TW200831489A - Methods for treating hepatitis C - Google Patents

Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

Description

200831489 IX. INSTRUCTIONS: Before and after the relevant application, refer to this application for part of the serial number of application No. 11/331,180 filed on January 13, 2006, and the case was filed on July 14, 2005. Part of the continuation of the application No. 11/180,961 and the International Application No. PCT/US2005/024881 filed on July 14, 2005, the two applications claiming the US provisional application filed on July 14, 2004. Application No. 60/587,487, December 13, 2004, filed US Provisional Application No. 60/634,979, filed on January 24, 2005, filed US Provisional Application No. 60/645,586, March 28, 2005 U.S. Provisional Application No. 60/665,349, filed on Apr. 28, 2005, filed on Apr. 28, 2005, the benefit of the U.S. Provisional Application No. 60/675,440, filed on Jan. 13, 2006. The rights of 60/758,527, the entire contents of each of which are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions to treat infection by viruses or affect viral IRES activity. [Prior Art] It is reported that an estimated 170 million people worldwide are infected with the hepatitis C virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infection can cause chronic liver infections, which in turn can cause severe liver disease, including hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (115). The HCV line constitutes the genus #106 of the side disease #106, and contains the positive strand 9.6 128244-1 200831489 kb RNA genome. The HCV genome features a 5'-untranslated region (UTR) that encodes an internal ribosome entry position (IRES) that directs a single long open translation backbone encoding 3,010 amino acid polyproteins (ORF) Translate. The HCV ORF is then a variable length 3'-UTR, depending on the HCV variant, which encodes the sequence required to prime the anti-genomic strand synthesis (79). Both HCV IRES and 3'-UTR encode regions of the RNA structure required for genome translation and replication. The HCV polyprotein line is processed into at least 10 mature viral proteins in a post-translational manner, including structural protein cores (putative chitin nucleic acids), E1 and E2, and non-structural (NS) proteins NS2 to NS5B. Three different elements have been shown to be involved in the translation of HCV IRES media: (1) the integrity of the overall structure of HCV IRES, (2) the 3'-end region of the HCV genome; and (3) the processing of cytokines, which will interact with HCV IRES Elemental interactions and help with translation initiation (35). The initiation of protein synthesis in eukaryotic cells is mainly based on 5' end dependence, the first AUG rule (61). However, an increasing number of viruses (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128) and cellular mRNA (18, 39, 45, 78, 91, 130) have been shown to utilize IRES Elements, triggered by guided translation. In 1992, the IRES element was reported in the 5TJTR of the HCV RNA genome (129), indicating that the synthesis of viral proteins was initiated in an end-independent manner. A bicistronic expression system can be used to define and evaluate the function of the IRES element. This test system lurks two different reporter genes, of which the 5'-proximal reporter gene is expressed by a terminal-dependent translation mechanism, whereas the second reporter contains IRES only in the upstream of the inserted intergenic space. The order element will be represented. Using this system, the putative IRES line 128244-1 200831489 in HCV 5fUTR is clearly presented as an IRES (133) involving viral protein translation control. Further evidence for the presence of IRES elements in HCV 5TJTR is provided in in vitro translation, RNA transfer infection and mutagenic studies (23, 41, 42, 108, 129, 132, 133, 134). Both in vitro and cell-based studies have demonstrated that HCV IRES directs cell translation of the priming factor to the internal location of viral RNA (56, 58, 120), thus functionally exhibiting HCV IRES activity. Together, these results confirm that HCV 5'-UTR contains the IRES element, which plays an active and decisive role in the internal triggering mechanism of HCV protein translation. IRES is one of the most conserved regions of the HCV genome, reflecting its essential properties for viral replication and protein synthesis (13, 118, 122). Although the 5' and 3' sequences of the IRES appear to play a role in triggering the translation control (42, 109, 110, 113, 136), the minimum order of the HCV IRES function requires that the condition has been mapped to nucleotides. Area between 44-354 (40). Biochemical detection and computer modeling revealed that HCV IRES and its 5' sequence were folded into a different structure containing four major functional sites and one pseudojunction (11, 42, 122). Functional site I contains a small stalk loop structure that does not appear to be a functional part of the IRES element, whereas functional sites II, III and IV contain HCV IRES activity (43, 111). The relationship between the secondary and tertiary structure of HCV IRES and its function has recently been established (5, 55, 56, 99, 124). Both functional sites II and III contain multiple stalks, loops and ridges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142). Functional site II induces a conformational change associated with the decoding process on the ribosome (124). Functional site III has the highest degree of structural conservation among different HCV species. It contains the core of the flavivirus IRES and has 12 sub-functional sites (40) with 128244-1 200831489. Various studies have confirmed that the sub-functional site Illd forms a complex secondary/tertiary structure and is important for initiating active lines (55, 56, 57, 124, 129). Functional site IV has a stalk loop spanning the initiation codon and is specific for HCV IRES (41, 122), but the clear role of functional site IV in IRES activity remains controversial (41, 112). The role of HCV IRES is to localize the translation mechanism to an internal initiation codon that is close to the viral mRNA. The translation initiation mechanism of HCV and other viral IRES is significantly different from that of 5'-end-dependent translation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123). Most cell end-of-line mRNA systems utilize a number of elicitors (elF), which are required for translation initiation processes. The most preliminary step in this process is to interact with the 5' end structure and to supplement the protein of the 40S ribosome subunit to the end-proximal region of the mRNA. This complex then scans the 3' of the end until the AUG codon is reached and the translation is initiated (21, 114). However, in the case of HCV, the IRES is functionally substituted for the 5' end structure, allowing the 40S ribosomal subunit to bind directly to eIF3 to RNA. The functional site of the HCV IRES, Illd, is hidden from the binding site of the 40S ribosome subunit, and the only triggering factors required for translation initiation are eIF2, eIF3 and eIF4E (15, 58, 94, 100, 120, 124). . Polypyrimidine binding protein (PTB) and La autoantigen are non-regular translation triggers that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53) . PTB, a 57-kDa protein involved in RNA ligation, is also required for mediator translation of picornavirus mRNA and some cellular mRNAs for effective IRES (10, 11, 36, 53, 59, 89, 92). La autoantigen, a 52 kDa double-stranded RNA-cleaving protein, also increases the activity of poliovirus and cells 128244-1 200831489 IRES (38, 85, 86). Other cytokines involved in translation by HCV IRES, including protein degrading alpha-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33) ). However, the role of these RNA-binding proteins in the translation of HCV IRES media is unclear. Recently, it has been reported that the activity of interferon (IFN) alpha against HCV replication may be mediated by HCV IRES-mediated translation in a manner that results in a decrease in La protein content (117). Some HCV proteins, such as NS5A, core and NS4A/4B, have also been reported to be involved in HCV IRES function (143-146). Therefore, inhibitors that block the interaction between IRES and non-regular factors may effectively inhibit HCV replication without cytotoxicity. Currently, only interferon (IFN) alpha and the nuclear analog, Sanjun nuclear, are commercially available in combination for the treatment of HCV infection. However, these two agents are immunomodulators with limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138). Although the treatment outcome is variable among the six major HCV genotypes, only about half of all treated patients responded to the therapy, indicating that the virus encodes a protein product that directly or indirectly attenuates the antiviral activity of IFN. effect. The IFN system is naturally produced in response to viral infection, and exposure of the cells to IFN results in the induction of a variety of IFN-stimulated genes (ISG), many of which have antiviral functions. The ISG role limits viral replication at multiple points within the replication cycle. There is still a need for more effective treatment of patients with HCV. Specifically, there remains a need for novel antiviral drugs that do not have cross-resistance with current therapeutic modalities and that exhibit synergistic effects with other anti-HCV agents. All documents cited in this document are incorporated by reference in the present application, and the same is incorporated herein by reference. SUMMARY OF THE INVENTION The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions to treat infection by viruses or affect viral IRES activity. DETAILED DESCRIPTION OF THE INVENTION A. Compounds of the invention f One aspect of the invention pertains to compounds of formula (I)

R

Wherein: X is: hydrogen, nitro; cyano; CORa group, wherein Ra is: -0^ to (6 alkyl, -Q to Q aryl' is optionally alkoxy or halogen Substituted, or -dialkyl-amino;, -COORx group, wherein Rx is Ci to q alkyl; carbaryl; 128244-1 -11-200831489 -Q to Q aryl 'as alkoxy Substituent; or • 5 or 6-membered heteroaryl, optionally substituted by: -Ci to C6 alkyl, _C0 to C8 aryl, optionally substituted by alkoxy or one or more halogens or -5 To 6-membered heteroaryl; Y is: - nitrogen, - anthracenyl; - a hydroxyl group - an amine group 'optionally substituted with one or more Cl to Q alkyl groups; - benzofuran; - benzothiophene - dibenzofuran; - dibenzo p-phene; - benzopyrazole; - benzene; - hydrazine, optionally substituted with hydrazine on the nitrogen;

Wherein Rb is hydrogen or CiSQ alkyl, and η is 0 or 1; 128244-1 -12- 200831489

definition

Or -SC^RX ' where Rx is as defined above VRd 〇 where Rx is as above or

, the center of which is ^ to 匸6 alkyl or 〇6 to (:8 aryl; -NHCORe group, wherein Re is: -q to C6 alkyl; -C6 to aryl, optionally substituted by: - Heart to decyl, -alkyloxy, -cyano, -nitro, or -halogen; -NHCOORx group, wherein Rx is as defined above; -CH2〇-Rf group, wherein Rf is q to Q aryl; _ -NRgRh group 'where \ is hydrogen or (^ to ^: 6 alkyl) and 1 is hydrogen or hydrazine to Cs aryl, optionally substituted by alkoxy; -Ci to C6 alkyl -5 or 6 membered heteroaryl, as the case may be replaced by: 128244-1 -13· 200831489 -C1 to q alkyl, optionally substituted by c6sc8 aryl, -Q to Cs aryl, optionally by 〇 〇Rx substituted, wherein Rx is as defined above, or -amino group; -5 or 6 membered heterocyclic ring, optionally substituted by: ...CO〇Rx group, the center of which is as defined above, or --nhco〇rx Group, the center of which is as defined above; _ A to Q aryl, optionally substituted by one or more of the following groups: - alkoxy groups are optionally substituted by the following: - alkoxy, - hydroxy, - one or Multiple halogens, -5 or 6 member heterocycles, as appropriate : -Ci to C6 alkyl, or -hydroxyl, -amino, optionally substituted by one or more q to c6 alkyl, -NRiS02Rx group, the center of which is as defined above, and Ri is -hydrogen, - 〇^ to (:6 alkyl, --CORx group, wherein Rx is as defined above, -haloalkyl, or -haloalkoxy, -NRj CORk group, wherein Rk is: -(^ to ( :6 alkyl, 128244-1 -14- 200831489 - Hydrogen, or monthly female base 'optionally substituted by one or more Ci to q alkyl groups, and Rj is: - hydrogen, -C〗 to C6 alkyl, - a -CORx group, as defined above, -haloalkyl, or -halooxy, -N=N+ =!Sr group, or --COR group, wherein & is 5 or 6 members A heterocyclic ring, optionally substituted by a hydroxy group, - an amine group, optionally substituted by one or more Ci to q alkyl groups, - a stone base, a -Q to Q alkyl group, optionally substituted by the following: -NHS〇2Rx group 'wherein, as defined above, or --NRxS〇2Rx group, wherein Rx is as defined above, - alkoxy, -halo, -hydroxy, -COORx group, wherein Rx is as defined above, -CORm a group wherein Rm is: - an amine group, optionally one or more q to c6 Substituted 'where one or more Q to c6 alkyl groups are optionally substituted by the following groups - 128244-1 -15- 200831489 -5 or 6-membered heterocyclic ring, -amino group, optionally one or more Cl to c6 alkyl substituted '-alkoxy, -3 to 7 membered heterocyclic ring, optionally substituted with q to C6 alkyl, which is optionally substituted with dialkyl-amino group, ...NHRn group, Wherein Rn is: -_CH2C〇NH2, or -C6 to aryl, optionally substituted by the following -alkyl group, or a plurality of halogens, -nitro group, or -one or more alkoxy groups, -NR. a CORp group, wherein Rp is: -ci to C:6 alkyl, optionally substituted by the following: _halogen, -alkoxy, or -C6 to C8 aryl, -5 or 6 membered heterocyclic ring, -A to Cs aryl, optionally substituted by halogen '-5 or 6 membered heteroaryl, optionally substituted by one or more Q to C: 6 alkyl, - hydrogen, 128244-1 • 16 - 200831489

And where R. For: - hydrogen, -(^ to decyl,

a -CORx group whose center is as defined above, - anthracenyl' or -1⁄4 alkoxy 5 -NRqCONRqR^• group, wherein \ is: -hydrogen, -haloalkyl, -halooxy , or --CORx group, the center of which is as defined above, and wherein Rr is: -C6 to C8 aryl, which is optionally replaced by:

-CiSC6 alkyl, -ifialkyl 9-ORs group centered at C6SC8 aryl, or 128244-1 -17-200831489 • _COORx group, centered as defined above, -C! to C6 alkyl , optionally substituted by one or more of the following groups: - halogen, -alkylene, -c6 to c8 aryl, and / or -CO〇Rx groups, the center of which is as defined above, -COORx The group, whose center is as defined above, --NRtCOORu group, whose center is: -Cl to Ci2 alkyl, which is optionally substituted by the following: -C6 to A aryl, optionally Ci to q thiol or oxygenated Substituted, -alkylene, alkoxy, alkyne, -halogen, or -5 or 6 membered heterocyclic ring, -Q to C8 aryl, optionally substituted by the following: - alkoxy, -halogen, Or • ci to C6 alkyl, or a 5- or 6-membered heterocyclic ring, and Rt is: - hydrogen, • Ci to C6 alkyl, 128244-1 • 18- 200831489 - CORx group, the center of which is as defined above , a haloalkyl group or a haloalkyloxy group, a NRvS02Rw group centered at: -hydrogen, a -CORx group, wherein Rx is as defined above, or -^ to decyl, as the case may be The following substitutions: -halogen, --CORx group, where The heart is as defined above, --OCORx group, wherein 1 is as defined above, -trans-based, or -alkyloxy' and wherein Rw is: -q to C6 alkyl, optionally substituted by the following - halogen , -_alkyl, -c6 to c8 aryl, or -5 or 6 membered heterocyclic ring, -C2 to C6 alkyl, -alkyl- or dialkyl-amino, optionally substituted by halogen, -5 Or a 6-membered heterocyclic ring, or a -5 or 6-membered heteroaryl group, optionally substituted by the following: -^ to decyl, -5 or 6 membered heterocyclic ring, or 128244-1 -19- 200831489

•N

V

NH

N——Rv

Ry is optionally replaced by a CiSQ alkyl group, wherein

Is (^ to 仏alkyl or hydroquinone>

128244-1 -20- 200831489 wherein Rz is hydrogen or a group, optionally substituted by a qC8 aryl group, the -SRX group, the center of which is as defined above, ...S02Raa group, wherein Raa is: -Ci to Cs alkyl , -Amino, -alkyl- or dialkyl-amino, optionally substituted by hydroxy or _c〇〇Rx group, centered as defined above, -5 or 6 membered heteroaryl, "&quot ; Q to Cg square, and / or ... NHRbb group, where Rbb is: ★

-C(=S)NH2 group, or ...P〇(ORx)2 group, the center of which is as defined above; --& group, wherein Rcc is: - Nai' -5 or 6 member hetero base,

-Q to Cs aryl, optionally substituted by one or more of the following groups: 128244-1 -21 - 200831489 - alkoxy, -yl, halogen, -Q to c6 alkyl, optionally cyano Substituted, 'amino, optionally substituted by one or more C! to c0 alkyl, -NHPORxRx, centered as defined above, -NReeCONRffRff group, wherein Ree is hydrogen or CisC6 alkyl, optionally halogen Substituted, and Rff is: -hydrogen, -halooxy-'-Ci to C6 alkyl, or -CORx group, wherein Rx is as defined above, ... NRggCORhh group, wherein Rhh is: -hydrogen, -Ci To c6 alkyl, as the case may be substituted by: - alkoxy, -halogen, or -amino group, optionally substituted by one or more (^ to a cardiac alkyl group, -amino group' as appropriate by one or more C! to c6 lei group substitution 'where the alkyl group is replaced by _, optionally, 5- or 6-membered heterocyclic ring, -5 or 6-membered heteroaryl, and Rg g is · 128244-1 -22- 200831489 - Hydrogen, -G to c6, - haloalkyl, -halooxy, or -CORx group, the center of which is as defined above, -13⁄4 alkyl, -5 or 6 membered heterocyclic group, - Amine, as the case may be one or more (^ to : 6 alkyl substituted, and / or --NRnS02Rx group, wherein rx is as defined above, and Rn is: - hydrogen, -C to C6 alkyl, -haloalkyl, -halooxy, - a CORx group, wherein rx is as defined above; Z is: - hydrogen; -Q to A alkyl, optionally substituted by: - alkoxy, - one or more halogens, or -C6SC8 aryl; _ c2 To a C6 alkyl group; -C0 to cs; a group, optionally substituted by an alkoxy group or one or more C1 to q alkyl groups; ... a COORx group, the center of which is as defined above; or 128244-1 -23 - 200831489

R is hydrogen, halogen or alkoxy; Ri is --trans group; -_alkyl, -nitro; -5 or 6-membered heteroaryl; -5 or 6-membered heterocyclic; -alkoxy, optionally Substituted by: - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -C6 to C8 aryl, optionally substituted by alkoxy; -CORx group, center As defined above; • Cardiac to cardioalkyl, optionally substituted with dialkyl-amine or 5 or 6 membered heterocycle; or

Ri and R2 are joined together to form: ✓

128244-1 -24- 200831489 R is -nitro group, -nitrogen; -halogen; -hydroxyl group; -C! to c6 alkyl group, optionally substituted by one or more _ 素; -amino group; Base, optionally substituted by: - one or more halogen, -OCORx groups, wherein Rx is as defined above, -dialkyl-amine, optionally substituted by alkoxy, -5 or 6 a cyclic group, optionally substituted by a q to C6 leumino group, a 5- or 6-membered heteroaryl group, or a -C6 to C8 aryl group; a -COORx group, wherein Rx is as defined above; -13⁄4 alkyl; Amine groups, optionally substituted by: - thiol, or -c6sc8 aryl; -5 or 6 membered heteroaryl; -OCORx group, wherein Rx is as defined above; -NHCORjj group, wherein Is an alkoxy group, or an -amino group, optionally substituted by one or more q to C6 alkyl groups; 128244-1 -25- 200831489 -ORkk group, wherein Rkk is a 5- to 6-membered heteroaryl group ; --NHS02Rx group, the center of which is as defined above; or R2 and Ri are joined together to form: 〆

R3 is - hydrogen; or CH2OCORx, and Rx is as defined above; or a pharmaceutically acceptable salt thereof. In some specific embodiments of Formula I, X is: -nitro; -lacty, -CORa group, centered at: -^ to decyl, -C6 to C8 aryl, optionally alkoxy Substituted or halogen-substituted, or -dialkylamino, -COORx group, the center of which is (^ to decyl; -carbenyl; -c6 to c8 aryl, optionally substituted by alkoxy; or a -5 or 6-membered heteroaryl, optionally substituted by the following: -^ to decyl, -C6 to C8 aryl, optionally substituted by alkoxy or one or more halogens, 128244-1 -26- 200831489 -5 to 6 membered heteroaryl; Y is: -haloalkyl, -halogen, -amino group, optionally substituted by one or more Ci to c6 alkyl groups; -benzofuran; -benzoquinone p-cetin , - dibenzofuran; - diphenyl hydrazine p-cetin, - benzopyrazine; - hydrazine; hydrazine, optionally substituted with <^ to (6 alkyl) on nitrogen;

Rb wherein Rb is hydrogen or CiSC6 alkyl, and η is 0 or 1;

128244-1 -27- 200831489 1°

N

Wherein is hydrogen, _CONHRx, wherein Rx is as defined above, or -S〇2Rx, where 1 is as defined above; \/d

Its center is ^ to decyl or c6sc8 aryl; f - NHCORe group, wherein Re is: -Ci to Cg alkyl; - 〇6 to C: 8 aryl 'as replaced by the following: -^ to Alkyl, -alkoxy, -cyano, -nitro, or -halo; -NHCOORx group, wherein 1^ is as defined above; -CH2 0-Rf, wherein Rf is c6 to c8 Aryl; - NRgRh group, centered from decyl or hydrogen, and 仏 to aryl, optionally substituted by alkoxy; q to C6 alkyl; -5 or 6 member hetero The base is optionally substituted by the following: -C! to C6 alkyl, optionally substituted by q to q aryl, -C0 to Q aryl, optionally substituted by -C00Rx, centered as above 128244-1 -28 - 200831489 Definitions 'or amine group; -5 or 6 membered heterocyclic ring, optionally substituted by: -COORx group, wherein Rx is as defined above, or -NHCO〇Rx group, the center of which is as defined above -C0 to Q aryl, optionally substituted by one or more of the following groups: - an alkoxy group, optionally substituted by the following: - alkoxy, -hydroxyl, - one or more halogens, -5 or 6 Heterocyclic ring, as the case is replaced by the following · · -Cl a C6 alkyl group, or a hydrazino group, an amine group, optionally substituted by one or more q to c6 alkyl groups, a -NRiS〇2Rx group, wherein the chemical system is as defined above, and the population is: -hydrogen, - 0^ to (6 alkyl, --CORx group, wherein Rx is as defined above, -haloalkyl, or -haloalkoxy, -NRj CORk group, wherein Rk is: alkyl, -hydrogen , or -amino group, optionally substituted by one or more Ci to c6 alkyl groups, 128244-1 -29- 200831489 and Rj is: -hydrogen, -0^ to (:6 alkyl, --CORx group, Wherein rx is as defined above, -haloalkyl, or -haloalkoxy, _-N=N+=N_ group, or --COR! group, wherein & is 5 or 6 membered heterocyclic ring, wish The situation is replaced by a hydroxy group, an amine group, optionally substituted by one or more C! to c6 alkyl groups - 'ci to Q alkyl, optionally substituted by the following: -NHS02 Rx group, wherein rx is as defined above Or an NRX S〇2 Rx group, wherein rx is as defined above as '-haloalkoxy' -halogen, -transcarbyl, -COORx group, wherein Rx is as defined above, -CORm group Wherein Rm is: - an amine group, optionally substituted by one or more q to C6 alkyl groups - or more The q to C6 alkyl group is optionally substituted by the following: _hydroxyl, -5 or 6 membered heterocyclic ring, -amino group, optionally substituted by one or more Cl to C6 alkyl groups - alkoxy group, 128244-1 -30- 200831489 -3 to 7-membered heterocyclic ring, as the case may be (^ to decyl-substituted 'the alkyl group is optionally substituted by a dialkyl-amino group, -NHRn group, wherein Rn is ·· _ -CH2 CONH2, or -c6 to c8 aryl, optionally substituted by the following - alkyl group, - one or more halogens, -nitro group, or one or more alkoxy groups, -_NR〇C〇Rp group a group, wherein ~ is - ci to Q alkyl, optionally substituted by the following - halogen, - alkoxy, or -c6 to c8 aryl, -5 or 6 membered heterocyclic ring, (-C0 to eg fang Base, optionally substituted by halogen, -5 or 6 membered heteroaryl, optionally cleaved into multiple C! to Q alkyl substituted, - hydrogen,

128244-1 200831489 -Cl to C6 alkyl'-CORx group, the center of which is as defined above, -_alkyl group or -halooxy group -NRqCONRqR^• group, wherein Rq is: -hydrogen , -CiSCgalkyl, -haloalkyl-haloalkoxy, or --CORx group, wherein 1 is as defined above, and wherein Rr is: -C6 to C8 aryl, optionally substituted as follows:

-^ to decyl, -13⁄4 alkyl, - 〇Rs group, wherein 匕 is a C6 to C8 aryl group, or a -COORx group, the center of which is as defined above, -q to C6 alkyl, The situation is replaced by one or more of the following groups: _halogen, - sub-alkyl, -c6 to c8 aryl, and / or 128244-1 -32-200831489 -COORx group, the center of which is as defined above, - a -COORx group, the center of which is as defined above, the -NRtCOORu group, the center of which is: -(^ to €12 alkyl, as the case may be replaced by the following: -C6 to C8 aryl, optionally by C! C6 alkyl or alkoxy substituted, -alkylene '-alkoxy' / " -alkyne, -halogen' or -5 or 6 membered heterocyclic ring, -C6 to C8 aryl, optionally replaced by : - alkoxy, -halogen, or -toxin to decyl, or f -5 or 6-membered heterocycle, and Rt is: -氲, -(^ to 仏alkyl, --CORx group, center thereof As defined above, -_alkyl group or -decyloxy, -NRV S〇2 Rw 圑' wherein Rv is -hydrogen, 128244-1 -33 - 200831489 -CORx group, wherein Rx is as above The text, or -qSQ alkyl, is replaced by the following: - alizarin, --CORx , the center of which is as defined above, -OCORx group, the center of which is as defined above, -trans-based, or -alkoxy, and wherein Rw is: -q to C6 alkyl, as the case may be replaced by: Halogen, -haloalkyl, -C6 to c8 aryl, or -5 or 6 membered heterocyclic ring, -〇2 to 0:6 alkyl, -alkyl- or dialkyl-amine, optionally halogen Substituted, -5 or 6-membered heterocyclic ring, or -5 or 6-membered heteroaryl, optionally substituted as follows: -<^ to (:6 alkyl, -5 or 6 beta, or

128244-1 -34- V200831489

_N

〇 -N

NH / l. 〇

•N

NH 〇

Ry

-N

N - Ry ' is optionally substituted by q to c6 alkyl' where $4 to (: 6 alkyl or hydrogen,

:S

N -N

Wherein: is gas or (^ to decyl, optionally substituted by Q to csaryl, SRx is 圏' wherein Rx is as defined above, ^8244^1 -35-200831489 -S02Raa group, wherein Raa is : -(^ to decyl, -amino, -alkyl- or dialkyl-amino, optionally substituted by hydroxy or _c〇〇Rx groups, wherein Rx is as defined above, -5 or 6 a heteroaryl group, a -C6 to C8 aryl group, and/or a -NHRbb group, wherein Rbb is: *

a C(=S)NH2 group, or a -PO(ORx)2 group, the center of which is as defined above; a _- Rcc group, wherein Rcc is: -5 or 6 membered heteroaryl,

Q to C8 aryl, optionally substituted by one or more of the following groups: - alkoxy, - thiol, 128244-1 - 36 - 200831489 - halogen, -c! to c6 alkyl, optionally cyano Substituted, -amino group, optionally substituted by one or more C! to c6 alkyl groups, -NHPORxRx, centered as defined above, -NReeCONRffRff group, wherein Ree is hydrogen or C#C6 alkyl, The situation is replaced by i, and Rff is: - hydrogen, -haloalkyl, -13⁄4 alkoxy, -cardi to decyl, or -CORx group, the center of which is as defined above, -•NRggCORhh group Wherein Rhh is: - hydrogen, -C! to C6 alkyl, optionally substituted by: - alkoxy, -halogen, or -amino, optionally substituted by one or more Ci to c6 alkyl groups, - An amine group, optionally substituted by one or more Ci to c6 alkyl groups, wherein one or more Ci to c6 alkyl groups are optionally substituted by i, -5 or 6 membered heterocyclic rings, -5 or 6 members of heteroaryl And Rgg are: - hydrogen, -Q to c6 alkyl, 128244-1 -37- 200831489 • haloalkyl, -haloalkoxy, or --CORx group, wherein Rx is as defined above, -13⁄4 Acryl group, -5 or 6 membered heterocyclic group, -amino group The condition is replaced by one or more C! to Q alkyl groups, and/or --NRi i S〇2 Rx groups, wherein Rx is as defined above, and &丨 is: -hydrogen, -C〗 to C6 , - haloalkyl, -haloalkoxy, -CORx group, the center of which is as defined above; Z is: -C! to C6 alkyl, optionally substituted by the following: - alkoxy, - Or a plurality of halogens, or -c6 to c8 aryl; -c2 to c6 alkyl; -C: 6 to Cs aryl, optionally substituted by alkoxy or one or more Cl to C6 alkyl; a COORx group whose center is as defined above; or 128244-1 -38- 200831489

R is an anthracene, a halogen or an alkoxy group; Ri is a - a thiol group; - a aryl group, a -13⁄4 alkyl group, a - a aryl group; a -5 or 6 membered heteroaryl group; , optionally substituted by: - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -C6SC8 aryl, optionally substituted by alkoxy; ...CORx group, center Is defined as above; -^ to the cardinyl group, optionally substituted by a dialkyl-amine group or a 5 or 6 membered heterocyclic ring; or & and 112 joined together to form: ✓

128244-1 -39- 200831489 R is -nitro group; -nitrogen; -13⁄4 element; -hydroxyl group; -C1 to C6 alkyl group, optionally substituted by one or more li's; -amino group; -alkoxy Substituents, optionally substituted by: - one or more halogens, -OCORx groups, wherein Rx is as defined above, -dialkyl-amino, optionally substituted by alkoxy, -5 or 6-membered a cyclic group, optionally substituted with Ci to -5-substituted 5- or 6-membered heteroaryl, or -c6 to c8 aryl; -_COORx group, wherein Rx is as defined above; -13⁄4 alkyl; Amine, optionally substituted by: -hydroxy, or -c6 to c8 aryl; -5 or 6 membered heteroaryl; -OCORx group, the center of which is as defined above; -NHCORj group, wherein Rjj is: - alkoxy, or -amino, optionally substituted by one or more Cl to c6 alkyl; 128244-1 -40 - 200831489 • -〇Rk k group 'where Rk k is 5 to 6 Heteroaryl; -NHS〇2 Rx group 'where Rx is as defined above; or R2 is bonded to the core to form:

R3 is: -nitrogen; or -CH2OCORx, and Rx is as defined above; with the proviso that when X is a phenyl group substituted by an alkoxy group, Y is a phenyl group, R is hydrogen, Ri is a halogen, and R2 is hydrogen. And when R3 is hydrogen, and the condition is, when X is a phenyl group, a hydroxyphenyl group or a pyridyl group, γ is an alkyl group, R is hydrogen ' Ri is hydrogen or a radical 'R2 is hydrogen or a radical, and R3 When it is hydrogen, then Z is: -(^ to 匸6 alkyl, substituted by: - alkoxy, - one or more halogen, or -C6 to C8 aryl; -C2 to C6 alkyl; a C6 to C8 aryl group, optionally substituted by an alkoxy group or one or more q to C6 alkyl groups; a COORx group centered as defined above; or 128244-1 -41 - 200831489

Or a pharmaceutically acceptable salt thereof. In some embodiments, X is nitro or cyano. In other specific embodiments, X is cyano. In some embodiments, γ is q to Cs aryl, optionally substituted with one or more of the following groups: - Months, optionally substituted by one or more to C6 alkyl groups, -Ci to C6 Alkyl, optionally substituted by -NHS〇2rx group, --NR〇CORp group, wherein: -Q to C0 alkyl, optionally substituted by: -halogen, or -c6 to c8 aryl, or -5 or 6 membered heterocyclic ring, and wherein R. Is a hydrogen, —NRqCONRqRr group, wherein 1^ is: -hydrogen, or -(^ to decyl, and wherein Rr is C! to C6 alkyl) is optionally substituted by one or the following groups. Halogen, - sub-alkyl, or 128244-1 -42- 200831489 -c6 to c8 aryl, --NRtCOORu group, the center of which is: _Cl to Ci2 alkyl, as the case is replaced by the following · · - 仏 to heart Base, optionally substituted with hydrazine or alkoxy, -alkylene, alkoxy, f-alkyne, -halogen, or -5 or 6 membered heterocyclic ring, -Q to Q aryl , optionally substituted by alkoxy, • 5 or 6 membered heterocyclic ring, and wherein Rt is: • hydrogen, or —<:1 to 〇6 alkyl, _ _NRvS02Rw group, wherein Rv is hydrogen,

And wherein, 匕 to 仏alkyl, as the case is replaced by halogen; 128244-1 -43 - 200831489 ο

Wherein Rz is a CiSQ alkyl group, and/or an NHRbb group, wherein Rbb is a _p〇(〇Rxh group. In a further embodiment, γ is a to Cs aryl, substituted by: -_NRqC〇NRqRr a group, -_NRtCO〇Ru group, -_NRvS02Rw group, or -_NHRbb group, wherein Rbb is a ρ〇(〇Κχ)2 group. C6 to Cs aryl groups may be in the para, meta and/or Substituted in the ortho position. In some specific Bega examples, the 'C:6 to C:8 aryl group is a phenyl group. In other specific embodiments, the C6 to cs aryl group is a phenyl group substituted in the para position. In some embodiments, Y is a phenyl group substituted with a -NRqCONRqRr group in the para position. In other embodiments, γ is a phenyl group substituted with a -NRtCOORu group at the para position. In the examples, γ is 128244-1 -44-200831489 phenyl substituted at the para position by a -NRV S02 Rw group. In still other embodiments, Y is -NHPO(ORx)2 in the para position Substituted phenyl group. In some embodiments, Z is: -C" to c6 alkyl" is optionally substituted with - alkoxy, or - one or more halogens, or -C2 to C6 times base In other specific embodiments, z is q to c6 alkyl. In still other embodiments, Z is a c2 to c5 alkyl group. In still other embodiments, Z is a % butyl, a bad propyl, a ring Propylmethyl, ethyl or cyclopentyl. In some embodiments, R is hydrogen. In some embodiments, R1 is: - hydrogen; - alkoxy, optionally substituted as follows: - or a plurality of halogens, C6 to a square group, or a -5 or 6-membered heterocyclic ring; or R1 and % are joined together to form:

In some embodiments, r2 is: -halogen; 128244-1 -45-200831489 -hydroxyl; -ci to C6 alkyl group optionally substituted with one or more halogens; -amino group; -alkoxy group, optionally Substituted by: — or a plurality of halogens, ... 〇CORx groups, the center of which is as defined above, a -dialkyl-amine group, optionally substituted by an alkoxy group, a -5 or 6 membered heterocyclic group, The case is substituted by Cl to q alkyl -5 or 6 membered heteroaryl, or -C6 to C8 aryl; -COORx group; or R2 and Ri are joined together to form:

In other specific embodiments, at least one of Rii and R2 is hydroxy or alkoxy is optionally substituted by: - or a plurality of halogen '-C6 to C8 aryl, or a -5 or 6 membered heterocyclic group; Or R2 is a -ocorx group '-〇Rkk group, or alkoxy group, substituted by ... OCORx group, 'dialkyl-amine group, optionally substituted by alkoxy group, • 5 or 6 members a cyclic group substituted with a q to C6 alkyl group; or a 128244-1 -46 - 200831489 -5 or 6-shell heteroaryl group. In still other embodiments, φ, d ^ β Du, Nikhan 2 is an -ORk k group, or an alkoxy group is optionally substituted by the following: - a dialkyl group - an amine group is optionally substituted by an alkoxy group, _ 5 or 6 membered heterocyclic group, optionally substituted by a to Q alkyl; or -5 or 6 y heteroaryl. In still a further embodiment, the core is q to q alkoxy, optionally substituted by the following: -5 or 6 membered heterocyclic groups, optionally substituted with q to q alkyl; or -5 or 6 members Heteroaryl. In some embodiments, r3 is hydrogen. In some embodiments, X is cyano; γ is C6 to Cs aryl, substituted by: _-NRqC0NRqRr group, --NRtC00Ru group, ...nrvso2rw group, or --NHP0(0Rx)2 group Z is: _C1 to C6 alkyl, optionally substituted by a-alkoxy, or a plurality of halogens, or • c2 to c6 alkyl; R is hydrogen; 128244-1 -47- 200831489 R! At least one of R2 is a hydroxy or alkoxy group, optionally substituted by: - or a plurality of halogens, - 匸6 to 〇8 aryl, or -5 or 6 membered heterocyclic groups; or & -OCORx a group, a 〇κ^ group, or an alkoxy group, which is substituted by: -OCORx group, -dialkylamino group, optionally substituted by alkoxy group, -5 or 6 membered heterocyclic group, Substituted by q to q alkyl; or -5 or 6 membered heteroaryl; and the heart is hydrogen. In some embodiments, Y is a phenyl group substituted with a _NRtC〇〇Ru group. In a further embodiment, Rt is hydrogen, and Ru is: -(^ to q2 alkyl, optionally substituted with one or more groups independently selected from: -Q to Cs aryl, optionally halogen Substituted, - alkoxy, optionally substituted by one or more alkoxy groups, - the amine group 'optionally substituted by one or more Ci to c6 alkyl groups, - halogen, or -5 or 6 membered heteroaryl, _ C2 to C6 alkyl, -Q to Q aryl, optionally substituted with halogen. In yet a further embodiment, Ru is C! to C6 alkyl. In some embodiments, Y is - a phenyl group substituted with a NTRqCONRqRr group. In the specific embodiment, it is hydrogen, and Rr is · 128244-1 -48- 200831489 6. The elementary group is optionally substituted by one or more of the following groups. - hydroxy, - alkoxy, -5 or 6 membered heterocyclic ring, _ 5 or 6 membered heteroaryl, or -A to c: 8 aryl, optionally substituted by halogen, -C2 to C6 alkyl, - Ci to decyloxy, • 5 or 6 membered heterocyclic group. In still further embodiments, K is Ci to q alkyl. In some embodiments, γ is phenyl substituted with a group. In a further embodiment Wherein Ry is hydrogen and wherein is a to oxime group. In some embodiments, γ is a phenyl group substituted with a -NHP〇(〇Rx)2 group. In some embodiments, Y is a phenyl group substituted at the para position: ... NRqCONRqRr group, --NRtCOORu group, --NRV S02 Rw group, or ...nhpo(orx)2 group; Z is Ci to G alkyl group; and r2 Is an alkoxy group, optionally substituted by the following: -5 or 6 membered heterocyclic group, optionally substituted with a C6 alkyl group, or 128244-1 -49 - 200831489 -5 or 6 membered heteroaryl. In a particular embodiment, the compound of formula I is not compound 1. In yet another embodiment, the invention includes the following compounds: 1. A compound of formula I

Wherein: X is: -nitro group; -cyano; ...C〇Ra group, wherein ^ is: - heart to decyl group, -c6 to c8 aryl group, optionally substituted by alkoxy or _ s, or "monoalkyl-amino; %C〇〇Rx group, the center of which is ^ to ^alkyl; -methanoyl; • to Q aryl, optionally substituted by alkoxy; or 5 or 6- A heteroaryl group, optionally substituted by the following: -01 to 〇6 alkyl, -C6 to csaryl, optionally substituted by alkoxy or one or more halogens, or ^8244-1 -50- 200831489 - 5 to 6 membered heteroaryl; Y is: -_alkyl, -13⁄4, -benzofuran; -benzopyrene; -dibenzofuran; -diphenyl sulfonate, / \ -benzopyrene Azole; -na, -啕哚, as the case may be replaced by nitrogen

, (CH2)n \ where Rb is nitrogen or Ci to C6 alkyl' and n is ° or 1;

Definition, or -S02Rx, where Re is hydrogen, -CONHRx is centered as defined above; its center is as above or 128244-1 -51 - 200831489

- The center is 匸丨. Alkyl or c6sc8 aryl; --NHCORe group, wherein Re is: -(^ to (:6 alkyl; -C:6 to csaryl) is optionally substituted by the following: alkyl, -alkoxy, - cyano, -nitro, or -halogen; -NHCOORx group, wherein Rx is as defined above; -CH2〇-Rf group, wherein Rf is q to q aryl; -NRgRh group' Rg is hydrogen or (^ to ^alkyl, and is converted to hydrogen or ^ to Q aryl, optionally substituted by alkoxy; -^ to decyl; -5 or 6 membered heteroaryl, optionally as follows Substituted: -Ci to C6 alkyl, optionally substituted with: (6 to (8 aryl), -c0 to q aryl, optionally substituted by _C00Rx, centered as defined above, or -amino group; a 5- or 6-membered heterocyclic ring, optionally substituted by the following: -COORx group, the center of which is as defined above, or the -NHCOORx group, the center of which is as defined above; 128244-1 -52- 200831489 -q to The qaryl group, optionally substituted by one or more of the following groups, is an alkoxy group, optionally substituted by the following: - alkoxy, -hydroxyl, - one or more halogens, -5 or 6 membered heterocyclic ring , as the case may be replaced by: a Ci to C6 alkyl, or - Base, Γ % -amino, optionally substituted by one or more q to c6 alkyl, -NRiS02Rx groups, wherein rx is as defined above, and the team is: - hydrogen, -C! to C6 alkyl, a -CORx group, wherein Rx is as defined above, -haloalkyl, or -haloalkoxy, /CORk group' wherein Rk is: v -cardi to decyl, -hydrogen, or -amine, Optionally substituted by one or more Ci to c6 alkyl groups, and Rj is: -hydrogen, -cardi to decylalkyl, _-CORx group, wherein 1^ is as defined above, -haloalkyl, or 128244- 1 •53- 200831489 -haloalkoxy, -_N=N+ =N_ group, or --COR丨 group, wherein Ri is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group, • an amine group 'as appropriate Substituted by one or more Ci to C6 alkyl groups, -Ci to C6 alkyl, optionally substituted by the following -NHS〇2Rx group, wherein Rx is as defined above, or --NRxS〇2Rx group, Its center is as defined above, -13⁄4 alkoxy, -halo, -hydroxyl, -COORx group, the center of which is as defined above, ...CORm group, wherein Rm is: -amine group, optionally as a case Multiple to phantom substitutions, one or more of Ci The c6 alkyl group is optionally substituted by the following: -hydroxyl, -5 or 6 membered heterocyclic ring, -amino group, optionally substituted by one or more Ci to c6 alkyl groups, -alkyloxy group, -3 to 7 members A ring, optionally substituted with an alkyl group, optionally substituted by a dialkyl-amine group, a -NHRn group having a center: ...CH2 C〇NH2, or -C6 to aryl, Substituted as follows: 128244-1 -54· 200831489 - alkyl, - one or more halogen, -nitro" or - one or more alkoxy groups, -NRQCORp group, where Rp is: -q To C6 alkyl, as the case may be replaced by: _halogen, - alkoxy" or

-c6 to c8 aryl, -5 or 6 membered heterocyclic ring, -c6 to c8 aryl group, optionally substituted by i, -5 or 6 membered heteroaryl, optionally with one or more Ci to C6 alkyl groups take

And where R. Is: - hydrogen, -(^ to decyl, -CORx group, wherein 1 is as defined above, _haloalkyl, or -1⁄4 alkyloxy'-NRqCONRqF^• group, wherein Rq is: 128244-1 -55- 200831489 - hydrogen, -^ to decyl, -haloalkyl, -haloalkoxy, or --CORx group, wherein Rx is as defined above, and wherein Rr is: -Q to C8 aryl, as the case may be replaced by:

-(^ to (6 alkyl, -haloalkyl, --ORs group, wherein Rs is q to q aryl, or --COORx group' wherein rx is as defined above, -Q to Q alkyl And optionally substituted by one or more of the following groups: a halogen, a -alkyl group, a -C6 to C8 aryl group, and/or a -COORx group, wherein Rx is as defined above, ... a COORx group, wherein Rx is as defined above, ... NRtCOORu group, the center of which is ... - (: 丨 to heart 2 alkyl, as the case is replaced by _C0 to Q aryl, as the case is ^ to ^ alkyl or alkoxy Base: 128244-1 -56- 200831489 generation, - sub-alkyl group - alkoxy, - alkyne, - _' or -5 or 6 member heterocyclic ring, -C6 to C8 aryl, optionally replaced by · · _ hospital oxy ' -halogen, or -toxin alkyl, or -5 or 6-membered heterocyclic ring, and Rt is: - hydrogen, -^ to decyl, -CORx group, its center As defined above, a -haloalkyl or -halooxy"-NRvS02Rw group centered at: -hydrogen, -CORx group, centered as defined above, or -q to C6 alkyl, Substituted as follows: - Halogen, -CORx group, centered as defined above - OCORx group, the center of which is as defined above, 128244-1 -57- 200831489 - via a base 'or - alkoxy" and wherein Rw is: -q to C6 alkyl, as appropriate substituted by: - halogen , -13⁄4 alkyl, -c6 to c8 aryl, or • 5 or 6 membered heterocyclic ring, -C2 to C6 alkyl, -homo- or dialkyl-amino, optionally substituted by halogen, -5 Or a 6-membered heterocyclic ring, or a -5 or 6-membered heteroaryl group, optionally substituted by the following: -(^ to (:6 alkyl, -5 or 6 membered heterocyclic ring, or

128244-1 -58- 200831489

Substituted by q to a alkyl group, wherein Ry $ q to c6 alkyl or hydrogen

O /Rz II / N

〇=s I

Wherein Rz is hydrogen or (^ to (6 alkyl, optionally substituted by C6sC8 aryl, ...SRX group' wherein is as defined above, ... S02Raa group, wherein Raa is: -^ to decyl, &quot Amine 5 • alkyl- or dialkyl-amine, optionally substituted by hydroxy or _c〇〇 group, wherein Rx is as defined above, • 5 or 6 membered heteroaryl, 128244-1 - 59- 200831489 _C6 to C: 8 aryl, and / or - _NHRbb groups, * where:

a C(=S)NH2 group, or a ...P〇(〇Rx)2 group, the center of which is as defined above; =Rcc group, wherein Rcc is: -荇, -5 or 6 membered heteroaryl,

_ C: 6 to csaryl, as the case may be substituted by one or more of the following groups: - alkoxy, -hydroxy, -halogen, -(^ to (6 alkyl, optionally substituted by cyano, - Amine, optionally substituted by one or more Ci to c6 alkyl groups, -NHPORxRx, wherein Rx is as defined above, _-NReeCONRffRff group 'where Ree is hydrogen or (^ to (6 alkyl, optionally) Substituted by halogen 'and Rff is: 128244-1 -60- 200831489 - hydrogen, -haloalkyl, -_alkoxy, -4 to fluorene: 6 alkyl, or --CORx group, wherein rx is as above Definitions, -NRggCORhh group, wherein Rhh is: - hydrogen, -G to C0 alkyl, optionally substituted by: - alkoxy, -halogen, or -fe-based as appropriate by one or more Ci Cg alkyl substituted-amino group, optionally substituted by one or more Cl to c6 alkyl groups, wherein one or more Ci to c6 alkyl groups are optionally substituted by halogen - 5 or 6 membered heterocyclic ring, -5 or 6 a heteroaryl group, and Rgg is: -hydrogen, -C to c6 alkyl, - arylalkyl, -haloalkoxy, or -C〇Rx group, wherein lanthanide is as defined above, -haloalkyl , -5 or 6 membered heterocyclic group, -amino group, as the case may be (^ to 仏alkyl substitution, and/or 128244-1 -61 - 200831489 -NRhSC^Rx group, wherein Rx is as defined above, and Rii is: - hydrogen, - heart to decyl, -_ An alkyl group, a hydrazine oxy group, a -CORx group, wherein 1^ is as defined above; a -q to C6 alkyl group, optionally substituted by the following: - alkoxy, - or a plurality of halogens, or - C6SC8 aryl; -c2 to c6 alkyl; -Q to C:8 aryl, optionally substituted by alkoxy or one or more q to c6 alkyl;

a COORx group whose center is as defined above; or R is hydrogen, a halogen or an alkoxy group; h is: - hydrogen; - a hydroxyl group; - a halogen; 128244-1 - 62 - 200831489 - a halogen group; - 5 or 6 membered heteroaryl; -5 or 6 membered heterocyclic ring; - alkoxy group 'substituted as follows · · " or multiple halogens, f -C6 to c8 aryl, or -5 or 6 membered heterocyclic ring; -Q to C:8 aryl group, optionally substituted by alkoxy group; ...CORx group, the center of which is as defined above; • ^ to decyl group, optionally dialkyl-amino group Or a 5- or 6-membered heterocyclic ring;

Ri is joined together to form:

/0, / R2 is - stone succinyl; - chloro; - halogen; - hydroxy; -q to c6 alkyl, optionally substituted by one or more halogen-amino groups; - alkoxy groups are optionally replaced by the following: 128244 -1 -63 - 200831489 - one or more halogen, -OCORx groups, the center of which is as defined above, -dialkyl-amino, optionally substituted by alkoxy, -5 or 6 membered heterocyclic a group, optionally substituted by a q to q alkyl group -5 or 6 membered heteroaryl, or a -C6 to C8 aryl group; -COORx group, the center of which is as defined above; - anthracenyl; 'Substituted as follows: -hydroxyl, or -C6 to C8 aryl; -5 or 6-shell heteroaryl;

- an alkoxy group, or an amine group 'optionally substituted with one or more Ci to c6 alkyl groups; -ORk k group, wherein Rk k is a 5 to 6 membered heteroaryl group;

R3 is 128244-1 -64-200831489 -CH2〇CORx, and Rx is as defined above; the condition is, when X is a phenyl group substituted by an alkoxy group, γ is a phenyl group, R is a hydrogen, and Ri is a halogen. When R 2 is hydrogen and r 3 is hydrogen, and when X is a phenyl 'hydroxyphenyl or pyridyl group, γ is an alkyl group, R is hydrogen, Ri is hydrogen or a hydroxyl group, and & is hydrogen or a hydroxyl group. And when r3 is hydrogen, then Z is: -(^ to (6 alkyl, substituted by: alkoxy, - one or more halogen, or -C6SC8 aryl; -c2 to c6 alkyl; - a C0 to Q aryl group, optionally substituted by an alkoxy group or one or more Ci to Q alkyl groups; a COORx group, wherein rx is as defined above;

Or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1, wherein X is nitro or cyano. 3. The compound of embodiment 1, wherein X is a cyano group. 4. A compound according to embodiment 1, wherein Y is a C6 to C8 aryl group, optionally substituted by one or more of the following groups: - an amine group, optionally substituted by one or more C! to C6 alkyl groups , 128244-1 -65- 200831489 -C^c6 alkyl, optionally substituted by _nhs〇2Rx group, --NRoCORp group, wherein Rp is: -Q to Q alkyl, as the case may be replaced by: - Halogen, or -C6 to c8 aryl, or -5 or 6 membered heterocyclic ring, and wherein R. Is a hydrogen, ... NRqCONRqRr group, the center of which is: - nitrogen, or - (^ to 〇: 6 alkyl, and wherein Rr is a C1 to C6 alkyl group, optionally substituted by one or more of the following groups: ι _ Halogen, -alkylidene, or -c6 to c8 aryl, ~NRtCOORu group, wherein: _Cl to Cl2 alkyl, as appropriate substituted by: -C6 to Q aryl, optionally Ci to C6 alkane Substituted or alkoxy substituted, -alkylene, '•alkoxy, alkyne, halogen, or 5- or 6-membered heterocyclic ring, 128244-1 -66 - 200831489 optionally substituted by alkoxy -06 To (8 aryl-5 or 6 membered heterocyclic ring and wherein Rt is: -hydrogen, or -CiSC6alkyl r' wherein Rv is hydrogen and wherein Rw is q to C6 alkyl, optionally substituted by halogen 〇- Nrvso2rw group

Z P

128244-1 -67- 200831489 The center thereof is a ^^ to ^alkyl group, and/or a -NHRbb group, wherein Rbb is a -P〇(〇Rx)2 group. 5. The compound of embodiment 4, wherein γ is a Q to Cs aryl group, substituted by: -NRq CONRq Rr group, -NRtCOORu group, -NRvS〇2Rw group, or --NHRbb group Wherein Rbb is a -PO(ORx)2 group. < 6. The compound of embodiment 5, wherein the <^ to 〇8 aryl group is a phenyl group. 7. The compound of embodiment 6 wherein the phenyl group is substituted in the para position. 8. The compound of embodiment 7, wherein Y is phenyl substituted by a -NRqCONRqRr group at the para position. 9. The compound of embodiment 7, wherein Y is phenyl substituted by a -NRtCOORu group in the para position. 10. The compound of embodiment 7, wherein Y is phenyl substituted by a -NRvS02Rw group in the para position. 11. The compound of embodiment 7, wherein Y is phenyl substituted in the para position with a -NHPO(ORx)2 group. 12. The compound of embodiment 1, wherein Z is: - heart to decyl, optionally substituted by the following - alkoxy, or - one or more halogens, or -C2SC6 alkyl. 128244-1 -68- 200831489 13. The compound of embodiment 1, wherein Z is C! to C6 alkyl. 14. The compound of embodiment 13 wherein Z is -c2 to C5 alkyl. 15. The compound of embodiment 14, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl. 16— The compound of embodiment 1, wherein R is hydrogen. 17. The compound of embodiment 1, wherein R1 is: - hydrogen; - alkoxy, optionally substituted as follows:

C - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic rings; or Ri and R2 are joined together to form:

18. Specific embodiments! a compound wherein & is: - hydrogen; - halogen; - hydroxy; - G to Q alkyl group is optionally substituted with one or more _ mers; - amine group; - alkoxy group is replaced by the following: - one or more halogen, -OCORx groups, the center of which is as defined above, 128244-1 -69 - 200831489 -dialkyl-amino group, optionally substituted by alkoxy group, -5 or 6 membered heterocyclic ring The group 'as the case may be. to. Alkyl substituted, -5 or 6 membered heteroaryl, or -C6 to c8 aryl;

-COORx group; or R2 and R are bonded together to form a compound of the specific embodiment, wherein: 2, y to y are a trans group or an alkoxy group, and are optionally replaced by the following - One or more halogen, -C6 to C8 aryl, or -5 or 6 membered heterocyclic group; or R2 is a -ocorx group, -0Rkk group, or alkoxy group, substituted by -_〇CORx group a group, a dialkyl-amino group, optionally substituted by an alkoxy group, a -5 or an anthracene heterocyclic group, substituted with an alkyl group; or a -5 or 6 membered heteroaryl group. The compound of Embodiment 19, wherein & is an alkoxy group, optionally substituted by the following: -5 or 6 membered heterocyclic group, optionally substituted by q to q alkyl; or -5 or 6 members Heteroaryl. 21. The compound of embodiment 20, wherein the center is a ^ alkoxy group, 128244-1 - 70 - 200831489 is optionally substituted by the following: _ 5 or a heterocyclic oxime, wishing to be a Cl to C6 alkyl group Substituted, or -5 or 6 membered heteroaryl. 22. The compound of embodiment 1, wherein R3 is hydrogen. 23. The compound of Specific Example 1 wherein: X is a cyano group; Y is a C6 to C8 aryl group, which is substituted by the following: _-NRqC〇NRqRr group, f \ X -_NRtCO〇Ru group, --NRV S 〇2 Rw group, or --NHPO(〇Rx)2 group; Z is: -Ci to c6 alkyl, optionally substituted by the following - alkoxy, or - one or more halogens, or -c2 to (: 6-alkyl; R is nitrogen;

At least one of Ri and & is a hydroxy or alkoxy group, optionally substituted by the following - or a plurality of halogens, -C6 to C8 aryl, or a -5 or 6 membered heterocyclic group; or & is -OCORx group a group, an -ORkk group, or an alkoxy group, which is substituted by -OCORx group, -dialkyl-amino group, optionally substituted by alkoxy group, 128244-1 •71 · 200831489 -5 or 6 members a heterocyclic group substituted with q to C6 alkyl; or a -5 or 6 membered heteroaryl; and R3 is hydrogen. The compound of Example 23, wherein Y is a phenyl group substituted with a -NRq CONRq Rr group. 25. The compound of embodiment 24, wherein: 2 is 4 to (6 alkyl; and 2 is an alkoxy group, optionally substituted by the following: -5 or 6 membered heterocyclic groups, optionally as q C6 alkyl substituted; or -5 or 6 membered heteroaryl. 26. The compound of embodiment 23, wherein Y is phenyl substituted with a -NRtCOORu group. 27. The compound of embodiment 26, wherein: 2 is <^ to (:6 alkyl; and & is alkoxy, optionally substituted by: • 5 or 6 membered heterocyclic group, optionally substituted by C to C6 alkyl; or -5 or 6 28. The compound of embodiment 23, wherein Y is phenyl substituted with a -NRv S〇2 Rw group. 29. The compound of embodiment 28 wherein Z is ci to C6 alkyl; And h is alkoxy, optionally substituted by the following: -5 or 6 membered heterocyclic group, optionally substituted by Ci to C6 alkyl; or -5 or 6-shell heteroaryl. 128244-1 • 72- 200831489 The compound of Embodiment 23, wherein Y is a _NHP0(0Rx)2 group. 31. A compound according to Example 3, wherein: Z is ci to C6 alkyl; and is converted to an alkoxy group, Replaced by the following as appropriate: a -5 or 6 membered heterocyclic group, optionally substituted with (^ to decylalkyl; or -5 or 6 membered heteroaryl. 32. A compound of embodiment 1, wherein: X is: "cyano; Or -methanoyl; Y is: _ 5 or 6 membered heteroaryl, optionally substituted by c6 to C8 aryl, which is optionally substituted by -COORx, wherein Rx is as defined above; -& Cs aryl, optionally substituted by one or more of the following groups: -^ to ^alkyl; -amino, optionally substituted by one or more q to C6 alkyl; -halogen; -hydroxyl; -CORm a group wherein Rm is: - an amine group, optionally substituted by one or more (^ to a decyl group; -NR.CORp group, wherein: -Q to C6 alkyl, optionally alkoxy And wherein R. is: - gas; 128244-1 -73- 200831489 -NRqCONRqRr group, wherein Rq is hydrogen, and wherein Rr is: -CiSC6 alkyl; -NRtCOORu group, wherein Rt is hydrogen, And wherein Ru is: -CiSCualkyl, optionally substituted by: -C6 to C8 aryl; -halogen; or -5 or 6 membered heterocyclic ring; -NRvS02Rw group, wherein Rv is hydrogen, and wherein Rw is : -(^ to 仏alkyl; or -alkyl- or secondary Base-amine group;

〇

Wherein Rz is hydrogen or (^ to decyl; -S02Raa group, wherein Raa is: -amino, or -alkyl or dialkylamino; -NHRb b group, wherein Rbb is: -PO (ORx)2 group, the center of which is as defined above; 128244-1 -74-200831489 z is: -^ to ^alkyl; or -COORx group, the center of which is as defined above; R is hydrogen,

Ri is - nitrogen, -5 or 6 membered heterocyclic ring; - alkoxy group, optionally substituted by the following: f - one or more halogens; or -5 or 6 membered heterocyclic rings; R] is - rat, - a hydroxy group; a -q to C6 alkyl group, optionally substituted by one or more halogens; an alkoxy group, optionally substituted by: - one or more halogens; ί -5 or 6 membered heterocyclic groups, optionally Substituted by q to C6 alkyl; or -5 or 6 membered heteroaryl; -COORx group, the center of which is as defined above; - amidino group; -5 or 6 membered heteroaryl; or - 〇Rkk a group wherein Rkk is a 5 to 6 membered heteroaryl; and R3 is a nitrogen. 33. The compound of embodiment 32, wherein: 128244-1 -75- 200831489 χ is cyano; γ is: -C6 to C:8 aryl, substituted by one or more of the following groups: - an amine group, The situation is substituted by one or more q to c6 alkyl; -NRqCONRqRr groups, wherein Rq is hydrogen, and wherein Rr is: -alkyl; -NRtCOORu group, wherein Rt is hydrogen, and wherein & -CiSC!2 alkyl, optionally substituted by: -C6SC8 aryl; -NRvS〇2Rw group, wherein Rv is hydrogen, and wherein Rw is: -Cl to C6 alkyl; R is hydrogen, I is hydrogen; R is - an alkoxy group, optionally substituted by the following: - one or more halogens; - 5 or 6 membered heterocyclic groups, optionally (^ to ^ alkyl Substituent; -5 or 6 membered heteroaryl; or R3 is nitrogen. 34. The compound of embodiment 32, wherein: X is cyano; Y is: -C0 to Q aryl, by one or more of the following groups Substituted: 128244-1 -76 - 200831489 -Heart to decylalkyl; -Amino group, optionally substituted by one or more (^ to decyl group; -halogen; -NRtCOORu group, wherein Rt is hydrogen, and Its center is: - (: 丨 to heart? alkyl; --NRV S〇2 Rw group 'wherein Rv is hydrogen, and wherein: -(^ to decylalkyl; or -alkyl- or dialkyl-amine; (2 is (^ to (:6 alkyl; R R is hydrogen; R 2 is a -ORkk group, wherein Rkk is a 5- to 6-membered heteroaryl; R 3 is hydrogen. 35. A compound of embodiment 32, wherein: X is: -cyano; i γ Is: -Q to Q aryl, substituted by one or more of the following groups: - (: fluorenyl to decyl; - halogen; - NRtCOORu group, wherein Rt is hydrogen, and wherein % is ·· -qscu Alkyl; --NRV S〇2 Rwyl 圑' wherein Rv is hydrogen and its center is: -Heart to decylalkyl; or 128244-1 -77·200831489 -alkyl- or dialkyl-amino group, Or --NRqCONRqRr group, wherein Rq is hydrogen, and wherein Rr is: -(^ to decyl; Z is: -cardi to decyl; R is: -hydrogen,

Ri is: - nitrogen, R 2 is - alkoxy, optionally substituted by: - one or more halogens; - guanamine; -ORkk group, wherein Rkk is a 5 to 6 membered heteroaryl; or 5 or 6 members of heteroaryl; R3 is · - hydrogen. 36. The compound of embodiment 35, wherein: X is: -cyano, Y is: -c6 to c8 aryl, substituted by one or more of the following groups: - alizarin, -NRtCOORu group, wherein Rt Is hydrogen, and wherein Ru is · 128244-1 -78 - 200831489 - (^ to ^? alkyl; or -NRV S〇2 Rw group, wherein Rv is hydrogen, and its center is: -q to C6 Alkyl; Z is: -^ to ^alkyl; R is -hydrogen, R! is

\ -Nitrogen; R2 is: --ORkk group, wherein Rkk is a 5- to 6-membered heteroaryl; R3 is a hydrogen-hydrogen. 37. The compound of embodiment 36, wherein the aryl group is a phenyl group. 38. The compound of embodiment 37, wherein the phenyl group is substituted in the para position. 39. The compound of embodiment 38, wherein : Y is: - a phenyl group substituted by a -NRtCOORu group, the center of which is, 卜, 且 and wherein: (^ to (: 12 alkyl. 40. The compound of the specific example 38, wherein: Y is: Wherein Rt is hydrogen, and the phenyl group substituted with a halogen and -NRtCOORu* group has a center (:1 to (:12 alkyl group. 128244-1 -79-200831489 41 - a compound of the specific example 38, wherein Y is: a phenyl group substituted by a _NRV S〇2 core group, wherein hydrogen is a heart to a decyl group. 42. The compound of embodiment 38, wherein ·· Y is: and wherein Rw - is (^ to a phenyl group substituted with a -NRtCOORu group, wherein ^ is hydrogen, and wherein Ru is: (^ to (: 12 alkyl. 43. The compound of embodiment 35, wherein: X is: • a gas group; Y is: - a Q to C8 aryl group substituted with a -NRtCO〇Ru group wherein Ru is Ci to C! 2 alkyl. 2 is: 'where \ is hydrogen, and -ci to c6 alkyl; the reverse is: hydrogen玟1 is: - hydrogen; Han 2 is: - alkoxy, optionally substituted by: - one or more halogens; inverse 3 is: 128244] -80- 200831489 - hydrogen. 44. Compound-substituted alkoxy group. 45. Compound 46 of Example 43. Compound of Example 45. 47. Compound X of Example 35 is: - a gas group, wherein R2 is one or more仏 wherein 仏 to aryl is phenyl. wherein the phenyl is taken in the para position: Y is -C6 to C; 8 is based on one or more of the following groups - NRtCOORu group, the center Is hydrogen, -(^ to (:12 alkyl; group substituted: and wherein Ru is a --NRq CONRq Rr group, wherein r is a gas-C! to a C6 alkyl group; and wherein 1 is:

Z is ···〇^ to 〇: 6 alkyl; R is ··-hydrogen, is hydrogen-hydrogen; R2 is: -5 or 6-membered heteroaryl; R3 is · 128244-1 200831489 - hydrogen. 48. The compound of Embodiment 47, wherein the Q to q aryl group is a phenyl group. 49. The compound of embodiment 48, wherein the stupid base is substituted in the para position. 5. The compound of embodiment 49, wherein: Y is: and wherein Ru

a phenyl group substituted with a -NRtCOORu group, wherein R is a therapeutic group of Ci to Ci 2 . 51. The compound of embodiment 49, wherein: Y is: wherein Rq is hydrogen, • c0 to & aryl substituted by the -NRqCONRqRr group and the center of which is ^ to decyl. 52. The compound of embodiment 35, wherein: X is: - cyano; Y is: • Q to q aryl substituted by -NRtC〇〇Ru group wherein Ru is cjCl2 ray; " where & Hydrogen, and Z is: _(::1 to €6 alkyl; R is ··-hydrogen, Ri is: 'hydrogen; 128244-1 •82- 200831489 r2 is ···-decylamine; R3 is ··· 53. The compound of Embodiment 52, wherein the aryl group is a phenyl group. 54. The compound of Embodiment 53 wherein the phenyl group is substituted in the para position. 55. The compound of Example 35, The center is: an alkoxy group substituted by one or more halogens. 56. The compound of Embodiment 35, wherein the compound is: _〇Rkk group, wherein Rk k is 5 to 6 shell heteroaryl. The compound of embodiment 32, wherein X is: - formic acid; Y is: -Q to Q aryl, substituted by one or more of the following groups: -NRt COORu group 'where Rt is hydrogen, and wherein尺为··〇1 to (:12 alkyl; --NRq CONRq Rr group' wherein Rq is hydrogen, and wherein the reverse is -^^ to decyl; Z is ·· " Ci to C6 alkyl; R is: - hydrogen; 128244-1 -83 - 2008 31489

Ri is · -chloro, R 2 is - alkoxy; R3 is - hydrogen. 58. The compound of embodiment 32, wherein: X is: - a gas group; Y is: a -c6 to c8 aryl group, substituted by one or more of the following groups: - cardinyl to decyl; _, - An NRtCOORu group, wherein Rt is hydrogen, and wherein Ru is: -(^ to (^12 alkyl, optionally substituted by the following: -C6SC8 aryl; -NRvS02Rw group, wherein Rv is hydrogen, and wherein Rw is : -〇 to (:6 alkyl; or -alkyl- or dialkyl-amino, 〇

Z is: -CiSCs alkyl; 128244-1 -84- 200831489 R is: ~ ml, R! is -SL, R2 is: - alkoxy substituted by one or more halogens; R3 is - hydrogen. r % 59. The compound of embodiment 32, wherein X is: - a gas group; Y is: a -c6 to c8 aryl group, optionally substituted with one or more of the following groups: - NRQCORp group, wherein Rp is: -q to C6 alkyl, optionally substituted by alkoxy; and its center is: / .SL, Z is: -Cl to alkyl, R is: - rat,

Ri is · - hydrogen; R is · 128244-1 -85- 200831489 Alkoxy substituted by 5 or 6 membered heteroaryl; inverse 3 is: hydrogen. 60. The compound of embodiment 32, wherein: X is: '• cyano; ¥ is: C6 to csaryl, optionally substituted with one or more of the following groups: - cardinyl to decyl; , as the case may be, by one or more < ^ to (: 6 alkyl substitution; - halogen; ... NR. C0RP group, wherein RP is: • ^ to decyl; and wherein R is: - hydrogen; a -NRq CONRq Rr group, wherein is hydrogen, and wherein han r is: -(^ to decyl; -NRt COORu group, wherein Rt is hydrogen, and wherein the ruth is -CiSC12 alkyl; ...NRvS〇 a 2Rw group, wherein rv is hydrogen, and its center is --heart to decyl; -NHRb b group 'wherein Rbl^: --PO(ORx)2 group, wherein Rx is as defined above : ' ^8244-1 86- 200831489 -(^ to 仏alkyl; R is: -hydrogen,

Ri is - hydrogen; R2 is: -5 or 6 membered heteroaryl; R3 is: - hydrogen. 61. The compound of embodiment 32, wherein: X is: -cyano; Y is: -A to Q aryl, optionally substituted with one or more of the following groups - an amine group, optionally as the case may be a plurality of q to C6 alkyl substituted; ... NRqCONRqRr groups, wherein Rq is hydrogen, and wherein Rr is: -Ci to alkyl; -NRtCOORu group, wherein Rt is hydrogen, and the center thereof is: -C! C: 2 alkyl, optionally substituted by: -Cg to Cg square; or -5 or 6-membered heterocyclic ring; -NRvS〇2Rw group, wherein & is hydrogen, true where rw is: -Ci to Burning base; 128244-1 -87- 200831489

Wherein Rz is hydrogen or (^ to cardinyl; Z is: -Ci to C6 alkyl, R is -hydrogen,

Ri is a -5 or 6-membered heterocyclic ring; - alkoxy, substituted by: - one or more dentates; or -5 or 6-membered heterocycles;

R2 is - rat and R3 is - hydrogen. 62. The compound of embodiment 61 wherein & is a 5 or 6 membered heterocyclic ring. 63. The compound of embodiment 61 wherein & is an alkoxy group substituted by one or more halogens. 64. The compound of embodiment 61, wherein: 128244-1 -88-200831489 γ is: -C6 to aryl, substituted by: -NRtCO〇Ru group, centered on hydrogen, and wherein Ru is: Ci to ci 2 alkyl, optionally substituted by the following: -c6 to c8 aryl; or -5 or 6 membered heterocyclic;

Ri is: - an alkoxy group substituted by one or more halogens. 65·Formula Ilia compound

Wherein: X is: - gas; Y is: -Q to C: 8 aryl, optionally substituted by one or more of the following groups: _-NRqC〇NRqRr group, wherein Rq is hydrogen, and its center is: -qSQ alkyl; -NRtC00Ru group, wherein Rt is hydrogen, and its center is: alkyl; -NRvS〇2Rw group, wherein Rv is hydrogen, and its center is: 128244-1 -89- 200831489 - Ci to the base, z is: -Cl to C6, R is: - hydrogen,

Ri is · · - rat, R is - alkoxy, optionally substituted by: - one or more halogens; or - 〇Rkk group, wherein Rkk is a 5- to 6-membered heteroaryl; R3 is · - Hydrogen. 66. The compound of embodiment 65, wherein: X is: -nitrogen, Y is: - a C6SC8 aryl group substituted with a -NRtCOORu group, wherein Rt is hydrogen, wherein Ru is (^ to (^2 alkyl; Z For: -(^ to 仏alkyl; R is: - hydrogen,

Ri is. 128244-1 -90- 200831489 - Hydrogen; R_2 is a -〇Rk k group, wherein Rkk is a 5- to 6-membered heteroaryl; R3 is a chlorine. 67. The compound of embodiment 65 wherein the fluorenyl to aryl group is phenyl. 68. The compound of embodiment 65 wherein the phenyl group is substituted in the para position. (69) A pharmaceutical composition comprising: (0 compound of formula I

Wherein: X is: - triphenyl; - gas group; - CORa group, wherein hydrazine is: - (^ to decyl, • Q to Q aryl 'optionally substituted by alkoxy or halogen, or - a dialkyl-amino group; a C〇〇Rx group having a center of ^ to ^alkyl; 128244-1 •91 - 200831489 -methanoyl; -C6 to Cs aryl, optionally substituted by alkoxy Or a -5 or 6-membered heteroaryl, optionally substituted by the following: ... C1 to C6 alkyl, _C6 to c8 aryl, optionally substituted with alkoxy or one or more aryl or • 5 to 6 members Heteroaryl; Y is: -haloalkyl; -halogen; -amino group, optionally substituted by one or more Cl to c6 alkyl groups; -benzopyran; -benzobenzophenone; -dibenzofuran - dibenzopyrene; - benzo far; sit; - naphthalene; 嗓 'optionally on the nitrogen (^ to decyl group;

Wherein Rb is hydrogen or C^C6 alkyl, and η is 〇 or 1; 128244-1 • 92- 200831489

Wherein is the mouse '-CONHRx' where Rx is as defined above or -S02 Rx ' where Rx is as defined above; or 〇

The center is a heart to a decyl group or a 06 to (8 aryl group)--NHCORe group, wherein Re is: -(^ to decyl group; -C6 to c8 aryl group, which is optionally replaced by the following: -( ^ to alkranyl, -alkoxy, -cyano, -nitro, or -halogen; -NHC00Rx group, wherein Rx is as defined above; -CH2〇-Rf group, wherein Rf is q to a NRgRh group, wherein Rg is q to C6 alkyl or hydrogen, and Rh is <:6 to (8 aryl, optionally substituted by alkoxy; -Ci to q alkyl; -5 or 6 membered heteroaryl, as the case may be replaced by: 128244-1 -93- 200831489 -Cl to A hospital base, optionally substituted by q to C8 aryl, -C6 to cs aryl, as the case may be - a C00Rx substitution wherein Rx is as defined above, or -amino; -5 or 6 membered heterocycle, optionally substituted by: -COORx group, as defined above, or -NHCO〇Rx group, The center is as defined above; -C6 to Q aryl, optionally substituted by one or more of the following groups: - a hospitaloxy group, optionally substituted by the following: • alkoxy, - thiol, - one or more Halogen, -5 or 6-membered heterocyclic ring, as the case may be replaced by the following: -C To C6 alkyl, or -hydroxyl, -amino, optionally substituted by one or more C! to C6 alkyl, -NRiS02Rx groups, the center of which is as defined above, and Ri is: -hydrogen, -Q To a c6 alkyl group, a _-CORx group, wherein Rx is as defined above, -alkyl, or -haloalkoxy, -NRjCORk group, wherein Rk is: -(^ to decyl, 128244- 1-94-200831489 - Hydrogen, or -amino group, optionally substituted by one or more Ci to q leumino, and Rj is: - hydrogen, -c!sc6 alkyl, -CORx group 'where rx is As defined above, -haloalkyl or -halooxy, -Ν=Ν+=> oxime group, or --<:0& group, wherein & is 5 or 6 membered heterocyclic ring , optionally substituted by a hydroxy group, an amine group, optionally substituted by one or more q to C6 alkyl groups, a -, -q to C6 alkyl group, optionally substituted by the following: -NHS〇2 Rx group Wherein Rx is as defined above for the 'or-nrxso2rx group, the center of which is as defined above - -13⁄4 alkoxy, -halogen, -trans-based, -COORx group, wherein Rx is as defined above, a CORm group, wherein Rm is: - an amine group, optionally one or more C! to C6 alkyl groups Wherein the Q to c6 alkyl group is replaced by the following: -hydroxyl, 128244-1 -95- 200831489 -5 or 6 membered heterocyclic ring, -amino group, optionally by one or more q to C6 alkyl groups Substituting '-alkoxy, -3 to 7 membered heterocyclic ring, optionally substituted by Cl to c6 alkyl, which alkyl group is optionally substituted with dialkyl-amino group, ...NHRn group, wherein % is: - -CH^COISTH^, or -Q to Q aryl, optionally substituted by the following: - one or more halogens, - nitro, or - one or more alkoxy groups, -1^. a 〇3\ group in which 1^ is a -C1 to c0 alkyl group, optionally substituted by the following: -halogen, -alkoxy, or -C6 to C8 aryl, -5 or 6 membered heterocyclic ring, - Q to aryl, optionally substituted by halogen, • 5 or 6 membered heteroaryl, optionally substituted by one or more C! to C0 alkyl, hydrogen, 128244-1 • 96- 200831489

And wherein rq is: - hydrogen, -^ to decyl, -CORx group, wherein 1 is as defined above, - haloalkyl or haloalkyloxy, -NRqCONRqR^, wherein Rq is : -^ to ^alkyl, - anthracenyl, - alkoxy" or -CORx group, the center of which is as defined above, and wherein R1• is: -C6 to C8 aryl, optionally as follows Replace:

- a heart to a decyl group, a halogen-based group, a fluorene Rs group, wherein 1 is a fluorene 6 to C8 aryl group, or a 128244-1 -97-200831489 • -COORx group, the center of which is as defined above, -C〗 to c0 alkyl, optionally substituted by _ or more of the following groups: - halogen, -alkyl, to Cg, and / or -COORx groups, the center of which is as defined above, - -COORx group 'wherein rx is as defined above, --NRtCOORu group, wherein Ru is: • (^1 to (^2 alkyl, as the case is replaced by the following · to C8 aryl, as appropriate (^ Substituted to alkyl or alkoxy, -alkylene, -alkoxy, -alkyne, -halogen, or -5 or 6 membered heterocyclic ring, -Q to Q aryl, optionally substituted by: - Alkoxy, -halogen, or -ci to C6 alkyl, or -5 or 6 membered heterocyclic ring, and Rt is: -hydrogen, • Ci to C6 alkyl, 128244-1 -98- 200831489 -CORx group , wherein 1 is as defined above, a -alkyl group or a -1⁄4 alkoxy'-NRvS02Rw group, the center of which is: - hydrogen, a -CORx group, wherein Rx is as defined above, or -〇丨To a 0:6 alkyl group, as the case may be substituted by: _ _ 素, -•CORx group, Its center is as defined above, the -OCORx group, the center of which is as defined above, - via, or - alkoxy, and wherein Rw is: -C! to C6 alkyl, as the case may be replaced by: Halogen, -haloalkyl '-c6 to c8 aryl, or -5 or 6 membered heterocyclic ring, -C2 to C6 alkyl, -alkyl- or di-homo-amino, optionally substituted by halogen, - 5 or 6 membered heterocyclic ring, or • 5 or 6 membered heteroaryl, optionally substituted by the following - to - alkyl group, -5 or 6 membered heterocyclic ring, or, 128244-1 -99- 200831489

•N

V

_N

NH

-N

NH

N——Rv

Rv is replaced by <^ to (:6 alkyl, as appropriate, where Ry

〇=s I /N

128244-1 > 100- 200831489 wherein Rz is hydrogen or cjc6 alkyl, as the case may be. 6 to. 8 aryl substituted, ...SRX group, the center of which is as defined above, -S〇2Raa group, wherein Raa is: -Ci to c6 alkyl, -amino group, alkyl- or monoalkyl-amino group , as the case may be substituted by a hydroxyl group or a group, the center of which is as defined above, -5 or 6 membered heteroaryl,

a -C6 to C8 aryl group, and/or a ... NHRbb group, wherein Rbb is: *

a -c(=s)nh2 group, or a ...P〇(ORx)2 group, the center of which is as defined above; =Rcc group, wherein rc c is: -荇, -5 or 6 membered heteroaryl ,

-Q to A aryl, optionally substituted by one or more of the following groups: 128244-1 -101 - 200831489 - alkoxy, -yl, -halogen, -C! to C6 alkyl, optionally Cyano substituted, -amino group, optionally substituted by one or more Ci to c6 alkyl groups, -NHPORxRx, wherein Rx is as defined above, ... NReeCONRffRff group, wherein Ree is hydrogen or c^c6 alkyl, The situation is replaced by i, and Rff is: - hydrogen, -haloalkyl, -haloalkoxy, -^ to cardioalkyl, or -COR1 group, wherein 1 is as defined above, -NRg g CORh h The group 'wherein Rhh is · - hydrogen, -C! to c6 alkyl, as the case may be substituted by: alkoxy, -halogen, or -amino group, optionally substituted by one or more C! to C6 - the amine group 'optionally substituted by one or more Cl to C6 alkyl groups', the alkyl group optionally substituted by halogen, -5 or 6 membered heterocyclic ring, -5 or 6 membered heteroaryl, 128244-1 - 102- 200831489 - Hydrogen, -Ci to C6, - haloalkyl, -haloalkoxy, or -CORx group, wherein Rx is as defined above, -halo, -5 or 6 membered heterocyclic a group, an amine group, optionally one or more q to C6 alkyl groups And/or ... the NRiiS〇2Rx group, the center of which is as defined above, and 1^ is: - hydrogen, -^ to (:6 alkyl, -haloalkyl, -haloalkoxy, -CORx a group whose center is as defined above; Z is -Ci to c0 alkyl, optionally substituted by the following: - alkoxy, - one or more halogens, or -c6 to c8 aryl; -c2 to c6 Alkyl; _C6 to csaryl, optionally substituted by alkoxy or one or more. to alkyl; COORx group, wherein Rx is as defined above; or 128244-1 200831489

R is hydrogen, halogen or alkoxy; Ri is hydroxy-halogen; -13⁄4 alkyl; -nitro, -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclic ring; -alkoxy, optionally Substituted by: - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -C6 to C8 aryl, optionally substituted by alkoxy; -CORx group, center Is defined as above; -^ to the cardinyl group, optionally substituted by a dialkyl-amine group or a 5 or 6 membered heterocyclic ring; or bonded to R2 to form: /

128244-1 -104- 200831489 R2 is -nitro group; -chloro; -halogen; -yl group; -Ci to c6 alkyl group, optionally substituted by one or more halogens; -amino group; -alkoxy group, Optionally substituted by: - one or more halogens, -OCORx group, centered as defined above, -dialkyl-amino group, optionally substituted by alkoxy group, -5 or 6 membered heterocyclic group a group, optionally substituted by Cl to q alkyl -5 or 6 membered heteroaryl, or -c6 to c8 aryl; -COORx group, wherein Rx is as defined above; -13⁄4 alkyl, - amidino , optionally substituted by: -hydroxyl, or -C6 to C8 aryl; -5 or 6 membered heteroaryl; -OCORx group, the center of which is as defined above; -NHCORj j group, where Rj" To: - a calcined base, or an -amino group, optionally substituted by one or more Ci to c6 alkyl groups; 128244-1 200831489 - an ORkk group, wherein Rkk is a 5 to 6 membered heteroaryl; a 〇2Rx group, wherein Rx is as defined above; or R2 is bonded to Ri to form:

R3 is · - nitrogen; or

f \ -CH2 0C0Rx, and Rx is as defined above; the conditions are: when X is phenyl, hydroxyphenyl or pyridyl, γ is alkyl, R is hydrogen, R1 is hydrogen or hydroxy, and R2 is hydrogen or hydroxy And when R3 is hydrogen, then Z is: -C〗 to Qalkyl, substituted by: - alkoxy, - one or more halogens, or -c6 to c8 aryl; - c2 to c6 alkyl _ Q to c8 aryl, optionally substituted by alkoxy or — or a plurality of alkyl groups; or —COORx group, wherein Rx is as defined above

Or one or more pharmaceutically acceptable salts thereof; and 128244-1 -106 to 200831489 (11) one or more pharmaceutically acceptable excipients. 70_ A method of treating a viral infection in a patient in need thereof, wherein the side virus contains an internal ribosome entry site (IRES), the method comprising administering to the patient one or more compounds of formula I, or a pharmaceutical composition This composition comprises one or more compounds of formula I

- nitro; - cyano; -CORa group, wherein hydrazine is: • Ci to C6 alkyl, -C6 to csaryl, optionally substituted by alkoxy or halogen, or "one yard-amine -COORx group 'centered from center to decyl group; -methano group; -C0 to Q aryl group, optionally substituted by alkoxy group; or -5 or 6-membered heteroaryl group, as appropriate Substituted by: -ci to C6 alkyl, -A to Cs aryl, optionally substituted by alkoxy or one or more halogens, 128244-1 -107 - 200831489 -5 to 6 membered heteroaryl; Y is : - a calcination group; - a halogen; - an amine group, optionally substituted by one or more q to C6 alkyl groups; - a benzofuran; a benzoquinone p-cephen; a dibenzofuran; Benzene; - benzopyrazole; - hydrazine, optionally substituted by C! to C6 alkyl group on nitrogen;

Rb, wherein Rb is hydrogen or (^ to cardinyl, and η is 0 or 1;

128244-1 -108- 200831489

-CONHR. Definition, or -S02Rx,

Wherein is hydrogen, -C0NHrx, the center of which is as defined above wherein Rx is as defined above; or • 'the center is ^ to decyl or (:6 to (:8 aryl; broad--NHCORe group, where Re To be: -(^ to decyl; -C6 to Cs^' group' is optionally substituted by the following: - heart to decyl, - alkoxy, -cyano, -mercapto, or -halogen; a w^cooRx group, wherein Rx is as defined above; • a -CH20_Rf group, wherein Rf is q to q aryl; --NRgRh group, wherein Rg is q to Q alkyl or hydrogen, and Rh is to c8 Aryl, optionally substituted by alkoxy; -(^ to decyl; -5 or 6 membered heteroaryl, optionally substituted as follows: -^ to decyl, as appropriate (:6 to (: 8 aryl substituted, -Q to C:8 aryl, optionally substituted by -C00rx, centered as defined above 128244-1 •109-200831489, or -amino group; 5 or 6 membered heterocyclic ring, as appropriate Substituted: -COORx group, wherein Rx is as defined above, or ...NHCOORx group, wherein ^ is as defined above; A to c8 aryl, optionally substituted with one or more of the following groups: '•烧Oxyl group, as the case may be replaced by - alkoxy, - thiol, - one or more halogen, -5 or 6 membered heterocyclic ring, optionally substituted by the following: -Ci to C6 alkyl, or -transyl, -amino, optionally Or a plurality of q to c6 alkyl substituted, -NRiS〇2Rx groups, wherein Rx is as defined above, and & is: - hydrogen, • Ci to Cs alkyl, -CORx group, centered as above Definition, - haloalkyl, or -halooxy, -NRj CORk group, wherein Rk is: -Q to C6 alkyl, -nitrogen, or -amino group, optionally by one or more Ci C6 alkyl substituted, ^8244.1 • 110- 200831489 and Rj is . -hydrogen, -cardi to decyl, -CORx group 'where & is as defined above, - haloalkyl, or -haloalkoxy , a group, or a --COR! group, wherein & is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group, an amine group, optionally substituted with one or more Ci to c6 alkyl groups, -nitro , _ Ci to alkyl, optionally substituted by: -NHS〇2Rx group, wherein & is as defined above, or --NRxS〇2Rx group, the center of which is as defined above, -haloalkoxy , -halogen, -transcarbyl, -COORx group, its center As defined above, the --CORm group has the center: - an amine group, optionally substituted by one or more (^ to ^ alkyl groups, wherein one or more C! to c6 alkyl groups are optionally replaced by : -hydroxyl, -5 or 6 membered heterocyclic ring, -amino group, optionally substituted by one or more Ci to q alkyl groups' and / 128244-1 -111 - 200831489 or -alkoxy, -3 to 7 members A heterocyclic ring, optionally substituted by a C to a C6 alkyl group, optionally substituted by a dialkyl-amino group, a -NHRn group having a center of ··-ch2conh2, or a -C6 to c8 aryl group , as the case may be substituted by the following - a burnt group, - one or more halogens, - nitro, or - one or more alkoxy groups, • NR 〇 CORp group, where \ is · · -Ci to C: 6 alkyl, optionally substituted by the following: - halogen, - alkoxy, or -c6 to c8 aryl, -5 or 6 membered heterocyclic ring, -C6 to C:8 aryl, optionally substituted by halogen, - 5 or 6 membered heteroaryl, optionally substituted by one or more Ci to c6 alkyl groups, 128244-1

• 112- 200831489 and wherein rq is: - hydrogen, -^ to ^alkyl, -CORx group, the center of which is as defined above, - haloalkyl ' or - alkoxy" - NRqCONRqR^• a group wherein Rq is: -hydrogen, -heart to (:6 alkyl, -haloalkyl '-13⁄4 calcined base' or -CORx group, the center of which is as defined above, and wherein Rr is: -C6 To C8 aryl, as the case is replaced by:

-Ci to alkyl, -haloalkyl--ORs group, centered at 0:6 to (:8 aryl, or -COORx group, centered as defined above, -q to C6 alkyl , optionally substituted by one or more of the following groups: _halogen, 128244-1 -113 - 200831489 - sub-alkyl, -c6 to c8 aryl, and / or -COORx group, the center of which is as defined above , -COORx group, the center of which is as defined above, -NRtCOORu base, wherein Ru is: -CiSCu alkyl, optionally substituted by the following: -C6SC8 aryl, as appropriate (^ to (: 6 alkanes) Substituted by alkoxy or alkoxy, -alkyl, alkoxy-alkyne, -halogen, or -5 or 6-membered heterocyclic ring, -C6 to C8 aryl, optionally substituted by: - alkoxy , -halogen, or -(^ to 0:6 alkyl, or -5 or 6 membered heterocyclic ring, and Rt is - hydrogen, -(^ to decyl, -CORx group, the center of which is as above Definition, -haloalkyl, or -halooxyl' 128244-1 -114- 200831489 -NRV S〇2 Rw group 'where Rv is . -hydrogen, --CORx group, wherein Rx is as above Definition, or -q to C6 alkyl, as the case may be substituted by: - halogen, -CORx group Its center is as defined above, the -OCORx group, the center of which is as defined above, -trans-based, or -alkoxy" and wherein Rw is: -^ to the cardinyl group, as the case may be replaced by the following - Halogen, -13⁄4 alkyl, -C6 to C8 aryl, or -5 or 6 benzophenate -C2 to C6 alkyl, -alkyl- or dialkyl-amino, optionally substituted by halogen, -5 or 6 membered heterocyclic ring, or -5 or 6 membered heteroaryl, optionally substituted by the following: -^ to decyl, -5 or 6 membered heterocyclic, or

128244-1 -115 - 200831489

〇

N——R.

Ry, optionally substituted by Ci to C6 alkyl,

Is (^ to (: 6 alkyl or hydroquinone)

〇

〇=s wherein Rz is hydrogen or <^ to (:6 alkyl, optionally substituted by 06 to 08 aryl, --SRX group, wherein 1^ is as defined above, 128244-1 -116- 200831489 - a -S〇2Raa group, wherein Raa is: -(^ to decyl, -amino, -alkyl- or monoalkyl-amino, optionally substituted by hydroxy or _c〇〇Rx groups, wherein Rx is as defined above, -5 or 6 membered heteroaryl, -C6 to Cg square' and/or -NHRb b group, wherein Rbb is: *

a C(=S)NH2 group, or a -PO(ORx)2 group, wherein the lanthanide is as defined above;

Rcc group, wherein Rcc is: -5 or 6 membered heteroaryl,

-Q to Q aryl, optionally substituted by mono-alkoxy, or a plurality of groups: - thiol, 128244-1 -117- 200831489 _halogen, -C! to C6 alkyl, optionally cyanide Substituent, an amine group, optionally substituted by one or more C! to C6 alkyl groups, ... NHPORxRx, wherein Rx is as defined above, ... NReeCONRffRff group, wherein Ree is hydrogen or c^c6 alkyl, as appropriate Substituted by i, and Rff is: - hydrogen, -13⁄4 alkyl, -haloalkoxy, -Cl to C6 alkyl' or -CORx group, wherein Rx is as defined above, -NRggC0Rhh group, Wherein Rhh is: - hydrogen, -C" to C6 alkyl, optionally substituted by the following: - alkoxy, -halogen, or -amino group, optionally substituted by one or more Ci to c6 alkyl groups - an amine a group, optionally substituted by one or more q to 0:6 alkyl groups, wherein the alkyl group is optionally substituted by halogen, a -5 or 6-membered heterocyclic ring, -5 or 6-shell heteroaryl, and Rg g is : - hydrogen, -ci to C6 alkyl, 128244-1 -118· 200831489 - a halogen group, a gas group, or a -CORx group, wherein Rx is as defined above, -_alkyl, -5 or 6-membered heterocyclic group, -amino group, as appropriate Or a plurality of C! to C6 alkyl substituted, and/or --NRhSC^Rx groups, the center of which is as defined above, and Rn is: - hydrogen, mono-, alkyl, haloalkyl, -halo Alkoxy, a -CORx group, wherein rx is as defined above; Z is: -Q to C0 alkyl, optionally substituted by the following: - alkoxy, - one or more halogens, or -c6 to c8 Aryl; -c2 to c6 alkyl; C0 to C8 aryl, optionally substituted by alkoxy or one or more Cl to qalkyl; -COORx group, centered as defined above; or 128244 -1 -119- 200831489

R is a rat, a halogen or an alkoxy group; Ri is a -hydroxy group; -halogen, -13⁄4, - triazole; -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclic ring; - alkoxy group, Substituted as follows: - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -C6 to C8 aryl, optionally substituted by alkoxy; -CORx group, Its center is as defined above; - heart to decyl, optionally substituted by dialkyl-amine or 5 or 6 membered heterocycle; or core bonded to r2 to form: ✓

128244-1 -120- 200831489 R〗 ─ - broken base; - gas; - halogen; - warp group; _ C〗 to c6 alkyl, optionally substituted by one or more halogens; - amine group; - oxygenated The base is optionally substituted by the following: ('-one or more halogen, -〇CORx group, wherein Rx is as defined above, -dialkyl-amino group, optionally substituted by alkoxy group, -5 or a 6-membered heterocyclic group, optionally substituted by a q to C6 alkyl group -5 or 6 membered heteroaryl, or -〇6 to Cg aryl; -COORx group, wherein the lanthanide is as defined above; - _ i κ -Amidino, optionally substituted by: -hydroxy, or -c6 to c8 aryl; -5 or 6 membered heteroaryl; ...0C0Rx group, wherein Rx is as defined above; -NHCORj a group wherein Rj" is: - an alkoxy group, or an amine group 'optionally substituted with one or more Ci to c6 alkyl groups; 128244-1 -121 - 200831489 〇Rk k group 'where Rk k is 5 To 6 members of the heterosexual group - NHS 〇 2 Rx group, wherein Rx is as defined above, Ge R2 and Ri are joined together to form

R3 is · - hydrogen; or

-CH2OCORx, and Rx is as defined above or one or more of its pharmaceutically acceptable salts. (d) A method of treating hepatitis C virus (HCV) infection in a patient in need thereof, which comprises administering to the patient one or more compounds or a pharmaceutical composition comprising one or more compounds of formula J

R3 wherein: - succinyl; - gas group; - C0Ra group, wherein \ is · (^ to (: 6 alkyl, • Q to Q if the base '枧 condition is replaced by alkoxy or halogen, or 128244- 1-122-200831489 - Dialkyl-amino, -COORx group, the center of which is (^ to (6 alkyl; -methanyl; _ c6 to c8 aryl, optionally substituted by alkoxy) Or a -5 or 6-membered heteroaryl, optionally substituted by the following: -CjSQ alkyl, -C6 to C8 aryl, optionally substituted by alkoxy or one or more halogens, or

-5 to 6 membered heteroaryl; Y is: - a halogen group, -13⁄4 element, - an amine group, optionally substituted by one or more q to C6 alkyl groups - benzoheptin; - benzopyrazole; -dibenzofuran; -dibenzopyrazole; -benzothiazole; -na, - orthoquinone, optionally on the nitrogen to (:6 alkyl substitution;

128244-1 123 _ 200831489 (CH2)n , wherein Rb is hydrogen or c^c0 alkyl, and n is 〇 or 1;

Rb

Rc

Wherein Re is hydrogen, -C〇NHRx, the center of which is as defined above, or -S〇2Rx, the center of which is as defined above; or, Rd, S: 'where Rd is CiSC6 alkyl or Q to q aryl -NHCORe group, wherein Re is: -Heart to decyl group; -C6 to Cs aryl group is optionally substituted by the following: -CiSC6 alkyl, -alkoxy, -cyano, -mercapto, or a halogen-;NHCOORx group, wherein Rx is as defined above; -CH20-Rf group, wherein Rf is c6 to c8 aryl; -•NRgRh group, the center of which is ^ to ^alkyl or hydrogen, And ^ is 仏 to & 芳128244-1 -124- 200831489 base, optionally substituted by alkoxy; -C1 to c6 alkyl; -5 or 6 membered heteroaryl, as the case is replaced by _Ci to Q alkyl, optionally substituted by C6SC8 aryl, -C0 to Q aryl, optionally substituted by _c〇ORx, wherein 1^ is as defined above, or -amino group; C, 5 or 6 membered heterocyclic ring, Substituted as follows: -CO〇Rx group, wherein & is as defined above, or --NHCOORx group, the center of which is as defined above; to Q aryl, as the case may be one or more of the following Substituting a group of alkoxy groups, as appropriate Substituted by: - alkoxy, - hydroxy, - one or more halogens, (-5 or 6 membered heterocyclic ring, optionally substituted by the following: -Ci to C6 alkyl, or -hydroxyl, -amino" The situation is replaced by one or more Cl to c6 alkyl, -NRiS〇2Rx groups, wherein the lanthanide is as defined above, and is: -hydrogen, -ci to decyl, -CORx group, wherein As defined above, -dentyl, or 08244"-125-200831489-haloalkoxy, --NRj CORk group, wherein Rk is: -(^ to (:6 alkyl, -hydrogen, or -amine, Optionally substituted by one or more Ci to c6 alkyl groups, and Rj is: -hydrogen, -cardi to decyl, -CORx group, wherein Rx is as defined above, -haloalkyl, or -haloalkane Oxyl, --Ν=Ν+=> oxime group, or --COR! group, wherein & is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group, and the amine group is optionally treated as one or A plurality of q to c6 alkyl substitutions, - stone Schottky, -ci to Q alkyl, optionally substituted by: -_NHS〇2Rx group, wherein Rx is as defined above, or --NRX S〇2 Rx group Wherein rx is as defined above, -haloalkoxy, -halogen, _ a COORx group whose center is as defined above, a -CORm group, wherein: 128244-1 -126- 200831489 - an amine group, optionally replaced by one or more q to C6 leuko A plurality of q to C6 alkyl groups are optionally substituted by the following: -hydroxyl, -5 or 6-membered heterocyclic ring, -amino group, optionally substituted by one or more q to C6 alkyl groups - alkoxy group, - a 3 to 7 membered heterocyclic ring, optionally substituted by a q to C6 alkyl group, which is optionally substituted with a dialkyl-amino group, ...NHRn group, the center of which is: -CH〗 CONH, or - The C6 to c8 aryl group is optionally substituted by the following: - an alkyl group, or a plurality of _ s, - nitro, or - one or more alkoxy groups, - NR 〇 C0RP groups, wherein Rp is: - Ci to Q alkyl, optionally substituted by _halogen, -alkoxy, or -c6 to c8 aryl, _5 or 6 membered heterocyclic ring, -C6 to C8 aryl, optionally substituted by halogen' _ 5 or 6 membered heteroaryl, optionally substituted by one or more ^ to ^ alkyl, 128244-1 -127- 200831489

And where R. Is: -^ to the heart alkyl, -CORx group, the center of which is as defined above, - a halogen group, or a -halooxy group, a -NRqCONRqRr group, wherein \ is: - hydrogen, -q to C6 alkyl, -haloalkyl-haloalkoxy, or --CORx group, the center of which is as defined above, and wherein Rr is: -C6 to C8 aryl, optionally substituted by the following

128244-1 -128- 200831489 ...ORs group, wherein ^ is 仏 to ^ aryl, or ... COORx group, the center of which is as defined above, -q to A alkyl, optionally by one or more of the following groups a group substituted with a halogen, a -alkylene group, a fluorene 6 to a C8 aryl group, and/or a COORx group, wherein & is as defined above, a -COORx group, wherein Rx is as defined above, a NRt COORu group, wherein Ru is: -Cl to Ci 2 alkyl, optionally substituted by the following: -Q to q aryl, optionally substituted by q to Q alkyl or alkoxy, -alkyl , - alkoxy, - alkyne, - halogen, or -5 or 6-membered heterocyclic ring, -Q to Cs aryl, optionally substituted by the following: - a gas group, a halogen, or a -Ci to C6 alkyl group , or a -5 or 6-membered heterocyclic ring, and the hydrazine is: - hydrogen, 128244-1 -129- 200831489 -^ to decyl, a -CORx group, the center of which is as defined above, -13⁄4 alkyl' or - alkoxy-'-NRvS02Rw group, the center of which is: hydrogen, a -CORx group, wherein Rx is as defined above, or -q to C6 alkyl, optionally substituted by the following: -13⁄4 素, - -CORx group, where 1 is as defined above, _ -OCORx a group whose center is as defined above, - a thiol group, or an alkoxy group, and wherein Rw is: -q to C6 alkyl, optionally substituted by the following: - _, -13⁄4 alkyl, -C6 to C8 Aryl, or -5 or 6 membered heterocyclic ring, -02 to 06 alkyl, -alkyl- or dialkyl-amino, optionally substituted by halogen, -5 or 6 membered heterocyclic ring, or -5 or 6-membered heteroaryl, as the case may be replaced by: - heart to decyl, 128244-1 -130- 200831489 5 or 6 member heterocycle, or

Ry

N-Rv, as the case may be (^ to (6 alkyl substitution, where is Ci to c6 alkyl or 〇 〇 >

128244-1 -131 - 200831489

"Rz is hydrogen or Ci to C0 alkyl, optionally substituted by q to q aryl, -SRX group, the center of which is as defined above, -_S〇2Raa group, wherein Raa is: -C! a C6 alkyl, -amino, -alkyl- or dialkyl-amino group, optionally substituted by a hydroxy or _COORX group, the center of which is as defined above, -5 or 6 membered heteroaryl, -C6 to a C8 aryl group, and/or an NHRb b group, wherein Rbb is: *

a -C(=S)NH2 group, or a -PO(ORx)2 group, wherein rx is as defined above; - Rcc group, wherein Rce is: - Nai, -5 or 6 member heteroaryl Base, 128244-1 -132- 200831489 rv0^

C6 to. The 8 aryl group is optionally substituted by one or more of the following groups: - alkoxy group, - via group, - halogen,

Ci to C6 alkyl group is optionally substituted with an aryl group, an amine group, optionally substituted by one or more (^ to .alkyl, ... NHPORx Rx 'where Rx is as defined above, ... NReeCONRffRff group, where Ree Is hydrogen or CiSQ alkyl, optionally substituted by i, and Rff is: - hydrogen, - alkoxy, -haloalkoxy, -C! to C6 alkyl, or -CORx group, wherein Rx is As defined above, a --NRggCORhh group, wherein Rhh is: -hydrogen, -G to C6 alkyl, optionally substituted by: -alkoxy, -halogen, or -amine, optionally by one or more Ci to c6 alkyl substituted '-amino group, optionally substituted by one or more q to 06 alkyl groups' wherein 128244-1 -133 - 200831489 one or more c to c6 alkyl groups are optionally substituted by halogen, 5 5 or 6 membered heterocyclic ring, _ 5 or 6 membered heteroaryl, and Rg g is: - hydrogen, • 01 to 〇6 alkyl, -haloalkyl, _ alkoxy, or f -_c〇Rx a group wherein Rx is as defined above, - haloalkyl, -5 or 6 membered heterocyclic group, -amino group, optionally substituted by one or more q to C6 alkyl groups, and/or -•NRnS02Rx group , its center is as defined above, and the heart is - hydrogen, -4 to hydrazine: 6 alkyl, -alkyl, i-haloalkoxy, -CORx group, wherein Rx is as defined above; Z is - (: 丨 to decyl, see The situation is replaced by the following: - alkoxy, - one or more halogens, or -c6 to c8 aryl; -c2sc6 alkyl; 128244-1 -134 - 200831489 - C0 to q aryl, optionally alkoxy a group or one or more q to q alkyl groups; a -COO^x group, the center of which is as defined above; or

R is hydrogen, halogen or alkoxy;

Ri is - nitrogen, -hydroxyl; -halogen; -haloalkyl; -stone succinyl, -5 or 6-membered heteroaryl; -5 or 6-membered heterocyclic ring; -Hyun-based base' is replaced by the following: - Or a plurality of halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -Q to Q aryl, optionally substituted by alkoxy; -CORx group, the center of which is as defined above; Cl to C6 alkyl, optionally substituted by dialkyl-amine or 5 or 6 membered heterocyclic ring 128244-1 -135- 200831489

Ri and R_2 are joined together to form · ✓

R2 is: - a primate; - a mouse, - a halogen; - a hydroxy group; - a Ci to a c6 alkyl group, optionally substituted by one or more _ alkene; an amine group, an alkoxy group, optionally substituted by the following: Or a plurality of halogens, a -OCORx group, the center of which is as defined above, - a dialkylamino group - optionally substituted with an alkoxy group - a 5- or 6-membered heterocyclic group, optionally as a q to C6 alkane Substituent, -5 or 6 membered heteroaryl, or -C6 to C8 aryl; -COORx group, the center of which is as defined above; - a halogen group; - an amidino group, optionally substituted by: - Oryl, or -c6 to c8 aryl; -5 or 6 membered heteroaryl; 128244-1 -136-200831489 -OCORx group, the center of which is as defined above; -NHCORjj group, where Rjj is: -oxy, or -amino 'optionally substituted by one or more Ci to q alkyl--Rkk groups, wherein Rkk is a 5- to 6-membered heteroaryl; -NHS〇2Rx group, the center Is as defined above; or & is joined to Ri to form:

R3 is - gas, or -CH2?CORx, and 1 is as defined above; or one or more pharmaceutically acceptable salts thereof. 72·Formula Illb compound

Wherein: X is · · - rat, Y is: the aryl is -5 or 6 membered heteroaryl, as the case is ^ to (: 8 aryl substitution 128244-1 -137 - 200831489 as the case -C〇〇 Rx is substituted, wherein Rx is as defined above; -C: 6 to csaryl, optionally substituted with one or more of the following groups: - an amine group, optionally substituted with one or more q to c6 alkyl groups; Halogen; -transcarbyl; -CORm group, centered on: -amino group, optionally substituted by one or more q to C6 alkyl groups; -NR.CORp group, wherein Rp is: -q to C : 6 alkyl, optionally substituted by alkoxy; and wherein R is: -NRqCONRqRr group, wherein Rq is hydrogen, and wherein hydrazine is: alkyl; -NRtCOORu group, wherein Rt is hydrogen, and Its center is: -Q to q2 alkyl, optionally substituted by: -C6iC8 aryl; -halogen; or -5 or 6 membered heterocyclic ring; ...NRvS〇2Rw group, wherein Rv is hydrogen, and wherein : -Ci to C6 base; or

-alkyl- or monoalkyl-amine; 128244-1 -138- 200831489

〇

o=s wherein Rz is hydrogen or (^ to (6 alkyl; -S02Raa group, wherein Raa is: amine group, or -alkyl group or dialkyl group-amino group; -NHRbb group, wherein Rbb is: -PO(ORx)2 group, the center of which is as defined above; Z is: -(^ to decyl; or -COORx group, wherein lanthanide is as defined above; R is: - hydrogen ,

Ri is - nitrogen, -5 or 6 shells, - alkoxy, optionally substituted by: - one or more halogens; or -5 or 6-membered heterocycles; R_2 is - rat, 128244-1 -139- 200831489 - Meridyl, -Ci to C: 6 alkyl, optionally substituted by one or more halogens; - alkoxy, optionally substituted by: - one or more halogens; - 5 or 6 members a heterocyclic group, optionally substituted with a Ci to C6 alkyl group, a -5 or 6-shell heteroaryl group; or a -COORx group, wherein Rx is as defined above; - amidino group; -5 or 6 member heteroaryl Or an ORrk group, wherein Rkk is a 5- to 6-membered heteroaryl; and R3 is: - hydrogen. 73. The compound of embodiment 72, wherein X is: - nitrogen, Y is: /, - c# 8 fluorenyl substituted by -NRtCOORu group, JL + p goes & wherein Ru is (^ to (: 12) Alkyl; t is oxygen, and Z is: -(^ to (:6 alkyl; R is: -murine; & is: gas, 128244-1 -140-200831489 R) is ·•_ORkk group, Wherein Rkk is a 5- to 6-membered heteroaryl; R3 is a hydrogen-hydrogen. 74. A compound selected from the group consisting of: 866-1329, 1484-2127, 2129-2545.

128244-1 -141 - 200831489

128244-1 -142- 200831489 As used herein, the term "alkyl" generally refers to a straight chain, branched or cyclic configuration, or a saturated hydrocarbon group in a combination of cyclic and branched or straight chain. , including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl 'n-pentyl, n-hexyl' cyclohexyl, N-heptyl, octyl, n-octyl and the like. In some embodiments, the alkyl substituents <:1 to (:12 or (:1 to (:8 or (:1 to (:6 alkyl), linear, branched or ruthenium (:2) To (6th alkane as used herein, "alkylene," generally refers to a cyclic olefin group having one or more carbon-carbon double bonds, including 3-propenyl groups. The base refers to a carbon ring aryl A ..... to explain that 〇 is contained in the range of the aryl group and is right, and H is an aromatic ring having five to twenty carbon atoms. The aryl ring structure includes and t ^ ^ , π includes a compound having - or a plurality of ring structures, and examples of the early-, double- or tricyclic group of 舲^^^ m-square groups include a phenyl group and a tolyl group. , ring name M / Ganokee, non-base (meaning phenanthrene) and naphthyl (meaning benzene)

%structure. In some cases and every quot; J ~ this article ^ aryl can be replaced by the case. In the ring, the #方方(四)日(四)aromatic ring structure, the ΜE second atom, the hetero atom, is the carbon other than the helium. The hetero atom is typically 7 以外 other than 〇. s or N atom. It is contained in the target range of the heterogeneous and independently selectable An 3 doped square. The ϋ, S, S heteroaryl ring structure. The cyclosporine π a includes one or more ring junctions / conformable inclusions. In some specific cases, such as early-, double- or tricyclic, heteroatoms, tri-&' Heteroaryl ring junction = hydrazine or heteroaryl atom of four or more heteroatoms or eight or more:: contains five: or more atoms, six or more ', . Examples of the heterocyclic ring structure include ··········································· Alkene, benzofuran, T-azol, 1 4 II - miso" (four), different ^ sitting, different as Lin, Li = tea "Fu, Xia, H sitting" than biting, then set, sitting on the ten, Mouth 呤... oxazole, cumphin, 1,3,5-three 4, 彳u _ porphyrin, porphyrin, pyrimidine, 4-two wells, ^ 2 3 : bucket used in this article #,一唯,tetrazole and quinazoline. In the ring - or a plurality of atoms, miscellaneous + clothing - structure 'wherein this is typically 〇, _ atom. The element other than =. := rsheterocyclic structure. The ring structure may include a compound having a structure of -2:, , , , such as a mono-, di- or tricyclic compound. A pyridinium tetrapyrrolidine group I, a tetrahydropyrrolyl group, Helm, hexahydro, carbendazim, pentyl fluorenylamine, % acetonitrile, propylene propylene, tetrahydroanthracene, tetrachloropyranyl, tetrahydroanthracene a bite group, a tetrahydrotetrazole group, a tetrahydrothiophenyl group or a tetrahydrothiocarbamate group. In some embodiments, a heterocyclic ring may be optionally substituted. As used herein, "alkyloxy means a structure having the structure =0 nucleus' wherein R is an alkyl group as defined above. The halogen substituent may be independently selected from a hydroxyl group such as fluorine, chlorine, bromine or iodine. The haloalkyl group is an alkyl group as defined above, substituted by one or more halogens. The alkoxy group is as above Alkoxy as defined, substituted by one or more iS. For the purposes of the present invention, X, Y, Z, R, R1, R2 & R32 - or a plurality of functional groups are incorporated into the molecule of Formula I Wherein, each functional group present at any position within the disclosed compound can be independently selected and, as appropriate, 128244-1 -144-200831489, independently substituted. Further, wherein the more general substituents are in the molecule of the invention In any position, it should be understood that a general substituent may be replaced by a more specific substituent, and the resulting molecule is within the scope of the molecule of the invention. The so-called "substituted" or "optionally substituted" Means that a particular substituent can be heated Chemical group substitutions of the indicated substituents are known, unless the chemical group is specifically indicated. In some embodiments, the X system is selected from the group X of the compounds 866-1329, 1484-2127, 2129-2545. Non-limiting examples of X substituents include the following, wherein * represents a linkage bond of a backbone molecule:

128244-1 -145 - 200831489 sy^N * * *-Η 0 In some embodiments, the X substituent is hydrogen; cyano; or -CORa*, the center of which is ^ to ^alkyl or dialkyl - Amino group. In other specific embodiments, the X substituent is selected from the group consisting of: V Ν f * *-Η In still other embodiments, the X substituent is selected from the group consisting of: Ν f ic In some embodiments, the γ system A Y substituent selected from the group consisting of compounds 866-1329, 1484-2127, 2129-2545. Examples of generations include the following: *_ ic Λ *-〇 Η *-N *P. \ /° Η \ V *-N \ H *>〇 \ Η Η *-Nl 128244-1 -146- 200831489

128244-1 -147- 200831489

128244-1 -148- 200831489

128244-1 -149- 200831489

128244-1 -150- 200831489

128244-1 -151 - 200831489

128244-1 -152- 200831489

128244-1 -153 - 200831489

128244-1 -154- 200831489

128244-1 -155 - 200831489

128244-1 -156- 200831489

128244-1 -157- 200831489

128244-1 -158- 200831489

128244-1 -159- 200831489

128244-1 -160- 200831489

128244-1 -161 - 200831489

128244-1 -162- 200831489

128244-1 -163 - 200831489

128244-1 -164- 200831489

128244-1 -165 - 200831489

128244-1 -166- 200831489

128244-1 -167- 200831489

128244-1 -168- 200831489

128244-1 -169- 200831489

128244-1 -170- 200831489

Η A〆"丫〇ΝΗ ΟγΝΗ, γ^γ"ΝΗ 尸/=\ ν〇*-ν/~ΝΗ *普* \^ΝΗ士* > 0 丫1〆* 八Ύ\ ΝΗ r^j Η *, ν -171 - 128244-1 200831489

128244-1 -172- 200831489

128244-1 -173 - 200831489

824 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 It is selected from the Z substituents of the compounds 866-1329, 1484-2127, 2129-2545.

128244-1 -175 - 200831489 * * ic k * c / * * b * F * 〇乂0 * σ' * ie o) \ * Λ ie * 6 In some embodiments, the Z substituent is hydrogen; Ci To a c6 alkyl group, optionally substituted with an alkoxy group, one or more halogens or a c6 to c8 aryl group; a c2 to c6. alkylene group; or a c6 to c8 aryl group, optionally substituted with an alkoxy group. In other specific examples, the Z substituent is selected from the group Ί F: /° * ic y ★ * \ * * h * ic k * * 6 * F * cy * * In still other embodiments, The Z substituent is hydrogen; Ci to c6 alkyl, 128244-1 • 176-200831489 is optionally substituted by the following: -C6 to c8 aryl; -c2 to C6 alkyl; and -c6 to Cg aryl, optionally It is replaced by an alkyl group. i further into one also #体实%, Z substituents are selected from the following:

★ In some specific embodiments, R is selected from the group consisting of R substituents of compounds 866_1329, 1484_2127, 2129-2545. The limitation of the base includes the following CI 1 ★ *-- Η In some specific 1 *-Η Γ, the R substituent is the following ------: In some embodiments, & Heart substituent of compound 2129-2545. 866-1329, 1484-2127, Examples include the following: 〇-(A r* cr connects R1 and R2 FrF 〇\* 〔,,: Nr connects R1 with "~~ ci, <λ* ΟχΓ F〆* — -- 128244-1 -177- 200831489 \〇0^* ?^Ί I,* H,〇,* 义[.] N *-H π 〈\n,nv^〇/ ★ 0 〇N^^^〇 , * nY~〇, /^N II 〇.Va t>-NH p On^〆N^N \^〇\* In some embodiments, the & substituent is hydrogen; a lignin; a nitro group; Or a 6-membered heterocyclic ring; an alkoxy group, optionally substituted by a C6 to C8 aryl group; or a C6 to C8 aryl group, optionally substituted with an alkoxy group. In other specific embodiments, the cardiac substituent is selected from the group consisting of: /〇,* 〇.〇九 C|\* F, \〇0L k/N, * *-H , V/0 In still other embodiments, the & substituent is selected from the group consisting of: /〇,* 〇M N+\ cr \* ci, \〇dx k/N, * *-H */\/0 In some embodiments, R2 is selected from the group consisting of compounds 866-1329, 1484-2127, 128244-1 -178 - R2 substituents of 200831489 2129-2545. Non-limiting examples of R2 substituents include the following: 丄* 〇人〇 / Y* H, 〆〇,, N+/* 1 〇 _ person /* (X°&σ; σν 乂V 1 H Λ * F~/ <0, 〈〇,: Connect R1 and R2 [.': connect R1 and R2 -v 〇N , hr 〇Yn person N〆* 1 1 Η HH, Jy * 〇〇人Ν' 1 Η * / F * / Cl〆Fv V^N * 〇 / y C丨~〆cw 'ο 'Ο N^N ^-N 〇-* H 乂F * F>v ic 〇 / * 〇 / * 〇 / ★ CT C"N oo 179- 128244-1 200831489

128244-1 -180- 200831489 n r n,n,n l〇,* Cl/ N, <〇, * H cu. , * H NX/. , H H cu " Pi n, n, nl 〇, * In some embodiments, the r 2 substituent is nitro; hydrogen; halogen; hydroxy; C 〗 〖 to c6 alkyl, optionally substituted by one or more halogens Alkoxy, optionally substituted by one or more halogen, -〇CORx group, wherein Rx is as defined above, -dialkyl-amino, optionally substituted by alkoxy, -5 or 6 a heterocyclic group, as the case may be (^ to (6 alkyl substitution, or -5 or 6 membered heteroaryl; - amidino group; or -NHS02Rx group, wherein Rx is as defined above. In the examples, 112 substituents are \〇〆H, 〇/* 〇, 〆1 〇- 八〇/* HH, V* 〇Cl〆N 八v^〇/* \=^N * y C丨~ 〆?"Ί --- H^/F * F>v * 〇/ 128244-1 -181 - 200831489

In still other embodiments, the r2 substituent is hydrogen; q to c6 alkyl, optionally substituted with one or more halogens; or alkoxy, optionally substituted by one or more halogens, 5 or 6 A heterocyclic group, optionally substituted by C! to (6 alkyl) or 5 or 6 membered heteroaryl. In still further embodiments, the R2 substituent is selected from the group consisting of: ic 〇/ c/ C丨~〇/* * 〇/ /Ο ★ 〇' * 〇/ σ' * 〇/ c/ 128244-1 -182- 200831489

★ 〇 / c / (X, NF * - 0 - FF * - Η On0 〇 _ * F * - 〇 - FH In some embodiments,: R3 is selected from compounds 866-1329, 1484- R3 substituents of 2127, 2129-2545. Non-limiting examples of R3 substituents include the following: * Human *-Η In some embodiments, the r3 substituent is the following: *-Η Non-limiting examples of compounds of formula I Includes the following:

128244-1 -183 - 200831489

128244-2 184- 200831489 N 891 N ^4〇^〇ν;,η F ^ o~ ^- 892 NF^xxi^-VNH f ; 〇, 893 N , ° 894 N ^0χχί^1 895 n^-^ °y calving^>VW, H 896 ^ jCCM>^ 897 ηΛ-fvH production, H 898 aJOC^oR 899 900 ^xi-{y〇y~^ production, H 901 N 902 N 903 NF 0 ^ 〇, 904 NF 905 N /° 906 N ^o^Ccf^ 〇夕^° 907 908 oJO^-K 909 1 , F 910 1 l F 911 128244-2 -185 - 200831489

128244-2 -186- 200831489

128244-2 -187- 200831489

128244-2 -188- 200831489

128244-2 -189- 200831489

1002

1005

Ν—Η / Ν—Η ΟΛ 1008

128244-2 190- 200831489

128244-2 -191 - 200831489

128244-2 -192- 200831489

1063 1062

1064

128244-2 -193 - 200831489

128244-2 -194- 200831489

128244-2 -195- 200831489

128244-2 -196- 200831489

128244-2 197- 200831489

128244-2 -198- 200831489

64 65 inih

66

h

>-〇, H 1167 1168 1169

1177 1176 1178

128244-2 199- 200831489

83

84

1186

1189

ο

h 1192 1193

1194

Si H h 1197 \^0,

V〇/ 1195 \/〇

1198

>-〇 1196

>-〇 1199 128244-2 200 - 200831489

128244-2 -201 - 200831489

Vn 1221

1224 \/°

1222

1225

1223

1226

h 1227 1228 1229

128244-2 202- 200831489

128244-2 -203 - 200831489 ^ h 1260 6 O^i〇-〇-y ^ h 1261 [:] ^ h 1262 u \> 1263 h 1264 h 1265 NP^oXX^-^VN^ 1266 NV 〇1267 people J〇^ two KV. 1268 f 〇cS<y^° h 1269 1270 ...! Oo ^ 1271 ^ 0iD^a--〇v 1272 s/\ ^ k/O ^ 1273 "0I^f〇--h 1274 CO ^ 1275 〇xxf^N^° Vn_J ^ 1276 //N <6 H 1277 ^ 〇v On" ^ 1278 fY/y^V VnV v° h 1279 V^/ , HI h 1280 128244-2 -204- 200831489

128244-2 -205 - 200831489

128244-2 -206 - 200831489

128244-2 -207 - 200831489

128244-2 -208 - 200831489

128244-2 -209 - 200831489

128244-2 •210- 200831489

128244-2 -211 - 200831489

128244-2 -212- 200831489 f

128244-2 -213 - 200831489

128244-2 -214- 200831489

128244-2 -215 - 200831489

128244-2 -216- 200831489

128244-2 -217- 200831489

128244-2 -218- 200831489

128244-2 -219- 200831489

128244-2 -220- 200831489

128244-2 -221 - 200831489

128244-2 -222- 200831489

128244-2 -223 - 200831489

128244-2 -224 - 200831489

128244-2 -225 - 200831489

128244-2 -226 - 200831489

128244-2 -227 - 200831489

128244-2 228 - 200831489

128244-2 -229 - 200831489

128244-2 230 - 200831489

128244-2 -231 - 200831489

128244-2 232 - 200831489

128244-2 - 233 - 200831489

128244-2 -234 - 200831489

128244-2 - 235 - 200831489

128244-2 -236 - 200831489 / t / i

128244-2 -237 - 200831489

B. Preparation of Compounds of the Invention The compounds of the invention can be obtained via standard conventional synthetic procedures. Many (5) starting materials can be made using the routes described below or by those skilled in the art. The compound of formula I represented by structure II can be prepared by the procedure described in Scheme A below: The alpha-nitroketone derivative A2 can be derived from an activated carboxylic acid derivative, such as a mercapto imidazolium compound. An anion of nitrodecane is obtained which is obtained by treating nitrodecane with a base such as sodium or potassium butoxide or sodium hydride. The reaction of guanidino ketone oxime 2 with the amine derivative A3 gives nitroenamine oxime 4 by mixing component A3 with hydrazine 4 and heating in a suitable solvent such as an alcohol or an aprotic solvent. The nitroenamine oxime 4 is obtained as a π compound in a polar protic solvent such as vinegar 128244-3 -238 - 200831489 acid; or at a temperature close to the ambient temperature.

Schema A

The compound of Formula 1 can be prepared as shown in the following Scheme B: B1 is a reactive alkyl or aryl group containing a leaving group L, in a suitable solvent, with or without #, In the presence of a treatment such as an inorganic test such as sodium or potassium carbonate, or an organic base such as triethylamine, a compound of structure m can be obtained. Examples of the cleavage group include, but are not limited to, a steroid (e.g., gas, bromine or iodine) or an alkyl group. Or an aryl acid salt.

Π.图B { N〇2 i_R R6—L N〇2 HO’ B1 / K5 , Ν 'r4 'r4 III

The compound of formula I, represented by structure IV, can be prepared as shown in Scheme c below: The compound of structure IV can be obtained in the following manner to nitrate the structure 01 to give 3-nitroindole C2. This nitration can be carried out via a C1 treatment with a nitrating agent such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichloromethane. The reaction can be carried out at a temperature of from -30 ° C to +5 ° C. The C2 is treated with a reactive functional group & (C3) containing a suitable cleavage group L to obtain a structure of 128244-3 - 239 - 200831489. Reactive functional groups can include, but are not limited to, an alkyl group and an aromatic group. B may represent an S compound, especially a chloro, bromo or iodo or alkyl sulfonate. The reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine. Alternatively, the group 9 may represent an aryl or heteroaryl group, and L may represent a halide, particularly a chloro, bromo or iodo group. The reaction can be carried out in a polar or non-polar solvent, at ambient temperature to 200 C, in a copper catalyst such as Cui, a base such as Cs > c〇3 or K3P〇4, and optionally an amine ligand such as hydrazine, It is carried out in the presence of 2_bis(methylamino)ethane or l2*·cyclohexanediamine. An alternative route is to convert alpha to C4 in a similar manner as described above and then carry out a nitration reaction to obtain a compound of structure IV.

III·Picture C

The compound of formula I represented by structure V can be prepared as shown in Scheme D. The ketoester of structure D1 is dissolved in a suitable solvent such as alcohol or aprotic

The mixture is heated to give a compound of structure V between amine D D3 and 醌D4, 128244-3 -240-200831489.

IV. Schema D nhr4 r^A^co2-alkyl D3

R4NH2 —----- (〇2) 〇 烧 D1 The compound of the present invention represented by the compound of the structure vi can be produced by the chemistry described in the following Figure μ.

/ 啕哚-3-carboxylate hydrazine can be converted to 吲哚·3_carboxylic acid κ by way of, for example, an acid or a base in an aqueous solution or a mixed aqueous solution-organic solvent, Treatment at ambient or elevated temperature, or by treatment with a nucleophile such as boron tribromide or trimethyl decane iodide in a suitable solvent. The compound of type Ε2 can then be activated and treated with a type of amine of the type 3 to obtain the compound Ε4. The activation of the carboxylic acid can be carried out, for example, by any standard method. For example, the acid hydrazine 2 can be coupled to a reagent such as EDCUtDC (: with or without HOBt, activated in the presence of amine E3, or the acid can be activated to cesium chloride by, for example, dichloride Treatment with thioindigo or chlorinated grass mash, or thiol imidazolium, which is obtained by treatment of the acid with carbonyldiimidazole followed by treatment with amine E3. Compound E4 can be converted to a compound of structure VI. E4 is treated with a reactive sulfhydryl group R9 (E5) containing a suitable cleavage group, as described above. Alternatively, a compound of type E1 can be converted to a structurally secret compound via treatment with E5. The E6-like group can then be converted to the carboxylic acid E7 by the above method. The compound converted to the structure vi of E7 can be carried out by activation and reaction with the amine E3, as described above. 128244-3 -241 - 200831489

V. Schema E

f The compound of the invention represented by the compound of structure VII can be prepared by the chemistry described in the scheme p below. W哚F1 can be a reagent such as phosphonium chloride, and the formic acid is clarified in the presence of DMF to obtain indole-3-carboxaldehyde F2. The compound which is converted to the structure VII can be obtained by treating the compound F3 with F2 as described above. Alternatively, the type of compound can be first converted to F4 and then converted to the compound of structure νπ by the guanidinium.

VI. Schema F

R

The compound of the formula G represented by the structure VIII can be made as shown in [g 4 r mountain * pattern G 128244-3 -242- 200831489 structure G1 + the more money can be used by oxidation, using reagents, such as excessive酉夂if is converted into a derivative under the condition of water>column.

The compound of formula H represented by structure IX can be prepared as shown in Scheme H.

VII. Scheme G Structure (1) The carboxylic acid of H1 can be converted into a piperonitrile derivative H2 by various methods. H1 is treated with a nitroalkane such as nitropropane in the presence of an amine source such as ammonium hydrogen phosphate to obtain the hydrazine each monitrile derivative. An alternative route to achieve compound H2 is via intermediate H3. The conversion of H1 to an anthracene derivative H3 can be followed by dehydration, for example, treatment with acetic anhydride and a base, or reaction with a second gasified sulfinium to obtain H2. Compound H2 can then be reacted with a reactive functional group R9(H4) containing a suitable cleavage group L, as described above, to give a compound of structure IX. Alternatively, H1 can be reacted with a reactive functional group containing a suitable cleavage group L (H4) to obtain an intervening substance H5 which can be reacted with a nitroalkane as described above to obtain a samarium-3-carbonitrile IX compound. Compound IX can also be obtained by conversion to hydrazine H6 followed by a dehydration reaction as described above. 128244-3 -243 - 200831489 VIII·图η

H1 Η2 R9-L (H4) Rg-L (H4)

The compounds of the invention represented by structure x can also be prepared as described in Scheme I below. (9) 哚II may be a suitable cyanating agent such as chlorosulfonyl isocyanate (12) or dialkylphosphonium isocyanate, cyanide in a suitable solvent or solvent mixture such as DMF, CH3CN or dioxane. Acidification gives the compound of structure 13. Compound 13 can then be reacted with a reactive functional group & (14) containing a suitable cleavage group L, as described above, to obtain compound X. Alternatively, compound II can be reacted with a reactive functional group R9 containing a suitable cleavage group L to provide a compound of structure 15, which can then be cyanated as described above to provide a compound of formula X. 128244-3 -244- 200831489

IX. Schema I

The compound of formula j represented by structure XI can be prepared as shown in Scheme J. Amino crotonate J1 can be reacted with an amine J2 to obtain J3. The reaction is carried out in the presence of a polar solvent such as acetic acid to obtain a compound of the structure χ. \

Made by the present invention represented by structures XII and XIII. The XI compound can be reacted with azide acetate in the following formula K1 according to the formula K1 in the following formula, in such a manner that the components are in a suitable organic solvent, for example, such as beibei or non- The protic solvent is heated together in the presence of an organic or inorganic base, and is then subjected to α-azeto acrylate Κ3. Κ3 is heated in the presence of a suitable non-reactive organic solvent such as toluene or xylene to obtain an alkoxycarbonyl 吲哚y-functional group with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent such as ether Or the reduction in THF is used as 128244-3 -245 - 200831489 to obtain the intermediate K5. K5 is reacted with a reactive functional group R9(K6) containing a suitable cleavage group L, and as described above, compound K7 is obtained. The compound XII can be obtained by K7 with a cyanating agent such as chlorosulfonyl isocyanate, as described above for cyanidation. Alternatively, K5 is cyanated with an isocyanatosulfonyl ester to obtain K8 which can be reacted with a reactive functional group R9(K6) containing a suitable leaving group L, as described above, to obtain compound XII. An alternative use of intermediate K4 is exemplified below. The hydrolysis of the 2-alkoxycarbonyl group of 吲哚K4, whether under acidic or basic conditions followed by decarboxylation, gives the intermediate K9. The decarboxylation can be carried out thermally, meaning heating in a suitable solvent such as toluene, xylene or quinoline. Alternatively, a source of copper, such as bronze, may be added to promote mitigation. K9 is reacted with a reactive functional group R9(K6) having a suitable leaving group L, and as described above, compound K10 can be obtained. Compound XIII can be obtained by subjecting K10 with a cyanating agent such as cyanuric acid chloroacetic acid acetonate as described above for cyanidation. Alternatively, K9 is cyanated with chlorosulfonyl isocyanate to obtain K11 which can be reacted with a reactive functional group R9(K6) containing a suitable leaving group L, as described above, to obtain compound XIII. 128244-3 -246- 200831489 χι.图κ

The compound of the formula L represented by the structure XIV can be produced as shown in the scheme L. The compound of formula L1 can be ylated on the 2-methyl group to give 2-bromomethyl or chloromethyl hydrazine L2. This halogenation reaction can be carried out with a reagent such as sulphur bromide or chlorosuccinimide. This reaction can be carried out in a suitable solvent, such as gas, four carbonized carbon or THF, and is carried out at ambient temperature in the range between 8 and rc. Optionally, a free radical initiator such as benzoic acid peroxide or AIBN. Compound L2 can then be reacted with a nucleophile (L3) to obtain a compound of the structure 。νν. This reaction can be carried out in a suitable solvent such as THF, hydrazine: 3⁄4⁄4 or DMF at a temperature ranging from 〇C to 120 c. A base such as an inorganic test such as potassium carbonate, 128244-3 -247-200831489 or an organic base such as a trialkylamine may be used to remove the acid formed in the reaction. The group W may refer to an N, 0 or S atom.

ΧΠ.图L

The compound of the present invention represented by the structure XV can be produced as described in the following Scheme M. The aniline of the structure M1 can be diazotized, and the formed diazonium salt can be reduced to obtain a phenyl hydrazine compound] VT2. The compound M4 can be obtained by reacting 肼M2 with ketone M3 under acidic conditions. The conditions for the cyclization reaction can be carried out under typical conditions used by those skilled in the art, for example, acid conditions using an acid such as a Bronstead acid such as acetic acid, hydrochloric acid or polyphosphoric acid, or Lewis acid such as chlorinated. The reaction can be carried out in the presence of a cosolvent such as C^Cl2 or THF, typically at temperatures ranging from 〇°〇 to mot. The reaction of M4 with a reactive functional group r9 (M5) containing a suitable cleavage group L, as described above, provides the compound M6. The compound of structure XV can be obtained by cyanation of hydrazine M6 with a cyanating agent such as chlorosulfonyl isocyanate. Alternatively, Larva M4 can be cyanated to obtain a compound of structure M7. The reaction of M7 with a reactive functional group r9 (M5) containing a suitable cleavage group, as described above, provides a compound of structure XV. 128244-3 -248 - 200831489 XIII. Schema Μ R I NaN02 RiyS production nh2 SnCI2 r3 r3 M1 M2 0 ΝΗΝΗ, [H+]

Ri

%人(M3) R

.....*Net, 丄, Y are not made. The compound of formula 可1 may be combined with a dialkylformamidine dialkyl acetal, such as dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent such as scorpion or dioxane, in the temperature range The compound is obtained from the environment to the boot. The reduction of the exact group of the type N3 compound can be obtained in the standard article ^. The reduction can be carried out by chlorination, catalyzed by a catalyst such as pin or palladium in the presence of a hydrogen source in a protic or non-transient 4 ^ o s & non-bei shell solvent. This reduction is carried out in the temperature range of ° % 80 to 80 C, by chemical reduction, for example in stoichiometry: the diene effect can be carried out in a suitable solvent, in the presence of a compound, in / The dryness is carried out under ambient to boot. 128244-3 -249-200831489 N4 can then be reacted with a reactive functional group r9(N5) containing a suitable cleavage group L, as described above, to obtain a compound of structure N6. The compound of structure XVI can be obtained by cyanation of N6 with a cyanating agent such as isocyanatosulfonyl ester in a suitable solvent. Alternatively, the compound of structure N4 can be cyanated to obtain a compound of structure N7. The reaction of N7 with a reactive functional group r9(n5) containing a suitable cleavage group L, as described above, provides a compound of structure XVI.

XIV schema N

[H]

R

Rq-L (N5)

Cis〇2nco N4 ciso2nco

RiyS CN Λ R RlvV CN r2-V (N5) Ruler 3 N7 R3 XVI r9 The compound of formula i represented by structure XVII can be prepared as shown in the scheme. The compound of structure οι can be converted to 2-iodo- or bromo, 5丨嗓〇2. Typically, a strong base such as n-butyllithium or a second mercaptolithium or lithium diisopropylamine, or a hexamethyldifluoride lithium or potassium nitride is used, with the formation of 2, fluorenyl 128244- 3 - 250 - 200831489 Ions are produced in a non-reactive; cereal, such as _ or thf, or a solvent mixture containing them. The reaction is typically carried out in the range of -78 t to ambient temperature. The 2-chatyl anion can then be quenched with an electrophilic dentate source, including but not limited to iodine, bromine or N-bromosuccinimide to obtain a compound of structure 02. The reaction of 2-moth- or bromo-based ruthenium 2 with di- thiol ruthenium (often referred to as Suzuki reaction) or with trialkylstannane (often broken into Stille reaction) gives the structure χνπ Compound. The coupling reaction is carried out by a method known to the art, and is included in the presence of a catalyst such as ruthenium (triphenylphosphine) palladium (ruthenium), bis(triphenylphosphine) dichloride (π) or palladium acetate. The reaction is carried out along with the added phosphine ligand'. The reaction is carried out in a suitable solvent such as DMF, toluene, dimethoxyethane or dioxane, at a temperature ranging from a ring to a 150 ° C. Regarding the Suzuki reaction, it is usually added. This test can be carried out in an aqueous solution, such as sodium carbonate or an aqueous solution of sodium hydrogencarbonate, or it can be used under anhydrous conditions, such as fluorinated planer or potassium. Regarding the Stille reaction, a copper assisting catalyst such as a copper moth compound may be added. Or '吲哚01 can be converted into hydrazine dihydroxyborane or ruthenium sulphide derivative 〇3 in such a way that the above 2_ 哚 anthracene anion is individually associated with rotten acid trisodium or chloro group Alkylstannane derivative reaction. The compound of type 03 can be reacted with an aryl group and a heteroaryl bromide with an iodide under conditions similar to those described above to form a compound of the structure χνπ. 128244-3 -251 - 200831489 XV. Schema ο f

01 1. Test 1. Alkali 2. Iodization or desertification

R12 - B(〇H)2 Pd° or v R12-Sn(Rii)3 2. B(OR9)3 or CISn(R9)3

The compound of formula I represented by structure XVIII can be prepared as shown in Scheme p. The compound of structure P1 can be converted to compound P3 in such a way that pl is treated as an aryl or heteroaryl group (P2) in the presence of organometallic catalysis. Such a catalyst combination may comprise a palladium catalyst, such as palladium acetate, with a source of copper, such as a steel moth. The reaction can be carried out in the presence of, for example, a carbonic acid planer. Reaction y is at ambient temperature to 150. It is carried out within the temperature range of 〇. 4哚P3 is cyanidated by cyanidation of 4, such as chlorosulfonyl isocyanate, to obtain a structure χνιπ compound. 1 patternΡ

R 12 XVIII system: The compound of the invention represented by structure XIX can be as described in the following formula Q 128244-3 -252 - 200831489

The compound is protected, for example, as the N-Boc derivative Q2. Alternatively, other protecting groups which may be utilized but are not limited thereto include, for example, a benzyl group, an alkyl group or an aryl group, or a dicalcium group. Q2 is subjected to a strong test, for example, diisomethyleneamine, in an aprotic solvent such as THF, followed by quenching the reaction with a trialkyl borate derivative to obtain mercapto-2-dihydroxyborane q3. With aryl or heteroaryl halide Q4, in the presence of palladium catalysis, such as ruthenium (triphenyl scale), (9), two gasified bis(triphenylphosphine), (II) or palladium acetate, accompanied by the addition Compound Q5 can be obtained by the reaction of a scaly ligand. The removal of the protecting group can be obtained by q6. Q6 is reacted with % of a reactive functional group containing a suitable cleavage group L, and as described above, a compound of structure Q7 can be obtained. Cyanation of compound Q7 gives a compound of structure XIX.

XVII. Schema Q

The compound of formula I represented by structure XX can be prepared as shown in Scheme R. 128244-3 - 253 - 200831489 The compound of structure R2 can be prepared by protecting the ten compounds of the structure as, for example, the (10) OC derivative, as described above. The combination of structure R2: can be converted to 2-iodo- or desert-based. Typically, a strong base is used, such as n-butyl or a second or butyl or diisopropylamine, or a hexamethyldicarboxylic acid or potassium, accompanied by the formation of a 2+ radical anion. It is produced in a suitable non-reactive solvent, such as sputum or chat, or a solvent-mixed person containing them. The reaction is typically carried out in the range of Russia to ambient temperature. The anion can then be quenched with an electrophilic (tetra) source, including but not limited to, dimethyl or guanyl succinimide, to obtain a compound of structure R3. After removal of the protecting group, the R4 compound can be reacted with an aryl or heteroaryl diacetone or vinegar (R5) (often referred to as the Wki reaction) to obtain a compound at the structure. The coupling reaction is carried out by methods known to those skilled in the art, and is included in the presence of a catalyst such as trit (triphenylphosphine (9), dichlorobis(triphenyl), (II) or acetic acid The phosphine is coordinated to the hydrazine to carry out the reaction. The reactive functionalization reaction with a suitable cleavage group L, as described above, gives the compound of structure XX.

XVIII. Schema R

[H]+

M2 L-R9

128244-3 • 254· 200831489 The invention is made of the structure ΧΧΪ. The '" thing can be as described in the following figure S. Shore ♦ or Moji can be reacted with a rare type in the presence of a catalyst to obtain a type of compound. The coupling reaction can be as previously described. Square 4仃°_ is similar to the choice of solvent XIX·图 s

^13 R /~1 (or Br) ~~----- (S2) N ΪΙ Τ v Pd° , N r3 vr4 XXI AAI

(V S1 is represented by the structure XXII. The formula of the human-made m'1 can be made as shown in the figure. The 2-构- or 2-bromo-based T of the mouthpiece T1... , J J acetylene, reacted in the presence of palladium catalyst (often referred to as Sonagashira anti-shore), only /曰a long-term), obtained type χΧΙΙ compounds. The coupling reaction can be known by the skilled person. A typical combination of reaction conditions includes the formation of a structure T1 of 7 human 51 wood and an acetylene compound T2, in the presence of a palladium source, a copper promoter and an amine source, the reaction is in a suitable non-reactive solvent. Performed and carried out within the temperature range from ambient to boot. XX. Schema τ

R

R 13 Compounds represented by structure XXIII can be prepared as shown in Figure π. The compound of structure XXIII can be obtained from the reduction of the compound hydrazine. Conditions for deactivating may include, but are not limited to, catalytic reduction, 128244-3 - 255 - 200831489, for example, on a source of platinum or palladium, hydrogenation in a suitable solvent such as CHS%, ether, τΗρ methanol or a combination of solvents.

XXI·图u R

R 13

XXIII

f The compound of the invention which is represented by the structure νιν can be produced as described in the following Scheme v. The structure VI can be reacted with a suitable base such as lithium diisopropylamine or hexamethyldisodium hydride to produce a 2-mercapto anion in a suitable non-reactive solvent such as ether or THF. Or contain a solvent mixture of them. The reaction is typically carried out at a temperature ranging from -78 ° C to ambient temperature. The 2_ fluorenyl anion may then be quenched by a source of i, such as a dentate metal or a solution containing the same, to obtain an organozinc compound of structure V2. (V2 and aryl complex (V3), in the presence of a palladium catalyst (often referred to as

Negishi reaction), obtaining a compound of the structure χχιν. Alternatively, the oxime iodide or bromohydrazine of the structure v4 can be reacted with the organic compound of the structure % as described above, and the compound of the structure XXIV can be obtained by appropriately reacting T in the presence of a catalyst. The organic compound ¥5 can be derived from, for example, an alkyl or alkenyl complex after treatment with activated zinc, or from an aryl or heteroaryl lithium or magnesium compound after treatment with a zinc tooth. Furthermore, the reaction of V2*V4 can be carried out in the presence of a palladium source, such as ruthenium (triphenylphosphine) (0) or bis(triphenylphosphonium) dichloride (II), in a suitable solvent, and in a temperature range. For the environment to 15 128 128244-3 -256- 200831489.

Figure V XXII. f

R F

Zn—R13 (V5) Pd° R c

(V3)

R F

1 (or Br)

R13 — l Pd° R

The compound of formula I wherein R 12 is represented by the structure XXV-XXVIII can be prepared as shown in Scheme w. The 2-iodo- or bromo-hydrazine of the structure W1 can be reacted with the acetylene of the structure W2 in the presence of a ▲ bar catalyst (often referred to as the Sonagashira reaction) to obtain a compound of the type χχν. This coupling reaction can be carried out by methods known to those skilled in the art. A typical combination of reaction conditions involves reacting the oxime of structure W1 with the acetylene compound W2' in the presence of a palladium source, a copper promoter and an amine source. The reaction is carried out in a suitable non-reactive solvent and in a temperature range of from 15 ° C to ambient. XXV reacts with a reactive functional group containing a suitable cleavage group L, as described above, to obtain a structure XXV; [a compound. The 2-iodo- or bromo-hydrazine of the structure W1 can also be reacted with an olefin in the presence of a palladium catalyst (often referred to as a Heck reaction) to obtain a compound of the type χχνπ. This coupling reaction can be carried out by methods known to those skilled in the art. The choice of catalyst and solvent is similar to that previously described. The reaction of XXVII with a functional group R9 containing a suitable cleavage group, 128244-3 - 257 - 200831489, as described above, provides a compound of structure XXVIII. XXIII. Schema w

The compound of formula I represented by structure XXIX can be prepared as shown in Scheme X. The structure XI can be thiolated by a sulfhydryl halide of structure X2 to obtain a compound of structure XXIX. The reaction can be promoted by Lewis acid. The choice of Lewis acid can be selected from, but not limited to, aluminum chloride, iron chloride, tin chloride or diethyl aluminum. The reaction is typically carried out in a suitable non-reactive solvent, including CH2 (3⁄4, monosulfide, or gas-fired, and is typically carried out at temperatures ranging from -20 °C to 80 °C).

XXIV. Schema X

The compound of formula I represented by structure XXX can be formed as shown in Scheme γ. The cyano group (9) of the structure Y1 can be converted into the tetrasole of the structure Y2 by, for example, treatment with sodium azide. Heating the mixture of Y2 and reagent Y3 to obtain 128244-3 -258 - 200831489

It can be carried out in the mouth of the 3-(1,2,4-Sakijiri sit-up) mouth of the mouth of the mouth, including the case and by Y2 and Y3, 醯, or by reagent such as the second ring An acid derivative activated by hexylcarbodiimide imine. The reaction can be carried out by heating in various solvents such as toluene, dioxane, pyridine and dichloroethane, and at a temperature ranging from 30 ° C to 130 ° C.

XXV. Schema Y

The compound of formula I represented by structure XXXI can be prepared as shown in Scheme z. The 3-cyanoguanidine of structure Z1 can be treated with an amine to obtain a compound of formula Z2 via a base pulse. The hydroxyindole of the structure Z2 is reacted with a compound of the structure Z3 to obtain a 0-acid group via the hydrazine Z4. The compound Z3 may represent, for example, a mercapto halide or a carboxylic acid activated with a reagent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide. The compound of structure Z4 can be obtained by heating in a non-reactive organic solvent such as toluene, di-hexane or dioxane in a temperature range of from 30 ° C to 150 ° C. 128244-3 259 - 200831489 xxvi. Schema z

Rs OH nh2oh

Z2

L (Z3)

24 is prepared as a compound of the invention represented by structure XXXII. The keto group (5) which can be of the type AA in the following formula AA can be obtained by using a ketone group with hydroxylamine (free base or acid salt) in a suitable solvent - 刼 + your ία田 / The scorpion is heated and converted into a structure ΑΑ2. The type ΑΑ2 compound is deprotonated by a strong organic base (for example, n-butyllithium or \t-butyllithium or tert-butyllithium), followed by reaction with DMF to obtain a compound of the formula χχχπ. XXVII. Schema ΑΑ

The compound of formula I represented by structure XXXIII can be prepared as shown in the scheme. The 3-keto(9)fluorene of the structure ΑΒ1 can be homologated to the vinyl amide of the structure AB3 by reaction with a dialkylguanamine dialkyl acetal 128244-3 -260-200831489 AB2. The dialkyl decylamines may include, for example, lower alkyl amides such as formamide, acetic acid amine and acrylamide. Examples may include dimethyl mercapto dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be carried out to ambient 150 by using AB1 and AB2 with or without other solvents. The reaction is carried out at a temperature of 〇. AB3 The compound of structure XXXIII can be obtained by treatment with hydroxylamine (free base or acid salt) in a suitable solvent. This reaction is typically carried out at ambient temperatures up to 12 (rc).

XXVIII. Schema AB

The compound of formula I represented by structure XXXIV can be made as shown in Scheme AC. The vinyl amide of the structure AC1 (prepared as above) can be treated with 肼ac2 in a suitable organic solvent (foot, alcohol or acetic acid) at a temperature ranging from ambient temperature to 150 C to obtain a compound of structure xxxiv .

XXIX. Schema AC

The compound of the present invention represented by the structure XXX V is prepared. Can be made with the isocyanic acid to the structure of the AD3 ox-3-carboxaldehyde (according to Figure 124, 128244-3 • 261 - 200831489 - (toluenesulfonyl) methyl ester (as in the drawing below AD) TOSMIC), which is reacted in the presence of a base to obtain a compound of the structure XXXV. The base may include potassium carbonate or 1,8-diazabicyclo[5A0]undec-7-ene, and the reaction may be carried out in an appropriate organic solvent from the environment. The temperature is carried out at 150 °C.

XXX. Schema AD

The compound of formula I represented by structures XXXVI and XXXVII can be prepared as shown in Scheme AE. The 3-indole carboxylic acid of structure AE1 (from Figure E) can be converted to the guanamine of structure AE2. The compound of structure AE2 can be activated by any standard method. For example, acid AE1 can be coupled to a reagent, such as EDCI or DCC, with or without HOBt, activated in the presence of ammonia. Alternatively, the acid can be activated to become chlorinated acid or to form an acid group 1:7 m squat as 'previously' followed by treatment with ammonia. The indole-3-carboxamide of the structure ΑΕ2 can be reacted with a substituted aldehyde or ketone (ΑΕ3) containing a suitable cleavage group L in a suitable solvent at a temperature above ambient and up to 200 °C. The reaction can be carried out with or without the addition of a base to give the carbazole of structure XXXVI. The (9) indole-3-carboxamide of structure AE2 can also be converted to the thioguanamine of structure AE4 by using the primary acid amine as Lawesson's reagent or phosphorus pentasulfide at or above ambient temperature in a suitable organic solvent. Processing. The formed thioguanamine AE4 may be substituted with a suitable cleavage group L or a ketone of 128244-3 -262-200831489 ketone (AE3) in a suitable solvent, above ambient and up to 150 ° C The next reaction. The reaction can be carried out with or without the addition of a base to give a thiazole of the structure XXXVII.

XXXI. Schema AE

The compounds of the invention represented by structures XXXVIII and XXXIX can be prepared as described in Scheme AF below. The 3-keto oxime of structure AF1 can be halogenated (e.g., brominated) to provide a compound of structure AF3. Suitable brominating agents can include, but are not limited to, phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine, and can be carried out in a variety of organic solvents. Compound AF3 can be obtained as a carbazole of structure XXXVIII by treatment with a hydrazine of the type AF4 in a suitable solvent at a temperature above ambient and up to 200 ° C with or without the added base. Compound AF3 is sulphate of type AF5, in a suitable solvent, at a temperature higher than 128244-3 -263 - 200831489 and up to 150 ° C. The thiophene of structure XXXIX can be obtained without using the added base.

XXXII. Schema AF

Compounds of formula I which are represented by structure XL can be prepared as shown in Scheme AG. The structure AG1 can be brominated or iodinated to obtain a compound of structure AG2. The brominating agent may include, but is not limited to, bromine or bromine succinimide, and the iodinating agent may include iodine monochloride or bis-trifluoroacetoxyiodobenzene. The reaction of 3_iodo or bromoguanidine AG2 with dihydroxyborane AG3 (often referred to as the Suzuki reaction) provides the compound of structure XL. The coupling reaction is carried out by methods known to the art, and is included in the presence of a catalyst such as ruthenium (triphenylphosphine), (9), bis(triphenylphosphine)palladium(II) or palladium acetate, accompanied by The added phosphine ligand is reacted. The reaction is carried out in a suitable solvent such as DMF, toluene, dimethoxyethane or dioxane, at a temperature ranging from ambient to 15 Torr. The underarms, and 128244-3 - 264 - 200831489 are typically employed in the presence of a base such as sodium carbonate or aqueous sodium bicarbonate, or such tests can be employed under anhydrous conditions, such as cesium or potassium fluoride. ,,? Eucalyptus AG2 can be converted into 啕哚j dihydroxyborane derivative AG5, ^, in a manner such that 3-halo hydrazine AG2 reacts with a strong organic base (alkyl lithium or $, hydrazine) and forms an anion Reacting with the trialkyl borate reagent AG4, the il AG5 compound can be combined with aryl and heteroaryl desertification and telluride,

The reaction is carried out under conditions similar to those described above to form a compound of structure XL. XXXIII·Graphic AG

Pd° R12 - β(0Η)2 (AG3) Pd° Ri2—L (AG6)

/ The compound of the present invention represented by the structure XLI can be produced as described in the following scheme ah. The 3-iodo- or bromo-hydrazine of structure AH1 can be reacted with an ethylenic AH2 in the presence of a palladium catalyst (often referred to as a Heck reaction) to obtain a compound of the type red quinone. This coupling reaction can be carried out by methods known to those skilled in the art. The choice of catalyst and solvent is similar to that described in Scheme AG. 128244-3 -265 - 200831489

XXXIV. Schema AH

R3 R4 XLI

R3 R4 produces r13 (AH2)

Pd° The compound of formula I, represented by structure XLII, can be prepared as shown in Scheme VIII. The 3-All- or bromo-based p?- of the structure All can be reacted with acetylene Ai2 in the presence of a catalyst (often referred to as the Sonagashira reaction) to obtain a compound of the type XLn. This coupling reaction can be carried out by methods known to those skilled in the art. A typical combination of reaction conditions involves reacting the (5) fluorene of the structure All with the acetylene compound AI2 in the presence of a palladium source, a copper cocatalyst and an amine source, and reacting at a temperature ranging from ambient to 150 °C.

XXXV. Schema AI

The compounds of the invention represented by structures XLIII and XLIV can be prepared as described in Scheme AJ below. The nitroaniline of structure AJ1 can be converted to the β丨嗓 of structure XLIII via the condensation and cyclization of the nitrile of structure AJ2. This reaction can be carried out in a suitable organic solvent such as DMF or dioxane. The compound of structure XLIII is treated with a base and then reacted with a reactive functional group R9 containing a suitable cleavage group L to provide a compound of formula XLIV. 128244-3 266 - 200831489

XXXVI.图AJ EE / jf^YF —~— J (AJ2> V base of- Η rVy-NH; o2n^^^n r9 AJ1 XLIII XLIV The compound of formula I represented by structure XLV-XLVIII can be as shown Manufactured as shown in AK. The 2-amino hydrazine of structure XLV may contain a reactive functional group Rl 5 suitably deprotected from the group L, in the presence of, for example, sodium hydride or carbonic acid, alkylated in a suitable organic solvent. A compound of structure XLVI is obtained. A compound of structure XLVII can be obtained in a similar manner using a second alkylation reaction containing a reactive functional group R\5 suitably separated from the group L.

The structure XLV compound is obtained by the oximation of ruthenium chloride of the structure AK1 to obtain a compound of the structure XLVIII. The reaction is typically carried out in the presence of an organic base such as a trialkylamine or an inorganic base such as potassium carbonate in a suitable organic solvent. XXXVII. Schema AK

(AK1) 〇2n test

Nhr15 test R'15-L

E

The compound of the present invention represented by the structure XLIX can be produced as described in the following scheme AL. 128244-3 -267 - 200831489 The structure of the ALl quinone-3-carboxylic acid can be activated to obtain a compound of the structure AL2. The compound of structure AL2 can represent, for example, an acid group! a compound, or a tickacid activated by a reagent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide. The reaction of the structural AL2 compound with the structure of the AL3 group gives a ruthenium-S group via the base AL4. Hydroxyl hydrazine is commercially available or can be obtained by treating a nitrile compound with an amine. The compound of the structure AL4 is heated in a temperature of from 30 ° C to 150 ° C in a non-reactive organic solvent such as methyl, trichloroethane or monooxon to obtain a compound of the structure XLIX.

XXXVIII·图 AL co2h R Vl < activation R1x fVVi R3 R4 r4 clever AL2 r5 NH Rl3~< HN-OH (AL3) NH Rl3

R

Rv i AL1

AL4

The compound represented by the structure XLX can be prepared as shown in the scheme AM. a compound of the formula AM1 (the R group & defined above as being on (4): 1-3 substituents), when a base, copper (I) iodide and a substituted amine, wherein z is defined as When treated as described above, a compound of formula am2 is provided. The intermediate product AM3 is provided in a solvent such as, but not limited to, dichloromethyl 9, tetrahydrofuran or toluene at a temperature ranging from ambient to reflux, in the presence of 2-oxoacetyl chloride, with a base such as triethylamine. The system is then cyclized to form a compound of structure 128244-3 -268 - 200831489 AM4 using palladium acetate (II) as a catalyst, a phosphine ligand, and a base such as triethylamine in a solvent, such as but not Limited to tetrahydrofuran, dimethylformamide or toluene, at ambient to reflux temperature. The reduction and removal by hydride source, such as DIBAL-H, provides the intermediate AM5 in a solvent such as, but not limited to, methylene chloride, tetrahydrofuran or toluene at a temperature from Ot to reflux. The subsequent steps leading to the product XLX are described above.

XXXIX. Schema AM

AM1

Cicoch2ci a^nh base 0 z AM2

AM5 AM6 Z - nh2 -> K3PO4/ Cul

The compound of formula I represented by structure XLXI can be prepared as shown in the scheme AN. The compound of the formula AN1 may be derived from a trifluoromethanesulfonate source such as trifluoromethanesulfonic anhydride, and a base such as pyridine in a solvent such as, but not limited to, tetrahydrofuran, 128244-3 -269-200831489, or a benzene in the environment. Treatment to reflux temperature to provide intermediate AN2. AN2 can be directly substituted with palladium (9) and a core 2 substituted trialkyltin compound in the presence of cesium fluoride and copper (I), in a solvent such as, but not limited to, tetrahydrofuran, dimethylformamide Or toluene, reacting at ambient to reflux temperature to provide product XLXI, or in a two-step sequence, with dimethyl butanediol borane source, such as bis-quinone diborane, palladium (9) and base For example, in the presence of potassium acetate, in a solvent such as, but not limited to, tetrahydrofuran, -oxoindene or a|, coupled at ambient to reflux temperature to provide a tick, followed by (9), gasification and appropriate r12l compound The second palladium coupling is provided in a solvent towel such as, but not limited to, tetrahydrofuran, dimethoxyethane or toluene at a temperature to reflux to provide a red edge. XL.图AN R\17 E r17 , E (R”0)3B-L R1

Tf-L base

Tfc/ , N , R4 AN2

Ri2SnBu3

Pdc

V17 E Pd (||) (Rh〇) 3B

c. Method of the Invention Another aspect of the present invention relates to the treatment of one or more of C in a patient suffering from a hepatitis C virus (HCV) infection! Compound or 1% disease: administration of an effective amount of a pharmaceutical composition 'This composition comprises an effective amount of a compound of formula i 128244-3 -270. 200831489, or one or more of them pharmaceutically acceptable salt. The term "treatment" as used herein means: (1) prevention of a disease, condition or symptom occurring in a patient who may be susceptible to the disease, condition and/or symptom but has not yet been diagnosed as having the disease; (9) Inhibiting a disease, disorder, or condition, that is, curbing its development; and/or (iii) reducing a disease, disorder, or condition, that is, causing degradation of the disease, disorder, and/or condition. The term "patient" as used herein refers to an animal or any living organism that has the ability to perceive consciousness and free will, and which requires its existing oxygen and organic food. Non-limiting examples include members of human, horse, pig, cow, mouse, canine, and feline species. In some embodiments, the patient is a mammal or a warm-blooded vertebrate. In other specific embodiments, the patient is a human. The term "patient" as used in this article can be used interchangeably with, human, and human. Without being limited to any particular theory, it is believed that the compounds of the invention inhibit the initiation, elongation and termination of the IRES mediator, i.e., by directly interfering with the function of Peng and/or the interaction of IRES with cellular and/or viral factors. Translation. Accordingly, another aspect of the invention relates to a method of treating a viral infection that is resistant to a wild-type virus or to an currently available antiviral agent in a patient in need thereof, wherein the wild-type or drug-resistant virus system comprises Internal ribosome entry site (IRES), the method comprising administering to the patient an effective amount of one or more compounds of the invention or one or more pharmaceutically acceptable salts thereof, or a pharmaceutical composition, the composition comprising an effective One or more compounds of the invention as described above, or one or more pharmaceutically acceptable salts thereof. Non-limiting examples of such viruses include diseases of the picornavirus species 128244-3 -271 - 200831489 such as poliovirus, hepatitis A virus, coxsackie virus, and nasal sputum The virus, such as _; the disease of the genus of the arbovirus, the virus of the genus of the genus 'such as yellow fever, dengue fever and gamma-heavy virus; the virus, such as the cancer-only virus associated with Kaposi's sarcoma (four) virus, And other viruses with similar replication patterns; and (iv) 'human leukemia virus (HT^ and other viruses with similar translation patterns.) Another aspect of the invention relates to a vector that inhibits HCVIRES in a patient in need thereof And a method of translating and/or replicating comprising administering to the patient one or more compounds of formula J or one or more pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising an effective amount One or more compounds of formula I as described above, or one or more pharmaceutically acceptable salts thereof. Some methods of the invention comprise administering one or more compounds of formula J, or a pharmaceutical composition The composition comprises one or more compounds of the formula J, wherein: X is: -nitro; -cyano; -CORa group, wherein Ra is: -(^ to decyl, -A to Cs aryl, Substituted by alkoxy or halogen, or • dialkyl-amino group; ...COORx group, the center of which is ^ to ^ alkyl; - fluorenyl; 128244-3 -272 - 200831489 -c6 to c8fang a group, optionally substituted by an alkoxy group; or a -5 or 6-membered heteroaryl group, optionally substituted by the following: -^ to decyl, -C6 to C8 aryl, optionally alkoxy or one or a plurality of halogen substitutions, or -5 to 6 membered heteroaryl; Y is: - a calcinyl group, - a halogen; - an amine group, optionally substituted by one or more (^ to a C6 alkyl group; - a benzoquinone - benzopyrene; - dibenzofuran; - dibenzopyrene; - benzopyrene; sitting; - hydrazine; - hydrazine, optionally substituted with Ci to c6 alkyl on nitrogen;

Wherein Rb is hydrogen or CiSQ alkyl, and η is 0 or 1; 128244-3 -273 - 200831489

Wherein R is hydrogen, -CONHRx, the center of which is as defined above, or -S02Rx, the center of which is as defined above; or \, /\, where Rd is a Ci to C6 alkyl or a C6 to C8 aryl; NHCORe group, wherein Re is: -(^ to (:6 alkyl; -C6 to Cg square group) is optionally substituted by the following - -^ to ^alkyl, -alkoxy, -cyano, -tridyl , or -halogen; -nhcoorx group, wherein 1 is as defined above; -CH2〇-Rf group, wherein Rf is c6sc8 aryl; -NRgRh group, the center of which is ^ to ^alkyl or hydrogen And 1^ is 〇6 to (:8 aryl, optionally substituted by alkoxy; -Ci to c6 alkyl; -5 or 6 membered heteroaryl, optionally substituted by: 128244-3 -274 - 200831489 -Cl to C6 thiol, optionally substituted by c6sc8 aryl, -C6 to CS aryl, optionally substituted by -COORx, wherein Rx is as defined above, or -amino; 5 or 6 membered heterocycle, optionally Substituted by: —COORx group, wherein & is as defined above, or --NHCO〇Rx group, the center of which is as defined above; Α to Q aryl, optionally substituted by one or more of the following groups : - Alkoxy, as appropriate Lower substitution: - alkoxy, -hydroxyl, - one or more halogen, -5 or 6 membered heterocyclic ring, optionally substituted by the following: -Ci to C6 alkyl, or -hydroxy, -amino, optionally One or more (^ to decyl-substituted '-NRiS02Rx groups, wherein Rx is as defined above, and Ri is - hydrogen, -q to c6 alkyl, -CORx group, wherein Rx is as above Definition, - haloalkyl, or -haloalkoxy, -NRj CORk group 'where Rk is -CiSC6 alkyl, ^28244-3 -275 - 200831489 -nitrogen, or -amine, optionally as appropriate - Or a plurality of cac6 alkyl groups, and Rj is: - hydrogen, -CiSQ alkyl, _-CORx group, the center of which is as defined above, - anthracenyl, or -halo alkoxy, -Ν=Ν + = oxime group, or --COR! group, wherein & is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group, and the -amino group is optionally substituted by one or more Ci to q alkyl groups, _ The base, C! to C6 alkyl, optionally substituted by the following: ...NHS〇2Rx group, wherein Rx is as defined above, or --NRX S〇2 Rx group, wherein as defined above - Alkoxy, -halogen, _hydroxy, -COORx group, where rx As defined above, a --CORm group, wherein 1^ is: - an amine group, optionally substituted by one or more q to C6 alkyl groups, wherein one or more ci to C6 alkyl groups are optionally substituted as follows: - thiol, 128244-3 - 276 - 200831489 -5 or 6 membered heterocyclic ring, -amino group, optionally substituted by one or more <^ to 0:6 alkyl and ' or 7 or -alkoxy, - a 3 to 7 membered heterocyclic ring, optionally substituted by Cl to (6 alkyl, which is optionally substituted with a dialkyl-amino group, a -NNRn group, wherein Rn is: -CH2CONH2, or -Q To the c8 aryl group, as the case may be substituted by: -alkyl, or a plurality of hormones, -nitro group, or -one or more alkoxy groups, -NR. a CORp group, wherein Rp is: -Q to Q alkyl, optionally substituted by: -halogen, -alkoxy, or -c6 to C8 aryl, -5 or 6 membered heterocyclic ring, -C0 to Cs aryl a group, optionally substituted by halogen, -5 or 6 membered heteroaryl, optionally substituted by one or more G to C:6 alkyl groups,

128244-3 •277- 200831489

And where R. Is: - hydrogen, -Ci to C6 alkyl '-CORx group, the center of which is as defined above, -haloalkyl, or -haloalkoxy, -NRqCONRqRr group, wherein Rq is: - heart to A decyl group, a -13⁄4 alkyl group - a halogenated alkoxy group, or a -CORx group, the center of which is as defined above, and wherein Rr is: -C6 to C8 aryl, optionally substituted as follows:

-Cl to alkyl group - an ORs group, wherein 1 is a <:6 to 08 aryl group, or 128244-3 -278 - 200831489 ...COORx group, the center of which is as defined above, -q to C6 alkyl , optionally substituted by one or more of the following groups: _halogen, -alkylidene, -匸6 to C8 aryl, and / or -COORx group, the center of which is as defined above, -COORx group Wherein Rx is as defined above, a --NRt COORu group, wherein ru is: -(: 丨 to (: 12 alkyl, as appropriate substituted by: • C6 to C8 square, optionally Ci to C6) Substituted or alkoxy substituted, - sub-alkyl, - alkoxy, - alkyne, - halogen, or -5 or 6 membered heterocyclic ring, - to c8 aryl group, optionally substituted by the following - alkoxy group, - halogen, or • 01 to .6 alkyl, or -5 or 6 membered heterocyclic ring, and Rt is: - hydrogen, -ci to c6 alkyl, 128244-3 -279 · 200831489 - CORx group, center As defined above, -_alkyl group or -_alkoxy'-NRvS02Rw-based fluorene, the center of which is: - hydrogen, -CORx group, wherein Rx is as defined above, or -(^ to alkane Base, as the case may be replaced by: -13⁄4 prime, --CORx group, its The heart is as defined above, the _-OCORx group, the center of which is as defined above, -transformyl, or -alkyloxy, and wherein Rw is: -q to C6 alkyl, optionally substituted by: - halogen, - a halogen group, a -c6 to c8 aryl group, or a -5 or 6 membered heterocyclic ring, -C2SC6 alkyl group, -alkyl- or dialkyl-amino group, optionally substituted by halogen, -5 or 6 members Heterocycle, or -5 or 6 membered heteroaryl, optionally substituted by the following: -Ci to alkyl" -5 or 6 membered heterocyclic ring, or 128244-3 -280 - 200831489

128244-3 -281 - 200831489 wherein Rz is hydrogen or ClSC0 alkyl, as the case may be. Aryl substituted, -SRX group, the center of which is as defined above, -s〇2Raa group, wherein Raa is: -ci to C6 alkyl, -amino group, -alkyl- or dialkyl-amino group , optionally substituted by a hydroxy or _c 〇〇 Rx group wherein Rx is as defined above, -5 or 6 membered heteroaryl, -C6 to Cg square, and/or --NHRb b group, wherein Rbb For: *

a C(=S)NH2 group, or a -P〇(〇Rx)2 group, the center of which is as defined above; —=Rcc group, wherein Rc c is: -荇, 5 or 6 members Aryl J^Y. '-Q to aryl, optionally substituted by one or more of the following groups. 128244-3 -282 - 200831489 - alkoxy, -yl, -halogen, -q to c6 alkyl, optionally cyano Substituted, -amino group, optionally substituted by one or more q to c6 alkyl groups, -NHPORx Rx, wherein Rx is as defined above, ... NReeCONRffRff group, wherein Ree is hydrogen or (^ to (36 alkyl, The situation is replaced by a halogen, and Rff is: -hydrogen, -haloalkyl, -haloalkoxy, -Ci to Cs, or -CORx group, wherein, as defined above, ... NRg g CORh h group Wherein: - hydrogen, -C! to Q alkyl, optionally substituted by: - a gas group, a halogen, or an -amine group, optionally substituted by one or more Ci to C6 alkyl groups, -amine a group, optionally substituted by one or more Ci to a decyl group, wherein the alkyl group is optionally substituted by il, -5 or 6 membered heterocyclic ring, _ 5 or 6 membered heteroaryl, and Rg g is: 128244-3 -283 - 200831489 - hydrogen, -Ci to C6 alkyl"-haloalkyl, -haloalkoxy, or --CORx group, wherein Rx is as defined above, -haloalkyl, -5 or 6-membered heterocyclic group, ί

The I-amino group is optionally substituted with one or more Q to c6 alkyl groups, and /戍-NRi i SO. An Rx group, wherein Rx is as defined above, and wherein i is: - hydrogen, -C to c6 alkyl, - anthracenyl, -haloalkoxy, -CORx group, wherein rx is as defined above Z is: -Q to Q alkyl, optionally substituted by the following - alkoxy, - one or more halogens, or -c6 to c8 aryl; -c2 to c6 alkyl; -Q to Q An aryl group, optionally alkoxy or one or more. Alkyl substitution; -_COORx group, the center of which is as defined above; or 128244-3 200831489

R is nitrogen, halogen or alkoxy;

Ri is: - murine, -hydroxyl; -halogen; -haloalkyl, -accord, -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclic ring; -alkoxy, optionally substituted as follows: - One or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -C6 to C8 aryl, optionally substituted by alkoxy; -CORx group, the center of which is as defined above; a -q to C6 alkyl group, optionally substituted by a dialkyl-amino group or a 5 or 6 membered heterocyclic ring; or

Ri and R2 are joined together to form. ✓

128244-3 - 285 - 200831489 R2 is: - bowl base; - nitrogen; - halogen; - warp group; -C! to c6 alkyl group, optionally substituted by one or more halogens; - amine group; - alkoxy group Substituted as follows - one or more halogen, - 〇CORx groups, wherein Rx is as defined above, • dialkyl-amino group, optionally substituted by alkoxy group, -5 or 6 members a heterocyclic group, optionally substituted by a q to C6 alkyl group -5 or 6 membered heteroaryl, or a -c6 to c8 aryl group; a _-COORx group, wherein Rx is as defined above; - a halogen group; The guanamine group is optionally substituted with: -hydroxyl, or -C6 to c8 aryl; -5 or 6 membered heteroaryl; ...OCORx group, the center of which is as defined above; -NHCORj" group, wherein Rj"· is: - alkoxy group, or -amino group 'optionally substituted with one or more Ci to c6 alkyl groups; 128244-3 -286 - 200831489 -ORkk group 'where Rkk is 5 to 6 members Aryl; --NHS〇2Rx group' whose center is as defined above; or R2 is bonded to &

R3 is: - nitrogen; or -CH2 OCORx ' and Rx is as defined above. The term "effective amount" as used herein refers to the amount required to produce the desired effect. For example, an effective amount can be in a patient, or more specifically, in humans, > The amount of hepatitis virus (HCV) infection required to treat the amount of virus required to contain the internal erythrosome into position _s, the amount required to inhibit the initiation and/or translation of the mediator of HCV IRES, or inhibition The amount required for viral replication or infection. In some cases, the desired effect can be determined by analyzing the following conditions: (1) the presence of Hcv; (7) the presence of anti-HCV antibodies; and (3) serum alanine transaminase (ALT) and aspartate transaminase (AST) content (ALT and AST are improved in chronic patients with chronic infection); (4) liver cell damage due to HCV infection, including Fat fe: sex, fibrosis and cirrhosis; (5) hepatocellular carcinoma due to chronic HCV infection; and (6) extrahepatic sputum infection by HCV or other virus containing 111 £§ element (non-limiting example) Including scrapie, encephalopathy, mental illness, such as anxiety or depression) The effective amount of the patient depends on various factors, including the weight, size and health of the patient. The effective amount for a particular patient can be 128244-3 -287 - 200831489 ' It is within the scope of the clinician's technology and judgment. For any compound, an effective amount can be estimated first, either in cell culture assays or in associated animal models such as 狨 and lion#. Animal models can also be used to determine the appropriate concentration range and route of administration. This information can be followed by a dose and route of administration that can be used in humans. Therapeutic efficacy and toxicity can be determined in cell cultures or experimental animals by standard medical procedures, such as ED- in 5% of the individual population, therapeutically effective agents, (up to 5G% of individual group lethal doses) ). The dose ratio between therapeutic and toxic effects is the therapeutic index and it can be expressed as a ratio called. . In some specific embodiments, the effective (4) results in a large therapeutic index. In a further embodiment, the dosage of Formula I is within a range of circulating concentrations, including EDw having a polar J or innocuous. This dosage can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration. Further, the concentration-biological relationship found for the compounds of the present invention indicates that the initial target plasma concentration ranges from about 微1 μg/ml to about 100 μg/ml, from about 1 μg/ml to about 5 μg. /ml, about 5 micrograms/ml to about 50 micrograms/ml or about 1 microgram/ml to about 25 micrograms/ml. In order to achieve such a plasma concentration, the compound of the present invention can be administered at a dose varying from 〇1 μg to 1 〇〇, depending on the administration of the drug. Guidance on specific dosages and delivery methods is provided in the literature and is generally available to practitioners in the art. Generally, the dosage is from about i mg/day to about 1 g/day or from about 1 to about 3 g/day or from about 0.3 to about 3 g/day or from about 5 to about 2 g. In the range of /day, 'single, differentiated or continuous dose, for about 4 〇 to about 1 〇〇 kg body weight 128244-3 200831489 病病(5海剂E can be higher or lower than this weight range The patient is dying, especially for children under 40 kg). In the correct case, the practitioner will make a decision after understanding the factors associated with the patient. Dosage and administration can be adjusted to provide a sufficient level of active agent or to maintain the desired effect. Factors that can be taken into account include the severity of the disease state, the general health of the patient, the age, weight and sex of the patient, diet, time and frequency of administration, drug combination, response sensitivity, and resistance to therapy. /Respond. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, weekly or biweekly, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions of this invention can be administered to a patient via any of the drug delivery routes known in the art. Non-limiting examples include oral, ocular, rectal, cheek, topical, nasal, ocular, subcutaneous, intramuscular, intravenous (a bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration. D. Metabolites of the compounds of the invention Also within the scope of the invention are in vivo metabolites of the compounds described herein. Such products may be caused, for example, by the oxidation, depressive action, hydrolysis, amide amination, esterification, etc. of the administered compound, primarily due to the enzyme process. Accordingly, the invention includes a compound produced by a method comprising contacting a compound of the invention with a mammalian tissue or mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by the preparation of a radiolabel (e.g., C14 or H3) compound of the invention at a detectable dose (e.g., greater than about 0.5 mg/kg) for mammals such as rats. , rats, guinea pigs, monkeys, or humans, allowing sufficient time for the development of the new 128244-3 -289 - 200831489 metabolism (typically about 3 sec to 3 hrs), and from urine, liquid or other organisms The sample is isolated from its conversion product. These products are easily isolated, as they are identified (others are isolated by antibodies that bind to the original site of the metabolic product). The structure of the metabolite is determined in a conventional manner, for example by _ or surface analysis. In general, the analysis of metabolic products can be carried out in the same manner as the conventional drug metabolism studies known to the artist. These transformation products, as long as they are not otherwise found in the living body, can be used for the treatment of a diagnostic test for taking the person of the present invention even if they do not have their own biological activity. E. The pharmaceutical composition of the present invention Yet another aspect of the invention relates to a pharmaceutical composition comprising: (1) one or more compounds of the formula ι as described above or one or more pharmaceutically acceptable salts thereof; and (8) one Or a plurality of pharmaceutically acceptable agents. In some embodiments, the pharmaceutical composition comprises one or more illusion characters, wherein: " X is: -nitro; -cyano; -CORa group, wherein: -(^ to (:6 alkane) a group, _ Q to Cs aryl, optionally substituted by alkoxy or halogen, or ~ -^alkyl-amine; -COORx group ' wherein alkyl; 128244-3 -290- 200831489 - formazan ; -c0 to c: 8 aryl, optionally substituted by alkoxy; or -5 or 6-membered heteroaryl, optionally substituted by the following: -(^ to (:6 alkyl, _ C6 to Cs aromatic a group, optionally substituted with an alkoxy group or one or more i-members -5 to 6 membered heteroaryl; hydrazine: haloalkyl; -halogen; an amine group as the case may be one or more q to c6 alkyl groups Substituted - benzofuran; - benzothithiophene; - dibenzo benzophenanthene; - dibenzothiophene; - benzophenanthrene; f chlorophyll, optionally substituted with Cl to C6 alkyl on nitrogen;

Wherein Rb is hydrogen or ClSC6 alkyl, and η is 0 or 1; 128244-3 -291 · 200831489

R〇

Wherein Rc is hydrogen, -CONHRx, the center of which is as defined above or -S02 Rx, wherein Rx is as defined above; or /Rd \ 'where Rd is C! to C6 alkyl or C6 to C8 aryl; -NHCORe group, wherein Re is: -(^ to (:6 alkyl; -c6 to c8 aryl, optionally substituted by the following - (^ to 〇: 6 alkyl, - alkoxy, - cyanide a group, a moth group, or a -halogen; -NHCOORx group, wherein rx is as defined above, a -CH20-Rf group, wherein is converted to a c6 to C8 aryl group; -NRgRh group, wherein R^C ^c6alkyl or hydrogen' and Rh is (:6 to <:8 aryl, optionally substituted by alkoxy; -(^ to (:6 alkyl; -5 or 6 membered heteroaryl, optionally) Substituted by: 128244-3 -292 - 200831489 -ci to C6 thiol, optionally substituted by c6 to c8 aryl, to csaryl, as appropriate (00Rx substituted, where I is as defined above, or fenamine a 5- or 6-membered heterocyclic ring, optionally substituted by the following: -C00Rx group, the center of which is as defined above, or ...NHCO〇Rx group, the center of which is as defined above; -C0 to Q aryl , as the case may be replaced by one or more of the following groups: - alkoxy, as appropriate Substituted by: - alkoxy, - thiol, " one or more 13⁄4 prime, -5 or 6 membered heterocyclic ring, optionally substituted by the following: -4 to 0:6 alkyl, or -hydroxyl, - An amine group, optionally substituted by one or more q to C6 alkyl groups, a -NRiS02Rx group, wherein Rx is as defined above, and & is: - hydrogen, -C! to C6 alkyl, -CORx group a group wherein Rx is as defined above, -_alkyl, or -haloalkoxy, -NRjCORk group, wherein Rk is: -4 to (:6 alkyl, 128244-3 -293 - 200831489 - rat, Or -amino group, optionally substituted by one or more (^ to decyl, and Rj is - hydrogen, -^ to decyl, -CORx group, wherein Rx is as defined above, -13⁄4 a group, or a -haloalkoxy group, a -_N=N+ =N_ group, or a -COR! group, wherein R1 is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group, an amine group, optionally Or a plurality of C! to C6 alkyl substituents, - a base group, -C! to a C6 alkyl group, optionally substituted by the following: -NHS02 Rx group, wherein rx is as defined above, or --NRxS02Rx group, Wherein 1 is as defined above, -13⁄4 alkoxy 5-halogen, _trans-based, -COORx group Wherein Rx is as defined above for the '-CORm group, wherein: - an amine group, optionally substituted by one or more C! to C6 alkyl groups, wherein the far Q to C6 alkyl group is optionally substituted as follows: -hydroxyl, 128244-3 -294- 200831489 -5 or 6 membered heterocyclic ring, amine group, optionally substituted by one or more (^ to decyl group - alkoxy group, -3 to 7 membered heterocyclic ring, The situation is replaced by a C! to C6 alkyl group which is optionally substituted by a dialkyl-amine group, a -NHRn group having a center of: -_ch2conh2, or -Q to c8 aryl, optionally as follows Substituting: - an alkyl group, - or a plurality of _ primes, - triazole, or - one or more alkoxy groups, _ -NR. a CORp group, wherein ~ is -C- to A alkyl, optionally substituted by the following - halogen, - alkoxy, or -C6 to C8 aryl, -5 or 6 membered heterocyclic ring, -Q to C:8 aryl, optionally substituted with '-5 or 6-membered heteroaryl, optionally substituted by hydrazine or multiple C! to Q alkyl groups,

128244-3 -295 - 200831489

And where R. To be: - hydrogen, -(^ to (:6 alkyl, --CORx group, the center of which is as defined above, -13⁄4 alkyl) or -haloalkoxy, -NRqCONRclRI based, wherein Rq is: - hydrogen, -CiSQ alkyl, -haloalkyl, -13⁄4 alkoxy' or -CORx group, wherein 1 is as defined above, and wherein Rr is: -C6 to C8 aryl, optionally substituted as follows :

-^ to a decyl group, a _-〇Rs group, wherein RsSC6SC8 aryl, or 128244-3 -296 - 200831489 -COORx group, the center of which is as defined above, -C to C6 alkyl, as appropriate Substituted by one or more of the following groups: - halogen, -alkylidene, -C6 to c8 aryl, and/or --COORx group, wherein Rx is as defined above, -COORx group, centered as above Definition, -NRtCOORu group, the center of which: - (^ to ^ 2 alkyl, as the case is replaced by -·c0 to q aryl, optionally substituted by Ci to q alkyl or alkoxy, - alkylene, -alkoxy, -alkyne, -halogen, or -5 or 6 membered heterocyclic ring, -C6 to Cs aryl, optionally substituted by: -alkoxy, -halogen, or Ci to C6 alkyl, or -5 or 6-membered heterocyclic ring, and Rt is: -chloro, -C^C6 alkyl, 128244-3 -297- 200831489 -CORx group, the center of which is as defined above, -13⁄4 A radical or a "haloalkoxy"-nrvso2rw group, wherein 1^ is: hydrogen, a -CORx group, wherein Rx is as defined above, or -q to C6 alkyl, optionally substituted as follows: - halogen, --CORx group, the center of which is as defined above , --OCORx group, the center of which is as defined above, -trans-based, or -alkoxy, and wherein Rw is: -q to C6 alkyl, optionally substituted by the following - halogen, - dentate 5 -c6 to c8 aryl, or -5 or 6 membered heterocyclic ring, -02 to (: 6-alkyl, -alkyl- or dialkyl-amino) as appropriate by halogen - '5 or 6 members Heterocyclic ring, or -5 or 6 membered heteroaryl, optionally substituted by the following -CiSC6 alkyl, -5 or 6 membered heterocyclic ring, or 128244-3 -298 - 200831489

For (^ to (: 6 alkyl or hydrogen,

128244-3 -299 - 200831489 八中 Rz is 虱 or (^ to decyl, optionally substituted by q to aryl, -_SRX group, the center of which is as defined above, -s〇2Raa group, its center 3 is -Ci to C6 alkyl, -amino, -alkyl or dialkyl-amino, optionally substituted by hydroxy or a 70RX group, wherein Rx is as defined above, -5 or 6 members Heteroaryl, -C6 to aryl, and/or ...NHRbb group: wherein Rbb is: '

a ...c(=s)nh2 group, or a -PO(ORx)2 group, wherein Rx is as defined above

Rcc group, wherein Rcc is: -5 or 6 membered heteroaryl,

Or a plurality of the following groups substituted: -Q to Q aryl, optionally as a 128244-3 -300 - 200831489 • alkoxy, -yl, _halogen, -C! to c6 alkyl, optionally cyanide Substituent, -amino group, optionally substituted by one or more q to c6 alkyl groups, -NHPORxRx, centered as defined above, -NReeCONRffRff group, wherein Ree is hydrogen or (^ to 06 alkyl, Substituted by spectrin, and is: - hydrogen, - haloalkyl, - haloalkoxy, -4 to (: 6 alkyl, or -CORx group, wherein Rx is as defined above, ... NRggCORhh group, wherein Rhh is: - hydrogen, -q to c0 alkyl, optionally substituted by: - alkoxy, -halogen, or -amino, optionally substituted by one or more Ci to C6 alkyl , an amine group, optionally substituted by one or more q to C6 alkyl groups, wherein the alkyl group is optionally substituted with a _ mer, a -5 or 6 membered heterocyclic ring, a -5 or 6 membered heteroaryl group, and Rgg Is: 128244-3 -301 - 200831489 - hydrogen, -Ci to q alkyl"-haloalkyl, -haloalkoxy, or --CORx group' wherein Rx is as defined above, -haloalkyl, - 5 or 6-shell heterocyclic group, -amino group, as appropriate Or a plurality of C! to C6 alkyl substituted, and/or --NRj丨S02 Rx groups, wherein Rx is as defined above, and Rj丨 is: -hydrogen, -Ci to C6 alkyl, -halogen, a haloalkoxy group, a -CORx group, wherein Rx is as defined above;

-Q to C6 alkyl, optionally substituted by: - alkoxy, - one or more halogens, or - 匸6 to (:8 aryl; -c2 to c6 alkyl; -C6 to C8 aryl , optionally substituted by alkoxy or one or more to Q alkyl; -COORx group 'the center of which is as defined above; or 128244-3 - 302 - 200831489

R is hydrogen, halogen or alkoxy; & is: - nitrogen; - thiol, - halogen; - calcyl, - decyl, -5 or 6 membered heteroaryl; - 5 or 6 membered heterocyclic; - alkoxy, optionally substituted by: - one or more halogens, -C6 to C8 aryl, or • 5 or 6 membered heterocyclic ring; -C6 to C8 aryl, optionally substituted by alkoxy; a CORx group whose center is as defined above; -C! to C6 alkyl group is optionally substituted with a dialkyl-amino group or a 5 or 6 membered heterocyclic ring;

Ri and R_2 are joined together to form · ✓

128244-3 - 303 - 200831489 R is - fluorenyl; - nitrogen; - halogen; - thiol; -C! to C6 alkyl, optionally substituted by one or more halogens; - amine group; - alkoxy Base, optionally substituted by: - one or more halogens, -OCORx group, wherein rx is as defined above, • dialkylamino group, optionally substituted by alkoxy, -5 or 6 members a cyclic group, optionally substituted by Cl to q alkyl, -5 or 6 membered heteroaryl, or -C6SC8 aryl; ...COORx group, wherein rx is as defined above; - octyl; , optionally substituted by: - a thiol group, or a -Cg to C&aryl; - 5 or 6 membered heteroaryl; - an OCORx group, wherein Rx is as defined above; - NHCORjj group, wherein : alkoxy, or -amino, optionally substituted by one or more q to C6 alkyl; 128244-3 -304- 200831489 -ORkk group, wherein Rkk is 5 to 6 membered heteroaryl; a -NHS〇2Rx group, wherein 1 is as defined above; or is joined to Ri to form:

R3 is - rat; or -CH2〇CORx, and Rx is as defined above; with the proviso that when X is phenyl, hydroxyphenyl or pyridyl, γ is alkyl, R is hydrogen, and Ri is hydrogen or hydroxy When R2 is hydrogen or hydroxy, and when r3 is hydrogen, then Z is: -Q to C0 alkyl, substituted by: - alkoxy, - one or more halogens, or -C6SC8 aryl; \ -02 to (^6 alkyl); -CJC8 aryl, optionally taken by alkoxy or - or a plurality of c private alkyl groups - CO〇Rx group

Wherein Rx is as defined above or or one or more of its pharmaceutically acceptable salts 128244-3 -305 - 200831489. The pharmaceutical composition can be formulated to achieve a physiologically compatible cation ranging from about pH 3 to The pH is about 11. In some embodiments, the composition is compared to ~τ' to achieve a pH of about 3 to a pH of about 7. In other specific embodiments, the pharmaceutical composition is formulated to achieve a pH of from about 5 to about pH about 8. i Pharmaceutical compositions may comprise a combination of compounds of the invention, or may comprise a second active ingredient useful for the treatment of viral infections, such as antiviral agents, including but not limited to: PEGylated interferon, by way of non-limiting example Including PEGylated pest interferon; interferon without PEGylation, including, by way of non-limiting example, non-PEGylated pest interferon; triazole nucleoside or a prodrug or derivative thereof; protease inhibitor; Polymerase inhibitors; ρ7 inhibitors; entry inhibitors, including fusion inhibitors, such as Fuze〇nTM (Trimeris); helicase inhibitors; generic tax-like receptor agonists, caspase inhibitors, anti-fibres Denaturing agent; aIMPDH is the target drug (inosine monophosphate 1 氲 enzyme inhibitor), such as MerimepadibTM (vertex pharmaceutical company); synthetic thymosin al (ZADAXINTM, SciClone Pharmaceuticals); glycooxidase inhibitor; glucose enzyme Inhibitors; vaccines, such as those produced by Chir〇n and immunogens; and immunomodulators, such as histamine, antibodies against HCV, antisense RNA, nuclear such as XTL -6865 and XTL-002 (XTL Biomedical) Glycoprotein, RNAi and an anti-unknown mechanism of action. "Pharmaceutically acceptable excipient" means an excipient for administration of a pharmaceutical agent such as a compound of the invention. This term refers to any pharmaceutical excipient that can be administered without undue toxicity. The pharmaceutically acceptable excipient can be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, solvents, amphibians, adjuvants, diluents, and the like. Therefore, there are a wide variety of suitable formulations of the pharmaceutical compositions of the present invention (see, for example, Remingt〇n's Medical Sciences). Suitable excipients can be carrier molecules including large, slow-metabolizing macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virions. . Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA, hydrophobic compounds such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils , water, salt water, glycerin and ethanol, · wetting or emulsifier; pH buffer substances. The vesicles are also included within the definition of pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention can be formulated into any form suitable for the intended method of administration. Suitable formulations for oral administration include solids, liquid solutions, liquefied liquids and suspensions, however suitable inhalable formulations for pulmonary administration include liquids and powders. Alternative formulations include sugar, creams, ointments, tablets, and roll-dried solids, which can be dispensed. ^Physicalally compatible solvent weights when intended for oral use, such as gas preparation, such as tableting, spinning, sugar ingots, aqueous or oily suspensions, non-aqueous soluble powders or granules (including A composition which is intended to be orally administered, may be (iv) a capsule, a syrup or a human being. According to the art, it is known to be used in the manufacture of the quotient group "Do not make any method" and such a composition may contain ten kinds. The agent, including a sweetener, a flavoring or a household preparation, a coloring agent and a preservative, and a pharmaceutically acceptable excipient suitable for use in combination with a tablet, for example, an inert layer of 128244-3 -307-200831489 f, Such as cellulose, carbonic acid or sodium, lactose, squaric acid about or sodium; disintegrants, such as croscarmellose sodium, cross-linked povidone (p〇vid〇ne), corn starch or alginic acid a binder such as povidone, starch, gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. The sheet d may be uncoated or may be coated by known techniques. Including microencapsulation to delay decomposition and adsorption in the gastrointestinal tract, thus providing longer coverage The continuation of the period. For example, a time-delayed substance such as glyceryl monostearate or glyceryl distearate alone or accompanied by wax may be used. The formula for oral use may also be presented as a hard gelatin capsule. The active ingredient is mixed with an inert solid diluent, such as cellulose, lactose, phosphoric acid or N-type clay, or as a soft gelatin capsule, wherein the active ingredient is mixed with a non-aqueous I* or oily medium, such as glycerin or propylene glycol. , Polyethylene H peanut oil, liquid paraffin or eucalyptus oil. County In other specific embodiments, the pharmaceutical composition of the invention may be formulated into 7 days and nights comprising one or more compounds of the invention, and at least one suitable suspension for manufacture The pharmaceutically acceptable excipients are admixed. In still other specific compounds, the pharmaceutical compositions of the present invention can be formulated as dispersible powders and granules which are suitable for the preparation of a suspension by the addition of one or more excipients. L. The excipient used in the suspension includes a suspending agent, such as a methyl cellulose, a hydroxypropylmethylcellulose, a sodium alginate, a polyvinyl group such as hydrogen sulphonone, West yellow gum, gum arabic, dispersing or wetting agent, 天然2 naturally occurring phospholipids (such as lecithin), condensation of alkylene oxides with fatty acids such as ♦ ethylene oxide stearate), Ethylene Ethylene and long a chain aliphatic & combined product (eg, Ethyl Hexaoxide), Ethylene Ethylene and 128244-3 200831489 a condensation product derived from a partial ester of a fatty acid and a hexitol anhydride (eg, polyoxyethylene B) a thin oleic acid sulphate brewing; and a thickening agent, such as a carbomer, beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as acetic acid, p-hydroxyl _ benzoic acid methyl ester and/or n-propyl ester; - or a plurality of color formers; - or a plurality of flavoring agents; and one or more sweeteners, such as sugar or saccharin. The pharmaceutical composition of the invention may also be oil in water Form of emulsion.

The oil phase may be a plant &ample, such as eucalyptus oil or peanut oil, mineral oil, such as liquid paraffin' or a mixture of such. Suitable emulsifiers include naturally occurring gums, 拉 拉 拉 胶 and 西 黄 (四) 胶; naturally occurring scales, such as soybean 2 Η月曰, He derived from fatty acid esters or partial esters; hexitol Anhydrides, such as oleic acid monoterpenoids; and such partial esters and ethylene oxide: condensation products such as polyoxyethylene oleic acid phytosan. The emulsion may also contain sweetening and flavoring agents. The syrup money can be sweetened, such as glycerin, sterol or cane. Such formulations may also contain emollients, preservatives, or colorants. Tablet 2 The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation such as a sterile injectable aqueous emulsion or an oily suspension. Such milk liquids or suspensions may be formulated according to the known art using the appropriate "dispersion or sputum and suspending agent" as mentioned above. The injection preparation may also be in the absence of a liquid or suspension, in a non-toxic parenteral. A solution which is acceptable for use in a diol such as 〜 diol. Sterile injectable preparation: It is a dry powder. The acceptable medium and solvent can be used as water, Ringer's solution and special gas. (d) solution. In addition, sterility does not wave 128244-3 200831489 oil can be used as a solvent or suspension medium. For the purposes of this project, any mild non-volatile oil can be used, including synthetic mono- or di- glycerol In addition, fatty acids, such as oleic acid, can likewise be used in the preparation of injectables. The compounds of the invention are substantially insoluble in water and are sparingly soluble in most pharmaceutically acceptable protic solvents. And vegetable oils, but generally can be combined with medium chain fatty acids (for example, caprylic acid and decanoic acid) or glycerol triacetate and propylene glycol esters of medium chain fatty acids. Therefore, Italian slaves are covered. In the present invention Compounds that have been modified by substitution or addition of chemical or biochemical moiety, which makes them more suitable for transport (eg, increased solubility, biological activity, palatability, reduced adverse reactions, etc.) By acetification, glycosylation, PEGylation, etc. In some embodiments, the compounds of the invention are formulated in a lipid-based composition suitable for low-rotation compounds for oral administration. The enamel-based formula generally increases this rate. Field κ cuts < Oral bioavailability, the pharmaceutical composition of the present invention may comprise an effective amount of a compound of the invention, accompanied by at least one pharmacy The species is selected from the group consisting of medium chain fatty acids or propylene glycol esters thereof (for example:::::::: propylene glycol (tetra) of caprylic acid and capric acid fatty acid), and further a surfactant, such as polyoxyl 40 hydrogenated t sesame oil. In an alternative embodiment, the pharmaceutical composition may be further exemplified by an aqueous solution solubility enhancer, such as a cyclodextrin. ^3 - or a plurality of examples including, a tablet, and a "p-dextrin", limit Maltosyl and maltotriosyl derivatives, and; propyl glucosyl, propyl-cyclodextrin 128244-3 - 310. 200831489 (HPBC). In some embodiments, the pharmaceutical composition further comprises From about 0.1% to about 20% hydroxypropyl _/3-cyclodextrin, from about 1% to about 15% hydroxypropyl n-dextrin or from about 2.5% to about 10% hydroxypropyl-cyclodextrin. The amount of solubility agent used may depend on the amount of the compound of the invention in the composition. 曰F· Combination therapy

Any of the compounds of the invention may also be combined with any of the other active ingredients (including compounds) useful in the treatment of Hcv infection, in a single dosage form, or in an individual dosage form intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination can be administered in two or more administrations. In an alternate embodiment, one or more compounds of the invention and one or more additional active ingredients may be administered by different routes. The skilled artisan (iv) active ingredient can be administered in combination with a compound of the invention, which can be used to enhance or synergistically potentiate the virus of the compounds of the invention: · Health. Such active ingredients include anti-HCV agents. The agent includes a virus-targeted agent' and an agent having an immunomodulatory action. For example, an anti-HCV agent includes, but is not limited to, an interferon, including, for example, but not limited to, a trisupride or a prodrug or derivative thereof; a white enzyme inhibitor, a polymerase inhibitor, a helicase inhibitor, Tax-like receptor agonists, caspase inhibitors, and enzyme inhibitors 'anti-HCV antibodies, such as XTL_ secret and XTL-002 (XTL biomedicine), anti-sense, ribozyme, surface and unknown The anti-HCV agent of the mechanism of action. Further, the compounds of the present invention can also be administered in combination with other compounds which affect the activity of Peng. And root = the method of the present invention, the combination of active ingredients can be: (1) co-mixed, simultaneously administered or transported in a 5 formula; (2) transmitted in an individual formulation by alternating means or parallel 128244-3 -311 - 200831489; Or _ this (4) is known to be used in combination. The method of the present invention may comprise sequentially administering or transferring the active ingredient i ^, for example, in individual solutions, emulsions, suspensions, when alternately 瘩沬 green recognizing + %, and 'five treatments'. , tablets, pills or capsules in #胗襄, or hunted by different injections to individual syringes. In general, during the alternate waste process, the effective doses of the active ingredients are administered sequentially, i.e., continuously 1 and in concurrent therapy, the effective doses of two or more active ingredients are administered together. Various sequences of intermittent combination therapies can also be used. To aid in the understanding of the invention, the following examples are included. The experiments of the present invention should of course not be construed as limiting the invention in particular, and such variations of the invention, which are currently known or developed in the sequel, are considered to be within the scope of the skilled person. It is as described herein and is intended to be within the scope of the invention. It will be apparent to those skilled in the art that the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Specific embodiments are pointed out below, as well as other specific embodiments. Except in the examples, or as otherwise stated therein, all numbers used in the patent specification and the claims, indicating the amount of ingredients, reaction conditions, etc., should be understood to be modified by the term "about." Accordingly, unless indicated to the contrary, the number is an approximation that may vary depending upon the nature desired to be sought by the invention. In rare cases, rather than attempting to limit the application of the equivalent theory of the scope of the request, each numerical parameter should be interpreted after understanding the value of the meaningful number and the general integer technique. 128244-3 -312-200831489 Although the numerical ranges and parameters of the broad scope of the invention are described as approximations, the values set forth in the examples are reported as accurately as possible. However, 'any numerical value inherently contains certain errors due to the individual test metrics; standard deviations are found. [Embodiment] Example

The invention is described in more detail with reference to the following non-limiting examples, which are set forth to more fully illustrate the invention, but are not to be construed as limiting. The examples illustrate the preparation of certain compounds of the invention, and the like, and the testing in vitro and/or in vivo. It will be apparent to those skilled in the art that the techniques described in the examples t represent the techniques described by the inventors, and are used in the practice of the present invention, and are themselves constructed in relation to their implementation. Preferred mode. However, it should be understood that those skilled in the art should understand that the present invention may be practiced in a particular method disclosed without departing from the spirit and scope of the invention. result. Example 1 · Preparation of the compound of the present invention Preparation of κ Α 1 Α 1-ethyl methoxy_1H•啕哚_3_carbonitrile (Compound 5)

MeO

DMF

MeO

MeO

Into CIS02NC0 NaH QN

Etl

DMF One Step A: Cool the methoxy hydrazine (10.0 g, 68·0 mmol) in DMF (12 〇L) in a solution of chlorosulfonate isocyanate. · 4 moles) processing. After the addition, the reaction mixture was stirred at this temperature for 1 hour. The dark solution was poured into ice water (600 ml), and the pale brown solid was collected by filtration from 128244-3 -313 - 200831489, washed with additional H2, and dried to give 9·9 g (85%) 6-Methoxy-1H-4indole-3-carbonitrile as a pale brown solid.

Step B: Add NaH (6 矿 in mineral oil) to a solution of 6-methoxy-1H, indole-3-carbonitrile (9.9 g, 57·6 mmol) in DMF (150 mL) % dispersion, 3.45 g, 86.3 mmol. The reaction mixture was stirred for 15 min then ethyl iodide (5. 53 mL, 69 J m. The reaction mixture was then diluted with 吒0 and extracted (2X) with hydrazine. The organic phase was washed with a solution of ruthenium (3X) and saturated NaCl, then dehydrated to dryness and concentrated to a semi solid. The crude product was purified by column chromatography on silica gel (2 (8) g) using CI^Cl2/hexane (5 (M 〇〇%) as the eliminant to give 6-methoxy-1-ethyl -1H-oxime carbonitrile, a tan solid. Using the above steps A and B, and substituting different hydrazines and alkyl halides, the following compounds were obtained: compounds 43, 45, 51, 52, 108, 109 , 115, 118, 120, 123, 126, 179 and 714. / Shell Example 1B·6-Ethoxy-1·ethyl·ιη-啕哚-3-carbonitrile (Compound 9) Preparation CN CN CN — ΒΒ_"3 + ίΓ^τΛ K2C〇3

CH2CI2 0°C

Etl MEK

Step A: 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2·85 g, 14.2 mmol) prepared in Step B of Example 1A in CH2Cl2 (40 mL) In a solution in solution, a 1 M solution of BBi*3 in CH2C12 (28.5 ml, 28.5 mmol) was added at 〇 °C. The mixture was allowed to warm to room temperature and held for 25 hours. The dark reaction mixture was then poured onto ice and sufficient 1 M Na〇H was added until pH 8-9. The product was extracted with CH2C12, and the combined organic phases were washed with sat. NaHC. After dehydration and drying with MgS(R)4, the solution was concentrated, and the product was purified by chromatography (EtOAc (EtOAc), EtOAc (EtOAc) - 吲哚-3-carbonitrile as a yellow solid. Step B: Adding anhydrous K2c〇3 to a solution of 6-hydroxy-1-ethyl-1H-indole_3_carbonitrile (10 mg, 〇·43 mmol) in 5 ml of methyl ethyl ketone (71 mg, 0.52 mmol) with methyl iodide (〇〇 5 ml, 〇 6 〇 millimolar). After stirring overnight under reflux, the reaction mixture was cooled, diluted with H.sub.2, and extracted with Et EtOAc (3X). The combined organic phases were dried and dried and concentrated. A flash chromatography (CHfl2) gave 94 mg (1%) of 6-ethoxys. In a similar manner, following the above steps A and B, the following compounds were also prepared: Compounds 6, 10, 11, 12 and 24. Example 1C: Preparation of 5-(4-decyloxyphenyldioxolane[4,54吲哚^carbonitrile (Compound 44)

Cul, ligand, toluene, reflux

Will be p-toluene (85 mg, 〇·36 mmol), anhydrous K3P〇4 (1〇2 mg, 0·48 耄mol), Cul (4.6 mg, 0.024 mmol) and a mixture of n, Nl dimethyl hexane-1,2-diamine (14 mg, 〇·〇 96 mM) was added to anhydrous benzene (0.4 mL) as described in Example 1 511-[1,3] Dioxin and [4,5-f]e prasin-7-carbonitrile (45 mg, 0.24 mmol) 128244-3 -315- 200831489. After heating under reflux for 24 hours, the solvent was evaporated in vacuo. The residue was dissolved in CH2C12 (5 mL) and filtered. The filtrate was concentrated to give the crude product, which was purified by chromatography eluting with EtOAc EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) Dioxolino[4,5-f]indole-7-methyl moon cream. Using the above private sequence 'and replacing the different aryl adducts, the following compounds were obtained: compounds 4, 8, 102, 103, 111 , 112, 117 ' 119, 124, 125, 127, 154 mussel example ID. Preparation of 1-ethyl _6 succinyl -2- -2- oxybutrol-3- carbonitrile (compound 13)

V human α DMF, 110 ° C prepared as described in Example 1A, Step A, i-ethylhydroxy-1H-indole-3-methylpyre (60 oz, 〇·32 house Moule) in DMF In a solution (5 ml), K:2C〇3 (55 mg, 0.40 mmol) was added with 2-chlorohydrazine (45 mg, 0.40 house mole). The mixture was heated at 110 ° C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (EtOAc). The combined organic phases were washed with H 2 〇 and saturated NaCl, dried and concentrated. The product was isolated on silica gel eluting EtOAc (EtOAc /EtOAc. -iH-indole-3-carbonitrile as an off-white solid. Preparation of Example 1E · · 3-cyano-1-ethyl-lH-p?丨嗓-6-t-acid phenyl decylamine (Compound 15) 128244-3 -316- 200831489

CN

0

(COCI)2 1N NaOH THF reflux DMF CH2CI2

f / Step A: Methyl 3-cyano-1·ethyl-1H-indole-6-carboxylate prepared from m_啕哚_6•methyl decanoate by the method described in Example 1A ( 1·6 gram, 7 〇 2 mmoles) A solution of THF (35 mL) was taken in EtOAc (7.7 mL, 7.7 mmol) and heated under reflux for 2.5 hours. After cooling to room temperature, most of the THF was removed and the solution was diluted at 0 and extracted with ether (2 EtOAc). Discard the ether extract. The aqueous phase was then acidified to ΡΗ2 with 6NHC1 then extracted with EtOAc (3×). The combined EtOAc layers were washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Step B: A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (42 g, 196 mmol) in CH2C12 (15 mL) was cooled to EtOAc. The suspension was treated with qing (2 drops), then chlorinated grass mash (〇·34 ml, 3.92 mmol) was added via syringe, followed by removal of the ice bath and at μ hr. During the reaction, the reaction mixture was allowed to warm to ambient temperature to give a yellow solution. The solution was then concentrated in vacuo, and the product was obtained in vacuo. Cyanium chloride, a yellow solid. Step C: mp 3:Cyanoethylethyl 1 Η 吲哚-6-chlorocarbazide (70 mg, 〇 3 〇 mM) in THF (5 mL) The suspension was cooled to 〇χ: and treated with aniline 128244-3 -317-200831489 (0.08 ml, 〇·9 〇 millimolar). After the addition, the reaction was allowed to warm to ambient temperature and stirred again. After 16 hours, the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) elute elute ¢13⁄43⁄4 ' 2/98), obtained 44 mg (51%) of 3-cyano-1·ethyl-1H-indole-6-carboxylic acid phenyl decylamine. Basically, using the above procedure, The following compound: Compound 89. Example 1F · (3-Cyano-1-ethyl)anthracene &gt; Preparation of tert-butyl carbamic acid (Compound 16)

A solution of the cyano small ethyl hydrazine carboxylic acid (〇6〇g '2.80 mmol) in the third-butanol (2 〇 ml) was obtained from the procedure of Example 1Ε, 耻ν〇 46 pens, 3.36 house moles) were treated with diphenylphosphonium azide (0.73 ml, 3.36 mmol) and heated under reflux for 4 hours. After cooling to room temperature, most of the third sterol was removed in vacuo to give an oil which was then taken in EtOAc. After washing with η2 ,, the organic phase is back-extracted in paragraph (d), sub-combined with organic layer' and successively in another % ◦, saturated viscous (7) 3 and saturated strip. The organic phase is dehydrated and dried, and the crude product formed is purified by chromatography on (4), so that (4) (5) is called 12 ((4)), and 52 g (_) is obtained, (3-cyano + ethyl-bubu Base)_Amino-Yin acid third-butyl vinegar white solid. ': Compound 90. The following compounds were prepared in a similar manner to 128244-3 -318-200831489. Example lGa: 2-(4-Aminophenyl) 1-ethylethylmethoxy-1H, hydrazine carbonitrile via Suzuki pathway (Compound 55 Preparation

-70 ° C - room temperature

PdC 丨 2 (PPh3>2 CsF DME reflow

CN

Step A: A 2M solution of lithium diisopropylamine in THF / hexanes (Acr.sub.s.) (3.9 mL, 7.8 mmol) was evaporated in EtOAc (5 mL). After the reaction was cooled to _3 (TC, 1-ethyl-6-decyloxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) was added dropwise over 1 min. The solution in THF (10 ml) was kept at -3 (rc). After stirring for 30 minutes at this temperature, a moth (2 jig, 91 mmol) was added in THF during 5 Torr (5 After the addition, the solution was allowed to warm to ambient temperature over 1 h. The reaction was then diluted with EtOAc EtOAc (EtOAc) (EtOAc) The combined organic phase was washed with saturated Na.sub.1 and then concentrated to a brown solid. EtOAc (EtOAc: EtOAc (EtOAc) -Methoxyindole-3-indoleonitrile as an off-white solid. Step B: 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (1·25 g , 3.83 millimolar), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxazolidine-2-yl-aniline (〇·96 g, 4·90 mmol) a mixture of CsF (1.46 g, 9.58 mmol) and pd(PPh3)2Cl2 (110 mg '0.15 mmol) in DME (20 mL) was added to "Spoke" and alternately pump and flush with n2. Then, the reaction was heated under reflux for 24 hours, then cooled to room temperature. The reaction mixture was diluted with h2 ,, 128244-3 -319-200831489 and extracted with EtOAc (2X). The combined organic phases were washed with H.sub.2 and EtOAc (EtOAc) elute elute elute , 765 mg (69%) of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellow solid. Procedure, and replacing the different dihydroxyboranes, the following compounds were obtained: compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110, 229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282, 283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429, 476, 543, 578, 758. Example 1Gb: 2-(4-Aminophenyl)-1-butyl-6-decyloxy-1H-4indole-3-carbonitrile via an alternative to the Suzuki pathway Equipment

rM 1. iPr2NH, n-BuLi, THF

To a solution of (i-Pr) 2NH (1·35 mL, 9.65 mmol) in THF (30 mL) cooled to -78 ° C, one portion of n-BuLi (3.7 mL, 2.5M, In the burnt, 9.21 millimoles). The acetone/dry ice bath was exchanged into an ice/water bath and the solution was stirred for a further 40 minutes. The solution was cooled to -78 ° C, and 1-butyl-6-methoxy-1H-indole-3-carbonitrile (2.0 g, 8.77 mmol) prepared in Example 1A was added dropwise. Solution in THF (10 mL). The solution was stirred at -78 °C for 15 minutes and then at -20 °C for 20 minutes. Add trimethyl borate (1.0 ml, 8.77 mmol), stir the reaction mixture at -20 ° C for 15 minutes, then transfer 128244-3 -320 - 200831489 to remove the cooling bath, and then leave the solution at room temperature. Stir for 丨 hours. Add a solution of Κ3Ρ〇4 (11.7 ml, 3 Μ aqueous solution, Μ.! millimolar), followed by 4_Ethyl aniline (2.5 g, η. 40 mmol) with! &gt;2 2 A solution of 13 £·catalyst (64 〇 mg, 〇88 mmol) in DMF (40 ml, plus 5 ml of rinse). The reaction mixture was stirred overnight (ca. 18 h) then water (8 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated. The crude product was purified on a silica gel by flash chromatography (5 - 60% EtOAc/hexanes as solvent) to give the desired 2-(4-aminophenylH-butyl-6-methoxy) Buy _3_carbonitrile as a tan solid (2.4 g, 86% yield). The following compounds were prepared in a similar manner using other lath and aryl and heteroaryl bromide and iodide: Compounds 656, 659, 660, 66, 682, 712 731, 732, 733, 806, 807, 808, 809, 810, 811, 812, 813, 814, 827 〇

Shell example lGc· 2-(4-month-female phenyl)-6-methoxy+propyl 丨嗓·3_carbonitrile

Preparation by the Negishi pathway CN

1. LDA, ZnCI2 THF νσΝΗ: Pd2dba3 PPh3 THF

In a nitrogen gas cylinder fitted with a septum and a nitrogen needle, anhydrous thf (all additions by 'main shot) (20 ml) was added. Diisopropylamine (Aldrich is indeed sealed, 2 mL, 14.3 mmol) is added and the solution is allowed to cool to 〇c. Add n-butyllithium (8.5 mM, ΐ6 Μ in hexane, 128244-3 -321 - 200831489 μmmol). The flask was briefly warmed to room temperature and then cooled to scratch. Slowly add a 6-methoxy propyl-purine carbonitrile solution (2 77 g) 2,9 mmol; similarly, the compound 5 was made) and the solution formed was Hold for -30rc for 30 minutes. Next, the flask was transferred to a water-ice bath and allowed to return to (TC for about 15 minutes. The solution was again cooled to -78 °C and slowly added /η% (in THF) 〇5M solution, 27 〇 ml, 13.5 mmol). At this time, a precipitate was found, which could be a double (tetra) 哚) compound, i_田&quot;』, when adding the whole volume of zinc chloride solution, the solution became Evenly. After about a minute, the solution was allowed to return to room temperature, and 4_mercaptoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 129 mmol) of τ Η ρ solution (m) were added. Separate the septum and add solid Pd2 (dba) 3 (295 mg, 0 322 mmol). A reflux condenser was attached to the flask, and the solution was degassed by three consecutive cycles of vacuum pumping of scrubbing gas. The solution is then heated to reflux. After cooling to room temperature, the solution was poured into 4 volumes of water and 4 volumes of ethyl acetate were added. The resulting mixture was vigorously stirred for 3 minutes and then filtered through diatomaceous earth (washed with ethyl acetate) to remove the solid-containing Pd-containing material. The liquid phase was separated and the aqueous phase was extracted with more ethyl acetate. The organic phase was washed with saturated brine, combined, dried over anhydrous sodium sulfate, filtered, and evaporated. At this point a solid precipitate was formed which was a sufficiently pure product which was collected by trituration with ether and filtered. The residual material was purified by column chromatography (dissolved 1: 2 ethyl acetate-hexane, on silica gel 60). The total yield of the product 2_(4-amino-phenyl)·6-methoxysuccinyl-1H-indolecarbonitrile was 2.75 g (8·99 mmol, 70%). The following compounds were prepared using substantially the same procedure and substituting other aryl 哎128244-3 - 322 - 200831489 heteroaryl iodide or bromide: Compounds 393, 408, 430, 431, 436, 437, 438, 459 , 460, 461, 462, 483, 484, 632, 633, 634, 635, 636, 650, 651. Example lGd: Preparation of 1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-1H-W哚-3-indoleonitrile (Compound 288)

Pd(PPh3)2CI2, Mea Cul, THF

Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) was cooled to -78. n-Butyllithium (14.5 mL, 2.5 M in hexanes, 36.2 mmol) was added dropwise over 5 min. The LDA mixture was stirred at -78 °C for 10 minutes and then at 〇 °C for 20 minutes. The solution was again cooled to -78 °C. 1-Ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol) prepared as in Example 1A was dissolved in THF (30 mL) and In the LDA mixture, it took 15 minutes. The reaction was stirred at -78 °C for 10 minutes and at 0 °C for 30 minutes. The reaction mixture was again cooled to -78 °C. Tributyltin iodide (10 ml, 35 mmol) was added dropwise. It was stirred at -78 °C for 15 minutes, then at 0 °C for 30 minutes. The reaction mixture was adsorbed onto silica gel and concentrated. Purification by chromatography (CH2) gave 1-ethyl-6-methoxy-2-dibutylstannyl-1H-indole-3-carbonitrile (12.05 g, 98%). Step B: 1-ethyl-6-methoxy-2-tributylstannyl-1H-indole-3·carbonitrile (1.0 g, 2.05 mmol) prepared in Step A and 3-iodine Phenol (474 mg, 2.15 mmol), Pd(PPh3)2Cl2 (67 mg, 0.102 mmol), Cul (75 mg, 〇 39 mmol) and THF (4.0 mL) were combined. This mixture was charged at 128 ° C with a 128244-3 - 323 - 200831489 heat meter. The reaction mixture was diluted with EtOAc and filtered over EtOAc. The filtrate was concentrated and the residue was purified on silica gel chromatography (4:1, CH2Cl2/EtOAc) to yield crude product. Ethyl ether was developed to give the title compound (3-hydroxy-phenyl)- 6· methoxy-l-indole-3-carbonitrile (430 mg, 72%) as a white solid. The following compounds are prepared in a similar manner as described above using other commercially available iodides and bromides, or by using a single step of the hydrazine chlorinated p-indene sulfonate. Compounds 275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678. Example lGe: ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-indole-ethyl_ιη_啕哚_2_yl)-phenyl]-acid amine via the Heck pathway ( Preparation of Compound 519)

Step A ··6-Difluorodecyloxy-1-ethyl-1H-4丨嗓 (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodophenyl)-decylamine (712.1 mg) , 2.29 millimolar), carbonated planer (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5·7 mg, 0.025 mmol) in DMA (5 ml) The solution was heated to 135 ° C for 48 hours. The reaction mixture was diluted with EtOAc (EtOAc) The combined organic phases were washed with brine, dried over MgSO 4 and then concentrated. The residue was purified by column chromatography (25 g) eluting with EtOAc/hexane (10-20%) as eluent, and 129 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s [4-(6-Difluorodecyloxy-1-ethyl-1H-iodo-2-yl)-phenyl]-decylamine, compound 516, was obtained as a pale brown solid. Step B: Conversion of [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-decylamine ethanesulfonate to B according to Procedure A, Step A Alkylsulfonic acid [4-(3-cyano-6-dimethoxymethoxy-1-ethyl-1Η-ρ5丨嗓-2-yl)-phenyl]-bristamine, compound 519. Following the above steps A and B, the following compounds were prepared in a similar manner: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579, 580, 611, 612, 613, 614. Example 1H: Preparation of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile (Compound 67)

80 ° C 1-ethyl-2-iodo-6-methoxy-oxime- koubend-3-methyl moon cream (150 mg, 0.46 mmol) prepared as described in Example Ig Step A Ear), 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine)palladium dichloride (11) (6 mg, 0.009 mmol) and Cul (4 mg, 0.018) A mixture of millimoles was added to the sealable tube and alternately pumped and rinsed with N2. Then, DMF (4 ml) and Et3N (0-25 ml, 1.84 mmol) were added to the tube, and the reaction was heated at 80 ° C for 20 hours, then cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) The phases were washed with H20 (3X) and saturated NaCl with 128244-3 - 325 - 200831489, then dehydrated with MgS04 and concentrated. The crude reaction mixture was adsorbed onto silica gel (0.6 g) and chromatographed on silica gel using EtOAc/hexane (10-20%) as solvent. (4-Fluorophenylethyl)-6-methyllacyl-3-methyl wax as a yellow solid. Substantially using the same procedure described above and substituting the different acetylene derivatives, the following compounds were obtained: Compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133, 134, 135, 136, 137 , 143, 144, 145, 146, 147, 148, 149, 150, 151, 158, 159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184, 185 , 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231, 232, 233, 234, 235, 236, 237, 238. Example II: Preparation of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole (Compound 28)

Step A: A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL). Treated with 0.38 mL, 6.25 mmol, and heated under reflux for 18 h. After cooling to room temperature, the heterogeneous mixture was filtered to give 525 mg of desired product as a tan solid. The filtrate was concentrated to an oil, which was taken crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The total yield of 1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxyformamide was 820 mg (70%). 128244-3 - 326 - 200831489 Step B: CH2C12 (10 ml) of the above hydrazone hydroxycarboxamide (5 mg, 0.21 mmol), polystyrene-diisopropylethylamine (165 mg) , 3 9 〇 * mol / gram load) and gasification propylene (〇 · 〇 3 ml, 〇 · 32 mmol) placed in the tube and rotated at room temperature for 22 hours. After this time, the tromethamine resin (77 mg, 2.71 mmol/g load) was added and the tube was spun for 30 minutes at room temperature. The solid was filtered, then the filtrate was concentrated and diluted with a br. Heat underarm for overnight. The crude reaction mixture was concentrated and purified by chromatography (EtOAc /EtOAcjjjjjjjjjjjjjjjjjjjjjj Disani-3-yl)-6-methoxyindole as a white solid. The following compounds were prepared using the procedure described above and substituting the appropriate hydration: Compound 29. Example 1J: Preparation of 1-ethyl-6-methoxy-3·(5-ethyl-[1,3,4]oxadiazol-2yl)-1Η-indole (Compound 54)

Et3N HCI MeO toluene

Step A: A mixture of 1-ethyl-6-methoxy-1H-M-p--3-carbonitrile (1 gram, 5.00 mmol) in toluene (30 mL). The amine hydrochloride (1.03 g, 7.50 mmol) was treated with sodium azide (yield: 49 g, 7.50 mmol) and heated under reflux for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc EtOAc. The organic layer (2X) was then washed with additional NaHC03. The combined aqueous phases were acidified to pH 2 with 6N HCl. The resulting thick precipitate was extracted with hot EtOAc (3×), and the combined organic phase was washed with saturated NaCl and dried from &lt;RTI ID=0.0&gt;&gt; Ethyl winter methoxy-3-(1 Η-tetra. sitting _5_ kibdone, as a yellow solid. Step B: The above tetrazole (50 mg, 0.21 mmol) and propyl chloride (〇) 〇3 ml, 0.31 mmol, in a suspension of di-ethane (5 ml), heated under reflux for 21 hours. After the reaction mixture was cooled to room temperature, polystyrene tromethamine resin was added ( 7 〇 mg, 3.4 meq/g), and the reaction was spun at room temperature for 4 hours. After the resin was filtered off and the solvent was removed, the crude product was adsorbed onto the cerium gel and the product was subjected to chromatography. (EtOAc/CH2Cl2, 5-10%) isolated to give 30 mg (53%) of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazole 2-yl HH-indole, a tan solid. Example 1K: 5-difluoromethoxy-l-(4-methoxyphenyl)-2.methyl-1H-indolecarboxylic acid ethyl ester ( Preparation of compound 49)

Froon-22 (HCF2 C1) gas was bubbled into 5-hydroxy small (4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (250 mg) at 〇 °C , 0.77 mmol) A solution containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst in CH2C12 (5 ml). A 50% solution of Na〇H was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 ° C for 2 hours. After adding 0, the organic phase was separated, washed with brine, and dried with Ν々δ〇4. The solvent was then concentrated, and the residue was purified by chromatography eluting eluting eluting eluting eluting elution The following compounds were prepared by the above procedure and substituting the appropriate hydroxy hydrazine to make 128244-3 -328 - 200831489: Compounds 18, 46 and 5〇. Example 1L: Preparation of oxime, oxy-transfer, oxyphenyl H-H-+-3-yl]-ethanone (Compound 42)

Under the procedure of Example 1, the 5-methoxy small (4-methoxyphenyl) ten (5 〇 mg, 〇. 2 mmol) was dissolved in i ml. After the addition of Et2A1C1 (3 〇〇 microliters, in the burned, 0.3 millimoles). After stirring for 30 minutes, add a solution of acetonitrile (2) microliters, μmmol) in 13⁄4 liters of CH2CI2. Mix it again under 〇〇c for a minute. The reaction mixture was quenched with H.sub.2, and extracted with CH.sub.2.sub.2, and concentrated in vacuo. The title compound was obtained as a white solid (42 mg, 71%). Substantially using the same procedure described above and substituting different gasified oximes, the following compounds were prepared: Compounds 32, 33, 34, 37, 38, 39, 47, 48. Example 1M: Preparation of 1-ethyl_3_iso-salt _3_yl_6_methoxylated core compound 57)

〇 OH

Step A - The ethyl group of ethoxyethyl 1H? eucalyptus ethyl 6-methoxyl H_吲哚_3·yl) ethyl ketone (mg, 128244-3) was prepared by the procedure described in Example 1L. -329- 200831489 〇·92 mmol, a mixture of hydroxylamine hydrochloride (128 mg, 1.84 mmol), Na0Ac (151 g, 1.84 mmol) and EtOH (7 mL) at 85. Heat underarm for 4 hours. Then, the reaction mixture was subjected to liquid separation between % 〇 and Et 〇 Ac. The organic phase was dried and dried and concentrated in vacuo. Purification by column chromatography, using EtOAc/CH.sub.2Cl.sub.2 (1/9), yielding 1-(1-ethyl methoxy η η-p-indol-3-yl)ethanone oxime as a white solid (189 mg) , 92%). Step B: Dissolve μ(1-ethyl methoxy oxime _3_ yl) ethyl ketone in TC (1 〇〇 mg, 0.43 mmol) in THF (900 μl) Add n-BuLi (450 μl, 2.5 Μ, in hexane, 1.12 mol) dropwise, causing immediate smothering of the solids. DMF (70 μl, 0.9 m) was then added dropwise. Stir at 0 ° C for 1 hour and then at room temperature for 1 hour. The reaction mixture was pipetted into a mixture containing 1 ml of H 2 hydrazine, 1 ml of THF and 1 liter of microliter of concentrated H 2 SO#. This mixture was heated at 75 °C for 1 hour, then partitioned between EtOAc and EtOAc. The organic phase was dried and dried, and concentrated to yield to ethylbenzene. 3-isomeric α--3-yl-6·decyloxy-1-indene-indole as a white solid (π mg, 12%). Example 1 Ν · 1-ethyl-3 s. Preparation of 5-amino-6-methoxy-1Η-ρ丨嗓 (Compound 58)

1-(1-ethyl-6-methoxy-1H) of 1-ethyl-6-methoxy-1H-indole was prepared by the procedure described in Example 1L at ll EtOAc. -indol-3-yl)ethanone (1 mg, 0.46 mmol) with 1.5 ml of dimethylformamide dimethyl acetal and 1 〇〇128244-3 -330 - 200831489 microliter of tetrahydrogen The pyrrole was heated together overnight. Then, dimethylformamide dimethyl acetal was concentrated in vacuo. The residue was redissolved in 125 mL of EtH and 25 liters of EtOAc and EtOAc (EtOAc &EtOAc) The partitioning effect between $〇 and Et〇Ac, and the dehydration drying and concentration of the organic phase, followed by purification by gelatin chromatography (Et〇Ac/CH2C12, 5/95) to obtain 1-ethyl isoform -5 · methoxy-H-H, a white solid (72 mg, 66%). Basically, using the same procedure as above, the following compound was obtained: Compound 6〇. Example 1 〇 ·······························

Under U 〇 C, it will be prepared from 1-ethyl-6-methoxy 1H by the procedure described in Example 1L; 1 servoethyl methoxy n phenyl group of eucalyptus) (10) milli

克 ' 〇 · 46 millimoles) with u ml of dimethyl ketoamine dimethyl carboxylic acid and slightly micro liters of tetrahydro ρ ratio slightly together; ^ 屹 force ..., the instrument. The DMF dimethyl reduction was removed in vacuo. The residue was redissolved in 3 ml of acetic acid, cultivating hydrate (7 〇 microliters &lt; 1.38 mM) and the mixture was heated to EtOAc over 2 hours. In true

The acetic acid was removed in the air and the residual residue was partitioned between EtOAc and sat. NaHC. The organic phase was dehydrated and the muscles were not depleted, sub-concentrated, and the product was purified by ruthenium (EtOAc/hexane, 1/l), y.镘 %% pen gram! Ethyl methoxy-3-(2H_ylpyrazin-3-yl)-1Η-吲哚 (54%) is a two colorless semi-solid. Developed in Et20, a white crystalline powder was obtained. 128244-3 -331- 200831489 The following compounds were prepared using the procedure described above: Compound 61. Shell Example 1Ρ·1-Ethylcarbazole_5_ylindole Methyl Carboxylic Acid (Preparation of Compound %)

CHO

PQCl3 T0SM, C DMF Me02C^^" K2C03

MeOH Me02C Step A: Ethyl _m_p? </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; It was added dropwise to p冰cl3 (43 μL, 4.5 moles) in ice-cold solution in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was then treated with 6NNa 〇H (35 liters). Next, the mixture was subjected to liquid separation between % 〇 and ethyl acetate. Purification by silica gel chromatography (5-10%EtOAcEtOAcEtOAc) Step Β ·1·Ethyl-3-methylmercapto-1Η-4丨嗓-6-carboxylic acid methyl g (1〇〇 mg, 〇·42 mmol), TOSMK: (100 mg, 0.52 毫Mohr), K2C〇3 (178 mg ' 1.29 mmol) and MeOH (800 μL) were heated at 8 ° C overnight. Then, the reaction mixture was subjected to liquid separation between 0 and ether. After the organic phase is dehydrated, dried and concentrated, the product is purified by ruthenium chromatography (Et〇Ac/CH 2 Cl 2 , Chuan / 9 〇) to obtain 1-ethyl-3-oxazol-5-yl-1H-indole carboxylic acid. Methyl ester (26 mg, 23%) was obtained as an off white solid. Example 1Q: Preparation of 1-ethyl-3-oxazolidine-based EM-methyl carboxylic acid (Compound 75) 128244-3 -332 - 200831489 CHO Μθ〇2〇

ΚΜη04

1· (COCI>2DMF 2. NH4OH

Step A ········^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 98 ml). A solution of ΚΜη〇4 (655 mg, 4.15 mmol) in η 2 〇 (31 mL) was added. The reaction mixture was stirred at room temperature for 90 minutes. Another portion of η 2 〇 (6 mL) of ΚΜ 〇 4 (108 mg) was added, followed by stirring for another 45 minutes to drive the reaction to completion. Then, the reaction mixture was quenched with 10% 4 〇 2 (1.5 mL). The mixture was filtered through celite. The filtrate was stripped under vacuum to about a 1/3 volume. The residue was acidified with 6NHC1 and extracted with ethyl acetate. The solid isolated from the ethyl acetate layer was triturated with acetone to give 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as pale orange solid. . Step B·························· . Chlorella grass mash (470 μL, 5.38 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was slowly poured into a concentrated NH4〇H solution (1 ml) which was rapidly stirred. Next, it is subjected to liquid separation treatment in Malang and Duan &amp; The residue from the ethyl acetate layer was triturated with acetone to give &lt;RTI ID=0.0&gt;&gt; 128244-3 -333 - 200831489 Step C: 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1Η-啕哚 in diethylene glycol dimethyl ether (3.6 mL) A mixture of 3-carboxyguanamine and bromoacetaldehyde dimethyl acetal (430 μl, 3.7 mmol) was heated at 125 t for 2 hours. The reaction mixture was cooled and partitioned between H20 andEtOAc. The organic phase was dried <RTI ID=0.0>: </RTI> to <RTI ID=0.0> The product-containing fractions were combined and concentrated, and the solid was crystallised from hexane to yield ethyl 1-ethyl-3-carbazol-2-yl-1H.sup.-6-carboxylic acid methyl ester (75 mg, 46% ), as a yellow solid. Example 1R: Preparation of 1-ethyl-6-methoxy-3-pyrazol-2-yl-1H-indole (Compound 73)

Step A: 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) was dissolved in DMF (1.5 mL). It was added dropwise to an ice-cold solution of POCl3 (500 μL, 5.2 mmol) in DMF (1.75 mL). After stirring at room temperature for 90 minutes, the reaction mixture was cooled EtOAc EtOAc m. The reaction mixture was partitioned between EtOAc and H20. Purification by EtOAc (EtOAc/EtOAc (EtOAc)MeOH) Step B: 1-Ethyl-6-methoxy-1H-indole-3-carboxaldehyde (600 mg, 2.95 128244-3 - 334 - 200831489) was dissolved in acetone (85 mL). A solution of KMn〇4 (450 mg, 2.85 mmol) in hydrazine (28 mL) was added. It was stirred at room temperature for 5 hours. Then, another solution of KMn〇4 (450 mg, 2.85 mmol) in h2 (25 mL) was added. After stirring for an additional hour at room temperature, the reaction was completed. The reaction mixture was quenched with 10% Η 2 〇 2 (ΐ·5 mL) and then passed through celite. The filtrate was stripped under vacuum to approximately 1/3 volume. The residue was acidified with 6 Ν Ηα and extracted with ethyl acetate. Purification by a hydrazine column (hexane/acetone/acetic acid, 70/30/1) yielded crude product. Trituration with ether gave pure 1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid. Step C · Suspending 1-ethyl-6-decyloxy-1H-indole-3-carboxylic acid (250 mg, ι 4 耄 mol) in 0^(^(12.5 ml) with DMF (10 micron) Add chlorinated grass mash (230 μl, 2.64 mmol) and stir the reaction mixture at room temperature for 1 hour. Then, slowly pour the mixture into concentrated NH4 with rapid stirring. 〇H solution (5 ml). Then, it was subjected to liquid separation treatment in H2〇 and Et〇Ac. The residue obtained from the ethyl acetate layer was developed with acetone to give 1-ethyl-6-A. oxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid. Step D: 1-ethyl-6-methoxy-1H-indole-3-carboxamide (12 〇 mg, 〇·55 mM), Lawesson's reagent (240 mg, 〇·6 mmol) and toluene (2 ml) were heated at 90 ° C for 90 minutes. The reaction mixture was concentrated and the gum was concentrated. Chromatography (EtOAc / EtOAc / EtOAc / EtOAc)丨-Ethyl-6-methoxy_1H_吲哚 硫 thiocarbamate (83 mg, 128244-3 - 335 · 200831489 0.36 house Moer), ethylene glycol dimethyl ether (3.6 ml) and bromoacetaldehyde dimethyl shrinkage (220 μl, L86 millimolar) heated at 8〇t: Add more bromoacetic acid dimethyl acetal (25 〇 microliters), heat it at 8 Torr for 2 hours, add 250 μl of bromoacetaldehyde dimethyl acetal, then heat again. After 2 hours, the reaction mixture was cooled to room temperature, adsorbed on silica gel, and purified by silica gel chromatography (hexane / EtOAc '7/3) to give μethyl-6-methoxy-3-pyrazole The base compound was a brown oil (44 mg, 47%). The following compounds were obtained according to the procedure described above: Compounds 78, 1 〇 1, 1 〇 4, 105 and 106. Example is : 1-ethyl Preparation of -6-methoxy-2-phenoxymethyl-1Η-吲哚-3·carbonitrile (Compound 99)

LiAIH4

Dioxoland 0°C

CN

Bismuth benzamidine

DMF

NBS clumsy base CN

The procedure was carried out in a suspension of LiA1H4 (7.6 g, 〇·2 mol) in dioxane (1 mL) at 0 C, and 6-methoxy_1Η_^哚_2 was added dropwise. A solution of carboxylic acid methyl vinegar (8.2 g, 0.04 mol) in dioxane (50 mL). After the addition, the mixture was stirred at room temperature for a few hours and then heated under reflux for 5 hours. After the cold part to 0 C, the reaction was carried out by water (drop by drop), followed by 15% Na〇H water 128244-3 -336 - 200831489 Lok solution. After stirring at room temperature for 1 hour, the mixture was filtered through Celite. The solid was washed with a large amount of EtOAc. The solvent was washed with brine, dried over Na.sub.2.sub.4, and evaporated. The residue was purified by flash column chromatography using EtOAc EtOAc (EtOAc) elute Step Β: in a solution of 6-methoxy-2-methyl-1Η-啕哚 (39 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) A solution of ClS 2NCO (4 mL, 1.3 eq.) in EtOAc (EtOAc) After the addition, the mixture was stirred at room temperature for 3 hours. Then, it was poured into ice water, and saturated NaHCOs was added thereto until it became alkaline. The aqueous phase was extracted with (3⁄4⁄4⁄4), followed by evaporation. The residue was purified by flash column chromatography on EtOAc EtOAc EtOAc (EtOAc) 2_Mercapto-1H-indole-3-carbonitrile. Step C: Add 6-methoxy in a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) a solution of benzyl-2-methyl-1H-indole carbonitrile (1.3 g, 7·mmol) in DMF (8 mL) followed by ethyl iodide (12 mL, 2 eq.) After stirring for a few hours, the mixture was poured into ice water and extracted with CHzCi2. The organic layer was washed with brine and dried over Na?s?4. The solvent was evaporated in vacuo and Purification by column chromatography using EtOAc/petrole ether (1/5) as a solvent to afford 92% of EtOAc EtOAc EtOAc. Adding peroxydiphenyl peroxide to a solution of 1-ethyl-6-methoxy-methanol methyl 1H-indole carbonitrile (ι·38 g, 6.45 houser) in benzene (13 mL)醯 (226 mg) and marriage 8 (1.21 g, h 〇 5 equivalents). Then 'will The compound was added to 128244-3 - 337 - 200831489 and heated to reflux for 3 hours. After cooling and filtration, the filtrate was concentrated in vacuo. using crude 2-bromomethyl-[pi]ethyl-6-methoxy- 1H-rhodium-3-carbonitrile (1.6 g, 86%) without further purification. / Step Ε: 2-bromo, in NaH (44 mg, 4 eq.) in DMF (0.5 mL) Methyl ι_ethyl methoxy-1H-rhodium-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20 hours, the mixture was poured into ice water. And the organic layer was washed with brine and dried over NasSO4. ) as a dissolving agent to produce 1-ethyl-6.methoxy-2-phenoxymethyl-1H4 oxime carbonitrile, compound 99 〇

Example 1T: Preparation of 6-nitro-2-pyrrole+yl_1H•indole carbonitrile (Compound 7)

CN

Step A: a solution of 2-fluoro-5-nitroaniline (11·7 g, 74·9 mmol) in dimercaptoamine (ΐ2〇 ml) to malononitrile (5· 28 g, 8 〇〇 millimolar) and treated with carbonic acid unloading (11.05 g, 80 〇 millimol) (c/zm fine 7W, 9, 37 (2〇01)). The resulting heterogeneous mixture was heated to gentle reflux for 3 hours, then cooled and poured into water (5 mL). The formed temple was collected by filtration and dissolved in ethyl acetate (3 liters). The solution was dehydrated and dried at %8 〇4, filtered, and partially evaporated to give a precipitate which was collected by filtration. Further evaporation and filtration gave a second portion of the product. The two parts were combined and dried under vacuum, 128244-3 - 338 - 200831489 to give 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (7.90 g, 52 %), an orange powder. Step B · A solution of 2-amino-6-nitro-lH-p indole-3-indolonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL), 2,5-dimethyl Treatment with oxytetrahydrofuran (30 liters, 2.27 millimoles) and heating the solution to reflux over 14 hours. After cooling to ambient temperature, the solution was poured into water (1 mL) and solid sodium bicarbonate was added until c〇2 was stopped. The mixture was extracted with EtOAc (2 mL) and washed with saturated brine. The residual material was separated by EtOAc (EtOAc/hexanes, 1/4) to give 6-nitro-t-pyrrolidine s s s s s s s. 〇/〇). Example 1U: Preparation of N-(3-cyano-1-ethyl-6-nitro]H, anthracene) acetamide (Compound 25)

i i Step A: Sodium hydride (42 mg, 1 〇 5 mmol, 6% w/w suspension in mineral oil) was washed with hexane and dissolved in dimethyl sulfoxide (1 mL). A solution of 2 -amino nitro-oxime carbonitrile in dimethyl sulfoxide (1 ml) prepared in Procedure 1T was added by the ejector, and the resulting mixture was stirred for 2 Torr. Ethyl iodide (77 μl, 〇·96 mmol) was then added by syringe and the contents were stirred for 14 hours. Next, the reaction was poured into Et 〇Ac (9 mL) and this was washed with water (3×50 mL) and saturated brine (4 mL). The aqueous phase was back-extracted with EtOAc and the organic extracts were combined to dryness, dried, filtered, and evaporated. The residue was separated on silica gel by column chromatography (EtOAc / hexanes / hexanes / EtOAc) to give the first portion of the dialkylated analog, followed by the desired compound, 2-amino-1- Ethyl-6-nitro-1Η_吲哚 each carbonitrile (114 house, 52%), and finally the unreacted starting material. The desired product is isolated as an orange powder. ί \ Step Β · · Sodium hydride (44 mg, U 〇 millimolar, 6 〇 % w / w, in mineral oil) washed with hexane and suspended in 1,4-dioxane (3 ml) )in. Adding a solution of the 2-amino small ethyl winter nitro]H_吲哚_3_carbonitrile (120 mg, 0.521 mmol) prepared in the above step B in dioxane (2 ml) The resulting mixture was stirred for 30 minutes. Then, cesium chloride (45 μL, 0.63 mmol) was added by a syringe, and the solution was further stirred for 12 hours. The reaction was partitioned between water and EtOAc (20 mL each) and the organic phase was washed with brine. The aqueous phase was back-extracted with ethyl acetate in that order, and the organic extracts were combined, dried, dried, filtered, and evaporated. The solid formed was triturated in % hydrazine, collected by filtration, and dried under vacuum to give the compound (3-cyanoethylethyl-6-nitro-1H-indol-2-yl)-acetamide (1 mg, 71%), compound 25, as an off-white powder. Using this procedure and substituting the appropriate acid chloride or chloroformate, the following compounds are obtained. Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216 〇 Example IV ·· N-ethyl-3 Preparation of _phenyl-5-nitroguanidine (Compound 41) 128244-3 • 340- 200831489

Step A: To a solution of 5-nitroguanidine (5.00 g, 30.8 mmol) in pyridine (200 mL), add brominated brominated toluene in drops at -4 ° C under nitrogen ( 10.99 g, 34.3 mmol of a solution in pyridine (200 mL) and stirred. After the addition was completed, the reaction mixture was stirred at 〇 ° C for 5 minutes. The reaction mixture was diluted with water (200 mL) EtOAc. The organic layer was washed with 6M HCl (300 mL), 5% NaHC03 (300 mL) and brine (3 mL). The organic phase was dried over MgS 4 and the solvent was removed to give 3-bromo-5-nitroindole as a yellow powder, 8 % pure, with 2 % nitro 5- oxime (6.80 g) , 74% yield). Step B: From 3-bromo-5-nitroindole (625 mg, 2.1 mmol), phenyl dipyridyl (381 mg, 3.13 mmol), triphenylphosphine ( 109.3 House gram '0.417 house Moule' degassed in a solution of dimethoxyethane (4·ΐ6 ml). To this mixture was added 2N sodium carbonate (6.25 mL) and the reaction mixture was again degassed. To the reaction, palladium acetate (23. 4 mg, 0.104 mmol) was added, and the reaction was refluxed under dry nitrogen and stirred for 8 hr. The reaction mixture was then diluted with 1 Μ HCl (100 liters) and extracted with ethyl acetate (100 liters). The organic phase was washed with water (1 mL) and brine (丨(8) mL) 128244-3 • 341 - 200831489. The organic phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by chromatography on EtOAc (EtOAc EtOAc (EtOAc) ).

Step C: Add 3_phenyl-5-nitroguanidine (4〇) to a mixture of 60% NaH (8.7 mg, 0.630 mmol) and DMF (1·〇宅升) in mineral oil. 〇mg, 2.1耄mol) A solution in DMF (〇·75 ml). The reaction mixture was stirred at 〇C and Ν2 for 20 min. Ethyl iodide (14. 8 microliters, 0.185 4 • mole) was added dropwise and the reaction mixture was stirred for additional 3 hours. The reaction mixture was diluted with EtOAc (30 mL). The organic phase was washed with water (250 liters), then dried over MgSO 4 and evaporated in vacuo. The desired N-ethyl phenyl benzyl nitroindole was obtained as a yellow powder (40.0 mg, 89.5% yield). In a similar manner, the following compound was prepared: Compound 4〇. Preparation of 1W · [3-Cyano-1-(4-methoxyphenyl)_1H_吲哚-6•yl]•Aminomethyl propylate (Compound 97)

128244-3 -342 - 200831489 Another cartridge column (3/2, ether/hexane) is required to completely purify the product, [3-cyano-1-(4-methoxy-phenyl)_1Η-吲哚 基 ] _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Example IX: Preparation of Ν-[4-(3-cyanoethylidene methoxy-1Η-吲哚_2-ylethynyl)-phenyl]-nonanesulfonamide (Compound 130)

2-(4)Aminophenylethynyl)ethylidene-6-methoxyl-indole-3-indene-3-carbonitrile (50 mg, 0.16 mmol) prepared according to the method of Example 1 at room temperature ) Soluble in the outer 1: bite (550 μl). Acacia sulphate (17 μl, 〇.21 mmol) was added dropwise while stirring at room temperature overnight. The reaction mixture was then diluted in ethyl acetate and washed with an aqueous solution of HCl, followed by brine. The organic layer was dehydrated and dried, and concentrated. Purified by ruthenium chromatography _, CH2Cl2 / EtOAc) to give N-[4-(3-cyano-1_ethyl methoxy _m•吲哚_2_ ethynylphenyl) 曱 曱石The decylamine (58 mg, .92%) is an off-white solid. The following compounds were prepared by substituting the appropriate aminophenyl phenylethynyl hydrazine with a gasified sulfonium compound using the procedure shown above: Compound 131 , 132, 208, 209 and 210. Example 1Y: N-[4-(3-cyano small ethyl-6-decyloxy-1H-indol-2-yl)-phenyl]-methane jaundice Preparation of amine (compound 129)

MeS02CI

Et3N

THF room temperature 128244-3 - 343 - 200831489 2-(4-Aminophenyl)-1-ethyl-6-methoxy-1H-W哚-3 prepared as described in Example Ig Step B - a solution of carbonitrile (70 mg, 0.24 mmol) in THF (3 mL) cooled to EtOAc EtOAc (EtOAc) , 0.29 mmol), stirred and allowed to warm to room temperature overnight. Then, the reaction mixture was diluted with H20 and extracted with ethyl acetate (3×). The organic phase was washed with H.sub.2 and sat. Na.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssss -Cyano-ethyl-6-methoxy-1H-(9)indol-2-yl)-phenyl]-methanesulfonamide as a tan solid. Substantially using the same procedure as described above, and substituting the appropriate aminophenyl (tetra) oxime with gasification oxime, or reacting in a bite as both the test solvent, the following compounds are obtained: compound 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629 , 630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789 , 790, 791, 850, 851, 867, 868, 890, 891, 912, 919, 920, 921, 922, 923, 924, 932, 933, 934, 935, 941, 953, 968, 982, 988, 990 , 995, 996, 997, 998, 1035, 1038, 1041, 1103, 1105, 1115, 1116, 1117, 1123, 1140, 1141, 1155, 1160, 1161, 1170, 1175, 1181, 1182, 1188, 1189, 1 228, 1229, 1230, 1231, 1280. 128244-3 -344 - 200831489 Example IZa: N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamidine Preparation of amine (compound 138)

2-(4-Aminophenylethynyl)ethylidene methoxy-1H-4indole-3-carbonitrile (95 mg, 0.29 mmol) prepared as described in Example 1H In Tfjp (ι·4 ml). Triethylamine (84 μL, 〇·6 mmol) was added, followed by dropwise addition of chlorohydrazine (44 μL, 0.5 mmol). It was stirred at room temperature for 1 hour. The reaction mixture was partitioned between 13⁄4 EtOAc and EtOAc. The organic layer was dehydrated, dried, and concentrated. Purification by gelatin chromatography (9/1, CH.sub.2Cl.sub.2/EtOAc) to yield N-[4-(3-cyano-1-ethyl-6-methoxy-1H&gt;??-2-ylethynyl) -Phenyl]-acetamide (1 〇 3 mg, 96%) as a yellow solid. The following compounds were prepared by substituting the appropriate aminophenyl phenyl hydrazide with a gasified acid by the procedure shown above: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206, 207, 211, 212, 213, 219, 224, 225, 228 〇Example IZb ··N-[4-(3-cyanosuccinyl-6-methoxy-1H-anthracene ethynyl) Preparation of -phenyl]-carboxamide (compound 241)

Acetic anhydride (2.5 ml) and 98% formic acid (1.0 ml) were heated at 65 ° C for 1 hour. Allow to cool to 0 °C. 2-(4-Aminophenylethynyl H-ethyl-6-decyloxy-1H-anthracene-3-carbonitrile (100 mg, 0.32 mmol) prepared in Example 1H. 3 - 345 - 200831489 Dissolved in THF (1.2 ml) and added to the formic acid anhydride mixture. It was allowed to stand at 0 C for 30 minutes. Then, the reaction mixture was partitioned between Η2 Ο and EtOAc. The KOAc layer was washed with saturated NaHC03, followed by saturated brine. The organic layer was dried, dried and concentrated, and purified by silica gel chromatography (4A, CI^CVEtOAc) to give Ν-[4-(3· cyano-1-B -6-methoxy-1H-indol-2-ylethynyl)-phenyl]-carboxamide (1 〇 5 mg, 96%) as a yellow solid. Preparation of Compound 218. Example 1 : Preparation of Ν-[4-(3·cyanoethylidene methoxy-1 fluorenyl)-phenyl]-acetic acid amine (Compound 128)

2-(4-Aminophenyl)·1-ethyl-6-methoxy-3- carbonitrile (70 mg, 〇·24 mmol) prepared as described in the Example IGa step. The solution in THF (3 mL) was cooled to 0.degree. C. and was taken with triethylamine &lt;RTI ID=0.0&gt;&gt; Warm to room temperature. The reaction mixture was then diluted with H2O and extracted with EtOAc (3X). The organic phase was washed with EtOAc (EtOAc) EtOAc (EtOAc) elute 3-cyano-1-ethyl-6-methoxyindol-2-yl)-phenyl]acetamide, as a tan solid. Substantially using the same procedure as above, and substituting the appropriate aminophenyl garnish and gasification to make the following compounds · Compounds μ, 242, 244, 324, 325, 326, 327, 328, 329, 330, 383 , 420, 421, 422, 423, 128244-3 - 346 - 200831489 424, 425, 544, 558, 559, 560, 561, 565, 566, 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857, 858, 859, 895, 896, 897, 898, 899, 900, 901, 913, 914, 915, 916, 983.

Example 1AB: Preparation of l-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]-3-ethylurea (Compound 220)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-indolecarbonitrile (100 mg, 0.32 mmol) prepared as described in Example 1H The ear) is dissolved in pyridine (670 μl). Ethyl isocyanate (62 microliters, 0.75 millimolar) was added. Then, the reaction mixture was heated at 1 ° C for 2 hours. The mixture was then diluted in EtOAc and washed with aq. HCI then brine. The organic layer was dehydrated, dried, and concentrated. Purification by gel chromatography (4/1, CH.sub.2Cl.sub.2.sub.EtOAc) then hexane/acetic (l/1) to give 1-[3-(3-cyano-1-ethyl-6-methoxy) -1H-Indol-2-ylethynyl)-phenyl]-3-ethylurea (44 mg, 36%) as a white solid. Example 1AC· 1-(2-Vethylethyl)-3-[4-(3-carbyl-1-ethyl-6-decyloxy-ΙΗ-17?丨嗓-2-ylethynyl)- Preparation of phenyl]urea (compound 156)

2-(4-Aminophenylethynyl) small ethyl-6-128244-3 - 347 - 200831489 methoxy-lH-β丨嗓-3-indenecarbonitrile prepared as described in Example 1H 100 mg, 〇·32 mmoles, suspended in toluene (600 μl). 2-Chloroethyl isocyanate (32 μL, 〇·37 mmol) was added, and the mixture was heated at 100 ° C for 5 hours. Then, the reaction mixture was cooled, diluted in acetone, and adsorbed onto silica gel. Purification by column chromatography (5-10% EtOAc in EtOAc) to give 1-(2-chloro-ethyl)-3-[4-(3- cyanoethylethyl -1H-Indol-2-ylethylidene)-phenyl]urea (73 mg, 54%) as a yellow solid. The following compounds were prepared using the above procedure. Example 1AD: Preparation of ethanesulfonic acid [4-(3-cyanosuccinyl-6-methoxy-1??-indolylethynylphenyl)methyldecylamine (Compound 157)

N-[4-(3-cyanoethylideneoxylHH-w嗓-2-ylethyl methoxy)-based base made according to Example IX] Ethyl sulphate (70 gram '0 · 17 millimoles) 2 CO, (49 mg, 0. 35 mmol) and DMF (1.0 mL) combined. Mothella (16 liters '0.26 house moles' was added and the mixture was thrown at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc and washed with EtOAc EtOAc. The organic layer was dehydrated and dried, and concentrated. Purification by chromatography on EtOAc (95/5, CH2Cl2 /EtOAc) Developed to obtain ethanesulfonic acid (3-cyano-1-ethyl-6-methoxy-iH-p?doxa-2-ylethynyl)-phenyl]decylamine (61 mg, 85 %), an orange-white solid. The following compounds were prepared using the above procedure in place of the appropriate sulfonamide: Compound 182, 652, 840. 128244-3 -348 - 200831489 Example 1AE: 1-Ethyl-5-nonyloxy-2-[4-(morpholine-4C carbonyl)-phenyl]-1H-indole-3-carbonitrile ( Preparation of Compound 245)

Step A: 4-(3-Cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoic acid methyl ester (350) prepared as described in Example lGa Step B The mixture was combined with NaOH (40 mg, 1 mmol), η 2 Ο (0.8 mL) and THF (3.4 mL) and heated at 80 ° C for one hour. The reaction mixture was diluted in hydrazine 20 and then washed with ether. The aqueous layer was acidified with an aqueous HCl solution and extracted in Et EtOAc. The organic layer was dried and dried to give 4-(3-cyanoethylethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a white solid. . Step B · Suspending 4_(3·cyano-1-ethyl-6-methoxylΗ·indol-2-yl)-benzoic acid (50 pg '0.16 mmol) in CH2Cl2 (2.2 ml) with the catalyst DMF (2 μl). Chlorella grass mash (22 μL, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour at which time complete dissolution occurred. The reaction mixture was pipetted into a solution of oxaline (1 mL) in CH2 (3⁄4 (5 liter) in a vigorously stirred pipe. After the addition, the reaction was washed with an aqueous solution of HC]1. The mixture was dehydrated and dried, and concentrated. Purified by a hexane column (1:1 CH2 CL /EtOAc) to yield of ethyl ethyl methoxy hydrazide [4_(ffofolin)-phenylHH- Each of the carbonitriles (56 mg, 90%) was a white solid. 128244-3 - 349 - 200831489 The following compounds were prepared in a similar manner as described above: Compounds η, 114, 246, 270, 271, 290, 291, 292, 323, 377, 378, 379, 380, 381, 382, 384, 385, 386, 387, 388, 389, 39, 391, 392, 432, 433, 564, 568, 569, 570, 571 , 572, 573, 647, 648, 853, 860, 861, 862. Example 1AF: Cyclopropanone [4-(3-cyano + ethyl hydroxy-m(tetra) 嗓 2· yl yl) Preparation of phenyl]decylamine (Compound 194)

A cyclopropanecarboxylic acid prepared as described in Example IZa in ΒΒγ3 (800 μl, 1 M in 03⁄43⁄4, 〇·8 mmol) [4-(3-cyano-indole-ethyl) Oxy-1H-indol-2-ylethynyl)-phenyl]-nonylamine (60 mg, 〇16 mmol) was stirred at room temperature for 1 hour. The reaction mixture was quenched with EtOAc and extracted with CH.sub.2Cl. The organic layer was dehydrated and dried&apos; and concentrated. Purification by chromatography; 6 oxime gel chromatography (Centre Ac) to obtain impure products. This crude product was triturated with 1/1 hexanes/acetone to give cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indole-2-ylethyl) • Phenyl] • decylamine (32 mg, 54%) as an off-white solid. The following compounds were prepared using the above procedure, substituting the appropriate sulfonamide (from Example lx) or the guanamine (from Example iz): Compounds ι 64, 168, 183, 193, 195. Example 1AG · 1-Ethyl-6-methoxy-2-[4-(2-keto-tetrahydro-sodium. Sodium-based)·Phenylethynyl]-1H-indole carbonitrile (Compound 166 Preparation of 128244-3 -350- 200831489

( \ H2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-W嗓-2-ylethynylphenyl) prepared according to Example 1AC Urea (55 mg, 〇13 mmol) was combined with K:2C 〇3 (50* g, 0.36 mmol) and DMF (55 〇 microliter). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with Et.sub.Ac and washed with EtOAc. Oxy-2-[4-(2-keto-tetrahydroimidazolium)-phenylethynyl hh-oxime carbonitrile (47 mg, 94%) as a white solid. Prepared by substituting the appropriate urea: Compound 222. Example 1AH: N-[4-(3-Cyano-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]- Preparation of decyl dimethylphosphinate (compound 227)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-indolecarbonitrile prepared as described in Example m at room temperature under 〇 ° C (100 mg, 〇32 mmol) in hexapyridine (300 μl). Add dimethyl chlorinated &amp; phosphine (60 mg, 0.53 mmol) in thf (300 μl). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and EtOAc. The organic layer was dehydrated and dried, and concentrated.矽 噌 噌 噌 丙 丙 丙 丙 128 128 128 128 128 128 128 128 128 128 128 244 244 244 244 244 244 244 244 244 244 244 244 244 244 244 244 244 244 128 128 128 128 128 128 128 128 -Phenyl]-dimethylphosphinic acid decylamine (65 mg, 52 °). Compound 227 was obtained as a white solid. Then, the ruthenium column was rinsed with 9/1 CH 2 Cl 2 /MeOH to give 9 mg. N-[4-(3-Cyano-1-ethyl-6.methoxy-1H.indol-2-ylethynyl)-phenyl l·bis-(dimethylphosphinic acid) decylamine , as a by-product. Example 1AI: Preparation of 1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-iso-saltyl]-1H·indole (Compound 116)

Step A: Preparation of the aldehyde of the aldehyde precursor of Example 1R, each of methoxy-1H^丨哚-3-carboxaldehyde oxime (0.20 g, 0.92 mmol) in dichloroethane (3 mL) The mixture was treated with N-chlorosuccinimide ((U2 g, 〇·92 mmol) and pyridine (0.04 mL &lt;&lt;RTIID=0.0&gt; The reaction mixture was poured into a hydrazine and acidified with EtOAc (EtOAc) to EtOAc (EtOAc). This was used in the next step 'no further purification. Step B: The above-prepared chloroguanidine mixture was dissolved in cH 2 Cl 2 (5 ml) and added 4-methoxyphenyl group at 〇 ° C Acetylene (9) 24 g, 1.84 mmol) with triethylamine (25 ml, U4 mmol), then the reaction was stirred overnight and warmed to room temperature. The reaction was then diluted with Η2 , and extracted with EtOAc (3×). The organic phase was washed with H.sub.2 and sat. Na.sub.1, dried and dried. &lt;RTI ID=0.0&gt;&gt; Chromatography on ruthenium (EtOAc / hexanes, 10-20%) affords EtOAc (EtOAc) -Different slogan ° sit-3-yl]嗓, a tan solid. Example 1AJ: Preparation of [4-(3-Cyano-1-ethyl-6-methoxy-1H-4indol-2-yl)-phenyl]-amine methyl acid ethyl ester (Compound 121)

2-(4-Amino-phenyl)-1-ethyl-6-methoxy-1Η-β|哚-3-carbonitrile (70 mg, 0.24 mmol) prepared as described in Example Ig Step B Prepared with a mixture of two phases of ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and sat. NaHC.sub.3 (3 mL) and then warmed to room. Warm and stir for 24 hours. The reaction was then diluted with H20 and EtOAc (EtOAc). The organic phase was washed with H20 and saturated NaCl, then dried and dried. Flash chromatography (EtOAc/hexane 20-40%) to give 48 mg (55%) [4-(3-carbyl-1-ethyl-6-methoxyindol-2-yl)-benzene The amino group-amino acid ethyl acetate 5 is an off-white solid. The following compounds were prepared in a similar manner: Compounds 122, 293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372, 434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502, 503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581, 582, 583, 584, 585, 585, 586, 587, 588, 589, 128244-3 - 353 - 200831489 590, 591, 592, 593, 594, 595, 596, 597, 603, 604, 605, 606 , 607, 618, 619, 624, 625, 637, 640, 641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739, 744, 745, 746, 747 , 787, 788, 792, 793, 794, 795, 796, 797, 819, 822, 823, 824, 825, 826, 849, 925, 926, 945, 946, 947, 948, 949, 950, 951, 970 , 971, 972, 973, 974, 975, 976, 977, 978, 979, 98 1, 984, 985, 986, 991, 992, 993, 1015, 1020, 1021, 1022, 1029, 1030, 1031, 1032, 1033, 1034, 1037, 1040, 1042, 1044, 1055, 1056, 1057, 1058, 1059, 1062, 1063, 1064, 1065, 1071, 1073, 1074, 1075, 1077, 1078, 1079, 1107, 1109, 1111, 1112, 1113, 1114, 1122, 1127, 1128, 1129, 1145, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1169, 1174, 1176, 1177, 1178, 1179, 1180, 1186, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302. Example 1AK: Preparation of 1-ethyl-5-pyrimidin-3-yl-1H-W哚-3-carbonitrile (Compound 141)

CsF DME was added to the tube with 5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol), and pyromphenyl-3-dihydroxyborane (72 mg, 0.56). Mixture of millimolar), PdCl2(PPh3)2 (ll mg, 0.016 mmol) and CsF (152 mg, 1 mmol) 128244-3 •354 - 200831489, then alternately pump and fill with nitrogen (3X And diluted with dimethoxyethane (3 liters), followed by heating to 9 Torr for 19 hours. After cooling, the crude reaction mixture was diluted with EtOAc (3 mL). The combined organic phases were washed with saturated NaCl and dried over EtOAc. Rapid chromatography on ophthalmic gum (o^cv hexane, 40/60) to give 25 mg (25 〇/〇) 1_ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile , as a white solid. The following compounds were prepared in a similar manner: Compounds 14 and 142.

Example 1AL: Ν-[4·(3-Cyano-1-ethyl-6-decyloxy-1H-indol-2-yl)-phenyl]-indole-methylmethanesulfonamide (Compound 18 Preparation of 〇)

Ν[[(3-Cyano-1-ethyl methoxyindol-2-yl)-phenyl]nonanesulfonamide prepared according to Example 1 (13 mg, 〇·35 m The solution in DM (1 mL) was taken up in NaH (21 mg, EtOAc &lt;RTI ID=0.0&gt; Methyl iodide (1). 〇 3 ml, 〇·53 mmol was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with EtOAc (EtOAc) (EtOAc) The organic phase was washed with η; 2 Torr and saturated NaCl, then dried and dried. Purification by flash chromatography (Et〇Ac/CI^Cl2 '(Μ%) on silica gel to obtain 6 mg (45%) N_[4_(3-cyano + ethyl

Methoxy-1H-indole-2-ylphenyl]-N-methylmethanesulfonamide is a white solid. In a similar manner, the following compounds were prepared: Compounds 181, 642, 643, 672, 673, 816, 852, 1002, 1003, 1004, 1005, 1006, 1007. 128244-3 - 355 - 200831489 Example 1AM: N-[4-(3-Cyano_1_ethyl-6-trans)-1H-called noise_2-yl)-phenyl]-methanesulfonamide Preparation of Compound 189)

Ν-[4-(3·Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (85 g, 0.23 mmol) The solution in CH2Cl2 (2 mL) was cooled to -5 °C. A solution of boron tribromide (115 ml, U5 mmol, 1 M solution in water) was added and the reaction mixture was allowed to warm to 1 Torr. Hey, it took 4 hours. The reaction mixture was poured into H.sub.2 and extracted with EtOAc. The combined organic phases were washed with H.sub.2 and saturated NaCl, dried and dried. Chromatography on EtOAc (EtOAc/CH 2%, 5%) ) _ stupid base methane sulfonamide, a tan solid.

(B〇C) 2〇 DMAP CH2CI2 The following compounds were prepared in a similar manner. · Compounds i9〇, i9i, 192. Shell Example 1AN · 3-[5_(3·Cyano-6-methoxy (4)-4) slogan disali-3-yl]benzoquinone c, vinegar (preparation of compound Na

C02 (g)

CN

, LDA 1 y —

Step A as described in the previous example: 6-methoxy-1H-indole-3-128244-3 • 356 - 200831489 carbonitrile (5·88 g, 40 mmol) and (Boc) 2 〇 (9·59 g, 44.0 mmol) in a mixture of DCM (50 mL), DMAP (0.10 g, 0.8 mmol) was added. The mixture was stirred at room temperature for 48 hours, then treated with water (30 mL) and dried over anhydrous Nas. The crude product was chromatographed on EtOAc (EtOAc/EtOAc,EtOAc) %).

Step B: The above intermediate (2.72 g, 10.0 mmol) was dissolved in dry THF (20 mL) and cooled at </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> C, followed by the addition of LDA (1. 5 环 in cyclohexane) THF, 10·0 ml, 15 mmol. After stirring for 45 minutes, C〇2 gas was introduced for 2 hours. Then, the mixture was allowed to come to room temperature, and the solvent was removed in vacuo, and the residue was treated with water and acidified to pH = 2 with 6N HCl. The precipitate was collected, washed with water and dried to provide the acid intermediate, 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tri-butyl ester (2.40 g, 73 %) 〇Step C: 3_Cyano methoxy hydrazine dicarboxylic acid μ 3 · Butyl ester (474 mg, 1.5 mmol) and HOBt (200 mg, 1.5 mmol) prepared above In a solution of DCE/DMF (10 ml / 1 ml), add Dcc (31 〇 I gram '1.53⁄4 mol)' followed by carbaminoimine) benzoic acid formazan (291 mg) , 1.5 millimoles). The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was collected, and the solvent was replaced with chlorobenzene, followed by heating at EtOAc (c) for 48 hours. After cooling to room temperature, the solvent was removed in vacuo and residue was chromatographed eluted (CH2Cl2/EtOAc, 8/2), obtaining an intermediate, 3-cyano-methoxy-2·[3-(3-methoxycarbonylphenyl)·[ι,2,4]oxadiazol-5-yl; |_第三 Small carboxylic acid tri-butyl ester, treated with 5〇% TFA (1〇〇ml) in DCM at room temperature 128244-3 - 357 - 200831489 for 1 hour · 〇力:吉^? rb # After removal of the volatiles from the human dimethyl dimethyl ether, the residue was suspended in water and neutralized with K2C 〇3 to provide the desired product, 3-[5-(3-cyano-6-methoxy oxime- Hh wood·2·yl_)[l52,4]oxadiazoleyl]methyl benzoate, compound 226 (350 mg, 62%). Example 1A: 丨-ethyl-sulphonylphenyl) Preparation of -6-methoxy-1EM丨哚-3-carbonitrile (Compound 265)

CN

m-CPBA SMe --^ C_ Me0

a solution of 1·ethyl-6-methoxy-2-(4-methylthiophenyl)_1Η4丨哚 each niobonitrile 1·12 g, 0.37 houser in CH2C12 (5 ml) at room temperature The mixture was treated with m-chloroperbenzoic acid (Aldnch, &lt;77 ° /, 0.26 g), and the reaction was stirred at room temperature for hr. The reaction was then diluted with hydrazine and sat. NaHC.sub.3 and extracted twice with EtOAc. The organic phase was washed with NaHC 3 (2X) and sat. &lt;RTI ID=0.0&gt;&gt; The crude product was purified by flash chromatography (EtOAc/EtOAc (EtOAc) elute Each methoxy-2·(4·methylthiophenyl anthracene-3-carbonitrile is an off-white solid. Shell Example 1ΑΡ ·Ν-{4-[3-cyano-1-ethyl-6_(2 -Preparation of moffolin-4-yl-ethoxy)_ιη_indol-2-yl]-phenyl}nonanesulfonamide (compound 478)

Nal CH3CN

N-{4-[6-(2-chloroethoxy)cyanoethylethylethyl hydrazide-4-yl]-phenyl}methanesulfonamide (90 mg) at 10 °C '〇·21 mmol, morphine (〇〇6 毫 128244-3 -358 - 200831489 liters, 〇·65 mmol), Nal (32 mg, 〇·21 mmol) and diisopropyl A solution of the ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) The reaction mixture was cooled to rt. The combined organic phases were washed with saturated NaCI, dried and dried. The crude solid was triturated with EtOAc (EtOAc) and filtered to afford 41 mg (41%) of N-{4-[3-cyanoethylethyl-6(2). -吲哚-2_yl]-phenyl}methanesulfonamide as a tan solid. The following compounds were prepared in a similar manner: Compounds 479, 48, 481, 482, 496, 497 and 498. Shell Example 1AQ · 2-Florinine Ice-Based Ethyl Sulfonate [4-(3-Cyano-indole-ethyl-methoxy-1H-indol-2-yl)-phenyl]decylamine ( Preparation of Compound 653)

Step A: 2-(4-Aminophenyl)succinylethyl methoxyindole-3-carbonitrile prepared by the procedure of Example 1Ga at room temperature (〇·82 mg, 2.82 m) Mol) A solution of pyridine (1 mL) was treated dropwise with chloroethyl sulfonium (0.38 mL, 3.66 mmol). After stirring for 4 hours, the reaction mixture was quenched with ice water and sufficient 6NHC1 was added until the pH was reduced to 2. This suspension was extracted with hot EtOAc (3×). The organic phase is then washed successively with in HC1, H2〇 and saturated NaCl, dehydrated and concentrated, and concentrated to obtain ethylene sulfonate 128244-3 - 359 - 200831489 acid [4-(3-cyano-1-ethyl methoxy) The base _m, anthraquinone) phenyl phenylamine as a light orange solid was used directly in the next step without further purification. Step B: The above prepared ethylene sulfonate (3-cyano small ethyl + methoxy-1H_W嗓-2-yl) phenyl phenylamine (7 〇 mg, 〇 18 mmol), A suspension of morphine (5 liters of 0.55 mmol) in CH3cN (1.5 ml) was heated under reflux for 1.5 hours. After cooling to room temperature, the reaction was concentrated and residue was evaporated. Purification by flash chromatography (acetone, 2/98) on silica gel to give 89 gram (100%) 2_fopholine-4-yl-ethanesulfonic acid [4-(3-cyano-1) -ethyl-6-methoxy-oxime-pyridin-2-yl)-phenyl]decylamine as a tan foam. The following compounds were prepared in a similar manner: Compound 654. Shell Example 1AR · 2-? Fulin ice-ethane sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-indolyl-2-yl)-phenyl]methyl decylamine (Compound 668) Preparation 0

0, etc. κ1 1Q in '成之2_?福ρ林冰基·乙烧sulfonic acid [4_(3_cyanoethyl 6methoxy oxime-2-yl)-phenyl] decylamine (6〇 mg , 〇13 mmol) solution in DMF (3 ml), treated with j^co (3 mg, 〇·26 mmol) and decane iodide (0.02 mL, 0·26 mmol). After stirring at room temperature for 15 hours, the reaction mixture was diluted with EtOAc and extracted with EtOAc (2 EtOAc). The organic phase is then washed with hydrazine (3 Torr) and saturated NaCI, then dried and dried and concentrated to yield residue. Rapid chromatographic chromatography on acetone (acetone, 〇·2%), 31 gram (50%) 2 phlomatolin ice-based ethanesulfonic acid [4_(3_cyano small ethyl _6·A) 128244-3 -360- 200831489 oxy-1Η-indop-2-yl)-phenyl]methyl decylamine, a gray solid solid. The following compounds were prepared in a similar manner: Compounds 、 4, 685, 686 687, 689, _, 691, 692, Willow, _, milk, 6%, 698. EXAMPLE IAS: 2-[4-(1,1-Dione-U6-isopyrazolidineyl)phenyl]sodiumethyl-6-methoxy-1H-indole carbonitrile (Compound 84) Preparation

Step A: 2-(4-Aminophenyl)-1-ethyl-wintermethoxy-1H-indole-3·carbonitrile (2.78 g, 9.55 mmol) prepared by the procedure iGa. The solution in pyridine (40 ml) was treated dropwise with 3-chloropropane sulfonium chloride (1.45 mL, 11-9 mmol) and the mixture was stirred at room temperature for 4 hr. The reaction was diluted with water and sufficient 6N HCl to reduce the pH to 2. The reaction mixture was extracted with EtOAc (3×). [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]decylamine as a brown foam which was used directly in the next step . Step B: 3-chloropropane-1-sulfonic acid [4·(3-cyano-1-ethyl-6-decyloxy-1HW丨哚-2-yl)-phenyl] prepared above A solution of the guanamine (3.65 g, 2.33 mmol) in DMF (100 mL) was taken eluted with K.sub.2 C. 128244-3 -361 200831489 After cooling to room temperature, the reaction mixture was diluted with H.sub.2 and EtOAc. The hot organic layer was washed with warm η 2 〇 (3 Torr) and saturated NaCI, dried and dried, and concentrated to a solid. Developed (CH2C12/hexane) to obtain 2·27 g (68°/〇) 2-[4-(1,1-dione-1-V-isopyrazolidine-2-yl)phenyl] Base-6-methoxylΗβΙ哚-3-carbonitrile as a pale brown solid. The following compounds were prepared in a similar manner: Compounds 649, 775, 809, 969, 980. Example 1ΑΤ: 2-[4-(1,1-dione-yttrium λ6-isothiazolidin-2-yl)phenyl]sodiumethyl-6-methoxy-lH-p?丨嗓_3_A Preparation of gambling (compound 666)

ΜΕΚ Δ Step A: According to the procedure in Example 1ΒStep ,, at a _15 ° C, 2-[4-(1,1-dione-l_1-6-isothiazolidinyl)phenyl] The carbonitrile oxime-1H-oxime carbonitrile is treated with 1M BBr3 solution in 3⁄43⁄4 for 5 hours, then poured into ice water, filtered, and dried to obtain a quantitative yield of 2_[ Φ_(ι,ι_diketo-1 λ6-isothiazolidinyl)phenyl]-μethyl hydroxy-1Η_蚓哚-3_carbonitrile. Step Β: according to the procedure in Example 1, step β,孓[4-(u_Diketo-1 λ6-isopyrimidin-2-yl)phenyl]ethyl_6_hydroxy_1H^丨哚 each carbonitrile, &amp; CO3, 2-iodinated Propane and mercaptoethyl ketone are heated under reflux, after flash chromatography (EtOAc/CH2Cl2, 0-2%), to give 61% </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Base]-1·ethyl_6_isopropoxy_1H_indenecarbonitrile as an off-white solid. The following compounds were prepared in a similar manner: Compounds 667, 699. 128244-3 - 362- 200831489 Example 1AU: 2-[4-(l,l-diketo-1-6-isopyrazol-2-yl)-phenyl]+ethyl-6-(2- Preparation of whallin-4-yl-ethoxypto-3-carbonitrile (compound 729)

K2CO3

MEK/DMF

2-[4-(l,l-dione)]isoindyl)phenyl]_1_ethyl-6 prepared in the above Example 1AT at 100 ° C at 10 ° C -hydroxy-1Η-Θ丨嗓-3-carbonitrile (70 mg, 0.25 house mole), K2C〇3 (75 mg, 0.51 mmol), moth (27 mg, 0.18 mmol), 4 A mixture of -(2-chloroethyl)morphine hydrochloride (42 mg, 〇25 mmol) in methyl ethyl ketone (3 mL) was heated in a sealed tube. After 13 hours, DMF (3 mL) was added and the mixture was evaporated and evaporated. After this time, another portion of 42 mg of 4·(2-chloroethyl)fosfolin hydrochloride and 135 g of K:2C〇3 were added, and the reaction was further heated for 6 hours to complete the reaction. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (EtOAc). The combined organic phases were washed with water (2 Torr) and saturated NaCI and dried and dried. By flash chromatography (MeOH/C^d2, 〇_6%), pure 2_[4_(1,丨_二)

Ketopropyl-1 λ6-isoxazolidinyl)·phenyl H_ethyl each (2_folfofolin-ethoxy) 1H to 3-carbonitrile' yielded 29 mg (34%) Yellowish brown solid. The following compounds were prepared in a similar manner: Compounds 728 and 730. Shell Example 1AV· 2_[4_(2,5-dioxaindyl)-tetrahydroimisyl)phenyl]Ethoxyethoxyethyl-1H-indole; Preparation of carbonitrile (Compound 779) 128244-3 • 363 - 200831489

CN

OCN^COaEt Dioxide Park

t-BuO'K+ THF/t-ΒυΟΗ Δ

Step A: 2-(4-Aminophenyl) winter ethoxy small ethyl]H_吲哚 ice carbonitrile (585 gram, 1.92 house mole) in 1 〇 ml, 4 dioxin The solution in hydrazine was treated with isocyanoacetic acid (0.25 mL, 2.12 mmol) and the resulting solution was heated to reflux overnight. This solution was allowed to cool and the solvent was removed by rotary evaporation. The residue was triturated with ether, and the formed precipitate was collected by filtration and dried under vacuo to yield compound 773 (587 mg: 1.35 mM, 70%). A similar procedure was used to prepare 2_{3_[4_(3-cyano-6-ethoxy+ethyl-out 4-indol-2-yl)-phenyl]-ureido-p-phenyl-propionic acid Vinegar (Compound 777). Soil 'Step B: {3-[4-(3-Cyano-6-ethoxy+ethyl_m-啕哚_2-yl)phenyl]-legyl}-ethyl acetate (Compound 773 , 1〇1 mg, 232·232 mmol) solution in TM (1 ml) 'solution of potassium tert-butoxide in third-butanol_mL, U)M,_m The ear was treated and the resulting mixture was stirred overnight. The reaction mixture was partitioned between water and ethyl acetate (50 mL each) and the organic phase was washed with saturated brine. The aqueous phase was extracted with more ethyl acetate, and the combined extracts were dried over anhydrous sulphuric acid, dried, and evaporated. The residual material was separated by column chromatography (dissolved 2/1 ethyl acetate/hexane, on Shishijiao 60) to obtain 2 angyl, 5-dibenyl-tetrachloro(tetra)+yl)-benzyl]- 6-ethoxyl small ethyl ruthenium -3-carbonitrile, compound π, was collected by filtration with hydrazine 'further purification' and collected under high vacuum 128244-3 -364 - 200831489 dry (76 Mg, 0.196 mmol, 84%). Example 1AW: Preparation of 2-[4-(2,4-dione-tetrahydroimidazolyl)-yl)phenyl]Ethoxyethoxyethyl-indole-indole N-carbonitrile (Compound 776)

2-(4-Aminophenyl)Ethoxyethyl-1H_吲. τ 目 yjiy ~

a solution of 1.04 mmol of 1,4-dioxane (3 ml) in chloroethyl phthalocyanate (0.10 mL, U7 mmol) and the resulting solution Warm to 6 (TC overnight. Allow the solution to cool and add dbu (2 mL, 1.31 mmol). This mixture is stirred at ambient temperature overnight and then partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and evaporated. The title product was obtained (319 mg, 〇 821 mmol, 79%). Example 1AX··N,N-dimethyl-2, 4-dimethyl-diyl-tetrachloro-propanyl-- ]]-ethoxy-ethyl-ethyl _ _ _ _ 3 carboxy carbamide "chelate · thief m -6-ethoxy + ethyl o- _ (3 · methyl do bis copper · four Preparation of chlorine. Sodium-1·yl)-based ΗΗβΙ _3·Carboxylamidine (Compound 781) Preparation 128244-3 -365 - 200831489

Step A: {3-[4-(3-Cyano-6-ethoxy-1-ethyl-ΙΗβ丨哚-2-yl)-phenyl]-ureido which was prepared in the procedure iAV step a A solution of ethyl acetate (Compound 773, 325 mg &lt;RTI ID=0.0&gt;&gt;&gt; The reaction mixture is allowed to cool 'and the precipitate formed is collected by filtration, washed with ether and dried under vacuum to give the product, 6-ethoxysethylethyl-2-[4·(2,5•dione)一-tetrahydroimidazol-1-yl)-phenyl]indole Carboxamide (264 mg, 〇·65 〇 millimolar, 87%) 〇Step Β · Dissolve sodium hydride in mineral oil (75 mg I washed I with a small portion of hexane and decanted the hexane layer. Add 6_ethoxy_丨_ethyl·2_[4_(2,5-dione-tetrahydroimidazolium)-stupyl-indole-3-carboxamide (190 mg, 0.468 penmo) The ear was solution in monomethylamine (2 mL) and the mixture was stirred for a day. Then, methane iodide (0.10 ml, 1.61 mmol) was added by syringe to stir the resulting mixture at ambient temperature overnight, then poured into 5 〇 = liters of sulphuric acid, in water (3 x 50 ml) and saturated. Brine (2 〇 ml), ^ organic only, then dehydrated and dried with anhydrous sulphuric acid, sputum, and evaporation.:, call the object to the column chromatography (10) acetic acid acetonitrile / hexane, dissolved on 〇 6 〇 ) isolated to give the title product, compound and 781. 128244-3 -366- 200831489 Example 1AY ··N-[4-(3-Cyano+ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-NOhydroxyethyl) ·Preparation of methanesulfonamide (Compound Magic 8)

Step A: The sodium hydride dispersion (1 〇 8 mg) in the mineral oil was washed with a small portion of hexane and the hexane layer was decanted. Slowly add N_[4_(3_cyanosuccinylethyloxy)-phenyl]methanesulfonate amine (compound 129, 5 mg, 1.35 mol) ) A solution in DMF (5 mL). After the gas evolution is completed, 2-bromoethyl acetate (0.30 ml, 2.64 mmol) and sodium iodide (2 mg) are added to the mixture at ambient temperature overnight, then Pour into 5 ml of ethyl acetate. This was washed with water (3 Χ 5 mL) and saturated brine (2 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was separated by column chromatography (1/1 ethyl acetate /hexanes eluted eluted eluted eluted elution ν Β Ν Ν ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Compound 815, 164 mg, 0.360 mmoles, and a mixture of lithium hydroxide hydrate (45 mg, 1 〇 7 mmol) in 5 mL THF / 1 mL water was warmed to 6 〇χ: overnight. And poured into ethyl acetate (50 ml), washed with water (5 ml) and brine (2 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated to give a solid. The ether was developed, collected by filtration, and dried under high vacuum, 128244-3 • 367 · 200831489 to give N-[4-(3-cyanosuccinyl-6-methoxy-1H-Kbdu-2 -yl)-phenyl]-N-(2-ethyl-ethyl)-methyl S-amine, Compound 828 (137 mg, 0.331 mmol, 92%). Example 1AZ: 1-ethyl-6- Preparation of oxy-2-[4-(2-decyloxyethoxy)-phenyl; μΗ_吲哚_3_carbonitrile (Compound 248)

1-Ethyl-2-(4-hydroxy-phenyl)·6-methoxy-1Η-indole-3-carbonitrile (40 mg, 〇·14 mmol) prepared according to the procedure of Example IGA. ) Combined with K2C03 (77 mg, 0.56 house Moule), Mo, ethyl methyl _ (26 μl, 〇 · 28 mmol) and DMF (450 μL). It was stirred at room temperature for 1 hour and then at 75 ° for 3 hours. The reaction mixture was then partitioned between EtOAc and EtOAc. The organic layer was dehydrated and dried&apos; and concentrated. Purification by chromatography, (CH2Cl2, 0-5% EtOAc) to give 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl] _1H-indole-3-carbonitrile (44 mg, 90%) was obtained as a white solid. The following compounds were prepared in a similar manner as described above: Compound 249. Example 1BA ··1-ethyl·6-methoxy-2-[4-(2-hufolin-4-yl-ethoxy)-phenyl]-lH-p? Preparation of bet (compound 261)

Acetonitrile 85qC ΜθΟ*

Step A: at 0 ° C, will be prepared as in Example 1AZ; U ethyl-6-methoxy 128244-3 -368 - 200831489 2 [4 (2-ethoxy)-benzine] 3-methyl wax (450 mg, ι·34 mmol) was combined with PPh3 (878 mg, 3.35 mmol) in CH2C12 (32 mL). Add N-bromosuccinimide (600 mg, 3.37 mmol) in one portion. The reaction mixture was stirred at room temperature for 3 minutes. The reaction mixture was washed with a NaHC〇3 aqueous solution. The organic layer was dehydrated and dried, and concentrated and purified by silica gel chromatography (CH2C12) to give 2-[4-(2-bromoethoxy)phenyl]ethylethyloxy-1H_ _3_carbonitrile (506 homes '95%), compound 253, as a white solid. Step B: 2-[4-(2-Bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole_3_ prepared according to the above step a Formaldehyde (40 mg, 〇·ΐ mmol) was combined with holpharine (50 μL, 〇·58 mmol) and acetonitrile (1.0 mL). It was heated at 85 C for 2 hours. Then, the reaction mixture was subjected to liquid separation between ch2 Cl2 and Η2 。. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (6/4, acetone / hexane) to give 1-ethyl-6-decyloxy-2-[4-(2-hofolinol-yl-ethoxy)-phenyl] -1Η-Η卜朵-3-carbonitrile (39 mg, 96%) as a white solid. The following compounds were prepared in a similar manner as described above using different amines: Compound 262, 263, 264. EXAMPLE IBB : Ν-{2-[4-(3-Cyano-1-ethyl-6-methoxy-1Η-β-indolinyl)-phenoxy]-ethyl}decanesulfonamide (Compound 268 Preparation

Step A: 2-[4-(2-bromoethoxy)benzene 128244-3 -369-200831489-based] small ethyl 4-methoxy-1H_吲哚-3 prepared in Example 1 -Methonitrile (258 mg, 0.65 mmol) combined with Na% (M4 g, 2. 2 mmol) and Me 〇H (32 mL). It was heated at 75 C overnight. Then, the reaction mixture was subjected to a liquid separation treatment between c% a and hydrazine. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (CH2Cl2) to give 2-[4-(2-azidoethoxy)phenyl]sodiumethylmethoxy-1H-(5) _ 3-carbonitrile (187 mg, 8 〇) %), Compound 266, as a white solid. Step B: 2-[4-(2-azidoethoxy)phenyl]ethylidene ice methoxylHH oxime carbonitrile (410 mg, prepared in the above step A) U4 millimolar) was suspended in a solution of MeOH (20 mL) and concentrated HCl (5 liters). Pd/c (150 mg, 1%) was added, and the mixture was hydrogenated at 3 〇 p s L for 1 hour. It was filtered&apos; and the filtrate was concentrated. The filtrate residue was partitioned between Et〇Ac and 〇 5N Na〇H. The organic layer was dehydrated and dried, and concentrated. Purification by silica gel chromatography (10-30% MeOH/C^Cl2) yields 244-(2-aminoethoxy)phenyl]succiethyl-6-methoxy----- 3-carbonitrile (298 mg, 78%), compound 267, as a white solid. Step c: 2_[4_(2_Aminoethoxy)phenyl]·^ethyl-6-methoxy-1H-indole carbonitrile (3 〇 mg, prepared in the above step B, 〇〇 9 mmol) dissolved in pyridine (300 μL). Add methane chloride sulfonium (8 μl, 〇 1 mmol). It was stirred at room temperature for 45 minutes. Add more chlorinated methane sulfonate (4 microliters, 〇.〇5 house Moer). Stirring was continued for an additional hour. The reaction mixture was subjected to a liquid separation between a 〇Ac and an aqueous HCl solution. The organic layer was dehydrated and dried, and concentrated. Purified by gel chromatography (1/1 CI^C^/EtOAc) to give N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H, anthracyl)benzene Ethyl]ethyl}methanesulfonamide, compound 268 (32 mg, 86%). 128244-3 -370- 200831489 The following compounds were prepared in a similar manner as described above: Compound. Example! BC : N-{2-[4-(3-Cyano-Ethyloxyethyl)-purine (嗓_2-yl)benzene-based]-ethyl}Ethylamine (Compound 274)

2_[4_(2_Aminoethoxy)phenyl]+ethyl-6-methoxy-1Η·« -3·carbonitrile (3G mg, _mmol) prepared in the step B of Example 1BB The ear is soluble in τΗρ (400 μl) and Et3N (24 μL, 〇17 mmol). The chlorinated ethylene (9) was added to a 0.14 house mole) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between Et0Ac and Malang. The organic layer was dehydrated and concentrated. Purification by gel chromatography (Et〇Ac) gave cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}acetamide (33 mg, 97) %), as a white solid. Κ1 BD · 1_{2-[4-(3-Cyano-1-ethyl-6-methoxy_iH_啕哚1yl)-phenoxy]ethyl b-ethyl-urea Preparation of Compound 279)

2 2_[4_(2_Aminoethoxy)phenyl H_ethyl_6_methoxy-1H-indole-3-carbonitrile (3 〇 mg, 〇·〇) prepared in Example 1BB 9 mmoles combined with ethyl isocyanate (18 μL, 〇 21 mmol) and pyridine (3 μL). The mixture was stirred at room temperature for 90 minutes, then the org. 1-{2-[4_(3-Alkyl-1-ethyl-6-methyllacyl-1H-4丨嗓_2_yl)-phenoxy is purely produced by the electroplating chromatography (Et〇Ac) 128244-3 -371- 200831489 yl]-ethyl}_3_ethyl-urea (34 mg, 93%) as a white solid. Example 1BE: Ν-{2-[4·(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}carbenamide (compound) Preparation of 280)

CN

Ο

CN Ac2Q, HCOOH THF

NHCHO heated acetic anhydride (700 microliters) and 98% formic acid (280 microliters) at 65 ° C for 1 hour. Allow to cool to 0 °C. 2-[4-(2.Aminoethoxy)phenyl]succinyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, hydrazine) prepared according to Example 1BB 〇9 mmol is dissolved in THF (400 μL) and added to the mixed anhydride. It was stirred at 〇 C for 45 minutes. Then, the mixture was partitioned between EtQAc and NaHCO03 aqueous solution. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (4/1, C^CV acetone) gave Ν-{2_[4·(3-cyanosuccinylethylmethoxy-1Η-indol-2-yl)phenoxy] -ethyl}carbamamine (28 mg, 86%) as a white solid. Example 1BF . 1_Ethyl-2-{4-[2-(3-hydroxytetrahydroρylo_1_yl)_2-keto-ethoxy]phenyl b-6-methoxy-1Η- Preparation of 啕哚-3·carbonitrile (compound 285)

Step A: Basically using the same procedure as in Example ι, using 丨-ethyl-2-(4-hydroxyphenylmethoxy Η Η 吲哚 3 3 3 ( (559 mg, i 9 i millimoles) To prepare [4-(3-cyano small ethyl-6-methoxyindole-2-yl)- oxo 128244-3 -372 - 200831489 base]-acetic acid tert-butyl ester (780 mg, Loo%) Step B: [4-(3-Cyano-1-ethyl-6-foxy-1H•indole-2-yl)-phenoxy]-acetic acid tert-butyl ester ( 745 mg, ι·83 mmol, stirred in 20% TFA in CH2Cl2 for 3 hr at room temperature, concentrated, and partitioned between EtOAc and EtOAc. The layer is dehydrated and dried, and concentrated. The residue is triturated with CI^Cl2 to give [4-(3-cyanosuccinylethyl methoxy-1 Η-4-indol-2-yl)-phenoxy]- Acetic acid (634 mg, 99%) was obtained as a white solid.

Step C: Suspension of [4-(3-cyano-1-ethylmethoxybutan-2-yl)-phenoxy]-acetic acid (40 mg, 0. 12 mmol) in CH.sub.2Cl.sub.2 (1) 65 millimoles) with DMF (2 microliters). Add chlorinated grasshopper (17 μl, 〇19 mmol). It was stirred at room temperature for 30 minutes. Then, the resulting solution was pipetted into a stirred solution of S-3-hydroxytetrahydropyrrole (150 μL) and CH 2 C 12 (3.0 mL). The mixture was washed with an aqueous solution of HCl. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (3/2 CI^Cl2/acetone) to give μethyl-2-{4-Ρ_(3·hydroxy-tetrahydropyrrole-i-yl-ethoxyphenyl) oxy-lHWh carbonitrile (40 mg, 79%), Compound 285, as a white solid. Example 1BG · 1-ethyl-w-methoxy-2-(2-keto-2,3-dihydro) -Preparation of benzoxazole-5-ylindole_3_indene nitrile (compound 332)

Step A: 丨_ethyl_2_(4_hydroxy_3_nitrobenzene 128244-3 -373 - 200831489)-6-methoxy-1H-indole carbonitrile prepared according to Example 1Gd (369 mg, 1.1 mmol) combined with Et〇Ac (20 mL) and Pd/C (150 mg, 10%). This mixture was hydrogenated at 3 Torr to 1 hour. It was filtered through diatomaceous earth. The filtrate was concentrated and triturated with ether to give 2-(3-amino-4-phenyl-phenyl)ethyl-ethyl-6-methoxy-1H-indole-3-carbonitrile (307 mg, 91%) Compound 322, as a white solid. Step B: 2-(3-Amino-4-hydroxyphenyl)-1-ethyl peroxyl-1H-indole-3-carbonitrile (1 〇〇 mg, 0.33) prepared in Step A Millol) combined with CDI (83 mg '0.51 Torr) and THF (1.1 mL). It was heated at 65 for 1 hour. The reaction mixture was partitioned between EtOAc and EtOAc. The organic layer was dehydrated and dried, and concentrated. Purification by 5-Ethyl gel chromatography (9-8, /£t〇Ac) to produce 1-ethyl-6-methoxy-2-(2-keto-2,3-dihydrobenzo-3-azole _5·基)-1Η-啕哚 each carbonitrile (89 mg, 81%) as a white solid. 128244-3 Example 1 1- · 1-Ethyl methoxy-2-(3-keto-3,4-dihydro-2 fluorene-benzo[1,4] oxa-6-yl)-1=吲Preparation of hydrazine carbonitrile (compound 334)

Millions of 〇·4 mmoles and acetonitrile (9 〇〇 microliters) were combined to form a homogeneous solution. 2-(3_Amino hydroxyphenylethyl-6-methoxy-1H-? 丨哚 ice carbonitrile (1 〇〇 mg, 〇·33 mmol) prepared according to the procedure of Example 1BG. Adding to the solution immediately formed a thick paste. Add another 1.1 ml of acetonitrile, then, - 374 - 200831489, and mix the mixture at room temperature for four hours. Then, the reaction mixture was partitioned between H2 〇 and EtOAe. The organic layer was dehydrated and dried, and concentrated. Purified by silica gel chromatography (4/1 'CH2Cl2/EtOAc) to yield 2-chloro-N_[5_(3- cyano + ethyl-6- decyloxy oxime) 2-yl&gt;2-hydroxyphenyl]acetamide (82 mg, 6〇%), compound 333, as a white solid. Step B. 2_Chloro_team [5_(3) prepared in Step A _Cyano small ethyl winter methoxy oxime-2-yl &gt; 2-hydroxy phenyl] acetamamine (57 mg, 〇 13 mmol) with K2C 〇 3 (55 mg, 〇·4 毫Mol) and DMF (400 μL) were combined and heated at 80 C for 1 hour. Then, the reaction mixture was partitioned between hydrazine and Et.Ac. The organic layer was dried and concentrated. Purified by gel chromatography (9/1, CI^CV EtOAc) to give Oxy-2_(3,yl·3,4-dihydro-2-indole-benzo[1,4]indole-6-yl)-1Η-indole-3-carbonitrile (45 mg, 90%), It is a white solid. Example 1 · · · ethyl-6-methoxy-2-(2-keto-2,3-dihydro-benzo-p-α α--6-yl)·1Η·啕哚Preparation of -3-carbonitrile (compound 340)

Pd(PPh3)2CI2, Cul, THF CN

Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) was suspended in H2SO4 (26 mL, 2.7M) at -5 °C. Sodium nitrite 128244-3 - 375 - 200831489 (1.8 g, 26.1 mmol) in H20 (6.5 mL) was cooled to ice bath temperature and added dropwise to a mixture of amines for 5 minutes. The resulting suspension was stirred under _5 for 15 minutes. A solution of ruthenium (6.8 g, 41 mmol) in H2S 4 (13 ml, 1 M) was added dropwise to the diazonium salt with a large amount of n2 evolution. The reaction mixture was heated at 7 (T.sub.2) for 20 min. then the mixture was partitioned between EtOAc and EtOAc. Purification of acetone, 1% acetic acid to give the iodosalicylic acid (5·33 g, 85-90% pure). Step Β: Dissolve the crude 4-Ethalistic acid (1. gram, 38 mmol) In thf (28 ml) and ^ Ν (1.15 ml, 8.2 mmol), add DppA (17 ml, 7.8 mmol). Heat it at 7 (TC). Then, make the reaction mixture. The mixture was partitioned between EtOAc and EtOAc (EtOAc m. Bromine base benzoxazole 2_ hydrazine (369 mg 37%) as a white solid. Step C: Basically using the same procedure as in Example 1Gd, using ioodo-3H-benzazole- 2·ketone (118 mg, 0.45 mmol) to prepare 丨_乙美6 methoxy-2-(2-keto-2,3-dihydro-benzoxazole_6•yl)_1H_吲哚 each carbonitrile, compound 340 (75 mg, 55%) Example 1BJ: 1-ethyl-6-methoxy-2-(4-mercaptoketo)-3,4-dichloro- _benzo[M] slogan · base)-1Η-θ丨Preparation of each carbonitrile (compound 339)

128244-3 376 - 200831489 1-Ethyl-6-methoxy-2_(3-keto-3), wood dioxin-2H-benzo[1,4]$call-made in Example 1BH 6-yl)-1Η-indole-3-carbonitrile (2 mg, q Q58 mmol) was combined with NaH (14 mg, 60% suspension in oil, 〇·35 mmol). Add THF (300 μl). It was stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 microliters) in THF (100 microliters) was added. It was allowed to be allowed to work at room temperature for hours. The reaction mixture was partitioned between EtOAc and EtOAc. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (9/b CH2Cl2/Et〇Aq to give 1-ethyl-6-methoxy-2-(4-methyl-3-keto-3,4-dihydro-2H_ And [1,4]哼耕-6·yl)-1Η-吲哚-3-carbonitrile (16 mg, 76%) as a white solid. The following compound was obtained in a similar manner: Compound 341. Example 1BK: Preparation of 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indoleacetonitrile (compound 4)

Suspending each of the acetonitrile (50 mg, 〇·15 mmol) prepared in the step i of the example iGa in Example A, methoxy-1H-oxime carbonitrile (50 mg, 〇15 mmol) In acetic acid (62 〇 microliters). Nitric acid (4.25 Torr in AcOH) was added. It was stirred at room temperature for 2 hours. Then, the reaction mixture was subjected to liquid separation between 12^(:12 and hydrazine. The organic layer was washed with aq. NaHC 〇3, then dehydrated and concentrated, and concentrated by chromatography (6/4, CI^C) Purification by ^/hexanes, followed by triethyl ether to give 1-ethyl-2-iodomethoxymethyl nitro hydrazide- carbonitrile (16 mg &lt;RTIgt; Example 1BL: Ethidium xanthine-1-ethyl-6-methoxy-2,,3,-digas 128244-3 -377- 200831489 -1Η,1Η,-[2,6'] biguanide Preparation of -3-carbonitrile (Compound 753) o2n

H2, Pd/C EtOAc 1. NaN02l H2S04i h2o

Ac

H2N

Step A: 6-Nitroporphyrin (3.0 g, 18.3 mmol) was dissolved in THF (45 mL) and EtsN (3.4 mL, 24.4 mmol) at 0 °C. Chloroacetic acid (1.5 ml, 21 mmol) was added dropwise. The mixture was mixed for 3 minutes at room temperature. The mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dehydrated and concentrated to give 1-ethyl-bromo-6- stone succinyl (3 g, 100%) as a yellow solid. Step B: 1-Ethyl-6-nitroindole 4 (3.8 g, 18.3 mmol) was suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) was added and the mixture was hydrogenated at 40-55 p.s. Then, the mixture was filtered through celite. The filtrate was concentrated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step C: Basically using the same procedure as in Example ι, using 1-ethyl-decyl-6-aminodihydroindole (1.5 g, 8.5 mmol) to prepare oxime-yl- 6-Ethyl indoline (1 〇 6 g, 43%). Step D: 1-ethylindenyl-6-iodoindoline (1〇6g, 3.7mmol), 128244-3 - 378 - 200831489

Na〇H (U6 g '29 mmol), EtOH (8 mL) and H.sub.2 (6 mL) were heated at 90 C overnight. Then, the reaction mixture was subjected to a liquid separation treatment between % 〇 and Et 〇 Ac. The organic layer was extracted in an aqueous solution of HCl. The aqueous layer was basified &lt;RTI ID=0.0&gt; The organic layer was dehydrated and dried, and concentrated. Hexane was triturated to give 6-Ethylindole (577 mg, 64%) as a brown solid. Step E·· basically using the same procedure as in Example 1Gd, Step B, using 1_mercaptoindoline (600 mg, 2.45 mmol) to prepare oxime ethyl methoxy-2 ,, 3,-Dihydro·ιη, 1Η42,6,] bis-indenyl_3-carbonitrile (535 mg, 67%). Step F··Using the procedure in the example, using μethyl each methoxy-2,,3,_dihydro-1Η,1Η42,6']bisindolyl_3_carbonitrile (3〇, 〇〇95 millimolar) to prepare Γ-ethane sulfonyl sulfhydryl small ethyl _6_methoxy 2,3,_dihydro-1 fluorene, 1 Η, _[2, phantom fluorenyl- 3-carbonitrile (24 mg, 62%). The following compounds were prepared in a similar manner as described above. The compounds were 2 and 754. Preparation of Shell Example IBM · 5-Ethyl-1-ethyl-6-methoxynitro-phenyl)_ΐΗ_β 哚-3-carbonitrile (Compound 844)

The oxime-ethyl-whenyloxy-2_(4-nitrophenylHH-indole carbonitrile (100 mg, 〇3 mmol) prepared by the method iGc was suspended at 〇 °C. ^ Dichloroethane (500 μl). Add cesium chloride (5 〇 microliters, 〇 · 69 mmol), then add A1C13 (55 mg, 0.4 mmol) in one portion. It was stirred at room temperature for 1 hour, at room temperature for 4 hours, and at 45 t overnight. Then, the reaction mixture was subjected to liquid separation between CP 2 Cl 2 and 0. The organic layer was dehydrated and dried 128244-3 -379· 200831489 Drying and concentration. Purification by gel chromatography (195: 5 CH2Cl2 / EtOAc) yields 5-ethyl-l-yl-ethyl-ethyl methoxy (4-nitro-phenyl;) Η Η (5)哚_3_carbonitrile (33 mg, 29%) as an orange solid. Example 1 ΒΝ : 1-ethyl-6-methoxy-5·morpholine_4_ylmethyl-2-(4- Preparation of nitro-phenyl)-1Η-indole phthalonitrile (compound 845)

Step A: 丨Ethyl methoxy·2_(4_nitrophenyl)-1Η-indole-3-carbonitrile (1 〇〇 mg, 〇·3 mmol) prepared by the method of Example 1Gc Ear) combined with sputum, trioxane (64 mg, 〇71 mmol) and acetic acid (2 〇 ml). 33% HBr (2.0 ml) in acetic acid was added. It was stirred at room temperature for 4 hours. Then, the reaction mixture is subjected to liquid separation between (:3⁄4⁄4⁄4 and 吒0. The organic layer is washed with a NaHC〇3 aqueous solution, and then dehydrated and dried, and concentrated. The crude material is taken to the next step. Step B: Crude 6-bromomethyl + ethyl methoxy winter (4) nitro-phenyl HH_(9) 哚-3-carbonitrile (〇·3 mmol) with morphine (15 〇 microliter, 175 mmol) And DCE (1.0 liter) were heated together at 9 ° C overnight. Then, the reaction mixture was partitioned between 氐0 and EtOAc. The organic layer was dried and dried, and concentrated. (5 (M 〇〇 %, Et 〇 Ac / CH 2 Cl 2 ) was purified, and was developed in 1/1 hexane/acetone to give 1-ethyl-6-methoxy-5- as 128244-3 -380 - 200831489 Morpholine-4-ylmethyl-2-(4-stone succinyl phenyl-3-indolene (57 gram, 44% total yield), as a yellow solid. Example 1BO: 2-[4-( 1,1-diisoxazolidin-2-yl)phenyl]-1-cyclopropylmethyl-6-methoxy-1H-indole-3-carbonitrile (Compound 716)

I, Step A: 6-methoxyindole (5.88 g, 40.0 mmol) and di-tert-butyl ester dicarbonate (9.59 g, 44 〇 mmol) in DCM (50 mL) In the solution, at 40 ° C, DMAP (0.10 g) was added while stirring. After stirring overnight, the mixture was washed successively with 〇·1Ν HCl, water and brine, and dried.

Na] SO4 is dehydrated and dried. The solvent was evaporated, and the residue was chromatographed eluted with EtOAc EtOAc EtOAc EtOAc EtOAc , 86%). Step Β: The above Boc-啕哚 (3.08 g, 12.5 mmol) and isopropyl 128244-3 -381 - 200831489 ester (4.83 ml, 21.9 mmol) were dissolved in anhydrous THF (2 mL) And the solution was allowed to cool at 0 °C. When stirring, LDA (12.5 mL, 1.5 M mono-THF complex in cyclohexane, 18.7 mmol) was added dropwise. The mixture was stirred at 〇 ° C for 15 minutes and then at room temperature for 5 hours, followed by the addition of Ηα (6N, 3.0 ml '18 耄mol) in an ice water bath. The organic solvent was removed in vacuo and the residue was suspended in EtOAc (EtOAc) and acidified to pH 4~5. The precipitate was collected via filtration, washed with water and hexanes and dried in air to afford l-Boc-6·methoxy-4-indole-2-dipyridyl (3.38 g, 93%) . Step C: Adding a gasified 3-aeropropane sulfonium sulfonate at 0 ° C in a solution of 4-money aniline (3·18 g, 14.5 mmol) in pyridine (15 ml) · 3 ml, 18.9 millimoles). After the addition, the mixture was stirred at room temperature for 2 hours and poured into ice water (200 liters). The organic material was separated and the aqueous layer was extracted (2×50 mL). The combined organic material was washed successively with EtOAc (2 EtOAc, EtOAc (EtOAc) The solvent was then evaporated, and the residue was crystallisjjjjjjjjjj Then at 5 〇. (^, the obtained chlorosulfonamide (3.47 g, 9·6 mmol) was treated with &amp;(:3 (3.33 g, 24.1 mmol) in DMF (50 ml) for 2 hours. The mixture was poured into ice water (300 ml), and the precipitate was collected and dried in air to provide substantially pure 2-(4-mothenyl)isothiazolidine-oxime, i-dioxide (311 g, ι〇〇%). Step D. i-Boc-6-methoxyindole-2-di-based side-burning prepared in the above step B (0.36 g '1.25 ^: Mo Ear), 2-(4-iron phenyl) iso-ρ plug n υ · ι, ι· dioxide (0.32 g '1·0 mmol) and PdC! 2 (dppf) (〇.〇37克, 0.05 mmol. 128244-3 - 382 - 200831489 In a mixture of DMF (4.0 ml), add κ2 C03 in water (1.5 mL, 2.0 mL, 3.0 mmol). Stir the mixture at room temperature. After overnight, it was poured into ice water (100 ml). The precipitate was collected, washed with water and purified by flash column chromatography (EtOAc, DCM/EtOAc, 9/1). -2-yl)phenyl]-6-methoxy-1Η-oxime (0.43 g, 98%). The system was made in a similar manner: Compound 768. Step D': l-Boc_2-[4-(l,l-diisothiazolidine-2-yl)phenyl]-6-A at room temperature oxy-1H-indole (1_63 g, 3.7 mmol) was treated with TFA (25 mL) in DCM (25 mL) for 4 h. After removal of volatiles, the residue carefully and sat. NaHC〇3 was stirred for 5 hours. The precipitate was collected by filtration, washed thoroughly with water, and dried to provide substantially pure lH-2-[4-(l, lc oxidized isopyridinyl) Phenyl] ten methoxy groups (U7 g, 92%) 〇Step E: at 0 ° C, diisothiazolidine winter) phenyl]-6-methoxy oxime (〇· 95 g, 2.8 mmol (m) was dissolved in DMF (1 mL) and treated with <RTI ID=0.0> Then, the mixture was stirred at room temperature overnight, poured into ice water (15 ml), and then stirred for 0.5 hour. The precipitate was collected by filtration, washed thoroughly with water, and dried in air to obtain diisothiazolidinesyl)phenylmethoxyindole_3_carbonitrile (0·89 g, 87〇/〇) ). The following compounds were prepared in the same manner as above: Compound 829. Step F: 1-Η-2-[4-(1,1-Diisoisothiazolidinyl)phenyl]-6-methoxyindole-3-indoleonitrile (73 mg, 〇·2 mmol) To the solution of K2C〇3 (69 mg, 〇·5 mmol) in DMF (3.0 ml), add cyclopropylmethane iodide 128244-3 - 383 - 200831489 _29 ml, 0.3 mmol) . The mixture was transferred to the underside overnight and poured into ice water (10 mL). The precipitate was collected by filtration, washed with water, and purified by column chromatography to afford 2WU-dioxyisoindole 2 phenyl] methoxy succinyl propyl hydrazide; carbonitrile, Compound 716 (7) mg, 87%). The hair compound 717, the following compounds were prepared in the same manner as described above, 718, 719, 782, 783, 784. Preparation of diketo-1 λ6-isopyrazolidine-2-yl)-6-oximeoxy-3-3-oxazol-5-yl-1-propyl-1Η-indole (Compound 8〇5)

1. POCI3, DMF 2. TOSMIC, MeOH K2C03

Step A: Basically using the same procedure as in Example i A, Step B, using 2-[4-(1,1,-diketo]isopyrazolidine-2-yl)_6_ prepared in Example 1BO Step D Methoxy hydrazine (900 mg, 2.62 mmol) to prepare 2_[4&lt;1,1 L diketo-1 λ6-isopyrimidine-based 2-yl)-6-methoxy+propyl -1H...丨哚(6〇8 mg, 60%). Step B: According to the example in the example ip, use 孓Bu (1) dimethyldiketo-oxazolidin-2-yl)-6-methoxy-1-propyl hydrazine (5 〇 mg, 013 毫Moer)' to prepare 2-[4-(1, fluorenyl-dione) 6-isopyrazolidine-2-yl) methoxy each indazole-5-yl-1-propyl-1Η - 啕哚 (9 mg, 15% total yield). 128244-3 - 384- 200831489 Example 1BQ: 2-[4-(cyclopropylsulfonyl)hexahydropyrrole]_丨_ethyl(trifluoromethyl)-1Η-吲哚-3-甲Preparation of nitrile (compound 842)

Step A: μethylmethylenetrifluoromethylhydrazine-3-carbonitrile (2.54 g, 1 〇. 〇 mmol) prepared by the procedure of Procedure 1A in anhydrous THF (2 mL) In the solution, LDA (8.3 ml, "!^ mono-THF, 12.5 mmol" in cyclohexane was added dropwise at -78 ° C. After the addition, the mixture was allowed to continue for 5 hours, then Adding hexahydrogen b', then, the mixture was slowly brought to room temperature and stirred for 0.5 hours. The solvent was evaporated and the residue was taken up in water. The organic material was extracted with dichloromethane and washed with water and brine. Drying with anhydrous n々s〇4. The crude product obtained after removal of solvent was chromatographed (EtOAc, methylene chloride/hexane, 3/2) to afford 2-ethyl-1-ethyl-6 -(Trifluoromethyl)-iH-indole-3-carbonitrile (1.75 g, 64%). Step B: EtOAc (yield: 27 g) obtained from DMF (5.0 ml) 1·〇毫莫耳), K:2CO3 (0.35 g, 2_5 mmol) and N-Boc-hexahydropyridyl (0.28 g, 1.5 mmol) were stirred at 7 (TC for 3 days, then poured In water (5 ml), collect sediment by filtration And washing with water. Chromatography of this crude product (gelatin, methylene chloride / ethyl acetate, 9/1) affords 4_(3-cyanoethylethyl-difluoromethyl-lH-W -2-yl)_hexahydroindole p-well-1·sodium sulphate third-butyr, compound 785 (0.30 g, 71%). 128244-3 • 385 - 200831489 The following compounds were used in the same manner as above. Other amines are prepared: compound 514, 785, 786. Step C · 4_(3-cyanoethylidene trifluoromethyl-1H, indol-2-yl)·hexahydropyridinium at room temperature The third-butyric acid (0. 26 g, 6.1 mmol) was treated with TFA (5 ml) in methylene chloride (53⁄4 L) for 1 hour. After removal of volatiles, The residue was treated with saturated NaHC〇3, and the precipitate was collected by filtration, washed thoroughly with water, and dried in air to obtain substantially pure ethyl-2-hexahydro _-1-yl-6- (Trifluoromethyl hydrazine-3-carbonitrile (〇·2 gram, 100%) 〇Step D: 1-ethyl-2-hexahydropyrrolidine-6-(trifluoromethyl)_1Η - 吲哚 each such as (32 mg, 0. 1 mmol), pyridine (〇 毫升) in dioxane Q 〇 ml) Into the solution, a gasified cyclopropane sulfonate (28 mg, 〇 2 mmol) was added, and the mixture was stirred at room temperature overnight. Then, it was diluted with a gas (5 ml) to HC1. (2N, 2X2 ml), water (2 χ 5 ml) and brine (5 liters) were washed and chromatographed on silica gel (dichloromethane / ethyl acetate, 9/1) to provide 2-[4-(ring Propylsulfonyl) hexahydropyranyl] small ethyl (trifluoromethyl)-1 Η-Η 朵 -3- carbonitrile, compound 842 (3 gram, 7 〇 0 / 〇). The following compounds were prepared in the same manner as above using the corresponding gasified sulfonium compounds: Compounds 841, 843. Example 1BR: Ethanesulfonic acid [3-cyano·2_(4-ethoxyphenylhydrazine-ethyl_m_called _6-yl]-decylamine (Compound 835) 128244-3 -386- 200831489

Step A: 64-formyl-2-(4-ethoxyphenyl)·1-ethyl-1H-W哚-3-carbonitrile from 6-bromohydrazine as described in Example 1Gb (〇· 74 g, 2.0 mM, compound 831, with K2CO3 (0.55 g, 4.0 mmol), Cul (0.02 g, 〇丨mole), and butyl succinate (0.35 g, 3.0 millimolar), N, N, dimethylcyclohexane-1,2-diamine ligand (0.028 g, 〇·2 mmol) and anhydrous toluene (5 〇 house liter) in a sealed tube Mixed in. The reaction system was flushed with nitrogen and then stirred at 11 ° C overnight. After cooling, the solvent was replaced with methylene chloride and chromatographed (EtOAc, methylene chloride) to afford [3 <RTI ID=0.0>哚-6-yl]-aminomethyl acid tert-butyl ester (〇·68 g, 84%), compound 832. Step B: Compound 832 (0.63 g, 1.56 mmol) obtained in step a above was treated with tfA / DCM (7.5 mL / 7.5 mL) for 2 h at room temperature and removed in vacuo. Sexual substance. The residue was treated with saturated NaHC(R)3, and was collected by filtration, washed thoroughly with water and dried in air to afford 6-amino-2-(4-ethoxyphenyl) Η-啕哚-3-carbonitrile (〇·45 g, 96%), compound 833. Step C: The above amine pi mg, 〇1 mmol) was treated with chlorosulfonium sulfonate (19 mg, 〇15 mmol) in pyridine (1 mL) at room temperature overnight. After purification by column chromatography, ethanesulfonic acid [3-cyano-2-(4-ethyl 128244-3 -387-200831489 oxyphenyl) small ethyl] Ηβ 卜 _6-yl p醯 is provided. Amine (83%), compound 835. The following compounds were prepared in the same manner as above: the compounds illusion, 834, 836 and 837. EXAMPLE IBS: Preparation of [3-cyano-2-(4-ethoxyphenyl)ethylidene-1H-fluorenyl &gt; Aminoethyl Methacrylate (Compound 838)

6-Amino-2-(4-ethoxyphenyl)- _ethyl carbonitrile (31 mg, 〇·1 mmol) prepared in Example 1BR, Step B, Compound 833, Ethyl chloroformate (16 mg, 〇15 mmol) in pyridine (1 mL) was taken at room temperature overnight and purified by column chromatography to afford [3- cyano. Ethoxyphenanthracene Ethyl-1-indole-6-yl]-amine methyl acid ethyl ester (3 〇 mg, 79 〇 / 〇). Example 1 ΒΤ : 1-[3-Cyano_2_(4_ Preparation of ethoxyphenyl)sodiumethyl_1H-indole-6(yl)^ethyl-monthly urine (compound 8; 39)

6-Amino-2-(4-ethoxyphenyl)ethylidene·1Η•吲哚_3•carbonitrile (μmg, 〇.1 mmol) in dichloromethane (1·0 mL) Ethyl isocyanate (14 mg, 〇 2 mmol) was treated at 40 C overnight. The precipitate was collected by filtration, washed with methylene chloride and dried in air to obtain Η3_cyano-2-(ethoxyphenyl)-1-ethyl-1Η-Η丨-6-yl] Base-urea (36 mg, 95%). Example 1BU· 1-(2-chloroethyl)-3·[4-(3-cyano-1-ethyl-6-methoxy-p-butyryl)-phenyl]-urea (compound) Preparation of 442) 128244-3 -388- 200831489

a solution of 2-(4-aminophenyl)-1·ethyl-6-decyloxy-1H-W哚-3-carbonitrile (50 mg, 0.172 mmol) in THF (2 mL) Inside, at room temperature, 2-isoethyl isocyanate (22 μL, 0.258 mmol) was added. After stirring overnight under reflux, the reaction mixture was evaporated mjjjjjjjj The resulting semi-solid was triturated with hexanes, and the precipitate was collected by filtration and washed thoroughly with 50% ethyl acetate in hexanes and dried in vacuo to give (62 mg, 91%) 1- ( 2-Chloroethyl)-3-[4-(3-cyanosuccinyl-6-decyloxy-1H-indol-2-yl)-phenyl]-urea. Basically, the same procedure was used to make the following compounds: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620, 626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751, 774, 817, 818, 846, 847, 848, 954, 955, 956, 957, 958, 987, 999, 1000, 1001, 1008, 1009, 1010, 1011 1012 1013, 1014, 1016, 1017, 1018, 1019, 1023, 1024 1027 1036, 1039, 1043, 1045, 1060, 1061, 1066, 1067 1070 1080, 1092, 1094, 1095, 1096, 1097, 1098, 1099 1100 1101, 1102, 1106, 1108, 1118, 1120, 1124, 1125 1126 Λ 1136, 1137, 1138, 1139, 1143 1144, 1156, 1157 1162 Λ 1163, 1164, 1165, 1171, 1172, 1173, 1197, 11% 1214 Λ 1221, 1223, 1224 &gt; 1225, 1225, 1227, 1256, 1279 1301 1303, 1304, 1305. 128244-3 - 389 · 200831489 Example 1BV: 1-ethyl-6.methoxy-2-[4-(2-keto-tetrahydroimidazole+yl)-phenyl]·1Η-啕哚 each carbonitrile Preparation of (Compound 771)

(1-(2-Chloroethyl)-3·[4-(3-cyano small ethyl-6-methoxy-ex- 吲哚-yl)-phenyl]-urea (100 mg, 0.252) To a solution of MeOH (1 mL), 1 M aqueous KOH (504 liters), and then stirred at 49 ° C for 24 hours. The solvent was removed under reduced pressure. The ester was diluted and then washed with water. The organic layer was dried over anhydrous EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj And washed thoroughly with 50% ethyl acetate in hexane, and dried in vacuo to give 1-ethyl-6-methoxy-2-[4-(2-keto, hydrogen. -yl)-phenyl]-1H_4 prasin-3-carbonitrile (56 mg, 62%). Basically the same procedure was used to make the following compounds: Compounds 77 〇, 778 〇

Example 1BW: 1-ethyl-6-isopropoxy-2-[4-(2-keto-tetrahydrocarbazole)·phenyl]-1H4丨哚-3-carbonitrile (Compound 638) Preparation

K2co3 DMF 50°C

CN

[4-(3-Cyano-1·ethyl_6-isopropoxy-IH-H) 2-phenyl]-phenyl]-amine methyl 2-oxide-ethyl ester (30 mg In a solution of 〇]^17 (1 ml), an aqueous solution of CO3 (10 mg) was added, followed by 5 Torr. Stir under the arm for 18 hours. The reaction mixture was poured into cold water and the title compound was obtained (yield: 21 mg, 128244 - 390 - The following compounds were prepared in a similar manner: Compound 82 〇, 821, 8 Magic 864. Example 1BX · {3-[3-Cyano-1-ethyl 4(3-tetrahydropyrrole small-propoxy)] ke oxi-2-yl]-phenylmethyl acid ethyl ester (Compound 53 Preparation of 〇)

MeO

CH2CI2

f Step A ··[3-(3-Cyano-1-ethyl-6-methoxy-1H-吲 -2--2-yl)_ stupid]

A solution of ethylamine methylate (1.65 g, 4.37 mmol) in DCM (2 mL) was added 1M BBr3 (13.12 mL) in DCM over 2 min. The reaction mixture was further stirred at room temperature for 1 hour, and then the solvent was removed under reduced pressure. The residue was dissolved in MeOH and poured into cold water. The precipitate was taken up by hydrazine, washed with hexane, and dried in vacuo to give the succinyl-1-ethyl-6-hydroxy-1 Η-indol-2-yl)-phenyl]-amine A酸 旨 旨 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Ethyl acetate (1.2 g, 2.91 mmol) in DMF (1 mL), VI, K2C〇3 (538 mg, 3·9 mmol) and 3-bromo+chloropropyl After burning (383 μl, 3.9 mmol) and the reaction was dropped at 50 ° C overnight, 128244-3 -391 - 200831489, the reaction was poured into cold water, and the precipitate was collected by filtration. The product was washed with hexanes and dried in vacuo to give &lt Step C: on {3-[3-cyano-1-ethyl_6_(3-tetrahydropyrrole+yl-propoxy)-1Η·(4)indol-2-yl]-phenyl-p-aminomethyl acid Ethyl ester (5 〇 mg, 〇 12 mmol) in CH3 CN (2 liter), add DIEA (31 μl, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) And tetrahydropyrrole (3 〇 microliters, 〇 · 36 millimoles). The resulting mixture was stirred at reflux temperature overnight. Evaporate the solvent' and dilute the residue with ethyl acetate, then triturate with hexane, and collect the precipitate by filtration, and wash thoroughly with 5% ethyl acetate in hexane and dry in vacuo to give 1 _Ethyl isopropoxy-2-[4-(2-keto-tetrahydro'-tert-3)-phenyl]-1Η-indole-3-carbonitrile, compound 638 (46 mg, 85 %). The following compounds were prepared in a similar manner according to steps A-c above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 536, 537, 538, 539. 529, 531, 532, 533, 534, 535, Example 1BY · [3-(3-Ironylethyl-6-methoxyindol-2-yl)-phenyl] Thiourea (Compound 767) preparation

Step A: The starting material is 2-(3-amino-phenyl)+ethyl-6•decyloxy-ex-indole 128244-3 -392- 200831489 哚-3-carbonitrile (187 mg, 〇· 642 mmoles were dissolved in anhydrous acetone (3 ml). To the solution t, phenyl isothiocyanate (1 〇 7 mg, 〇 656 mmol) was added at room temperature, and the mixture was stirred for 17 hours, during which time a precipitate was formed. The precipitate was filtered, washed with acetone and dried to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&& (90% yield) as a pale yellow solid. (Step B) When adding sodium hydroxide (31 mg, 〇·78 mmol), benzathion-3-[3-(3-cyano-1-ethylmethoxy)_哚Base) _phenyl]_ thiourea gram, 〇·53 〇 millimolar) in a suspension of methanol (2 〇 ml) and water (10) mbar), stirring at room temperature. The reaction mixture was heated to a pit for 17 days. The reaction mixture was concentrated to remove methanol. Water was added to the mixture, and the solid was filtered, washed with water and dried to give 179 mg of [3-(3-cyano-indole-ethyl methoxy) η, anthracene) phenyl] Thiourea, 767 (96% yield) as a white solid.

Example 1BZ: Preparation of 1-ethylmethyloxy-2-[[4-(2-phenyl-4-saltylamino)phenyl]-1H-indole-3-carbonitrile (Compound 458)

2-(4-Aminophenyl)"-ethyl methoxy_a eucalyptus-3-carbonitrile (100 gram 0.343 house Mo), 4 _ ke-2-phenyl-mouth A solution of 嗤琳 (83 古 一 , ,, 0.34 mmol) and diisopropylethylamine _ml, 〇.57 mmoles in absolute ethanol (3 mL) was heated to reflux overnight. The solution was allowed to cool, and the residue was dissolved in ethyl acetate (br.). It was washed with water and saturated brine, 128244-3 - 393 - 200831489 (50 ml each), then dried over anhydrous sodium sulfate, filtered, and then evaporated. The solid formed is triturated with ether, collected by filtration, and dried under vacuum to give 1-ethyl-6-methoxy-2-[4·(2·phenylcarbazole 4 _4-ylamine Base) _ stupid base -1 Η -4 prasin-3-carbonitrile (139 mg, 〇 · 280 mmol, 82 ° / 〇). Example 1CA: [4-(3-Cyano-6-ethoxyl+ethyl_1Η_吲哚1yl)·phenyl]· Preparation of Dendrobium Oxide Diethyl S (Compound 772)

CN

f

2-(4-Aminophenyl)-6-ethoxy_;[_ethyl-1Η_吲哚_3•carbonitrile (148 mg, 〇·484 mmol), diethyl chlorophosphate A solution of the ester (0.086 ml, 0.58 mmol) and diisopropylethylamine (0.10 mL, EtOAc EtOAc) (EtOAc) Then heat up to 8 〇C, and t t 24 hours. The solution was allowed to cool and poured into 5 mL of ethyl acetate. This was washed with water and saturated brine (5 mL each), then dried over anhydrous magnesium sulfate, filtered, and evaporated. The residual material was separated by flash chromatography (dissolved 2/1 ethyl acetate / hexanes on silica gel), and after evaporation, [ winter (3 - cyano-6 - ethoxys _吲哚_2•Base&gt;Phenyl]-diphosphoric acid diethyl ester (108 mg, 0.245 mmol, 51%) as a white powder. The following shell examples were prepared in a similar manner. 936, 937, 舛2, 94S, 944, 1081. Example 1CB· L ethyl decyloxy-2_[M5-methyl_ι, ι·二_基-1λ6-[1,2,5] pyrimidine Preparation of oxazolidinyl)-phenyl hydrazine hydrazine hydrazide (compound 726) 128244-3 - 394- 200831489

Step A: a solution of 2-(4-aminophenyl)succinyl-6-methoxyindolocarbonitrile (2〇2 mg, 693·693 mmol) in pyridine (2 mL) Inside, a gasified bismuth-/3-(chloroethylamino) scutellaria (222 mg, ΐ·39 mmol) was added. The mixture was stirred at room temperature for 17 hours, then water (12 mL) was added and the mixture was extracted with ethyl acetate (3.times.2 mL). The extract was washed with a 10% aqueous solution of Ηα (2 χ 2 liters), water (2×2 mL), dried over MgSO 4 , filtered, and concentrated on a rotary evaporator. The crude product was purified by flash chromatography ( 〇 5%, ethyl acetate / di-methane) to afford 217 mg (2 chloroethyl) _N, -[4_(3_ cyano-1-ethyl) -6-Methoxy-indole-indol-2-yl)phenyl]inosinamine Compound 724 was a tan solid (75% yield). In a similar manner, the following compounds were prepared: Compounds 540, 541, 542, 574, 576, 704. Step Β: Ν_(2-chloro-ethyl)-Ν'-[4-(3-cyano-1-ethyl-6-methoxy-1Η-indol-2-yl)phenyl] To a solution of the decylamine (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL). The mixture was stirred at room temperature for 17 hours and then diluted with water (7.5 mL). The reaction mixture was extracted with the wrong acid B (3 X 2 house liter), and the extract was 128244-3 •395 · 200831489

Yield). In a similar manner, the following compounds were prepared:

Potassium carbonate (25 mg, 〇18 mmol) was added to the solution in DMF (1.0 mL). The mixture was obtained at room temperature. The precipitate was filtered, and the methylene chloride (20.4 mg, 0.144 mmol). The mixture was mixed for 2 hours, then diluted with water (6.0 ml), or washed with water, washed with water, and dried to obtain ethyl 2-methoxy-butyryl (5-methyl-U-dione), -[丨2, thiazolidine 2 yl) _ phenyl hydrazine, compound 726, as a white solid (35 mg, 98% yield). In a similar manner, the following compounds were prepared: Compound 727, 111 〇. EXAMPLE ICC: Preparation of [4-(3-Cyano-1-ethyl-6-methoxy-1H-indenyl)-2-fluorophenyl]-aminomethyl propylate (Compound 877)

2-(4-Amino-3-fluorophenyl)·ι_ethyl methoxy-1 Η·(9) methoxycarbonitrile (74 mg, 〇·24 mmol) prepared as described in Example 1Gb And a mixture of two phases of propyl chloroformate (0.033 liters of '0.29 mmol) in Et 〇Ac (3 ml) and saturated NaHC 〇 3 (3 ml), made under 〇, and then It was warmed to room temperature' and stirred for 24 hours. The reaction was then diluted with h.sub.2 and extracted (2×) with Et.sub. Called Yu and Yu and Cawash Organic #, then dehydrated and dried, and concentrated. Rapid chromatography (Et〇Ac / hexane 1 〇 〇 〇 ) ) , , , , , , , , , , , , 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Phenyl]-aminomethyl propylate as an off-white solid. The following a system was made in a similar manner: Compound 8 is 876, 879. The following compounds were prepared using 2_(4-amino-3_methylphenyl H_ethylxymethoxy- 1 Η- _3_ carbonitrile): Compound: 963, 964, 965. Using Example 1Y The same starting materials and procedures are described to give the following compounds: Compounds 871, 872, 873, 874. In a similar manner, using 2(4-amino-3-mercaptophenyl)succinyl-6-methoxy _1H_吲哚-3_carbonitrile was made into the following compound: Compound 959, 960 '961, 962. Using the same starting materials and procedures as described in Example 1BU, the following compounds were prepared: 909, 910, 911. In a similar manner, the following compounds were prepared using 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile: Compound: 966, 967 Example CD: Preparation of cyclopropanecarboxylic acid {4-[3-cyano-indole-ethyl each (2-imidazolyl-ethoxycarbonyl)-phenyl}_S&amp;amine (Compound 1183) 397 - 128244-3 200831489

ΒΒγ3 DCM, -10 °C

咪吐 CN 〇

Ch3cn,

K2C〇3 Nal, 90 °C

Step A: The compound 2-(4-aminophenyl)-6-ethyllactylethylethyl-1H-4bend-3-indenecarbonitrile (3·66 g, prepared as described in Example 1Gb, 12 mmoles of Et3N (3.37 mL) and cyclopropane gasified carbonium (1.6 mL '18 mmol) were added to a solution of 2 mL of THF. The mixture was stirred at room temperature for 3 hours. Then, water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with brine (2×), dried over anhydrous Na? The residue was recrystallized from ethyl acetoate and hexane to give 99% cyproterilic acid [4-(3-carbyl-6-ethoxy-1-ethyl-1H-H fluorenyl) )-Phenyl]-acid amine. Step B: Cyclopropanecarboxylic acid [4-(3·Cyanoethoxyethoxyethyl-2-yl)-phenyl]-decylamine (4.4 g, 11.8 mmol) in 60 mL DCM In the solution, BBr3 (6.65 ml, 70 mmol) was added at -10 °C. After the addition, the mixture was stirred at 0 ° C for 3 hours. Then, an aqueous NaHC03 solution was carefully added to the mixture until it became inspective. The crude solid was collected by filtration to obtain 91% cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-W-indol-2-yl)-phenyl; In the next step, no further purification was required. Step C · In the case of j-expanded Wei acid [4-(3-carbyl-1-ethyl-6-pyridinyl-2_128244-3 - 398 - 200831489)-phenyl]-decylamine (4 g, η·6 mmol) in a solution of 15 ml of “Εκ, K:2C〇3 (8 g '58 mmol) and μ bromyl chloride-ethane (6 7 ml, millimolar) Then, the mixture was heated under reflux overnight. After cooling to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with brine (2 hr), dried over anhydrous NazSO4, filtered and concentrated. Yielding 81% crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)_3. cyano + ethyl-gristyl]-phenyl}-guanamine. Step D: in a sealed tube, Cyclopropanecarboxylic acid {4-[6-(2-gasethoxy)cyano-1-ethyl-1H-rhodium-2-yl]-phenyldoxime (1〇2 mg, 〇· 25 mmol. In a solution of 1.5 ml of acetonitrile, add NaI (46 mg, 〇·275 mmol), K2C03 (138 mg, 1 mmol) and imidazole (51 mg, 〇·75 mmol). Then, the mixture was heated to 90 ° C and stirred overnight. After cooling to room temperature, water and acetic acid B were added. The organic layer was separated, washed with brine (2×), dried over anhydrous NasSO4, filtered, and concentrated. The crude compound was purified by preparative HPLC to give &lt;RTI ID=0.0&gt; -6-(2-imidazol-1-yl-ethoxy)indole-2-yl]-phenyl-p-guanidamine. Using the same procedure and substituting the appropriate nucleophilic reagent, the following compounds were obtained: Compound 952, 1025, 1054, 1090, 1091, 1092, 1093, 1184. Example CE: [4-(3-cyanosuccinyl-6-trifluoromethoxyindol-2-yl)phenyl]decylamine Preparation of (Compound 881) 128244-3 -399- 200831489

XX:

CuC 丨 2&quot;-BuON〇 CH3CN/61 0C/3 hours p:3C〇

K2CO3/DMF/45 °C f3co

F3co

Step A: Add in portions of t-BuONO (8_01 ml, 67·5 mmol) and CuC12 (7.26 g, 54 mmol) in acetonitrile (50 mL) at 61 ° C 2- moth _4_ di-methoxy aniline (10.0 g '45.0 house Moules'' and gently stirred. After the addition, the mixture was stirred at this temperature for 2 hours. The solvent was removed on EtOAc (EtOAc) (EtOAc) The extracts were combined, dried over anhydrous Na 2 SO 4 , and passed through a pad. The solvent was removed and the residue was taken to EtOAc EtOAc (EtOAc:EtOAc: Then, the mixture was stirred at 45 ° C overnight, poured into ice water (700 ml), and extracted with methylene chloride (3×100 ml). The organic material was dehydrated and dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub. Next, the solvent 128244-3 • 400-200831489 was replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL) and the reaction mixture was taken at 5% Pd/C (2.80 g) at 50 psi. Hydrogenation overnight. The mixture was filtered on diatomaceous earth and the volatiles were removed in vacuo. The residue was dissolved in di-methane (200 mL), washed with Na2C EtOAc (2M, 2 X 50 mL), water (2 X 50 mL), brine (5 mL) and 4 Dehydrated and dried. The crude product obtained after removal of the solvent was chromatographed (D.sub.2, DCM/hexane, 1/1) to afford 6-trifluoromethoxy oxime (5.70 g, 63%, 2-nitro -4-trifluoromethoxyaniline is the basis). Step B: Add chlorosulfonyl isocyanate (2.35) in a solution of 6-trifluoromethoxy 4 oxime (2.68 g, 13.3 mmol) in anhydrous DMF (10 mL). Gram ' 1.44 ml, 16.6 mmol). Then, the mixture was slowly brought to warmness and scrambled for 1 hour. The mixture was poured into ice (1 ml) and mixed for 1 hour. The precipitate was collected by filtration, washed thoroughly with water and dried in vacuo, and then dissolved in DMF (15 mL). To the solution, KfO3 and Etl (2.59 g, 1.34 ml, 16.6 mmol) were added, and the mixture was stirred at 50 C overnight. Then, pour it into ice water (2 ml). The sediments were collected by the transition, washed with water, dried in the air, and purified by chromatography (Dicang, DCM) to obtain 1-ethyl-6-trifluoromethoxy 丨嗓·3_A Nitrile (2.90 g, 86%). Step C: Intermediate obtained above (2 〇 3 g, 8 〇 mmol), triisopropyl borate (2.16 g, 2.65 mL, 12.0 mmol) in anhydrous THF (15 liters) In the solution, LDA (6.7 ml, L5M, 1 〇·〇耄mol) was added at _78 °c. After the addition, the mixture was stirred at -78 ° C for 15 minutes, then slowly brought to room temperature and stirred for 30 minutes. Next, let it be at _78. 〇128244-3 -401 - 200831489 Under cooling, then add 4-iodoaniline (2.10 g, 9·6 mmol), PdCl2 (dppf) (0.29 g, 0.4 mmol), DMF (30 mL) and K2 C03 (12.0 ml, 2.0 M, 24.0 mmol). The mixture was allowed to slowly reach room temperature and stirred overnight, and poured into ice water (400 ml). The precipitate was collected, washed with water and chromatographed eluted eluted eluted eluted eluted 3-carbonitrile (1.99 g, 72%). Step D: a solution of the compound obtained in step C (31 mg, s. 1 mmol) in anhydrous pyridine (1.0 mL) Sulfonium sulfonate (14 μL, 0.15 mmol). The mixture was stirred at room temperature overnight and diluted with water (5 mL). Washed with water (2 x 4 ml) and brine (3 ml), and chromatographed (EtOAc, EtOAc/DCM, 0.5/9.5) to afford product, ethanesulfonic acid [4-(3-cyano) 1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]bristamine (33 mg, 83%). Compounds 882, 883, 884, 885, 886, 887, 888, 889 The above route was prepared using either an alkyl sulfonium vapor (program ιγ) or a chloroformate (procedure 1AJ). Example 1CF: 2-[4-(1,1-diisoxazole) _2_yl)phenyl]-μethyl each (trifluoromethoxyindole-3-carbonitrile) Was 903) 200 831 489 The prepared 128244-3402-

(Boc) 2〇/DMAP

Boc F3C〇 DCM f3c〇 BiO^POa/LDA THF/0oC~ room temperature 2NHCI 0〇C~room temperature

Step A · · 6-trifluoromethoxyindole (3.01 g, 15.0 mmol) and di-tert-butyl dicarbonate (3.59 g, 16.5 mmol) in DCM (30 mL) In the solution, DMAP (0.04 g) was added at 40 ° C while stirring. After stirring overnight, the mixture was washed successively with 0.1 N HQ, water and brine, and dried over anhydrous NazSO4. The solvent was evaporated, and the residue was crystallisjjjjjjjjjjjjjjjjjjjjj Step B: The above Boc-oxime and triisopropyl borate (4·73 g, 5·8 ml, 26.3 mmol) were dissolved in anhydrous ΤΗρ (2 〇 ml), and the solution was cooled to the 〇 . When stirring, LDA (15 mL, 15 M mono-THF complex in cyclohexane, 22.5 mmol) was added dropwise. The mixture was stirred under hydrazine: 15 minutes and then at room temperature for 0.5 hour, followed by the addition of Ηα (6 Ν, 3.75 mL, 22.5 mM) in an ice water bath. The organic solvent was removed in vacuo and the residue was taken in H.sub.2 (100 mL) and acidified to pH 4~5 with Ηα (6 Ν). The precipitate was collected by filtration, washed with water and hexane, and dried in air, 128244-3 - 403 - 200831489 to provide Boc-6-trifluorodecyloxy-2-dihydroxyborane (2.56) Gram, 49°/〇).

Step C: i-Boc-6-trifluorodecyloxy-2-dihydroxyborane prepared above (〇·74 g '2.1 house mole), 2-(4-anthracenephenyl) Iso-p plug α sigma _i, i-dioxide (0.76 g, 2·4 house Mo) and pdCl2 (dppf) (0.08 g, 〇·ΐ mM) in DMF ί (6·0 ml) In the mixture, K2C〇3 solution (3.2 mL, 2 〇μ, 6.4 mmol) was added. The mixture was stirred at room temperature overnight and then poured into ice water (100 mL). The precipitate was collected, washed with water and purified by flash column chromatography (EtOAc, DCM /EtOAc, 9/1) to afford kbomku-dioxide oxime. Methoxy oxime, which was treated with 50% TFA (15 liters) in dCm at room temperature for ί hours. After removal of the volatiles, the residue was carefully stirred with saturated NaNaHCl 3 for 5 hours. The precipitate was collected via filtration, washed thoroughly with water and dried to provide essentially pure 1-indole-2-[4-(1,1-diisoisoxazole-2-yl)phenyl] Fluoromethoxy hydrazine. Step D: Under (TC), the solution of the intermediate obtained above in anhydrous water (10 ml) was chlorosulfonyl isocyanate (〇 38 g, 〇 mL, 2 68 house Mo) Dispose of. Then 'stir the mixture overnight at room temperature and pour into ice water (10 ml), then mix. Collect the sacred objects through the sputum, and wash them thoroughly with water, and get the scent of the scent of the scent of the sulphuric acid. 90%). Step E: 1-, 2-[4-〇1-- 童jbg,, L (, emulsified isothiazolidinyl)phenyl]_6_trifluoromethoxyindole-3-carbonitrile (63 mg, 〇15 旲 旲) and heart 〇: 03 (62 mg, 0.45 house Moer) in DMF (2.0 ml) solution from Μ Add iodine ethane (36 micro 128244-3 -404- 200831489 liters, 0.45 millimoles). The mixture was stirred at 5 rc overnight and poured into ice water (10 mL). The precipitate was collected by filtration, washed with water and purified by column chromatography to afford 2-[4-(1,1_ Dioxazolidine-2-yl)phenyl%^difluoromethoxy-1-ethyl-4-di-3-carbonitrile (59 mg, 88%). The following compounds were prepared in the same manner as above. Formation: Compound, 904, 905, 906. Example ICG ··[4-(3-Cyano-1-cyclopropyl-6-methoxyindole-2-yl)phenyl]aminemethyl isopropylate Preparation of ester (compound 1234)

〇H DCC/HOBt/ t&gt;-NH2 DCM-DMF/room temperature/4 hours, Q

-NhHN-K2C03/Cul/ Ο Benzene / 110 ° C / 48 hours

D Old AL-H DCM/0oC-Room 4 hours

1). B(0/-Pr)3/LDA/THF/-78°C 2).PdCI2(dppf)/K2C03 ‘Iodophenylamine

^ — b

Step A: In a suspension of 2-glycosyl-4-methoxyphenylacetate (24.5 g, 100 mmol) in DCM (100 mL), add DMF (~10 mL) and stir until all The solid disappeared, followed by DCC (22.66 g, 11 mmol) and HOBt (14.85 g, 110 mmol). After stirring at room temperature for 10 minutes, cyclopropylamine (8.55 g, 10.4 ml, 150 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 4 hr. The solid was filtered and washed thoroughly with DCM (300 mL). The filtrate was cooled to -10 ° C and gently stirred for 1 hour and filtered again to remove additional urea by-product. The filtrate of 128244-3 -405 - 200831489 was passed through a silicone pad and dissolved in DCM/Et0Ac (8/2). After removal of the solvent, the cyclopropyl decylamine intermediate was obtained as a white solid (28.34 g, 1%). Step Β: The above guanamine (14.2 g, 5 〇〇 millimolar), K2c 〇 3 (138 g, 100 lm) 'CuI 74 g, 5 〇 millimolar) and N, N, dimethyl A mixture of cyclohexanediamine (1.42 g, 1.57 ml, 10.0 mmol) in toluene (15 mL) was stirred at 11 (TC and N2 atmosphere for 48 hrs. The mixture was filtered on celite and washed with EtOAc EtOAc EtOAc (EtOAc) Propyl methoxy methoxy ruthenium, a pale yellow solid (4.30 g, 42%). Step c: yttrium oxide (5 g, 24.6 mmol) obtained above in anhydrous DCM ( In a solution of 25 ml), dibal_h (1.0 M in DCM, 35.0 ml, 35.0 mmol) was added in 5% cc. After the addition, the mixture was stirred at room temperature for 4 hours and then cooled. 〇〇c, followed by dropwise addition of HCl (2N). The DCM layer was washed with HCl (2N, 10 mL), water and brine, and dried over anhydrous Na.SO4. Hexane/EtOAc, 9.5/0.5) to give </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt;哚 (3.29 g, 17.6 mmol) in a solution of anhydrous DMF (30 ml), under 〇.〇, add isocyanate gas sulphate (3.11 g ' 1.91 4: liter ' 22.0 耄 Mo Er After the addition, the mixture was stirred at room temperature for 2 hours' followed by aqueous solution. Chromatography (gelatin, hexane / EtOAc '9/1) 'sup.3 - cyano-1-cyclopropyl. Oxime (3 〇 5 g, 82%). 128244-3 -406- 200831489 Step E · The intermediate obtained above (2.65 g, 12.5 mmol) and triisopropyl borate (3.38 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Stir at -78 ° C for 15 minutes, then slowly bring to room temperature and stir for 30 minutes. Then, let it cool at -78 ° C, and then add 4-iodoaniline (3.29 g, 15.0 m) Mohr), pdCl2 (dppf) (0 46 g, 0.6 mmol, DMF (40 ml) &amp; K2C03 (18.8 ml, 2.0 M, 37.6 house Moule). Bring the mixture slowly to room temperature and stir overnight, then pour in ice water (400 ml). The precipitate was collected, washed with water and dried (yield, EtOAc/DCM, 0.5/9.5) to give 2-(4-aminophenyl)-1-cyclopropyl-6-methoxy Based on each carbonitrile (2.84 g, 75%). Step F: In a solution of the compound obtained in Step E (61 mg, 〇·2 mmol) in anhydrous pyridine (2.0 ml), isopropyl benzoate (0.3 ml, 1·〇) Oh, 0.3 millimoles). The mixture was stirred at room temperature overnight and diluted with water (10 mL). The organic layer was extracted with EtOAc EtOAc EtOAc (EtOAc) /9.5) to provide the product, [4-(3-cyanosuccinylpropyl-6-methoxyindol-2-yl)phenyl]aminemethyl isopropylate (66 mg, 85%) . Compounds 1235 and 1236 were prepared using the above chemistry. Example 1CH: Preparation of 1-allyl-6-methoxy-2-[4-(2-ketotetrahydropyrrole-1-yl)-phenylindole-3-indolecarbonitrile (Compound 938) 128244 -3 -407 - 200831489

MeCT

CN 1. iPr2NH, n-BuLi, THF CN i&gt; 2. B(OMe)3 ίΎν N ► MeO^^^N 3· K3P04 (3M. Aqueous solution) 4. rv1 PdCI2dppft DMF O Using the procedure described in Example 1Gb , substituted μallyl_6_decyloxy]H_ 吲哚-3-carbonitrile (92·3 mg, 〇43 mmol) and ΐ_(4·iodophenyl)_tetrahydropyrrole-2- The ketone gave 99.0 mg (61.3% yield) of compound 938. Example 1CI: 6-Cyclopropoxy-2-[4-(1,1-dione-1,6-isopyrazolidine-2-yl)-phenyl]sodiumethyl-1Η·蚓哚- Preparation of 3-indene nitrile (compound ι 46)

CN

ΒΒΓ3 ch2ci2, o〇c H.

^ υ , K2C03l DMF, 80°C N\ Vk^Bu), 80°C ~

CN CICH2I, Et2Zn

(CH2)2CI2.-10UC•Room, LDA, THF, -78°C • B(0’pr)3 • K2C03 (3M, aqueous solution)

PdCI2dppf, DMF Step A: Using the procedure described in Example IB (Step A), the hydroxyl group • 1_ethyl_1Η-β丨嗓_3-carbonitrile was obtained. Step B ·········································································································· U2 g, 8.12 mmol) and 1-bromo-2-fluoroethane (4) mg, 3.29 mmol. The resulting mixture is then assigned (d) until the time is determined by tlc. The mixture was completely consumed. The reaction mixture was cooled, and the solution in the third butanol unloading was added, 5·5 ml, 5.43 mmoles, and stirring was continued overnight. The mixture was made in Et 〇Ac (9) ml. HC old 128244-3 • 408- 200831489 liters) for liquid separation treatment. Saturated NaHc 〇 3, saturated Na (: 1 wash organic phase, and K dry, and concentrate. Make the product on the silicone (EtOAc/hexanes, 1 〇 25%) singly isolated to give 430.2 mg (74.9%) of 1-ethyl-6-vinyloxy-1H-(9)indole-3-carbonitrile as a white solid Step C · Add diethylzinc to a solution of 丨_ethyl each vinyloxy-1Η·Η木-3-carbonitrile (288.1 mg, 1.36 mmol), chloromethyl iodide (268 9 mg) via syringe , 1.53 millimolar) and 5 ml 丨In a mixture of 2_di-ethane, the temperature is maintained at -1 (rc) over a period of ί. The mixture is allowed to warm to 2 〇 _25 for 20 minutes, then cooled back to 〇r. At this temperature Add saturated NH4C1 (15 liters), concentrated ammonium hydroxide (15 ml) and ethyl acetate (15 ml), and stir for 10 minutes. After separating the liquid phase, ethyl acetate (1 ml) The aqueous phase was extracted with aq. This gave 14 〇·5 mg (45 7% yield) of 孓cyclopropoxy-1-ethyl-1 Η-4 prasin-3 carbonitrile as a yellow solid. Step D: using the method described in Example 1Gb The same procedure, hydrazine iodophenyl &gt; isoxazole was substituted for 1,1-dioxide to replace 4-anthranilide to give the title compound. In a similar manner, according to steps A to C above, compound 1 was also prepared. 〇 47. Example CJ · propane citicoic acid [4-(3-cyano-6-difluoromethoxyethylidene-2-yl)-phenyl]-decylamine (Compound 928) 128244- 3 409-200831489

Step A: 6-Difluoromethoxy-1-ethyl-1H-4 prasin-3-carbonitrile (316.3 mg, 1.34 mmol) with triisopropyl borate (402.9 mg, 2.14) The solution in MeOH (15 mL) was cooled to -78.degree. C. and was taken from &lt;RTI ID=0.0&gt;&gt; After the addition, the acetone/dry ice bath was exchanged into an ice water bath, and the solution was stirred for another 30 minutes. The solution was cooled to _78 ° C, and Φ·iodoaniline (299.5 mg, ι·37 mmol) was added sequentially in DMF (8 mL), K2C03 (2M, 2.01 mL, 6·02 mmol) and

A solution of PdC^dppf (51.3 mg, 0.07 mmol). The mixture was degassed by three cycles of vacuum pumping/N2 scrubbing and allowed to mix overnight (about 16 hours). The reaction mixture was poured into 4 volumes of water and 4 volumes of ethyl acetate were added. The phase was extracted with more ethyl acetate. The organic phase was washed with water and saturated NaCl, then dried over anhydrous MgSO 4 , filtered and evaporated. Dissolve in 55% 5% ethyl acetate / hexane to give a 5 mg (7 %) aniline intermediate as a white solid. Step B: Using the same procedure as described in Example 1Y, and replacing the chlorination - propyl sulfonium hydrazine, the title compound was obtained. 128244-3 -410- 200831489 The following compounds were prepared using essentially the same procedure and substituted for other chlorinated hydrazines. Compounds 929, 930, 931. Example 1CK: [ 4-(3-Cyanodifluoromethoxy-μethyl-breast bromide-2-yl)·Phenyl]-aminomethyl methylate (compound 11%) / 〇々XX^C^〇 ~nh2 -g|A〇&quot; ^ Pt^v=Vmh —γ ΡΛ0ΛΛΜ&gt;ν〇/ K2C03 aqueous solution / Ο 2-(4-Aminophenyl)-6·Duntown Oxy-1-ethyl-1 Η-+-3-carbonitrile (fine house gram, 0.611 耄 Mo) with methyl formate (95 μl, 123 mmol) in ethyl acetate (2 mL) The solution was treated with a 2 Μ aqueous solution of EtOAc (3················································ The organic layer was removed, dried over anhydrous sulphuric acid, dried, and evaporated, and evaporated. White solid. In a similar manner from the appropriate reagents: compound 1131, Η%, 1 1134, 1135. Example 1CL: 1-[4-(3-cyano-6-difluoromethoxyethylethyl hydrazide) •吲哚_2•基> phenyl; 1-3·propyl-urea (compound 893)

2_(4-Aminophenyl&gt;6.difluoromethoxy+ethyl-excited oxime; carbonitrile (2 (nine) pg, 0.611 mmol) in 1,2 dioxaethane (2 ml) The solution was treated with n-propyl isodecanoate (115 ml, L23 mmol) and triethylamine (17 mL, ^ 128244-3 -411 . 200831489 * Moel). After the mixture was stirred for 12 hours at ambient temperature, and then condensed, the residue was separated by chromatography (1/2 ethyl acetate-hexane) to give the title product as a solid. The reagents were: Compounds 892, 894. Example 1CM: Moffin-4-carboxylic acid [4-(3-cyano-I-cyclobutyloxy) 4H-p-bend-2-yl)- Preparation of phenyl]-nonylamine (compound 1166)

h Step A: In the capped tube, 6-ethoxy-1H-H b--3-carbonitrile (2·8 g, 15 mmol) prepared as shown in Example 步骤a, step a Ears were combined with Cs2C03 (11.6 g, 35.6 mmol), DMF (21 mL) and brominated butyl ketone (1.73 mL, 17.9 Torr). The reaction mixture was heated under 8 liters for 8 hours. The reaction was quenched with EtOAc (EtOAc)EtOAcEtOAc The EtO Ac layer was backwashed with brine at Η20. The organic phase is dehydrated and dried, and concentrated. Purification by silica gel chromatography (hexane / EtOAc / EtOAc (EtOAc) Step B: Substituting Suzuki coupling with μcyclobutylethyl 128244-3 -412- 200831489 oxy-ββ丨嗓-3-carbonitrile (3·〇g, 12.4 mmol) according to the procedure in Example 1Gb It was converted to give 2-(4-aminophenyl)succinyl butyl-6-ethoxy-1H-indole carbonitrile (2_60 g, 68%) as an off white solid. Step C: 2_(4-Aminophenyl) small cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitrobenzene chloroformate The ester (60 mg, 0.30 mmol), 03⁄4 (3⁄4 (400 μl) and pyridine (25 μL, 0.31 mmol) was stirred at room temperature for 1 hour. Add morpholine (60 μl, 〇. After stirring for 30 minutes at room temperature, the reaction mixture was diluted in CH 2 C 12 and washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer was dried and concentrated. Purification by gelatin chromatography (CH2Cl2 / EtOAc, 7/3) to give fluflurin-4-weilic acid [4·(3-cyano-1-cyclobutyl-6-ethoxy-1H-H丨嗓_ 2_yl)-phenyl]-guanamine (53 mg, 100%) as a white solid. The following compounds were obtained in a similar manner using the appropriate amine in the final step: Compounds 1087, 1088, 1089, 1119, 1159 , 1168, 1191, 1266, 1288, 1324, 1325, 1326. Example 1CN: rac-[4-(3-cyanocyclobutanyl-6-ethoxy-lHl嗓_2_yl)-phenyl Preparation of 1-aminomethyl 1-cyclopropyl-ethyl ester (compound 1147)

h 2-(4-Aminophenyl)·1_cyclobutyl each prepared according to Example 1CM Step B 128244-3 -413 - 200831489 Ethoxy-1H-W哚-3-carbonitrile (50 Milligrams, 0.15 millimoles) combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL) and pyridine (30 [mu]L, 0.37 mmol). The suspension was stirred at room temperature for 1 hour. Add rac-cyclopropylethanol (100 μL, 0.98 mmol). This mixture was heated at 75 ° C overnight. Then, the reaction mixture was diluted in CH2C12 and washed with a dilute aqueous solution of NaOH to remove the yellow sulfhydryl by-product. The organic layer was dehydrated and dried, and concentrated. Purification by gel chromatography (CH2C12) gave racemic-[4-(3-carbyl-1-ί哀butyl-6-ethoxy-1Η-ρ5丨嗓-2-yl)-phenyl] -Aminomethyl 1-cyclopropyl-ethyl S (40 mg, 60%) as a white solid. The following compounds were prepared in a similar manner: using the appropriate alcohols: Compounds 1146, 1158, 1167, 1192, 1208, 1209, 1210, 1215, 1216, 1240, 1241, 1242, 1243, 1244, 1246, 1247, 1248 , 1249, 1250, 1264, 1265, 1267, 1268, 1281, 1282, 1283, 1286, 1287, 1289, 1290, 1291, 1292, 1294, 1295, 1296, 1297, 1298, 1299, 1312, 1313 〇 Example ICO: Preparation of 1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1Η-β哚-3_carbonitrile (Compound Π39) 128244-3 414- 200831489

Step A: 孓(4_Aminophenyl)-丨-cyclobutyl-6-ethoxy-1Η-蚓哚-3-carbonitrile (600 mg, 丨81 mil) prepared according to the procedure of Example 1CM. Mohr) was suspended in CHAdS ml) with EtsN (390 μl, 2.7 mmol). Difluoroacetic anhydride (310 μl, 2.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, after which time the dissolution was completed. Then, the reaction mixture was washed with a saturated NaHC 3 solution. The organic layer is dehydrated and dried, and concentrated to give N-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H•吲哚_2_yl)·phenyl]-2. 2,2-Difluoro-acetamide (8 〇 2 mg, ι〇〇〇/〇) as a yellow solid. Step B: Making N-[4_(3-cyanocyclobutylidene-6-ethoxy-1H-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (8 〇〇 mg, ι·8 mmol) dissolved in DMF (1 mL). NaH (140 mg, 60% oil suspension, 3.5 mmol) was added. It was stirred at ambient temperature for a few minutes, followed by the addition of ethidium bromide (176 μl, 2.2 mmol). It was allowed to mix overnight at room temperature and then at 75. Kneeling for 6 hours. A further portion of NaH (200 mg, 5.0 mmol) and ethyl iodide (200 μL, 2.5 mmol) are necessary to push the reaction further. It was heated at 75 C overnight. Additional iodine iodide (2 〇〇 microliters, 2·5 mM 128244-3 -415-200831489 ears) was added. It was heated again for 2 hours. The reaction mixture was then diluted in kh.sub.2 and extracted in EtOAc. The Et0Ac layer was dehydrated and concentrated, and concentrated. Chromatography (03⁄4 (3⁄4), yielding 384 mg of desired N_[4-(3-cyanosuccinyl-6-ethoxy-1H-W哚-2-yl)-phenyl]-N. Ethyl·2,2,2-trifluoro-acetamide and hydrolyzed 1-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-ιη-吲哚-3- An inseparable mixture of carbonitrile. Step C: The crude mixture from the previous step was dissolved in methanol (5 mL). 6 NaOH (1.0 mL, 6 mM) was added and the mixture was heated at 80 ° C for 1 hour. Then, the reaction mixture was diluted in H20 and extracted in CH2C12. The organic layer was dried, dried and concentrated, and purified by chromatography (CH2C12) to yield pure 1·cyclobutyl-6-ethoxy-2- (4-Ethylaminophenyl)-1Η-indole-3-indene nitrile (343 mg, 53% over two steps) as a white solid. 1-cyclobutyl-2-(4-diethylamine) The phenyl-phenyl)-6-ethoxy-1H-indole carbonitrile (Compound 1217, 77 mg, 11%) was isolated as a by-product of the reaction described in Example ICO Step B. Example 1CP: [4 -(3-cyano-1-cyclobutylethoxyl-1H-M丨哚-2.yl)-phenyl]-ethyl-amine methyl acid cyclopentyl ester (compound 1251) Preparation

h 1-cyclobutylethoxyethoxy-2-(4-ethylaminophenyl)-1Η-indole-3-carbonitrile (35 mg, 〇·1 〇 制成) prepared according to the example ICO step C Mohr) is dissolved in pyridine (300 μl). Add cyclopentyl chloroantimonate (25 μl, 0·17 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. Add more gas phthalate (10 μl, 128244-3 -416 - 200831489 〇·〇 7 mmol) to drive the reaction to completion. After stirring for an additional 9 minutes, the reaction mixture was partitioned between aqueous EtOAc and EtOAc. The organic layer was dehydrated and dried, and concentrated. Purification by Shixi gum chromatography to give [4_(3-cyanamide 1 cyclobutyl winter ethoxy-1H-indol-2-yl)-phenyl]-ethyl-amine decyl acid cyclopentane (41 house gram '87%), as a white solid.

Compound 1252 was prepared in a similar manner using appropriate chloroformic acid vinegar. Example 1CQ · {4-[3-Cyano-1_cyclobutyl-6-(3-[1,2,4]tris-l-yl-propoxy) 1H-Hb-but-2-yl [-phenyl}-aminomethyl acid isopropyl g (compound 1255)

Step A: isopropyl [4-(3-cyano-1-cyclobutyl methoxy-1H-indol-2-yl)-phenyl]-amine methyl acrylate (950 mg, 2.35 m In a solution of DCM (10 mL), ΒΒι*3 (556 μl, 5.9 mmol) was added over a period of 20 minutes. The reaction mixture was stirred at room temperature for additional 1 hour then water (1 mL) was added. The solvent was removed under reduced pressure. The residue was dissolved in MeOH and poured into cold water. The precipitate was collected by filtration, washed with hexane, and dried in vacuo to give [4-(3 - cyano-1-cyclobutyl-when-hydroxyl-H-H-indol-2-yl)-phenyl] - Isopropyl methacrylate (650 mg, 71%). Step B: isopropyl [4-(3-cyano-1-cyclobutyl-6-hydroxy] η-indol-2-yl)-phenyl]-128244-3 -417- 200831489 Add a solution of K2C〇3 (132 mg, 〇·96 mmol) to 3-bromo-based chloropropyl-propylate (172 mg, 〇·87 mmol) in DMF (2 mL). Microliter, 1.75 house Moule), and the reaction was mixed for 5 hours under 6 art. Then, the reaction mixture was poured into cold water, and the precipitate was collected by filtration, washed with hexane, and dried in vacuo to give 37 g of the desired product. Step C: isopropyl {4-[6-(3-a-propoxycyanosuccinyl-2-yl)-2-phenyl}-aminomethyl methacrylate (37 mg, 0.08 mmol) In a solution of CH3CN (1 mL), sodium iodide (71 mg, 〇·48 mmol) was added. The resulting mixture was stirred overnight at reflux temperature. The solvent was then evaporated and dried with DMF. (1 ml) The residue was diluted with EtOAc EtOAc (EtOAc m. Then it was washed with water. The organic layer was concentrated and triturated with hexane, and the precipitate was collected by filtration, and washed thoroughly with 5% ethyl acetate in hexane, and dried in vacuo to give {4·[3- Cyano + cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)_1Η-indol-2-yl]-phenyl}-amine methyl isopropylate Ester, compound 1255 (31 mg, 78%). The following compounds were obtained in a similar manner, according to the above procedure AC: Compounds 1253, 1254, 1260, 1261, 1262, 1427, 1430. Example 1CR: {4-Cyanide Small cyclobutyl-6-(2-[1,2,4 Preparation of Triazole Small Group-Ethoxy y 1H-啕哚_2-yl]-Phenyl-P-Amino Acid Isopropyl Ester (Compound 1276) 128244-3 -418- 200831489

Step A ··[4-(3-Cyano-1_cyclobutyl-6-yl-1H-H丨嗓-2-yl)-phenyl]-aminomethyl isopropylate (390 mg , in a solution of CH3CN (5 ml), add K:2C〇3 (414 mg, 3.0 mmol) and 3-bromo-dichloroethane (250 μl, 3.0 millimoles) and the reaction was stirred for an hour at 8 Torr. Then, the reaction mixture was poured into cold water, and the precipitate was collected by filtration and washed with hexane, and dried in vacuo to give the desired product. Step B: isopropyl {4-[6-(3-chloroethoxy)_3_cyanocyclobutyl-1H•indenyl]-phenyl]-amine methyl acrylate (42 mg, hydrazine) • 〇 9 mM) Sodium iodide (56 mg, 〇37 mmol) was added to the solution in ch3 CN (1 mL). The resulting mixture was stirred at reflux temperature overnight. The solvent was evaporated and the residue was diluted with EtOAc EtOAc (EtOAc) The solvent was removed under reduced pressure and the residue was diluted with EtOAc EtOAc. The organic layer was concentrated and developed as a burn. The precipitate was collected by filtration, washed with 5 〇% ethyl acetate in hexanes and dried in vacuo to give [4_[3-cyanosuccinyl butyl each (3_[1,2, 汨Monoazole-ethoxylated aspartame] phenyl phenylaminomethyl isopropylate, compound 1276 (28 mg, 64%). The next step is in a similar manner, according to step A above. Made with B: 128244-3 • 419- 200831489 Compounds 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278. Example 1CS · {4·[3-Cyano-1-ring Butyl-6-(2-[1,2,4]triin-1-yl-ethoxy)-1H-W哚-2-yl]-phenyl-benzamidinoic acid μcyclopropyl-B Preparation of ester (compound 1329)

Step A: 2-(4-Aminophenyl) small cyclobutyl-6-hydroxy-1Η-吲哚! To a solution of carbonitrile (909 mg, 3 mmol) in pyridinium (5 ml), add 4-nitrophenyl chloroformate (6 mmol) at room temperature, then stir at room temperature 2 hours. To the reaction, cyclopropylethanol was added, followed by stirring at 80 ° C for 8 hours. The reaction mixture was diluted with 1 HCl and then extracted with ethyl acetate. The organic layer was concentrated and the residue was crystallisjjjjjj The precipitate was collected by filtration, washed with hexane, and dried in vacuo to give [4-(3 - cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-benzene Base]-amine methyl hydrazine _ cyclopropyl-ethyl ester (996 mg, 80%). Step B: 1-[4-(3-Cyano-1-cyclobutyl-6-hydroxy-1H4丨哚-2-yl)-phenylaminomethyl 1-cyclopropyl-ethyl ester (1.5 g, 3.61 millimoles) K2C〇3 (1.5 g, 1 〇·8 mmol) and 2 bromo + chloroethane in a solution of CHsCN (8 mil 128244-3 -420 - 200831489 liters) 895 microliters, 10.8 millimoles) and the reaction was stirred at 8 Torr for 8 hours. Then, the reaction mixture was poured into cold water, and the precipitate was collected by filtration, washed with hexane, and dried in vacuo to give 146 g, 84% of desired product. Step C: {4_[6-(2-chloroethoxy)-3-cyano-indole-cyclobutyl_m_indol-2-yl]· stupyl}-fe methyl acid 1·ring A solution of propyl-ethyl ester (146 g, 3.05 mmol) in CH3CN (10 mL) was added sodium sulphate (1. 84 g, 12.22 mmol). The resulting mixture was stirred at reflux temperature overnight. The solvent was evaporated, and the residue was evaporatedjjjjjjjjj Add '1,2,4-triazole sodium salt (〇·3ΐ mmol) to 1 ml dmf solution containing decyl ethyl intermediate (0153 mmol) and place the reaction at temperature Stir overnight. The reaction mixture was diluted with 5 ml of DMF, and the desired product was purified by preparative LC to afford &lt;RTIgt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; --ethoxy)_m-吲哚-2_yl]-phenyl-p-aminomethyl acid μ cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%). The following compounds were prepared in a similar manner according to the above procedure AC: Compound 1327, 1328 〇 Example 1CT: Η4-Ρ-cyano-1-cyclobutyl-6-(3-[1,2,4]3 Preparation of oxazol-1-yl-propoxy hydrazino-p-butan-2-yl]-phenyl} each isopropyl-urea (compound 1314) 128244-3 -421 - 200831489

Step A: Η4·(3-cyano-1-cyclobutyl-6-methoxy-1H-H丨哚-2-yl)-phenyl]·3-isopropyl-urea (2.21 g, A solution of BBr3 in CH2C12 (16.5 mL, 16.5 mmol) was added at <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; The mixture was allowed to warm to room temperature and held for 1 hour. Then, the reaction mixture was poured onto ice, and a 1 M aqueous NaHCO 3 solution was added until pH 7-8. The product was extracted with 1 mL of ethyl acetate (3 EtOAc) and organic phase washed with 1 mL of saturated NaCl. The organic phases were combined and dried by dehydration with MgS 4 . The solvent was removed to recover 1.95 g (92%) of 1-[4·(3-cyano-1-cyclobutyl-6-hydroxy-1Η-indol-2-yl)-phenyl]-3-iso Propyl-urea is a tan solid. Step Β: 1-[4-(3-cyano-μcyclobutylhydroxyl_1Η_4哚_2-yl)-phenyl]-3-isopropyl-urea (750 mg, L93 mmol) Add anhydrous &amp; CO3 (800 mg, 5.79 mmol) to 1-bromoisopropane (382 μl, 3.86 mmol) in 10 ml of acetonitrile. After stirring under the ribs overnight, the reaction mixture was allowed to cool&apos; and the solvent was removed. The reaction was resuspended in 丨(8) mL of ethyl acetate. The organic phase was washed with 200 liters of H.sub.2 and the aqueous phase was re-extracted 2X with 1 liters of ethyl acetate. The organic phases were combined, dried over MgSO4, and transferred to EtOAc EtOAc EtOAc EtOAc (EtOAc) _Cyanocyclobutylidene-1Η-indol-2-yl]-phenyl}winter isopropyl urea, a yellow-brown powder. Step C · 1-{4-[6_(3-Chloropropyl Oxycyanocyanatocyclobutanyl 1 Η 吲哚-2-yl]-phenyl b 3-isopropyl-urea (4 〇〇 mg, 0.860 mmol) in 8 ml of acetonitrile / DMF (4 Anhydrous Nai (258 mg, I.?) millimolar was added to the solution in /1). After stirring overnight at 60 ° C, the reaction system showed conversion to product to cool the reaction mixture by LCMS-UV. The solvent was removed and redissolved in Dmf to give a total volume of 14.0 ml. Step D: above H4_[3-cyanocyclobutanyl-6-(3-iodopropoxy)&gt;1H_b. ]-Phenylisopropyl-urea (Μmg, 〇〇62 mmol) in 1 ml of DMF solution, add anhydrous hydrazine, 2,4-triazole sodium salt (1 〇〇 mg, 〇11 〇 莫After stirring at room temperature overnight, the reaction mixture was filtered and purified by preparative LC/UV purification. The solvent was removed to give 12.3 mg. (4〇%) cyano-1-3⁄4 butyl winter (3-[1,2,4]triazol-1-yl-propoxy)_1H蚓哚-2.yl]-phenyl}-3- Isopropyl-urea (compound 1314) as a white powder. The following compounds were prepared according to the procedure described above: Compounds 13〇6, 13〇7, 1308, 1309, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1323 and 1324. Example 1 CU. [4-(3-Cyano-s-cyclobutylpyrimidin-2-yl-1Η-β哚·2_yl)-phenyl]-amine-hydrazinoic acid 1-cyclopropyl-ethyl ester Preparation of (Compound 2419) 128244-3 -423 - 200831489

Step Α·[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-W哚-2-yl)-phenyl]-amine methyl acid 1-cyclopropyl-ethyl ester ( 1·8 g, 4.3 mmol. In a solution of CH2C12 (20 mL), pyridine (2.74 g, 34.6 mmol) was added at 0 ° C, then Tf20 (3.67 g, 13.0 mmol) was slowly added. Ear) A solution in CH2C12 while maintaining the temperature below l〇 °C. Upon completion, the reaction mixture was washed with dilute HCl, water and brine. It was then dried over MgSO4, EtOAc (EtOAc) Step B·Trifluoro-methanesulfonic acid 3-cyano-1-cyclobutyl-2-[4-(l-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indole-6 - base ester (1.1 g, 2.0 mmol), double (. 呐 呐 可), two sheds (〇 · 56 g ' 2.2 mM), Pd (dppf) Cl 2 (49 mg, 〇. 〇 6 mM A mixture of dppf (24 mg, 〇·〇 6 mmol) and potassium acetate (〇·59 g, 6.0 mmol) in dioxane (12 ml) was stirred at 8 Torr overnight. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) Step C·{4_[3_Cyano_1_cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxosulfan-2-ylindole] -2-yl]-phenyl}-aminomethyl acid μcyclopropyl·ethyl hydrazine 128244-3 -424- 200831489 (0.2 g '0.38 mmol), 2-chloropyrimidine (39 mg, 0.34 mg) ,

A mixture of Pd (PPh3 h (22 mg, 〇·〇 95 mmol) and fluorinated planer (0·116 g, 〇76 mmol) in DME (2.0 ml) was stirred at 1 Torr for 16 hours at rc. Then, the mixture was diluted with EtOAc (20 mL), washed with water and brine, dried with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc -1-cyclobutyl-6-pyrimidin-2-yl-1H_吲哚_2_yl>phenyl]-aminomethyl 1-cyclopropyl-ethyl ester as a solid (015 g, 82 〇) /〇). Example 1CV. [4_0Cyano-1-cyclobutyl-6-pyridin-2-yl-1H-indol-2-yl)_

Trifluoro-methane acid 3-cyanocyclobutanyl 2-[4-(1-cyclopropyl-ethoxycarbonylamino)phenyl]_1H_吲哚 prepared according to Example 1CU Step A In a solution of each of the base esters (2 mg, 0.37 mol) in DMF (2.0 ml), add 2_(tributyltin-based bite (160 mg, 〇·44 mmol), pd(pph3) 4 (21 mg, 〇·〇ΐ 8 mmol), CuI (7 mg, 0·037 mmol) and CsF (m mg, 〇73 mmol). The mixture was stirred at 8 (TC for 2 hours, Treated with ether (2 ml) and potassium fluoride (5 g). The mixture was stirred for an additional hour and filtered. The filtrate was washed with water and brine, dried over N?SO? Purification (CHA/EtOAc) afforded [4_(3-cyanocyclobutanyl), hydrazinyl-2-indolyl] phenyl]-amine methyl hydrazine-cyclopropyl-ethyl , as solid (82 ^ g, 47%) 〇 Example 1CW : (RH4-[3-cyano-oxime-cyclobutyl·6_(啸咬_2_基基128244-3.425. 200831489 嗓-2 -Based on -phenyl}amine methyl acid 1-cyclopropyl-ethylidene (compound 2210)

CN LDA,-780C~ room temperature B(OiPr)3lTHF; h

HO, v, N DMF·aqueous solution K2C03 (2MXh〇., Pd((ippf)CI2, room temperature nW (H

&quot; C^CI CN ! NH ~~ CS2CO3, DMF, 70 BC N 〇

~NH h

OH CH2CI2

NCO

Step A: Add (R)-l-cyclopropylethanol (〇·67 ml) to a suspension of 4-nonylphenyl isocyanate (0.84 g, 3.5 mmol) in CH2 ci2 (6 mL) , 6.9 millimoles). Next, the solution was directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-mothylphenyl)amine methyl acid 1-cyclopropyl-ethyl chloroform (5 g, 93%).

Step Β: (R)-l-cyclobutyl-6-hydroxy-1Η-吲哚 each carbonitrile (0.53 g, 2.5 mmol), triisopropyl acid (0·86 ml, 3.75 mmol) In a solution of THF (7.5 mL), LDA (L5M THF in hexanes, 3.. The mixture was stirred at -78 °C for 10 minutes and then at room temperature for 30 minutes, followed by the addition of (4-iodophenyl)-amine methyl acid 1-cyclopropylethyl ester (0.83 g, 2.5 mmol) With PdCl2 (dppf) (0.055 g, 0.075 mmol). The reaction mixture was cooled to -78.degree. C. and washed with EtOAc then EtOAc EtOAc (EtOAc) The cooling bath was removed and the mixture was stirred overnight, poured into ice water (1 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-Hydroxy-1H-indol-2-yl)-phenyl]-aminomethyl 1-cyclopropyl-ethyl ester as a solid (0.58 g, 56%). Step C · (R)-[4-(3-Cyano-1-cyclobutyl-6-carbyl-1H-Wbd-2-yl)-benzene 128244-3 -426- 200831489 base]- Aminomethyl 1-cyclopropyl-ethyl ester (〇·〇 83 g, 〇·2 mmol), Cs2C〇 (0.163 g, 0.5 mmol), 2-carbylpyrimidine (0.046 g, The mixture was stirred at 70 ° C for 2 hours at 0.4 mmol. After cooling to room temperature, the mixture was poured into water (15 ml), and the precipitate was collected by filtration, washed with water and purified on silica gel (CH2Cl2/Et〇Ac, 9 5 : 〇5) (R)-{4-[3-Cyanocyclobutyl-6-tetradecyloxy)-lH-indoleylphenyl}amine methyl 1-cyclopropyl-ethyl ester (0.073 g, 74%).

Shell Example 1CX · (R)-{4-[3-Cyano-1-cyclopropyl-6-(Bist-2-yloxy)_1 迅 丨 嗓 嗓-2-yl]-phenyl Aminomethyl acid μ-cyclopropyl ethyl ester (compound 221 is made [&gt;-νη2 K3PO4, Cul

Pd(OAc)2, Et3N, toluene/80°C

H〇(CH2)2〇H /-PrOH, 80 °C

CIC0CH2CI CH2CI2i KOH EOAc/ H20

1) DIBAL-H CH2CI2 〇QC~ room temperature

l 2) CSI DMF, 0°C CN LDA, -780Ο room temperature CN B(0iPr)3, THF; ^ r (χν N DMF, aqueous solution K2C03 (2M)· HO^ \ Pd(dppf) CI2, room temperature BBr3 , CH2CI2 ----)

-78 °C - 0 °C

a,

Cs2C03, DMF 70 °C

Step A ·· 3-iodophenylene ether (2·38 ml, 20·0 mmol), cyclopropylamine (2·10 ml, 30.0 mmol), Κ3ρ〇4 (8·48 g, a mixture of 40.0 mmol, CuI (0·19 g, 1 mmol), ethylene glycol (2.23 mL, 40.0 mmol) and isopropyl 128244-3 -427- 200831489 alcohol (20 mL) at 80 Stir at ° C overnight. The reaction mixture was concentrated and suspended in CH.sub.2Cl.sub.2 (1 mL) and water (100 mL). Next, the mixture was treated with a 28% aqueous ammonium hydroxide solution until the solid was dissolved. The organic layer was separated and dried over Na.sub.2SO.sub.2 and purified on silica gel (CH.sub.2.sub.2/hexane, 6:4) to provide the cyclopropyl hydroxy phenylamine as a colorless oil (1·52 g, 47%). . Step Β·A mixture of cyclopropyl(3-methoxyphenyl)amine (152 g, 9·3 mmol), hydrazine (1.57 g, dissolved in 8 ml) and EtOAc (15 ml) In the middle, chloroacetic chloride (U2 ml, 14.0 mmol) was added dropwise at 0 ° C and stirred vigorously. The mixture was stirred for a further 30 min, washed with water (3.times.350 mL), concentrated and purified on EtOAc (EtOAc (EtOAc) Phenyl) acetamidine, solid (18 g, 81 〇 / 〇). Step C: 2-Chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (L25 g, 5.2 mmol), Pd(OAc) 2 (0-06 g, 0.26) Millol), Et3N (0.79 g, 1.10 ml, 7.8 mmol), biphenyl-2-yl-di-tertiary-butyl-phosphane (0.155 g '0.52 house Moule) in toluene (6· The mixture in 〇 ml) was 8 〇. The underarm is mixed with the instrument. After cooling to room temperature, the mixture was purified on a celite gel to yield Ci2 / EtOAc '9·5 : 〇·5) to provide 1-cyclopropyl-6-methoxy-1,3-dihydroindole Butanone, a solid (0.89 g, 84%). Step D: In a solution of 1-cyclopropyl-6-methoxy-1,3-dihydrooxan-2-one (5.0 g, 24.6 mmol) in 〇^ 2 (25.0 mL) Add DIBAL-H (1.0 M in CH2C12, 33.3 mL, 33.3 mmol) under TC. Then, the mixture was stirred at room temperature for 4 hours and treated with HCl (1.0N). , washed with water, and purified on silica gel (CH^C! 2), provided with 啕哚 intermediate 128244-3 -428 - 200831489 'then, then dissolved in anhydrous DMF (4 〇〇 ml), and in 〇 Cool at a C. Treat the solution with chlorosulfonyl isocyanate (5 〇 9 g, 313 ml, 36 〇 mmol) and stir at 0 °C for 2 hours and pour ice water (300 ml) The precipitate was collected by filtration, washed with water, and purified on silica gel (hexane / EtOAc ' 9 : 1) to provide the propyl propyl methoxy hydrazide - carbonitrile as a solid. (3.60 g, 69%). Step Ε: 1_cyclopropyl-whenyloxy-1Η•吲哚_3-carbonitrile (3·6 g, 17 〇 mmol) at a^ClWO.O The solution in ML) was cooled to _78 ° C and used as BBr3 (21.27 g, 8.03 ml) After treatment at 84. 9 mmol, stir for Η), then warm to room temperature and stir for another 30 minutes. The reaction mixture was poured into ice water (150 mL), EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjjj Base-6.hydroxy-1H-indole-3-carbonitrile as a solid (3.02 g, 9%). Step F: 1-cyclopropyl hydroxy-1H-indole-3·carbonitrile (0.59 g, 3.0 mmol) with triisopropyl borate (1.03 mL, 4.5 mmol) in THF (15 mL In the solution, LDA (1.5 M mono THF in cyclohexane, 4_60 mL, 6.9 mmol) was added at -78 ° C and stirred. The mixture was stirred at -78 ° C for 10 minutes and at room temperature for 30 minutes, followed by the addition of (8) carbon phenyl)-amine mercapto acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6 mmol). pdCl2 (dppf) (0·11 g, 0·15 mmol). The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (1 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in EtOAc EtOAc (EtOAc) (EtOAc) 1-cyclopropyl-6-3⁄4yl-lH-W-indol-2-yl)-phenyl]-aminemethyl acid i-cyclopropyl-ethyl ester as a solid (1·16 g, 97%). Step G: (R)-[4-(3-Cyano-1-cyclopropyl-6-carbyl-lH-p?doxa-2-yl)-phenyl]-aminoindenic acid 1- Cyclopropyl-ethyl ester (0-060 g, 0.15 mmol), Cs2c〇3 (0.122 g, 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) The mixture was stirred at 70 ° C for 2 hours. After cooling to room temperature, the mixture was poured into water (15 ml), and the precipitate was collected by filtration, washed with water, and purified on silica gel (CH2Cl2 / EtOAc, 9.5: 0.5) to provide (8)-{4- [3-Cyano-1-cyclopropyl-6 dicene-2-yloxyindol-2-yl]-phenyl}amine methyl acid 1-cyclopropyl-ethyl ester as a solid (72 Mg, 1%). EXAMPLES ICY : 1-{4-[3-Cyano-p-butyl-6-(glycin-2-yloxybuxo-2-yl)-phenyl}-3-isopropyl Preparation of compound 2263)

Csi, ch2ci2&gt;o°c; 丨-

CN 1; /-PrOH, DIAD, PPh3&gt; CH2CI2i 0QC ~ room temperature 2) TFA, CH2CI2 0eC~ room temperature

LDA, -78UC~ room temperature 'B(〇iPr)3l THF; .6 DMF, aqueous solution K2C03 (2M), Pd(dppf)CI2, room temperature

-—►►

h

Cs2C〇3, DMF 70 °C Step A: In a solution of the third-butanol (10. 5 ml, 11 〇〇 mmol) in CH 2 Cl 2 (1 宅 升), in 〇. Add chlorinated chlorinated jaundice (9_55 ml, 110.0 mmol) under the armpit. The mixture was stirred for 5 minutes and added to 4_magnetic aniline 128244-3 -430 - 200831489 (21·9 g '100.0 mmol), Et3N (15 43 ml, 11 〇〇 millimolar) in CH2Cl2 (100 The mixture was stirred in a cold (〇 ° C) mixture in ML). The reaction mixture was stirred at 0 C for 30 minutes and at room temperature for 4.5 hours. The reaction mixture was concentrated, taken up in water (EtOAc) and stirred overnight. The precipitate was filtered, washed with water and dried in vacuo to give &lt;RTI ID=0.0&gt;&gt;&gt; Step B · Add DIAD (5.94 ml, 30.0 mmol) at 〇 ° C in a solution of PPh3 (7·32 g, 3〇·〇 mmol) in CH 2 Cl 2 (2 mL). Stir for 5 hours, then add to N-Boc-N,-4,-iodophenylsulfonamide (7·96 g, 20.0 mmol) and isopropanol (2·29) at 〇 °C ML, 3 〇〇mol) in a mixture of DCM (20 liters) while stirring. The resulting mixture was stirred at 0 C for 1 hour, then at room temperature for 4 hours and chromatographed (EtOAc, EtOAc). The obtained crude product was suspended in hexane, stirred for 2 minutes, filtered and washed with hexane and dried in air. Then, it was suspended in CH2C12 (40 ml), and treated with TFA (1 mL) for 4 hours at room temperature. The mixture was carefully neutralized with EtOAc (3 mL) (EtOAc/EtOAc) %). Step C: 1-cyclopropyl-6-carbyl-1H-Mb--3-carbonitrile (0.42 g, 2.0 mmol), triisopropyl succinate (0.80 mL, 3.5 mmol) In a solution of THF (6 ml), LDA (m. 5 Μ THF, 3.33 mL, 5.0 mmol) in cyclohexane was added and stirred. The mixture was stirred at _7 y for 1 Torr and at room temperature for 30 minutes, followed by the addition of N-isopropyl-N,-4,-iodophenyl sulphonyl urea (0.96 g '2_4 house Moule) and PdCl2 (dppf) (〇·〇7g, 0.1 millimeter 128244-3 -431- 200831489 ears). The reaction mixture was cooled at -78.degree. C. and washed with EtOAc then EtOAc (EtOAc) The cooling bath was removed and the mixture was stirred overnight, poured into ice water (1 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in EtOAc EtOAc (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Indole-2-yl)-phenyl]-3-isopropyl benzoic acid, solid (0.45 g, 74%). Step D: 1-[4-(3-Cyano-1-cyclobutyl-6-carbyl-1H-W)-2-yl)-phenyl]-3-isopropylsulfonium urea ( 〇·〇85g, 0.2mmol), Cs2C03 (0.163g, 0.5耄mol), 2-Chlorine bite (0.034g, 0.3mmol) in a mixture of DMF (2.0ml) at 70° Stir overnight at C. After cooling to room temperature, the mixture was poured into water (15 ml), and the precipitate was collected by filtration, washed with water and purified on silica gel (O^C^/EtOAc, 8.5: 1-5) {4-[3-Cyano-1-cyclobutyl-6-bumimid-2-yloxy)·ιη·吲嗓-2-yl]-phenyl-p- 3-isopropylsulfonamide 0.061 g, 61%). Example 1CZ: 1-cyclopropyl-2-(4-isopropylamino-phenyl) each (pyrimidinyloxy)-1Η-4bido-3-beet (preparation of compound 243)

CN

--——) CS2CO3, DMF, 90 °C

CN

LDA, -78qO room temperature B(〇iPr)3, THF; ------^ DMF, aqueous solution K2C03 (2M), Pd(dppf)CI2, room temperature ^

Να NH --

Cs2C03t DMF 70 °C 128244-3 -432- 200831489 Step A: 4-iodoaniline (4·38 g, 2〇〇 mmol), &amp;(7)&quot;Μ克50·0毛莫耳), 2 _ 峨 烧 烧 (3 〇 ml, 3 〇〇 millimoles) in a mixture of 丽 f (five) t liter), in a sealed tube, at 7 〇. Stir under the arm for 24 hours. The mixture was allowed to cool to room temperature and poured into water (2 liters). The organic layer was separated, washed with water and brine and purified eluting eluting eluting eluting Step Β: on 1-cyclopropyl·6_hydroxy]Η_吲哚! Benzonitrile (〇·59 g, 3 〇 mmol), triisopropyl borate (1.03 mL, 4·5 mmol) in THF (15 mL) / gluten, added at -78 C LDA (1 THF THF in cyclohexane, 4.60 mL, 6.9 mmol) was stirred. The mixture was taken at _78. Stir under the arm for 1 Torr and at room temperature for 30 minutes, then add 1-iodophenyl-ethylamine (U9 g, 3.6 mmol) and PdCl2 (dppf) (0.11) Gram, 0.15 耄 Mo Er). The reaction mixture was cooled to -78 ° C, washed with EtOAc and EtOAc (EtOAc) The cooling bath was removed and the mixture was stirred overnight, poured into ice water (1 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water and CH.sub.2Cl.sub.2, and dried in air to afford &lt;RTI ID=0.0&gt; (〇·85 g, 86%) Step C: (1·cyclopropyl each hydroxy_2_(4-isopropylamino-phenyl)-1Η-indole-3-indoleonitrile (0.099 g, A mixture of 0.3 mM, Cs2C 〇3 (0.244 g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70 ° C overnight. After cooling to room temperature, the mixture was poured into water (15 ml), and the precipitate was collected by filtration, washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) Base-2-(4-isopropylamino128244-3 •433 - 200831489-phenyl)-6-(pyrimidin-2-yloxy)-1Η-indole-3-carbonitrile as a solid (0104 g, 85%). Example IDA: [4-(3-Cyano-1-cyclobutyl-6-cyclopropylbuxo-2-yl)-phenyl]-amine methyl acid tert-butyl ester Preparation of (Compound 2513)

Step A: 6-Molyl-1-cyclobutyl-1H-H丨嗓-3-indenenitrile (1.38 g, 5.0 mmol) with triisopropyl borate (1.37 mL, 6.0 mmol) In a solution of THF (15.0 ml), LDA (1.5 M mono THF in hexanes, 3.. The mixture was taken at _78. (: stirring for 10 minutes and at room temperature for 30 minutes, followed by addition of (4-iodophenyl)-amine methyl acid to the third-butyl ester (1.75 g, 5 · 5 mmol) and PdCl 2 (dppf) (0.37 g, 〇.5 mmol). The reaction mixture was cooled to -78 ° C, washed with nitrogen and DMF (30 mL), and K2C03 aqueous solution (2·0 Μ, 7.5 ml, 15.0 mmol) The mixture was stirred at -78 ° C for 20 minutes, at rt overnight, and poured into ice water (200 mL). 9 · 1 to 8 ·· 2), obtain [4-(6-glycol-3_cyanosuccinyl-1H-indot-2-yl)-phenyl]-amine methyl acid -Butyl ester, solid (ι·23 g, 53%). 128244-3 -434- 200831489 Step B: [4-(6-Bromo-3-cyano-1-cyclobutyl-1H-indole) Indole-2-yl)-phenyl]-aminocarbamic acid tert-butyl ester (0.17 g, 0.4 mmol), cyclopropyldihydroxyborane (0.047 g, 0.55 mmol), ( Third·butyl)3Phbf4 (0.014 g, 〇·_ millimolar), KF (0.093 g, 1.6 min) and Pd2 (dba)3 -CHC13 (0·〇21 g, 0.02 m The mixture was stirred overnight at 6 ° C. The mixture was concentrated, dissolved in ch2ci2 and filtered over celite. The solid was washed with CH.sub.2Cl. Purification (CH2Cl2), providing [4-(3-cyano•1-cyclobutyl-6-cyclopropyl-1Η-indol-2-yl)-phenyl]-amine methyl acid -Butyl ester, as a solid (0.10 g, 59%). Example 1DB · {2-carbyl·4·[3-cyano-1-cyclobutyl-6-decamazin-2-yloxy) · 1Η-Indol-2-yl]-phenyl}-amino decyl isopropyl ester (Compound 2339):

Step A: 1-Lutylbutyl-6-pyridyl-3-carbonitrile (3.0 g, 14.1 mmol) with isopropyl borate (5 mL, 21.1 mmol) in anhydrous THF (40 mL LDA (16.2 ml, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) was added dropwise at 〇 °C. The mixture was stirred at 0 °C for 15 minutes, then at room temperature for 1 hour. After the reaction mixture was cooled to 0 ° C, a solution of 2-carbyl-4-phenyliodophenylamine (3.9 g, 15.5 mmol) in DMF (40 mL), followed by PdCl2 (dppf) (0.3 g) , 0.4 mM) with K2C03 128244-3 • 435 · 200831489 Aqueous solution (14 ml, 2.0 M). Allow the mixture to warm to room temperature and continue to stir the apparatus. The reaction was diluted with water' followed by extraction with ethyl acetate. The organic layer was dried, concentrated, and purified with chloroform to afford 2-(4-amino chlorophenyl)-1 - cyclobutyl-6-hydroxy-1H-indole carbonitrile (3·1 g, 64 %) is an off-white solid. Step Β: Dissolve 2_(4_amine chlorophenyl)+cyclobutyl-6-hydroxy-1Η4丨哚-3-carbonitrile (0.67 g, 2 mmol) prepared in the step ΖΑ. In DMF (7 ml) 'then added 2-chloro-continuous bite (0.34 g, 3 mmol) with cesium carbonate (1·3 g, 4 mmol). The mixture was warmed to 7 (TC) and stirred for EtOAc. EtOAc was filtered and evaporated. EtOAc EtOAc. Amino-based phenyl)-i-cyclobutyl-6-decamidyl 1-yloxy)_1H-indole-3·carbonitrile (〇·76 g, 91%) as a white solid. Step C: 2 in the CH2Cl2 (0.5 ml) and pyridine (〇·5 ml) (4-amino-3-chlorophenyl &gt; 1-cyclobutyl-6 hexamidine-2·yloxy) a solution of isopropyl chloroformate in toluene (1.0 Μ '0.8 ml), and the mixture was allowed to stand at room temperature. Stir overnight. The mixture was diluted with aqueous hydrazine (IN) and extracted with CH2Cl. The organic layer was washed with water and brine; strips, dried, concentrated, and purified on EtOAc (4% 〇 〇 EtOAc / hexane) to provide {2-chloro-4-[3-cyano- 1-cyclobutyl-6-(glycine-2-yloxy)_iH_W嗓-2-yl]-phenyl-b-aminomethyl isopropyl ester (〇·29 g, 93%) as a white solid . Example 2: Low Molecular Weight Compounds The screening chemical library using the cell-based HCV IRES monocistronic translation assay uses a single-shun based cell designed to closely mimic the native Hcv mRNA translation 128244-3-436-200831489 The anti-HCV IRES-regulated translation test is screened and then compounded based on the key points in the chemical library and screened. A DNA construct, designated pHCVIRESmono, was prepared in which the HCV IRES sequence (HCV 2b, nuclear aluminate 18-347) was inserted between the promoter and the firefly luciferase (Flue) reporter gene. A stably transfected HepG2 (hepatoblastoma) cell line (called HepGmono-4) or a Ηιώ7 cell line (called Huhmono 7) or a Hela-cell line (called Helamono), which is transferred via pHCV IRESmono DNA Infection is established by selecting resistance to hygromycin. Example 3: Determination of selectivity for HCV IRES-regulated translation using a cell-based end-dependent translation assay Since the use of translational assays to screen for HCV IRES inhibitors, the selected points can be specifically applied to HCV IRES - Drive translation, or general protein synthesis can be modulated in mammalian cells. Compounds that act on general translation will most likely be significantly toxic. In an effort to address this possibility, various cell-based end-dependent translational assays were established for further evaluation of all selected compounds. Plasmid DNA containing the vector sequence 5' to Flue 130 nucleotides was constructed. This construct is referred to herein as pLuc. A stable cell line was established in a terminal-dependent translation assay using 293T cells (human embryonic kidney cell line). HepGmono-4 and pLuc were treated with the compound for 20 hours, and the activity was measured by quantifying the Flue signal. A five-fold selectivity between HCV IRES and end-dependent translation is considered desirable. For example, using these cell-based end-dependent translational assays, compounds have been shown to exhibit IC5G values in end-dependent translational assays, 128244-3 -437 - 200831489 greater than at least in HCV IRES translation assays. 5 times. Figure 1 shows an example of a hit that is selective against HCV IRES_regulated translation, better than end-dependent pLuc translation. Importantly, the compounds had the same level of activity in the HCV IRES monocistronic 293T cell line as in HepGmono-4 (data not shown). Therefore, the selectivity of compounds between HepGmono-4 (HepG 2) and end-dependent translation (293T) is unlikely to be due to the different cell types used. Furthermore, Western blotting is used to selectively inhibit HCV IRES-driven translation. HepGm__4 and the two cells of the team were treated with the compound as described above, and after treatment with the test compound for 20 hours, the cells were collected and dissolved in valeric acid buffer containing 5% 5% SDS. The protein was separated on 1·SDS-PAGE and transferred to a nitrocellulose membrane and blotted with antibodies against Fluc (RDI) and Oncogene. For example, some of the compounds of the invention are tested in this manner and, as expected, will serve as an endpoint in the assay, while selectively inhibiting the HCVIRES-driven translation of the compound, indicating that the luciferase reporter protein content is It was comparable in HepGm〇n〇_4 cells and was relatively inactive against a chest blotting (data not shown). Importantly, these compounds do not inhibit the performance of endogenous dysfunction. Their translation is end-dependent in both cell lines. - To the ground, the compound that does not show selectivity in the translation test inhibits protein accumulation in both Peng: end-dependent translational detection (data not shown HCvZr, general egg-translation inhibitors Both HCV secret drive and end (4) protein production were inhibited (data not shown in 128244-3 -438 - 200831489). Therefore, Western blotting results confirmed that the compounds of the present invention selectively inhibited HCV IRES-driven translation. The test conditions for such cell lines are optimized, and the effect of mRNA content on compound activity is controlled by quantification of Flue mRNA content by RT real-time PCR. For example, some of the compounds of the invention are tested in this manner, And in the Flue mRNA content, no significant difference was found between the HepGmono-4 or Helamono cells or Huhmono cells and the end-dependent translational cell lines used (data not shown). Example 4: Translation using the media IRES medium Detection of selectivity for HCV IRES-driven translation Many human mRNAs have been shown to lurk IRES elements (18, 19, 39, 44, 45, 91, 126, 130). Although HCV IRES The primary and secondary structural lines differ from the cellular IRES, but an important test for selectivity is to determine whether the selected compound is active against the cellular IRES. VEGF IRES has poor initial activity in in vitro assays but in cells Substantial activity is exhibited in a translational assay based on (45). For example, some of the compounds of the invention are tested and all compounds with good selectivity for end-dependent translation are at least 5 for VEGF IRES compared to HCV IRES. Higher IC5 devaluation (data not shown). These data indicate that the selected compound has selectivity against viral IRES. In addition to having a different structure, VEGF IRES also has different interactions with non-regular cell translation factors. These differences may help us to confirm the selectivity of HCV IRES inhibitors. Example 5 · The assessment of cytotoxicity on cell proliferation is a burden on any drug discovery effort 128244-3 -439- 200831489 The problem is. Therefore, the 'cell proliferation/cytotoxicity test is used to rule out the effects that affect the growth of mammalian cells. What is the compound? The effect of the sister-in-law on the cell proliferation is measured in the human cell line 293 T盥Hnh7 phase π, “—/, nun/ (human hepatoblastoma cell line). The cells were grown in Dulbecco's denatured Eagle medium supplemented with 0% fetal bovine serum, l-branamide, penicillin and streptomycin. The cells in the log phase were treated with the test compound for three days, of which 25〇 - is for

The highest concentration of the compound to be tested used. The effect of compounds on cell proliferation was assessed using the CellTiter 96 Single Aqueous Cell Proliferation Assay (p_ega, Madison, WI). Compounds having at least a 5-fold higher CQ 0 value relative to the π 〇 value in HepGm 〇 n 〇 4 are considered to have sufficient window between activity and cytotoxicity and are therefore selected for further evaluation. For example, some of the compounds of the invention were tested in this manner, and it is important that all compounds with good selectivity for end-dependent translation also exhibit a greater than 5-fold ratio of CC5 〇 to IC5 〇 values. Example 6: Evaluating the efficacy of compounds in the HCV replication system The lack of reliable and easy access to cell culture and small animal models to allow HCV replication has limited the development of novel resistance. Automated replication of the subgenomic HCV system, known as HCV replicon, has been described and is widely used to assess the efficacy of anti-HCV inhibitors (8, 9, 46, 70, 103, 104). Interferon (IFN) alpha and HCV protease and inhibitors of polymerase have been reported to be active in the HCV replication system (8, 17, 32, you, still, 117). HCV replicon lines including bicistronic and monocistronic systems are available and can be used to test HCV inhibitors. In the bicistronic replicon, HCv IRES directs the expression of a selectable marker (Neo and/or Fluc reporter), while 128244-3 -440-200831489 EMCV IRES is a mediator of non-structural protein . In the monocistronic replicon, HCV IRES is a direct vector viral protein synthesis. The HCV IRES inhibitor is in the bicistronic replicon and is analyzed by quantising the Flue reporter message. The cell line containing the replicon is cultured for 2 or 3 days with the compound of the present invention. Interferon (IFN)a was used as a positive control group. For example, the compounds of the present invention were tested in this manner, and experiments have shown that compounds that selectively inhibit the translation of the mediators of HCV IRES inhibit Flue expression in bicistronic replicons. In the table below (Table 1), * = replicon or HCV-PV IC5G> 2 //M ** = replicon or HCV-PV IC50 between Ο·5 /zM and 2 //Μ*** = Replicon or HCV-PV IC5G &lt;0. 5 //Μ The copy of the ic5 value is measured by the firefly luciferase message. The HCV-PV IC5 enthalpy was measured by a decrease in viral RNA. Table 1 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50/zM 2-day Replicon IC50/zM 3-day Wnmr data 866 143-145 382. 5 氺氺 867 198-200 448. 26 氺氺 868 188-190 446. 23 氺氺氺 869 869 205-206 354. 3 氺氺 870 328. 28 871 158-161 402. 24 氺 872 176-179 416. 28 氺 873 183-187 414. 27 * 874 182-186 448. 26 氺氺 875 136-140 368. 15 氺氺 128244-3 -441 - 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC50 β Μ 2-day Replicon IC50 β Μ 3-day ^NMR data 876 382. 18 氺氺 877 396. 19 氺* 878 396. 19 氺氺 879 400. 14 氺氺 880 310. 26 氺氺 881 194-195 438. 2 氺氺氺 882 882 181-183 452. 3 氺氺氺 883 198-200 450. 2 氺氺氺 884 884 195-196 452. 3 氺氺氺 885 885 148-150 466. 3 氺氺* 886 173-175 404. 2 氺氺 887 181-183 418. 2 氺氺 888 187-189 436. 3 氺氺 889 160-162 432. 2 氺氺 890 158-160 450. 3 ** 891 144-146 452. 3 氺氺 892 225-226 417. 2 氺氺 893 191-193 431. 3 氺氺 894 180-182 445. 3 氺氺 895 225-226. 7 348. 4 氺氺 ^ NMR (DMSO-d65 300 ΜΗζ), δ 10. 17(s,1H), 7. 73 (d, J=7. 2Hz, 2H), 7. 48-7. 43 (m, 3H), 7. 17 (s, 1H), 6. 61 (d, J=7. 5Hz, 1H), 4. 13-4. 05 (m, 4H), 2. 03 (s, 3H), 1. 31 (t5 J=6. 6Hz, 3H), 1. 12 (t, J = 7. 5Hz, 3H)· 896 245. 9-247 362. 1 eucalyptus ^NMR (DMSO-d65 300MHz), δ 10. 13 (s, 1H), 7. 77 (d5 J=8. 7Hz, 2H), 7. 51-7. 45 (m, 3H), 7. 20 (s, 1H), 6. 88 (dd, J=6. 9Hz and 2. 1Hz, 1H), 4. 16-4. 05 (m, 4H), 2. 34 (q, J=7. 5Hz, 2H), 1. 33 (t, J=6. 9Hz, 3H), 1. 19-1. 04 (m, 6H).  128244-3 -442- 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon ic5〇//m 2-day Replicon ic50&quot;m 3-day iHNMR data 897 254. 4-256. 3 374. 1 氺氺 1H NMR (DMSO-d6? 300MHz), δ 10. 45 (s, 1H), 7. 78 (d, J=8. 7Hz, 2Η), 7. 51-7. 45 (m, 3H), 7. 20 (d, J=1. 8Hz 1H), 6. 88 (dd5 J=6. 6Hz and 2. 1Hz, 1H), 4. 16-4. 05 (m, 4H), 1. 81-1. 75 (m, 1H), 1. 34 (t, J=6. 9Hz, 3H), U4 (t, J two 6. 9Hz, 3H), 0. 81-0. 79 (m, 4H).   898 &gt; 300 °C decomposition 374. 5 氺氺 ^NMR (DMSO-d6? 300MHz), δ 10. 09 (s, 1H), 7. 80 (d, J=8. 7Hz, 2H), 7. 62- 7. 45 (m, 3H), 7. 20 (d, J=1. 5Hz, lH), 6. 88 (dd, J=8. 7Hz and 2. 4Hz, 1H), 4. 18-4. 05 (m, 4H), 2. 62- 2. 56 (m, 1H), 1. 33 (t, J=6. 9Hz, 3H), 1. 19-1. 04 (m, 9H).   899 246. 8-249. 7 386. 5 氺氺 lU NMR (DMSO-d6? 300MHz), δ 9. 99 (s, 1H), 7. 80 (d, J=8. 4Hz, 2H), 7. 51-7. 45 (m, 3H), 7. 20(s, lH), 6. 89 (dd, J=8. 7Hz and 2. 4Hz, 1H), 4. 16-4. 05 (m, 4H), 2. 25-2. 02 (m, 4H), 2. 01-1. 86 (m, 1H), 1. 84-1. 76 (m, 1H), 1. 34 (t, J=6. 9Hz, 3H), 1. 17(t, J=7. 8Hz, 3H).   900 185. 7 422. 4 氺氺 ^NMR (DMSO-d6? 300MHz), δ 10. 44 (s, 1H), 7. 79 (d, J=8. 7Hz, 2H), 7. 52-7. 48 (m, 3H), 7. 32-7. 19 (m, 6H), 6. 88 (dd, J=8. 7Hz and 2·1Ηζ, 1H), 4. 16-4. 05 (m, 4H), 3. 66 (s, 2H), 1. 35 (t5 J=7. 2Hz, 3H), 1. 14 (t? J=7. 2Hz? 3H).  128244-3 -443 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC5〇//M 2-day Replicon IC50 β Μ 3-day ^NMR data 901 160. 4 436. 5 氺氺 1H NMR (DMSO-d6, 300MHz), δ 10. 18 (s,lH), 7. 76 (d, J=8. 7Hz, 2Η), 7. 52-7. 45 (m5 3H)? 7. 26-7. 13 (m, 6H), 6. 89 (dd, J=8. 7Hz and 1. 8Hz, 1H), 4. 16-4. 05 (m, 4H), 2. 92 (t, J=2. 7Hz? 2H)? 2. 68-2. 62 (m? 2H), 1. 33 (t, J=6. 9Hz, 3H), 1. 14 (t? J=6. 9Hz, 3H).   902 233-235 436. 1 氺氺 903 230-232 450. 2 904 193-195 464. 1 氺氺 905 171-173 468. 2 氺氺氺 906 246-247 480. 1 ** 907 224-225 410. 17 氺氺 ^NMR (300 MHz? CDC13): δ 7. 63 (1H? d? J = 8. 8 Hz), 7. 53 (lH,td,J = 7. 7? 1. 1 Hz)? 7. 41-7. 32 (2H? m)5 6. 96 (1H, dd, J = 8. 5, 2. 0 Hz), 6. 89 (lH,d,J = 2. 0 Hz), 4. 16(2H,q,J = 7. 0 Hz), 4. 12 (2H,q,J = 7. 0 Hz), 3. 86 (2H,t,J = 6. 6 Hz), 3. 42 (2H,t,J = 7. 4 Hz), 2. 58 (2H,p,J = 7. 0 Hz), 1. 48 (3H,t,J = 7. 0 Hz), 1. 38 (3H,t,J = 7. 0 Hz).   908 186-189 476. 2 氺氺 909 180-182 381. 24 氺氺 910 195-198 409. 26 氺* 911 228-230 395. 24 ** 912 217-221 428. 2 [MH]' 氺氺 913 200-202 388. 2 914 212-214 402. 2 氺氺 915 200-202 430. 2 氺氺 916 183-185 478. 2 氺氺 128244-3 -444 - 200831489 Compound No. Melting point (C) Mass Spectrum [M+H] Replicon IC5〇 β Μ 2-day Replicon ic50&quot;m 3-day ^NMR data 917 207-209 266. 2 ** 918 219-221 277. 4 氺氺 919 181-183 474. 2 氺氺 920 182-183 453. 3 921 921 237-238 460. 2 氺氺 922 246-248 474. 2 923 923 225-229 488. 2 氺氺 924 221-223 486. 2 925 925 190-192 440. 2 氺氺 926 195-196 454. 3 927 927 204-206 306. 25 氺氺 928 206-208 432. 14 (M-H+) 氺氺氺 氺氺氺 929 177-178 432. 09 氺氺氺 氺氺* 930 183-184 468. 02 氺氺氺 931 931 196-197 432. 15 (M-H+) **氺 氺氺氺 932 184-185 438. 22 氺氺氺 933 933 156-157 438. 21 氺氺 934 192-193 436. 15 氺氺氺 935 935 152-153 472. 14 氺氺氺 ** 936 191-192 468. 23 氺氺氺 氺氺氺 ^NMR (300 MHz, CDCI3): δ 7. 62 (1Η, d? J = 9. 1 Hz), 7. 38 (2H,d,J = 8. 3 Hz)? 7. 23 (1H? d? J = 2. 3 Hz), 7. 12 (2H,d,J = 8. 3 Hz), 6. 95 (lH, dd, J = 8. 8, J = 2. 2 Hz), 6. 12 (lH,d,J = 9. 0 Hz), 4. 93 (1H, m), 4. 20 (6H, m), 2. 85 (2H, m), 2. 35 (2H, m), 1. 96 (2H, m), 1. 48 (3H,t,J = 6. 9 Hz ), 1. 37(6 H,t,J = 6. 3 Hz) 937 204-205 440. 17 氺氺* 938 147-148 372. 21 氺氺 939 253-255 332. 29 氺氺 128244-3 -445 - 200831489 Compound No. Melting point (°c) Mass spectrometry [M+H] Replicon IC50/zM 2-day Replicon IC50 β Μ 3-day iHNMR data 940 58-59 263. 20 氺氺 941 460. 19 氺氺氺 942 209-210 412. 18 (M-H+) 氺氺 lH NMR (300 MHz, DMSO-d6): δ 8. 48 (1H,d,J =9. 0 Hz), 7. 48 (1H,d,J = 8. 8 Hz), 7. 46 (2H,d,J = 8. 5 Hz), 7. 21 (1H, shaded), 7. 20 (2H? d? J = 8. 5 Hz), 6. 90 (lH, dd, J = 8. 8, 2. 2 Hz), 4. 16 (2H,q,J = 7. 3 Hz), 4. 10 (2H, q, J = 7. 0 Hz), 3. 69 (6H,d,J= 11. 4 Hz), 1. 36(3H,t,J = 7. 0 Hz), 1. 18 (3H,t,J = 7. 0 Hz).   943 219-220 428. 25 NMR (300 MHz, DMSO-d6): δ 8. 40 (1H,d,J =9. 0 Hz), 7. 49 (lH,d,J = 8. 8 Hz), 7. 45 (2H,d,J = 8. 5 Hz), 7. 23 (1H, shaded), 7. 21 (2H,d,J = 8. 5 Hz), 6. 91 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 17(2H,q,J = 7. 0 Hz), 4. 13-3. 97 (4H, m), 3. 84 (3H, s), 1. 24(6H,td,J=7. 0, 0. 6 Hz), 1. 15 (3H,t,J =7. 0 Hz).   944 223-224 400. 20 氺 4 NMR (300 MHz, DMSO-d6): δ 8. 48 (1H? d5 J = 9. 0 Hz), 7. 49 (1H5 d? J = 8. 8 Hz), 7. 46 (2H,d,J = 8. 5 Hz), 7. 22 (lH,d,J = 2. 0 Hz)? 7. 20 (2H, d? J = 8. 5 Hz), 6. 91 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 17 (2H, q, J = 7_0 Hz), 3. 84 (3H, s), 3. 68 (6H, d, J= 11. 1 Hz), 1. 19 (3H,t, J = 7. 0 Hz).   945 190-193 414. 2 氺氺 946 163-172 410. 2 氺氺本 氺氺氺 947 146-148 424. 3 氺氺氺 948 948 166-167 458. 2 氺氺氺氺氺氺128244-3 -446 - 200831489 Compound number melting point CC) Mass spectrum [M+H] Replicon IC5〇//M 2-day replicon IC50 β Μ 3-day iHNMR data 949 Decomposition &gt;300 392. 2 氺氺 lH NMR (DMSO-d65 300MHz), δ 9. 94 (s, 1H), 7. 66 (d, J=8. 7Hz, 2H), 7. 51-7. 45 (m, 3H), 7. 20 (s, lH), 6. 88 (d, J = 8. 7Hz, 1H), 4. 16-4. 02 (m, 6H), 1. 64-1. 61 (m, 2H), 1. 34 (t, J=6. 9Hz, 3H), 1. 15 (t5 J=6. 9Hz, 3H), 0. 92 (t, J=7. 5Hz? 3H).   950 decomposition &gt; 300 396. 3 氺氺 lH NMR (DMSO-d6? 300MHz), δ 10. 13 (s51H), 7. 67 (d, J=8. 4Hz, 2H), 7. 52-7. 46 (m, 3H), 7. 20 (s, lH), 6. 89 (d, J = 8. 7Hz, 1H), 4. 73 (br, 1H), 4. 57 (br, 1H), 4. 40 (br, 1H), 4. 30 (br, 1H), 4. 16-4. 05 (m, 4H), 1. 33 (t, J=7. 2Hz, 3H), 1. 15 (t, J=7. 2Hz, 3H).   951 decomposition &gt; 300 405. 1 氺氺 ^NMR (CD3C1, 300MHz), δ 7. 62 (d, J=8. 4Hz, 1H), 7. 52-7. 42 (m, 4H), 6. 96 (dd, J=1. 8Hz and 8·4Ηζ, 1H), 6. 88 (d, J=1. 8Hz, 1H), 6. 71 (s, 1H), 4. 86-4. 82 (m, 1H) 9 4. 12(q? J=6. 9Hz, 4H), 3. 29 (q5 J=6. 3Hz, 2H), 1. 52-1. 31 (m, 10H), 0. 95 (t? J=7. 5Hz? 3H).   952 not measured 472. 3 ^ NMR (CD3CN, 300MHz) 5 δ 9. 01 (s, 1H), 7. 79 (d, J=8. 7Hz, 2H), 7. 58-7. 49 (m, 3H), 7. 11 (d, J=1. 5Hz, lH), 6. 96(d, J=8. 4Hz, 1H), 4. 31 (t, J=4. 2Hz, 2H), 4. 16 (q, J=6. 9Hz, 2H), 3. 34-3. 19 (m, 10H), 2. 77(s,3H), 2. 35-2. 30 (m5 1H), 1. 25 (t, J=6. 9Hz? 3H)? 0. 92-0. 82 (m? 4H).    184-186 442. 2 [ΜΗ]- 氺氺 954 232-234 395. 2 氺氺 128244-3 -447 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50 // Μ 2·day Replicon IC50 &quot; Μ 3-day ^NMR data 955 203-206 409. 2 氺氺 956 956 217-220 409. 2 氺氺* 氺氺氺 957 192-195 423. 3 氺氺氺 958 958 210-212 407. 2 氺氺 氺氺氺 959 169-171 384. 19 氺氺 960 178-180 398. 25 氺氺 961 174-177 412. 24 氺氺 962 172-174 410. 24 963 203-206 364. 24 氺* 964 153-155 378. 28 氺氺 965 156-157 392. 27 氺氺 966 212-215 377. 25 967 967 218-221 391. 27 氺氺 968 241-244 412. 18 氺氺氺 969 969 264-266 434. 15 氺氺氺 970 970 206-208 390. 22 氺氺氺 971 213-215 404. 27 氺氺氺 972 972 195-196 418. 27 氺氺氺 *氺* 973 190-192 418. 27 氺氺氺 *氺* !HNMR (300 MHz, CDC13): δ 7. 63 (1H? d?J = 8. 5 Hz), 7. 54 (2H,d,J = 8. 5 Hz), 7. 43 (2H,d,J = 8. 5 Hz), 7. 21 (lH,d,J = 2. 2 Hz), 6. 95 (lH, dd, J = 8. 8, J = 2. 2 Hz)? 6. 70 (1H? s)? 5. 05 (1H, m), 4. 94 (lH,m), 4. 14 (2H, q, 6·9 Hz), 2·82 (2H, m), 2. 33 (2H, m), 1. 87 (2H, m)5 1. 51 (3H,t,J = 4. 6Hz), 1. 33 (6H? d? J = 6. 1Hz).   974 215-217 422. 22 氺氺氺 氺氺氺 975 140-141 434. 27 氺氺 976 158-159 428. 25 氺氺 977 181-182 452. 22 978 978 185-186 482. 28 氺氺 979 179-180 432. 26 氺氺氺*** 128244-3 -448 - 200831489 Compound number melting point CC) Mass spectrum [M+H] Replicon IC5〇//M 2-day replicon IC50 β Μ 3·day iHNMR data 980 236-238 436 . 24 * 981 201-203 416. 26 氺氺氺 982 982 169-171 422. 22 氺 lHNMR (300 MHz, DMSO-d6): 5 10. 16 (1H? br), 7. 57 (2H,d,J = 8. 5 Hz), 7. 52 (1H,d,J = 8. 5 Hz), 7. 42 (2H,d,J = 8. 5 Hz), 7·33 (1H, d, J = 2. 0 Hz), 6. 93 (lH, dd, J = 8. 5, 2. 0 Hz), 4. 13 (2H,d,J = 7. 0 Hz), 3·85 (3H, s), 2·77 (1H, p, J = 6. 3 Hz), 0. 98 (6H, d5 J = 6. 3 Hz), 0. 96-0. 88 (1H, m), 0. 34-0. 27 (2H,m), 0. 05-0. 00 (2H, m).   983 217-219 386. 22 氺氺 4 NMR (300 MHz, DMSO-d6): δ 10. 48 (1H? s)? 7. 80 (2H,d,J = 8. 8 Hz), 7. 53 (2H,d,J = 8. 8 Hz), 7. 52 (1H,d,J = 8. 6 Hz), 7. 32 (lH,d,J = 2. 0 Hz), 6. 92 (lH, dd, J = 8. 6, 2. 0 Hz), 4. 13 (2H,d,J = 6. 8 Hz), 3. 84 (3H, s), 1. 82 (1H, p, J = 6. 0 Hz), 0. 99-0. 90 (1H, m), 0. 89-0. 75 (4H, m), 0. 33-0. 27 (2H,m), 0. 05-0. 00 (2H? m).   984 179-180 390. 25 氺氺 ^ NMR (300 MHz? DMSO-d6): δ 9·95 (1H, s), 7. 67 (2H, d, J = 8. 4 Hz), 7. 52 (2H,d,J = 8. 4 Hz), 7. 51 (lH,d,J = 8. 8 Hz), 7. 32 (1H,d,J = 2. 3 Hz), 6. 91 (lH, dd, J = 8. 8, 2. 3 Hz), 4. 15(2H,q,J = 7. 0 Hz), 4. 12 (2H,d,J = 7. 0 Hz), 3·84 (3H, s), 1. 26 (3H5 t, J = 7. 0 Hz), 1. 00-0. 90 (1H, m), 0. 33-0. 25 (2H,m), 0. 05-0. 00 (2H? m).  128244-3 -449- 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC501± Μ 2-day Replicon IC5〇//M 3-day ^NMR data 985 124-125 404. 21 ** lU NMR (300 MHz, DMSO-d6): δ 9. 96 (1Η? s)? 7. 67 (2Η,d,J = 8·5 Hz), 7. 52 (2Η? d? J = 8. 5 Hz)? 7. 50 (lH,d,J = 8. 8 Hz), 7. 32(lH,d,J = 2. 0Hz) 5 6. 92 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 12 (2H,d,J = 6. 7 Hz), 4. 07 (2H,t,J = 6. 8 Hz), 3. 84 (3H, s), 1. 65 (2H, hx, J = 7. 3 Hz), 0. 94 (3H,t, J = 7. 3 Hz), 0. 93-0. 89 (1H, m), 0. 33-0. 26 (2H,m)5 0. 05-0. 00 (2H? m).   986 157-158 404. 21 氺氺 lU NMR (300 MHz? DMSO-d6): δ 9. 90 (1H? s)? 7. 67 (2H,d,J = 8. 5 Hz), 7. 53-7. 49 (3H, m)? 7. 32 (lH,d,J = 2. 0 Hz), 6. 92 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 92 (lH, hp, J = 6. 3Hz), 4. 12 (2H? d? J = 6. 7 Hz), 3·84 (3H, s), 1. 27 (6H,d,J =6. 3 Hz), 1. 00-0. 90 (1H, m), 0. 33-0. 26 (2H? m)? 0. 07-0. 01 (2H, m).   987 183-184 403. 26 4 NMR (300 MHz, DMSO-d6): δ 8. 59 (1H, s), 7. 56 (2H,d,J = 8. 5 Hz), 7. 47(lH,d,J = 8. 8Hz), 7. 42 (2H,d,J = 8. 5 Hz), 7. 29 (lH,d,J = 2. 0 Hz), 6·89 (1H, dd, J = 8. 8, 2·0 Hz), 6. 11 (lH,d,J = 7. 6 Hz), 4. 10 (2H,d,J = 7. 0 Hz), 3. 82 (3H, s), 3. 75 (1H, m, J = 7. 0 Hz), 1. 08 (6H,d, J = 6. 5 Hz), 0. 97-0. 88 (1H, m)5 0. 31-0. 25 (2H,m), 0. 04-0. 02 (2H? m).  128244-3 450 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50//M 2-day Replicon IC50 β Μ 3-day ^NMR data 988 168-169 398. 25 (M-H+) 氺氺 ^NMR (300 MHz, DMSO-d6): 5 10. 22(1H? s)5 7. 63 (2H,d,J = 8. 8 Hz), 7. 54 (1H,d,J = 8. 5 Hz), 7. 39 (2H,d,J = 8. 8 Hz), 7. 35 (1H,d,J = 2. 0 Hz), 6. 96 (lH, dd, J = 8. 8, 2. 0 Hz), 5·46 (2H, s), 3. 84 (3H, s), 3. 22(2H,q5 J = 7. 3Hz), 3. 17(3H,s), 1. 23(3H,t,J = 7. 3 Hz).   989 195-196 380. 18 (M-CH30') 氺氺 ^NMR (300 MHz, DMSO-d6): δ 7. 68 (2H,d,J =8. 8 Hz), 7. 54 (lH,d,J = 8. 5 Hz), 7. 38 (2H,d,J = 8. 8 Hz), 7. 36 (lH,d,J = 2. 2 Hz), 6. 97 (lH, dd, J = 8. 5, 2. 2 Hz), 5. 47 (2H, s), 3. 86-3. 81 (2H, m), 3. 84 (3H, s), 3. 58 (2H, t, J = 7. 3 Hz), 3. 17(33⁄4 s)? 2. 47-2. 41 (2H, m).   990 179-180 412. 27 (M-H+) 氺氺 ^NMR (300 MHz, DMSO-d6): 5 10. 22(1H, s)? 7. 63 (2H? d5 J = 8. 8 Hz)? 7. 54 (1H,d,J = 8. 5 Hz), 7. 38 (2H,d,J = 8. 8 Hz), 7. 34 (1H,d,J = 2. 0 Hz), 6. 96 (lH, dd, J = 8. 5, 2. 0 Hz), 5·46 (2H, s), 3.84 (3H, s), 3. 20 (2H,t,J = 7. 6 Hz), 3. 16 (3H, s), 1. 72(2H, hx, J = 7. 6 Hz)? 0. 96 (3H? t? J = 7. 5 Hz).   991 179-180 348. 17 (M_CH30') 氺氺 ^NMR (300 MHz, DMSO-d6): δ 9. 97 (1H, s), 7. 67 (2H, d5 J = 8. 8 Hz), 7. 58 (2H,d,J = 8. 8 Hz), 7. 53(lH,d,J = 8. 8Hz), 7. 33 (lH,d,J = 2. 0 Hz), 6. 96 (lH, dd, J = 8. 8, 2. 0 Hz), 5. 45 (2H5 s)? 4. 15(2H? q, J = 7. 0 Hz), 3. 83 (3H, s), 3. 16 (3H, s), 1. 26 (3H,t,J = 7. 0 Hz).  128244-3 -451 - 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50/zM 2-day Replicon IC50/zM 3-day^NMR data 992 155-157 362. 23 (M-CH30') 氺氺 ^NMR (300MHz? DMSO-d6): δ 9. 67 (1H, s), 7. 68 (2H,d,J = 8. 8 Hz), 7. 58 (2H,d,J = 8. 8 Hz), 7. 53 (lH,d,J = 8. 5 Hz), 7. 34 (1H,d,J =2. 0 Hz), 6. 96 (lH, dd, J = 8. 5, 2. 0 Hz), 5·45 (2H, s), 4. 07 (2H, t, J = 6. 7 Hz), 3. 84 (3H, s), 3. 31 (3H, s), 1. 65 (2H, hx, J = 7. 0 Hz)? 0. 94 (3H, t? J = 7. 3 Hz).   993 146-148 392. 29 (M-H+) 氺氺 ^NMR (300 MHz? DMSO-d6): δ 9. 90 (1H9 s)? 7. 67 (2H,d,J = 8. 6 Hz), 7. 57 (2H,d,J = 8. 6 Hz), 7. 53 (1H,d,J = 8. 8 Hz), 7·33 (lH,d,J = 2. 0 Hz), 6. 96 (lH, dd, J = 8. 8, 2. 0 Hz), 5. 45 (2H, s), 4. 92 (1H, hp, J = 6·3 Hz), 3·83 (3H, s), 3. 15 (3H, s), 1. 26 (6H,d, J = 6. 3 Hz).   994 266-267 375. 22 氺* lU NMR (300 MHz, DMSO-d6): 5 11. 32(lH? s)? 7. 83 (2H,d,J = 8. 8 Hz), 7. 62 (2H? d? J = 8. 8 Hz), 7·52 (1H,d,J = 8. 5 Hz), 7. 25 (lH,d,J = 2. 0 Hz), 6. 93 (lH, dd, J = 8. 5, 2. 0 Hz), 4·52 (2H, s), 4. 20 (2H, q, J = 7. 0 Hz), 3. 85 (3H, s), 1. 18 (3H? t? J = 7. 0Hz).   995 179-181 384. 2 氺氺 996 996 200-201 398. 2 氺本氺 ** 997 169-171 412. 2 氺氺 998 166-167 410. 2 氺氺 999 172-174 377. 3 氺氺 1000 156-158 391. 3 氺氺 1001 120-124 389. 3 氺氺 氺氺 1002 166-158 422. 15 氺氺 1003 189-191 436. 15 氺氺 128244-3 -452 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3·day ^NMR data 1004 191-193 450. 15 氺氺 1005 169-171 436. 15 氺氺 1006 187-188 450. 15 氺氺氺 氺氺 1007 179-180 464. 20 氺氺氺 1008 114-115 405. 3 氺氺 1009 202-203 363. 3 氺氺 1010 196-197 377. 3 氺氺 1011 205-206 377. 3 氺氺 1012 165-166 391. 3 氺氺 1013 192-193 375. 3 氺氺 1014 178. 1-183. 5 453. 1 氺氺氺 ^ NMR (DMSO-d6, 300MHz), δ 8. 80 (s, 1H), 7. 58 (d, J=6. 3Hz, 2H), 7. 48-7. 42 (m? 3H)? 7. 29 (t? J=5. 1Hz, 2H), 7. 24-7-19 (m, 4H), 6. 89 (d, J=6. 6Hz, 1H), 6. 22 (br,1H), 4. 16-4. 08 (m, 4H)? 3. 35-3. 33 (m? 2H)? 2. 75(t, J=5. 1Hz, 2H), 1. 34 (t? J=5. 1Hz? 3H)? 1. 16 (t? J=5. 7Hz, 3H).   1015 150. 1-155. 6 424. 0 氺氺 lU NMR (CD3CN? 300Hz)? δ 8. 06 (s, 1H), 7. 66 (d, J=8. 7Hz, 2H), 7. 55-7. 50 (m, 3H), 7. 04 (d, J=1. 8Hz, 1H), 6. 91 (dd, J=6. 6Hz and 2·1Ηζ, lH), 4. 73(t, J=3. 9 Hz, 1H), 4. 57 (t, J=3. 9Hz, 1H), 4·43 (t, J=3. 9Hz, 1H), 4. 34 (t, J=3. 9Hz, 1H), 4. 16-4. 09 (m, 4H), 1. 65-1. 61 (m, 2H), 1. 40 (t, J=7. 2Hz, 3H), 1. 18-1. 06 (m, 2H), 0. 74 (U=7. 2Hz, 3H).  128244-3 453 - 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50//M 2-day Replicon IC50//M 3-day^NMR data 1016 204. 2-209. 7 405. 2 氺氺 ^ NMR (DMSO-d6? 300Ηζ), δ 8. 74 (s, 1H), 7·59 (d, J=8. 4Hz, 2H), 7. 49-7. 42 (m, 3H), 7. 20 (s, 1H), 6. 90 (dd, J=8. 4Hz and 2. 4Hz, 1H), 6. 22 (t, J=5. 7Hz, 1H), 4. 17-4. 09 (m, 4H), 3. 14-3. 10 (m5 2H), 1. 52-1. 50 (m, 2H), 1. 32 (t, J=7. 2Hz, 3H), 1. 13-1. 03 (m, 5H), 0. 68 (t? J=6. 9Hz? 3H).   1017 181. 3-187. 8 419. 2 氺*氺 氺氺氺 ^NMR (DMSO-d6? 300Hz), δ 8. 67 (s, 1H), 7. 58 (d, J=8. 7Hz5 2H), 7. 49-7. 41 (m, 3H), 7·20 (s, 1H), 6. 92 (dd, J=8. 7Hz and 2. 4Hz5 lH), 6. 16(d, J=7. 2, 1H), 4. 32-4. 02 (m? 4H)? 3. 80-3. 70 (m, 1H), 1. 50-1. 49 (m, 2H), 1. 35 (t, J=6. 6Hz, 3H) 1. 11-1. 00 (m, 8H), 0. 68 (t, J=7. 2Hz, 3H).   1018 172. 7-177. 6 433. 2 氺氺氺 氺氺* 1H NMR (DMSO-d6? 300Ηζ), δ8·71 (s, 1H), 7. 59 (d, J=8. 1Hz, 2H), 7. 49-7. 41 (m5 3H), 7. 20 (s, 1H), 6. 90 (dd, J=8. 7Hz and 2. 4Hz, 1H), 6. 23 (br,1H), 4. 17-4. 09 (m, 4H), 3. 10-3. 09 (m? 2H) 1. 50-1. 30 (m, 9H), 1. 05-1. 03 (m, 2H) 5 0. 88 (t, J=6. 6Hz, 3H), 0. 69 (t, J=7. 2Hz, 3H).   1019 153. 7-160 481. 2 氺氺氺 ^NMR (DMSO-d6? 300Hz) 5 δ 8. 80 (s, 1H), 7. 59 (d, J=8. 4Hz5 2H), 7. 46-7. 45 (m, 3H), 7. 31-7. 20 (m, 6H), 6. 90 (dd, J=8. 7 Hz and 2. 4Hz? 1H)5 6. 25-6. 24 (m? 1H), 4. 17-4. 09 (m, 4H), 3. 37-3. 31 (m, 2H), 2-78-2. 71 (m, 2H), 1. 53-1. 51 (m, 2H), 1. 35 (t, J=6. 9Hz, 3H) 5 1. 13-1. 00 (m, 2H), 0. 67 (t, J=7. 2Hz, 3H).  128244-3 -454 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50 β Μ 2· Day Replicon IC5〇//M 3-day iHNMR data 1020 135-141. 7 406. 0 氺氺氺 氺氺 lU NMR (CD3CN? 300Hz)? 5 7. 91 (s? 1H)? 7. 68 (d? J=8. 7Hz5 2H)? 7. 55-7. 49 (m? 3H), 7. 36(d, J=2. 1Hz, 1H), 6. 91 (dd, J=6. 3Hz and 2. 4Hz? 1H)? 4. 36-4. 02 (m? 4H), 1. 66-1. 56 (m, 2H), 1. 40(t, J=7. 2Hz, 3H), 1. 31 (t? J=7. 2Hz? 3H)? 1. 22-1. 07 (m, 2H), 0. 74 (t, J=7. 2Hz, 3H).   1021 112. 1-119. 5 420. 0 氺氺氺 氺氺氺 ^NMR (CD3CN? 300Hz)? δ 7. 94 (s, 1H), 7. 65 (d, J=8. 7Hz5 2H), 7. 55-7. 49 (m, 3H), 7. 37 (d, J = 2. 1Hz, 1H), 6. 91 (dd, J=6. 6Hz and 2·1Ηζ, 1H), 4. 16-4. 07 (m, 4H), 1. 72-1. 56 (m, 4H), 1. 40 (t5 J=7. 2Hz? 3H)5 1. 16-1. 06 (m, 2H), 0. 98 (t, J=7. 2Hz, 3H), 0. 76 (t, J=7. 2Hz5 3H).   1022 104. 3-109. 7 420. 0 氺氺氺 * lU NMR (DMSO-d65 300Hz), δ 9. 87 (s, 1H), 7. 67 (d, J=8. 7Hz, 2H), 7. 51-7. 47 (m, 3H), 7. 21 (s, 1H), 6. 90 (dd, J=8. 7 Hz and 2. 4Hz, 1H), 4. 96-4. 89 (m, 1H), 4. 16-4. 06 (m, 4H), 1. 51-1. 47 (m, 2H), 1. 35 (t, J=6. 9Hz, 3H), 1. 21-1. 27 (m, 6H), 1. 06-0. 99 (m, 2H), 0. 67 (t, J=7. 2Hz, 3H).   1023 152. 7-161. 3 433. 2 氺氺 ^NMR (DMSO-d65 300Hz), δ 8. 71 (s, 1H), 7. 58 (d, J=9. 0Hz, 1H), 7. 49-7. 42 (m, 3H), 7. 20 (d, J=1. 8Hz, 1H), 6. 89 (dd, J=6. 6 Hz and 2·1Ηζ, 1H), 6. 23 (br5 1H), 4. 17-4. 09 (m, 4H), 3. 13-3. 06 (m? 2H)? 1. 53-1. 28 (m, 9H), 1. 05-1. 03 (m, 2H), 0. 89 (t, J=7. 2Hz? 3H)? 0. 68 (t? J=7. 2Hz,3H)· 128244-3 -455 - 200831489 Compound No. Melting point (°c) Mass Spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3-day ^NMR data 1024 160. 2-167. 8 481. 2 氺氺氺 氺** ^NMR (DMSO-d6? 300Ηζ), δ 8. 80 (s, 1H), 7. 59 (d, J=8. 7Hz, 2H), 7. 49-7. 42 (m, 3H), 7. 33-7. 20 (m5 6H), 6. 90 (dd, J=6. 9Hz and 2·1Ηζ, 1H), 6. 23 (br,1H), 4. 17-4. 07 (m, 4H), 3. 39-3. 34 (m, 2H), 2. 79-2. 71 (m, 2H), 1. 52-1. 49 (m, 2H), 1. 36 (t, J=6. 9Hz, 3H), 1. 08-1. 01 (m, 2H), 0. 68 (t, J=7. 2Hz, 3H).   1025 133. 3-141. 8 459. 2 氺氺 ^NMR (CDC13? 300MHz), δ 7. 98 (s5 1H), 7. 71 (d, J=7. 8Hz, 2H), 7. 61 (d, J=8. 4Hz, 1H), 7. 41 (d, J=7. 8Hz, 2H), 6. 91-6. 88 (m, 2H), 4. 49 (br, 2H), 4. 12-4. 02 (m? 6H), 3. 73-3. 53 (m, 4H), 3. 09 (br, 2H), 1. 64 (br, 1H), 1. 28-1. 26 (m, 3H), 1. 11 (br, 2H), 0. 89-0. 87 (m, 2H) V 1026 220-222 432. 16 氺氺 氺氺氺 1027 138-140 443. 31 *氺氺 *氺氺 1028 氺氺氺 氺氺氺 1029 188 412. 8 氺氺 1030 173 440. 2 氺氺氺 1031 195 426. 2 氺氺氺 1032 145 424. 2 氺氺氺 1033 181 444. 2 氺氺氺 1034 154-155 491. 3 氺** 1035 173-175 497. 3 氺氺 1036 230-235 510. 3 氺氺 1037 155-156 430. 25 (M-H+) *氺 1038 236-238 410. 2 氺氺 1039 243-248 391. 3 氺氺 1040 215-217 392. 2 氺氺 氺氺 128244-3 -456 - 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC50//M 2-day Replicon IC50 β Μ 3·day ^NMR data 1041 164-166 412. 2 氺氺 氺氺氺 1042 135-138 505. 4 氺氺 1043 165-166 476. 3 氺氺 1044 167-168 511. 3 氺氺氺 1045 117 460. 3 *氺氺 1046 232-234 422. 21 氺氺氺 氺氺氺 1047 422. 24 Η«氺氺 **氺 1048 200-203 440. 0 氺氺 1049 247-249 481. 3 氺氺氺 1050 246-248 381. 2 氺氺 1051 177 423. 2 氺氺 1052 194 424. 2 *氺 1053 236-238 460. 2 氺氺 1054 187. 6-195. 2 443. 2 氺* lU NMR (CDC13, 300MHz), δ 7. 91 (br,1H), 7. 71 (d, J=8. 1Hz, 2H), 7. 61 (d? J=8. 7Hz? 1H)? 7. 42 (d? J=8. 4Hz, 2H), 6. 95-6. 88 (m, 2H), 4. 44 (br, 2H), 4. 08 (q, J=6. 9Hz, 2H), 3. 94-3. 90 (m, 2H) 5 3. 62-3. 56 (m? 2H)? 3. 14(br,lH), 2. 90(br, 2H), 2. 17-2. 07 (m, 4H), 1. 28 (t, J=7. 2Hz, 3H), 1. 15-1. 11 (m, 2H) 5 0. 87-0. 73 (m? 2H).   1055 148. 1-153. 2 406. 0 氺氺氺 ^NMR (DMSO-d6? 300Hz), δ 9. 94 (s, 1H), 7. 67 (d, J=8. 7Hz, 2H), 7. 51-7. 47 (m, 3H), 7. 23 (d, J=2. 4Hz, lH), 6_90 (dd, J=1. 8Hz and 6. 6Hz9 1H)? 4. 15-4. 04 (m? 6H), 1. 68-1. 52 (m, 4H), 1. 35(t, J=6. 9Hz, 3H), 0. 94 (t, J=7. 2Hz, 3H), 0. 63 (t, J=7. 2Hz, 3H).  128244-3 457 - 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50 β Μ 2-day Replicon ic50&quot;m 3-day iHNMR data 1056 169-173. 9 406. 0 氺氺 氺氺氺 ^ NMR (DMSO-d6? 300Ηζ)? δ 9. 87 (s? 1Η)? 7. 67 (d5 J=8. 7Hz? 2H)? 7. 51-7. 47 (m, 3H), 7. 23 (d, J=1. 8Hz, lH), 6. 90 (dd, J=2. 1Hz and 6. 6Hz? 1H)? 4. 94-4. 90 (m? 1H), 4. 15-4. 09 (m, 4H), 1. 54-1. 52 (m, 2H), 1. 35 (t, J=6. 9Hz, 3H), 1. 28-1. 25 (m, 6H), 0. 63 (t, J=7. 2Hz, 3H).   1057 184. 5-193. 9 406. 0 氺氺 !HNMR (DMSO-d6? 300Ηζ)? δ9. 41 (s? 1H)? 8. 26 (d, J=6. 9Hz, 2H), 8. 01-7. 94 (m, 3H), 7. 70 (d, J=2. 1Hz, 1Η), 7·41 (dd, J=2. 1Hz and 6. 6Hz, 1H), 5. 21-5. 15 (m, 1H), 4. 64-4. 53 (m, 4H), 2. 17-2. 12 (m, 2H), 2. 07 (d, J=6. 9Hz, 6H), 1. 86 (t, J=6. 9Hz, 3H), 1. 41 (t, J=7. 5Hz? 3H).   1058 160. 1-166. 5 406. 0 *氺氺 **氺 ^NMR (DMSO-d6, 300Hz), δ 9. 87 (s, 1H), 7. 66 (d, J=8. 4Hz, 2H), 7. 51-7. 43 (m, 3H), 7. 20 (d, J=2. 1Hz, lH), 6. 92 (dd, J=2. 1Hz and 6. 6Hz5 1H), 4. 94-4. 89 (m, 1H), 4. 57-4. 53 (m, 1H), 4. 10 (q? J=6. 9Hz? 2H)? 1. 52 (d, J=6. 6Hz, 6H), 1. 35 (t, J=6. 9Hz, 3H), 1. 25 (d5 J=6. 6Hz? 6H).   1059 135-142. 6 424. 0 氺氺 lH NMR (CD3CN5 300Hz)? δ8·07 (s, 1H), 7. 65 (d, J=8. 7Hz, 2H), 7. 55-7. 49 (m, 2H), 7. 04(d, J=1. 8Hz, 1H), 6. 91 (dd, J=6. 6Hz and 2·1Ηζ5 1H), 5. 30 (br, 1H), 4. 16-4. 09 (m, 4H), 4. 73 (t, J=4. 2Hz, 1H), 4. 57 (t, J=3. 9Hz, 1H), 4. 43 (t, J=4. 2Hz, 1H), 4. 34 (t, J=3. 9Hz, 1H), 4. 15-4. 01 (m, 4H)? 1. 40 (t? J=6. 9Hz5 3H)? 0. 87-0. 85 (m? 6H).  128244-3 -458 - 200831489 Compound No. Melting point (°c) Mass Spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50//M 3-day iHNMR data 1060 193. 2-199. 2 405. 1 氺氺 ^NMR (CD3CN? 300Hz)? 57. 65-7. 51 (m? 3H)? 7. 45-7. 42 (m, 2H)? 7. 36-7. 31 (m, 1H), 7. 04 (d, J=2. 1Hz, 1H), 6. 94-6. 89 (m, 1H), 5. 25 (br5 1H), 4. 15-4. 07 (m, 4H), 3. 20 (br, 2H), 1. 39(t, J=6Hz, 3H), 1. 10 (t, J=7. 2Hz, 3H), 0. 63 (d, J=6. 6Hz, 6H).   1061 182. 7-186. 3 419. 1 氺氺 ^NMR (CD3CN? 300Hz), 57. 66-7. 53 (m3 3H)? 7. 45-7. 43 (m, 2H), 7. 38-7. 33 (m, 1H), 7. 06-7. 05 (m? 1H)? 6. 94-6. 91 (m, 1H), 5. 34 (br, 1H), 4. 15-4. 02 (m, 4H), 3. 16-3. 13 (m? 2H)? 1. 55-1. 50 (m, 2H), 1. 50-1. 39 (m? 3H)? 0. 98 (t? J=7. 2Hz, 3H), 0. 63 (d, J=6. 6Hz? 6H).   1062 156. 7-162. 2 378. 0 氺氺 lH NMR (CDC13? 300MHz)? δ 7. 62 (d, J=8. 7Hz, 1H), 7. 56 (d, J=8. 1Hz, 2H), 7. 46 (d, J=8. 7Hz, 2H), 6. 94 (d, J=8. 4Hz, 1H), 6. 85 (m, 2H), 4. 11 (q, J=6. 9Hz, 2H), 4. 03 (U=7. 8Hz, 2H), 3. 82 (s, 3H)? 1. 72 (q? J=7. 5Hz? 2H)? 1. 49 (t, J two 6. 9Hz, 3H), 0. 78 (t, J=7. 5Hz, 3H).   1063 183. 2-187. 6 392. 1 氺氺 NMR (CDC13? 300MHz) 5 δ 7. 62 (d, J=8. 4Hz, 1H), 7. 56 (d, J=7. 8Hz, 2H), 7. 45 (d5 J=8. 1Hz, 2H), 6. 94 (d, J=8. 4Hz, 1H), 6. 86 (s, 1H), 6. 81 (s5 1H), 4. 26 (q, J=6. 9Hz, 2H), 4. 11 (q, J=6. 9Hz, 2H), 4. 03 (t, J=7. 8Hz, 2H), 1. 72(q, J=7. 5Hz, 2H), 1. 49(t, J=6. 9Hz, 3H), 1. 34 (t, J=7. 2Hz, 3H), 0. 77 (t, J=7. 5Hz, 3H).  128244-3 -459 - 200831489 Compound No. Dissolved point CC) Mass spectrum [M+H] Replicon IC50 β Μ 2-day Replicon IC50 β Μ 3-day ^NMR data 1064 103. 2-107. 7 410. 0 氺氺 lK NMR (CDC13? 300MHz)? δ7·62 (d, J=8. 7Hz, 1H), 7. 57 (d, J=8. 7Hz, 2H), 7. 47 (d5 J=8. 7Hz, 2H), 6. 97 (s, 1H), 6. 95 (dd, J=8. 7Hz and 2·1Ηζ, lH), 6. 86(d, J=2. 1Hz, 1H), 4. 75 (t, J=4. 2Hz, 1H), 4. 59 (t, J=4. 2Hz, 1H), 4. 50 (t5 J=4. 5Hz? 1H)? 4. 41 (t? J=4. 2Hz? 1H)? 4. 11 (q? J=6. 9Hz, 2H), 4. 03 (t, J=7. 5Hz, 2H), 1. 72 (q, J=7. 5Hz, 2H), 1. 47(t, J=6. 9Hz, 3H), 0. 78 (t, J=7. 2Hz, 3H).   1065 196. 3-220. 2 392. 0 氺氺 氺氺氺 lU NMR (CDC13? 400MHz)? δ 7. 63 (d, J=8. 8Hz, 1H), 7. 56 (d? J=8. 4Hz, 2H)? 7. 42 (d, J=8. 4Hz, 2H), 7. 10 (s, 1H), 6. 94 (d, J=8. 4Hz, 1H), 6. 85(s,1H), 4. 68-4. 61 (m, 1H)? 4. 26 (q3 J=7. 2Hz? 2H)? 4. 12 (q? J=6. 8Hz? 2H), 1. 58 (d, J=6. 8Hz, 6H), 1. 48 (t, J=7. 2Hz, 3H), 1. 34 (t, J=7. 2Hz, 3H).   1066 198. 3-205. 6 419. 0 氺氺 lU NMR (CD3CN? 300Hz)? δ 7. 61 (d, J=8. 7Hz, 2H), 7. 53 (d? J=8. 7Hz? 1H)? 7. 44 (d, J=8. 7Hz, 2H), 7. 38 (s, 1H) 7. 03 (d? J=1. 8Hz? 1H)? 6. 91 (dd, JN6. 6Hz and 2. 1Hz, lH), 5. 30(br,1H), 4. 16-4. 09 (m, 4H), 3. 18-3. 11 (m, 2H) 5 1. 66-1. 46 (m, 4H), 1. 40 (t, J=6. 9Hz, 3H), 1. 16-1. 06 (m5 2H), 0. 92 (t, J=7. 5Hz, 3H), 0. 76 (t, J=7. 5Hz5 3H).   1067 95-100 504. 4 氺氺 1068 170-174 474. 3 氺氺 1069 155-156 475. 3 *氺 128244-3 -460- 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3-day hNMR data 1070 208-209 437. 22 氺氺 ^NMR (300 MHz, DMSO-d6): δ 8. 86 (1Η? s)? 7. 67(lH,d,J = 2. 0Hz), 7. 65 (1H,d,J = 8. 5 Hz), 7. 61 (2H,d,J = 8. 8 Hz), 7. 47 (2H,d,J = 8. 8 Hz), 7. 25 (lH,t,J = 74. 4 Hz), 7. 11 (lH, dd, J = 8. 5, 2. 0 Hz), 6. 40(lH,t,J = 5. 8 Hz), 5. 86 (lH,ddt,J= 17. 1, 10. 4,5. 1 Hz), 5. 15 (lH, ddt, J = 17. 1,1. 8, 1. 7 Hz), 5. 06 (lH, ddt, J= 10. 4, 1. 8, 1. 7 Hz), 4. 12 (2H,d,J = 7. 0 Hz), 3. 73 (2H, narrow m), 0. 93-0. 84 (1H,m), 0. 32-0. 23 (2H,m), 0. 05-0. 00 (2H m).  19F NMR (300 MHz, DMSO-d6): δ 82. 03 (2F,d,J = 73. 3 Hz).   1071 125-126 452. 22 (M-H+) 氺氺 七 VII NMR (300 MHz, CDCls): δ 7. 69 (1H? d5 J = 8. 2 Hz), 7. 56 (2H,d,J = 8. 5 Hz), 7. 44 (2H,d, J = 8. 5 Hz), 7. 24(lH,d,J= 1. 8 Hz), 7. 07 (lH, dd, J = 8. twenty one. 8 Hz), 6. 80 (lH, s), 6. 52 (lH,t,J = 74. 0 Hz), 3. 98 (2H,d,J = 7. 0 Hz), 3. 96 (2H,d,J = 7Hz), 1. 97(1H, m, J = 6. 7 Hz), 1. 03-0. 94 (1H, m), 0. 95 (6H,d,J = 6. 7 Hz)? 0. 46-0. 39 (2H, m)? 0. 05-0. 00 (2H, m).  19F NMR (300 MHz, CDC13): δ -80. 76 (2F,d,J = 73. 3 Hz).   1072 197-198 430. 30 (M-H+) 氺氺氺 氺氺氺 1073 191-192 390. 25 氺氺 1074 140-141 404. 27 氺氺 1075 140-141 418. 27 ** 氺氺 1076 175-176 404. 27 氺氺氺 氺氺氺 1077 187-188 418. 27 氺氺氺 128244-3 -461 - 200831489 Compound No. Solt Point CC) Mass Spectrum [M+H] Replicon IC50 β Μ 2-day Replicon IC50 β Μ 3-day ^NMR Data 1078 188-189 430. 30 (M-H+) *氺氺 氺氺 1079 178-179 452. 25 氺氺* 氺氺氺 1080 221-223 417. 28 氺氺氺 **氺 lH NMR (300 MHz, CDCls): 7. 61 (lH,d,J = 8. 5 Hz), 7·58 (2H, d, J = 8. 3 Hz), 7. 37 (2H,d,J = 8. 3 Hz), 7. 23 (lH,d,J= 1. 0 Hz)? 6. 96 (1H? dd? J = 8. 8? J =1. 7Hz), 4. 90 (lH, s), 4. 15 (2H? q?J = 6. 9), 4. 01 (1H? m), 2. 82 (2H, m), 2. 33 (2H, m), 1. 81 (2H, m), 1. 48 (3H5 t, J = 6. 9 Hz)), 1. 21 (6H,d, J = 6. 6 Hz).   1081 179-180 452. 23 (M-H+) 氺氺 1082 206-207 403. 27 氺氺 1083 156 495. 3 1084 167 457. 2 氺氺 1085 162 458. 4 氺氺氺 1086 170 378. 2 氺氺氺 1087 205 405. 2 氺氺 1088 215 403. 2 氺氺 1089 195 389. 2 氺氺 1090 145. 6-149. 7 475. 2 氺氺 lU NMR (CD3OD5 300MHz)? δ 7. 80 (d? J=8. 7Hz, 2H), 7. 58-7. 49 (m, 3H)? 7. 22 (d? J=2. 1Hz? 1H)? 7. 04(d, J=2. 1Hz and 8. 7Hz, 1H), 4. 48 (t, J=4. 8Hz, 2H), 4. 23 (q, J=6. 9Hz, 2H), 4. 01-3. 73 (m, 6H), 3. 02(br, 4H), 1. 86-1. 77 (m, 1H), 1. 28 (t5 J=7. 2Hz? 3H)? 1. 00-0. 87 (m, 4H).  128244-3 462- 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC50//M 2-day Replicon IC50 β Μ 3-day iHNMR data 1091 81. 4-86. 2 461. 2 氺氺 ^NMR (CD3OD, 300MHz), δ 7. 78 (d, J=8. 4Hz, 2H), 7. 55-7. 47 (m, 3H)? 7. 20 (d? J=1. 8Hz? 1H)? 7. 02 (dd, J=1. 8Hz and 8·4Ηζ, 1H), 4. 46 (t, J=4. 8Hz, 2H), 4. 21 (q, J=6. 6Hz, 2H), 3. 81-3. 64 (m, 6H), 3. 55 (s, 3H), 3. 03 (s, 3H), 1. 84-1. 78 (m, 1H), 1. 26(t, J=7. 2Hz, 3H), 0. 99-0. 86 (m? 4H).   1092 193. 8-197. 4 441. 2 氺氺 ^NMR (CD3OD? 300MHz), δ 9. 03 (s, 2H), 7. 79 (d, J=8. 7Hz, 2H), 7. 56-7. 49 (m, 3H), 7. 14 (d, J=1. 8Hz, lH), 6. 99 (dd, J=2. 1Hz and 8. 4Hz, 1H), 4. 68 (t? J=4. 8Hz5 2H)? 4. 44 (t, J=5. 1Hz, 2H), 4. 21 (q, J=6. 9Hz, 2H), 1. 85-1. 77 (m, 1H)? 1. 27 (t5 J=6. 9Hz? 3H)? 1. 01-0. 93 (m? 2H)? 0. 91-0. 87 (m? 2H).   1093 130. 7-134. 3 441. 2 氺氺 1094 205. 3-208 391. 0 氺氺 ^NMR (DMSO-d6? 300Hz), δ 8. 74 (s, 1H), 7. 59 (d5 J=8. 4Hz, 2H), 7. 49-7. 41 (m, 3H), 7. 22 (s, 1H), 6. 89 (dd, J=1. 8Hz and 6. 9Hz, 1H), 6. 22 (t, J=5. 4Hz, 1H), 4. 15-4. 06 (m, 4H), 3. 14-3. 10 (m? 2H)? 1. 58-1. 51 (m, 2H), 1. 35 (t, J=6. 9Hz, 3H), 1. 05 (t, J=7. 2Hz, 3H), 0. 63 (t, J=7. 5Hz? 3H).  128244-3 463 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC5〇//M 2-day Replicon ic50&quot;m 3-day ^NMR data 1095 195. 3-200. 1 405. 1 氺氺氺 氺氺氺 ^NMR (DMSO-d6? 300Ηζ)? δ 8. 72 (s5 1Η)? 7. 59 (d, J=8. 7Hz, 2Η), 7. 49-7. 41 (m? 3H)5 7. 22 (s? 1H)? 6. 89 (dd, J=1. 8Hz and 6. 9Hz5 1H), 6. 26 (t, J=5. 4Hz, 1H) 5 4. 20-4. 07 (m, 4H), 3. 09-3. 03 (m, 2H), 1. 58-1. 41 (m, 4H), 1. 35 (t, J=6. 9Hz, 3H) 5 0. 87 (t, J=6. 9Hz, 3H), 0. 64 (t5 J=7. 2Hz, 3H).   1096 192. 1-196. 2 405. 1 氺氺氺 氺氺氺 ^NMR (DMSO-d6? 300Hz)? δ 8. 60 (s? 1H)? 7. 58 (d? J=8. 4Hz? 2H)? 7. 49-7. 41 (m, 3H), 7. 22 (s, 1H), 6. 89 (dd, J=2. 1Hz and 6. 6Hz, 1H)? 6. 12 (d5 J=7. 5Hz? 1H)? 4. 15-4. 06 (m, 4H), 3. 80-3. 73 (m, 1H), 1. 58-1. 50 1. 35 (t, J=6. 9Hz, 3H)? 1. 10 (d? J=6. 6Hz, 6H), 0. 64 (t, J=7. 2Hz? 3H).   1097 196. 4-202. 3 419. 1 氺氺氺 氺氺氺 ^NMR (DMSO-d6? 300Hz)? δ 8. 72 (s5 1H)? 7. 59 (d, J=8. 4Hz, 2H), 7. 49-7. 41 (m, 3H), 7. 22 (s5 1H), 6. 89 (dd, J=1. 8Hz and 6. 9Hz, 1H), 6. 24 (t, J=5. 4Hz, 1H), 4. 15-4. 06 (m, 4H), 3. 12-3. 06 (m, 2H), 1. 58-1. 51 (m9 2H)? 1. 44-1. 21 (m,7H), 0. 89 (t, J=7. 2Hz, 3H), 0. 83 (t, J=7. 2Hz, 3H).  128244-3 464- 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50//M 2-day Replicon IC50/zM 3-day iHNMR data 1098 217. 8-221. 4 391. 0 氺氺 ^NMR (DMSO-d6, 300Ηζ), δ 8. 74 (s, 1H), 7·59 (d, J=8. 7Hz5 2H), 7. 49 (d, J 2:8, 7Ηζ, 1H), 7. 38 (d, J=8. 4Hz, 2H) 5 7. 20 (d5 J=2. 1Hz, 1HX 6. 92 (dd, J=2. 1Hz and 6·6Ηζ, 1H), 6. 22 (t, J=5. 4Hz, 1H), 4. 62-4. 53 (m, lH), 4. 11 (q, J=6. 9Hz, 2H), 3. 16-3. 07 (m, 2H)? 1. 52 (d? J=6. 6Hz? 6H)? 1. 35 (t? J=6. 9Hz? 3H)? 1. 05 (t, J=7. 2Hz, 3H).   1099 162. 1-165. 1 405. 1 氺氺 ^NMR (DMSO-d6? 300Hz)? δ 8. 73 (s? 1H), 7. 59 (d, J=8. 4Hz, 2H), 7. 49 (d, J=8. 1Hz, lH), 7. 38(d, J=8. 7Hz, 2H), 7. 20 (d, J=2. 1Hz, 1H), 6. 92 (dd, J=2. 1Hz and 6. 6Hz, 1H), 6. 26 (t, J=5. 7Hz, 1H), 4. 62-4. 53 (m, lH), 4. 11 (q, J=6. 9Hz, 2H), 3. 09-3. 02 (m, 2H), 1. 52 (d, J=6. 6Hz, 6H), 1. 48-1. 41 (m, 2H), 1. 35 (t, J=6. 9Hz, 3H), 0. 87 (t, J=7. 2Hz, 3H).   1100 228. 6-231. 4 405. 1 hibised ^NMR (DMSO-d65 300Hz), δ 8. 60 (s, 1H), 7. 57 (d, J=8. 1Hz, 2H), 7. 49 (d, J=8. 7Hz, 1H), 7. 38 (d5 J=8. 7Hz, 2H), 7. 20 (d, J=2. 1Hz, 1H), 6. 92 (dd, J=2. 1Hz and 6·6Ηζ, 1H), 6. 11 (d, J=7. 8Hz, 1H), 4. 62-4. 52 (m? 1H)? 4. 11 (q? J=6. 9Hz, 2H), 3. 79-3. 72 (m, 1H), 1. 53-1. 51 (m, 6H), 1. 35 (t, J=6. 9Hz, 3H), 1. 11-1. 09 (m,6H)· 128244-3 465 - 200831489 Compound No. Melting point (°c) Mass Spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3-day iHNMR data 1101 157. 2-160. 5 419. 1 氺氺氺 (DMSO, 300Hz), δ 8. 72 (s, 1Η), 7. 58 (d5 J=8. 7Hz, 2Η), 7. 49 (d, J=8. 7Hz, 1H), 7. 37 (d, J two 8. 4Hz, 2H), 7. 20 (d, J=2. 1Hz? 1H)? 6. 92 (dd? J=2. 1Hz and 6. 6Hz, 1H), 6. 23 (t, J=5. 7Hz, 1H), 4. 62-4. 55 (m, 1H), 4. 11 (q, J=6. 9Hz, 2H), 3. 12-3. 06 (m, 2H), 1. 52 (d, J=6. 6Hz, 6H), 1. 47-1. 21 (m, 7H), 0. 86(t, J=6. 9Hz? 3H).   1102 197. 3-201. 6 467. 0 **氺 氺氺氺 ^NMR (CD3CN? 300Hz)? δ7·58_7. 46 (m, 4H), 7. 38 (d, J=8. 7Hz, 2H), 7. 30-7. 15 (m, 5H), 7. 15 (s, 1H), 6. 89 (dd, J=2. 1Hz and 6·6Ηζ, 1H), 5. 31 (br, 1H), 4. 64-4. 59 (m, 1H), 4. 09 (q, J=6. 9Hz, 2H), 3. 44-3. 42 (m, 2H), 2. 80 (t, J=6. 6Hz, 2H), 1. 54 (d5 J=6. 6Hz, 6H), 1. 38 (t, J=6. 9Hz, 3H)· 1103 162-163 424. 27 氺氺 1104 245-248 422. 29 氺氺 1105 175-176 422. 27 ** 1106 217-219 429. 32 氺氺氺 氺氺氺 1107 157-158 428. 25 (M-H+) 氺氺氺 1108 213-215 435. 28 氺氺氺 氺*氺 1109 155-156 444. 31 氺氺氺 氺氺氺 1110 191-195 425. 2 氺氺 1111 180-183 406. 2 氺氺 1112 173-175 463. 2 氺氺 1113 151. 155 495. 4 氺氺 1114 171-176 511. 2 氺氺氺 1115 155-156 497. 2 氺氺 1116 218-220 511. 2 氺氺 1117 106-109 509. 2 氺氺 128244-3 -466- 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC50//M 2-day Replicon IC50//M 3-day iHNMR data 1118 126-130 462. 2 氺氺 1119 184-186 405. 31 ** 1120 223-225 417. 37 氺氺氺 氺氺* ^NMR (300 MHz, CDC13): 7. 61 (lH,d,J = 9. 2 Hz) 5 7. 51 (2H? d? J = 8. 5 Hz), 7. 43 (2H,d,J = 8. 5 Hz), 7. 10 (2H, m), 4. 90 (2H, m), 4. 13(2H,q,J = 6. 9Hz), 3. 97 (2H, d5 J = 6. 6 Hz), 1. 47 (3H,t,J = 7. 0 Hz), l_20 (6H, d, J = 8_6Hz), 1. 05(lH,m),0. 43(2H,m), 0. 06 (2H,m) 1121 162-164 501. 17 氺氺氺 1122 170-173 491. 4 氺氺氺 1123 75-80 525. 4 氺氺氺 1124 100-104 474. 5 [M-Η]- 氺氺氺 氺氺 1125 188-190 488. 4 氺氺氺 *** 1126 130-134 510. 3 氺氺 1127 112-115 418. 3 氺氺氺 氺氺氺 1128 203-204 432. 3 氺氺氺 氺*氺 1129 115-116 432. 3 氺氺氺 氺氺 氺氺 1130 177-178 386. 26 氺氺 ^NMR (300 MHz, DMSO-d6): 5 10. 02(1H? s)? 7·69 (2H,d,J = 8. 8 Hz), 7. 67 (1H,d,J = 8. 5 Hz), 7. 61 (lH,d,J = 2. 0 Hz), 7·55 (2H,d,J = 8. 8 Hz), 7. 28 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 5, 2. 0 Hz)? 4. 20 (2H? q? J = 7. 3 Hz), 3. 70 (3H, s) 5 1. 18 (3H, t? J = 7. 3 Hz).  19F NMR (300 MHz3 DMSO-d6): δ -81. 95 (2F?d? J = 73. 3 Hz).  128244-3 467- 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50//M 2-day Replicon IC50//M 3-day iHNMR data 1131 174-175 400. 26 ** ^NMR (300 MHz, DMSO-d6): δ 9. 98 (1Η? s)? 7. 69 (2Η? d? J = 8. 8 Ηζ)? 7. 67 (1Η,d,J = 8·8 Ηζ), 7. 61 (lH,d,J = 2. 0Hz), 7. 54 (2H,d,J = 8. 8 Hz), 7. 28 (1H, t, J = 74. 4 Hz), 7. 13 (1H? dd? J = 8. 8?2. 0 Hz)? 4. 20 (2H? q? J = 7. 0 Hz), 4. 15 (2H,q,J = 7. 3 Hz), 1. 26 (3H,t,J = 7. 0 Hz), 1. 18 (3H,t,J = 7. 3 Hz).  19F NMR (300 MHz, DMSO-d6): 6-81. 95 (2F5 d? J = 75. 3 Hz).   1132 148-149 414. 25 氺氺 VII NMR (300 MHz, DMSO-d6): δ 9. 99 (1H, s), 7. 70 (2H,d,J = 8. 8 Hz), 7. 67 (1H,d,J = 8. 5 Hz), 7. 61 (lH,d,J = 2. 0 Hz), 7. 54 (2H,d,J = 8. 8 Hz), 7·28 (1H, t, J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 5, 2. 0 Hz), 4. 20 (2H, q, J = 7. 0 Hz), 4. 07 (2H,t,J = 6. 7 Hz), 1. 65 (2H, hx, J = 7. 6 Hz), 1. 18 (3H? t? J = 7. 2 Hz), 0. 94 (3H, t, J = 7. 5 Hz).  19F NMR (300 MHz? DMSO-d6): δ -81. 96 (2F? d? J = 73. 3 Hz).  128244-3 468 - 200831489

Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50/zM 2-day Replicon IC50 β Μ 3-day ^NMR data 1133 139-140 428. 25 氺氺 4 NMR (300 MHz, DMSO-d6): δ 9. 98 (1H? s)? 7. 72-7. 66 (3H, m), 7. 61 (lH,d,J = 2. 0 Hz), 7. 54 (2H,d,J = 8. 8 Hz), 7. 28 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 20 (2H, q, J = 7. 3 Hz), 4. 11 (2H,t,J = 6. 9 hz), 1. 66-1. 56 (2H? m)? 1. 45-1. 35 (2H, m) 5 1. 18 (3H,t,J = 7. 3 Hz), 0. 91 (3H,t,J = 7. 3 Hz).  19F NMR (300 MHz, DMSO-d6): 5-81. 92 (2F? d? J II 73. 3 Hz).   1134 142-143 426. 30 (M-H+) ** !HNMR (300 MHz, DMSO-d6): δ 9·99 (1H, s), 7. 70 (2H,d,J = 8. 8 Hz), 7. 67(lH,d,J = 8. 8Hz), 7. 61 (lH,d,J = 2. 0 Hz), 7. 54 (2H5 d5 J = 8. 8 Hz)? 7. 28 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 8, 2. 0 Hz)? 4. 20 (2H? q? J = 7. 0 Hz), 3. 90 (2H,d,J = 6. 7 Hz), 1. 93 (lH,m,J = 6. 7 Hz), 1. 18 (3H,t,J = 7. 0 Hz), 0. 93 (6H,d,J = 6_7 Hz).  19F NMR (300 MHz, DMSO-d6): 5-81. 92 (2F? d? J = 73. 3 Hz).   1135 144-145 412. 24 *** lU NMR (300 MHz, DMSO-d6): 5 10. 10(1H? s)? 7. 72-7. 66 (3H, m), 7. 62 (1H? d? J = 2. 0 Hz) 5 7. 55 (2H,d,J = 8. 8 Hz), 7. 28 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 5, 2. 0 Hz), 6. 06-5. 93 (lH,m), 5. 41-5. 22 (2H? m)? 4. 64 (2H, dt? J = 5. 5, 1. 3 Hz), 4. 20 (2H,q, J = 7. 3Hz)? 1. 18 (3H51? J = 7. 3 Hz).  19F NMR (300 MHz? DMSO-d6): δ -81. 92 (2F,d,J = 73. 3 Hz).  128244-3 •469- 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 &quot; Μ 3-day iHNMR data 1136 172-174 413. 25 氺氺 NMR (300 MHz, DMSO-d6): δ 8. 77 (1H, s), 7. 66 (1H, d5 J = 8. 8 Hz), 7. 62 (2H? d? J - 8. 8 Hz), 7. 47 (2H,d,J = 8. 8 Hz), 7. 46 (lH,d,J = 2. 0 Hz), 7. 27 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 8, 2. 0 Hz), 6. 28 (lH,t,J = 5. 7 Hz), 4. 20 (2H, q, J = 7. 3 Hz), 3. 05 (2H, q, J = 6. 2 Hz), 1. 44 (2H, hx, J = 6. 7 Hz), 1. 19 (3H,t,J = 7. 2 Hz), 0. 87 (3H,t,J = 7. 5 Hz).  19F NMR (300 MHz, DMSO-d6): 5-81. 92 (2F? d? J = 73. 3 Hz).   1137 180-182 413. 26 氺氺 ^ NMR (300 MHz, DMSO-d6): δ 8. 65 (1H? s)? 7·66 (1H,d,J = 8. 8 Hz), 7. 61 (lH,d,J = 2. 0 Hz), 7. 60 (2H,d,J = 8. 8 Hz), 7·47 (2H,d,J = 8. 8 Hz), 7. 27 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 8, 2. 0 Hz), 6. 14 (lH,d,J = 7. 6 Hz), 4. 20 (2H, q, J = 7. 0 Hz), 3. 77 (lH,m,J = 7. 3 Hz), 1. 18 (3H,t,J = 7. 3 Hz), 1. 10(6H,d,J = 6. 5 Hz) · 19F NMR (300 MHz, DMSO-d6): 5-81. 92 (2F? d? J = 73. 3 Hz)· 128244-3 470- 200831489 Compound No. Melting point ΓΟ Mass spectrometry [M+H] Replicon IC50 β Μ 2-day Replicon IC5〇 β Μ 3-day ^NMR data 1138 146-149 427. 27 氺氺 ^NMR (300 MHz, DMSO-d6): δ 8. 76 (1Η? s)? 7. 66(lH,d,J = 8. 8Hz), 7. 62 (2Η5 d? J = 8. 8 Hz)? 7. 61 (lH,d,J = 2. 0 Hz), 7. 47 (2H,d,J = 8. 8 Hz), 7. 27 (lH,t,J = 74. 4 Hz), 7. 13 (1H? dd?J = 8. 8? 2. 0 Hz)? 6. 25 (1H? t?J = 5. 7 Hz), 4. 21 (2H,q,J = 7. 3 Hz), 3. 09 (2H, q, J = 5. 8 Hz), 1. 47-1. 25 (4H, m), 1. 18 (3H? t? J = 7. 0Hz), 0. 89 (3H,t,J = 7. 0 Hz).  19F NMR (300 MHz, DMSO-d6): δ -81. 92 (2F,d, J = 73. 3 Hz).   1139 179-180 411. 27 氺氺 NMR (300 MHz, DMSO-d6): δ 8. 92 (1H5 s), 7. 66 (1H,d,J = 8. 8 Hz), 7. 63 (2H,d,J = 8. 8 Hz) 5 7. 61 (lH,d,J = 2. 0 Hz), 7. 48 (2H? d? J = 8. 8 Hz), 7. 28 (lH,t,J = 74. 4 Hz), 7. 13 (lH, dd, J = 8. 8, 2. 0 Hz), 6. 43 (lH,t,J = 5. 8 Hz), 5. 95-5. 80 (1H? m)? 5. 22-5. 07 (2H? m)? 4. 21 (2H,q,J = 7. 3 Hz), 3. 75 (2H, t, J = 6 Hz), U9 (3H, t? J = 7. 3 Hz).  19F NMR (300 MHz, DMSO-d6): δ -81. 92 (2F? d? J = 73. 3 Hz).   1140 198-202 450. 2 [M-Η]' 氺氺 1141 156-160 448. 2 [Μ-ΗΓ 氺氺 1142 110-111 487. 41 氺*氺 氺氺氺 1143 215-218 417. 5 氺氺氺 氺氺氺 1144 207-210 429. 5 氺*氺 *** 1145 205-208 445. 2 氺氺 1146 187-191 430. 32 氺氺氺 氺氺氺 128244-3 -471 - 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon IC5〇 β Μ 2-day Replicon IC50 β Μ 3-day iHNMR data 1147 154-158 444. 25 氺氺* 氺氺氺 iHNMRpOOMHz, ^-propanone): δ 8. 92 (s, 1H), 7. 82 (d, 2H? J = 8. 7Hz)? 7. 62-7. 49 (m, 3H), 7. 30 (d, 1H, J = 2. 1 Hz), 6. 98 (dd, 1H, J = 8. 7, 2. 1 Hz), 5. 095 (Five peaks, 1H, J = 9. 0 Hz), 4·32 (m, 1H), 4. 17 (q, 2H, J = 6. 9 Hz), 2. 7-2. 8 (m, 2H)? 2. 35-2. 5 (m, 2H), 1. 8-2. 0 (m, 2H), 1. 42(t,3H,J = 6. 9Hz), 1. 34(d, 3H, J = 6. 3Hz), 1. 0-1 · 1 (m, 1H), 0. 6-0. 8 (m, 3H), 0. 5-0. 59 (m, 1H) 1148 193-195 402. 24 (M-H+) *氺氺 *氺氺 1149 158-159 416. 37 (M-H+) 氺氺氺 氺** 1150 173-175 416. 32 (M-H+) 氺** 氺氺氺 ^NMR (300 MHz, CDC13): δ 7. 62 (1H? d? J = 9. 3Hz), 7. 58(2H,d, J = 8. 8 Hz), 7. 46 (2H,d,J = 8. 8 Hz), 7. 10 (2H, m), 6. 77 (1H, s), 5. 05 (lH, m), 4. 13 (2H, q5 J = 7. 2 Hz), 3. 97 (2H,d,J = 6·6Ηζ), 1. 47(3H,t,J = 6. 9 Hz), 1. 32 (6H,d,J = 6. 0 Hz), 1. 05 (lH, m), 0. 43 (2H, m), 0. 05 (2H, m) 1151 171-172 432. 30 氺氺氺 氺氺氺 1152 198-199 444. 31 (M-H+) 氺氺氺 氺氺氺 1153 154-155 466. 28 氺氺氺 氺氺氺 1154 207-208 444. 31 (M-H+) 氺氺氺 氺氺氺 1155 200-202 466. 28 氺氺 1156 226-228 444. 31 (M-H+) 氺氺氺 氺氺氺 1157 199-201 466. 28 氺氺氺 氺氺氺 128244-3 -472 - 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3-day ^NMR data 1158 173-179 442. 27 (ES-) 氺氺氺 氺氺* 1159 206-208 (weak ionization) *** 氺氺氺 1160 193-194 422. 3 氺氺氺 氺氺 1161 183-185 410. 2 氺氺氺 氺氺 1162 192-193 403. 3 氺氺 1163 188-189 403. 2 氺氺 1164 188-190 417. 2 氺氺氺 氺 1165 190-192 429. 3 氺* 氺氺 1166 260-266 445. 25 氺氺 1167 208-212 430. 25 *氺氺 氺氺氺 1168 218-221 (weak ionization) 氺氺氺 氺氺氺 ^NMRpOOMHz, /-propanone): δ 8. 08 (s5 1H), 7. 69 (d, 2H, J = 8. 7 Hz), 7. 54 (d, 1H, J = 8. 7Hz), 7. 43(d, 2H? J = 8. 7 Hz)? 7. 30 (d, 1H5 J = 2. 1 Hz), 6. 97 (dd, 1H, J = 8. 7, 2. 1Hz), 6. 10 (d, 1H, J = 8. 1 Hz), 5. 08 (five peaks, 1H, J = 9. 3 Hz), 4. 32 (six ♦, :lH, J = 8. 1Hz), 4. 16 (q, 2H, J = 6. 9 Hz), 2. 7-2. 85 (m? 2H)? 2. 35 2. 5 (m, 2H), 2. 15-2. 35 (m, 2H), 1. 8 2. 0 (m? 4H)? 1. 6-1. 7 (m 2H), 1. 42(t,3H,J = 6. 9Hz) 1169 224-226 432. 3 氺氺氺 *氺氺 1170 180-181 469. 3 氺氺 1171 219-220 431. 2 氺氺氺 *氺氺 1172 198-199 431. 33 氺氺氺 *氺氺 1173 203-205 443. 31 氺氺氺 氺氺氺 1174 180-181 436. 28 氺氺氺 氺氺氺 1175 202-203 456. 27 Η«氺氺 氺氺氺 1176 170-172 390. 2 氺氺 1177 145-147 404. 2 氺氺 1178 182-183 418. 3 氺氺氺氺氺氺128244-3 -473 - 200831489 Compound number Hyun point (°C) Mass spectrometry [M+H] Replicon IC5〇β Μ 2-day replicon IC50&quot;M 3-day iHNMR data 1179 173- 174 430. 2 氺氺 1180 179-180 402. 2 氺* 1181 179-180 424. 2 氺氺 1182 162-163 422. 2 **氺 * 1183 202. 3-205. 9 440. 3 氺氺氺 {H NMR (CD3CN, 300MHz), δ 8. 86 (s, 1H), 8. 66 (s5 1Η), 7. 80 (d, J=8. 7Hz, 2Η), 7. 58-7. 49 (m, 4H), 7·42 (s, 1H), 7. 09 (d, J=2. 1Hz, 1H) 5 6. 95 (dd, J=2. 1Hz and 8·7Ηζ, 1H), 4. 58 (t, J=4. 8Hz, 2H), 4. 42 (t, J=4. 8Hz, 2H), 4. 16 (q, J=6. 9Hz, 2H), 1. 76-1. 67 (m, 1H), 1. 25 (t, J=7. 2Hz, 3H), 0. 95-0. 89 (m, 4H).   1184 165. 4-170. 1 440. 3 氺氺 ^NMR (CD3CN, 300MHz), δ 8. 81 (s, 1H), 7. 79 (d5 J=8. 7Hz? 2H)? 7. 70 (d, J=2. 1Hz, 1H), 7. 54-7. 49 (m, 4H), 7. 02 (d, J=2. 1Hz, lH), 6. 88 (dd, J=2. 1Hz and 8·7 Hz, 1H), 6. 30 (t, J=1. 8Hz, lH), 4. 57(t, J=4. 8Hz, 2H), 4. 44 (t, J=5. 1Hz, 2H), 4. 13 (q, J=7. 2Hz, 2H), 1. 73-1. 68 (m, 1H), 1. 24(t, J=7. 2Hz, 3H), 0. 95-0. 82 (m, 4H).   1185 211-213 454. 30 4 NMR (300 MHz, DMSO-d6): δ 8. 76-8. 70 (2H,m),8·53 (1H,d,J = 4. 7 Hz), 7. 91 (lH,d,J = 7. 9 Hz), 7. 60 (2H,d,J = 8·5 Ηζ), 7·51 (lH,d,J = 8. 5 Hz), 7. 46-7. 38 (8H, m), 7. 00 (1H? dd?J = 8. 5, 1. 2 Hz), 6. 27 (lH,t,J = 5. 6 Hz), 5. 25 (2H, s), 4. 18 (2H, q? J = 7. 0 Hz)? 3. 05 (2H5 q? J = 6. 4 Hz), 1. 44 (2H, hx, J = 7. 3 Hz), 1. 17 (3H,t,J = 7. 0 Hz)? 0. 87 (3H? t? J = 7. 4 Hz).  128244-3 -474- 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50 // Μ 2-day Replicon IC50 &quot; Μ 3·day hNMR data 1186 150.  464. 34 (M-H+) 氺氺 lU NMR (300 MHz, DMSO-d6): δ 9. 90 (1H5 s)? 7. 67(lH,d,J = 8. 8Hz), 7. 66 (2H,d,J = 8. 8 Hz), 7. 58 (lH,d,J = 2. 0 Hz), 7. 48 (2H,d,J = 8. 8 Hz), 7. 29 (lH,t,J = 74. 4 Hz), 7. 15 (lH, dd, J = 8. 8,2. 0 Hz), 5. 13-5. 08 (lH,m), 4. 99 (1H,p,J = 8. 5 Hz), 2. 55-2. 40 (2H? m)? 2. 37-2. 24 (2H, m), 1. 92-1. 57 (10H, m).  19F NMR (300 MHz, DMSO-d6): δ -82. 08 (2F,d, J = 73. 3 Hz).   1187 198-199 439. 29 氺* !HNMR (300 MHz, DMSO-d6): δ 8. 76 (1H? s)? 7. 67(lH,d,J = 8. 5Hz), 7. 59 (2H? d? J = 8. 8Hz) 3 7. 58 (lH,d,J = 2. 0 Hz), 7. 42 (2H, d? J = 8. 8 Hz), 7. 29 (lH,t,J = 74. 4 Hz), 7. 14 (lH, dd, J = 8. 5, 2. 0 Hz), 6. 28(lH,t,J = 5. 7 Hz), 5. 00 (lH,p,J = 8. 6 Hz), 3. 05 (2H, q, J = 6. 1 Hz)? 2. 59-2. 42 (2H? m)? 2. 39-2. 24 (2H, m), 1. 84-1. 66 (2H, m), 1. 44 (2H, hx, J = 7. 0 Hz), 0. 87 (3H,t,J = 7. 4 Hz).  19F NMR (300 MHz, DMSO-d6): δ -82. 05 (2F, d5 J = 73. 3 Hz).  128244-3 475 - 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC5〇//M 3-day iHNMR data 1188 222-223 474. 25 本氺 JH NMR (300 MHz, DMSO-d6): 5 10. 26(1H? s)? 7. 70 (1H,d,J = 8. 8 Hz), 7·54 (2H,d,J = 8. 8 Hz), 7. 40 (1H? d, J = 2. 0Hz)? 7. 39(2H,d,J = 8_8Hz)5 7. 29 (lH,t,J = 74. 4 Hz), 7. 16 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 71 (lH,p,J = 9. 1 Hz), 3. 24-3. 19 (2H, m), 2. 22-1. 60 (10H? m)? 0. 97 (3H,t,J = 7. 4 Hz)· 19F NMR (300 MHz, DMSO-d6): δ -82. 05 (2F? d? J = 73. 3 Hz).   1189 183-158 472. 24 氺氺氺 氺氺* towel NMR (300 MHz, DMSO-d6): 5 10. 24(1H? s)? 7. 70 (1H, d5 J = 8. 8 Hz), 7. 55 (2H,d,J = 8. 8 Hz), 7. 44 (2H,d,J = 8. 8 Hz), 7. 40 (1H,d,J = 2. 0 Hz), 7. 30 (1H, t, J = 74. 4 Hz), 7. 16 (lH, dd, J = 8. 8, 2. 0 Hz), 4. 71 (lH,p,J = 9. 1 Hz), 2. 84-2·75 (1H, m), 2. 20-1. 84 (6H, m), 1. 65-1. 60 (2H, m), 1. 05-0. 95 (2H,m), 0. 60-0. 49 (2H,m)· 19F NMR (300 MHz, DMSO-d6): δ -82. 05 (2F,d, J = 75. 3 Hz).  128244-3 476 - 200831489 Compound No. Solt Point CC) Mass Spectrum [M+H] Replicon ic50&quot;m 2_ day Replicon IC50//M 3-day hNMR data 1190 185-186 465. 27 氺氺 lU NMR (300 MHz, DMSO-d6): δ 8. 60 (1Η? s)? 7. 67 (1Η,d,J = 8. 8 Ηζ), 7. 58(lH,d,J=1·9Ηζ), 7. 57 (2H? d5 J = 8. 8Hz)? 7. 42 (2H,d,J = 8. 8 Hz), 7. 29 (lH,t,J = 74. 4 Hz), 7. 14 (1H? dd, J = 8. 8, 1. 9 Hz), 6. 30 (1H,d,J = 7. 3 Hz), 5. 00 (lH,p,J = 8. 6 Hz)? 3. 94 (lH9hx?J = 6. 7 Hz), 2. 60-2. 40 (2H, m), 2. 38-2. 23 (2H? m)? 1. 90-1. 34 (10H, m).  19F NMR (300 MHz5 DMSO-d6): δ -82. 05 (2F,d,J = 75. 3 Hz)· 1191 216-219 415. 31 氺氺 1192 159-162 489. 37 氺氺 1193 213-214 404. 3 氺氺氺 1194 196-197 418. 3 氺氺氺 1195 114-115 418. 3 *** 氺氺氺 1196 124-125 416. 3 氺氺氺 氺氺氺 1197 118-119 432. 3 氺氺 **氺 1198 181-182 432. 3 氺氺氺 氺氺氺 1199 187-188 444. 3 氺氺氺 1200 1200 188-189 446. 3 *氺氺 氺氺氺 1201 182-183 466. 3 氺氺氺 氺氺氺 1202 195-197 406. 3 氺本氺 氺氺氺 1203 184-187 420. 3 氺氺氺 氺氺氺 1204 168-169 420. 3 氺氺氺 1205 155-157 445. 3 氺氺* 氺氺氺 1206 178-180 434. 3 氺氺氺 氺氺氺 1207 204-205 448. 3 氺氺氺 128244-3 -477- 200831489 Compound No. Melting point CC) Mass spectrum [M+H] Replicon ic50&quot;m 2-day Replicon IC50 β Μ 3-day ^NMR data 1208 186-190 444. 30 氺氺* 1209 189-192 456. 30 (ES-) 氺氺氺 1210 148-152 503. 36 氺氺氺 *氺氺 1211 203-205 458. 3 氺氺氺 氺氺* 1212 192-193 480. 34 氺氺氺 1213 192-193 480. 33 氺氺* 1214 170-173 457. 3 氺氺氺 氺氺氺 1215 200-204 446. 26 *氺氺 氺氺氺 1216 205-209 460. 31 氺氺 1217 135-141 388. 34 氺氺 1218 192-193 481. 31 氺氺氺 氺氺氺 1219 192-193 507. 35 氺氺氺 *氺氺 1220 192-193 481. 28 氺氺氺 氺氺氺 1221 222-225 431. 3 *氺氺 氺氺氺 1222 191-192 446. 35 氺氺 1223 206-208 417. 3 氺氺氺 氺氺氺 1224 191-192 417. 3 ** 1225 183-184 431. 3 氺氺 1226 189-190 443. 3 氺氺氺 氺氺氺 1227 168-169 479. 3 氺氺氺 氺氺氺 1228 174-175 423. 5 氺氺 1229 163-164 438. 3 氺氺 1230 179-180 436. 3 *氺 1231 189-191 424. 2 氺氺 1232 184-185 404. 2 氺氺 氺* 1233 192-193 430. 4 氺氺氺 氺氺* 1234 204-205 390. 1 氺氺 1235 209-211 410. 1 氺氺 1236 196-197 404. 14 氺氺氺 氺氺氺 1237 150-151 432. 1 氺氺 1238 176-177 458. 4 氺氺 128244-3 -478 - 200831489 Compound No. Melting point CO mass spectrum [M+H] Replicon IC50 β Μ 2-day Replicon IC50//M 3-day ^NMR data 1239 187-193 360. 35 氺氺氺 氺氺氺 1240 168-170 460. 38 氺*氺 氺氺氺 1241 151-168 432. 3 氺氺氺 氺氺氺 1242 134-136 446. 3 氺氺氺 氺氺氺 1243 161-163 446. 3 氺*氺 氺氺氺 1244 145-147 446. 3 氺氺氺 氺氺氺 1245 245-246 318. 3 ** 1246 157-163 434. 4 氺氺氺 氺氺氺 1247 188-190 432. 4 *** 氺氺氺 1248 207-210 462. 4 氺氺氺 氺氺氺 1249 181-184 448. 4 氺氺氺 氺氺氺 1250 144-148 448. 38 氺*氺 氺氺氺 1251 137-142 (weak ionization) 氺氺 氺氺 1252 131-134 446. 37 ** 1253 224 517. 3 氺氺 1254 189 498. 6 氺氺氺 氺氺氺 ^NMR (300 MHz, DMSO-d6): δ 9. 89 (1Η)? 7·64(3Η), 7. 46 (3Η), 7. 19 (2Η), 6. 94 (1Η), 6. 87 (1Η), 4. 91 (2Η), 4·19 (2Η), 4. 01 (2Η)? 2. 48 (2Η)? 2. 21 (2Η)? 2. 17 (2Η), 1. 71 (2Η), 1. 27 (6Η) 1255 208 499. 4 氺木氺 氺氺氺 ^NMR (300 MHz, DMSO-d6): 5 9. 91 (1Η)? 8. 53 (1Η), 7. 97 (1Η), 7. 65 (2H), 7. 46 (3H), 7. 19 (1H), 6. 92 (1H), 4. 95 (2H), 4. 39 (2H)? 4. 06 (2H)? 2. 48 (2H), 2. 67 (4H)? 1. 72 (2H)? 1. 24 (6H).  128244-3 479- 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50 // Μ 2-day Replicon lC5〇yaM 3-day iHNMR data 1256 188. 4-191. 3 467. 1 氺氺氺 lU NMR ((CD3CN? 300Hz)? 5 7. 60 (d, J = 9. 0Hz, 2H), 7. 53 (d, J=8. 7Hz, 1H), 7. 47-7. 23 (m5 7H), 7. 04 (s, 1H), 6. 91 (dd, J=2. 1Hz and 6. 6Hz? 1H)? 5. 31-5. 27 (m? 1H), 4. 16-4. 07 (m, 4H), 4. 45 (q? J=6. 6Hz? 2H)? 2. 83 (t, J=6. 6Hz, 2H), 1. 69-1. 61 (m, 2H), 1. 41 (t, J=6. 9Hz, 3H), 0. 71 (t, J=7. 5Hz, 3H).   1257 541. 55 氺氺氺 1258 527. 55 氺氺氺 1259 526. 57 氺氺氺 1260 208 503. 5 氺氺氺 1261 156 530. 5 *氺氺 1262 167 533. 5 *氺 1263 155-157 458. 4 (ES-) 氺氺氺 1264 177-180 467. 40 氺氺氺 1265 164-167 432. 37 氺氺氺 1266 175-176 453. 34 氺氺 NMR (300 MHz, CDC13): δ 7. 70 (1H? d, J = 8_8 Hz), 7. 55 (2H,d,J = 8. 8 Hz), 7. 42 (2H,d,J = 8. 8 Hz)? 7. 29 (1H? d? J= 1. 8 Hz), 7. 22 (lH, brs), 7. 13 (lH, dd, J = 8. 8, 1. 8 Hz), 6. 81 (lH,t,J = 74. 4 Hz), 4. 02 (2H,d,J = 6. 7 Hz), 3·82 (1H, hx, J = 6. 4 Hz), 1. 51 (2H,p,J = 7. 1Hz), 1. 17 (3H? d? J = 6. 7Hz)5 1. 07-0. 99 (lH,m),0. 94 (3H, t, J = 7. 4 Hz), 0. 48-0. 41 (2H5 m)? 0. 09-0. 04 (2H, m).  19F NMR (300 MHz? CDC13): δ -80. 81 (2F,d,J = 73. 3 Hz)· 128244-3 -480- 200831489 Compound No. Melting point CC) Mass Spectrum [M+H] Replicon IC50 β Μ 2-day Replicon ic50&quot;m 3-day iHNMR data 1267 139-140 466. 06 氺氺 ^NMR (300 MHz, CDC13): 5 7. 72 (1H? d, J = 8·8 Hz), 7. 59 (2H,d,J = 8. 8 Hz), 7·47 (2H, d, J = 8. 8 Hz), 7. 28 (lH,d,J= 1. 8 Hz), 7. 12 (lH, dd, J = 8. 8, 1. 8 Hz), 6. 79 (lH, brs), 6. 56 (lH,t,J = 74. 4 Hz), 4. 35 (lH, dq, J = 8. 6, 6. 7 Hz), 4. 02 (2H,d,J = 6. 7 Hz), 1. 39 (3H,d,J = 6. 7 Hz), 1. 11-0. 99 (2H, m)5 0. 64-0. 43 (5H,m), 0. 34_0. 28(lH,m), 0. 09-0. 04 (2H? m).  19F NMR (300 MHz, CDC13): δ -80. 75 (2F,d,J = 75. 3 Hz).   1268 145-146 454. 30 氺氺 ^ NMR (300 MHz, CDC13): δ 7·73 (1H, d, J = 8. 5 Hz), 7. 60 (2H,d,J = 8. 8 Hz), 7. 47 (2H,d,J = 8. 8 Hz), 7. 28 (lH,d,J= 1. 8 Hz), 7. 12(lH,t,J = 8. 5, 1. 8 Hz), 6_76 (1H, br s), 6. 56 (lH,t,J = 74. 4 Hz), 4. 89 (lH, hx, J = 6. 4Hz), 4. 02 (2H? d? J = 6. 7 Hz)? 1. 74-1. 59 (2H? m)? 1. 30 (3H? d? J = 6. 1 Hz), 1. 11-1. 00 (1H? m)? 0. 97 (3H, t, J = 7. 4 Hz), 0. 49-0. 43 (2H,m), 0. 09-0. 04 (2H? m).  19F NMR (300 MHz, CDC13): δ -80. 75 (2F,d,J = 73. 3 Hz).   1269 112 461. 4 氺氺氺 1270 158 475. 5 氺氺氺 1271 192 503. 5 *氺氺 1272 199 515. 6 *氺氺 1273 212 519. 5 ** 1274 139 505. 5 本氺氺 1275 115 484. 5 氺氺氺 1276 214 485. 4 氺氺氺 128244-3 -481 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50//M 2-day Replicon IC50 β Μ 3_day hNMR data 1277 208 473. 5 氺氺氺 1278 181 489. 5 氺氺氺 1279 205-207 473. 43 氺氺氺 1280 175-176 490. 35 (M-H+) *氺氺 1281 168-169 500. 47 *氺氺 1282 196-197 486. 43 1283 169-170 486. 42 (M-H+) 氺氺氺 1284 154-155 498. 31 (M-H+) *氺氺 1285 168-170 472. 39 (M-H+) 氺氺氺 1286 161-163 486. 43 氺氺氺 1287 141-143 498. 27 (M-H+) 氺氺氺 1288 211-213 485. 42 氺氺氺 1289 178-185 478. 32 (ES-) 氺氺氺 1290 172-174 444. 39 (ES-) 氺氺氺 1291 177-178 430. 4 氺氺氺 1292 202-203 430. 4 氺氺氺 1293 193-194 430. 4 氺氺* 1294 155-157 444. 4 氺本氺 1295 174-175 444. 4 氺氺氺 1296 170-171 444. 4 氺氺 1297 163-165 446. 4 ** 1298 178-180 446. 4 氺氺 1299 150-152 448. 4 氺氺 1300 201-203 432. 31 氺氺氺 1301 216-218 431. 37 氺氺氺 1302 226-227 417. 4 氺氺 1303 215-216 417. 3 ** 128244-3 -482- 200831489 Compound No. Melting point (°c) Mass Spectrum [M+H] Replicon IC5〇 β Μ 2-day Replicon IC50 // Μ 3·day iHNMR data 1304 209-211 415. 3 氺氺 1305 443. 4 氺氺氺 1306 155-160 516. 5 氺氺 1307 115-119 529. 5 氺氺 1308 109-110 497. 7 氺氺氺 1309 210-212 500. 6 *氺氺 1310 129-131 374. 4 氺氺 1311 205-207 346. 4 氺氺氺 1312 180-185 458. 43 (ES-) 氺氺氺 1313 155-160 448. 07 氺氺氺 1314 88-90 498. 5 氺氺氺 1315 125-130 502. 5 氺* 1316 110-112 472. 5 氺氺氺 1317 122-125 472. 5 氺氺氺 1318 130-134 484. 5 氺氺氺 1319 108-113 460. 5 1320 98-101 474. 5 1321 83-87 504. 6 氺氺 1322 112-115 483. 5 氺氺氺 1323 148-150 432. 4 氺氺氺 1324 227-229 433. 4 氺氺氺 1325 195-198 417. 4 1326 246-248 431. 4 氺氺 1327 93 487. 5 氺氺氺 1328 162 510. 5 1329 98 511. 4 氺氺氺 128244-3 483 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50/zM 3_day Wnmr data 2129 175-180 472. 4 (M-1) 氺氺氺 2130 180-182 450. 2 氺氺氺 2131 521. 1 * 2132 541. 2 氺 2133 221-227 445. 4 氺** 2134 185-190 446. 4 氺氺氺 2135 180-185 444. 3 (M-1) 氺氺本 2136 135-137 404. 2 氺氺 lH NMR (CDC13? 300MHz)? δ7·57 (d, J=8. 7Hz, 2H), 7. 47 (d, J=9. 0Hz, 2H), 7. 37 (d, J=6. 6Hz, 1H), 7. 18 (d, J=1. 5Hz, 1H), 6. 97 (dd, J=6. 6Hz and 1. 5Hz, 1Η), 6.73 (s, 1H)5 5. 09-5. 03 (m, 1H), 4. 01 (d, J=4. 8Hz, 2H), 3. 90 (s, 3H), 1. 33(d, J=4. 8Hz, 6H), 1. 07-1. 04 (m, 1H), 0. 43 (q, J=6_9Hz, 2H), 0. 07 (q5 J=3. 6Hz, 2H).   2137 176-177 440. 1 (M+Na) 氺氺 NMR (CDC13? 300MHz) 5 57. 54 (d, J=8. 7Hz, 2H), 7. 46 (d, J=8. 7Hz, 2H), 7. 36 (d, J 2 9. 0Ηζ, 1H), 7. 18 (d, J=2. 4Hz, 1H), 6. 97 (dd, J=6. 6Hz and 1. 5Hz, 1Η), 6.73 (s, 1H), 4. 01 (d5 J=6. 6Hz, 2H) 5 3. 89(s,3H), 1. 55(s,9H), 1. 07-1. 02 (m, 1H), 0. 43 (q, J=6. 9Hz, 2H), 0. 05 (q, J=3. 6Hz, 2H).  128244-3 484- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 β Μ 3-day iHNMR data 2138 181-182 418. 1 氺氺氺 !Η NMR (CDC13? 300MHz)? 67. 56 (d? J=8. 7Hz? 2H)? 7. 46 (d, J=8. 7Hz, 2H), 7. 36 (d, J=9. 0Hz, lH), 7. 17(d, J=2. 4Hz, 1H), 6. 97 (dd, J=9. 0Hz and 2. 1Hz, 1H), 6. 72 (s, 1H), 5. 07-5. 03 (m, 1H), 4. 11 (q, J=6. 9Hz, 2H), 4. 00 (d, J=6. 6Hz, 2H), 1. 46(t, J=7. 2Hz, 3H)? 1. 32 (d5 J=6. 3Hz, 6H), 1. 09-1. 01 (m, 1H), 0. 48-0. 40 (m, 2H), 0. 08-0. 01 (m5 2H).   2139 185-186.  417. 1 氺 lU NMR (DMSO? 400MHz) 5 δ8. 77 (s, 1H), 7. 65 (d, J=8. 8Hz, 1H), 7. 59 (d, J=8. 4Hz, 2H), 7. 45 (d, J=8. 4Hz, 2H), 7. 04 (d, J=2. 0Hz, 1H), 6. 94 (dd, J=9. 2Hz and 2. 4Hz, 1H), 6. 30 (t, J=8. 8Hz, 1H), 4. 10-4. 07 (m5 4H), 3. 05 (q, J=6. 8Hz, 2H), 1. 47-1. 43 (m, 2H), 1. 37 (t, J=6. 8Hz, 3H), 0. 89-0. 85 (m, 4H)? 0. 31-0. 27 (m5 2H)? 0. 04-0. 00 (m? 2H).   2140 169-170 392. 3 氺 NMR (CDC13, 400MHz), 57. 58-7. 51 (m? 3H)? 7. 43 (d? J=8. 4Hz, 2H), 7. 18 (d, J=2. 4Hz5 1H), 6. 93 (dd, J=9. 2Hz and 2. 4Hz, 1H), 6. 72 (s, 1H), 5. 09-5. 03 (m, 1H), 4. 69-4. 62 (m? 1H)? 3. 89 (s, 3H), 1. 59 (d, J=7. 2Hz, 6H), 1. 33 (d, J=6. 0Hz, 6H)· 2141 201-202 398. 2 氺氺 NMR (CDC13? 300MHz)? 57. 52 (dd, J=8. 7Hz and 2·1Ηζ, 2H), 7. 37 (dd5 J=7. 2Hz and 1·8Ηζ, 2H), 7. 32 (d, J=9. 0Hz, lH), 7. 17(d, J=2. 1Hz, 1H), 6. 99 (dd, J = 9. 0Hz and J=2. 4Hz, 1H), 6. 81 (s, 1H), 4. 18-4. 08 (m, 4H), 3. 25 (q, J=7. 5Hz, 2H), 1. 49-1. 42 (m, 6H), 1. 36(t, J=7. 2Hz? 3H).  128244-3 -485 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day iHNMR data 2142 164-165 412. 2 ln ln NMR (CDC13? 300MHz)? δ7·52 (d, J=8. 1Hz, 2H), 7. 47-7. 38 (m, 3H), 7. 18 (s, 1H), 6. 98 (d, J=9. 0Hz, 1H), 6. 90 (s, 1H) 5 4. 19-4. 04 (m, 4H), 3. 23 (t, J=7. 2Hz, 2H), 1. 99-1. 83 (m, 2H), 1. 46 (t, J=6. 6Hz, 3H), 1. 36(t, J=7. 2Hz, 3H), 1. 06(t, J=7. 2Hz? 3H).   2143 204-205 410. 0 氺氺 lU NMR (CDC13? 400MHz)? 57. 52 (d? J=8. 7Hz? 2H)? 7. 42 (d, J=8. 7Hz, 2H), 7. 33 (d, J=9. 0Hz, lH), 7. 17(d, J=2. 1Hz, 1H) 5 7. 03 (s, 1H), 6. 99 (dd, J=9. 0Hz and 2. 4Hz, 1H), 4. 19-4. 08 (m, 4H), 2. 66-2. 27 (m, 1H), 1. 46 (t, J=6. 9Hz, 3H), 1. 36(t, J=7. 2Hz? 3H)? 1. 27-1. 23 (m, 2H), 1. 08-1. 03 (m, 2H).   2144 167-169 403. 3 * !H NMR (CDC135 400MHz)? 57. 70 (br5 1H)? 7. 52 (d? J 2 8.0 Ηζ, 2H), 7. 45 (d, J=8. 0Hz, 2H), 7. 38 (d, J=8. 8Hz, 1H)? 7. 17 (d? J=2. 0Hz, 1H), 6. 99 (dd, J=9. 2Hz and 2. 4Hz, 1H), 4. 12 (q, J=7. 2Hz, 2H), 4. 01 (d, J=6. 4Hz, 2H), 3. 37 (q, J=6. 8Hz5 2H), 1. 47 (t, J=6. 8Hz, 3H), 1. 24 (t, J=7. 2Hz, 3H), 1. 10-1. 04 (m, 1H), 0. 45 (q, J=4. 2Hz, 2H), 0. 09-0. 03 (m? 2H).  128244-3 486 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC5〇 β Μ 3-day ^NMR data 2145 189-192 417. 3 氺氺 lU NMR (CDC13? 400MHz) 5 57. 50-7. 43 (m, 4H) 5 7. 38 (d? J=9. 2Hz, 1H), 7. 22 (s, 1H), 7. 17 (d5 J=2. 4Hz5 1H)? 6. 99 (dd, J=9. 2Hz and 2. 4Hz5 lH), 4. 12(q, J=6. 8Hz, 2H), 4. 04-3. 97 (m, 3H), 1. 47 (t, J=7. 2Hz, 3H), 1. 21 (d, J=6. 4Hz, 6H), 1. 06-1. 04 (m5 1H)5 0. 42 (q, J=6. 4Hz, 2H), 0. 06 (q? J=4. 8Hz, 2H).   2146 162-163 406. 3 氺 lH NMR (CDC13? 400MHz)? 37. 57-7. 44 (m, 4H), 7. 18-7. 17 (m, 2H), 6. 94 (dd, J=9. 2Hz and 2·4Ηζ, 1H), 6. 70 (s, 1H), 5. 06-5. 00 (m, 1H), 4. 73-4. 66 (m, 1H), 4. 11 (q, J=6. 8Hz, 2H), 1. 61 (d, J=6. 8Hz, 6H), 1. 46(t, J=7. 2Hz, 3H), L31 (d, J=6. 4Hz, 6H).   2147 182-184 360. 2 氺氺氺 2148 142-146 416. 4 **氺 2149 134-136 346. 4 *氺氺 2151 202-204 468. 1 氺氺氺 NMR (CDC13? 400MHz)? 61. 33 (d? 6H)? 1. 73-1. 95 (m? 2H), 2. 26-2. 38 (m, 2H), 2. 71-2. 85 (m? 2H), 4. 90-5. 10 (m, 2H), 6. 72 (s, br, 1H), 7. 08(t,1H), 7. 14-7. 18 (dd, 1H), 7. 43 (d, 2H), 7. 56 (s, 1H), 7. 59 (t5 2H), 7. 79 (d51H), 8. 60 (d, 2H) 2152 164-168 393. 3 氺氺* 2153 207-211 392. 3 氺本氺 2154 185-195 470. 3 (M-1) 氺氺氺 128244-3 487- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC5〇//M 3-day ^NMR data 2155 194-195 378. 2 *氺 lU NMR (CDC13? 300MHz)? δ7·57 (d, J=8. 4Hz, 2H), 7. 48 (d5 J=8. 7Hz, 2H), 7. 31 (d, J=9. 0Hz, lH), 7. 17(d, J=1. 8Hz5 1H)? 6. 99 (dd? J=9. 0Hz and 1. 8Hz, 1Η), 6·76 (s5 lH), 4. 26 δ q, J=6. 9Hz, 2H 6, 4. 19-4. 07 (m? 4H)? 1. 46 (t, J=6. 9Hz, 3H), 1. 37-1. 32 (m, 6H).   2156 179-180 392. 1 *氺 lU NMR (CDC13? 300MHz)? δ7·57 (d, J=8. 7Hz, 2H), 7. 48 (d, J=8. 7Hz, 2H) 5 7. 31 (d, J=9. 0Hz, 1H), 7. 17(4 J=2. 1Hz, 1H), 6. 97 (dd, J=8. 7Hz and 2. 4Hz, 1H), 6. 71 (s, 1H), 5. 07-5. 03 δ m, ΙΗδ, 4. 19-4. 07 (m, 4H), 1. 46 (t, J=6. 9Hz, 3H), 1. 37-1. 32 (m, 9H).   2157 223-224 377. 2 * lU NMR (CDC13? 400MHz), δ7. 52 (d, J=8. 4Hz, 2H) 5 7. 44 (d, J=8. 4Hz, 2H), 7. 32 (d, J=9. 2Hz? 1H)3 7. 17-7. 13 (m? 2H), 6. 98 (dd, J=8. 8Hz and 2·4Ηζ, 1H), 5. 10 (br,1H), 4. 17-4. 10 (m 4H) 5 3. 32 5 q5 J=7. 2Hz, 2H5, 1. 47(t, J=7. 2Hz, 3H), 1. 34(t, J=7. 2Hz, 3H) 1. 20 (t, J=7. 2Hz, 3H).   2158 193-194 391. 2 氺氺 NMR (CDC13? 300MHz) 9 57. 72 (br? 1H), 7. 52-7. 42 (m? 4H), 7. 33 (d, J=9. 0Hz, 1H), 7. 17 (d, J=2. 4Hz, 1H), 6. 99 (dd, J=8. 7Hz and 2·1Ηζ, 1H), 4. 18-4. 08 (m5 4H)? 4. 06-3. 97 5 m? 1Ηδ? 1. 47 (t? J=6. 9Hz? 3H), 1. 35(t, J=7. 2Hz, 3H), 1. 23(d, J=6. 6Hz,6H)· 128244-3 488 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC5〇//M 3-day hNMR data 2159 199-200 405. 3 * NMR (CDC13? 400MHz)? δ7·54-7. 52 (m, 3H), 7. 37 (d, J=8. 4Hz? 2H)? 7. 30 (s? 1H)? 7. 15 (d, J=2. 4Hz, lH), 6. 94 (dd, J=8. 8Hz and 2. 4Hz, 1H), 5. 25 (br, 1H)? 4. 72-4. 65 (m5 1H)?4. 11 5q, J=6. 8Hz? 2H δ? 3. 24 (t, J=7. 2Hz, 2H), 1. 62-1. 52 (m? 8H)? 1. 47 (t? J=7. 2Hz, 3H), 0. 95 (t, J=7. 6Hz, 3H).   2160 226-227 404. 3 氺氺 NMR (CDC13? 300MHz)? δ7·57 (d, J=8. 4Hz, 2H), 7. 47 (d, J=8. 7Hz, 2H), 7. 37 (d, J=9. 0Hz, 1H), 7. 17 (d, J=2. 4Hz, 1H), 6. 97 (dd, J=9. 0Hz and 2·4Ηζ, 1H), 6. 75 (s, 1H), 4. 26 (q5 J=7. 2Hz, 2H), 4. 11 (q, J=7. 2Hz, 2H), 4. 00 (d, J=6. 6Hz5 2H)? 1. 46 (t5 J=7. 2Hz, 3H), 1. 34(t, J=6. 9Hz, 3H), 1. 09-1. 01 (m, 1H)? 0. 47-0. 40 (m? 2H)? 0. 08-0. 01 (m? 2H).   2161 177-183 456. 3 (M-1) 氺氺氺 2162 210-212 504. 3 氺氺氺 2163 136-138 505. 3 氺氺氺 2164 160-164 442. 3 (M-1) 氺氺氺 2165 179-180 406. 2 氺氺 lU NMR (DMSO? 400MHz)? δ9·69 (s, 1H), 7. 67 (d, J=8. 4Hz, 2H)? 7. 60 (d5 J=8. 8Hz, 1H), 7. 49 (d, J=8. 8Hz, 2H), 7. 05 (d, J=2. 0Hz, 1H), 6. 94 (dd, J=8. 8Hz and 2. 4Hz, 1H), 4. 16 (q5 J=6. 4Hz, 2H), 4. 07 δ q, J=6. 8Hz5 2H δ? 1. 49 (s? 9H)? 1. 34(t, J=6. 8Hz5 3H), 1. 18 (t, J=6. 8Hz, 3H).  128244-3 -489- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 β Μ 3-day iHNMR data 2166 181-182 430. 1 氺氺 lU NMR (CDC13? 300MHz)? 67. 54 (d? J=8. 4Hz? 2H)? 7. 46 (d, J=8. 4Hz, 2H), 7. 36 (d, J 2 9. 0Ηζ, 1H) 5 7. 17 (d, J=2. 7Hz, 1H), 6. 97 (dd, J=8. 7Hz and 2. 1Hz, 1H), 6. 65 (s, 1H), 4. 11 (q, J=6. 9Hz, 2H), 3. 99 (d, J=6. 6Hz, 2H), 1. 55 (s, 9H), 1. 46 (t, J=6. 9Hz, 3H) 5 1. 08-1. 01 (m, 1H), 0. 47-0. 40 (m? 2H)? 0. 09-0. 02 (m? 2H).   2167 185-187 538. 3 氺氺氺 2168 148-149 539. 4 氺氺氺 2169 197-198 555. 4 氺氺氺 2170 141-143 513. 4 氺氺氺 2171 202-204 429. 3 氺氺氺 2172 179-183 421. 3 氺氺 2173 190-194 420. 3 氺氺 2174 161-166 442. 3 (M-1) 氺氺氺 2175 193-195 502. 3 氺氺氺 2176 187-189 502. 3 氺氺氺 2177 167-196 476. 3 氺氺氺 2178 235-237 530. 3 氺氺* 2179 195-197 504. 4 氺氺氺 2180 203-205 488. 3 氺氺氺 2181 207-209 530. 4 (M-1) 氺氺氺 2182 202-204 494. 3 本氺氺 2183 225-227 474. 9 氺氺氺 2184 220-222 503. 4 氺氺氺 2185 212-215 487. 4 **氺 128244-3 490 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC5〇 // Μ 3-day ^NMR data 2187 &gt;250.  (decomposition) 395. 8 氺氺 lU NMR (CDC13? 400MHz), δ8. 08 (d, J=7. 6Hz, 2H), 7. 67-7. 65 (m, 3H), 7· 19 (s, 1H), 6. 99 (d, J=8. 8Hz, 1H), 4. 94-4. 88 (m, 3H)? 4. 14 (q? J=6. 8Hz, 2H), 2. 80-2. 72 (m5 2H), 2. 40-2. 35 (m5 2H)? 2. 01-1. 83 (m, 2H), 1. 50 (t, J=6. 8Hz, 3H).   2188 210-212 437. 9 氺氺 lH NMR (CDC13? 400MHz)? δ 8. 03 (d? J=8. 4Hz5 2H)? 7. 67-7. 63 (m, 3H), 7. 18 (d, J=1. 6Hz, 1H), 6. 99 (dd, J=8. 8Hz and 2. 0Hz, 1H), 4. 91-4. 87 (m, 1H), 4. 35 (d, J=7. 6Hz, 1H), 4. 14 (q, J=6. 8Hz, 2H), 3. 61-3. 56 (m, 1H), 2. 77-2. 72 (m, 2H), 2. 38-2. 32 (m? 2H)? 1. 96-1. 82 (m, 2H), 1. 49(t, J=7. 2Hz, 3H), 1. 16 (d, J = 6. 8Hz, 6H).   2189 170-171 438. 0 氺氺 lU NMR (CDC13? 400MHz)? δ 8. 01 (d, J=8. 0Hz, 2H), 7. 67-7. 63 (m, 3H), 7. 18 (s, 1H), 6. 99 (d, J=8. 8Hz, 1H), 4. 94-4. 85 (m, 1H), 4. 45 (t, J=6. 4Hz, 1H), 4. 14 (q, J=7. 2Hz? 2H)? 3. 03 (q, J=6. 4Hz, 2H), 2. 81-2. 70 (m, 2H)? 2. 39-2. 32 (m5 2H)? 1. 99-1. 80 (m, 2H), 1. 62-1. 54 (m, 2H), 1. 49 (t, J=7. 2Hz, 3H), 0. 95 (t, J=7. 2Hz? 3H).  128244-3 491 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day iHNMR data 2190 191-193 451. 9 * lU NMR (CDC13? 400ΜΗζ)? δ 8. 03 (d, J=8. 4Hz, 2Η), 7. 67-7. 63 (m, 3H), 7· 17 (d, J=1. 6Hz, 1H), 6. 98 (dd, J=8. 8Hz and 2·0Ηζ, 1H), 4. 93-4. 85 (m, 1H), 4. 31 (d, J=8. 4Hz? 1H)? 4. 13 (q? J=7. 2Hz, 2H), 3. 40-3. 33 (m, 1H), 2. 78-2. 68 (m, 2H), 2. 38-2. 32 (m? 2H)? 2. 01-1. 81 (m, 2H), 1. 57-1. 42 (m, 5H), 1. 12 (d, J=7. 2Hz, 3H) 5 0. 82 (t, J=7. 2Hz, 3H).   2191 185-187 450. 0 氺氺 lU NMR (CDC13? 400MHz)? δ 8. 00 (d, J=8. 0Hz, 2H), 7. 67-7. 62 (m53H), 7. 17 (d, J=1. 6Hz, lH), 6. 99 (dd, J=8. 8Hz and 2·0Ηζ, 1H), 4. 91-4. 84 (m? 1H)? 4. 69 (d? J=8. 8Hz, lH), 4. 12(q, J=6. 8Hz, 2H), 3. 92-3. 86 (m, 1H), 2. 79-2. 69 (m, 2H), 2. 38-2. 32 (m, 2H), 2. 26-2. 18 (m, 2H), 1. 98-1. 82 (m, 4H), 1. 80-1. 61 (m, 4H), 1. 50 (t, J=7. 2Hz, 3H).   2192 463. 9 氺 4 NMR (CDC13, 400MHz), δ 8. 00 (d, J=8. 0Hz, 2H), 7. 67-7. 63 (m, 3H), 7. 18 (s, lH), 6. 99 (d, J=8. 8Hz, 1H), 4. 94-4. 85 (m, 1H), 4. 45 (d, J=6. 8Hz, lH)?4. 14(q5 J=7. 2Hz, 2H), 3. 72-3. 67 (m5 1H)? 2. 80-2. 70 (m, 2H), 2. 38-2. 32 (m, 2H), 1. 98-1. 80 (m, 4H), 1. 65-1. 43 (m, 9H).  128244-3 492 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day WNMR data 2193 218-221 410. 2 * lH NMR (CDC13? 400ΜΗζ)? δ 8. 02 (d, J=8. 4Hz, 2H), 7. 67-7. 59 (m, 3H), 7. 19 (d, J=2. 0Hz, 1H), 7. 00 (dd, J=8. 8Hz and 2. 0Hz, 1H), 4. 94-4. 85 (m, lH), 4. 40-4. 37 (q, J=5. 2Hz, lH), 4. 14(q, J=6. 8Hz, 2H), 2. 82-2. 73 (m, 5H), 2. 36 (q, J=8. 4, 2H), 2. 01-1. 83 (m, 2H), 1. 57 (t, J=7. 2Hz, 3H).   2195 203-210 431. 3 氺本氺 2196 203-210 431. 3 氺氺氺 2197 180-182 525. 46 2198 197-200 524. 37 氺氺氺 2199 160-163 511. 44 氺氺氺 2200 196-198 510. 43 氺氺氺 2201 146-147 486. 4 2202 152-153 474. 4 氺氺氺 2203 215-216 485. 4 氺氺氺 2204 164-165 500. 4 氺氺氺 2205 179-181 510. 4 (M-1) 氺氺氺 NMR (300 MHz, CDC13): 7. 62 (1H5 d, J = 8. 8 Hz), 7. 58 (2H,d,J = 8. 5 Hz), 7. 43 (2H,d,J = 8. 5 Hz), 7. 20 (1H, d, J = 2. 0 Hz), 6. 95 (lH, dd, J = 8. 8, 2. 0 Hz), 6. 81 (lH, brs), 4. 94 (1H,p,J = 8. 7 Hz), 4. 40 (lH,q,J = 0. 7 Hz), 4. 13 (2H, q? J = 7. 0 Hz), 2. 89-2. 76 (2H? m), 2. 39-2. 28 (2H, m), 2. 00-1. 50 (7H, m), 1. 25-1. 12 (2H, m), 1. 17(3H,s), 1. 12 (3H, s), 0. 88 (3H, s).  128244-3 493 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day WNMR data 2206 138-139 529 氺氺氺 lU NMR (300 MHz, CDC13): 7. 63 (1H? d? J = 8. 8 Hz), 7·57 (2H,d,J = 8. 5 Hz), 7. 43 (2H,d,J = 8. 5 Hz), 7. 20 (1H, d, J = 2. 0 Hz), 6·95 (1H, dd, J = 8. 8, 2. 0 Hz), 6. 76 (lH, brs), 5. 11 (lH,p,J = 5. 1 Hz), 4. 94 (lH,p,J = 8. 5 Hz), 4. 13 (2H5 q, J = 7. 0 Hz), 2. 90-1. 65 (7H, m)5 1. 48 (3H? t? J = 7. 0Hz)? 1. 25 (3H, s), 1. 17(3H,d,J = 7. 6 Hz), 1. 00 (3H, s).   2207 166-168 510. 4 氺氺 lK NMR (300 MHz, CDC13): 7·62 (1H,d, J = 8. 8 Hz), 7. 57 (2H, d5 J = 8. 5 Hz), 7. 50 (2H,d,J = 8. 5 Hz), 7. 20 (1H, d, J = 2. 0 Hz), 6. 95 (lH, dd, J = 8. 8, 2. 0 Hz), 6. 83 (lH, brs), 4. 96 (1H, narrow m), 4. 13(2H, q? J = 7. 0 Hz), 2. 88-2. 77 (2H? m), 2. 40-2. 29 (2H, m), 2. 17-1. 50 (19H, m).   2208 blister 482. 1 氺氺氺 2209 Swim 482. 1 氺氺氺 2210 194-196 494. 4 氺氺氺 lU NMR (300 MHz, CDC13): 0. 27-0. 37(m,1H), 〇. 44_〇. 65(m,3H), 0. 98-1. 11 (m, 1H), 1. 40 (d, 3H), 1. 69-1. 97 (m, 2H), 2. 25-2. 38 (m, 2H), 2. 69-2. 87 (m, 2H), 4. 29-4. 41 (m, 1H), 4. 88-5. 04 (m, 1H), 6. 76 (s5 br, 1H), 7. 07 (t5 1H), 7. 14-7. 19 (dd, 1H), 7. 40-7. 46 (m? 2H)? 7. 53-7. 62 (m, 3H), 7. 79 (d, 1H), 8. 59 (d, 2H) 2211 119-120 510. 4 氺氺氺 2212 151-153 448. 4 *氺氺 2213 202-204 472. 4 氺氺氺 2214 213-215 472. 4 氺氺氺 2215 80-82 486. 4 氺氺氺 2216 498. 4 128244-3 -494- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC5〇 β Μ 3-day iHNMR data 2217 154-156 480. 1 氺氺氺 NMR (300 MHz, CDC13): 0. 26-0. 35(m, 1H), 〇. 44_〇. 73 (m, 5H), 0. 96-1. 10 (m, 3H), 1. 40(d,3H)5 3. 36-3. 45 (m? 1H)? 4. 30-4. 41 (m, 1H), 6. 77 (s, br, 1H), 7. 06 (t, 1H), 7. 13-7. 17 (dd, 1H), 7. 51 (d, 1H), 7. 56-7. 64 (q, 4H), 7. 76 (d, 1H), 8. 59 (d, 2H) 2218 233-235 446. 1 氺氺 2219 241-244 460. 2 氺氺氺 2220 189-192 474. 2 氺氺氺 2221 218-220 474. 2 氺氺氺 2222 145 (Decomposition) 472. 2 2223 195-197 434. 2 (M-1) 氺氺氺 lU NMR (CDCIb, 300MHz)? δ 8. 06 (d, J=8. 4Hz, 2H), 7. 68-7. 65 (m, 3H), 7. 18 (d5 J=2. 1Hz, 1H), 6. 99 (dd, J=8. 4Hz and 1·8Ηζ, 1H), 4. 93-4. 87 (m, 2HX4. 18-4. Il (m5 2H), 2. 79-2. 71 (m, 2H), 2. 41-2. 35 (m, 3H), 1. 97-1. 82 (m, 2H), 1. 49 (t, J=6. 9Hz5 3H), 0. 71-0. 68 (m, 4H)· 2224 161-163 480. 2 氺氺氺 2225 174-175 494. 2 氺氺氺 2226 163-164 494. 2 氺氺氺 2227 174-176 492. 2 氺氺氺 2228 208-210 492. 2 氺氺 2229 192-195 460. 2 氺氺氺 2230 220-222 474. 2 氺氺氺 2231 259-261 488. 2 氺氺氺 2232 178-180 488. 2 氺氺氺 2233 239-240 486. 2 2234 120-123 488. 3 2235 140-147 423. 2 (M-1) 氺氺 2236 Glass material 516. 5 (M-1) 128244-3 •495 - 200831489 Compound No. Melting point (°C) Mass Spectrum [M+H] Replicon IC50 // Μ 3_day iHNMR Data 2237 178-179 504. 2 2238 Glass material 536. 4 (M-1) 氺氺氺 2239 209-211 454. 5 氺*氺 2240 91-93 482. 5 2241 122-124 470. 4 氺氺 2242 186-188 466. 4 氺氺氺 2243 161-163 480. 4 氺氺氺 2244 178-180 416. 2 氺氺 NMR (CDC13, 400MHz), 57. 65 (d? J=8. 4Hz5 lH), 7. 55-7. 52 (m, 4H), 7. 24 (d, J=1. 6Hz5 1H), 6. 98 (dd, J=8. 8Hz and 2. 0Hz, 1H), 4. 94-4. 89 (m, lH), 4. 14(q, J=6. 8Hz, 2H), 3. 59 (b, 2H), 3. 34 (b9 2H)? 2. 88-2. 83 (m? 2H), 2. 36-2. 29 (m, 2H), 1. 97-1. 80 (m, 2H), 1. 49 (t5 J=6. 8Hz, 3H), 1. 43-1. 18 (m, 6H).   2245 235-236 402. 1 氺氺 lU NMR (CDC13, 400MHz)? 57. 90 (d? J=8. 4Hz, 2H)? 7. 64 (d5 J=8. 8Hz, 1H), 7. 56 (d, J=8. 0Hz, 2H), 7. 19(s,1H), 6. 97 (dd, J=8. 8Hz and 2. 0Hz, 1H), 5. 97 (d, J=7. 6Hz, 1H), 4. 94-4. 90 (m, 1H), 4. 35-4. 30 (m, lH), 4. 13(q, J=6. 8Hz, 2H)? 2. 80-2. 74 (m5 2H)? 2. 37-2. 33 (m, 2H), 1. 95-1. 79 (m, 2H), 1. 49(t, J=6. 8Hz, 3H), 1. 30 (d? J=6. 8Hz, 6H).   2246 201-202 氺氺 lU NMR (CDC13? 300MHz)? δ7. 65 (d, J=8. 7Hz, 1H), 7. 59-7. 52 (m, 4H), 7. 23 (d, J=2. 1Hz, 1H), 6. 98 (dd, J=8. 7Hz and 2. 1Hz, 1H), 4. 94-4. 88 (m, lH), 4. 14(q, J=6. 9Hz, 2H), 3. 79-3. 54 (m, 8H), 2. 88-2. 80 (m, 2H), 2. 37-2. 29 (m, 2H), 1. 98-1. 80 (m, 2H), 1. 49 (t, J=6. 9Hz, 3H).  128244-3 -496- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 β Μ 3-day ^NMR data 2247 154-156 400. 2 氺氺 lU NMR (CDC13? 400MHz)? 57. 77 (d? J=8. 0Hz? 2H)? 7. 65 (d? J=8. 8Hz? 1H)? 7. 53 (d? J=8. 0Hz, 2H), 7. 19(d, J=1. 6Hz? 1H)? 6. 98 (dd? J=8. 8Hz and 2. 0Hz, 1H), 4. 93-4. 88 (m, 1H) 5 4. 33 (t, J=6. 8Hz? 4H)? 4. 14 (q9 J 2 6. 8Ηζ, 2H), 2·82·2·76 (m, 2H), 2. 44-2. 30 (m, 4H), 1. 95-1. 80 (m, 2H), 1. 49 (t, J=6. 8Hz, 3H).   2248 217-218 414. 2 氺氺 lU NMR (CDC13? 400MHz)? 57. 89 (d? J=8. 0Hz? 2H)? 7. 64 (d, J=8. 8Hz5 1H), 7. 56 (d, J=8. 0Hz? 2H)? 7. 19 (d? J=1. 6Hz, lH), 6. 97 (dd, J=8. 4Hz and 2·0Ηζ, 1H), 6. 29 (d, J=7. 6Hz, 1H), 4. 94-4. 89 (m, 1Η), 4·64-4·62 (πι, 1H), 4. 13 (q, J=6. 8Hz, 2H), 2. 80-2. 74 (m, 2H), 2. 48-2. 47 (m, 2H), 2. 38-2. 31 (m, 2H), 2. 02-1. 78 (m, 6H) 1. 49 (t? J=6. 8Hz? 3H).   2252 105-109 419. 9 氺氺* 2253 261-265 304. 6 *氺 2254 204 (Decomposition) 515. 3 氺氺* 2255 228-231 426. 2 氺氺氺 2256 194-196. 5 440. 3 ** 2257 208-210. 5 438. 3 氺氺氺 2258 182-187. 5 440. 3 氺氺 2259 62-65 456. 3 氺氺氺 2260 155-157 486. 3 氺** 2261 Glass material 494. 4 氺氺 2262 Glass material 496. 4 氺氺氺 128244-3 -497- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50#m 3-day ^NMR data 2263 223-224 503. 4 氺氺氺 lH NMR (300 MHz, CDC13): 1. 15(d,6H), 1. 70-1. 92 (m, 2H), 2. 31-2. 45 (m, 2H), 2. 64-2. 81 (m, 2H), 3. 52-3. 63 (m5 1H), 5. 05-5. 16 (m, 1H), 6. 62 (d, 1H), 7. 15-7. 25 (m, 2H), 7. 47-7. 52 (m, 2H), 7. 56-7. 61 (m, 2H), 7. 70-7. 75 (m, 2H), 8. 562 (d, 2H), 9. 03 (s, br, 1H) 2264 196-201 373. 0 * 2265 168-173 443. 5 * 2266 218-223 473. 5 ** 2267 206-211 465. 5 氺氺 2268 172-178 485 2269 442. 3 氺氺氺 2270 228-233 484. 2 氺氺氺 2278 Glass material 496. 1 氺氺氺 2279 200-205 494. 1 * 2280 155-160 458. 5 氺氺氺 2281 180-185 456. 5 氺 2282 181-185 470. 5 氺氺氺 2283 198-203 459. 5 氺氺氺 2284 Glass material 514. 2 (M-1) 氺氺氺 2285 Glass Matter 518. 2 氺氺氺 2286 191-193 389. 0 氺*氺 2287 Glass material 488. 3 氺氺氺 2288 216-217 475. 4 氺氺氺 2289 145-150 490. 5 氺 2290 195-200 490. 5 氺 128244-3 -498 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50&quot;m 3-day ^NMR data 2291 240-245 470. 5 氺氺氺 2292 195-196 475. 1 氺氺 2298 172-177 496. 5 *** 2299 146-148 539. 4 氺氺氺 2300 186-189 484. 6 氺氺 2301 241-243 481. 5 氺氺氺 2302 197-202 467. 4 氺氺 2303 414. 3 ln ln NMR (CDC13? 300MHz) 5 δ7·69-7. 64 (m, 3H), 7. 52 (d, J=8. 1Hz, 2H), 7. 22 (d, J=2. 1Hz, 1H), 6. 97 (dd, J=8. 7Hz and 2·1Ηζ, 1Η), 4. 94-4. 88 (m? 1H), 4. 14 (q? J=6. 9Hz, 2H), 2. 73-3. 50 (m, 4H) 5 2. 87-2. 79 (m, 2H) 5 2. 35-2. 32 (m, 2H), 1. 97-1. 83 (m, 6H), 1. 49 (t, J=6. 9Hz, 3H)· 2304 428. 2 氺氺 lU NMR (CDC13? 300MHz), 57. 65 (d? J=8. 7Hz? 1H)? 7. 57-7. 50 (m5 4H), 7. 23 (d, J=2. 1Hz, 1H), 6. 98 (dd, J=8. 7Hz and 2·1Ηζ, 1H), 4. 91-4. 88 (m, 1H), 4. 14 (q5 J=7. 2Hz, 2H) 5 3. 75 (b, 2H), 3. 43 (b, 2H), 2. 88-2. 81 (m, 2H), 2. 34-2. 30 (m, 2H), 1. 97-1. 58 (m, 8H), 1. 49 (t, J=6. 9Hz, 3H)· 2305 Glass Matter 516. 4 (M-1) 氺氺氺 2306 Glass material 536. 4 (M-1) 氺氺氺 2307 509. 3 氺氺 2308 78-80 444. 4 (M-1) **氺 2309 217-222 470. 5 氺氺氺 2310 178-183 496. 5 2311 172-175 468. 2 氺 2313 Glass material 502. 3 (M-1) 氺氺氺 128244-3 -499 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50&quot;m 3-day ^NMR data 2314 Glass material 488. 4 氺氺氺 2315 Glass Matter 488. 5 氺氺氺 2316 Glass Matter 502. 4 氺氺氺 2317 Glass material 474. 8 氺氺氺 2318 199-201 500. 1 (M-1) 氺氺氺 2319 186 (Decomposition) 503. 2 氺氺氺 2320 134 (deomp. ) 503. 2 氺氺氺 2321 234-235 489. 2 氺氺氺 2322 187-189 480. 3 氺氺氺 2323 247-250 470. 3 氺氺氺 2324 224-226 497. 4 氺氺氺 2325 203-207 510 氺氺氺 2326 142-144 462. 4 氺氺氺 2327 153-155 496. 4 (M-1) 氺氺氺 2328 74-80 466. 1 氺氺氺 2329 78-84 500. 0 (M-1) * 2330 160-163 480. 2 氺氺* 2331 188-192 472. 1 氺氺氺 2332 180-184 486. 2 * 2333 198-202 460. 2 氺氺 2334 199-203 474. 1 氺氺氺 2335 208-212 472. 1 氺氺* 2336 179-180 486. 5 氺氺氺 2337 225-226 458. 3 氺氺氺 2338 262-263 444. 2 氺氺 128244-3 - 500 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50&quot;m 3·day iHNMR data 2339 165-165. 5 502. 0 氺氺氺 2340 186-187 506. 5 氺氺氺 2341 93-95 469. 4 氺氺氺 2342 163-165 498. 6 氺氺氺 2343 174-175 490. 5 氺氺 2344 98-99 482. 6 氺氺氺 2345 166-167 498. 5 (M-1) 氺氺 2346 177-178 476. 6 氺氺氺 2347 Glass Matter 476. 6 氺氺氺 2348 Glass material 440. 5 氺氺 2349 183-184 476. 3 * 2350 223-224 504. 3 氺氺 2351 180-181 500. 3 (M-1) *** 2352 255-256 520. 0 * 2353 148-149 498. 6 氺氺氺 2354 217-219 483. 7 氺氺氺 2355 205-207 490. 5 氺氺 2356 200-201 472. 4 (M-1) 氺 2357 181-182 456. 4 (M-1) * 2358 194-196 458. 3 (M-1) 氺 2359 234-236 486. 5 氺氺 2360 177-179 488. 5 氺氺氺 2361 243-245 454. 7 2362 260-262 448. 5 氺 2363 225-227 462. 7 氺氺 2364 250-251 476. 6 *氺氺 128244-3 -501 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 β Μ 3-day iHNMR data 2365 202-204 474. 6 氺氺 2366 241-243 490. 6 氺氺氺 2367 214-216 476. 5 氺氺氺 2368 178-182 460. 6 氺氺 2369 189-191 474. 6 氺氺 2370 177-179 502. 6 氺氺氺 2371 213-215 492. 5 氺氺氺 2372 225-227 518. 6 氺氺氺 2373 179-180 472. 5 氺氺氺 2374 113-115 446. 5 氺氺氺 2375 227-229 488. 8 氺氺氺 lU NMR (300 MHz, CDC13): 8. 58 (d, 2H, J = 4. 5 Hz), 7. 79(d,lH,J = 8. 7 Hz), 7. 51 (d, 1H, J = 8. 7 Hz), 7. 05-7. 36 (m, 6H), 6. 58 (s, 1H), 3. 99 (d, 2H, J = 6·6 Hz), 3. 20 (t, 2H, J = 7. 8Hz)? 1. 96 (m? 2H)? 1. 09 (t, 3H, J = 7. 5 Hz), 1. 04 (m, 1H), 0. 56 (m, 2H), 0. 04 (m, 2H).   2376 181-183 494. 6 氺氺氺 2377 166-168 488. 6 氺氺氺 2378 179-180 499. 8 氺氺氺 2379 211-213 498. 9 (M-1) 氺氺氺 lU NMR (300 MHz, CDC13): 8. 58(d, 2H, J = 4. 5Hz), 7. 79(d,1H,J = 8. 4 Hz), 7. 60 (d5 1H, J = 1. 5 Hz), 7. 06-7. 46 (m, 6H)? 6. 42 (s? 1H)? 4. 85 (m? 1H), 4. 02 (t, 1H, J = 8. 1 Hz), 2. 57-2. 79 (m? 4H)? 2. 30-2. 37 (m, 4H), 1. 78-2. 07 (m, 4H).   2380 221-223 502. 9 氺氺氺 2381 218-221 488. 0 氺氺氺 128244-3 - 502- 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day ^NMR data 2382 113-118 488. 6 氺氺氺 2383 114-122 503. 3 氺氺氺 2384 183-185 472. 6 氺氺 2385 211-213 470. 4 氺氺 2386 194-196 472. 7 * 2387 222-224 484. 4 氺氺 2388 215-216 470. 7 氺氺氺 2389 201-202 472. 7 氺 2390 234-238 487. 0 氺氺氺 2391 222-224 488. 9 氺氺氺 2392 106-109 456. 4 氺氺氺 2393 143-144 512. 8 氺氺氺 2394 203-204 488. 2 *氺 2395 221-222 494. 0 **氺 2396 179-180 468. 8 氺氺氺 2397 143-145 452. 7 氺 2398 Glass material 466. 7 氺氺 2399 94-104 468. 7 2400 193-196 442. 7 氺氺氺 2401 107-110 477. 7 氺氺氺 2402 193-195 400. 6 氺氺 2403 189-191 414. 6 * 2404 168-170 450. 9 氺氺 2405 173-175 456. 9 氺 2406 176-178 474. 6 氺氺氺 2407 210-212 436. 9 128244-3 - 503 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3-day Wnmr data 2408 230-236 466. 8 氺 2409 168-174 438. 7 氺氺 2410 143-144 462. 7 氺氺 2411 91-92 492. 7 氺氺 2412 144-145 472. 7 氺氺氺 2413 92-93 497. 9 氺氺氺 2414 91-93 485. 9 氺氺氺 2415 88-90 513. 0 2416 215-219 477. 7 氺氺 2417 118-120 477. 8 氺氺氺 2418 235-237 478. 8 氺氺氺 2419 212-214 478. 6 氺氺氺 2420 237-241 436. 7 氺氺 2421 211-215 450. 8 氺氺 2422 157-165 452. 8 氺氺氺 2423 218-220 488. 7 氺氺 2424 220-222 501. 0 氺氺氺 2425 233-236 448. 6 氺氺 2426 243-246 478. 9 氺氺 2427 150-154 451. 0 ** 2428 216-222 477. 1 氺氺 2429 189-192 472. 7 *** 2430 198-201 471. 6 氺氺氺 2431 234-237 472. 7 氺氺 2432 478. 9 氺 2433 Glass material 478. 7 氺氺氺 128244-3 - 504 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50/zM 3-day iHNMR data 2434 215-217 410. 1 氺氺氺 lH NMR (300 MHz, CDC13): 0. 67-0. 76 (m, 2H), 0. 96-1. 05 (m, 2H), 1. 27(d,6H), 3. 33-3. 42 (m5 1H) 5 3. 64-3. 79 (m, 1H), 3. 82 (d, br, 1H), 6. 68 (d5 2H), 7. 05 (t, 1H), 7. 10-7. 13 (dd5 1H), 7. 45-7. 53 (m, 3H), 7. 72 (d, 1H), 8. 458 (d, 2H) 2435 108-113 467. 0 氺 2436 lU NMR (300 MHz, CDC13): 7. 78-7. 74 (2H, m), 7. 56 (2H, d, J=6. 9 Hz) 5 7. 44 (2H,d, J=6. 9 Hz), 7. 33-7. 29 (2H,m), 6. 77 (lH, brs), 4. 99 (lH, 5, J = 9. 3 Hz), 4. 37-4. 33 (1H? m)? 2. 89-2. 82 (2H, m), 2. 39-2. 33 (2H, m), 2. 02-1. 76 (2H,m), 1. 39(3H,d,J=6. 6Hz), 1. 12-0. 98 (1H? m)? 0. 62-0. 44 (3H? m)? 0. 36-0. 27 (1H? m) 2437 186-190 451. 3 2438 234-237 485. 3 氺氺氺 2439 209-211 501. 3 *氺氺 2440 152-154 450. 1 氺氺氺 2441 434. 8 氺氺氺 2442 228-230 448. 9 氺氺氺 2443 208-210 471. 3 氺氺氺 2444 105-110 477. 3 氺氺氺 2445 94-95 487. 9 氺氺氺 2446 82-83 501. 8 氺氺氺 128244-3 - 505 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon ic50&quot;m 3-day ^NMR data 2447 89-90 481. 8 氺氺氺 2448 192-195 487. 9 *氺氺 2449 209-210 467. 0 氺氺 2450 211-213 490. 8 (M-1) ** 2451 194-196 424. 6 (M-1) 氺氺 2452 267-269 459. 7 *氺 2453 165-169 486. 6 氺氺氺 2454 182-185 501. 8 2455 72-84 511. 0 氺氺氺 2456 176-178 485. 0 2457 152-155 504. 7 *氺氺 2458 209-211 446. 0 氺氺氺 2459 205-207 458. 9 氺氺氺 2460 200-202 469. 9 2461 230-232 472. 1 氺氺氺 2462 218-219 471. 4 氺氺氺 2463 228-230 483. 6 *** 2464 222-223 497. 6 氺*氺 2465 227-229 485. 6 氺*氺 2466 144-145 499. 9 氺本氺 2467 89-90 442. 8 氺氺氺 2468 153-154 441. 6 氺*氺 2469 210-212 423. 5 氺** 2470 187-189 423. 5 氺氺氺 2471 171-176 436. 5 氺氺氺 2472 191-194 436. 4 *氺氺 2473 87-88 469. 4 氺氺氺 2474 91-92 443. 4 氺氺氺 2475 90-91 463. 3 氺氺 2476 228-229 450. 6 氺氺氺 128244-3 - 506 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 &quot; Μ 3-day iHNMR data 2477 178-179 477. 8 氺氺氺 2478 157-159 451. 8 氺氺氺 2479 102-103 527. 8 氺氺氺 2480 221-222 474. 1 氺氺氺 2481 193-194 440. 0 氺氺氺 2482 212-214 442. 4 氺氺氺 2483 92-98 485. 0 氺氺氺 2484 207-208 502. 0 氺氺氺 2485 222-224 383. 1 *氺氺 2486 239-241 469. 0 氺氺氺 2487 199-201 528. 9 氺氺氺 2488 226-228 528. 8 氺氺氺 2489 166-169 527. 7 氺氺氺 2490 114-115 508. 0 氺氺氺 2491 177-178 516. 0 氺氺氺 2492 215-216 502. 0 * 2493 170-171 507. 9 *氺氺 2494 466. 0 氺氺氺 2495 159-160 477. 6 (M-1) 氺氺氺 2496 195-196 465. 8 氺氺氺 2497 195-196 453. 9 氺氺氺 2498 452. 8 氺氺氺 2499 226-228 475. 4 (M-1) ** 2500 524. 4 氺氺氺 2501 516. 0 氺 2502 529. 9 氺氺 2503 497. 9 氺* 2504 82-88 460. 9 氺氺氺 2505 203-204 410. 1 氺氺氺 2506 214-215 487. 6 *氺氺 128244-3 - 507 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50 μ Μ 3-day iHNMR data 2507 222-223 501. 9 氺氺氺 2508 203-205 488. 1 氺氺氺 2509 126-130 522. 0 氺氺氺 2510 165-169 477. 7 (M-1) 2511 209-228 452. 9 氺氺氺 2512 175-177 453. 9 氺氺氺 2513 206-208 425. 7 氺氺 2514 150-152 416. 1 氺氺 2515 184-185 410. 1 氺氺氺 2516 201-203 436. 0 氺氺氺 2517 190-191 469. 9 [M-1] 2518 140-142 486. 0 (M-1) 氺氺氺 2519 204-207 472. 0 (M-1) 氺氺氺 2520 170-171 469. 9 (M-1) 氺氺本 2521 198-200 485. 9 (M-1) 氺氺氺 2522 248-258 440. 0 氺氺氺 2523 521. 9 氺氺氺 2524 236-245 438. 9 氺氺氺 2525 169-195 466. 0 氺氺氺 2526 196-197 467. 9 氺氺氺 2527 151-152 471. 8 氺氺氺 2528 168-169 485. 6 (M-1) *氺氺 2529 174-175 493. 9 氺氺氺 2530 165-166 497. 8 氺氺* 2531 173-174 511. 8 (M-1) 氺氺氺 2532 67-68 442. 1 2533 94-95 468. 8 氺氺氺 128244-3 - 508 - 200831489 Compound No. Melting point (°C) Mass spectrometry [M+H] Replicon IC50//M 3_day iHNMR data 2534 108-115 505. 8 氺氺氺 2535 192-194 516. 0 氺氺 2536 231-238 502. 1 氺氺氺 2537 190-201 486. 1 氺氺氺 2538 229-237 499. 9 氺氺氺 2539 216-218 517. 9 氺*氺 2540 149-152 505. 9 氺氺氺 2541 96-108 528. 2 氺氺氺 2542 115-122 549. 7 *氺氺 2543 115-124 550. 6 氺氺氺 2544 148-150 483. 5 (M-1) 氺氺氺 2545 87-89 485. 5 (M-1) Example 7: Evaluation of compound activity using HCV-poliovirus chimera In HCV-poliovirus (HCV-PV) chimera, PV 5' UTR is HCV 5' UTR and part ( The initial 123 amino acid) core coding sequence (nucleotides 18 to 710 of HCV lb) was replaced as shown in Figure 1 (130, 140). Therefore, the expression of gray virulence virus protein is regulated by HCV IRES. The poliovirus is a picornavirus in which protein translation initiation is mediated by IRES elements located in the 5&apos; UTR. At the 5' end of the HCV-PV chimeric genome, there is a PV-like leaf-like RNA structure, a necessary cis-acting replication message, terminating with the genomically linked protein VPg. The replication kinetics of HCV-PV chimeras are consistent with the kinetics of Mahoney and can cause cytopathic effects (CPE) in cell culture. Heptazyme (29), a ribozyme labeled with HCV IRES, has been shown to be resistant to chimeric viruses in cell culture (76, 77). 128244-3 - 509 - 200831489 To assess the activity of the compounds against chimeric viruses, HeLa cells were seeded and cultured for 24 hours at 37 ° C and 5% CO 2 . Then, the cells were infected with HCV-PV at a multiplicity of infection (MOI) of 0. The infection was carried out for 1 minute for 1 minute, and then treated with the compound for 1 day (the treatment time was optimized). The activity of the compound is measured by changes in cytopathic effect, plaque assay and/or viral RNA production (see, e.g., Table 1). Example 8: Evaluation of compounds against wild-type poliovirus (WT-PV) activity and poliovirus IRES translation assay (WT-PV single luc) Preparation of DNA constructs, designated pPVIRESmono, in which the PV IRES sequence was inserted (nuclei) The number of nucleotides 1-742) is between the promoter and the firefly luciferase (Flue) reporter gene. The stably transfected 293T cell line was established by infection with pPVIRESmono DNA by selecting resistance to hygromycin. The cells were treated with the compound for 20 hours as described above, and the activity was measured by quantifying the Flue message. Further, in order to evaluate the activity of the compound against wild-type poliovirus, HeLa cells were inoculated and cultured at 37 ° C and 5% CO 2 for 24 hours. Then, the cells are made wild-type poliovirus, at MOI at 0. The infection was carried out for 1 minute for 1 minute, followed by treatment with the compound for one day. The activity of the compound was measured by changes in cytopathic effect, plaque assay and RT-PCR using the poliovirus IRES primer and probe (see, e.g., Table 2). Furthermore, if the compound is active against poliovirus and other viral IRES, the compound can be used to treat a virus infected by any virus containing IRES. 128244-3 -510- 200831489 Table 2 Compound number WT-PV CPE (100 //M)* WT-PV CPE (10 WT-PV CPE (1 //M)* WTPV single luc IC5 〇(μΜ) 4 3 2 1 0. 8 5 3 2 1 9 9 3 2 2 &gt;100 10 3 2 2 &gt;100 19 3 2 1 15 24 3 2 2 1. 5 Example 9: In vitro translational assays In vitro translation assays can be used to distinguish between compounds that act on HCV IRES RNA or cellular translation factors. In an exemplary assay, the translated translational mRNA is the product of transcriptional efflux, obtained from the T7 RNA polymerase promoter of pHCVIRESmono plasmid DNA produced by the Ambion RNA MegaTranscript kit (Ambion, Austin, TX). The in vitro translation system uses HeLa cell lysate and is carried out by methods known to those skilled in the art. Preliminary results showed that the compound was pre-incubated with the HCV IRES RNA transcript, compared to the HeLa cell lysate pre-incubated at 37 ° C for 30 minutes, or without pre-culture (data not shown), or A variety of compounds of the invention have a relatively high activity against HCV IRES regulated translation. This indicates that this compound can interact with HCV IRES RNA in an in vitro translation assay. To confirm whether the compound selectively acts on HCV IRES, PLuc was used together with the cellular IRES mRNA transcript as a control group for in vitro translation. All of the publications and patent applications cited in this application are hereby incorporated by reference in their entireties as if individually, individually, individually, individually, individually, individually, individually. The same degree. While certain embodiments have been described in the foregoing, the embodiments of the present invention will be apparent to those skilled in the art. 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Internal ribosome entry in the cryptographic region of mouse hepatitis virus mRNA 5 .J Gen Virol. 75 (Pt 11) : 3041-3046. 129. Tsukiyama-Kohara, K., N. Iizuka, M. Kohara and A. Nomoto. 1992. Internal ribosome entry position in hepatitis C virus RNA· J Virol 66 : 1476-1483. % 130. Vagner, S., MC Gensac, A. Maret, F. Bayard, F. Amalric, H.

Prats and A. C. Prats. 1995. Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes. Mol Cell Biol 15 : 35-44. 131. Varaklioti A, Georgopoulou U, Kakkanas A , Psaridi L, Serwe M, Caselmann WH and Mavromara P. 1998 · HCV RNA 5, Mutational Analysis of Two Unstructured Functional Sites in Untranslated Regions · Biochem Biophys. Res Commun. 253 * 678-685. ^ 132. Wang, C·, S· Υ· Le, Ν· Ali and A· Siddiqui. 1995. RNA pseudo-knot is an essential structural element for the internal ribosome entry site in the uncoded region of hepatitis C virus S. RNA 1 : 526-537. 133. Wang, C., P. Sarnow and A. Siddiqui. 1993 • Translation of human hepatitis C virus RNA in cultured cells is mediated by internal ribosome binding machinery. J Virol 67 : 3338-3344. 134. Wang, C” P· Sarnow and A· Siddiqui. 1994·Conservative spiral single system is necessary for internal triggering of hepatitis C virus RNA translation· J Virol 128244-3 -531 - 200831489 68 : 7301 -7307. 135. Wang, S· M·, S· C· Fears, L· Zhang, J· J Chen and J. D. Rowley. 2000. Screening poly (dA/d!&gt; cDNA for genetic identification. Proc. Natl. Acad. 97: 4162-4167. 136. Wang, Τ·H·, R·C· Rijnbrand And S. M. Lemon. 2000. The core protein coding sequence, rather than the core protein, modulates the efficiency of the end-independent translation guided by the internal ribosome entry site of the hepatitis C virus _ J Virol 74 : 11347-11358. ( 137. Wimmer, E·, C· U· Hellen and X· Cao_ 1993. Genetics of poliovirus • Annu Rev Genet 27 : 353-436. 138. Wong, J· Β·, Τ· Poynard, Μ· Η· Ling, J· Κ· Albrecht and S·G· JPauker· 2000. Cost-effectiveness of interferon a-2b alone or with triazole nucleoside as initial treatment for chronic hepatitis C for 24 or 48 weeks. International Hepatitis Interventional Therapy Group · Am. J Gastroenterol. 95 : 1524-1530. 139. Zhao W· D· and Ε · Wimmer. 2001. Genetic analysis of poliovirus/hepatitis C virus chimera: hepatitis C virus internal nucleus The novel structure of the functional part II of the protein body into the I position. J Virol 75 : 3719-3730. 140. Zhao, W· D·, E·Wimmer and EC·Lahser· 1999. poliovirus/hepatitis C virus (internal ribosome entry into position-core) chimeric virus: improved growth properties corrected by proteolytic cleavage position and requiring core RNA sequence rather than core related Peptide · Virology 73 : 1546-1554. 141. Lukavsky, PJ·, I· Kim, G. A. Otto and J. D. Puglisi· 2003. Structure of HCV IRES Functional Site II as measured by NMR Nat Struct Biol 128244-3 - 532- 200831489 10 : 1033-1038. 142. Otto, G. Α· and JD Puglisi· 2005. Approaches to media translation by HCV IRES. Cell 119: 369-380. 143. Boni, S·, LJ Ρ· Lavergne, S. Boulant and A. Cahour· 2005. The hepatitis C virus core protein is used as a trans-modulation factor in the internal translation of viral RN A. J Biol Chem 280 : 17737-17748· 144. He, Y·, W· Yan, C. Coito, Υ· Li, Μ· Gale, Jr· and Μ·G· Katze. 2003. Interpretation of the internal ribosome-into-location of hepatitis C virus (HCV) Regulation by HCV replicons and non-structural proteins · J Gen Virol 84 : 535-543. 145. K Ato, J., Ν· Kato, H. Yoshida, S·Κ· Ono-Nita, Υ· Shiratori and Μ· Omata·2002· Hepatitis C virus NS4A and NS4B proteins are repressed in vivo. J Med Virol 66 : 187-199· 146. Li, D·, S· Τ· Takyar, W· Β· Lott and Ε·J· Gowans· 2003· Hepatitis C virus (HCV) core protein amino acid 1-20 in HepG2 Cells specifically inhibit HCV IRES-dependent translation and inhibit both HCV IRES- and end-dependent translation in HuH7 and CV-1 cells. J Gen Virol 84: 815-825. All documents cited herein This is incorporated herein by reference in its entirety as if it is incorporated herein in its entirety. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing an HCV-PV chimera structure. The leaf-like RNA structure of PV, a cis-acting replication message terminated by the genomic linker protein VPg, is located at the 5' end of the genome. Solid (HCV) and Open (PV) 128244-3 - 533 - 200831489 The block depicts an open translational backbone that encodes viral polypeptides. The position of the HCV core fragment (initial 123 amino acid) gene is represented by the Δ core. Overall, the HCV-specific sequence in HCV-PV spans from nucleotides 18 to 710 (139). (128244-3 534-

Claims (1)

200831489 X. Patent application scope: 1. A compound of formula I Wherein z X is — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Amino, --COORx group, the center of which is (^ to (: 6 alkyl; -methanyl; -c6 to c8 aryl, optionally substituted by alkoxy; or -5 or 6-membered heteroaryl) The base is optionally substituted by the following: -(^ to (6 alkyl, -C6 to C8 aryl, optionally substituted by alkoxy or one or more halogens, or -5 to 6 membered heteroaryl; Y To be: - a halogen group, 128244-3 200831489 -13⁄4 element, - benzofuran; - benzoquinone p-cephen; - dibenzofuran; - diphenyl hydrazine p-cephen; - benzopyrazole; 哚, as the case may be on the nitrogen (^ to (: 6 alkyl substitution; 1 ^ human. Rb, where Rb is hydrogen or (^ to decyl, and η is 0 or 1 Wherein Rc is hydrogen, -CONHRx, wherein Rx is as defined above, or -S02Rx, the center of which is as defined above; or 128244-3 200831489 Oh, Rd , wherein (1 is €1 to (6 alkyl or fluorene: 6 to (8 aryl; -NHCORe group, wherein Re is: -(^ to decyl; -C6 to Cs aryl, It is replaced by the following: - Ci to base, - alkoxy, -cyano, -nitro, or -halogen; -NHCOORx group, the center of which is as defined above; -CH2〇-Rf group, wherein Rf is q to q aryl; -_NRgRh a group wherein Rg is hydrogen or ^ to ^alkyl, and ^ is hydrogen or q to Q aryl, optionally substituted by alkoxy; -Ci to c6 alkyl; -5 or 6 membered heteroaryl, The situation is replaced by the following: -Cl to alkyl, as appropriate (: 6 to (8 aryl substituted, • C6 to Q aryl, optionally substituted by -COORx, where Rx is as defined above, or -amino) a -5 or 6-membered heterocyclic ring, optionally substituted by the following: -CO〇Rx group, the center of which is as defined above, or ...nhco〇rx group, the center of which is as defined above; 128244-3 200831489 - C6sc8 aryl, optionally substituted by one or more of the following groups: - an alkoxy group, as the case may be substituted by: - an alkoxy group, a hydrazino group, - one or more halogens, - 5 or 6 membered heterocyclic rings , as the case may be replaced by: -C! to C6 alkyl, or -hydroxyl, -amino group, optionally substituted by one or more (^ to decyl, -ΝΡ^02ΓΙΧ group, where Rx is as above Text definition, and R i is: - hydrogen, -Ci to C6 alkyl, -CORx group, the center of which is as defined above, -alkyl group or -haloalkoxy, -NRZ CORk group, wherein Rk is: - heart To alkranyl, -hydrogen, or an amine group, optionally substituted by one or more Ci to c6 alkyl groups, and Rj is: -hydrogen, -^ to ^alkyl, -CORx group, center system As defined above, -haloalkyl' or 128244-3 200831489 -haloalkoxy, -Ν=Ν+ =]ΝΓ group, or -COR! group' wherein R1 is a 5 or 6 membered heterocyclic ring, The situation is replaced by a hydroxy group, an amine group, optionally substituted by one or more Ci to q alkyl groups, and a -C! to C0 alkyl group is optionally substituted as follows: -•NHS〇2Rx group, wherein Rx is as above Definition, or --NRxS〇2Rx group, wherein lanthanide is as defined above, - halo alkoxy, -halogen, -transradyl, _-COORx group, wherein Rx is as defined above, -CORm group, Its center is: - an amine group, optionally substituted by one or more q to C6 alkyl groups, wherein one or more C! to C6 alkyl groups are optionally substituted by the following: - via group, -5 or 6 members Ring, -amine group, as appropriate Multiple (^ to decyl-substituted '-alkoxy, _3 to 7-membered heterocyclic ring, optionally substituted with (^ to 0:6 alkyl, optionally substituted with dialkyl-amino group) , --NHRn group, wherein Rn is: -CH2C〇NH2, or -C6SC8 aryl, as appropriate substituted by: 128244-3 200831489 - alkyl, - one or more 13⁄4, - exact, or - one or more alkoxy groups, ... NR 〇 CORp groups, the center of which: -Ci to C: 6 alkyl, optionally substituted by the following - halogen, - alkoxy, or -C6 to C8 aryl , a 5- or 6-membered heterocyclic ring, a C6- to-yl group, optionally substituted by halogen, a -5 or 6-membered heteroaryl group, optionally substituted by one or more q to Q alkyl groups, - hydrogen, And where R. a hydrogen radical, -(^ to 0:6 alkyl, _-CORx group, wherein &amp; is as defined above - haloalkyl, or -haloalkoxy, ... NRqCONR^r group, wherein </ RTI> 128244-3 200831489 - hydrogen, -Cl to alkyl, -13⁄4 alkyl, -haloalkoxy, or --CORx group, wherein Rx is as defined above and wherein Rr is: -C:6 to C8 aryl, as the case may be replaced by: -&lt;^ to (6 alkyl, -haloalkyl, --ORs group, wherein hydrazine is aryl, or --COORx group, the center of which is as defined above, -q to Q alkyl, depending The situation is replaced by one or more of the following groups: _halogen, a secondary alkyl group, a -C6 to C8 aryl group, and/or a -COORx group, the center of which is as defined above, the -COORx group, the center system As defined above, the --NRt COORu group has a center: -(^ to 匸丨2 alkyl, optionally substituted by the following: Q to Q aryl, optionally 〇1 to cardinyl or alkoxy 128244-3 200831489 Generation, -alkylene, alkoxy, -alkyne, -halogen, or -5 or 6-membered heterocyclic ring, -C6 to C8 aryl, optionally substituted as follows: - alkoxy, - halogen, or -CiSC6 alkyl, or -5 or 6 membered heterocyclic ring, and Rt is: hydrogen, -0^ to (6 alkyl, -CORx group, the center of which is as defined above, -_ a '' or -1⁄4 calcined base'-NRV S〇2 Rw group, wherein Rv is -hydrogen, a -CORx group, wherein Rx is as defined above, or -q to C6 alkyl, as appropriate Substituted: _halogen, -_CORx group, its The heart is as defined above, -OCORx group, wherein 1 is as defined above, 128244-3 200831489 - thiol, or -alkoxy, and wherein Rw is: -q to C6 alkyl, optionally substituted as follows : - halogen, -c6 to c8 aryl, or -5 or 6 membered heterocyclic ring, - 〇2 to 0: 6 alkyl, -alkyl- or dialkyl-amino, optionally substituted by i -5 or 6 membered heterocyclic ring, or -5 or 6 membered heteroaryl, optionally substituted as follows: - heart to ^ alkyl, -5 or 6 membered heterocyclic ring, or 128244-3 200831489 〇 Substituted by Ci to c6 alkyl, where Ry Wherein Rz is hydrogen or (^ to (6 alkyl, optionally substituted by a to c:8 aryl, ...SRX group, wherein 1 is as defined above, a _S02Raa group, wherein Raa is: -^ To the alkyl, -amino '-alkyl- or dialkyl-amino group, optionally substituted by a hydroxy group or a group, the center of which is as defined above, -5 or 6 membered heteroaryl, 128244*3 - 10- 200831489 -C6 to C:8 aryl, and / or --NHRbb group, * which is: , --C(=S)NH2 group, or --po(orx)2 group, the center of which is as defined above; &quot;Rcc group, where Rcc is: -荇, -5 or 6 members base, -A to C; 8 aryl, optionally substituted by one or more of the following groups: - alkoxy, -hydroxy, -halogen, -^ to decyl, optionally substituted by cyano, -amino, Optionally substituted by one or more C! to c6 alkyl groups, the -NHPORxRx group, centered as defined above, -NReeCONRffRff group, wherein Ree is hydrogen or alkyl, optionally substituted by halogen' and Rff Is: 128244-3 -11- 200831489 - hydrogen, -haloalkyl, -haloalkoxy, -^ to decyl, or -CORx group, wherein rx is as defined above, --NRggCORhh group, Wherein Rhh is: - hydrogen, -C to Q alkyl, optionally substituted by: - alkoxy, -halogen, or -amine, optionally substituted by one or more Cl to c6 alkyl, -amine a group, optionally substituted by one or more q to c6 alkyl groups, wherein one or more q to c6 alkyl groups are optionally substituted by halogen, -5 or 6 membered heterocyclic rings, -5 or 6 membered heteroaryl groups, And Rg g is: - hydrogen, -Q to C6 alkyl, -alkyl, -halooxy, or -CORx group, wherein 1 is as defined above, -13⁄4 alkyl, -5 or 6 members Heterocyclic group, -amino group, optionally substituted by one or more Ci to C6 alkyl groups, and/or 128244-3 -12-200831489 -NRi丨S〇2 Rx group 'where Rx is as defined above 'and Rj i is: -hydrogen, -^ to ^alkyl, -haloinyl-haloalkyloxy--CORx group, the center of which is as defined above; Z is: -q to C6 alkyl, Substituted as follows: - calcined base - one or more halogens, or -c6 to c8 aryl; - 〇2 to &lt;: 6th alkyl; - C6SC8 aryl, optionally alkoxy or One or more CiSQ alkyl substitutions; -COORx groups, the center of which is as defined above; or R is hydrogen, iS or alkoxy; : - murine, - thiol, -halogen, 128244-3 -13- 200831489 - halogen; -nitro, _ 5 or 6 hexamethylene; -5 or 6-membered heterocyclic ring; - alkoxy group is optionally substituted by: - one or more halogens, -C6 to C8 aryl, or -5 or 6 membered heterocyclic ring; -Q to Q aryl, optionally as an alkane Oxy substituted; ...CORx group, the center of which is as defined above; -C! to C: 6 alkyl, optionally substituted by dialkyl-amine or 5 or 6 membered heterocyclic ring; or Ri and R2 are bonded Together to form: R2 is - a certain group, - a mouse, - a halogen; - a hydroxyl group; - (: a hydrazine to a decyl group, optionally substituted by one or more _ sins; - an amine group, - an alkoxy group, as the case may be replaced by · 128244-3 .14- 200831489 - one or more halogens, • _OCORx group, the center of which is as defined above, -dialkyl-amine group, optionally substituted by alkoxy group, -5 or 6 membered heterocyclic ring a group, optionally substituted with q to 〇6 alkyl -5 or 6 membered heteroaryl, or -c6 to c8 aryl; -COORx group, wherein Rx is as defined above; -i alkyl; Amine groups, optionally substituted by: - thiol, or -c6 to c8 aryl; • 5 or 6 membered heteroaryl; ...OCORx group, wherein as defined above; -NHCORjj group, wherein Rjj is : - alkoxy groups, or -amino groups 'optionally substituted by one or more Ci to q alkyl groups; ...ORkk group, wherein Rkk is a 5 to 6 membered heteroaryl group; ...NHS〇2Rx group, the center thereof As defined above; or R2 and Ri are joined together to form: R3 is: -nitrogen) or 128244-3 •15·200831489 -03⁄4 OCORx, and Rx is as defined above; the condition is 'when X is a phenyl group substituted by an alkoxy group, γ is a phenyl group, and R is a hydrogen' Ri is halogen, R2 is hydrogen, and r3 is hydrogen, and when X is phenyl, hydroxyphenyl or pyridyl, γ is alkyl, R is hydrogen 'heart is hydrogen or hydroxyl, &amp; hydrogen Or hydroxy, and when r3 is hydrogen, then Z is: -Q to A alkyl, substituted by: - alkoxy, - one or more halogens, or -c6 to c8 aryl; - C2 to c6 nalkane Base; -Q to Cs aryl, optionally alkoxy or one or more. to. An alkyl group; a group, as defined above; or; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein X is nitro or cyano. 3. A compound of the formula, wherein X is a cyano group. 4. The compound of claim 1, wherein y is a Q to q aryl group, optionally substituted with one or more of the following groups: The amine group 'optionally substituted with one or more Ci to C6 alkyl groups, 128244 -3 -16- 200831489 -(^ to ^alkyl, as the case may be replaced by _nhS〇2Rx group, ...NR0CORp group, where ~ is · · · C to C6 alkyl, as the case is replaced by a halogen, or a -C6 to C8 aryl group, or a -5 or 6 membered heterocyclic ring, and wherein R. is a hydrogen, ... NRqCONRqRr group, wherein Rq is hydrogen, or -C! to C6 alkyl, Wherein \ is a Cl to G alkyl group, optionally substituted by one or more of the following groups: 1 - halogen, - sub-alkyl, or -c6 to c8 aryl, ... NRtCOORu group, wherein ~ is: -ci to Q 2 alkyl, optionally substituted by the following: -C6 to aryl, optionally substituted by Ci to Q alkyl or alkoxy, -alkylene, -alkyl, alkyne, -halogen, or 5 or 6 membered heterocyclic ring, 128244-3 -17- 200831489 -c6 to c8 aryl, optionally substituted by alkoxy, -5 or 6 membered heterocyclic ring, and wherein Rt is: -hydrogen, or -(^ to仏alkyl, --NRvS02Rw group, where R v is hydrogen, and wherein, is (^ to (36 alkyl, optionally substituted by halogen; 〇 128244-3 -18- 200831489 wherein 匕 is ^ to ^ alkyl, and / or • NHRbb group, wherein Rbb is a -PO(ORx) 2 group. 5. The compound of claim 4, wherein γ is (^ to aryl, substituted by: ... NRqC 〇 NRqRr group, ... MKtC00Ru group, -NRvS02Rw group, or --NHRbb group, wherein Rbb Is a compound of the formula -P0(0Rx)2. 6. The compound of claim 5, wherein the (6 to c8 aryl group is a phenyl group. 7. The compound of claim 6 wherein the phenyl group is in the para position 8. The compound of claim 7, wherein γ is phenyl substituted by a -gqCONRqRr group at the para position. 9. The compound of claim 7, wherein γ is _NRtC〇〇Ru in the para position A phenyl group substituted by a group. The compound of claim 7, wherein γ is a phenyl group substituted by a _NRvS〇2rw group at the para position. Π. The compound of claim 7, wherein γ is in the para position A phenyl group substituted with a -NHPO(ORx)2 group. 12. The compound of claim i, wherein Z is: • Ci to h alkyl, optionally substituted by the following - alkoxy, or - one or more And a compound of claim 13, wherein Z is a C5 alkyl group. 4-3 -19- 200831489 15. The compound of claim 14, wherein z is cyclobutyl, cyclopropyl, cyclopropylindenyl, ethyl or cyclopentyl. Wherein R is hydrogen. 17. The compound of claim 1, wherein Ri is a hydrogen atom; - an alkoxy group, optionally substituted by the following or a plurality of halogens, -C6 to C8 aryl, or -5 Or a 6-membered heterocyclic ring; or Ri and R2 are joined together to form: 18. The compound of claim 1, wherein the % is: - murine, - _ mer; - hydroxy; - Q to c6 alkyl, optionally substituted by one or more halogens; - amine; - alkoxy, The situation is replaced by: - one or more halogens, -OCORx groups, wherein Rx is as defined above, -dialkylamino, optionally substituted by alkoxy, -5 or 6 membered heterocyclic group, Optionally substituted by q to C6 alkyl, 128244-3 -20-200831489 -5 or 6 membered heteroaryl, or -C6 to c8 aryl; ...C〇〇Rx group; or R2 bonded to Ri form: 19. The compound of claim i, wherein: 1 to V are hydroxy or alkoxy, optionally substituted as follows: - one or more halogens, - fluorene to heart aryl, or -5 or 6 members a heterocyclic group; or 2 is a 0C0Rx group ' 〇 Rkk group, or an alkoxy group, which is substituted by: 〇C〇Rx group, -dialkyl-amino group, optionally substituted by alkoxy group a 5 or 6 membered heterocyclic group substituted with q to C6 alkyl; or -5 or 6 membered heteroaryl. A compound according to claim 19, wherein &amp; is an alkoxy group, optionally substituted by the following: 5 or 6 beta heterocyclic groups, optionally substituted by q to C6 alkyl; or • 5 or 6 membered heteroaryl . 21. The compound of claim 2, wherein A is (^ to (6 alkoxy, optionally substituted by the following: 128244-3 -21 - 200831489 5 or 6 membered heterocyclic group, as the case may be) And a compound of claim 1, wherein r3 is hydrogen. 23. The compound of claim 1, wherein: X is a cyano group; To the csaryl group, substituted by: -MqCONRqRr group, -_i^tC〇〇Ru group, -_nrvso2rw group, or __nhpo(〇Rx)2 group; Z is: Ci to Q alkyl group, The situation is replaced by - alkoxy, or - one or more halogens, or -c2 to c6 alkyl; R is hydrogen; at least one of K and & is a hydroxy or alkoxy group, optionally substituted by: — or a plurality of halogens, -6. to (8 aryl, or 5- or 6-membered heterocyclic groups; or %-OCORx groups, _ORkk groups, or alkoxy groups, substituted by: —OCORx a group, a -dialkyl-amino group, optionally substituted by an alkoxy group, a -5 or 6 membered heterocyclic group, substituted by a q to q alkyl group; or 128244-3 -22-200831489 -5 or 6 members Heteroaryl; and R3 is a mouse. 24. The compound of claim 23, wherein γ is phenyl substituted with a -NRqCONRqRr group. 25. The compound of claim 24, wherein: z is ci to C6 alkyl; and the heart is alkoxy, optionally Substituted by: -5 or 6 membered heterocyclic group, optionally substituted with (^ to decyl; or -5 or 6 membered heteroaryl. 26. The compound of claim 23, wherein γ is NR-COORu A phenyl group substituted by a group. 27. The compound of claim 26, wherein: Z is a C6 alkyl group; and R2 is an alkoxy group, optionally substituted by the following: -5 or 6 membered heterocyclic groups, optionally And a compound of claim 23, wherein γ is a phenyl group substituted with a -NRvS02Rw group. 29. The compound of claim 28, Wherein: Z is a Ci to C6 alkyl group; and R2 is an alkoxy group, which is optionally substituted by the following: -5 or 6 membered heterocyclic groups, optionally substituted by G to C6, or 5 or 6 30. The compound of claim 23, wherein γ is a --NHPO(ORx) 2 group. 128244-3 -23- 200831489 31. The compound of claim 30, wherein: To Fo ^ alkyl; and &amp; is a burning group, optionally substituted with the-5 or 6-membered heterocyclic group, optionally substituted Cl to C6 alkyl; or -5 or 6-membered heteroaryl. 32. The compound of claim 1, wherein X is: -Cyano; or -methylindenyl; Y is: • 5 or 6 membered heteroaryl, optionally substituted by q to C8 aryl, which is optionally substituted by a -COORx group, centered as above Definition; or - to eg aryl, optionally substituted by one or more of the following groups: - (^ to ^ alkyl; - month female base 'optionally substituted by one or more to c6 alkyl; - halogen; - a carboxylic group, wherein Rm is an amine group, optionally substituted by one or more to a C6 alkyl group; -NR〇CORp纟 group, wherein Rp4CjC6 is a group, n is replaced by an alkoxy group, and Wherein R is hydrogen; ...NRqCONRqRr group, wherein ^ is hydrogen, and wherein ^ is ^ to ^ alkyl; -NRtCOORu group wherein Rt is hydrogen, and wherein Ru is cjc12 128244-3 -24- 200831489 'Substituted as follows: -c6 to c8 aryl; -halogen; or -5 or 6 membered heterocyclic ring; •NRvS〇2Rw group, wherein Rv is hydrogen, and wherein, is Cj to g alkyl; or- Burning or dialkyl-amine groups; Wherein Rz is hydrogen or (^ to (6 alkyl; -S02Raa group, wherein Raa is: - keto-based; or -alkyl or dialkylamino; or ... NHRb b group is defined above; Rbb is a -P〇(〇rx)2 group, wherein rx is, for example, Z: -(^ to decyl; or -COORx group, the center of which is as defined above; R is hydrogen, 128244-3 - 25 · 200831489 R! is · - hydrogen; - 5 or 6 membered heterocyclic ring; or _ alkoxy group, as the case may be replaced by: one or more dentate • or • 5 or 6 member heterocyclic ring; R 〗 - Hydrogen; - Hydroxy; - C1 to C6 alkyl, optionally substituted by one or more halogens; - Alkoxy, optionally substituted by: - one or more halogens; - 5 or 6 membered heterocyclic groups a group, optionally substituted by Cl to C6 alkyl; or • 5 or 6 membered heteroaryl; -CO〇Rx group, the center of which is as defined above; - amidino group; -5 or 6 membered heteroaryl Or - 〇 Rkk group 'wherein Rkk is a 5- to 6-membered heteroaryl; and R 3 is hydrogen. 33. A compound of claim 32, wherein: X is cyano; Y is ceu' is - or Substituted by a plurality of groups: - Amine 'as appropriate - or more Substituted by a pyridyl group; qC〇NRqRr group '纟中~ is hydrogen' and wherein Rr is Ci to. alkane 128244-3 -26- 200831489 base; • _NRtCOORu group 'where Rt is hydrogen and its center is ^ to ^ a base, optionally substituted by a C6 to Q aryl group; or a -nrvs〇2rw group, wherein Rv is hydrogen, and wherein ~ is a Ci to a w group; Z is a Cl to a sulphur group; R is a nitrogen, Ri is a hydrogen ; &amp; is a hospitaloxy group, which is optionally substituted by one or more halogens; _ 5 or 6 membered heterocyclic groups, as the case may be. to alkyl substitution; or _5 or 6 member heteroaryl Or a compound of claim 32, wherein: X is cyano; γ is C0 to Q aryl, substituted by one or more of the following groups: -ci to C6 alkyl; ** The substrate 'optionally substituted by one or more q to C6 alkyl groups; - halogen; -NRtCOORu group, wherein Rt is hydrogen, and its center is: *&quot; Ci to Ci 2 alkyl, ... NRvS 〇 2Rw a group wherein Rv is hydrogen, and wherein Rw is: -^ to decyl; or -alkyl- or dialkyl-amino, z is Ci to c6 alkyl; 128244-3 -27- 200831489 R is Hydrogen; Ri is hydrogen; R2 is -ORkk a group wherein Rkk is a 5- to 6-membered heteroaryl; and R3 is hydrogen. 35. A compound according to item 32, wherein: X is cyano; Y is a Q to Q aryl group, one or more of the following groups Group replaces ··-heart to decyl group; Halogen; and its center is a Ci to c12 alkane...NRtCOORu group, wherein Rt is hydrogen, a group; -NRvS〇2Rw group, wherein Rv is hydrogen, and its center is: -^ to decyl group; or a phenyl- or dialkyl-amino group; or a - NRqCONRqRr group, wherein Rq is hydrogen and its center is ^ to ^alkyl; z is Ci to c6 alkyl; R is hydrogen, Ri is gas; To: - alkoxylate, optionally substituted by one or more _ s-; - guanamine; ... 0Rkk group, wherein Rkk is a 5- to 6-membered heteroaryl; or -5 or 6-membered heteroaryl; and 128,244 -3 -28- 200831489 r3 is hydrogen. 36. The compound of claim 35, wherein: X is cyano; Y is C0 to Q aryl, substituted by one or more of the following groups: - halogen; ... NRtCO 〇 Ru group, wherein Rt is hydrogen, and Its center is. To [ηalkyl; or -_NRvS〇2Rw group, wherein Rv is hydrogen, and its radical is a heart to a decyl group; R is hydrogen; Ri is hydrogen; and the heart is a 〇Rkk group, wherein Rkk is 5 to 6 membered heteroaryl; and R3 is chlorine. 37. The compound of claim 36, wherein the q to q aryl group is a phenyl group. 38. The compound of claim 37, wherein the phenyl group is substituted at the para position. A compound of the epoxide term 38, wherein γ is a benzene substituted by a _N]^c〇〇Ru group, such as a group &amp; wherein Rt is hydrogen, and its &quot;u is: ah alkyl. A compound of 2 member 38, wherein Y is taken by a halogen and a -NRtCOORu group. 41.1:: group ' wherein ~ is hydrogen, and wherein R^Ci to Ci2 alkyl. It is a compound of the genus 38, wherein Y is a benzene 42 which is substituted by a -NRvS02Rw group, and the middle is hydrogen, and wherein - is . 1 to alkyl. A compound of the present invention, wherein Y is a group of Cl to C6 and -NRtC〇〇Ru 43 : instead of a base wherein \ is hydrogen, and wherein Ru is a C4C12 alkyl group. 43. The compound of claim 35, wherein: 128244-3 -29- 200831489 χ is a cyano group; Y is a Q to Cs aryl group substituted by a -NRtCOORu group, wherein Rt is hydrogen, and wherein Ru is Q to Q 2 alkyl; Z is C! to C6 alkyl; R is hydrogen; Ri is hydrogen; & is an alkoxy group, optionally substituted by one or more halogens; and R3 is chlorine. (44) The compound of claim 35, wherein r2 is alkoxy substituted by one or more halogens. 45. The compound of claim 43, wherein Q to q aryl is phenyl. 46. A compound wherein the phenyl group is substituted in the para position. 47. The compound of claim 35, wherein: X is cyano; Y is C0 to Q aryl, substituted by one or more of the following groups: a NRtC00Ru group, wherein Rt is hydrogen, and its center is 匸丨 to. alkyl; or -•NRqCONRqRr group, wherein Rq is hydrogen and its center is Q to ^alkyl; Z is &lt;^ to ( : 6 alkyl; R is chlorine, Ri is hydrogen; R 2 is 5 or 6 membered heteroaryl; and R 3 is gas. 128244-3 -30- 200831489 48. 々: Compound of claim 47 wherein Q to C8 aryl Is a phenyl group. 49. The compound of claim 48, wherein the phenyl group is substituted at the para position. 50_ The compound of claim 49, wherein γ is a phenyl group substituted with a na(7)% group, wherein &amp; Is hydrogen, and wherein: 丨 to Ci2 alkyl. 5L is a compound of claim 9, wherein γ is a C6 to .8 square group substituted by an nr&amp; group, and is hydrogen, and wherein Shu to Q is alkyl 52. The compound of item 35 of the request, wherein:.. X is cyano; Y is a COORu group* instead of a aryl group, wherein Rt is chlorine and wherein Ru is (^ to (: 12 alkyl; z is €1 to (6 alkyl; R is gas; Ri is R2 is decylamine; and R3 is oxygen. 53. The compound of claim 52, wherein the aryl group is a phenyl group. The compound of claim 53 wherein the phenyl group is substituted at the para position. The compound of claim 35, wherein &amp; is an alkoxy group substituted by - or a plurality of dentates. 56. The compound of claim 35, wherein the center is a 〇1 group, wherein Rkk is from 5 to 6 members 57. A compound according to claim 32, wherein X is a methyl group; Y is a C6 to q aryl group, substituted by one or more of the following groups: 128244-3 -31 · 200831489 --NRtCOORu a group; or Rt is hydrogen and the center thereof is a q to c12 alkane--NRqCONRqRr group group; wherein Rq is hydrogen and its center is. To (:6 alkane is a heart to a decyl group; R is Hydrogen; Ri is chloro; R 2 is alkoxy; and R 3 is hydrogen. 58. The compound of claim 32, wherein: X is cyano; Y is C6 to Q aryl, substituted by one or more of the following groups ·· -(^ to decylalkyl; -halogen; -NaCOORU group' wherein Rt is chloro, and wherein ^ is ^ to yl group is optionally substituted by C6 to Cg aryl; ...NRvS〇2Rw group 'where Rv is Hydrogen, and its center is - (^ to 〇: 6 alkyl; or W · -alkyl- or dialkyl-amine, or 〇 Redundant to decylalkyl; R is hydrogen; 128244-3 • 32- 200831489 Ri is chlorine; &amp; is an alkoxy substituted by one or more halogens; and R3 is nitrogen. 59. The compound of claim 32, wherein: X is cyano; Y is Q to Q aryl, optionally substituted by one or more of the following groups: --_. (: 〇1115 group, where \ is (:1 to (:6 alkyl, optionally substituted by alkoxy, and wherein R is hydrogen; Z is Ci to C6 alkyl; R is hydrogen; Ri is nitrogen) &amp; is an alkoxy group substituted by a 5- or 6-membered heteroaryl; and R3 is a nitrogen. 60. The compound of claim 32, wherein: X is cyano; Y is C6 to C8 aryl 'as appropriate Substituted by one or more of the following groups: -(^ to decylalkyl; -amino, optionally substituted by one or more. to alkyl; halo; _/NR °C 〇 Rp group, wherein RpMk6, and wherein the residue is hydrogen; -NRqCONRqRr group, wherein &amp; is fluorenyl; -NRtCOORu group wherein Rt is hydrogen, and wherein Ru is Ci to Cl2 alkane 128244-3 -33 - 200831489 a NRvS〇2Rw group, wherein Rv is hydrogen, and wherein ~ is ^ to ^alkyl; or ... NHRbb group, wherein Rbb is a -PO(ORx)2 group, and wherein &amp; Z is C! to the alkyl group, R is hydrogen, R! is a rat; R2 is a 5- or 6-membered heteroaryl; and R3 is hydrogen. 61. The compound of claim 32, wherein: X is a cyano group; For q to C: 8 aryl, as appropriate Or a plurality of the following groups substituted: - an amine group, optionally substituted by one or more C! to C6 alkyl groups; a _-NRqCONRqRr group, wherein Rq is hydrogen, and its center is . to ^ alkyl; An NRtCOORu group, wherein Rt is hydrogen, and the center thereof is from [n] to the hospital, optionally substituted by the following: -c6 to c8 aryl; or -5 or 6 membered heterocyclic; -_NRV S 0. 2 Rw group, wherein Rv is hydrogen, and wherein the alkyl group; 128244-3 -34- 200831489 Wherein Rz is hydrogen or (^ to decyl; 2 is &lt;^ to (6 alkyl; R is gas, Ri is: -5 or 6 membered heterocyclic ring; or alkoxy group, substituted by the following - One or more halogens; or a -5 or 6-membered heterocyclic ring; R2 is hydrogen; and R3 is a salt I. 62. A compound according to claim 61, wherein Ri is 5 or a heterocyclic ring. 63. The compound of Item 61 wherein &amp; is an alkoxy group substituted by one or more halogens. 64. The compound of claim 61, wherein: Y is a Q to Q aryl group substituted by a _NRtCOORu group, wherein Rt is Ru, wherein Ru is a Q to q 2 alkyl group, optionally substituted by the following: -c6 to c8 aryl; or • 5 or 6 membered heterocyclic ring; and R1 is an alkoxy group substituted by one or more i elements 65·—Formula nia compound 128244-3 -35- 200831489 Where: x is hydrogen Ga is a cjc8 aryl group, optionally substituted by one or more of the following groups: --NRqCONRqRr group, wherein R 4 is found to be (^ to (: 6 alkane, -NRtCOORu group; or wherein Rt is Hydrogen and its center is (^ to (: 12 alkane-NRvso2Rw group, its tRv is hydrogen, and wherein Z is (^ to 〇: 6 alkyl; P, :: to decyl; R is chloro' Ri is Hydrogen; R2 is - alkoxy, optionally substituted by one or more elements; or - 〇Rkk group, wherein Rkk is 5 to 6 membered heteroaryl · '〆r3 is hydrogen. Earth, and 66. The compound of claim 65, wherein X is hydrogen; Y is a Q to Q aryl group substituted by a _NRtCOORu group, wherein Ru is C! to Ci 2 alkyl; /, Rt is hydrogen, and 128244 -3 •36- 200831489 Z is a C1 to c6 alkyl group; R is hydrogen; Ri is hydrogen; is converted to a -Rkk group, wherein Rkk is a 5- to 6-membered heteroaryl; and R3 is a gas. 67. The compound of Item 65, wherein the 6 to Q aryl group is a phenyl group. 68. The compound of claim 65, wherein the phenyl group is substituted in the para position. 69. A pharmaceutical composition comprising: (i) a compound of formula I - nitro; -cyano; -CORa group, wherein &amp; is: C! to Cg alkyl; to Q aryl, optionally substituted by alkoxy or _; - «-alkyl-amino group; -COORx group, wherein 1 is q to q alkyl; -methanyl; 128244-3 -37- 200831489 • C0 to Cs aryl, optionally substituted by alkoxy Or a -5 or 6-membered heteroaryl group, optionally substituted by the following -Ci to C6 alkyl; _C6 to C8 aryl, optionally substituted by alkoxy or one or more elements or -5 To 6-membered heteroaryl; Y is: -haloalkyl; beta halogen; -amino group 'optionally substituted with one or more Ci to c6 alkyl groups; -benzofuran; -benzothiophene; 'diphenyl And furan; - diphenothiophene; &quot;this and P plug; naphthalene; -Τ?ί1 * Substituted by q to c6 alkyl on nitrogen; Or 1 ; 128244-3 -38- 200831489 Text definition, or _S02Rx, Wherein Rc is hydrogen, -C〇NHRx, wherein Rx is as defined above, wherein Rx is as defined above; -V, wherein Rd is (^ to (:6 alkyl or (:6 to (:8 aryl; -NHCORe) a group wherein -··C to a C6 alkyl group; or a -C0 to Q aryl group is optionally substituted by the following: -(^ to 〇: 6 alkyl; - alkoxy; - cyano; Or a halogen group, the center of which is as defined above; a CH2〇-Rf group, wherein Rf is a Q to q aryl group; and an NRgRh group, wherein Rg is a q to C6 alkyl group Or hydrogen, and Rh is c6 to C8 aryl 'substituted by an alkoxy group; -^ to ^alkyl; -5 or 6 membered heteroaryl, optionally substituted by: 128244-3 -39- 200831489 _Cl To a C6 alkyl group, optionally substituted by a c6sc8 aryl group; -Q to a Cs aryl group, optionally substituted by -COORx, wherein Rx is as defined above; or -amino group! -5 or 6 membered heterocyclic ring, optionally Substituted: -COORx group, the center of which is as defined above; or -NHCOORx group, as defined above; -C6 to Q aryl 'optionally substituted by one or more of the following groups: - alkane Oxyl, as the case may be Generation: - alkoxy; - thiol; - one or more halogen; - 5 or 6 membered heterocyclic ring, optionally substituted by the following: -C! to C6 alkyl; or - thiol; The situation is substituted by one or more q to c6 alkyl groups; - RDiS〇2Rx group, wherein Rx is as defined above, and wherein Ri is: - hydrogen; -Cl to alkyl; -CORx group, wherein Rx Is as defined above; - anthracenyl; or -haloalkoxy; -NRjCORk group, wherein: 128244-3 -40- 200831489 -CiSQ alkyl; -hydrogen; or -amine, optionally One or more (^ to ^alkyl substituted; and wherein Rj is: -hydrogen; -(^ to decylalkyl; -_CORx group, wherein Rx is as defined above; haloalkyl; or -haloalkoxy ; N=N+ =N_ group; or -COR^ group 'where &amp; is a 5 or 6 membered heterocyclic ring, optionally substituted by a hydroxy group; - an amine group, optionally one or more Ci to q Alkyl substituted; -nitro; -ci to C0 alkyl, optionally substituted by: -NHS〇2 Rx group 'where &amp; is as defined above; or --NRxS〇2Rx group, centerline As defined above; - haloalkoxy; a hydroxy group; a COORx group, wherein 1 is as defined above; a -CORm group, wherein: - an amine group 'optionally substituted by one or more C! to C6 alkyl groups' The G to C6 alkyl group is optionally substituted by the following: 128244-3 -41 - 200831489 -yl group; -5 or 6 membered heterocyclic ring; -amino group, optionally substituted by one or more C! to C6 alkyl groups; Or alkoxy; -3 to 7 membered heterocyclic ring, optionally substituted by Ci to (alkyl), which is optionally substituted by dialkyl-amino group; -NHRn group, centered on · --ch2 C〇NH 2 , · or -c0 to c8 aryl, optionally substituted by the following - -alkyl; - one or more halogens; - nitro; or - one or more alkoxy groups; NR〇C0RP group, wherein Rp is: -Ci to alkyl, optionally substituted by: -halogen; -alkoxy; or -C6 to c8 aryl; _5 or 6 membered heterocycle; -Q to g An aryl group, optionally substituted by halogen with '-5 or 6-membered heteroaryl, optionally substituted by one or more (^ to Q alkyl; - hydrogen; 128244-3 -42- 200831489 And where R. Is: -ml, -^ to decyl; -CORx group, the center of which is as defined above; - a calcinyl group, or a -halooxy group, a -NRqCONRqK group, wherein Rq is: - heart to仏alkyl; -13⁄4 alkyl, -halooxy; or -CORx group, the center of which is as defined above, and wherein RI is: -C6 to C8 aryl, optionally substituted by: -CiSC6 alkyl; -13⁄4 alkyl, -〇Rs group, wherein Rs is C6 to C8 aryl; or 128244-3 •43-200831489 ...COORx group, the center of which is as defined above; _ C! a C0 alkyl group, optionally substituted with one or more of the following groups: - halogen; - alkylene; - C6 to C8 aryl; and/or - _COORx group, wherein Rx is as defined above; or - COORx The group 'the center is as defined above; --NRt COORu group, wherein Ru is: -Cl to Ci2 alkyl, optionally substituted by the following: -Q to Cs aryl, optionally as the heart to the alkyl group or Alkoxy substituted; - sub-alkyl; - alkoxy; - alkyne; - halogen; or -5 or 6-membered heterocyclic ring; - C6 to Cs aryl, optionally substituted by: - alkoxy; Alizarin; or -G to C6 alkyl; or -5 or 6-membered heterocyclic ring; and Rt is: -hydrogen, -Ci to C6 alkyl; 128244-3 •44-200831489 -CORx group, center system As defined above; - a halogen group, or a -halooxy group; a NRvS02Rw group centered at: -a nitrogen, a -CORx group, the center of which is as defined above; or -(^ to a cardyl , as the case is replaced by - _, -CORx group, the center of which is as defined above; -OCORx group, the center of which is as defined above; - the radical; or - alkoxy, and wherein Rw is -q to C6 The base is optionally substituted with: - halogen; - -alkyl, -c6 to c8 aryl; or -5 or 6 membered heterocyclic; -C2 to C6 alkyl; -alkyl- or dialkyl-amine Base, optionally substituted by halogen; -5 or 6 membered heterocyclic ring; or -5 or 6 membered heteroaryl, optionally substituted by the following: -^ to decylalkyl; -5 or 6 membered heterocyclic ring; or 128244- 3 -45- 200831489 R.. , optionally substituted by Ci to C6 alkyl, wherein Ry is (^ to decyl or hydrogen; Wherein Rz is hydrogen or q to C6 alkyl, optionally substituted by Q 128244-3 -46-200831489 to Cg; (SRX group, wherein RX is as defined above; -S02Raa group, wherein Raa is: -(^ to decylalkyl; -amino; -alkyl- or dialkyl-amino, optionally substituted by hydroxy or _c〇〇Rx groups, wherein Rx is as defined above, or -5 or 6 a heteroaryl group; a C6 to C8 aryl group; and/or a NHRbb group, wherein Rbb is: * a -c(=s)nh2 group; or a -PO(ORx)2 group, wherein rx is as defined above; or a ~&amp; group, wherein Rcc is: -na, -5 or 6 member heteroaryl base; -Q to Cs aryl, optionally substituted by one or more of the following groups: 128244-3 -47 - 200831489 - alkoxy; - thiol; - halogen; - (^ to cardinyl, optionally cyano Substituted; -amino group, optionally substituted by one or more than q to c6 alkyl; -NHPORxRx group, wherein Rx is as defined above; - NReeCONRffRff group, wherein is hydrogen or CiSC6 alkyl, optionally Substituted by i, and Rff is: -nitrogen, -haloalkyl; -halooxy; -cardi to decyl; or -CORx group, wherein Rx is as defined above; -NRggC0Rhh group, Wherein Rhh is: -nitrogen; -(^ to (6 alkyl, optionally substituted by: -alkoxy; -halogen; or -amine, optionally substituted by one or more alkyl groups; -amino group) , optionally by one or more q to (6 alkyl substitution 'where the alkyl group is optionally substituted by i; -5 or 6 member heterocycle; -5 or 6 member heteroaryl; 128244-3 - 48-200831489 - nitrogen; -CiSQ alkyl; -haloalkyl; -haloalkoxy; or -CORx group, wherein the system is as defined above; -haloalkyl; -5 or 6 membered heterocyclic group ; -Amine' And substituted by one or more q to c6 alkyl groups; and/or --NRi丨S〇2 Rx group 'wherein Rx is as defined above, and Rj i is - nitrogen; -Ci to G alkyl; a halogen group; a halogen alkoxy group; or a CORx group, wherein rx is as defined above; Z is a -ci to C6 alkyl group, optionally substituted by the following: - alkoxy group; - one or more Halogen; or - to (8 aryl; -c2 to c6 alkyl; -C6 to C: 8 aryl, optionally substituted by alkoxy or one or more Ci to c6 alkyl; -COORx The group 'the center is as defined above; or 128244-3 -49- 200831489 R is hydrogen, halogen or alkoxy; Ri is · SL 9 -hydroxyl; • halogen; - halogen group, - base, -5 or 6 membered heteroaryl; - 5 or 6 membered heterocyclic ring; - alkoxy Substituents, optionally substituted by: - one or more halogens; - C6 to C8 aryl; or -5 or 6 membered heterocyclic; _C6 to C8 aryl, optionally substituted by alkoxy; -CORx Group, the center of which is as defined above; -C! to C6 alkyl, optionally substituted by dialkyl-amine or 5 or 6 membered heterocyclic ring; or R1 bonded to ruler 2 to form 128244-3 -50- 200831489 R_2 is - wall group, - nitrogen, - halogen; - hydroxyl; • C! to C: 6 alkyl, optionally substituted by one or more _ prime; - amine; An oxy group, optionally substituted by: - one or more halogens, -OCORx group, wherein Rx is as defined above, -dialkyl-amino group, optionally substituted by alkoxy group, -5 or 6 members a heterocyclic group, optionally substituted with -5 to 6 or 6 membered heteroaryl, or -c6 to c8 aryl, -_COORx group, wherein Rx is as defined above; - halogen; Amine amino group, optionally substituted by a hydroxyl group; or -C6SC8 aryl; -5 or 6 membered heteroaryl; -OCORx group, the center of which is as defined above; -NHCORjj group, wherein Rjj Is: - an alkoxy group; or an amine group, optionally substituted by one or more q to C6 alkyl groups; 128244-3 -51 - 200831489 • - 〇Rkk group, wherein Rkk is a 5 to 6 membered heteroaryl group --NHS〇2Rx group, wherein Rx is as defined above; or joined to Ri to form: R3 is: - hydrogen; or -CH2〇CORx, and RX is as defined above; the condition 疋 'When X is phenyl, phenyl or 峨 σ, γ is alkyl, R is hydrogen ' Rl is hydrogen or a hydroxyl group, R2 is hydrogen or a hydroxyl group, and when it is a ruthenium, then Z is: -(^ to (6 alkyl group, substituted by: - alkoxy group; - one or more halogens; or -G to Cg aryl group) • c2 to c6 alkyl; -C0 to C8 aryl, optionally substituted by alkoxy or one or more Ci to alkyl; -COORx group, centered as defined above; or 128244-3 -52- 200831489 or alternatively a pharmaceutically acceptable salt thereof; and: two or more pharmaceutically acceptable excipients. 70. - a pharmaceutical composition of the formula I, a seed compound or a compound comprising one or more compounds of the formula 1; a preparation for the treatment of a virus infection in a patient in need thereof, the complex φT Internal ribosome entry location (IRES), the treatment comprising Swallow, T. The patient is administered one or more compounds of formula I or a pharmaceutical composition comprising one or more compounds of formula R R3 z wherein: X is: -nitro group; -cyano; ...C0Ra group, wherein Ra is: • 4 to (:6 alkyl; -C6 to C8 aryl, optionally substituted by alkoxy or i; Or -1-alkyl-amino; -COORx group, wherein Rx is Ci to Q alkyl; carbhydryl; -Q to c8 aryl, optionally substituted by alkoxy; or -5 or 6- Heteroaryl, as the case may be replaced by: 128244-3 -53 - 200831489 -C6 to csaryl, optionally substituted by alkoxy or one or more halogens -5 to 6 membered heteroaryl; Y is :--alkyl; -halogen; -amino group 'optionally substituted with one or more Ci to c6 alkyl-benzofurans; -benzobenzophenone; -dibenzofuran; ; - benzo far σ sitting; Ή丨嗓' is optionally substituted on the nitrogen by a q to c6 alkyl group; wherein Rb is hydrogen or CiSC6 alkyl, and η is 0 128244-3 -54- 200831489 Wherein Rc is hydrogen, _CONHRx, the center of which is as defined above, or -g〇2Rx, the center of which is as defined above; or — 'The center is &lt;^ to 0:6 alkyl or C6SC8 aryl; _ -NHCORe group, the center of which is: -C! to C6 alkyl; or -C0 to C8 aryl, optionally replaced by : -c - sc6 alkyl; - alkoxy; - cyano; - nitro; or - halogen; - nhcoorx group ' wherein 1 is as defined above; -CH2 〇-Rf group, wherein Rf is a C6 to c8 aryl group; an NRgRh group, wherein Rg is a Ci to C6 alkyl group or hydrogen, and Rh is a C6 to c8 aryl group, optionally substituted with an alkoxy group; -Cl to c6 alkyl; -5 or 6-membered heteroaryl, optionally substituted by the following -Cl to C6 alkyl, optionally as 〇6 to (:8 aryl substituted; -CG to C8 aryl, optionally substituted by -C〇〇Rx, Wherein Rx is as defined above in 128244-3 -55-200831489; or -amino group; _ 5 or 6 membered heterocyclic ring, optionally substituted by: C00Rx group, wherein Rx is as defined above; or - Li CO a 〇Rx group, wherein Rx is as defined above; -C6 to Q aryl' is optionally substituted by one or more of the following groups: - an alkoxy group is optionally substituted by the following: - alkoxy; (-hydroxyl ; - one or more halogens; -5 or 6 a heterocyclic ring, optionally substituted by the following: -Ci to C6 alkyl; or -hydroxy; -amino 'optionally substituted with one or more Ci to C6 alkyl; - NRiS〇2Rx group, wherein Rx is as above Definitions, and Ri is: - hydrogen; (-C! to C6 alkyl; -CORx group, the center of which is as defined above; - calcination; or -haloalkoxy; - -NRj CORk group Wherein Rk is: _C" to C6 alkyl; -hydrogen, or -amino group, optionally substituted by one or more q to c6 alkyl groups, 128244-3 -56- 200831489 and wherein Rj is: -hydrogen • ci to C6 alkyl; a -CORx group, wherein the lanthanide is as defined above, a halogen group; or a halooxy group; a group; or a -COR! group, wherein &amp; Or 6-membered heterocyclic ring, optionally substituted by a radical; -amino group, optionally substituted by one or more (^ to ^alkyl; -nitro; -G to C; 6 alkyl) is replaced by : --NHS〇2Rx group, wherein 1 is as defined above; or --NRxS〇2Rx group, wherein ^^ is as defined above; - alkoxy; - halogen, - thiol, -COORx Group, where Rx is as defined above a -CORm group having the center: - an amine group, optionally substituted by one or more q to c6 alkyl groups, wherein one or more Q to c6 alkyl groups are optionally substituted by the following: - hydroxyl; -5 Or 6-membered heterocyclic ring; -amino group, optionally substituted by one or more q to c6 alkyl groups; and / 128244-3 -57. 200831489 or - alkoxy; -3 to 7 membered heterocyclic ring, optionally Cl to C6 alkyl substitution, which is optionally substituted by a dialkyl-amine group; -NHRn group, the center of which is: -ch2conh2; or -C6 to c8 aryl, optionally substituted by the following · -alkyl; - one or more halogens; - stone Schottky; or - one or more alkoxy groups; a CORp group, wherein: -C! to C6 alkyl, optionally substituted by the following - halogen; - alkoxy; or -Cg to c8 aryl; -5 or 6 membered heterocyclic; - C6 to Cs aromatic a group, optionally substituted by a halogen, a -5 or 6 membered heteroaryl, optionally substituted by hydrazine or a plurality of qSQ alkyl groups; Or r^T^0, 128244-3 -58 - 200831489 and wherein rq is: - cardinyl to decyl; -CORx group, the center of which is as defined above; - halogen group; or - halogen alkoxy And a NRqCONRqRr group, wherein Rq is: -(^ to decyl; -13⁄4 alkyl; -13⁄4 alkoxy; or -CORx group, wherein Rx is as defined above; and wherein RI* is: -C6 to Cg aryl group' is replaced by the following as appropriate -CiSQ alkyl; -alkyl group, -〇Rs group, wherein &amp; is (:6 to (:8 aryl; or -COORx group, the center of which is as defined above; -q to C6 alkane Substituents, optionally substituted by one or more of the following groups: -halogen; 128244-3 -59- 200831489 - sub-alkyl, -c6 to c8 aryl; and/or -COORx group, centered as above Definition; -COORx group, the center of which is as defined above; -NRtCOORu group, wherein Ru is: -(^ to 0:12 alkyl, optionally substituted by the following: -C6 to C8 aryl, optionally Substituted by q to C6 alkyl or alkoxy; - sub-alkyl, - alkoxy, - alkyne; - halogen; or -5 or 6 membered heterocyclic; - C6 to C8 aryl, optionally replaced by : - alkoxy; - halogen; or -^ to ^alkyl; or -5 or 6 membered heterocyclic; and wherein Rt is: - murine, - heart to decyl; -CORx group 'where Rx is As defined above; - a halogen group, or a -1⁄4 alkoxy group; 128244-3 -60-200831489 - a nrvso2rw group centered at: - hydrogen; - a CORx group, wherein 1 is as defined above; -q to c6 alkyl, as replaced by : - Halogen; -CORx group, the center of which is as defined above; - OCORx group, the center of which is as defined above; Or alkoxy; and wherein Rw is: • q to C6 alkyl, optionally substituted by the following: - halogen; -13⁄4 alkyl, -C6 to C8 aryl; or -5 or 6 member a ring; -C2 to C6 alkyl; -alkyl- or dialkyl-amino, optionally substituted by halogen; -5 or 6 membered heterocyclic ring; or -5 or 6 membered heteroaryl, optionally as follows Substitution: -alkyl; -5 or 6 membered heterocyclic ring; or 128244-3 -61 - 200831489 -N NH -N NH Ο , Substituted by q to C6 alkyl, as appropriate Is C! to C6 alkyl or hydrogen; 0&gt; - N Wherein Rz is hydrogen or Ci to C6 alkyl, optionally substituted by C6 to C8 aryl; ...SRX group, the center of which is as defined above; 128244-3 -62-200831489 -S02Raa group, wherein Raa is : -(^ to (:6 alkyl; -amino; -alkyl- or dialkyl-amino, optionally substituted by hydroxy or _COORx group, wherein Rx is as defined above; or -5 or 6 a heteroaryl group; a C6 to C8 aryl group; and/or a NHRbb group, wherein Rbb is: a .c(=s)NH 2 group; or a -p〇(〇Rx) 2 group 'wherein rx is as defined above; or an Rcc group, wherein Rcc is ·· -荇; -5 or 6 members of heteroaryl base; G to aryl, optionally substituted by mono-alkoxy; • hydroxy; or substituted by: 128244-3 -63- 200831489 - halogen, -Q to Q alkyl, optionally substituted by cyano; Amine, optionally substituted by one or more (^ to alkalyl; -NHPORx Rx, wherein Rx is as defined above; _-NReeCONRffRff, wherein is hydrogen or ^ to ^alkyl, as appropriate Substituted by halogen, and Rff is: -nitrogen; -13⁄4 alkyl; -haloalkoxy; -^ to decylalkyl; or -CORx group, wherein Rx is as defined above; - NRGGCORhh group, wherein Rhh And: -Ci to c6 alkyl, optionally substituted by: - alkoxy; - halogen; or - an amine group, optionally substituted by one or more q to c6 alkyl; - an amine group, The situation is replaced by one or more q to (6 alkyl groups, wherein the salty alkyl group is optionally substituted by halogen; -5 or 6 membered heterocyclic ring; -5 or 6 membered heteroaryl; and Rg g is: - hydrogen ; -ci to C6 alkyl; 128244-3 -64- 200831489 -haloalkyl; -haloalkoxy; or -CORx group, wherein Rx is as defined above; -haloalkyl; a group; an amine group, optionally substituted by one or more C! to C6 alkyl groups; and/or a —NRiis〇2Rx group, wherein Rx is as defined above, and Rii is: - hydrogen; • ci to c6 Alkyl; -haloalkyl; -haloalkoxy; or -CORx group, wherein rx is as defined above; Z is -Q to Q alkyl, optionally substituted by the following: -oxyl; One or more halogens; or -C6 to c8 aryl; -c2 to c6 alkyl; _C6 to csaryl, optionally alkoxy or one or more. to alkyl; COORx Group, where Rx is as defined above; or 128244-3 -65- 200831489 R is hydrogen, halogen or alkoxy; Ri is - - murine, - thiol; / _ halogen; - haloalkyl, - fluorenyl; - 5 or 6 membered heteroaryl; - 5 or 6 membered heterocyclic; Alkoxy, optionally substituted by: - one or more halogens; - c6sc8 aryl; or (-5 or 6 membered heterocyclic ring; - C6 to C8 aryl, optionally substituted by alkoxy; a CORx group, the center of which is as defined above; - a heart to a decyl group, optionally substituted by a dialkyl-amine group or a 5 or 6 membered heterocyclic ring; or Ri and R2 are joined together to form a 128244-3 -66- 200831489 R_2 is - a certain group, - nitrogen; - halogen; - a thiol group - a Ci to a C0 alkyl group, optionally substituted by one or more halogens; - an amine group; - an alkoxy group, which is optionally substituted by the following: Or a plurality of halogen; - 〇CORx group, the center of which is as defined above; - a dialkyl-amino group, optionally substituted by an alkoxy group; a 5 or 6 membered heterocyclic group, optionally q to q Substituted by a ketone group; -5 or 6 membered heteroaryl; or -匸6 to C8 aryl; ...C〇〇Rx group, wherein Rx is as defined above; -haloalkyl; guanidinium 'as appropriate Substituted: -hydroxyl; or to c8 aryl; a 5 or 6 membered heteroaryl; - OC〇Rx base map, 1 having an alpha Rx as defined above; 128244-3 -67-200831489 -NHCORj j a group, wherein \ is: - an alkoxy group; or an amine group, optionally substituted by one or more C! to C6 alkyl groups; -ORkk group, wherein Rkk is a 5 to 6 membered heteroaryl group; a nhs〇2Rx group, wherein Rx is as defined above; or R2 is bonded to Ri to form: And R3 is - hydrogen; or -CH2〇CORx, wherein Rx is as defined above; or one or more pharmaceutically acceptable salts thereof. 71. A compound of formula I or a compound comprising one or more compounds: a composition for the preparation of a medicament for the treatment of a hepatitis C sputum (HCV) infection in a patient in need thereof, the treatment comprising Administering to the patient a compound of formula I, or a pharmaceutical composition, which comprises one or more compounds of formula I Wherein: X is ·· 128244-3 -68- 200831489 -nitro group; - gas group; -_CORa group, wherein 匕 is: -Ci to C6 alkyl; -C6 to Q aryl, optionally alkoxy Or a halogen substituted; or a -dialkyl-amino group; a -C00Rx group centered at the valence to the alkyl group; -carbenyl; ('-Q to Q aryl, optionally substituted by alkoxy group Or 5 or 6_membered heteroaryl, optionally substituted by the following: -Ci to C6 alkyl; -C: 6 to C8 aryl, optionally substituted by alkoxy or one or more halogens, or - 5 to 6 membered heteroaryl; Y is: -haloalkyl; (-halogen; -amino group, optionally substituted by one or more q to C6 alkyl groups; -benzofuran; -benzoxephene; -dibenzofuran; -dibenzopyramine; -benzo-P-Serm sitting; -na; 128244-3 -69- 200831489 &lt;bow eucalyptus, optionally substituted with Cl to q alkyl on nitrogen; k(CH2)r NT Rb Wherein Rb is hydrogen or (^ to decyl, and n is 0 rr^S- 'wherein Rc is hydrogen, -CONHRx, wherein Rx is as defined above, or f〇2Rx, the center of which is as defined above; ^Rd.s: 〇-N, whose center is ^ to cardinyl or (: 6 To (:8 aryl; •NHCORe group, wherein ^ is: -Ci to C6 alkyl; -c0 to Q aryl, optionally substituted by the following: -CiSC6 alkyl; -alkoxy; - gas radical; 128244-3 -70- 200831489 - Alkyl; or -halogen; -_NHC00Rx group, the center of which is as defined above; -CH2〇_Rf group, wherein Rf is q to q aryl; - NRgRh group Wherein ^ is ^ to ^ alkyl or hydrogen, and is converted to a fluorenyl to aryl group, optionally substituted by an alkoxy group; -C〗 to C6 alkyl; -5 or a heteroaryl group, as the case may be Substituted: -CiSQ alkyl, optionally substituted by (6 to 〇:8 aryl; -C0 to Cs aryl, optionally substituted by _C00Rx, wherein rx is as defined above; or -amino group; A 6-membered heterocyclic ring, optionally substituted with: -COORx group, wherein rx is as defined above; or ...NHCOORx group, wherein ^ is as defined above; -&amp; to c8 aryl, optionally by one or Multiple Column group substitution: • Alkoxy group, optionally substituted by: - alkoxy; - hydroxy; - one or more halogen; - 5 or 6 membered heterocyclic ring, optionally substituted by: - Ci to C6 Or a hydroxyl group; an amine group, optionally substituted by one or more q to c6 alkyl groups; 128244-3 • 71 - 200831489 --NR4 S〇2 Rx group, wherein Rx is as defined above, Is - rat, -^ to decyl; -CORx group 'wherein Rx is as defined above; - anthracenyl; or -1⁄4 alkoxy; -NRj CORk group, wherein Rk is: -4 To (:6 alkyl; -murine; or -amine, optionally substituted by one or more Cl to c6 alkyl; and Rj is: -murine; -0^ to (:6 alkyl; -CORx a group whose center is as defined above; - an alkyl group; or a - alkoxy group; a group; or a -COR! group, wherein r! is a 5- or 6-membered heterocyclic ring, optionally substituted by a hydroxy group; The amine group 'optionally substituted with one or more Ci to q alkyl groups; - schochyl group; -C! to c0 alkyl group, optionally substituted by the following -NHS〇2Rx group, the center of which is as defined above; Or --NRxS〇2Rx group, The heart is as defined above; 128244-3 -72- 200831489 -haloalkoxy; -halogen; -hydroxyl; -COORx group, the center of which is as defined above; -CORm group, wherein is -amine a group, optionally substituted by one or more q to C6 alkyl groups, wherein one or more of the q to c6 alkyl groups are optionally substituted by the following: - a thiol group; a -5 or 6 membered heterocyclic ring; - an amine group, The situation is replaced by one or more C! to C6 alkyl substituted '-alkoxy; -3 to 7 membered heterocyclic ring, optionally substituted by Cl to (6 alkyl, which is optionally dialkyl- An amine group; or an NHRn group, wherein Rn is: --ch2conh2; or a -c6 to c8 aryl group, optionally substituted by the following: - an alkyl group; - or a plurality of halogens; - a nitro group; Or a plurality of alkoxy groups; -NR〇CORp group, wherein Rp is ··-Ci to c6 alkyl, optionally substituted by the following - halogen; - alkoxy; or 128244-3 200831489 -c6 to c8 a 5- or 6-membered heterocyclic ring; a -C6 to C8 aryl group, optionally substituted by halogen; a -5 or 6-membered heteroaryl group, optionally substituted with one or more q to C6 alkyl groups; And where R. Is: - nitrogen; - heart to decyl; - CORx group, the center of which is as defined above; - a halogen group; or a halogen alkoxy group, - NRqCONRqRr group, wherein 1 ^ is: - nitrogen , -^ to decylalkyl; -co-alkyl; -13⁄4 alkoxy; or -CORx group, the center of which is as defined above; and wherein Rr is: -C6 to C8 aryl, optionally replaced by ··128244-3 -74- 200831489 - (^ to octyl; - fluoroalkyl, - 〇Rs group, centered at (: 6 to (: 8 aryl; or - COORx group, wherein Rx is as defined above; -C! To a C6 alkyl group is optionally substituted with one or more of the following groups: - halogen; - a secondary alkyl group; - a C6SC8 aryl group; and/or a -COORx group, the center of which is as defined above; - COORx group Group, the center of which is as defined above; - NRtCOORu group, the center of which is: - (^ to 匚 "alkyl" is replaced by the following: -Q to q aryl, as the case is (^ to ^ alkyl Or alkoxy substituted; 1 -alkylene; -alkoxy; -alkyne; -halogen; or-5 or 6 membered heterocyclic ring; to C8 aryl, optionally substituted by: 128244-3 -75- 200831489 - alkoxy; -halogen; or -toxin alkyl; or -5 or 6-membered heterocyclic; and Rt is -chloro; -q to C6 alkyl; -CORx group, centered as above Definitions; - aryl group; or - halooxy group; - nrvso2rw group, centered at: - murine, -CORx group, wherein Rx is as defined above; or -q to C6 alkyl, as The situation is replaced by the following: - Halogen; -CORx base , the center of which is as defined above; -OCORx group, the center of which is as defined above; - thiol; or - alkoxy; and wherein Rw is: -Ci to Ce alkyl" is replaced by the following: _ prime; -13⁄4 alkyl; - (: 6 to (: 8 aryl; or 128244-3 - 76 - 200831489 • 5 or 6 membered heterocyclic; • C2 to C6 alkyl; alkyl- or dialkyl - an amine group, optionally substituted by a halogen - 5 or 6 membered heterocyclic ring; or a 5 or 6 membered heteroaryl group, optionally substituted by the following: • C to C6 alkyl; • 5 or 6 membered heterocyclic ring; or 128244 -3 4 to (: 6 alkyl or hydrogen; -77- 200831489 'wherein Rz is hydrogen or C1 to C6 alkyl' is optionally substituted by Q to C8 aryl; ...SRX group, the center of which is as defined above; -S〇2Raa group, wherein Raa is: -Ci to An alkyl group or an alkyl- or dialkyl-amino group, optionally substituted by a hydroxy or -COORX group, wherein Rx is as defined above; or -5 or 6 membered heteroaryl; -C6SC8 a base; and/or a NHRbb group, wherein Rbb is ... -•c(=s)nh2 group; or 128244-3 -78-^0831489—PO(ORx)2 group, the center of which is as defined above; a Rcc group wherein Rcc is 5 or 6 membered heteroaryl; And to a Cs aryl group, optionally substituted by one or more of the following groups: - alkoxy; - thiol; - halogen; - Q to C6 alkyl, optionally substituted by cyano; - amine, The case is substituted by one or more q to C6 alkyl groups; -NHPORxRx group, the center of which is as defined above; -NReeCONRffRff group, wherein Ree is hydrogen or CjC6 alkyl, optionally substituted by halogen, and Rff is : - hydrogen; - haloalkyl; - haloalkoxy; - (^ to (: 6 alkyl; or - CORx group, wherein Rx is as defined above; - NRggCORhh group, wherein Rhh is: - hydrogen; • q to C6 alkyl, optionally substituted by: 128244-3 -79- 200831489 - alkoxy; -halogen; or -amine, optionally substituted by one or more Ci to c6 alkyl; -amino , optionally substituted by one or more Ci to c6 alkyl groups, wherein one or more q to c6 alkyl groups are optionally substituted by dentate; -5 or 6 membered heterocyclic ring; -5 or 6 membered heteroaryl; And Rg g is: - hydrogen; -Q to C6 alkyl; -haloalkyl; -haloalkoxy; or -_CORx group, the center of which is as defined above; -haloalkyl; -5 or 6-membered a cyclic group; an amine group, optionally substituted by one or more C! to C6 alkyl groups; and/or an NRhSC^Rx group, wherein rx is as defined above, and Rii is: - hydrogen; - Ci To a C6 alkyl group; -13⁄4 alkyl; -haloalkoxy; or -CORx group, the center of which is as defined above; Z is: -Q to C6 alkyl, optionally replaced by the following: 128244-3 -80- 200831489 - Alkoxy, - one or more halogens Or -c6 to c8 aryl; -c2 to c6 alkyl; -C6 to C8 aryl, optionally substituted by alkoxy or one or more CiSQ alkyl; -COORx group, centered as above Definition of text; or R is hydrogen, halogen or alkoxy; Ri is - mouse, -hydroxyl; -halogen; -genyl, -nitro, -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclic; -alkane Alkoxy, optionally substituted by: - one or more halogens; - C6 to C8 aryl; or -5 or 6 membered heterocyclic; 128244-3 -81 - 200831489 - A to q aryl, optionally alkane Oxy substituted; ...CORx group, wherein ^^ is as defined above; - heart to ^alkyl, optionally substituted by dialkyl-amine or 5 or 6 membered heterocyclic ring, &&lt; To form: R is · - nitro; - nitrogen; - a hydroxyl group; - a mercapto group; - a Cl to a C6 alkyl group, optionally substituted by one or more halogens; - an amine group; - an alkoxy group, as the case may be replaced by : - one or more halogens; -OCORx group, the center of which is as defined above; - an alkyl group - an amine group, optionally substituted by an alkoxy group; - a 5 or 6 membered heterocyclic group, optionally Ci to Q alkyl substituted, -5 or 6 membered heteroaryl; or -C6SC8 aryl; -COORx group, centered as defined above; -haloalkyl; 128244-3 -82- 200831489 -guanamine The base is optionally substituted with: -hydroxyl; or -c6sc8 aryl; -5 or 6 membered heteroaryl; -OCORx group, the center of which is as defined above; -NHCORj j group, wherein Rj j is : - alkoxy, or -amino, optionally substituted by one or more Ci to c6 alkyl; -ORkk group, wherein Rkk is a 5 to 6 membered heteroaryl; -NHS02Rx group, centered Is defined as above; or ^ is combined with &amp; to form: R3 is - hydrogen; or -CH2OCORx, the center of which is as defined above; or one or more of its pharmaceutically acceptable salts. 72. - Compound of formula Illb 128244-3 -83 · 200831489 where: X is hydrogen; Y is: -5 or 6 membered heteroaryl, optionally substituted by Q to Q aryl, which is optionally replaced by -COORx* group Or as defined above; or c0 to a group, optionally substituted by one or more of the following groups: _amino group, optionally substituted by one or more c to c6 alkyl; f - halogen; - hydroxy; a -CORm group centered on an amine group, optionally substituted with one or more q to c6 alkyl groups; --NR0CORp group 'where R, CiiC6 alkyl, optionally substituted with an alkoxy group, and wherein R. Is a hydrogen; -NRqCONRqRr group, wherein Rq is hydrogen, and its center is a ruthenium to a ruthenium group, a 1-wind (10) core group, wherein Rt is hydrogen, and wherein R4CjCi2 alkyl, as the case may be replaced by: - C6SC8 aryl; -halogen; or -5 or 6 membered heterocyclic ring; -NRvS〇2Rw group, wherein Rv is hydrogen, and complex /, T Kw is: -CiSC6 alkyl; or -alkyl- or dialkyl -amino group; 128244-3 -84- 200831489 v〇 -N Wherein Rz is hydrogen or (^ to decyl-S02Raa group, wherein Raa is: -amino group; or -alkyl- or dialkyl-amino group, or -NHRbb group, wherein Rbb is - PO(ORx)2 group, as defined above; wherein Rx is as Z is: -^ to decyl; or -COORx group, the center of which is as defined above; R is nitrogen 'R! is - mouse, -5 or 6 member heterocyclic ring; or - alkoxy group, depending on The situation is replaced by the following: - one or more halogens; or -5 or 6-membered heterocycles; R2 is · 128244-3 -85- 200831489 - nitrogen; - via, -C! to C6, depending on the situation Or a plurality of halogen-substituted '-alkoxy' groups are optionally substituted by the following: - or a plurality of halogens; - 5 or 6 membered heterocyclic groups, as the case may be (^ to (6 alkyl substitution; or -5) Or a 6-membered heteroaryl; -_COORx group, the center of which is as defined above; - an amine group; - 5 or 6 membered heteroaryl; or - a Rkk group, wherein Rkk is 5 to a member heteroaryl And R3 is hydrogen. 73. The compound of claim 72, wherein X is: - hydrogen; Y is: - a cjc^ group substituted by a - mtox) Ru group, wherein &amp; is nitrogen, and wherein Ru (^ to (: 12 alkyl; Z is: • C! to c6 alkyl; R is: - hydrogen; Ri is: - hydrogen; 128244-3 -86 - 200831489 1^2 for · -ORkk group Wherein Rkk is a 5- to 6-membered heteroaryl; R3 is a hydrogen-hydrogen. 74. ·· compound is selected from the range 866-1329,1484-2127, 2129-2545. 128244-3 87- 200831489 128244-3 88 - 200831489 4 128244-3 •89-