aryl 0 alkyl, cycloalkyl, (cycloalkyl) (CH=CH)m, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl (CH=CH)m_ ,heterocyclylalkoxy,heterocyclylalkyl,heterocyclylalkyl,hydroxyalkyl, RcRdN- ' RcRdN(CH 2 ) n- &gt; (RcRdN)(CH=CH)m- &gt; (RcRdK 156H5.doc 201200517 alkyl, (RcRdN)C(=0)-, optionally up to 9 halo substituted Cw alkoxy groups and optionally up to 9 dentate substituted Ci_6 alkyl groups, the aryl group And heteroaryl groups are each optionally substituted by the following groups: cyano, dentate, nitro, hydroxy, optionally up to 9 self-substituted Ci 6 alkoxy groups and optionally up to 9 a dentate-substituted Cl_6 alkyl group; each R RdN is independently selected, wherein Re and Rd are each independently selected from the group consisting of hydrogen, alkoxy c (=〇)_, c 6 alkyl, Cw Alkyl C(=0)-, C!·6 alkylsulfonyl 'arylalkyl〇c(=〇), arylalkyl, arylalkyl C(=〇)-, aryl c ( =〇)·, arylsulfonylheterocyclylalkyl, heterocyclylalkyl C(=〇)·, heterocyclyl C(=〇)...(ReRfN)alkyl, (ReRfN)alkyl C( =〇)- and (ReRfN)c(=〇)_, wherein arylalkyl, arylalkyl (:( = 〇)-, heterocyclylalkyl and heterocyclylalkyl C(= 〇)- The alkyl moieties are each optionally substituted with a ReRfN group; and wherein the arylalkyl group, the arylalkyl group C(=〇)_, the aryl group C(=〇), and the aryl group of the arylsulfonyl group, And a heterocyclic group of a heterocyclylalkyl group, a heterocyclylalkyl group c(=〇)_ and a heterocyclic group C(=0)-, each optionally up to three groups independently selected from the group consisting of Substituent substitution: cyano, halo, nitro,, optionally, up to 9 dentyl substituted Cl-6 alkoxy and, optionally, up to 9 ytyl substituted C 6 alkyl; Each ReRf&gt;HS is independently selected, wherein Re and Rf are each independently selected from the group consisting of hydrogen, c] 4 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl , heterocyclyl, heterocyclylalkyl, (RXRyN)alkyl and (RxRyN)C (=C〇-; each RxRyN is independently selected, wherein Ry is independently selected from 156l15.doc 201200517 free composition Group··hydrogen, alkyl oc(=o)-, cN6 alkyl, Cl 6 alkyl C(=〇)-, aryl, arylalkyl, cycloalkyl and heterocyclic; each C(RU) 2 is independently selected, wherein each Rh is independently selected from the group consisting of hydrogen, optionally up to 9 halo-substituted C6 alkyl, aryl (CHA- and heteroaryl (CH2)n) • the aryl and heteroaryl groups are each optionally substituted by a cyano group, a aryl group, a nitro group, a hydroxy group, a Ci_6 alkoxy group substituted with up to 9 dentate groups, and optionally up to 爻) . 9 halo-substituted Cl.6 alkyl groups, or (:(^^!1)2 are; each R3a is independently selected from the group consisting of hydrogen and optionally substituted cu system; each R3b system Independently selected from the group consisting of Cw alkyl, heteroaryl, -(CH2)nC(=〇)NR4aR4b, _(CH2)nC(=〇)〇RSa and (CH2)nC (optionally substituted) -〇)R, the heteroaryl group being optionally substituted by the following groups: cyano, i-, nitro, thiol, optionally up to 9 (tetra)-substituted C 丨 6 alkoxy and optionally up to 9 Each of the RRNs is independently selected, wherein R4a and R4b are each independently selected from the group consisting of hydrogen, optionally substituted Ci.6 alkyl, and aryl (CH2)n And each R5a is independently selected from the group consisting of C. 6 alkyl and aryl (CH 2 ) n- which are optionally substituted; each R, independently selected from the group consisting of: Ci-6 alkyl and aryl (CH2)n-; 156115.doc 201200517 X1 is (C(R2)2)q, Y1 is selected from the group consisting of 0 (oxygen), S (sulfur), S(O), S〇2, NR2 and C(R2)2, with the constraint that when X1 is absent, γ1 is C(r2)2; ' or X2 does not exist; X2 is (C(R2)2)q, \Y is selected from 〇 (oxygen), s (sulfur), s(o), S〇2, NR2 and C(R2)2, The limiting condition is that when X2 is absent, γ2 is C(R2)2; each R2 is independently selected 'where R2 is selected from the group consisting of 虱, C丨·6 alkoxy, c丨·6 a ci 6 alkyl group substituted with up to 9 functional groups, or optionally 2 adjacent R 2 together with the carbon to which it is attached, as the case may be up to 2 Cl 6 alkyl substituted fused 3-member to 6-membered carbocyclic ring; each A-line is independently selected from the group consisting of cr3 and n (nitrogen); each R3 is independently selected from the group consisting of hydrogen, alkane Oxy' CK6 alkyl 〇Cl6 alkyl, Ci6 alkyl 〇c (=(7)·, arylalkyl 〇C( 〇)-, -COOH, halo, hydroxy, RaRbN_, (RaRbN) alkyl (RRN) c(=〇)-, and optionally up to 9 halo groups and up to 5 mercapto substituted c. .6 alkyl; 0 Each L1 is independently selected from the group consisting of: X3, -C(=〇XCH2)m〇c(=〇)_, -C(CF3)2NR2c- is selected from the group consisting of hydrogen, Ci_6 alkyl , c2 6. 156115.doc 201200517 base, C2·6 block, C3 7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, The alkyl group is optionally substituted with ReRfN-, alkoxy or Cl-6 alkyl; each X3 is independently selected from the group consisting of NH, NC丨-6 alkyl, hydrazine (oxygen) and s (sulfur). Each R7 is independently selected from the group consisting of hydrogen, Cl_6 alkyl 〇C(=0)-, arylalkyl 〇c(=〇)_, -c〇OH, (RaRbN)C (=0 And a dialkyl-based fluorenyl-based alkyl group and, optionally, up to 9 dentate-substituted Cm alkyl groups; independently selected, wherein only ^ and ... are each independently selected from the group consisting of: Hydrogen, C2_6 alkenyl and (: 丨-6 alkyl; each Z series is independently selected, wherein z is selected from the group consisting of: hydrazine (oxygen) and CH2, or Z is absent; each m is independently 1 Or 2; each η is independently 〇, 1 or 2; each ρ is independently 1, 2, 3 or 4 Each q is independently 1, 2, 3, 4 or 5; each r is independently 0, 1, 2, 3 or 4; B1 is fused and replaced by saturated or unsaturated 3 to 7 members A carbocyclic or fused, optionally substituted, saturated or unsaturated 3 to 7 membered heterocyclic ring, each of which is optionally substituted with one or more R 4 ; B 2 is a fused or substituted saturated or unsaturated 3 a 7-membered carbocyclic ring or a slightly substituted, saturated or unsaturated 3 to 7 membered heterocyclic ring, each of which is optionally substituted by one or more R 4; and 156115.doc 201200517 Free group consisting of: (: genus base, burnt base 〇 Cl, courtyard base, Cl.6 yard base 〇 c (, aryl ketone 〇 c (= 〇) _, -COOH, dentate, Cl -6g, transradical, RaRbN, (RaR&gt; alkyl, (RaRM)C(=〇)- and optionally up to 9 dentate groups and up to 5 thiol-substituted Cl.6 alkyl groups, or as appropriate Take a r position of r4 together as a pendant oxy group (0X0) 〇 2. The compound of claim 1, wherein: And wherein each X4 is independently selected from the group consisting of cRjN (nitrogen); and each Y4 is independently selected from the group consisting of c(R4)2, NR4, hydrazine (oxygen), and s (sulfur). 156115.doc • 6 · 201200517 3 • The compound of claim 1 wherein each Z is absent. 4. The compound of claim 1, which has the structure of the formula Vila Vila or a pharmaceutically acceptable salt thereof. A compound of claim 1, which has the structure of formula V11b 156115.doc 201200517 or a pharmaceutically acceptable salt thereof. 6. The compound of claim 5 wherein each R1 is RlaC(=0)-. 7. The compound of claim 6 wherein each Rla is CHR2aNHR3b. 8. The compound of claim 7, wherein each R2a*Ci-6 alkyl group; each R3b is -C(=0)0R5; and each R is 匕^alkyl" 9 such as a compound of the request, wherein β1 A saturated or unsaturated 3 to 7 carbon ring, optionally mixed with one or more conditions. 1〇 ‘: the compound of the requester, where B2 is the case-by-case or a plurality of...the fused or unsaturated 3 to 7 carbon rings of the factory. 11. A compound according to claim 1 wherein B is a saturated or unsaturated 3 to 7 heterocyclic ring which is optionally fused by one or more R4. 12. The compound of claim 1, wherein B2A is a fused saturated or unsaturated 3 to 7 membered heterocyclic ring, optionally substituted by one or more R4. 13. The compound of claim 1, wherein: 156115.doc 201200517 14. The compound of claim 1, wherein: 156115.doc 201200517 15. The compound of claim 1 wherein: 156115.doc -10- 201200517 17. The compound of claim 1 which has the structure: 156115.doc • 11 · 201200517 156115.doc -12- 201200517 156115.doc -13- 201200517 156115.doc -14- 201200517 156115.doc -15- 201200517 156115.doc 16- 201200517 156115.doc 17- 201200517 156115.doc 18- 201200517 156115.doc -19- 201200517 156115.doc -20- 201200517 Or a pharmaceutically acceptable salt thereof. 18. The compound of claim 1 which has the structure of the formula Vile: 156115.doc -21 · 201200517 Vile or a pharmaceutically acceptable salt thereof, wherein: each X4 line is independently selected from the group consisting of CR4 and N (nitrogen); and each Y4 line is independently selected from the group consisting of C(R4)2 , NR4, antimony (oxygen) and S (sulfur). 19. The compound of claim 1 which has the structure of formula V11d: Vlld 156115.doc -22 201200517 or a pharmaceutically acceptable salt thereof, wherein: R is Ci6 alkyl substituted with up to 9 halo groups, as appropriate. 20. The compound of claim 19, wherein R6 is fluorenyl. 21. A compound having the structure of formula VI, VI or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of hydrogen, RlaC(= 〇), and RlaC(=S)-; each anaphylaxis is independently selected from the group consisting of :_c(R2a)2NR3aR3b, alkoxyalkyl, Cw alkyl 〇C(=〇)-, Cl.6 alkyl OCpCOCw alkyl, C!-6 alkyl CpCOCu alkyl, aryl, aryl (CH =CH)m-, arylalkyl 0-, arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl)(CH=CH)m-, (cyclohexyl) fluorenyl, ring Anthracenyl, heterocyclic, heterocyclic (Ct^CHL-, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyl fluorenyl, phenyl group, ReRdN-, (RcRdN) (CH=CH) _ , (RcRdN)alkyl, (RcRdN)C(=0)_, optionally substituted by up to 9 dentyl groups, C, 6 alkoxy and optionally substituted by up to 9 functional groups Ci 6 alkyl; each ruthenium is independently selected, wherein Re and R 〇 are each independently selected from hydrogen, alkoxy c (=0)-, C -6 alkyl, Cl. 6 alkyl c(=〇)_, Ci 6 156115.doc ·23· 201200517 alkylsulfonyl, arylalkylhydrazine C(=〇)-, arylalkyl, arylalkyl c(=0)-, Aryl c (=0) -, arylsulfonyl, heterocyclylalkyl, heterocyclyl c(=0)- 'heterocyclyl C(=0)-, (ReRfN)alkyl, (ReRfN) alkyl C (= 〇)- and (ReRfN)c(=〇)_, wherein arylalkyl, arylalkyl C(=〇)-, heterocyclylalkyl and heterocyclylalkyl c(=〇)-alkane The base moieties are each optionally substituted with a ReRfN- group; and wherein the arylalkyl group, the arylalkyl group C(=〇)-, the aryl group c(=〇)-, and the aryl group of the arylsulfonyl group, And a heterocyclyl moiety of a heterocyclylalkyl group, a heterocyclylalkyl group C(=0)- and a heterocyclic group Cho)-, respectively, optionally substituted by up to three substituents each independently selected from the group consisting of : cyano, dentate, nitro, optionally up to 9 halo-substituted C1-6 alkoxy and optionally up to 9 halo substituted C.. 6 alkyl; each ReRfN is independently Selected, wherein, and Rf are each independently selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (RXRyN) Alkyl and (RxRyN)C(=〇).; Each RxRyN is independently selected 'its tRX&amp; Ry are each independently selected from hydrogen, a group OC (=0)-, a pyridyl group, a pyridyl group c (= 〇) _, an aryl group, an aryl group, a cycloalkyl group, and a heterocyclic group; each R group is independently selected from the group consisting of hydrogen And an alkyl group, an aryl group (CH2) n•• and a heteroaryl group (CH2)n-; each R3, independently selected from the group consisting of hydrogen and optionally substituted cN6 alkyl; each R3b« Free group consisting of: 156115.doc -24- 201200517 Cw alkyl, heteroaryl ' _(CH2)nC(=〇)NR4aR4b, _(CH2)nC(=〇)〇R5a and _ (CH2)nC( = 〇)R6a 'The heteroaryl group is optionally substituted by the following groups: an aryl group, a dentate group, a nitro group, a hydroxy group, optionally up to 9 groups of substituted iCw alkoxy groups and optionally Each of the R4aR4bN groups is independently selected, wherein R4a and R4b are each independently selected from the group consisting of hydrogen, optionally substituted Ci 6 alkyl, and aryl (CH2). )n-; Each R5a is independently selected from the group consisting of C--6 alkyl and aryl (CH2)n, optionally substituted; each R6a is independently selected from the group consisting of Cm substituted as appropriate Alkyl and aryl (CH2)n-; L is selected from the group consisting of: -C(=〇)(CH2)m〇C(=〇)- &gt; -C(CF3)2NR2c- ruler 2. Is selected from the group consisting of: hydrogen ' Ci6 alkyl, CM alkenyl, C: 2·6 alkynyl, C3.7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkane a group, a heterocyclic group and a heterocyclic alkyl group, which are optionally substituted by RRN-, alkoxy or (6-6 alkyl); each X is independently selected from the group consisting of NH, NCi-6 Base, oxime (oxygen) and S (sulfur); each m is independently 1 or 2; each η is independently 〇, 1 or 2; 156115.doc • 25· 201200517 Each R is independently selected from the group consisting of : hydrogen, Cm alkyl 〇c (which, aryl group oc (=0) _, _c 〇〇 H, (RaRbN) c (which, dialkyl decalkyl alkyl decyl group and optionally up to 9 a dentate group Cw alkyl group; the ninth Q1 group is selected from the group consisting of L2 &amp;L3_L4; and the L2 system is selected from the group consisting of: Each of the A lines is independently selected from the group consisting of cr3 and n (the gas R3 lines are independently selected from the group consisting of nitrogen, Ci. 6 oxime, CV6 alkyl 0.25. alkyl, q - Alkyl 〇c(=〇), arylalkyl 〇C( 〇)_, -C〇〇H, halo, hydroxy, RaRbN-, (RaRbN) a radical, (RaRbN)C(=0)... and optionally up to 9 dentate groups and up to 0.001 radically substituted Cl_6 alkyl groups; each RaRbN system is independently selected, wherein Ra&amp;Rb are each independently selected from the group consisting of a group consisting of: hydrogen, hydrazine 2_6 alkenyl and cN6 alkyl; 156115.doc 26. 201200517 Each R8 is independently selected from the group consisting of hydrogen, Ci6 alkoxy, Cl6 alkyl 〇Cl.6, Ci6 alkyl 〇c (which, arylalkyl OC(-O)-, - COOH, dentate, hydroxy, RaRbN·, (RaRbN)alkyl, (RaRbN)C(=〇)_, optionally substituted with up to 9 dentate groups [Η 基 and up to 5 substituents, Or, as the case may be, two niches R8 are pendant oxygen; X6 is selected from the group consisting of rhodium (oxygen), NR9 (nitrogen) and C(R8)2; and R is independently selected from the group consisting of Group: hydrogen, aryl, Ci.6 炫基〇(CH2)n, C!_6 烧基〇c(=〇)_, Ci 6 burning*NHC(=〇)_, Cw yard base C(=0 )-, aryl C(=〇)_, aryl 〇c(=〇), aryl NHC(=0)_, arylalkyl〇c(=〇)_, (RaRbN)(CH2)n, (RaRbN)C(=0)- and optionally up to 9 _ group-substituted CM alkyl groups, the aryl (CH2)n-, aryl c(=〇)_, aryl 〇c(=〇) And aryl NHC (=0) - each optionally substituted with up to 5 substituents each individually selected from the group consisting of halo, hydroxy, cyano, nitro, optionally up to 9 dentations Substituted Cl·6 alkyl and, as appropriate Up to 9 halogen substituents of (: 1_6 alkoxy 156115.doc • 27 201200517.. Or a pharmaceutically acceptable salt thereof. 156115.doc -28· 201200517 23. A combination of structures with the formula νιπ, R2A &gt; 2 VIII or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, Rlac (=〇)_&RlaC(=S)-; 1!| is independently selected from the group consisting of _c(R2a)2NR3aR3b, alkoxyalkyl, (^_6 alkyl 〇c(=〇)-, Ci6 alkyl 〇(:(=〇)(: 1-6 alkyl, C 6 · 6 alkyl hydrazine: (=0) (^-6 alkyl, aryl, aryl (CH 2 ) n _, aryl (CH 2 ) n 〇 -, aryl (CH = CH M- 'Arylalkyl〇, arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cycloalkyl〇 Alkyl, heterocyclic, heterocyclic (CH=CH)m_, heterocyclylalkoxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, RR N- &gt; RcRdN(CH2) N- &gt; (RcRdN)(CH=CH)m- '(RcRdN)alkyl, (RRN)C(=0)-, optionally up to 9 halo-substituted Cw alkoxy groups and, optionally, up to 9 yl-substituted Ci 6 alkyl groups, each of which is optionally substituted by a cyano group, a halogen group, a nitro group, a hydroxyl group, and optionally up to 9 yl group-substituted Cl 6 groups; Alkoxy and depending on the situation Each of the hexyl groups substituted by up to 9 halo groups; 156115.doc -29-201200517 are each independently selected, wherein Re&amp;Rd are each independently selected from hydrogen, alkoxy (: (=〇)·, Cl 6 alkyl group, Ci 6 alkyl group c (= 〇), aryl group, aryl group, aryl group, aryl group, aryl group C (-0)-, square group C ( =〇)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl (: (=0)-, heterocyclyl c(=〇)·, (ReRfN)alkyl, (ReRfN) a group C(=0)- and (ReRfN)c (wherein arylalkyl, arylalkyl c(=0)-, heterocyclylalkyl and heterocyclylalkyl c(=0)_ The alkyl moieties are each optionally substituted by a rRfN- group; and wherein the arylalkyl group, the arylalkyl group C(〇)-, the aryl group c(=0)· and the aryl moiety of the aryl group And a heterocyclyl moiety of a heteroalkylalkyl group, a heterocyclylalkyl group c(=0)_, and a heterocyclic group c(=0&gt;, respectively, optionally up to three groups each independently selected from the group consisting of Substituent substitution: cyano group, dentate group, macro group, Ci6 alkoxy group substituted with up to 9 dentate groups, and optionally CN6 alkyl group substituted with up to 9 functional groups; ReRfN is independently selected to select 'its&quot;jRf are each independently selected from the group consisting of hydrogen, Cw, aryl, arylalkyl, cycloalkyl, (cyclohexyl)alkyl, heterofluorenyl, heterocycloalkyl (RXRyN)alkyl and (RxRyN)C(=〇)-; Each WN is independently selected, wherein RjRy is independently selected as f gas, C].6 alkyl 0C (Which, Ci6 alkyl, hospital a group c(=〇)-, aryl, arylalkyl, cycloalkyl and heterocyclic; each C(R2a)2# is independently selected, wherein each R2a is independently selected from the group consisting of: hydrogen , as the case may be replaced by up to 9 dentate Cl 6 , aryl (CH 2 ) „• and heteroaryl (CH 2 ) n ·, t aryl and heteroaryl each 156115.doc 201200517 Substituted by: cyano, dentate, nitro, hydroxy, optionally up to 9 yl substituted icy alkoxy and optionally The following group of components: hydrogen and, as the case may be, substituted by 9 south groups, each of the R groups is independently selected from the group consisting of Cu alkyl groups; each R3b system is independently selected from the group consisting of: Substituted C, -6 alkyl, heteroaryl, _(CH2)nC(=〇)NR4aR4b, _(CH2)nC(=〇)〇RSa and -(CH2)nC(=〇)R6a 'the heteroaryl The base-view condition is replaced by the following groups: cyano's nitro group, hydroxyl group, optionally up to 9 halo-substituted 匸丨6-alkoxy groups and optionally up to 9 dentate-substituted Gy-alkanes Each R4aR4bNS is independently selected, wherein ya and R4b are each independently selected from the group consisting of hydrazine, optionally substituted C"6 alkyl and aryl (CH2)n-; Each RSa# is independently selected from the group consisting of optionally substituted Cw alkyl and aryl (CH2:)n_; each independently selected from the group consisting of CiAC alkyl which is optionally substituted and Aryl (cn2;)n_ ; X is (C(R2)2)q ' or X1 is absent; Y1 is selected from 〇 (oxygen), S (sulfur), s(0), s〇2, nr^c(r2)2, with the constraint that when χ1 is absent, γΐ is C (R2)2; or x2 does not exist; X2 is (c(R2)2)q, χΗΤ 156115.doc -31 · 201200517 γ2 is selected from 〇 (oxygen), s (sulfur), s(0), s〇 2. nr2 and c(r2)2, the restriction is that when x2 is absent, Y2 is C(R2)2; each R2 is independently selected 'where R2 is selected from the group consisting of hydrogen, Cm alkane Oxyl, Cl_6 alkyl 'aryl, halo, hydroxy, RR N- and, optionally, up to 9 halo-substituted alkyl groups, or optionally 2 adjacent R 2 together with the carbon to which they are attached Up to 2 Cw-based substituted fused 3-member to 6-membered carbocycles; each RaRbN system is independently selected, wherein Ra&amp;Rb are each independently selected from the group consisting of hydrogen, CM alkenyl, and c丨6 alkane L4 is selected from the group consisting of: Each X system is independently selected from the group consisting of _NH_, hydrazine (oxygen), S (sulfur), and -CH2-; each A is independently selected from the group consisting of cr3 and n (nitrogen); Independently selected from the group consisting of hydrogen, Cu alkoxy, Cw alkyl 〇 cN6 alkyl, Cw alkyl ocpoh, arylalkyl 0C (=0) _, -COOH, ii, hydroxy, RaRbN _, (RaRbN)alkyl, (RaRbN)C(=0)-, Ci 6 alkyl substituted with up to 9 functional groups, and CK6 alkyl substituted with up to 5 hydroxyl groups; 156I15.doc •32· 201200517 L6 is selected from the group consisting of The L7 is selected from the group consisting of: Each Ls is independently selected from the group consisting of 袢丨 and -(CH=CH)-; CR4 and N(nitrogen); :C(R4)2, NR4, each X4 is independently selected from the group consisting of the following. Each Y4 is independently selected from the group consisting of oxime (oxygen) and s (sulfur); each R is independently selected from the group consisting of: oxy, ketone C, -6 alkyl, Cl .6 alkyl oc (which, arylalkyl 〇 c (four) · '-COOH, halo, c!.6 dentate alkyl, hydroxy, RaRbN_, (RaRbN) alkyl, (RaRbN) C (= 〇)-, Optionally, up to 9 _ group-substituted q 6 alkyl groups and up to 5 hydroxy-substituted Cl 6 alkyl groups, or optionally 2 valences R 4 - are pendant oxy groups; each m is independently 1 or 2; 156115.doc •33· 201200517 each η is independently 0, 1 or 2; each ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; r is independently 0, 1, 2, 3 or 4, with the constraint that L6-L4-L7 is not The compound is not selected from the group consisting of: 156115.doc • 34-201200517 24. The compound of claim 23, wherein each R1 is RlaC(=0)-. The compound of claim 24, wherein each of the compounds of claim 23, wherein each of the feet 23 is a Cm alkyl group; each of the groups is -C(=0)0R5; and each 115 is a Cm alkyl group. 27. The compound of claim 23, wherein: 156115.doc -35· 201200517 L6-L4-L7 is selected from the group consisting of: 156115.doc 36· 201200517 28. The compound of claim 23, wherein: L6 is selected from the group consisting of: The L7 is selected from the group consisting of: 29_ The compound of claim 23, which has the structure of the formula Villa: Villa or a pharmaceutically acceptable salt thereof, wherein R6 is a Ci.6 hospital base substituted with up to 9 halo groups, as appropriate. The compound of claim 29, wherein R6 is fluorenyl. 156115.doc •37·201200517 31. The compound of claim 23 which has the following structure: 156115.doc -38 · 201200517 32. a compound having the structure of formula IX, 156115.doc • 39· IX 201200517 or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, Rlac(= 〇)_&amp;RlaC(=s&gt;-; The 13 series are independently selected from the group consisting of: alkoxyalkyl, Cw alkyl 〇c(=〇)-, Cl 6 alkyl OC(=0)Cl 6 alkyl, Cw alkyl CPCOCu alkyl, Aryl, aryl (CH2)n_, aryl (CH2)n〇-, aryl (CH=CH)m-, arylalkyl〇, arylalkyl, arylalkyl, cycloalkyl (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cycloalkylnonalkyl, heterocyclic, heterocyclic (CH=CH)m_, heterocyclylalkoxy, hetero Cycloalkyl, heterocyclylalkyl, hydroxyalkyl, RcRdN- ' RcRdN(CH 2 ) n - &gt; (RcRdN)(CH=CH)m- &gt; (RcRdN) alkyl, (RcRdN)C ( =0)·, as the case may be up to 9 _ group-substituted Ck alkoxy groups and optionally up to 9 functional groups substituted by a Cl. 6 alkyl group, the aryl group and the heteroaryl group each optionally via the following groups Substitution: cyano, dentate, nitro, hydroxy, optionally up to 9 south-substituted Cl. 6 alkoxy groups and optionally up to 9 Substituted c N6 alkyl; each ReRdN is independently selected, wherein R&lt;= and Rd are each independently selected from the group consisting of hydrogen, alkoxy c(=0)_, Cm alkyl, c丨a alkyl C(=〇)-, C]-6 alkylsulfonyl, arylalkylhydrazine (: (==〇)_, arylalkyl, arylalkyl C(=〇)-, Aryl C(=0)_, arylsulfonyl, hetero-%: aryl, heterocyclyl c(=0)-, heterocyclyl c(=〇, alkyl, (ReRfN) Base C(=0)- and (ReRfN)C(=〇)·, wherein aryl, arylalkyl C(=0)-, heterocyclylalkyl and heterocyclyl are 156115.doc • 40· 201200517 c( 〇)-the alkyl moiety is each substituted by a ReRfN_ group; wherein arylalkyl, arylalkyl c(=〇)·, aryl c(=〇)· The aryl moiety 'and the heterocyclylalkyl group of the aryl group, the heterocyclic group c(=0)_ and the heterocyclic group of the heterocyclic group C(=〇) are each independently up to three independent Substituted from a substituent consisting of a group consisting of a cyano group, a halogen group, a nitro group, optionally a Cw alkoxy group substituted with up to 9 dentate groups, and optionally up to 9 _ group substituted Cn6 groups Group; Each ReRfN is independently selected 'wherein RjRf are each independently selected from the group consisting of hydrogen, c16 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl) or &lt; heterocyclyl And a heterocyclic alkyl group, (WN)alkyl group and (RxRyN)C(;=C))_; each WN system is independently selected, wherein R^Ry are each independently selected from the group consisting of hydrogen and Base C(=0)··, Cl.6 alkyl, c,·6 alkyl C(=C)), aryl, arylalkyl, cycloalkyl and heterocyclic; each c(R2a 2 is independently selected, wherein each R2a is independently selected from the group consisting of: 1. optionally up to 9 i-substituted C.6 alkylaryl (CH2) n- and heteroaryl ( CH2)n_, the aryl and heteroaryl groups are each substituted by the following bases &amp; ^ 'r ntyl groups, cyano groups, self groups, nitro groups, hydroxyl groups, and up to 9 cases 1U®-substituted (^.6 alkoxy group and optionally up to 9 dentyl substituted Cm alkyl groups, or c(R2a)2* y , each & is independently selected from the group consisting of: hydrogen And optionally substituted cN6 alkyl; each R3b is independently selected from the following Group of constituents: 156115.doc 201200517, as appropriate, alkylene, heteroaryl, _(CH2)nC(=〇)NR4aR4b, (ch丄c(=〇)〇RSa and -(CH2)nC(= 〇)R", the heteroaryl group is optionally substituted by the following groups: cyano, li, nitro, hydroxy, optionally up to 9 _ group substituted 匸! 6 alkoxy and optionally 9 yl-substituted Cw alkyl groups; each RRN is independently selected, wherein R4a and R&lt;tb are each independently selected from the group consisting of hydrogen, optionally substituted Cw alkyl, and aryl (CH2) N-; Each RSa is independently selected from the group consisting of CK6 alkyl and aryl (CH2)n_ substituted by up to 5 R2 groups; each line is independently selected from the group consisting of: Substituted C!-6 alkyl and aryl (CH2)n-; X is (C(R2)2)q, , gate r, or χ1 is absent; γ is selected from 0 (oxygen), S (sulfur), s(0), S〇2, NR2, and C(R2)2 The limitation is that when χ1 is not present, γι is c(r2)2; X2 is (C(R2)2)q, or X2 is absent; γ is selected from 〇 (oxygen), S (sulfur), S ( O), S〇2, NR2 and C(R2)2, with the constraint that when X2 is absent, γ2 is C(R2)2; each R2 is independently selected 'where R2 is selected from the group consisting of Gas, chaos, Cl.6 alkoxy, Cl.6, aryl, yl, thiol, RaRbN- and, optionally, up to 9 halo substituted cN6 alkyl, or optionally 2 R2 The attached carbon together comprises, as appropriate, one or two 156115.doc 201200517 fused 3 member to 8 member carbon rings each independently selected from the group consisting of oxime (oxygen), oxime) and 3 (sulfur) (four); The 3- to 8-membered carbocyclic ring is optionally substituted with a plurality of substituents selected from the group consisting of: gas, dentate, thiol, pendant oxy, RH R (c), RXRyNCi 6 alkyl, a heteroaryl group, an aryl group, a CM alkyl group substituted with up to 9 (tetra) groups, optionally substituted with up to 9 dentate groups, Ci 6 alkoxy, at least one of which is 氖.; Each RaRbN# is independently selected, wherein Ra&amp;Rb are each independently selected from the group consisting of hydrogen, c2 6 alkenyl and alkyl; each L1 is independently selected from the group consisting of: , -C(=〇)(CH2)mOC(=〇)_, „c(cf3)2NR2c- 1^ is selected from the group consisting of hydrogen, c丨·6 alkyl, c2-6 alkenyl, C2 -6 alkynyl, C:3·7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, the alkyl optionally being RR N - alkoxy or ^16 alkyl s_substituted; each X3 is independently selected from the group consisting of NH, NCi 6 alkyl, oxime (oxygen) and S (sulfur), each m being independently 1 Or 2; each η is independently 〇, 1 or 2; 156115.doc -43- 201200517 each P is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5;犷 is independently 0, 1, 2, 3 or 4; and each R is independently selected from the group consisting of hydrogen, Cl·6 〇C(〇)·, ^基烧基〇C(=0) )-, -COOH, (RaRbN)C(=〇),, Cl-6 alkyl. A calcined base-based base-based alkyl group and optionally substituted by up to 9 functional groups. 33. a compound wherein each R1 is Rlac(= 〇)_. 34. The compound of claim 32 wherein each Rla is CHR2aNHR3b. 35. The compound of claim 32, wherein each R2» is a Cl_6 alkane Each R3b is -C(=0)0R5; and each is considered to be "alkyl." 36. The compound of claim 32, which has the structure of formula lXa: R1 R. L1 L1 R2, R1 R2 Y2 or a pharmaceutically acceptable salt thereof, wherein R6 is, as the case may be, up to 9 156115.doc 201200517 i-substituted C1-6 alkyl. 37. The compound of claim 35, wherein R6 is a odor 38. a compound having the structure of hydrazine, IX or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, Rlac (=〇)-, and RlaC(=S)-; each RlaS is independently selected from the group consisting of Group: alkoxyalkyl 'C!_6 alkyl 〇 C (= 〇) _, Ci 6 alkyl 〇 c (= 〇) Ci 6 alkyl, Cu alkyl ¢: (=0) (^-6 Alkyl, aryl, aryl (CH2)n·, aryl (CH 2 ) nO-, aryl (CH=CH) m-, arylalkyl hydrazine, arylalkyl, aryl decyl, Cycloalkyl, (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cyclo-k-decylalkyl, heterocyclyl, heterocyclyl (CH=CH)m_, heterocycle 156115.doc -45- 201200517 oxooxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, RR Ν- ' RcRdN(CH2)n- ' (RcRdN)(CH=CH)m- ' (RcRdN a calcinyl group, (RcRdN)C(=0)-, optionally up to 9 dentate-substituted Cl.6 alkoxy groups, and optionally up to 9 halo-substituted C6 alkyl groups, the aryl group and The heteroaryl groups are each optionally substituted by a cyano group, a dentate group, a nitro group, a hydroxyl group, optionally an ei_6 alkoxy group substituted with up to 9 dentate groups, and optionally up to 9 halo groups. And a plurality of ReRdN groups are selected independently, wherein each of them is independently selected from the group consisting of hydrogen, alkoxy C(=〇)-, cN6 alkyl, c]-6 alkyl C (= 0)-,〇].6 alkylsulfonyl, arylalkyl OC(=〇)...arylalkyl, arylalkyl C(-O)-, aryl C(=〇)-, aromatic Sulfosyl, heterocyclylalkyl, heterocyclylalkyl C(=0)-, heterocyclyl C(=0)-, (ReRfN)alkyl, (ReRfN)alkyl c(=〇)- And (]rRfN)c(=0)_, wherein the alkyl moiety of the arylalkyl group, the arylalkyl group c(=0)-, the heterocyclylalkyl group and the heterocyclylalkyl group c(=〇) Substituting a ReRfN- group; and wherein the arylalkyl group, the arylalkyl group C(=〇)-, the aryl group of the aryl C(=〇)_ and the arylsulfonyl group, and the heterocyclic ring The heterocyclyl moiety of the alkyl, heterocyclylalkyl (:(=〇)_ and heterocyclyl c(=〇)_ groups, respectively, optionally up to three substituents each independently selected from the group consisting of Substituted: cyano, yl, nitro, optionally up to 9 halo substituted Ci. 6 alkoxy and optionally up to 9 halo substituted C.. 6 alkyl; each ReRfN is independently Selected, where Re&amp;Rf Each independently selected from the group consisting of hydrogen, C. 6 alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (RxRyN)alkyl and 156115.doc •46- 201200517 (RxRyN)C(=〇).; Each RxRyN is independently selected, among them! ^ and Ry are each independently selected from the group consisting of chloro, phenyl (((〇), cN6 alkyl, (: 丨.6 alkyl c(=〇)-, aryl, arylalkyl, cycloalkyl and Heterocyclic group; Each C(R2a)2 is independently selected, wherein each R2a is independently selected from the group consisting of hydrogen, optionally substituted Ci6 alkyl, aryl (CHA- and heteroaryl (CH2)) N_, the aryl and heteroaryl are each optionally substituted by a cyano group, a halogen group, a nitro group, a hydroxyl group, optionally a Ci 6 alkoxy group substituted with up to 9 dentate groups, and optionally up to 9 One halogen base is taken). Instead of Ci-6, or 〇(^2!1)2 is \ / ; each R3a is independently selected from the group consisting of hydrogen and optionally substituted C!_6 alkyl; each R3b is independent The group is selected from the group consisting of: -(CH2)nC(=〇)NR^R4b . .(C:H2)nC(=0)0R5a and -(CH2)nC(=0)R ", the heteroaryl group may be substituted with a cyano group, an i group, a nitrate group, a base group, a base group, and optionally up to 9 halogen groups, as the case may be substituted by the following groups. 6 pure base and optionally up to 9 Each of R4aR4bN is independently selected from the group wherein R4a and R4b are independently, freely underarm, and formed into a group of hydrogen, optionally substituted alkyl and aryl (CH2)n-; Each R5a substituted in the case is independently selected from the group consisting of: and a aryl group (CH2)n-; : each R6a which is optionally substituted is independently selected from the group consisting of 156115.doc-47·201200517 C 1 · 6 alkyl and aryl (CH2) n- X1 is (C(R2)2)q, Y or X1 is absent; Y1 is selected from 0 (oxygen), S (sulfur), S(O), S02, nr2 and C(R2): When X1 is absent, γ1 is C(R2)2; X2 is (C(R2)2)q, Υα' or X2 is absent Υ2 is selected from 0 (oxygen), S (sulfur), S(O), S02, NR2 and C(R2)2, and its restrictions In the absence of X2, each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, C. 6 alkoxy, aryl, halo, hydroxy, RaRbN, and optionally 9 groups of substituted Cl. 6 alkyl groups, or as the case may be, together with the carbon to which they are attached, optionally contain one or two, each independently selected from the group consisting of hydrazine (oxygen), N (nitrogen) and S (sulfur a heteroatom fused 3- to 8-membered carbocyclic ring; wherein the 3 to 8 membered carbocyclic ring is optionally substituted with or a plurality of substituents selected from the group consisting of halogen I, hydroxy, pendant oxy, WN, R, C(:0), wNCi6 alkyl, heteroaryl, aryl, Ci6, substituted by up to 9 functional groups, and optionally up to 9 functional groups, C!.6 alkane Each of the lines is independently selected, wherein R^Rb are each independently selected from the group consisting of hydrogen, C26 alkenyl, and c"6 alkyl; each L is independently selected from the group consisting of: 156115 .doc •48- 201200517 C(=0)(CH2)m0C(=0). X -C(CF3)2NR2c· R is selected from the group consisting of hydrogen, Ci 6 alkyl, Earth—C 2 ·6 alkynyl, C 3 7 cycloalkyl 'aryl, arylalkylheteroaryl, heteroalkyl t, heterocyclyl and heterocyclyl, which are optionally subjected to ReRfN-, Alkoxy or Cl6 alkyl s_substituted; each x is independently selected from the group consisting of NH, NCu alkyl, hydrazine (oxygen), and S (sulfur); each m is independently 1 or 2; Independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2, 3 or And each R7 is independently selected from the group consisting of hydrogen, halo, Ci_6 alkyl 0C(=0)-, arylalkyl 0C(=0)_, -COOH, (RaRbN)C(= 0)-, a trialkylsilylalkylalkylalkyl group and, optionally, up to 9 yl-substituted Cw alkyl groups; wherein at least one of R2a, R3a, R4a, R4b, only 53 and R6a is at least one A substituted Cw alkyl group substituted with a non-alkyl substituent or substituted aryl group substituted with at least one non-alkyl group substituent. 156115.doc -49·201200517 39. The compound of claim 38, wherein each R1 is R "C (where. 4〇. The compound of claim 38, wherein each Rla is a gamma 23 leg 3, a sample request A compound of 38, wherein each R2a is optionally substituted, each R3, -c(=o)〇Rsa; and each Rsa is optionally substituted c16 alkyl. 42. The compound of claim 38 And wherein at least one R, c(R2a)2NR3aR3t and in the at least one Ru, at least one R2a is substituted with at least one non-alkyl substituent substituted substituted Clm substituted with at least one non-fluorenyl substituent 43. The compound of claim 38, wherein at least one R, a is wherein R3bKCH2)nC(=0)0RSa and Rsa is substituted Ci_6 alkyl substituted with at least one non-alkyl substituent or at least one a substituted aryl group substituted with a non-alkyl substituent. 44. The compound of claim 38, wherein R3a, R4a, R4b, only "and at least one of R6at are Ci 6 alkyl substituted with up to 9 halogens or An aryl group substituted with up to 9 dentants. 45. The compound of claim 38, wherein each R2 is independently selected from the group consisting of hydrogen, C丨·δ alkoxy, aryl, halo, hydroxy, RaRbN_ and, optionally, up to 9 dentations Substituted CN6 alkyl. 46. The compound of claim 38, wherein at least one of R2a, R3a, R4a, EGFR4|) and R6a is C -6 alkyl substituted with up to 9 halogens or aryl substituted with up to 9 halogens . 47. The compound of claim 38, which has the structure of formula IXa: 156115.doc • 50· 201200517 Or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted with up to 9 halo-substituted Cr6 alkyl groups. 48. The compound of claim 47, wherein R6 is methyl. 49. A compound having the structure of formula X, Or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, RlaC(=0)-, and RlaC(=S)-; 156115.doc-51 - 201200517 each 1113 Independently selected from the group consisting of: _C(R2a)2NR3aR3b, alkoxyalkyl group "alkyl group", alkyl group 丨^(6)^alkyl group, CN6 alkyl group (:(=0)( ^.6 alkyl, aryl, aryl (CH2)n... aryl (CHAO-, aryl (CH=CH) m-, arylalkyl hydrazine, arylalkyl, aryl decyl, Cycloalkyl, (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cycloalkylalkylalkyl, heterocyclyl, heterocyclyl (CH=CH)m_, heterocyclyloxy , heterocyclylalkyl, heterocyclylalkyl, hydroxy, RcRdN- ' RcRdN(CH 2 ) n - &gt; (RcRdN)(CH=CH)m- &gt; (RcRdN) alkyl, (RcRdN C(=0)-, as the case may be up to 9 _ group substituted 6 alkoxy groups and optionally up to 9 dentate substituted Ci6 alkyl groups, the aryl and heteroaryl groups each optionally via the following Substituted cyano, cyano, nitro, hydroxy, Ci 6 alkoxy substituted by up to 9 groups, and optionally up to 9 halo Cl_6 alkyl; each ReRdN is independently selected, wherein Re&amp;Rd are each independently selected from hydrogen, alkoxy c(=o)-, Cl_6 alkyl, Ci 6 alkyl c(=〇)·, burned Continued shouting, aryl-based oc (four)), aryl-based, aryl-based C (-〇)-, aryl C (= 〇)-, aryl sulfonyl, heterocycloalkyl, miscellaneous Cycloalkyl group c(=0)_, heterocyclic group c(=〇)·, (ReRfN)alkyl, (ReRfN), and (RTN)C(=0)·, wherein aryl group, The alkyl moiety of the aryl group c(=〇)-, heterocyclylalkyl and heterocyclylalkyl c(=〇)_ are each optionally substituted with a ReRfN• group; and wherein the aryl group is substituted , an aryl group c(-g)· m(=C))· and an aryl group of an aryl group, and a heterocyclic group, a heterocyclic group c (which and a heterocyclic group c) The heterocyclyl moieties are each optionally substituted with up to three substituents each independently selected from the group consisting of 156115.doc 201200517: cyano, dentate, fluorenyl, optionally up to 9 dentate substituted Cl -6 alkoxy and optionally C 1 -6 alkyl substituted by up to 9 functional groups; each ReRfN is independently selected, wherein Re and Rf are each Site selected from the group consisting of hydrazine, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (WN)alkyl and (RxRyN)C ( Each RxRyN is independently selected, wherein π and Ry are each independently selected from the group consisting of hydrogen, Cu-based 〇c(=〇)-, Cu-based, Cu6-based c(=〇)-, 芳Each of the C(R2a)2 groups is independently selected, wherein each R2» is independently selected from the group consisting of hydrogen, optionally substituted C| 6 alkyl, aryl (CH 2 ) n - and heteroaryl (CH 2 ) n ·, the aryl and heteroaryl groups are each substituted by the following groups. Cyano, _ group, base, base, view In the case of up to 9 halo-substituted Cl.6 alkoxy groups and optionally up to $halo group Instead, C 1 ·6 alkyl, or C(R 2a) 2 is , / ; each R 3a is independently selected from the group consisting of hydrogen and optionally substituted c 1 ·6 alkyl; each R3b is independently Select from the following group: Ci6 alkyl, heteroaryl, -(CH2)nC(=〇)NR4aR4b, _(CH2)nC(=〇)〇RSa and (CH2)nC(-〇 R a , the heteroaryl is optionally substituted by the following groups: cyano, i-, nitro, hydroxy, optionally up to 9 _ group substituted &lt;^·6 alkoxy and optionally up to 9 thiol-substituted CM alkyl groups; 156115.doc -53· 201200517 each R4aR4b Aryl (CH2)n- , · Ci-6 alkyl and aryl (CH2) n-; Ci.6 leucoyl and aryl (CH2)n-; X1 is (C(R2)2)q,,, Or X1 is absent; Y is selected from 0 (oxygen), s (sulfur), s(0), s〇2, NR2, and C(R2). The limitation is that when X1 is absent, γι is c(r2) 2 ; . X2 is (C(R2)2)q, Y2 is selected from the group consisting of 0 (oxygen), S (sulfur), S(O), S〇2, NR2 and C(R2)2, with the constraint that when χ2 is absent, γ2 is C(R2)2; R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, C. 6 alkoxy, aryl, halo, hydroxy, RaRbN and, depending on the situation! Up to 9 halo-substituted c]-6 alkyl groups, or optionally 2 R2 together with the carbon to which they are attached, optionally containing one or two, each independently selected from the group consisting of hydrazine (oxygen), N (nitrogen) and s a fused 3-member to 8-membered carbocyclic ring of a (sulfur) hetero atom; wherein the 3 to 8 membered carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, and side oxygen Base, RXRyN, RX^NC(= 〇), RXRyNCl 6 alkyl, heteroaryl, aryl, optionally 156115.doc 201200517 Cls alkyl substituted with up to 9 dentate groups and optionally up to $halo Substituted Ci_6 alkoxy; each RaRbN is independently selected, wherein Ra&amp;Rb are each independently selected from the group consisting of hydrogen, C2-6 alkenyl and C丨6 alkyl; L8 is selected from the group consisting of Group: The L9 is selected from the group consisting of: 156115.doc •55· 201200517 Is selected from the group consisting of: R2 ΝΗ, NCw alkane Each X3 system is independently selected from the group consisting of hydrazine (oxygen) and s (sulfur); each m is independently 1 or 2; each η is independently 〇, 1 or 2; each P is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; and each r is independently 〇, 1, 2, 3 or 4, wherein R2a, R3a, R4a are substituted for Cw alkyl. 50. The compound of claim 49. 51. The compound 52 of claim 49, such as the compound of claim 49, and the at least one of R' RSa and R6a, each of which is RlaC(=〇)_ . Wherein each Rla4 -CHR2aNHR3b. Wherein each R is optionally substituted 匸1 6 156115.doc -56 - 201200517 each R3l^-C(=0)OR5a; and each R5a is optionally substituted Cy alkyl. The compound of claim 49, wherein at least one Ria is c(R2a)2NR3aR3b and at least one of ten, at least one is substituted alkyl. 54. The compound of claim 49, wherein at least one Ri And _c(R2a)2NR3aR3b, wherein R3*^-(CH2)nC(=0)〇R5a is a substituted Ci 6 alkyl group. 55. The compound of claim 49, wherein at least one of R2a, R3a, R4a, R4b, 5), and R6at is a C16 alkyl group substituted with up to 9 ketones. 56. The compound of claim 49, wherein each R2 is independently selected from the group consisting of quinone, Cu alkoxy, aryl, halo, thio, RaRbN, and optionally up to 9 halo. cN6 alkyl. 57. The compound of claim 49, wherein at least one of R2a, R3a, R4a, ft. 41) and at least one of the C16 alkyl groups substituted with up to 9 halogens. 58. For example, a compound of item 49, wherein L9 is selected from the group consisting of ρ2 ιΛΛΛΛ» ^〇-ρ 59. The compound of claim 49 which has the structure of formula Xa: 156H5.doc R/ Re l8-L9 L10 R2 R1 Xa-57·201200517 60 61 or a pharmaceutically acceptable C-1-6 alkyl group as the compound of claim 59, wherein R6 is as defined above, wherein R6 is methyl. And at most 9 a compound having the structure of formula XI, R2 X\1 , Ν-/-L20-J2 R1 R2 XI or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of hydrogen And Rlac(=〇)_ and R, aC(=S)-; ruler "selected from the group consisting of: _C(R2a)2NR3aR3b, alkoxyalkyl, C〗.6 alkyl 〇C (=〇 )-, C丨.6 alkyl 〇c(=〇)Ci.6 alkyl, cN6 yard-based CdCw, aryl, aryl (CH2)n_, aryl (CH2)n〇_, aryl ( CHsCH, -, arylalkyl hydrazine, arylalkyl, aryl decyl, cycloalkyl, (cycloalkyl) (CH=CH)m-, (cycloalkyl)alkyl, cycloalkyl Alkyl, heterocyclic, heterocyclic (CHHCH, -, heterocyclylalkoxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, RcRdN(CH2)n-, (ReRdN (CH=CH)m-, (RcRdN)alkyl, (RcRdN)C(=0)-, optionally up to 9 self-substituted C丨-6 alkoxy groups and up to 9 letters, as appropriate Substituted c -6 alkyl, the aryl and heteroaryl are each optionally substituted by the following groups: cyano, halo, nitro, hydroxy, optionally up to 9 halo Substituted Cw alkoxy and optionally 156115.doc -58-201200517 Cu alkyl substituted by up to 9 dentate groups; R and R are each independently selected from the group consisting of hydrogen, alkoxy C (=〇 )-, Cw alkyl, CN6 alkyl C(=0)·, Cl.6 alkylsulfonyl, arylalkyl 0C(=0)-, arylalkyl, arylalkyl c (=〇 ), aryl C(=0)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl c(=〇)_, heterocyclic C(=0)-, (WN)alkane (ReRfN)alkyl c(=〇) and (ReRfN)C(=〇)- 'wherein arylalkyl, arylalkyl c(=〇)·, heterocyclylalkyl and heterocycloalkane The alkyl moiety of the group C(=0)- is each optionally substituted with a ReRfN- group; and wherein the arylalkyl group, the arylalkyl group c(=〇)_, the aryl group C(=0)- and the aryl group The aryl moiety of the sulfenyl group, and the heterocyclylalkyl, heterocyclylalkyl C(=〇)-, and heterocyclic C(=〇)_2 heterocyclyl moieties are each independently up to three independent Substituted from a substituent consisting of a group consisting of a cyano group, a dentate group, a nitro group, optionally substituted with up to 9 dentate groups, a 6 alkoxy group, and optionally up to 9 _ group substituted Cls 6 a base; each of the rulers is independently selected, wherein Re&amp; Rf are each independently selected from the group consisting of hydrogen, C -6 alkyl 'aryl, arylalkyl, cycloalkyl, (ring Alkyl)alkyl,heterocyclyl,heterocyclylalkyl, (RXRyN)alkyl, and (RxRyN;)C(=〇); fWN are independently selected, wherein R1Ry are each independently selected from hydrazine, Ci-6 an alkane a group OC (which, Ci 6 alkyl, Ci 6 alkyl c (= 〇) ·, aryl, arylalkyl, cycloalkyl and heterocyclic; R 2a is selected from the group consisting of: hydrogen, as the case may be Substituted &amp;yard, aryl (CH2)n- and heteroaryl (eg., (4) and heteroaryl each 156115.doc -59· 201200517 Self-viewing is replaced by the following groups: cyano, tooth a hexyl group, a nitro group, a hydroxy group, a Ci_6 alkoxy group substituted by up to 9 dentate groups, and optionally a C hexyl group substituted by a P 9 halogen group, or c(R 2a) 2 ; R3, selected from the group consisting of hydrogen and optionally substituted alkyl; R3b is selected from the group consisting of: optionally substituted alkyl, heteroaryl, -(CH2)nC (=〇 )NR4aR4b, _(CH2)nC(=〇)〇R 5a and -(CH2)nC(=0)R6a' The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of cyano, benzyl, hydroxy, hydroxy, optionally 9 dentate-substituted Cw alkoxy groups and, optionally, up to 9 dentate-substituted cN6 alkyl groups; only 43 and 114|&gt; are each independently selected from the group consisting of hydrogen, optionally substituted Ci -6 alkyl and aryl (CH2)n_; each Rsa is independently selected from the group consisting of Ci.6 alkyl and aryl(CH2)n-, as the case may be substituted; each line is independently selected from the following Group consisting of: Ci-6 alkyl and aryl (CH2)n-, as appropriate; X is (C(R2)2)q, V^Hr, or χΐ is absent; Υ1 is selected from 〇 (oxygen) ), s (sulfur), s(0), so2, NR2, and c(R2)2, with the constraint that when X1 is absent, Y1 is c(R2)2; each R2 is independently selected, where R2 It is selected from the group consisting of hydrogen, C..6, oxy, aryl, dentate, hydroxy, RaRbN_, and 156, 156. doc • 60·201200517, in the case of up to 9 halo substituted Ci_6 alkyl, Or as the case 2 &amp; 2 and the carbon to which it is connected a fused 3- to 8-membered carbocyclic ring containing one or two heteroatoms independently selected from the group consisting of 0 (oxygen), N (nitrogen) and 8 (sulfur), as appropriate; wherein the 3 to 8 member carbon Cyclic conditions are substituted by one or more substituents selected from the group consisting of halo, thiol, pendant oxy, RXRyN, ' WNCi 6 alkyl, heteroaryl, aryl, Ci.6 alkyl substituted with up to 9 dents, and optionally up to 9 halo substituted Cw alkoxy, or 2 as appropriate The position R2 together with the carbon to which it is attached is a carbonyl group, or, as the case may be, 2 偕R2 together with the carbon to which it is attached, as the case may be up to 2 (^.6 alkyl substituted 3 to 6 carbon rings; each R The RbN is independently selected 'where only 3 and Rb are each independently selected from the group consisting of hydrogen, C26 alkenyl, and Ci6 alkyl; L is selected from the group consisting of q1_q2, q3_q4, Q is selected from the group consisting of: j5, j4_j5, jl_j5 Jl0, 』丨_jS j3, 156115.doc -61· 201200517 Q2 is The q3 is selected from the group consisting of ms m1G, JJ, K R2 R2 And z1 A A Q4 is selected from the group consisting of: z is selected from the group consisting of hydrazine (oxygen), s (sulfur), NR, and c(R2)2; each A is independently selected from the group consisting of CR3 and N (nitrogen); each R3 is independent It is selected from the group consisting of hydrogen, Gw alkoxy, Cw alkyl 0Cl.6 alkyl, Ci 6 alkyl 〇c (=〇), arylalkyl 〇C(=0)-, -COOH, Halogen, hydroxy, RaRbN_, (RaRbN)alkyl, (R RbN)C(=〇)_, and optionally up to 9 _ groups and up to 5 hydroxy groups substituted by C..6 alkyl; I56115.doc -62- 201200517 G1 is -CH2- or -CH2CH2-; a group, a C2·6 alkynyl group, a c: 3 7 cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylf-alkyl group, a heterocyclic group and a heterocyclic alkyl group, the alkyl group being optionally used Substituted by RRN-, alkoxy or Ci6 alkyl s_; J is an aryl, heteroaryl, heterocyclic or polycyclic hydrocarbon, each of which is optionally selected from the group consisting of: Substituent substitution: dentate, hydroxy, WN, WNC (=〇), RXRyNCi 6 alkyl, heteroaryl, aryl, Ci 6 alkyl optionally substituted with up to 9 halo and optionally up to 9 a halo-substituted Ci 6 alkoxy group, each of which is optionally substituted with one or more R14; each R is independently selected from the group consisting of: hydroxy, optionally up to 9 Fluoro substituted (^^ alkoxy, alkyl 6 alkyl, 6 alkyl OC(=〇)-, arylalkyl 〇c(=〇)_, _c〇〇H, halo, and optionally Up to 9 self-substituted Ci 6 alkyl groups; J is C2.4 alkyl, nh, oxime (oxy), -(10) ketone (9)...s(f), (CH2)nX8(CH2)m· or -X7=X7-; -C(CF3)2NR2c- or 156115.doc •63· 201200517 丨人Λ &gt; j is an aryl group, a heteroaryl group, a heterocyclic group or a polycyclic hydrocarbon, each of which is optionally substituted by one or more R3; X7 is independently selected from the group consisting of N (nitrogen) and CR2; each X8 is independently selected from the group consisting of NH, NBi", oxime (oxygen), and s (sulfur); J10 is -C (R2)2-, -NR-, oxygen (9) or sulfur (8); each m is independently 1 or 2; each η is independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; q is independently 1, 2, 3, 4 or 5; each 1* is independently 〇, 1, 2, 3 or 4; each R is independently selected from the group consisting of hydrogen, Cm alkyl 〇C ( = 〇)-, arylalkyl 〇C(= 0)_, (RaRbN)c(= 〇) and optionally up to 9 Cw alkyl groups substituted by a base; and R7 is selected from the group consisting of: Hydrogen, South base, C丨·6 alkyl 0C(=0)-, arylalkyl〇c(=〇)-, -COOH, (RaRbN)c(=〇), dialkyldecylalkyl group Alkyl and, as the case may be, up to 9 dentyl substituted C!-6 alkyl groups. 62. The compound of claim 61, wherein l2g is selected from the group consisting of: 156115.doc -64·201200517 156115.doc -65- 201200517 B is an aliphatic or aromatic ring in the definition of an aromatic ring 'B2, as the case includes an aliphatic ring of hydrazine (oxygen), S (sulfur) or NH or, as the case may be, substituted by one or more RS; And each R8 is independently selected from the group consisting of halo, hydroxy, up to 9 fluoro-substituted Ci-6 alkoxy groups, and optionally up to 9 dentate-substituted Cl. 6 alkanes. base. 63. The compound of claim 61, wherein the lanthanide is selected from the group consisting of: 156115.doc • 66 · 201200517 B is an aromatic ring including hydrazine (oxygen), s (sulfur) or NH, or optionally an aromatic ring of N (nitrogen), and the aliphatic or aromatic ring in the definition of B2 is one or more Rg replaced; and Each is independently selected from the group consisting of a halo group, a hydroxyl group, a Ci 6 alkoxy group substituted with up to 9 fluoro groups, and optionally a C 6 alkyl group substituted with up to 9 halo groups. 64. The compound of claim 61, wherein the Q3 is selected from the group consisting of: 65. A compound of claimant having the following structure: 156115.doc -67· 201200517 156115.doc -68- 201200517 156115.doc -69- 201200517 156115.doc •70- 201200517 66·—a compound having the structure of a hydrazine, R2 R1'N^V_L4 I R2 R1 Υ~~Ν' &gt; R2 Y2 XII or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of nitrogen, Rlac (which RlaC(=s)-; Each R system is independently selected from the group consisting of _C(R2a)2NR3aR3b, alkoxyalkyl, Cu alkyl 〇C(= 〇)·, Ci 6 〇c( = 〇)Ci 6 alkyl, C!·6 alkyl C(=〇)Cl 6 alkyl, aryl, aryl (CH丄·, aryl (CH 2 ) n〇 ·, square (CH=CH) m_ , arylalkyl hydrazine, arylalkyl, aryl fluorenyl, ring-based, (cycloalkyl) (CH=CH) m·, (ring-based) alkyl, cycloalkyl fluorenyl, Heterocyclyl, heterocyclic (CH=CH)m_, heterocyclyloxy, heterocyclyl, heterocyclyl (10), ketone, 156115.doc •71-201200517 RcRdN- ^ RcRdN( CH2)n- ^ (RcRdN)(CH=CH)m- &gt; (RCR«»N) Alkyl, (RcRdN)C(=0)-, optionally up to 9 halo-substituted Cl6 alkoxy groups And optionally, up to 9 substituents (^-6 alkyl groups, the aryl and heteroaryl groups are each substituted by the following groups: cyano group, self group, stone succinyl group, hydroxyl group, as appropriate Further, up to 9 dentate-substituted Ck alkoxy groups and, optionally, up to 9 halo-substituted Cw alkyl groups; each ReRdN is independently selected, wherein each of Rd and R is independently selected from the group consisting of hydrazine and alkoxy C (=0)-, the base, the base C (= 〇) _, Cj_6 alkyl sulfonyl, arylalkyl 〇 c (= o) ·, aryl alkyl, aryl alkyl c (=0 )-, aryl c(=0)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl C(=〇)-, heterocyclyl C(=〇)-, (ReRfN) (ReRfN) alkyl C(= 〇)- and (ReRfN)C( = 〇)_, wherein arylalkyl, arylalkyl c(=0)-, heterocyclylalkyl and heterocyclic The alkyl moiety of alkyl c(=0)_ is each optionally substituted with a ReRfN- group; and wherein arylalkyl, arylalkyl c(=〇)-, aryl c(=o)_ and The aryl moiety of the arylsulfonyl group, and the heterocyclyl group of the heterocyclylalkyl group, the heterocyclylalkyl group c(=0)_&amp;heterocyclyl group c(=0)_, respectively, up to 3 Each is independently selected from a substituent selected from the group consisting of a cyano group, a functional group, a nitro group, a Ci 0 alkoxy group substituted with 9 halo groups as appropriate, and optionally substituted with up to 9 halo groups. C m alkyl; each ReRfN is independently selected, wherein Re&amp;Rf are each independently selected from the group consisting of nitrogen, Cl.6 alkyl, aryl, arylalkyl, ring-based, (cycloalkyl)alkyl, hetero Cyclol, heterocyclylalkyl, (RXRyN)alkyl, and (RxRyN)C(=0)-; 156115.doc 201200517 *RXRyN is independently selected 'wherein and each independently selects 2 nitrogen, Cw alkyl oc (Which, Ci 6 alkyl, q - theater c (which, aryl, arylalkyl, cycloalkyl and heterocyclic; Each C (R2ah is independently selected, wherein each Rla is independently selected from the group consisting of hydrogen, optionally up to 9 halo-substituted Cl 6 alkyl, aryl (CHA- and heteroaryl ( CH2)n_, the aryl and heteroaryl groups are each optionally substituted by a cyano group, a cyano group, a nitro group, a methoxy group, and optionally a methoxy group, and optionally Up to 殳). 9 halo substituted C!·6 alkyl, or C(R2a)2 is \Α/; Each R3a is independently selected from the group consisting of hydrogen and optionally substituted C 1 · 6 alkyl; each R3b is independently selected from the group consisting of: Ci6 alkyl, heteroaryl, -(CH2)nC(=0)NR4aR4b, _(CH2)nC(=〇)〇 R5a and (CH2)nC(-〇)R, the heteroaryl group being substituted by the following groups: cyano group, dentate group, nitro group, hydroxyl group, optionally substituted with up to 9 dentate groups An oxy group and optionally up to 9 dentate-substituted c 丨 6 alkyl groups; each R 4aR 4bN is independently selected, wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, optionally substituted Ci6 alkyl and aromatic (CH2)n-; Each R5a is independently selected from the group consisting of optionally substituted Cw alkyl and aryl (CH2)n-; each R6a is independently selected from the group consisting of: Substituted C!.6 alkyl and aryl (CH2)n-; 156115.doc •73- 201200517 X1 is (C(R2)2)q, nr, or X1 is absent; Y1 is selected from 0 (oxygen), S (sulfur), s(0), S〇2, NR2, and C(R2): The condition is that when X1 is not present, Y1 is c(r2)2; X2 is (C(R2)2)q, Y port r, or X2 is absent; Y2 is selected from 0 (oxygen), S (sulfur), S(O), S〇2, NR2, and C(R2)2 , the restriction condition is that when X2 is absent, γ2 is C(R2)2; each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, C, .6 alkoxy, c〗 6 alkyl, aryl, halo, hydroxy, RaRbN- and optionally CM alkyl substituted with up to 9 dentate groups, or optionally 2 adjacent R: together with the carbon to which they are attached . a fused 3-membered to 6-membered carbocyclic ring; each RaRb_ is independently selected, wherein R^Rb are each independently selected from the group consisting of hydrogen, C2-6 alkenyl, and decyl; each A The group is independently selected from the group consisting of: (3) 3 and ^(nitrogen) 丨/money free of the following group: -uVCLV W (LVJ2·, 〇, , , -c(=0)_, 〇 (oxygen), - Oc(r2)2_, H, -C(CF3)2NR2c-, nh and -(CH=CH)·; J is an arylheterocyclyl, heterocyclyl, cycloalkyl, cycloaliphatic or polycyclic hydrocarbon, Each of them is optionally substituted by one or more π; each R14 is independently selected from the group consisting of hydroxy groups, optionally 156115.doc 201200517, up to 9 fluoro groups substituted by Cl.6 alkoxy, c "6-burning base. Burning base, c].6 burning base OC (-〇)-, square base burning oc (= 〇) _, _c 〇〇 H, tooth base and depending on the situation up to 9 | | Substituted Cl 6 alkyl; each 15 is independently selected from the group consisting of fluorenyl, hydroxy, Cm alkyl OCw alkyl, Cl. 6 alkyl 〇 c (= 〇) _, aryl alkyl OC ( 0)-, _c〇〇H, R9, RxRyN, RXRyNC (=〇) RR NC · 6 alkyl, heteroaryl, aryl, optionally up to 9 halo substituted Cw alkyl, substituted by up to 5 hydroxy substituted Ci 6 alkyl, optionally up to 9 functional groups a Cl-6 alkoxy group, a Ci6 haloalkyl group, a RaRbN-, a (WN) alkyl group, (RaRbN)c (=〇), a Ck alkyl group substituted with up to 5 hydroxy groups, the substituent aryl group and the hetero group The aryl groups are each substituted by one or more R14 as appropriate, or as the case 2 adjacent R1S together with the gorge to which they are attached, as the case may be up to 2 C!-burning substituted fused 3 to 6 carbon rings 'Or 2 偕Rls, as the case may be, together with the carbon to which they are connected, up to 2 as appropriate (: 1 to 6 alkyl substituted 3 to 6 carbon rings, or 2 偕 R1S as appropriate) Each L5 is independently selected from the group consisting of: \ = \, \-=~=-\ s Λ , Η , -C(CF3)2NR2c-, I, A 2 2 , C(R )2 , -C(R)20-, -C(=〇)_, 〇(oxygen), ΝΗ and -(CH=CH)-; R ^ is selected from the group consisting of hydrogen, c丨_6 alkyl , c2_6 dilute group, C: 2.6 alkynyl group, C3-7 cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, 156115.doc • 75- 201200517 Heteroarylalkyl, heterocyclyl and heterocyclylalkyl, ReRfN-, alkoxy or C,-6 alkyl S-substituted; the alkyl group optionally selected from the group consisting of L6 : The L7 is selected from the group consisting of: Each X4 system is independently selected from the group consisting of: wherein if X4 is N (nitrogen), then Y4 is not NH; each X6 is independently selected from the group consisting of: each Y4 is independently selected from the group consisting of 〇 (oxygen) and s (sulfur); each Y9 is independently selected from the group consisting of s (sulfur); each X9 is independently selected from the group consisting of 156115.doc CR4 and N (nitrogen), N ( Nitrogen) and CR8; :C(R4)2, NR4, :-NH-, 0 (oxygen) and: CH and N (nitrogen), if -9 - 201200517, if X9 is N (nitrogen), then Y9 is not NH; each ¥1 (&gt; is independently selected from the group consisting of: _CH2 and _ΝΗ·; 0 each L11 is independently selected from the group consisting of: 丨人^丨, -C(CF3)2NR2c- and ΝΗ ; each L12 is independently selected from the group consisting of: _CH and -CH2CH2-; Each L13 is independently selected from the group consisting of: _CH2, N=CH-(CH2)mNR4(CH2)n-, -CH=CH-, -CH2CH2-, and _(CH2)m〇(CH2)n-; Each m is independently 1 or 2; each η is independently 〇, 1 or 2; each Ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; • independently 〇, 1, 2, 3 or 4; each s is independently 〇 or 1; each R3 is independently selected from the group consisting of hydrogen, Ci 6 alkoxy ' ci·6 alkyl 0C , ·6 alkyl, Cu alkyl 〇 c (= 〇) _, arylalkyl 〇 C (- 〇) _, _ base, trans group, Wn, (RaRbN) 炫, (RaRbN) C (= 0)-, and optionally up to 9 groups and up to 5 groups of substituted C_6 alkyl groups; each R group is independently selected from the group consisting of H (hydrogen), Ci-6 alkoxy, CN6 alkyl OCl 6 alkyl, Ci 6 alkyl 〇 c (= 〇), arylalkyl 〇 c ( 〇) _, _C00H, halo, Ci 6 haloalkyl, hydroxyl, wn · 156115.doc • 77· 201200517 , (RaRbN)alkyl, (WN)c(=〇)4 optionally up to 9 dentities and up to 5 hydroxy-substituted Cl·6 alkyl groups, or 2 oxime R4 together as a pendant oxy group; R is selected from The following group: hydrogen and _C(=〇)R9*»; R is selected from the group consisting of _NR9bR9C, _〇R9d, optionally up to 9 halo-substituted Cl·6 alkyl groups and, as appropriate Substituted aryl group; R is selected from the group consisting of hydrogen, optionally substituted with up to 9 halo groups (: 6 alkyl and optionally substituted aryl groups; R is selected from the group consisting of: 9-group substituted CI·6 alkyl and optionally substituted aryl; and R is selected from the group consisting of C1-δ alkyl substituted by up to 9 functional groups, as appropriate, and optionally substituted The Fang, 67. The restriction is that L6-L4-L7 is not The compound of claim 66, wherein L4 is selected from the group consisting of: &gt; -Λ'Α α=α a~a R8^8R8, K Α~A A-A K. A-A A-A A= A A-A /H A...L3, /A, 1561I5.doc •78· 201200517 The L2 is selected from the group consisting of -(:(=〇)-, -(0^2(:1^2)-, -(CH20)-, -(CH2S)-, -(CH=CH)- , -(CH=N)-, -NH-, oxime (oxygen), s (sulfur) and -CH2-; L3 is selected from the group consisting of S (sulfur) and -CH2-; L5 is selected from the following consisting of Group NH and -(CH=CH)-; -(NR9)-, 0 (oxygen), , 〇 (oxygen), 156115.doc • 79- 201200517: NH, 0 (oxygen) and each x3 system are independently selected from the group consisting of s (sulfur); the following group: -NH-, 〇 (oxygen) Each X system is independently selected from the group consisting of s (sulfur) and -CH2_; each X: is independently selected from the group consisting of n (nitrogen) and ... each R8 is independently selected from the group consisting of hydrogen, C丨6 alkyl oCm topography, Ci 6 alkyl 〇c(=〇)·, arylalkyl (tetra), dentate (RRN) alkyl, (RaRbN)c(=〇)_ and optionally 9 halo groups and up to 5 hydroxy-substituted Ci 6 alkyl groups; each B-line is independently selected, wherein B is a fused, optionally substituted, saturated or unsaturated 3 to 7 membered carbon ring or fused. Optionally substituted saturated or unsaturated 3 to 7 membered heterocyclic rings, each of which is optionally substituted with one or more R 4 groups; each R 4 is independently selected from the group consisting of: Cu alkoxy, 】 6 Burning base 0Cl.6 alkyl, C!-6 alkyl 0C(=0)-, arylalkyl 〇c (=〇y, -COOH, halo, alkyl, hydroxy, RaRbN-, (RaRbN) Base, (RaRbN)C(=〇)- and up to 9 letters and as appropriate ! R4- from two geminal oxygen compounds such as side 66 of the requested item by 5 substituents of C · 6 alkyl group, or optionally 0 68, having the structural formula xna: 156115.doc Xlla • 80-201200517 or a pharmaceutically acceptable salt thereof wherein R6 is optionally substituted with up to 9 halo-substituted C1-6 alkyl groups. 69. A compound of the formula 68, wherein r6 is methyl. 70. A compound having the structure of χιπ, A1 2 R. R1 丨N 2 2 R R 07 I L4lL7 I L6 R2 XIII or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from the group consisting of hydrogen, Rlac(= 〇)_&amp;RlaC(=S)-; The group is independently selected from the group consisting of _c(R2a)2NR3aR3b, alkoxyalkyl, Cm alkyl 〇C(=0)-, Cw alkyl 0 (:(=0)(^.6 alkyl hydrazine) "Alkyl" is a aryl group (CHAO., aryl (ciKHh-, arylalkyl hydrazine), arylalkyl, arylalkyl, ring Alkyl, (cycloalkyl)(CH=CH)m·, (cycloalkyl)-based, cycloalkylalkyl, heterocyclic, heterocyclic (Cii=CH)m_, heterocyclic , heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, RcRdN- &gt; RcRdN(CH2)„- ' (RcRdN)(CH=CH)m- &gt; (RcRdN) alkyl, (RcRdN C(=0)-, optionally, up to 9 halo-substituted c丨.6 alkoxy groups and optionally up to 9 dentate-substituted C6 alkyl groups, the aryl and heteroaryl groups being each The situation is replaced by the following groups: cyano, halo, nitric acid I56ll5.doc • 81 - 201200517 base, trans group, optionally up to 9 halo substituted Cw alkoxy And optionally, up to 9 halo-substituted (: 丨_6 alkyl; each C(R2a)2 is independently selected, wherein each R2a is independently selected from the group consisting of hydrogen, as appropriate 9 halo substituted c丨.6 alkyl, aryl(CH2)n- and heteroaryl(CH2)n-, the aryl and heteroaryl are each substituted by the following groups: cyano, halo a base, a nitro group, a hydroxyl group, optionally a Cw alkoxy group substituted with up to 9 dentate groups, and optionally as described above. Or C(R2a)2 is \8/; 9 substituents substituted by C-6-6 alkane The radical R3a is independently selected from the group consisting of hydrogen and optionally substituted CN6 alkyl; each R3b_ is selected from the group consisting of: optionally substituted. Alkyl, heteroaryl, -( CH2)nC(=0)NR "R4b, _(CH2)nC(=〇)〇R5a and -(CH2)nC(=〇)R6» 'The heteroaryl group is optionally substituted by the following groups: cyano group, a functional group, a nitro group, a hydroxyl group, optionally substituted with up to 9 dentate groups, a C..6 alkoxy group and, optionally, up to 9 groups of substituted Gy alkyl groups; each R4aR4bN# is independently selected, wherein R4a And R4b are each independently selected from the following Group k: hydrogen, optionally substituted Cm alkyl and aryl (CH2)n-; each R is independently selected from the group consisting of: below, 圯目田: Cw alkyl optionally substituted Aryl (CH2)n-; each R is independently selected from the group consisting of: Cu alkyl and aryl (CH2)n- which are optionally substituted; each R1® is ReRdN- 136115.doc -82- 201200517 Each R&quot; is independently selected from the group consisting of hydrazine (hydrogen), alkoxyalkyl, Cw alkyl 0C (=0) Cl_6 alkyl, Cl-6 alkyl ( :(=〇)(:"Alkyl, aryl(CH2)n-, arylalkyl, arylsulfonyl, cycloalkyl, (cycloalkyl), cycloalkylalkyl, hetero a cycloalkyl, a heterocycloalkylalkyl group, a carbyl group, a ReRdN(CH2)n-, a (ReRdN)alkyl group, and optionally a C1-6 alkyl group substituted with up to 9 halo groups; each ReRdN system is independently The ground is selected 'wherein Rc and Rd are each independently selected from hydrogen, alkoxy C(=〇)-, CN6 alkyl, Cu alkyl c(=0)-, Ck alkylsulfonyl, arylalkyl 0C(=0)_, arylalkyl, arylalkyl c(-o)-, aryl C(=0)-, arylsulfonyl, heterocyclic Alkyl, heterocyclylalkyl (:( = 〇)-, heterocyclyl C(= 〇)_, (ReRfN)alkyl, (ReRfN)alkyl C( = 〇)- and (ReRfN)C( = 〇), wherein the alkyl moiety of the arylalkylarylalkyl C(=0)-, heterocyclylalkyl and heterocyclylalkyl c(=〇)- groups are each optionally subjected to a ReRfN_ group Substituted; and wherein the arylalkyl group, the arylalkyl group C(=〇)-, the aryl group c(=0)_, and the aryl moiety of the arylsulfonyl group, and the heterocyclylalkyl group, heterocycloalkane The heterocyclic group of the group c(=0)_ and the heterocyclic group c(=0)_ are each optionally substituted with up to three substituents each independently selected from the group consisting of cyano, dentate, and nitrate a Cy6-alkoxy group substituted with 9 groups as the case may be, and optionally a CN6 alkyl group substituted with up to 9 halo groups; each ReRfN system is independently selected, wherein Re&amp; Rf are independently selected Self-winding, Cl·6· 'aryl, arylalkyl, ring-based, (cyclohexyl)alkyl, heterocyclylalkyl, (RfN)alkyl and (RxRyN)C(=0 )-; 156115.doc -83- 201200517 Each RxRyN is independently selected, wherein RX&amp;Ry are each independently selected from hydrogen Cw alkyl 〇C(=0)-, Cw alkyl, Ci6 alkyl c(=〇)_, aryl, arylalkyl, cycloalkyl and heterocyclic; γ is selected from 0 (oxygen), S (sulfur), S (O), s 〇 2, NR 2 and C (R 2 ) 2 ; each A is independently selected from the group consisting of c 2 6 alkenyl, Cl -alkyl and each, as the case may be One or more R2 substitutions; Each R2 is independently selected, wherein R2 is selected from the group consisting of hydrogen, Cw alkoxy, Cw alkyl, aryl, functional, hydroxy, RaRbN- and, optionally, up to 9 y. . 6 alkyl, or optionally 2 adjacent R, together with the carbon to which it is attached, is a fused 3- to 6-membered carbocyclic ring optionally substituted with up to 2 c Μ alkyl groups, or optionally 2 偕R2 The carbon to be joined together is a 3-member to 6-membered carbocyclic ring substituted with up to 2 Cw alkyl groups as appropriate; L4 is selected from the group consisting of: _(J2)s_(L5)s (J2)s (LS) s J2_, j^^ = \, 〇 (oxygen), -〇c(r2)2., -C(=0)-C(CF3)2NR2c-, NH and -(CH=CH)-; J is an aryl group, a heteroaryl group, a heterocyclic group, a cycloalkyl group, a cycloalkenyl group or a polycyclic fluorene, each of which is optionally substituted by one or more Rls; each R is independently Is selected from the group consisting of hydroxyl groups, optionally substituted with up to 9 fluoro groups (^^ alkoxy, Cw alkyl 〇Ci6 alkyl, Gy alkyl OC(=〇)-, arylalkyl hydrazine c(=〇)_ ' c〇〇H, keel and 156115.doc •84· 201200517 Condition: up to 9 South Substituted C!_6 alkyl; each R15 is independently selected from the group consisting of : South base, warp group, Ci.6 alkyl-based OCu base, C!-6 base 〇C( = 〇).·, Fangbing base 0C(=0)-, -COOH, R9, RH RXRyNC( =〇) RXRyNC〗 6 alkyl, heteroaryl, aryl, optionally up to 9 halo-substituted Cw alkyl, Ci_6 alkyl substituted with up to 5 hydroxy groups, optionally up to 9 halo substituted Gw Alkoxy, Ci6^alkyl, RaRbN-, (RaRbN)alkyl, (RaRbN)c(=〇)... C 。 6 substituted by up to 5 hydroxy groups, the substituent aryl and heteroaryl Each of which is optionally substituted by one or more R14, or optionally 2 adjacent Rls together with the carbon to which it is attached, as the case may be up to 2 (: 1_6 alkyl substituted fused 3 to 6 carbon rings, or Optionally, the two niches Rb together with the carbon to which they are attached are, as the case may be, two Ci-6 alkyl substituted 3 to 6 carbon rings or, as the case may be, 2 偕 RlS together are pendant oxy; The R RbN is independently selected, wherein Ra &amp; Rb are each independently selected from the group consisting of hydrogen, C 2 6 alkenyl, and alkyl; each Ls is independently selected from the group consisting of: AC(CF3)2NR2 C(r)2, -C(R2)20_, _c(=〇)-, 〇(oxygen), nh and _(CH=CH)-; 156115.doc -85· 201200517 The L7 is selected from the group consisting of: ^糸 is independently selected from the group consisting of: cr3 and 戦); each group is independently selected from the group consisting of hydrogen, C&quot; oxy-1-6 alkyl 0Cl.6 alkyl, Cl-6 alkyl hydrazine c(=〇), arylalkyl () C00H, halo, meridine, RaRbN_, (RaRbN) alkyl, (RaRbN)C(=〇)-, and optionally up to 9 dentations and up to 5 a thio group substituted with a Cu alkyl group; the RN is selected from the group consisting of argon, Ci6 alkyl, ~ dilute, Cw alkynyl, fluorene: 3-7 cycloalkyl, aryl, arylalkylheteroaryl, a heteroarylalkyl group, a heterocyclic group and a heterocyclylalkyl group, the alkyl group being optionally substituted with a ReRfN-, alkoxy or Cl.6 alkyl group s; each X group is independently selected from the group consisting of: CH and N (nitrogen); each X1 ❶ is (C(R2)2)q; each Y1() is independently selected from the group consisting of: _Ch2_&amp;-NH-; each Y11 is independently selected from the group consisting of Group: -〇(C(R2)2)n·, -S(C(R2)2)n-, -S(0)(C(R2)2)n-, -S02(C(R2)2) N-, -NR2(C(R2)2)n- and (C(R2)2)q; 156115.doc •86· 201200517 each m is independently 1 or 2; each η is independently 〇, 1 or 2 Each ρ is independently 1, 2, 3 or 4; Each q is independently 1, 2, 3, 4 or 5; each ** is independently 〇, 1, 2, 3 or 4; each s is independently 〇 or 1; X2 is (C(R2)2)q Or X2 is absent; Y is selected from the group consisting of 0 (oxygen), S (sulfur), s〇2, NR2 and c(r2)2; R is selected from the group consisting of hydrogen and _C(=〇)R9a ; R is selected from the group consisting of _NR9bR9c, _〇R9d, optionally up to 9 halo-substituted cu 6 alkyl groups and optionally substituted aryl groups; R9b is selected from the group consisting of hydrogen, The case is replaced by up to 9 halo-substituted C! _6 hospital bases and optionally substituted aryl groups; R c is selected from the group consisting of: C1 · 6 yards and up to 9 halo groups, as appropriate a substituted aryl group; and R~ is selected from the group consisting of up to 9 halo-substituted C 1 ·6 alkyl and optionally substituted aryl, 156I15.doc -87-201200517 The limitation is that the compound is not selected from the group consisting of: 156115.doc -88 - 201200517 156115.doc -89- 201200517 156115.doc -90- 201200517 156115.doc -91 - 201200517 71. The compound of claim 70, wherein L4 is selected from the group consisting of: 156115.doc -92- 201200517 L2 is selected from the group consisting of: &lt;( = 〇)_, _(CH2CH2), -(CH2〇)-, -(CH2S)·, _(CH=CH)...(CH=N),·ΝΗ ... 〇 (oxygen), S (sulfur) and -CH2-; L3 is selected from the group consisting of: S (sulfur) and -CH2-; , -(NR9)-, 0 (oxygen), L5 is selected from the group consisting of ΝΗ and -(CH=CH)-; each X3 is independently selected from % of the following groups of 曰田: NH, 〇 (oxygen) and S (sulfur); each Xs is independently selected from the group consisting of: NH-, 〇 (oxygen), S (sulfur) and - CH2-; each X6 is independently selected from the group consisting of: N (nitrogen) and CR8; each R8 is independently selected from the group consisting of 2 έ ^ k mesh consisting of: hydrogen, Ci e alkyl OCu Base, Cu alkyl group 0C (=0 aryl base 〇 Cd ·, dentate, (RaRbNm based, (RaRbN) c (which, as the case may be up to 9 _ groups and up to 5 hydroxy substituted c -6 alkane Each B-line is independently selected to be 'substituted 156115.doc •93- 201200517 saturated or unsaturated 3 to 7 carbon rings or fused as saturated or unsaturated 3 a member to a 7-membered heterocyclic ring, each of which is optionally substituted with one or more r 4 ; and each R 4 is independently selected from the group consisting of 〇16 alkoxy, alkyl OCu alkyl, Cl 6 alkyl 0C (= 0) _, arylalkyl 〇 c (= 〇) _, -COOH, li group, CN6 _ alkyl, hydroxyl, RaRbN_, (RaRbN) alkyl, (RaRbN) C (=0) - and as the case may be Up to 9 _ groups and up to 5 hydroxy groups Instead, C is a 6-alkyl group, or as the case, the two units R4 together are pendant oxy groups. 72. For example, the compound of 7 ,, where q7 is: ^\R6 R1 J-H R2乂&gt;2 R2 v2 · n R6 is a Cl_6 substituent which is optionally substituted with up to 9 halo. 73. The compound of claim 72, wherein R6 is methyl. 74. The compound of claim 70, wherein the L is selected from The following composition groups: 〇 (oxygen), _〇c(r2) 2 ^ ' -C(CF3)2NR2c- . NH and -(CH=CH)-, Y6, Y6-Y6, γ6·γ, γ6; Is independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, polycyclic hydrocarbons, each of which is optionally substituted with one or more substituents selected from the group consisting of: R2, R3, only 4 and R8; each R2 is independently selected, wherein R2 is selected from the group consisting of C 1 _6 alkoxy, C 1.6 alkyl, aryl, functional, thiol, RaRbN 156115.doc •94·201200517 And optionally, up to 9 dentate-substituted Ci 6 alkyl groups, or optionally 2 adjacent Rs, together with the carbon to which they are attached, are fused 3 to 6 carbons, optionally substituted with up to 2 Gw alkyl groups. Ring, or 2 as appropriate R2, together with the carbon to which it is attached, is a 3- to 6-membered carbocyclic ring optionally substituted with polyalkyl; each R3 is independently selected from the group consisting of Ci6 alkoxy, Cu alkylOCualkyl, cN6 Alkyl 〇c(=〇)-, arylalkyl〇c(=〇)_, -COOH, _ group, hydroxy, RaRbN_, (RaRbN)alkyl, (RaRbN)C(=〇)· and optionally Up to 9 dentate groups and up to 5 hydroxy substituted CN6 alkyl groups; each R4 group is independently selected from the group consisting of 6 alkoxy, 6 alkyl ocu alkyl, Cl 6 alkyl 0C (=0) ·, arylalkyl 〇 c (= 〇) _ COOH, _ group, Cwil alkyl, thiol, RaRbN_, (RaRbN) alkyl, (RaRbN) C (= 〇) - and optionally up to 9 halogen And a group of up to 5 groups of substituted C t 6 alkyl groups, or optionally 2 units of R 4 together are pendant oxy groups; and each R 8 group is independently selected from the group consisting of Ci 6 alkyl hydrazine Ci. 6 Alkyl Cl·6 alkyl hydrazine C(=0)-, arylalkyl hydrazine C(=〇)-, dentate group, (RaRbN) fluorenyl group, (RaRbN)c(=0)_A as the case may be up to 9 a group of up to 5 hydroxy substituted C 6 alkyl groups. 75. The compound of claim 7 which has the structure: 156115.doc -95· 201200517 °Y° Or a pharmaceutically acceptable salt thereof. 76. a compound having the structure of formula XIV, Or a pharmaceutically acceptable salt thereof, wherein: 156115.doc -96- 201200517 Each X1G is (C(R2)2)q; Each X11 line is independently selected from the group consisting of: (C(R2)2)q and each Y&quot; are independently selected from the group consisting of: 〇(〇(Κ2)2)η-, S(C( R2) 2) n-, -S(0)(C(R2)2)n-, -S02(C(R2)2)n-, -NR2(C(R2)2)n- and (C(R2) 2) q; each R1 is independently selected from the group consisting of: hydrogen, RhC(= 〇)_&amp;RlaC(=S)-; each "series is independently selected from the group consisting of: _C(R2a) 2NR3aR3b, alkoxyalkyl, cN6 alkyl 〇c(=o)-, Cw alkyl 0 (: (=0) (:, -6 alkyl, CN6 alkyl ¢: (=0) (:, - 6 alkyl, aryl, aryl (CH 2 ) n — , aryl (CH 2 ) n 0 —, aryl (CH=CH) m, arylalkyl hydrazine, arylalkyl, aryl decyl, ring Alkyl, (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cycloalkylfluorenyl, heterocyclyl, heterocyclyl (CH=CH)m_, heterocyclylalkoxy ,heterocyclylalkyl,heterocyclylalkyl,hydroxyalkyl, RCRdN-, WN(CH2)n_, (ReRdN)(CH=CH)m_, (RCRdN)alkyl, (RcRdN)C(=0 -, optionally, up to 9 dentate-substituted Cw alkoxy groups and optionally up to 9 dentate-substituted Ci_6 alkyl groups, the aryl and heteroaryl groups Substituted by the following groups: cyano, dentate, nitro, hydroxy, Ci.6 alkoxy substituted by up to 9 groups, and optionally c16 alkyl substituted by 9 halo; Wherein ReARd independently selects a group, C!_6 alkyl group c(=〇)_, q 6 each ReRdN system is independently selected, and its bow is from hydrogen, alkoxy c(=o)·, Cl_6 alkyl, 156115 .doc •97· 201200517 Alkylsulfonyl, arylalkyl 0C(=0)_, arylalkyl, arylalkyl c(=0)-, aryl C(=〇)-, aryl Sulfhydryl, heterocyclylalkyl, heterocyclylalkyl C(=〇)-, heterocyclyl C(=〇)_, (ReRfN)alkyl, (ReRfN)alkyl C(=〇)- and (ReRfN)C(=〇)_, wherein the alkyl moiety of the arylalkyl group, the arylalkyl group c(=0)-, the heterocyclylalkyl group and the heterocyclylalkyl group c(=0)_ are each considered The case is substituted by a ReRfN_ group; and wherein the arylalkyl group, the arylalkyl group C(=〇)-, the aryl group c(=0)_ and the aryl moiety of the arylsulfonyl group, and the heterocyclic group The heterocyclic moiety of the alkyl, heterocyclylalkyl C(=0)- and heterocyclyl c(=〇)- groups are each optionally independently selected from the group consisting of: Substituted substituents: cyano, functional, nitro, optionally up to 9 functionally substituted C 6 alkoxy and optionally up to 9 halo substituted Cw alkyl; each ReRfN is independently Selected, wherein Re&amp;Rf are each independently selected from the group consisting of hydrogen, Cw alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (RxRyN) And RxRyN are each independently selected, wherein R*&amp; C] 6 院基基(=〇)_, aryl, arylalkyl, cycloalkyl and heterocyclic; each C (R h is independently selected, wherein each R 2a is independently selected from the group consisting of Group: hydrogen, optionally substituted with up to 9 halo groups C!.6 alkyl, aryl (CH2)n- and heteroaryl (CH2)n_, the aryl and heteroaryl groups are each optionally subjected to the following groups Substituted for: cyano, halo, nitro, hydroxy, optionally up to 9 hexyl substituted Cl. 6 alkoxy and optionally up to 156115.doc 201200517 The 9-group-substituted C1-6 alkyl group is independently selected from the group consisting of hydrogen and optionally substituted CN6 alkyl; each R3b# is independently selected from the group consisting of: alkyl groups substituted as appropriate; Heteroaryl, (CHAC^NRWb, _(CH2)nC(=〇)〇R5a and -(CH2)nC(=0)R6a' The heteroaryl group is optionally substituted by the following groups: Chaotic, dentate, nitro, hydroxy, optionally up to 9 ytyl substituted oxime, 6 alkoxy and optionally up to 9 dentate substituted Gw alkyl; each R4aR4bN is independently selected Wherein ya and R&lt;b are each independently selected from the group consisting of hydrogen, optionally substituted Cw alkyl, and aryl (CH2)n-; each RSa is independently selected from the group consisting of: Substituted Ci-6 Hyun: aryl and aryl (CH2)n-; each line is independently selected from the group consisting of C!-6 alkyl and aryl (CH2)n_ which are optionally substituted; X1 is (C(R2)2)q, Y wr , or χι does not exist; Y1 is selected from 0 (oxygen), S (sulfur), S(O), S02, NR2, and C(R2)2 In the absence of X1, γι is c(r2)2; X2 is (C(R2)2)q, \wr, or χ2 is absent; Υ is selected from 〇 (oxygen), S (sulfur), s ( 0), S02, NR2, and C(R2)2, with the constraint that when X2 is not present, γ2 is C(R2)2; 156115.doc •99· 201200517 each, 2 series are independently selected, where r2 is The group consisting of the following components a &amp; hydrogen Cl-6 alkoxy, Cw alkyl, aryl, halo, hydroxy, RRN and, optionally, up to 9 halo substituted saponins, or optionally 2 phases The neighboring R and the carbon to which it is attached are fused 3 to 6 carbon rings which are optionally substituted with up to 2 Cu alkyl groups; each RRN is independently selected 'wherein Ra and Rb are each independently selected from 4 The following group of components: hydrogen, C2-6 alkenyl, and C]-6 alkyl; L4 is selected from the group consisting of: -(J2MLs)s-(J2)s-(I/)s_j2_, , -C(= 〇)-•C(CF3)2NR2c-, I ——1 'I-~=~=—\ NH 〇 (oxygen), -oc(r2)2- and _(CH=CH)-; J is Fang Base, heteroaryl, a cycloalkyl, cycloalkyl, cycloalkenyl or polycyclic hydrocarbon, each of which is optionally substituted by one or more rIS; each R14 is independently selected from the group consisting of hydroxy, optionally up to 9 fluoro groups. Cl·6 alkoxy, Cu 6 alkyl 〇 Ci 6 alkyl, alkyl 0 (: (=0)-, aryl alkyl 0C (=0) ·, _c 〇〇 H, _ base and optionally 9 halo-substituted Cl-6 alkyl; each 1^15 is independently selected from the group consisting of halo, hydroxy, Ct. 6 〇c!_6 alkyl, Ci-6 alkyl 〇c ( = 〇), arylalkyl 0C (=0)-, -COOH, R9, RXRyNC (= 〇), R RyNCN6 alkyl, heteroaryl 'aryl, optionally up to 9 halo substituted Cw A group of up to 5 hydroxy-substituted Cl_6 alkyl groups, optionally up to 9 halo-substituted Ci. 6 alkoxy groups, Cl_6 haloalkyl groups, 156115.doc -100-201200517 RaRbN-, (Wn) alkane a radical, (RaRbN)c(=〇)_, and a C..6 substituent: substituted by up to 5 hydroxy groups, the substituent aryl and heteroaryl are each substituted by one or more R14, or as appropriate Two adjacent R13s together with the carbon to which they are connected are up to two C]_6 a fused 3-member to 6-membered carbocyclic ring, or optionally 2 偕 R15, together with the carbon to which it is attached, may be up to 2 as appropriate (: 1 to 6 alkyl substituted 3 to 6 carbon rings) Or, as the case may be, 2 positions R1S - as a pendant oxy group; Each L5 line is independently selected from the group consisting of: j -C(CF3)2NR2c-, -C(R2) 2-, -C(R2)2〇-, _C(= 〇)_, 〇(oxygen), NH and -(CH=CH)-; Each A line is independently selected from the group consisting of CR3 &amp; N (nitrogen); r2c is selected from the group consisting of hydrogen, 6 alkyl, Cw alkenyl, C2.6 alkynyl, C3-7 cycloalkyl , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, the alkyl being optionally substituted with ReRfN_, alkoxy or c -6 alkyl S-; L6 is selected from the group consisting of: 156115.doc -101- 201200517 The L7 is selected from the group consisting of: a group of: hydrogen, Cw alkyl AaRbN) c (= 〇) - and optionally, each R is independently selected from the group consisting of 0 (: (= 〇) _, arylalkyl 〇 c (= 〇) _, Up to 9 _ group-substituted Cl-6 alkyl groups; each X4 system is independently selected from the group consisting of CR4 and N (nitrogen), wherein if X4 is N (nitrogen), Y4 is not NH; each Y4 They are independently selected from the group consisting of C(R4)2, NR4, 〇(oxygen), and S(sulfur); each γ9 is independently selected from the group consisting of: ΝΗ_, 〇 (oxygen) and 156115.doc •102-201200517 s (sulfur); each x9 series is independently selected from the group consisting of CH&amp;N (nitrogen), wherein if X9 is N (nitrogen), then Y9 is not NH; each Υ1 ϋ is independent The group is selected from the group consisting of: _CH2_&amp;_NH_; 0 each L11 is independently selected from the group consisting of hydrazine and NH; each L12 is independently selected from the group consisting of: _cH2_ and -ch2ch2-; Each L13 is independently selected from the group consisting of -CH2-'-N=CH-, -CH=CH-, -CH2CH2-, and -(CH2)m〇(CH2)n-; -(CH2)mNR4(CH2 N- each m is independently 1 or 2; Each η is independently 〇, 1 or 2; each ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2 3 or 4; each s is independently 〇 or 1; each R3 is independently selected from the group consisting of CN6 alkyl 〇Cl.6 alkyl, CN6 alkane C (=〇)-, -C〇〇H, a group of a halogen group and a hydroxyl group: hydrogen, CN6 alkoxy 〇C(=〇)-, arylalkyl RaRbN-, (RaRbN)alkyl, (RaRbN)C(=〇)-, and, as the case may be 9 dentate groups and up to a plurality of hydroxy-substituted Cw alkyl groups; and each R4 group is independently selected from the group consisting of: a group, a CN6 alkyl group 0C.6 alkyl group, a C.6 alkyl hydrazine (hydrogen), a cumane group. Oxime c(=〇)-, arylalkyl 156115.doc 201200517 〇C(=〇)-, -COOH, self-based, Ci 6 haloalkyl, M-based, RaRbN_, (R RbN) alkyl, ( RaRbN)C(=〇)- and optionally up to 9 halo groups and up to 5 hydroxy groups substituted by c!·6 alkyl, or 2 oxime R4 together as a pendant oxy group; R9 is selected from the following Group consisting of: hydrogen &amp;_C( = 〇)R9a; ruler "selected from the group consisting of: _NR9bR9C, _〇R9d, optionally up to 9 dentate bases And the optionally substituted aryl group; R is selected from the group consisting of hydrogen, optionally up to 9 halo substituted C 1 -6 alkyl and optionally substituted aryl; R is selected from the group consisting of C 1 ·6 alkyl and optionally substituted aryl substituted with up to 9 functional groups; and R is selected from the group consisting of up to 9 as appropriate A C 1 alkyl group substituted with a dentate group and optionally an substituted aryl group. 77. The compound of claim 76 which has the structure: 156115.doc 104· 201200517 156115.doc -105- 201200517 156115.doc •106- 201200517 156115.doc -107- 201200517 156115.doc •108· 201200517 156115.doc •109· 201200517 156115.doc -110· 201200517 156115.doc -Ill - 201200517 O^NH HN 156115.doc -112- 201200517 156115.doc 113- 201200517 156115.doc •114· 201200517 156115.doc • 115- 201200517 156115.doc 116· 201200517 156115.doc 117- 201200517 78. The compound of claim 76, wherein Q7 is: /C R6 R1 y—n R 2 乂 R 2 Υ 2 ; and R 6 is optionally substituted with up to 9 halo Cw alkyl groups. 79. The compound of claim 78, wherein R6 is thiol. 80. The compound of claim 76, wherein L4 is selected from the group consisting of: 156115.doc -118- 201200517 R2xV and R2 L2 are selected from the group consisting of _c( = 〇)_, -(Ch2ch2)-, -(ch2o)-, -(ch2s)-, _(CH=CH)_, _(CH;= N) _NH_, 〇 (oxygen), s (sulfur) and -ch2-; o L3 is selected from the group consisting of: Human [f丨, _(nr9)_, 〇 (oxygen), S (sulfur) and -CH2-; ο L5 is selected from the group consisting of: t human, 丨 NH and -(CH=CH)-; Niobium (oxygen) Each X3 system is independently selected from the group consisting of S (sulfur), which is composed of NH, 0 (oxygen) and each Xs system independently selected from the group consisting of -NH-, 0 (oxygen), S (Sulfur) and -CH2-; 156115.doc ' 119- 201200517 Each x is independently selected from the group consisting of N (nitrogen) &amp;CR8; each R8 is independently selected from the group consisting of hydrogen, Cw Alkyl OCw alkyl, Cw alkyl 〇 c (= 〇) _, aryl alkyl 〇 c (= 〇), dentate, (RRN) alkyl, (RaRbN) c (= 〇) _ and optionally Up to 9 functional groups and up to 5 hydroxy-substituted Cl-6 alkyl groups; each B-series is independently selected, wherein B is fused, optionally substituted, saturated or unsaturated, 3 to 7 carbon rings or thick A saturated or unsaturated 3 to 7 membered heterocyclic ring which is optionally substituted, each of which is optionally substituted by one or more r 4 ; and each R 4 is independently selected from the group consisting of: c] 6 alkoxy Base, Cm alkyl OC, -6 alkyl, Cw alkyl 0C (=0)-, arylalkyl 〇 c (=0) _, -COOH, functional group, Cr6 dentate alkyl, hydroxy, RaRbN_, ( RaRbN) calcination, (RaRbN)C (=〇)- and up to 9 _ groups and as appropriate 5 of substituents by ci · 6 alkyl group 'or optionally two geminal groups R4- oxygen from a side. 81. a compound having the structure of the formula χν, Or a pharmaceutically acceptable salt thereof, wherein: 156115.doc -120- 201200517 Each χ2 is (C(R2)2)q, X(7)·, or X2 does not exist; Each lanthanide is selected from the group consisting of ruthenium (oxygen), S (sulfur), s (〇), s〇2, NR2, and c(R)2, with the constraint that when x2 is absent, γ2 is c(r2)2; Each X1. (C(R2)2)q; The present X 1 system is independently selected from the group consisting of: (C(R2)2)q and Λτ, . } Each Υ11 is independently selected from the group consisting of: _〇 (C(R2)2)n_, -S(C(R2)2)n- &gt; -S(0)(C(R2)2)n- ' -S02(C(R2)2)n- . - NR2(C(R2)2)n- and (C(R2)2)q; each R12R13N is independently selected, wherein Ri2 and each are independently selected from hydrogen, -[(Y14)(C(R2)2) r(NR2)s(C(R2)2)rHY"(C(R2)2)r(NR2)s(C(R2)2)r]s-(Y")s-R8. ,~[(Y14)(C(R2)2)r(NR2)s (C(R2)2)r]-Y14(C(R2)2)r〇(C(R2)2)r-(Y14) s-R8&lt;), alkoxy group, alkoxy c(=o)-, Cl.6 alkyl, c2.6 alkenyl, c2_6 alkynyl, C3 7 cycloalkyl, Ci.6 alkyl c (=0)-, c3.7 cycloalkyl c(=0)-, CU6 alkylsulfonyl, arylalkyl 0C(=0)-, aryl, arylalkyl, aryl sulfonyl C (=0)-, aryl C(=〇)-, arylsulfonyl, heterocyclic, heteroaryl 156115.doc • 121 _ 201200517 base, heteroarylalkyl, heterocyclylalkyl, heterocycle Alkyl c(=0)...heterocyclic group C(=〇)-, heteroaryl c(=0)_, heteroarylalkyl c(=〇)_, (ReRfN)alkyl, (ReRfN) Alkyl c(=0)- and (ReRfN)C(=0)-, the alkoxyalkyl group, alkoxy C(=0)_, Cl 6 alkyl group, C3 7 cycloalkyl group, CV6 alkyl group C(=〇)-, c3.7 cycloalkyl C(=〇)·, Cl6 alkylsulfonyl, arylalkyl 0C(=0)-, aryl, arylalkyl, arylalkyl C(=〇)-, aryl C(=C))_, arylsulfonyl, heterocyclic, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkyl C ( =〇)_, heterocyclic group C(=0)-, heteroaryl C(=〇)_, heteroarylalkyl c(=〇)_&amp; in (ReRfN)alkyl The alkyl groups of (ReRfN)alkyl c(=0)_ are each optionally substituted by one or more Rlab; or R12R13N is a heterocyclic group attached via a ring nitrogen atom optionally substituted by one or more of the following: side Oxygen, -[(yi4)(c(r2)2)^nr2)s (C(R2)2)r]-[Y^(C(R2)2)r(NR2)s(C(R2)2 )r]s.(Y14)s_R80 ^ _[(γ14) (C(R2)2)r(NR2)s(C(R2)2)r]-Y14(C(R2)2)r〇(C( R2) 2) r-(Y^)s. R80, alkoxyalkyl, alkoxy C(=0)·, Cl 6 alkyl, c2 6 alkenyl, C 2_6 alkynyl, (:3·7 ring Alkyl, Ci6 alkyl c(=〇)_, C37 cycloalkyl C(=〇)-, Cm alkylsulfonyl, arylalkyl 〇c(==〇)_, arylarylalkyl , arylalkyl C(=〇)-, aryl (:(=0)-, arylsulfonyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heterocycle Alkyl c(-0)-, heterocyclyl C(=〇)-, heteroaryl c(=0)-, heteroaryl d-c(=0)-, (ReRfN)alkyl, (ReRfN Alkyl c(=0)_ and (ReRfN)C(=〇)., alkoxyalkyl, alkoxy C(=〇)-, c..6 alkyl, (:3·7 ring Alkane 156115.doc •122· 201200517 base, CN6 alkyl c(=〇)-, c3.7 cycloalkyl c(=o)-, c 〖.6 alkyl sulfonate, Alkyl 〇C(=〇)-, aryl, arylalkyl, arylalkyl c(=0)-, aryl c(=〇)-, arylsulfonyl, heterocyclic, hetero Aryl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkyl c(=0)-, heterocyclyl C(=〇)-, heteroaryl c(=0)-, heteroaryl Alkyl c(=0)- and alkyl groups of (ReRfN)alkyl and (R*RfN)alkyl c(=0)__ are each substituted by one or more Rlab; each Rlab is independently selected Free group consisting of: _[(γι&lt;») (C(R2)2)r(NR2)s(C(R2)2)r]-[Y14(C(R2)2)r(NR2)s( C(R2)2)r]s-(Y14)s-R80 ^ -[(Y14)(C(R2)2)r(NR2)s(C(R2)2)r]-Y14(C(R2) 2) rO (C(R2)2)r-(Y14)s-R8❶, _C(R2a)2NR3aR3b, alkoxyalkyl group, Cw alkyl group 0C(=0)-, Cl.6 alkyl group 0C (=0 )Cl 6 alkyl, Cl.6 alkyl CpCOCu alkyl, aryl, aryl (CH 2 ) n —, aryl (CH 2 ) n 〇, aryl (CH=CH) m-, arylalkyl fluorene-, Arylalkyl, arylalkyl, cycloalkyl, (cycloalkyl)(CH=CH)m-, (cycloalkyl)alkyl, cycloalkylindolyl, heterocyclyl, heterocyclyl (CH=CH)m-,heterocyclylalkoxy,heterocyclyl,heterocyclylphosphonyl, mercapto group, RcRdN (CH2)n-, (ReRdN)(CH=CH)m_, (RcRdN)alkyl, (ReRdN)C(=0)-, Ci 6 alkoxy substituted by up to 9 functional groups, as appropriate, and optionally Up to 9 halo-substituted Cw alkyl groups, each of which is optionally substituted with a cyano group, a dentate group, a nitro group, a hydroxyl group, optionally a C group substituted with up to 9 halo groups. Alkoxy and optionally up to 9 i-substituted cN6 alkyl; each R8° is independently selected from the group consisting of hydrogen, alkoxy 156115.doc-123-201200517, Ci.6 Base, C3·7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl and (ReRfN)alkyl Alkoxyalkyl, Ci.6 alkyl, 〇3·7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocycle The ketone group and the alkyl group in the (ReRfN) group are each optionally substituted by one or more Rlac; each RlaM^, independently selected from the group consisting of: -C(R2a)2NR3aR3b, alkoxyalkyl , Cw alkyl 0C (=0)-, Cw alkyl OCpCOCK alkyl, Cu alkyl hydrazine: (=0 (^-6 alkyl, aryl, aryl (CH2)n-, aryl (CH2)n〇-, aryl (CKNCHU•, arylalkyl〇, arylalkyl, aryl decane) , cycloalkyl, (cycloalkyl) (CH=CH)m-, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl (CH=CH)m-, hetero Cycloalkyl alkoxy, hetero arylalkyl, heterocyclyl fluorenyl, carbyl, RcRdN-, ReRdN(CH2)n-, (RcRdN)(CH=CH)m·, (RcRdN) alkyl , (RcRdN)C(=0)-, optionally up to 9 halo-substituted Cl.6 alkoxy and optionally up to 9 halo substituted c]_6 alkyl, the aryl and heteroaryl The groups are each substituted by the following groups: cyano, _ group, nitro 'hydroxy group, optionally up to 9 _ group substituted Cw alkoxy groups and optionally up to 9 halo groups substituted C _ 6 alkane Each Y14 is independently selected from the group consisting of -C( = 〇)_, -S(=〇)·, -C(=S)-, -s(=0)2-, -c( =0) 0-, -C(=〇)NR2c-, -S(=〇)2NR2c-, -C(=0)NR2cC(=0)-, and -C(CF3)2NR2c-; Rl is selected from the following Group of constituents: Rlaa, Rlac (= 〇) and RlaC (=S)-; 156115.doc •124· 201200 517 Each R is independently selected from the group consisting of _c(R2a)2NR3aR3b, alkoxyalkyl, Cw alkyl 〇c(=〇)-, Cb6 alkyl oc(=〇)Ci 6 alkyl, Cu Alkyl hydrazine: (=0) (^.6 alkyl, aryl, aryl (CH2)n_, aryl (CHAO-, aryl (CH=CH) m_, arylalkyl hydrazine _, aryl alkane Alkyl, arylalkylalkyl, cycloalkyl, (cycloalkyl)(CH=CH)m_, (cycloalkyl)alkyl, cycloalkylalkylalkyl, heterocyclyl, heterocyclic (CH:= CH) m_, heterocyclic alkoxy, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, RcRdN- ' RcRdN(CH 2 ) „- ' (RcRdN)(CH=CH)m- ^ ( RcRdN) alkyl, (RcRdN)C(=0)-, optionally substituted with up to 9 halo groups (^.6 alkoxy group and optionally up to 9 dentyl groups (^_6 alkyl group) The aryl and heteroaryl groups are each optionally substituted by the following groups: cyano, dentate, nitro, hydroxy', optionally up to 9 functional groups substituted c丨_6 alkoxy and optionally up to 9 _ group substituted (^.6 alkyl; RlaiW^, selected from the group consisting of: _[(γ14) (C(R2)2)r(NR2)s(C(R2)2)r]-[ Y14(C(R2)2)r(NR2)s(C(R2)2)r]s- (Y14)s-R8°,-[(Y14 (C(R2)2)r(NR2)s(C(R2)2) small Y14(C(R2)2)r〇(C(R2)2)r-(Y14)s-R8G, alkoxy Alkyl, alkoxy c(=〇)_, d_6 alkyl, C2-6 alkenyl, C2.6 alkynyl, c3.7 cycloalkyl, (: _6 alkyl C(=0)-, C3_7 Cyclosyl C(=0)-, Cu alkyl sulfonyl, arylalkyl 〇C(=0)-, aryl, arylalkyl, arylalkyl c:(=〇)_, aromatic Base c(=0)-, arylsulfonyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkyl c(=0)-, heterocyclyl c (=〇)-, heteroaryl C(=0)-, heteroarylalkyl C(=0)-, (ReRfN)alkyl, (ReRfN) alkyl C(=〇)- and (ReRfN)C (=0)-, 156115.doc •125· 201200517 The alkoxyalkyl group, alkoxy group C(=0)·, Cw alkyl group, c3.7 cycloalkyl group, Ci-6 alkyl group C (= 0 )-, C3-7 cycloalkyl C(=0)-, Ci.6 alkyl thiol, arylalkyl oc(=o)-, aryl, arylalkyl, arylalkyl c ( =o)-, aryl c(=o)-, arylsulfonyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkyl c(=o) -, heterocyclic group C(=0)-, heteroaryl c(=0)-, heteroarylalkyl c(=0)- and in (ReRfN)alkyl and (ReRfN)alkyl The alkyl groups in c(=0)- are each optionally substituted by one or more Rlab; each R1(^RcRdN-; each R11 is independently selected from the group consisting of H (hydrogen), alkoxyalkyl , Cw alkyl 0 (: (=0) (^.6 alkyl, cN6 alkyl hydrazine: (=0) (:, .6 alkyl, aryl (CH2) n_, arylalkyl, aryl hydrazine Aryl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkyl, hydroxyalkyl, ReRdN(CH2)n-, (RcRdN) And optionally, up to 9 halo-substituted c丨_6 alkyl groups; each R is independently selected, wherein each is independently selected from the group consisting of hydrogen, alkoxy c(=o)-, (:丨_6 alkane) Base, c^_6 alkyl c(=0)_, Ci 6 alkylsulfonyl, arylalkyl 0C(=0)_, arylalkyl, arylalkyl c(mono)-, aromatic Base C(=〇)-, arylsulfonyl, heterocyclylalkyl, heterocyclylalkyl c(=0)·, heterocyclyl c(=0)_, (ReRfN)alkyl, (ReRfN Alkyl C(= 0)_ and (ReRfN)c( = 〇)_, wherein arylalkylarylalkyl C(-O)- 'heterocyclylalkyl and heterocyclylalkyl c(= The alkyl moiety of 〇) is each substituted by an irRfN_ group; and wherein aryl An aryl moiety of a aryl group, a arylalkyl C(0)-, an aryl c(=0)., and an arylsulfonyl group, 156115.doc -126-201200517 and a heterocyclyl-hortyl, heterocyclyl-based group The heterocyclyl moieties of c(and heterocyclyl c(=〇)· are each optionally substituted with up to three substituents each independently selected from the group consisting of: cyano ', nitro, optionally Cl_6 morphoxy substituted with up to 9 functional groups and Cw alkyl substituted with up to 9 dentate groups as appropriate; independently selected by the system 'where R and Rf are each independently selected from hydrogen, c, .6 Anthracenyl, aryl, arylalkyl, cyclodecyl, (cycloalkyl), heterocyclyl, heterocyclylalkyl, (RXRyN)alkyl and (RxRyN)C(=0)-; Independently selected 'they are independently selected from 虱, C丨.6 alkyl 〇C(=0)_, Ci 6 院基, c丨·6 院基, aryl, arylalkyl, ring An alkyl group and a heterocyclic group; each C (Rh is independently selected, wherein each R2a is independently selected from the group consisting of: 1 and optionally up to 9 (tetra) group substituted c&quot; alkylaryl (CH2)n _ and heteroaryl (CH2)n-, the aryl and heteroaryl Substituted by the following groups: cyano group, dentate group, nitro group, hydroxyl group, optionally substituted with up to 9 halo groups, Ci. to oxy group and, as the case may be, C(R2a)2 is \xp 9 _ The substituted C1-6 alkyl group, or optionally each R3a, is independently selected from the group consisting of hydrogen and, optionally, substituted (^.6 alkyl; each R is independently selected from the group consisting of: Substituted Ci-6 alkyl, heteroaryl, _(CH2)nC(=〇)NR4aR4b, -(CH2)nC(=0)0RSa and (CH2)nC(-〇)R6a 'the heteroaryl The situation is superseded by: 156115.doc -127· 201200517 Cyano, halo, nitro, hydroxy, as appropriate, up to 9 dentate substituted 'alkoxy and optionally up to 9 self-substituted Each R4aR4b_ is independently selected, wherein R4a and R4b are each independently selected from the group consisting of hydrogen, optionally substituted C丨-6 alkyl, and aryl (CH2)n- Each RSa is independently selected from the group consisting of CiAC alkyl and aryl (CH2)n_, as the case may be substituted; each R6a is independently selected from the group consisting of: Ci-6 alkyl and aryl (CH2)n_; each A1 is independently selected from the group consisting of 6 alkenyl, Gy alkyl and -(CH2)n-〇-(CH2)m-, each of which Optionally substituted by one or more R 2 ; each R 2 is independently selected, wherein R 2 is selected from the group consisting of hydrogen, a hydroxyl group, a hydroxyl group, a c -6 alkoxy group, (: an alkyl group, a c 2 6 group) Alkenyl, C2.6 alkynyl, alkoxyalkyl, C3 7 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, ( ReRfN)alkyl, RaRbN_, which may optionally be via one or more halo groups, -OR2b, -C(=0)〇R2b, -C(=0)NHR2b, -NHC(=NH)NHR2b, :NHR2b, SR2b, imidazolyl, fluorenyl, _SCH3, phenyl and 4_ylphenyl substituted, the Cl_6 alkoxy, alkoxyalkyl, aryl, c26 fluorenyl, CM alkynyl, c:3 • 7-cycloalkyl, arylalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, and alkyl in (ReRfN)alkyl, each optionally via one or more R4 Substituting, or optionally 2 adjacent R2 together with the carbon to which they are attached, as the case may be as thick as 2 C -6 alkyl substitutions 156115.doc •128- 201200517 A 3-member to 6-membered carbocyclic ring; R is selected from the group consisting of hydrogen, CU6 alkyl, C2.6 alkenyl, Cw alkynyl, CM cycloalkyl, aryl, aromatic Alkylheteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; mi free of the following group: ammonia, Ci w, cj, C2·6 alkynyl, C3·7 naphthenic Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, the alkyl optionally being RRN-, alkoxy or C -6 alkyl S - Substituent; each RaRblSHS is independently selected, wherein Ra and Rb are each independently selected from the group consisting of: U2_6 alkenyl and Cl_n L4 are selected from the group consisting of: _(j2)s_(lS)s_(j2) S_(lS)s-j2_, C(=0)·, -C(CF3)2NR: NH 〇(oxygen), -oc(r2)2 and -(CH=CH)-; • Each 12 series is independently selected Free group consisting of aryl, heteroaryl, hetero &amp; base, % alkyl, cycloaliphatic and polycyclic hydrocarbons, each optionally substituted by one or more R1S; each R14 is independently selected from the group consisting of Group consisting of: Cl-6 alkoxy, Ci 6 substituted by up to 9 ruins, depending on the situation院基〇c“alkyl, c】-6 alkyl 〇C(-〇)-, arylalkyl hydrazine (: (=〇), dentate base and, where appropriate, replaced by up to 9 functional groups Ci- 6 alkyl; each Rls is independently selected from the group consisting of: a dentate group, a hydroxyl group, a cardinyl group 0. 6 alkyl group, a Ci 6 yard group 〇c (which, arylalkyl 156115.doc -129· 201200517 OC(=0)-, -COOH, R9, RxRyN, RxRyNC(=〇), WNCw alkyl, heteroaryl, aryl, optionally up to 9 halo-substituted Cu alkyl groups, optionally up to 9 Substituted C丨·6 alkoxy, Cw Ii alkyl, RaRbN-, (RaRbN)alkyl, (RaRbN)C(=0)-, and Cw alkyl substituted with up to 5 hydroxy groups, the substitution The aryl and heteroaryl groups are each optionally substituted by one or more R 14 or, as the case may be, 2 adjacent R 15 together with the carbon to which they are attached, as the case may be fused with up to 2 C 6·6 alkyl groups. A member to a 6-member carbon ring' or, as the case may be, 2 positions R15 together with the carbon to which it is attached, as the case may be up to 2 Cw alkyls, 3 to 6 carbon rings, or 2 as appropriate Rls together are pendant oxy; each L5 is independently selected from the group consisting of ^ Ζ · I, \ = = \ , -C(CF3)2NR , ____Λ -C(=0)-, 〇(oxygen), NH, -C(R2)2_, _c(R2)2〇·, and -(CH=CH)-; L is selected from the group consisting of CR3 and N (nitrogen); 156115.doc -130· 201200517 L7 is selected from the group consisting of: / K γ1〇- Cf' Γ10_χ9, 丨 x9-x9, «, •c(cf3)2nr: Group of 7 r: CR4 and Ν (nitrogen); Each lanthanide is independently selected from the group consisting of the following: and each of the Y4 lines is independently selected from the group consisting of C(R4)2, NR' 〇 (oxygen), and s (sulfur); X9 is independently selected from the group consisting of CH and N (nitrogen is independently selected from the group consisting of: and _ wins each m independently of 1 or 2; each η is independently 〇, 1 or 2; Each Ρ is independently 1, 2, 3 or 4; each q is independently 1, 2, 3, 4 or 5; each r is independently 〇, 1, 2, 3 or 4; each s is independently 〇 or 1 ; group of components: hydrogen, CN6 alkoxyalkyl 〇C(= 〇)-, arylalkyl, each R3 is independently selected from the group consisting of cN6 alkyl 0Cl_6 alkyl, Ci 6 (〇) C〇〇 H, halo, fine, :R», (RaRbN)alkyl, (RaRbN)C(=0)_, and, optionally, up to $unit and up to 5 hydroxy substituted CN6 alkyl; each R4 The system is independently selected from the group consisting of hydrazine (nitrogen), oxygen 156115.doc-131 - 201200517, Cw-based OCI.6 alkyl, Ci-6 alkyl 〇c(=〇)_, aryl burning Base OC(-O)-, -COOH, _ group, Ck calcining group, mercapto group, Wn_, (RRN) alkyl group, (RaRbN)C(=〇)- And optionally, up to 9 halogen groups and up to 5 radicals substituted C!·6 alkyl, or 2 oximes r4 together as a pendant oxy group; R6 is selected from the group consisting of hydrogen, _, hydroxy, CN6 alkoxy, CN6 alkyl, C2.6 dilute, c2.6 alkynyl, alkoxyalkyl, c3 7 cycloalkyl, aryl, arylalkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group, a heterocyclylalkyl group, a (ReRfN)alkyl group, a RaRbN., the C16 alkyl group optionally having one or more dentate groups, -R2b, _C(=0)0R2b, _(:(=0)ΝΙ1Ι121*, -NHC(=NH)NHR2b, _NHR讪, SR2b, imidazolyl, fluorenyl, -SCH3, phenyl and 4-hydroxyphenyl substituted, and the a 6 alkoxy group , alkoxyalkyl, aryl, C:2·6 alkenyl, c 2_6 alkynyl, c3.7 cycloalkyl, arylalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocycle The alkyl group and the alkyl group in the (ReRfN) alkyl group are each optionally substituted by one or more R 4 ; R 9 is selected from the group consisting of hydrogen and _C(= 〇)R9a; Group consisting of: _NR9bR9c, _0R9d, as appropriate, up to 9 halo-substituted Cl·6 alkyl groups and, as appropriate Substituted aryl; R9b is selected from the group consisting of hydrogen, optionally up to 9 halo substituted C丨.6 alkyl and optionally substituted aryl; r9c is selected from the group consisting of: Whereas, up to 9 halo-substituted C 1 ·6 pit groups and optionally substituted aryl groups; and 156115.doc -132* 201200517 feet 9&lt;1 are selected from the group consisting of: up to 9 A halogen-substituted C u alkyl group and optionally substituted aryl group, with the proviso that the compound is not selected from the group consisting of: 156115.doc -133- 201200517 156115.doc -134- 201200517 156115.doc -135- 201200517 156115.doc -136- 201200517 8 2. The compound of claim 8 1 wherein The L4 is selected from the group consisting of: 156115.doc •137- 201200517 R2 L2 is selected from the group consisting of _c(=〇)_, _(ch2CH2)-, -(CH20)- '-(CH2S)- ' -(CH=CH)- ' -(CH=N)- '-NH- &gt; 0 (oxygen), S (sulfur) and -CH2-; O L3 Select the group consisting of the following: 丨 _ (nr9) _, 〇 (oxygen), s (sulfur) and -ch2-; ο Ls is selected from the group consisting of 丨N and -(CH=CH)-; each X3 is independently selected from S (sulfur), a group consisting of NH, 0 (oxygen) and 156115.doc 138 * 201200517 The following groups of Xs are independently selected from the group consisting of S (sulfur) and -CH2-, and the group: -NH-, oxime (oxygen), each X6 is independently selected from the group consisting of U: N (nitrogen) and CR8; and each B series is independently selected, ^ 千千B is fused, optionally substituted or unsaturated, 3 to 7 carbon rings or _ Unsaturated 3 to 7 heterocyclic rings, each of which is optionally substituted by one or more r4. 83. The compound of claim 81, wherein the rule 6 is a CK6 alkyl group substituted with up to 9 halo groups, as appropriate. 84. The compound of claim 81, wherein l6 is selected from the group consisting of: The L7 is selected from the group consisting of: 85. The compound of claim 81, which has the structure: 156115.doc -139· 201200517 86. The use of a compound as claimed in any one of claims 1 to 85, or a composition as claimed in the claims, for the manufacture of a medicament for the treatment of liver deuteration. The use of a compound according to any one of claims 1 to 85 or a composition according to claim (10) for the manufacture of a medicament for enhancing liver function in an individual having a hepatitis C virus infection. 156115.doc 140· 201200517 IV. Designation of Representative Representatives (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 156115.doc VII 201200517 156115.doc XI 201200517 XIII XIV L4 I l7-q7 156115.doc -4