TW200800149A - HIV protease inhibitors - Google Patents

Abstract

Compounds of the formula I: wherein R1, R2, X and N are as defined in the specification; L is F, NH2, NHAlk or N(Alk)2 n is 1 or 2; A' and A" are terminal groups as defined in the specification. The compounds have utility as HIV-1 protease inhibitors.

Description

200800149 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to HIV protease inhibitors. [Prior Art] Two different retroviruses: human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2) in pathogenic and immunosuppressive diseases, acquired immunodeficiency syndrome ( AIDS) related. HIV seropositive individuals are initially asymptomatic but usually develop AIDS-related syndromes (ARC), followed by AIDS. Infected individuals exhibit severe immunosuppression, which makes them prone to weakness and ultimately lead to fatal opportunistic infections. AIDS disease is the final result of the development of HIV-1 or HIV-2 viruses according to their own complex life cycle. The life cycle of the virion begins with the virion attaching itself to the host human T-4 lymphocyte immune cell by binding the prion on the surface of the virion protective coat to the CD4 glycoprotein on the lymphatic cell. Once attached, the virion removes its glycoprotein coat, infiltrates into the host cell membrane, and exposes its RNA. Viral enzymes (reverse transcriptase) direct the process by which RNA is transcribed into a single strand of DNA. Viral RNA is degraded and produces a second DNA strand. Immediately double-stranded DNA is integrated into human cell genes and their genes are used for virus propagation. At this time, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into a precursor gag-pol fusion polyprotein, which is then cleaved by HIV protease to produce a mature viral protein. Thus, HIV protease is responsible for modulating the cascade of lytic events that cause viral particles to mature into a virus with sufficient infectious capacity. I15688.doc 200800149

Because the virus infects and kills the T cells of the immune system, it puts pressure on the typical response of the human immune system to kill invading virions. In addition, viral reverse transcriptase (an enzyme used to produce new virions) is not extremely highly specific and produces transcriptional errors that result in sustained changes in glycoproteins on the surface of the virus-protected coat. This lack of specificity reduces the efficacy of the immune system because antibodies raised specifically for one glycoprotein may reduce the number of antibodies available against the virus against another glycoprotein. The virus continues to multiply and the immune response system continues to weaken. Ultimately, HIV has a significant advantage over the body's immune system, causing opportunistic infections and, if not administered, antiviral agents, immunomodulators, or both, can result in death. There are at least three critical points in the life cycle of the virus that have been identified as anti-viral drugs: (1) virions initially attach to n-lymphocytes or macrophage sites; (2) viral RNA is transcribed into viral DNA ( Reverse transcriptase '; and (3) the process by which HIV protease processes gag_p_white. The genome of the retrovirus encodes a protease that is responsible for deproteinization or a variety of polyprotein precursors (such as pol and gag gene products). Retroviral proteases usually add the gag precursor to the core protein f, and the precursor is processed into a reverse transcriptase and a retroviral protease. The viral protease is required for the assembly of infectious agents. Xingyue produces a protease-deficient virus that produces an immature core form that lacks infectivity. Therefore, reverse,;,: 毋 from enzyme inhibition provides an attractive target for antiviral therapy. 2^1 sold and clinical Protease inhibitors in the test have shown that it has been studied as a possible HIV protease inhibitor. No. 115688.doc 200800149 A so-called anti-infection The inhibitor of retroviral aspartic acid protease is saquinavir, followed by other inhibitors, including indinavir (Merck), ritonavir (Abbott). Amprenavir and its prodrugs are filled with amprenavir (Vertex/GSK), lopinavir (Abbott), nelfinavir (Aguoron/Pfizer), and tira Tipranavir (Pharmacia/Boehringer) and atazanavir (Novartis/BMS) 〇 each of these prior art compounds causes suboptimal treatment regimens, side effects (such as lipid malnutrition and poor patient compliance) Responsibility in the treatment of sexually transmitted diseases. Combining the replication distortion of the HIV genetic machine with the extremely high viral turnover rate in the body, the prior art of suboptimal potency and pharmacokinetics, the protease inhibitors make the drug resistant mutants fast. This occurs because Hi ν is rapidly resistant and/or the patient is aversed by the drug itself or its side effects, which in turn greatly limits the effective treatment time of existing HIV drugs. hair The object is to provide a novel type of compound which has a high inhibitory activity against viral replication in cells, and a multi-drug resistant strain (including those resistant to such as saquinavir, ritonavir and ketal) The high antiviral activity of the virus strain of known compounds and particularly advantageous pharmacological properties, such as good pharmacokinetics, such as high bioavailability and gastric acid content and/or high selectivity. According to the invention, there is provided a compound of formula I: 115688.doc 200800149

Wherein R is 'R1, -OR1', -SR1·; R is CVQAlk, Co-C3 alkanediylcarbocyclyl or cG_3 alkanediyl heterocycle

Any one of which may optionally be substituted with up to 3 substituents independently selected from RiG; R is <^-(:6 八11^, C(rC3 alkanediylcarbocyclyl, cG_c3 alkanediyl) a heterocyclic group, either of which is optionally substituted with up to 3 substituents independently selected from r1g; X is a fluorenyl group; OH, CVCsAlk or CVC3 succinyl-OC^Cs alkane L is F, NH2, _NHCl -C3Alk, -N(Cl-C3Alk)2; η is 1 or 2; Α is a bicyclic system comprising a first 5 or 6 membered saturated ring fused to each other and a first 5 or 6 membered unsaturated ring, wherein A 5- or 6-membered saturated ring contains an oxygen hetero atom and is optionally substituted by a hydroxyl group and/or a methyl group. The second 5 or 6 member unsaturated % optionally contains one or two heteroatoms selected from the group consisting of s, hydrazine and N. And optionally substituted by fluorine or disubstituted; or A' is a group of formula (II), (Ir), (m) * (Iv) · 115688.doc 200800149

R is Η; or 113 is cc A1 C (rC3 alkanediylcarbocyclyl, C(rC3 alkane-yl-heteroradyl) 壬, this 'g. See h condition, up to three independently selected from Substituted by a substituent of R11; R is q C6Alk, (:.-(: 3 calcined diylcarbocyclyl, C"C3 calcined diyl heterocyclyl", optionally, up to three independently selected from... Substituted by a substituent; R^CAAlk, (VM: carbocyclyl, '(tetra)diylheterocyclyl, either optionally substituted with up to three substituents independently selected from the ruthenium 10; Z is a bond , -NH_ or;

Rx is C, CVC3 alkoxy 'C1-C3 straight bond or branched bond group substituted by halogen group, hydroxyl group or alkoxy group as the case may be; or Rx together with adjacent carbon atoms, as defined by halogen group or C1- C3Aik substituted fused 吱Nan smile bite, t is 0 or 1; A" is a group of formula (V), (VI), (VII) or (VIII):

(V) where: 5. Ry Η 乂/Ν—S—R9 0 R8 inch VcrM15 (VI) (VIII) 115688.doc -10- 200800149 R is Η, or R8 is Ci-C6Alk, CQ_C3 alkanediylcarbocyclyl, Cn alkane-based The soil base 'either of them is optionally substituted with up to three substituents independently selected from R11; R is CVC6Aik, C(rC3 alkanediylcarbocyclyl, c(di)alkyldiylheterocyclyl' The case is substituted with up to three substituents independently selected from R1❹; W is a bond '-NR13- or ·〇»; R is Η, CrC^Alk, or R13 is defined in conjunction with the n atom to which it is attached 5 or A saturated, partially saturated or aromatic n-ring of 6 ring atoms is optionally substituted with up to three substituents selected from rIG; D is deuterium or NH;

Ry is deuterium, or Ry together with an adjacent c atom defines a fused furan ring or a piper ring; Q is 0, CHR8 or a bond; R 5 is a carbocyclic or heterocyclic group, either of which may be up to three Substituents independently selected from the group consisting of Cl-C3Alk, hydroxy, pendant oxy, halo; r and q are independently hydrazine or i; R is _yl' pendant oxy, cyano, azide, nitro , CVC^Alk, c〇-c3垸diylcarbocyclyl, c❹_C3 alkanediylheterocyclyl, Y-NRaRb, γ_ 〇-Rb, Yc(=〇)Rb, Y-(〇〇)NRaRb, Y- NRaC (=0) Rb, Y-NHS 〇 pRb, Y_s (= 〇) pRb, Y_s 〇 〇) pNRaRb, YC (= 〇) 〇 Rt ^ Y-NRac (= 〇) ORb; where: Y is a bond or Ci -c^烧二基; 115688.doc -11- 200800149

Ra is HiCVC^Alk;

Rb is q-QAlk, CVC3 alkanediylcarbocyclyl or c〇_C3 alkanediylheterocyclyl; p is 1 or 2; R11 is a dentate group, a pendant oxy group, a cyano group, an azide group, a nitro group, Ci_C3Aik, Y-NRaRa', YO-Ra, where:

Ra' is Η or CVC^Alk; or with 1, and the nitrogen atom to which it is attached

A pyrrolidine, a morphine, a bite or a sputum which is optionally substituted with a thiol or acetamino group at 4 positions; and a pharmaceutically acceptable salt thereof, as defined above. Another aspect of the invention includes a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier or diluent thereof. Another aspect of the present invention contemplates 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 medical treatment or prevention of HIV infection, the method comprising administering an effective amount of a compound as defined above to an individual infected with HIV or at risk of infection, 0 does not wish to be subject to any theory in any way Binding, or due to the knot of a particular variable> ^Schechter & Berger, (1976) Biochem Biophys heart ^111 27 157_162, as used herein, the ideographic centering PI, PI 'P2 and P2' are only Conveniently provided and generally have their conventional meanings, and indicates that they are believed to fill the enzymes S1 'S1, 82 and 82, respectively, the inhibitor portion of the subsite, complex c, α & Contrary to the cleavage site located on one side and S 2 is away from the site, and gj 1 丨 phase recognition is located at the cleavage site located on the other side and S2, 115688.doc -12- 200800149 away from the site . Compounds defined by formula i are intended to fall within the scope of the invention, regardless of the mode of combination. It is not only conceivable that R1 and R2 fill the S1 and Sr subsites, respectively, and A' and A" interact with S2 and S2f, and the opposite configuration can be envisaged. Appropriately described in Equation 1 by the radical and R1 The compounds of the invention exhibit an enantiomeric purity of at least 75%, preferably at least 90% (such as more than 95%) in the vicinity of the carbon shared by the functional groups. It is presently preferred that the compounds exhibit a high enantiomeric purity. Such as the stereoisomers shown in the following partial structure:

〇 X

The stereocenter to which the group X is attached may have a ruler or an 8 stereochemical configuration. The compound of the present invention exhibits an enantiomeric purity of at least 75%, preferably at least 90% (e.g., 95% or more) in the vicinity of the carbon to which the group X is attached. It is presently preferred that the compounds exhibit a high enantiomeric purity as shown in the following partial structure:

For example, the compounds of the invention include those compounds having the stereochemical configuration as shown in the following section: 115688.doc -13- 200800149

X is H, OH, Cl_C3Alk or CG_C3 alkanediyl-0-CVC3 alkyl as defined above. Suitable values for X include alkanedialkyl, especially decyloxy (i.e., C〇) and hydroxymethyl. A preferred value for x is generally 1? or OH and especially η. As described above, L is F, NH2, NHCVC3Alk, NCCV C3Alk)2, wherein NHCVCAlk and Ν((^_(:3Α11〇2 are preferably NHMe and NHMe2, respectively. The preferred value of L is preferably fluorine). Is a compound of the invention. The compound of the invention may have 3 or 4 chain atoms between the carbonyl group described in formula I and the β-nitrogen of the hydrazine functional group (i.e., n is 1 or 2). Preferred in the present invention. In the examples, the compounds have 3 chain atoms between the carbonyl group and the hydrazine functional group, i.e., η is 1. As defined above, R1 is R1, OR1 or SR1', where Ri is Ci_C6 An alkyl group, but especially a C〇-C3 burnt dicarbyl carbocyclyl or a cG-3 calcined diyl heterocyclyl. Typical examples of such materials are described below. Any of these materials may be up to 3 depending on the situation. Substituted independently from a substituent of rig as defined above. Suitable optional substituents for R include one or two selected from the group consisting of a yl group, a pendant oxy group, a cyano group, a CrC^Alk, a (:()-0:3 alkane a substituent of a dibasic carbocyclyl group, a CVC3 calcined diylheterocyclyl group, Y-NRaRb, Υ-0-Rb; wherein γ is a bond or C3Aik 'Ra is Η or C1-C3AIIC and Rb is Η or Ci_C3Aik. Μ: Preferred substituents include fluorine, (VC^Alk, Co-Ci alkanediylcarbocyclyl, C(rCl^diylheterocyclyl. 115688.doc -14 - 200800149 suitably, such as R1, or an alternative thereof) The C (rC3 alkanediyl linker moiety of the isocenter <3 alkyldiylcarbocyclyl or Gw alkanediyl heterocyclyl species defines a methylene group or even a more preferred defined bond, i.e., R1, or a substituent The group is only a carbocyclic or heterocyclic group which may be optionally substituted, such as optionally substituted phenyl or optionally substituted D-pyridyl, pyridazinyl, pyrimidinyl or pyridazinyl. R1 is preferably R1· or OR1· In one embodiment of the invention, the R1G substituent of R1 is Y_〇_Rb, wherein Y is a bond and Rb is optionally substituted C(rC3 alkanediylaryl or alkane The heteroaryl group is preferably a Ci_C3Aik such as a methyl group. The preferred structure of R1 according to this embodiment includes:

Tx is especially in the para position of the phenyl R1 group. Therefore, other suitable values for R1 include phenyl, pyridine-2-yl, pyridine-3-yl, pyridin-4-yl, pyrimidine-2-yl, pyrimidine-4.yl, pyrazine-2-yl, pyrazine a -3-yl or pyridazinyl, pyridazinyl or triazinyl group; or a phenyl group which is mono- or disubstituted by a dentate group, such as a phenyl group which is mono- or disubstituted with fluorine. Typical preferred substituents for phenyl R1 include 11, methyl, methoxy, fluoromethyl or trifluoromethyl. Preferred R1 groups include H, m-fluoro, orthofluoro or p-fluoro. When R represents two non-! substituents, typical configurations include 2,5-difluoro or 2,5-methyl, 2,4-difluoro or 2,4-dimethyl, 2. 3-difluoro or 2,3-dimethyl or 3,4-difluoro or 3,4-dimethyl and especially 2,6-difluoro or 3,5-diI. 115688.doc -15- 200800149 As defined above, R2 is Cl_C0Alk, but especially ^-decanediylcarbocyclyl, C"alkyldiylheterocyclyl, any of which may pass up to Three substituents independently selected from R1G are substituted. The optional substituents are one or two selected from the group consisting of _ group, pendant oxy group, cyano group, CVC^Alk, (VC3 alkanediylcarbenyl group, CG_C3 alkanediyl heterocyclic group, Y_NRaRb, Y_〇_ a member of Rb, wherein Y is a bond or Ci-C3Alk, Ra is ruthenium or Cr-C3Alk and Rb is η or CVCAlk. Usually the ruthenium substituent includes fluorine, Ci_C3Alk, methylene carbocyclyl or methylene heterocycle. , especially, for example, a substituent such as an optionally substituted carbocyclic group or a heterocyclic group at the para position of the R 2 cyclic group. Suitably, such as R 2 or an optional substituent thereof (3 () _(: 3 alkanediyl carbocycle or C 〇 (^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A carbocyclic or heterocyclic group which is optionally substituted, such as an optionally substituted phenyl group or an acridinyl group, a pyridazinyl group, a pyrimidinyl group or a pyridazinyl group which has been substituted. Thus, 'R2 Suitable values include phenyl, pyridin-2-yl, pyridine G-yl, pyridin-4-yl, pyrimidine-2-yl, pyrimidinyl, pyrazine-2, pyrazinyl or pyridazin-3-yl, Pyridazinyl or triazinyl; or especially in para Substituted by an aryl carbocyclic ring (such as a phenyl group) or a heterocyclic ring (such as a heteroaryl group as defined hereinafter, such as, for example, a quinol-2-yl group, a 1,3-yl group, and especially a sigma-4-yl group) Phenyl. The preferred values of r2 include:

Especially at the para position of the phenyl R2 group. 115688.doc -16 - 200800149 Turning now to the terminal guanamine A', a suitable embodiment comprises a bicyclic ring system comprising a first 5 or 6 member saturated ring fused to each other and a second 5 or 6 member The unsaturated ring, the first 5 or 6 member saturated ring optionally contains an oxygen hetero atom and optionally substituted by a hydroxyl group or a methyl group, and the second 5 or 6 member unsaturated ring optionally contains one or two selected from the group consisting of S, hydrazine and A hetero atom of N and optionally substituted by fluorine or disubstituted. Suitably, in this embodiment, the guanamine of the linking molecule and the remainder of the bond extend from the carbon 1 of the saturated ring. Suitably, in this embodiment, an optional base substituent is at the carbon 2 position of the saturated ring. Alternatively, the oxygen heteroatom is typically provided at the 3 position of the 5 member saturation ring or at the 4 position of the 6 member saturation ring. In this embodiment, suitably, the second ring of A is a 5-membered ring and contains a sulfur hetero atom or an oxygen hetero atom. Alternatively, the second ring is typically a fused pyridyl group or an optionally substituted phenyl group as described in WO9845330, such as a fused phenyl group wherein the substituent is monofluoro or difluoro. In this embodiment, representative groups of the invention include: 115688.doc 17- 200800149

Particularly preferred variants in this embodiment include cis-indanol-based and cis-chromanol groups as described in the following partial structures:

ΩΗ OH

Alternative embodiments of the compounds of the invention include those in which A' is a group of formula (II), thereby defining a compound of the formula: 115688.doc -18 - 200800149

In the eighth formula, another alternative embodiment of the compounds of the invention includes the compounds of the (ΙΓ) group thereof, thereby defining a compound of the formula:

As described above, R3 is H; or the ruler 3 is (:1<6 octadecyl, alkanediylcarbocyclyl, CG.3 alkanediylhydrazine, either of which may be independently selected up to three independently Substituted from a substituent of R 11. Suitable values for R3 include optionally substituted CQ-C3 alkylheterocyclyl and especially η or optionally substituted Ci_C0Alk. Preferred R3 values include CVCAlk, such as optionally via hydroxy Or a methoxy group or an isopropyl group or a third butyl group such as a fluorine group. Preferred values for R3 are isopropyl, tert-butyl, fluoro"-mercaptoethyl, 2_hydroxy_1_ Methyl ethyl, 2-methoxy_ι_methylethyl, fluorenyl fluoride, dimethyl dimethyl, 2-hydroxy-1,1-dimethylethyl and 2-methoxy-di Methyl ethyl. The optional substituent of R3 is as defined above. Representative values include pendant oxy, cyano or especially i group or Υ-0-Ra, where Y is a bond or Cl-C3 Aik, and Ra is Η or Cr-QAlk. As described above, K^^CpC^Alk, C(rC3 alkane 115688.doc -19- 200800149-based carbocyclyl or Co-C3 alkanediyl) in formula I, Ila and II, a a heterocyclic group, either of which is optionally taken up to three substituents independently selected from R1G Preferred values for R4 include optionally substituted CrCAlk, especially methyl or ethyl or optionally substituted methyl or ethyl. Suitable optional substituents for R include halo, pendant oxy, cyano , azido, nitro, CrC&Alk, CVC3 alkanediylcarbocyclyl, Cg_C3 alkanediylheterocyclyl, Y-NRaRb or Υ-0-Rb, wherein: Y is a bond or CrCsAlk; ® Ra^H ^C^CsAlk ;

Rb is HS CVCsAlk, CVC3 alkanediylcarbocyclyl or. ^; alkanediyl heterocyclic group. Preferred values for R4 are fluoroethyl, difluoroethyl, trifluoroethyl and methoxyethyl. Preferred optional substituents for R4 include a benzyl group, a pendant oxy group, a Ci_C6Aik, a c〇_C3 succinylcarbocyclyl group, a C()-C 々diylheterocyclyl group or a Y_〇_Rb, especially a halogen group. Or Υ-Ο-Rb. < II may be the s or R stereochemical configuration at the palm center to which R is attached, or a racemate thereof, but generally it preferably has a stereochemical configuration as shown in the following partial structure; : μ R3 R4-Nyx Ο (Π) or Α' can contain the following substructures: 115688.doc -20· 200800149 R5v\々Η (Hi) where R3 is H; or R3 is Ci_C6Alk. a decanediylcarbocyclyl group or a Coyalkyldiylheterocyclyl group, which may be optionally substituted with up to three substituents independently selected from R"; R5 is a ^^尬'

a CG.3 alkanediylheterocyclyl group, any of which is optionally substituted with up to three substituents independently selected from R1G; and 2 is a bond, _Nh...supplements of _; Defined by Formula II. Formula III may comprise a stereochemical configuration of 8 or 玟 at the palm center of the R3 to which it is attached, and it is generally preferred to have a stereochemical configuration as shown in the following partial structure:

The usual preferred value is 〇. Preferred values for R5 include optionally substituted C^C: 6Aik, especially a methyl group or an optionally substituted fluorenyl group. A, preferred value is Formula IV, thereby defining a compound of the formula: 115688.doc

Representative values of formula IV include monocyclic furans wherein R is H, CpC3 alkoxy-21-200800149, optionally ei_C3 linear or branched alkyl substituted by dentate, hydroxy, Ci_C3 alkoxy. Representative values belonging to the series include those in which Rx is the value of c "Cal" substituted with a halogen group, a hydroxyl group or a Ci_C2Alk at the 1-position of the chain carbon. Preferred values include those in which "is hydroxymethyl, ^ hydroxyethyl a value of a group, a 1-hydroxypropyl group, a fluoroindenyl group, a U-fluoroethyl group or a fluoropropyl group, and wherein Rx is a decyloxymethyl group, an ethoxylated fluorenyl group, a methoxyethyl group, p The value of ethoxyethyl, 1-methoxypropyl or 丨-ethoxypropyl. Particularly preferred compounds according to formula IVa are those wherein i is and/or B is 〇h. Or Rx defines another furanyl or piperazine group which is fused to the furan ring and optionally substituted by halo or f3Alk. Representative examples include those wherein the heterocyclic oxygen is positioned as follows:

and

Turning now to the other terminal indole A", as defined above, which is selected from the formula v, VI, VII or VIII, especially when A, having the formula Π, IV or bicyclic ring system, the representative value of the formula νι includes the Value of the following formula: Object: 115688.doc

P

Preferred compounds according to this embodiment include compounds according to formulas VIa and VIb -22- 200800149

Particularly preferred compounds according to the formulae Via and VIb are those wherein ^1, the reverse 1 is phenyl and/or L is NH2.

The basic components suitable for the preparation of the compounds according to this embodiment of the invention are described herein and in WO 99/48885 and WO 94/05639. The stereochemical synthesis of hexahydrofuran succinyl alcohol is described in PCT 2003 22853 and 〇〇 5 6377 ’ where the corresponding synthetic methods are applicable to mirror images. The preferred stereochemical configuration of Formula VI includes the configurations shown in the following partial structures.

, H7~fH or >〇,,Ίο suitably, Απ has the formula V, thereby defining a compound of the formula:

As described above, R8 is hydrazine; or R^Cl_C6Alk, CQ-C3 calcined diylcarbocyclyl, CG-3 alkanediyl heterocyclyl', either of which may optionally be substituted by up to three independently selected from R11. Substituted. Suitably, R^H, optionally substituted Cl-CiAlk or optionally substituted Cq_C3 alkanediylcarbocyclyl. ^115688.doc -23· 200800149 Generally preferred values include hydrazine or optionally substituted c^C^Alk, especially isopropyl or tert-butyl. R is optionally substituted by 1 to 3 members independently selected from r1 1. Representative optional substituents include pendant oxy, cyano, Cl_C3Alk or especially halo or γ_O-Ra, wherein Υ is a bond or c^CsAlk, and Ra is K^ Ci-C^Alk. As described above, the C〇-C3 alkanediylcarbocyclyl, C〇_3 alkyldiylheterocyclyl' is optionally substituted with up to three substituents independently selected from R10; key,. Suitably, the iCrC^Alk or Co-C3 alkanediylcarbocyclyl, especially a methyl or unsubstituted methyl group, as appropriate, is substituted. Representative optional substituents for R include —yl, pendant oxy, cyano, azide, nitro, cvcAik, cvc3 alkanediylcarbocyclyl, Cq_C3 alkanediylheterocyclyl, Y-NRaRb or Y- 〇_Rb, wherein γ is a bond or Ci-C3Alk, Ra is Η or Cl-C3Alk and the milk is a triazole-based or CG-C3 alkanediyl heterocyclic group. For example, when r9 is a methyl group, particularly preferred optional substituents include a _ group, a side oxomethine 1~虱丞Li-C6Alk, a cvc3 alkanediylcarbocyclyl group, a C(rC3 oxadiylheterocyclyl group or Y_Q_Rb. When A" has the formula v, W is generally preferred. The s or r stereochemical configuration 'or its racemate at the palm center of the R is connected, but it has the following The stereochemical configuration shown in some structures is generally preferred: 115688.doc -24 - 200800149

(V). An embodiment when A" conforms to Formula V includes where R9 is directly bonded to w (ie, C〇) or via a CrC3 burnt dibase chain (eg, a fluorenylene chain (ie, cj) linkage to W) Compounds of substituted heterocyclic groups. Preferred compounds according to this example include those compounds having the structure of formula va:

Particularly preferred compounds according to formula Va are those in which 11 is i, r1 is phenyl and/or 1> is >〇12.

The basic components suitable for the preparation of the compounds according to this embodiment of the invention are described herein and in WO 98/00410 and WO 96/039398. Another embodiment when A'·conforms to Formula V includes a compound wherein W is a bond and R9 is a C〇-C3 alkanediylcarbocyclyl or a CQ_C3 alkanediylheterocyclyl group, the carbocyclic group and the heterocyclic group The situation was replaced. Preferred compounds according to this example include those compounds having the structure: 115688.doc -25- 200800149

Particularly preferred compounds according to formulae Vc and Vd are those in which 1, 1 is phenyl and/or L is NH2.

The basic components of the compounds suitable for the preparation of this example of the invention are described herein and in U.S. Patent 5,1964,438. When Απ has the formula VII, R8 is as described above and R9 is Ci-C6Alk (such as methyl) is usually preferably q suitably, A" has the formula VIII, thereby defining the formula v„Iai compound··

As described above, R 5 is a carbocyclic group or a heterocyclic group, and any of them may be optionally substituted with up to three independently selected |Ci-CsAlk, a hydroxyl group, a pendant oxy group, a substituent derived from a group, and Q is 〇, NR8 or key and r&q is independently seven or equal. The broad 15 represents a substituted aromatic ring of 5 to 6 members containing from 〇 to 2 heteroatoms, which are independently selected from N, oxime and s. Suitable optional substituents for R 5 include Ci-C3Alk, such as methyl, ethyl, propyl or isopropyl. The representative compounds in this example of the invention are those in which the oxime is a bond 115688.doc -26 - 200800149 and both r and q are zero. Preferred compounds according to this embodiment are those having a structure of the formula V11lb:

Particularly preferred compounds according to formula V11lb are those wherein η is 1, R1 is phenyl and/or L is ΝΗ2. The basic components of the compounds suitable for the preparation of this example of the invention are described herein and in U.S. Patent Nos. 5,484,926 and 5,952,343. Among other preferred compounds which are in accordance with formula VIII are those in which Q is oxime. Preferred compounds according to this embodiment include those compounds having the structure of formula VIIIc and Vllld:

Particularly preferred compounds according to formula VIIIc and Vllld are those wherein η is 1, R1 is phenyl and/or L is ΝΗ2. The basic components of the compounds suitable for the preparation of this example of the invention are described in 115688.doc -27-200800149 herein and in W098/00410 and W096/39398. Other preferred compounds wherein A" conform to formula VIII are those wherein Q is CR8. Preferred compounds according to this embodiment include those compounds having the structure of formula Vllle:

Particularly preferred compounds according to formula Vlllh and Vim are those wherein η is 1, R1 is phenyl and/or L is ΝΗ2. The basic components of the compounds suitable for the preparation of this example of the invention are described herein and in US 6,372,905 and W097/21,685. Other preferred compounds of the invention are those having the formula IX:

Wherein R 1 " is one or two substituents independently selected from the group consisting of hydrazine, halo, amide, anthracene, cyano, nitro, CVC 4 alkyl, OCi-C# alkyl, CVC 4 haloalkyl; 115688.doc - 28 - 200800149 R2 is _yl'phenyl or acridine; X is hydrazine or OH; L is F, ΝΗ2, NHCr-CsAlk or NCCr-CsAlkh; A is a color-filled fluorine and/or methyl group as appropriate Alcohol group, indanol group, or A is a group of formula (a):

Where R3 is H^CrC^Alk; R^CVC^Alk; A" has the following partial structure:

Or R8 is Η or (VC6Alk; W is _NR13- or; R13 is Η, (VC6Alk; its stereoisomeric form and pharmaceutically acceptable salt. As used herein, alkanediyl-O-Ci- Cs alkyl, meaning to include direct linkage (ie, C〇) or via an intermediate methylene, ethylenediyl, indole, 3-propanediyl or 1,3-propanediyl chain linkage such as methoxy, C1-C3 alkoxy groups of ethoxy, n-propoxy, iso-oxooxy. *Cr CsAlk' as used herein is meant to include 1 to 6 carbon atoms 115688.doc -29- 200800149 Linear and branched aliphatic carbon chain substituents such as decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl And any simple isomer thereof. The Aik group may have an unsaturated bond. Further, any C atom in 'CrC6Aik may optionally be one, two or (if valence permits) three dentates and/or heteroatoms S, Helium, NH. If a hetero atom is at the end of the chain, it is suitably substituted with 1 or 2 hydrogen atoms, such as OH or NH2. Preferably, CrCfAlk is a small molecule, saturated and unsubstituted or via Substituted by a halogen halide. C1-C4Alk&C1-C5Aik has the meaning corresponding to Cr-GAlk, and if necessary, the carbon number of Cl_C0Alk is adjusted. Me represents a fluorenyl group. As used herein, 'CrCsAlk, which means methyl, Ethyl, propyl, isopropyl, cyclopropyl, either of which may be substituted as described above or in the case of C2 or C3 with an unsaturated bond such as ch=CH2. The C0-C3 calcined base used herein is meant to include divalent straight bonds and branched aliphatic carbon chains such as methylene, ethylenediyl, 1,3-propanediyl, U-propyldiyl. The base 'includes NH2, NHCKC3Alk or N(C!-C3Alk) 2. As used herein, 'i-group' or halogen means F, Cl, Br, I, especially chlorine and preferably fluorine. The 'CVC3 alkanediylaryl' used is intended to include a phenyl group, a naphthyl group or a phenyl group fused to a Cy-C7 cyclopropyl group such as indanyl, wherein the aryl group is directly bonded (ie, C〇). Or via an intermediate methylene, B'-yl, 1,2-propanediyl or 1,3-propanediyl group as defined above for C (rC3 alkanediyl) unless 115688.doc -30- 200800149 It is understood that the aryl group and/or its fused cycloalkyl moiety is optionally selected from the group consisting of i group, thiol group, schiffyl group, cyano group, secret group, CA slit, alkoxy group, Ci-C6 alkoxy group-CrCeAlk, Substituent substitution of Ci-C6 alkyl fluorenyl, amine, azide, pendant oxy, fluorenyl, nitro, Cg_C3 alkanedicarbocycloalkanediyl heterocyclyl. "aryl" . As used herein, "Co-C: 3 alkyldicarbocarbyl" is intended to include c〇_c3 alkanediylaryl and Co-C3 alkanediyl qc:7 cycloalkyl. Unless otherwise stated , otherwise the aryl or cycloalkyl group is optionally selected from the group consisting of dentyl, hydroxy, nitro, cyano, carboxy, Cl-C6Alk, Cl-C6 alkoxy, Ci_C6 alkoxy C, i-C6Alk Substituted by a substituent of an alkylhydrazine group, an amine group, an azide group, a pendant oxy group, a thiol group, a nitro group, a CG-C3 alkanediylcarbocyclyl group and/or a Cq_C3 alkanediyl heterocyclic group. The base " has a corresponding meaning, that is, it does not exist. {3 alkanediyl linkage. C0-C3 calcined diylheterocyclyl as used herein, meaning to include a monocyclic saturated or unsaturated hetero atom. Ring, such as piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isotazolyl, thiazinyl, isothiazinyl, thiazolyl, oxadiazolyl, ^ , hongzozolyl, i, 2,4-oxazolyl, tetrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyridyl, oxime or fused to a benzene ring Any of the groups, such as quinolinyl, awkward Azyl, benzoxazole, benzoxazole, benzothiazinyl, benzodiazepine, benzothiazolyl, benzoxazole, benzoquinone-1,2,3- Triazolyl, benzoquinone-1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzoquinone, benzidine, phenylpyrimidinyl, benzoxazinyl, Phenylhydrazine, pyrazinyl, benzoxazolyl, etc., wherein the ring is directly bonded (also 115688.doc -31-200800149 ie (c〇)) or via an intermediate methyl, ethyl, propyl or isopropyl group ( The linkages are as defined above for the Co-C3 alkanediyl group. Any such unsaturated ring having an aromatic character is referred to herein as a heteroaryl group. Unless otherwise stated, the heterocyclic ring and/or its fused benzene The base moiety is optionally selected from the group consisting of 1-3, thiol, nitro, cyano, carboxy, Ci-GAlk, Cl_C6 alkoxy, Ci_C6 alkoxy CVC^Alk, CKC6 alkyl fluorenyl, amine group, Substituted by an azide group, a pendant oxy group, a fluorenyl group, a nitro group, a Co-C3 carbocyclic group, or a Co-C3 heterocyclic group. The "heterocyclic group, and the π heteroaryl group" have corresponding meanings, That is, there is no - two-base linkage. Usually the term 'CVC3 alkanediylcarbocyclyl substituted as appropriate, and optionally substituted Co-C3 calcined diylheterocyclyl' preferably refers to a carbocyclic or heterocyclic ring. Usually such a heterocyclic group and carbon A cyclic group is a monocyclic ring having 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6-membered ring fused to a 4-membered ring, a 5-membered ring or a 6-membered ring. Typical such groups include CrCs rings. Alkyl, phenyl, benzyl, tetrahydronaphthyl, fluorenyl, arachidyl, heterocyclic, such as aziridine cycloheptyl, azacyclooctyl, pyrrolidinyl, piperidinyl, morpholinyl , thiomorpholinyl, piperazinyl, porphyrinyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazole Base, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, fluorenyl, benzofuranyl, benzoquinone, benzene Indazole group, benzoxazolyl, benzoxazolyl, benzoxazole, quinolyl, tetrahydroquinolyl, isoquinolinyl, tetrahydroisoquinolinyl, quinol 115688.doc -32 - 20080 0149 Porphyrin group, tetrahydroquinazolinyl group and quinoxalinyl group, either of which may be substituted as defined herein. Thus, a saturated heterocyclic ring includes a group such as a pyrrolidinyl group, a pyridyl group, a pyrazolinyl group, a pyrazolyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piper group. , thiopyranyl, piperazinyl, porphyrinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, 1,4, 5,6-tetrahydropyrimidinylamine, dihydrooxazolyl, i,2-thiazolidine-1,1-dioxide, 1,2,6-thiadiazepine a vaporized, isodecyl-1,1-dioxide and an imidazole, 4-di-unsaturated heterocyclic ring including a group having an aromatic character, such as a fluorenyl group, an anthranyl group, Laroki, 嗤 嗤, 嗟 基, imipenyl, σ 嗤 、, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetradecyl, oxime, bite A group, a fluorenyl group, a pyrimidine group, a quinone group, a fluorenyl group, a fluorenyl group, a hydrazinyl group, a hydrazinyl group, and a heterocyclic group. Under various conditions, the heterocyclic ring may be condensed with a benzene ring to form a bicyclic ring system. The compound can form a salt which forms another aspect of the invention Suitable pharmaceutically acceptable salts of the compounds of formula I include the salts of organic acids, especially the carboxylates, including but not limited to acetates, trifluoroacetates, lactates, gluconates, citrates, Tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, two Gluconate, cyclopentanoate, glucoheptanoate, glycerol phosphate, oxalate, heptanoate, acid salt, fumarate, nicotinate, palmitate, pectic acid Salt, phenylpropionate, picrate, pivalate, propionate, tartrate, milk 115688.doc '33- 200800149 saccharate, pivolate, camphorate, undecanoate and succinic acid Salt; organic lactate, such as methanesulfonate, ethanesulfonate, hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, besylate, p-chlorobenzenesulfonate And p-toluenesulfonate; and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, hemisulfate, thiocyanate Salts, persulfates, phytates, and sulfonates. In some cases, the compound of the formula can be isolated as a hydrate. It should be understood that the present invention encompasses the prodrug, solvate, and error of the release of the compound in vivo. And other forms. The active agent may be administered alone, but is preferably provided as part of a pharmaceutical formulation. The formulation will comprise an active agent as defined above and one or more acceptable carriers/fudies. And other therapeutic ingredients as the case may be acceptable for compatibility with the other ingredients of the formulation, and the carrier is acceptable and harmless to the recipient. The formulations include those suitable for transrectal administration. Formulations for nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably, the formulation is formulated orally. Things. The formulations may conveniently be presented in unit dosage form, such as lozenges and sustained release capsules, and may be prepared by any of the methods known in the pharmaceutical art. The methods include the step of associating an active agent as defined above with a carrier. In general, the formulations are prepared by uniformly and finely associating 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 encompasses a method of preparing a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, in association with or pharmaceutically acceptable carrier or vehicle, 115688.doc-34-200800149 . If the pharmaceutical formulation is made by finely mixing the pharmaceutical excipient with the active ingredient in the form of a salt, it is generally preferred to use an excipient which is non-alkaline (i.e., acidic or neutral) in nature. The formulation for oral administration in the present invention may be provided in a discontinuous I-form, such as a capsule, a sachet, or a spin each containing a predetermined amount of the active agent, which may be provided in the form of a powder or granules. Provided in the form of a solution of the active agent in an aqueous liquid • I non-aqueous liquid (IV); or in the form of an oil-in-water or water-in-oil emulsion, and in the form of a bolus Wait. With regard to compositions for oral administration (eg, lozenges and capsules), the term suitable carrier includes vehicles such as ordinary excipients such as binders such as syrup, acacia, gelatin, sorbitol, Yellow gum, polyethylene, sputum (Pcmdone), methyl cellulose, ethyl cellulose, sodium sulfonate cellulose, sucrose and starch; fillers and carriers, • For example, jade: starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin glycol alcohol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium sulphate, sodium stearate and other metals Fatty acid, stearic acid glycerol - 曰 日 I I, Shi Xi oxygen fluid, talc, 4, oil and colloidal dioxide dioxide. Flavoring agents such as mint, wintergreen oil, cherry flavor or the like may also be used. It may be possible to add a coloring agent to make the dosage form easy to identify. The tablet may also be coated by a method well known in the art. Or a variety of compounding agents can be compressed or molded together, and the left-handed tablet can be borrowed. The active agent in a free-flowing form (such as powder or H5688.doc -35- 200800149 granules) is compressed in a suitable machine, optionally with a binder, lubricating N (raw diluent, preservative, surfactant or dispersion) The preparation of the syrup 1 syrup can be prepared by molding a mixture of the powdered compound in an appropriate machine and moistening the mixture with an inert F* raw liquid diluent. The rotatory agent may be coated or scored, and may be formulated. To provide a slow release or controlled release of the active agent. Other formulations of the two-portion tablet include an oral active agent comprising the active agent in a flavoring base (usually sucrose and gum arabic or tragacanth); An active agent in an inert matrix (such as gelatin and glycerin or sucrose and gum arabic); and a mouthwash comprising the active agent in a suitable liquid carrier. The appropriate dosage will depend on the indication and the patient. It is easy to determine by conventional animal drug metabolism and pharmacokinetics (DMPK) or clinical trials and computer prediction software. In the treatment of HIV, the compound of formula I usually obtains about 1 〇〇 to 5 〇〇〇 nM ( The amount of plasma is administered, for example, from 300 to 2000 nM. Depending on the bioavailability of the formulation, it is equivalent to about 0. 01 to 10 mg/kg/day, preferably 〇1 to 23⁄4 g/kg/day. To the rate of music. The typical feeding rate for normal adults is about 0.05 to 5 grams per ounce, preferably 0. 1 to 2 grams (such as 500-750 milligrams), and one to four dose units per ounce. Like all medicines, give The drug rate will vary depending on the size of the patient and the metabolic conditions and the severity of the infection, and may require adjustment for co-administration. In general, each person is divided into 1 to 3 single doses of about 3 mg to about 1.6. The dose of gram is appropriate. The typical dose for adult patients is 5〇-8〇〇, 115688.doc -36- 200800149 more preferably 400-600 twice daily or optimal once a day. As described below, HIV inhibitors are usually administered in unit dosage form together with other HIV inhibitors or metabolic modulators, and the modes of administration of such co-administered drugs (QD, BiD, TiD, fasting/concomitant eating, etc.) are of course It is desirable to simultaneously adjust the mode of administration of Formula I. f As a good prescription for antiviral therapy, the compound of formula I is usually co-administered with other HI V therapeutic agents to avoid the development of drug resistant mutants. However, certain anti-infective agents induce a synergistic response, allowing one or both of these active ingredients to be administered at a lower dose than the corresponding monotherapy. For example, in the drug Cyp3 A4, which is susceptible to rapid metabolism, co-administration with the HIV protease inhibitor ritonavir may allow for administration of lower doses. The compounds of the present invention and each of the other antiviral agents are usually co-administered with a molar ratio of their respective activities and bioavailability. In general, the ratio is from about 25:1 to 1:25 relative to the compound of formula I, but may be lower, e.g., in the case of a cytochrome antagonist such as ritonavir. Representative HIV antiviral agents include: NRTI, such as alovudine (FLT), udoudoviidine (AZT, ZDV), stavudine (d4T, Zerit), Tashi Hebin. (zalcitabine) (ddC), didanosine (ddI, Videx), abacavir (ABC, Ziagen), lamivudine (3TC, Epivir), Android Emtricitabine (FTC ' Emtriva), racevir (racemic FTC), adefovir (ADV), entacavir (BMS 200475), alovudine (FLT) ), tenofovir 115688.doc -37- 200800149 disoproxil fumarate (TNF ' Viread) amdoxavir (DAPD), D-d4FC (DPC-817), -dOTC (Shire SPD754) ), Afstabin 〇 1 ¥ 11 (^ 钍 1311 ^) (eight. 111111 〇 11 eight (: 11-126443), BCH 10681 (Shire), SPD-756, raxivir, MIV- 606 (Medivir), D-FDOC, GS7340, INK-20 (thioether phospholipid AZT, Kucera), 2V31-dideoxy-3'-fluoroguanosine (FLG) and its prodrugs (such as MIV-210), Leva Reverset (RVT, D-D4FC, Pharmasset D PC-817) 〇_ Representative NNRTI includes delavirdine (Rescriptor), efavirenz (DMP-266, Sustiva), nevirapine (BIRG-587, Viramune), (+ ) calano[ide A and B) (Advanced Life Sciences), capravirine (AG1549f S-1153; Pfizer) > GW-695634 (GW-8248; GSK), MIV-150 (Medivir), MV026048 (R-1495; Medivir AB/Roche), NV_05 2 2 (Idenix Pharm·), R-278474 (Johnson & Johnson), RS-1588 (Idenix Pharm·), TMC_ Xin 120 /125 (Johnson & Johnson), TMC_125 (R_165335;

Johnson & Johnson) > UC-78 l (Biosyn Inc.) and YM215389 (Yamanoushi) o Representative HIV protease inhibitors include? 8-457 (卩311&〇〇8), 1^0 2 (Kucera Pharm.), 5 HGTV-43 (Enzo Biochem), amprenavir (VX-478, Agenerase), atazanavir (atazanavir) (Reyataz), indinavir sulfate (MK-639, Crixivan), Lexiva (Fusanavir 115688.doc -38- 200800149 #5 (fosamprenavir calcium), GW -433908 or 908, VX-175),

Ritonavir (Norvir), lopinavir, lopinavir + ritonavir (ABT-378, Kaletra), telanavir, nelfinavir, and nelflnavir Mesylate) (Viracept), saquinavir (Invirase, Fortovase), AG1776 (JE-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), P (PL) _ 100 (P -1946; Procyon Biopharma), P-1946 (Procyon

Biopharma), R-944 (Hoffmann-LaRoche), RO-0334649 (Hoffmann-LaRoche), TMC-114/D aruna vir (Tib otec/Johns on & Johnson), VX-385 (GW640385) ; GSK/Vertex), VX-478 (Vertex/GSK). Other HIV antiviral agents include entry inhibitors, including fusion inhibitors, CD4 receptor inhibitors, CCR5 co-receptor inhibitors, and CXCR4 co-receptor inhibitors, or pharmaceutically acceptable salts or prodrugs thereof. Examples of entry inhibitors are: \10-070 (eight^1011070; eight 11 (^)^^4), 61〇^^8 1 (16/«1 (ADVENTRX Phann.), BMS 806 (BMS-378806) ; BMS), Enfurvirtide (T-20, R698, Fuzeon), KRH1636 (Kureha Pharmaceuticals), ONO-4128 (GW-873140, AK-602, E-913; ONO Pharmaceuticals), PRO-140 (Progenies

Pharm), PRO-542 (Progenics Pharm.), SCH-D (SCH-417690; Schering-Plough), T-1249 (R724; Roche/Trimeris), TAK-220 (Takeda Chem. Ind.), TNX-35 5 115688.doc -39- 200800149 (Tanox) and UK_427,857 (Pfizer). An example of an integrase inhibitor is! ^ 870810 (Merck & Co·), c-2507 (Merck & Co.) and S(RSC)-1838 (shionogi/GSK) ° Many HIV patients are simultaneously infected or susceptible to repeated infections with other infectious diseases. Accordingly, another aspect of the invention provides a combination therapy comprising a compound of the invention co-formulated in the same dosage unit or co-encapsulated with at least one other anti-infective drug. The compound of the present invention and at least one other anti-infective agent can generally be administered simultaneously or sequentially in a dose equivalent to a single therapeutic dose of the agent. Typical co-infections or repeated infections include hepatitis B virus (HBV) or hepatitis C virus (HCV). Thus, the compounds of the invention are advantageously co-administered with at least one HCV antiviral agent and/or at least one HBV antiviral agent (in the same dosage unit, co-encapsulated or separately prescribed dosage unit). Thus, the compounds of the invention are advantageously co-administered with at least one HCV antiviral agent and/or at least one HBV antiviral agent (in the same dosage unit, co-encapsulated or separately prescribed dosage unit). Examples of HBV antiviral agents include lamivudine and 2f, 3f-dideoxy-31-fluoroguanosine (FLG) and prodrugs thereof, such as 5'-0-chymidylisohumamamine sulfhydryl prodrug MIV. -210. These HBV antiviral agents are particularly suitable when they have both anti-HBV and HIV activity. Examples of HCV antiviral agents for co-administration with Formula I include immunomodulators such as ribavirin or interferon, nucleoside HCV polymerase inhibitors or HCV protease inhibitors, many of which are currently under development. . The compounds of the present invention are believed to counteract the high LDL-cholesterol and/or triglyceride levels typically present as side effects of the prior art HIV protein 115688.doc -40-200800149 enzyme inhibitor. Thus, the compounds of the invention are suitable for use in replacing such prior art inhibitors in the mode of administration in which the patient is performing. Typically, the patient has experienced or is undergoing antiretroviral therapy with one or more conventional HI V protease inhibitors and exhibits high plasma LDL-cholesterol and/or triglyceride levels. The other HIV protease inhibitors may be used as monotherapy or as antiretroviral therapy (which also includes one or more other antiretroviral drugs, such as reverse transcriptase inhibitors or non-nucleoside reverse transcriptase inhibitors). Part of it is given. These candidate inhibitors, while exhibiting satisfactory viral suppression, may increase the risk of hyperlipidemia and early cardiovascular events. The term 'high plasma LDL-cholesterol and triglyceride content' as used herein is based on the Clinical Cholesterol Education Program (NCEP) clinical practice guidelines for the prevention and management of high cholesterol in adults. In the latest guidelines issued in 2001, the content of LDL cholesterol > 150 mg/dL triglyceride in plasma was considered high. The method of the present invention is particularly applicable to patients whose plasma triglyceride content > 200 mg/dL and those having an <160 mg/dL LDL-cholesterol content but no risk factors or cardiovascular events as described above. As NCEP is continuing to assess risk factors for heart attack, the definition of "high" LDL-cholesterol and triglyceride content may of course change in the future. Therefore, it is desirable to use the term "high LDL-cholesterol and triglyceride content π in accordance with current NCEP guidelines.

In one aspect thereof, the invention comprises disabling the protease inhibitors from the above regimen (drugs causing high plasma LDL-cholesterol and/or triglyceride levels) HIV 115688.doc -41 - 200800149, and thus Substituting a compound of formula j effective to inhibit HIV and reduce plasma LDL-cholesterol and/or triglyceride levels. The dosage of the compound of the present invention depends on factors such as the body weight, age and individual conditions of the patient to be treated, and the manner of administration. The compounds according to some embodiments of the present invention may advantageously interact with cytochrome 450 monooxygenase in certain formulations and may improve the pharmacokinetics of the drug metabolized by the enzyme, particularly Other HIV protease inhibitors are included, such as saquinavir, gram flu, nelfinavir, _ phenavir, telanavir, and lopinavir. Thus, it can act in a similar manner to ritonavir as described in U.S. Patent No. 6, 37,157 to increase the blood content of co-administered HIV protease inhibitors. Conveniently, and in contrast to ritonavir, the compounds of the present invention can be used in combination therapy with other HIV protease inhibitors at normal therapeutic dose levels other than the subtherapeutic dose levels used in ritonavir. Any synergistic effect on other HIV protease inhibitors metabolized by cytochrome (10) monooxygenase may allow the compound of & $ to be accompanied by such other HIV protease inhibitors: thereby allowing the use of such Other HIV protease inhibitors reduce the dose while maintaining the same degree of viral inhibition. It is envisaged that the compounds of the invention may be used in combination with other HIV protease inhibitors to reduce LDL-cholesterol and triglyceride levels in AIDS plaques undergoing protease inhibitor therapy while still maintaining the desired degree of viral inhibition. The appropriate dose of the mv protease inhibitor of the combination of the two compounds of the present month is determined by the method used for the combination of the atazana (tetrazide) and the following as disclosed in W〇03〇2〇2〇6. Atazanavir is a moderate inhibitor of cytochrome P450 3A enzyme comparable to nelfinavir and 115688.doc -42- 200800149 grams, with a Ki of 2.4 μΜ. At steady state, the latter two compounds increased the exposure of zanzanvir administered 1200 mg three times daily (TID) by 392% and 364%, respectively. A multi-dose pharmacology study was performed to assess whether a similar increase was expected for the combination of azafene and saquinavir. This study demonstrates that exposure to a combination of atazanavir is more than three times greater than that of the currently marketed savannavir regimen of 1200 mg TID, supporting a daily dose of 1200 mg of saquinavir. The dose range of saquinavir was studied using a constant dose of atazanavir with a target similar to the amount of saquinavir exposure (AUC (area under the curve) and CMIN (minimum concentration)) in their literature. Similarly, an appropriate dose of other HIV protease inhibitors to be used in combination with the compounds of the invention can be calculated. The compounds of the invention are typically synthesized as outlined below. The preparation of cis-aminoindanol is described in detail in the literature and many are commercially available. The preparation of cis-aminochromanol is shown in Biorg Med Chem Lett 2005 15 5311-5314 and Biorg Med Chem Lett 2004 14 4651-4654. Suitable intermediates for the preparation of compounds of the formula (I) wherein L is NH2 are α,α-disubstituted amino acids according to Khalil et al., J. Med. Chem., 42, (1999), 2977. The procedure modified by the method described in -2989 is prepared as illustrated in Scheme 1. 115688.doc -43- 200800149

The appropriately protected amino acid with the desired side chain R1 can be converted to the oxazolidinone (lb) by treatment with benzaldehyde diacetal in the presence of a Lewis acid such as BF3xOEt2. An olefinic alkylating agent (for example, an alkenyl halide, such as an olefin chloride, bromide or iodide of a suitable chain length, that is, an allyl halide for preparing a compound wherein η is 1 and used for the preparation of η The buty-3-alkenyl i) of the compound of 2 is alkylated with an oxazolidinone to give an α,α-dialkyl group. Occasion ketone (1 c). Alkaline hydrolysis of the lactone is achieved by treatment with a hydroxide solution (e.g., sodium hydroxide in decyl alcohol, or an analog thereof) to provide an alpha, alpha-dialkylated amino acid (Id). The compound of formula (I) is then prepared from an unsaturated acid as illustrated in Scheme 2.

Process 2 115688.doc -44- 200800149

In the presence of a base such as n, n-diamine (th. A) in a solvent such as dimethylformamide (DMF), or in the case of the material known as the technical towel (iv), for example, using 0_( a reagent for the determination of the above acid (Id) to the desired amine Α··ΝΗ2 (1 Η 幷 幷 丨 丨 基 基 基 & & & & & & & & & & & ( ( ( ( ( ( ( ( ( ( ( Wherein a, as defined above, provides a guanamine derivative (2a). In the presence of a catalytic amount of a molybdenum moth, oxidative cleavage of the double bond is achieved by a suitable reagent such as a high (tetra) nanoparticle to give ^(2b)' The ruthenium derivative (2d) is obtained by reacting 15(2b) with the desired cultivating derivative (2c) in a reductive amination ruthenium using any suitable reducing agent such as NaBH(〇Ac)3 or the like. The amine protecting group is removed using standard methods well known in the art, for example, when a B〇c or Cbz protecting group is used, optionally treated in the presence of phenyl hydrazine (eg, TFA) to give the first amine derivative. (2e). As is well known to those skilled in the art, the synthetic steps of the compounds of the invention and the introduction of various moieties can be carried out in any suitable order. For example, the acyl hydrazine portion (2c) may be introduced into the amine A'-NH2, as illustrated in Scheme 3.

a,-nh2

3b

Hatu DIEA

Scheme 3 115688.doc •45- 200800149 as described in Scheme 2 'oxidation of the double bond of the acid (ld) to the corresponding 叩a), followed by reductive amination with hydrazine (2c) to give hydrazine (3b) . The guanamine (2e) is then obtained by coupling the peptide to the desired amine a, -nh2 as described in Scheme 2. Alternatively, an unsubstituted or optionally a temporary N-protected anthracene derivative is used in the reductive amination step of Schemes 2 and 3, and then the nitrogen-nitrogen substituent -CHyR2 is introduced, as in Scheme 4 Aldehyde 2b is exemplified.

Process 4

The disk was reacted with the first anthracene derivative (4a) in a reductive amination reaction as described in μ private 1, to obtain hydrazine (4b). Next, an N-substituent CH2-R2 can be introduced by alkylation of the β-nitrogen of hydrazine with the desired alkylating agent r2'_CH2-X, wherein R2 is as defined above for R2 or R2 is subsequently a group which can be converted to R2, and X is a leaving group such as a halide such as a chloride, bromide or iodide, or a sulfonic acid derivative such as a triflate, a formazan or The benulinic acid salt gives the alkylated compound (4c). Alternatively, the introduction of an N-substituent can be achieved by reaction with an aldehyde in reductive amination using any suitable reducing agent such as NaB(〇Ac)3 or the like, if desired, by means of alkylation or by reduction The first amine of the compound if is alkylated one or two times by amination or any other suitable method described in the literature, in the literature, in the literature, to obtain a compound of formula (I) wherein L is NHCCVCOAlk or NCCrCJAll. Compounds of formula (I) wherein ϋ is 1, L is F and XgF4〇H are conveniently prepared from intermediate cyclic monofluoro or difluoro derivatives which can be synthesized as shown in Scheme 5.

0s04 NMMO

Scheme 5 A commercially available ethyl acetoacetate ethyl acetate is alkylated by standard methods well known in the art, and then the ring closure is effected by treatment with bromine at elevated temperature as appropriate to give the lactone (5a). Amination with pyrrolidine, followed by reduction with a reducing agent such as NaCNBH3 or the like, affords the olefin (5b) which is subsequently dihydroxylated using any suitable oxidation system (eg Os04-NMMO) to give Hydroxylactone (5c). The obtained dihydroxy lactone (5c) is treated with sulfinium chloride in the presence of triethylamine, and treated with tetrabutylammonium fluoride in the presence of RuC13 and NaI04 to obtain fluoroquinone (5d), and the dihydroxy group is The ester is treated successively with DAST, diisopropylamine-HF-complex to give the difluoro compound (5e). 115688.doc -47- 200800149 The resulting fluorine-based derivatives (5d) and (5e) can then be further reacted as shown in Scheme 6.

The cyclic fluoro derivative (6a) is ring-opened with the desired amine A'-NH2 to give the alcohol (6b). The first alcohol is selectively oxidized to the corresponding aldehyde using any suitable reagent such as Dess-Martin high-breaking, followed by reductive amination with an appropriate anthracene derivative as described above to give hydrazine (6C). The various amines A, _NH2 used in the above schemes are commercially available or can be prepared according to literature procedures. For example, it can be like B.

An amine of formula (IV) wherein A, conforms to formula (IV), is prepared as described by Samuelsson et al., Bio. Med. Chem" 11, 2003, pp. 1107 - 1115. Alternatively, it can be converted from the corresponding alcohol Af-OH to This can be prepared by an amine group. This conversion can be achieved by any suitable method known to the skilled person, for example by converting a mesogenic group to a leaving group such as a halide such as bromide, chloride or moth; or sulfonic acid. a derivative, such as a methanesulfonate, trifonite or tosylate, followed by a nucleophilic displacement reaction with the azide, and finally the azide using any suitable reduction method such as catalytic hydrogenation Reduction to an amine. Suitable alcohols are described in AK Gosh et al., J. Med. Chem., 1996 39, 3278-3290, 〇 115688.doc -48- 200800149 Preparation of an amine α'_ΝΗ2 in which A' conforms to formula (IV) Another alternative is illustrated in Flow 7.

(<D 7a NBS oxidation (€rBr 7b X is 〇 or S, η is 1 or 2 «ξι 4 0-benzylic-based 7d A w 7e Process 7 Bu3SnH AIBN

Os〇4 NalO,

LiAIH4

For example, the addition of a bromide and a propargyloxy group to a double bond of an unsaturated ring (7a) is carried out by reaction with N-bromosuccinimide and propargyl alcohol, followed by a radical initiator (for example, 1, The reductive ring closure reaction is initiated by hydrogenation of tri-n-butyltin in the presence of 1'-azobis(isobutyronitrile) or an analog thereof to produce a bicyclic olefin (7C). The olefinic compound is then subjected to oxidative cleavage by subjecting the olefinic compound to a suitable oxidizing condition, such as a combination of iron sulphate and sodium sulphate, to obtain a _derivative (7d). The resulting ketone group is reacted with a benzyl group-based amine, followed by reduction with a reducing agent such as hydride, to give the corresponding amine (5) as a racemic mixture. The racemic mixture is then separated according to procedures known in the art. For example, a standard peptide coupling method can be used to prepare a diastereomeric mixture which can be separated by chromatography using a palmitic auxiliary compound such as a palmitic amino acid such as phenylalanine. The mixture is separated and the auxiliary amino acid is cleaved to give the pure diastereomer of the desired amine (7f) from 115688.doc -49 to 200800149. An example of the preparation of the amine derivative A'-NH2 used in the scheme 1 is shown in the following Scheme 8, wherein Y conforms to the formula (II).

R4—NH2 8b

EDC NMM HOBT

8 c

8d process 8

N-protected with the desired side chain R3 (eg, Boc protection) using standard peptide coupling conditions, such as the use of coupling reagents (such as EDAC, NMM, and HOBT) in an inert solvent such as dimethylformamide The amino acid (8a) is coupled with an amino derivative (8b) wherein R3 and R4 are as defined above to give the decylamine (8c). The N-protecting group is removed by acid treatment in the presence of a Boc protecting group, for example, by trifluoroacetic acid in dichloromethane to give the amine (8d). The amino acid (8a) used in the above scheme is commercially available or it can be prepared according to literature procedures. A method of preparing an amino acid having a branched side chain is exemplified in Scheme 9.

Scheme 9 115688.doc -50- 200800149 The amino acid (9a) obtained will be described in one or two times as described by Rapoport et al., J. 〇rg. Chem., 55, (1990) pp. 5017-5. A continuously added base such as bis-(tridecyldecylalkyl) decylamine potassium (KHMDS) and methyl iodide are treated to obtain a monomethylated or dimethylated amino acid (9b), respectively. The side chain ester is reduced using a reagent such as DIBAL, and then the exchange of the PhF1 group with the Boc group is carried out by catalytic hydrogenation in the presence of B〇C2〇 and a catalyst such as pd/c to obtain an alcohol (9c). If desired, the hydroxyl group of the resulting alcohol can then be methylated, e.g., by treatment with an appropriate hydrazylating agent such as methyl and a treatment such as NaH to give the methoxy compound (9e). Alternatively, the alcohol can be converted to the corresponding fluoro-based compound (9d) by treatment with a fluorinating agent such as dast or the like, or any other suitable fluorination method as described herein or elsewhere can be used. As exemplified in Scheme 10, an amine A, _NH2 wherein A, conforms to formula (ΠΙ) can be prepared.

Old CF NMM nh4oh BTI pyridine nh4oh Η2ΝγΝ R3 10d

h2nWw, R5 R3 Ο 10 c Η) cl, xR5 «Ο 0=C=N

Y R5 Scheme 10 The natural or unnatural amino acid (10a) having the appropriate side chain Han 3 as defined above is reacted with the (iv)ing agent, and the desired brewing agent is used to form a compound in which w is ruthenium. Chlorophthalic acid vinegar (i); acid chloride (ii) used to form a compound in which w is a bond or an isomeric acid used to form a compound thereof as a dish at 200800149 (111) 'to obtain an acid (l〇b) . Next, the acid (10b) is converted to the corresponding first guanamine by treatment with an ammonia solution in a solvent such as dimethoxyethane in the presence of isobutyl _ & N-methyl morpholine. 〇c), and then the rearrangement reaction is carried out by treatment with [bis(trifluoroethyloxy)iodo]benzene in the presence of pyridine (eg J_A. Fehreentz, J. Med. Chem., 2003, 46, 1191-1203) In the above), the amine A^NHdlOd) is obtained.

The anthracene derivative R2CH2NHNHC) used in the above scheme can be produced by reacting an acid A"c〇〇H or a derivative thereof (e.g., acid chloride or acid anhydride) with hydrazine R2CH2NHNH2 under standard peptide coupling conditions. Scheme 1 shows an example in which A'' in the acid A''COOH conforms to the formula (v) as defined above.

i, ii or m i) Cl R8 Ο 11b η2ν Η /N, ^R2 11c

EDC HOBT NMM

Ii) Civ, R9 T O 〇 iii) 〇=c=N \ R9

Scheme 11 The natural or non-natural amino acid (11a) bearing the appropriate side chain R8 as defined above is reacted with the desired oximation agent as described in Scheme 3 to provide the acid (8b). Then, using the standard peptide coupling conditions as described above, an anthracene derivative (11 sentences is obtained by coupling with a commercially available or commercially available anthracene derivative (11c). wherein A1' conforms to formula (VII) The compound can be conveniently prepared according to the above route, but in the reaction with the amino acid 11a, in the presence of a base such as sodium hydroxide, the use of, for example, a sulphur-based acid chloride r9-S (=0) 2 C1 is suitable for continued brewing. The agent replaces any of the agents i, ii or iii of 115688.doc-52-200800149, wherein the AM conforming to the formula (VI) can be suitably made by using a chlorophthalate or an activated carbonate. The electrophilic carbonyl compound is prepared by reaction with the hydrazine derivative r2CH2NHNH2 (as illustrated in Scheme 12).

OH A dipyridyl ester O-C Et3N ^

Ry 12a 10 Scheme 12 The alcohol (12a) can be reacted with a suitable oxime (such as a carbonate such as dipyridyl carbonate, or p-nitrobenzene) by the presence of an appropriate oxime such as a carbonate such as triethylamine or imidazole. The chloroformate is converted to the corresponding activated carbonate (12b) or gas phthalate, or converted to chlorodecanoate by reaction with carbon chlorohydrazine in the presence of a base such as sodium bicarbonate. . Next, the obtained electrophile compound is reacted with the desired anthracene derivative (12c) to give the corresponding oxime (12d). Alcohol (12a) is commercially available or can be as J. A. K. Ghosh et al.

Prepared as described in Med. Chem., 1996, 39, 3278-3290. For example, the stereochemical synthesis of bis-THF alcohol (that is, the alcohol according to formula i2a, wherein Ry and the adjacent c atom together define a fused furan ring) is described in WO2003 having a corresponding method suitable for mirroring imitation organisms. The procedures described in Scheme 22 of /22853 and W005/63770 can also be applied to other alcohols, such as optionally substituted carbocyclic methanol, optionally substituted heterocyclic methanol, optionally substituted carbocyclic ring. a base alcohol or a optionally substituted heterocyclic alcohol, thereby obtaining 115688.doc -53 - 200800149 wherein A, a hydrazine according to the formula (νΠΙ) as defined above. The synthesis of unsubstituted anthracene (4a) is described in the literature, see for example J. Med. Chem. 1998, 41, page 3387, and a general example thereof is shown in Scheme 13.

The EDC recognizes that NH is also T-recognition and H+ is re-entered. Human N, NH2 + ΗΟ8 A"——^ 八Α·. Η I, 13a 13b 13c 4a Scheme 13 # The standard peptide coupling reaction procedure can be used to make commercially available tert-butyl carbazate (13a) A" The acid (13b) as defined above is coupled to give the corresponding Boc protected oxime (13c). Removal of the Boc group by TFA treatment using standard conditions such as acidic treatment, for example, treatment with TFA to give deprotected oxime (4a), a compound of formula (1) wherein the R2 group is a substituted aryl group Substituting a substituent after the synthesis by using a suitable anthracene derivative having the desired R2 group in any of the above schemes, or by using any suitable method known in the literature. A method of addition to an aryl group is exemplified in Scheme 14

Process 14 115688.doc -54· 200800149 Palladium such as Pd(PPh3)2Cl2 or its analog is used in the presence of CuO in a solvent such as dimethylformamide, for example, by means of microwave heating. (0) A reagent in which an aryl group of the compound (14a) is substituted with, for example, an aryl group or a heteroaryl group such as a pyridyl group by reacting with a tri-n-butyltin derivative of a desired substituent in a coupling reaction. While Scheme 14 illustrates the aromatic substitution on the indoleamine derivative (ALNH-C(=0)-), it will be appreciated by those skilled in the art that the same procedure can be applied to the corresponding acid derivative. In addition, it should be further recognized that the strategy described in Scheme 13 is not limited to pyridyl groups, but is also applicable to other optionally substituted alkyl, aryl or heteroaryl groups. At the same time, it should be recognized that for the substitution of the R2 group, many other methods widely described in the literature can be used. a compound wherein R1 or R2 is usually substituted at the para position of the phenyl R1 or R2 moiety with a 2-mercapto pyrazole-4-ylmethoxy residue, usually by 2-methylthioben-4-yl Methyl chloride alkylation corresponding benzene was prepared. The substituent may introduce Ri or R2 prior to coupling of the Ρ1/Ρ2 and ΡΓ/Ρ2' basic components, for example, when lactone lb or 5a or 醯肼11c or 12c is prepared. A suitable synthetic monomer for the 2-methyl-oxazol-4-ylmethoxy substituent of R1 or R2 is a phenol whose hydroxy group is protected by a benzyl protecting group, because under atmospheric pressure, under neutral conditions, The benzyl protecting group is readily removed by, for example, H2/palladium catalysis to activate the phenolic hydroxyl group without substantially accompanying activation of other hydroxyl functional groups on the backbone to permit coupling with the alkylating agent. The following general conditions are generally used: 2-methylthiazole_4_ylmethylene chloride, 25 called CsC〇3, a cacao, 80 C, 2-4 hours. Similar alkylation conditions and representative routes for the synthesis of R2 methylene chloride reagent 115688.doc -55-200800149 are reported in J Med Chem 1992 1688. Additional guidance is provided in WOOO/76961 and JOC 2000, 65(22) on page 7464. However, if other first or second hydroxyl groups are present, such as in the indole alcohol amine V, protection is required. Any functional group present in any of the component compounds used to prepare the compounds of the present invention may be suitably protected as necessary. For example, a functional group on a natural or non-natural amino acid can generally be suitably protected as in peptide synthesis. Those skilled in the art should be aware of the choice of appropriate protecting groups and their use depending on the reaction conditions. Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York In (1981), the disclosures are incorporated herein by reference. [Embodiment] Various embodiments of the compounds of the invention and key intermediates of such compounds will now be referenced to the accompanying non-limiting chemical and biological The examples are described by way of illustration only. Chemical methods. General information. Using MeCN as a mobile phase in 0.05% HCOOH aqueous solution, Chromolith Performance RP-18e 4.6x100 mm (Merck KGaA) at a flow rate of 4 mL/min Pipe column, analytical RP-LC-MS was performed on a Gilson HPLC system equipped with a Finnigan AQA quadrupole mass spectrometer. MeCN in a 0. 05% HCOOH aqueous solution was used as the mobile phase, and at a flow rate of 15 mL/min, Zorbax was used. SB-C8, 5μπι 21.2x150 mm (Agilent technologies) column, performing preparative R on a Gilson HPLC system 115688.doc -56-200800149 equipped with a Finnigan AQA quadrupole mass spectrometer P-LC-MS. Optical rotation was obtained on a Perkin-Elmer 241 polarimeter, the specific rotation (〇] D) is reported in deg/dm, and the concentration (c) is given in g/100 mL in a specific solvent. The 1Η and 13C NMR spectra were recorded on a Varian Mercury Plus instrument at 300 and 75.45 MHz or 399.78 and 100.53 MHz. The chemical shift was reported as a delta value (ppm) indirectly referenced to TMS via the solvent residual signal. In Merck Shiki 60 ( Flash column chromatography was performed on 40-63 μηι) or Merck Shijiao 60 RP-18 (40-63 μηι). Analytical thin layer chromatography was performed using an aluminum sheet precoated with silicone 60 F254. A solution of phosphomolybdic acid in ethanol, followed by heating of the visual component. Analytische Laboratorien, Lindlar, Germany, performing elemental analysis 0 Example 1: Synthesis of {1-(S)-[N'_[3-(S)·Aminos_3 -((lS,2R)-2-hydroxy-indan-1-ylamino)-4-phenyl-butyl]-NL(4-pyridin-3-yl-benzyl)-fluorenylcarbonyl 】-2,2-Dimethyl-propyl-ammonium carbamate step a

[1-(S)-Benzyl-l-((lS,2R)-2-hydroxy-indan-1-ylaminocarbamimidyl)·benzyl-3-butenyl bromide (la) (2S)-N-(Hydroxycarbonyl)-2-allylphenylalanine (0.97 g, 2.86 mmol) prepared as described in J. Med. Chem. 42, (1999), 2977_2987 A solution of 1S,2R)-cis-1_amino-2-indanol (0.427 mg, 2. 86 mmol) in DMF (20 mL) was cooled to 0. HATU (1_03 115688.doc -57-200800149 g ' 2.86 mmol) was added in one portion, followed by the addition of hydrazine, hydrazine-diisopropylethylamine (2·5 ml '1 7 3 mm 〇 1). The reaction mixture was placed in a crucible. The mixture was stirred for 2^ and then diluted with DCM. The resulting solution was washed with water, saturated NaCICl 3 and concentrated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut !H NMR (CDC13): 7.36 (m5 4H)5 7.3-7.15 (m5 8H)5 7.〇(m,2H),6_52(m,m),5.85(m,lH),5.44(m5lH),5.25 -5.12 (m,3H), 4.95 (m5 2H), 4.71 (m,1H), 3.38 (AB q,2H), 3.06 (AB m,2H),2·72 (br,1H),2.56 (AB m , 2H). Step b

{1-(S)-Benzyl-l-((lS,2R)-2-hydroxy-indan-1-ylaminecarbinyl)·3-[Ν,_(2-(8)-methoxy Benzyl-amino-amino-3,3-dimethyl-butanyl)-;^-(4_0 butyl-3-yl-benzyl)-mercaptopropyl}-benzyl carbamate (lb) 〇°C, NaIO4 (0.544 g, 3.2 mmol) and catalytic amount (~2.5 mol%) of Os〇4 were added to compound la (0.6 g, 1-28 mmol) in THF/H2O (10 ml, 4 :1) in the solution. After stirring for 4 h, the solution was extracted with EtOAc (EtOAc)EtOAc. The obtained aldehyde and decyl {1-(8)-[Ν'-(4-oxaridin-3-yl-benzyl)-fluorenylcarbonyl]- 2,2-dimercapto-propyl-p-carboxylate (0.472 g, 1.28 mmol) was dissolved in 115688.doc • 58-200800149 1,2-dichloroethane (20 ml) and stirred for 20 min. NaBH(OAc)3 (0·81 g, 3.82 mmol) was added in three portions over 1 h, and the mixture was stirred for 1 h. The reaction was quenched by the addition of water, followed by washing with brine and evaporation in vacuo. The residue was purified by EtOAc (EtOAc (EtOAc) MS (ESI+): m/z 827 (M+l)+ 〇 Step c

{1-(S)_[N'-[3_(S)_Amino-3-((lS,2R)_2_hydroxy-indan-1-ylamine-methyl)-4-phenyl-butyl Methyl pyridine-3-yl-benzyl)-fluorenylcarbonyl] 2,2-dimethyl-propyl-propylcarbamate Compound lb (95 mg, 0.12 mmol), benzoic acid at ambient temperature A solution of the ether (26 μM, 0.24 mmol) and tris-sodium sulphate (36 μM, 0.42 mmol) in DCM (3.5 ml) The reaction mixture was diluted with EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc) eluting MS (ESI+): m/z 693 (M+l) + NMR (CDC13): 8·76 (br·s,1Η),8·58 (br·s,1Η),7·94 (d,1H) ), 7.78 (d, 1H), 7.5-7.05 (m, 15H), 6·76 (bn s, 1H), 115688.doc • 59 - 200800149 5.28 (m, 2H), 4.38 (m, 1H), 4.16 (d,1H), 3.95 (d,1H),3·61 (m,3 + 1H), 3.26 (d,1H),3·11 (m,2H)5 2·92 (m,2H),2 · 61 (d, 1H), 2·44 (m, m) 5 1.70 (br. m, '4H), 〇 · 82 (s, 9h). Example 2: Synthesis of {1-(8ΜΝ,_[3-(8)·Amino-3_((1S 2r) 2 hydroxyindan-1-ylaminocarbamoyl)-4-phenyl-butyl babi 2,2,2-methyl-propyl}-carbamic acid for the purpose of: bit a

U-(S)-nodal group-l-((lS,2R)-2-yl-based-small-small-amine-based mercapto) small [N,_

Benzyl)-mercapto]-propyl-K benzyl carbamate (2a) {(S)-l-[N'-(4-bromo-benzyl)-fluorenylcarbonyl]_2,2-dimethyl Methyl propyl propyl carbamate was reacted with compound ia according to the procedure described in Example 1 step b to give the title compound (33%). MS (ESI+): m/z 828, 830 (M+l) + 〇lH NMR (CDC13): 7.6-7.0 (m, 22H)5 5.42 (m5 1H), 5.14 (m,3H),4·65 ( m,1H), 3.87 (d,1H), 3.65 (d5 1H), 3.59 (m, 1H), 3.55 (s, 3H), 3·47 (m, 1H), 3.3-2.9 (m, 5H), 2·6 (br.m, 2H), 2.00 (m5 2H), 0_64 (s, 9H) 〇Step b 115688.doc -60- 200800149

{1-(S)-Benzyl-l-((is,2R)-2-hydroxy-indan-1-ylaminoindolyl)-3-[N,-(2-(S)-oxime Benzyl-carbonylamino-3,3-dimethyl-butanyl)-N-(4-pyridin-2-yl-benzyl)-indenyl]-propyl- propyl carbamate (2b) and

X

{1-(8)-[]^'-{2-[4-(8)-]-benzyl-1-((18,2)-2-yl------1-yl)-2, 5-tertiary oxy-imidazolidine-4-yl]•ethyl}-N'-(4-pyridyl-benzyl)·nonylcarbonyl]-2,2-dimethyl-propylamino Methyl formate (2bb) Compound 2a (58 mg, 0.07 mmol), 2-(1,1,1-tri-n-butyltinpyrenepyrene (51 mg, 0·14 mmol) and CuO (ll mg, 〇 · 14 mmol) The mixture in DMF ( 2 m 1 ) was degassed with argon for 5 min. Pd(PPh3)2Cl2 (2.4 mg, 5 mol%) was added and the reaction mixture was heated at 120 °C for 2 h. The mixture was diluted with ethyl acetate, washed with EtOAc EtOAc (EtOAc m. Purification of % CH3CN in water (15 min) gave compound 5 (19 mg, 33%) and compound 6 (8 mg, 15%). Compound 5 MS (ESI+): m/z 827 (M+l)+ Compound 6 MS (ESI+): m/z 719 (M+l) + 〇H NMR (CDCls): 8.67 (d5 1H)5 8.44 (br.s, 1H), 7.94 (d5 2H), 7.73 (dt, 1H) 7.66 (d,2H)5 7.29 (m,4H), 7.21 (m,5H), 115688.doc -61- 20080 0149 7·04 (m,1H), 6.54 (br.s,1Η),6·23 (d,1H), 5.29 (d,1H), 5·19 (d,1H),4.51 (m,1H) , 4.08 (d, 1H), 3.68 (d, 1H), 3.61 (s, 3H), 3.58 (d, 1H), 3.09 (m, 3H), 2.87 (m, 4H), 2.00 (m, 2H), 0.72 (s, 9HV. Step c

{l-(S)-[Nf-[3-(S)-Amino-3-((lS,2R)-2-hydroxy-indan-1-ylaminocarbamoyl)-4-phenyl- Butyl]-N '_ ( 4 - σ 淀 _ 2 _ yl - benzyl) _              2 Prepared by treating compound 2b according to the method described in Example 1, step c. MS (ESI+): m/z 693 (M+l)+. lH NMR (CDCI3): 8.63 (d5 1H)3 8.06 (br. d5 1H), Ί.12-7.66 (m,3H), 7.52 (d,1H), 7.40 (d,2H), 7.32-7.19 (m , 7H), 7.02 (m, 2H), 6.92 (m, 2H), 6.79 (br. s, 1H), 5.33 (m, 1H), 5.10 (m, lH), 4.28 (t, lH), 4.05 ( d5lH)5 3-94 (d,lH),3.7-3·6 (s+m,3H+1H), 3.27 (d,1H),3·04 (m,2H), 2.79 (m, 2H), 2.57 (d, 1H), 2.34 (br. m, 1H), 1.85 (br. m, 3H), 0.92 (s, 9H). Example 3 Synthesis of 1-(S)-benzyl-1-[1-(S)-methylaminecarbamimido-2,2-dimethylpropyl]amine 115688.doc -62- 200800149 Mercapto- 3-[N'-(2-(S)-nonyloxycarbonylamino-3,3-dimercaptobutyl)-N-(4-bromobenzyl)indolyl]propylamine: Step a

{1-(S)-Benzyl-1-carboxy-3-[N,-(2-(S)-methoxycarbonylamino-3,3-dimethyloctanyl)-N-(4- Benzyl bromide) benzyl] propyl} carbamic acid benzyl ester (3 phantom at 0 C NaI04 (512 mg, 2. 5 mmol) and catalytic amount (~2.5 mol%) of Os〇4 was added to (2S) -N-(benzyloxycarbonyl)_2-allylphenylalanine (prepared as described in J. Med. Chem. 42, (1999), 2977-2987) (373 mg, 1.00 mmol) in THF/H20 ( In a solution of 15 ml '4:1). After 5 h of stirring, the solution was evaporated to a small volume, diluted with water (1 () melon), extracted with EtOAc (20 ml) and organic extracts were combined And dried over Na2SCM~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -(S)-[N,-(4-bromobenzyl)indolylcarbonyl]-2,2-dimethylpropyl}carbazinate (447 mg, 1.20 mmol) dissolved in 1,2-di Ethyl chloride (8 ml) and stirred at RT for 1 h. NaBH(OAc)3 (3 18 mg, 1.5 mmol) was added in three portions over 0.5 h and the mixture was stirred for 2 h. (5 ml), CHC13 (10 ml) and water (10 Ml) was diluted and stirred for 15 min. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo. The title compound (656 mg, 94%) was obtained as a white foam. MS (ESI.): m/z 697/ 699 (M+l) + l NMR (CDC13): 7.4-7.0 (m5 16H) 3 6.3 (br s? 1H), 5.6 (br s, 1H), 5.22 and 5.06 (AB q, 2H), 3.90 and 3.75 (AB q, 2H), 3.70-3.62 (m, 3 + 1 H) , 3.47 and 3.16 (AB q, 2H), 2.95 (dispersion m, 1H), 2.72 (dispersion m, 1H) 5 2.53 (m5 1H), 2.14 (m, 1H), 0.79 (s, 9H) 〇Step b

U-(s)-benzyl-l-[l-(s)-methylamine-mercapto-2,2-dimethylpropyl]amine-mercapto-3-[N,-(2-( S)-Methoxycarbonylamino-3,3-dimethylbutanyl)-water (4-bromobenzyl)decyl propyl propyl carbamate (3b) Compound 3a (210 mg, 0-30 mmol) , (S)-T-butylglycine N-methylguanamine (90 mg, 0.36 mmol), H0BT.H20 (; 27 mg, 0.20 mmol) and triethylamine (ι〇! mg, loo mmol) Dissolved in dichloromethane (1 〇 ml) and added EDAC (92 mg, 0.48 mmol). After stirring overnight, ethyl acetate (20 ml) and aq. NaHC. After stirring for a few minutes, brine (5 ml) was added and the organic phase was washed with 2×5 mL of saturated KH2P04 aqueous solution, dried (^2804) and evaporated. The title compound (123 mg, 115688.doc -64 - 200800149 50%) 〇MS (ESI+): m/z 823/ was obtained by chromatography on EtOAc: EtOAc: 825 (M+l)+ 〇rH NMR (CDC13): 8·17 (br s,1H),8·0 (br d,1H), 7.4-7.0 (m,14H),6.74 (br s,1H) ,6·44 (bi* s,1H),5.71 (br d,1H), 5·17-5·02 (AB q,2H), 4.28 (d,1H),3.91 (d,1H),3.84 ( d, ; 1H), 3.63 (s + d, 3 + 1H), 3.55 (d, 1H), 3.35 (d5 1H)5 2.92- yield 2.80 (m, 2H), 2,78 (d, 3H), 2.23 (m, 1H), 2.02 (m, 2H), 1.06 (s, 9H), 0·73 (s, 9H). Step c

1-(S)-benzyl·1-[1-(8)-nonylaminocarbamimido-2,2-dimethylpropyl]amine-carbazino-3_[N'-(2-(S )-methoxycarbonylamino-3,3-dimethylbutylidene)-N-(4-bromobenzyl)indolyl]propylamine (3c) Compounds in DCM (3 ml) at ambient temperature 3b (80 mg, 0.097 mmol), anisole (21 mg, 0.194 mmol) and trifluoromethanesulfonic acid (81 mg, 0. 54 mmol) were stirred overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The title compound (59 mg, 88%) 〇MS (ESI+): m/z 689/691 (M+l) + 〇H NMR ( (C. s. 1H), 7.7 (br. 5·47 (d,1H), 4.24 (br·d,1H), 3.93 and 3.74 (AB q,2H), 3.87 (d,1H), 3.65 (s,3H), 3.20 (d,1H) , 2.98 (dispersion m, 1H), 2.75 (d, 3H), 2·68 (d, 1H), 2·6 (dispersion m, 1H), 2·25 (m5 1H), 1·9 (br· s , NH2), 1.76 (m, 1H), 0.98 (s, 9H), 0.83 (s5 9H). Example 4

{1-(S)-Benzyl-1-carboxy-3-[N,-(2-(S)-methoxycarbonylamino-3TM-dimethylbutanyl)-Ν-(4-(4) ·"Byridinyl" benzyl) fluorenyl] propyl guanidino citrate vinegar (4) Compound 3a (70 mg, 0·10 mmol), 4 ton. Benzylboronic acid (31 mg, 0.25 mmol) A mixture of triethylamine (66 mg, 0.66 mmol) and PEPPSI (7 mg, 0.01 mmol) in DME + H20 + Et0H 7:3:2 (1 ml) was reacted in a microwave oven at 140 ° C for 1 h. After cooling, ethyl acetate (3 ml) was added and the mixture was washed with 2×1 mL of saturated aqueous K.sub.2H.sub.4.sub.4, dried (Na.sub.2.sub.4) and evaporated to a small volume. The title compound (20 4 mg, 29 3%) was obtained.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2H), 7.5-7.0

(m, 17H), 6.15 (br. s, 1H), 5.45 (b, d) 1H), 5.28^5.04 (AB q, 2H), 4.56 (br. d, 1H), 3.89 (d, 1H), 3.7-3.6 (m, 3+2 H), 3.41 (d, 1H), 3.11 (d, 1H), 2.88 (t, 1H), 2.70 (d, 1H), 2.40 115688.doc -66- 200800149 (t , 1H), 0.70 (s, 9H) 〇 Example 5

{i-(s)-benzylcarbonyl_3-[N, gas 2_(s)-methoxycarbonylamino-3,3-dimethyl

Benzyl hydrazide, benzylidene, benzyl, hydrazino, propyl, benzyl carbamate, benzyl ester (5) The title compound (25 mg, 36β/sequence and 3-pyridylboronic acid) was obtained according to the procedure of Example 4.反MS (ESI.): m/z 696 (M+1), !H NMR (CDCls): 8.54-8.49 (m 7.3 and 7.2-7.0 (m, 17H), 6.22 (br, s2H ), 7.78 (4) 1H), 7.45- 5.26 Λ 5.07 (AB q, 2H), 4.36 (ds lH H), 5'4? d, 1H), , 3 ), 3·95 (d, 1H), 3.7 -3.55 (m,3+2 H),3.31 (d,1H),3.13 ^ ιυΛ 〇^ ιχτλ π 7W γλ ' 1JI), 2.90 (t,1H),2·65 (d,1H),2·34 (t, 1H), 0.75 (s, 9jj). \ " ό ό ό -1- -1- 基 -1- ) ) -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- [N'-(2-(S)-methoxycarbonylamino-3,indenyl)indenyl]-propyl-N-methylamine: Step a 115688.doc -67- 200800149

Benzyl l-(s)-benzyl-1-(carboxy)allyl-N-decylaminocarbamate (6a) 60% sodium hydride (440 mg, 11 mmol) in oil first with n-pentane The mixture was washed and then added in small portions to (2S)-N-(benzyloxycarbonyl)·2·allyl-phenylalanine (e.g., J. Med. Chem. 42, (1999), 2977-2987. (144; 680 mg, 2.0 mmol) and a stirred solution of thiol (1·〇ml, 16 mmol) in 6 mL anhydrous THF. After 3 days at RT, the mixture was cooled with ice water and 0.55 ml of water was added dropwise. After 0.5 h of mixing at RT, 10 drops of 2 M aqueous NaOH and 1 ml of MeOH were added to obtain a homogeneous solution. After a further 2 h, a portion of the solvent was removed in vacuo and the residue was washed with EtOAc EtOAc (EtOAc) Drying over Na.sub.2SO.sub.4 and evaporation in vacuo gave an oil which solidified to a pale yellow solid. Yield of the title compound: 644.5 mg (91%). MS (ESI+): m/z 354 (M+l)+. Step b

2-benzyl-2-(benzyloxycarbonyl-methyl-amino)-4-oxo-butyric acid (6b) NaI〇4 (943 mg 5 4.4 mmol) and catalytic amount at 〇 °C (~2.5 mol%) of 0s04 was added to a solution of olefin (6a, 623 mg, 1.763 mmol) in THF/H20 (25 nd, 4:1). After stirring for 5 h, the solution was evaporated to EtOAc (30 mL). The organic extract was dried over NazSO4 and concentrated in vacuo to afford crude aldehyde as a white solid. MS (ESI+): m/z 356 (M+l)+. Step c

{1-(S)-Benzyl-1-carboxy-3-indole N'-(2-(S)-nonyloxycarbonylamino-3,3_: f butyl fluorenyl)-fluorene-(4-(4) -η-pyridyl)benzyl)indenyl]propyl benzyl N-methylcarbamate (6c) Crude aldehyde (6b) and {l-(S)- with acetic acid (120 mg, 2.0 mmol) [N,-(4-Mo benzyl)decylcarbonyl]-2,2-dimercaptopropyl} carbamic acid hydrazine vinegar (745 mg, 2.0 mmol) was dissolved in 1,2·dichloroethane (15 ml) and stirred at RT for 1 h. Sodium hydride triacetate (5 30 mg, 2.5 mmol) was added in aliquots over 5 h and the mixture was stirred for 2 h. The reaction mixture

Diluted with EtOAc (7 ml), CH.sub.3 (15 ml) and water (15 ml) and stirred for 15 min. The organic phase was washed with brine, dried over Na.sub.2.sub.4, and evaporated in vacuo. The title compound (359 mg) was obtained as a white foam. MS (ESI+): m/z 711 / 713 (M+l)+. Step d 115688.doc -69- 200800149

{1-(S)-Benzyl-l-((lS,2R)-2-hydroxyindan-1-ylaminocarbamoyl)-3-[N'-(2_(S)-methoxycarbonyl Benzyl-3,3-dimercaptobutyl)-N-(4-bromobenzyl)indolyl]propyl-N-methylcarbamic acid benzyl ester (6d) acid (6d, 78.mg·, 0.11 mmol), (lS, 2R)-(-)-cis-1-amino-2-indanol (25 mg, 〇·164 mmol), ΗΟΒΤ·Η2Ο (10 mg, 0.074 mmol) and triethylamine (33 mg, 0.33 mmol) was dissolved in dichloromethane (3 ml) and EDAC (30 mg, 0.154 mmol). After stirring overnight, ethyl acetate (5 ml) and aq. NaH.sub.3 (2 mL). After stirring for a few minutes, brine (2 ml) was added, and the organic phase was washed with 2x 2 ml of saturated aqueous solution of ΚΗβΟ4, dried (Najcu) and evaporated to a colorless glass. Si〇2 column chromatography was carried out with 2.5-53⁄4 MeOH in CH2C12 to afford title compound (19 mg, 20.5%). MS (ESI+): m/z 842/844 (M+l)+ 〇 step e

1-(8)-Benzyl-1-((18,211)-2-hydroxyindan-1-ylaminocarbamoyl)_3_[]^,_(2-(S)-methoxycarbonylamino- 3,3-Dimethylbutylidene bromoxybenzyl) decyl 1 propyl-N-methylamine (6e) 115688.doc -70- 200800149 Compound (6d, in DCM (1 ml) at ambient temperature 13 mg '0.0154 mmol), phenyl ether (30 mg, 0.28 mmol) and trifluoromethanesulfonic acid (50 mg, 0.33 mmol) were stirred overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The title compound (7·67 mg, 70%) was obtained from EtOAc EtOAc EtOAc MS (ESI.): m/z 708/710 (M+1). !H NMR (CDC13): 8.2 (br. d3 1H), 7.7 (br. s, 1H)? 7.40- 7.07 (m, 2+5+2H), 6.54 (br·s, 1H), 5·47 ( d,1H), 4.24 (br·d,1H), 3.93 and 3.74 (AB q,2H), 3.87 (d; 1H), 3.65 (s,3H), 3.20 (d,1H), 2.98 (m,1H) ), 2·75 (d, 3H), 2.68 (d, 1H), 2.6 (m, 1H), 2.25 (m, 1H), 1·9 (br·s, NH2), 1.76 (m, 1H), 〇·98 (s, 9H), 0·83 (s, 9H) 一般 General procedure for the preparation of sorghum benzyl 肼 x 2 HCl and Et 3 N in EtOAc (20 mL) It was then added to a solution of the N-functional amino acid (below), EDAC, HOBT and NMM in EtOAc (40 mL), and then the mixture was stirred overnight at room temperature. Diluted with EtOAc, washed with EtOAc EtOAc (EtOAc)EtOAc. Purine, CHCl3/MeOH, 100:0-95:5). Example 7

115688.doc -71 - 200800149 [(lS)-l-(Nf-Benzyl-fluorenylcarbonyl)-2-methyl-propyl]-carbamic acid benzyl ester (7) using Cbz-(L)-缬Amino acid (0,540 g, 2.15 mmol), EDAC (0.450 g, 2.35 mmol), HOBT (0.320 g, 2.37 mmol), hydrazine (0·260 mL, 2.36 mmol), benzyl hydrazine x 2 HCl (0.500 g) The title compound (0.52 g, 66%) was obtained. [a] D21-41.7° (c 0.35, MeOH/CH 2 Cl 2 5 (h 50); MS (m/z 356, Μ + H+); Anal·(C2〇H25N303) C,H,N. 4 NMR (DMSOd6 + 2 Drop D20) δ 7.42-7.18 (m5 10H), 5.01 (s, 2H), 3·82 (s5 2H), 3·72 (d, J = 7.61, 1H), 1·83 (m5 1H), 0.78 ( d, J = 6·86, 3H), 0.76 (d, J = 6.86, 3H); 13C NMR (DMSO-d6 + 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. Example 8

[(IS)-l-(N'-Benzyl-fluorenylcarbonyl)-2,2-dimethyl-propyl]-carbamic acid benzyl ester (9) using Cbz-(L)-third amine Acid (2.00 g, 4.48 mmol), EDAC (0.969 g, 5.05 mmol), hydrazine (0·669 g, 4.95 mmol), hydrazine (0·542 nxL, 4.93 mmol), benzyl 肼χ 2Η (:1 (0·962 g, 115688.doc -72-200800149 4·93 mmol) and Et3N (1.3 8 mL, 9.85 mmol) were subjected to the above general procedure for the preparation of hydrazine to give the title Compound (L11 g, 67%) [a]D19 _17_50 (c 1·〇5 CHC13); MS (m/z 370,M + H+); Anal· (C2iH27N3〇3) C,H,N 〇!H NMR (CD3OD) δ 7.38-7.15 (m3 10H), 5.05 (d5 J = 12.3 Hz, 1H), 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, 129.2, 128.9, 128.7, 128.3, 67.6, 62.5, 56.2, 35, 2, 27·0 〇Example 9

[(lS)-l-(N'-Benzyl-fluorenylmethyl-propylaminomethyl decanoate (10) using hydrazine-(methoxycarbonyl)-(L)-terinic acid ( 1.1^(1.(:1^111.,39,3203-3216,1996) (2.11 g, 12.0 mmol), EDAC (2.41 g, 12.6 mmol), hydrazine (1·70 g, 12·6 mmol), The above procedure for the preparation of hydrazine was carried out by hydrazine (1·38 mL, 12·6 mmol), benzyl hydrazine x2HC1 (2.45 g, 12.6 mmol) and Et3N (3.52 mL, 25.0 mmol) to give a pale yellow solid. The title compound (2.08 g, 65%). [m] D19 -45.5. (c 1.0, CHC13); MS (m/z 280, Μ + H+, 559); Anal· (C14H21N303) C, Η, N. .doc -73- 200800149 1H NMR (CDC13) δ 8.00 (s,1H) 7.40-7.25 (m,5H),5·50 (d,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), 0·94 (d, J = 4·94 Hz, 3H), 0.92 (d5 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. Example 10

[(lS)-l-(N'-Benzylfluorenylcarbonyl)_2,2-dimethyl-propyl]-carbamic acid methyl ester (11) using Ν-(methoxycarbonyl)_(L)_ Third leucine (J. Med. Chem., 41,

3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g, 9.08 mmol), hydrazine (1·22 g, 9.03 mmol), NMM (0.995 mL, 9.05 mmol), benzyl hydrazine The title compound (i, 2i g, 50%) was obtained as a pale yellow solid. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj [a]D19 ·40·7. (c 0.98, CHC13); MS (m/z 294, Μ + H+); Anal·(C15H23N3O3) C,H,N 〇!H NMR (CDCI3) δ 8.07 (s5 1H) 7.38-7.24 (m3 5H)? 5.63 (d, J = 9.64 Hz, 1H), 4.95 (s5 1H), 4.00 (d5 J = 12·4 Hz, 1H)5 3.95 (d, J = 12.4 Hz, 1H), 3.92 (d, J = 9_64 Hz,1H), 3-68 (s3 3H)5 0.98 (s, 9H); 13C NMR (CDC13) 6170.25 157.1, 115688.doc -74- 200800149 137.3, 128.9, 128.4, 127.6, 61.1, 55.8, 52·3 , 34.5, 26.4 〇 Example 12,

1-benzyl-3_[(lS)-l-(Nf.benzyl-indenylcarbonyl)-2,2-dimethyl-propylidene (13) (L)-third leucine ( 0.500 g, 3.81 mmol) was dissolved in dioxane (23 mL) and 2 M NaOH (6_3 mL, 12.6 mmol). After stirring for 10 min, phenyl isocyanate (0.900 mL, 7.29 mmol) was added dropwise to give a transparent solution. The reaction mixture was stirred at room temperature for 18 h, then was then taken to EtOAc EtOAc EtOAc. The organic phase was dried and evaporated to give (2S)-2-(3-benzyl-ureido)-3,3-didecyl-butyric acid (0.36 g, 36% yield). And can be used without further purification. Next, crude (2S)-2-(3-benzyl-ureido)-3,3-dimercapto-butyric acid (0.646 g, 2.44 mmol), EDAC (0.515 g, 2.67 mmol), hydrazine (0·) was used. 363 g, 2.69 mmol), hydrazine (0·300 mL, 2.73 mmol), hydrazine 肼x2HCl (0.528 g, 2.71 mmol) and Et3N (0.753 mL, 5.38 mmol) were used to prepare the above-mentioned hydrazine. General procedure. The product was filtered through a short ceria column (CHCl3 / MeOH, 100:0 - 95:5) and then used in the next step without further purification. 115688.doc -75 - 200800149 Example 13

{(lS)-l_[N'-(4-Bromo-benzyl)-fluorenylcarbonyl]-2,2-dimethyl-propyl}-carbamic acid methyl ester (14) N-(oxime Carbonyl)-(L)-third leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.74 g, 9.20 mmol) was dissolved in EtOAc (50 mL) and EDAC (1.94 g) , 10.1 mmol), HOBT (1.37 g, 10.1 mmol) and NMM (1.11 mL, 10.1 mmol). The reaction mixture was stirred at rt for 30 min then EtOAc (EtOAc (EtOAc) 2·3 1 g, 11.5 mmol), and continue to disturb overnight. The reaction mixture was washed with aq. EtOAc (aq.). The crude product was purified by EtOAc EtOAcjjjjjjj [a] D22 -26.4. (c 0.84, MeOH); Anal. (Ci5H22BrN3〇3) C, Η, N 〇4 NMR (CD3OD) δ 7·45 (m, 2H), 7.29 (m, 2H), 3·90 (s5 2H)5 3.81 (s5 1H)5 3.64 (s5 3H)5 0.90 (s5 9H); 13C NMR (CD3OD) δ 170.5,157.9,137.2,131.3,130·8,121.0, 61.7, 54.2, 51·5,33.9,25· 8; MS (m/z 372, Μ + H+, 374, Μ + Η+). 115688.doc -76- 200800149 Example 14

UlS)-l-[Nf-(4-bromo-p-]-mercaptocarbonyl bromide 2-methyl-propyl- propylaminocarbamate (15) Cbz_(L)-proline (1_〇 4 g, 4·14 mmol) was dissolved in EtOAc (50 mL), and EDAC (〇87〇g, 4 54 mm〇1), H〇BT (〇61〇g '4.51 mm〇i) and hydrazine ( 0·500 mL, 4·55 mmol). The reaction mixture was stirred at room temperature for 30 min then EtOAc EtOAc (EtOAc) After evaporating the solvent, CHCI3 was added, and the solution was washed with saturated NaHC03 (aq.) and brine, then dried (Na2SO4), filtered and evaporated. The crude product was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (c 0.47, DMF); MS (m/z 434, Μ + H+, 436, Μ + H+); Anal· (C20H24Bi: N3O3) C,H,N 〇4 NMR (DMSO-d6 + 2 drops D20) δ 7.53-7.18 (m,9H), 4.98 (s,2H), 3.79 (s,2H), 3.69 (d,J = 7·65 Hz,1H),1·80 (m, 1H)5 0.75 (d5 J = 6.92 Hz, 3H)3 0.72 (d3 J = 6.92 Hz3 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. 115688.doc -77- 200800149 Example 15 Synthesis of l-(s)-benzylmethylamine fluorenyl 2,2-dimethylpropyl] Amidino-3-[N'-(2-( S)-methoxycarbonylamino-3,3-dimethylbutanyl)_1^-(4-(4-acridinyl)benzyl)indolyl]propylamine Step a

{1-(S)-Benzyl-1-[1-(S)-methylaminecarbamimido-2,2-dimethylpropyl]aminecarbamyl_3-[N,-(2- (S)-methoxycarbonylamino",3. dimethylbutanyl)_n_(4-(4-acridinyl)benzyl)indolyl]-propyl} benzyl carbamate (15 cores performed for The procedure described for compound 3b was synthesized, but using acid 4 (14 8 , (Mm3 mm 〇 1) in place of acid 3a. Si〇2 column chromatography was carried out with 25-5% Me〇H in CH 2 Cl 2 to give the title compound. (63 mg, 36%). MS (ESI+): m/z 822 (M+l) + 〇. Step b

L-(s)·cleavage group-1-[1-(S)-methylamine-mercapto-2,2-dimethylpropyl-l-amine-methyl-3-yl-[N,_(2_(8)-- Oxydylamino-3_3,3-dimethylbutyryl)_n (4_115688.doc -78 - 200800149 (4 bite base)) fluorenyl]-propylamine (15b) according to Example 6 Step e The procedure described in the Cbz group was removed from compound 15b (6.3 mg, 0.00766 mmol). The title compound (4.6 mg, 93%) 〇 MS (ESI+): m/z 688 (M+l)+ was obtained from EtOAc EtOAc. lH NMR (CDC13): 8.2 (br. d5 1H)5 7.7 (br. s5 1H)5 7.40-7.07 (m, 2 + 5+2H), 6.54 (br.s, lH), 5.47 (d, lH) , 4.24(br·d,1H),3·93 and 3.74 (AB q,2H),3.87 (d,1H),3·65 (s,3H), 3.20 (d,1H),2.98 (m,1H) ), 2.75 (d5 3H), 2.68 (d, 1H), 2.6 (m, 1H), 2.25 (m5 1H), 1.9 (br· s5 NH2), 1.76 (m, 1H), 0.98 (s, 9H), 0.83 (s, 9H). Example 16 Synthesis of {1-(S)-benzyl-{l-((lS,2R)-2-hydroxyindan_{l-ylaminemethanyl:)-3-[Ν*-(2-( 8) Benzyloxycarbonylamino-3(3-dimethylbutylidene)-N-(4-bromobenzyl)indolyl]-propyl}amino phthalic acid benzyl ester: Step a

"-(S)·Benzyl-{l-((ls,2R)-2.hydroxyindan-1-ylaminocarbamoyl)-3_[Nf_(2-(S)-methoxycarbonylamino) _3,3_Dimercaptobenzyl bromobenzyl) benzylidene propyl} carbamic acid benzyl ester (16a) Compound 3a (31.5 mg, 0.0452 115688.doc -79-200800149 mmol) was treated as described in Example 3, step b. ), but using (1 S,2R)-(-)-cis-1 1-amino-2-indanol (11 mg, 0.074 mmol) instead of (S)-t-butylglycine N-methyl The title compound (23·6 mg, 63%) was obtained from EtOAc (EtOAc): m/z 828/830 (M+l) Step b

{1-(S)-Benzyl-{1-((1S,2R)_2-hydroxyindan-1-ylaminocarbazyl)-3-[Nf-(2-(S)-methoxycarbonyl) Benzyl-3,3-dimethylbutylidene)benzyl)indenyl]-propyl}aminobenzyl phthalate (16b): Compound 16a (22.8 mg, 0.0275 mmol), 4-port ratio Frequent acid (17. 5 mg, 0.142 mmol), triethylamine (15 mg, 0.15 mmol) and PEPPSI (2 mg, 0.003 mmol) in DME + H20 + Et0H 7:3:2 (0.6 ml) The mixture was reacted in a microwave oven at 140 ° C for 1 h. After cooling, ethyl acetate (2 ml) was added and the mixture was washed with 2×0.5 ml of saturated aqueous KH 2 〇 4 aqueous solution and 1 ml of aqueous EDTA, dried (Na 2 SO 4 ) and evaporated to a small volume. The title compound (8.0 mg, 35%) was obtained from EtOAc eluting eluting MS (ESI+): m/z 827 (M+l) + 〇 Step c 115688.doc -80- 200800149

1-(S)-benzyl-l_((1S,2R)-2-hydroxyindanylamine-ylamino)-3_[ν,_(2-(S)-methoxycarbonylamino-3 , 3_Dimethylbutyridinylpyridinyl) acetonyl]-propylamine (16c) Compound 16b (8 〇mg, 0.00967 mmol) was deprotected according to the procedure described in Example 6 Step e. The title compound (4.2 mg, 62.7%) was obtained from EtOAc EtOAc EtOAc EtOAc MS (ESI+): m/z 693 (M+l)+. lU NMR (CDC13): 8.2 (br. d, 1H)? 7.7 (br. s5 1H)5 7.40- 7·07 (m, 2 + 5+2H), 6.54 (br·s, 1H), 5.47 (d ,1H), 4.24 (br. d,1H),3·93 and 3.74 (AB q,2H)5 3·87 (d,1H),3.65 (s,3H), 3·20 (d,1H ), 2·98 (m, 1H), 2.75 (d, 3H), 2·68 (d, 1H), 2.6 (m, 1H), 2.25 (m, 1H), 1·9 (br·s, NH2) ), 1.76 (m, 1H), 〇 · 98 (s, 9H), 0.83 (s5 9H) 〇 Example 23 Step a)

5,6-Dihydro-cyclopenta[b]thiophene-4-one (23a) A solution of trifluoromethanesulfonic anhydride (84·7 g, 0.30 mol) in DCE (300 mL) over a period of 10 min. Add to a cold solution of N,N-dimercaptopropenylamine (29·8 115688.doc -81-200800149 g, 0.30 mol) in DCE (2700 mL). The mixture was stirred at 〇 ° C for 15 minutes. A solution of porphin (25.3 g, 0.30 mol) was added and the mixture was refluxed for seven hours. Add potassium carbonate solution (150 g in 2000 mL water). 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%. W-NMR CDC13 7.32 (dd, 1H), 7.14 (dd, 1H), 3.20 (m, 2H), 3.00 (m, 2H). Step b

5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one (23b) 5,6-dihydro-cyclopenta[b] in MeOH (1000 mL) at about 5 °C Thiophen-4-one (36.8 g, 0·266 mol) was added to a solution of 85% potassium hydroxide (52.7 g, 0.798 mol) in MeOH (500 mL). Iodobenzene diacetate (94.4 g, 0.293 mol) was added portionwise between 0 ° C and 5 ° C, and the mixture was allowed to return to room temperature. The mixture was stirred overnight at room temperature. The mixture was evaporated and a 20% solution of potassium carbonate (500 mL) was added. The mixture was extracted several times with DCM, dried over sodium sulfate and evaporated. The residue was dissolved in 1,4-dioxane (400 mL) and water (150 mL) The mixture was stirred at room temperature for two hours. The mixture was neutralized by the addition of potassium carbonate and extracted four times with dichloromethane. The organic phase was dried over sodium sulfate 115688.doc - 82 - 200800149 and evaporated under reduced pressure. The product was crystallized from ethyl acetate ethyl acetate. Yield: 33.5 g = 81.6% 0 iH-NMR CDC13 δ 7·36 (dd, 1H), 7.18 (d, 1H), 4.76 (m5 1H), 3·64 (m, 2H), 3.10 (m, 1H) . Step c

5-hydroxy-5,6-dihydro-cyclopenta[b]thiophenone oxime-benzyl-indole (23c) Ο-benzylhydrazine hydrochloride (38.3 g, 0.240 mol) was added to 5-hydroxy-5, 6-Dihydrocyclopenta[b]a ceto-4-ol (33.4 g, 0.216 mol) in a solution of 11 唆 (300 mL), and the mixture was stirred at room temperature for a week. The mixture was evaporated under reduced pressure and co-evaporated twice with toluene. Ethyl acetate was added and the organic phase was washed with 5% citric acid and brine. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Yield: 55.1 g = 98%. ^-NMR CDCI3 δ 7.40-7.20 (m5 7H)? 5.20 (m5 3H), 3.45 (m, 2H), 3.0 (m5 1H). Step d

cis-amino-5,6-dihydro-4H-cyclopenta[b]porphin-5-ol (racemate) (23d) 5-hydroxy-5,6-dihydro- in about 5 art Cyclopenta[b]thiophenone oxime-benzyl _ 115688.doc -83- 200800149 A solution of (5 5.1 g, 〇·212 mol) was added dropwise to a solution of κο M in THF (650 mL). And the mixture was stirred overnight at room temperature. The mixture was refluxed for two hours and cooled to about 5 〇c. Water (7 〇 mL) and 20% potassium hydroxide solution (80 mL) were added dropwise. The mixture was refluxed for two hours and cooled. Brine was added and the THF was removed under reduced pressure. The mixture was extracted five times with DCM, dried over sodium sulfate and evaporated. The product was purified by DCM and 10% methanol by chromatography. Yield: I?』g = 54% W-NMR DMSO-d6 δ 7.30 (d, 1H), 6.92 (d, 1H), 4·46 (m, 1Η), 4·20 (m, 1Η) 3.99 -3.84 (dd5 2Η) Example 24 Separation of the enantiomer from Example 23 Step a

[1-(5-Hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ylaminocarbazyl)-2-phenyl-ethyl]-amino decanoic acid tert-butyl ester (24a) Boc-L-phenylalanine (30.51 g, 0.115 mol), HOBT (15.6 g, 0.115 mol) and EDAC (22.0 g, 0.115 mol) were added to the racemic cis-4-amino-5,6 - a mixture of dihydro-4H-cyclopenta[b]thiophene (17. 5 g, 0.112 mol) in anhydrous DMF (400 mL). TEA (16 mL, 0-115 mol) was added to the stirred mixture and the mixture was stirred overnight at room temperature. The mixture was added to 5% citric acid and extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium bicarbonate (twice). 115688.doc -84· 200800149 The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Production · 43 95%.里· g step called b)

Private base - Ν-(5 · benzyl _5,6 · bismuth _4H_cyclopenta [b] fluorenyl) _3 phenyl propyl amide (24b) compound 24a > glutathion in chloroform (400 In mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for three hours. The organic phase was washed twice with 2 〇乂 / / 谷 谷 (30 〇 mL) and brine. The organic phase was dried over sodium sulfate and evaporated. The product was purified by gel chromatography using DCM and 3% to 1% methanol. Yield A: 12.5 g of the first diastereomer = 40%. Yield B: 12.5 g of the second diastereomer = 40%. Step c〇

NH2 nh2 4-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-5-ol (24c) The first diastereomer (12.4 g, 41 mmol) was dissolved in EtOH (400) A solution of <RTIgt; </ RTI> <RTIgt; </ RTI> in water and in water (g 〇〇 mL). The mixture was refluxed overnight. The ethanol was removed and the base phase was extracted six times with DCM. The organic phase was washed with brine, dried over sodium sulfate, &lt;RTI ID=0.0&gt;&gt; Yield: 6.2 g = 97%. ^-NMR DMSO-d6 δ 7.30 (d5lH)3 6.92 (d3 1H)5 4.46 (m5 1H), 4.20 (m, 1H), 3.99-3.84 (dd, 2H). Example 25

{(lS)-l-[N'-(3-Bromo-benzyl)-fluorenylcarbonyl]-2,2-dimethyl-propyl-p-aminocarbazate (25) N-(methoxy Carbonyl)-(L)-third leucine (3.25 g, 17.1 mmol) was dissolved in EtOAc (40 mL) and then EtOAc (2·55 g, 18.9 mmol), EDAC (3.62 g, 18.9) Methyl) and NMM (2.08 mL, 18·9 mmol). To the reaction mixture was added 3-bromo-benzyl hydrazine (4·14 g, 20.6 mmol) dissolved in EtOAc (20 mL). The organic phase was washed with saturated aHC.sub.3 (aq. 50 mL), H.sub.2 (50 mL) and brine (50 mL). The combined aqueous phases were extracted with EtOAc (3×50 mL). The combined organic phases were dried (Na2SO4) filtered and concentrated under reduced pressure. The crude product was purified by column chromatography EtOAc (EtOAc:EtOAc:EtOAc A small portion of the residue was subjected to RP-LC-MS (35-35% gradient of 35-80% CH3CN in aq. EtOAc) to give a sample of higher purity for characterization and the product was isolated as a white solid. [a]D20 -28.0° (c 1.2, CH3OH); !H NMR (CD30D) δ 7·56 (m5 1H), 7.40 (m,1Η), 7.32 (m5 115688.doc -86- 200800149 1Η),7 · 22 (m5 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, 131.1, 128.8, 123.3, 62.9, 55.5, 52·7, 35·1, 26.9; MS (m/z 372, Μ + H+, 374, Μ + H+).

General procedure for Pd-catalyzed reactions: Method A: aryl bromide 19 or 26, tin reagent, Pd(PPh)3Cl2, CuO and DMF (2 mL) in a microwave chamber at 130 ° C in thick wall Stir in the heavy-walled Smith process vial; mix for 20 min. CH2C12 (30 mL) was added to the mixture, which was washed with saturated NaHC03 (aq. The organic phase was dried (Na2SO4) filtered and evaporated. The residue was redissolved in CH.sub.3CN (EtOAc) (EtOAc) (EtOAc) Method B: Stirring aryl bromide 19 or 26, iPic acid, Pd(PPh)3Cl2, 2 Μ Na2CO3 (aqueous solution), EtOH and DMF in a microwave chamber at 120 ° C in a thick-walled Smith reaction bottle 30 min. Five drops of formic acid were added to the mixture and the solvent was then evaporated. The residue was redissolved in CH3CN / H20 / DMF and filtered and then purified by RP-LC-MS. Method C: Aryl bromide 26, acetylene, Et2NH, Pd(PPh3)2Cl2, Cul and DMF were stirred at 140 ° C for 30-40 min in a thick-walled Smith reaction flask. The treatment was carried out by extracting the mixture with CH2C12 (2 mL) and H20 (2 x 2 mL). The organic phase was filtered and evaporated, then the product was purified by RP-LC-MS. 115688.doc -87- 200800149

Method D: arylidene 19, acetylene, which, Pd(m3)2Cl2, CuI and DMF were filtered at 13 (TC) in a thick-walled Smith reaction flask and filtered to evaporate most of the solvent to give a crude product. It was purified by RP_LC_MS. Example 26 Basic component of bismuth acid

Step a

0

NC

1 A mixture of 1 (1·2 g, 5.22 mmol) and Rany nickel (4 〇〇 mg) in 70% formic acid was heated to 1 〇〇 ° C for 3 hours under high pressure in a microwave oven. The cooled mixture was filtered and concentrated, diluted with H20 and EtOAc EtOAc The organic layer was dried and concentrated to give a pure product 2 in near quantitative yield. Step b 115688.doc -88- 200800149

A solution of 2 (900 mg, 3.86 mmol) and 3 (785 mg, 3. 86 mmol) in 2-propanol (15 ml) was heated to 80 ° C for 4 hours to give 4 The alcohol-dichlorodecane oxime was purified to 5% by a ruthenium gel column. Compound 4 was collected and concentrated. NaBH3CN (186 mg, 2.96 mmol) was added to a stirred solution of &lt A solution of camphorsulfonic acid (654 mg, 2.82 mmol) in THF (10 ml) was added dropwise to the mixture. After 16 hours, the mixture was diluted with EtOAc, stirred and filtered then filtered over Na. The organic solution was concentrated and redissolved in THF. A solution of about 7 ml of NaOH (200 mg) in MeOH (10 ml) was added to decompose the resulting complex. The mixture was diluted with EtOAc and H20. The organic layer was separated, dried and concentrated. After dissolving in a 0 to 5% MeOH SiO 2 column in DCM, a pure compound was obtained. Biological instance

HIV Laboratory DAIDS Virology Manual for HIV in the Division of AIDS, NIAID USA 1997

In Laboratories, extensive guidance is available on assays for enzyme levels at the enzyme level and in cell culture, including isolation and/or selection of mutant HIV strains and mutant RT. Resistance studies including theories of various resistant mutants are described in the HIV Resistance Collaborative Group Data Analysis Plan for Resistance Studies, August 31, 1999 and subsequent revisions 115688.doc -89 - 200800149. Cell assay to characterize the HIV activity of a compound of the invention, for example, using multiple assays using XTT in MT-4 cells (Weislow et al, J Nat Cancer Inst 1989, Vol. 81, No. 8, 577 and below), Preferably, the assay is performed in the presence of 40-50% human serum to indicate the effect of protein binding. In short - XTT assays are grown in 96-well microtiter plates in RPMI 1640 medium supplemented with 10% fetal bovine serum (or 40-50% human serum if appropriate), penicillin and streptomycin ( 2.104 cells/well) Human T cells infected with 10-20 TCID50 of HIV-1iiib (wild type) or mutant virus (such as those with RT lie 100, Cys 181 or Asn 103 mutations) per well. Plant MT4 cells. The serially diluted test compound was added to each well, and the culture was incubated at 37 ° C in an enriched CO 2 atmosphere, and cell viability was measured on the 5th or 6th day with XTT live dye. Results are usually presented in ED5G μΜ format. ^ The performance of HIV-1 protease suitable for enzyme assays is also described in Danielsson et al. Adv. Exp. Med. Biol., 1998, 436, 99-103. Fluorescent assays for Ki assays are also described in Antimicrob. Agents Chemother., 1997, 41, 2383-2388. This journal also describes the use of MT4 cells for ED50 cell assays and colorimetric XTT assays. The following table shows Ki and ED50 plots for representative selection of compounds according to the invention. Class A indicates inhibition of Ki less than 10 nM, Class B indicates inhibition of 11-5 0 nM, and Class C indicates inhibition of 50-100 nM, Class D indicates ED5G &lt; 2 μΜ, and steroid indicates 2 -10 μΜ and steroid Instruction &gt;10 μΜ : 115688.doc -90- 200800149 Table 3 · Enzyme inhibition and antiviral activity in cell culture Compound Ki(nM) Ε〇50(μΜ) 1 BD~~ ~~ 2 BD 16 A . The time at which resistance was generated was such that 2xl〇4 MT4 cells per well in the titration dish infected 5-1〇TCID5〇mv-iIIIB. Eight replicates were used for each concentration and a test compound at a concentration of ed5 g was added. After 6 days of incubation, the activity in the 1 〇 clear layer was measured.

The following procedure was performed during the subsequent passage of the culture once a week. The virus produced at the concentration of the test compound exhibiting greater than 5% of the Hanting activity of the untreated infected cells is subcultured into fresh MT4 cells. The 15 卟 supernatant layers from the eight replicates were transferred to cells without test compound (control) and to cells having test compounds of the same concentration and five further concentrations, respectively. (See Table 2 below) When the virus is allowed to grow under the highest non-toxic 澧; μ 1Λ open f / □ (5_4 〇 μΜ), collect 2_4 parallel wells, and expand to obtain Nu (7)% sequence analysis and cross Resistance 115688.doc 91· 200800149 Table 2 Virus production inhibited by the allowed virus growth

‘ 125 X SIC

125 X SIC 25 x SIC

25 x SIC 5 x SIC 25 x SIC 5 x SIC No compound 25 x SIC 5 x SIC No compound

5 X SIC SIC SIC — no compound SIC — no compound 1 generation 1 generation 2 generation 3 generation 4 generation 5

P450 Metabolism The metabolism of the major isoforms of the compounds of the invention via the human cytochrome system P450 is conveniently transfected with a baculovirus infection of the human cytochrome P450 cDNA (Genest Corp. Woburn USA). Determined in insects. Excessive expression of various cytochrome P450 isoforms (including CYP1A2 + P450 reductase, CYP2A6 + P450 reductase, CYP2C9-Arg 144 + P450 reductase, CYP2C19 + P450 reductase, CYP2D6-Val 374 + P450 reductase and CYP3A4) Test compounds at concentrations of 0.5, 5, and 50 μΜ were double-replicated in the presence of a superbody of P450 reductase. The culture contains a fixed concentration of cytochrome Ρ450 (e.g., 50 picomoles) and is administered over 1 hour. The involvement of a given isoform in the metabolism of a test compound is determined by UV HPLC by chromatographic measurement of the disappearance of the parent compound. Plasma and Human Liver Metabolism Following the disappearance of compounds, the stability in plasma or whole blood was assessed by MS or HPLC according to conventional techniques. Sensitivity to first pass metabolism was measured in human liver 115688.doc -92-200800149 microsomes (such as HLM 1037 from Invitr(R) Techn〇logies lnc according to the manufacturer's instructions. In addition, the disappearance of the compound cultured in the preparation of hlm is usually monitored by MS or HPLC. Transmittance This example measures the delivery of inhibitors through cells of the human gastrointestinal tract. This assay uses well-known Caco-2 cells with a sub-algebra between 40 and 60. Top to bottom delivery

Typically, each compound is tested in 2-4 wells. The bottom and top holes contain 1. 5 mL and 0.4 mL of delivery buffer (TB), respectively, and the standard concentration of the test substance is 1 μ μΜ. In addition, all test solutions and buffers contained 1% DMSO. Prior to the experiment, the delivery plates were pre-coated with medium containing 1% serum for 30 minutes to avoid non-specific binding to the plastic material. After 21 to 28 days of incubation on the filter holder, the cell preparation for the permeability test was ready. 0 The first transport plate contained 3 columns of 4 wells per column. Columns are marked as lotion, column 2 is marked as "30 minutes &quot; and column 3 is marked as,, 6 minutes &quot;. The second conveyor plate contains 3 columns of 4 holes per column '-歹|] by mark, column 4 is marked as &quot;90 minutes&quot;, column 5 is marked as &quot;12〇 minutes&quot; and the remaining columns are unspecified. The medium is removed from the top hole, and the person is transferred to the washing plate (No.) in the plate (the plate). The conveying plate is in the transport of 2 without inserts, which are in columns 1 to 5 The TB in the outer pore of the h5 rainbow transport buffer also contains 1% bovine serum albumin. - Will be 5 mL of delivery buffer (HBSS, 25mMMEs, pH 6.5) w 115688.doc -93- 200800149 to the insert Medium' and the cell monolayer was equilibrated at 37. under the armpit, in a polyinix vibrator, in a transport buffer system for 30 minutes. After balancing with the buffer system, it was measured in each well by the EVOM cut-off instrument. Transepithelial electrical resistance (TEER). The TEER value is usually between 4 〇〇 and 1 〇〇〇 Ω per well (depending on the number of passages used). The delivery buffer (ΤΒ, pH 6.5) is removed from the apical side, And the insert was transferred to the 30 minute column (N〇2), and a new 425 called test substance called ΤΒ(ΡΗ 6.5) was added to the top (donor) hole. The plates were at 37π, at The polymix was shaken; the medium was incubated at a low shaking speed of about 15 〇 to 3 rpm. After incubation for 30 minutes in column 2, the insert was moved every 3 minutes. New pre-warmed bottom (acceptor) wells; column 3 (6 min), column 4 (9 min) and column 5 (120 min). ~2 min and at the end of the experiment, from the top solution The sample σα represents the donor sample taken from the beginning and the end of the experiment. At each predetermined time point, 3 自 is taken from the bottom outer (acceptor) hole, and the TEER period value is measured at the end of the experiment. Acetonitrile was added to all collected samples until the final concentration in the sample was 50%.The collected samples were stored at -20 ° C until analyzed by HPLC or LC-MS. Each compound was tested in 2 to 4 wells. The bottom and top = wells contained L55 red and 0.4 mL TB, respectively, and the standard concentration of the tested substance was 10 ―. In addition, all test solutions and buffers contained DMSO. Prior to the experiment, transfer the plate to 115688.doc -94-200800149 for 30 minutes with medium containing 1 〇 0 / / month to avoid non-specific binding to the plastic material. After 21 to 28 days of incubation on the filter holder , cells for permeability experiments are ready. The top hole is removed and the insert is transferred to the wash column (No. 1) in the new plate (transport plate) without insert. The transfer plate contains 3 columns of 4 holes per column. Column 1 is labeled &quot;wash The liquid &quot; and the column 3 is, the experimental column &quot;. The conveying plate is prepared in advance in the washing liquid column N〇1 with 15 melons 7_4), and is preliminarily 1 in the experimental column No. 3 (donor side). 55 mL of the test substance was prepared in TB (pH 7.4). 〇·5 mL of delivery buffer (HBSS, 25 mM MES, pH 6.5) was added to the insert in column Ν1·1 and the cell monolayer was at 37.平衡, in a polymix oscillator, in a transport buffer system for 3 minutes. After balancing with the buffer system, the TEER value was measured in each well by an EVOM cut-off instrument. Delivery buffer (TB, pH 6.5) was removed from the apical side and the insert was transferred to column 3 and 400 pL of fresh TB (pH 6.5) was added to the insert. After 30 minutes, 250 μ £ was taken from the apical (acceptor) well and replaced with a new delivery buffer. Thereafter, a 250 μί sample was taken every 30 minutes and replaced with a new delivery buffer until the end of the 120th minute experiment, and the TEER post-term value was finally measured at the end of the experiment. After ~2 minutes and at the end of the experiment, 25 pL samples were taken from the bottom outer (donor) chamber. These samples represent donor samples taken at the beginning and end of the experiment. Acetonitrile was added to all collected samples until the final concentration in the sample was 50%. The collected samples were stored at -2 (rc) until analyzed by shift or LC-MS. 115688.doc -95- 200800149 Calculated the cumulative fraction of absorption FAeum relative to time. FAcum is calculated by: FAcum =J^,

^DI . where CRi is the acceptor concentration at the end of interval i and CDi is the donor concentration at the beginning of interval i. A linear relationship should be obtained. The measurement of the permeability coefficient (Papp, cm/s) is calculated by: 10 P = (k. VR), αρρ' (Α: 60) where k is the transport rate (min-1), which is defined by linear The slope obtained by regression of the cumulative fraction of absorption (FAcum) as a function of time (min), VR is the volume in the receptor chamber (mL), and A is the area of the filter (cm2). Reference compound human body absorption class label human body absorption % passive transport low (0-20%) mannitol 16 methotrexate 20 (21-75%) acyclovir 30 high (76-100%) propranolol Propranolol 90 Caffeine 100 Active delivery of amino acid transport agent L-phenylalanine 100 Active discharge of PGP-MDR1 Digoxin ODigoxin) 30 115688.doc -96-

Claims (1)

200800149 X. Patent application scope: 1. A compound of formula I: Where R is -Ri, an Or1·, SR1,; R1 is CVQAlk, cvq alkanediylcarbocyclyl or c(tetra)alkyldiylheterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from Rio; R2 is CVCAlk, C(rc3 alkane) a carbocyclyl group, a Cc-q alkanediylheteroyl group, which is optionally substituted with up to 3 substituents independently selected from R1G; is HF, OH, CrC^Alk or C〇-C3 alkane Dibasic _〇_Cl-c3 alkyl; L is F, NH2, -NHCi_C3Alk; -N(c"C3Alk)2; η is 1 or 2; Α is a double-% ring system containing fused to each other One or six members of the saturated ^ and the second 5 or 6 member unsaturated ring 'where the first 5 or 6 members of the saturated product 2 contain oxygen heteroatoms and are optionally substituted by hydroxyl and/or methyl groups, long first 5 Or a 6-membered unsaturated ring-containing case containing one or two heteroatoms selected from the group and optionally substituted by fluorine or disubstituted; or N A ' is a formula (11), (II,), (ΠΙ) or (IV) )The group··115688.doc 200800149 Of which: R3 R4^ Cf3 (Π,) Rx (IV) R is η, or r3 is Ci_c6Alk, (^-naphthyldiylcarbocyclyl, Q_C3 alkyl-heteroyl, either of which is optionally substituted with up to three substituents independently selected from R11; Is 1 C6Alk, cG-C3 alkanediylcarbocyclyl, Cg_C3 alkanediyl a ring group, either of which is optionally substituted with up to three substituents independently selected from the group consisting of: 1 (C3), C(rc3 alkanediylcarbocyclyl, c〇_C3 alkanediylheterocyclyl, any of Optionally, up to three substituents independently selected i r1g; Z is a bond, -NH-, -0-; Rx is hydrazine, Cr_C3 alkoxy, optionally halogenated, hydroxy, Ci-C3 An oxy-substituted Ci-C3 linear or branched alkyl group; or a Chinese-incorporated carbon atom together with an adjacent carbon atom, which is optionally substituted by a halogen group or a Ci-CsAlk, or a sigma-based ring; t is 0 or 1; A" is a group of formula (V), (VI), (VII) or (VIII): Wherein: 115688.doc -2- 200800149, a R8 is Η; or R, Ci: c6Alk, 'Μ二基carbocyclyl, 一, a oxadiphenyl group, any of which is optionally independently selected up to three independently selected from three The substituent of R11 is substituted; and R9 is cvc6Aik. -(^-alkyldiylcarbocyclyl, C(rC3 alkanediylheteroyl, either optionally substituted with up to three substituents independently selected from r1g; W is a bond, -NR13- or; R13 Η, CVCsAlk, or R&quot; and R9 together with the ^^ atom to which they are attached, define a saturated, partially saturated or aromatic N-containing ring containing 5 or 6 ring atoms, the N ring optionally being up to three selected from Substituents for RlG are substituted; &amp; D is 0 or NH; Ry is η, or Ry defines a fused furan or a piper ring together with an adjacent c atom; Q is 0, CHR8 or a bond; R15 is a carbocyclic group or a heterocyclic group, either of which is optionally substituted with up to three substituents independently selected from the group consisting of CrCAlk, hydroxy, pendant oxy, and halo; q and r are independently hydrazine or 1; R is halo, pendant oxygen 'cyano, azido, nitro, C6Alk, CVC3 alkanediylcarbocyclyl, C(rC3 alkanediylheterocyclyl, 孓NRaRb, Y-〇-Rb, YC(=Q)Rb, Y- (C=〇)NRaRb, Y·NRaC(=〇)Rb, Y-NHSOpRb, YS(=〇)pRb, γ_S(=0)pNRaRb, YC(=0)0Rb or Y-NRaC(=〇)QRb Where: 115688.doc 200800149 Y is a bond or (VC3 alkanediyl; Ra is Η or CVCsAlk; Rb is H^CKC^Alk, CVC3 alkanediylcarbocyclyl or ^^-diylheterocyclyl; P is 1 or 2; R11 is halo, pendant oxy, cyano, stack Nitrogen, nitro, C3Alk, Y-NRaRa1, Υ-Ο-Ra; wherein: Ra' is 11 or Ci-CsAlk; or Ra and Ra' together with the gas atom to which they are attached are defined as 4 Or pyridinyl-substituted pyrrolidine, morpholine, piperidine or piperazine; and a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein ... is !^, and wherein the ruler is The substituted CG-C3 calcined diyl carbocyclyl or cQ-C3 calcined diyl heterocyclyl. 3. The compound of claim 2, wherein Ri is optionally substituted carbocyclyl or heterocyclyl. 4. A compound according to claim 2 or 3, wherein the 1 carbocyclyl moiety is a phenyl group which is optionally substituted, or the Ri. heterocyclyl moiety is optionally substituted acridinyl or fluorene. A compound according to any one of the preceding claims, wherein at least one of the optional substituents of the chemical plant is selected from the group consisting of an I group, a pendant oxy group, a cyano group, a Ci_C6Alk, C (rC3 Alkyldiylcarbocyclyl, CG_C3 alkanediylheterocyclyl, Y_NRaRb, Y-〇-Rb, wherein γ is a bond or Ci_C3Alk, or C1-C3Aik. 1 6. The compound of claim 5, wherein R1, the optional substituent is selected from the group consisting of 115688.doc 200800149 fluorine, ci_C3Alk, Co-q succinylcarbocyclyl, cn-c b radical. The compound of claim 4, wherein Rr is a phenyl group which is monosubstituted by a halogen group. Substituting or substituting 8. The compound of claim 7, wherein 1 is a phenyl group by fluorine. Or a disubstituted product. The compound of claim 4, wherein ^ is phenyl. 10. A compound according to any one of the preceding claims, which is characterized by the stereochemical configuration shown in the &amp; p, U lower structure: 〇 X </ RTI> The compound of any one of the preceding claims, wherein R2 is optionally substituted with a monocarbocarbyl group or a Cg-C:}dicarboxylic heterocyclic group. 12. A compound according to claim U, wherein r2 is optionally substituted carbocyclyl or heterocyclyl. 13. The compound according to claim (1), wherein the stilbene 2 carbocyclyl moiety is an optionally substituted phenyl group, or the R2 heterocyclyl moiety is optionally substituted pyridyl, pyridazinyl, pyrimidinyl or Pyridazinyl. 14. A compound according to any one of the preceding claims, wherein at least one "optional substituent" is selected from the group consisting of halo, pendant oxy, cyano, Ci_C6Alk, Ce_c3 alkanedicarbocyclyl, Cq_c3 alkanediyl Ring group, Y_NRaRb, γ_〇_ Rb; where Υ is a bond or Ci_C3Alk,]^ is ^1 or (:1_(::3 octave and 1^ is 11 115688.doc 200800149 or Ci_C3Aik. 15. as requested a compound of 14, wherein the optional substituent of R2 is selected from the group consisting of fluorine, qC^Alk, Co-Ci alkanediylcarbocyclyl, c〇_Ci-alkyldiylheterocyclyl. 16. The compound of claim 13 And R 2 is a phenyl group substituted by a carbocyclic group or a heterocyclic group. The compound of claim 16, wherein R 2 is a phenyl group substituted with an aryl group or a heteroaryl group. And a compound of any one of the preceding claims, wherein the compound is a compound of any one of the preceding claims, wherein the compound is a compound of any one of the preceding claims, Wherein η is 1. The compound according to any one of the preceding claims, wherein Α· is a genus of the formula (π) or (ιν). 22. The combination of claim 21 And wherein R3 is hydrazine, optionally substituted c" CAlk or optionally substituted cQ_c3 alkanediylheterocyclyl. _ 23. The compound of claim 22, wherein R3 is η or optionally substituted by Ci C6Alk 〇24. The compound of claim 22, wherein r3 is Ci-(CsAlk or especially isopropyl or tert-butyl, optionally substituted by halo. _ 25. The compound of claim 22, wherein R3 The optional substituent is pendant oxy, cyano or especially halo or Υ-Ο-Ra, wherein Y is a bond or Cl-C3 Aik, and Ra is Η or (^&lt;3 Aik. .26. A compound according to any of the preceding claims, wherein R4 is optionally substituted C^C^Alk, especially methyl or optionally substituted methyl. 115688.doc 200800149 27. Any of the foregoing claims A compound mouthwash wherein the optional substituent of R4 is halo, pendant oxy, cyano, azide and fluorenyl, nitro, CVC6Alk, C(rC3 alkanediylcarbocyclyl, C( rC3 alkane-A# 0 3 play-ylheterocyclyl, Y-NRaRb or Υ-0-Rb, wherein: Y is a bond or CVC3Alk; Ra is 11 or CVC3Alk; Rb is 11 or Cl-C6Alk, CG-C3 is burned Base carbon Or a Cq_C3 calcined diyl heterocyclic group. 28. The compound of claim 27, wherein the optional substituent is a halo group, a pendant oxy group, (VC^Alk, CG-C3 alkanediylcarbocyclyl, Cq_C3 alkane) Dibasic heterocyclic group or fluorene-fluorene-Rb. The compound of claim 28, wherein the optional substituent is a group or a γ_〇_Rb 〇 30. The compound of claim 29, wherein r4 is methyl. The compound of any one of claims 21-30, which has the stereochemical configuration shown in the following partial structure: 32. The compound of claim 21, wherein RX is hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, fluoroindolyl, 1-fluoroethyl or 1-fluoropropyl. 33. The compound of claim 21, wherein RX is methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methoxypropyl or 1- 115688.doc 200800149 Ethoxypropyl. 34. The compound of claim 21, wherein A is 3. A compound according to any one of the preceding claims, wherein A is a bicyclic ring system comprising a first 5 or 6 membered saturated ring and a second 5 or 6 membered unsaturated ring fused to each other, wherein The first 5 or 6 membered saturated ring optionally contains an oxygen heteroatom and is optionally substituted by a hydroxy or methyl group, and the second 5 or 6 membered unsaturated ring optionally contains one or two heteroatoms selected from the group consisting of S, hydrazine and N. Substituted by mono- or di-fluoro as appropriate. 36. The compound of claim 35, wherein the bond to the remainder of the molecule extends from the carbon 1 position of the saturated ring. 37. The compound of claim 36, wherein the optional hydroxy substituent is at the carbon 2 position of the saturated ring. 38. The compound of claim 35 or 36, wherein the oxygen heteroatom is at the 3 position of the $membered saturation ring or at the 4 position of the 6 member saturation ring. The compound according to any one of items 35 to 38, wherein the second ring is a 5-membered ring and contains a sulfur hetero atom or an oxygen hetero atom. The compound according to any one of claims 35 to 38, wherein the second ring is a phenyl group which is optionally substituted. 41. The compound of claim 4, wherein the substituent is a monofluoro or difluoro group. 42. The compound of claim 35, wherein a is selected from the group consisting of: 115688.doc 200800149 The compound of any one of the claims, wherein A&quot; has the formula (V). 45. The compound of claim 44, wherein R8 is H, optionally substituted Ci_CsAlk or, as appropriate, substituted (^_(:3 alkanediylcarbocyclyl). 46. The compound of claim 45, wherein R8 is η or optionally substituted Cl_CVAlk, especially isopropyl or tert-butyl. The compound of any one of claims 44 to 46, wherein the optional substituent of R8 is pendant oxy, cyano, Ci_C3Alk or especially halo or Y_〇_Ra; 115688.doc 200800149 wherein Y is Key or C^CsAlk; Ra is Η or Ci-CsAlk. The compound of any one of claims 44 to 47, wherein R9 is optionally substituted CVC^Alk or C(rC3 alkanediylcarbocyclyl. 49. The compound of claim 48, wherein R9 is The compound of any one of claims 44 to 49, wherein the optional substituent of R9 is a halo group, a pendant oxy group, a cyano group, an azide group, a nitro group, a Ci_c6Alk group. , C()_c3 alkanediylcarbocyclyl, c❹-c3 alkanediylheterocyclyl, Y-NRaRb or YO-Rb, wherein: Y is a bond or Ci-CsAlk; Ra is 11 or CrCsAlk; Rb is CVC3 alkanediylcarbocyclyl or Cg_C3 alkanediylheterologous. 51. The compound of claim 50, wherein the optional substituent is halo, pendant oxy, CVC^Alk, C(rC3 alkanediyl carbon) The compound of claim 47, wherein R9 is a fluorenyl group, the compound of any one of claims 44-52, wherein the arm is 54. The compound of any one of claims 44 to 53 which has the stereochemical configuration shown in the following partial structure: R9 (V) 〇 li5688.doc 200800149 5 5. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier or diluent thereof. 56. The pharmaceutical composition of claim 55, further comprising from 1 to 3 additional HIV antiviral agents. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the prevention or treatment of HIV infection. 58. A method for treating or preventing HIV infection, comprising administering an effective amount of a compound of any one of claims 1-55 to an individual infected with or at risk of HIV infection. 115688.doc 11- 200800149 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 115688.doc