TW200848057A - 1,1-dioxo-1-thia-5,10-diazadibenzocycloheptenes useful as hepatitis C virus inhibitors - Google Patents

Abstract

Inhibitors of HCV replication of formula (I) the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof wherein R1a; R1b R2; R3; R4a and R4b have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.

Description

200848057 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a U-two-side oxygen such as a plug, which has an active activity, and has a compound containing such a compound as an activity. dilute. Additional compounds and methods of compositions. 77 MMSUf This [Prior Art] Hepatitis C is the scream of chronic hepatitis in the world. Hcv is a flavivirus family in c-type hepatitis 2:: medical staff, closely related to the genus of the genus, the virus associated with the disease of the jaundice, such as dengue virus and: = disease: species closely related to the human plague virus family 'Plague virus family:: Include cattle::: and virus (BVDV). The HCV line is a positive-stranded single-stranded virus 9-base ^ gene. The gene body also contains 5, and 3, untranslated regions, and coded singles, approximately 3, 〇1〇 to 3, 〇3〇 and = open reading frames. The polyprotein encodes ten gene products, which are produced by the - series of both the host and the viral protease, which are co-translated and translated by endogenous proteolytic cleavage. Viral structural protein lines include nucleocapsid proteins and two envelope glycoproteins E1 and Ε2. These non-structural _ proteins encode certain essential viral enzyme functions (helixase, polymerase, protease) and proteins with unknown functions. Replication of viral genomes is mediated by RNA-dependent RNA polymerase encoded by non-structural protein 5b (NS5B). 6 20 200848057 In addition to polymerases, viral helicase and protease functions (both encoded in bifunctional NS3 proteins) have been shown to be required for HCV RNA replication. In addition to the NS3 serine protease, HCV also encodes a metalloproteinase in the NS2 region. 5 HCV preferentially replicates in hepatocytes, but does not directly cause cell damage, but rather causes persistent infection. In particular, the lack of active lymphocyte response and the high mutational propensity of the virus clearly contribute to a high rate of chronic infection. There are six major HCV genotypes and more than 50 subtypes, with geographical differences. Type 1 HCV is the major genotype in the United States and Europe. For example, 1〇 Type 1 HCV is the cause of 70 to 75 percent of all HCV infections in the United States. The extreme genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps indicating the difficulty of vaccine development and the lack of response to treatment. It is estimated that 170 million people worldwide are infected with hepatitis C virus (HCV). After the initial acute infection, most of the infected individuals develop chronic liver inflammation, which develops into liver fibrosis, leading to cirrhosis (end liver disease) and HCC (liver cancer) (National lnstitutes 〇f Heakh - café

Development Conference Statement: Management 〇f Hepatitis C· Hepatology, 36, 5 Suppl S3_S2〇, 2〇〇2). Because HCV (4) causes cirrhosis alone, r causes about 1 每年 per year in the United States, 〇〇〇 20 people die, and is the main cause of liver transplantation. Infection with HCV can occur through exposure to contaminated blood or blood, such as after transfusion or after intravenous drug use. Diagnostic tests used in the introduction of blood screening have reduced the incidence of HCV after transfusion. However, because of the slow development of end-stage liver disease, the current infection is still a serious medical and economic negative for the next few decades, 7 200848057 W.R. Hepatology, 36, 5 SuppL S30-S34, 2002). 10 15 20 The current HCV therapy is based on (pegylated) interferon-a (IFN_a) combined with ribavirin. This combination therapy produces a sustained viral response to more than 40% of patients infected with genotype 1 virus, compared with approximately 80% of those infected with genotypes 2 and 3. In addition to the limited effect on type I HCV, combination therapies have the side effects and many patients are poorly tolerated. For example, in the registration test of pegylated interferon and ribahan, about 1 to 14 percent of the affected phase interrupted treatment for obvious side effects. The main side effects of combination therapy include flu-like symptoms, blood abnormalities, and = god symptoms: the development of more effective, read, and more tolerant treatments is a #的之何生生政策. Therefore, the treatment of such chronic diseases does not achieve the desired side effects. For the purpose of the treatment is only partially effective and limited by the lack of the ship into the field - a field of special concern to find the leg problem - dependent county red (four) structural homology discovery can provide more specialized I: two: in the ' The inhibitor of the inhibitor of the polymerase _, directly with the nucleus; higher specificity, which can be: high C active site. The nni can achieve a high failure rate and a heterozygous interaction in the bed test. Prepare for the need. And the discovery of novel NS5b inhibitors 8 200848057 [Summary of the Invention] It has been found that specific 1,1 -di- oxo-1 -喧_5,10-diπ丫dibenzo-cycloheptene derivatives are infected with HCV. Antiviral activity is exhibited in mammals. These compounds are therefore useful for treating or combating HCV infection. The present invention relates to an inhibitor of HCV replication, which can be expressed as formula (1):

And stereoisomers, prodrugs, tautomers, racemates, salts, hydrates or solvates thereof, wherein the RU is hydrogen, hydroxy, amine, Cm alkoxy, halo or, as appropriate Substituted Cl_6 alkyl; 1 Id R is hydrogen, hydroxy, amine, Cw alkoxy, -〇-CH24 azolyl, 2 yl, difluoroindenyl or Ci_6 substituted by I group as appropriate The R system is IL, -C(=〇)-R5, -C(:0)-C(=0)-R5, -C(=〇)_〇R6 or -C(dioxin)_NR7aR7b; R Is a Cu alkyl group optionally substituted by a C3_7 cycloalkyl group, an aryl group or a Het; a heart 7 alkyl group; an aryl group; or Het; each of R4a and R4b is independently hydrogen, Cw alkyl, C2_6 alkenyl Or R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form a C3_7 cycloalkyl or oxetane group; 9 200848057 R is one or two substituents selected from the group consisting of: Substituted heart-6 alkyl: i group, cycloalkyl, phenyl hydrazine as a thio group, a cyano group, a polyhalo CK6 alkyl group, a pendant oxy group, a fluorene R9, -C(=0)- 0R6, -C(=0)-〇H, C(,-NR7aR7b, 5-C(=0)-NH-S(=〇)2-R8, -NR7aR7b, _s(=0)2-aryl, Aryl and Het; a C2-6 alkenyl group substituted by an aryl group; a polyhalo group (^6 alkyl group; a c3_7 cycloalkyl group; an aryl group; or a _; r6 system is optionally a -or9, -cc=〇)-cm9, -C (risk NR7aR7b, _c(=〇)_nh s(=〇)2_r8, aryl or Het 10 substituted aryl or Cu alkyl; each R and R is independently hydrogen; as the case may be one or two a Cl-6 alkyl group substituted with a substituent selected from the group consisting of _or9, mono or diCi 6 alkylamino group, -C(=0)_0R9, _c(=〇) NH2, _c(=〇)_NH_c^ Alkyl, -C(=〇)_NH-hydroxy CV6 alkyl, -C(=〇)_Het, C3_7 15 cycloalkyl, aryl and Het; Cw alkenyl; C3_7 cycloalkyl substituted by hydroxy group as appropriate ; aryl; or fjet; R§ is a complete, ^cycloalkyl, bis(Cl.3 fluorenyl)amine or aryl; R9 is hydrogen; optionally selected by one, two or three Substituted by the following '° substituents. -6 alkyl group, hydroxy group, c3-7 cycloalkenyl group, =3-=beta group, cyano group, Gw alkoxy group, phenyl group or Het, where ' The phenyl group may be optionally substituted by a halogen group, a hydroxyl group, a Q 6 alkyl group, a C 6 alkyl group, a Ci 6 alkoxy 6 alkoxy group, a nitro group or an amine group, as appropriate. _ With one or two groups selected from halo and multi 10200848057

a c2-6 alkenyl group substituted by a substituent of a Cw alkyl group; a c2_6 alkynyl group; a c3-7 cycloalkenyl group; or a phenyl group optionally substituted with one or two substituents selected from the group consisting of a hydroxyl group and a Cw alkoxy group. a halogen group, a polyhalogen group, a C 6 alkyl group, an amine group, a nitro group, a Ci_6 alkyl group and a phenyl group; the aryl group as a group or a part of a group is a phenyl group, a naphthyl group, a hydrogen group or a 1, 2,3,4-tetrazine-negyl' can be optionally substituted by one, two, two or four substituents independently selected from the group consisting of c: 3-7 cycloalkyl, benzene a base Ck alkyl group, a phenyl poly-yl ci 6 dentate group, a base Ck alkyloxy group, a yl group, a polyhalogen group. "Acetyl, cyano, Cw alkyl, polyhalo C1-6 alkoxy, _〇R9, -C〇K)) 〇H, Cw alkylcarbonyl, c1-6 alkylthio, c!_6垸A fluorenyl group, a 4-brexyl group, and a pyrrolyl group, wherein the phenyl group may be optionally substituted with a halogen group; or two substituents on the aryl ring may form _o-ch2- o or a 〇_c(CH3)2_CH2

Het, as part of a group or a moiety, is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring, the human being 1 to 4, each independently selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, </ br> </ br> </ br> Alkyl; Cl_6 alkylthio, side collar 9; pendulum % 'predicate; as the case depends on 9, =, ' _NR10aRH) b or phenyl substituted silk; _c (= 〇),; -c (which phenyl; C3-7 cycloalkyl; the base substituted by 6 gas-burning groups, as the case may be; oxime-based; 吼 σ σ base; 吼 夷 · 11 200848057 base; tetradecyl, and thienyl; and each R10a and R1^ is independently hydrogen, Cl.6 fluorenyl, aryl Ci6 alkyl or Rl〇a and R together, the nitrogen to which it is attached may form a saturated, partially non- 5 10 15 ; end, = 5 to 8 members a single ring, wherein the single ring optionally comprises: (iv) additional heteroatoms of the group consisting of: oxygen, hydrazine, and nitrogen, and wherein the remaining single ring members are carbon atoms; the single ring may be optionally in the carbon Atomic One or two substituents are selected from the group consisting of: a secret, a Cin or a pendant oxy group. In a specific embodiment, the invention relates to inhibition of H c v replication and salts and stereoisomers thereof, wherein θ

Rla is hydrogen, hydroxyl, amine or halo;

Rlb is hydrogen, sensible, i-based, trifluoromethyl or optionally substituted cyano-substituted Cu alkyl; R2 is 氲, -C(=0)-r5, -C(=〇)-C(K ))-R5, -C(=〇)-〇R6 or -C(=0)-NR7aR7b ; is a q 6 cadaver base substituted by alkyl, aryl or Het, 〇3_7 bad base; Each of the Cb alkyl groups or R4lR4b, together with the carbon atom to which the tricyclic ring is attached, may form a C3_7 cycloalkyl group; 'R5 is optionally selected one or two. [1_6$ methoxy group, polyhalogenated Cu alkyl group, pendant oxy group, Han 9, -C(-0)_Het, -C(=0)-0R6, -C substituted from the following substituents (=〇^qj^ 12 20 200848057 _C(=0)-NR7aR7b, _C(=0)-NH-S(=0)2-R8, _NR7aR7b, aryl and Het; C2_6 substituted by aryl group as appropriate Alkenyl; polyhalo-Ci_6 alkyl, 3-7 bad alkyl; aryl; or Het; R6 is optionally treated by -OR9, -C(=0)-〇R9, -C(=〇)- NR7aR7b, 5-C(=0)-NH-S(=0)2-R8, aryl or Het substituted C1-6 alkyl; each R and R are independently nitrogen, optionally one or two ^:!·6 alkyl group substituted with a substituent selected from the group consisting of _〇r9, mono or diCl-6 alkylamino group , -C(=0)-〇R9, -C(=0)-NH2, -C(=0)-NH-C alkyl, -C(=0)-NH-hydroxy Ci_6 alkyl, -C( =0)-Het, C, i〇cycloalkyl, aryl and Het; C2_6 dilute; C3_7 cycloalkyl substituted by a radical; aryl; or Het; r8 is Ck alkyl, Cp ring An alkyl group, a di(Cu alkyl)amino group or an aryl group; R9 is hydrogen; optionally a CV6 15 alkyl group substituted with a Cu alkoxy group, a phenyl group or a Het group, wherein the phenyl group may be optionally subjected to the following groups Substituted: halo, Cu alkoxy, nitro or amine; or phenyl substituted by one or two substituents selected from the group consisting of halo, amide, nitro, Ck alkyl and benzene When the aryl group is a part of a group or a group, it is a phenyl group, a naphthyl group, a hydroquinone 20 group or a 1,2,3,4-tetraar-naphthyl group, which may be one or two each depending on the case. Substituted independently from a group consisting of a substituent: a halogen group, a polyhalogenated Cu alkyl group, a cyano group, a CV6 alkyl group, a polyhalogenated Cu alkoxy group, -OR9, -C(=0)0H, Ck Alkyl group, Ck sulfur group, C!_6 alkylsulfonyl group, -S〇〇)2NH2 and pyrrolyl group; 13 200848057

Het as part of a group or group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, Depending on the case, it may be slightly conjugated to a benzene ring and wherein the group Het may be substituted by one or two substituents each independently selected from the group consisting of: a dentate group; a pendant oxy group; -NR1GaR1Gb; -CN; Ci 6 alkane substituted by -OR9, -CN, -NR1()aR1()b4 phenyl group, group; -c(=〇)-NH2; -C(=0)- Phenyl; Cw cycloalkyl; phenyl substituted by Ci_6 乳 乳 ;; 吗 琳 基; 吼 10 10 base; pyrrolyl; furyl; tetrazolyl; and thienyl; . And "(10) is independently hydrogen, Cu alkyl, aryl (^16 alkyl ruthenium and kiwi together with the nitrogen to which it is attached to form a saturated, partially unsaturated or fully unsaturated 5 to 8 member single ring Wherein the monocyclic ring optionally contains an additional heterologous 15 selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining single ring members are carbon atoms; wherein the single ring may be in any carbon The atom is substituted by one or two substituents selected from the group consisting of a halogen group, a Q.6 alkyl group, and an I group 2 side oxy group. The present invention is additionally related to the preparation of the compound of the formula (I). The use of the oxide, the 20th amine, the metal complex and the stereochemically isomeric form, the intermediate thereof and the use of the intermediate in the preparation of the compound of formula (I). The present invention thus encompasses a preparation having the formula (1- 8) The method of the present invention, comprising the steps of: reacting a compound of the formula (1-2) with a compound of the formula (1-4) to form a compound of the formula (1-5), and 14 200848057

The compound of the formula (1-5) is reacted with an aldehyde of the formula (1) in the presence of an acid as appropriate to give a compound of the formula (1-8).

5 wherein RU, Rlb, R4a, Hanxian and R3 have the meanings as defined by the present invention. The invention also encompasses a process for the preparation of a compound of the invention having formula (1-9) which comprises the steps of:

The compound of the formula (IV) is deuterated by acid or by living to give a compound of the formula (I) having the formula (1-9) wherein Rla, Rlb, R4a, "," and have the meanings as defined in the present invention. 15 10 200848057 The invention also encompasses a process for the preparation of a compound of the invention having formula (1-10), which comprises the steps of:

1-10 R7i A compound of the formula (1-8) is reacted with an isocyanate of the formula (I-8a) to give a compound of the formula 5 (1-10) wherein R7bS is hydrogen or a compound of the formula (1-8) Phosgene or an equivalent phosgene reaction of the formula (I-8b), wherein the LG group represents a leaving group, followed by treatment with an amine of the formula (I-8 c) to give a compound of the formula (I-10), wherein Rla, Rlb, R4a, R4b, R3, ninth and scale have the meaning as defined in the present invention. The invention also encompasses a process for the preparation of a compound of the invention having formula (1-11) which comprises the steps of:

The compound of the formula (1-8) is reacted with a chloroformate of the formula (I-8d) 16 200848057 in an inert solvent in the presence of a base to give a compound of the formula (1-11) wherein Rla, Rlb, R4a, R4b, R3 and R6 have the meanings as defined in the present invention. The present invention relates to a compound of the formula (I) itself, an N-oxide, a salt, a hydrate, a solvate, a quaternary amine, a metal complex, a prodrug and a stereochemically isomeric form, which are used as a medicament. The present invention relates to the compound of the formula (1) itself, its N-oxide, salt, hydrate, solvate, quaternary amine, metal complex, prodrug and stereochemically isomeric form for treating hepatitis C . The invention further relates to a pharmaceutical composition comprising a carrier and an antiviral effective amount of a compound of formula (I) according to the invention. Such pharmaceutical compositions may comprise a composition of the foregoing compounds with other anti-HCV agents. Such pharmaceutical compositions may comprise a composition of the foregoing compounds with other anti-HIV agents. The invention further relates to the aforementioned pharmaceutical compositions for administration to an individual having an HCV infection. The invention also relates to the use of a compound of formula (1) or an N-oxide, salt, hydrate, solvate, quaternary amine, metal complex, prodrug or stereochemically isomeric form thereof, which is used in the manufacture for inhibition The agent used for HCV replication. Or the present invention relates to a method for inhibiting HCV replication in a warm-blooded animal. The method comprises administering an effective amount of a compound of formula (I) or a prodrug thereof, an N-oxide, a salt, a hydrate, a solvate, A quaternary amine, metal complex, prodrug or stereochemically isomeric form. DETAILED DESCRIPTION The invention will now be further described. In the following paths, different aspects of the invention are defined in more detail. Each of the defined aspects can be combined with any other 17 200848057, unless otherwise stated. In particular, the better features are available for fishing - ^ can be shown as a better or a combination of the previous and the following illusion. The application of the month J and the Chinese language is based on the term "base". As used herein, the term "c is the general term for the hardening of the base. The time is defined and there are 5 yuan of soil":,, or a part of the group or group of groups h, a linear or branched platinum of eight to four carbon atoms such as, for example, Methyl, ethyl, propyl small group, propyl ketone group, = saturated = group, isobutyl group, 2-methyl propyl group - d; "-1-yl group, but-2- 10 15 2: two = have 1 to The straight chain of 3 carbon atoms, such as, for example, methyl, ethyl, propyl+yl, propylidene, covers q 3 calcination; ^ r #土, 1-6 sub- and its 5 or 6 a carbon atom such as, for example, pentyl, pentyl-2-yl, pentyl-3-yl, hydrazine, its own _2-yl, 2-methylbutyl]-yl, 2-methylpenta-1 _ base, 2-ethidin-1-yl, 3-mercapto-4-yl and the like. Wherein the alkyl group is a cM alkyl group and a Ci_3 alkyl group. w The term "C2_6 dilute group" as a group or a group of a group:: and a C hydrocarbon group, which is a straight chain or a branched chain 'containing- or a plurality of carbon-anti-two 2-6 alkenyl groups have Vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and isomers thereof, 2-hexenyl and 2,4-pentadienyl and the like. The term "polyhalogenated core 6 alkyl group" as a group or a group of two or more of them: hydrogen is - or a plurality of halogens defined as before: 1-6 2 /, Ci_6 alkyl having the meaning of derogatory. Non-limiting examples of such polyhalogenated seven alkyl groups include chloromethyl, bromoethyl, fluoromethyl 18 20 200848057 gas methyl, triclinyl and u mountain trifluoroethyl. And G. 3'7^ is a general term for cyclodecyl, cyclobutyl, cyclopentyl, cyclohexyl and % heptyl.丞 5 10 15 20 The term "Cw alkoxy" A "group-partial; base" as a group or as defined above Cl. Remaining r, f^_()R ^ group® 'where Ra is Non-limiting examples of butoxy, butyloxy, isopropoxy, butoxy, and isopropanol alkoxy groups including decyloxy and ethoxylated calcinations include: : Milk base::oxy group and hexyloxy group. Suitable groups, butoxy groups, isobutylene oxime &quot;: ethoxy, propoxy, isopropoxy terms "(4). 2;: butoxy 2 and its butyloxy. Time-sharing, which means 1 = minus" as a group or a group-substitutional substitution having the above definition - a non-limiting alkoxy group of the previously defined dentate:: Cl-6 pure base. The multidentate gas oxime, dioxetane, diterpene oxime and 1,1,1-trifluoroethoxy have the term (tetra) or pendant oxy group as used herein before to be attached to the group. The atomic time-shaped partial base portion is formed when the sulfur atom is attached to the sulfur atom, and when the two terms are attached to the sulfur atom, the sulfone portion is formed. - When the ring or ring system is replaced by a pendant oxy group, the carbon atom to which the pendant oxy group is bonded; is saturated with carbon. The term "Ck:!: complete basestone yellow wine" as a group or a part of a group is a group representing the formula -S(=〇)2-Rb, wherein Rb is the meaning of the invention Ci-6 alkyl. Non-limiting examples of Cw alkylsulfonyl groups include carbendrexate, ethyllithic acid, butyl stellite, propan-1-yl sulphate, Li 19 200848057 sill page and hexyl sulphate . The term "C1-6 alkylcarbonyl" is defined as a radical of the formula -C(=0)_Rc. As a group or a part of a group, wherein the RC is as previously described for the alkane

The term "C 5 10 15 means that when connected to the second part of the == group - part of the 'system (SCh2CH3), n-propylthio group, iso (tetra) group, playing B: kenong dibutylthio group, ruthenium tributyl sulphide Base and the like. - Butyl-based, it should be noted that the position of the group on any of the molecular moieties defined in the definition can be located anywhere on the moiety as long as it is chemically stable. The groups used in the definition of variables include all possible isomers unless otherwise stated. For example, piperidinyl includes piperidinyl, piperidinyl-2-yl, piperidin-3-yl and piperidin-4-yl; and pentyl includes pentyl, pent-2-yl and pent-3-yl. When any of the variables occurs more than once in any of the components, each time the definition is independent. The term "compound of formula (I)" or "compound of the invention" or like terms is intended to include a compound of formula (1), a prodrug thereof, an N-oxide, a salt, a quaternary amine, a metal complex, whenever and after use. And stereochemically isomeric forms. A specific embodiment comprises a compound of formula (1) or any of the subgroups of formula (I) listed herein and their N-oxides, salts (possible stereoisomeric forms thereof). Another embodiment comprises a compound of formula (I) or a compound of any of the subgroups (I) of the present invention and a salt thereof (for its possible stereoisomeric form 20 20 200848057). The compound of formula (I) may have one or more pairs of palmitic central stereochemically isomeric forms. As used herein, the term "立立为形式" is defined to mean that a compound of formula (I) may have a bond that is bonded by a phase-by-synchronous bond, but has a different three-dimensional structure. Compound. °, may be used in the use of (and) or 〇 s) in the name of the substitution of the palm of the name of the shield 2 atomic absolute configuration of the name of the naming system considers the whole compound rather than the single , J put the substituent. Unless otherwise stated or indicated, the substance of the compound 々f ^ 10 15 20 7 The name of the chemical name covers all possible stereochemically isomeric bands, 曰 humans that the compound may have. The mixture may contain the basic molecular structure of the compound and the isomer and/or mirror image isomer. All of the stereo 2 and isomeric forms of the compounds of the present invention are in the form of a mixture of 35 in the present invention. The pure stereoisomeric forms of the compounds and intermediates of the invention are defined as being substantially free of the same basic molecules of the compounds or intermediates = isomers of other mirror-isomeric or non-image-isomeric forms of the structure. . In particular, the phrase "stereoisomerically pure" means having at least 80% stereoisomeric excess of at least 90% of one isomer and up to 10% of another possible isomer) to 100% stereoisomeric excess (ie a compound or an intermediate of 100% of one isomer and no other, in particular, having a stereoisomeric excess of 90% to 10,000%, more particularly having a stereoisomeric excess of 94% to 100% and most In particular, there are compounds or intermediates having a stereoisomeric excess of from 97% to 1%. The terms "mirror isomerism pure" and "non-mirror 岂 21 200848057 constitutively pure" should be understood in the same manner, but with a view to the image constitutive excess and non-imagewise heterogeneous excess of the mixture studied. ~ 10 15 The pure stereoisomeric forms of the compounds and intermediates can be prepared by methods known in the art. For example, the mirror image isomers can be separated from each other by selective crystallization with a salt of an optical acid or a base. Examples thereof are tartaric acid: benzoyl tartaric acid, xylyl tartaric acid, and camphor sulfonic acid. Alternatively, the image isomer can be separated using a palm-type static phase-by-molecular chromatography technique. , the chemical isomeric form of the vertical f can also be derived from the corresponding pure ΐΐ of the appropriate starting material: the heterogeneous form is derived from the 'difficult part, the bite is selectively generated, the right is required, and the specific stereoisomer is required'. Sexual products. The scaly method is advantageously employed as a non-mirromeric isomer of the compound of the image-isomerized compound. The appropriate physical separation method can be used for the appropriate physical separation methods, such as selective knotting and chromatography, such as column Chromatography. Absolute stereochemistry for certain compounds of formula (I), prodrugs thereof, oxy-oxides, salts, hydrates, solvates, quaternary amines or metal complexes and intermediates used in their preparation Type is not an experimental decision. Those skilled in the art can determine the absolute configuration of such compounds by methods known in the art, such as, for example, m-diffraction. In one embodiment, the invention encompasses compounds of formula (π) and (πι). In a specific embodiment, the compound of formula (1) is preferably configured to have the formula (Π). 22 20 200848057

Wherein R, ^^^, and ^^ have the meanings as defined by the present invention. This description also includes all isotopes of the atoms present on the compounds of the invention. Isotopes include atoms having the same atomic order but different mass numbers. For the general non-limiting example, the isotopes of hydrogen include deuterium and tritium. Carbon isotopes include C-13 and C-14. The term "prodrug" as used throughout the context of the present invention means a pharmaceutically acceptable derivative, such as an ester, an acid amine or an acid salt, such that the derivative is bioswitched in vivo as defined by the compound of formula (1). Active drug. Reference is made herein to Goodman and Gilman for a general description of prodrugs (The Pharmacological Basis of Therapeutics, 8th ed McGraw-Hill, Int Ed. 1992, "Biotransformation of Drugs" P 13-15). Prodrugs are preferably of excellent water solubility, high bioavailability and are readily metabolized into active inhibitors in vivo. The prodrug of the compound of the present invention can be prepared by modifying a functional group present in the compound so that the modification can be carried out by routine manipulation or in vivo to become a parent compound. Preferably, it is a pharmaceutically acceptable ester prodrug which is hydrolyzable in vivo and 23 200848057 is derived from a compound of formula (i) having a hydroxyl or carboxyl group. Hydrolyzable in vivo is intended to be a vinegar which can be hydrolyzed in humans or animals to produce a parent acid or alcohol. ^ Suitable pharmaceutically acceptable esters at the carboxy group include Cl.6 alkoxy/methyl esters such as methoxy-indenyl, Cw oxyalkyloxymethyl esters such as steroid 5 hydroxy group Base, azlactone ester, C3_8 cyclodecyloxy, oxymethane-6, ketone vinegar 'example # 1-cyclohexyloxyethyl; α-dioxanthene-2-yl fluorenyl Vinegar' such as 5-mercapto-1,3-dioxolyl fluorenyl, and Cl -6 alkoxy-Wikioxyethyl vinegar, such as 1 曱 曱 臭 某 某 某 某It can be formed on any of the carboxyl groups of the compounds of the invention. The in vivo hydrolysable ester of the compound of the formula (1) containing a hydroxyl group includes inorganic esters such as a phosphate ester, and an α-decyloxyalkyl ether, and related compounds which produce a parent hydroxyl group as a result of hydrolysis decomposition of the ester in the body. Examples of the α-methoxy group &amp; base group include an ethoxycarbonyl-methoxy group and a 2,2-dimethylpropyloxy-methoxy group. The selection of the hydrolyzable ester-forming group for the hydroxyl group includes a burnt acid group, a benzoquinone group, a phenylethyl group, a substituted benzamidine group, a phenylethyl group, and a thiol group. (generating acid-burning), dialkylamino-based broth and di-(dialkylaminoethyl)-#-alkylamino 曱g blue (producing urethane), secondary burning Aminoethyl thiol and thioglycol. Examples of the substituents on the phenyl hydrazine group include a ruthenyl group and a piperidinyl group which are attached to the 3- or 4-position of the azene 2 ring via a methylene ring. For therapeutic use, the salt of the compound of formula (I) is one in which the relative ion system is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases have also been found to be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included in the scope of this publication 24 200848057. The pharmaceutically acceptable acid and base salts mentioned above are intended to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. Pharmaceutically acceptable acid addition salts can be conveniently prepared by treating the drug with the appropriate acid. Suitable acids include, for example, mineral acids such as hydrohalic acids such as hydrochloric acid or hydrazine bromate, sulfuric acid, phytic acid, phosphoric acid and the like; or organic acids such as, for example, acetic acid, propionic acid, transacetic acid, lactic acid, pyruvic acid Oxalic acid (ie oxalic acid), malonic acid, succinic acid (ie succinic acid), maleic acid, fumaric acid, malic acid (ie hydroxysuccinic acid), tartaric acid, 10 bar acid , fluorite, sulphuric acid, benzoic acid, p-benzoic acid, cyclohexylamine sulfonic acid, salicylic acid, p-aminosalicylic acid, bishydroxynaphthoic acid, and the like. Conversely, the salt forms can be converted to the free form by treatment with a suitable base. 15 A compound of formula (1) containing an acidic proton may also be converted to its non-toxic metal or amine addition salt form by treatment with a suitable organic and inorganic base. Suitable salt forms include, for example, money salts, metal and soil metal salts (eg, lithium, sodium, potassium, magnesium, J-balone salts, and the like), and organic salts (eg, benzathine, thiol- D-glucosamine, a sea bamamine salt) and a salt with an amino acid, such as, for example, arginine, lysine, and the like. The term "quaternary amine" as used hereinbefore is defined by the basic nitrogen of the compound of formula (I) and a suitable quaternizing agent such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide. A quaternary ammonium salt of a compound of formula (I) formed by a reaction between, for example, mercapto iodide or benzyl iodide. Other reagents with good 25 200848057 四 (4) can also be used, and τ 赖 is intended to be a 5%. A quaternary amine (four) positively charged nitrogen. Pharmaceutically available 2 relative ion systems include chlorine, H trifluoroacetate and acetate. The relative ions of the ginseng can be introduced using an ion exchange resin. The oxime-oxide form of the compound of the invention is intended to include a compound of formula (1) wherein one or more of the nitrogen atoms are oxidized to the so-called ruthenium osmium compound. 10 15 20 It will be appreciated that the compounds of formula (I) may have metal bonding, clamping, complex 2 properties and may therefore be in the form of metal complexes or metal chelates. = Metallized derivatives of the compounds of equation (I) are included within the scope of the invention.

Ha, f compounds of formula (1) may also exist in their tautomeric form. These forms, although not explicitly stated in the preceding formula, are intended to be included in the scope of the present invention. A specific embodiment of the invention relates to any subgroup of cowpea of the compound of formula (I), wherein: /, R system &amp; is hydrogen, hydroxy, amine, hydroxy c^6 alkyl or halo; preferably R Is hydrogen, hydroxyl, amine or hydroxy Ci4 alkyl, more preferably Rla is hydrogen, hydroxyl or amine, the best Rla is hydrogen or hydroxyl; re-ib optimal Rla is hydroxyl, R is hydrogen, hydroxyl , halo, amine, Cw alkoxy, -0-Ch2-thiazolyl, trifluoromethyl or optionally cyano substituted c16 alkyl; preferably R.sup.l is hydrogen, hydroxy, amine, C. alkoxy , -〇_CHr thio, or Cw alkyl; more preferably Rib is hydrogen, hydroxy, amine, alkoxy or (^-3 alkyl; optimal Rlb is hydrogen, hydroxy or amine; r2 is the most The Chinese system is hydrogen or hydroxyl, which is hydrogen, -C(=〇)_R5, _C(=〇)_Cd_R5, 26 200848057 or _c(, tear 7aR7b; preferably R2 is hydrogen, or C(-〇) -〇R6; the most preferred R2 is hydrogen or -C(=0)-R5; R3 is optionally substituted by Cp cycloalkyl, aryl or Het. ^Alkyl, C3·7 cycloalkyl; Or a fine; preferably R3 is an aryl group; 5 or Het; the most preferred R3 is an aryl group; each R and R system The site is hydrogen, Gw alkenyl, Gw alkyl; or an oxetane group can be formed with a ruthenium atom such as R4b together with the tricyclic ring to which it is attached; preferably each is known to be a flax independent The ground is hydrogen, C26 alkenyl or Cw alkyl; most preferably each R4a &amp; R4b is independently a Cyalkyl 10 group; R is a Cw alkyl group optionally substituted with one or two substituents selected from the group consisting of: _ group, Cp cycloalkyl, phenyl (cyclodecylthio, cyano, polyhalo (^_6 alkyl, pendant oxy, -OR9, -c(=0)_Het, -C(=0) -〇R6, -C(二〇)-〇H, -c(二0)-NR7aR7b, 15 -C(=0)-NH- s(=〇)2-R8, -NR7aR7b, -s(=0 a 2-aryl, aryl and Het, optionally substituted by an aryl group; a polyhalogenyl group; a CP cycloalkyl group; an aryl group; or a Het; preferably a r5 system C!-6 alkyl substituted by one or two substituents selected from the group consisting of halo, C3_7 cycloalkyl, phenyl_q-6 alkylthio, 20 oxy, oxiranyl Ci-6 Alkyl, -R9, -S(=〇)2•aryl, aryl and Het; c2_6 alkenyl optionally substituted by aryl; polyhalo cK6 alkyl; C3_7 cycloalkyl; aryl; Or Het; the best R5 system selection Free group consisting of C··6 alkyl; polyhalo Cw alkyl; C3_7 cycloalkyl Cm alkyl; phenyl Cw alkylthio (^_6 alkyl, · cyano CK6 27 200848057 10 R6 15 Each R 20 R8 R9 alkyl; R 9-0 alkyl; poly-yl (^-6 alkylalkyl, aryl-spovcw alkyl; aryl-Cl-6 alkyl; HetCi 6 alkyl; C; 2- 6-based 'aryl C2-6 dilute; C3-7 cycloalkyl; aryl; or Het; optimal R5 is selected from the group consisting of: Cl-6 alkyl; polyhalo-Cu alkyl; c3_7 ring Alkyl Ci_6 alkyl; phenyl Ck alkylthio Cw alkyl; cyano Cle6 alkyl; r9_decyl; polyhalo (^_6 alkyl CV6 alkyl, aryl_s(=0)2_Ci 6 Alkyl; aryl Cl 6 alkyl; HetCw alkyl; c2 6 alkenyl; aryl C2 6 dilute; 〇3_7 cycloalkyl, aryl; or Het; as the case -OR9, _C (=0) -ORR, -C(di0)-NR7aR7b, c(=〇)-NH-S(20)2-R8, aryl or Het substituted aryl or Ci_6 alkyl; preferably R6 is a phenyl group substituted by a Cl6 alkyloxy group; or a Ck alkyl group substituted by a hydrazine R9, an aryl group or a Het, preferably a phenyl group substituted by a c13 alkyloxy group; or a Cl_6 Alkyl group And R7b# is independently hydrogen; optionally substituted by one or two substituents selected from the group consisting of: 〇R9, mono or di-Cu-alkylamino, -C(=〇)_〇R9 , _C卜〇)_丽2, -C(=〇)-丽-q 6 alkyl, -C(=〇)-NH_ via CV6 alkyl, -C(=0)-Het, C3_7 naphthenic a aryl group, an aryl group and a Het; C2_6 alkenyl group; a CP cycloalkyl group optionally substituted by a hydroxy group; an aryl group; or a Het; is a Ck alkyl group, a CP cycloalkyl group, a di(c1-3 alkyl)amino group or An aryl group; a hydrogen atom; optionally a C1-6 alkyl group, a hydroxyl group, a C3-7 ring substituted by one, two or three independently selected from the following 28 2〇〇848〇57 Alkenyl, aryl, cyano, Cw alkoxy, phenyl or Het, wherein U phenyl can be optionally substituted by the following groups: · halo, hydroxy, 5 Cl 6 alkanol, Cw alkyl, Ci alkoxy-Ci_6 alkoxy, nitro or amine; optionally substituted by one or two substituents selected from halo and polyhalo q.6 alkyl; alkynyl, a Cycyclic ring; or, as the case may be, a phenyl group of _ or two substituents selected from the group consisting of: a thiol group, a urethane group, a (tetra) group, and a phenyl group a base, an amine group, an exact group, a C!-6 alkyl group and a phenyl group; preferably R9 is a hydrazine, optionally substituted by one, two or three substituents independently selected from the following substituents. Halo, hydroxy, c37 cycloalkenyl, Cp cycloalkyl, Cl-6 alkoxy, phenyl or Het, wherein the phenyl group may be substituted by the following groups: halo, hydroxy, c16 alkoxy, Cm Alkyl, Ci-6 alkoxy Cl 6 alkoxy; c 2 6 alkenyl; 15 C 2 · 6 alkynyl, or optionally substituted by one or two substituents selected from the group consisting of hydroxy, Ci-6 alkoxy a base, a dentate group, a polyalkyl group Cw alkyl group, a Cw alkyl group and a phenyl group; more preferably the R9 group is hydrogen; optionally, one, two or three Ci_6 alkyl groups each independently substituted with a substituent selected from the following Halogen, Cp cycloalkenyl, Cp cycloalkyl, phenyl or 20 Het, wherein the phenyl group may be substituted by the following groups: a halogen group at the group Ci-6 alkoxy, c!-6 burning base, burning Oxyl q 6 alkoxy; C 2_6 alkenyl; C 2-6 block; or phenyl substituted by one or two substituents selected from the group consisting of hydroxy, C 16 alkoxy, halo, poly iSCu alkyl , c1-6 thiol; 29 200 848057 aryl 5 10 15

Het as a group or a part of a group is a phenyl group, a naphthyl group, a hydrogen group or a 1,2,3,4-tetrahydro-naphthyl group, each of which may be one, two, two or four Independently selected from the group consisting of a substituent consisting of a Cp cycloalkyl group, a phenyl Cl-6 alkyl group, a phenyl polynanyl Ci 6 alkyl group, a phenyl Cw alkyloxy group, a halogen group, a polyhalogen group c1- 6 alkyl, cyano, Cw alkyl, polyhalo 〇 6 alkoxy, -0R9, C(~0) 〇H, Cu alkyl group, Ck sulphur group, Ci_6 fluorenyl group, -S(=0)2NH2 and a fluorenyl group, wherein the phenyl group may be optionally substituted with a halogen group; or two substituents on the aryl ring may form -0-CH2-0- or - 0-C(CH3)2-CH2-; a preferred moiety as a group or a moiety of a group is each optionally substituted by one, two, three or four substituents independently selected from the group consisting of Substituted phenyl: C3_7 cycloalkyl, phenyl c16 alkyl, phenyl polyhalo Ci-6 alkyl, phenyl Ck alkyloxy, halo, polyhalo Cu thio, cyano, Ck alkyl, More _ base (^_6 alkoxy, •OR9, Ci-6 sulphur, -ShOLNH) and fluorene; better The aryl group as a group or a part of a group is a phenyl group which may be optionally substituted by one, two, three or four substituents independently selected from the group consisting of C3·7 cycloalkyl, benzene.基-Ck alkyl, phenyl polyfluorenyl Ci_6$, benzyl Ck alkyloxy, halo, polyhalo Cu, cyano, Ci_6 alkyl, poly) 3⁄4 alkyloxy, OR9, Ci-6 alkylthio, _s(=〇)2NH2; as a group or a part of a group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing 1 to 4 30 20 200848057 A hetero atom independently selected from nitrogen, oxygen and sulfur, optionally fused to a benzene ring, and wherein the group Het as a whole may be optionally selected from the group consisting of: Substituted by a substituent: halo; poly-based Ck alkyl; Ck thiol, pendant oxy; 5 - 〇R9; optionally substituted with -OR9, -CN or phenyl q6 alkyl; -C( =〇)_NH2; _C(=0)·phenyl; 03-7 cycloalkyl; phenyl substituted by Ck alkoxy as appropriate; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl ; tetrazolyl; and thienyl; Good

Het is selected from the group consisting of pyridyl, porphyrin, isoindolinyl, pyridinyl, fluorenyl 10, decyl, sulfenyl, oxime, sulfhydryl, octapeptide, turmeric, imidazolyl, 2 , 3-dihydrobenzofuranyl, tetrahydrofuran, and wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: _ group; poly-yl 016 15 alkyl group Cw alkylthio, pendant oxy; -OR9; -CN; Cw alkyl substituted by -OR9, -CN or phenyl optionally; -C(K))-NH2; -c(=0)_benzene a C3_7 cycloalkyl group; a group substituted by a c!_6 alkoxy group as appropriate; a fluorenyl group; a fluorenyl group; a tonyl group; a thiol group; a tetrazolyl group; and a thienyl group; Het is selected from pyridyl, 2-carbolinyl, isodecyl, pyridinyl, furyl, thienyl, decyl, thiazolyl, pyrimidinyl, hydrazine, imidazolyl, 2,3-di a hydrobenzofuranyl group, a tetrahydrofuran, and wherein the group Het as a whole may be optionally substituted with one or two substituents independently selected from the group consisting of: a polyhalogenyl Ci_6 alkyl group; a CV6 sulfur-burning group Side oxygen; -OR9; depending on the situation By -OR9, -CN or phenyl instead take 31200848057 C! _6 burn group, C3-7 cycloalkyl group burning. A specific embodiment of the invention relates to a compound of formula (1) or any subgroup of compounds of formula (1) wherein R is hydrogen, hydroxy, amine or hydroxy CV6 alkyl; 5 10 15 lb R is hydrogen, hydroxy, halo a group, an amine group, a hydrazine-6 alkoxy group, a -〇-CH2_thiazide group, a difluoromethyl group or a C1-6 alkyl group optionally substituted by a cyano group; the R system is hydrogen, -C (=0) )-R5, -C(=0)-C(=0)-R5, a C(=〇)-〇R6 or -C(=〇)-NR7aR7b; R3 is optionally Cn cycloalkyl, aromatic Substituted or Het substituted 〇^6 alkyl, C3_7 cycloalkyl; aryl; or jjet; each R4a&amp; R4b is independently hydrogen, C2 6 alkenyl or Ci 6 alkyl, or both ruthenium and R4b The oxetane group may be formed together with the carbon atom of the tricyclic ring to which it is attached; R is a heart 6 alkyl group substituted by one or two substituents selected from the group consisting of: 13⁄4, C3 • 7-cycloalkyl, phenyl Ci 6 alkylthio, cyano, polyhalo c “6 alkyl, pendant oxy, _OR9, _c(=〇)-Het, -C(=0)-0R6, _C (, _〇H, _c(=〇)NR7aR7b, -c(二0)-NH-S(,2-R8, NR7aR7b, |〇)r aryl, aryl and Het; optionally via aryl Replace C2 6 alkenyl; polyhalo-Cl-6 leumino; cycloalkyl; aryl; or Het; is _or9, _c(n9, -c), depending on the situation, which is ¥, _c(:0) marriage_s (=〇) 2_r8, aryl or substituted aryl or Ci_6 alkyl; each R7a and R, independently hydrogen; optionally one or two selected from the following 32 20 200848057 5 R8 R9 10 15 base

Ci-6 alkylcarbonyl, Cl6 alkylthio, substituted core 6 alkyl: -OR9, mono or di Cw alkyl

Amino group, -C(=0)-〇R9, -C(=0)-NH2, -C(=〇)-NH-C 1-6

Alkyl, -C(=0)_NH-hydroxyalkyl, _C(=〇)-Het, C cycloalkyl, aryl and Het; Cm alkenyl; C3_7 cycloalkyl optionally substituted by hydroxy; aryl Or Het; is Cm alkyl, CD cycloalkyl, bis(Cw alkyl)amine or aryl; is hydrogen; optionally substituted by one, two or three substituents independently selected from the following Cw alkyl: halo, hydroxy, (^3_7 cycloalkenyl, Cp cycloalkyl, cyano, C!-6 alkoxy, phenyl or fjet, wherein the group may be optionally substituted by the following groups) Halogen, mercapto, Cu alkoxy, Cu alkyl, Cw alkoxy Cl 6 alkoxy, nitro or amine; optionally one or two selected from halo and polyhalo Cw alkyl a Cm alkenyl group substituted by a substituent; a C2 6 alkynyl group; a C3 7 cycloalkenyl group, or, as the case may be, or two substituents selected from the group consisting of a hydrazino-Ci_6 aryl halide-based Ci_6 alkyl group , cyanide, 〇r9, -c(=o)oh,

Cl-6 alkyl acid group, 33 20 200848057 -s (=〇) 2NH2 and pyrrolyl, wherein the phenyl group may be optionally substituted by a halogen group; or two substituents on the aryl ring Form -〇-CH2-0_ or -0-C(CH3)2-CH2-; 10 15

Het as part of a group or group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, Optionally, fused to a benzene ring, and wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: halo, poly-iSCi.6 alkyl; Cw alkane -OR9; -CN; optionally substituted with -0R9, _CN or phenyl group C1_6 = kib c ('NH2; -c(=0)-phenyl; c3 7 cycloalkyl; a phenyl group substituted with a Cw alkoxy group; a morpholinyl group; a pyrrolidinyl group; a pyrrolyl group; a furyl group; a tetrazolyl group; and a thienyl group. The specific embodiment of the present invention relates to a compound of the formula (1) or Any subgroup, wherein: R is hydrogen, a base or an amine; R1 is a hydrogen, a minus, a pyloryl, a trifluoromethyl group substituted with a cyano group; the R is hydrogen, -C(=〇)-R5, -C(=〇)-C(=〇)_R5, _C(=〇)_〇r6 or -C(dioxin)-NR7aR7b ; R3 is optionally cyclized , aryl or Het substituted Cl_6 alkyl; C3_7 cycloalkyl; Or Het; each 1^ and 11413 are independently C1-6 alkyl; 34 20 200848057 R5 5 R6 10 Each R 15 , R8 R9 is optionally substituted with one or two substituents selected from the group consisting of ^6 alkyl: from the group, c3-7 cycloalkyl, cyano, polyhalogenated fluorene, pendant oxy, 'OR9, -C (=0)-Het, -C (K))- 〇R6, -C(=0)-0H, -C(=〇)_NR7aR7b, _c(=0)-NH-S(=0)rR8, -NR7aR7b, 4di) 2-aryl, aryl and Het ; optionally cv6 alkenyl substituted by aryl; polydentate Cl 6 alkyl; cycloalkyl, aryl; or Het; as the case _〇R9, -C(-0)-〇R9 &gt; substituted aryl or c16 alkyl; and ^^ are independently hydrogen; optionally substituted by one or two substituents selected from the group consisting of C^6 alkyl-·-R9, single or DiCl_6 alkylamino group, -0:(=〇)-〇119 ...c(=〇)_NH2,6 alkyl, -C(K))-NH-hydroxy Cw alkyl, -C(=0)- Het, C3_7 cycloalkyl, aryl and Het; c2_6 alkenyl; CP cycloalkyl substituted by hydroxy group as appropriate; aryl; or Het; is Cw alkyl, c3_7 cycloalkyl, di(Cl_3 alkyl) Amine or aryl; argon; one, two or three depending on the situation a C 6 alkyl group, a hydroxyl group, a c3 7 cycloalkenyl group, a Cp cycloalkyl group, a C 6 alkoxy group, a phenyl group or a Het, which are independently substituted with a substituent selected from the group consisting of Substituted by: halo, Cm alkoxy, Cw alkyl, cK6 alkoxy Cl 6 alkoxy, nitro or amine; c2 6 alkenyl; Cw alkynyl; or one or two, as appropriate a phenyl··halo group, a Ck alkoxy group, a polyhalogenated Cw alkyl group, an amine group, a nitro group, a C1-6 alkyl group and a phenyl group substituted by a substituent selected from the following 35 20 200848057; a group or a part of a group is phenyl, naphthyl, hydroquinone or 1,2,3,4-tetramurinyl', each of which is independently selected by one, two, three or five Substituted by a substituent of a group consisting of 〇3-7, a base group, a base group, a C6 alkyl group, a phenyl polyalkyl group, a Ck alkyl group, a phenyl Cu alkyl group, a halogen group, a polyhalogen Base Cw alkyl, cyano, Ci_6 alkyl, polyhalo Ci-6 alkoxy, -OR9, -C(=0)0H, Ci-6 alkyl base, Ci_6 sulfur-burning group, Cu burning base continued Stuffed base, 0-S〇-0)2NH2 and pyrrolyl;

Het as part of a group or group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, Optionally fused to a benzene ring, and wherein the group Het as a whole may be optionally substituted with one or five substituents independently selected from the group consisting of: halo; polyhalo Cw alkyl; Cl-6 an alkane Thio group, pendant oxy group; -OR9; -CN; optionally substituted by 〇R9, _CN or phenyl ci 6 alkyl; -cc-Li 2; _c(=〇)-phenyl; C3 7 naphthenic a phenyl group substituted by a Cm alkoxy group; a morpholinyl group; a pyrrolidinyl group; a pyrrolyl group; a furyl group; a tetrazolyl group; and a thienyl group. A specific embodiment of the invention relates to any subgroup of a compound of formula (1) or formula (1), wherein one or more of the following restrictions apply: (a) Rla is hydrogen, hydroxy, amine or halo; (8) Rlb It is hydrogen, silk, halogen, trifluorodecyl or, as the case may be, cyano; 36, 2008, 480, 570; calc.; (c) R2 is hydrogen, -C(=0)-R5, -C(= 0) -C(=0)-R5, -C(=0)-0R6 or -C(=0)-NR7aR7b; (d) R3 is a Ci substituted by Cp cycloalkyl, aryl or Het as appropriate 6 Hyun 5 base,. 3-7: a aryl group; an aryl group; or a Het; (e) each of R4a and R4b is independently a C1-6 alkyl group; (f) R5 is optionally substituted with one or two substituents selected from the group consisting of Ck alkyl: cyano, polyhalo c1-6 alkyl, pendant oxy, -〇R9, -C(dihydro)-Het, -C(=0)-〇R6, -C(=0)- OH, -C(=0)-NR7aR7b, 10-C(=0)-Li-S(=〇W, _NR7aR7b, aryl and Het; Cw alkenyl substituted by aryl group as appropriate; multidentate core ^alkyl; 〇3_7 cycloalkyl; aryl; or Het; (g) R6 is optionally 〇R9, _c(=〇)_〇R9, {(二〇)_NR7aR7b, -C(=0) -NH-S(=0)rR8, aryl or Het substituted Ci 6 alkyl; 15 (^) each R and R are independently hydrogen; optionally, one or two substituents selected from the group consisting of Substituted Cw alkyl: - 〇R9, mono or diCi 6 alkylamino, -C(=〇)_〇r9, {(=〇)-丽2, _c(=〇) NH Ci 6 alkyl C (〇)-NH_|^^Ck alkyl, _c(=〇)-Het, C3-7 cycloalkyl, aryl and Het; C: 2·6 dilute; q 7 20 ring optionally substituted by carboxyl group An alkyl group; an aryl group; or a Het; (1) R8 is a Ck alkyl group, a CP cycloalkyl group, a bis(Gy alkyl)amino group or an aryl group; the CD R system is hydrogen; Or an alkyl group substituted by a Cw alkoxy group, a phenyl group or a Het group, wherein the phenyl group may be optionally substituted by the following group: · a halogen 37 200848057 ~ alkoxy group, a nitro group or an amine group; or as the case may be a phenyl H amine group, a thiol group, a hexyl group, and a phenyl group substituted with two substituents; (8) is a group or a part of a group, which is a phenyl group, a naphthyl group, and a nitrogen group. Twenty-two, ^3,4&quot;&quot; tetrahydronaphthyl, each of which may be substituted by one or two substituents of the group consisting of: a functional group, a 3-based Cl-6 alkyl group, a cyano group , Cl ▲ base, polyhalogen group, alkoxy group, ίο 15 20 0) 0H, Cl_6 alkyl carbonyl, c "6 sulphur group, Cl_6 sulphate group, -S (= 〇) 2NH2 and pyrrolyl group (1) as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing from 丨 to 4 independently selected from nitrogen, oxygen and hydrazine. a hetero atom, optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents independently selected from the group consisting of: dentate; pendant oxy, -OR 9 ; -CN ; optionally as defined by -OR9, _CN or phenyl substituted Cw alkyl; _c(=o)- nh2 ; -c (=〇)_phenyl; C3 7 cycloalkyl; Substituted phenyl; morphinyl; pyrrolidinyl; pyrrolyl; furyl; tetrazolyl; and thienyl. A specific embodiment of the present invention relates to a compound of the formula (1) or any subgroup of the compound of the formula (1), wherein: ^ is a nitrogen, a trans group or an amine group;

Rlb ^ is a hydrazine, a hydroxy group, a halogen group, a trifluoromethyl group or a CV6 alkyl group optionally substituted by a cyano group; 38 200848057 R3 is hydrogen, ·C(=〇)-R5, -C(二0)- 〇R6 or -C(=0)-NR7aR7b; R3 is a C1-6 alkyl group optionally substituted by C3-7 cycloalkyl, aryl or Het; C3-7 cycloalkyl; aryl; or Het; γ and R is independently alkyl; R5 is optionally substituted by one or two substituents selected from the group consisting of f Cw alkyl · halo, c 3-7 cycloalkyl, cyano, poly-yl ci 6 Indenyl, pendant oxy, _0R9, -C(=〇)_〇R6, _c(=〇)〇H, -s(=〇)2_aryl, aryl AHet; C3 7 cycloalkyl; aryl Or Het; r6 is aryl or cv6 alkyl; each 9R7aAfb is independently hydrogen; Cl 6 alkyl; aryl; or Het; R is hydrogen; optionally selected by one, two or three a C1-6 alkyl group substituted with a substituent: a dentate group, a hydroxyl group, a C3 7 cycloalkenyl group, a C3-7 cycloalkyl group, a Ck alkoxy group, a phenyl group or a Het, wherein the phenyl group may optionally be subjected to the following groups Substituted: halo, Ci6 alkoxy, decyl, Cu alkyl, Cl-6 alkoxy Cl 6 alkoxy or amine; alkenyl; C2·6 alkynyl Or a phenyl group substituted by one or two substituents selected from the group consisting of halo: Ck alkoxy, polyhalogenated Cu alkyl, amine, nitro, alkyl and phenyl; As a group or a part of a group, it is a group substituted by one, two, three or four substituents independently selected from the group consisting of C3-7 cycloalkyl, phenyl C^. 6:!: a complete group, a phenyl complex, a Ci_6 alkyl group, a phenyl Cu alkyloxy group, a benzyl group, a polyhalogenated 6 alkyl group, a cyano group, a Cw alkyl group, a polyhalogenated Cu alkoxy group, -0R9, 39 200848057 -C(=0)0H, Cw alkylcarbonyl, Ci 6 alkylthio, 6 alkylsulfonyl and -s(=o)2nh2;

Het as part of a group or group is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, And wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: self-based, poly-i-based Cl-6 alkyl; Cl_6 sulfur-burning, pendant oxy, -〇R9 , _CN and Ck alkyl. A specific embodiment of the invention relates to a compound of formula (1) or any subgroup of compounds of formula (1), wherein - or a plurality of the following restrictions apply: (a) Rla is hydrogen, hydroxy, amine or halo; (b) Rlb Is a hydrogen, a trans group, a halo group, a trifluoromethyl group or a Ci_6 alkyl group substituted by a cyano group; (C) R2 is hydrogen, -C(=0)_R5, _c(=〇) 〇r6 or _c(=〇) NR7aR7b; (8) R3 is a C37 cycloalkyl group, an aryl group or a substituted alkyl group; C3-7 cycloalkyl group; aryl group; or ^; (e) each R4a&amp; R4b system Independently Ci 6 alkyl; (1) R is optionally substituted with two substituents selected from α, 6 alkyl cyano, polyhalo Ci 6 alkyl, pendant oxy group, _R9, c(〇)-〇R, aryl and Het·'^7 cycloalkyl; aryl; or Het; (g) R6 is Ci_6 alkyl; 40 200848057 (8) Each Rm is independently Hydrogen; Ci 6 alkyl; aryl; or like; (1) R is hydrogen; optionally referred to as alkoxy, phenyl or substituted &amp; calcined, which may be substituted by the following groups: a base of Cu alkoxylate Schottky or an amine group; or one or two as appropriate A phenyl group substituted with a substituent: a halo group, an amine group, a schlossyl group, a Cu alkyl group, and a phenyl group; (k) an aryl group as a group or a t- moiety of a group, as the case may be one or two a silyl group, a polyhalogenated Q-6 alkyl group, a cyano group, a Ci 6 alkyl group, a polyhalogen group (^-6 alkoxy group, each independently selected from the group consisting of a substituent consisting of: OR9, _C(=0)0H, c16 alkylcarbonyl, Ci-6 thiol, Ci-6 succinyl and 4(=〇)2ΝΗ2; (l) Het as a group or part of a group Is a 5 to 12 membered saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may be One or two substituents each independently selected from the group consisting of halo, pendant oxy, -OR9, -CN, and Cw alkyl. In one embodiment, the invention is related to formula (I) a compound or any subgroup thereof, wherein R2 is hydrogen, -C(dio) or _c(=〇)_〇r6, such as any of the following structural formulae (Ic), (M) or (Ie) Compounds indicated: 41 200848057

And salts and stereoisomers thereof, wherein Rla, Rib, R3, 5 and R6 are as defined for the compound of formula (1) or any subgroup thereof. The compound of the formula (I) of a specific subgroup is a compound represented by any one of the following formula (I_f), (Lg) or (I-h):

And salts and stereoisomers thereof, wherein the Rla, Rlb^ groups are as described for the compound of formula (I) or any subgroup thereof a M R . , R6 and 芳 10 A specific embodiment of the present invention relates to a subgroup, wherein: #式(I)化合物或任任任

Rla is hydrogen, hydroxy or amine; 42 200848057 R is hydrogen, hydroxy, amine, Cw alkoxy or alkyl; R2 is hydrogen, -C(=〇)-R5 or -C(=〇) _R6; R is an aryl group; or Het; each R4a&amp; R4b* is independently hydrogen, C2_6 alkenyl or Cl_6 alkyl; 10 15 R5 is selected from the group consisting of C·_6 alkyl; Halo-Ci_6 alkyl; Cp cycloalkyl CV6 alkyl; phenyl Cl-6 alkylthio cv6 alkyl; cyano Cw alkyl; r9-decyl; polyhalo-Cl6 alkyl c^6 alkyl, aryl -SO-Oh-Cw alkyl; aryl Cw alkyl; HetCi_6 alkyl "Cw fine group, aryl 〇 2_6 dilute; C3-7 cycloalkyl; aryl; or Het; R6 is cv6 as appropriate Alkoxy substituted phenyl; or optionally substituted by -OR9, aryl or Het; C9 alkyl; R9 is hydrogen; optionally substituted by one, two or three substituents independently selected from Ci_6 alkyl: halo, hydroxy, C3_7 cycloalkenyl, C3_7 cycloalkyl, CV6 alkoxy, phenyl or Het, wherein the phenyl group may be substituted by the following groups: halo, hydroxy, CV6 alkane Oxyl, Ci_6 alkyl, Cw alkoxy Cw alkoxy; c2_6 alkenyl a C2_6 alkynyl group; or a phenyl hydroxy group, a Cm alkoxy group, a dentate group, a polyhalogenated Cw alkyl group, a Cu alkyl group and a phenyl group, optionally substituted by one or two substituents selected from the group consisting of: The base as a group or a part of a group is a phenyl group which is optionally substituted by one, two, three or four substituents independently selected from the group consisting of: ^3-7 cycloalkyl, benzene Base Ck alkyl, phenyl poly[^-based Ci_6 alkyl, phenyl Ck alkyloxy, _ group, 43 20 200848057 polyhalo C!_6 alkyl, cyano, C!-6 alkyl, polyhalo (^_6 alkoxy group, -OR9, Cm alkylthio group, _s(=0)2NH2 and pyrrolyl group;

The Het is selected from the group consisting of 吼σ定基, σ奎17林基, isolinyl, well group, fluorenyl group, 0-thenyl group, present 12-seat group, Τ1 sevo-kid group. a sulfhydryl group, a tower II well group, a 5 imidazolyl group, a 2,3-dihydrobenzofuranyl group, a tetrahydrofuranyl group, and wherein the group H et al as a whole may be independently selected from the group consisting of one or two Substituted by a halogen group; polyhalo-Cu alkyl group; Cu alkylthio group, pendant oxy group; -OR9; -CN; Cw alkyl group optionally substituted by -OR9, -CN or phenyl group; -c(=o)-nh2; -c(=o)-phenyl; C3-7 cycloalkyl; phenyl substituted by alkoxy group as appropriate; fenofyl; pyrrolidinyl; a base; a sulfonyl group; a tetrasyl group; A specific embodiment of the invention relates to a compound of formula (1) or any subgroup thereof, wherein: 111&amp; is hydrogen or hydroxy; 15 Rlb is hydrogen or hydroxy; V R2 is hydrogen, -C 〇)- R5 or -c(=o)-〇R6; R3 is an aryl group; each of 1^ and 11413 is independently a Ci_6 alkyl group; and R5 is optionally substituted by one or two substituents selected from the group below 2 〇之C〗 _6 烧基·· iS base, C3_7 cycloalkyl, cyano, poly-alkyl, pendant oxy, -OR9, -sb 0)r·aryl, aryl and Het; aryl Or Het, R9 is a C.6 alkyl group substituted by one, two or three substituents independently selected from the following: 2008, 2008, 57, 570. a cycloalkyl or phenyl group; or, as the case may be, or two substituents selected from a substituent selected from the group consisting of a C-group or a Ck-alkyl group; Optionally, one, two, three or four phenyl groups each independently selected from the group consisting of: a halogen group, a polyalkyl group, a cyano group, a alkyl group, a polyhalogen group C 6 alkoxy group and a QR9;

Het as part of a group or a group is a 5 to 6 membered saturated, partially 10 unsaturated or fully unsaturated monocyclic ring containing from 1 to 4 heteroatoms independently from nitrogen, oxygen and sulfur, And wherein the group Het is optionally substituted by one or two substituents independently selected from the group consisting of: a halogen group, a pendant oxy group, a 〇R9, a _CN, and a (^_6 alkyl group. The embodiment is related to the compound of formula (1) or any subgroup thereof, wherein:

Rla is hydrogen or a hydroxyl group; preferably Rla is a hydroxyl group.

Rlb is hydrogen, hydroxy or amine; preferably 1111) is hydrogen or hydroxy, R2 is hydrogen or -C(K))-R5; R3 is aryl; 20 each is independently Cu a calcined group; r5 is selected from the group consisting of Cm alkyl; polyhalo Ck alkyl, C3-7 bad alkyl Cl-6 alkyl; phenyl Ci-6 thiol Ci_6 alkyl; cyano Cu alkyl R9-0 alkyl; polyhalogenated Cu alkyl Cw alkane 45 200848057 base, aryl-S(=0)2-Ci_6 alkyl; aryl Ci_6 alkyl; HetCi_6 alkyl; C2-6 Kunky, square Base C2-6 fine base,. 3-7 calcyl; aryl; or Het; R6 is phenyl substituted by cv3 alkyloxy group; or cv6 alkyl; R9 is hydrogen; optionally by one, two or three a Cu alkyl group substituted with a substituent selected from the group consisting of a halogen group, a fluorene: 3-7 cycloalkenyl group, a c3-7 cycloalkyl group, a phenyl group or a Het, wherein the phenyl group may be optionally substituted by a halogen group, Peryl group, Ck alkoxy group, Ci_6 alkyl group, Ci_6 alkoxy Ck alkoxy group; C2_6 alkenyl group; C2_6 alkynyl group; or phenyl group substituted by one or two substituents selected from the following Base, C -6—alkoxy, dentate, poly-yl c16 alkyl, alkyl; aryl as a group or a part of a group, each of which can be independently determined by one, two, three or four a phenyl group substituted with a substituent of the following group: Cp cycloalkyl, phenyl c16 alkyl, phenyl polyhalo Ck alkyl, phenyl Ci-6 alkyloxy, self-based, polyhalogen q · 6 alkyl, cyano, Cw alkyl, polyhalo Ci6 alkoxy, -OR9, Cw alkylthio, -S (= 〇) 2NH2;

Het is selected from the group consisting of pyridyl, fluorenyl, isoindolyl, pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, pyrimidinyl, hydrazine, imidazolyl, 2,3-dihydrobenzene And a furyl group, a tetrahydrofuranyl group, and wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: a halogen group; a polyhalogen group 46 200848057

Cl-f group; Cl·6 thiol group, pendant oxy group; -OR, optionally, -CN or phenyl substituted q-virtual group' ring-alkyl group. DETAILED DESCRIPTION OF THE INVENTION - A specific embodiment relates to a compound of formula (1) or any subgroup of formula (1) a: wherein one or more of the following restrictions apply: Θ) R is hydrogen or hydroxy; (b) Rlb is hydrogen or hydroxy; (c) R is hydrogen or -c(=o)-R5; (d) R3 is aryl; (8) each R4^R4b is independently Ci 6 fluorenyl; 10 15 (f) R5 is Cu (g) r9 is a phenyl group-substituted cl6 alkyl group, and (h) an aryl group as a group or a group--particularly, one or two independently selected from the town Substituents substituted by a group of substituents: a dentate group, a polyfunctional monoalkyl group, a cyano group, a Ci6 alkyl group, a polydentate group CV6 alkoxy group, and -〇R9; (1) Het as a group or a part of a group The time is a (five) saturated, partially unsaturated or fully unsaturated monocyclic ring containing a hetero atom independently selected from nitrogen, oxygen and sulfur, and wherein the group is fine or green - or two Each of the substituents independently selected from the group (10) is substituted with a halo group, a pendant oxy group, -OR9, and . "Alkyl. Compound of Formula (1) or Formula (1) A specific embodiment of the invention is any subgroup of related compounds wherein Rla is a trans-group; 47 20 200848057 R is hydrogen; R is gas or _C (= 0) -R, R is an aryl group; each of R and R4b is independently a Ck alkyl group; 5 R5 is a CK6 alkyl group or Het; R is a C1-6 alkyl group substituted by a phenyl group as the case may be. The base as a group or a moiety is a phenyl group optionally substituted with one or two halo groups or -OR9;

Het as part of a group or group is a 5 to 6 membered saturated, partially 10 unsaturated or fully unsaturated monocyclic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, And wherein the group Het may be optionally substituted with one or two substituents independently selected from the group consisting of halo, -OR9 and Cw alkyl. The compound of the formula (1) of a specific subgroup is a compound represented by the following structural formula (I_a):

And a salt thereof and a stereoisomer thereof, wherein Rla, Rlb, R2 and R3 are as defined in the definition of the compound of the formula (1) or the compound of the subgroup (1) according to any one of the inventions. The present invention encompasses compounds of the formula (ΙΙ-a) and (ΙΙΙ-a). In a specific embodiment, in the case of the compound of the formula (I-a), the preferred configuration has the formula (ΙΙ-a). 5

R1b R2 (Il-e)

The compound of the formula (I) of a specific subgroup is a compound (I-b) represented by the following structural formula:

And (4) a salt thereof and a stereoisomer thereof, wherein Rla, Rlb, R2, and an aryl group are as defined in the definition of the compound of the formula (I) or the compound of the formula (I) according to any one of the inventions. In one embodiment, the invention encompasses compounds of the formula (ΙΙ-b) and 49 200848057 (ΙΙΙ-b). In a specific embodiment, the preferred configuration for the compound of formula (Ib) has the formula (ΙΙ-b).

The compound of the formula (I) of a specific subgroup is a compound represented by the following formula or (I-k):

The compound of the formula (I) or any subgroup thereof is defined by the specific subgroup of the compound of the formula (1) which is a compound (1-1), (I-m) or (I_n) represented by any one of the following structural formulas: ^ 50 10 200848057

And salts and stereoisomers thereof, wherein Rla, Rlb, R2, R5, R6 and aryl are as defined for the compound of formula (I) or any subgroup thereof. In a specific embodiment, the present invention covers the formulas (II-1), 5 (m-1), (II-m), (III-m), (ΙΙ-η), and (ΙΙΙ-η). Compound. In a specific embodiment, in the case of the compound of the formula (1-1), (Im) or (In), the preferred configuration has the formula (II-1), (ΙΙ-m), (ΙΙ-η). ).

(Π-ιή 51 200848057

^本舍月中知* is a compound of formula I or any subgroup thereof having the following inhibitory values when determined by appropriate detection (such as the following deterministic detection) in the inhibition test described below: below 100 μΜ, preferably less than 50 μΜ, more preferably less than 1 μμΜ, preferably less than 5 μΜ, still more preferably less than ΙμΜ, preferably less than 1〇〇ηΜ, and especially less than 1〇ηΜ. It is to be understood that the subgroups of the formula (Ι-a) to (Ι-η) defined above and any other subgroups defined by the invention also comprise any of the compounds 之-oxides, salts, quaternary amines, Drugs, tautomers, hydrates, solvates, metal complexes, and stereochemically isomeric forms. Preparation of the compound of the formula (1), and salts and stereoisomers thereof, can be produced according to the following Schemes 1, 2, 3 and 5. 52 200848057

Flowchart 1 Step Il-&gt; 1-2 5 Intermediate (1_1) can be based on (i) Lansbury, Ρ·Τ·; Scharf, D·j·J CAem j%· 1968, 90, 2, 536-53 and (ii) Lansbury, Ρ·τ·; Nienhouse, EJ; Scharf, DJ; Hilfiker? FRJ Chem.

Soc·1970, 92, 19, 5649-5657 or synthesized according to the method described in Scheme 4. The intermediate (Ι·1) is reacted with a strong oxidizing agent to oxidize the cyclic sulfide (Ι·2). The oxidizing agent can be used to carry out this reaction, peroxy phthalic acid, hydrogen peroxide, sulphur, sulphuric acid, acetic acid. The meta-/treat agent may be selected from chloroform or dichlorodecane. 53 10 ♦ 200848057

1-4 -&gt; I-5 + K The intermediate (1-2) is then reacted with an o-phenylenediamine derivative (1-4) having a substituent Rla&amp;Rib. The reaction of (1_2) with (1)4) is usually selected from the group consisting of tetrafurfuran (THF), mercaptotetrahydrofuran (MeTHF), methyl isobutyl ketone, ci4 alcohol, monomethylcarbamide (dmf), methyl It is carried out in a solvent of tributyl-(MTBE), hydrazine f or any mixture thereof. The condensation of (1_2) with (1_4) is carried out in a Dean_stark apparatus as appropriate. Acid or Lewis k is added to the reaction mixture as appropriate to catalyze the reaction. The isomers and (1-6) are obtained. 10 Step 1-5 + The intermediate (1, 5) can be reacted with an aldehyde (1-7) of the formula R3-CHO. The reaction takes place in the presence of hydrazine (all = acetic acid) in a suitable solvent. The compound of formula (I8) is prepared according to the procedure described in Scheme 2 below, which can further react to introduce an R2 substituent other than t2. 54 200848057

R thing

R* Enterprise 1-8 - 1-9 · - Substituting a certain - two to deuterate to deuterate the amine to form guanamine. The compound of the formula (1-8), which is also an intermediate in itself, is present in an appropriate solvent in the presence of an acid or an active acid or a mercaptochlorine such as pyridinium chloride in the presence of a suitable base in the case of 200848057 (in the case of a suitable base) In the presence of a compound such as triethylamine or diisopropylethylamine, a coupling agent such as EDC (1_ethyl_3_(3-dimethylamino silk) carbonized di-f, acid salt) / H0BT (L) Hydroxybenzotriazole), HATU (2-(1Η_7-nitrogen: 隹 并 Π Π )) tetradecylurea rust hexafluorocyclohexanate) and the like. The decyl chloride can be activated in situ with DMAp (&apos;dimethylaminopyridine) and the like, and the reaction can be carried out in the presence of a suitable base such as tris-amine or diisopropylethylamine. When the active acid is an anhydride, an acid catalyst such as p-TSA _toluenesulfonic acid may be added. The solvent suitable for the styling reaction may be selected from the group consisting of u-bite, dichlorohydrazine, phosgene, THF and DMF. A compound of the formula (1-9) is obtained. Longji-1-8 -&gt;1-10: Introduction-Substituent-α2-OVNRhR^ Method The compound of formula (1-8) can be subsequently reacted with isocyanate to produce a compound of formula (ι_ι). When an isocyanate is used, a compound of the formula (1-10) wherein R?b represents 氡 is obtained. Alternatively, the compound of the formula (1-1) is reacted with an equivalent phosgene of a compound of the formula (L8) with phosgene or a formula of LG-C(=0)-LG (wherein the LG system represents a leaving group), after which It is prepared by treatment with an amine of the formula HNR7aR7b in a suitable solvent, if appropriate. Step 1-8-&gt;1-11: Introduction of a hydroxy-C (a OVOR6^^ formula (1-8) compound can be subsequently reacted with a chlorodecanoate to introduce the desired -C(=〇)- OR6 substituent. The reaction is suitably tested (such as alkali metal or soil metal nitride, such as LiH or sodium nitride or metal alkoxide, 56 200848057 such as methanol or sodium or potassium ethoxide, potassium butoxide) In the presence of an inert solvent such as a dipolar aprotic solvent such as DMA (dimercaptocarbamide), DMF, THF, and the like. A compound of the formula (1-11) can be obtained. One or more mercapto groups are introduced into the compound of the formula (1-8) (when Rla represents a hydroxyl group) or (1-12), as shown in the following Scheme 3. In this case, the structure (I-13a), (I) is obtained. -13b) or a compound of (I-13c). In some cases, a mixture of the compound (I-13a), (I-13b) or (I-13c) can be obtained.

Scheme 4 These additional sulfhydryl groups may be derived from hydroxides (such as hydroxides) by a suitable solvent such as water, C!_4 57 200848057 alcohol, THF, 2-methyltetrahydrofuran (MeTHF) or any mixture thereof. Sodium, potassium hydroxide or lithium hydroxide) treats the corresponding compounds of formula (1-9), (1-1〇), (I_ll), (L^a), (i)3b) and (I-13c) resection. 5 Thus, in the case of the intermediate (1-8) or (M2), when Rla is a hydroxyl group, it may be necessary to introduce a substituent C-(=〇)_R5 or _C(=〇)_NR7aR7b or -C. (=〇)-〇R6 protects the hydroxyl group before it. The protecting group for the hydroxy group may be a benzyl group or a substituted benzyl ether (for example, 4-methoxybenzyl ether), a benzylidene group or a substituted benzamyl ester (for example, 4-nitrobenzylidene group). Ester) or a trialkyl ο 矽 矽 alkyl group (such as trimethyl sulfonyl or table butyl dimethyl fluorenyl) or by intramolecular cyclization with CDI (1, 1L carbonyl diimidazole) to form a cyclic amine A carboxylic acid ester derivative is achieved. The introduction of -C(=0)-R5 or -C(=〇)-NR7aR7b *-C(=0)_0R6 is carried out as described above. The intermediate formed thereafter is further reacted with an alkali metal hydroxide (LiOH, NaOH, KOH) in a hydrolysis medium comprising water and a water-soluble organic solvent such as an alkanol (melanol, ethanol) and THF. . The reaction is carried out by removing an acid group-protecting group (e.g., a benzoquinone or a substituted phenyl decyl ester or a cyclic amino phthalate) to produce a formula or compound wherein Rla represents a hydroxy group. The intermediates (ϊ·^), (1-10) and (Ml) having a trialkylsulfonyl 20 protecting group in Rla are further reacted with a tetraalkylammonium fluoride to deprotect the decyl group to produce a formula or a compound of [_9), (1_10) and (Ml), wherein Rla represents a hydroxyl group. Intermediates with a 4-nonoxybenzyl ether protecting group in Rla (); _9), (PiO) and (PH) are further combined with DDQ (2,3-dicyano-5,6-dichloro- Reaction to benzoquinone to produce a compound of the formula (1-14) 58 200848057 which shows a hydroxyl group or (ϊ-9), (MO) and (Ml), wherein the Rla series method synthesizes a compound of the formula (Μ) according to a flow chart 4 of the steps to buy)

fT

Ci 〇,

(M) H2N\^NH Π ' Xtx (IV-5) (IV-3)

Ci

HsJl:

(IV-3) (IV-6) Scheme 4, Step ΙΛΜ-&gt;IV_2 2,3*Dichloropropanthide IV-1 (commercially available from Aldrich) is based on thioacetic acid in organic (eg acetone) Potassium is monosubstituted to give (IV-2). ^ Steps IV-2 - IV-4 are carried out by hydrolysis of 1) thioester to basic conditions (methanol in methanol) to sulfide, followed by 2) sulfide and disubstituted valvide (IV-) The single-pot reaction consisting of the reaction of 3) produces a compound of formula IV.4. Step IV-4-&gt; I_l Compound IV-4 is cyclized under acidic conditions such as aqueous sulfuric acid, in organic solvent 59 15 200848057 (such as DCM (CHei2)), decanesulfonic acid or better formic acid to give Formula 1- Compound of 1. Alternatively, the compound of formula IV-4 can be prepared from 2,3-dichloropropene IV-1 via intermediates IV-6 and IV-6 as shown in Scheme 4. Step IV-1—IV-5 Diqi propylene IV-1 (commercially available from Aldrich) in a suitable solvent such as ethanol at a temperature between 〇 ° C and 120 ° C (preferably about 80. Reacting with thiourea to provide intermediate IV-5. Step IV-5-&gt; IV_6 Intermediate IV-5 in the presence of a hydroxide such as sodium hydroxide in a suitable solvent such as water at between 20 And the temperature of l2〇t^a] (preferably about 100. Hydrolysis to the thiol derivative IV-6. Steps IV-6-IV-4 at temperatures between 0 ° C and 50 ° C (cf.约约2〇. In the presence of a suitable base such as sodium decyl alcohol in the sterol, the intermediate IV-6 is treated with a substituted epoxide of the formula Iv_3 to provide the intermediate IV_4. ''2 200848057

Scheme 5 Substituent R9 can be protected from a hydroxy group of Rla via a thiol protecting group (e.g., a cyclic amino phthalate protecting group) as described in Scheme 5 - such as the structure in which the X 5 is a halogen - a precursor The substance V-3 was introduced.

61 200848057 Step Vl-&gt;V-2: PGi-protected hydroxyl group is introduced from compound (V-1) or (1-14) into PGi (wherein PG2 is another base-protecting group such as a vinyl ether) to form a compound ( V-2) is achieved in an organic solvent using, for example, CDI. Step V-2 - V-3: Removal of PG2 Group PG2 is produced by, for example, catalytic hydrogenation to produce phenol V-3. Step V-3-&gt;V-4: introduction of the R9 substituent The R9 substituent can be introduced from the intermediate V-3 via, for example, the SN2 reaction Mitsunobu reaction. Step V-4 - &gt; V-5: removal of the PGi group 15 20 formed intermediate V-3 in an aqueous medium containing water and a water-soluble organic solvent (such as alkanol·methanol, ethanol) and THF The alkali metal oxide (LiOH, NaOH, KOH) is reacted to produce a compound of the formula /v_5. The compound of the formula (1) can be converted to each other by a functional group known in the art. For example, the amine group can be alkylated, the nitro group can be reduced to an amine group, and the other atom can be exchanged from the atom. The method described in the Examples section constitutes a method of introducing a substituent in the scope of the present invention. The compound of formula (I) can be converted to the corresponding group oxide form by methods known in the art for converting trisphenol to its n-form. The reaction is usually carried out by reacting (iv) f from the formula (1) with an appropriate organic or inorganic emulsifier (2008). Suitable inorganic Weihualin hydrogenated, alkali metal or alkaline earth metal persulfide (such as peroxide J, °, potassium); suitable organic peroxides may comprise peroxyacid, emulsified benzoic acid or substituted by halogen Perbenzoic acid, for example, for example, peroxyacid, such as peroxyacetic acid, mercaptohydrogen peroxide, for example, Mannich = hydrogen. Suitable solvents such as water, low carbon paste, such hydrocarbons, hydrocarbons (e.g., methyl bromide), terpenes (e.g., 2-butanone), and blockages such as methylene chloride, and mixtures of such solvents. Self-generating hydrocarbons (for example, 10 pure stereochemically isomeric forms of the compound of formula (1) are known by methods known in the art. Non-mirror heterogeneous papers are separated by application of technical crystallization and chromatographic techniques such as inverse methods such as selectors. L-type distribution, liquid material and the like; ====, -, the compound of formula (I) can be followed by selective or stepwise H-salt by individual and acidic ablation. The non-image-image isomerized salt-shaped construct. The mirror-self-release image of the compound of the formula (1) is separated from the liquid crystal, and in particular, the stereochemically isomeric form of the """ or "the melon" can be used. Liquid chromatography from the phase of the =# phase. The purified isomeric form is derivatized, and its restriction strip; == the corresponding pure stereoscopic line of the mass. It is preferred that the specific Iti should be stereoselectively prepared by the preparation method. The quinone b compound can be stereoselectively pure starting material. The oscillating method can advantageously employ mirror image isomerization 63 200848057 In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount The compound of the formula (1) or the formula (1) of the present invention A compound of any subgroup of the compounds and a pharmaceutically acceptable carrier. The therapeutically effective amount is herein a viral infection sufficient to prevent, stabilize or reduce the risk of an infected individual or an individual at risk of infection, in particular Is a Hc^ virus infection. In another wickedness, the present invention relates to a method of making a pharmaceutical composition as described herein, which comprises a well-mixed medicine ===

A carrier and a therapeutically effective amount of a compound of the formula (1) as described in the present specification, or a compound of any one of the compounds of the formula (1) according to the present invention. X; or in the case of powders, pills, capsules and lozenges, such as starch, sugar, kaolin, lubricants, adhesives,

Thus, the compounds of the invention or any subgroup thereof can be formulated into a variety of dosage forms for administration. All-fourth (four) composition of the whole body cast: can be listed as a suitable composition. When preparing the drug composition of the present invention, an effective amount of a specific compound (as a salt form or a metal I 曰 = as a case of a salt form or a metal I 曰 =) is a combination of a side charge that is acceptable for riding a drug, and the carrier is considered to be The form of preparation required is in a variety of forms. These instructions are particularly suitable for oral, rectal, transdermal or parenteral injection. For example, when preparing a composition of an oral dosage form, the pharmaceutical medium, such as an oral liquid preparation such as suspended dihydrate, elixirs, emulsions and solutions, is, for example, water, glycol, oil, hydrazine &amp; $士口的咖咖_ ^ . It is a solid carrier, a disintegrating agent and the best medicinal carrier. 64 200848057 Heart-enhanced dissolution: sugar-salt and salt:: solution: = 5 10 15 m When liquid preparation, suspension, and composition such as time conversion into a preparation for transdermal administration, The carrier can be inhaled or blown by the mouth according to the situation: =r axis, the addition force,; = into + the compound of the present invention can also be inhaled or blown by the technical community through the inhalation or inhalation of the H-shaped method and the formulation. Into the drug. It is preferred that the solution can be administered to the lungs in the form of a dry powder of mm. Any system developed to deliver a liquid or dry powder by oral inhalation or insufflation is suitable for administration of the hybrid of the present day. Thus, the present invention also provides a medical composition suitable for oral inhalation or insufflation, comprising a compound of formula (1) and a pharmaceutically acceptable carrier. The compounds of the invention are preferably administered by inhalation spray or aerosolized dose. The 4-inch system is formulated into a unit dosage form which is easy to administer and has a uniform dose. The unit dosage form used in the present invention is a physically discrete unit suitable as unitary unit 1, each unit containing a predetermined amount of the active ingredient which is calculated to produce the desired therapeutic effect together with the desired pharmaceutical carrier. Examples of such single-part dosage forms are lozenges (including scored ingots or ingots), capsules, pills, suppositories, powder packets, thin tablets, injectable solutions or suspensions, and the like and their separate multiparticulates. The compound of formula (1) and any subgroup thereof exhibit antiviral properties. Viral infections and related diseases which can be treated using the compounds and methods of the invention include infections caused by HCV and other pathogenic xanthoviruses, such as yellow fever 5 disease (types 1 to 4), St. Louis brain St. Louis encephalitis, Murray valley encephalitis, West Nile Virus, and Kunjin vims. Diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and Hcc; while other pathogenic xanthovirus diseases include yellow fever, dengue fever, hemorrhagic fever, and encephalitis. Because of its antiviral properties, especially anti-HCV properties, the compound of formula (1) or any subgroup thereof, prodrugs thereof, oxidizers, salts, quaternary amines, metal complexes and stereochemically isomeric forms can be used for secrets. Individuals with viral infections (especially HCV infections) and for the prevention of such infections. Typically, 15 纟 of the invention compounds can be treated with H to infect a warm jk animal of a virus, particularly a xanthovirus, such as HCV. The compounds of the invention or any subgroup thereof can therefore be used as a medicament. The drug (4) or method of treatment is included in an individual infected with a virus or an individual susceptible to a virus, and is administered systemically to an amount effective against a condition associated with a viral infection (especially 2 〇 HCV infection). The invention also relates to the use of a compound of the invention or any subgroup thereof, which is a medicament for the treatment or prevention of a viral infection, in particular an hcv infection, which is additionally used to treat an infected virus or to be infected with a virus. 66 200848057 (especially HCV) method of dangerous warm-blooded animals, including

An antiviral effective amount of a compound of the formula (1) according to the invention or a compound of the formula (1) of any of the subgroups of the invention. X The invention also relates to a combination of a compound of formula (1) according to the invention or any subgroup thereof with other anti-HCV agents. In one embodiment, the invention relates to a combination of a compound of formula (I) or any subgroup thereof and at least one anti-agent. In a particular embodiment, the invention relates to a combination of a compound of formula (1) or any subgroup thereof and at least two anti-HCV agents. In a particular embodiment, the invention relates to a combination of a compound of formula (1) or any subgroup thereof and at least three anti-HCV agents. In a particular embodiment, the invention relates to a combination of a compound of formula (1) or any subgroup thereof and at least four anti-HCV agents. An anti-HCV compound known in the art, such as, for example, interferon-〇1 (IFN-α), pegylated interferon-α, ribavirin or a combination thereof, and a compound of the formula (1) can be used as a combination therapy. Pharmacy. In a specific embodiment, the "combination therapy" relates to a product containing the specified compound of formula (a) (I) and (b) at least one other anti-HCV compound, which is simultaneous, separate or dependent. The sequence is used in the form of a combined preparation for the treatment of HCV infection, especially for the treatment of HCV infection. The anti-HCV compound encompasses agents selected from the group consisting of hcv polymerase inhibitors, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283, R803, R-1626, BILB-1941, HCV-796, JTK-109 and JTK-003; HCV protease (NS2-NS3 and NS3-NS4A) inhibitors, compounds of w〇〇2/18369 (see, for example, 67th 200848057, page 273, lines 9 to 22, and page 274, line 4) Go to page 276, line 11), BI-1335, TMC435350, MK70009, ITMN-191, BILN_2061, VX-950, VX-500, SCH 503034; other inhibitors of the flag in the HCV life cycle, including helicase and Metalloproteinase inhibitors, 5 ISIS-14803; immunomodulators such as α-, β- and γ-interferons, polyethylene glycol-derived interferon-α compounds, compounds that stimulate the synthesis of interferon in cells, and interleukin , Toll like receptor (TLR) agonists, compounds that promote the development of type 1 helper T cell responses, and thymosin; other antiviral agents such as ribavirin, amantadine, and Telbivudine, an inhibitor of internal ribosome entry, a broad-spectrum virus inhibitor such as IMPDH Formulations (for example, US 5,807,876, US 6,498,178, US 6,344,465, US 6, G54,472, W097/40028, WO 98/40381, WO 00/56331 compounds and mycophenolic acid and its derivatives and include but not limited to VX - 497, VX-148 and/or VX-944); or any combination of the foregoing. Thus, to combat or treat HCV infection, the compound of formula (I) can be determined, for example, with interferon-a (IFN-a), pegylated interferon-alpha, ribavirin or a combination thereof, and based on the antigen against HCV. The therapeutic agent of the site, small interfering RNA (si rNa), ribozyme, DNa enzyme, antisense rNA, sputum such as NS3 protease, NS3 helicase and small molecule antagonist of NS5B polymerase are co-administered. μ The composition of the invention can be used as _. Accordingly, the present invention relates to the use of a compound of formula (I), or any subgroup thereof, as defined above, for the manufacture of a medicament for inhibiting activity in a mammalian susceptible to HCV disease, in which the agent is in 2008 2008. For use in combination therapy, the combination therapy comprises a formula (I) = a compound and at least one of its hydrazine Hcv inhibitory compounds, such as IFN-α, pegylated IFN_a, ribavirin or a combination thereof. In addition, it is known that patients infected with type 1 human immunodeficiency virus (HIV) are also highly infected with HCV, that is, they are HCV/HIV co-infection. HIV infection clearly has a negative impact on all stages of HCV infection, resulting in increased persistence of toxicity and accelerated progression of liver disease associated with Hcv. Following HCV infection, this can affect the treatment of HIV infection and increase the incidence of liver poisoning caused by anti-virus agents. The invention therefore also relates to a combination of a compound of formula (I) or any subgroup thereof and an anti-HIV agent. Moreover, a combination of one or more additional anti-HIV compounds and a compound of formula (1) can be used as a medicament. The term "combination therapy" also encompasses a product comprising (a) a compound of formula (1) or any subgroup thereof and (b) at least one anti-HIV compound and (c) optionally at least one other anti-HCV compound. A combination preparation for simultaneous, separate or sequential use in the treatment of HCV and HIV infection, especially for the treatment of HCV and HIV infection. Accordingly, the invention also relates to a product comprising at least one compound of formula (I) or any subgroup thereof and (b) or a plurality of additional anti-HIV compounds for simultaneous, separate or sequential use. In the form of a combined preparation for anti-HCV and anti-HIV treatment. Different drugs can be combined with a pharmaceutically acceptable carrier into a single formulation. The other anti-HIV compound can be any known anti-retroviral carrier compound, such as suramine, pentamidine, thymopentin, castanosperm 69 200848057 (castanospermine), dextran ( Glucan sulfate), sodium phosphinate (trisodium phosphite carboxylate); nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT), didanosine (ddl), Zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), erntricitabine (FTC), abacavir ( Abacavir) (ABC), amd〇xovir (DAPD), evucitabine (ACH-126, 443), AVX 754 ((-)-dOTC), fuzifidine (f〇) Zivudine tid〇xil) (FZT), phosphazide, HDP-990003, KP_ 1461, MIV-210, ίο Racivir (PSI-5004), UC-781 and the like; non-nuclear Reverse transcription stalk inhibitors (NNRTIs), such as delavirdine (DLV), efavirenz (EFV), nevirapine (NVP), dabivyl (dapiv) Irine) (TMC120), etorvirine (TMC125), riipivirine (TmC278), 15 DpC-082, (+)_caolin A, BILR-355, and the like; nucleotides Reverse transcriptase inhibitors (NtRTIs), such as tenofovir ((R)-PMPA) and tenofovir disoproxil fumarate (TDF) and the like; nucleotides Competitive reverse transcriptase inhibitors (NcRTIs), such as NcRTI-1 and the like; derivatives of transactivated proteins, such as TAT-inhibitors, such as r〇_5_3335, bi-2〇1, and the like; REV inhibition Protease inhibitors such as saquinavir (SQV), ibinavir (ABT-378 or LPV), indinavir (IDV), amprenavir (amprenavir) (VX_478), TMC126, nelfinavir (AG_1343), A 200848057 tazanavir (BMS 232, 632), darunavir (TMC114), fasapunavir (fosamprenavir) (GW433908 or VX-175), brecanavir (GW_640385, VX-385), P-1946, PL_337, PL-100, tilanavir (tipran) Avir) 5 (PNU-140690), AG-1859, AG-1776, R0-〇334649, and the like; an invasion inhibitor comprising a fusion inhibitor (eg, enfuvirtide (T-20)), Attachment inhibitors and co-receptor inhibitors, the latter comprising CCR5 resistance (eg ancrivir〇c, CCR5mAb004, maraviroc (UK-427, 857), i〇PRO-140, TAK-220 , TAK-652, vicriviroc (SCH-D, SCH-417, 690) and CXR4 antagonists (eg AMD-070, KRH-27315), examples of invasion inhibitors are pro-542, TNX-355 , BMS-488, 043, BlockAide/CRTM, FP 21399, hNMO1, nonakine, VGV-1; maturation inhibitors such as PA_457; inhibitors of disease 15 toxic integrase, such as raltegmvir ( MK-0518), ertetegravir (JTK-303, GS-9137), BMS-538, 158; ribozyme; immunomodulator; monoclonal antibody; gene therapy; vaccine '· siRNA; antisense RNA Microbicides; zinc finger inhibitors. Therefore, it also has HIV-related or even other pathogenic retroviruses 20 (such as AIDS, AIDS-related syndrome (ARC), progressive systemic lymphadenopathy (PGL), and chronic CNS caused by retroviruses. Diseases, such as HCV-infected patients such as HIV-mediated dementia and multiple sclerosis, can be suitably treated with the compositions of the present invention. The composition can be formulated into a suitable pharmaceutical dosage form such as the aforementioned dosage form. Every 71 200848057 - the active ingredients can be matched, and the general item can be used to contain both and (if necessary) other ingredients - Na Na · · ^ f The term "composition" used in the invention covers specific The product of ingredient 5 10 15 20 and any product produced directly or indirectly from the composition of the particular ingredient. The term "treatment dose" of the Japanese (4) refers to an active compound, or a part or agent that induces research in a tissue, system, animal or human to be sought by a human, medical, physician or other clinical staff. The amount of biological or medical response (including the silk of the disease to be treated) (for the purposes of the present invention). =, also relates to a composition comprising two or more types, so that in combination with a therapeutically effective amount of hexahydrate, it is also a remedy that causes the combined effect to induce an amount of biological or medical reaction of rt. For example, 'the therapeutically effective amount of the composition of the other anti-HCV agent containing (8) formula (1) is a therapeutically effective combined effect of the compound of formula (1) and another anti-HCV. The amount of the agent. It is often expected that the effective dose of antiviral sputum is 〇〇1 mg / kg to H ^ / kg body 4 'better G · 1 mg / kg to 5 (3 mg / kg ^ + can be appropriate to two, three, Four or more sub-doses are administered at the appropriate time: the same daily dose. The sub-dose can be formulated as a unit dosage, for example, containing 1 to mg, especially 512 〇 0 mg of active knives/early dosage form. It is well known to the skilled artisan that the actual dosage and frequency of administration are as follows: the compound of the formula (1), the specific condition to be treated, the condition of the condition to be treated, the severity, the age, weight, sex, degree of the particular patient and 72 200848057 The general physiological condition and other agents employed by the individual will, in addition, it will be apparent that the effective daily dose may be reduced or increased depending on the response of the individual to be treated and/or the assessment of the physician prescribing the compound of the invention. Merely a guideline. In one embodiment of the invention, there is provided an article comprising a composition 2 and a packaging material effective for treating HCV infection or inhibiting hcV NS5B polymerase, comprising an indication The composition can be used to treat a type C: a label of a fire virus infection; wherein the composition comprises a compound of the formula (1) or any subgroup or a composition of the present day (four). Set or container, its

^ 3 can be used as a standard or a compound of formula (1) or any subgroup thereof in determining the potential ability of the agent to inhibit HCV NS5B polymerase, HCV 2 or both. This aspect of the invention can be used in medical research programs. The present invention can be used for high-throughput target-analyte detection, such as LV, ΒΪ e 乂 / !! Examination of the efficacy of the composition in the treatment of HCV [Embodiment] The examples are intended to illustrate and not to limit the invention. Dichlorophenyl fluorenyl 73 200848057

m. Potassium thioacetate (1·23 g, ι·8 mmol) was added 2,3-dichloropropene (1 g, 9 〇 1 mmol) to a mixture of acetone (1 mL). The reaction mixture was refluxed for 3 hours, then cooled to room temperature, diluted with water and extracted with CH2C12. The organic layer was then dried <RTIgt; The pale yellow liquid was filtered on a cerium oxide plunger with CH2C12 / pentane 50 · · 50. After evaporation (25 mbar, 45 〇, a colorless liquid of y_(2-chloroallyl) ester of thioacetic acid (1) was identified as the target product of 1.29 g (95% yield).

(2) (3) Bis(2-chloroallyl) thioacetate (1) (1.29 g, 8.56 mmol) Sodium decoxide (463 mg, 1 eq.) was added to a solution in hot water sterol. 74 10 200848057 5 The reaction mixture was stirred for 40 minutes, then 2,2-dimethyl-epoxy-(2) (618 g, 1 eq.) was added and the reaction mixture was stirred at room temperature for 1 hour. After addition of Ηβ, The pH was adjusted to 7 with 1N HCl, and EtOAc (EtOAc) (EtOAc) eluted eluted with EtOAc (EtOAc) Colorless oil of chloroallylsulfanyl)-2-nonylpropan-2-ol (3). 2 step 3

10 1-(2-Chlorallylsulfanyl): mercaptopropanol (7) (5 g, 277 mmol) was refluxed in decanoic acid for 4 hours. After cooling, the mixture was poured into H20 and then extracted with chaI2. The organic layer was then washed with h.sub.2, dried over EtOAc EtOAc. The resulting oil was purified by flash chromatography (solvent CHzCl2) to yield 2.4 g (yield: 60% yield) of the product 5,5-dimercaptoin-3-one (4). Step 4

^ (§) (6) m-CPBA (豕chlorobenzylidene; ι·5 g, 70-75 w/w 0/〇, 6.52 耄mol) added to CHC13 (50 liters) Cyclic thioether (4) (8〇0 75 15 200848057 Zucker ' 5.55 house Moh). After 3 hours, add extra milk _cpba (750 mg, 70-75 w/w %, 3.26 mmol). After 1 hour, the reaction mixture was diluted with CH 2 C 12 and then washed with 1 Μ NaHC03 (2 X 125 liters). The aqueous layer was extracted with CH.sub.2 (2.times.150 mL) and the combined organic layers were dried (M.s.) and evaporated. The residue was purified by column chromatography ( gradient CH2C12 / ethyl acetate: 1 : 0 to 1 : 1) to yield 652 mg (67 〇 / 〇) of sulfone (5) as a white solid: Rf (CH2C12) = 0. 19, Rf (ethyl acetate) = 0.48; !H NMR (400 MHz? CDC13) δ ppm 1.24 (s? 6 H)5 2 52 (s, 2H), 3.23 (s, 2H), 3.99 (s, 2H) ), followed by the sub-rock (6) · · Rf (ethyl ethyl citrate) = 〇 · 12 ; 4 NMR (400 MHz, CDC13) δ ppm 104 (s, 3 H), 1.25 (s, 3 H) , 2·34 (d, 13·1 Hz, 1 H), 2·5〇 (d, J = 13.1 Hz? 1 H)? 2.95 (d5 J = 13.1 Hz? 1 H)? 3.22 (d? J- 13 i Hz, 1 H), 3·61 (d, / 2 11.9 Hz, 1 H), 3·98 (d, J = ΐι·9 Hz H) 〇' Step 5

(5) (51·3 mg, 0.291 mmol), o-phenylenediamine (3·5 mg '0.291 mmol), 4 Α molecular sieve and acetic acid (π μL, 〇·291 mmol) The mixture in benzene was stirred at room temperature for 3 hours and then heated under reflux. After 12 hours, the reaction mixture was continuously cooled to room temperature, filtered on a shovel, and evaporated to give the titled product (7), which was used as it is in 76 20 200848057. Subsequent reaction: m/z = 267 (M+H) +. Step 6

, enamine (7) (77.5 mg, 0.291 mmol), ^ (2.5 mg, 0.015 mmol) and 2,4-dichlorobenzidine (8) (51 mg, 0.291 mmol 5 ears) The solution in DMS hydrazine (dimethyl hydrazine; 2 ml) was at 75 under nitrogen.加热 Heat. After 12 hours, the reaction mixture was continuously cooled to room temperature and then diluted with water. The precipitate was collected by filtration and washed with H.sub.2 and diethyl ether to give &lt;RTI ID=0.0&gt;&gt; 4 NMR (400 MHz, DMSO 〇 δ ppm 1·19 (s, 3 Η), 1·20 (s, 3 ίο Η), 2.57 (d, J 2 7.6 Ηζ, 1 Η), 2.68 (d, 16·7 Ηζ,1 Η), 3·11 (d,h 13.5 Ηζ,1 Η),3·18 (d,13·5 Ηζ,1 Η),5·71

(d? J — 6.2 Ηζ 5 1 Η), 5.92 (d? J = 6.2 Ηζ? 1 Η)? 6.46 (d5 J — 7·6 Ηζ, 1 Η), 6.58 (t5 / 2 7.6 Ηζ, 1 Η),6·66 (t,/= 7·6 Ηζ,1 Η),6·89 (d,8·3 Ηζ,1 Η),6·93 (d,7.6 Ηζ,1 Η), 7.13 15 (d,8·3 Ηζ,1 Η), 7·52 (s,1 Η), 8.55 (s,1 Η). 13C NMR (101 ΜΗζ, DMSOO δ ppm 27·9 (CH3), 28·2 (CH3), 31·4 (C), 42·8 (CH2), 52·9 (CH), 60·4 (CH2) ,105·6 (C),119.6 (CH)5 121.2 (CH)5 121.3 (CH)5 122.4 (CH)9 126.5 (CH)9 128.6 (CH)5 129.3 (CH)? 132.0 (C)? 132.5 ( C)? 133.4 (C)? 77 200848057 136.2 (C)9 139.4 (C)5 144.9 (C) 〇Step 7

10 (9) (15 house grams, 0.035 耄mol) and f TSA (1 毫克 mg, 耄 耄 耳) in acetic anhydride (1.5 house liters) in 7 〇. Stir under nitrogen. After 6 hours, the reaction mixture was cooled to room temperature and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Dimercapto-i,i-di-oxo-1,2,3,4,5,11-hexahydro-1 human 6-thia-5,1〇-dioxadibenzo[仏刃环庚卸( 10) · Rf (CH2CI2/acetic acid, 70:30) = 〇1; RT = 2 21 m/z = 465 (M+H)+. Example 2"10-ζ&gt; Brewing base-1]^_Benzene gas _2_Fluorum 芏)_3.3_二二笨笨Γα,&quot;1环庚灿(13) 78 200848057

ί

m step 1

2-fluoro-4-hydroxybenzaldehyde (2.92 mmol), benzyl bromide (534 μl, 4.38 mmol) and Cs2C03 (1.14 g, 3.50 mmol) in anhydrous DMF (condition, dimethyl The mixture of methotrexate (10 ml) was stirred at room temperature for 35 days. After that, the reaction mixture was diluted with water (200 mL). The formed precipitate was filtered off and dried in vacuo to give the desired product 4-benzyloxy-2-fluorobenzaldehyde (11) (94.4%) as a white solid·· w/z 231 (M+H) +. Step 2

79 200848057

Enamine (7) (159 mg, 0.597 mmol), Tomachi (5 mg, 0.030 mmol) and aldehyde (11) (137 mg, 〇·597 mmol) in DMSO (5 liters) The solution was heated at 75 C under nitrogen. After 4 hours, the reaction mixture was cooled to room temperature and then diluted with water. The resulting mixture was continuously extracted with 03⁄43⁄4 and AcOEt. The resulting organic layer was washed successively with brine, dried (NaJO4) and evaporated. The residue was wet ground in water. The precipitate was collected by filtration, washed with water and dried in vacuo to yield 243 mg of product (12): Rt = 2.48 min, w/z = 479. Step 3

A solution of (12) (54 mg, 0.113 mmol) and pTSA (21 mg, 0.124 mmol) in acetic acid (5 mL) was stirred at 75 ° C under nitrogen. After 2.5 hours, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) _3,3_Dimethyl-1,1-di-oxo-1,2,3,4,5,11-hexahydro-1 into 6-thia-5,10-dioxadibenzo[α,blade White solid of cycloheptene (13) · Rt = 2.42 min, m/z = 521 (M+H) + 〇80 200848057 Example 3 · "11-(4 5 -卞乳基-2 - chaos - Stupid)-3,3-dimethyl-1,1-bilateral 氲-L2,3A5J1-hexam-1λ6-thia-5J0-dioxime-two jasmine "a, dl ring waste cloth _ 1 mouth T-1 is a certain ratio; ^-甲酉同(14)

11-(4-decyloxy-2-disorgano-phenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro 4-thia-5,1〇-dioxin -Dibenzo[a,d]cycloheptene 1,1-dioxide (12) (36 mg, 0.075 mmol) and Hunig's base (Λ^-diisopropylethylamine, DIPEA; 68 A solution of benzylidene chloride (40 mg, 3 eq.) was added at rt. After 4 hours, the reaction mixture was diluted with CH2C12 and extracted with brine. The organic layer was separated, dried over MgSO4, filtered and evaporated. Purification by flash chromatography (solvent CH2C12 / ethyl acetate 50: 50 to 30: 70) yielded 16 mg (yield: 36% yield) of desired product (I4) as a yellow solid; m/z = 584 (M+H )+. 15 Example 4 · "11-(4-卞气基-2-气-笨基)_3,3_二曱基_1,1_二侧氧-1,2,3,4,5,11-六Milk-1 into 6-mouth base-5,10-di-mouth-two stupid &gt; (open "&amp;, (11 by Geng Shaoxi-10-yl 1-pyrrol-2-yl-fluorenone (15 ) 81 200848057

The title compound (15) was prepared according to the chemical loading of [11-(4-alkoxyfluoro-phenyl)-3,3-dimercapto-1,1-di-side oxy-1,2,3,4,5 ,11-hexahydro-1 human 6-is-5,1(^2.丫-dibenzo[a,d]cyclohepten-10-yl]pyridin-2-yl-fluorenone (14) Method, using pyridinium carbonyl chloride instead of pyridinium chloride, prepared in 71% yield; m 厶 585 (Μ + Η) +. Example 5: 1 Μ 4-benzyl carbyl-2- hydrazine V6-hydroxyl Α 氲 · · · · · · · · · · · · · 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 _1^_二侧氲-1·2 丄4·5·11-hexahydro-1λ6_ 唼-5·10-di^ene (19) 82 200848057

m (iQ (I?) TFA (trifluoroacetic acid; 230 μl, 3.07 mmol) was added to sulfone (5) (541.3 mg, 3.07 mmol), 2,3-diaminophenol (381.3 mg, 3.07 millimolar) and 4A powder molecular sieve in a solution of DMF (30 ml). 5 The resulting mixture was stirred at 50 ° C for 6 hours to give the desired product (16) ·· Rt = 1·00 min, m/ z = 283 (M+H)+, contaminated with the regioisomer (17). The mixture was used in the next step without further purification.

(1Φ (18) (19) 83 200848057

NaHCCb (232 mg ' 2.76 mmol) was added to the reaction mixture of the above (16) and (17) which was obtained through the steps. Thereafter, a mixture of ^(Tn) (707 mg, 3.07 mmol) was added and given at 5 °C. After a few hours, the reaction mixture was cooled to room temperature, filtered and washed with Cjj. The aqueous layer was extracted with CHei2. The combined organic layer was dried over MgS(R) 4, filtered and evaporated. The residue was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Base_3,3_dimethyl-1,1-dimer milk-1,2,3,4,5,11-six rats-1 person-mouth plug-5,1〇-di-n- 丫-benzo Ίο [flj]cycloheptene (18): Rt = 2.26 min, m/z 495 (M+H)+. 4 NMR (400 MHz, DMSO 〇 δ ppm 1.18 (s5 3H), 1.19 (s, 3 H), 2.64 (d, 16·2 Hz, 1 H) 5 2·70 (d5 16·2 Hz5 1 H), 3.09 (d5 J = 13.4 Hz? 1 H)5 3.15 (d5 J = 13.4 Hz, 1 H)? 4.98 (s5 2 H)? 5.58 (d9 J = 6.0 Hz? 1 H)5 5.86 (d5 J = 6.0 Hz 1 H)9 15 6.02 (dd, /= 7.8 ; 1.1 Hz, 1 H), 6.26 (dd, 7·8, 1·1 Hz, 1 H), 6.40 (t, / 2 7.8 Hz, 1 H) ,6·55 (dd, /= 8·6, 2·5 Hz, 1 H), 6.74-6.83 (2 H), 7.00 (s, 1 H), 7.27-7.44 (m, 5 H), 9.22 ( s,1 H) ; 13C NMR (101 MHz, DMSO 〇 ppm 27.6 (CH3), 28.3 (CH3), 31.5 (C), 43.1 (CH2), 49.3 (CH), 60.5 (CH2)5 69.5 2〇 (CH2 ), 101.8 (CH, d, J = 25.6 Hz), 106.2 (C), 106.8 (CH), 109·6 (CH, d, / = 1.5 Hz), 11L9 (CH), 119·7 (C), 121.8 (CH)? 122.7 (C5 d, J = 14.6 Hz)? 127.9 (CH)5 128.0 (CH)5 128.4 (CH)5 128.8 (CH, d5 J= 5.9 Hz)? 136.6 (C)? 137.8 (C ) 5 143·9 (C), 146.1 (C), 158·3 (C, d, 11.0 Hz), 160·3 (C, d, 84 200848057 &gt; 24-5, 2 Hz); and 21 〇 mg u_ (44 oxy-2 _ phenyl) 3,3 Γ methyl_1,1_two-side oxygen-1,2,3,4,5,11_ Ϊ́1λ6-^-5ΐ〇_: Oral dibenzo[Μ]cycloheptene (19) : Rt = 2.26 *钟:二(M+H)+. ^ 495 赵就^-10_碰基基-2 -Fluoromoxa 3_ One or two side oxyhexahydro-U6·

1 〇 11-(4 哼 oxy 1 gas benzene private 6 _ _ 3, 3 __ mg '_2 millimoles) and ~ 62 = millimolar) in acetic acid Xuan (1.5 ml) solution at 75. After 〇 = 3 hours, the mixture was cooled to room temperature and the solvent was evaporated. The mixture was dissolved: (tetrahydrofuran) / h2 〇 t and 15 mg of Li 添加 添加 was added to adjust the pH of the mixture to ~3 (using 1NHC1), and the resulting compound was drawn with CH 2 C12. The organic layer was washed with brine, dried over MgSO 4 , filtered and evaporated. The residue was purified by chromatography (EtOAc: EtOAc:EtOAc: EtOAc: EtOAc: EtOAc H)+ 〇1^例___ 7—·1 醯丁醯基氲氲基)-6-hydroxy iU·-二-甲—基二侧氧-1,^4 立立 U_六氤^6_.5,1 〇_二立一苯苯[long along the cycloheptene (21)

Isobutyl chloride (33·8 μl, 0·323 mmol) was added to 11-(4-octyloxy-2-fluorobenzyl)-6-carbyl-3,3-dimercapto-1 ,1-di-side oxygen_i,2,3,4,5,1 1_ 10 hexamethylene-5,10-diπ丫dibenzo[aj]cycloheptene (18) (39.9 mg, 0.081 m Mole) and mPEA (7 〇·3 μL, 〇·4 〇 3 mmol) in CH2C12 (5 mL). After 3 hours, the solvent was evaporated and the residue was taken from THF/H. Thereafter, 5 mg of Li〇H was added. After 3 hours of scramble, 'HW was added and the pH was adjusted to ~5 with dilute HC1. After that, 15 reaction mixture was concentrated under reduced pressure, extracted with CH2C12, dried (NaJO4) and evaporated. The residue was purified by chromatography (Ch2ci2 / ethyl acetate, 70: 30) to give 35.3 mg of the desired product (21) as white solid: Rt 2.40 min, /z 565 (M+H)+ . 86 200848057 Example 8: 11-(4-Benzyloxy-2-fluoromethyl V6-hydroxy-3,3-dimethyl-U-di-oxo-10--(2-pyridylcarbonyl V1.2mil) - 六氪-1λ6-thia-5J0-二吖二笨和环庚娇(22)

The title compound (22) was prepared according to the description of 10-isobutyl decyl-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-5 1,1-di-oxo- 1,2,3,4,5,11-hexahydro-1 human 6-thia-5,10-dioxadibenzopyrene^]-cycloheptene (21), from 11-(4-benzyl Oxy-2-fluorophenyl)-6-hydroxy-3,3-diindenyl ίο -1,1-di-oxo-1,2,3,4,5,11-hexahydro-1 6- Preparation of thia-5,10-dioxadicyclohexene (18) and pyridinecarboxamidine chloride: Rt = 2.21 min, w/z = 600 (M+H) + 〇 Example 9: 11-(4-氧基oxy-2-fluorophenyl)-6-carbyl-3,3-dimethyl-1,1-15 dihedral-104 (2,5-dimethyloxazole-4-yl) Carbonyl 1-1 on 3Α5·11-hexa-1λ6-唼-5.10-二吖二茉和87 (23| 200848057 OH 丨一

The title compound (23) is prepared according to the description of the preparation of l-isobutyl decyl-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-1,1-dioxy -1,2,3,4,5,11-hexahydro-1λ-indole-5,10-diργdibenzo[flj]cycloheptadene(21) 5 method, 11-(4-octyloxy 2-fluorophenyl)-6-carbyl-3,3-dimercapto-1,1_di-milk-1,2,3,4,5,11-hexanitro-1λ-oral-5 Preparation of 10-di-n-dibenzo-cycloheptene (18) and 2,5-dimethyloxazol-4-carbonyl chloride: Rt = 2.28 min, w/z = 618 (M+H) + ; NMR (400 MHz, DMSO-A) δ ppm 1·15 (s, 3Η), 1·22 (s, 3 Η), 2·13 (s, 3Η), 2·18 (s, 3Η), ίο 2 · 76 (d, J 2,6·0 Ηζ, 1 Η), 2·84 (d, J = 16.0 Ηζ, 1 Η), 3.08-3.19 (m, 2 Η), 4·98 (s, 2 Η) ,5·82 (d,/= 7·5 Ηζ5 1 Η), 6·42 (t, J 27.5 Ηζ, 1 Η), 6.52-6.61 (m, 2 Η), 6·72-6· 83 (m, 2 Η), 7·27-7·40 (m, 5 Η), 7·45 (s, 1 Η), 7.66 (s, 1 Η), 10.16 (bs, 1 H); 13CNMR(101 ΜΗζ,DMSO-A)·δρριη 10·6 (CH3)5 15 13.1 (CH3)? 28.1 (CH3)5 29.0 (CH3)5 32.0 (C)5 42.3 (CH2)? 49.2 (CH)? 61.3 (C H2)5 69.5 (CH2)? 101.9 (CH5 d, J = 24.9 Hz), 104.6 (C), 109.8 (CH), 112.9 (CH), 118.9 (C, d, "/II 14.6 Hz) 5 119.5 (CH ) 5 122.2 (CH)? 125.6 (C)? 127.8 (CH)5 127.9 (CH), 128.4 (CH), 130.1 (C), 130.9 (CH, d, J 25.1 Hz), 131·1 (C) ,136·4 (C),146.1 (C)5 147.1 (C),150.0 (C), 88 20 200848057 157.6 (C)5 159·1 (C,d,ιι·〇Ηζ),160·0 (C ,d,247·4

Hz), 160.2 (C).丰1 例 -10 ··Fluoryl)-6-hydroxy-3,3-diindenyl iL-1 dioxo oxycarbonyl V1,2,3,4,5J1-hexahydrodi 6 -thia-5,10-didecene oxime 24,

The title compound (24) is prepared according to the description of 1〇-isobutylhydrazino_η_(4-benzyloxy-2-fluorophenyl)-hydroxyl_353_dimethyl-1,1-di-oxo-1,2, Method for 3,4,5,11-hexahydro-1 human 6-thia-5,1 fluorenyldibenzo[^]cycloheptene (21) from 11-(4-benzyloxy-2 -fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-oxo-1,2,3,4,5,11-hexahydro-116-thia-5,10-di Preparation of fluorene dibenzo[仏^/]cycloheptene (18) and thiazole-4-carbonyl gas: Rt = 2.19 min, w/z = 606 (M+H)+. i^~JLLUJd[4^^ 基-2-Fluorol V6-hydroxyl-3·3-dimethylhydrazine·^-yl-2-pyridine 1 hetero-vim'ii-hexahydro-p-k-decene (25, 89 200848057

The title compound (25) is prepared according to the description of ι〇-isobutyl fluorenyl_11_(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-oxo- 1,2,3,4,5,11-hexahydro-:^6-thia-5,1〇-dioxadibenzo[^-cyclohexene heptene (21), from 11-(4-benzyl Oxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-oxo-1,2,3,4,5,11-hexahydro-1 human 6-thio -5,10-dibenzoic acid|&gt;, edge ring heptane (18) and 6-mercaptopurine 曱驴 chloride preparation: Rt = 2.30 minutes, m/z = 614 (M+H)+.堂子例12: 丄Benzyloxy-2-氤笑V6-hydroxy-3,3-dimethyldimethyl 磲吔_4·某)鞲一1-1 3A5J1-二吖二1 徘" Fljl ring waste olefin (26) and 氤 某 V6-recording base _3.3_ dimethyl-1,1_di-side oxazol-4-yl, hetero-l-1.2.3.4丄11-hexahydrodimo And k terpene (27) 90 200848057

U-(4-decyloxy-2-fluorophenyl)_6-hydroxy-3,3-diindolyl-1,1_di-oxo-61〇-[(2,5-dimethylcarbazole+ 2) carbonyl]-1,2,3,4,5,11-hexahydro-1 9'-5,10-dioxadibenzo[2]cycloheptazone (23) 2 mirror image isomers Purified by SFC (Supercritical Fluid Chromatography) on the palm column AD_H (solubilizer · COV isopropanol 5 〇: 5 〇). Collect the two dissolving fractions and evaporate the solvent to produce (27) ·Retention time ι·28 min, w/z = 618 (M+H)+; and (28) ·· ait stay in the day for 1 · 47 minutes, w/z = 618 (M+H)+ ruthenium compound (28) to (142, the compounds (28) to (142) described in Table 1 were prepared according to Example 7 using 10-isobutyl fluorenyl _n_(4-benzyloxy) Base 2_fluorophenyl)-6-hydroxy-3,3-,methyldi-oxo-1,2,3,4,5,11-hexahydro-1 to 6-thia-5,10_2 &lt;Dibenzo[〇U]cycloheptene (21), using u_(4-benzyloxy-2_fluoro-phenyl)-3,3-dimethyl_l5l_di-side oxygen_1Η_1λ64 -5,1〇-di-f-dibenzo[a,d]-cycloheptene-6-ol (18) and the appropriate mercapto chlorides listed in Table 1. 91 200848057 Table 1

92 200848057

93 200848057

94 200848057

95 200848057

96 200848057

97 200848057

98 200848057

99 200848057

100 200848057

101 200848057

102 200848057

103 200848057

104 ¥ 200848057

105 200848057

106 200848057

107 200848057

108 200848057

109 200848057

110 200848057

111 200848057

112 200848057

113 200848057

114 200848057

115 200848057

116 200848057

117 200848057

Example 14: Synthesis of Compounds (143) to (190) The pure mirror image isomers (143) to (190) were obtained after purification as described in Example 12 from the corresponding racemic mixture shown in Table 2. Table 2. Oscillating mixture (j?)-mirrible isomer 〇S&gt; Mirror isomer condition number structure number Rt (minutes) No. Rt (minutes) Column/solvent 24 143 144 AD-H/50% ιχ VrVF 2.88 1.85 i-PrOH 钤XX) 118 200848057

119 200848057

120 200848057

121 200848057

122 200848057

Racemic mixture (i?)-mirroromer 〇S&gt; Mirror isomer condition number structure number Rt (minutes) No. Rt (minutes) Column/solvent 263 Thief \ 187 2.51 188 AD-H/40% i- PrOH 241 F 十 F 189 5.0 190 OD-H/25% i-PrOH 414 /&quot;K Η 437 438 AD-H/45% Q 2.90 2.11 i-PrOH Example 15: 1-"1M4-Benzyl group- 2-fluoro-mosyl)-9-hydroxy-3,3-dimethyl-1,1-di-oxo-1,2,3,4,5,11-hexanitro-1 into 6-port- 5,10-diphthoquinone-two stupid and "a, dl cyclohepten-10-yl 1-ethyl ketone (191)

123 5 200848057 The title compound (191) is synthesized according to the synthesis of 1[1Η4-noonoxy-2_fluoro-phenyl)6/work-based _3,3-dimercapto- &quot;,: side hexahydro: 1 λ6 exaggeration 5 , 1 〇 · bis + dibenzo[a, d] cycloheptene-based]-ethanone (2 〇) ^ ^ ^ ^ ^ ^ n_ (4_ Wei Ke, 2 _ _ _ phenyl side ^ 2,3,4,5,10,11-hexahydropenic _1 person 6_喧_5,1〇_bis(dibenzo[a,d]-cycloheptenyl (19)(10) , 〇·2〇8 mmol), yielding 104 g (93% yield) of off-white solid; 厶=537 (Μ+Η)+. ν3·3- dimethyl 丄 VL2JA5J1_ six gas- 1λ-thiazolium 〇ϋ_diphenyl into £^j^^_1〇n_ketone ί192,

(192) Compound (191) (40 mg, 〇·〇 75 mmol), 4-chloromethyl hydrazine hydrochloride (16 oz '1.3 eq.) and carbonic acid (73 mg, 3 eq.) The mixture in DMF was stirred at room temperature. After 16 hours, 8 mg of 4-chloromethyl-thiazole hydrochloride was added, and the reaction mixture was heated at 60 ° C for 2 hr. The reaction mixture was then diluted with water and taken in the presence of CI^Cl2 and subsequent acetic acid. The organic layer was dried over MgSO4, filtered and concentrated. The quick-discovery analysis was carried out. 124 15 200848057 Purification (solvent: ethyl acetate) gave 23 mg (yield: 49%) of desired product (192) as an off-white solid; Gas-based 2-fluoro-jamma V9-methyl gas a dimethyl group side oxygen hexahydro·1λ6_^_5·10_: ν丫-dibenzoheptene -10- 1-ketone (193)

〇- (拠) Compound (191) (24 mg, 0.045 mmol), methyl iodide (7 mg, U equivalent) and cesium carbonate (22 mg, 1.5 eq.) in DMF. . The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, filtered with EtOAc EtOAc EtOAc. The resulting solid was washed with isopropyl ether to give 13 mg (yield: 54%) of desired product (193); m. Recuperation d^Ll8 : 11-(4_芊氢某_2-Fluoro)_3·3·9_三甲其"i - wing ^^3,4,5,10,11-six-1 -1 6 6嗔 _5,10-二吖_二y and [丄丄还息焦-6-ol (197) 125 200848057

step 1

OH άΓ y νη2 |1§4| ο

F

(Ifi) (19€)

Sulfone (5) (191 mg, 1.084 mmol), 2,3-diamino-4-methyl-phenol (194) (150 mg, 1 eq.), trifluoroacetic acid (138 mg, 1.1 eq. And a mixture of 4 Α molecular sieves in DMF (10 ml) was heated at 50 °C for 6 hours. After cooling to room temperature, the reaction mixture was filtered and washed with DMF. The filtrate containing the two regioisomers (195) and (196) was used in the next step without further purification; w/z = 297 (M+H)+. Step 2

(195) (19 sentences (11)

(197) (198) 126 200848057 Add 4-benzyloxy 1fluorobenzaldehyde (11) (251 mg, 1 equivalent) and NaHC03 (81 mg, 0.9 equivalents) to the above reaction mixture containing (195) and (196) ). The reaction mixture was heated at 50 ° C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. A mixture of two regioisomers (197) and (198) was obtained by flash chromatography (solvent·ethyl acetate/03⁄43⁄4 30: 70); m/z = 509 (M+H)+. 19 : "11-(4-nineoxy-2-fluoro-1yl, _6_ via a certain -3:3,9-trimethyl-oxy-1,2,3,4,5,11-hexaquinone One person 6-mouth chamber-5,1〇-two (two molybdenum "3" 10-base 1-(6-methyl port than bite-2-yl V 曱i same

6-Methyl-pyridine-2-carbonyl chloride (99 mg, 4.7 equivalents) and Hunig's base (219 mg, 12.7) were added to the above-mentioned positional isomers (197) and (198) dissolved in 03⁄4⁄4. equivalent). After 15 minutes, the solvent was evaporated and the residue was taken up in THF/H.sub.2. Thereafter, 50 mg of LiOH was added. After stirring for 16 hours, h2 hydrazine was added, and the pH was adjusted to ~4 with dilute HC1. After that, the reaction mixture was concentrated under reduced pressure and dried with CH2Cl2, 127 200848057, dried (Na2S04) and evaporated. The residue was purified by chromatography (CH2C12 / ethyl acetate 70: 30) to yield 14 mg of the desired product of the product (199) as a single res.; w/z = 628 (M+H) + 〇5 Example 20 Synthesis of Compounds (200) to (217) Compounds (200) to (217) are synthesized according to the synthesis of 11-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-1,1- Bis-oxo-2,3,4,5,10,11-hexahydro-lH-λ6-thia-5,10-diindole-dibenzo[a,d]cyclohepten-6-ol (18) The method described was prepared by substituting the appropriate aldehyde shown in Table 3 for 4-benzyloxy-2-fluoro-benzoquinone 10 aldehyde. Table 3 Numbered structure vine yield m/z (M+H)+ 200 & 8% 422 201 ::Ό ΟγΗ φ&quot; CC 16% 516 202 M || 〇,yH Ιγ丄36% 507 128 200848057 No. Structure aldehyde Yield m/z (M+H)+ ^ Ρ V Μ 203 % frr~η 51% 513 9Μ Η 204 (Ζο Q 0 11% 507 205 wN&gt;t &quot;2ο r0=T 13% 519 206 ά:Λ ΧΟ r:^k \_/ \j 23% 512 207 〇« 〇L. ίο CL. 38% 560 208 σΐ uo r F~F f-r\ 13% 545 209 Η Q ^ 12% 517 ώ , 一Γ 129 200848057 No. Structure aldehyde yield m/z (M+H)+ 210 TO Ο. Η3〇fH 〇Ρ 21% 491 211 F ψ Fxx 5% 578 212 η Λ{ Saki-Q /ρ b ΟγΗ Ο 37% 531 213 Q 03⁄4 φτρ 03⁄4 29% 483 214 ά| F gF F 38% 433 215 Γ Β.^( h gF 0 29% 449 216 Χβ-&lt;^ α^ςι Βγ b 43% 548 130 200848057

Example 21: Synthesis of Compounds (219) to (259) Compounds (219) to (259) were synthesized as 10-isobutylindolyl-11-(4-benzyloxy-2-fluorophenyl)-6-carbyl group_ 3,3_Dimethyl-1,1-di-side oxygen 5 _1,2,3,4,5,11-hexahydro-116-thia-5,10-dioxadibenzo|^-cycloheptene (21) ^ The method described is 3,3-dimercapto-1,1-di-oxo-2,3,4,5,10,11-hexahydro-1Η-1λ6-thia-5,10 - bis(dibenzo[a,d]cyclohepten-6-ol derivatives (200) to (218) and the mercapto chloride substituted n_(4-benzyloxy-2_gasphenyl) shown in Table 4 )-6-hydroxy-3,3-dimethyl-1,1_di-oxo six gas ίο -1%6_thia-5,10-dioxadibenzo[α, Cycloheptene (18) Preparation of isobutyl sulfonium chloride began. 131 200848057 Table 4

132 200848057

133 200848057

134 200848057

135 200848057

136 200848057

137 200848057

138 200848057

139 200848057

140 200848057

141 200848057

Example 22: 6-(2,5-Dimercapto-oxazol-4-carbonyl)-7-(2-indol-4-hydroxy-jamyl)-10,10-dimercapto-8,8- Bilateral gas-6,7,8 and 10,11-hexa-2-pyrene-8λ6-thia-6,llb-dioxa-dimos and "cdhl chamomile-1-one (261)

142 200848057 [11-(4-Benzyloxy_2_fluoro-phenyl)_6_ carbyl _3,3 dimethyl _ U,3,4,5,n_ hexahydro·11645,1G_; And [soil = 10-base; H2,5 dimethyl-s- oxazolyl) ketone (23) g, millimolar) and several groups of dimethicin (574 mg, L4 equivalent) in CH2Cl2 (5〇 The solution in Zhaisheng) was stirred at room temperature for #16+. The reaction mixture is then diluted with c^ci2, washed with a saturated NaHC〇3 solution, dried with MgS〇4, filtered, and then condensed to dryness, yielding 1.62 g (maximum yield) of 7-(4_; Base gas-phenyl)_6-(2,5-dimercaptoindazole-4-carbonyl)-1〇,1〇_dimethyl_8,8_dioxine 6,7'8,9,1 〇, 11-hexamethyl-2-oxo-8-member 6-嗔-6,1 lb-di-v丫·dibenzo[cd,h]Azurin ring ketone (260); m/z two 644 (M+ H)+. Step 2

A solution of compound (260) (1.56 g, 2.24 mmol) in ethyl acetate (1 mL). After completion, the reaction mixture was filtered and concentrated. The resulting white precipitate was filtered to give the desired product 6-(2,5-dihydrazinyl oxazol-4-yl) 1 (2-fluoro-4-hydroxy-benzene). Base: Μ0,10-dimercapto-8,8-two-sided oxygen '7'8,951 〇, 11-hexanitro-2-lacto-8λ-mouth group-6,1 lb-di-n- 丫- a stupid [cd,h] 143 200848057 Chamomile ring-1-ketone (261); w/z = 554 (M+H)+ 〇f^L 23 : allyl group -2-fluoro-mosas 篡·6-hydroxyl -3,3- 2 shame [1,1-two side 氲-1,2,3 into 5,11-hexa 1-1 person 6-4'11〇_二吖-二茉迸ΙΜΜheptene-10 -yl 1-(2,5-dimethyl-carbazole_4_ its)-methanone (263)

P_ Compound (261) (300 mg, 0·542 mmol) was added to a solution of acetonitrile ( 177 mg, 1 eq.) and 3-bromopropan-1- </RTI> The reaction mixture was stirred at room temperature for 1 hr then concentrated over EtOAc EtOAc. Organic layer

The MgS(R) 4 was dried, filtered and concentrated to dryness to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& Now. sit 4-carbonyl)-10,10__methyl-8,8·di-oxo-6,7,8,9,1〇,11-hexahydro-2-oxa-8λ6-thio-6, Llb-dibenzo[delta][cd,h]chamomile ketone (262); m/z = 15 594 (M+H)+. (262) A solution of THF/nonanol in a mixture of 1:1 (10 ml) was added to water (2 mL) in water (2 mL) at room temperature (13 mg, vol.). After the reaction was completed, HA was added and diluted. HC1 adjusts the pH to ~5. / Afterwards, the reaction mixture was concentrated under reduced pressure, extracted with EtOAc (EtOAc, EtOAc (EtOAc), EtOAc (EtOAc) /z = 568 (M+H)+. Example 24: Synthesis of Compounds (264) to (270) Compounds (264) to (270) were synthesized according to [11-(4-allyloxy-2-fluoro-5-phenyl)-6-hydroxy-3 ,3-dimethyl-1,1-di-oxo-1,2,3,4,5,11-hexahydro-116-thia-5,10-diindole-dibenzo[a,d] ring Second-order method for heptene-10-yl H2,5-dimercapto-norkuzol-4-yl)-methanone (263) from 6-(2,5-dimercaptoindazole-4-yl) - 7-(2-mur-4-pyridylphenyl)-10,10-dimethyl-8,8-di-side oxygen_6,7,8,9,10,11_hexa-2-oxo Preparation of hetero-8λ6-thiazolidine-6,1 lb-dioxadibenzo[cd,h]10 chamomile cyclo-1-one (261) and the appropriate alkylating agent shown in Table 5.

145 200848057 No. Structure Burning agent m/z (M+H)+ 266

ΒΓ 595.69 267

,Βγ 579.647 268

,Βγ 581.663 269

Βγ 581.663 146 200848057 No. Structure Alkylating agent m/z (M+H)+ f T Mo 270 y^&amp; Bf II Μ 566.608 o ί

OH (261) bis-methyl-norzole-4-one Wil-"2-fluoro-4-(2-"?:diyldiyl-V-m-methyl-6-hydroxy-3,3-dimethyl Base-1,1-diphase i!,2,3,4,5,1 1_ 六盟' ·1λ _ mouth base-5,l〇_ two 丫一二二笨和[a,dl 环庚,味zl〇-L·}^ mmi)

6-(2,5-dimethylazolylcarbonyl)_7_(2-fluoro.4-hydroxy-phenyl M〇, 10-didecyl-8,8-di-side oxygen-6,7,8,9 , 1〇, 11_ hexahydro-2-oxa, Km-gong benzo[, a solution of chamomile ketone (261) (5 〇 ^ 毫 millimol) in THF (2 ml) in (TC In n2T (嗔-phen-2-yl)ethanol (7 mg mg, 2 equivalents), triphenylphosphine (7 i mg lower riji) and DIAD (monoisopropyl azodicarboxylate; %). The reaction mixture was 0. 〇 〇 — — — — 毛 毛 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 40% yield) of 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-[2-fluoro-4-(2-thien-2-yl-ethoxy)-benzene Base]-i〇,i〇-dimethyl-M-di-side oxygen-6,7,8,9,10,11-hexahydro-2-oxa-816-thio-6,111&gt; -5 dibenzo[cd,h]sargarylcyclo-1-one (271) ^ m/z = 664 (M+H) + (Γ71) in THF / decyl alcohol 1:1 mixture (5 ml) Add a solution of LiOH (1 eq.) in water (1 mL) at room temperature. After the reaction is complete, add H2 hydrazine to dilute HC1. The pH was adjusted to ~4. After that time, the reaction mixture was concentrated under reduced pressure, dried over CH.sub.2 C.sub.sub.sub.sub.sub. +. 实遂剑-% : cyclopropyl-ethane-based V2-fluoro-caxene 1-6-hydroxy--3,3-mercapto-side-oxygen-1,2,3,4,5,11 - 六氤-1乂6-口塞-5,10-二口丫-ζΞ:—Benzene “a, rainbow ^heptene_10_yl^〇dimethyl-carbazole-4_)) 15 ketone (273 ;)

The compound (273) is based on the second-order method of synthesizing compound (272), and is replaced by 2% propyl alcohol. 2_(thiophene-2 _ 乙μ2 (Μ+Η)+ 〇148 200848057 Example: 〇二Methyl-carbazole_4_V (ll-"2-fluoromethoxybenzyl-based V-methyl-l-1-6•蕤-3,3-dimethyl-1,2,3,7-5, 11-六氲-1人6-嚓-5.10-二吖-二茉和&&;,(11泽^^ -10-基}_曱_Γ274,

The title compound (274) is prepared according to the second-order method of the compound (272), using (3-methoxymethoxy-phenyl) decyl alcohol in place of 2-(thiophen-2-yl)ethanol; m/z II 678 (Μ+Η)+. Example 28·(2,5-Dimethyl-Oxo-sodium-4-yl Vi 11-"2-disorder-4-(3-carbyl-oxyl-1-6-hydroxy-3.3-dimethyl a -U-bilateral gas -1,2,3 ζ1λ6_thia-5,10-diindole-diindole and "a,(TI cyclohepten-10-yl ketone (275)

149 200848057 Compound (274) (54 g, 8.0 mmol) was added EtOAc (1 mL). The reaction mixture was then concentrated in vacuo, redissolved, washed with saturated NaHCI 3 and then brine, dried with &lt;RTIgt; Purification by flash chromatography to give the desired product (275); 634 (M+H) + 〇t. Example 29 · 5-B; methyl-i, i-dioxin, gas-mouth 嘀 ketone ") \ 〇

P80J Ο Step 1

&lt;27β) (278) 2-Chloroprop-2-en-1-thiol in sterol (276) (10.11 g, 93.1 mmol) - as (1) Lansbury, Ρ·Τ· ; Scharf, D · J. CTzem. 1968, 90, 2, 536_53 and (ii) Lansbury, Ρ·Τ·; Nienhouse, Ε·J.; Scharf, DJ; Hilfiker, FRJ Am. Chem. Soc. 1970, 92? 15 19, Sodium decoxide (5 〇 3 g, 1 eq.) was added as described in 5649-5657. After 30 minutes at room temperature, 2-ethyl-2-mercapto-oxirane (277) (7.82 g, 1 eq.) was added and the reaction mixture was stirred for 16 h then diluted with water and sat. NaH. Change to pH 10. The aqueous layer was extracted with ethyl acetate and the organic layer was dried with &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&&& A colorless oil of propylsulfanyl)-2-methyl-butan-2-ol. 〇

Step 2

€1 〇(27) "Addition of the title compound (279) according to the method described in the synthesis of 5,5-dimercaptodihydrothiopyran-3-one 5 (4) 'Using 1-(2-aerobic C 2-thiol-butan-2-ol (278) substituted 1-(2-chloro-allylsulfanyl)-2-methylpropan-2-ol (3) at 55 Prepared at % yield.

ό 〇(271) (280) The title compound (280) is as defined in the synthetic compound 5,5-dimercapto-1,1-di 10 side milk-four mouse-a-based 嗣-3-嗣(5) The procedure 'prepared using 5-ethyl-5-mercapto-di-rhamyl-3-indole 5,5-dimethyl-di- oxetan-3-yl' at 8% yield. Example 30: 11-(4-Mercapto-2-fluoro-methyl)-3-ethyl-3-methyl-1,1-15 dihedral-2,3,4,5,1 ( U1-hexahydro-IH-Ιλ6-thia-5J0-diindole-dimo-"a, dl cyclohepten-6-ol (281) 151 200848057

The title compound (281) is synthesized according to the compound (18) 11 -(4-benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-1,1-di-oxy-1 , 2,3,4,5,11-hexam-1λ6υ, 1〇-dibenzo[pij]cycloheptene, described in the 2nd-order 5 method 'using ethyl-5-methyl-1, 1-dihydroxyl-tetrahydrofuran-3-one (280) Substituted compound (5) was prepared in 32% overall yield; w/z = 509 (M+H)+. Black Example 31 ·〖11-(4-卞气基-2-气-笨基)·3_ethyl_6·transalkyl-3-methane-1 33·4·5·11-hexa-1λ6 -mouth 窠-5·10-two U 丫-two y and 10 [aA cycloheptene-10- Γ 1-Γ2-fluoro-methyl ketone (282,

The title compound (282) is synthesized according to the synthesis of 10-isobutyl decyl-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-side oxy-1. 2,3,4,5,11-hexa-1λ6-thia-5,l〇-dioxadibenzo[β/]cycloheptene (21) as described in the formula 152 200848057 by the compound (281) And 2-fluorobenzhydryl chloride substituted η#-octyloxy_2_fluorophenyl)-6-hydroxy-3,3-dimethyl'μ di-side oxygen], 2,3,4,5,u_ Hexahydro-1 to 6-thia-5,10-dioxadibenzo[^, pecycloheptene (18) and isobutyl hydrazine starting at a 65°/❹ yield to prepare a racemic mixture; /z = 631 (M+H)+. The four stereoisomers of (282) are further isolated from the palm of the hand by SFC to produce compounds (282a), (282b), (282c), (282d). tExample 32 ·· [11-(4•Benzyloxy 4^2-fluoro-benzene)-3-乙某_6_ See base-U-two-side oxygen-1,2,3,4,1〇1 ^£^6_thiazide 10-dioxime-shi 1 package fa,d~]%heptene_1〇_yl~]-(2,5-dimethyl-π et al. _4_ ketone ( 283,

The title compound (283) is synthesized according to the synthesis of 10-isobutyl aryl__ιι_(4_octyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-1,1-dihydrogen. -1λ6_|5,10-dioxadibenzo[fl, cyclohexene heptene (21), substituted with compound (281) and 2,5-dimercaptocarbazole-4-ylcarbonyl chloride 11-(4-Benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-oxo-1,2,3,4,5,11-hexaquinone -1 person 6-thia-5,10-dioxadibenzo[^, Cycloheptene (18) and isobutyl hydrazine start 'prepared at 70% yield; w/z = 632 (Μ+Η )+. 153 200848057 Isobutyl-5-methyl cover: person

The title compound (284) is prepared according to the third order described in the synthesis of the compound (28〇), and 2-ethylbutyl oxime-oxirane is substituted for 2-ethyloxirane (277). . -Methyl^^^ΙΙΙΗϋoxyphenyl K3-isobutylene q dihexahydro-1Η-ΐλ6-唼-5.10-di" alcohol (285)

^The title compound (285) is synthesized according to the compound 11-(4-benzyloxy_2_qi,) heptahydroxy-3,3-dimethyl-u-di-oxo-hexachloro-indole _5,1 〇 _ 丫 苯 苯 苯 [ [ [[β,7] Cycloheptene (18) 斤 记载 记载 记载 记载 记载 2 2 2 , 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 , , , , , , 化合物 化合物 化合物Thiazone (5), prepared at 30% overall yield; = 537 (M+H)f. 154 2〇〇848〇57

Benzyloxyfluoro-jamyl viayl-3-different ^^ 1 body L milk-1,2,3,4^^ii- six remains _ι人6_口塞_5,ι〇-二

Base l_(2i-Momotone V ketone (286) The title compound (286) is synthesized according to the synthesis of 1 〇 异 异 醯 苄 benzyloxy ' fluoro, yl)-6-hydroxy-3,3- dimethyl _ 151 Two side oxygen _l52,3,4,5,u_hexahydro 1λ-prepared 5,1〇_dioxadibenzo[β,&quot;] Cycloheptene GO is described as a compound (285 And 2-fluorobenzhydrazyl chloride-substituted benzyloxy-2_fluorophenyl)-6-hydroxy-3,3-dimethyl-ij-di-oxo^2,3,4,5,11-hexahydro • 4λ-thia-5,l〇-dioxadibenzo[α, cyclohexene (18) and isobutylphosphonium chloride were prepared; m/z = 659 (Μ+Η)+. : 5-Methyl-1,1-Side Side Oxygen-B-M--Four-Poke

Pi?) 15 The title compound (287) is a third-order method according to the synthesis compound (28〇), and 2-ethyl-2-propyl oxirane is substituted for 2-ethyl-2-methyl ring. 155 200848057 Preparation of oxyethylene. Example 37: 11__L4: in the oxy 2 - gas - y 芊 υ 1- 1- 1- 1- 1- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- i i i i i i i i i i i i J J J J J J J J J J J J J J J Diphenyl is supplied to "a, d1 cyclohepten-6-ol (288)

The title compound (288) is a compound of benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-diindenyl], [2-dioxy", 2,3,4,53μ hexahydro 2-step method of -1λ6-thia-5,10-dioxadibenzo[β,^Γ]cycloheptene (18), using compound (287) in place of 5,5-dimercapto-1,1_2 Preparation of oxo_tetrahydro-thiopyran-3-one; m/z = 523 (Μ+Η)+. Oxygen m-based V6 shoulders a | T ^ &quot;&quot; _ ---2B, = side ritual -1,2, K5,11-six 氤-1λ6-喧-5,10-two τι丫- · Stupid and £§„,引%^庚;|:布_1〇-基&quot;|-(2_气_笨基)-甲嗣(289) 156 200848057

The title compound (289) is synthesized according to the synthesis of 1 〇-isobutyl decyl-11-(4-benzyloxy-2-fluorophenyl) hydroxy-3,3-diindenyl 2-oxo-1,2,3,4 , 5,11-hexahydro-1λ6-thia-5,10-dioxadibenzo[β, &lt;1 cycloheptene (21), the compound (288) and 2-fluorophenylhydrazine Chlorine substituted 11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-1,1-di-oxo-1,2,3,4,5,11_ Hexahydro-1λ-is-5,10-di-p-p-dibenzo[[3,^/] bad Geng (18) and isobutyl brewing began to be prepared; = 645 (M+H)+. (289) The four stereoisomers were further isolated by palm chromatography using SFC to give compounds (289a), (289b), (289c), (289d). Example 39: Synthesis of Compound 290-348 Compound 290-348 Synthesis of 10-isobutyl decyl-11(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-side oxygen_1,2,3,4 , 5,11-hexahydro-116-prepared 5,10-dioxadibenzo[(^]cycloheptene (21) as described in the section 'to 2,3,4,5,10,11_6 Hydrogen_1-喧-5,10-di-n-oxime-dibenzo[&amp;, (1) cycloheptene 1, L·dioxide derivative (reagent oxime) and thiol chloride as shown in Table 6 11-(4-benzyloxy) -2-fluorophenyl)_6_hydroxy_3,3_dimethyl_ι,ι_two-side oxygen_1,2,3,4,5,11-hexahydro-116-thia-5,1〇 Preparation of bis-dibenzo[beta]cycloheptene (18) 157 200848057 and isobutyl sulfonium chloride.

158 200848057

159 200848057

160 200848057

161 200848057

162 200848057

163 200848057

164 200848057

165 200848057

166 200848057

167 200848057

168 200848057

169 200848057

170 200848057

171 200848057

172 200848057

P5_ Step 1

A solution of 2,3-dinitroaniline (1 gram, 54.61 mmol) was catalyzed by pd/c catalysis, and after filtration and concentration to dryness yielded 6420 mg (95% yield of 5 &amp;); 124 (M+H)+. Step 2 ◎

_ ()

〇 P50)

P51) Title Compound (350) #-(5,5-Dimethyl-1,1-dihydro-l,4,5,6-tetrahydro-thiopyran-3-yl)-benzene-i,2 6-triamine according to the method described in the synthesis of the compound (16), by reducing the reaction time to 1 hour and using 1,2,3-benzenetriene 173 10 200848057 amine (349) to replace 2,3-diamine Prepared with a phenol to give a mixture containing the regioisomer (35i); w/z 282 (M+H)+. This mixture was used in the next step without purification. Step 3

(3S2) 5 10 mixture of positional isomers (35 〇) and (351) (3200 mg, 5 67 mM) Fmoc-Cl (amino carbamic acid 9 _ odor methyl ester) was added to DMF (200 ml) Chlorine; 1468 mg, 1 equivalent). The reaction mixture was followed by 5 Torrs. Next, acid (Η) (1306 mg, 1 eq.) and Najjc 〇3 (477 g, i eq.) were added and the reaction mixture was further heated for 16 hours, filtered over celite, diluted with saturated aqueous NaHCI3 and acetic acid. ^ Ester extraction. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (solvent: (3)^^ ethyl acetate) to yield 1200 mg (21% of total yield) of the title product [^(^benzyl, phenyl-phenyl)-3,3曱基], i di-side oxygen^-1Η-1λ-thia-5,10-diindole-dibenzo[a,d]cycloheptene_6-ylamino fluorene __9-yl曱基@旨(352) ; m/z = 716 (M+H)+ 〇174 15 200848057 Step 4

Add 6-fluorenyl-pyridine-2-carbonyl chloride (326 mg, 5 eq.) and Hunig's base to a solution of the intermediate (352) (300 mg, 0·419 mmol) in THF (50 mL) 0.69 ml, 10 equivalents). After 4 hours at room temperature, lithium hydroxide (5 eq.) dissolved in water was added and the mixture was stirred for 1 hour then diluted with brine and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was purified by flash chromatography to give 4 mg of the desired product (353); w/z = 613 (M+H)+. ο 贯 Example 41 · Synthesis of "11-(4-decyloxy-2 - gas-stupyl)-3,3-dimercapto-1,1 - II side gas-2JA5J0J1-hexa-1氤1λ6- Thio-5J0-diterpene-dimosane for "a, dl cyclohepten-6-yl sterol (354) 175 200848057

The title compound (354) is synthesized according to the compound 11-(4-benzyloxy-2-fluorobenzene f)_6_hydroxy_3,3_2? 2nd-order method of thio-U-di-oxo-1,2,3,4,5,11-hexahydro-ΐλ-thiaz,i(^dioxobis[beta], penetene heptene (18) The 2,3-diamino group was replaced with (2,3-diaminophenyl)methanol to give an off-white solid of 34% of the total yield; w/z = 5〇9 (μ+Η)+. _iaj2 丄 处 苄 苄 苄 其 其 其 《 《 《 《 《 《 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

The title compound (355) is synthesized according to the synthesis of 10-isobutyl decyl-11-(4-benzyloxy-2-fluorophenyl)-6-carbyl-3,3-dimercapto-1,1-di-oxo- 1,2,3,4,5,11-hexahydro-1λ6-prepared by 5,1〇_diπ丫dibenzocycloheptazone (21) 176 200848057 method, with compounds (354) and 2 -Fluorobenzoquinone chloride substituted n_(4_co-oxy-2_fluorophenyl)-6-hydroxy-3,3-dimercapto-l,i-di-side oxygen_1λ6-thia-5,10-di Starting from quinone dibenzo[α, &lt;|cycloheptene (is) and isobutyl fluorene chloride, prepared in 69% yield; m/z = 631 (M+H)+. 5 Paste Example 43: Synthesis of Compounds 356-440 and 472-473 Compounds 356-440 and 472-473 are based on the method shown in Table 7, from 2,3,4,5,10,11-/,hydrogen-1 -嗔-5,10-di&lt;-dibenzo[3,(^)cycloheptene_1,1_dioxide derivative (Reagent 1) and optionally as shown in the table below Method A ·· The reagent 1 shown in the table is synthesized according to the synthesis of 1 〇 异 异 醯 - 丨 苄 苄 苄 苄 苄 苄 苄 苄 ) ) 苄 苄 苄 苄 ι ι ι ι ι _ two-side oxygen q, 2,3,4,5,^ 15 hexahydro-m5,10-dioxadibenzo[a,d]cycloheptene (21), as shown in Table 7 The mercapto chloride is substituted for isobutyl sulfonium chloride to purify. Method B ·· The reagent 1 shown in the table is synthesized according to [1L(4_allyloxy_2_fluoro, 2〇phenyl)-6_carboxy_3,3_dimethyl-1,1-di Side oxygen-1,2,3,4,5,11-hexa-1,6-thia-5,10-diindole-dibenzo[a,d]cycloheptene_1〇_yl]_( 2,5-Dimethyl-oxazole-4-yl)-fluorenone (263), from 6-(2,5-dimethylazole-4-carbonyl)-7-(2-fluoro- 4-Hydroxy-phenyl)-10,10-didecyl_8,8-di-oxo-6,7,8,9,10,11-hexahydro-2-oxa-8- 6-.塞-6,1115-二#-二笨和 177 200848057 [cd,h] amaranthene (261) and the appropriate alkylating agent shown in Table 7 as reagent 2 were alkylated. Method C: Reagent 1 shown in the table is synthesized according to (2,5-diindolyl)-{4-yl]{11-[2-fluoro_4_(2_喧-phen-2-yl-ethoxyl) ) _phenyl]_6_ benzyl dimethyl-1,1-di-side oxy-1,2,3,4,5,11-hexahydro-1, _ thia _5,1 〇 吖 吖 吖 benzene And [a, d] cycloheptene_10_ carbomer (272), 6-(2,5--fluorenyl azole-4-ylcarbonyl)-7_(2_fluoro_4 _hydroxy-phenyl)_1〇,1〇_二6甲, 乙二侧氧-6,7,8,9,10,11-hexahydro_2_ oxazepines _6,11|&gt; 17丫_Dibenzo[()] azurin ring ketone (261) and the appropriate alcohol (substituting 2-(thiophen-2-yl)ethanol) as reagent 2 shown in Table 7 were used to form a base. Ώ : Reagent 1 (racemic mixture) shown in Table 1 is as in Example 12, ^-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-anthracene , ΐ-bilateral oxy-1 〇-[(2,5-dimercaptocarbazol-4-yl)carbonyl]^^, hydrazine hexahydro-1λ6-喧-5,1〇·dioxadibenzo[ a, d] Cycloheptene (23) racemic isomerization separation of the racemic mixture, purified by SFC on a palm column, and the resulting stereochemical series is shown in the table. 178 200848057 Table 7·

179 200848057

180 200848057

Method Reagent 1 Reagent 2 or stereochemistry m/z (M+H)+

A (2-ethoxy-stupyl) indigo blue 446 619.72 base chlorine 364

OH

A 447 (2-ethoxy-phenyl)ethyl hydrazine 621.74 365

OH

A 213 (2-ethoxy-phenyl)ethyl hydrazine 619.65 366

DH

[2-(Trifluoro-methyloxy) A 217 phenyl]ethinyl chloride 703.74 181 200848057

182 200848057

183 200848057

184 200848057

185 200848057 No. Chemical reagent 1 Reagent 2 or stereochemistry m/z (M+H)+ 383 pH 丫 fly X 0, Ο. D 265 (S) 582.66 384 OH Yf □ 〇rF D 265 (R) 582.66 385 pH r sub-H 〇^ CJ D 340 (s) 607.69 386 pH ~C^uj D 340 (R) 607.69 186 200848057

187 200848057 No. Chemical Method Reagent 1 Reagent 2 or stereochemistry m/z (M+H)+ 391 pH / peak ί%ί D 113 (R) 673.77 392 ON; o heat. Vn D 113 (S) 673.77 393 QH /Κ华Vic) D 247 (S) 624.72 394 OH v from NH 9C D 247 (R) 624.72 188 200848057 No. Chemical reagent 1 Reagent 2 or stereochemistry m/z (M+ H)+ 395 OH cT! U 夂o = u άρ D 311 (S) 538.57 396 OH ΛΤΗ ΛΤΗ °ά D 311 (R) 538.57 397 DH /K Us D 317 (R) 620.73 398 m ΓΙ Χ Λ h T c ^ 0 EUD 317 (S) 620.73 189 200848057

190 200848057

191 200848057 No. Chemical reagent 1 Reagent 2 or stereochemistry m/z (M+H)+ 417 OH Production &lt; r D 345 (R) 633.77 418 OH v /&quot;1 ki J\ Ttt^ 〇rF w&gt; C 261 Thiophen-2-yl-nonanol 624.72 419 Household H cYlW ~Cr' 1U&gt; D 345 (S) 633.77 420 pH ) D 315 (8) 575.67 192 200848057 No. Chemical reagent 1 Reagent 2 or stereochemistry m/z (M+ H)+ 421 pH wide La, furnace $^6r Χλ D 329 (S) 637.74 422 pH 0 &amp; u , D 315 (5) 575.67 423 pH 0 1 J°&gt; ◎, person D 329 (R) 637.74 425 PH 1 / 〇° A 203 17 than cultivating carbonyl chloride 619.66 193 200848057

194 200848057

195 200848057

196 200848057

Example 44: Synthesis of Compounds (441) to (453) Compounds (441) to (453) were synthesized according to the synthesis of 11-(4-benzyloxy-2-fluoro-phenyl)-3,3-didecyl-1 , 1-di-side oxygen-2,3,4,5,10,11-hexahydro 5 -1Η-1λ -σ|-5,10-: "丫-dibenzo[a,d]cycloheptene- The method described in 6-Sf·(18) was prepared by substituting the appropriate aldehyde described below for 4-benzyloxy-2-fluoro-benzoic acid. 197 200848057 Table 8

198 200848057 No. Structure Aldehyde m/z (M+H, 445

443.509

199 200848057

200 200848057

Example 45: Synthesis of 6,6-di-side gas-2-gas hetero-6λ6-thia-spiro"3.51 decane-8-one (458)

step

Br ί ΟΗ

Br

OH

201 200848057 2,2_bis(bromopurinyl)propane-1,3-diol (25 g, 95 mmol) and potassium hydroxide (6.1 g, 92 mmol) in ethanol (250 ml) The mixture was scrambled at room temperature for 2 hours. The reaction mixture was then filtered with EtOAc (EtOAc)EtOAc. Sodium cyano (5.39 g, 1.15 eq.) was added to the previous intermediate (3-(bromomethyl) oxetane-3-yl)methanol in EtOAc (EtOAc). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give 3.8 g (yield: 31%) of the desired product of 2-(3-(hydroxymethyl) oxetane-3-yl)acetonitrile (455). Step 2

Intermediate (455) (3.8 g, 29.9 mmol), decanesulfonium chloride (6.94 mL, 90 mmol) and at -20 were placed in a 250 mL round bottom flask. (Hunig's test (24.76 ml, 149 mmol) in CH2C12 (100 ml) gave a colorless solution. The resulting solution was warmed to room temperature overnight. After that, the solution was poured into ice-cold water. The ester was extracted and the combined organic layer was dried over MgS 〇 4 and filtered over celite, then the solvent was removed under reduced pressure. The residual oil was purified by column chromatography (gradient heptane / ethyl acetate, 1 : 〇 〇·1) Yellow oil was produced. The previously obtained oil (3700 mg, 18.03 mmol) and sodium thiomethoxide in DMF (20 ml) were placed in a 100 liter round bottom flask (1895 mg, 27.0 mM) The resulting solution was heated to 65 at 202 200848057 for 3 hours. After that, the reaction mixture was filtered and evaporated to give (3-mercaptothioalkylsulfonyloxybutane-3-yl)acetonitrile (456). Used as is in the subsequent steps. Step 3

m-CPBA was added to the intermediate (456) in CH2CL2 at 〇 °c. The solution was allowed to warm to room temperature overnight. Thereafter, additional heart CPBA was added and the reaction mixture was stirred for an additional 4 hours. Next, the reaction mixture was quenched with NaHC03 solution and the product was extracted with ethyl acetate. The combined organic layers were dried over MgSCU and the solvent was removed under reduced pressure. Purification of the residue by column chromatography (gradient heptane / ethyl acetate, 1 : 0 to 0 : 1) yields (3- methanesulfonyl decyl oxetane 3-yl) acetonitrile (457) : h -NMR (400 MHz, CDC13): 4·80 (2H, d, J = 7.3 Hz); 4.52 (2H, d, 7.4 Hz); 3·61 (2H, s) ; 3·29 (2H, s) ; 3.04 (3H, s). Step 4

Potassium tert-butoxide was added to the agitated solution of intermediate (457) in anhydrous THF. After 1.5 hours, TLC analysis (CK^Cl2 / decyl alcohol 90: 10) showed complete conversion of starting material. Thereafter, water was added and the aqueous layer was gradually acidified with a concentration of HC1. The organic layer was dried over MgSO.sub.4, evaporated and evaporated. The solvent was removed under reduced pressure in combination with the fractions containing the product to give 6,6-dioxaxo-2-oxa-6λ6-thia-spiro[3.5]decane-8-one (458): !H-NMR (400 MHz, DMSO): 4.60 (2H?d, J= 6.4 Hz); 4.28 (2H, s); 4.19 (2H, d, 6·4Ηζ); 3.93 (2H, s); 3.04 (2H, s). 13C-NMR (40 MHz, DMSO): 36.6 (C); 49.1 (CH2); 55.4 (CH2); 64.8 (CH2); 78.4 (CH2); 78.4 (CH2); 195.8 (C). Example 46: Synthesis (459)

I〇 the title compound (459) is a compound (18) 11-(4-benzyloxy-2 -oxyphenyl)-6-carbyl-3,3-dimethyl-1,1-dioxy -1,2,3,4,5,11-hexahydro-1 human 6-thia-5,10-dioxadibenzo[the second-order method of the reticulated cycloheptene, using compound (458) instead of 5, 5-Dimercapto-1,1-di-oxo-tetrakis-thiopyran-3-one (5) Preparation; m/z = 509 (M+H)+. Example 47: Synthesis of (461) to (465) Compounds (461) to (465) are synthesized as 10-isobutyl decyl-11-(4-benzyllacyl-2-phenylphenyl)-6-pyridyl-3 , 3-dimercapto-1,1-di-side oxygen 204 15 200848057 -1,2,3,4,5,11_hexahydro_;^6_thia_5,1〇-dioxadibenzo[ Fl, anthraquinone (2l), as described in u_[Winter (2_5 bromo-phenoxy)_2-fluoro-phenyl]_3,3_didecyl-1,1-di- oxydibenzo [a,d]cycloheptene alcohol (207) and decyl chloride shown in the table below substituted 11-(4-octyloxyfluorophenyl)-6-hydroxy-3,3-dimercapto-l, L-Two-sided oxygen-1,2,3,4,5,11-hexahydro_1516_thia_5,1〇-dioxadibenzo[^, Cycloheptene (18) and Isobutylphosphonium chloride Start preparation. Table 9· No. Structure Stearic Chlorine m/z (M+H)+ 461 — —*-- OH | 6NtX Λ 2-Fluorobenzoquinone Chloride 682 462 3d ~---- 6-Methyl-pyridine- 2-carbonyl chloride 679 205 200848057

Example 48: Synthesis of 5-mercapto-U-dihydro-5-vinyl-tetrahydro-indol-3-one (466)

206 200848057 The title compound (466) is based on the third-order method described in the synthesis of compound (280). 2-2-ethyl-2-indenyl-epoxy substituted with 2-methyl-2-ethylidene-3⁄4 oxyethane Preparation of ethane. 5 Example 49: Synthesis of 11-(4-fluorenyl-2-fluoro-methyl K3-methyl-U-bilateral gas-3-vinyl-2,3,4,5,10,11-six Hydrogen-111-:^6-thia-5,10-diindole-dimosyl"a, dl-cycloheptene-6-ol (467)

The title compound (467) is synthesized according to the synthesis of 11-(4-benzyloxy-2-fluorophenyl)_6_1〇hydroxy-3,3-dimercapto-1,1-di-sideoxy-1,2,3. a second-order method of 4,5,11-hexahydro-1λ6-thia-5,10-dioxadibenzo[aj]cycloheptene (18), using compound (466) in place of 5,5-dimercapto- Preparation of 1,1-di-oxo-tetrahydro-indol-3-one (5); m/z = 507 (M+H)+. 15 Implementation &gt; Example 50: Synthesis of 1,1-di{ then oxy-tetrahydro-oroxan-3-g with (470) 207 200848057

4 m Preparation of methyl 4-(methylthio)butanoate (468) (27.62 g, 186 mmol) in chloroform. m-cPBA (84 g, 2 eq.) was added portionwise at 0 °C. After 4 hours, a saturated NaHCO 3 solution was added, followed by a portionwise addition of solid sodium hydrogencarbonate salt until no gas evolution was observed. The reaction mixture was then extracted with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. A colorless oil of ester (469). Step 2

10 4m 470 Compound (469) (1.5 g, 8.32 mmol). After 1.5 hours, 5NHC1 was added until a milky white solution was obtained. Dioxide 208 200848057 was subsequently added and the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (solvent: CH.sub.2Cl. Example 51: Synthesis of 11-(4-benzylidene-2-fluoro-phenyl VU-bilateral gas 5-2, 4,5,10,11-hexahydro-111-1 human 6-indole-5, 10_二吖-二茉和"3,(1~]cyclodecene-6-ol (471)

The title compound (471) is synthesized according to the synthesis of 11-(4-benzyloxy-2-fluorophenyl)-6-1〇hydroxy-3,3-dimercapto-1,1-di-sideoxy-1,2. a 2nd-order method of 3,4,5,11-hexahydro-1λ6-thia-5,10-dioxadibenzo[], using compound (470) instead of 5,5-di Preparation of keto-1,1-di-oxo-tetrahydro-thiopyran-3-one (5); w/z = 467 (M+H)+. 15 Example 52: Synthesis of aldehyde The aldehyde of Example 52 was synthesized by nucleophilic displacement of a phenol derivative in the presence of a base with a suitable halide derivative, as described for the synthesis of aldehyde (11). 209 200848057 Table ίο

210 200848057

211 200848057 The synthesis of m-difluoromethylbenzene is carried out according to the method of Journal Fif FiUQfine Chemistry (2004), 125(4), 595-601. Rain: Undebted. Steam application example 53_: a representative method·synthesis of 4-(2-bromo-phenoxy)V2 legacy_benzidine

2-bromophenol (5.57 g '32.2 mmol) was added to a solution of DMF with cesium carbonate (11.31 g 'u equivalent) and 2_gas _4-fluorobenzaldehyde (4 96 g, ίο 31.3 mmol) . The reaction mixture was stirred at 75 for 16 h then cooled to rt. The organic layer was washed with EtOAc (EtOAc m. 15 Example 54: Synthetic acid: _ The following aldehydes were synthesized according to the procedure of Example 53 using the appropriate haloaryl or haloheteroaryl derivatives and substituted. 212 200848057 Table 11

213 200848057 Aldehyde halo-derivatives 1------ Phenol yield m/z (M+H)+ 6 Br Of Ο oiT ΒΚό 67% 317 ο F hA6CQ ftS -— OH BrsrS 25% 314 T Br F -------1 The synthesis of 4,5-dichloro-indolylfurfural is carried out according to the method of j. pmkt chemie 1964, 4, 24, p38. 3: Example 55 · Selection of baskets, friends, gilt, glutinous glutenyl 2, fluoromethyl

A solution of benzyl alcohol (619 mg, 5.73 mmol) in DMF (4 mL) was added EtOAc (EtOAc, EtOAc, EtOAc) After 15 minutes, 4-fluoro-2-trifluoromethylbenzaldehyde was added, and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSCU, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (solvent: gradient of CH2C12 in heptane: 〇: 100 to 100: 0) to yield the target aldehyde, yield 20%; w/z = 281 (M) +H)+. 214 200848057 Example 56: Synthesis of aldehyde The following aldehyde was synthesized according to the procedure of Example 55 using the appropriate haloaryl or haloheteroaryl derivative and phenylmethanol.

Example 57: Representative method: Synthesis of 2-fluoro-4-((15)-1-phenyl-ethoxy)benzaldehyde

OH 10 2-fluoro-4-hydroxybenzaldehyde (250 mg, 1.4 equivalents), (R)-(+)-phenyl-ethanol (156 mg, 1.274 mmol) and triphenylphosphine (468 mg, L4) A mixture of the equivalents in dry THF was added DIAD (361 mg, 1.4 eq.) under N2. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj The standard aldehyde. Fluorine-4-f 唼 color

The tray of the 5 j ticket was substituted with (R)-(m-based ethanol) using a porphin-3-yl-methanol instead of the representative method disclosed in Example 57. The product was synthesized as a pale yellow liquid at the oxime yield.

10 standard aldehydes are substituted according to the method disclosed in the synthesis of 2-fluoro-4-((lS)-l-phenylethoxybenzaldehyde, using 3, fluorinated difluorobenzyl alcohol to replace (RM+)-phenylethanol , synthesized as a white solid at 25% yield. Synthesis of 4-hydrazine-hydrogen-2-iso-m-formaldehyde

15 4-benzyloxy-1-bromo-2-isopropyl-benzene (56.5 g, 185.12 mmol, synthesized as described in WO 98/34919 PCT/IB98/001 12) at 216 200848057 anhydrous THF (400 ml) The solution was applied in 10 ml portions of /i-BuLi (n-butyllithium; 135 ml, 1.6 hexane in hexane) at -78 °C for several minutes under N2. The reaction mixture was then stirred at -78 °C for 30 min and anhydrous DMF (2·6 mL, 1.55 eq. After 20 minutes at -78 ° C, the reaction mixture was quenched by the addition of 1 EtOAc (200 mL). Water (100 ml) was added and divided into two layers. The aqueous layer was extracted with diethyl ether. EtOAc (EtOAc)EtOAc. Purification by flash chromatography on a silica gel (solvent: CH2C12 in heptane in a gradient of 1:9 to 10:0) yielded a pale yellow liquid of 28 g (60% yield) of the desired product; w/z = 255 (M+H)+. Example 61: Synthesis of 4-benzyloxy-2-fluoro-5-methoxy-benzoquinal

15 5-fluoro-2-indolyl-phenol (5 g, 35·18 mmol), benzyl bromide 217 200848057 (6.1 g, 1.01 equivalent) and K2C〇3 (6.3 g, 1· A mixture of 3 equivalents in ethanol was stirred at 50 ° C for 17 hours. The reaction mixture was filtered and concentrated to dryness afforded </RTI> </RTI> </RTI> </RTI> Step 2

A solution of 2-benzyloxy-4-fluoro-1-methoxy-benzene (4.8 g, 20.67 mmol) in acetonitrile (100 mL). 1 bromosuccinimide (4.05 g, 1.1 eq) was added under the arm. The ice bath was removed and the reaction mixture was stirred at room temperature over 16 h. The reaction mixture was concentrated and the residue was filtered over EtOAc EtOAc EtOAc EtOAc EtOAc a white solid of phenyl group; m/z = 3 11 (Μ+Η)+. Step 3

The title product 4-benzyloxy-2-fluoro-5-methoxy-benzaldehyde was prepared according to the method of Example 47 using benzyloxy_4_bromo-5-fluoromethyl 218 200848057 oxy-substituted 4 - +oxy-l-bromo-2-isopropylbenzene was synthesized in 9% yield; w/z = 261 (M+H)+. 62 per compound: Synthesis of 4 2^1^2-cyclopropyl-phenylfurfural

4-benzyloxy-2-hydroxy-phenylfurfural (2.4 g, 1 〇·53 mmol), hydrazine, hydrazine bis (tris-fluorononylsulfonyl) aniline (3.95 g, 1〇5 equivalent) and a mixture of K2C03 (4.3 65 g, 3 equivalents) in anhydrous THf (1.5 ml) in a microwave oven at 12 (rc stirred for 12 minutes. After cooling to room temperature, the reaction mixture is CH^Cl2 Dilution, washing with water, followed by 1N NaOH solution followed by brine, dried over MgSO 4 , filtered and concentrated to give 3.77 g (99% yield) of the desired product trifluoro-methanesulfonic acid 5-benzyloxy-2 - mercapto-phenyl ester, which was used in the next step without further purification; w/z two 361. 219 200848057 step 2

5-Benzyloxy-2-carboxyl-phenyl ester of trifluoro-methionine (2.25 g, 6.245 mmol), KF (1.524 g, 4.2 eq.), KBr (743 mg, 1 eq.) , a mixture of tetrakis(triphenylphosphine)palladium (361 mg, 〇·〇 5 equivalents) and cyclopropyl S-p-acid (1 g, 1.86 eq.) in toluene - degassed in a microwave oven by nitrogen bubbles The 120QC was stirred for 15 minutes. After cooling to room temperature, the reaction mixture was diluted with CH.sub.2 C.sub.sub.sub.sub. ;= 253 (M+H)+ 〇...·0 : Synthetic JdU^A-2-phenyl-B)-2_ϋ -Sheep

step 1

4-Bromo-3-fluorobenzyl acid (5·6 g, 25.6 mmol) was refluxed in sulfinium chloride 200848057 (50 liters of stomach) for 2 hours. The reaction mixture was then concentrated under reduced pressure to give 4-bromo-3-fluorophenylindole (6·7 g, maximum yield) of oil, which was used directly in the next step. 4-bromo-3-fluorophenylhydrazine chloride (6 〇 7 g, 25·6 mmol), benzyl bromide (4.81 g 'u equivalent), zinc 34 g, 14 equivalent) and (PPh3)2PdCl2 ( 〇·9 g, 〇·〇5 eq.) A mixture of 〇μΕ (dimethoxy ethane, 55 liters) was stirred at room temperature for 2 hours. The reaction mixture was then filtered over celite, and then purified on silica gel and purified by flash chromatography (solvent: heptane / CH2Cl2 10 75 · 25) yielding 4.18 g (56%) of desired product 1(4-Bromo-3-fluoro-phenyl)-2-phenyl-ethanone. Step 2

Acetic acid

:elic a〇4BF3-〇fE% ----- SHGI-^CH^SH, DCM

15 1-(4-Bromo-3-fluoro-phenyl)_2-phenyl-ethanone (4 18 g, 1426 mmol), ethane-1,2-dithiol (2·69 g, 2 Equivalent), a mixture of trifluoro, boron etherate (2. 2 g, 1 eq.) and acetic acid (1.71 g, 2 eq.) in CH.sub.2 C. After 1 h, more boron difluoride etherate (05 eq.) was added and the mixture was stirred at room temperature overnight. Following dilution with CH2C12, the saturated NaHC(R) 3 solution was carefully added with vigorous stirring. The organic layer was then washed with a 15% NaOH solution then brine, dried over MgSO 4 , filtered and concentrated to yield 3.86 g (73%) of desired product 2 benzyl </ br </ br </ br Fluorine·Phenyl)-[1,3]dithiapentane. Step 3 10 Step 4

In CH2C12 (15 ml) 丨·Iopyrrolidine-2,5_dioxin (9·41 g, 41·8 mmol) in ——3 (TCkN2 carefully added pyridine hydrofluoride (10 ml) Then, 2_千基-2-(4-bromo-3-fluoro-phenyl)-[1,3]dithiapentane ring (3·86 g, 1〇.45 pen) was added to the mixture. a solution of CH2C12 (20 liters). The reaction mixture was stirred for 2 hours, then diluted with CH^Cl2, filtered over basic alumina to saturate NaHC03 solution, followed by 1% / Washed with MgSO4, filtered and concentrated, purified by flash chromatography to yield of EtOAc (EtOAc) It cures when placed 0

0-ByU, DMF THFT -78°C

The title product 4-(1,difluoro-2-phenyl-ethyl)-2-fluoro-benzaldehyde is prepared according to the method used for the preparation of 4-hydroxy-2-isopropyl-benzoquinone 1 - &gt; Stinky 4-(1,1-difluoro-2-phenyl-ethyl)-2_fluorobenzene (1.21 g '3·84 house Wuer) replaces 4-+oxy-1_ _2-isopropylbenzene 222 15 200848057 A colorless oil of 80% yield was obtained which solidified upon standing. Synthesis of Compounds 510, 547-569 and 571-573, ^21^176 and 583-... Compounds 510, 547_569 and 571-573, 575, 576 and 583_585 are according to the method shown in Table 7, from 2, 3, 4, 5,10,11_hexahydro-1-thia-5,l-difluorene-dibenzo[a,d]cycloheptene 4,^dioxide derivative (reagent 1) and the following table Prepared according to reagent 2 used as appropriate. ^ &gt;ir A · The reagent 1 shown in the table is synthesized according to the synthesis of 10-isobutyl decyl-11-(4-octyloxy-2-fluorophenylhydroxy-3,3-dimethyl), -1,2,3,4,5,11 - hexahydro-1 hexa-6- thia _5,1 〇 吖 吖 dibenzo[^, (1) % heptane (21) method, used The sulfhydryl group shown in Table 7 was substituted with Xing Ding & gas. Method B: The reagent 1 shown in the table was synthesized according to [11-(4-allyloxy 1 gas-phenyl)- 6_hydroxy_3,3_dimercapto_u_di-oxo-1,2,3,4,5,11-hexahydro_1λ6_thia_5,1〇_diindole-dibenzo[a , d] cycloheptyl-10-yl]-(2,5-dimethylcarbazole-cardiacyl)-methanone (263), from 6-(2,5-didecyl-hydrazine Azole_4_carbonyl)-7-(2-fluoro-cardiacyl-phenyl)-ΐο, ι〇-di-T-group _8,8_di-side oxygen_6,7,8,9,10,u_ 223 200848057 Hexahydro-2-oxa- 8λ6-thia-6,1 lb-di-n-dibenzo[cd,h]-anthracycline-1-one (261) and the appropriate alkylation as reagent 2 shown in Table 7. The reagent is started and calcined. 5 Method C ·· The reagent 1 shown in the table is synthesized according to (2,5-dimercapto-oxazol-4-yl)-{11-[2-fluoro- 4· (2-σ-cephen-2-yl-ethoxy )-Phenyl]-6-trans-yl-3,3-dimercapto-1,1-di-oxo-l,2,3,4,5,ll-hexahydro-1λ6-thia-5,10_ Di-dibenzo[a,d]cycloheptene-1〇-yl}-methanone (272) Recorded by 6-(2,5-dimethylisoxazole-4-carbonyl) -7-(2-fluoro-4-hydroxy-phenyl)-10,10-dimethyl-8,8-di-oxo-6,7,8,9,10,11-hexahydro-2-oxa -8λ6-thia-6,1 lb-di-p-dibenzo[cd,h]-anilancyclo-1-one (261) and the appropriate alcohol as reagent 2 shown in Table 7 (substituted 2_(喧-phen-2-yl) Ethanol) starts and is alkylated. 15 Method D: Reagent 1 (racemic mixture) of Table 1 is as in Example 12, 11-(4-decyloxy-2-fluorophenyl)_6-hydroxyl 3,3_dimercapto'-T-based 吟U--4-yl)-based group]-1,2,3,4,5,11-hexahydro_1'0 plug_5,1()_two &lt;Dibenzo[^,(1)cyclo[(10) racemic mixture of the image isomerization separation, purified by hand 1^5 column' and the obtained stereochemical series are shown in Table 13 〇224 20 200848057 13

225 200848057

226 200848057

227 200848057

228 200848057

229 200848057

230 200848057

231 200848057

232 200848057

233 200848057

234 200848057

Example 65: Synthesis of 1142,3-difluoro-4彳2-methyl-allyl-yl-methyl-l,3-dimethyl-1,1-di-side gas-2,3,4, 5,1(U1-hexa-IH-Ιλ6-thia-5,10-diindole-dimo-and-a, dl-cycloheptene-6-ol (570) 235 200848057

(§70) Step 1: Synthesis of 2,3-difluoro-4-(2-.nonylallyloxy)benzialdehyde

The title product 2,3-difluoro-4-(2-methylallyloxy)benzoquinal is a method for preparing the intermediate (11) from 2,3-difluoro-4-hydroxybenzene. Furfural and 3-chloro-2-mercaptopropene were synthesized at maximum yield; m/z = 213 (M+H)+. % Step 2: The title product (570) is prepared according to the description of 11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-U-di-side oxygen_1,2 ,3,4,5,11-hexahydroίο -1λ6-thia-5,10-dioxadibenzo[-), from 2,3-difluoro-4-(2) Synthesis of - mercaptopropyl-oxy)benzaldehyde and intermediate (16): m/z = 477 (M+H)+. Example 66: Synthesis of difluoro-4-(2-mercaptopropyloxy) molybdenum 236 200848057 base·^A-based dihydrogen_m4丄n_hexa-heptane bridge-ίο- a U2,5-two Methyl zi--4-yl)methanone M74,

OH

The title compound (574) was prepared according to the description of i...isobutyl fluorenyl_n_(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl], ι_di-side oxy-1 3,4,5,11-hexahydro-1 human 6-indole-5,10-dioxadibenzo[by]cycloheptene (21), from compound (570) and 2,5-dimethyl Preparation of carbazole _4_carbonyl chloride: w/z = 600 (M+H)+ 〇10 旌 Example β7: Synthesis (6) Main group 1-6_ residue-3,3-dimethyl-14^ ^Oxygen _1234511^^::1λ6_ 喽-5,10-dibenzodibenzo"a, dl ̄ heptyl | Γ2·5 m) ketone) benzene 11:6-hydroxy-·3;曱-基_ _ 12 丄4· 5 ιΐ入-口基:·5,10-一口丫-,本_ί幵fa,d]友庚稀_ι 芊} Γ2 5--曱美咩azole-4 -based) ketone [577) 237 15 200848057

The title compounds (578) and (577) were prepared according to Example 12 (and) _11_(4·benzyloxy-2-fluorophenyl&gt;6-hydroxy-3yidinyl-i,l - two sides,-10-[(2,5-didecyloxazol-4-yl)-carbonyl]-1,2,3,4,5,11-hexa-5hydro-1λ6•thiophene-5,1 〇_Di-dibenzo[aj]cycloheptene (26) and 〇S&gt;ii_(4-benzyl

Oxy-2-fluorophenyl)-6-hydroxy-3,3-dimercapto-1,1-di-oxo-i〇-[(2,5-dimercapto-salt-4-yl)carbonyl ]-1,2,3,4,5,11-hexahydro-1 human 6-indole-5,10-dioxadibenzo-[chemically-cycloheptene (27), from compound (574) Preparation: (577) m/z = 600 (M+H) + ; (578) ; m/z = 600 (M+H) + ; Rt = in 4.34 min ; lR NMR (400 MHz, DMSO-J6) δ Ppm NMR ^ (400 MHz, DMSO 〇 δ ppm 1.14 (s5 3H), 1.22 (s, 3 H), 1.70 (s, 3H), 2.12 (s, 3H), 2.21 (s, 3H), 2·78 ( d,16.0 Hz, 1H)5 2.83 (d,16·0 Hz,1H),3·20-3·13 (m,2 H),4·45 (s, 2H),4·93 (m,1H ) 4·98 (m,1H),5·84 (d,7.8 Hz,1H), 15 6.45 (t,J 2·7·8 Hz, 1 H), 6.55 (d, J 2 7.8 Hz, 1H), 6.60 (m, 1H), 6.74 (m, 1H), 7·48 (s, 1H), 7.75 (s, 1H), 10.21 (bs, 1H); measured on SFC using an ADH column at 20% MeOH Rt: 1.68 minutes. 238 200848057 (4) Example 6..8:&quot;_合-坐mni_"2_i 土(2,f- allylmethyl-7S surname hydrogen^1,21441_1 -friend ργ_二茉兔趣二10_基[曱酮(38j^j^jgj^

10 Step 1: Synthesis of 11 -[2_5fluoro_4_(2-mercaptopropyloxy)phenyl]_3,3_-methyl-1,1_di-oxo-2,3,4,5,10, 11_hexahydro_1//-1 into 6_thia-5,10-dibenzo-benzo[a,d]cycloheptene-6-ol (579) and 1]2-fluoro-4-(2 -mercaptopropyloxy 6)-phenyl]-3,3-dimercapto-1,1-di-side oxygen-2,3,4,5,1〇,11_hexahydroiH-U』塞5,1〇_Dioxadibenzo[a,d]cycloheptenyl (58〇)

OH

m

(5i〇) 239 200848057 The title compounds (579) and (580) were prepared as described in Example 5 for the preparation of 11-(4-dodecyl-2-fluorophenyl)-6-carbyl-3,3- Dimethyl-l,i-di-oxo-1,2,3,4,5,11-hexa-1-6-thia-5,10-dioxadibenzo-, ^|cycloheptene 18) and 1+oxy-2_fluorophenyl)-9-predomyl-3,3-dimercapto-1,1_di-side oxygen 1,2,3,4,5,11-hexahydro- 1 person 6-mouth plug-5,10-di-dibenzoquinone [(3,(^)cycloheptyl (19) method from 2-fluoro-4-(2-methylallyloxy) ) benzaldehyde and compound (16) and ("mixture of hydrazine. 10 step 2: synthesis of 11-[2-fluoro-4-(2-mercaptopropyloxy) phenyl]_8,8-dimethyl Base-10,10-di-side oxygen-6,7,8,9,10,11-hexahydro-2_oxa'10 into 6-喧_6,113-di&lt;dibenzo[.(^] Chamomile ring-1-嗣(581) and 7-[2-敦冰(2-mercaptopropyloxy)phenyl]-10,10-dimethyl-8,8-di-side oxygen 6'7' 8,9,1〇,11-hexanitro-2-lacto-8-hydroxyl-6,1113-di-dibenzopyrene [(^,}1] chamomile ring-1-ketone (582)

CDI (1.5 eq.) was added to the compound (579) and (58 〇) in the DMF to disturb the turbid liquor. After 45 minutes at room temperature, the reaction mixture was passed on the ground soil and then stopped in water. The resulting solution was filled under reduced pressure and diluted with water at 240 15 200848057. The resulting solid was collected by filtration. Purification by column chromatography (CH2C12) yielded the desired product: (581); m/z = 485 (Μ + H)+, (582); m/z - 485 (Μ + Η) + ; lU NMR (400 ΜΗζ5 DMSO-^) δ ppm 1·21 (s,3Η),1·24 (s,3 Η),1·70 (s,3Η),2·79 (d,&gt; 17·7 Ηζ, 5 1 Η),3·41 (d,13·5 Ηζ,1 Η),3·52 (d,/= 17·7 Ηζ,1 Η), 3.55 (d5 13.5 Ηζ? 1 Η)? 4.40 (s5 2 Η ) 4.91 (m? 1Η) 4.99 (m5 1 Η), 5·59 (d, 6·0 Ηζ, 1 Η), 6·54-6·66 (m, 3 Η), 6·78 (dd, 2.5 , 12.9 Ηζ,1 Η),6·88 (t,J 2·8 Ηζ,1 Η),6·93 (d, / 2 6.00 Ηζ, 1 Η), 7·07 (t, 9· 0 Ηζ,1 Η) ; 13C NMR (101 ίο ΜΗζ, DMSO j6) δ· ppm 19·1 (CH3), 25·1 (CH3), 29·7 (CH3), 31·8 (C), 39· 2 15 (CH2),48·7 (CH),58·4 (CH2),71.2 (CH2), 100·1 (CH),102.8 (CH,d,/= 25.6 Hz),110.1 (CH),112 ·5 (CH), 112·7 (CH2), 115·4 (C), 118.0 (C, d, J = 13.2 Hz), 124.5 (CH), 125.9 (C), 128·7 (CH), 135 · 4 (C), 140.4 (C), 15 141.6 (C)? 142.2 (C) 5 150.3 (C) 5 159.2 (C? d, J = 11.7 Hz) 5 16 0.7 (C, d, 247.4 Hz). Step 3: Synthesis of 1-fluoro-4-(2-mercaptopropyloxy)phenyl]-3,3-dimercapto-1,1. di-oxo, 2,3,4,5,10, 11_hexahydro-1 ugly-1 person 6-prepared 5,10-dioxime 20 a stupid [a,d]cycloheptan-6-ol (579) 241 200848057

An aqueous solution of Ll〇H (51.7 mmol) was added to a mixture of compound (582) (8·35 g, 17.2 mmol) in THF (2 mL) and methanol (5 mL). After 3 minutes at room temperature, the pH of the resulting solution was adjusted to 6 with 2M HCl. The reaction mixture was concentrated under reduced pressure. The sediment formed by the collection was filtered, and then dried to give a white powder of title product (579). The maximum yield: m/z = 459 (M+H)+. Step 4: Synthesis of (6)-(2,5-dimercaptosylazole)-{ll-[2-fluoro+(2-10-methyl-allyloxy)phenyl]-6-hydroxy-3, 3-dimercapto-1,1-di-oxo-1'2'3'4,5,11-hexanitro-indenyl-laminyl-5,10------a copy of [a,d环庚少希-10-基}-methanone (383)

242 200848057 The title product (383) was prepared from compound (579) according to the method described in Table 7: m/z 582.66 (M + H) + ; 4 NMR (400 MHz, DMS 〇〇 δ ppm 1·14 ( s,3H),1·22 (s,3 Η),1·69 (s,3H), 2·12 (s,3H),2·18 (s,3H),2.76 (d,16·0 Hz , 1 H), 2.83 (d, 5 16·〇Hz, 1 H), 3·10_3·19 (m, 2 H), 4.36 (s, 2H), 4.90 (m5 1H) 4·97 (m, 1 H), 5.80 (d5 7·8 Hz, 1 H), 6.41 (t, 7.8

Hz,1 H),6·47-6·57 (m,2 H),6·68 (dd,J 2 12.4, 2.2 Hz, 1 H), 6·76 (t, 8.8 Hz, 1 H), 7.44 (s, 1 H), 7·67 (s, 1 H), 10.15 (bs, 1 H). 13C NMR (101 MHz, DMSO 〇 δ · ppm 10.6 i 〇 (CH3), 13·1 (CH3), 19·1 (CH3), 28.1 (CH3), 29·0 (CH3), 32.0 (C), 42.3 (CH2), 49.2 (CH), 61.3 (CH2), 71.1 (CH2), 101.8 (CH, d, 24.9 Hz), 104.6 (C), 109·7 (CH), 112.6 (CH2), 112.9 (CH) 118.8 (C9 d, J = 14.6 Hz), 119.5 (CH) 5 122.2 (CH) 5 125.6 (C) 5 130.1 (C) 5 130.8 (CH? d, J = 5.1 Hz) 5 131.1 15 (C), 140.4 (C), 146.2 (C), 147.1 (C), 150.0 (C), 157·5 (C), 159.0 (C? 11.0 Hz)? 159.9 (C5 d5 J- 247.4 Hz)? 160.3 (C). Synthesis of (2,5-dimercapto-oxazolfluoro-4-hydroxy-20methyl)-6-hydroxy-3,3-diindenyl 2-oxo-1 and 3,5-11- Hexahydro-1λ6-嚓-5,10-dioxazol and 1^,41 cycloheptane 2〇〇_一1_methanone (528) 243 200848057

6-(2,5-Dimethyl-carbazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)-10,10-dimercapto-8,8-di-side oxygen_ 6,7,8,9,10,11-hexahydro-2-oxo

A solution of -8λ6-thia-6,llb-dibenzodibenzo[cd,li]chamomile ketone (261) in THF was treated with aqueous LiOH (5 eq.). After 1 hour at room temperature, the pH of the reaction mixture was adjusted to 6 with HCl. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried (NajCU) and then evaporated. Residues borrowed from the column chromatography pure domain line question money (10)) from the color: m / zmB + H) +.

(S42) F 244 200848057 The title product (542) is prepared according to the description of the preparation of 丨 ( (4-n-butyloxy-2-fluorophenyl)-6-carboxy-3,3-dimethyl mountain two side oxygen mw- Hexahydro-1λ6-prepared 5,10-dioxadibenzo &amp; cyclohexene heptene (18), from intermediate (16) and 4H (2-fluorophenoxy) stupaldehyde synthesis: m/z = 499 (M + H)+.罝 气 气 气 硫 2- 2- 2- 2- 2- 2- 2- 2- : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : NH AS H-CI (543)

EtOH

MaOH water Thiourea (164.85 g &apos; 1 equivalent) was added to a suspension of 2,3-dichloropropene (240 32 g, 2.17 mol) in ethanol (1.2 L). The reaction mixture 15 was heated to reflux for 12 hours and then cooled to room temperature. A solution of NaOH in water (650 ml) was added dropwise. The reaction mixture was then heated at $/5 hours and then cooled to room temperature over 78 hours. The 彳3 _7()C is separated from the water layer. The pH of the aqueous layer was acidified with HAO4 (~75 mL), and the flooded solution was extracted with diethyl ether. The ether portion was formed with the previously obtained brown oil. The organic portion was dried (NajO4) and used as it is in the synthesis: Continuation 245 245 20 200848057 Step 2 α

HS Ίί (S44&gt; /Cl OH (3) decyl alcohol (1.5 L) was added to the fraction obtained in step 1 containing the fraction (544). Thereafter, sodium decoxide (43 g, 0.8 mol) was added in portions at Ot: After 1 hour, 2,2-didecyloxirane (60 g, 0.8 mol) was slowly added at 〇 ° C. The resulting solution was stirred at room temperature for 12 hours. Thereafter, the pH of the reaction mixture was diluted with HC1. (0.5 N aqueous solution) was adjusted to 7. The organic layer was separated successively, washed with water and brine and dried (Na.sub.2SO.sub.sub.).

246 200848057

Example 72: Compound of formula (T) Primary. Replicon detection The inhibitory activity of the compound of formula (1) on HCV RNA replication was examined in a cell assay. The test demonstrates that the compound of formula (I) inhibits the HCV functional cell replication cell line, also known as the HCV replicon. Cell detection is based on a bicistronic expression structure as described by Lohmann et al. (1999) Science ν〇ΐ 285 pp. 110-113 as described in Krieger et al. (2001) Journal of Virology 75: 4614-4624. Modify the multi-standard screening strategy. Basically, the method is as follows: The detection uses a stably transfected cell line Huh_71uc/ne〇 (hereinafter referred to as Huh-Luc). This cell line possesses an RNA encoding a bicistronic expressional structure containing the wild type NS3-NS5B region of lb-type HCV transduced by the internal ribose 247 200848057 body entry site (IRES). The gene portion (FfL-luciferase) and the selectable marker portion (neoR, neomycin phosphotransferase) are then reported. The structure is separated from the first-type HCV by 5, and 3, NTR (untranslated regions). The continuous culture of replicon cells in the presence of G418 (ne〇R) 5 depends on the replication of HCV RNA. Antiviral compounds are screened using stably transfected replicon cells that express HCV RNA encoding the luciferase (especially autonomously and highly replicated). Replicon cells were seeded in 384-well plates containing assay and control compounds added at increasing concentrations. After three days of incubation, by detecting luciferase ίο activity (using standard luciferase to detect receptors and reagents and perkin Elmer)

ViewLuxTMultraHTS microplate imager) measures Hcv complexes. Replicon cells in control cultures have high luciferase performance in the absence of any inhibitor. The inhibitory activity of the compounds was detected on Huh-Luc cells to obtain a dose-response curve for each compound. A 15% EC value is then calculated, which is the amount required for the compound to reduce the level of luciferase activity (or more specifically, the ability of HCV to replicate in RNA replication) by 5%. Enzyme detection 2〇a) Protein purification The cDNA encoding NS5B amino acid 1-570 (HC-J4, genotype lb, pCV_J4L6S, gene bank accession number AF054247) was sub-selected to NHE I and Xho I of pET-21 b Limit the site. Subsequent expression of the His-tagged iron c_terminal 21 amino acid-deficient NS5B was carried out as follows: 248 200848057 The NS5B expression structure was transferred to five (7)// BL21 (DE3) (Novagen, Madison'WI). Five milliliters supplemented with amin penicillin (5〇盹尬) (3) culture / base j weight - a colony. When the preculture was measured to reach 光学6 optical density at 600 nm, it was transferred to a freshly supplemented ampicillin lb 5 ^ ίί ratio of 1:200. The cells were grown to 0.6 light 4* L degrees at 000 nm after induction with isopropyl-1-thio-β-D-galactopyranoside and MgCl2 at a final concentration of mM and 1 〇μΜ, respectively. Performance culture $ switch to growth temperature 2 (TC. After ten hours of induction, by centrifugation and resuspension in 20 mM Tris-HCl, pH 7.5, 300 mM NaQ, 10% glycerol,

Ίο 〇·1%ΝΡ40,4mMMgCl2,5 mMDTT was supplemented with EDTA wangwang white inhibitor (Roche, Basel, Switzerland) to collect cells. The cell suspension was disrupted by ultrasonic vibration and incubated for 15 minutes at 15 mg/L DNase I (Roche, Basel, Switzerland). The cell debris was removed by centrifugation at 30,000 xg for 1 hour, and the clarified cell lysate was snap frozen and stored at -80 °C until purification.

The clarified cell lysate was thawed and then placed on a 5 ml pre-filled HisTrap FF column equilibrated with 25 mM HEPES, pH 7.5, 500 mM NaQ, 10% glycerol and 5 mM DTT. The protein was eluted with 500 mM imidazole at a flow rate of 1 ml/min. The 20 fraction containing the desired protein was applied to a prefilled 26/10 HiPrep desalting column equilibrated with 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol and 5 mM DTT. The buffer exchanged NS5B peaks were then applied to a 20 ml Poly-U Sepharose column. The protein was eluted with an increasing salt gradient and the fractions were collected. Protein purity was assessed on a Nu_PAGE precast gel (Invitrogen, Carlsbad, CA) 249 200848057. Purified NS5B samples were concentrated using a Centri-Prep concentrator (Millipore, Billerica, MA, USA) and the protein concentration was determined by Bradford assay (Pierce, Rockford, IL, USA). 5 b) Protein sequence PDB: lnb4, Apo type. The protein sequence is described in WO 2007/026024. The molecular properties of the calculation: 64941.4 g / m. c) Inhibition assay The measurement of the polymerization activity of HCV NS5B was carried out by evaluating the amount of radiolabeled GTP incorporated by enzyme in the newly synthesized RNA using the heteropolymer RNA template/introduction. RdRp assay is used in 384-well plates for 25 mM Tris-HC1, pH 7.5, 5 mM MgCl2, 25 mM Κα, 17 mM NaCl 15 and 50 mM enzyme in 3 mM DTT, 300 nM 5,-biotin Oligomeric (rG13)/poly(rC) primer-template, 600 nM GTP and 0·1 pCi [3H]GTP &quot; The test compound was dissolved in DMSO. The test compound was added to a preformed polymerase template complex and incubated at room temperature for 15 minutes, after which NTP was added. After 2 hours at 25 ° C, the 30 μΐ reaction was terminated with the addition of 30 μM of streptavidin 20 avidin-coated SPA beads (GE Heathcare, Uppsala, Sweden 5 mg/ml in 0·5 M EDTA). At 25. (: After 30 minutes of incubation, the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 minute count delay) and the ICso value was calculated. The IC5G value represents the concentration of the compound that reduces the amount of RNA produced by 50%. The resulting rna 250 200848057 was measured by detecting the incorporated radiolabeled GTP. Table 14 below lists the activity of the compounds prepared according to any of the above examples in the detection of replicon (EC50) and enzyme (IC50). 5 Table 14 No. 50: 50 (μΜ) Ε05〇 (μΜ) 7 2.7267 8.6449 10 0.0708 4.4862 13 0.0199 0.2688 14 0.0410 4.5334 15 0.0639 0.2518 17 0.0813 0.0638 18 0.0893 0.0255 19 0.0459 0.0989 20 0.0803 0.0523 21 4.0835 1.5740 22 0.1117 0.0129 23 0.1016 2.3608 28 0.0643 0.2493 29 0.2740 4.3868 30 0.6919 2.0221 31 0.3600 2.8544 32 1.2995 &gt;32.00 251 200848057 No. IC50(pM) Ε(:50(μΜ) 33 0.2718 11.0370 34 0.2403 3.4514 35 1.7266 36 0.0648 1.5438 37 0.0752 0.1366 38 0.0686 0.9096 39 0.1164 0.0602 40 0.0887 0.0314 41 0.0960 0.1951 42 0.1052 0.2544 43 0.1786 0.0505 44 0.2502 0.4443 45 0.0905 0.0630 46 0.1964 4.8546 47 0.3836 0.2135 48 0.3113 1.3770 49 0.0804 0.6593 50 0.1534 2.2123 51 0.1392 .&gt;32.00 52 0.1225 0.8147 53 0.0418 0.0625 54 0.0572 1.2510 252 200848057 No. Ι〇50(μΜ) Ε〇5〇(μΜ) 55 0.1117 0.0588 56 0.0373 0.1000 57 0.0497 0.2271 58 0.1093 2.2702 59 0.2943 60 0.0885 1.2058 61 0.0517 1.4982 62 0.0388 0.2082 63 0.0613 0.5518 64 0.1177 0.2217 65 0.0613 0.5310 66 0.0655 0.2878 67 0.0573 0.2550 68 0.2984 0.0400 69 0.0246 0.6655 70 0.1410 1.4007 71 0.1702 2.0671 72 0.0771 0.1563 73 0.0877 0.9664 74 0.1184 4.2038 75 0.1655 0.2489 76 0.2103 0.5192 253 200848057 No. 5〇(μΜ) Ε05〇(μΜ) 77 0.1897 1.0355 78 0.1366 0.5139 79 0.0367 1.1857 80 0.2222 1.3079 81 0.1790 1.0970 82 0.0150 7.9943 83 0.1199 2.2786 84 0.1681 0.7257 85 0.0601 0.7480 86 0.1552 0.6901 87 0.1070 1.5863 88 0.0967 0.9345 89 0.2834 0.8184 90 0.0779 0.4882 91 0.1870 0.8809 92 0.8819 10.1527 93 0.1160 9.1580 94 0.1204 0.422 2 95 0.0628 0.3410 96 4.3349 &gt;32.00 97 0.1891 1.1036 98 6.8919 8.5247 254 200848057 No. Ι〇50(μΜ) Ε05〇(μΜ) 99 0.2698 1.1942 100 0.2841 12.9972 101 0.0937 0.2656 102 0.5858 1.8571 103 0.8660 18.5340 104 0.2299 3.5540 105 0.1788 2.0778 106 0.9083 1 1.8730 107 0.2266 13.5425 108 0.2144 3.3032 109 0.2109 1.6930 110 0.3453 111 0.8206 112 2.4704 113 0.0280 114 0.3850 115 2.1179 116 0.5641 117 4.7870 118 0.5785 119 0.0656 120 1.8086 255 200848057 No. 50€50(μΜ) EC50(ihM) 121 0.5056 122 1.9010 123 0.0663 124 0.2354 125 0.0312 126 2.0298 127 3.2333 128 2.4513 129 4.9193 130 0.2432 131 1.1315 132 0.5571 133 1.2937 134 0.2462 135 2.9037 136 0.7490 137 0.1356 0.5191 138 0.1304 0.5839 139 0.1283 0.0198 140 0.7091 0.4631 141 0.6700 0.2646 142 0.7928 0.7074 256 200848057 No. Κ50(μΜ) ec50(_) 143 2.9584 2.9142 144 0.0257 0.0365 145 5.3960 4.7700 146 0.0731 0.0296 147 13.8896 14.9661 148 0.0202 0. 0384 149 &gt;33.33 14.4651 150 0.1131 1.2575 151 4.1553 3.9377 152 0.0443 0.0248 153 9.7192 25.0467 154 0.0199 0.0925 155 1.5962 2.4341 156 0.0169 0.0400 157 3.2230 4.4666 158 0.0742 0.1706 159 3.1084 8.3530 160 0.0130 0.0313 161 0.0223 0.0176 162 0.8039 7.8654 163 0.0495 3.3630 164 2.5635 &gt;32.00 257 200848057 No. IC50(|liM) Ε〇5〇(μΜ) 165 0.0679 0.3037 166 0.0252 0.2677 167 3.3827 &gt;32.00 168 0.0056 0.1556 169 0.9242 5.8019 170 0.0456 1.3558 171 &gt;33.33 27.3332 172 0.0252 1.1914 173 7.5434 8.9314 174 0.0493 1.2249 175 3.7702 176 0.1774 177 5.1423 178 0.4360 179 1 1.3334 180 0.4993 181 5.6629 182 0.1511 0.1679 183 13.8411 184 0.2499 185 0.1570 14.1124 186 0.1511 0.1655 258 200848057 No. 50€50(μΜ) Ε&lt;:50(μΜ) 187 7.9075 12.1655 188 0.0363 0.0701 189 20.5703 23.5201 190 0.2131 0.1960 191 0.0478 1.5269 192 0.7200 3.7457 193 0.2412 5.7734 199 0.1760 0.8213 200 19.3821 18.7577 201 0.1283 3.7694 203 0.1011 0.7427 211 0.0058 12.0141 212 0.1570 14.1124 213 0.3376 3.1191 217 0.0965 0.5276 219 2.1057 29.9054 220 3.4594 &gt;32.00 221 1.3898 0.2056 222 0.8734 0.3325 223 0.4726 0.8807 224 0.1534 2.2616 225 0.5214 1.1194 259 200848057 No.Ι〇50(μΜ) EC5〇(jliM 227 0.2734 0.0601 228 8.8105 0.9446 229 0.0848 0.2539 230 0.1917 1.8384 231 0.6306 232 0.1841 233 3.9793 234 1.1460 235 0.2592 236 1.6899 237 17.7443 27.3187 238 0.3574 4.9297 239 0.1903 0.7752 240 0.1491 0.7365 241 0.1152 0.0823 242 0.2031 2.8392 243 0.3129 2.9084 244 3.4205 15.3950 245 1.1509 10.7414 246 1.0010 5.6197 247 0.1514 0.0562 248 2.2695 6.1814 260 200848057 No. IC5〇bM) ec50(_) 249 3.0491 7.3389 250 0.1260 0.1228 251 0.2127 7.0141 252 0.3930 0.3046 253 0.2407 0.4670 254 0.1846 0.4365 255 0.1289 0.0439 256 0.3789 0.0683 257 0.2414 1.0299 258 0.0823 0.3383 259 1.0693 3.3244 263 0.0889 0.1706 264 0.0788 0.0942 265 0.1479 0.0226 266 0.5063 1.1600 267 0.0933 0.037 9 268 0.3410 3.0188 269 0.2226 3.6077 270 0.1291 25.5841 272 1.9600 4.8710 273 0.6890 10.2991 275 0.0968 0.0870 261 200848057 No. IC5〇bM) EC50〇iM) 281 0.0508 0.4824 282 0.4475 282a 1 1.7563 3.2969 282b 7.9413 2.7424 282c 0.2883 0.2283 282d 0.1425 0.2319 283 0.2173 0.1629 285 &gt;42.67 0.7134 286 0.1592 289 0.4395 0.2071 289a 29.9151 3.1204 289b 32.4377 2.8792 289c 1.2694 0.3058 289d 1.3817 0.0588 290 0.7997 0.8414 291 0.6475 2.7208 292 16.8202 4.5944 293 0.0375 0.2978 294 0.0743 0.3903 295 1.6556 10.2073 296 4.3156 2.8832 297 &gt;42.67 &gt; 32.00 262 200848057 No.: 50 (μΜ) ec50(_) 298 0.1083 0.2059 299 0.2826 0.1597 300 0.0260 0.1774 301 0.0289 0.4189 302 0.0063 0.1559 303 0.0642 0.3400 304 0.1902 0.7523 305 0.2208 0.1943 306 0.0832 0.2807 307 0.0914 0.2790 308 0.0467 0.0567 309 0.1218 0.0788 310 0.0546 0.0601 311 0.0211 0.0953 312 0.1868 10.598 313 0.0723 0.1761 314 0.0979 0.1758 315 0.1020 0.0524 316 0.0239 0.1382 317 0. 0502 0.1649 318 0.1726 0.1602 319 0.2654 0.1594 263 200848057 No. IC5〇bM) Ε〇5〇(μΜ) 320 0.0744 0.2561 321 0.0654 0.6454 322 0.0537 0.5486 323 0.0165 0.0502 324 0.1144 0.2118 325 0.1985 0.1004 326 0.0693 0.1661 327 0.0446 0.1238 328 0.1950 0.1197 329 0.4218 0.0223 330 0.0319 0.0282 331 0.0274 0.0631 332 0.0610 0.2549 333 0.0959 0.1549 334 0.2532 0.2712 335 0.3038 0.0748 336 0.0787 0.0848 337 0.0137 0.0944 338 0.3146 0.0485 339 0.7166 0.0156 340 0.1231 0.0376 341 0.0565 0.1666 264 200848057 No. 50€50(μΜ) ΕΟ:50 Μ 342 Μ 342 342 342 342 342 342 361 0.3376 1.0321 362 0.1982 0.2066 363 0.3905 0.5514 364 0.3965 0.4147 365 0.4147 0.9988 366 0.5999 0.6876 367 1.1620 0.6941 265 2008480 57 No. Ι(:50(μΜ) Ε05〇(μΜ) 368 0.3574 0.7737 369 0.1319 0.1317 370 0.3467 0.2849 371 0.3771 0.1760 372 0.9065 0.4178 373 0.3303 0.6482 374 0.8161 0.3027 375 0.6246 0.6801 376 0.4288 0.2215 377 0.1290 0.1701 378 5.7687 10.7818 379 1.6958 28.3896 380 2.5692 &gt;32.00 381 0.0511 0.3087 382 2.3140 5.7443 383 0.0455 0.0094 384 3.4816 2.5810 385 0.0561 0.0480 386 4.9032 9.1403 387 0.4302 0.3420 388 1.2094 5.2857 389 1.7788 1.3113 266 200848057 No. 〇€5〇(μΜ) Ε(:50(μΜ) 390 0.4185 0.0166 391 8.7866 2.8186 392 0.7065 0.0222 393 0.0839 0.0164 394 1.8508 0.5952 395 0.0132 0.1195 396 1.4038 31.8713 397 8.8259 12.3749 398 0.0878 0.0407 400 0.5204 3.0963 410 5.7642 4.1079 411 0.2230 0.0803 412 0.3207 4.1902 413 3.1675 0.9137 414 0.3348 0.0307 415 0.5431 0.0684 416 0.9691 1.6921 417 10.4064 2.2254 418 0.1272 0.0254 419 0.3902 0.0455 420 0.9784 2.4779 421 0.2430 0.0134 267 200848057 No.Κ50(μΜ) Ε(:50(μΜ) 422 0.0657 0.0 316 423 4.4236 3.3701 425 0.4625 0.1891 426 1.5389 0.2753 427 1.1686 0.0931 428 0.4047 2.4188 429 1.4716 1.4308 430 1.7170 0.7099 431 0.6612 1.0649 432 0.3741 0.0379 433 0.2527 0.1256 434 1.1405 0.1176 435 1.2858 0.0481 436 0.5930 0.1251 437 6.2230 3.5755 438 0.4383 0.0390 439 0.9487 1.3993 440 0.3013 0.3215 441 19.7806 8.2018 442 5.7488 12.8189 443 &gt;42.67 3.3664 444 0.0788 3.0203 268 200848057 No. IC5〇bM) Ε(:50(μΜ) 445 0.0599 0.9507 446 0.1042 1.5506 447 0.0783 0.0842 448 29.0202 &gt;32.00 449 0.3351 10.7140 451 0.0776 0.1820 452 0.3571 11.1378 453 3.1494 &gt;32.00 454 0.8558 3.0810 467 0.0813 0.3451 471 1.5879 &gt;32.00 472 0.3514 14.7982 473 0.8804 9.8292 500 0.0594 1.2502 504 0.9592 2.2879 505 2.8945 13.0305 510 0.0948 1.1003 528 2.5738 &gt;32.00 542 0.3400 4.1778 547 0.3689 0.7969 548 1.0446 2.9420 549 0.7881 5.7261 269 200848057 No. ic5〇^M) Ε€5〇(μΜ) 550 1.1346 17.1739 551 5.1015 28.4872 552 5.6159 &gt;32.00 5 53 2.2777 &gt;32.00 554 1.5606 17.2791 555 1.1161 14.6518 556 3.8720 25.9663 557 1.1514 5.3810 558 4.2017 25.3980 559 4.2623 &gt;32.00 560 0.5589 0.5192 561 2.9864 12.3600 562 0.2971 0.1265 No Ι〇50(μΜ) Ε05〇(μΜ) 563 1.0714 0.5229 564 1.1814 4.3623 565 1.2353 1.1740 566 0.8616 0.7999 567 0.2900 0.1519 568 0.5223 0.1546 569 0.2279 0.1052 570 0.1889 14.9297 270 200848057 No. Ι〇50(μΜ) EC50(]liM) 571 0.1889 14.9297 572 0.1889 14.9297 573 0.1889 14.9297 574 0.1077 575 0.0394 576 0.1139 577 578 586 0.2749 1.70 587 0.5107 19.29 588 0.9706 &gt;32.00 589 0.1156 0.31 590 0.2074 0.15 591 1.4743 &gt;32.00 592 0.8827 1.56 593 0.4216 18.56 594 0.1281 0.0984 595 0.0706 0.18 596 0.1515 0.34 271

Claims (1)

200848057 X. Patent application scope: L A compound of formula (I): a salt, hydrate or solvate wherein R is hydrogen, hydroxy, amine, ci-6 alkoxy, halo or, optionally, C1-6 alkyl substituted by hydroxy; R is hydrogen, hydroxy, amine, CV6 alkoxy, -0-CH2.thiazolyl, halo, trifluoromethyl or Cw alkyl optionally substituted by cyano; 2 R is hydrogen, -C(dioxin)-R5, -Cb , -C(=〇)-〇R6 or _c(=〇)-NR7aR7b; R is a Ci·6 alkyl group substituted by c:3_7 cycloalkyl, aryl or Het as the case; [ηcycloalkyl Aryl; or Het; each R and ^ are independently hydrogen, Ci-6 alkyl, C2_6 alkenyl or both R and R4b together with the tricyclic ring of the tricyclic ring may form a Cp cycloalkyl group or Oxetane; 1 is a Cl. 6 alkyl group optionally substituted with one or two substituents selected from the group consisting of halo, c3 7 cycloalkyl, 272 200848057 phenyl Ci-6 thiol, Cyano, polyhalo c1-6 alkyl, pendant oxy, -OR9, -C(=0)-Het, -C(=0)_〇R6, -C(2), -C(=0 )_NR7aR7b, _C(=0)_NH_S(=0)2-R8, _NR7aR7b, _S(dioxin) 2-aryl, aryl 5 group and Het; c2 substituted by aryl group as appropriate 6 alkenyl; polyhalo-based; 〇3-7 cycloalkyl; aryl; or Het; R6 is optionally OR-OR9, -C(=0)-〇R9, -C(=0)_NR7aR7b , -C(=〇)-NH-S(=0)2-R8, 0 aryl or Het substituted aryl or (^-6 alkyl; each is ~ and the meaning is independently hydrogen; A Ci_6 alkyl group substituted by one or two substituents selected from the group consisting of: -OR9, mono or di CV6 alkylamino group, -C(dioxin)_〇R9, -C(=〇)-NH2 -c(diCO-NH-Cu alkyl, -C(=〇)-NH-hydroxy-Cw alkyl, -C(=〇)-Het, C3-7 cycloalkyl, aryl and Het; C2_6 olefin a C3_7 cycloalkyl group substituted by a hydroxy group; an aryl group; or a Het; δ ^ system is a cle6 alkyl group, a c3_7 cycloalkyl group, a di(Cl 3 alkyl group). an amine group or an aryl group; J R9 ... system Is hydrogen; optionally, one, two or three Cu alkyl groups each independently substituted with a substituent: a halogen group, a hydroxyl group, a C3-7 cycloalkenyl group, a C3-7 cycloalkyl group, a cyano group, a Ci_6 Alkoxy, phenyl or Het, wherein the phenyl group may be substituted by the following groups: _ group, hydroxy 273 200848057, Ck alkoxy, Ck alkoxy Cw alkoxy, C 1 -6 alkyl, a base or an amine group; optionally, a Cw alkenyl group; a c2_6 alkynyl group; a c3-7 cycloalkenyl group; or a case optionally substituted by one or two substituents selected from a halogen group and a polyhalogenyl Ci-6 alkyl group; Or a phenyl hydroxy group, a cle6 alkoxy group, an i group, a polyhalogenated Cw alkyl group, an amine group, a nitro group, a C 6 alkyl group, and a phenyl group substituted with two substituents selected from the group consisting of: The base or a part of the group is phenyl, naphthalene 10, hydroquinone or 1,2,3,4-tetrahydronaphthyl, each of which is independently selected by one, two, three or four Substituted by a substituent of a group having the following composition: C3_7 cycloalkyl group, phenyl group Ck alkyl group, phenyl polydentate group c16 alkyl group, phenyl group-6 alkyloxy group, halogen group, polyhalogen group c16 , 15 cyano group, Cl-6 alkyl group, polyhalogenated Cw alkoxy group, -OR9' _C(=〇)〇H, Cu alkylcarbonyl group, Cw alkylthio group C 1 _6 fire element slate page fc group, -S ( = 〇) 2 ΝΗ 2 and ϋ 洛 洛 ' ', wherein the phenyl group may be substituted by the following groups; or two substituents on the aryl ring may form _〇-CH 2 -〇 Or -〇-C(CH3)2_CH2-; Het as a group or a part of a group a 5- to 12-membered, partially unsaturated or fully unsaturated mono- or bicyclic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally fused to a benzene ring And in its 274 200848057 10 15 2, 20 the group Het as a whole may be substituted by one or two substituents independently selected from the group consisting of: halo; polyhalo Cw alkyl; Cw alkane , oxyl group; -OR9; -NR1GaR1Qb; -CN; Cw alkyl group substituted by -OR9, -CN, _NR10aR10b or phenyl group as appropriate; -C(=0)-NH2; -C(2) -phenyl; C3_7 cycloalkyl; phenyl substituted by C1-6 alkoxy as appropriate; fenofyl; pyrrolidinyl; pyrrolyl; furyl; tetrazolyl; and thienyl; and each R1Ga&amp R1()b is independently oxime, C1-6 alkyl, aryl ci6 alkyl or R10a and Ri〇b together with the nitrogen to which they are attached may form a saturated, partially unsaturated or fully unsaturated 5 to 8 member Rings wherein the monocyclic ring optionally contains an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining single ring members are carbon atoms; wherein the single ring Optionally, on any carbon atom: or two substituents independently selected from the group consisting of: halo, Cl-6, hydroxy or pendant. The compound of the formula i of the Rla π patent range is a hydrogen, a hydroxyl group, an amine group or a dentate group; the system is a hydrogen, a thiol group, a halogen, a bismuth bismuth Q&quot; a squirrel methyl group or, as the case may be, 3 Substituted Cw alkyl; hydrogen, -c(, r5, _c (which C(=0)R5, (~〇)-OR6 or dip)_NR7aR7b; R1 RlbR2 275 200848057 R is C3_7 ring as appropriate Alkyl, aryl or Het substituted for 0's "alkyl"; C3_7 cycloalkyl; aryl; or Het; each R and R4b are independently C16 alkyl or R4a &amp; R4b together with the tricyclic ring to which they are attached The carbon atom of the ring may form a C3_7 cycloalkyl group; R is a Cw alkyl cyano group, a polyhalogeniyl Ci6 fluorenyl group, a pendant oxy group, optionally substituted with one or two substituents selected from the group consisting of -〇R9, _C( = 〇)_Het, -c(-0)-〇R6, _C(=〇)_〇H, -C(=Q)_NR7aR7b, -C(=〇)-NH-S(= 〇) 2-R8, -NR7aR7b, aryl and Het; optionally substituted by an aryl group (: 2-6 alkenyl; poly 6-dentyl-based alkyl; (: 3-7 cycloalkyl; aryl; or Het; R is as appropriate -OR9, -C〇〇)-〇R9, _C(=0)_NR7aR7b, -C(2)_NH_s(=〇)2_r8, aryl or Het substituted cK6 alkyl; u and R are independently hydrogen; optionally substituted with one or two substituents selected from the group consisting of: -OR9, mono or diCl 6 alkylamino, _c (zz;〇)_〇r9, —c(=o)-nh2, _c(=0)_Nh-cK6 alkyl, —C(=〇)-NH_hydroxyCl 6 alkyl, _c(=〇)_Het, Cycloalkyl, aryl and Het; Cw alkenyl; c3_7 cycloalkyl substituted by a benzyl group; aryl; or Het; R is Ci-6 alkyl, c3_7 cycloalkyl, di (Cw) Alkyl) Amine or aryl; 276 200848057 R is argon, optionally a Cu alkyl substituted by CK6 alkoxy, phenyl or Het, which allows the phenyl group to be replaced by the following groups: a phenyl group, a Ck alkoxy group, a nitro group or an amine group; or a phenyl group optionally substituted with one or two substituents selected from the group consisting of a dentate group, an amine group, a nitro group, a Ck alkyl group, and a phenyl group; When the aryl group is a part of a group or a group, it is a phenyl group, a naphthyl group, a hydroquinone group or a 1,2,3,4-tetrahydronaphthyl group, each of which can be regarded as one or two independent Substituted by a substituent of the following group: halo, polyhalogen Ci6, cyanide Base, Cw alkyl, polydentate alkoxy, -OR9, -C(=0)0H, Cw alkylcarbonyl, thiol group, Ck alkylsulfonyl, _s(=〇)2NH2 and pyrrole Het as a group or part of a group is a 5 to 12 member saturated, partially unsaturated or fully unsaturated mono or bicyclic ring containing 1 to 4 independently selected from nitrogen, oxygen and sulfur. An atom, optionally fused to a benzene ring, and wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: fluorenyl; pendant oxy; hydrazine R9; _NR10aR10b; -CN; Cu alkyl group substituted by _R9, -CN, _NRlGaRi〇b or phenyl group as appropriate; -c(=0)-NH2; -C(=0)-phenyl; c3-7 Cycloalkyl; phenyl substituted by alkoxy group according to Ci 6 277 200848057; fenofyl; pyrrolidinyl; pyrrolyl; furyl; tetrazolyl; and thienyl; and soil, each R1Ga and R1(10) Is independently hydrogen, Cw alkyl, aryl C 10 3 · alkyl or a group thereof; a saturated, partially unsaturated or fully unsaturated $ to 8 membered monocyclic ring, wherein the single ring system Include one as appropriate An additional hetero atom of the group consisting of free oxygen, sulfur and nitrogen and wherein the remaining single ring members are carbon atoms; wherein the monocyclic ring may optionally be substituted on one or two of each of the carbon atoms independently selected from the group consisting of A halogen group, a Cw alkyl group, a hydroxyl group or a pendant oxy group. For example, a compound of the formula (2) or (II), &quot;苒 15 m Wherein Rla, Rlb, R2, R3, R4a and R4b are described in any one of the following items. Shen &quot;Patent R is a compound of the first or third patent scope of the patent, Dragon &quot;D 1 a /, T · is hydrogen, hydroxyl, amine or hydroxy CK6 thiol 278 4. 200848057 Rlb is Hydrogen, hydroxy, halo, amine, 6 alkoxy, -CUCH2-decyl, trifluoromethyl or Cw alkyl optionally substituted by cyano; R2 is hydrogen, _C(=〇)-R5 , _c(=〇)_c(=C〇-R5, 5 -ChOyOR6 or -c(=〇)_NR7aR7b ; R3 is a &lt;^-6 alkyl group optionally substituted by Ch cycloalkyl, aryl or Het ; c3-7 cycloalkyl; aryl; or Het; each R and 1141) are independently hydrogen, C26 alkenyl or C&quot;alkyl; or both R and R4b together with the tricyclic ring to which they are attached 10 a carbon atom may form an oxetan group; R5 is a Ck alkyl group optionally substituted with one or two substituents selected from the group consisting of halo, c3-7 cycloalkyl, phenyl Ck alkylthio, Cyano, poly-based Cl_6 alkyl, pendant oxy, -OR9, -C(=0)-Het, -C(=0)-0R6, 15 -C(=0)_〇H, -C(two 0) -NR7aR7b, -C(=0)-NH-S(=0)2-R8, -NR7aR7b, -S(dio) 2-aryl, aryl and Het; optionally substituted by aryl group 〇2_6 alkenyl; polyhalo Cw alkyl; C3_7 cycloalkyl; aryl; or Het; 20 R6 is optionally OR-, -C(=0)-0R9, -C(=0)-NR7aR7b , -C(=0)-NH-S(=0)2_R8, an aryl group substituted by an aryl group or a Het or a Cu alkyl group; each of R7a and 1^71) is independently hydrogen; one or two, as the case may be A Cu alkyl group substituted with a substituent selected from the group consisting of: 279 200848057 -OR9, mono or diCl&gt;-6 alkylamino group, -C(=0)_0R9, -C(=0)-NH2, -COCO- NH-C&quot; alkyl, -C(=〇)_NH-hydroxy Cle6 alkyl, -C(=0)-Het, C3_7 cycloalkyl, aryl and Het; C2_6 5 alkenyl; optionally substituted by hydroxy 〇3_7 cycloalkyl; aryl; or Het; R8 is Cw alkyl, c3_7 cycloalkyl, bis(Cw alkyl)amino or aryl; R is hydrazine, optionally one, two or three Each of the Ci_6 alkyl groups independently substituted with a substituent: a halo group, a hydroxyl group, a c3-7 cycloalkenyl group, a c3-7 cycloalkyl group, a cyano group, a Cw alkoxy group, a phenyl group or a Het, wherein the phenyl group may be optionally used. Substituted by the following groups: functional group, hydroxyl group, Ci_6 alkoxy group, Cl_6 alkyl group, Cl_6 alkoxy group C 6 5 alkoxy group, nitro group An amine group; optionally a C2.6 alkenyl group substituted with one or two substituents selected from the group consisting of i- and poly-halogen Ci-6 alkyl; Cw alkynyl; c3-7-cycloalkenyl; or optionally one or two a phenyl group substituted with a substituent selected from the group consisting of a hydroxyl group, a Cl-6 alkoxy group, a poly-hydrazinyl Cw alkyl group, a halogen group, an amine group, a nitro group, a Ci6 alkyl group, and a base group; an aryl group as a group Or a part of the group is phenyl, naphthyl, hydroquinone or 1,2,3,4-tetrahydronaphthyl, each of which is optionally selected from the following 280 by one, two, three or four 200848057 Substituted by a group of substituents · c3_7 cycloalkyl, stupyl Ck alkyl, phenyl polyhalo ci6 alkyl, phenyl^6 alkyloxy, halo, polyhalogen c16 alkyl , cyano, C!-6 alkyl, polyhalo c1-6 alkoxy, -OR9, -C(=〇)〇H, CV6 alkylcarbonyl, d_6 alkylthio, C!·6 alkyl sulfonate Anthracenyl, _s(=〇)2NH2 and pyridyl ' wherein the phenyl group may be substituted by the following groups; or two substituents on the aryl ring may form -0-CH2-0 -or-〇-c(CH3)2-CH2_ ; Het as a group or part of a group is 5 a 12-membered saturated, partially unsaturated or fully unsaturated mono- or bicyclic ring containing from 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, optionally fused to a benzene ring, wherein the group The group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of: halogen group; poly-based Cl-6 alkyl group; Ci 6 alkylthio group, pendant oxy group; -OR9; _CN; </ RTI> 〇r9, -CN or phenyl substituted &amp;alkyl; -Ch〇)_NH2 '·&lt; 〇)) phenyl; c3_7 cycloalkyl; as the case (^_6 alkoxy Substituted phenyl; fenofyl; pyrrolidinyl; pyrrolyl; furyl; tetrazolyl; and thienyl. 5. A compound according to any one of claims 1-3, wherein: 281 200848057 Rla is hydrogen, hydroxy or amine; Rlb is hydrogen, thio, halo, trifluoromethyl or Cw alkyl group substituted by cyano group as appropriate; R2 is hydrogen, -C(=〇)-R5, -C(=〇)-cb0)-R5, 5 _C〇〇)-〇r6 or a c (7) _NR7aR7b; R3 is a Ci_6 alkyl group optionally substituted by Cp cycloalkyl, aryl or Het; c3_7 cycloalkyl; aryl; or Het; each R4a and R4b are independently Cu alkyl; R5 is Cw alkyl optionally substituted with one or two substituents selected from the group consisting of halo, C3 7 cycloalkyl, cyano, polyhalo Cw alkyl, pendant oxy, -0R9, -ChOyHet, - C(=0)-0R6, _c(二0)-0H, _C(二〇)_NR7aR7b, -C卜〇)-NH_se〇)2_R8, *&quot;NR7aR7b, _s(=〇)2_aryl, Fang And Het; C2_6 alkenyl substituted by aryl group as appropriate; polyhalo ci-6 alkyl; C3-7 cycloalkyl; aryl; or Het; R is optionally _〇R9, _C( = 〇)-〇R9, _C(=0)-NR7aR7b, -C(=0)_NH-S(=0)2-R8, aryl or alkane substituted by aryl or Het Each of R and R is independently hydrogen; optionally substituted by one or two substituents selected from the group consisting of: -OR9, mono or di-Cualkylamine, _c(=〇)- 〇r9, -CBu 0)-NH2, -CPOVNH-Cw alkyl '-C(=〇)-NH hydroxy C&quot;alkyl, -C(=〇)-Het, C3_7 282 200848057 R8 R9 decyl, Aryl and Het; c2 6 alkenyl; hydroxy substituted Cp cycloalkyl; aryl; c: 6 alkyl, c 3 7 cycloalkyl, diamine or aryl; optionally or Het; Cl- 3 alkyl) 10 to scare Hungarian, I wish to have one, two or three alkyl groups each independently substituted with a substituent selected from the group consisting of hydroxy: (3-7-cycloalkenyl, C3 7 cycloalkyl) , alkoxy, phenyl or Het, wherein the phenyl group may be optionally substituted by the following base ring: dentate group, Cl-6 alkoxy group, Cw alkyl group, Cl_6 alkoxy group C 6 alkoxy group, nitro group or Alkyl; C2-6 dilute; h alkynyl; or phenyl, halo, Cw alkoxy, polyhaloalkyl, optionally substituted with one or two substituents selected from the group consisting of 15 aryl Amino, nitro, C!-6 alkyl and phenyl; as part of a group or group Is a phenyl group, a fluorenyl group, a hydroquinone group or a 1,2,3,4-tetradecyl-naphthyl group, each of which is optionally selected from one, two, three or four substituents selected from the group consisting of Substituted: c37 cycloalkyl, phenyl C!-6 alkyl, phenyl polyhalo ci 6 alkyl, phenyl C!-6 alkyloxy, halo, polydentate (:; 1-6 alkyl, Cyano, Ci-6 alkyl, polydentate 6 alkoxy, -OR9, &lt;(=0)0Η, Cw alkylcarbonyl, Cw alkylthio, Cu alkylsulfonyl, 4( = 〇) 2 丽 2 and pirolo; 283 20 200848057 10 15 Het as part of a group or a group is a 5 to 12 member saturated, partially unsaturated or fully unsaturated mono or bicyclic, containing 1 to 4 Each of the heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, optionally fused to a benzene ring, and wherein the group Het as a whole may be optionally substituted by one or two substituents independently selected from the group consisting of I-group; polyhalo Cw alkyl; c1-6 alkylthio, pendant oxy; -OR9; _CN; optionally as defined by 〇R9, _CN or phenyl substituted Cl_6 alkyl; _c(=〇)_NH2; -c(-0)-phenyl; c3 7 cycloalkyl; optionally via Cu The phenyl group substituted; Fu it morpholinyl; pyrrolidinyl, laugh roar group; furanyl; tetrazolyl; and thienyl. 6. A compound according to any one of claims 1 to 3 to 5 wherein: RU is hydrogen, hydroxy or amine; R is hydrogen, hydroxy, halo, trifluoromethyl or, as the case may be Cyano substituted c1-6 alkyl; 2 R is hydrogen, -C(=0)-R5, _c(=〇)-〇R6 or -C〇〇)_NR7aR7b; R is optionally C3_7 naphthenic a aryl group, an aryl group or a Het substituted CK6 alkyl group; a c3-7 cycloalkyl group; an aryl group; or a Het; each 5R4a and R4b is independently a Cw alkyl group; and the R system is optionally selected from one or two a Ci_6 alkyl group substituted with a substituent: a halogen group, a c3-7 cycloalkyl group, 284 20 . 200848057 a cyano group, a polyhalogen group. "Alkyl, pendant oxy, -〇R9, -C(=〇)_〇r6,, -8(=0)2. aryl, aryl and Het; C3-7 cyclodextrin; aryl, Or Het ; ^ is a aryl group or a C 1 _6 炫 group, 5 each of R7a and R7b is independently hydrogen; Ci_6 alkyl; aryl; or Het; R is hydrogen; optionally, one, two or three Each independently selected is a CV6 alkyl group substituted with a substituent: _ group, hydroxy group, C3_7 cycloalkenyl group, C3_7 cycloalkyl group, Cl_6 10 alkoxy group, phenyl group or Het, wherein the phenyl group may be as follows: Substituted by a group: halo, Cw alkoxy, schlossyl, C!-6 alkyl, Ci-6 alkoxy Cw alkoxy or amine, C _6 dilute; C 2 _ alkynyl; or optionally Two phenyl 15 groups substituted with a substituent selected from the group consisting of a halogen group, a Ci-6 alkoxy group, a polyhalogenated Cw alkyl group, an amine group, a wall group, a C i 6 alkyl group, and a phenyl group; and an aryl group as a group a group or a part of a group is a phenyl group substituted by one, two, three or four substituents independently selected from the group consisting of C3_7 naphthenic 2 fluorenyl, phenyl Cl-6 Base, phenyl polyhalo Cb6 alkyl, phenyl Ci_6 alkyl , halo, polyhalo, murine, C 1 ·6 oligo, polyhalo C 1 -6 alkoxy, -OR9, -C(=0)0H, Cu alkylcarbonyl, cumane Sulfhydryl, Cu-based acid group and -s(=〇)2NH2; 285 200848057 10 8· 15 20 Η6ί as a group or part of a group is 5 to 12 members saturated, partially unsaturated or fully unsaturated Mono or bicyclic, containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may optionally be substituted by one or two groups independently selected from the group consisting of Substituted: halogen, polyhalo-Ci6 alkyl, Cu-sulfuryl, pendant oxy, _〇r9, _cn, and C 1 -6. i. A compound, wherein R is hydrogen, &lt;(dioxin)-R5 or ·C(=〇)_〇R6. A compound according to any one of claims i, 3 to 7, wherein: R is hydrogen or a hydroxyl group; is hydrogen or a hydroxyl group; is hydrogen, or -C(=〇)-〇R6; is an aryl group; Y4m4b is independently a Cl.6 alkyl group; R is a condition One or two Ci_6 alkyl groups substituted with a substituent selected from the following , c3 7 cycloalkyl, aryl, polyhalo C!-6 alkyl, pendant oxy, -OR9, 4(=0)2-aryl, aryl and Het; aryl; or Het; a C 6 alkyl group substituted by one, two or three substituents independently selected from the group consisting of halo, hydroxy, Cp cycloalkenyl, c 3-7 cycloalkyl or phenyl; or R lb 2 R R3 R9 286 .200848057 phenyl·.halo, polyhalo 0:1_6 alkyl or c alkyl optionally substituted with one or two substituents selected from the group consisting of a aryl group as a group or a part of a group The phenyl group is optionally substituted with a substituent selected from the group consisting of: a group, a polyhalogen group C!_6 alkyl group, Cyano, Ci6 alkyl, polyhalo r Cl-6 alkoxy and -〇R9 ; Η61: as part of a group or a group of 5 to 〇1〇 saturated, partially unsaturated or fully unsaturated Monocyclicity, which contains 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may optionally be substituted by one or two substituents independently selected from the group consisting of: Halo, oxo, -〇R9, _CN 15 and CV6 alkyl. The compound of any one of claims 1 to 8, wherein the compound has the formula (I-a) 287 200848057 wherein RIA, Rlb, R2 and R3 are as described in any one of claims 1 to 8. The compound of any one of claims 1 to 8, wherein the compound has the formula (I-b) As described in any of the eight items. 11. A compound according to any one of the preceding claims, wherein the compound has the formula (I_i), (1_』) or (I k) The compound of any one of claims 1 to 8 wherein the compound has the formula (1-1), (Im) or (In). ), 〃 R1^ Wherein Rla, r2, r5, r6 and an aryl group are as described in any one of claims 1 to 8. A pharmaceutical composition comprising a carrier and an antiviral effective amount as an active ingredient, a compound according to any one of claims 1 to 12. A pharmaceutical composition according to claim 13 which further comprises at least one other anti-HCV compound. For example, the pharmaceutical composition of claim 13 further comprises at least one other anti-HIV compound. A pharmaceutical composition according to any one of claims 2 to 12, or a pharmaceutical composition according to any one of claims 13 to 15, which is a pharmaceutical agent. A pharmaceutical composition according to any one of claims 1 to 12, or a pharmaceutical composition according to any one of claims 13 to 15, which is for inhibiting HCV replication. A pharmaceutical composition according to any one of claims 13 to 15, which is for the treatment of hepatitis C, as disclosed in any one of claims 1 to 12. 19. A pharmaceutical composition according to claim 15 which is for inhibiting HCV and HIV replication. A method for the compounding according to any one of claims 1 to 12, which is a method for producing HCV replication for use in inhibiting H c V replication using a 21% warm-blooded animal, the method A pharmaceutical composition comprising an effective amount of a compound as claimed in any one of claims 12 to 15 or a pharmaceutical composition according to any one of claims 13 to 15. And a composition comprising the compound according to any one of claims 1 to 12 and at least one other anti-HCV compound 23 as prepared according to any one of claims 1 to 12 A method of a compound of the formula (1-8), which comprises the steps of: reacting a compound of the formula (1-2) with a compound of the formula (1-4) to give a compound of the formula (5), and 290 200848057 The compound of formula (1-5) is reacted with an aldehyde of formula (1) 7) as appropriate in the presence of an acid to give a compound of formula ( + R3.. ό R4 □ wherein R, R, R4a, R4b and r3 have the meanings as defined in any of claims 1 to 12. A method of preparing a compound of the formula (1-9) according to any one of claims 12 to 12, which comprises the steps of: 10 Deuteration of a compound of the formula (1-8) with an acid or an active acid to give a compound of the formula (I) having the formula (1-9) wherein Rla, Rib, R4a, and 4b, R3 and R5 have the same patent application The meaning of any of items 1 to 12. A method of preparing a compound of the formula (I-10) according to any one of claims 1 to 12, which comprises the steps of: 291 200848057 The compound of the formula (I-8) is reacted with an isocyanate of the formula (I-8a) to give a compound of the formula (I-1) wherein R7b is hydrogen or a compound of the formula (1_ with phosgene or formula (I-8b) An equivalent phosgene reaction, wherein the LG system represents a leaving group, followed by treatment with an amine of formula (I-8c), to obtain a compound of formula (1-10) wherein Rla, Rlb, R4a τ &gt; 4b - ρ 3 d 7a and η 7b ρ ϊ , , RR have the meanings as any one of items j to 12 of the scope of the patent application. 26. A preparation having the formula (1) of any one of claims 1 to 12 The method of the compound of 11), comprising the steps of: The compound of the formula (1-8) is reacted with the gas of the formula (I8d) in an inert solvent in the presence of a base to obtain a compound of the formula (1-11) 292 200848057 wherein Rla, Rlb, R4a, R4b R, the scope of patent application No. 1 to 12 - and R6 have the meaning of the item. 293 200848057 VII. Designation of Representative Representatives (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: Benefit 10 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 5 15