TW200804246A - HIV protease inhibitors - Google Patents

Abstract

Compounds of the formula I: wherein R1, R2, X and N are as defined in the specification ; E is N, CH; A' and A" are terminal groups as defined in the specification. The compounds have utility as HIV -1 protease inhibitors.

Description

200804246 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a compound of formula I:

Wherein R1, R2, X and N are as defined in the specification: E is N, CH; A' and A" are terminal groups as defined in the specification. ίο The compounds may be used as HIV-1 protease inhibitors. [Prior Art] Two different retroviruses are known in the etiology: human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2), and immunosuppressive disease 15 Immune Deficiency Syndrome (AIDS) is associated with HIV seropositive individuals who initially have no symptoms, but typically develop after AIDS. AIDS-related complex syndrome (ARC). Patients develop severe immunorepression, which makes them vulnerable to weakness and ultimately It is possible to get a fatal infection. AIDS disease is the end result of HIV-1 or HIV-2 virus following its own 20-life cycle. The life cycle of virions begins with the sugar on the surface of the protective shell that itself passes through the virions. Protein and lymphocytes on the 200804246 C:: gas white host on human μ lymphocytes immune cells. 4 attached 'virage particles that are unloaded (four) eggs (four) penetrated into the host cell wealth, and removed its ship shell. Virus particles; Reverse transcriptase The 5 RNAs that are transcribed into a single strand of DNA will degrade the 'creation of the first strand: strands of DNAi are re-integrated into human cell genes in double-stranded d=a for propagation of the virus. Disease ♦ bribe A. The viral RNA is then translated into the precursor gag_p〇1 fusion polyprotein, which is then cleaved by (4) protease enzyme to produce mature virus egg. Therefore, pulse protein 贞 regulation - a series of touch To make the virions hot to form a fully infectious virus. Destroying the typical human immune system response of invading virions is a cumbersome task 'because the virus infects and destroys the tau cells of the immune system. In addition' the enzyme used to make new virions The viral reverse transcriptase is not highly specific, and the transcriptional errors caused by it often change the enzyme protein on the protective outer shell of the virus. The lack of specialized-specific materials reduces the effectiveness of m-systems. The antibodies produced may not be able to fight against another glycoprotein, thus reducing the amount of antibody that can be used to fight the virus. The virus continues to recoat, while the immune system reacts In the end, HIV has the advantage of the body and the epidemic system, making it vulnerable to opportunistic infections. If it is not administered antiviral agents, immune modulators or both, it will cause death. There are at least three in the life cycle of the known known virus. The key points can become disease resistance: the target of music: (1) when the virion is initially attached to the T-4 lymphocyte or macrophage site, and (2) when the viral RNA is transcribed into viral DNA (reversal of the enzyme 200804246, RT), and (3) HIV protease treatment of gag_p0l protein. The protease encoded by the genome of the retrovirus is responsible for proteolytic hydrolysis of one or more polyprotein precursors, such as: p〇l and gag gene products. Reverse transcriptase most frequently processes gag precursors to form core proteins, and also processes 5 P01 precursors to form reverse transcriptase and retroviral proteases. The combination of infectious virus particles requires the process of reverse transcription of the protease to properly process the precursor polyprotein. Protease-deficient viruses produced by mutagenesis in vitro are known to produce immature core types that lack infectivity. Therefore, retroviral protease inhibition has become an attractive target for antiviral therapy. 10 A number of compounds have been investigated as possible HIV protease inhibitors, as evidenced by current commercial protease inhibitors and clinical trials. The first inhibitor of the so-called retrovirus aspartate protease approved for combating infection is saquinavir. Since then, indinavir (Merck Pharmaceuticals), ritonavir (Abbott Pharmaceuticals), 15 amprenavir and its prodrug Amprenavir phosphate (Vertex/) have emerged. GSK Pharmaceuticals), l〇pinavir (Abbott Pharmaceuticals), nelfinavir (Aguoron/Pfizer Pharmaceuticals), tipranavir (Pharmacia/Boehringer Pharmaceuticals) and Astra ( Atazanavir) (Novartis/BMS Pharmaceuticals). 2〇 These prior art compounds are medically susceptible to treatments that are inferior to optimal treatments, with side effects such as lipodystrophy and poor patient adaptation. Coupled with the unfaithful replication of the HIV genetic machine and the extremely high viral metabolic rate in vivo, the prior art HIV protease inhibitors are second to best for their performance and pharmacokinetics, allowing the rapid escape of drug-resistant mutants. This 200804246 point significantly limits the current effective treatment period for HIV drugs because HIV is rapidly converted to resistance and/or the patient rapidly develops physical or psychological discomfort with the drug itself or its side effects. 5 SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel compound which has a high inhibitory activity against viral replication in cells, and for many viral strains, including those against known compounds (eg, saquinavir) , ritonavir and indinavir resistant viruses have a high degree of antiviral activity, and in particular have advantageous pharmaceutical properties, such as: good pharmacokinetics, such as: high bioavailability With high blood concentration, and / or high selectivity. According to the invention there is provided a compound of formula I:

among them

Ri is -R1', -SR1', R1' is a CrC6 alkyl group, a CVC3 alkanediylcarbocyclyl group or a C(r3 alkanediylheterocyclyl group, either of which may optionally be independently selected from 2 independently selected from 2 Substituting a substituent of 〇R1G; R2 is a CrC6 alkyl group, a C(rC3 alkanediylcarbocyclyl group, a C()-C3 alkanediyl heteropoly 200804246 ring group, and any one of them may optionally be independently selected from up to three Substituted by a substituent of R1G; X is Η, F, OH, CrC3 alkyl or C〇-C3 alkanediyl-O-CkQ alkyl; 5 L is OH, F, NH2, -NHCVCsAlk; -N(CrC3 alkyl 2 is 0, 1 or 2; Ε is Ν or CH; Α' is a bicyclic system comprising the first 5 or 6 which may optionally contain an oxygen heteroatom and may optionally be substituted by a hydroxy group and/or a thiol group. a saturated ring, 1 〇 and a second one may optionally contain one or two heteroatoms selected from the group consisting of S, fluorene and fluorene and may be fused by a 5 or 6 membered unsaturated ring which may be substituted by one or two fluorines; ' is a group of formula (II), (ΙΓ), (III) or (IV):

Wherein; R3 is hydrazine; or R3 is CrC6 alkyl, CVC3 alkanediylcarbocyclyl, CVC3 alkanediyl heterocyclyl, either of which may optionally be substituted with up to 3 substituents independently selected from R11; Is a CrC6 alkyl group, a CVC3 alkanediyl carbocyclyl group, a QrC3 alkanediyl heterocyclic group, any of which may optionally be substituted with at least three substituents independently selected from R1G; 200804246 R5 is a CrC6 alkyl group, C ( rC3 alkanediylcarbocyclyl, C(rC3 alkanediylheterocyclyl, any of which may optionally be substituted with up to 3 substituents independently selected from R1G; Z is a bond, -NH- or -0 - RX is Η, cvc3 alkyl oxygen, C1-C3 direct bond or branched alkyl group which may be substituted with a halogen group, a hydroxyl group, or a CVC3 alkyl group; or Rx and its phase' adjacent carbon atoms may form a halogen. a fused fluorenyl or fluorenyl ring substituted with a CrC3 alkyl group; t is 0 or 1; 10 A" is a group of formula (V), (VI) (VII) or (VIII);

Ry (V) (VI) (VII) (VIII) wherein; 15 R8 is Η; or R8 is CVC6 alkyl, C〇-C3 alkanediylcarbocyclyl, C〇-3 alkanediyl heterocyclyl, wherein Any one may be substituted with three substituents independently selected from R11 as needed; R9 is a CrC6 alkyl group, a CVC3 alkanediylcarbocyclyl group, or a 〇r3 alkanediyl heterocyclic group, either of which may be at most 3 substituents each independently selected from 20 R1G; W is a bond, -NR13- or R13 is H'CrG alkyl or R13 and R9 are bonded to the N atom to which they are attached - 10 200804246 Or a saturated, partially saturated or aromatic N-ring of 6 ring atoms, which may optionally be substituted with up to 3 substituents selected from R1G; D is hydrazine or NH; 5 Ry is hydrazine or Ry attached thereto The C atoms together form a fused oxime or σ-pyrene ring; Q is Ο, CHR8 or a bond; R15 is a carbocyclic or heterocyclic group, any of which may optionally be independently selected from up to three Substituted by the following substituents: CVC3 alkyl, hydroxy, ε oxo, halo, r and q are each independently 0 or 1; R1G is halo, oxo, gas, aroma, schwitz, Cl- C6 base cG-c3 alkanediylcarbocyclyl, cvc3 alkanediylheterocyclyl, Y-NRaRb, YO-Rb, Y_C(=0)Rb, Y-(C=0)NRaRb, is Y_NRaC(=0)Rb, Y-NHSOpRb, YS(=0)pRb, YS(=0)pNRaRb, YC(=0)0Rb or Y-NRaC(=0)ORb; where *Y is a bond or CVC3 alkanediyl; 2〇Ra Burning base for H or CVC3;

Rb is H or CrC6 alkyl, C(rC3 alkanediylcarbocyclyl or QrC3 alkanediyl heterocyclyl; p is 1 or 2; R11 is halo, oxo, cyano, azide, nitro , CrC3 alkane-11 - 200804246 base, Y-NRaRa, YO-Ra;

Ra, which is H or Cl-C3; or a pyrrolidine, morpholine, piperidine or piperene formed with the nitrogen atom attached thereto, which may be substituted at the 4_ position by a methyl or ethoxy group as needed And its pharmaceutically acceptable salts. Another aspect of the invention includes a pharmaceutical composition, which comprises a compound as defined above and a pharmaceutically acceptable carrier or diluent thereof. Another aspect of the invention includes the use of a compound as defined above for the manufacture of a medicament for the prevention or treatment of HIV infection. Another aspect of the invention provides a method of medically treating or preventing HIV infection comprising administering an effective amount of a compound as defined above to an individual who is at risk of or at risk of contracting HIV. The notion of P1, P1, P2, and p2 used herein is not intended to be convenient and substantially as defined in the art, and is not intended to be bound by any combination of theory or specific code. & Berger's (1976) Biochem Biophys Res comm 27 157-162, and each of them represents the inhibitory part of each of the enzymes Sl, si, ^ and S2, where the S1 adjacency side is cleaved. Position, and S2 is away from the side cracking position, S1, adjacent to the other side cracking position, and S2' is away from the other side cracking position. Regardless of the mode of binding, the compounds defined by Formula I are within the scope of the invention. I understand that "with R2, you can fill in the sub-positions of S1 and S1', and A, and a" interact with illusion and illusion, but you can use the opposite arrangement. The compound of the invention is preferably in the formula! The illustrated radicals exhibit at least 75%, preferably at least 9%, such as more than 95% -12 to 200804246 enantiomerically pure on the carbon shared with the methyl functional group. It is presently preferred that the compound have the high enantiomeric purity of the stereoisomers shown in the following partial structural formula:

〇 X

The X group can be in R or S stereochemistry. X as defined above is H, OH, CrC3 alkyl or QrC3 alkanediyl-〇-Cl_C3 alkyl. Suitable definitions for X include 0H and C (rC3 alkanediyl-0-Q-C3 alkyl, especially decyloxy (ie, C〇) and hydroxyindenyl. The purpose of X is preferably defined as hydrazine or OH. As described above, L is OH, F, NH2, NHCrC3 alkyl, N(CVC3 alkyl) 2, wherein NHQ-Q alkyl and alkyl) 2 are preferably NHMe and NHMe2, respectively. The presently preferred definition of L is fluorine, more preferably OH 〇 15 The compound of the invention may have 2 chain atoms between the carbonyl group of formula I and the functional group E (i.e., η is 0). Other embodiments of the invention include between 3 and 4 chain atoms between the carbonyl group and the functional group, i.e., η is 1 or 2, respectively. In a preferred embodiment of the invention, the compound has three chain atoms between the carbonyl group and the functional group ,, i.e., η is 1. When it is appropriate, the compound of the present invention comprises a monofunctional group, i.e., hydrazine, since this configuration allows the R2-indenyl side chain to have a favorable relative angle to the HIV protease S1' (or S1) pocket. For example, when Α" is as in Formula V. -13- 200804246 However, the 'best angle is of course still dependent on his interactive side mosquitoes, so the present, cis and the end of the E include CH. Specific examples are in the functional group. As defined above, RURi, 〇Γ alkyl, but especially CVC3 alkanediyl; f 'where Rl' is c-c6, a typical example of such a group, such as 7 wide c ° · 3 burned diyl heterocycle Up to 3 (four) independently selected from these bases, all of which may be suitable as needed... may be substituted by (4) R1G substituents. Substituent substituents 1, oxo = package, one or two selected from the group consisting of the lower two base carbons a ring group, a CVM dibasic hetero group, a calcining group, a .4 burning wherein Y is a -bonding or a cvc3 alkyl group UwNRaRb, Y-〇-Rb; a preferred substituent domain, a w-shing group, and a s-square ΐ" diyl group Heterocyclic group. When appropriate, such as 15 20, this C-C3-burning-based carbon ring, 々ρ c〇<3-alkyldiyl-linking moiety=dialkyldiylhomoinyl is defined as methylene or even More preferably, the substituent group is simply a carbon which is required to be substituted. = two, that is, R 'or the phenyl group to be substituted or may be optionally substituted with a ring group such as: a biting base or a base may be used. Preferably, R1 is R1' or OR1'. A specific embodiment of the present invention, Υ-Ο-Rb, wherein Y is a bond and Rb is a C substituent (the R substituent is a succinyl aryl group or a c s c3 succinyl aryl A) The rC3 group is preferably a county, such as T "replacement" > 14. 200804246 According to this embodiment, the preferred structural formula of R1 includes:

5 Therefore, other suitable definitions for R1 include phenyl, pyridin-2-yl, pyridin-3-yl, 11-butoxy-4-yl, ρ-hydrazin-2-yl, and -4- Base, ^ ratio 17 well-2-yl, ^-0 well-3-yl or tower 11 well-3-yl, t. well-4-yl or diterpenoid; or substituted by mono- or dihalo Phenyl group, such as phenyl substituted by mono- or difluoro. As defined above, the rule 2 is a CrQ alkyl group, but especially a C()-C3 alkanediyl 10 carbocyclyl group or a C〇-3 alkanediyl heterocyclic group, either of which can be independently selected up to 3 independently. Substituted from a substituent of R1G. The substituent which may be optionally used is preferably one or two members selected from the group consisting of halo, oxo, cyano, CrC6 alkyl, C()-C3 alkanedicarbocyclyl, C()-C3. Alkyldiylheterocyclyl, Y-NRaRb, Υ-0-Rb; wherein Y is a bond or a CVQ alkyl group, Ra - is a fluorene or CVC3 alkyl group, and Rb is a hydrazine or a CrC3 alkyl group. Substituted substituents at present include fluorine, crc3 alkyl, fluorenylene carbocyclyl or fluorenylene heterocyclyl, but especially such as substituents which may be substituted with a carbocyclic or heterocyclic group, for example: In the para position of the R2 cyclic group. Where appropriate, the definition of a CVC3 alkanediyl chain moiety on the C()-C3 alkanediylcarbocyclyl or CVC3 alkane 20 diylheterocyclyl group such as R2 or a substituent thereof optionally selected Is a fluorenylene group or even more preferably a bond, that is, R 2 or a substituent is a simple carbon-based group or a heterocyclic ring having a substituent of -15-200804246, such as: a phenyl group or a visible substituted phenyl group A substituted pyridyl group, a sigma-based morphine group, a ring sigma group or an α荅u well group is required. Therefore, the appropriate definition of R? includes stupid base, π ratio bite base, ° ratio -3- base, σ ratio biting winter base, mouth 唆-2_ base, mouth bite-4-base, β ratio η well- 2-based, pyridyl-3-5- or 嗒--3-yl, 嗒--4-yl or tri-rough; or substituted phenyl, especially para-aryl-carbon ring such as benzene A base or a heterocyclic ring, for example, a hydroxy group as defined below, for example, a 吼η定_2-yl group, a σ ratio -3-yl group or a phenyl group substituted with a -4-yl group. With respect to the terminal amidoxime', a convenient embodiment includes a bicyclic 10 line comprising the first 5 or 6 membered saturated ring which may optionally contain an oxygen heteroatom and which may optionally be substituted by a hydroxy or methyl group, and The two may need to contain one or two 5- or 6-membered unsaturated rings selected from the group consisting of 3, hydrazine and 1^[heteroatoms and optionally substituted by mono- or difluoro. Where appropriate, in this embodiment, the bond to the guanamine and the remaining molecules extends to the 1-carbon of the saturated ring. The base substituents which may optionally be employed in this embodiment are on the 2-carbon of the saturated ring. Alternatively, an oxygen atom is provided, typically in the 3-position of the 5-member saturation ring or the 4'-position of the 6-member saturation ring. In the specific example, the second ring should be 5 _ members and contain - Shi Ning 20 hetero atom or one oxygen hetero atom. Alternatively, the second ring is typically a fused base of the genus W09845330 or a phenyl group which may be substituted, for example, fused, wherein the substituent is mono- or di-gas. Representative of the specific embodiments of the present invention, the groups include: -16- 200804246

OH

F

OH

OH

Another embodiment of the compounds of the invention includes those wherein A' is a group of formula (II) by which a compound of the formula:

• 17- 200804246 Another specific embodiment of the compounds of the invention includes those wherein A' is a group of formula (ΙΓ), thereby defining a compound of the formula:

As described above, R3 is Η; or R3 is a CrC6 alkyl group, a C〇-C3 alkanediylcarbocyclyl group, or a Qr3 alkanediyl heterocyclic group, and any one of them may optionally be substituted with at least three substituents independently selected from R11. Substituted. Suitable definitions for R3 include QrC3 alkylheterocyclyl groups which may optionally be substituted, and especially those which may be substituted or substituted with a CrC6 alkyl group. Preferred R3 definitions include CVC6 alkyl groups such as isopropyl or tert-butyl which may optionally be substituted with a hydroxy or a decyloxy group or a halo group (e.g., fluoro). Preferred definitions for R3 are isopropyl, tert-butyl, 2-fluoro-1-methylethyl, 2-hydryl-1-indenylethyl, 2-methoxy-1-indenylethyl 2 - gas-1,1_ 15 dimethylethyl, 2-hydroxy-1,1-dimercaptoethyl and 2-decyloxy-1,1-dimethylethyl. The substituents required for the visual display of R3 are as defined above. Representative definitions include oxo, cyano or especially halo or oxime-0-Ra wherein Y is a bond or a CrC3 alkyl group and Ra is ruthenium or CrC3 alkyl. 2) As described above, R4 of the formula I, Ila and Il'a is a CVC6 alkyl group, a C〇-C3 alkanediylcarbocyclyl group or a C(rC3 alkanediylheterocyclic group, either of which may be required to be -18- 200804246 is substituted with up to 3 substituents each independently selected from R1G. A preferred definition of R4 includes a CrC6 alkyl group which may optionally be substituted, especially a fluorenyl or ethyl group or an optionally substituted thiol or ethyl group. Suitable substituents for R4 can be selected from the group consisting of halo, oxo, 5 cyano, azide, nitro, Crc6 alkyl, cvc3 alkanedicarbocyclyl, C(rC3 alkanediyl heterocyclyl, Y-NRaRb or Y-0_Rb, wherein Y is a bond or a cvc3 alkyl group;

Ra is hydrazine or CrC3 alkyl; ίο Rb is hydrazine or Ci-Cg alkyl, C0-C3 calcined diyl carbon soil or CQ-C3 succinyl heterocyclic. Preferred definitions for R4 are fluoroethyl, difluoroethyl, trifluoroethyl and decyloxyethyl. Preferred substituents for R4 may optionally include a ii group, an oxo group, a 15 CrC6 alkyl group, a C(rC3 alkanediylcarbocyclyl group, a cvc3 alkanediylheterocyclyl group or Y_0-Rb, especially a halogen group or Υ-Ο-Rb. Formula II may contain S or R stereochemistry, or its racemate, at the attached palm center of R3, but currently the preferred stereochemical configuration is as follows. : R3 R4』Y^< 0 20 (II) Alternatively, A' may include the following substructure: -19- 200804246 R5\

Wherein R 3 is hydrazine, or R 3 is a Ci-Cg alkyl group, a C0-C 3 calcined diyl carbocyclyl group, a 5 C0-3 alkanediyl heterocyclic group, either of which may optionally be independently selected from R 11 independently Substituted by a substituent; 115 is a CrQ alkyl group, a C(rC3 alkanediylcarbocyclyl group, a CV3 alkanediylheterocyclyl group, either of which may optionally be substituted with up to three substituents independently selected from R1G; Z is a bond, -NH_, -0-; R3 is preferably defined as described in Formula II above. 10 Formula III may contain S or R stereochemistry at the center of the R3 attached to the palm, or its racemization However, the current preferred stereochemical configuration is shown in the following structural formula:

Η (IN) R5 15 The current definition of z is 0. Advantageous definitions of R5 include crc6 alkyl groups which may be substituted as desired, especially sulfhydryl groups or methyl groups which may be substituted. — A' is advantageously defined as Formula IV, and is therefore defined as a compound of the formula -20- 200804246

Rx

R2 E, Λ" c c is two, and $ 疋 包括 includes monocyclic furan' where Rx is Η, λ, bis 1, r straight or branched alkyl, which can be used as needed

Rx; Η ΐ Γ Γ quot quot 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 x x x x x x x x r methoxypropyl hydrazine for work; ^ ^ ^ /. The special hard-to-finish compounds are those in which η j, Rx is defined as another material-based light-wire ring substituted with the C 15 or CVC 3 wire. Representatives see: Examples include those in which the heterocyclic oxygen position is as follows:

versus

As for the other terminal amidoxime "' as defined above, it is selected from the representative definitions of Formula V, 21 200804246 VII or VII Formula VI, especially when A' is a Formula II, IV or bicyclic system, including They are as follows:

>°V^ >N

Advantageous compounds according to this embodiment include compounds according to formulas Via and VIb:

Other advantageous compounds according to this embodiment include compounds according to formulas Vic and VId:

Particularly preferred compounds according to the formulae Via, VIb, Vic and VId are those of -22-200804246 and the like wherein η is 1, R1 is phenyl and/or L is 〇H. Suitable compositions for the preparation of compounds according to this embodiment of the invention are described herein and in WO 99/48885 and WO 94/05639. When appropriate, A" is a formula v, thus forming a compound of the formula:

Deng above, R. For u, from kappa, c〇_C3 alkane is 10 15 =, C〇-3 alkyldiyl heterocyclyl', any of which may be optionally substituted with a substituent independently selected from Ru. When appropriate, it is possible to use only the Cl-C6 alkyl group which may be substituted, or may optionally be subjected to alkanediylcarbocyclyl. At present, the more favorable R8 definition includes two or three substituted CrQ alkyl groups, especially isopropyl or tert-butyl group: σ, and R8 may be independently selected from R11 and substituted by 1 to 3, respectively. Representative optionally selected substituents include an oxo group, a 1st group, a Ci_C3 alkyl group, or especially a halo group or a Y- (MU, a complex medium, a murine group, a (tetra)alkyl group, and a Ra or a CVC3 alkane. Base: bonded or as described above, R9 is CVC6 alkyl, (VC3 alkanediylcarbanediylheterocyclyl, either of which may be passed to human soil, c〇-3 is selected from the substituent of w Substituting for -bonding, arbitrarily suitable for 'R9' is a qQ alkyl group which may be substituted or -23-20 200804246 Carbocyclic group, especially a methyl group which may be substituted, or an unsubstituted methyl group. Representative substituents of R9 may optionally include a halogen group, an oxo group, a cyano group, an azide group, a nitro group, a CrC6 alkyl group, a CVC3 alkanediylcarbocyclyl group, a CVC3 alkanediyl heterocyclic group, and Y. -NRaRb or Υ-0-Rb, wherein Y 5 is a bond or CVC3 alkyl group, Ra is hydrazine or CrC3 alkyl, and Rb is hydrazine or CrC6 alkyl, QrC3 alkanediylcarbocyclyl or C()- C3 alkanediylheterocyclyl. For example, when R9 is a methyl group, it is particularly preferable that the substituent which may be selected includes a halogen group, an oxo group, a CrQ alkyl group, a C()-C3 alkanediylcarbocyclic group, (:〇-(^3 alkyldiyl heterocycle) Or Υ-Ο-Rb. ίο When A" is of formula V, it is now preferred that W is -0-. Formula V can include S or R stereochemistry at the center of the R8 attached to the palm, or Spiral, but the current preferred stereochemical configuration is shown in the following structural formula:

(V) 15 A specific embodiment, when A" is as in Formula V, it includes a compound wherein R9 is a heterocyclic group which may be optionally substituted, which is a direct bond W (ie, C〇) or utilizes CrC3. An alkanediyl chain, for example, a fluorenylene chain (i.e., Q) is bonded to W. 20 Preferred compounds according to this embodiment include those compounds according to formulas Va and Vb: -24- 200804246

And 5 particularly preferred compounds according to formulae Va and Vb are those wherein η is 1, R1 is phenyl and/or L is ruthenium. Suitable compositions for the preparation of this embodiment in accordance with the present invention are described herein and in WO 98/00410 and WO 96/039398. In another embodiment, the compound when Α" is as defined in formula V includes U wherein W is a bond and R9 is C〇-C3 alkanediylcarbocyclyl or C(rC3 alkanediylheterocyclyl, The carbocyclic group and the heterocyclic group may be optionally substituted. Preferred compounds according to this embodiment include those compounds according to the formula Vc and Vd: -25- 200804246

5 Particularly preferred compounds according to formulae Vc and Vd are those wherein η is 1, R1 is phenyl and/or L is ruthenium. Suitable compositions for making this particular embodiment of the invention are described herein and in US 5,1964,438. When Α" is as in Formula VII, it is presently preferred that R8 is as described above, and R9 10 is CVC6 alkyl such as methyl. When appropriate, A" is as in Formula VIII, thus forming a compound of the formula Villa··

-26- 200804246, as defined above, R15 is carbocyclyl or heterocyclyl, any of which may optionally be substituted with up to three substituents independently selected from the group consisting of: CrC3 alkyl, hydroxy, oxo, halo, Q is 0, NR8 or a bond and r and q are each independently 0 or 1. 5 R15 is generally defined as an aromatic ring which optionally contains 0 to 2 members of 5 to 6 members independently selected from N, 0 and S heteroatoms. Suitable substituents for R15 may be selected to include (^-(:3 alkyl, such as fluorenyl, ethyl, propyl or isopropyl. Representative compounds of this embodiment of the invention are those of which Q 10 is a bond, and r and q are both zero. Preferred compounds according to this embodiment include those compounds according to formulas V11lb and VIIIc:

OH and

OH A, 15 Particularly preferred compounds according to formulas V11lb and VIIIc are those wherein η is 1, R1 is phenyl and/or L is OH. Suitable compositions for the preparation of this embodiment in accordance with the present invention are described herein and in US 5,484,926 and US 5,952,343. 20 </ RTI> wherein A's other advantageous compounds of formula VIII are those wherein Q is Ο -27 -27- 200804246. Preferred compounds according to this embodiment include those compounds according to the formulas Vllld, Vllle, Vlllf and Vlllg:

Particularly preferred compounds according to the formulae Vllld, Vllle, Vlllf and Vlllg are those wherein η is 1, R1 is phenyl and/or L is OH. 1-Preparation of suitable compositions in accordance with this embodiment of the invention is described herein and in W098/00410 and W096/39398. Wherein the other advantageous compounds of formula VIII are those wherein Q is CR8. Preferred compounds according to this embodiment include those compounds according to the formula isvmh and vim: -28· 200804246

Particularly preferred compounds according to formula Vlllh and vim are those wherein n is 1, R1 is phenyl and/or L is OH. 5 The preparation of suitable compositions in accordance with this embodiment of the invention is described herein and in US 6,372,905 and W097/21,685. Particularly suitable for the synthesis of a suitable intermediate of the compound of the formula (I) wherein η is 0. The epoxide comprising the following structural formula: 〇

Where Α' and R1 are as defined above. Other intermediates which are particularly suitable for the synthesis of compounds of formula (I) wherein η is 1 include epoxides and alcohols of the formula:

Wherein R1 is as defined above. -29- 200804246 ^Where adopted, cvc3 H〇_Ci_C3 alkyl, including Μ 2 melamine 1 such as direct bond (ie C〇) or using intermediate methylene, B 3 or u_ propylene The base chain is bonded to a methoxy group, an ethoxylated group, a n-propyl group, or an isopropoxy group. G 虱, the chain uses 'C1-C6 alkyl, including a straight tributary carbon bond substituent containing 1 to 6 carbon atoms, such as: methyl, ethyl, n-propyl, different ί 15 20 盥L-I^, isobutyl 't-butyl, pentyl, isopentyl and hexyl..., any single isomer. The burnt group may have an unsaturated bond. In addition, any carbon atom in the CrC6 alkyl group may be substituted with 3 halogens and/or a hetero atom s, hydrazine, NH, as desired, by two or two valences. If the hetero atom is at the end of the chain, then it may be substituted with 1 or 2 hydrogen atoms, such as: OH or NH2. Preferably, the cKC6 alkyl group is small, saturated and unsubstituted or substituted with a halogen such as fluorine. The CrC4 alkyl group and the CkCs alkyl group have a definition corresponding to the CrC6 alkyl group, and only need to be adjusted with the carbon number if necessary. Me refers to the base. As used herein, 'CrCs alkyl' includes fluorenyl, ethyl, propyl, isopropyl, cyclopropyl, either of which may be substituted as described above, or if C2 or C3, Unsaturated bonds, such as: CH two CH2. As used herein, &apos;QrC3 alkanediyl&apos; includes bivalent linear and branched aliphatic carbon chains such as, for example, anthracenylene, ethylenediyl, 1,3-propanediyl, 1,2-propanediyl. The guanamine group includes NH2, NHCrC3 alkyl or N(CirC3 alkyl)2. As used herein, &apos;halo, or halogen includes F, CH, Br, I, specifically chlorine, preferably fluorine. As used herein, 'QrC3 alkanediylaryl' includes phenyl, naphthyl or with -30-200804246 C3_C7 cyclopropyl copper (ie, as above; c:c=== linkage, E. Substrate, U-propanediyl or 13H; the intermediate of the sub-methylene, otherwise stated, otherwise, and /4_,, 3-propanyl-based bond 钇 unless the need to pass 1_3 in this article is selected from 1: column 4 ^ thick Some of the groups of the lysine group may be substituted by a cyano group, a county, or a base: a halogen group, a fluorenyl group, a succinyl group, a burnt group, a CA _diamine oxime 6, an oxy group, a CrC6 alkoxy group-Cl_C6 ^ Λ Γ r a A, a stack Nitrogen, oxo, thiol, stone-based c 『c3 burned two-base carbocarbanyl group, with a corresponding definition. 4 c 『c3&amp;-based ray. "Fang 10 15

2Q As used herein, 'C〇-C3 alkane II^^^#, ^ and II AC3C groups include C (&quot;C3 burnt diaryl or aryl or ring^ visible^ unless otherwise stated herein. The alkyl group has a 1-3 substituent selected from the following: its dentate group, thiol group, nitro group, cyano group, county, Crc6 alkyl group, C1-C6 alkyloxy C1-C6 Sulfhydryl, C1_C6 decyl, amide, =, aryl, thiol, nitro, C (rC3 alkanediylcarbocyclyl and / bis, dimethyl-heterocyclyl. "Carbocyclyl" There is a corresponding definition, that is, the CVC3 alkanediyl chain in the bean does not exist. h, ^ used the 'QrC3 alkanediyl heterocyclic group, including the monocyclic ring saturation or T saturated _ subring, ^ _ group,减减, (四)基&quot;比士土W基&quot;η基, (四)Salyl, base, heterogeneous base, stagnation 7-oxazolyl, •triazolyl, 1 and 4-3-triazolyl, IV Azolyl, ruthenium, fluorenyl group &quot; u 定 ” ” 、 、 、 、 、 、 、 、 、 、 、 比 比 比 比 比 比 比 比 比 , , , , , , , , , , , , , , , , , , , Such as: 啥琳基苯苯咪基, benzo-salt, stupid and hetero-sitting, benzo-- 31 - 200804246 10 15 2 mercapto, benzopyrene, benzoxyl, benzoxanthyl, benzo-1,2,3-: wow, benzo-1,2,4 -Triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzoacridinyl, benzopyrimidinyl, benzindene, benzopyryl, benzoxazolyl And so on, the ring is directly bonded (co), or bonded using a methyl, ethyl, propyl or isopropyl group as defined above for the C〇_C3 alkanediyl group. Any such aromatic system The characteristic unsaturated ring may be a heteroaryl group in the present invention. Unless otherwise stated herein, the heterocyclic ring and/or the fused phenyl moiety may optionally be selected from the group consisting of 1-3 Substituting f for a dentate group, a hydroxyl group, a nitro group, a cyano group, a carboxyl group, a Ci_c6 alkyl group, a sulphonic acid oxy group, a Cl_c6 alkoxy group, a Ci_C6 alkyl group, a Ci_C6 sinter base, a soil, a sulphur group, an oxo group, a hydrogen group Thio, nitro, Cg_c3 carbocyclyl, ^3 heterocyclyl. "Heterocyclyl," and "heteroaryl," have the corresponding definition, that is, "肀c〇-C3 alkanediyl linkage is absent. The ^3 burned two-base carbocyclic group to be recorded, and 4 The need to burn a dibasic heterocyclic group, the noun typically refers to the substituted soil: =:, 5 groups: has 5 ' or especially 6 bicyclic structures. 5 or 6 members of the ring fused 6-member ring Such groups typically include C3_Cc搢栌##^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ , base, fluorenyl, tetrahydro π-pyranyl, tetra = linyl, core well base, ahlin D south base, tetrahydrogen base, (tetra) base, base, light thiol, oxime base, nickname Azyl, isoxazolyl, -32- 200804246 fluorenyl, imi, (d), base, %, base, tetradecyl, (tetra), (iv), benzene, mat, benzene Miso-based, benzo-anthracene, benzo-deca- green, benzo-iso-decyl, fluorene-based, tetra-argonquin-like, hetero-isomeric, tetrahydroiso(tetra)yl, heptadyl, tetrahydroanthracene In contrast to the materials, any of them may be replaced as defined above. Thus, a saturated heterocyclic ring includes a group such as a pyrrolinyl group, a pyrrolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a pyranyl group, a thiopyranyl group, Piperidinyl, porphyrinyl, 吖σdyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydroindole, 1,4,5,6-tetra Pyrimidinylamine, dihydro-sazozolyl, anthracene, 2_thinyl-arylene-oxide, 1,2,6-thiadialkyl-l,i-dioxide, isothiazole bite a base-1,1·dioxide and an oxazolidinyl group 2,4_di-, wherein the unsaturated heterocyclic ring includes a group having the characteristics of a scented scorpion, such as σ 夫 喃 、, σ 塞 基, . Ratio π, Π, 唾, 嗟, 咪, 咪, σ, σ, 异, 异, 异, 嗟, σ, σ, σ, 嗤, 噻Salivation, π-mercapto group, towering base, % ° base, 11 ratio base, argon-based, sulfhydryl, iso-decyl. Each of the heterocyclic rings may be condensed with a phenyl ring to form a bicyclic ring system. The compounds of the invention may form salts and are a further aspect of the invention. Suitable pharmaceutically acceptable salts of the hydrazine compound include salts of organic acids, especially carboxylates, including but not limited to: acetates, trifluoroacetates, porates, gluconates, Citrate, tartrate, maleate, apalate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate , digluconate, cyclopentanoate, gluco-33- 200804246 heptanoate, glycerol phosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate, ALT, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivalate, camphorate, undecanoate and amber Acid salt; organic sulfonate 5 such as: mesylate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, besylate, p-chlorobenzenesulfonate Acid salt and p-toluenesulfonate; 'and inorganic acid salts such as: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, hemisulfate, thiocyanate, persulfate , Phosphate and sulfonate. The compounds of formula I can sometimes be isolated as hydrates. It is to be understood that the present invention includes prodrugs, solvates, and complexes of the compounds of formula I and other forms which liberate compounds of formula I in vivo. Although the active agent can be administered alone, it is preferred to be part of a pharmaceutical formulation. Such formulations will comprise an active agent as defined above together with one or more acceptable carriers/excipients, and 15 other parts of the medical treatment as may be desired. The carrier (group) must be acceptable below that it is compatible with the other ingredients of the formulation and is not deleterious to the recipient. The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferred formulations are administered orally. Use the formulation. When the formulation is convenient, it can be in a unit dosage form, for example, a tablet and a sustained release capsule, and can be prepared by any method known in the art of pharmacy. These methods include the steps of mixing the active agent with the carrier as defined above. Typically, the formulation is prepared by uniformly mixing the active agent with a liquid carrier or a finely divided solid carrier or both, and then, if desired, shaping the product. The present invention includes a method of preparing a pharmaceutical composition which is a mixture or combination of a compound of formula i or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle thereof. If the pharmaceutical formulation is prepared by uniformly mixing a pharmaceutical excipient with a salt-form active ingredient, it is generally preferred to use a non-basic excipient, also known as an acidic or neutral excipient. The oral preparation of the present invention may be in the form of a separate unit, such as: a capsule, a film-coated tablet or a tablet each containing a predetermined amount of the active agent; a powder or a granule; a solution or suspension contained in an aqueous liquid or a non-aqueous liquid; Oil-in-water emulsion or oil-in-water emulsion, and in the form of a bolus, and the like. 10 In oral compositions (eg, tablets and capsules), the term carrier includes vehicles such as: commonly used excipients such as binders such as syrup, acacia, gelatin, sorbitol, Astragalus gum, polyvinylpyrrolidone (Povidone), mercapto cellulose, ethyl cellulose, sodium methicone, hydroxypropyl decyl cellulose, sucrose and starch; fillers and carriers, for example: 15 Corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metal stearin Acid salts, glyceryl stearates, stearic acid, ketone liquids, talc, waxes, oils and colloidal vermiculite. Flavoring agents such as mint, wintergreen oil, cherry flavor and the like can also be used. It may also be necessary to add 20 colorants to facilitate the differentiation of the dosage form. Tablets may also be coated by methods known in the art. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. The compressed tablet preparation method can be used in a suitable machine to compress a free-flowing type of active agent, such as powder or granules, and can be mixed as needed. -35-200804246 ^Two lubricants, inert diluents, preservatives, and interface plastic lozenges It can be molded from a powder that has been wetted by an inert liquid diluent: the compound is molded in a suitable machine. The tablet may be coated with a coating or a strand as desired and may be formulated as a slow or controlled release active agent. And/or his orally suitable formulation includes a cachet containing an active agent in a flavoring base (usually acacia or tragacanth); in an inert base 2 (eg, gelatin and ganj, or sucrose) The gold-filled gel contains a hydrazine bond of a deuterium agent and a mouthwash containing an active agent in a suitable liquid carrier. When the dose will be determined according to the indication and the patient, it is easy to determine the typical drug dosage of the compound by the conventional animal drug metabolism and pharmacokinetics _ρκ) or clinical trials to estimate the ^ ^ / oral treatment of HIV. The plasma concentration is brought to about 100 to 5000 nM, such as: 300 to 2 〇〇〇 nM. It is determined by the bioavailability of the formulation, which is 0.01 to 1 mg/kg/day, preferably 01 to 2 mg/kg/day. Typical dosage ratios for normal adults range from about 0.05 to about 5 grams per day, preferably from 1 to 2 grams, such as /:, 500 to 750 * grams, and _ days can be administered to 4 unit doses. As with all drugs, the dose ratio will vary with the patient's size and metabolic conditions, as well as the severity of the infection, and may be adjusted with the drug being administered at the same time. The general agent i is from about 3 mg to about 1.6 g per person per day, and if appropriate, can be divided into 1 to 3 small doses. A typical dose for an adult patient is 50-800, more preferably 400-600 twice, or optimal once a day. The HIV inhibitors as described below are typically administered in unit dosage form in combination with other HIV inhibitors or metabolic modifiers. The dosing regimen of these combination administrations is -36-200804246 (QQ, (4), TiD, fasting/feeding, etc. Etc.) Of course, it is necessary to cooperate with the ^ medication treatment adjustment. As with good antiviral therapy prescriptions, the compounds of formula I are typically administered in conjunction with other HCV therapies to avoid the production of mutants that evade the drug. 5 35 and some anti-infective agents can induce a synergistic response, such that the activity of one or both of them is lower than the corresponding monotherapy. Examples of drugs that are rapidly metabolized by CyP3A4, when administered together with the HIV protease inhibitor ritonavir, reduce the dose of the course of treatment. When the compound of the present invention is administered together with other or other antiviral agents, the typical molar ratio should reflect its individual activity and bioavailability. This ratio is usually between 25:1 and 1:25, but may be lower, for example, when using a cytochrome antagonist such as rit〇navir. Representative HIV antiviral agents include NRTIs such as: alvudine (FLT), zudovudine (AZT, ZDV), stavudine (d4T, Zerit), 赛达本 ( Zaicitabine) (ddC), didanosiiie (ddI, Videx), acacavir, (ABC, Ziagen), lamivudine (3TC, Epivir), emtricitabine (emricitabine) FTC, Emtriva), racevir (racemic FTC), adefovir (ADV), entacavir (BMS 2〇200475), Aile > 'alovudine' (FLT), tenofovir disoproxil fumarate (TNF, Viread), amdoxavir (DAPD), D-d4FC (DPC-817), -dOTC (Shire SPD754), sulphate (elvucitabine) (Achillion ACH-126443), BCH 10681 (Shire), SPD-756, racivir, -37-200804246 MIV-606 (Medivir), D-FDOC, GS7340, ΙΝΚ-20 (sulfur Thioether phospholipid AZT, Kucera, 2'3'-dideoxy-3'-fluoroguanosine (FLG) and its prodrugs such as: MIV-210, reverset (RVT) , D-D4FC, Pharmasset DPC-817). 5 Representative NNRTIs include delavirdine (Rescriptor), efavirenz (DMP-266, Sustiva), nevirapine (BIRG-587, Viramune), (+) mulberry Calanolide A and B (Advanced Life Sciences), capravirine (AG 1549f Sl 153; Pfizer), ίο GW-695634 (GW-8248; GSK), MIV-150 (Medivir), MV026048 (R -1495 ; Medivir AB/Roche) ^ NV-05 2 2 (Idenix Pharm·), R_278474 (Johnson &amp; Johnson), RS-1588 (Idenix Pharm.), TMC-120/125 (Johnson &amp; Johnson), TMC -125 (R-165335; Johnson &amp; Johnson), 15 UC-781 (Biosyn Inc.) and YM215389 (Yamanoushi). Representative HIV protease inhibitors include PA-457 (Panacos), KPC-2 (Kucera Pharm), 5 HGTV-43 (Enzo Biochem), Amprenavir (VX-478, Agenerase), Adefi ( Atazanavir) (Reyataz), Indinavir Sulfate 2〇 (MK-639, Crixivan), Lexiva (Fosamprenavir Mom, GW-433908 or 908, VX-175), Litfi (ritonavir) (Norvir), lopinavir + ritonavir (ABT-378, Kaletra), tipranavir, nelfinavir valerate (Viracept),赛菲菲-38- 200804246 (saquinavir) (Invirase, Fortovase), AG1776 (J-2147, KNI-764; Nippon Mining Holdings), AG-1859 (Pfizer), DPC-681/684 (BMS), GS224338 (Gilead Sciences), KNI_272 (Nippon Mining Holdings), Nar-DG-35 (Narhex), 5 P(PL)-100 (P-1946; Procyon Biopharma) ^ P-1946 (Procyon

Biopharma), R-944 (Hoffmann-LaRoche), RO-0334649 (Hoffmann-LaRoche) - TMC-114 (Johnson &amp; Johnson), VX-385 (GW640385; GSK/Vertex), VX-478 (Vertex/GSK) 〇10 Other HIV antiviral agents include invasive inhibitors, including fusion inhibitors, inhibitors of CD4 receptors, inhibitors of CCR5 co-receptors and inhibitors of CXCR4 co-receptors, or pharmaceutically acceptable salts thereof or Prodrug. Examples of invasive inhibitors are AMD-070 (AMD11070; AnorMed), BlockAide/CR (ADVENTRX Pharm.), BMS 15 806 (BMS-378806; BMS), and Enfurvirtide (T-20,

R698, Fuzeon), KRH1636 (Kureha Pharmaceuticals), ONO-4128 (GW-873140, AK-602, -913; ONO

Pharmaceuticals), PRO-140 (Progenics Pharm), PRO-542 (Progenics Pharm.), SCH-D (SCH-417690; 2〇Schering-Plough), T-1249 (R724; Roche/Trimeris), TAK-220 ( Takeda Chem· Ind·), TNX-355 (Tanox) and UK-427, 857 (Pfizer), examples of integrase inhibitors are L-870810 (Merck &amp; Co.), c_2507 (Merck &amp; Co.) and S (RSC) ), 1838 (shionogi/GSK) 〇-39- 200804246 Many HIV patients co-infect or are susceptible to super-infectious other infectious diseases. Accordingly, another aspect of the invention provides a combination therapy comprising co-producing a compound of the invention with at least one other anti-infective agent in the same dosage unit or co-package. The compounds of the invention may be administered simultaneously or sequentially with at least one other anti-infective agent, typically a corresponding dose of a single drug therapy administered to the relevant agent. Typical co-infections or super-infections include hepatitis B virus (Hbv) or hepatitis C virus (HCV). Accordingly, the compounds of the invention are preferably co-administered (in the same dosage unit, co-packaged or divided dosage unit) with at least one HCV antiviral agent and/or at least one HBV antiviral agent. Thus, the compounds of the invention are preferably co-administered (in the same dosage unit, co-packaged or divided dosage unit) with at least one HCV antiviral agent and/or at least one HBV antiviral agent. Examples of HBV antiviral agents include lamivudine and 2,3,-dideoxy-3,-fluoroguanosine (FLG) and its prodrugs such as: 5Ό-•乳醯基缬胺醯基前Drug MIV_210. These HBV antiviral agents are particularly suitable for combating both HBV and HIV. HCV antiviral agents for co-administration with a compound of formula I include immunological modifying agents such as ribavirin or interferon, nucleotide hcv | synthase inhibitor or HCV protease inhibitor, many of which are If still in development. The compounds of the present invention are capable of counteracting elevated LDL-cholesterol and/or triglyceride concentrations in the side effects found in HIV protease inhibitors commonly used in the prior art. Thus, the compounds of the present invention are suitable for use in the 200804246 dose therapy performed by a patient in place of such prior preparations that such prior art collectors have used or are using. Typically, these * formulations are subjected to antiviral therapy and blood HIV&apos; and/or triglyceride concentrations. These other = see two LDL-cholesterol can be used as mono-therapies or as anti-reverse egg (10) inhibitors (groups) also include one or more other anti-reverse transcriptions;::: some: where 'inhibitors Or non-nuclear shirt transcriptase inhibits the reverse virus to suppress the viral suppression effect, but the music is dangerous to have cardiovascular disease. 4(10) Money and early development 10 15 20 The term “increasing blood Lr>T Hfe m t 门门求丫乙^ cholesterol and triglyceride concentration” is based on the National Cholesterol Education Program (Nad〇nal).

Cholesterol

Clinical Practice Guidelines for Prevention and Treatment of Adult High Cholesterol in the Education Program) (NCEP). In the latest guidelines published in 2001, plasma LDL cholesterol concentrations &gt; 130 mg/dL and triglyceride concentrations &gt; 150 mg/dL were considered elevated or "high concentrations". The method of the present invention is particularly suitable for patients with plasma triglyceride concentration &gt; 200 mg/dL and those who have no cardiovascular risk factors or have not had cardiovascular disease in the past, but the LDL-cholesterol concentration is &gt; 160 mg/dL The patient. To improve this, the definition of 'LDL-cholesterol and triglyceride concentrations will of course vary with NCEP's continued assessment of heart attack risk factors. Therefore, the use of increased LDL-cholesterol and triglyceride concentrations will be in line with current NCEP guidelines. One aspect of the present invention provides a Hev protease inhibitor involved in stopping the inoperative application of -41 - 200804246 (S &amp; blood LDL-cholesterol and/or triglyceride concentration), as opposed to suppressing HIV nucleus Compound substitution to reduce LDL-cholesterol and/or triglyceride concentrations in blood clots. The dosage of this hairy month &amp; the substance will be determined according to the body weight of the patient to be treated, the age and individual conditions and the mode of administration. It is believed that the compounds according to certain embodiments of the present invention may advantageously interact with cytochrome ρ45 〇 monooxygenase in certain formulations to improve the pharmacokinetics of the metabolism of the enzyme to the drug, Other drugs include other HIV protease inhibitors such as: SaqUinaVir, indinavir, nelfinavir, aprenavir, tipanavir and Lenofi (l〇pinavir). Therefore, its action is similar to that of ritonavir in U.S. Patent No. 6, 〇37,157, which can be used to increase the concentration of 蛋白酶ν protease inhibitors co-administered in blood. Where appropriate, contrary to rit〇navir, the 15 compounds of the present invention can replace rit〇navir, which is lower than the medical dose, with other mv proteases in its normal medical dose range. The inhibitor is administered in combination. Any of these potentiating effects of other HIV protease inhibitors can be metabolized by cytochrome Ρ450 monooxygenase, and thus the compounds of the invention can be used in conjunction with such other HIV protease inhibitors to reduce the use of these other mV protease inhibitors. Dosage and maintain the same level of repressive virus. The compounds of the present invention can be used in combination with other HIv protease inhibitors to reduce the concentration of LDL-cholesterol and triglyceride in AIDS patients receiving protease inhibitor therapy while still maintaining the desired level of repression. -42. 200804246 An appropriate agent for an HIV protease inhibitor which can be combined with a compound of the present invention can be determined by the method for the combination therapy of azanavir and saquinavir according to W003020206. Compared to nelfinavir and indinavir, Adefi is a moderate inhibitor of cytochrome 5 P450 3A enzyme with a Ki of 2.4 μM. The latter two compounds were stabilized, increasing the effect of seifei (three times a day (TID) dose of 1200 mg) by 392 and 364%, respectively. Multiple dose pharmacological tests have been completed if a combination of Adefi and Secfi can achieve similar enhancement effects. This trial showed that the combination of Adefi and the effect increased by more than 3 times, this support ίο - once a day 1200 mg Secphi dose is equal to the effect of the current product 克 菲 1200 mg TID treatment. Similar to the method described in the literature, the dose range (AUC (area under the curve) and CMIN (lowest concentration)) was explored for the Secphi effect using a constant dose of ardi. Similarly, an appropriate dose of 15 other HIV protease inhibitors administered in combination with a compound of the invention can also be calculated. A typical synthesis of the compounds of the invention is as follows. In the formula of the present invention, hydrazine is a hydrazine, and a compound having a η of 0 is reacted with a suitable epoxide and a desired hydrazine derivative as shown in Fig. 1. -43- 200804246

Reaction Scheme 1 takes a suitable malonic acid derivative (ia)' wherein r1 is converted into an acrylic acid bamboo (lb) by the Mannich reaction as described above, and then the decarboxylation reaction is carried out in situ. Many different malonic acid derivatives are commercially available or can be readily prepared by methods known to those skilled in the art. The acrylic acid is then subjected to a coupling reaction with the desired amine A, -NH2, wherein A' is as defined above, using standard peptide coupling conditions, for example: using 1 &lt;3_di-1 〇methylaminopropyl)-3-ethyl The coupling of carbodiimide hydrochloride (EDAC), hydrazine methylmorpholine (NMM) with 1-hydroxybenzotriazole (H0BT) or any other suitable conditions known to those skilled in the art to produce acrylamide derivatives (lc). The double bond is subjected to an epoxidation reaction by any suitable method, for example, using a peroxide such as 3-chloroperoxybenzoic acid (mcPBA) to give the corresponding ring. 15 Oxide (ld). Subsequent enthalpy (le) can then be used to open the epoxide formed in the presence of titanium (IV) isopropoxide in the presence of titanium (IV) isopropoxide in accordance with JC, 50, 1985 p 1557 to produce a tertiary alcohol. If desired, the resulting hydroxyl group can be converted to a fluoride ion or a primary or secondary amine, thus producing a compound according to formula I, wherein η is 〇, χ is ^^ is 1^ and [is f, NHCi_C3 200804246 burned or l^ CVC3 alkyl) 2 ' is shown in Figure 2 below.

Ftr&quot;nh diad

A,

I NFTR&quot; R1 2b

A&quot;

Rf is H or CrC3 alkyl R&quot; is H or CrC3 alkyl reaction Figure 2 Alcohol (If) with a suitable fluorinating agent such as: DAST or Deoxofluor, etc. 'in a solvent such as: di-methane, according to, for example: Singh R. p. reacts with the method described by Shreve, J. Synthesis in Synthesis, 17, 1999, ρ· 2561-2578 to produce the corresponding fluorine compound (2a). Alternatively, the hydroxyl group of the alcohol (lf) can be transferred to the amine by any convenient method described in the literature. For example, a Mitsunobu procedure can be used, that is, an alcohol (if) and an azodicarboxylate such as diad, etc., are reacted in the presence of triphenylphosphine, and then replaced with the desired amine. To produce the desired corresponding amine derivative (2b). Another way to form the amine (2b) is to convert the hydroxyl group to form a cleavage group such as a sulfonic acid derivative such as methanesulfonate, triflate, tosylate, etc., using a suitable sulfonating agent. , in a solvent (such as, for example, pyridine or dichlorof-alkane), if necessary, in the presence of triethylamine, etc., the substitution -45-200804246 reaction, and then use the desired primary or secondary amine NH2ci- C3 alkyl or NH (CKC3 alkyl h replaces the cleavage group. Alternatively, the azide may be used to displace the cleavage group, or the hydroxy group may utilize an azide transfer agent such as diphenylphosphonium azide (DPPA), Direct conversion to azide, and then reduction of the azide introduced to form an amine, for example, using triphenylphosphine, optionally in the presence of a base (eg, triethylamine), in the formula The compound of [112], the resulting amine is subjected to a reductive amination reaction with the desired aldehyde or ketone to produce a secondary or tertiary amine. Such as the above intermediate, for example: epoxide Id, wherein a, and R1 10 As defined above, it is a novel compound and constitutes another aspect of the invention. The different amines used in Reaction Scheme 1, A'-NH2, can be obtained from commercial products or can be prepared according to the literature. For example, A, such as the amine of formula (IV), can be based on Bioorg of Samuelsson et al. Med. Chem., 11, 2003, ρ·1107-1115, prepared by the method described. Alternatively, it may be prepared by converting a base group of an alcohol group to an amine group. The transformation reaction may be carried out by the related art. Any suitable method known to the person, for example: converting a hydroxyl group to form a cleavage group, such as a halide ion, such as a bromide ion, a chloride ion or a cesium ion, or a derivative of a rhein acid such as a fluorite, three Fluorofluoride or benzenesulfonate, followed by nucleophilic displacement of the azide counter 20 should be 'finally using any suitable reaction method such as catalytic hydrogenation, reducing the azide to form an amine. Suitable alcohols are described For example: Α·Κ. Gosh et al., J. Med. Chem., 1996, 39, 3278-3290. Another method for preparing A', such as formula (IV), amine A'-NH2 is illustrated in Reaction Scheme 3 -46- 200804246

3a 3b 3c X is O or S, n is 1 or 0

Reaction Scheme 3 The method of adding a bromide ion and a propargyloxy group to the double bond of the unsaturated ring (3a) is carried out by reacting N-bromosuccinimide with propargyl alcohol and then using tri-n-butyltin hydride. In the presence of a base initiator such as 1,1,-azobis(isobutyronitrile), or the like, a reductive ring-blocking reaction is carried out to produce a bicyclic olefin (3c). The ketone derivative (3d) is produced from the olefin compound by appropriate oxidation conditions such as treatment with tetrazoic acid and treatment with sodium periodate to oxidatively cleave the outer double bond. The resulting ketone group is reacted with a hydrazone-hydroxylamine and then reduced with a reducing agent such as lithium aluminum hydride to give a racemic mixture of the corresponding amine (3f). The racemic mixture is then separated according to methods known in the art. For example, a diastereomeric mixture which can be separated by chromatography can be used as a palmitic adjuvant compound, such as a palmitic amino acid, for example: B〇 (&gt; L_phenylalanine) Standard coupling is carried out by coupling reaction. After separation of the mixture, the amino acid is cleaved to produce the pure diastereomer (3f) of the desired amine. The amine derivative A, _NH2 is used (ie, in Figure 1) A, as in the formula (II)) -47- 200804246, is shown in the following reaction scheme 4.

NHBoc R3 4a

H+ 4c R4,

NH2 R3 4d R4—NH2 4b

EDC

NMM

HOBT Reaction Figure 4 A suitable N-protected (eg Boc protected) amino acid (4a) with the desired side chain R3, and an amine derivative (4b) (wherein R3 and R4 are as defined above) Standard coupling conditions, such as: using a coupling reagent, such as: EDAC, NMM and HOBT, in an inert solvent (such as dimethyl decylamine), a 1 〇 coupling reaction to produce guanamine (2Bc). In the case of the Boc protecting group, the N-protecting group is removed by an acid treatment, for example, using trifluoroacetic acid, and reacted in dichloromethane to give the amine (4d). The amino acid (4a) used in the above reaction scheme can be obtained from a commercial product or can be produced according to the method described in the literature. A method of preparing an amino acid having a branched side chain is exemplified in Reaction Scheme 4A.

R3 is Η or CH3

Reaction Figure 4 A -48- 200804246 Amino acid (4Aa) prepared by the method described by Rapoport et al., J. 〇rg. Chem., 55, (1990) p 5017-5025 via one or two bases such as • Shuang-(trimethyldecyl) potassium amide (KHMDS) and methyl iodide are added sequentially to produce mono- or dimethyl-amino acids (4Ab), respectively. A reagent such as DIBAL is used to transport the original side vinegar, and then reacted with b〇C2〇 in the presence of a catalyst (e.g., Pd/c) to convert the PhF1 group to a Boc group to produce an alcohol (4Ac). If desired, the hydroxyl group of the resulting alcohol can be subsequently thiolated, for example, by treatment with a suitable methylating agent such as mercapto iodide and a base such as NaH to give the oxirane compound (4Ae). Alternatively, the alcohol is treated with a fluorinating agent such as DAST, or the like, or treated by any other suitable fluorination method as described or used herein, to convert to the corresponding fluoro compound (4Ad). The method for preparing A', -NH2, such as the formula (ΙΠ), is exemplified in Reaction Scheme 5.

IBCF

ϋ) CI\^R5 T 5d 〇

R3 〇 5c

Hi) 〇=C=N R5 Ο 15 Reaction Figure 5 Reaction of the natural or non-natural amino acid (5a) with the appropriate side chain R3 as defined above with the desired oxime; used to form w Compound-49- 200804246 ί:! ΐ使: Chloroformic acid? (i) for the formation of a bond in which w is a bond, or a ruthenium chloride (9), or used to form a bond in the middle, which is acid Μ, Γ i ). The amine A, · 2 (10) is known to be converted into the corresponding first-stage guanamine (5 phantoms, for example: using a milk solution: in the presence of isobutyl chloroantimonate and N_f carbaryl, in the presence of dimethoxy Solvent treatment of thioacetone, followed by [bis(tri-I-ethoxy)iodo]benzene, optionally in the presence of pyridine, for example: j_A·Fehreentz in J· Med·Chem·, 2003, 46, 1191_1203 The method described is carried out to carry out the recombination reaction. The reaction method of the anthracene derivative (le) used in the reaction of Figure 1 can be prepared from the standard peptide by acid a, COOH or a derivative thereof, for example, mercapto chloride or anhydride, and 肼r2CH2NHNH2. The next reaction. Figure 6 illustrates the reaction in which the A' of the acid A''COOH is the formula (v) as defined above. 15 〇Η〇^γΝΗ2 R8 6a i) Cl

Ya i ii. or iii

H2N 6b 6c R2, EDC hobt nmm 〜vv, γ r9 R8 〇6d R9 *·) CIn^^RQ iii) 0=C=N^ T , R9 〇Reaction Figure 6 From 4, as defined above, the appropriate side chain r8 The natural or non-natural amine is reacted with the desired deuteration agent according to the method illustrated in Figure 3 to produce hydrazine (6b). Reconstitution of the standard peptide coupling conditions as described above, coupling with an anthracene derivative (6C) prepared by the method of the product or prepared according to the method described in the literature, yields an anthracene derivative (6d). Wherein A", when a compound of formula (VII) is suitable, can be prepared according to the above route, but wherein a suitable sulfonating agent (eg, alkylsulfonyl R9-S(=0)2C1) is used instead of a base such as: In the presence of sodium hydroxide, in place of the above-mentioned deuteration agent i, ii or Hi which reacts with the amino acid 3a. (1 e) The A" method of the formula (VI) can be prepared from a suitable nucleophilic carbonyl compound. Such as: chlorophthalic acid ester or activated carbonate, and the hydrazine derivative R2CH2NHNH2 as shown in Figure 7.

Reaction Figure 7 The hydroxyl group of the alcohol (7a) can be combined with a suitable hydrating agent such as a carbonate (such as: dipyridyl 15 pyridine carbonate or p-nitrophenyl phthalate), if necessary in the base (such as: three Reaction in the presence of ethylamine or imidazole), conversion to the corresponding activated carbonate (7b) or chloroformate, or reaction with carbon ruthenium chloride, if necessary in the presence of a test (eg sodium cesium carbonate), conversion Chloroantimonate. The resulting electrophilic compound can be further reacted with the desired anthracene derivative (7c) to give the corresponding oxime (7d). The alcohol (7a) 2〇 can be obtained from a product or can be, for example, J. Med·Ghosh et al.

Prepared by the method described in Chem., 1996, 39, 3278-3290. -51 - 200804246 The reaction diagram 7 illustrates that the shear requires a substituted carbocyclic group, such as a visible alcohol, a heterocyclic methyl alcohol which may be substituted as needed, and optionally substituted, thereby producing A, The aryl group of the formula I wherein EA \ is a formula (Vm) as defined above may be prepared by a cycloalcohol or a heterocyclic ring which may optionally be substituted. Figure 8.苟Ν, the compound pathway with η of 1 is shown in the reaction 〇

Reaction Figure 8 Butane lactone (8a) and a suitable aldehyde (8b) in the presence of a base (such as potassium tert-butoxide), _ in an inert solvent (such as: benzene, dichlorodecane, etc.), An olefin compound (8c) is produced. The epoxidation of the double bond can be carried out, for example, by using mCPBA' in the presence of a catalytic amount of a free radical initiator such as AIBN, etc. to produce an epoxide (8d). The reductive ring-opening reaction of the epoxide can be carried out, for example, in the presence of a catalyst such as Pt(IV)〇, etc. • 52- 200804246 眭 hydrogenation reaction, followed by opening with the desired amine A, -NH 2 a lactone ring that produces an oleyl alcohol (80. The primary alcohol is oxidized by any suitable oxidation method (eg, using Diss-Martin periodine) to produce an aldehyde (8 g) followed by a suitable bacterium (8h) ), using a reducing agent (such as: NaCNBH4) for reductive amination reaction 'production of bismuth (8i) 〇N-substituent CH2_R2 introduced by the system of nitrogen and the desired alkylating agent (8j) R2 is as defined above, and X is a leaving group such as a tooth ion (e.g., chloride ion, bromide ion or iodide ion) or a sulfonic acid derivative (e.g., triflate, sulfonate or tosylate). The alkylation reaction produces an N-alkylated compound (di). The above synthetic route can also be carried out by using β-propiolactone as a starting material to produce a compound of the formula I wherein η is ruthenium. (8k) can also be more directly from the aldehyde (8g) and the oxime-alkylated hydrazine derivative (eg, from the reaction diagram 3) 3d) The reaction is prepared as follows. The intermediates such as epoxide 8d and alcohol 8e (wherein R1 is as defined above) are novel compounds and constitute a further aspect of the invention. If desired, the hydroxyl group of compound (8k) can Conversion to a fluoride ion or a primary or secondary amine, thus producing a compound of the formula I wherein η is ΐ, χ is H, and E is N and L is F, NHCKC3 alkyl or N(CVC3 alkyl) 2, as described below Figure 9. -53- 200804246

9b

R' is H or CrC3 alkyl R" is a hydrazine or CrC3 alkyl reaction. Figure 9 Alcohol 8k with a suitable fluorinating agent such as DAST or Deoxofluor, etc., in a solvent such as dichloromethane, for example: Singh , RP· and Shreve, J. 之·Synthesis, 17, 1999, ρ· 2561-2578 The method described in the reaction 'produces the corresponding fluorine compound 9a. Alternatively, the base of compound 8k can be any suitable method described in the literature. Converted to an amine. For example, a Mitsunobu procedure can be used, that is, an alcohol (8k) and an azobis- oxalate such as DIAD, etc., are reacted in the presence of triphenylphosphine, and then Substitution with the desired amine yields the corresponding amine derivative (9b). Another way to synthesize the amine (9b) is to convert the hydroxyl group to form a cleavage group such as a sulfonic acid derivative (eg, sulfonate, triflate or Tosylate, and the like, which are reacted in a solvent (eg, σ ratio bite or dichloromethane), optionally in the presence of triethylamine, etc., using a suitable acid reductant, and then Required primary or secondary amine NH2CrC3 alkyl or NH(CrC3 alkyl) 2 replacement Alternatively, the cleavage group may be replaced by an azide, or hydroxycoli-54-200804246 may be directly converted to a superimide using a nitride conversion agent (eg, diphenyl fluorenyl azide (DppA)). The introduced azide is then reduced to form an amine, for example, using a tri-phenylphosphine, which may be reacted in the presence of a base such as triethylamine to produce a compound of the formula wherein L is ruthenium and the resulting amine is Reductive amination with a desired aldehyde or ketone to produce a secondary or tertiary amine. /, η is i in the formula I, E is dihydroxylated or difluorinated with N and X = L = OH or F The preparation of the compound is illustrated in Figure 1 of the reaction scheme.

DAST ----3^.

The olefin derivative (10a) can be prepared by the method described in the reaction scheme of Figure 8 - 55 - 10 200804246 Alcohol (8f), which is a conversion of a primary alcohol to form a cleavage group such as: methanesulfonate-specific 'and then elimination reaction, for example : For example, t.BuOK or DBU, in a solvent (such as ···dms〇, DMF or dichlorohydrazine), can be treated in the presence of crown ether as needed. The resulting unsaturated compound (10a) is further subjected to an epoxidation reaction in a solvent (e.g., dichlorohydrazine) by an appropriate oxidizing agent such as mCPBA or BuOOK, etc. to give an epoxide (1(10)). The epoxide ring is opened by the desired hydrazine derivative according to the method illustrated in Figure 1, to produce a diol (10d). Alternatively, the dihydroxylation of the double bond in the olefin (i〇a) can be carried out, for example, by an oxidation system such as 〇s〇4 and NMMO, or the like to produce a ίótriol (10c). The above-described converted primary alcohol forms a cleavage group and then subjected to a substitution reaction with a desired hydrazine derivative to produce dihydroxy hydrazine (1 〇 d). If necessary, the two thiol groups can be converted to fluorine ions by a fluorination reaction method known in the art, for example, using fluorinating agents such as DAST, Deoxofluor, etc.

Rajendra et al. Synthesis 17, 2002, ρ· 2561-2578 explains the reaction of 15 to produce difluoroanthracene (l〇e). According to the formula I, wherein η is 1, E is N, X is 〇H and L is F, NH (C "C3 alkyl" or N (CVC3 alkyl group h can be prepared according to the description of reaction diagram η. -56 - 200804246 〇

IF π 11c R, H or CrC3 alkyl R1 戋NR'r&quot;R&quot; is H or CVC3 alkyl 11d reaction Figure 11: Method prepared by the method - the conversion of the grade alcohol to the detachment acid radical, etc. Such as: tartrazine, three said methic acid, smectite and pyridine or two methods from the appropriate sulfonating agent, in the solvent (such as, for example, under the virtual methane), as needed Ethylamine, etc., Lu A _, in the elimination of the reaction 'for example: to test: coffee or in the crown; such as: DMS0, DMF or methylene chloride), as needed. The enthalpy X: under 'or under any other suitable elimination reaction conditions is as follows: the hydroxy group of the compound (Ub) can be converted into a fluoride ion, for example, a solvent (: a suitable fluorinating agent such as Li or In the case of Yueli, etc., according to the method described by Singh, R·P· and Shreve JM·Synthesis, I7, I&quot;9, ρ· 2561_2578, the corresponding fluorine compounds are produced. 11c). Alternatively, the base of the compound (lib) can be converted to an amine using any convenient method described in the literature. For example, the Mitsunobu process can be used, that is, from the alcohol (lib) to the azodicarboxylic acid. Esters such as: DIAD, etc., are reacted in the presence of triphenylphosphine, -57- 15 200804246 and then replaced with the desired amine to yield the corresponding amine derivative (Uc). Another way to synthesize amines (lie) (4) is to form a cleavage group, such as: sulfonic acid derivatives (such as · shishiyin, acid, trifluorosulfonate, toluene sulfonate, etc.), its system, two § 4 acidifier, in a solvent (such as: pyridine or dichloromethane) in the presence of diethylamine, etc., and then with the desired primary or secondary amine NH2CrC3 alkyl or ΝΗ((^-(:3 alkyl) 2 displaces the cleavage group. Or the 'debonding group can be replaced by an azide, or the hydroxy group can utilize an azide transfer agent such as diphenylphosphonium azide (DPPA) Directly converting to azide and then reducing the introduced azide to form an amine, for example, using triphenylphosphine, optionally reacting in the presence of a base such as triethylamine, in the formula L is a compound of NH2, and the resulting amine is subjected to a reductive amination reaction with a desired disk or ketone to produce a secondary or tertiary amine. Further, the olefin compound (11c) is treated according to the method described in the compound 10a of Figure 10, that is, Epoxidized by a double bond, then reacted with the desired anthracene derivative, or The bond is subjected to a dimerization reaction, followed by oxime sulfonation, a substitution reaction, and finally a reaction with a desired anthracene derivative to produce a hydrazine derivative. If necessary, the radical of the compound lid can be DAST as described above. , etc., is converted to fluoride ion to produce a compound of formula I wherein X is F. According to formula I, η is 1, E is N, X is F and L is OH, F, NH (CVC3 alkyl) Or the method for preparing N (CVC3 alkyl) 2 is shown in Reaction Scheme 12. -58- 200804246

A&quot; Reaction Figure 12 Using a fluorinating agent such as: (HF)X/pyridine to open the epoxide (l〇b) is described in Baklouti, A. et al., Synthesis 1999, ρ·85-89, or (i_PrO) 2TiF2_ET4NF-nHF, produced by the method described by Hara, S. et al., Tetrahedron 1999, ρ. 4947-4954, or by treatment with any other suitable fluorinating agent, produces a fluoroalcohol (12a). The conversion of a primary hydroxyl group to a cleavage group such as a sulfonic acid derivative (e.g., sulfonate, trifluorosulfonate, sulfonate, etc.) is carried out by a suitable sulfonating agent in a solvent (e.g., for example: In the presence of triethylamine, etc., it may be treated in the presence of triethylamine, and the like, and then reacted with the desired anthracene derivative to produce hydrazine (Pb). If desired, the hydroxy group of hydrazine (12b) can be converted to &amp; ionic by DAST, etc. to produce a compound of formula I wherein L is F, or a hydroxy group can be utilized, for example: Mitsunobu reaction Conversion to an amine which is treated by the presence of the two amines, in the presence of DIAD, or the like, or by conversion of the azide to form an azide and then dehydrogenation of the hydrazine to form an amine. - The compound of 200804246 or the resulting amine can be reacted in a reductive amination reaction with a desired aldehyde or hydrazine, as described above, to yield a compound of formula I wherein L is a substituted amine. In the general formula, L is F, X is a CVC3 alkyl group, and a method for preparing a compound wherein η is 1 and E is N is illustrated in Reaction Scheme 13.

Reaction Scheme 13 An epoxidation reaction of an olefin compound (llc) prepared according to Reaction Scheme 11 is carried out by reacting with a suitable oxidizing agent such as mCPBA or tJBuOOK, etc. in a solvent such as dichloromethane to produce an epoxide. (13a). The alkylated compound (13b) is prepared from the epoxide using, for example, an aluminum reagent (eg, (alkyl) 2A10A1 alkyl or (alkyl) 3A1) in the presence of water in a solvent (eg, : In the second gas, according to the method described by Maruoka, K. et al., Tetrahedron Lett., 40 1999, ρ 5369-5372 or by using an alkyl titanium reagent.

Tanaka, Τ· et al. Tetrahedron Lett. 45, 2004, ρ 75-78 Description 200804246 == Selective Λ should be prepared. The formed-grade alcohol is converted into a living such as an ion (such as a milk ion, a desert ion or a cesium ion) or a crude oil (such as mesylate, triflate, and the method uses a suitable sulfonating agent, In a solvent (eg,:: dipyridyl or a lactate), 'can be treated in the presence of triethylamine, etc.' and then with the desired anthracene derivative, as needed (eg: cis Reaction in the presence of t.BuOK', etc., yields 醯肼(i3d). The synthesis of 醯肼(8h) is described in the literature, for example: J Med C:hem. 1998, 41, p. 3387' A general example is shown in the reaction diagram μ. Fire again, 〇Η 14a, ΝΗ. Also HO A&quot; 14b

EDC HOBT NMM

Human NA" Η H H+ 14c h2n-n a&quot; 2 H 8h Reaction Figure 14 Tributyl phthalate (14a) available from the product can be combined with acid (14b), where A" is as defined above, In the peptide coupling reaction, coupling is carried out using standard methods to yield the corresponding Boc protected oxime (14c). The Boc group is removed using standard conditions (e.g., acid treatment, e.g., using TFA, reacted in methylene chloride) to give unprotected hydrazine (8h). Compounds of formula I wherein E is CH and η is 0 or 1 can be prepared as illustrated by the reaction scheme of Figure 15. -61 - 200804246

HO

NHBoc 15a n is 0 or 1 R2

1) HNMeOMexHCI EDC HOBT Et3N

H

15b R2 2) LiAIH4 NHBoc

H2 n 'NHBoc Pt(IV)0 R2

mCPBA

NaH

H aldehyde (15b) can be prepared by converting the desired amino acid or higher amino acid derivative (15a) to peptide coupling conditions, such as EDAC, HOBT, triethylamine, etc. The N,0-dimercaptohydroxylamine is then reduced using a reducing agent (e.g., UAIH1 2 3 4) to form the Weinreb amide. The acid formed and the phosphonate (15c) are reacted in a Horner-Emmons reaction, for example: A. Nadine et al., Bi〇〇rg Med·Chem. Lett., 2003, 13 , 37-41 illustrates the coupling of the method to produce an alkene (15e). The double bond is further subjected to epoxidation using, for example, mCPBA, and the epoxide (15f) formed in the presence of a catalyst (for example, Pt(IV)O) is subjected to a hydrogenation reaction according to the method illustrated in FIG. Open loop. Subsequent standard coupling of the remainder of the fragment group is used, wherein A" and a, as defined by Formula I, that is, the removal of the boc group, coupled with the acid A, CO〇H, and the absence of -62-1 H+ 1)〇H--^ ^ 2

AM-COOH 2)A'-NHP 3

EDC EDC 4

HOBT HOBT

Round NMM Reaction Figure 15 200804246 Post-hydrolysis S is coupled to the amine A'_NH2 to give the amine (i5h). Wherein A, if the compound of formula (VI) is suitable, the N-unprotected derivative (15g) can be reacted with an activated carbonate or chlorodecanoate of the desired derivative prepared according to reaction Figure 4, Substituting for the reaction with acid A"-COOH. The hydroxyl group of compound (I5h) can be converted to a fluoride ion or a primary or secondary amine'. In the formula I, X is H, E is CH and l is F, NHCVC3 alkyl or The compound of N (ci-C3 alkyl) 2 is shown in the following reaction scheme.

R,, n/R&quot;

DIAD

16b

R' is hydrazine or CrC3 alkyl R" is hydrazine or CrC3 alkyl η is 0 or 1 reaction Figure 16 alcohol (15!h) with a suitable fluorinating agent such as: DAST or Deoxofluor, etc. 'in solvent (eg: two In the case of chloranil, according to, for example, Singh, R·P. and

The method described by Shreve, J. M. Synthesis, 17, 1999, ρ. 2561-2578 produces the corresponding fluorine compound (16a). Alternatively, the base of compound 15h can be converted to the amine by any convenient method described in the literature. For example, a Mitsunobu process can be used, that is, an alcohol (1%) and an azodicarboxylate such as DIAD, etc., are reacted in the presence of triphenylphosphine, and then Substitution of the amine produces the corresponding amine derivative (16b). Further, -63- 15 200804246 5 A method for preparing the amine (16b) is carried out by using a suitable sulfonating agent in a solvent (for example, pyridine or dichloromethane), optionally in the presence of triethylamine, and the like. Substituting a transradical group to form a cleavage group such as a sulfonic acid derivative (eg, mesylate, trifluorosulfonate, sulfonate, etc.), followed by the desired primary or secondary amine NH2CrC3 alkyl or NH(CrC3 alkyl) 2 is substituted for the cleavage group. Alternatively, the azide may be substituted for the cleavage group, or the hydroxy group may be directly converted to an azide using a phosphide transfer agent such as diphenylphosphonium azide (DppA), and then the introduced azide may be reduced. Forming an amine, for example, using triphenylphosphine, if necessary, reacting with a base (eg, triethylamine) to produce a compound in which L is NH2, and the resulting amine is reductively aminated with two or a ketone. The reaction produces a secondary or tertiary amine. In the formula I, E is Ch and X = L = 〇H or j^n is hydrazine or 1 monohydroxylated or difluorinated compound is shown in Figure 17. 15

1) 〇H-A·,

1) H+ 17a 2) Α·-ΝΗ2 \\ hobt nmm 0 OH , R2,

17b

EDC HOBT NMM o OH &quot; H A,&gt; DAST

R2 AH ' 17c Reaction Figure 17 -64 - 200804246 Conditional treatment, such as: protonic acid, for example: diluted peroxyacid, sulfuric acid or citric acid' or using Lewis acid such as BiCl3 in solvent ( Treatment in, for example, tetrahydrofuran, etc., produces a glycol (17a). Subsequent coupling of the acids a, -COOH and the amines A, -NH2 according to the procedure illustrated in Figure 15 yields the dihydroxy decylamine (17b). If desired, the two hydroxyl groups can be converted to fluoride ions using a fluorinating agent such as DAST, Deoxofluor, etc. to produce difluoroanthracene (17c). In the synthesis of formula I, E is CH, X is OH, and L is The route of F and η is a compound of hydrazine or 1 is shown in Reaction Scheme 18. 10

1)Η+ 2) A&quot;-COOH EDC HOBT NMM 1)ΟΗ·

2) A, -NH2 EDC HOBT NMM Reaction Figure 18 Using a fluorinating agent such as: (HF) x / ° than the bite to open the epoxide (i5 〇 method 15 is described in Baklouti, Α· et al. Synthesis 1999, ρ· 85-89, or using (i_PrO)2TiF2_ET4NF-nHF, according to the method described by Hara, S. et al., etrahedr〇n 55, 1999, p. 4947-4954 or using any other suitable gasifying agent to produce fluorinated The alcohol (18a) is then coupled in any suitable order with the acid-65-200804246 A'':COOH and the amine A,·2, according to the procedure illustrated in Figure 7, to produce the fluoroalcohol (10)). If desired, any compound 18a, 18b or 18c can be converted to fluoride ion by treatment with DAST, etc. as described above, thus providing another compound which synthesizes X of formula I and B. In the formula I, E is CH, L is OH'F'NHeVc; alkyl or N(C "C3 alkyl" 2, X is C^c:3 alkyl and n is a compound of ruthenium or osmium. Figure 19.

1) OH·

R2 NBoc 1) Η

2) A,, -CO〇H EDC HOBT NMM 2) Α·-ΝΗ2 EDC HOBT NMM

n is 0 or 1 19c Reaction Figure 19 - The epoxide (15f) prepared according to the method illustrated in Figure 15 uses an organic copper reagent such as lithium dicalcium hydride, in a solvent such as diethyl ether or THF, etc. The alkylation is carried out to give the alkylated compound 〇9a). The acid A, -C〇〇H and the amine A-NH2 are coupled in any suitable order according to the method illustrated in Figure 15 to give the anthracene derivative (19b). If desired, the hydroxyl group of compound 19b can be converted to fluoride by DAST, etc. to give a formula! Medium 1-66-200804246 is a compound of F, or a hydroxyl group can be converted to an amine by, for example, a Mitsunobu reaction, which is treated with a desired amine, in the presence of DIAD, or the like, or converted to a hydroxyl group. Azide, then reducing the azide to form an amine, yielding a compound of formula I wherein L is NH2, or the resulting amine can be reacted with the desired aldehyde or ketone in a reductive amination reaction, as described above, L in formula I is a substituted amine compound. Another compound of the formula wherein E is CH and η is 1 is shown in Reaction Scheme 20.

Reaction Scheme 20 The process of the desert derivative (20b) can be prepared by a suitable hydrolyzed malonic acid g-street organism (20a) using a hydrolysis-reduction method, followed by Heterocycles of Jew et al., 46, 1997, ρ·65- The method illustrated by 70 converts the formed mono-alcohol to form a bromide. The alkylated malonate derivative can be obtained commercially or by alkylation of diethyl malonate via a desired alkylating agent according to the method known to those skilled in the art. The tertiary alcohol of the obtained bromine derivative (2〇b) can be protected, for example, by an acetate, which is treated with acetic anhydride, in a bite ratio, -67-200804246, etc., followed by Dudu et al. The method described by Tetrahedron 50, 1994, ρ 2415-2432 is coupled by a copper-zinc reagent (20d) prepared from a natural or non-natural amino acid to produce (2〇e). The remaining fragment moiety (A" and A' as defined in Formula I) can be introduced according to the method illustrated in Figure 15. Any R2 group in the above compounds can be subjected to the desired group using any suitable method known in the literature. The substitution method can be carried out according to any convenient synthesis step, wherein the addition reaction of the heteroaryl group and the aryl group is exemplified in the reaction diagram 21

Reaction Scheme 21 The aryl group of the compound (21a) may be substituted by, for example, an aryl group or a heterodentate group, and the tri-n-group of the desired substituent (eg, ton coupling reaction) is used as a reagent (such as CuO).丄一,· (Example: 21 The method described is not limited to the coupling reaction, using palladium [(1) 诂心,., &amp; field v. organism: Pd(PPh3)2Cl2,

Salty, 2', etc., in which the substituted alkyl, aryl or heteroaryl fines are substituted for other methods of substituting the pyridine group of Han 2, which is also applicable to other ♦ aryl groups. For salty understanding, a sulfonium group can be used. Understand, the reaction diagram Other visual needs can be used in the literature detailed '68 - 200804246 Formula I where η is 2 and e is in response to Figure 22. Description of the general synthetic route for compounds of N 〇

R1 22a

Oxygenated PPTS Ο Ο

-0 22b

22c A,,

Lda TFA

LiBH4 R1 22e 1 X〇,,. H P 荔 H (人 A., OH MsCI N A&quot;

Na(0Ac)3BH Reaction Figure 22

Rv iv. The desired 3'-substituted 2_-propionic acid (22a) is protected by a acetal, which is an acid with a suitable acetalizing agent (eg 2, dimethyl, Acetylene or 2·methoxy (tetra)), reacted under acidic conditions, for example, oxygen catalyst amount of pyridinium benzenesulfonate (PPTS), pts, CSA, etc. Acid reduction (22b). Subsequently, Michael addition is carried out with the obtained acetal in the presence of formazan acrylate such as LDA, etc., to produce an α-alkylated compound (22c).汝 % έ δ is hydrolyzed, and the obtained alcohol intermediate is treated with an acid such as TFA, and heated to form a lactone (22d). Amine A, -NH2 use standard conditions, such as: using reagents such as: EDAC, HOBt, and optionally containing a base such as: triethylamine, etc. after coupling, continued use of lactone for thick soil LiBH4, and the like, undergo a reductive ring-opening reaction to produce a glycol (22L^: ). With the -69- 15 200804246 arrogant derivative (22g) can be prepared by any of the methods described above, for example, the oxidation-reductive amination sequence described in Reaction Scheme 8 can be used, that is, any suitable oxidizing agent (such as 'for example: Diss Martin temper (Dess_M coffee periodina) oxidizes a primary hydroxyl group to form an aldehyde, which is then derivatized with the desired hydrazine, in the presence of a suitable reducing agent (eg, Na(〇Ac)3BH, etc.). Reductive amination reaction. Alternatively, the hydrazine moiety may be introduced as described in the above reaction, i.e., converted - (d) to form a cleavage group (e.g., a sulphuric acid ester, etc.). (d) The cleavage group is replaced with a desired hydrazine derivative. If desired, the hydroxy substituent of hydrazine (22g) can be converted to an amine or fluoro substituent by any of the methods 10 above, yielding L in the formula (I) as an alkyl group or N (CKC6 alkyl L, hydrazine 11 , 11 is a compound of 2 and £ ^ ^. Those skilled in the art of organic synthesis know that the synthesis step of the compound according to formula I can be carried out in another order, if appropriate. For example: 15 in the formula is Ν The substituent of the nitrogen atom of the compound _ch2-R2 can be introduced by using the substituted anthracene derivative according to the method described in the reaction scheme of FIG. 1, or an unsubstituted or optionally protected N-derivative derivative can be used. Later, according to the method described in the reaction diagram _8, the group substituents are introduced. For example, the amine groups and acid derivatives of the reaction diagrams 18 and 19 can be introduced in the reverse order, and the acid A"-COOH can be in the amine. A'-NH2 is previously coupled. Any functional group on any of the constituent compounds used in the preparation of the compound of the present invention can be suitably protected if necessary. For example, a functional group on a natural or unnatural amino acid can be synthesized by a peptide. Law, properly protect it. Those skilled in the art understand that the choice of appropriate protecting groups is determined by the reaction conditions. The appropriate protecting groups are described in Greene's "Protective Groups in Organic Synthesis", John Wiley &amp; Sons, New York (1981) and "Peptides: Analysis, Synthesis, Biology", Vol. 3, 5 Academic Press, New York (1981), the disclosure of which has been BRIEF DESCRIPTION OF THE DRAWINGS The various embodiments of the present invention and the key intermediates for the synthesis of such compounds 10 will be described by way of non-limiting chemical and biological examples. Chemistry. General Information. Analytical Grade RP- LC-MS was applied to a Gilson HPLC system using a Finnigan AQA quadrupole mass spectrometer using a chromolith Performance RP-18e 4·6 X 100 mm (Merck KGaA) column.

MeCN is 〇. 5% 5% HCOOH aqueous solution is the mobile phase, and the flow rate is 4 155 liters/min. Preparative RP-LC-MS was applied to a Gilson HPLC system using a Finnigan AQA quadrupole mass spectrometer using z〇rbax SB-C8,

5 μιη 21 · 2 X 150 mm (Agilent technologies) column with a solution of 0.05% HCOOH in MeCN as the mobile phase and a flow rate of i5 ml/min. The optical rotation was measured on a Perkin-Elmer 241 polarimeter ([a]D), expressed in deg/dm, and the concentration (c) is expressed in grams/100 ml contained in the specified solvent. The 1 Η and 13 C NMR spectra were recorded on a Varian Mercuiy Plus instrument at 300 and 75·45 MHz or 399.78 and 100.53 MHz, respectively. Chemical migration is indicated by indirect reference to TMS, using the delta value (ppm) of the solvent residual signal. The flash column chromatography was carried out on Merck Silicone-71 - 200804246 60 (40-63 μιη) or Merck Silicone 60 RP_18 (40_63 μιη). Analytical grade TLC was performed using an aluminum sheet precoated with silicone 60 F254. The solution was treated with UV light and a solution of phosphomolybdic acid in ethanol, followed by heating to visually examine the components. Elemental analysis was performed by the Analytische Laboratorien laboratory in Lindlar, Germany. Example 1

2-Benzyl hydrazino-based fluorenyl hydrazide] propyl hydrazide hydrazide (1) 10 15 2-benzo methacrylic acid (j· 〇rganomet, chem. 646, 212_222, 2002) (2.72 g, 16.8 mmol) The ear was dissolved in EtOAc (5 mL) and EDAC (3.54 g, 18.5 mmol), and H0BT (2 49 g, 18 4 moles) and hydrazine (2. 21 mL, 20.1 mmol) were added. After stirring the reaction mixture for 30 minutes at room temperature, (1 and 2 phantom-amino- 2 -indanol (2.75 g, 18.4 mmol) were added and stirring was continued overnight to sat. NaHC 3 (aq) After washing with brine, dehydration (NajO4) and evaporation of the organic solvent to give a crude product, which was purified by column chromatography (eelite, Et 〇Ac / pentane, 4 〇: 6 〇 _5 〇 · · 50), yielding 2 (3.34 g, 68%) of a white solid. [CC]d + 239 〇 (c 0·77, -OH); iH NMR (CDC13) S 7·4 〇 7.11 (m? 8H^ 6.97 (m9 1H), 6.42(d, J = 8.27 Hz? 1H)? 5.87(s,1H), 5.35(m,2H), 4.55(m,1H),3.77(d,15.6 Hz 1H), 3.70(d,J is called 5· 6 Hz, 1H), 3 14 (dd, j = 5 21, l6 6 屯-72- 20 200804246 1H), 2.89 (dd, 1.89, 16·6 Hz, 1H), 2.18 (d, /= 4.90) Hz, 1H) ; 13C NMR (CDC13) δ 168.9, 144·3, 140·7, 140.1, 138.5, 129.2, 128.9, 128.4, 127·4, 126.9, 125.5, 124·6, 120.5, 73·7, 57.9 ,40·0,39·2· MS(m/z 294,Μ + Η+,587); analysis (C19H19N02) C,Η,Ν 〇Example 2

(25)-2-Benzyl-epoxy Ethylene-|[(1&amp;2 and)-2-yl-based-indanyl] ίο carboxylic acid decylamine (〇S&gt;3)(2a) and 2 and)-2-benzyl-epoxyethyl -7-[[1*5,2 and)-2-yl-yl-indan-1-yl]-2-sodium sulphate ((and ) _3) (2b) Compound 1 (1.57 g, 5.36 mmol) was dissolved in ch2C12 (30 ml) 'mCPBA (77%, 2·40 g '1〇·7亳 Mo). The reaction mixture was heated to reflux for 48 hours. It was cooled and washed with i0% Na2S2 3 (aq), 15 sat. NaHC.sub.3 (aq.) and brine. The organic phase is dehydrated (Na2S〇4). After filtration and evaporation, the crude product is purified by column chromatography (mite, Et.Ac / pentane '40: 60-100: 0) to give two diastereomers An epoxide; 2a (〇.414 g) of a pale yellow solid with 2b (0.46 g) of white solid. 20 2a : Rf = 0.58 (EtOAc / pentane 50: 50); [&lt;9 _6 〇(8) CHC13); ^NMR^OD) δ 7.35-7.11Κ8Η)?7 〇7(ιη&gt;1Η;? -73- 200804246 5.18(d,5·12 Hz,1H), 4.42 (ddd, 1.50, 4·97, 5·12 Hz, 1H), 3.63 (d, 14·8 Hz, 1H), 3.11 (dd, /= 4 ·97, 16·5, 1H), 2.97 (d? J = 14.8 Hz, 1H), 2.91 (d, J = 4.99 Hz? 1H) 5 2.87 (dd? J = 1.50, 16.5, 1H) 9 2.85 (d5 J = 4.99 Hz? 1H) ; 13C 5 NMR (CDC13) δ 170.4, 140.4, 140.0, 136.0, 130.1, 128.7, 128.6, 127·38, 127.39, 125.6, 124.2, 73.4, 60·4, 57.5, 53.0, 39 MS (m/z 310, Μ + H+, 619); analysis (C19H19N03) C,H,N 〇2b Rf = 0.13 (EtOAc/pentane 50: 50); [oc]D19 +73.3〇 (c 1·00, ίο CHC13); 4 NMR (CD3OD/CDCl3 1 : 1 + 2 drops D20) δ 7.37-7.08 (m, 7H), 6.98 (m, 1H), 6.41 (m, 1H), 5.16 ( Ddd,1·14, 5·04, 9·23 Hz, 1H), 4.43 (ddd, 1·33, 4·97, 5·04 Hz, 1H), 3.73 (d, •7 = 14·5 Hz, 1H), 3.07 (m, 1H), 3.00 (d, = 5.09 Hz, 1H), 15 2.93 (d, / = 5.09 Hz, 1H), 2·84 (πι, 1H), 2.75 (d, J = 14 · 5 Hz, 1H); 13C NMR (C D3OD/CDCl3 1 ·· 1 + 2 drops D20) δ 171.3, 141.1,140·6, 136·7, 130·5, 129·0, 128.5, 127·6, 127·5, 125.6, 124.7, 73·3 , 60·8, 57·4, 53·4, 40·5, 37·8; MS (m/z 310, Μ + Η+, 619); analysis (C19H19N03) C, Η, Ν. 20 一般 一般 一般 一般 曱 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc After the EtOAc solution (4 mL), -74-200804246 was stirred at room temperature overnight. Diluted with EtOAc, washed with EtOAc (aq. EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CHCl3/MeOH, 100: 0-95: 5). Example 3

[(15&gt;1-(#'-benzoinyl)carbonylcarbonyl)_2_mercapto-propyl]-amine phthalic acid benzoic acid vinegar (3) 10 According to the general method of the above-mentioned hydrazine, Cbz_(L is used. )_proline (〇·540 g, 2.15 mmol), EDAC (0.450 g, 2.35 mmol), ΗΟΒΤ (0·320 g, 2.37 mmol), ΝΜΜ (0·260 ml, 2.36 毫) Mole), phenylhydrazinium X2HC1 (0.500 g, 2.56 mmol) and Εί3 Ν (0·710 ml, 5·09 mmol), yielding the title compound (〇········ solid.

[a] D21 -41.7° (c 0.35, MeOH/CH 2 Cl 2 50 : 50); lR NMR (DMS0-d6 + 2 drops D20) δ 7·42-7·18 (ηι, 10H), 5.01 (s, 2H) , 3.82 (s, 2H), 3.72 (d, 7.61, 1H), 1.83 (m, 1H), 0.78 (d, 6.86, 3H), (X76 (d, 6·86, 3H); 13C NMR (DMSO- D6 + 20 2 drops D20) δ 170.8, 156·7, 139.2, 137·7, 129.1, 129.0, 128.8, 128·5, 128.3, 127.6, 66·1, 59·5, 55.0, 30.9, 19·7, 19.0 ; MS〇/z 356, Μ + Η+); analysis (C20H25N3O3) C, Η, Ν 〇-75- 200804246 Example 4

[(15&gt;1_(Λ^benzoyl-fluorenylcarbonyldidecyl-propyl]-aminobenzoic acid benzoate (4) According to the general method as described above, Cbz-(L)-third Leucine (2·00 g, “48 mmol”), EDAC (0.969 g, 5.05 mmol), ΗΟΒΤ (0·669 g, 4.95 mmol), ΝΜΜ (0·542 ml, 4.93) mM, benzyl hydrazine x 2 HCl (0.962 g, 4.93 mmol) and Εΐ3 Ν (1·38 mL, 9.85 mmol) afforded the title compound (1.11 g, ίο 67%) [a]D19 -17.5°(c 1.05 CHC13) ; lR NMR(CD3OD) δ 7.38-7.15(m9 l〇H)5 5.05(d, J = 12.3 Hz, 1H)9 4.99(d, J = 12· 3 Hz, 1H), 3.99 (s, 1H), 3.90 (s, 2H), 0.92 (s, 9H); 13C NMR (CD3OD) δ 171.3, 158.0, 138.6, 137.9, 129.8, 129.3, I) 129.2,128 ·9,128·7,128·3, 67·6, 62·5, 56.2, 35·2, 27.0; MS(w/z 370, Μ + Η+); analysis (C21H27N303) C, Η, Ν 〇 Example 5

20 phenyl fluorenyl-fluorenyl)-2-methyl-propyl]-amine decanoic acid decyl ester (5) -76- 200804246 methoxycarbonyl) KL) 'jenamic acid according to the general method as described above (j Med chem·, 39, 3203-3216, 1996) (2.11 g '12.0 mmol), EDAC (2 41 g, 12 6 mmol), Η〇ΒΤ (1·7 gram, 12 6 毫) Mole), Gu M (1 38 ml, 12 6 mmol =), phenylhydrazinium x 2 HCl (2.45 g, 12.6 mmol) and Et3N (3.52 mL &lt; 25 〇 mM) gave the title compound ( 2 〇 8 g, 65%) of a pale yellow solid. [a] D19 -45.5° (c 1.0, CHC13) ; NMR (CDC13) δ 8.00 (s, 1H) 7.40-7.25 (m5 5H)? 5.50 (d5 J = 9.04 Hz, 1H), 4.85 (s, 1H) 3.96(s,2H), 3.89 (dd, J = 7.04, 9.04, 1H), 3.64(s,3H), 2.05(m? 1H)5 0.94(d? J = 4.94 Hz, 3H), 0.92(d , J = 4.94 Hz, 3H); 13C NMR (CDC13) δ 171.2, 157.3, 137.5, 129.2, 128.7, 127·9, 59.4, 56.1, 52·6, 31·2, 19·4, 18·2 ; MS 〇/z 280, M + Η+, 559); analysis (C14H21N303) C, Η, Ν. 15 Example 6

[(15&gt;1-(ΑΓ-benzoinyl-fluorenylcarbonyl]&gt; 2,2-didecyl-propyl]-carbamic acid methyl ester (6) 2〇 According to the general method of the above-mentioned hydrazine, 曱Oxycarbonyl HL)-third leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g, 9.08 mmol) 77- 200804246 ear), ΗΟΒΤ (1.22 g ' 9.03 mmol), NMM (0.995 ml, 9.05 mmol), benzoquinone x 2 HC1 (1.61 g, 8.25 mmol) and EtsN (2.53 ml, 18.0 m) The title compound (1 21 g, 50%) was obtained as pale yellow solid. 5 [a]D -40.7 (c 0.98, CHC13) ; lH NMR (CDC13) δ 8.07 (s, 1H) 7·38 ·7·24(πι,5H), 5.63 (d, J = 9·64 Hz, 1H), 4.95 (s, 1H), 4.00 (d, 12·4 Hz, 1H), 3.95 (d, 12·4) Hz, 1H), 3.92 (d, / = 9·64 Hz, 1H), 3.68 (s, 3H), 0.98 (s, 9H); 13C NMR (CDC13) δ170·2, 157·1, 137·3, 128·9,128·4, 127.6, 61·1,55·8, 52·3, ίο 34·5, 26·4, Ms(w/z 294, Μ + Η+); analysis (c15H23N303) C, Η, Ν 〇 Example 7 *一^ , [(1 benzyl-fluorenylcarbonyl)_2,2-di _ Yl propyl methanesulfonamide Amides ⑺

Add 1 Μ NaOH (7.60 ml '15·2 mmol) and THF (1 mL) solution containing sulfonium chloride (0·593 ml, 7.62 mmol) to 〇τ, containing (L ) - The second leucine (1 gram, 7.6 mmol) was dissolved in a stirred mixture of thf (7.6 20 pen liters) and ^0 (12 pen liters). The reaction mixture was stirred at 〇 ° C for 3 hours and then at room temperature overnight. The mixture was acidified with 4 EtOAc and extracted with EtOAc. The organic phase was separated, dehydrated (Na2Sa, filtered and decompressed -78-200804246 concentrated to give (25)-2-methylglycosylamino-3 -3-dimethyl-butyric acid (〇·486 g, 30%) After NMR analysis, it was used without further purification. According to the general procedure as described above, the crude product (2$)_2_methanesulfonylamino-3,3-dimethyl-butyric acid (0) was used. · 476 grams, 2.27 millimoles), EDAC (0.481 grams, 2. 51 5 millimoles), ΗΟΒΤ (0·338 grams, 2·50 millimoles), ΝΜΜ (0·275 ml ' 2.50 mils) Methyl), benzyl hydrazine X2HC1 (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) afforded the title compound (0.416 g, 58%) as a white solid. +24A° (C 1.02, CHC13) ; lU NMR (CD3〇D) δ 10 7 44 Bay 7 20 (m, 5H), 4.01 (d, /= 13·1 Hz, 1H), 3.95 (d, 13· 1

Hz, 1H), 3.47 (s, 1H), 2.71 (s, 3H), 0.94 (s, 9H); 13C NMR (CD3OD) δ 171.1, 139.0, 129.9, 129.5, 128.5, 64.5, 56·1, 40· 8,35·3,27·0; MS (m/z 314, M + H+); analysis (C14H23N303S) C, H, N. 15 Example 8

^Benzyl phenyl fluorenyl _ phenyl carbonyl) 2,2 dimethyl propyl]-urea (8) ^ Take (L) - third leucine (〇·5 gram, 3.81 Millol) dissolved in dioxane (23 liters) 'add 2 NaOH (6.3 ml, 12.6 mmol). After 10 minutes of stirring, phenyl isocyanate (〇·9 〇〇 ml, 7.29 mmol) was added dropwise, and -79- 20 200804246 produced a transparent: gluten solution. After mixing the reaction mixture at room temperature for an hour, concentrated HC1 was added to make it acidic, and then extracted with Et〇Ac. Dehydration of the organic phase with the formation of &lt;25&gt;2-(3-benzyl-methyl-uretido)-3,3-dimethyl-butyric acid (0.36 g, yield 36%), after NMR analysis It was used without further purification. According to the general procedure of the above hydrazine, the crude product (25&gt; 2-(3-benzyl-carbazolyl)-3,3-dimethyl-butyric acid (〇·646) was used.克, 2.44 mmol, EDAC (0.515 g, 2.67 mmol), η〇ΒΤ (0·363 g, 2.69 mmol), ΝΜΜ (0·300 ml, 2.73 mmol), benzene曱基肼χ2Η(:1 (〇·528 g, 2.71 mmol for Et3N (〇 753 ml, 5.38 mmol). The product was filtered through a short vermiculite column (CHCl3/MeOH, 100:0- 95 · 5), which was used in the next step without further purification. 丫., L {(15&gt;1-[#'-(4_漠_苯methyl)-fluorenylcarbonyl]-2,2-二Methyl decyl-propyl amidoxime (9) is depleted (曱 oxycarbonyl HL) _ third leucine (J. Med. Chem., 41 3387_34G1, trace) (1·74 g, 9· 2()亳莫耳) dissolved in Et〇Ae (5〇ml) and EDAC (1.94g, 1〇·1mmol), add hobtq 37 20g, 10” millimolar) and Li called 1· 1!ml, uu Milligram). After stirring the reaction mixture for 30 minutes at room temperature, add 4-bromo-benzoinyl hydrazine (the preparation method is described in Zh· Org Khim, 28, 43-50, 1992) (2.31 gram Ϊ -80-200804246 EtOAc (20 ml) EtOAc (20 mL) EtOAc EtOAc EtOAc (EtOAc) The crude product was purified by EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 0.84, MeOH); lU NMR (CD3OD) δ 7.45 (m, 2H), 7.29 (m, 2H), 3.90 (s, 2H), 3.81 (s, 1H), 3.64 (s, 3H), 0.90 (s, 9H" 13C NMR (CD3〇D) δ 170.5, 157·9, 137·2, 131·3, 130·8, 121.0, 61·7, 54·2, 51.5, 33·9, 25·8 ; MS〇 /z 372, Μ + ίο Η+, 374, Μ + Η+); analysis (c15H22BrN303) C, Η, Ν. Example 10

{(15&gt;l-[7V'-(4-Bromo-benzyl)-fluorenylcarbonyl]-2-methyl·propyl-p-propyl benzoate (10) Take Cbz-(L)-decylamine Acid (1〇4g, 414mmol) dissolved

EtOAc (50 liters) and EDAC (0.870 g, 4.54 mmol) were added with hydrazine (0·610 g, 4·51 mmol) and hydrazine (0·500 mL, (55 耄 Moel). After the reaction mixture was stirred at room temperature for 3 hrs, EtOAc (5 mL, EtOAc (EtOAc) The solution was washed with saturated NaHC 3 (aqueous solution) and brine, dried (NaJO 4 ), filtered and evaporated to give organic solvent. The crude product was purified by column chromatography (Metestone: 200804246 CHCl3/MeOH, 100: 〇·95 ··· 5) The title compound (1·42 g, 79%) was obtained as a white solid. 5 [oc]D21 +6.2° (c 0.47, DMF); b NMR (DMSO-d6 + 2 drops D20) δ 7·53- 7·18(ιη, 9H), 4.98(s, 2H), 3, 79(s, 2H), 3.69 (d, J = 7.65 Hz, 1H), 1.80 (m, 1H), 0.75 (d, 6·92 Hz, 3H), 0.72 (d, /= 6·92 Hz, 3H); 13C NMR (DMSO-d6 + 2 drops D20) δ 170.8, 156.6, 138·8, 137.7, 131·6, 131· 4, 129·0, 128·5, 128·3, 120·6, 66·1, 59.5, 54.2, 30.8, 19.7, 19·0 ; MS(m/z 434, Μ + Η+, 436, Μ + Η+); analysis (c20H24BrN3O3) C, Η, Ν. 10 Take epoxide 2a or 2b and hydrazine in ζ·Ργ〇η (6 ml), and react the mixture at 8 (rCT for a specified period of time, evaporate the solvent to give a crude product. Purified according to the method indicated below., x 15 20. &gt; ^7^dan taken % oxide or 2b and hydrazine dissolved in anhydrous THF (30 Ϊ nitrogen added under the gas) 4. Stir at room temperature 2.5 hours to play 2 〇, 'III% minutes' and then add NaHCC> 3 (aqueous solution) and phase, there is T_1G minutes. Separation of the two-night stone MeCN / H2 〇, 50: 50-90 ·· 1 〇). 11 -82- 200804246

{(15&gt;1-[7V'-Benzyl_Λ^((2,2-hydroxy-2-((15, hydroxy-indan-1-ylamine 曱Sat)-3)-propenyl-propyl Base)-Phenyl-based group]_2_Methyl-propyl}- benzylamine decanoate (11) j The title compound is prepared according to Method A, heating epoxide 2a (0.0950 g, 0.307 mmol) and醯肼3 (0.218 g, 0.614 mmol) for 90 hours. Purified by column chromatography (Shihashi, EtOAc/eluent 30: 70-100: 0) to give the product (0.112 g, 55%) white [a] D19 -10.8° (c 0.94, DMF) ; !H NMR (CD30D) δ ίο 7.38-6.97 (m, 18H), 6.81 (m, 1H), 5.04 (s, 2H), 4.99 (d) , = 4·92 Hz, 1H), 4.20 (d, 14·0 Hz, 1H), 4·11 (ηι, 1H), 4.02 (d, J = 14.0 Hz9 1H)? 3.87 (d, /= 14.0 Hz , 1H)? 3.61(d? J= 7.18 Hz, 1H), 3·08·2·76(ηι,5H), 1.61(m,1H), 0.60(d,6·81, 3H), 0.46(d , J = 6·81, 3H) ; 13C NMR (CD30D) δ 177·5, 15 173.2, 158·4, 142·1,141·4, 138·6, 138.2, 137.6, 131·6, 129·8 , 129·5, 129.2, 129.0, 128·9, 128.8, 128.7, 128·4, 127.7, 127.6, 126·0, 125.6, 79.3, 73.9, 68.1, 67.7, 62·9, 60.8, 58·5, 4 4.5, 40·8,31·7,19·2,18.4 ; MS(m/z 2011Μ + Η+); analysis (C39H44N4O6x0.25H2O) C,Η,Ν ·· Calculated value: 70·03,6 · 71, 20 8.38 ; measured value · · 69.98, 6.56, 8.15. *83- 200804246 Example 12

Benzyl-AT-((2i?)-2-hydroxy-2-((1&amp;27?)-2-hydroxy-indan-1-ylamine decanoyl)-3-phenyl-propyl) -Based on the group]-2-mercapto-propyl}-. Aminobenzyl phthalate (12) The title compound was prepared according to Method A, heating epoxide 2b (0.104 g, 0.336 mmol) with hydrazine肼3 (0.240 g, 0.676 mmol) for 120 hours. A solution of 0.170 g of crude product (30-80% EtOAc (EtOAc) elute [a]D19 +10.8°(c 0.58, DMF); lR NMR(CD3OD) δ 7.42-7.07(m5 17H)? 6.97(m, 1H)? 6.25(m? 1H), 5.04(d,5·22, 1H), 5.01 (s, 2H), 4.37 (m, 1H), 4.05 (s, 2H), 3.68 (m9 2H) 5 3.10-2.72 (m? 5H) 9 1.78 (m, 1H) 9 0.70 (d, J 15 = 6·74 Hz, 3H), 0.67 (d, / = 6·74 Hz, 3H); 13C NMR (DMSO-d6) δ 174.2, 171.1, 156.6, 142.7, 140.9, 138·5, 137.7, 137.4 , 131.3, 129.2, 130.0, 128.6, 128.44, 128.39, 128·3, 127.7, 127.6, 126·8, 126.7, 125·3, 124.7, 78·4, 72.7, 72·6, 68.0, 66·1, 61.7 , 59·5, 56.8, 43·3, 30·9, 19.5, 20 18.6; MS (m/z 664, Μ + Η+); analysis (C39H44N406) C, Η, Ν 〇-84- 200804246 Example 13

Benzoyl-indole-((25&gt;2-hydroxy-2-((1&amp;2)-2-hydroxy-indan-1-ylamino)-3-phenyl-propyl)-fluorenyl Carbonyl]_2,2-dimethyl-propyl-3-yl}-amine phenyl decanoate (13) The title compound was prepared according to Method A using epoxide 2a (0.0996 g '0.322 mmol) with 醯肼4 (〇·ΐ43 g, 0.387 mmol) was heated for 96 hours. Purified by column chromatography (Shihashi, EtOAc/pentane, 40: 60-100: 0), then RP-LC-MS (30 min 20) 00 〇 / 〇 10 CHfN of 0.05% aqueous solution of HCOOH in water) gave the product (0.0880 g, 40%) as a white solid. [a]D19 -61.6 (c 1.01, CHC13); lR NMR (CD3OD) δ 7· 38·7·02(πι,17H),6·95(ηι,1H), 6.75(m,1H),5.03(s,2H), 4.97(d,5·01 Hz,1H), 4.22(d, 14·3 Hz, 1H), 4.09 (ddd, is J = 1.50, 4.96, 5.01 Hz? 1H), 4.03 (d5 J = 14.3 Hz, 1H), 3.87 (d, J = 13·8 Hz, 1H), 3.64(s,1H),3·04-2·73(ιη,5H), 0.57(s,9H) ; 13C NMR(CD3OD) δ 177·5, 172·3, 158·3, 142.0, 141·4 , 138.8, 138.2, 137·6, 131.6, 129.6, 129.5, 129·3, 129·0, 128·9, 128·8 , 128·7, 128·4, 127·7, 127.5, 126·0, 125·6, 79.2, 2〇73·9, 68·4, 67·7, 63·0, 62·8, 58·5 , 44.4, 40·1, 34.9, 26·6 ; -85- 200804246 MS〇/z 679, Μ + H+); analysis (c40H46N4O6) C, H, N 〇 Example 14

J {(1Fantasy-1-[#'-benzylmethyl-based-2-((lS,2i?)-2-yl-indan-1-ylamine-methyl)-phenyl- Propyl)-mercapto-Weiyl]_2-mercapto-propyl-amine decanoate (14) The title compound was prepared according to Method A using epoxide '2a (0.100 g, 0.323 mmol) and hydrazine.肼5 (0.117 g, 0.419 mmol 1 〇) was heated for 96 hours. Purified by column chromatography (Shi Xishi, Et〇Ac / Eki, 40: 60-100: 0), then RP_LC-MS (30-minute 20-100% CHgCN 0.05% HCOOH aqueous solution gradient solution), produced The product (0.0358 g, 19%) was obtained as a white solid.

[a] D19, 50.9o (c 0.99, CHC13); 4 NMR (CDC13) δ 7.59 (s, 15 1H), 7.44-7.00 (m, 14H), 6.36 (s, 1H), 5.17 (m, 2H) , 4.30 (d, J = 13·0 Hz, 1H), 4.14 (m, 1H), 4.06 (d, J = 7.38 Hz, 1H), 4.02 (d, / = 7·38 Hz, 1H), 3.78-3.62 (m, 4H), 3.06-2.74 (m, 5H), 1.81 (m, 1H), 1.72 (s, 1H), 0·66-0·52 (πι, 7H); 13C NMR (CDC13) δ 174.8, 171.4, 157·2, 140·6, 140.2, 136.8, 2〇136.6, 130·9, 128.8, 128·7, 128.3, 128.1, 128·0, 127·2, 127.0, -86- 200804246 125.3 , 124·1,78·3, 73·4, 67·1,62·5, 59.3, 58.0, 52·8, 43·9, 39·1,30·8,18.9,17·7 ; MS(m /z 589,Μ + Η+); analysis (C33H40N4O6) C, Η, Ν 〇 Example 15

{(15&gt;1-[ΑΤ-benzylhydroxyphanyl_2_hydroxy-indan-1-ylaminoindenyl)_3_phenyl-propyl)-fluorenylcarbonyl]-2,2-dimethyl -propyl}-carbamic acid methyl ester (15) The title compound was prepared according to Method A, heated from epoxide 2a (0.101 g, 0·326 mmol) and 醯肼6 (0.125 g, 0.426 mmol). 96 hours. Column chromatography (meteorite, EtOAc/pentane, 40: 60-100: hydrazine) followed by RP-LC-MS (30% 20-100% CH3CN in 0.05% HCOOH 7jc gradient) (0 0919 g, 46%) of a white solid. [oc]D21 -44.8° (c 1.01, CHC13); 4 NMR (CDC13) δ 7.53 (s, 1H), 7·44-6.98 (m, 14H), 6.52 (s, 1H), 5.43 (d, J) = 9·04 Hz, 1H), 5.15 (dd, / 2, 4.64, 9.04 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 4.09 (m, 2H), 4.02 (d, J = Μ· 7 Hz, 1H), 3.71 (m, 4H), 20 3.05-2.74 (m, 5H), 1.76 (s, 1H), 0.69 (s, 9H), 〇.52 (m, 1H); -87- 200804246 13C NMR (CDC13) δ 174.8, 170.8, 157.3, 140.6, 140.2, 136.8, 136·7,131·0,128.8,128·6,128.2,128·1,128·〇,127·2,127·0, 125·2,124.3,78.3,73·4,67·6,62·2,61·6,57.8,52·9,43·9, 39.1,34.6, 26·2 ; MS(m/z 603, Μ + Η+); analysis (c34h42N406) C, Η, Ν 〇 Example 16

{(15&gt;Benzyl-anthracene-((2)-2-hydroxy-2-((1&amp;2)-2-hydroxy-indan-1-ylamino)-3-phenyl -propyl)-hydrazinocarbonyl] 2,2-dimethyl-propyl amidoxime oxime ester (16) The title compound was prepared according to Method A, from epoxide 2b (0.100 g, 0.323 house mole) Heated with 醯肼6 (〇·ΐ 47 g, 0.501 mmol) for 96 hours. Purified by RP-LC-MS (3 </ RTI> 20-100% CH3CN in 0.05% aqueous HCOOH gradient) to give product white solid (0.103 g) , 53%)· [oc]D -6.06° (c 0.99, CHC13) ; lU NMR (CD3OD) δ 7.44-7.05 (m, 11H), 6.97 (m, 2H), 6.25 (d, 7.44 Hz, 1Η), 5.08(m,1H), 4.4()(m,1H),4 G9(〇13 8 Hz,m),4 〇2(Mountain 20 13·8 Hz,1H),3·70(ηι, 2H), 3.56 (s, 3H), 3.10-2.77 (m, -88-200804246 5H), 0.76 (s, 9H); 13C NMR (CD3OD) δ 176.5, 172.1, 158.8, 141.9, 141.2, 138.5, 137.6, 131.9, 130.0, 129.2, 129·0, 128.7, 128·4, 127·61, 127·56, 125·8, 125.4, 79·4, 74·1, 67·8, 63·1, 62·9, 58·2, 52·7, 44.1, 40·8, 35·1, 26·8 ; MS〇/z 603, Μ + Η+); analysis (C34H42N4 6) C, Η, Ν. Example 17

Οο 15 (26&gt;2-Benzenyl-3-[,phenylindole-indole-((2幻-2-曱sulfonylamino-3,3-dimercapto-butyl)-decylhydroxyl -Indan-1-yl)-propanamide (17) The title compound was prepared according to Method A using epoxide 2a (0.100 g, 0.323 mmol) and 醯肼7 (0.131 g, 0.418 mmol) Heating for 96 hours. Purification by column chromatography (fluorite, EtOAc / pentane, 40: 60-100: 0), followed by Rp_LC-MS (30% 100-100% CHsCN in 0.05% HCOOH aqueous gradient) The product was obtained as a white solid (0.0864 g, 43%). m,1H), 5.12(d,5·04 Hz,1H), 4.29(ddd,J&quot; - 5· 11,5·04,1 ·94 Hz,1H), 4.24 (d,= 14·5 Hz, -89- 20 200804246 1H)? 4.00(d9 J = 14.5 Hz, 1H)? 3.93(d5 J = 14.1 Hz, 1H), 3.15(s,1H), 3.07-3.96(m,2H),2·90- 2·83(ιη, 2H), 2.74 (d, / = 14.4 Hz, 1H), 2.42 (s, 3H), 0.51 (s, 9H); 13C NMR (CDC13) δ 174.7, 170.2, 14〇·3, 139·9,136·4,136·2,130·8,128.5, 128.4, 128·3 , 128·0, 127.9, 127·0, 126·8, 125·1, 124·1, 77·8, 73.1, 67·2, 63.6, 62·3, 57·4, 43·4, 40·9 , 39.0, 34.2, 26·0 ; MS(m/z 623, Μ + Η'·analysis (C33H42N406S) C, Η, Ν. Example 18

(26&gt;2_benzoquinone_3lubenzenef-based|_[(25&gt;2_(3_phenylhydrazinyl-fluorenyl)-3,3-dimercapto-butanylhydrazyl 2_hydroxy_# _((1&amp;2 magic_2_hydroxy_

The titled &gt; compound method was heated according to Method A from epoxide 2a (〇 655 15 g, 0·212 houser) and 醯肼8 (0.102 g, 0.277 mmol) for 72 hours. Purification by RP-LC-MS (0-90% <RTI ID=0.0># </RTI> <RTIgt; </RTI> <RTIgt;

[a] D21 +30·7° ([ 〇·45, CHCl3/MeOH, 2: 1); A 2 NMR (CD3 〇D) δ 7.38_7.02 (m, 17H), 6.96 (m, 1H) , 6.77 (m, -90- 200804246 1H), 4.98 (d, 4·98 Hz, 1H), 4.28 (s, 2H), 4.25 (d, / = 19·1 Hz, 1H), 4.05 (m, 2H) ), 3.90 (d, J = 14·1 Hz, 1H), 3.76 (m, 1H), 3·05-2·76 (ηι, 5H), 0.58 (s, 9H); 13C NMR (CD3OD) δ 177.5 , 173.0, 160.3, 142·0, 141.4, 141·1, 138·9, 137·6, 131.6, 129·6, 5 129·5, 129·3, 128·9, 128.7, 128·4, 128.2, 128.0, 127·6, 127·5, 126·0, 125.6, 79.3, 73.9, 68·5, 62·8, 61.3, 58·5, 44·7, 44.5, 40.8, 34·9, 26·7; MS (w/z 678, Μ + Η+); analysis (C40H47N5O5) C, Η, Ν 〇ίο Example 19

Base-indan-ylamine-mercapto)-3_phenyl-propyl)-fluorenylcarbonyl]-2,2-dimethyl-propyl amidoxime oxime 〇9) 15 The process was carried out according to the procedure mp. mp. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [a]D +2.65°(c 〇.725 DMF) ; lU NMR(CD3OD) δ 7·35-7·〇3(πι,11H), 6.92(m,m),6 77(m,1H), 4 96 (d, j = 20 4·97 Hz, 1H), 4.14 (d, 14·7 Hz, 1H), 4 13 (m, 1H), 4 〇 2 (d, -91 - 200804246 / = 14· 7 Hz, 1H), 3.87 (d, J = 13·9 Hz, 1H), 3.60 (m, 4H), 3·09-2·75 (ηι, 5H), 0.60 (s, 9H); 13C NMR ( CD3OD) δ 177.5, 172·4, 158·9, 142·1, 141.4, 138·2, 137·5, 132·3, 131.6, 131.4, 128·9, 128.8, 127·6, 127·4, 126 · 0, 125.6, 122·0, 79.2, 73·7, 5 68.4, 62.9, 62·0, 58·4, 52.7, 44.3, 40·7, 34·8, 26·6 ; MS〇/z 681, Μ + Η+, 683, Μ + Η+); analysis (C34H41BrN406) C, Η, Ν. Example 20

Οο {(1 分漠-Benzylhydroxy-2-((1&amp;2 phantom-2-hydroxy-indan-1-ylaminocarbamoyl)-3-phenyl-propyl)-fluorenylcarbonyl] Benzyl-2-methyl-propyl}-amine phthalate (20) The title compound was prepared according to Method A, from epoxide 2a (0.550 g, 0.178 mmol) and 醯肼ι〇 (〇·〇) 650 g, 0.150 mmol, plus 15 heat 168 hr. Purified by RP-LC-MS (25 min, 30-80% CH3CN in EtOAc (EtOAc) [a]D22 -24.4° (c 0.88, MeOH/DMF 2 : 1); NMR (DMSO-d6 + 2 drops D2 〇) δ 7.40-7.01 (m, 16H), 6.76 (m, 2H), 4.97 ( d, J = 12·9 Hz, 1H), 4.93 (d, J = 12·9 Hz, 1H), -92- 20 200804246 4.87 (d9 4.99 Hz? 1H), 4.05 (m, 3H), 3.72 (d5 14.3 Hz, 1H), 3.51 (m, 1H), 3.02-2.55 (m, 5H), L53 (m, 1H), 0.53 (d, / = 6.70 Hz, 3H), 0.39 (d, J = 6.70 Hz, 3H) ; 13C NMR (DMSO-d6 + 2 drops D20) δ 175.2, 171.5, 156.6, 142.6, 5 141.1, 137.9, 137.6, 137.0, 131·3, 130.94, 130.86, 129.0, 128·5, 128·32, 128.27, 127.9, 126·9, 126.5, 125.5, 124·7, 12 0·6, 78·2, 72·3, 67.7, 66·1, 60·8, 59.5, 57·0, 43·4, 40·5, 30.5, 19·2, 18·6 ; MS(m/ z 743, Μ + Η+, 745, Μ + Η+); analysis (C39H43BrN406) C, Η, Ν ίο Example 21 Step a)

3-[1-Phenyl-arylene-(E)-yl]-disindol-2-yl (21a) 15 Preparation of the title compound in Tetrahedron, 57, 25, 2000, ρ· 5353-5360 . Step b)

2-phenyl-1,5-dioxa-spiro[2·4]heptan-4-one (21b) at 80QC, containing 3-[l-phenyl-methylene-(E)- group ]-Dihydro-furan-2-93- 20 200804246 Ketone (21a) (4.0 g, 22.9 mmol) and 3-chloroperoxybenzoic acid (618 g, 27.6 mmol) The amount of catalyst AIBN (50 mg) was added to a solution of 2-dichloroethane (70 ml) and refluxed for 6 hours in the dark. The resulting solution was cooled <RTI ID=0.0></RTI> then filtered. The organic phase was washed with EtOAc (aq) (EtOAc) (EtOAc (EtOAc) The product was purified by flash chromatography eluting with EtOAc EtOAc:EtOAc: MS (ESI+): m/z: 191 (M++1).H NMR (CDC 139 400 MHz): δ i 〇 7.39 (m, 3H), 7.26 (m, 2H), 4.54 (dt, J = 9· 5 Hz, 3·3 Hz, 1H), 4.39 (S, 1H), 4.29 (m, 1H), 2.49 (m, 1H), 2.07 (m, 1H); 13C NMR (CDC13, 100 MHz): δ 173 ·2,133.1,129·1,128 8, 126.4, 64.8, 62.4, 61·7, 22.7 15 Step C)

3-Benzyl-3-hydroxy-dihydro-furan-2-one (21C) Method A: adding platinum oxide ανχο”g) to 2-phenyldioxa-spiro[2.4]heptane_4, (21b) (2.0 g, 1 〇 5 mmol) in a solution of ethyl acetate 20 (4 mL), placed in a Parr hydrogenator set at 5 〇 Psi for 3 hours. The catalyst was filtered off, and the filtrate was evaporated. mjjjjjjjj -94- 200804246 m _ containing 2-phenyl-1,5-dioxa-spiro[2.4]heptane-4-one (21b) (1.903 g '1 〇 millimolar) with pd/c (Degussa) Type m〇1 NE/W '0.530g '2.5mol% Pd) mixed with 20ml EtOAc

Formic acid (0.604 ml, 16 mmol) and triethylamine (2. 09 mL, 15 mmol) were added to the reaction tube. A rotating lid was attached to the test tube and heated at 80 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature, the catalyst was filtered off, and the volatile material was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 10 MS (ESI+): m/z: 192 (M+).H NMR (CDC13, 400 MHz): δ 7·34-7·23 (πι, 5H), 4·26 (πι, 1H), 3·75 (ηι, 1H), 3.05 (s, 2H), 3.04 (s, 1H), 2·39-2·24 (ιη, 2H); 13C NMR (CDC13, 100 MHz): δ 178.9, 134.2, 130.1, 128 · 7,128·5,127.5, 75.5, 65.3? 43.4, 34.0 Step d)

(S)-2-phenylhydrazino-2,4-dihydroxy-AK(lS,2R)-2-hydroxy-indan-1-yl)-butanamine (21d-(S)) and 2〇( R)-2-phenylhydrazino-2,4-dihydroxy-AK(lS,2R)-2-hydroxy-indanyl)-butanamine (21d-(S)) -95 - 200804246 in 3 -Benzyl sulphate-3·hydroxy-dihydro sulphate 2 _ (21c) (〇 5 g, 2·6 mmol) and 2-transbasin t (0·27 g, 2·8 mmol) To the solution of anhydrous dichloromethane (15 ml) was added (1S,2RH_)-cis-amino-2-indanol (〇·43 g, 2.8 mmol). The reaction mixture was stirred at 5 ° C C for 24 hours and then evaporated. The residue was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by hydrazine gel chromatography using petroleum ether: acetone (3:1) to yield 0.26 g of the first fraction (compound 2id-(S)) and 0.33 g of a bath (compound) 21d-(R)), the title compound has a total yield of 66%.

21d-(S) : MS(ESI+) : m/z : 342(M++1) lU NMR (DMSO-i/6? 400 MHz) : δ 7.64(m5 1H)? 7.31-7.10(m? 9H) , 5.52(s,1H), 5.05(m,2H),4.73(s,1H),4·16(ιη,1H), 3.61(m,2H),3·05-3·00(ιη,2H) , 2.86 (d, J = 13.36 Hz, 1H), 15 2.76 (d, J = 16.48 Hz, 1H), 2.14 (m, 1H), L73 (m, 1H); 13C NMR (DMSOd6, 100 MHz): δ 174·8, 143·0, 141·0, 137·4, 130.9, 128·1, 127·7, 126·8, 126.6, 125.5, 124.5, 77·8, 72·4, 57.8, 56·9, 45·8, 41·4, 40·5 (hidden in DMSO) 21d-(R) ·· MS(ESI+) : m/z : 342(Μ++1) 2α 4 NMR (CD3OD, 400 MHz) : δ 7.61(d, J = 8.79 Ηζ, 1Η), 7·33-7·24(ιη, 5Η), 7.17 —7.10 (m, 2Η), 6.97 (m, 1Η), 6.25 (d, J = 7·32 Hz, 1H), 5.10 (m, 1H), 4.46 (m, 1H), 3.77 (m, 2H), 3.16 (d, J = 13.36 Hz, 1H), 3.07 (dd, J = 16.48, 4 · 94 Hz, 1H), 2.91 (d, J = 13.36 Hz, 1H), 2.82 (d, J = 16·48 Hz, 1H), 2.28 (m, -96- 200804246 1H), 1.91 (m, 1H) ; 13C NMR (CD3OD, 100 MHz) : δ 175·6, 14〇·4, 140.0, 136·5, 130·5, 127·6, 127·5, 1 26.2, 124·6, 123.8, 77·9, 72·7, 57·8, 56.9, 56·8, 45·5, 41·3, 39·3 5 Step e)

(S)-2-Benzyl-4-(t-butyl-diphenyl-decyloxy)·2-hydroxy-7V«((lS,2R)-2-yl-indenyl) _Butylamine (21e) containing (S)-2-benzyl-2,4-dihydroxy-, ((lS,2R)-2-hydroxy-茚ίο -1--1-yl)-butanamine (21d-(S)) (0.245 g, 0.72 mmol) and TMBPS-C1 (0.2 g, added to a solution of imidazole (0·73 g, 1.08 mmol) in anhydrous dichloromethane (25 ml) 〇·75 millimoles), let stand for one night. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. 15 MS (ESI+): m/z: 580 (M+) lU NMR (CDC13, 400 MHz): δ 7.71-7.66 (m, 4H), 7·48·7·36 (πι, 8H), 7·34- 7·24(πι,4H), 7·22-7·18(πι,2H), 7.12_7.04(m,2H), 5.37(s,1H), 5.24(m, 1H),4J7(m, 1H), 4.15 (dd, J = 1〇·4 Hz, 2·4 Hz, 1H), 4.10(m, 1H), 3.10(d, J = 13·6 Hz, 1H), 3.05(m, 2H) , 2.81 (d, J 2 16·4 20 Hz, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.09 (s, 9H); 13C NMR (CDC13, 100 MHz): δ 174·6 ,140·5,137·5,135·7, -97- 200804246 135.6, 132·4, 131·0, 130·4, 128·3, 128·2, 128.1, 127.1, 126.9, 125·3, 124.0 , 80·9, 73.4, 63·5, 57·4, 46.0, 39·0, 38·8, 30.0, 27.0 Step 〇

Oxygen)-l-((3aS,8aR)-2,2-dimethyl-8,8a-dihydroindole[1,2-&lt;Κ口-3-yl)-2-yl-butyl Burning 1-嗣(21f) 10 (S)-2-Benzyl-4-(t-butyl-diphenyl-cracking-oxyl)-2-nonyl group in cooling (0°c) -A^-((lS,2R)-2-carboxyl-indan-1-yl)·butylamine (21e) (0.325 g, 〇·56 mmol) and acridine p-toluenesulfonic acid ( Add 2 -methoxy propylene (0 · 4 g ' 5 · 6 mmol) to a solution of 15 mg, 0.05 mmol of anhydrous dichloromethane (2 mL). Stir at the same temperature for 6 min 15 Time. A saturated NaHC(R) 3 solution was added, and the organic phase was washed with saturated NaHCO.sub.3, brine, and then evaporated. The title compound crude product [(0.33 g), MS (ESI+): 620 (M+)] was used for the next reaction. (S)-2_Benzyl-4-(t-butyl-diphenyl-decyl) Step g) -98- 200804246

(S)-2-phenylhydrazinyl-1-((3 ena)-2,2-dimercapto_8,8&amp;_dihydro_pass_茚[l,2d] 十坐-3_基)-2,4-dihydroxy-butane-

'Add TBAF (0.278 g, 丨.06 mmol, 1 M THF 5 solution) to (8)-2-phenylyl-4-(t-butyl-diphenyl-decyloxy)-l at room temperature -((3aS,8aR)-2,2-dimethyl-8,8a-dihydrogen π 2 chlorof azole-3-yl)-2-hydroxy-butane-i-one (210 (0.33 g, 〇53 mmol (THF) in a solution of THF (20 liters) for 3 hours. Evaporate the solvent, the residue is dissolved in dichloromethane, washed with water, brine, dried and evaporated. Purification of the oil mystery propyl hydrazine (4 · 1) yielded 145 g of the title product, mp ield: 69%. MS (ESI+) · m/z : 382 (M++1) !H NMR (CDC13 , 400 MHz) : δ 7.34-7.25 (m, 4H), 7·20-7·09 (ιη, 5H), 5.25 (m, 1H), 4.23 (m, 1H), 4·10-4*00 ( m, 2H), 3" 5 (d, J = 12·8 Hz, 1H), 3.06 (dd, J 15 = 16·4 Hz, 5·6 Hz, 1H), 2.96 (d, J = 13.2 Hz, 1H), 2.83 (d, J = 16·4 Hz, 1H), 2.40 (m, 1H), 2.16 (s, 6H), 2.10 (m, 1H); 13C NMR (CDC13, 100 MHz): δ 175.4, 140.6, 140.4, 136.7, 130·9, 128·2, 128.0, 127.3, 127.2, 127·1, 125.4, 123.9, 80·2, 73.3, 61.2, 57.5 , 46·2, 39·3, 39.2, 31·1, 29·4 Step h) -99- 20 200804246

(S)-3-phenylmercapto-4-((3aS,8aR)-2,2-dimercapto-8,8a-dihydro-3a//-indole[l,2-i/]carbazole -3-yl)-3-hydroxy-4-oxo-butyraldehyde (21h) containing (S)-2-benzyl-l-((3aS,8aR)-2,2-didecyl-8 , 8a-dioxin 5 [[1,2-ί/] oxazol-3-yl)-2,4-dihydroxy-butan-1-one (21 g) (0.13 g, 0.34 mmol) Anhydrous CH2C12 (5 mL) solution was added over 1 min to a solution of Dess-Martin periodinate (0.16 g, 0. 37 mmol) in anhydrous CH2C12 (10 mL). After 30 minutes, the homogeneous mixture was diluted with ether and poured into cold saturated EtOAc NaHCO3 (10 mL) (Na2S203 (2.2 g)). Organic phase is saturated

Aqueous NaHC03, brine, and dehydrated (MgS04). The solvent was evaporated <RTI ID=0.0></RTI> to <RTI ID=0.0> The residue [MS(ESI+) ·· 380(M++1)] is used in the next step. 15 steps i)

((S)-l-{7V'-[(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-diaza-3a//- Neem [1,2-ί/]17-deficiency-3-yl)-3-yl-4-yl-oxo-butyl]-spin-100- 200804246 carbonyl}-2,2-didecyl- Propyl)-ammonium decanoate (21i) Take (S)-3-benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dioxin-3af茚[1,2-Isoazol-3-yl]3-hydroxy-4-oxo-butyraldehyde (21h) (0.082 g, 0.21 mmol) and [decyloxycarbonyl)-L-third A solution of leucine oxime (0.048 g, 0.23 mmol, prepared according to the method described in JMC, 4/3387, 1998) in anhydrous THF (10 mL) was stirred for 3 h, [LCMS (ESI+) )], then add Na(OAc)3BH (0.137 g, 〇·64 mmol) and stir overnight. The reaction mixture was quenched with water and evaporated. The residue was dissolved in dichloromethane, washed with water, brine, and dried. The crude product was analyzed by LCMS (ESI+) to show that the title compound of 567 (Μ+) still contains a small amount of compound (MS(ESI+): 527(Μ+)) which has no protecting group on the indanol moiety. This mixture was burned in the next step without purification. Step j)

((RHl-{N'-(4-Bromo-benzyl)hydroxy-3_((1S,2R)_2_hydroxy-indan-1-ylaminecarbamyl]&gt;4-phenyl-butyl] _Mercaptocarbonyl}_2,2-dimethyl-propyl)-carbamic acid methyl ester C22&gt; Compound 21ι (0·1〇5 g) was dissolved in 2-butanone (1 mL), and -101 - 200804246 K2C03 (〇.〇45 g, 0.32 mmol) and 4-bromobenzoguanidinium bromide (0.054 g, 〇·21 mmol), stirred at 80 ° C for 3 hours. Evaporate solvent, residue soluble Dichloromethane (15 ml), EtOAc (3 mL),EtOAc. Washed with NaHCO3 solution, water, brine, and dried with EtOAc EtOAc (EtOAc) (M+) 4 NMR (CDC13, 400 MHz): δ 7.40-7.12 (m, 11H), 7·04-6·98 (ηι, 2H), 6.42 (s, 1H), 6 〇8 (s, 1H) ,5·18(ιη,2H),4·16(ιη,1H), 3.97(d,J=14·0 Hz, out), 3.77(d, J = 13·2 Hz, 1H), 3.66(s ,3H),3.56(d,J = 9·6 Hz,i h),3·12-3·01(ηι,4H), 2.82(m,2H), 2.32(m,1H), l94(m,1H),0.79(s,9H) 22

((R), (1-{N, _(4-bromo-phenylhydrazino)_N,-[(S)-3-hydroxy-3-((lS,2R)-2-hydroxy·indan-1 -Aminoguanidino)-4-phenyl-butyl]-stiffylpyridyl 2,2-dimercapto-propyl)-amine decanoate (22) from compound 22d-(R) Example 21 Step aj Compound 22-(S) -102 - 200804246 Preparation of the method described, yielding the title compound Example 23 Step a)

5,6_Di-argon-cyclopenta-P]thiophen-4-one (23a) A solution of trifluoromethanesulfonic anhydride (84·7 g, 0.30 mol) in DCE (300 mL) was added over 10 min to the mixture. #一二曱 Acrylamide (29 8 g '0.30 mol) in DCE (27 ml) cold solution. The mixture was stirred for 15 minutes. A solution of thiophene (25. 3 g, 〇·3 Torr) was added and the mixture was refluxed for 7 hours. A potassium carbonate solution (15 g of water in 2 ml of water) was added. The mixture was extracted twice with DCM, dried over sodium sulfate and evaporated. The compound was purified by silica gel chromatography using ethyl acetate /hexane. Yield · 36.8 g = 53% 1H-NMR CDC13 7.32 (dd, 1 Η), 7.14 (dd, 1 Η), 3.20 (m, 2 Η), 3.00 (m, 2H) Step b

5-Hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one (23b) added with 5,6-dihydro-cyclopenta[Z&gt;]thiophene-4 at about 5 °C A solution of the ketone (36.8 g, 0.266 mol) in MeOH (1000 mL) to MeOH (500 mL) EtOAc (EtOAc: EtOAc (EtOAc) Between 〇°c and 5, iodophenyl diacetate (94·4 g, 〇·293 mol) was added in portions, and the contents were cooled to room temperature. The mixture was stirred at room temperature overnight. The mixture was simmered and a 20% potassium carbonate solution (5 mL) was added. The mixture was extracted with DCM (5 EtOAc). The residue was dissolved in 1,4-dioxane (400 mL), water (15 mL) and concentrated hydrochloric acid (15 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was neutralized by the addition of potassium carbonate and extracted 4 times with dioxane. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was crystallized from ether-ethyl acetate, and the mother liquid was purified by silica gel chromatography using ethylbenzene. Yield: 33.5 g = 81.6%. H-NMR CDC13 δ 7.36 (dd, 1H), 7.18 (d, 1H), 4.76 (m, 1H), 3.64 (m, 2H), 3.10 (m, 1H) C) 15

N,. ^0 5-Hydroxy-5,6-dihydro-cyclopenta[ft] porphin _4-ketobenzyl-indole (23〇) in 5-hydroxy-5,6-dihydro-cyclopenta [6] Thiophene-4-one (33.4 g, 0.216 mol) was added to the solution of the bite (300 ml) with benzylmethylamine hydrochloride (38.3 g, 0·240 mol) at room temperature. Stir the mixture for a weekend. The mixture was decompressed and evaporated, and co-evaporated twice with toluene. Ethyl acetate was added and the organic phase was washed with 5% citric acid and brine. It was dehydrated with sodium sulfate -104- 20 200804246 and evaporated under reduced pressure. Yield 55.1 g = 98% ^-NMR CDC13 5 7.40-7.20 (m? 7H)? 5.20 (m5 3H) 5 3.45 (m5 2H), 3.0 (m, 1H) Step d)

Cis-4-amino-5,6-diindole-4//-cyclopentamidine]thiophene-5-ol (racemate) (23d) 5-cyano-5,6-diaza- ί辰戍弁[h] 嗟 嗣Ο-4-嗣Ο-phenylhydrazine-Jiang 10 (55.1 g, 0.212 mol) solution was added dropwise to 1.0 M borane at about 5 ° C

The mixture was stirred at room temperature overnight in THF (650 mL). The mixture was refluxed for 2 hours and cooled to about 5 °C. Water (70 ml) and 20% hydrazine hydroxide solution (80 ml) were added dropwise. The mixture was refluxed for 2 hours with cooling. Brine was added and the THF was removed under reduced pressure. The mixture was extracted 5 times with DCM, dried over sodium sulfate and evaporated. The product was purified by silica gel chromatography using DCM eluting with 10% methanol. Yield: 17.8 g, two 54% h-NMR DMSO_d6 δ 7.30 (d, 1H), 6.92 (d, 1H), 4.46 (m, 1H), 4.20 (m, 1H) 3.99-3.84 (dd, 2H) 2〇Example 24 Enantiomeric separation of Example 23 Step a) -105- 200804246

(5-3⁄4 base_5,6_dihydro_4Η_cyclopenta[b]thiophene-4-ylamino) hydrazino-ethyl]-tert-butyl benzoate (24a) 5 · 10 15 5 ^ in anhydrous DMF containing racemic cis-4-amino-5,6-dihydro-4/ί-cyclopenta[6]thiophene-ol (17.5 g '0112 mol) (4 〇〇 ml) mixed with i i i 很 很 很 很 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The mixture was added to 5% citric acid and extracted with ethyl acetate. The organic phase was washed with brine (2 times) with saturated aqueous sodium bicarbonate. Dehydrated with sodium or sodium sulfate and evaporated under reduced pressure. Yield: 43 g = 95% Step b)

Amino-N-(5-hydroxy-5,6-dihydro-4H-cyclopenta strain "M*-based amine (24b) 4-opened phenanthyl-4-yl)-3-benzene is dissolved in gas 24b Imitation (4 〇〇亳弁, ^ liter), stir the mixture for 3 hours at room temperature. The machine has a machine, force (10) 100 milliliters (_ml), wash twice and wash with salt water. ^1f 〇 ammonia solution and evaporation. The product was purified by Dc sodium dehydration and purification (3 to 1% methanol) -106- 20 200804246 Yield A: 12·5 g di-copy Isomer = 40% Yield B: 12.5 g Second diastereomer = 4% % Step C) OC^〇h 〇〇 "&quot;·〇h 5 NH2 NH2 4-Amino-5, 6-Di-argon-4H·cyclopenta[b]nonanol (24c) The first mountain diastereomer (12·4 g, 41 mmol) was dissolved in EtOH (400 liters) 'Add a solution of sodium hydroxide (21 g, 525 mmol) in water (300 ml). The mixture was refluxed overnight. Exclude ethanol, alkaline 10 n DCM extraction 6 - owed. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Yield: 6.2 g = 97%. ri-NMR DMSO_d6 δ 7.30 (d, lH), 6.92 (d, 1 Η), 4.46 (m, 1H) 9 4.20 (m? 1H)? 3.99.3.84 (dd, 2H) 〇 : — money 25

Br 丫. , «Μ)-ΗΛΓ-(3-bromo-benzyl)-fluorenyl#carbon-based]_2,2-dimethyl-propyl}-carbamic acid methyl ester (25) ^Extracted (fluorenyloxycarbonyl) HL)-third leucine (3.25 g, 17·1 20 mol) dissolved in Et〇Ac (40 ml), sequentially added hydrazine (2.55 g, 18.9 mmol), EDAC (3.62 g, 18.9) Molly) and Li is. 〇 8 --107- 200804246 liters, 18·9 millimoles). 3-Bromo-stupylmethyl hydrazine (4 14 g, 2 〇 6 mmol) was dissolved in EtOAc (20 mL) and then stirred and then stirred at room temperature overnight. The organic phase was washed with aq. NaHC.sub.3 (aq. The combined aqueous phases were extracted with EtOAc EtOAc EtOAc. The combined organic phases were dried (Na2S 4), filtered, and concentrated. The crude product was purified by column chromatography (EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) A small amount of the residue was subjected to RP_LC-MS (35-80% CH3CN in 0.05% citric acid aqueous solution) to obtain a sample of higher purity for discriminating, and the product was isolated white. [a]D20 _28.0o(c 1.2, CH3OH); 4 NMR (CD3OD) δ 7.56 (m, 1H), 7.40 (m, 1H), 7·32 (ηι, 1H), 7.22 (m, 1H), 3.93 (s, 2H), 3.81 (s, 1H), 3.63 (s, 3H), 0.89 (s, 9H); 13C NMR (CD3OD) δ 171·7, 159·0, 141·8, 132.9, 131.5, 15 131·1,128·8, 123·3, 62.9, 55·5, 52·7, 35·1,26·9 ; MS (mA 372, Μ + Η+, 374, Μ + Η+). Example 26

2〇Bromo-phenylhydrazinyl)-indole-[(25&gt;2-hydroxy-2, recognize 2 and)-2-predomyl-indan-1-ylamine oxime)-3-phenyl-propyl ]--Pyrylamino]_2,2_didecyl-propyl}-amino decanoic acid methyl ester (26) -108- 200804246 Take (25&gt;2-benzoquinone-epoxyethyl bromide-|[(1&amp ; 2 and) 2-carbyl-indan-1-yl]-2-inconelamine (0.930 g, 3.01 mmol) and compound 25 (1.23 g, 3.31 mmol) are dissolved in anhydrous THF (40 ml), Ti(OzTr) 4 (1.79 ml, 6·02 mmol) was added, and the mixture was stirred for 5 hours at 4 ° C. Et 2 〇 (1 (9) ml) and saturated NaHC03 (aqueous solution, 100 ml) to the reaction mixture, the phases were separated, and the organic phase was washed with H2 EtOAc (2×200 mL). The crude product was purified by flash chromatography ( EtOAc EtOAc EtOAc (EtOAc) [a] D19 -55.2° (c 0.95, CH3OH); 1h NMR (CD3OD) δ 7.50 (m, 1H), 7.36-7.16 (m, 7H), 7·13-6·93 (ιη, 4H), 6.80 (m,1H), 4.96 (d,4·82 Hz,1H), 4.17(d, J = 14.7 Hz, 1H)5 4.14(m9 1H), 4.00(d, J = 14.7 Hz9 15 1H)? 3.88( D9 J = 13.9 Hz, 1H)9 3.60(m9 4H)9 3.07-2.77(m9 5H), 0.60(s,9H) ; 13C NMR(CD3OD) δ 177·5, 172.4, 159.0, 142·0, 141· 6, 141.4, 137·5, 132·2, 131·6, 131·5, 131·0, 128·9, 128·8, 128·2, 127.71, 127.67, 126·0, 125·5, 123.5, 79·2, 73·8, 68.6, 62·9, 62.0, 58.4, 52·7, 44·3, 40·7, 34.9, 26·6 ; 2〇MS(m/z 681,Μ + Η' 683 , Μ + Η+).

General method for Pd-catalyzed reaction ^^ Method for taking aryl bromide 19 or 26, tin reagent, Pd(PPh)3Cl2, CuO and DMF (2 liters) in thick-walled Smith reactor (Smith process -109- In 200804246 vial), stir in a microwave oven at 130oC for 20 minutes. CH2C12 (30 mL) was added to the mixture which was washed with saturated NaHC03 (aq., 3×20 mL). The organic phase is dehydrated (Na2S04), filtered and evaporated. The residue was redissolved in CH.sub.3CN (EtOAc) (EtOAc) Method B. Take aryl bromide 19 or 26, dihydroxyboric acid, pd(pph)3Cl2, 2M Na2C〇3 (aqueous solution), EtOH and DME in a thick-walled Smith reactor and stir in a microwave oven at 120 °C. minute. After adding 5 drops of formic acid to the mixture, the solvent was evaporated. The residue was redissolved in CH3CN/H20/DMF, 10 filtered and purified by RP-LC-MS. HC. Take aryl bromide 26, acetylene, Et2NH, Pd(PPh3)2Cl2, Cul and DMF in a thick-walled Smith reactor and stir in a microwave oven at 14 ° C for 30-40 minutes. The method of operation is with CH2C12 (2 ml) and

Purified by RP-LC-MS.

Purified by RP-LC-MS.

-110- 200804246 {(lR-lW-(biphenyl-4-yl-indenyl)-#'-[(25)-2-yl-2-((15&gt;, 2 and)-2) -茚满_1_基胺曱醯基)_3-styl-propyl]-fluorenylcarbonyl]-2,2-dimercapto-propyl-p-propyl carbamate methyl ester (27) The title compound is produced according to the method B, using compound 19 (90.0 5 house gram ' 〇 · 132 pen moles), phenyl di light side acid (80.5 house gram, 〇 · 660 millimoles), Pd (PPh) 3Cl 2 (4.60 mg, 0.0065 mM Ear), 2 Μ Na2C03 (aqueous solution, 0·198 ml, 0.396 mmol), ΕΚ) Η (0·6 mL) and DME (2.4 mL). Purification by RP-LC-MS (40% 10-100% CHsCN in EtOAc EtOAc) [a]D20 -59.30(c 1.4, CHC13); 'H NMR(CD30D/CDC135 1 : 1) δ 7.55-7.16(m? 14Η), 7·13-6·92(ιη,3Η),6·82 (ηι,1Η),5.05(d,J=4·80 Ηζ,1Η), 4.24(d,14·3 Ηζ,1Η),4.09(m,1Η),4.05(d,14·3 Ηζ, 15 1Η ), 3.92 (d, J = 14.0 Ηζ, 1 Η), 3.58 (m, 4 Η), 3·04-2·71 (ιη, 5H), 0.56 (s, 9H); 13C NMR (CD30D/CDC13, 1 : 1) δ 176·2, 171·3, 157.9, 141.5, 141·0, 140·6, 140.5, 136·81, 136.78, 131·0, 129·3, 129·2, 128·4, 128·3 , 127·6, 127·4, 127.3, 127.2, 127·1, 125.4, 124.8, 78.5, 73.3, 67.6, 61·9, 61.7, 57·8, 52.6, 2〇_ 43·8, 39.6, 34· 6, 26·2 ; MS(w/z 679, Μ+Η+) 〇Example 28 -Ill - 200804246

{(16&gt;l-[7V'-[(25&gt;2-Hydroxy-2-((1 and 27〇-2-hydroxy-indan-1-ylamino)-phenyl-propyl) Decidinyl-2-yl)-phenylhydrazinyl]-fluorenylcarbonyl]-2,2-dimercapto-propyl-p-butylamine decanoate (28) J The title compound is prepared according to Method A, using Compound 19 ( 100 mg '0.147 亳mol), (丨丄丨-tributylstannyl)pyridine (220 mg, 0.598 mmol), Pd(PPh)3Cl2 (5el2 mg, 0. 0072 mmol) and CuO ( Preparation of 11.7 mg, 0.147 mmol. Purified by RP-LC-MS (40 min of l 〇 〇〇 〇〇 CH 3 3 3 3 0.05 0.05 0.05 0.05 0.05 0.05 ) ) ) ) ) , , White solid. [a] D19 -28.8° (c 0.99, CH3OH); NMR (CD3OD) δ 8.57 (m, 1H), 7.94-6.93 (m, 15H), 6.75 (m, 4.12 (d, 14·) 3 Hz, 1H), 3.90 (d, J = 14·9, 1H), 3·68-3·52 (ιη, 15 4H), 3.08, 2.74 (m, 5H), 0.59 (s, 9H); 13C NMR (CD3OD) δ 176.4, 171, 2, 157·8, 157.5, 149·1, 140.9, 140.2, 138·9, 138.3, 137·7, 136.4, 130.5, 128·9, 127.7, 127.6, 126·8 , 126·5, 126.4, 124·8, 124·5, 122·5, 121 2, 78·1,72.7, 67·2, 61.8, 61.3, 57.3, 51·5, 43·2, 39·6, 33.7, 25·4 ; HRMS(M+H+): 680.3450, C39H46N506, theoretical value 680.3448 20 200804246 Example 29

{(lQ_l_[AT-[(2S)-2-hydroxy-2-((1 and 2i?)-2-hydroxy-indan-1-ylamine))-3-phenyl-propyl]- [4-(σ ratio σ定-3 -yl)-benzyl]-pyranyl 5-yl]-2,2-dimethyl-propyl amidoxime oxime ester (29) Method A, using compound 19 (90.0 mg, 0.132 mmol), 3-(1,1,1-tributylstannyl)acridine (194 mg, 0.527 mmol), Pd(PPh)3Cl2 (4.63 mg) Prepared with CuO (10.5 mg, 0.132 mmol). Purified by RP-LC-MS (40% 10-100% CH3CN in 0.05% aqueous formic acid gradient) (24.0 mg, 27%) [a] D19 -37.5° (c 1.4, CH3OH); NMR (CD3OD) δ 8.70 (m, 1H), 8.49 (m 1H), 7.99 (m, 1H), 7.56 -7·42(ηι,5H),7.34-7.18(m,5H),7·15_6·94(ιη,3H), 15 6.72(m,1H),4.99(m,1H), 4.27(d,Hz , 1H), 4.13 (m, 1H), 4.11 (d, 14·5 Hz, 1H), 3.91 (m, 1H), 3·66-3·53 (πι, 4H), 3.07-2.76 (m, 5H) ), 0.59 (s, 9H); 13C NMR (CD3OD) δ 176.4, 171, 2, 157.8, 147·5, 147.0, 140.9, 140·3 138.2, 137·3, 136·5, 136·4, 135.2, 130·5, 129.3, 127·7, 127.6, 126.8, 2〇126.5, 126.2, 124.8, 124.5, 124·3, 78·1,72· 6, 67·2, 61.7, 61.2, 57.3, 51·5, 43.2, 39.6, 33·7, 25·4; -113- 200804246 HRMS(M+H+): 680.3465, C39H46N506, theoretical value 680.3448. Example 30

{(1 phantom-l-[7\r-[(25&gt;2-hydroxy-2-((l*S,2i?)-2-hydroxy-indan-1-ylamino)-3- Phenyl-propyl]-Ar-[4-(acridin-4-yl)-benzoinyl]-fluorenylcarbonyl]-2,2-dimethyl-propyl amidoxime oxime (30) The title compound was prepared according to Method B using Compound 19 (90.0 mg, 0.132 mmol), pyridine-4-dihydroxyboronic acid (81.0 mg, 0.659 1 mM millimolar), Pd(PPh)3Cl2 (4.60 mg, 0.0065 Prepared by RP-LC-MS (40 min 0_8 〇 % CHsCN 0 〇 制备), 2M Na2C03 (aqueous solution, 0.198 ml, 0.396 mmol), EtOH (0.4 mL), and DME (1.6 mL). The product was obtained as a white solid (15.6 mg, 17%) as a white solid. 15[a]D20 -41.50 (c 0.47, CH3OH); 4 NMR (CD3OD) δ 8.55 (m, 2H), 7· 68_6·91(Π1,14H), 6.70(m, 1H), 4.97(d,5·15, 1H), 4.26(d,6 Hz,1H),4 14(m, 1H), 4.12(d,h 14.6 Hz, 1H), 3.9 〇 (m, 1H), 3·64·3·51 (πι, 4H), 3.07-2.75 (m, 5H), 0.58 (s, 9H); 13c NMR (CD3OD) δ 2 〇176.4,171,2,157.8,149.4,149·3,1 complex 9,i4〇3,i39 4 136·7, 136.4, 130·4, 129·3, 127·7, 127·6, 126·8, 126·5, 126·2, -114- 200804246 124.8, 124.5, 121.8, 78·1,72·6, 67· 3, 61·7, 61.2, 57·3, 51.5, 43·2, 39·6, 33·7, 25·4; HRMS(M+H+): 680.3432, C39H46N506, theoretical value 680.3448. Example 31

{(15&gt;1-[ΑΓ-[(25&gt;2-hydroxy-2-((l&amp;2i?)-2-hydroxy-indan_1_ylamine-methylmethyl)-3-phenyl-propyl] -7V'-[4-( ° ratio _-2-yl)-benzyl]-fluorenylcarbonyl]-2,2-dimercapto-propyl}-carbamic acid hydrazine (31) ίο 15 title compound The method is based on Method A, using Compound 19 (91.3 mg, 〇·134 亳 Mo), 2-(1,1,1-tributylstannyl argon (198 mg, 0.537 mmol), Pd (PPh) 3Cl2 (4.70 mg, 0.0067 mmol) was prepared with CuO (10.7 mg, 0.134 mmol). Purified by RP-LC-MS (35-90% CH3CN in 0.05% aqueous dec. 17.3 mg, 19%) of a white solid. [oc]D20 </ s </ s </ s </ s </ s> </ s> </ RTI> </ RTI> NMR (CD3OD) δ 9.00 (m, 1H), 8.65 (m, 1H), 8.49 (m, 1H) , 7.88(m,2H), 7.47(m,2H),7·34·6·91(ιη,8H),6.72(m,1H), 4.97(d,= 5·00, 1H), 4.27(d , J = 14.5 Hz, 1H), 4.14 (d, J = 14.5 Hz, 1H), 4.13 (m, 1H), 3.90 (d, 1H), 3.63 (s, 1H), 3.57 (s, 3H), 3.05 -2.77 (m, 5H), 0.59 (s, 9H); 13C NMR (CD3OD) δ -115- 20 200804246 177.5, 172·4 159 .0, 154.1, 145.7, 143.9, 142·9, 142·1, 141·4, 141.2, 137.6, 136.6, 131·6, 130.3, 128.9, 128·8, 127·9, 127·7, 127·5 , 126·0, 125·7, 79·3, 73.8, 68·4, 62.9, 62.5, 58.5, 52·7, 44·4, 40·8,34·9,26·6 ; HRMS(M+H+ ) : 681.3385, C38H44N606, theoretical value 681.3401. Example 32

Hydroxy-2-((15,270-2-hydroxy-indanyl)carbinyl)-3-phenyl-propyl]benzo[6]thiophen-2-yl)-benzoinyl]-fluorenylcarbonyl ]-2,2-Dimercapto-propyl amidoxime oxime ester (32) The title compound was prepared according to the procedure using 19 (83.4 mg, 〇·123 mmol), benzo[b]thiophene- 2-Dihydroboronic acid (109 mg, 0.613 mmol), Pd(PPh)3Cl2 (4.32 mg, 0.00615 mmol), 2 Μ Na2C03 (aqueous solution, 〇·185 ml, 0.369 mmol), EtOH (0.4 ML) was prepared with DME (1.6 ml). Purification by RP-LC-MS (35-100% EtOAc (EtOAc:EtOAc) [a]D19 -68.5〇(c 1.0, CHC13); !H NMR(CD30D/CDC13 2 : 1) δ 7.82-7.67(m,3H) 116* 200804246 7.58-7.06(m,11H),7.10(m, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.80 (m? 1H)? 4.96 (d5 5.04 Hz? 1H)? 4Al(d, J= 14.5 Hz, 1H), 4.06 (m, 1H) ), 4.01 (d, 14·5 Hz, 1H), 3.85 (d, 13.9 Hz, 1H), 3.55 (s, 1H), 3.53 (s, 3H), 3.05-2.72 (m, 5H), 0.53 (s) , 5 9H) ; 13C NMR (DMSO-d6, 60 °C due to the generation of rotamers at room temperature) δ 174·4,169·8,156.1,143·2,141.8,140·3,140·1, 138.3, 138·2, 136.3, 132.0, 130.0, 128.6, 127·3, 126·8, 125.8, 125.6, 125.3, 124·4, 124.2, 123·9, 123·3, 122·1, 119·3, 119.2, 77·3, 71·6, 66·7, 61.1, 60.4, 56·4, 56·3, 51·1, 42.7, 33·2, ίο 25·9 ; MS〇/z 735, Μ+Η +) 〇Example 33

{(15&gt;1-[ΑΓ-(4-Benzo[1,3] bis-oxo-5-yl-benzoinyl 15 via benzyl-Bp-full-1-ylamine oxime)-3 -Phenyl-propyl]-fluorenylcarbonyl]-2,2-dimercapto-propyl}-amine decanoate (33) The title compound was prepared according to Method B using Compound 19 (91.9 mg, 0.135 m Mohr), 3,4-methylenedioxyphenyldihydroxyboronic acid (112 mg, 0.676 mmol), Pd(PPh)3Cl2 (4.70 mg, 0.0067 mmol 2 〇), 2M Na2CO3 (aqueous solution, 0.203 ml, 0.405 mmol, -117- 200804246

EtOH (0.4 mL) was prepared with DME (1.6 mL). Purification by RP-LC-MS (35-100% <RTI ID=0.0></RTI> </RTI> <RTIgt; [oc]D19 -62.30(c 0·65, CHC13); 5 lR NMR(CD30D/CDC13 2 : 1) δ 7.36-7.15(m, 9H)? 7.12-6.90(m,5H), 6.85-6.73(m , 2H), 5.93 (s, 2H), 5.01 (d, J = 4·88 Hz, 1H), 4.22 (d, 14·2 Hz, 1H), 4.10 (m, 1H), 4.04 (d, J = 14.2 Hz? 1H), 3.90 (d? /- 13.8 Hz? 1H), 3.58 (m9 4H)5 3·07-2·72 (ηι, 5H), 0.56 (s, 9H); 13C NMR (CD30D/CDC13 Οο 3 : 2) δ 176·7,176.6,171·6,158·2,148·9,147·9,141·02, 141.00,140·9,140·7,136.9,136·7,136.1, 131·2,129·5, 128.50, 128·46, 127.29, 127·25, 125·6, 125·1,109·1,107·9, ί01·9, 78.7, 73·5, 67·8, 62·0, 58·05, 57·96, 52.7, 43·9, 40·0, 34.7, 26·3; MS(w/z 723, Μ+Η+). 15 cases 34

{(15&gt;1-[Λ^[4-(3,5-Dimethyl-isoxazol-4-yl)-phenylhydrazinyl]-indole-[(25&gt;2-hydroxy-2-((1&amp) ;2 and)-2-hydroxy-indan-1-ylamine,carin-2-yl)-3-phenyl-propyl]-pen-1ylcarbyl]-2,2-dimercapto-propyl} - carbamic acid oxime ester (34) -118- 200804246 The title compound was prepared according to Method B using Compound 19 (95.1 mg, 0.139 mmol), 3,5-dimercaptoisoxazole-4-dihydroxyboronic acid ( 98.5 mg, 0.699 mmol, Pd(PPh)3Cl2 (4.84 mg, 0.0069 mmol), 2M Na2C03 (aqueous solution, 0.210 mL, 0.419 mmol), 5 EtOH (0.4 mL) and DME (1.6 mL) Prepared by RP-LC-MS (35-90% <RTI ID=0.0></RTI> </RTI> <RTIgt; 0.72, CHC13); lH NMR (CD3OD) δ 7·42 (ιη, 2H), 7.34 earn 7.16 (m, 5H), ίο 7.15-6.96 (m, 5H), 6.71 (m, 1H), 4.97 ( d, J = 5·11 Hz, 1H), 4.27 (d, 14·5 Hz, 1H), 4.13 (m, 1H), 4.08 (d, 14.5 Hz, 3.93 (d, J = 13.9 Hz, 1H), 3.63(s,1H), 3.60(s,3H), 3.09-2.76(m,5H), 2.34(s 3H), 2.18 (s, 3H), 0.58 (s, 9H); 13C NMR (CD3OD) δ 177.6, 172.3, 166.8, 159.9, 159.0, 142·2, 15 141·5, 138.7, 137.5, 131·6, 130.4, 130.13, 130.10, 128.9, 128.7, 127·7, 127·4, 126.0, 125.7, 117·8, 79·3, 73·8, 68.5, 62·9, 62·4, 58·5, 52.7, 44·3, 40·8, 34.9, 26·7, 11·4, 1〇·7 ; MS(m/z 698, Μ+Η+). 2〇_ Example 35 -119- 200804246

(called 1_{ΛΜ(10)-2-carbyl-2-((10) 2-yl-based-small-small-amine amine)-3-phenyl-propyl]|·[4_((6)-styryl) Methyl phenylmethyl]-pyridyl}-2,2-dimethyl-propyl)-carbamic acid methyl ester (35) Soil compound method of compound 35 according to the method, using compound 19 (89·5 mg HU) House Mo), trans-benyl ethylene diper acid (π 3 mg, 0.658 mmol), Pd (PPh) 3Cl2 (4.56 mg, 〇〇〇65 mmol), 2M Na2C03 (aqueous solution) , 〇·197 ml, 395·395 mmoles, EtOH (0.4 ml) and DME (1.6 ml) were prepared. Purification by RP-LC-MS (35-90% <RTI ID=0.0></RTI> </RTI> <RTIgt; [a] D20 _68.0o (c 0.81, CHC13); 4 NMR (CD30D/CDC13 2 : 1) δ 7.48 (m, 2H), 7·39-6·91 (ηι, 17Η), 6.81 (m9 1Η) 5.01 (d? J = 4.97 Ηζ? 1Η), 4.20 (d? J = 14·5 Hz, 1H), 4.11 (m, 1H), 4.03 (d, /= 14·5 Hz, 1H), 3.88 ( d, 14·0 Hz, 1H), 3.63 (s, 1H), 3.59 (s, 3H), 3.05-2.74 (m, 5H), 〇.59 (s, 9H); 13C NMR (CD30D/CDC13 2 : 1) δ 176.9, 171.8, 158·4, 141·3, 140·9, 138·2, 137·7, 137.6, 137·1, 131·3, 129.5, 129.4, 129·1, 129·0, 128.61 , 128.56, 128.3, 127·4, 127·2, 127·1, 125.7, 125·2, 78·8, 73.6, 67.9, 62.4, 62·3, 58.1, 52.7, -120- 200804246 44·1,40 ·3, 34·7, 26.4 ; MS(m/z 705, M+H+) 〇Example 36

{(15&quot;)-1-[# _[(2*S)-2_Pyryl-2-((1,2)-2-yl)-indan-1-ylaminocarbamoyl) -3-Phenyl-propyl]phenylethynyl-benzyl&gt; fluorenylcarbonyl]-2,2-monomethyl-propyl amidinoic acid methyl vinegar (36) Compound 36 is produced according to method d Using Compound 19 (88.4 mg, 0. 130 mmol), phenylacetylene (0.0285 mL, 0.260 mmol), ίο Et3N (0.181 mL, L30 mmol), pd(pph3)2Cl2 (4 49 mg) , 0.0064 mM), CuI (2.46 mg, 〇·〇129 mmol) and DMF (2.1 mL) were prepared. The title compound (2 〇 4 mg, 22%) was obtained as a white solid. 15 [a]D19-58.0o(c 1.3, CHC13); 4 NMR(CD3OD) δ 7·59-7·04(ηι,16H), 6.95(m,1H),6·81(πι, lH), 4.98 (d, J = 4.97 Hz, lH), 4.22 (d, J = 14.5, 1 Η), 4·14 (πι, 1H), 4.07 (d, / = 14·5, 1H), 3.89 (d, 14) · 0, 1H), 3.63 (s, 1H), 3.61 (s, 3H), 3·07-2·77 (ιη, 5H), 0.62 (s, 9H); 13C 2〇 NMR (CD30D/CDC13 2 : 1) δ 176.7, 171.7, 162.2, 141.1, 140.8, 138·5, 137·0, 132·17, 132.16, 132.07, 131·2, 129.1, -121 - 200804246 129·0, 128·9, 128.6, 128.5 , 127.3, 125.6, 125·0, 124.0, 123·1, 89·7(2 C),78·6, 73·5, 68.0, 62·2, 62·1,58·0, 52·7, 44 · 0, 40·1, 34.7, 26·4; MS (m/z 703, Μ+Η+). Example 37

Hydroxy_2-((1&amp;27?)-2-hydroxy-indan-1-ylaminoindolyl)_3_phenyl-propyl]_Ar-(4-n-bipyridin-2-ylethynyl) Benzyl&gt;

10 Compound 37 was prepared according to Method D using compound 19 (92.7 mg, 〇·136 mmol), 2-(ethynyl)pyridine (0 〇 28 〇 ml, 〇.272 mp), Et3N (0.190 cc) , 丨.36 mM), pd(PPh3)2Cl2 (4 8 gram, 0.0068 house mole), CuI (2 6 〇 mg, 〇〇136 mmol) and DMF (2.1 mL). The title compound (34.2 mg, 34%) was obtained. [a] D19 -25.0° (c 0.565 CH3OH); 4.23 (d? 14.8 Hz? NMR (CD3OD) δ 8.52 (m, 1H), 7.85 (m, 1H), 7.62 (m, 1H), 7.46-6.90 (m, 13H), 6.78 (m, 1H), 4.97 (d, 5.10 Hz, 1H), 1H) 9 4.12 (m5 1H)? 4.10 (d? J = 14.8 Hz, -122- 200804246 1H), 3.89 ( d, /= 14·1 Hz, 1H), 3.62 (s, 1H)· 3.59 (s, 3H), 3·08-2·76 (ηι, 5H), 0.60 (s, 9H); 13C NMR (CD3OD) ) δ 177.5, 172·4, 159·0, 150·6, 144·0, 142·1,141·4, 140·7, 138·7, 137·5, 132.9, 131.6, 129.8, 128.92, 128.88, 128·7,127·7,127·5, 126.1,125.7, 124.7, 122.1,90.7, 88.7, 79·3, 73·8, 68.5, 62·9, 62·5,58·5,52.7,44.3, 40·8,34·9,26·6 ; MS〇/z 704, Μ+Η+)〇Example 38

{(1$) small [ν-[(2Χ)-2·hydroxy-2-((l*S,2 and)-2·)-based-indol-1-ylindolyl)-3-benzene Methyl-propyl]-indole-(4-oxaridin-3-ylethynyl-benzylmethylcarbonylcarbonyl]-2,2-dimethyl-propyl-p-butyl carbamate (38) According to Method D, compound 19 (85.8 mM 15 g '〇·126 mmol), 3-(ethynyl)pyridine (〇·〇 260 ml, 〇·252 mmol), Et3N (0·176 ml, 1.26 millimolar), Pd(PPh3)2Cl2 (4.42 mg, 0.0063 mmol), Cul (2.40 mg, 0·0126 mmol) and DMF (2.1 mL). Purified by RP-LC-MS (35) Minute 25-100% CHsCN in 0.05% aqueous solution of EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) ); towel NMR (CD3OD) δ 8.69 (m, 1H), 8.50 (m, 1H), 7.96 (m, 1H), 7.59-6.89 (m? 13H), 6.79 (m? 1H)? 4.98 (d, J = 5.05 Hz? 1H), 4.24 (d, 14·6 Hz, 1H), 4·12 (πι, 1H), 4.09 (d, 14.6 Hz, 1H), 3.90 (d, J = 14·1 Hz, 1H ), 3.63 (s, 1H), 3.60 (s, 3H), 3·08-2·73 (πι, 5H), 0.61 (s, 9 H) ; 13C NMR (CD3OD) δ 177.5, 172·4, 159·0, 152.4, 149·1, 142·1, 14ΐ·4, η〇·5, ΐ4〇·3, 137·5, 132·6 , 131·6, 129·8, 128.92, 128·86, 127·7, 127·5, 126·1, 125.6, 122.6, 93·9, 86·1, 79·3, 73.8, 68·5, 62.9 , 62·5, 58·4, 52·7, 44·4, 40·8, 34.9, 26·6 (two aromatic carbon signals overlap with other signals); MS (m/z 704, Μ+Η+ Example 39

15 •(Joining $ _3_ keylmethyl group 2 ((1&amp;2 and)-2-yl-based-segmented) amide group) phenylphenyl-propyl]-cultivated carbon group]-2 ,2-dimercapto, propyl}-carbamic acid decyl ester (39) The ancient method is not the same as the compound method. According to the method B, the compound 26 is used (8〇·5 2〇=g, 〇·118 mmol) ), phenyl diacyl acid (72·5 mg, 595·595 mmol), Pd(PPh3)2C1 50 mg, 〇·_26 mmol, 2 Μ Na2C〇3 (water, 〇· Ϊ́77 ml, G 354 mmol, dme (i 6 ml) and EtOH (0.4 mL), after Rp_L (%MS (35 min 4 (4) 〇% -124 - 200804246 CH3CN in 0.05% aqueous formic acid gradient) The product (21.2 mg, 26%) was obtained as a white solid. [O]D19 -88.0o (c 0.96, CHC13); lU NMR (CD30D/CDC135 4: 1) δ 7.62 (m? 1H)? 7.52- 7.17 (m? 5 14H), 7·04·6·87 (πι, 2H), 6.53 (m, 1H), 5.00 (d, J = 4·68 Hz, 1H), 4.28 (d, = 14·45) Hz, 1H), 4·10(ιη, 1H), 4.06 (d, J = 14·5 Hz, 1H), 3.93 (d, J = 14·1 Hz, 1H), 3.58 (m, 4H), 3.03 -2.70 (m, 5H), 0.52 (s, 9H); 13C NMR (CD30D/CDC13, 4: 1) δ 176.9, 171.8, 158.4, 142.1, 141.8, 141.1, 140.8, 10 138·7, 137·1, 131·3, 129·4, 128.6, 128.4, 128.1, 127·9, 127·77, 127.76, 127·72 , 127.42, 127·41, 126.9, 125·6, 125·0, 78.7, 73.5, 68.1, 62·4, 62.3, 58·1, 52.7, 44·1, 40·1, 34·7, 26.4; MS (m/z 680, Μ + Η+). 15 Example 40

' Magic-2-hydroxyl-indole small amidyl fluorenyl)-3·phenylpropyl]1'-[3-7-pyridin-2-yl)-benzyl)]-fluorenylcarbonyl]- 2,2-Dimercapto-propyl amidoxime oxime ester (40) 2 〇 The title compound was prepared according to Method A using Compound 26 (80.2 mg, 0.118 mmol), 2- (1,1,1) -Tributylstannyl)-pyridine (174 mg, 0.474 mmol), Pd(PPh3)2Cl2 (4.50 mg, 0.00641 mmol-125-200804246 ear), CuO (10.5 mg, 〇·ΐ32 mmol) and Prepared in DMF (2 mL). Purification by RP-LC-MS (EtOAc (EtOAc:EtOAc) [a] D19 -59.6 〇 (c 0.94, CHC13); 5 4 NMR (CD30D/CDC13, 1 : 1) δ 8·53 (ηι, 1H), 7.84 (m, 1H), 7·79-7·59 (ιη, 3H), 7·40-7·17 (ιη, 8H), 7.01 (m, 1H), 6.92 (m, 2H), 6.58 (m, 1H), 5.00 (d, /= 5.08 Hz, 1H ), 4.27 (d, / = 14.5 Hz, 1H), 4" 2 (d, / = 14 · 5, 1H), 4 · 10 (πι, 1H), 3.94 (d, / = 14 · 1 Hz, 1H ), 3.60 (s, 1H), 3.58 (s, 3H), 3.03-2.71 (m, 5H), 〇.51 (s, ίο 9H); 13C NMR (CD30D/CDC13, 1 : 1) δ 176·6 , 171·7, 158,1, 149·5, 141·0, 140·7, 139·7, 138·7, 138·3, 137·0, 132·6, 131·2, 129·8, 129 ·5, 128·5, 128.3, 127.7, 127·3, 127·2, 126.9, 125·4, 124·9, 123·1, 122.4, 78·5, 73·4, 67.8, 62·11, 62.08 , 57.9, 52.6, 43·9, 40·0,34·6, 26·3; HRMS(M+H+): 680.3428, 15 C39H46N506, mp 680.3448. Example 41

SN OH Η {(15&gt;ΗΑΓ-[(25&gt;2-hydroxy-2_((lS,2i?)-2-hydroxy·indenylamine 曱20 fluorenyl)-3-phenyl-propyl]- ΑΤ_[3 pyridin-3-yl)-phenylhydrazino)]-hydrazinocarbonyl]-2,2-dimercapto-propyl}-carbamic acid decyl ester (41) The title compound was prepared from compound 26 ( 79.1 mg, 0.116 mmol-126-200804246 ear), 3-(1,1,1-tributylstannyl)-acridine (175 mg, 〇·476 mmol), 卩 (1 (?? 113) 2 (: 12 (4.10 mg, 0.00584 mmol) and €: 11 〇 (11.0 mg, 0.138 mmol) and DMF (2 mL) were prepared according to the method described in the method. Purified by RP-LC-MS ( The product (19.7 mg, 25%) was obtained as a white solid. /CDC13, 1 : 1) δ 8.58 (m, 1H), 8.40 (m, 1H), 7.83 (m, 2H), 7·67-7·16 (ηι, 9H), 6.98 (m, 1H), 6.85 (m,2H), ίο 6.45(m,1H), 4.96(d,5.08 Hz,1H), 4.29(d,/= 14·5 Hz, 1H), 4.10(d,14·5, 1H),4.08 (m, 1H), 3.95 (d, 14·1 Hz, 1H), 3.58 (m, 4H), 3.03-2.71 (m, 5H), 0.48 (s, 9H); 13C NMR (CD30D/CDC13, 1 : 1) δ 176.9, 171, 8, 158.3, 148.0, 147·9, 141·3, 140·8, 139.4, 138·0, 137·0, 136.1(two carbons 15 according to ghsqc), 131.2, 129·8, 129.1, 128·6, 128.3, , 27.9, 127·4, 127·1, 126·7, 125.5, 125.0, 124.9, 78 ·8, 73·3, 68·1, 62·24, 62·21, 58·0, 52·7, 44·0, 40·2, 34·6, 26.3; HRMS(M+H+) ·· 680.3458 , C39H46N506, theoretical value 680.3448. 20. Example 42

-127- 200804246 ((15&gt;1-{#'_[(25&gt;2-carbyl-2-((15,2^)-2-yl-yl-indanyl) -3-) Phenyl-propyl]-indole-[3-((5)-styryl)-benzyl]-decylcarboxyl 2,2-dimethyl-propyl)-amine decanoic acid methyl ester (42 The title compound was prepared according to the method, using compound 26 (80 0 5 Neck '1117 Amor), trans-phenylethyl diper acid (86.9 g, 0.587 mmol), Pd (PPh3) Prepared by RP-LC-MS (2C2 (6.90 g, 0.00983 mmol), 2M Na2C03 (aq., 0.176 ml, 0·352 mmol), DME (1.6 mL) and EtOH (0.4 mL) 35 minutes 0-80% CH3CN in 0.05% aqueous formic acid gradient), yielding a white solid (19.7 mg, 48%) as a white solid. [A]D18 -71.0° (c 1.17, CHC13); 4 NMR (CD30D /CDC13, 5 : 2) δ 7.53(m,1H),7·46-7·13(ηι, 14H), 7·10-6·93(πι,4H),6·75(πι,1H), 5.00 (d, 4·69 Hz, 1H)? 4.24 (d?/= 14.5 Hz, lH) 94.11 (m, 1H), 4.05 (d, 7 = 14.5 15 Hz, 1H), 3.96 (d, 14·1) Hz, 1H), 3.60 (m, 4H), 3·04-2·75 (πι, 5H), 0.58 (s, 9H); 13C NMR (CD30D) /CDC13, 5 : 2) δ 176.7, 171.7, 158.3, 141·0, 140.8, 138.5, 138.3, 138.1, 137.0, 131.3, 129·5, 129.23, 129.19, 129.1, 128.6, 128·5, 128·3, 128·1, 127·6, 127.4, 127·2, 127.1, 126.2, 125·5, 125.0, 73·5, 68·1, 2 (κ 62.3, 62.2, 58.0, 52.7, 44.0, 40.1, 34.7, 26.4 (—the aliphatic carbon signal overlaps with other signals); MS(w/z 706, Μ + H+). Example 43 -128- 200804246

{(15&gt;ΗΛΓ_[(2) 2-hydroxy-2-((1&amp;27?)-2-yl-indenyl-smallylaminomethyl)_3_phenyl-propyl]-#'-( 3-Phenylethynyl-phenylhydrazino&gt; Mercaptocarbonyl]-2,2-monomethyl-propyl}-amine decanoic acid vinegar (43) 5 According to Method C, Compound 26 (79.2 mg, hydrazine) was used. · 116 millimolar), base B fast (0.0150 ml, 0.139 mmol), Et2NH (0.11 ml '1·〇1 mmol), Pd(PPh3)2Cl2 (6.10 g, 0.00869 mmol) Preparation of Cul (1.90 mg, 0.00998 mmol) and DMF (2 mL) eluting with EtOAc (EtOAc:EtOAc %) White solid. [a]D18 -96.6〇(c 0.87, CHC13); !H NMR(CD30D/CDC13? 3 : 1) δ 7.49(m5 1H), 7.45-7.14(m, 13H),7· 08(ηι,1H), 7.00(m,2H),6·83(ηι,1H), 5.01(d,J = 15 4·68 Hz,1H), 4.22(d,/= 14·5 Hz, 1H ), 4·13(ιη, 1H), 4.04 (d, 14·5 Hz, 1H), 3.91 (d, 14·1 Hz, 1H), 3.61 (m, 4H), 3·05-2·78 ( Ηι,5H),0.61(s,9H) ; 13C NMR(CD30D/CDC13, 3 : 1) δ 1 77.1, 172.0, 158.6, 141.4, 140·9, 138·9, 137.2, 132·3, 132.0, 131.40, 131·38, 129·24, 129.18, 129·16, 129.1, 20 1 28·7, 128· 6, 127·7, 127·5, 125·8, 125.3, 124·4, 124.3, 90·01, 90.03, 78·9, 73.6, 68·4, 62.5, 62·1, 58.1, 52·7, 44.1, 40.4, 34.8, 26.5; 200804246 MS(w/z 704, Μ + H+) 0 Example 44

f 0 Η Ν々丫, 5 {(1 outer 1-[#'-[(2&lt;2&lt;2&gt;2&apos;2&lt;2&gt; -3-phenyl-propyl]-indole-[3-(π-bi-2-ylethynyl)-benzyl]-indolyl]-2,2-dimethyl-propyl}&quot The title compound was prepared according to Method C using Compound 26 (79.4 mg, 0.117 mmol), 2-(ethynyl)pyridine (15.3 mg, 0.148 10 mmol), Et2NH. (0.105 ml, 1.01 mmol) Pd(PPh3)2Cl2 (6.50 mg, 0.00926 mmol), Cul (1.50 mg, 0.00788 mmol) and DMF (2 mL). Purified by RP-LC-MS ( The product was obtained as a white solid (15.9 mg, 19%) as a white solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

4 NMR (CD30D/CDC13, 1 : 1) δ 8·48 (ιη, 1H), 7.73 (m, 1H), 7·56-7·15 (ηι, 11H), 7.08-6.92 (m, 3H), 6.82 (m, 1H), 5.01 (d, J 2·6 Hz, 1H), 4.19 (d, J = 14.7 Hz, 1H), 4.09 (m, 1H), 4.02 (d, J = 14.7 Hz, 1H) ), 3.92 (d, / = 14.1 Hz, 1H), 3.60 (s, 20 3H), 3.59 (s, 1H) 5 3.00-2.74 (m? 5H), 0.59 (s, 9H); 13C NMR (CD30D/ CDC13,1 ·· 1) δ 176.3,171.4,158.0,149.8, 143·4, 140.7, 140.5, 138.6, 137.6, 136.8, 132.2, 131.6, 131·8, -130- 200804246 129.8, 129.0, 128·4, 128.3, 128·1, 127.3, 127·2, 125·4, 124.8, 123·8, 122.6, 90.4, 88.4, 78·6, 73·4, 68.0, 61.9, 61.6, 57·8, 52·7, 43·8, 39·7, 34.6, 26·2 ; HRMS(M+H+) ·· 704.3438, C41h46N5〇6, theoretical value 5 704.3448 〇Example 45

{(15&gt;l-[7V'-[(25&gt;2•hydroxy-2-((lS,2))-2-hydroxy-indan-l-ylamine-carbamoyl)-3-phenyl-propyl ] ' ' ' 3- 3- 3- 3- 3- 3- 3- 3- ' 3- ' 3- ' ' 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题According to Method C, compound 26 (89.5 mg, 0.131 mmol), 3-(ethynyl)pyridine (16 3 mg, 〇158 mmol), Et2NH (〇.ii 8 mL, 114 mmol), Pd ( PPh3) 2Cl2 (7.70 gram, o oiio millimolar 8 〇, 〇〇〇945 mM) prepared with DMF (2 ml). The crude product was purified by rP_lc_ms (35 min 10_85% CH/N 0.05% aqueous formic acid) The HCl solution of the product is prepared by dissolving the product in cH2C12 and then adding the ether solution of HCl until all the products are precipitated. After evaporation, the salt is dissolved in ch3cn and HW, followed by lyophilization to give the title compound ( 21.6 mg, 23%) of a white solid. [〇t]D19_65.70 (c 1.15, CHC13); -131 - 200804246 4 NMR (CD3OD/CDCl3, 9 ·· 1) δ 8.25 (m, 1H), 7.61 (m, 1H), 7·52-7·17 (ιη, 11H), 7·10-6·91 (πι, 3H), 6.74 (m 1H), 5.00 (d, / = 5.07 Hz, 1H), 4.23 (d, J = 14·5 Hz, 1H), 4·14 (ιη, 1H), 4.08 (d? J = 14.5 Hz, 1H)5 3.93 (d, J - 13.7 Hz, 1H), 3.62 (s,

5 1H), 3.60 (s, 3H), 3.05-2.77 (m, 5H), 0.59 (m, 9H); 13C NMR (DMSOd6) δ 174·6, 170.1, 156.5, 149.8, 147.2, 142.1, 14〇· 5, 140·4, 138·7, 136.4, 130·9, 130.2, 130.1,129·1,128·3, 127.6, 127.0, 126·2, 125.9, 124·7, 124.0, 121.1, (2 aromatic The carbon signal overlaps with other signals), 93.4, 85.1, 79.2, 77.5, 71.8, 67.6, ίο 61.3, 60.7, 56·4, 51·5, 42.9, 33.5, 26·1 ; HRMS(M+H+) ·· 704.3468, C41H46N506, theoretical value 704.3448 〇 Example 46

(R)-2-Benzyl-4-(t-butyl-diphenyl-decarboyloxy)-l-((3aS,8aR)-2,2-dimethyl-8,8a-di Hydroquinone [1,2-cursorzol-3-yl)-2-hydroxybutan-1-one (46) containing (R)-2-phenylhydrazin-4- in cooling (0 ° C) (Third butyl-diphenyl-2 hydrazine oxy)-2 -yl 1 S,2R)-2 -yl-imprinted-1 -yl butylamine (22) (0.4 g, 0.69 Add 2-methoxypropene to a solution of benzylidenesulfonic acid (15 mg, -132-200804246 〇·〇59 mmol) in anhydrous dichloromethane (25 ml) • 5 g, 6.9 mmol, stirred at the same temperature for 6 hours. A saturated NaHC(R) 3 solution was added, and the organic layer was washed with EtOAc EtOAc EtOAc. The title compound (〇·325 g) was used in the next reaction without further purification. MS(ESI+) : 620(Μ+)〇 Example 47

(8): benzoquinone is small ((3aS,8aR)-2,2-dimethyl-8,8a_dioxin_3a仏[1,2W]畤ϋ-3-yl)-2,4- Di-based-butyl ketone (47) TBAF (0.274 g, 1.05 mmol, iM THF solution) was added to room temperature containing (R)-2-phenylindenyl-4-(t-butyl- Diphenyl-nonyloxy)-H(3aS,8aR)-2,2-dimethyl-8,8a-dihydroindeno[1,2-present-salt-3-yl)_2-hydroxy-butyl A solution of the alkane ketone (46) (0.325 g, 〇52 mmol) in THF (2 mL) was stirred for 3 hr. The solvent was evaporated, the residue was dissolved in dichloromethane and washed with water and brine &lt; The product was purified by flash chromatography using EtOAc (EtOAc:EtOAc) MS (ESI+): m/z: 382 (M++1); - 133 - 200804246 lU NMR (CD3OD, 400 MHz): δ 7.62 (m5 1H)? 7.34-7.28 (m, 5H), 7.16-7.12 ( m, 3H), 5.20 (m, 1H), 4.02 (m, 1H), 3·91-3·85 (ηι, 2H), 3.12 (d, J = 13.20 Hz, 1H), 2.98 (d, J = 13.20 Hz, 1H), 2.82-2.68 (m, 2H), 2.58 (m, 1H), 2.00 (m, 1H), 5 1.56 (s, 3H), 1.13 (s, 3H); 13C NMR (CD3OD, 100 MHz) : δ 171·6, 142·4, 140·5, 136.6, 131·0, 127.8, 127.4, 126·8, 126.4, 126.2, 124.7, 98.0, 80.7, 79·6, 67.2, 59·0, 43·1, 35.1, 25·7, 23·9. Ίο Example 48

(R)-3-stupyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydroindeno[1,2-ί/]oxazol-3-yl) -3•hydroxy-4-oxo-butyraldehyde (48) containing (R)-2-phenylhydrazinyl ((3aS,8aR)-2,2-dimethyl-8,8a-di-argon 15 - 3&amp;/7-indole[1,2-^/]1:1咢嗤-3-yl)-2,4-dipyridin-1-one (47) (0.12 g, 〇·31 m Anhydrous CH2C! 2 (5 mL) solution was added to a solution of EtOAc &lt;RTI ID=0.0&gt;&gt; After 30 minutes, the homogeneous mixture was diluted with ether and poured into cold saturated NaHC.sub.3 (1 mL) (Na2S203 (2.2 2 g)). The organic layer was washed with a saturated aqueous solution of NaHC 3 , brine, and dehydrated (MgS04). Evaporation of the solvent below 20 cc afforded the title compound ( </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue is immediately used in the next step. MS (ESI+): 380 (M++1) 实例 Example 49

W (4's phenyl fluorenyl group [called 3 · carbyl-3-((1S, 2R)·&quot; 2- ylamine amide) _4_ stupyl. butyl] 肼 · · } _2 _Dimethyl-propyl)-amine decanoic acid vinegar (49) 10 15 One long contains (8) 1 alum + + ((3aS, 8aR)-2,2-di T 丞 - / one nitrogen 3 dip _ printing And [1,2 Today's Wow _3-Base)-3-Roylidene-4-oxo-butym Γ]82 2 - ° ^ ^ Ancient = anti-soil, - fluorenyl-propyl carbamic acid methyl vinegar (0.084 g, 0.23 Ο Δ.vl. of 'addition of acetic acid (0.027 g 'mamm') was stirred for 10 minutes, then Na(OAc)3BH (0.144 1.68 mmol) was added, _ „ night. The mixture was added with water to stop the reaction, ^, , ^. The residue was dissolved in dichlorohydrazine (2G G), washed with water, brine, di-trifluoroacetic acid (1·〇 ml), and the organic layer was stirred for 2 minutes. The mixture is steamed and washed with aqueous solution of NaHC〇3, water and brine, and dried. The product is purified by flash chromatography using acetone: petroleum ether (1··3), yielding -67-200804246 (0.057 g) 36%) the title compound MS (ESI+): m/z: 695, 697 ( Μ+); lU NMR (CDC135 400 MHz): δ 7.40-7.24 (m5 11H), 7.20-7·10 (ηι, 2H) , 7.00 (m, 1H) ), 6.24 (m, 1H), 5.18 (m, 1H), 5 4·42 (ιη, 1H), 3.85 (s, 1H), 3.66 (s, 3H), 3·12-2·82 (ηι, 6H), 2.62 (s, 1H), 2.20 (m, 1H), 1.90 (m, 1H), 0.88 (s, 9H); 13C NMR (CD3OD, 100 MHz): 69 176.2, 171.1, 159.0, 140.7, 140 ·2, 136·8, 131·5, 130.7, 127.8, 127.5, 124.7, 124.0, 121·2, 79·4, 73·1, 61·7, 57·0, 54·8, 51·6, 45 ·9, 39·5, 34·5, 33·4, ίο 28.3, 25·6 〇 Example 50

{(8)_1-[#'-[(8)-3-carbyl-3-((lS,2R)-2-yl-yl-indan-1-ylamine-methylphenyl-butyl] -Λτ_(4_σ-pyridyl-benzyl)-fluorenylcarbonyl]-2,2-dimercapto-propyl-p-butylamine (5〇) Add Pd(PPh3)2Cl2 (3.84 mg, 〇·〇) 〇54 mmol) to ((3)-1], (4-bromo-benzyl)-AT-[(S)-3-yl-3-yl((lS,2R)-2-hydroxyl) -茚满·1_基胺甲基基)_4_Phenyl-butyl; hydrazino-based bismuth-136- 200804246 propyl-propyl)-amino decanoate (22) (75 mg, 〇 1〇8 mmol), 3-(1,1,1-di-n-butyltin-based bismuth (159 mg, 〇·43ιιη) with Cu0 (8.6 mg, 0.108 mmol) In a solution of DMF (2.0 ml) in a thick-walled Smith flask, stir in a microwave oven at 120 °C for 50 minutes. The mixture was diluted with CH2C12 (20.0 mL) to saturate

Wash with NaHCCb aqueous solution (3 χ 15·〇 ml). The organic layer is dehydrated (MgS04) and evaporated. The residue was redissolved in CH.sub.3CN (50.0 mL). The acetonitrile phase was evaporated and EtOAc (EtOAc m.) MS (ESI+): m/z: 694 (M+); 4 NMR (CD3OD 400 MHz): δ 8·66 (πι, 1H), 8.45 (m, 1H), 8.00 (m, 1H), 7.52-7.44 ( m, 6H), 7·30-7·04 (πι, 9H), 5.04 (m, 1H), 4.24 (m, 1H), 3.82 (m, 2H), 3.68 (s, 1H), 3.60 (s, 3H), 15 3·10-2·78(ιη, 6H), 2.62 (s, 1H), 2.20 (m, 1H), 1.96 (m, 1H), 0.78 (s, 9H); 13C NMR (CD3OD, 100 MHz) : δ 176.9, 171.1, 157·8, 147·8, 147·0, 141·3, 140.3, 137.0, 136·8, 135.2, 130.5, 130·0, 127·6, 126.8, 126·5 , 126.3, 124·9, 124·1,78·7, 72·5, 61·9, 61·7, 57·2, 53·6, 51,5, 39.6, 34·3, 33·5, 28.3 , 25·7 20 Examples 51 -137- 200804246

{(8)-卜!^'-[(8) Winter Hydroxy Winter ((lS, 2R)-2-Hydroxy-indanylamine)-4-phenyl-butyl]-ΛΓ'-(4^ ratio Methyl pyridine-benzyl)-fluorenylcarbonyl]-2,2-dimethyl-propyl-p-propylamine (5 j) Add Pd(PPh3)2Cl2 (4.61 mg, 0 0 065 mmol) to ((S)-1-{AT'_(4-bromo-benzyl)-AT'_[(s) winter hydroxyk(1;5,2R)-2-hydroxy-indanylamine 4-phenyl-butyl]-mercaptocarbonyl bromide 2,2-dimethyl-propylamine decanoate (22) (90 mg, 〇·ΐ29 mmol), 2-(1 , 1,1_tri-n-butyltin-based) 11-bit (191 mg, 〇51 mmol) with CuO (10.3 mg, 0.129 mmol) in DMF (2. mM) solution, thick-walled In the Smith reaction bottle, stir in a microwave oven of 12 ° C for 5 〇. The mixture was diluted with CH.sub.2Cl.sub.2 (2.sub.2 mL). The organic layer was dehydrated (MgS〇4) and evaporated. The residue was redissolved in CH3CN (60.0 mL). The acetonitrile phase was evaporated. EtOAc (EtOAc m. MS (ESI+): m/z: 694 (M+); -138 - 200804246

4 NMR (CD3OD 400 MHz): δ 8.56 (m, 1H), 7.82 (m, 1H), 7.72-7.60 (m, 4H), 7·54 (πι, 1H), 7.44 (m, 1H), 7.34 7.16(m, 6H),7·06-7·00(ιη,3H),6·96(ηι,1H),4·96(ιη,1H), 4.16(m, 1H),3.82(m,2H) ), 3.70 (m, 1H), 3.60 (s, 3H), 3.08-2.78 (m, 5 6H), 2.10 (m, 1H), 1.94 (m, 1H), 0.78 (s, 9H); 13C NMR ( CD3OD, 100 MHz) : δ 176.9, 171.5,158·2,157·7, 149·1,141.5, 140·5, 138.6, 138·1,138·0, 137·2, 132·9, 132·3 , 132.2, 130·8, 129.9, 129.2, 129·1, 127.9, 127.3, 126.9, 126.6, 125·0, 124·5, 122.8, 121.7, 79·3, 73·1, 62·3, 57.7, 53.6 , 51.9, ίο 46·6, 39·8, 34·5, 33.9, 26·1. Example 52

15 (2^-2-Benzyl-N-((l*S)-2,2-dimercapto-1-indolylmethylmercapto-propyl)-2,4-dihydroxy-butane Amine (52S) Take 3-phenylhydrazino-3-hydroxy-dihydro-furan-2-one (21c) (0.961 g, 5.00 mmol), H-tLeu-NHM (1.80 g, 12·5 mmol) The ear was suspended in a reaction flask containing 10 ml of ι,2-dichloroethane with 2-pyridone (0.476 g, 5.00 mmol). The reaction flask was sealed with a rotating lid and heated at 80 ° C. The mixture was heated for 24 hours. The solvent was evaporated and the residue was redissolved in a minimum of 25% aqueous acetonitrile. The mixture was subjected to column chromatography using RP(C-18)- vermiculite and a manual 1 〇 50% acetonitrile aqueous solution gradient ( Purification with 0.05% HCOOH) and separation of diastereomers from -139 to 20 200804246. The obtained fractions were purified by analytical grade RP-LC-MS, and the purified fractions were separated and evaporated to yield (25 &gt;-N-((15&gt;2,2-dimercapto-1-methylaminoindolyl-propyl)-2,4-dihydroxy-butanamine (0.424 g, 25%) and (2 and Benzene (ESI+): m/) z 337(M+H)+ ; lB NMR (CD3OD9 400 MHz ) : 67.20-7.14(m9 5H)? 4.05(s? 1H),3·82·3·68(ιη,2H), 3.03(d,13.4 Hz,1H), 2.85(d,J = i〇13.4 Hz , 1H), 2.85 (s, 3H), 2·29-2·21 (ιη, 2H), 1·98-1·89 (ιη, 2H), 0.93 (s, 9H)· 13C NMR (CD3OD, 100 · 5 MHz): δ 176.2, 172.2, 137·3, 131.3, 128·8, 127·4, 79·6, 61·5, 59·6, 47·1, 41.7, 35·7, 27.0, 26· 0. 15 Example 53

(1-{Ν'-(4-bromophenylhydrazino)-Ν'-[3-(2,2-dimethyl-1-decylamine decyl-propylamine decyl)-3- Methyl hydroxy-4-phenyl-butyl]-fluorenylcarbonyl}2,2-dimercaptopropyl)amide (53) containing (25&gt;2-benzyl-N-((16&gt;2) ,2-dimercapto-1-indolylmethylmercapto-propyl)-2,4-dihydroxy-butanamine (52S) (0.337 g, 1.00 mmol-140-20), ΙΒΧ a reaction flask of 0·560 g, 2·〇 mmol, mixed with 10 ml of dichloroethane, sealed with a rotating lid, and heated at 8 ° C for 2 hours. The resulting suspension was transferred to a 20 ml syringe. It was filtered through a syringe filter into a 15 ml DCE solution containing 醯肼5 (9) (0·372 g, L00 mmol) in a 5 liter round bottom flask filled with a vial. Acetic acid (0.12 ml 2.0 mmol) was added, and the mixture was stirred for 1 hr. then sodium triethyloxy oxyborohydride (0.636 g, 3.0 mM) was added. The flask was sealed with nitrogen and sealed at room temperature. The reaction was stirred for 24 hours. The reaction was stopped by adding water, and the volatile matter was evaporated. The residue was dissolved in 50% MeCN/water and purified by preparative 10-RP-LC-MS. Injection of 1 ml) gave 91 g of the title compound (yield: 28%). MS (ESI+): m/z 690, 692 (M+H) + 4 NMR (CD3OD, 400 MHz): δ7·47 (ΑΑ , ΧΧ 'System AA', 2H), 7·33 (ΑΑ, ΧΧ 'system XX, 2H), 7·19-7·16 (ηι, 5H), 15 4.02 (s, lH), 3.85 ( s, 2H), 3.75 (s, 1H), 3.68 (s, 3H), 3·04-2·87 (ιη, 3H), 2.77 (d, = 13·2 Hz, 1H), 2.61 (s, 3H) ), 2.23-2.13 (m, 1H), 2.02-1.90 (m, 1H), 0.89 (s, 9H), 0.80 (s, 9H). 13C NMR (CD3OD, 100.5 MHz): 5176.5, 172.3, 172.1, 20 158·9, 137·5, 137.2, 132·3, 131·4, 128.7, 127.3, 122.4, 79·7, 63.0, 62.4, 61.5, 54·8, 52·8, 47.1, 35·7, 35· 6, 34·7, 27.1,26·9, 26·0 〇Example 54 -141 - 200804246

{1-[Ν'·〇(2,2-Dimercapto-1-methylamine decyl-propylamine decyl)-3-hydroxy-4-phenyl-butyl]-Ν'- (4^pyridin-3-yl-phenylhydrazinyl)-fluorenylcarbonyl]-2,2-dimercapto-propyl}carbamic acid guanidine vinegar (54) 10 15 containing compound (53) (69 mg, 〇·1〇 millimolar), 3-acridinyldihydroxyboronic acid (37 mg, 0.30 mmol), Pd(OAc) 2 (ll mg, 〇·〇〇5〇 mmol), [(^ Bn) 3PH] BF4 (3.0 mg, 0.010 mmol) with K2C03 (41.5 mg, 0.30 mmol), Η20 (0·30 mL) and 1,2-dimethoxyethane (1·0 mL) The 2.0 ml microwave reaction vial of the mixture was microwaved to 80 ° C for 20 minutes. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The residue was purified by preparative RP-LC-EtOAc to yield EtOAc (30%). MS (ESI+): m/z 690 (M+H) + 4 NMR (CD3OD, 400 MHz): δ8·78 (πι, 1H), 8.54 (m, 1H), 8.07 (m, 1H), 7·65 -7·51(ιη, 5H), 7.27-7.15(m, 5H),

4·03-3·89(πι,3H), 3.77(s, 1H), 3.62(s,3H), 3.08-2.92(m, 3H), 2.76(d,13·2 Hz,1H), 2.61( s, 3H), 2·24-2·15 (ιη, 1H), 2.04-1.93 (m, 1H), 0.89 (s, 9H), 0.79 (s, 9H)· 13C NMR (CD3OD, 100.5 MHz): Δ176·6,172.3,172.1,159.0,148.7, 148.2, 138.4, 138.3, 137.9, 137.6, 136·6, 136·5, 131·4, -142- 20 200804246 128·7, 128·1,127.3 , 125·5, 79·8, 63·1, 62·9, 61·6, 54·8, 52·7, 47·0, 35·7, 35·6, 34·8, 27.1, 26·9 , 26.0. Example 55

{1-[# -[3-]-yl-3-(2-carbyl-Ip-f-yl-ylamine)-4-phenyl-butyl]-iV-(4-11 ratio bite- 3-(Phenyl-phenylhydrazinyl)-ylidene green-based]·2,2-dimethyl-propyl}-amine decanoate (55) Add Pd(PPh3)2Cl2 (5.05 mg, 0.0072 mmol) To ίο ((S)-l -{TV -(4- &gt; odor-benzyl-[(S)-3-carbyl-3-((1 S,2R)-2-)-- Benzyl-1-ylamine-tertyl)-4-phenyl-butyl]-cultivated base}-2,2-dimethyl-propyl)-amine decanoate (12) (100 mg, 0.143 Millol), pyridine-4-dihydroxyboronic acid (71.0 mg, 0.575 mmol), 2M aqueous Na2CO3 (0.215 mL, 0.432 mmol), EtOH (0.4 mL) and 15 DME (1.6 mL) Stir in a thick-walled Smith flask for 30 minutes in a 120QC microwave oven. Add 5 drops of citric acid to the mixture and evaporate the solvent. The crude product was purified by RP-LC-MS (40 min 15-85% CH3CN 0.05% formic acid) Aqueous solution of the aqueous solution gave the product (35.3 mg, 35%) as a white solid. </RTI> MS (ESI+): m/z: 694 (M+) - 143 - 200804246 NMR (CD3OD 400 MHz): δ 8.52 (m, 2H), 7.57 (m, 4H), 7.46 (m, 2H), 7.29 ·············· ), 3·07-2·78 (ηι, 6H), 2.20 (m, 1H), 1.94 (m, 1H), 0.69 (s, 9H).

(S)-5-phenylhydrazino-2,2-dimethyl-[1,3]di-4-carboxan-4-one (56) containing (S)-2-hydroxy-3-phenyl-propyl Acid (1.662 g, 10·0 mmol), ίο 2,2-dimethoxypropane (8.328 g, 80.0 mmol) and PPTSA (1.257 g, 5.0 mmol) in chloroform at 70 ° C This was stirred for 1 h, EtOAc (EtOAc)EtOAc. lR NMR (CDC13? 400 MHz) δ 1.37 (s? 3Η)? 1.50 (s, 3Η), is 3.05 (dd, J = 14·4, 6·4 Ηζ, 1Η), 3.20 (dd, J = 14.4, 4·4 Hz, NMR (CDC13, 100 MHz) δ 26·4, 27·2, 37·9, 75·3, 111.1, 127.3, 128·6, 130.1, 136.0, 172.7.

3-(4-Benzyl-2,2-dimethyl-5-oxo-[1,3]dioxan-4-yl)-propionic acid-144- 200804246 decyl ester (57) At 78 ° C, 9.42 mL of LDA (1.8 THF in THF, 16 96 mmol) was added to a solution of compound 56 (3.180 g, 15.42 mmol). After 15 minutes, decyl acrylate (1.460 g, 16.96 mmol) was added to -78 Qc. The reaction was quenched with EtOAc EtOAc EtOAc (EtOAc). lR NMR (CDC13, 400 MHz) δ 0.95(s, 3Η)? 1.51(s? 3Η), ίο 2.15(t,c/ = 8·0 Ηζ, 2Η), 2.36-2.62(m,2Η), 2.92( d, = 13·6 Hz, 1H), 3.10 (d, 13·6 Hz, 1H), 3.67 (s, 3H), 7·15-7·30 (πι, 5H); 13C NMR (CDC13, 100 MHz ) δ 27·7, 28·8, 28·9, 33·1, 42·5, 52.1, 83.3, 110·4, 127·5, 128·6, 131.1, 135·1, 173·1, 174· 1 〇15 Example 58

58a

58b (R)-2-Benzenyl-5-oxo-tetrahydro-furan-2-carboxylic acid ((lS,2R)-2-hydroxy-indan-1 -yl)-bristamine (58 a) A solution of compound 57 (2.418 g, 8.272 mmol) in 6 ml of TFA\H2 (6:1) was stirred at 8 ° C overnight. The solution was concentrated, dissolved in ethyl acetate and concentrated several times to remove TFA. The resulting residue is vacuum dried -145- 20 200804246 Dry until the crude product solidifies. Add (ls, 2R)_(+ cis-small-amino-2_-segmental alcohol (1.234 g ' 8.272 亳 Mo), EDAC (1 744 g, 9 〇 99 mM), HOBt (1.229 g, 9.099) Milligram) and 60 ml of anhydrous two-gas toluene. Stir the mixture for several hours at room temperature. Stop the reaction in 3 ml of water, filter through 5, and extract with 2x30 liters of dichloromethane. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Structure (58b). The absolute configuration of the title compound was determined by X-ray. 10 NMR (CDC13? 400 MHz) δ 0.93 (d, J = 4.4 Hz, 1H? OH), 2·32-2·48 ( Πι,2H),2·50-2·64(πι,1H),2·76-2·86(πι,2H), 3.04(dd,/= 16.4, 5·2 Hz, 1H), 3.13(d , 14·0 Hz, 1H), 3.36 (d, J= 14·0Ηζ, 1Η), 4·18-4·26 (πι, 1Η), 5·23 ((1,1,/=8·8, 4·8 Hz, 1H), 6.68 (d, / = 8.8 Hz, 1H), 7.02-7.08 (m, 1H), 15 7·14-7·24 (ιη, 3H), 7.28-7.38 (m, 5H 13C NMR (CDC13, 100 MHz) δ 28.1, 31.0, 39.2, 44.2, 57.4, 73.0, 88.3, 123.7, 125.2, 127·1, 127·6, 128.3, 128·5, 130.5, 134.8, 139.4, 140·1, 171·4, 175.0. Example 59

(R)-2-Benzyl-2-(t-butyl-didecyl-decyloxy)-5-hydroxy-pentanoic acid-146- 200804246 [(1 S,2R) 2-(di Base-monomethyl-cracking base oxygen)_茚满-1-yl]_酿脸(59) ^ Yu Yu. (:, TBDMS_OTf (1.3606 g) was added to a solution of compound 58 (1·2〇6 g, 3.432 mmol) and triethylamine (1.042 g, 1〇·3〇 mmol) in dichloromethane. , 5.148 mmol, and the reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated and extracted with diethyl ether/water. The ether layer was dehydrated with MgSCU and filtered. Add LiBH4 (223.8 mg, 1 〇·3 〇亳mol To the ether solution at room temperature. After stirring for 1 hour, the reaction mixture was filtered, and the obtained solution was concentrated to give intermediate crude product. pyridine (15 ml) and 0.845 ml of PVC1 (0.828 g, 6.864 mmol) were obtained. In the middle crude product, the solution was stirred overnight. The reaction was quenched with a saturated aqueous solution of EtOAc (EtOAc) eluted with ether, dehydrated with EtOAc EtOAc (EtOAc) Concentrate to give 1.243 g of intermediate. Take intermediate (1.243 g, 2.245 mmol) with 937.4 μl of hydrazine (0·6815 g, 6.734 mmol) dissolved in 15 ml of DCM and add TBDMS_OTf (TC) 0.8899 g, 3.367 亳 Moel). Stir the solution at room temperature 1 The mixture was concentrated and extracted with diethyl ether/water. The ether layer was dried over <RTI ID=0.0></RTI> </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Purification of 20%-50% EtOAc-EtOAc (EtOAc) , 0.05(s, 3H), 〇.〇8(s,3H),0.75(s,9H),0.81(s,9H),1·04- 1.28(m,1H), M8-1.64(m,2H ), 1.75 (Br s, 1H), 1.92-2.06 (m, 1H), 2.83 (dd, J = 15·6, 6·0 Hz, 1H), 2.91 (d, J = 14.0 Hz, 1H) , -147- 200804246

2.99 (dd, J = 15.6, 6·0 Hz, 1H), 3.12 (d, J = 14·0 Hz, 1H), 3.26-3.42 (m, 2H), 4·54-4·62 (ιη, 1H) ), 5.13 (dd, 8.0, 6.0 Hz, 1H), 7.05-7.20 (m? 8H), 7.30-7.40 (m, 2H); 13C NMR (CDC13, 100 MHz) δ -4.7, -4.3, -2.0, -1.5, 18.5, 18.7, 5 26.2, 26·4, 27·1, 35·0, 39·9, 47·5, 56·6, 62·3, 74·1, 82·6, 124·9, 125·7, 126·7, 126.9, 128·0, 128·2, 130·4, 136.5, 139.6, 141.8, 174.4. Example 60

[(S)-l_(AT-(4-bromo-benzyl)-AT-{(R)-4-(t-butyl-didecyl-decyloxy)-4-[(lS,2R )-2-(tert-butyl-dimethyl-decyloxy)-indan-I-ylamine-aryl]-5-phenyl-fluorenyl}-cultivation base-2,2-two Methyl-propyl]-carbamic acid methyl ester (60) 15 Add 15 to a mixture of compound 59 (412.9 mg, 0.7070 mmol) and diss-Martin periodinane (314.9 mg, 0.7424 mmol)毫升 anhydrous dichlorodecane. After the mixture was stirred at room temperature for 1 hour, it was concentrated, evaporated and evaporated. The aqueous phase was extracted with 2 x 15 mL of ether. The ether layer was dehydrated with MgS04, filtered and concentrated. The residue was dissolved in 20 THF (20 mL), and then added {(S)-l-[AT-(4-bromo- apodolinylcarbonyl)-2,2-didecyl-propyl}-amine decanoic acid Oxime ester (263.2 mg, 0.7070 m-148-200804246 2. Add acetic acid (85·〇ί: gram, 1.414 mmol) in the night, and see the solution in the dish. After 15 minutes, add Na (〇Ac) 3BH (599 3 mM, _2·828 亳mol), continued to stir at room temperature for 2 hours. With saturated NH4C1 #/4: stop the reaction 'extracted with 3 χ 2 〇ml of dichlorohydrazine, dehydrated by m Liu 4 5 The title compound (3 〇〇·〇 mg, 45%) was obtained as a white solid. </RTI> 165 mg of compound 59. lU NMR (CDC 135 400 MHz) δ 0.05(s 3Η), 0.06(s9 3H)? 0.10(s9 3H), 0.11(s,3H), 0.806(s,9H),0.812(s,9H),0.90(s,9H), 10 1.25-1.40 (m? 1H)? 1.45-1.65(m9 2H)? 1.95- 2.12(m? 1H), 2.55-2.70(m9 1H), 2.80-3.00(m? 3H)9 3.07(dd, J = 15.6, 6.0 Hz , 1H), 3.12 (d, J = 13.6 Hz, 1H), 3·50-3·65 (πι, 4H), 3·75-3·90 (ιη, 2H), 4.60-4.70 (m, 1H) ,5·15-5·25(ιη,1H), 5J3(d, “7 = 9·2 Hz, 1H ), 6.77(s,1H),7·06·7·28(πι,10H), 15 7·34_7·46(ιη,4H) ; 13C NMR(CDC13, 100 MHz) δ -4·7, -4.3 , -1·9, -1·6, 18·5, 18·6, 21·8, 26·1,26·3, 26.4, 34·4, 36·9, 39·9, 46·7, 52 ·4, 55·7, 56·5, 59.4, 61·2, 74·2, 82·7, 121·2, 124·9, 125.9, 126.6, 126·8, 128·0, 128·2, 130.4 , 130·9, 131·3, 136·5, 136·6, 139·7, 141.9, 156.8, 169.7, 174·2. 20 Examples 61 -149- 200804246

{(S)-HA^-[(8)I-based |((ls,2R)-2_carbyl, full-small-amine carbazino)-5-phenyl-pentylpyridinyl-4-yl-benzoquinone ))-hydrazinocarbonyl]-2,2-didimethyl-propyl}-amine decanoate (61) Take compound 60 (100,0 mg, 〇1〇66 mmol), 'pyridyl group Lateral acid (39. 2 mg, 〇·3198 mmol), palladium catalyst (5.0 mg, 〇. 〇〇 533 mM), HP (t-Bu) 3BF4 (3.1 mg, 〇〇1) 〇66 mM), K2c〇3 (44 2 10 10 15 20 g '0·3198 mmol), DME (1.0 ml), Η2 Ο (0.3 ml) were added to a 2-5 ml vial. The mixture was irradiated under a microwave of 12 ° C for 2 minutes. The mixture was extracted with ethyl acetate. The organic layer was dried over Mgs(R) 4 and concentrated, and a THF (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; Water (10 ml) was added to the solution, extracted with dichlorohydrazine, and the organic phase was dried over MgS 4 and concentrated. The residue was purified with EtOAc EtOAc (EtOAc) lU NMR (CD3OD5 400 MHz) δ 0.75 (s9 9Η), 1.56-1.70 (m5 1H)? 1.70-1.86 (m, 2H), 2.03-2.16 (m9 1H)? 2.74-2.94 (m? 4H), 3.01- 3.14 (m, 2H), 3.46 (s, 3H), 3.70 (s, 1H), 3.88-4.00 (m, 2H), 4.16_4.22 (m, 1H), 5.09 (d, 4.8 Hz, 1H), 7.10-7.30 (m, -150- 200804246 9H), 7.50-7.70 (m, 6H), 8·50-8·60 (ιη, 2H); 13C NMR (CDC13, 100 MHz) δ 21·4, 25.7, 33.7, 36·6, 39·7, 45.8, 51.5, 57.1, 57·6,61·2,61·8,72·8,78·4,105·0,121.8,124·2,125·0, 126·3, 126.65, 126·68, 127·62, 127.67, 130.3, 130·5, 136.6, 137·0, 139·0, 140.4, 141·3, 149·4, 157·7, 170.7, 176· 1. Example 62

{(S)-HA^[(R)-4-面基|(〇s, 2R)士经基_节满+基胺曱ίο 醯ylphenyl-pentylpyridin-3-yl-phenylhydrazine )-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic acid decyl ester (62) (αηα_625) Take compound 60 (1〇〇·0亳g, 〇1〇66 mmol), 3_pyridyl dicarboxylic acid (39.2 mg, 1983198 mmol), palladium catalyst (5.0 mg, 〇〇〇533 mmol), 15 HP(t-Bu)3BF4 (3.1 mg , 〇〇1〇66 mM), K2c〇3 (44.2 mg '0.3198 house Moer), ι·〇 ml dme, 〇·3 ml H2O added to the 2-5 house liter vial. The mixture was irradiated under microwaves of i2〇〇c for 2 minutes. The mixture was extracted with ethyl acetate. The organic layer was dehydrated with MgS 4 and concentrated, and a solution of TBAF (1.06 ml) containing 1^^ (1·066 2 2 mol) was added to the resulting residue, and the solution was stirred overnight at room temperature. Water (10 ml) was added to a solution of -151 - 200804246, extracted with dichloromethane, and the organic phase was dried over MgS04 and concentrated. The residue was purified with EtOAc EtOAc (EtOAc) 4 NMR (CD3OD, 400 ΜΗζ) δ 0.76 (s, 9H), 1·56_1·71 (ιη, 1H), 5 1·71·1·86 (ιη, 2H), 2.04-2.16 (m, 1H), 2.74-2.95(m,4H), 3.00-3.14(m,2H), 3.46(s,3H),3.71(s,1H),3·88-3·98(πι, 2H), 4.16-4.22(m , 1H), 5.10 (d, 4·8 Hz, 1H), 7·10-7·30 (ιη, 9H), 7·46-7·56 (ιη, 5H), 7·98-8·06 ( Ηι,1H), 8.49 (dd, 4.8, 0·8 Hz, 1H), 8.74 (d, 1·2 Hz, 1H); 13C NMR (CDC13, 100 ίο MHz) δ 22.6, 26.9, 34.9, 37.8, 40.9 , 47.0, 52·6, 58.3, 58.7, 62·4, 63·0, 73·9, 79·5, 125.3, 125.5, 126.2, 127·5, 127·9, 128.8, 128·85, 131.5, 131 ·6,136.4,137.6,138·2,138·4, 138·8, 141.6, 142.5, 148·3, 148.6, 158.9, 171.8, 177·3· 15 Biological examples related to test compounds in their enzyme phase and in cells A detailed description of the analysis in cultures (including HIV strains and mutants RT isolated and/or selected for mutation) can be found in the DAIDS virus manual used by the AIDS department of NIAID USA in 1997 for HIV laboratories. The resistance test (including the mutations that can evade different drugs) is described in the resistance study of the HIV resistance joint research group data analysis plan (Resistance studies, including rational for various drug escape mutants is described in the HIV Resistance Collaborative Group Data Analysis Plan for Resistance Studies, August 31, 1999, re-152-200804246 and later.

Cell Analysis I Analysis of the HIV activity of the compounds of the invention, for example, multiplex assay using χττ in MT-4 cells 5 (Weislow et al. j Nat Cancer

Inst 1989, v〇l 81 no 8, 577 et seq), preferably includes measurements in the presence of .50〇/〇 human acid to indicate the distribution of protein binding. Briefly, the human tau cell line MT4 cell line used in the XTT assay was grown in supplemented with 10% fetal bovine serum (or 40-50% human blood supplement if appropriate), RPMI 1640 with penicillin and streptomycin. In a medium, inoculate into a 96-well microtiter plate that has been infected with 10-20 TCIDw HIV-1IIIB (wild-type) or mutant strains (eg, they have RTIle 100, Cys 181 or Asn 103 mutations). · 104 cells/well). A series of diluted test compounds were added to each well, and the culture was cultured at 37 ° C under a gas-filled atmosphere of C02, and cell viability was measured on days 5 or 6 after staining with XTT in vivo. The results are typically expressed as ED5G μΜ. The HIV-1 protease expression method suitable for enzyme assays is also described in Danielsson et al. Adv·Exp· Med·Biol” 1998, 436, 99-103 〇 20 Determination of Ki Fluorescence assay described in Antimicrob. Agents

Chemother·, 1997, 41, 2383-2388. This document also describes cell assays for the determination of ED50 using MT4 cells and colorimetric XTT assays. Time to develop resistance -153- 200804246 Infect 5-10 TCID50 HIV-1 πιβ in 2x 104ΜΤ4 cells per well of microtiter plate. A test compound having a concentration of about ED50 was added. After 6 days of culture, 10 μl of the RT activity of the supernatant was measured. The passage of the culture was performed once a week according to the following method. At the concentration of the test compound, the generated virus was subcultured to fresh MT4 cells at 50% of the RT activity of the untreated infected cells (SIC, initial inhibitory concentration). Eight replicates of each of the 15 treatments were transferred to cells without test compound (control group) and cells containing the same concentration of test compound and two other test compounds with a 5-fold higher concentration (see Table 2 below). ). 1〇 When the virus is grown at the highest non-toxic concentration (5-40 μΜ), 2-4 parallel wells are collected and expanded, resulting in materials for sequencing and cross-resistance. Table 2 15 Allowing virus growth Inhibiting virus production

125 X SIC 125 X SIC 25 x SIC 25 x SIC 5 x SIC 25 x SIC 5x67C 4 No compound 25 x SIC 5 x SIC No compound 5 x SIC SIC SIC — No compound SIC — No compound passage 1 Passage 2 Passage 3 passage 4 passage 5 -154- 200804246 P450 metabolism The compound of the present invention utilizes the human cytochrome system to completely metabolize the metabolism of the same isoenzyme to facilitate infection of human cytochromes (10) 5 · Α (super body (four) coffee Cong)) (measured by the baculovirus of insect cells of Woburn City, USA). Test compounds with a degree of 0.5, 5 and 5θμΜ for overexpression of cytochrome Ρ45 (^ isozyme (including CYpiA2 + ρ45〇 reductase, + P450 reductase, CYP2C9_Arg 144 + P450 reductase, 10 CYP2d9 + P450 reductase, Double-cover culture in the presence of CYP2D6_Val 374 + p45〇 reductase and CYP3A4 + P 450 reductase). The culture contains a fixed concentration of cytochrome P450 (for example: 5 〇 picomol) for more than 1 hour. The designated isozymes involved in the metabolism of the compound are determined by UV HPLC chromatography to determine the disappearance of the parent compound. 15 〃 For example, the following table shows the Ki and ED5 〇 patterns of representative compounds according to the present invention. Ki&lt;1〇nM inhibition, group B represents n-brother nM inhibition and group c represents 5〇_1〇〇nM inhibition, group d represents Εϋ50&lt;2μΜ, group E represents 2_1〇μΜ, and group F represents y 20 -155- 25 200804246 Table 1. Enzyme inhibition and antiviral activity in cell cultures Structural formula Κ{ηΜ) Εϋ5〇(μΜ)

-156- 200804246 20

B

F -157-

Claims (1)

200804246 X. Patent application scope: L A compound of formula I: 5 wherein R1 is -R1', -OR1', -SR1, and R1' is a CrQ alkyl group, a C0-C3 alkanediylcarbocyclyl group or a C〇-3 alkanediyl heterocyclic group, either of which may be optionally Substituting up to 3 substituents independently selected from R1G; ίο R2 is CrQ alkyl, CVC3 alkanediylcarbocyclyl, C〇-C3 alkanediyl heterocyclyl, either of which may be up to 3 as needed Substituted independently of a substituent selected from R1(); X is Η, F, OH, CVC3 alkyl or C(rC3 alkanediyl-0-CrC3 alkyl; 15 L is OH, F, NH2, -NHCVC3 alkyl ;-N(C!-C3 alkyl)2; N is 0, 1 or 2; E is N or CH; Af is a bicyclic system which contains the first one which optionally contains an oxygen heteroatom and which may optionally be via a hydroxyl group. / or methyl substituted 5 or 6 membered saturated ring, and -158- 200804246 The second may need to contain one or two heteroatoms selected from S, 0 and N and may be substituted by one or two fluorines. Or a 6-membered unsaturated ring fused; or A' is a group of formula (II), (ΙΓ), (III) or (IV): (II) (丨丨,) (III) (IV) where; 10 15 R3 is Η; or R3 is CVQ alkyl, CVC3 alkanediylcarbocyclyl, C〇-C3 alkanediyl heterocyclyl, One may optionally be substituted with up to three substituents independently selected from R11; R4 is a QQ alkyl group, a C()-C3 alkanediylcarbocyclyl group, a CVC3 alkanediyl heterocyclic group, either of which may be needed Substituting up to 3 substituents independently selected from R1G; R5 is alkyl, CG-C3 alkanediylcarbocyclyl, C〇-C3 alkanediyl heterocyclyl, either of which may be up to 3 as needed Substituted independently of substituents selected from R1G; Z is a bond, -NH- or -0-; Rx is fluorene, CVQ alkyl oxygen, CrQ linear chain which may be substituted with a halogen group, a hydroxyl group, or a CrC3 alkyl oxygen Or a branched alkyl group; or Rx and its adjacent carbon atoms together form a halogen- or alkyl-substituted 159- 20 200804246 fused 吱σ- or σ-pyranyl ring; t is 0 or 1; A' ' is a group of formula (V), (VI), (VII) or (VIII); η η η W Q bamboo R15 R8 (VII) (VIII) where; R8 is Η; or R8 is CkQ alkyl, C (rC3 alkanedicarbocyclyl, 〇Γ3 alkyldiyl heterocyclic, any Any one may be substituted with three substituents independently selected from R11 as desired; 10 15 R9 is CKC6 alkyl, C (rC3 alkanediylcarbocyclyl, C(r3 alkanediyl heterocyclyl), either of which can be visualized It is necessary to substitute up to 3 substituents each independently selected from R1G; W is a bond, -NR13- or -0-; R13 is Η, 0^-(:6 alkyl or R13 and R9 are attached thereto The N atoms together form a saturated, partially saturated or aromatic N-containing ring containing 5 or 6 ring atoms, which may optionally be substituted with up to 3 substituents selected from R1G; D is deuterium or NH; Ry is deuterium or Ry and its attached C atom together form a fused furan or ° ratio sigma ring; -160-20 200804246 Q is oxime, CHR8 or a bond; R15 is a carbocyclic or heterocyclic group, either of which is visible It is required to be substituted with up to three substituents independently selected from the group consisting of Ci-q alkyl, hydroxy, oxo, halo; 5 r and q are each independently 0 or 1; R1() is halo, oxo Base , azido group, nitro group, Ci_C6 alkyl group, C〇-C3 alkanediyl carbocyclyl group, CVC3 alkanediyl heterocyclic group, Y-NRaRb, YO-Rb, Y_C(=0)Rb, Y_(C= 0) NRaRb, Y-NRaC (=0) Rb, Y-NHSOpRb, YS (=0) pRb, 10 Y_S (two 0) pNRaRb, YC (=0) 0Rb or Y, NRaC (=0) ORb; wherein Y Is a bond or a CrQ alkanediyl; Ra is H or a CrC3 alkyl group; Rb is H or an alkyl group, a CG-C3 alkanediylcarbocyclyl group or a CVC3 alkanediylamino group; p is 1 or 2; R11 is halo, oxo, cyano, azide, nitro, alkyl, Y-NRaRa, YO-Ra; wherein Ra' is Η or C "C3 alkyl; or Ra and Ra' A total of 20 nitrogen atoms are attached to form 11 piroxime, morphine, brigade bite or slightly u-well, which may be substituted at the 4-position with methyl or ethoxylated groups; and pharmaceutically acceptable salts thereof. - 200804246 2. A compound according to claim 1 wherein R1' is a C〇-C3 alkanediylcarbocyclyl or a C()-C3 alkanediylheterocyclyl optionally substituted. The compound of claim 2, wherein R1' is a carbocyclic or heterocyclic group which may be optionally substituted. The compound of claim 2 or 3, wherein the R1 'carbocyclyl moiety is a phenyl or R1 'heterocyclyl moiety which may be optionally substituted, and may be substituted with a pyridyl group or pyridinium. Base, pyrimidinyl or hydrazine. 5. A compound according to any one of the preceding claims, wherein at least one of R1' may optionally be selected from the group consisting of: halo, oxo, cyano, 1 〇CVC6 alkyl, QrC3 alkanediyl Carbocyclyl, C〇-C3 alkyldiylheterocyclyl, Y-NRaRb, YO-Rb; wherein Y is a bond or a CrC3 alkyl group, Ra is 'Η or CrC3 alkyl and Rb is Η or CVC3 alkyl . 6. The compound according to claim 5, wherein the substituent which may be selected as the R1' is selected from the group consisting of fluorine, CrC3 alkyl, fluorenyl-naphthyldicarbocarbyl, 15 (^-canediyl) a heterocyclic group. The compound according to claim 4, wherein R1' is a mono- or dihalo-substituted phenyl group. 8. A compound according to claim 7 wherein R1' is a single Or a difluoro-substituted phenyl group. The compound according to claim 4, wherein R1' is a phenyl group. 10. The compound according to any one of the preceding claims, wherein the stereochemistry is as follows Partial structural representation; -162- 200804246 〇 X The compound according to any one of the preceding claims, wherein R2 is a C()-C3 alkanediylcarbocyclyl group or a C(rC3 alkanediylheterocyclyl group) which may be optionally substituted. A compound of Item 11, wherein R2 is optionally a substituted carbocyclyl or heterocyclic group. 13. A compound according to claim 11 or 12 wherein the R2 carbocyclic moiety is visually acceptable. Substituted phenyl or R 2 heterocyclyl moiety is a pyridyl, pyridinyl, pyrimidinyl or hydrazine group which may be substituted as desired. The compound according to any one of the preceding claims, wherein At least 1 R of R2 - a substituent which may be optionally selected is selected from the group consisting of: IS group, oxo group, cyano group, CVQ alkyl group, CG-C3 alkanediyl carbocyclyl group, CVC3 alkanediyl heterocyclic group, Y -NRaRb, YO-Rb; wherein Y is a bond or a CVC3 alkyl group, Ra is a ruthenium or a CVC3 alkyl group, and Rb is a ruthenium or a CVC3 alkyl group. 15. A compound according to the scope of claim 14 wherein R2 is visible The substituents selected for use in 15 are selected from the group consisting of fluorine, CVC3 alkyl, QrCi alkanedicarbocyclyl, and fluorenyl-dialkyldiyl heterocycle. 16. A compound according to claim 13 wherein R2 is a phenyl group substituted by a carbocyclic or heterocyclic group. 17. A compound according to claim 16 wherein R2 is aryl or heteroaryl. The phenyl group is substituted by a phenyl group. The phenyl group is a compound according to any one of the preceding claims, wherein X is a compound according to any one of the preceding claims. The compound according to any one of the preceding claims, wherein n is 1. The compound according to any one of the preceding claims, wherein the hydrazine is hydrazine. A compound according to any one of the preceding claims, wherein Α' is a group of formula (II) or (IV) 23. A compound according to claim 22, wherein R3 is hydrazine, visible 10 requires substitution of Ci-Ce Or a C()-C3 calcined diylheterocyclyl group which may be optionally substituted. '24. A compound according to claim 23, wherein R3 is hydrazine or may be substituted with a CrC6 alkyl group. Compound of the 23rd patent range Wherein R3 is a CrQ alkane K group, which may optionally be substituted by a halogen group, or especially an isopropyl group or a tert-butyl group. 26. A compound according to claim 23, wherein R3 may optionally be selected as an oxygen group. Alkyl, cyano, or especially halo or fluorene-fluorene, wherein Y is a bond or CVC3 alkyl, and Ra is hydrazine or CrC3 alkyl. 27. A compound according to any one of the preceding claims Wherein R4 is a CrC6 alkyl group which is required to be substituted, in particular a methyl group or a thiol group which may be substituted. A compound according to any one of the preceding claims, wherein R4 is optionally a halogen, an oxo group, a cyano group, an azido group, a nitro group, a CrC6 alkyl group, or a C, which may be selected from -164 to 200804246. (rC3 alkanediylcarbocyclyl, C(rC3 alkanediylheterocyclyl, Y-NRaRb or YO-Rb, wherein; Y is a bond or a CrC3 alkyl group; 5 Ra is a ruthenium or a CrC3 alkyl group; Rb is Η or CVQ alkyl, QrC3 alkanediylcarbocyclyl or C〇-C3 alkanediyl heterocyclyl. 21 A compound according to claim 28, wherein the substituent which may optionally be selected is a halogen group or an oxo group. a C,-C6 alkyl group, a C〇-C3 calcined dibasic ring 10 group, a cvc3 alkanediyl heterocyclic group or a fluorene-fluorene-Rb. 30. The compound according to claim 29, wherein the visible The substituent which is selected to be a halogen group or a YO-Rb. 31. The compound according to claim 30, wherein R4 is a mercapto group. 32. The compound according to any one of claims 22 to 31, Its stereoscopic 15 chemical system is represented by the following partial structural formula; u ?3 R4 〇(II) 33. A compound according to claim 22, wherein Rx is hydroxymethyl, 1-phenylethyl, 1-propylpropyl, fluoroindenyl, 1-fluoroethyl or 1- Fluoropropyl. 20 3 4. A compound according to claim 22, wherein Rx is methoxymethyl-165-200804246, ethoxylated, 1-methoxyethyl, 1-ethoxyethyl, 1 • Methoxypropyl or 1-ethoxypropyl. 35. A compound according to claim 22, wherein Α’ is The compound according to any one of claims 1 to 21, wherein Α' is a bicyclic ring comprising the first 5 or 6 members which may optionally contain an oxygen heteroatom and may optionally be substituted with a hydroxy or thiol group. The saturated ring, with the second optionally containing one or two heteroatoms selected from S, 0 and fluorene, may be fused by a 5 or 6 membered unsaturated ring which may optionally be substituted with one or two fluorines. 37. A compound according to claim 36, wherein the bond to the remaining molecules extends from the saturated 1-carbon. 38. A compound according to claim 37, wherein the hydroxy substituent optionally used is on the 2-carbon of the saturated ring. 15 39. The compound according to claim 36, wherein the oxo atom is in the 3-position of the 5-membered saturated ring or the 4-position of the 6-membered saturated ring. The compound according to any one of claims 36 to 39, wherein the second ring is 5 members and contains a sulfur hetero atom or a hetero atom. The compound according to any one of claims 36 to 39, wherein the second ring is a phenyl group which may optionally be substituted. -166- 200804246 42. The compound according to claim 41, wherein the substituent is mono- or di-d. 43. A compound according to claim 36, wherein Α' is: 44. A compound according to claim 36, wherein Α’ is The compound according to any one of the preceding claims, wherein a "(V). ^ 46. The compound according to claim 45, wherein y is η, optionally substituted q a C6 alkyl group or a cG_c3 alkane carbocyclyl group which may be substituted. A soil 47. A compound according to claim 46, wherein h or a CrC6 alkyl group which may be optionally substituted, especially an isopropyl group Or a butyl group. The compound according to any one of claims 45 to 47, wherein y may optionally be substituted with an oxo group, a cyano group, a Ci_Cs alkyl group, or, in particular, a halo group or a hydrazine group. -0-Ra; wherein Y is a bond or a CrC3 alkyl group; Ra is a η or a CrQ group. The compound according to any one of the claims 45-48, wherein y is substituted by CrC6 as needed Or a CG-C3 calcined diyl carbocyclyl group. A compound according to claim 49, wherein R9 is a substitutable thiol group, and 51. according to any one of claims 45_5 of the patent application. a compound wherein V may optionally be substituted with a halogen group, Substituent, cyano, azide/nitrogen, Schottky CKC6 alkyl, c〇-C3 calcined diyl carbocyclyl, C()-C3 calcined dibasin, Y-NRaRb or Υ-Ο-Rb Wherein Y is Y-bond or CrC3 alkyl; Ra is η or CVC3 alkyl; 匕 is Η or Ci-C6 alkyl, C〇-C3 burned diyl carbocyclyl or C〇-c3 burned - 20 200804246 A heterocyclic group. 52. A compound according to claim 51, wherein the substituent which may optionally be selected is a ke group, an oxo group, a CrC6 alkyl group, a CVC3 alkanediyl carbocyclyl group, a CVC3 alkanediyl group. a heterocyclic group or Y-0-Rb. 53. A compound according to claim 52, wherein r9 is a fluorenyl group. 54. A compound according to any one of claims 45-53, &amp; w is _ 〇- 〇 55. According to the towel, please refer to the compound of the 45th-54th towel, the stereochemistry of which is expressed by the following partial structural formula; R9, a western medicine composition comprising a compound according to any one of the preceding claims, and a pharmaceutically acceptable or diluent thereof. 15 20 ... The pharmaceutical composition of claim 56, which further comprises ... other HIV antiviral agents. 58. - In the case of the manufacture of medicines according to the scope of the application for patents, or for the treatment of money. σ ^ Medicine for the treatment or prevention of HIV infection i; according to the scope of the patent application... -169- 200804246 VII. Designated representative map: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R2 10