TWI292752B - Retroviral protease inhibiting compounds - Google Patents

Description

1292752 IX. INSTRUCTIONS: This is part of the continuation application of US Patent Application No. 08/572,226, filed on December 13, 1995. TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds and compositions for inhibiting retroviral proteases, and methods, and in particular, to human immunodeficiency virus (HIV) proteases, a composition and method for inhibiting retroviral infection, In particular, HIV infection, a method of producing the compound and a synthetic intermediate used in the method. [Prior Art] Retroviruses are viruses that reverse the enzymatic activity in their life history using ribonucleic acid (RNA) intermediates and RNA-dependent deoxyribonucleic acid (DNA) polymerases. Retroviruses include, but are not limited to, RNA viruses of the retroviridae family, as well as DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause various disease states in humans, animals and plants. From a pathological point of view, some of the more important retroviruses, including human immunodeficiency virus (HIV-1 and HIV-2), cause acquired immunodeficiency syndrome in humans, human T-cell lymphotropic virus I, II , IV and V, which cause acute cellular leukemia in humans, as well as leukemia viruses in cattle and cats, which cause leukemia in livestock. A protease is an enzyme that cleaves a protein at a specific peptide bond. Many biological functions are controlled or regulated by proteases and their complementary protease inhibitors. For example, the protease lycopene cuts the peptide angiotensinogen to produce peptide blood.

O:\106\106749.DOC 1292752 = Prime p vasopressin 1 is further stepped by the protease vasoconstrictor enzyme (ACE) to form a hypotensive peptide vasoconstrictor η. Kidneys, inhibitors, and ACE are known to reduce high blood pressure in living vessels. Retrovirus: Treatment of Egg Diseases Inhibitors of sputum will provide antiretroviral agents. The genome of a retrovirus that encodes a protease is responsible for proteolytic processing of one or more polyprotein precursors such as Μ and gene products. See WeUink, retroviral proteases most often process gag precursors into nuclear proteins, and also process precursors into reverse transcriptase and retroviral proteases. In addition, retroviral proteases are sequence specific. See Pearl, Chest (10) Ga. 482 (1987). ~~' For the collection of infectious virions, it is necessary to correctly process the precursor polyprotein by the retroviral protein aphid. It has been shown that barley production outside the living body produces a protease-incomplete virus that results in the production of an immature core form that lacks infectivity. See Crawford, J. Virol. 51 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, the protease inhibition of retroviruses provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987). For the treatment of viral diseases, it is usually involved in administering a compound that inhibits viral DNA synthesis. Current treatments for AIDS involve the administration of, for example, 3'-azido-deoxythymidine (AZT), 2,3,-dideoxycytidine (DDC), 2,3,dideoxyinosine ( Compounds such as dDI), d4T and 3TC, and the speculative sex caused by immunosuppression caused by HIV infection

O:\106\106749.DOC 1292752 Dyed compound. None of the current aids therapy has proven to be fully effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects, including low plate count, nephrotoxicity, and bone marrow cytopenia. Recently, HIV protease inhibitors ritonavir, saquinavir, and indinavir have been approved in the United States for the treatment of HIV infection. However, to improve HIV protease inhibition There is a continuing need for the agent. SUMMARY OF THE INVENTION According to the present invention, there is a compound of formula I:

Wherein 1 and 112 are respectively selected from the group consisting of a lower alkyl group, a cycloalkylalkyl group and an aralkyl group; • r3 is a lower alkyl group, a hydroxyalkyl group or a cycloalkylalkyl group; and r4 is an aryl group or a heterocyclic group. ; R5 is

O:\106\106749.DOC 1292752

C)

O:\106\106749.DOC -10- 1292752 Ο

Where η is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 〇, s or ΝΗ, Υ is -CH2- ' -Ο-, -S- or -N(R6 )- 'wherein R6 is hydrogen, lower carbon number, cycloalkyl, cycloalkyl, aryl or aryl, Y', is _CH2- or -N(R6")-, where RV' Is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y' is -N(R6>, wherein r6 is hydrogen, lower alkyl, cycloalkyl a cycloalkylalkyl group, an aryl group or an aralkyl group, and Z is hydrazine, S or NH; and a) -0-, b) · S - ' c) -N(R7)-, wherein R7 is hydrogen, Lower alkyl, cycloalkyl or cycloalkylalkyl, d) -0-alkylene-, e) -S -alkylene-f) -S(0)-alkylene_, O: \106\106749.DOC 11 1292752 g) -s(o)2-alkyl-, h)-N(R7)-alkylene-, wherein R7 is as defined above, i) - extendable group - Ο- ' j) - an extended alkyl group - S-' k) alkyl-N(R7)-, wherein R7 is as defined above, l) an alkyl group, or m) an alkenyl group; or Acceptable salts, esters or drug precursors. • Preferred compounds are those wherein I and R2 are aralkyl and R3 is a lower alkane.

Base, R4 is aryl, R5 is X

, .^N a ' (〇Η2) η^

b)

X

O:\106\106749.DOC -12- 1292752

R6.. e) wherein X, Y, Y, Y", z, R6", n, (5) and m, as defined above, and Li is a - extendable compound of formula i. More preferred compounds are those in which the center 2 is a benzyl group, or 1 is a fluorenyl group and 仏 2 is a lower alkyl group, R 3 is a lower alkyl group, and Han 4 is a two lower alkyl group. Substituted phenyl' may be substituted with a third substituent selected from the group consisting of a lower carbon group, a hydroxyl group, an amine group and a _ element, or b) substituted with two lower carbon number groups. Said sigma base or u-density base, and may be substituted with a third substituent selected from the group consisting of a lower alkyl group, a hydroxyl group, an amine group and a _ element, R5 is

a) where η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH-,

Z b) O:\106\106749.DOC -13- 1292752

Where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο, X \人 L λζ

C) id· Z where m' is 1, X is 0, Z is 〇 and γ is

(ch2w where m' is 1 ′ X is Ο ’ Y" is ΝΗ- and 丫, _NH_, or

X

Wherein X is hydrazine and R6n is hydrogen and a more preferred compound is wherein the ruthenium (4) is a Henyl group, or Ri is a aryl group and ~ is an isopropyl group, R3 is a lower alkyl group, and ^ is a 2,6-dimethyl group. The phenyl group can be optionally substituted with a third substituent selected from the group consisting of a lower alkyl group and a halogen, and Han 5 is a)

O:\106\106749.DOC 14- 1292752 where η is 1 or 2, X is Ο or S, and 丫 is _CH2 or -NH-,

Where m' is 1, X is 0, Z is 0 and Y is -NH-, \入" d) (CH2)m.

Where m' is 1, X is Ο, Y, ' is -NH_X Y, is -NH-, or X

^hT^N-Re-e) A compound of formula I wherein X is 0 and R6n is hydrogen and 1^ is -〇-CH2-. The most preferred compound is its center and 2 is a fluorenyl group, or 1 is a fluorenyl group and 112 is an isopropyl group, R3 is a low carbon number alkyl group, and R4 is a 2,6-dimethylphenyl group, which may optionally be The third is selected from a substituent including a low carbon number and a halogen, O:\106\106749.DOC - 15- 1292752 R5 is

X (CH2)n^ a) wherein n is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

Where m* is 1, X is Ο, Z is Ο and Y is -NH-, \人"

〇 (CHzW where m1 is 1, X is 〇, γ" is -NH- and Y is -NH-, or

X

d) a compound of the formula I wherein X is hydrazine and R6" is hydrogen and L! is -O-CH2-. The most excellent compounds are those in which 1 and 112 are benzyl, or the heart is benzyl and R2 is isopropyl. 'R3 is a low carbon number alkyl group, which is 2,6-dimethylphenyl group, which may be taken as a third substituent selected from the group consisting of a low carbon number group and a functional element. O: \106\106749. DOC -16-1292752 generation, r5 is x

(CH2)nV A compound of formula I wherein n is 1 or 2, X is hydrazine or S, and Y is -CH2 or -NH-, and 1^ is -0-CH2-. Examples of excellent and optimal compounds of formula I are selected from the group consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5- [2S-(l-tetrahydro-pyrimidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6 -Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3,3-dimethylbutanyl)amino-1,6- Diphenyl hexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(imidazolidin-2-ene) (2,3,5,6-diphenylhexane; (2S,3S,5S)-2-(2,4,6-trimethylphenoxyethyl) Amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amino-1,6-diphenylhexan; (28,38,5 8 )-2-(4-fluoro-2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(i-imidazolidin-2-one)-3-methylbutanyl Amino-1,6-diphenylhexanone; O:\106\106749.DOC -17- 1292752 (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl) Amino-3-hydroxy-5-(2S-(l-pyrrolidin-2-one)-3-indolylbutenyl)amino-1,6-diphenyl Hexane; (2S,3S,5S)-2-(2,6-diamidinophenoxyethyl)amino-3-hydroxy•5-(2S-(l-pyrrolidine-2,5-di Keto)-3-mercaptobutyl)amino-1,6-diphenylhexane; (28,38,58)-2-(trans-3-(2,6-dimercaptophenyl)propene Mercapto)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one)-3-mercaptobutyryl)amino-1,6-diphenylhexane; (28, 3 8,5 8)-2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one) (-3-methylbutanyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3- Hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3-methylbutanyl)amino-1,6-diphenylhexane; (2S,3S,5S)- 2-(2,6-dimercaptophenoxyethyl)amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydropyrimidin-2-one)-3-methyl (2S,3S,5S)-2-(2,6-diamidinophenoxy)amino-3-hydroxy-5-(2S -(1-tetrahydropyrimidin-2-one)-3-methylbutanyl)amino-1-phenyl-6-methylheptane; (2S,3S,5S)-2-(2,6 -dimercaptophenoxy Mercapto)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3indolylbutenyl)amino-1-phenyl-6-fluorenyl Alkane; and O:\106\106749.DOC -18-1292752 (2S,3S,5S)-2-(2,6-dimercaptophenoxyethyl)amino i-yi-5-(2S- (4-Aza-4,5-dehydro-1.pyrimidin-2-one)-曱曱丁丁醯基-1,6-diphenylhexane; or a pharmaceutically acceptable salt or ester thereof Or drug precursors. The extremely excellent compound of formula I is (2S,3S,5S)_2_(2,6_:mercaptophenoxyethyl)amino-3-hydroxy-5_[2S_(1-tetrahydropyrimidin-2-one) _3_methylbutyrylamido-1,6-diphenylhexanyl; or a pharmaceutically acceptable salt, hydrazine or drug thereof] precursor. ^ In some cases, it is preferred to be able to prepare (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3 in the form of an amorphous solid. -[2S-(l-tetrahydropyrimidin-2-yl)-3-methylbutenyl]amino-indole, 6, dimethyl hexane (or a pharmaceutically acceptable salt, ester or drug precursor thereof) . This type of = amorphous solid can be obtained by (2S,3S,5S)-2-(2,6-:methylphenidinyl)amino-3-hydroxy-5-[2S-(l-four Hydrogen pyrimidin-2-one)-3-mercaptobutyl hydrazine] Amino-1,6-diphenylhexane is dissolved in an organic solvent such as ethanol, isopropanolacetone, acetonitrile and the like, and then Add this solution to the water to prepare it. Preferred is (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-2- Keto)-3-methylbutanyl] saddle-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 ml/g) and the ethanolic solution is added to water (from about 1) Raise to about 1 mL/g) and stir to provide amorphous (2S,3S,5S)_2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5 -[28_(1_tetrahydropyrimidin-2-onemethylbutanyl)amino*-phenylhexan. Other embodiments of the invention include mv protease inhibiting compounds,

O:\106\106749.DOC -19- 1292752 which includes substituents of formula II:

II 〇 wherein R 3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and R 5 is

O:\106\106749.DOC -20-

X 1292752

X

Where η is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 0, S or NH, Y is -CH2-, -Ο-, -S- or -N(R6 )-, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y" is -CH2- or O:\106\106749.DOC-21- 1292752 W(R0")- 'wherein R6" is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y, wherein R6 is hydrogen, lower alkyl Preferred compounds having a base, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and 2 being 0, S or NH 〇 are HIV protease inhibiting compounds containing a substituent of formula II, wherein R3 is Low carbon number alkyl, and R5 is

a) (CH2)n^

O:\106\106749.DOC -22- 1292752

e) where X, Y, Y, Y", Z, R6", n, ❿ and m are as defined above. A more preferred compound is an HIV protease inhibiting compound containing a substituent of formula II wherein R3 is a lower alkyl group and 115 is

Y (CH2)n- a) wherein n is 1 or 2, X is p or S, and γ is -CH2 or -NH-,

b) where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο,

c) where m' is 1, χ is 〇, Z is Ο and 丫 is _ ΝΗ· O:\106\106749.DOC -23 - 1292752 d) where m' is 1, X is Ο, Y" is -NH - and Y' is -NH-, or

X e)

Wherein X is O and R6n is hydrogen. A further preferred compound is an HIV protease inhibiting compound containing a substituent of formula II.

R3 is isopropyl in formula II, and R5 is X(CH2)n^ a) wherein η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

Where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο,

X

Where m' is 1, X is Ο, Z is Ο and Y is -NH-, O:\106\106749.DOC -24- 8 1292752

(CH2W d) wherein m' is 1, X is Ο, Y" is -NH- and Y' is -NH-, or

X tf n-r6- e)

Wherein X is O and R6n is hydrogen. The most preferred compound is an HIV protease inhibitory compound containing a substituent of formula II.

R3 is isopropyl in formula II, and R5 is X(CH2)n^ a) wherein η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

X

\ΛΥ L λζ b) (CH2)m· where m' is 1, X is Ο, Z is O and Y is -NH-,

X

(CH2C O:\106\106749.DOC -25- 8 1292752 where m' is 1, X is Ο, γ" is _NH- and γ, is _NH•, or

d) wherein X is hydrazine and R6" is hydrogen. The most preferred compound is a mv protein salt-suppressing compound containing a substituent of formula II, wherein R3 is isopropyl and & 5 is

Wherein η is 1 or 2, X is 〇 or S and Y is -CH2 or -NH-. Examples of such HI V protease inhibiting compounds include: cis-N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(SH2S-(1-tetrahydropyridine- 2-keto)-3-mercaptobutylamino)aminobutyl]-(4aS,8aS)_isoquinoline-3(S)-carboxamide; cis-N-tert-butyl-decahydro-2 -[2(R)-radio-based p-sepeno-3(S)-(2S-(1-tetrahydro-exo-b-but-2-yl)-3-indolylbutanyl)amine butyl]-( 4aS,8aS)-isoindoline-3(S)-carboxamide; and 4-amino-1((2 ipsilateral, 3 8)-2-hydroxy-4-phenyl-3-(28- (1_tetrahydropyrimidin-2-one)-3-mercaptobutylamino)butyl)-N-isobutyl-benzenesulfonamide; and analogs thereof; or pharmaceutically acceptable thereof Salt. Such a HI V protease inhibiting compound containing a substituent of formula II may have an amine group (-NH2 or -NHR*, wherein R* is a lower alkyl number by O:\106\106749.DOC -26-1292752) A suitable intermediate or precursor of a hydroxy group (-0H) or a thiol group (-SH) is coupled to a compound of the formula guanidine or a salt thereof or an activated ester derivative thereof to prepare a HO-C^ ^Rc

II 〇

III wherein R3 is a low-permeability alkyl group, a hydroxyl-based group or a cycloalkyl group; and R5 is

O:\106\106749.DOC -27-

X 1292752

Where η is 1, 2 or 3, and m is 1, 2 or 3, m, for! Or 2, 〇, s or NH ' Y is _CH2-, _〇_, each or _N(R6)_, wherein & is & hydrogen, lower alkyl, cycloalkyl, cycloalkyl Alkyl, aryl or aralkyl, γ" is _cH2_ or -Ν〇ν,)_, wherein I" is hydrogen, lower alkyl, cycloalkyl, cycloalkylene, aryl or aralkyl Base, γ, is -N(R6,)_, where I is hydrogen, low carbon number

O: \106\106749.DOC -28- 1292752 alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, and z is ο, s or NH. Preferred compounds are compounds of formula III or activated ester derivatives thereof,

Where R3 is a lower alkyl group and r5 is X

, (CH2)nV

X

e) wherein X, γ, γ·, γ", z, R6", η, m and m' are as defined above. -29-

O:\106\106749.DOC 1292752 A more preferred compound is a compound of formula III or an activated ester derivative thereof.

Medium R3 is a low carbon number base and R5 is X

(CH2)nV a) wherein η is 1 or 2, X is Ο or S, and Y is -CH24-NH-,

X

.)—(CH2)m Ύ/ b) Ζ where m is 1 or 2, Χ is 0, Υ is -CH2- and Ζ is Ο,

Where m' is 1, X is 0, Ζ is 0, and Υ is -ΝΗ-,

X

(CH2W where m' is 1, X is Ο, Υπ is -ΝΗ- and 丫' is -ΝΗ-, or

X

e) wherein X is 0 and R6'' is hydrogen. O:\106\106749.DOC -30- 1292752 A more preferred compound is a compound of formula III or an activated ester derivative thereof,

Wherein R3 is isopropyl and R5 is X

a) where η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

Where m is 1 or 2, X is Ο, Y is -CH2- and Z is 0.

c) z

Where m1 is 1, X is Ο, Z is Ο, and Y is -NH-, X

(CH2)m·

Wherein m' is 1, X is Ο, · Y" is -NH- and Y' is -NH-, or X - R6m e) wherein X is O and R6n is hydrogen. O:\106\106749.DOC -31 - 1292752 The most preferred compound is a compound of formula III or an activated ester derivative thereof

R3 is isopropyl and r5 is X

Y

(CH2)nV a) wherein η is 1 or 2, X is Ο or S, and Y is -CH24-NH-,

X \火 L λ2 b) (CH2)m·

Wherein m' is 1, X is Ο, Z is Ο, and Y is -NH-, wherein 1, X is Ο, Y" is -NH- and Y' is -NH-, or

X R6··

d) wherein X is 0 and r6" is hydrogen. The most excellent compound is where r3 is isopropyl and r5 is

X

O: \106\106749.DOC -32- 1292752 A compound of formula m or an activated vinegar derivative thereof, wherein ... or 2, χ is 0 or S ' and Υ is -CH or -ΝΗ-. The compounds of the invention may include asymmetrically substituted carbon atoms. The results mean that all stereoisomers of the compounds of the invention are included in the invention;: a mixture of racemic mixtures, diastereoisomers, and a single diastereoisomer of the compound Things.

, "S" and "R" configuration, as in *IupAC 1974 Recommendation, Section e, Fundamental Stereochemistry, Pure AiJ

Chem. (1976) 45, 13-30. As used herein, the term N-protecting group, or, N-protected, means that those groups attempt to protect the terminal of the amino acid or peptide, or to protect the amine group during synthesis. Fight against unwanted reactions. The frequently used N-protecting group is disclosed in Greene* Wuts, "Protective Groups In 0rganic Synthesisn, (John Wiley & Sons, New York (1991)) It is hereby incorporated by reference. The N-protecting group includes a mercapto group such as a methyl group, an ethyl group, a propyl group, a propyl group, a trimethylethyl group, a first-butyl ethyl group, a 2-chloroethyl group, a 2-bromoethyl group. , trifluoroethyl fluorenyl, dichloroethyl fluorenyl, fluorenyl, o-nitrophenoxy acetyl, α chloropyridinyl, methionyl, 4-chlorophenyl fluorenyl, 4-bromobenzyl Sulfhydryl, 4-nitrobenzhydryl and the like; a fluorenyl group, such as a phenyl fluorenyl group, a p-toluene fluorenyl group and the like; a group formed by an aminocarboxylic acid, such as a fluorenyloxy group, a pair ~Chlorooxyloxy, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromoindoleoxycarbonyl, 3,4-dimethoxyoxyoxyl, 3 ,5-dimethoxybenzyloxymethyl, 2,4-dimethoxybenzyloxycarbonyl, 4-decyloxybenzyloxycarbonyl, 2-nitro-4,5_〇:\Η)6\] 06749 .DOC -33- 1292752 monomethoxy-oxyl, 3,4,5-trimethoxyoxyl, 1-(p-phenyl-l-methylethoxycarbonyl, α,α - dimethyl-3,5-dimethoxybenzyloxymethyl, diphenylmethoxycarbonyl, tert-butoxycarbonyl, diisopropyloximeoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, Anthraceneoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxy group, cyclopentyloxycarbonyl, diamond A carbonyl group, a cyclohexyloxycarbonyl group, a benzothio group, and the like; an alkyl group such as a benzyl group, a triphenylsulfonyl group, a benzyloxymethyl group, and the like; and a decyl group such as a trimethyl decyl group and the like. Preferred oxime-protecting groups are methyl fluorenyl, ethyl fluorenyl, benzhydryl, trimethyl ethane, second-butyl acetyl, benzoxyl, benzyl, and third-butoxy Carbonyl (B〇c) and benzyloxycarbonyl (Cbz). When the term ''activated ester derivative' is used herein, it means fluorenyl halide, such as sulfhydryl, and activated esters include but It is not limited to formic acid and acetic acid-derived anhydrides, anhydrides derived from alkoxycarbonyl halides, such as isobutoxy-Ik-based fluorine and its analogs, N-based, glass-based, and imine-derived, Terpene-derived esters, N-hydroxybenzotriazole-derived, N-hydroxy-5-norbornene-2,3-dicarboxyguanamine-derived esters, 2,4,5_ Trichlorophenol-derived esters, benzene Phenol-derived esters, propylphosphonic acid-derived anhydrides, and the likes. As used herein, the term "alkyl fluorenyl" means R^c(〇)_, where R9 is a low carbon The term "alkenyl" as used herein refers to a divalent derived from a straight or branched hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Examples of the group-extended alkenyl group include _CH=CH_, _c H=CH_, O:\106\106749.DOC-34-1292752-c(ch3)=ch-, -CH2CH=CHCH2- and the like. When the terms "alkoxy" and "thioalkoxy" are used herein, they mean 11150- and R15s-, respectively, wherein R15 is lower alkyl. When "alkoxyalkoxy," is used herein, it is meant R22〇_R23〇_, wherein R22 is lower alkyl as defined above, and r23 is alkylene. Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, 1,3-butoxymethoxy and the like. When "alkoxyalkyl" is used herein, it is meant that an alkoxy group is appended to a lower alkyl group. When the term "alkoxycarbonyl" is used herein, it is meant R20c(o)_, wherein R20 is alkoxy. When the term "alkylamino" is used herein, it means _NHR16, wherein r6 is a lower carbon number. When "alkylaminocarbonyl is used herein, the term means R2iC(〇)_' wherein R21 is an alkylamino group. When "extension base" is used herein, it means that by removing two nitrogen atoms, it is derived from a carbon atom containing from ... a divalent group of a straight or branched saturated hydrocarbon, such as methylene (even), anthracene, 2_ethylidene (_CH2CH2_), 1,1-extended ethyl (-ch=ch3), 1, 3-extended propyl (_CH2CH2CH2_), 2 2 dimethyl propyl propyl (-CH2C(CH3)2CH2-), and analogs thereof. When the term "amine carbonyl" is used herein, it means 4 ( 0^%. When the term "•aryl" is used herein, it means a mono- or bicyclic carbocyclic system containing 6 to 12 carbon houses and has - or two aromatic rings, including However, it is not limited to phenyl, tea base, tetrahydrocarbyl, hydrogen imprinted, although the base and the like O: \ 106 \ 106749. DOC • 35 - 1292752. The aryl group may be unsubstituted, or Two or three are respectively selected from a lower alkyl group, a halogen, Alkyl, alkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amine, alkylamino, dialkylamino, amine carbonyl, decyl, nitro, carboxaldehyde, carboxyl and Substituted by a hydroxy group. As used herein, the term "aralkyl" means that the previously defined aryl group is appended to a lower alkyl group, such as a fluorenyl group and the like. As used herein, the term 'cycloalkyl," is taken to mean an aliphatic ring system having from 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkylalkyl" as used herein, means that a cycloalkyl group is appended to a lower alkyl group, including but not limited to cyclohexylmethyl. "Dialkylamino" is used herein. The term means _NRi6Ri7, wherein Rl6 and R17 are each selected from lower alkyl. When the term "dialkylamino" is used herein, it means R22C(〇)_, wherein The ruler 22 means a dialkylamino group. It means -C-Br, -I or -F. In the term, it means R180-, wherein $, means a lower alkyl group such as a chloromethyl group, Ethyl, tri-alternative is used herein as the term "halogen", as used herein, "- alkoxy aryl 18 is _ alkyl. As used herein, "halogenated alkyl", one or more The hydrogen atom is replaced by a halogen with a fluoromethyl group and the like. When "heterocycle" is used herein, it means any 3 or 4 membered ring containing one hetero atom selected from the group consisting of oxygen, nitrogen and sulfur; Is a 5-, 6- or 7-membered ring containing one, two or three heteroatoms each selected from nitrogen, oxygen and sulfur, or

O:\106\106749.DOC -36- 1292752 A 5-membered ring of four nitrogen atoms; and includes one or one oxygen atom; one sulfur, one or two or three nitrogen atoms; one melon, one nitrogen and one One sulphur is one oxygen atom, in a non-adjacent position, one nitrogen and one oxygen and one sulphur in, 虱 atoms, in non-adjacent positions; two = two 在 in adjacent positions The position of the two sulphur atoms of the nitrogen atom and a 1U nitrogen atom, two adjacent sulfur atoms, two non-adjacent nitrogen atoms and one of the 'two non-adjacent atoms and one oxygen atom The 5_, 6_ or 7_ member 5-membered ring has 0_2 double bonds, and the 6_ and 7 rhymes have ^ double bonds. ^The nitrogen hetero atom is required to be recorded in four stages. The heterocyclic ring is also included. a bicyclic group wherein any one of the above heterocyclic rings is fused to a benzene ring or a cyclohexyl ring or other heterocyclic ring (for example, a phenyl group, such as a linyl group, a hydrazino group, a tetrahydro group such as a linoleyl group, a benzopyrene group) :, bistetrahydrofuran or benzothiophene and its analogs). Heterocycles include azaindole, P. loperyl, sulfonyl, p. piroxicam, fluorenyl, oxazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazole Pyridyl, pyridyl, hexahydropyridyl, homohexahydropyridyl, pyridinyl, hexahydropyrrole, ocaltidine, hydrazine, carbazolyl, oxazolidinyl, isoxazolyl, iso Oxazolidine, morpholinyl, oxazolyl, pyrazolyl, isoxazolyl, isoxazolidinyl, fluorenyl, hydrazinoyl, iso-r-quineyl, benzimidazolyl, Benzoindolizin, benzoxazolyl, furyl, pyrenyl, tetrahydrofuranyl, tetrahydropyrimenyl, oxazolidinyl, isoxazolyl, triazolyl, tetrazolyl, isoindole Azolyl, 4 dithyl, thiadiazolyl, pyrrolyl, pyrimidinyl and benzopyrhenyl. Heterocycles also include

Compound of O:\106\106749.DOC -37- 1292752, wherein X*g_CH2_, -NH- or -〇-, γ* is _c(0)_ or [•C(Rn)Hv where R" is hydrogen Or (VC4 alkyl, and v is 1, 2 or 3, and Z* is or -NH-, such as 1,3-benzodioxo, 1,4-benzodioxanyl and The heterocyclic ring may be unsubstituted or may be selected from one, two, three or four, respectively, including a trans group, a halogen, an oxo (=Q), an alkyl imino group (R*N= , wherein R* is a lower carbon number), an amine group, an alkylamino group, a dialkylamine group, an alkoxy group, a pyroxyalkoxy group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, Substituted by a substituent of C〇〇H, -S03H and a lower carbon number. Further, the nitrogen contained in the heterocyclic ring may be N-protected. When the term "hydroxyalkyl" is used herein, Refers to a lower alkyl group attached to a thiol group. As used herein, "lower alkyl," means a straight or branched alkyl group having up to 6 carbon atoms. a group, including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, second-butyl, Di-butyl, n-pentyl, i-methylbutyl, 2,2-dimethylbutyl, 2-indolyl, 2,2-propenyl, n-hexyl and the like. The term "thioalkoxyalkyl" as used herein, means that a thioalkoxy group is attached to a lower alkyl group. The formula of the invention can be prepared as shown in the scheme MV. ^Calculate. As outlined in Scheme I, intermediates i and 1 (wherein ?1 is an ice protecting group, such as a third-butoxycarbonyl group) can be coupled using standard peptide coupling reagents and methods, For example, in 1-hydroxybenzotriazole and such as dicyclohexylcarbodiimide (DCC) or N-ethyl-quinone-diaminopropylcarbodiimide (EDAC) and its O:\106\ 106749.DOC -38^ 1292752 In the presence of a diimine such as an analog, the hydrazine is reacted with it to obtain i. Alternatively, a salt of the intermediate L or a derivative of an activated ester (for example, decyl chloride) may be used. By reacting a carboxylic acid with sulfite gas to prepare a reaction with an intermediate. The compound i can be deprotected by N_ to give a compound. In the N-deprotection of i, P] (especially Where Pl is Tri-butoxycarbonyl) is an acid-labile N-protecting group which results in the formation of impurities due to the transfer of the thiol group R4-Li-C(0)- from the amine group to the hydroxyl group. Deprotection to reduce or eliminate the formation of impurities: 〇) use difluoroacetic acid in dichloromethane, or (2) use concentrated hydrochloric acid in acetic acid at about room temperature (from about 2 moles equivalent) Up to about 6 mole equivalents, preferably from about 2 mole equivalents to about 4 mole equivalents. A preferred method of N-deprotection comprises reacting a compound (wherein P1 is a third-butoxycarbonyl group) in acetonitrile (from about 2 to about 1) at a temperature of from about 〇 ° C to about 5 ° C. 〇 liters per kg of compound d is reacted with concentrated hydrochloric acid (from about 10 to about 20 mole equivalents). Compound 5 or its activated ester derivative can then be coupled to the compound to provide a compound of formula j. (ie, 6). Another method is shown in Scheme IIA. The compound κ can be conjugated to a protecting group, such as an anthraceneoxycarbonyl group, to the compound oxime, or an activated derivative thereof (eg, fluorenyl) Chlorine, prepared by reacting a carboxylic acid with sulfite gas, gives [. The compound can be deprotected by N-protection to give 9. Compound 9 can be coupled with Compound 1 or its activated ester derivative to provide a compound of formula j (i.e., mutual). Scheme IIB shows another preferred method wherein it is in an inert solvent (e.g., ethyl acetate, dimethylformamide, THF, acetonitrile, isopropyl acetate or toluene and the like) at about from about 0. From °C to about 50 ° C, the N-O:\I06\106749.DOC -39-1282952 protected amino alcohol domain 3 is hydrogen and? 4 secret protecting groups, or p々p4 are n_ protecting groups, preferably p3 and ? 4 is a genus), with a slow acid s or a salt thereof or an activated ester derivative (for example, decyl chloride) from about i to 3 mil = 1 by means of a slow acid in acetic acid or THF Prepared by reacting with sulphur chloride or in toluene wrist F and its analogs with grass cockroaches), from about 1 Torr to about 4 Torr molar equivalents (preferably from about 2.5 to about 35 moles) Equivalent organic amine base (eg imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, "imidazole, 4-nitroimidazole, pyridine, N,N-dimethylamino Pyridine, ^4-triazole, (tetra), 3-methyl(tetra), triethylamine or N-methyl?4 and its analogs), or an inorganic base (eg, carbonic acid) from 1 to 20 mils The reaction is carried out in the presence of sodium or sodium hydrogencarbonate and its analogs to give the compound Zhao. Preferred organic amine bases include imidazole and tris. Deamination of hydrazine (for example, using hydrogen and a hydrogenation catalyst, Or Pd/c and formate salts (such as ammonium formate and its analogs), or pd/c and formic acid and their analogs) are provided by the use of organic carboxylic acids (eg s_pyroglutamic acid, succinic acid or Anti-butene The catalytic action of the acid and its analogs advantageously enriches compound 2. The preferred organic carboxylic acid is s-pyroglutamic acid. The compound art (or organic carboxylate of the compound) is from about 1 〇 to about 莫The equivalent of carboxylic acid 1 or its activated ester derivative (e.g., sulfhydryl gas) is from about 4 to about 8 mole equivalents (preferably from about 5 to about 7 mole equivalents) in (1). In the presence of an inorganic base such as NaHC03, Na2C03, KHC03, K2C03, NaOH or KOH and the like, in an inert solvent (eg ethyl acetate/water of 丨··, or isopropyl acetate/water, or toluene) /water or THF/water and its analogues) 'react at about room temperature, or (2) at from about 1. 〇 to about 4 〇Mo:\106\106749.DOC -40-1292752 Equivalent (preferably from about 2. 5 to about 3.5 molar equivalents) of an organic amine base (e.g., sigma, 1-methyl sputum, 2-methyl glutinous rice, 2-isopropyl odor唆, 4-曱基咪 saliva, 4-triosyl taste. Sit, ρ ratio α,] Sf, N-diamine group ρ than bite, 1,2,4-tris, 峨, 3- Preservation of pyrrole, triethylamine or N-mercaptomorpholine and its analogues In the following, in an inert solvent (such as ethyl acetate, isopropyl acetate, THF, toluene, acetonitrile, dimethyl decylamine and the like), at a temperature of from about 〇〇c to 5 〇 ° C The reaction provides Compound 6. In a preferred embodiment of the invention (shown in the scheme), the intermediate compound i has the chemical formula of the compound (I is as defined in the formula) and is preferably isopropyl. Compound U can be prepared by various methods as shown in the scheme. In one method, the amino acid (free carboxylic acid or carboxylic acid) can be reacted by reacting with a suitable gasified formate and its analogs. The ester (that is, in the form of low-stone antibacterial vinegar) is converted to the carbamic acid g. q (R, phenyl, low sulfonic acid substituted phenyl, halogen substituted phenyl, nitro substituted Phenyl, difluoromethylphenyl and the like). The urethane U and the amine 丄i or its acid addition salt (1) from about 1 Torr to about 1.5 moles are excipients, such as ci, Br, I or sulfonates, such as f-alkanes Sulfonate, trifluorosulfonate, p-toluenesulfonate, besylate and the like) in an inert solvent (eg, methyl third-butyl ether, dimethoxyethane, THF/ In water, dimethoxyethane/water, toluene or heptane and the like, in the range of from about 2. 5 to about 3.5 molar equivalents (eg Li〇H, NaOH, Li2C) The reaction is carried out in the presence of ruthenium 3, Na2C〇3, benzene oxide or sodium phenoxide and the like to provide urea. The urea oxime can be isolated and made in an inert solvent (e.g., THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane, and the like), from about 2 Torr.

O:\106\106749.DOC -41 - 1292752 to the test of the content of about 5 · 〇 molar equivalent (such as potassium - potassium butoxide, sodium hydride, potassium hydride or dimethyl pyridine and its analogues Further reaction, or onion i is converted to cyclic urea. If the amino acid vinegar of Liao is the starting material, the ester is hydrolyzed to provide a carboxylic acid waste. Or by using an amino acid JJ_ (in the form of a free carboxylic acid or a carboxylic acid ester) in an inert solvent such as THF, dimethoxyethane, decyl-tert-butyl ether, toluene or heptane and In the analog), in the presence of a base, with from about 1 Torr to about h5 molar equivalents of isocyanate ii (Q is a cleavage group, for example, or a sulphonate such as methane sulfonate, trifluoro The sulfonate, p-toluenesulfonate, besylate and the like are reacted to convert it to urea. Alternatively, the amino acid can be used as a free carboxylic acid or a carboxylic acid ester. Form), in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, terpene or heptane and the like, at a molar ratio of from about 1 Torr to about 4 Torr. In the presence of a base such as NaH or a third potassium butyl sulfonate and the like, and an amine u or an N-protected derivative thereof from about 0 to about K5 molar equivalents (Q is a cleavage group, For example, C1, hydrazine or hydrazine, or a sulfonate such as methanesulfonate, trifluoroate, p-toluene, benzoate, and the like, are reacted and converted If the ice is protected diamine derivative of ^, N- deprotection is required. Diamine & carbonyl equivalents (such as phosgene carbonyl-imidazole and its analogs, wherein Q, and Q" are ex-ion groups, CCl Br I, -〇-lower alkyl, 〇_芳Or imidazolyl and analogs thereof, in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane and the like, at from about 2 Torr to about 4 The presence of 〇 molar content (NaH or third potassium butoxide and its analogues)

The reaction carried out by O:\106\106749.DOC -42-1292752 gives the cyclic urea. If the amino acid ester is the starting material, then the hydrolysis is carried out to provide a buffer acid. Alternatively, compound 11 (as a free carboxylic acid or a decanoic acid ester (ie, a lower alkyl number)) can be used as described in Scheme IV, according to j. Am. Chem. Soc. 21, 2599 (1950) and C. The guanonitrile is reacted to obtain an aminonitrile cluster. Alternatively, acrylonitrile is replaced by 3-chloropropionitrile to provide 21. The N-protection of the aminonitrile cluster is the same as that of the urethane (Rm is a low carbon number or a phenyl or a halogen group (for example, 2-gas ethyl, 2-diethyl and the like) and the like ) using standard conditions (such as an amine with a suitable pure chloroformate (C1C(0)OR3〇, where r3〇 is a lower alkyl, a benzyl, a halogen group, and the like), or In inert solvents (such as water, THF and the like), in inorganic tests (such as Na〇H, KOH, K2C03 and their analogs) or organic tests (such as alkyl or dialkyl amines and their analogues) The reaction in the presence of an analog thereof) provides the compound u. 19 in the presence of a catalyst (eg Ni-Al alloy (alkaline) or bismuth (neutral or basic) or 扒〇2 (acidic) and its analogues] in an inert solvent (eg water or Hydrogenation in methylation or ethanol or butyl HF and its analogs provides cyclic urea. In a preferred method, in the presence of a Ni-Al alloy catalyst, in an inert solvent such as water or methanol or ethanol or THF and the like, in the test from the content of about 1 Torr (for example, KOH) The compound is hydrogenated to provide cyclic urea oxime in the presence of NaOH or LiOH or an organic amine assay and the like. If the amino acid ester of 11 is the starting material, the ester is hydrolyzed to provide the carboxylic acid M. Alternatively, the diamine M provided by the hydrogenation of compound U (as described above for the compound) is converted to a compound as previously described. If the amino acid ester of 11 is the starting material, the ester is then hydrolyzed to provide the carboxylic acid M. O:\106\106749.DOC -43 -

1292752 Plan i

5

O:\106\106749.DOC -44- 1292752

Plan IIA

R

R5

O:\106\106749.DOC -45- 6 1292752

Plan IIB

Nh2

P3=P4=::t:

1

O:\106\106749.DOC -46 - 6

1292752 Plan in

O:\106\106749.DOC 1292752 Plan ιν

Plan I V

CN N( H2N\ /C02H Ra

R3 nh2 hnx^co2h NH丫^C〇2H r3 18

V

〇R30 · C02H ia

r3IS n HN\^V^^C〇2H o r3 A key intermediate for the preparation of the compounds of the invention, including a compound of formula III and a compound of formula IV as described above:

O:\106\106749.DOC -48, 1292752 or a salt thereof, wherein P3 and P4 are each independently selected from hydrogen or an N-protecting group;

RdaR2 is respectively selected from the group consisting of a lower alkyl group, a cycloalkylalkyl group and an aralkyl group; R3 is a lower alkyl group, a hydroxyalkyl group or a cycloalkylalkyl group; and R5 is

(CH2)m

e) (CH2W O:\106\106749.DOC -49- 1292752

ο

Where η is 1, 2 or 3, m is 1, 2 or 3, m, is 1 or 2, X is 〇, S or NH, and Y is -Ch2_, -〇-, _S_ or -N(R6)- Wherein R6 is hydrogen, a lower carbon alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and γ" is _CH2- or -N(R6")-, wherein is hydrogen, low carbon a number of alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl groups, Y' is -N(R6,)-, wherein r6 is hydrogen, lower alkyl, cycloalkyl, naphthenic Preferred are alkyl, aryl or aralkyl groups, and 2 is preferably 〇, s or NH 〇 wherein P3 and I are hydrogen or benzyl, core and 1 are aralkyl, and R3 is lower alkyl. , and Han 5 is O:\106\106749.DOC -50-

X X1292752

Wherein X, Y, Y, Y', Z, R6 ", η, m and m' are as defined above for the compound of formula IV. More preferred compounds are those wherein 1^ and 2 and fluorenyl, or 1 is benzyl and are lower alkyl, R3 is lower alkyl, and R5 is O:\106\106749.DOC •51 - 1292752, Ν^γ

(CH2)nV a) wherein n is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

b) z

Where m is 1 or 2, X is 0, Y is -CH2- and Z is Ο, X \人L λζ c) (CH2)m· where m' is 1, X is Ο, Z is 0 and γ is - , \Λυ"

d) (CH2w where m' is 1, X is 0, Y" is -NH- and Y' is ·νη_, or

Ν · Rs·· Ν e) A compound of the formula IV wherein X is deuterium and R0n is hydrogen. A still more preferred compound is its center and is 2 and benzyl, or R1 is benzyl and & 2 is isopropyl, R3 is lower alkyl, and R5 is -52-

O:\106\106749.DOC 1292752

a) where n is 1 or 2, X is 0 or S, and 丫 is _Ch24 -NH-,

Where m is 1 or 2' X is 0' Y is -CH2- and Z is Ο,

Where m' is 1 'X is 0' Ζ is 〇 and 乂

(CH2W where m* is 1 'X is 0' Y'' is -NH- and γ is, or

X hT^N-Re- e) A compound of formula IV wherein X is deuterium and RV· is hydrogen. The most preferred compound is its center and 仏2 and benzyl, or Ri is fluorenyl and the core is isopropyl, R3 is lower alkyl, and r5 is O:\106\106749.DOC •53- 1292752

a) where η is 1 or 2, X is Ο or S, and Y is _CH2 or -ΝΗ·

〇)

Where m is 1, X is Ο, Y" is _NH- and, or X rr^N-Re·* ❿

(CH2)m·d) A compound of the formula IV wherein X is deuterium and RV· is hydrogen. The most excellent compound is its center and meaning 2 is benzyl, or the heart is fluorenyl and isopropyl, R3 is lower alkyl, and 5 is

a compound of formula IV wherein η is 1 or 2, X is 0 or S, and Y is -Ch2 or _NH-

O:\106\106749.DOC -54 - 8 1292752 The preferred salt of the compound of formula ιν is an organic carboxy group.

Acid Salt [Embodiment J. Acid Coke Glutamine The following examples illustrate the preparation of the novel compounds of the present invention.角知供 further (2S,3S,5S)_(2,6- -5-[2S-(l-味唆唆' ethoxyethoxyethyl) saddle-based _3_pyridyl)) - propyl aryl] Aminodiphenyl A·N'N-Phenyl-(l)-phenylalanine monoester will contain L-phenylalanine (10) kg '975 moles), potassium carbonate (10) kg' A solution of 3220 moles, water (675 liters), ethanol (34 liters liters) and stearyl chloride (Chuan kilograms, 3275 moles), heated to alumina (1) for 1 〇 24 hours. The reaction mixture was cooled to 60. (:, and remove the water layer below. Add heptane (850 liters) and water (385 liters) to the organics, stir and separate the layers. Then rinse with water/methanol mixture (150 liters / 150 liters) Organic matter once. The organics are then dried to give the desired product as an oil which is taken to the next step without purification. IR (pure) 3090, 3050, 3030, 1730, 1495, 1450, 116 〇 - 1, iHNMRQOO megahertz, CDC13) (5 7.5-7.0 (m5 20H) 5 5.3 (d5 1H, J = 13.5 Hz), 5.2 (d5 1H, J = 13.5 Hz), 4.0 (d5 2H, J = 1 5 Hz), 3.8 (t, 2H, J = 8.4 Hz ()), 3.6 (d, 2H, J-15 Hz), 3·2 (dd, 1H, J = 8·4, 14.4 Hz), 13C NMR (300 megahertz, CDCl3) (5 172.0, 139.2, 138.0, 135·98·2, 128.1, 128.1, 126.9, O:\106\106749.DOC -55- 1292752 126.2, 66.0, 62.3, 54.3, 35·6 〇]d -79〇(c = 〇·9, DMF) Β·(4S)-4-(N,N-Dibenzylamino)-3-oxo-5-phenyl-pentanenitrile under nitrogen, will contain examples in 520 ml of tetrahydrofuran and 42 ml of acetonitrile A solution of the product of hydrazine (ie benzyl ester) (about 〇·45 mol) was cooled to -4 CTC. The second solution containing sodium aminate (48 7 g, 1.25 mol) in 850 ml of tetrahydrofuran. Cool to _4 (rc. Slowly add 75 ml of acetonitrile to the sodium azide solution and stir the resulting solution for 15 minutes at -40 ° C. Then azide/acetonitrile at -40 ° C The solution was slowly added to the benzyl ester solution. The mixed solution was mixed at -40 C for 1 hour, and then the solution was stopped with 25% (body weight/body weight) of 11% 体重ml. The slurry is returned to the ambient temperature and the organic matter is separated. The organics were then rinsed with 35 mL (v/v) sodium hydride solution and diluted with 9 mL heptane. The organics were then rinsed three times with 900 ml of a 5% (w/v) sodium sulphate solution. Rinse twice with 900 ml of 10% methanolic aqueous solution and rinse once with 9 〇 0 ml of a 1 5% decyl alcohol solution. It was then rinsed once with 9 ml of a 2% methanol aqueous solution. The organic matter was dried and the resulting material was dissolved in 700 ml of hot ethanol. When cooled at room temperature, the desired product precipitates. Filtration gave the desired product, which yielded 59% from L-phenylalanine. IR (CHC13) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 13〇〇, 1215 cm-1,4 NMR (CDC13) 7.3 (m, 15H), 3.9 (d5 1H, J = 19.5 Hz), 3.8 (d5 2H, J = 13·5 Hz), 3.6 (d, 2H, J = 13.5 Hz), 3.5 (dd, 1H, J = 4.0, 10.50 Hz), 3.2 (dd5 1H, J = ι〇·5, 13·5 Hz), 3.0 (dd, 1H, J = 4·0,

O:\106\106749.DOC -56- 1292752 13.5 Hertz), 3.G (4) Field 'J = 19.5 Hz), 13C NMR (300 MHz CDC13) ^ 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4 〇[, ]D -96»(〇= 〇·5, DMF) 〇C· (5S)-2-amino _5_(N,N-dibenzylamino Wide 4_oxo-M diphenylhex-2-carbene will be vaporized benzyl magnesium (378 kg, in _ 2 2), 7 〇 8 mol)

In the solution of the nitrile product (9) metric, 244 moles of the example (7) in tetrahydroanthracene, south (288 liters). The solution was warmed to ambient temperature and stirred until the analysis showed no starting material. The solution was then cooled to 5 ° C and slowly transferred to a solution of 15% citric acid (465 kg). The original container was rinsed with additional tetrahydrofuran (85 liters) and the rinse was added to the citric acid suspension container. The organics were separated and washed with 1 〇〇 / 〇 sodium chloride (235 kg) and then dried. The product was again dried from ethanol (289 liters) and then dissolved in 8 (TC acetonitrile (581 liters). After cooling to room temperature, stirring for 12 hours. The resulting product was filtered and at 3 〇〇c Dehydration in a vacuum oven yielded about 95 kg of the desired product. Melting point 1〇1_1〇2〇c, IR (CDC13) 363G, 350G, 311G, 3G6G, 3G3G, 223G, 1620, 1595, 1520, 1495, 1450 cm - 1,1 only]^]\411 (3 00 megahertz, €00:13) (19.8 (br s, 1H), 7·2 (m, 20H), 5.1 (s, 1H), 4.9 (br s, 1H), 3.8 (d, 2H, J = 14.7 Hz), 3.6 (d5 2H, J = 14.7 Hz), 3.5 (m, 3H), 3.2 (dd' 1H, J = 7.5, 14.4 Hz), 3.0 (dd , 1H, J = 6.6, 14·4 Hz), 13C NMR (CDC13) d 198.0, 162.8, 140.2, 140.1, 136.0, 129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 127.3, 126·7 O:\106 \106749.DOC -57- 1292752 125.6,96·9,66.5, DMF) 〇54·3, 42·3, 32.4

[α JD ]47°(c = 〇·5, benzylamino)>3_hydroxy-di

D·(2S,3S,5S)-5->S^|-2-(JV,]V phenyl burned two == Γ (157 liters) of 'sodium hydride ("kg, -, ear) The good dirty liquid is cooled to less than _10±5. (41·6 kg, 433 m is added to the f alkane sulfonic acid. 〇 The following one, w σ during the action to maintain the temperature at 0 ★. - Complete the addition For the purpose, slowly add water (6 liters, 333 gram of the product of 1C (20 kg, 43 Mo, hopper) and tetrahydrofuran (6 1 liter), while the temperature during the addition Maintain the following. Mix the mixture for at least 9 hours at 0 ± 5 C. /) Add the hydrogenated sodium (6.6 metric liters, Μ molar) and tetrahydrofuran (157 liters) to the separated simmer. _5±5. After that, add trifluoroacetic acid (24·8 kg, 218 mol) while maintaining the temperature below 15 ° C. Stir the solution at 15 ± 5 ° C for 30 minutes, then add it To the reaction mixture obtained in the step ,, keep the temperature below 2 〇t. Stir under 2 〇 ± 5 until the reaction is completed. Then cool the solution to 1 〇 ± 51, and 3 Ν ν & 195 kg) make it After stirring, the organic layer was separated after stirring with the third butyl butyl ether (162 liters), and washed with 〇·5Ν NaOH (200 kg) _ times to 20% by weight/volume of aqueous ammonium chloride (195 kg). Rinse once and rinse twice with 25% aqueous sodium chloride (160 kg). Dry the organics to give the desired product as an oil, which was used directly in the next step. IR (CHC13) 35 10, 3400, 3 110, 3060, 3030, 1630, centimeters -1, 1H NMR (3 00 megahertz, CDC13) (5 7.2 (m5 20H) 5 4.1 (d? 2H? O:\106\106749.DOC -58- 1292752 卜 13.5 Hertz), 3.65 (111, 111), 3.5 ((1, 211, 1 = 13.5 Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1·55 (m , 1H), 1·30 (m, 1H), 13CNMR (300 MHz, CDC13) δ 140.8, 140.1, 138.2, 129.4, 129.4, 128.6, 128.4, 128·3, 128·2, 126·8, 126.3, 125.7,72·0,63.6,54·9,53.3,46.2,40.1,30·2. Ε· (2S,3S,5S)-2-(N,N-di-arylamino)_3-carbo-5 -(T-butoxycarbonylamino)-1,6-diphenylhexane to BOC anhydride (65 kg, 373 mol) and 1% potassium carbonate (5 50 kg) is added to [28,3 8,5 8]-2-team 1^diamido-3-yl-5-amino-1 in 1\4 butyl 6 (1096 liters). A solution of 6-diphenylhexanone (about 1 〇 5 kg, 226 mol). The mixture was stirred until the reaction was completed (about 1 hour). Remove the bottom layer and rinse the organics with water (665 liters). The solution is then dried to give the desired product as an oil. 300 Hz centimeters ' b NMR (CDC13) 5 1.40 (s, 9H), 1·58 (s5 2H), 2·45-2·85 (m, 4H), 3.05 (m, 1H), 3·38 (d , 2H), 3.6 (m, 1H), 3.79 (m, 1H), 3·87 (d, 2H), 4.35 (s5 1H), 4·85 (s, broad, 1H), 7.0-7.38 (m5 20H). Fl·(2S,3S,5S)-2_Amino_3_hydroxy-5-(tris-butoxycarbonylamino)-1,6-·-phenylhexanone is stirred, in sterol ( [2S,3S,5S]-2-N,N_: benzylamino-3-hydroxy-5-tris-butoxycarbonylamino-1,6-diphenylhexane (12 g) In a solution of 21.3 millimoles, ammonium formate (8·5 g, 128 mmol, 6.0 equivalent) and 10% palladium carbon (2.4 g) were added. The solution was stirred at 60 ° C under nitrogen for three hours and then at 75 ° C for 12 hours. Additional ammonium formate (6 grams) and 10% palladium carbonium (5 grams) were added, along with 1 ml of glacial acetic acid. The reaction is made at O:\106\106749.DOC -59-1292752

It was completed in 2 hours at reflux temperature. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite. The filter cake was rinsed with methanol (75 mL) and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in 1N EtOAc (3 mL) andEtOAcEtOAc The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. The solution was concentrated under reduced pressure to give the desired product as a pale oil which slowly crystallised (5 g). Further purification of the product (gelatin, 5% decyl alcohol in dioxane) can be accomplished by flash chromatography. 300 MHz iH NMR (CDCl3) 5 142 (s, 9h), 158 plus, 1H), 1.70 (m, 1H), 2 2 〇 (s, broad, 2H), 厶52 (9), ih), 2·76 -2·95 (m, 4Η), 3·5〇 (m, 1H), 3% (m, 1H), 4 8〇 (d, broad, 1H), 7.15-7.30 (m, 10H). F_2·(2S,3S,5S)-2-Aminohydroxy 3rd-butoxycarbonylamino-1,6-diphenylhexyl benzoate

Adding 5 〇/〇 palladium carbon (24 kg) in methanol (285 ml) to [2S,3S,5S]-2-N,N-dibenzylamino hydroxy _ in methanol (437 liters) Third · Oxygen 1 -ylamino-1,6-monophenylhexan (about 127 kg, 225 mol) solution. A solution of ammonium formate (84 liters, U32 mole) in methanol liters was added thereto. The solution was heated to 75 艽 6_12 hours and then cooled to the approximate extent. Methanol was removed from the reaction mixture by heat and vacuum (up to 7 Torr) using a paper coated with (4) (Shiyoshizao). The residue was dissolved in isopropyl acetate (4400 kg), heated (40 C) and then rinsed with 1% sodium carbonate solution (725 kg) and finally rinsed with water (665 liters). Both rinsing steps are carried out at 40 ° C and will

O:\I06\106749.DOC -60-1292752 The product is stored in solution. The heat was removed in vacuo (up to 7 (rc) to remove the solvent. Then isopropanol (475 liters) was added and stripped to remove residual solvent. Isopropanol (1200 liters) was added to the residue, And stirred until homogenization. A solution of succinic acid (15_4 〇 kg) in isopropanol (12 liters liter) was added to the solution. The solution cannula was heated to 70 ° C to dissolve all solids. 'It was then allowed to cool slowly to room temperature and stirred for 6 hours. Then the solution was allowed to pass to give the desired product (55-8 〇 kg) as a white solid. Melting point: 145-146 C. 1HNMR· · (Me2SO-d6, 300 megahertz) (5 〇·97 (d, 3H, IPA), 1.20 (s, 9H), 1.57 (t, 2H), 2.20 (s, 2H, succinic acid), 2.55 (m5 2H), 2.66 (m, 2H), 2.98 (m, 1H), 3.42 (m, 1H), 3.70 (m, 1H), 3·72 (m, 1H, IPA), 6.60 (d, 1H) , guanamine NH), 7·0-7·3 (m, 10H). 4 NMR (CD3OD, 300 MHz) 5 1·11 (d, 3H, J = 7 Hz, IPA), 1·29 (s , 9H), 1.70 (m5 2Η), 2·47 (s5 2H, succinic acid), 2·65 (m, 2H), 2.85 (m5 2H), 3.22 (m,1H), 3.64 (m,1H),3·84 (m5 1H),7·05_7·35 (m,10H) 〇G· 2,6-xylyleneoxyacetate ethyl bromoacetate Ester (18.2 ml, 164 mmol) and carbonic acid planer (58 g, 176 mmol) added to 2,6-dioxol (8.0 g, 6 6 in dioxane (600 ml) The reaction mixture was heated to reflux for 小时$ hr, cooled to room temperature 'transition and concentrated in vacuo. Purified by Shixi hose column chromatography (5% to 20% in hexane) The diethyl ether) gave the desired compound (8 〇〇 / 〇). 300 MHz NMR (CDC13) 5 1.35 (t, J = 7.5 Hz), 2.30 (s, 6H), 4.31 (q, J = 7· 5 Hz, 2H) 5 4.40 (s, 2H), 7.0 (m, 3H). O: \106\106749.DOC -61 - 1292752 t H. 2,6-diphenoxyacetic acid at 0 ° C 5.3 g of lithium hydroxide was added to the compound from Example 1 (5.15 g, 24.7 mmol) in methanol (17 liters) and water (56 mL), in a solution, and at room temperature. The solution was stirred for 1.5 hours and concentrated in vacuo. The residue was acidified with EtOAc EtOAc (EtOAc) ML). The organic layer was dried and concentrated to give a white solid (4·5 g, 91%). 300 megahertz! H NMR (CDC13) δ 2.30 (s, 6 Η), 4.48 (s 2 Η) 7.0 (m, 3H). I·(28,38,58)-2-(2,6-xyloxyethenyl)amino-3-3-yl-amino-5-(tris-butoxycarbonylamino) 4,6-diphenyl The amine from Example ip was coupled with the acid from Example 1H using a standard EDAC coupling procedure to give the desired compound (78%). 3 〇〇 megahertz 1hnmr (CDC13) 5 1.40 (S, 9H), 1.65 (m, 3H), 2.18 (S, 6H), 2.78 (m, 2H), 2.98 (d, J = 9 Hz, 2H), 3.75 (m,1H), 3.90 (m,1H) 4.15 (m,1H), 4.20 (s,2H),4·60 (m,1H),7.0 (m,3H),7·25 (m,10H) ). Mass spectrum: (m = H) + = 547. J· 2-N-(benzyloxycarbonyl)amino-acetaldehyde 1.34 ml of oxalic acid chloride was added dropwise to a solution of 1·45 ml of DMSO in 2 mL of CH 2 Cl 2 at -78 °C. After 15 minutes at -78 °C, a solution of N-Cbz-aminoethanol in 40 ml of CHAl2 was added. At _78. After 5 minutes at 〇j and 2 minutes at 〇 °C, the solution was cooled to _78, and triethylamine (6.14 ml) was added dropwise. At _78. (The solution was stirred for 3 minutes, poured into 50 ml of ice-cold 1% aqueous citric acid, and extracted with diethyl ether (15 mL). The combined organic layer was washed with brine and dried with anhydrous ^s〇4

O: \106\106749.DOC -62- 1292752 Dehydrated; filtered and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) 3〇〇 megahertz hNMMCDCIO 5 (s, 2H), 5·40 (br s, 1H), 7.36 (m5 5H), 9·66 (s, 1H). Mass spectrometry: (Μ+ΝΗ4)+ = 21 Κ· Ν-(benzyloxy-demethylamino)-ethyl methionine methyl hydrazide hydrogenate (〇·72 g, 4.29 mmol) Sodium acetate (〇.7 g '8·58 mmol) and sodium cyanoborohydride (〇·54 g, 8.58 mmol) were added to 17 liters of sterol' from the example ij Chun (O ja gram, 4.29 millimoles) in solution. The mixture was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (1 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 3 〇〇 megahertz NMR (CDC13) occupies 0·91 (d, J = 3 Hz, 3H), 0·94 (d, J = 3 Hz, 3H), 1.90 (m, 1H), 2.55 (m, 1H) ), 2.80 (m5 1H), 2.98 (d, J = 6 Hz, ih), 3·20 (m, 1H), 3.30 (m, 1H), 3.71 (s, 3H), 5.10 (s, 2H), 5·27 (br s, 1H), 7.37 (m, 5H). Mass Spectrum: (M+H)+ = 309. Methyl L. 2S-(1-imidazolidin-2-one)-3-methylbutanoate was removed by hydrogenolysis to remove the Cbz-protection of the compound of Example 1K and was used in CHzCl2 1,1_carbonyldiimidazole was used to treat the crude product to give the desired compound (64%), 300 Hz iHNMR^CDCh) 5 0.95 (d,

O:\106\106749.DOC •63- 1292752 =7.5 Hz), 〇·98 (d, Bu 7.5 Hz, 3H), 2.15 (m, 1 Η), 3·47 (m5 3H), 3.71 (s , 3H), 3.73 (m, 1H), 4.23 (d, J = 10.5 Hz, 1H), 4·81 (br s, 1H), mass spectrum: (M+H)+ = 2〇1. Μ· 2S-(1-imidazolidinyl)-3•methylbutyric acid was added to lithium hydroxide monohydrate (20 equivalents) in ·5 ml of water and 5 liters of dioxane under 〇c , a solution of the compound from Example 1L (151 mg, 0.75 mmol). Stir the solution at 〇 ° C for 5 hours and at room temperature

Next hour. It was acidified with IN HCl, extracted with EtOAc (1 mL, EtOAc, EtOAc, EtOAc) ). 3 〇〇 megahertz iH NMR (DMSO-d6) 5 0.85 (d, J = 12 Hz, 3 Η), 0.92 (d, J = 12 Hz, 3H), 2·05 (m, 1H), 3.25 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 3.90 (d, J = 15 Hz, 1H), 6.40 (br s, 1H), 12.60 (br s, 1H). Mass spectrum: (M+H)+ = 187. Ν·(2S,3S,5S)-2-(2,6.Tolyloxyethyl)amino-3-3-phenyl-5-amino-1,6-diphenylhexyl at 4·5 g From the compound of Example II. Add 40 ml of each of ch2C12 and trifluoroacetic acid. The solution was left at room temperature for 1 hour. The solution was concentrated in vacuo to give the desired compound (100%). 300 MHz 4>^11(00€13) (5 1·48 (m, 1H), 1.62 (m5 1H), 2.05 (m, 1H), 2.24 (s, 6H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0-3.10 (m, 4H), 3.90 (d, J = 10 Hz, 111), 4.17 (111, out), 4.26 (eight 6951 = 13.5 Hz, 211), 7.0 (m, 3H), 7.10 (m, 2H), 7·30 (m, 7H), 7.41 (d, J = 10 Hz, 1H). Mass Spectrum: (M+H)+ = 447. O:\106\106749.DOC -64- 1292752 Q·(2S'3S,SS)-2_(2,6C-tolyloxyethyl)amino-3-3-hydroxymethane 唆_2_mercapto)_3_mercapto-butanyl]amino group Heart, 6-dihexane using standard coupling procedure [1-(3-dimethylaminopropyl)-wine in a DMF, a makeup j, such that the amine compound from Example IN was obtained from Example 1 The S coupling of '^' gives the desired compound (80%). 300 MHz 4 NMR (CDCl3) 5 〇·83 (d, J = 6 Hz, 3H), 0·86 (d5 J = 6H, 3H), U5 (m, 2h), 2.16 (m, 1 Η), 2 · 18 (s, 6H), 2.76 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3.14 (m, 2H), 3.30 (m, 2H), 3.70 (d, J = 1 - Her paper, 1H), 3.75 (m, 1H), 4.20 (m, 4H), 4.50 (br s, 1H), 6·70 (d, J = 7.5 Hz, 1H), 7·0 (m , 3H), 7.25 (m, 10H). Mass spectrum: (M+H)+ = 615. Example 2 (2S,3S,5S)-2-(2,6-xyloxyethenyl)amino-3-hydroxytetrahydropyrimidin-2-one)-3-methylbutanyl]amino- 1,6-Diphenylhexane A· 2S_(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid using the procedure described in Examples 1J to 1M, but with N-Cbz-3-amine Instead of the N-Cbz-aminoglycol in Example 1J, the desired compound was obtained. 300 MHz NMR (DMSO-d3) δ 0.82 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H), 1.77 (m, 2H), 2.10 (m, 1H), 3· 1〇-3·23 (m, 4H), 4.42 (d, J = 10.5 Hz, 1H), 6.37 (br s, 1H). Mass spectrum: (M+H)+ = 201. Β·(28,38,58)-2-(2,6-xyloxyethoxymethyl)amino-3-hydroxy O:\106\106749.DOC -65- 1292752 -5-[2S-( 1-tetrahydropyrimidin-2-one)-3-methylbutanyl]amino-1ί6-diphenylhexanhydride using standard procedures (EDAC in DMF), derived from the amine compound of the example ιΝ Example 2 Acid coupling of hydrazine gave the desired compound (7 〇./〇). 300 MHz NMR (CDC13) 5 0.80 (d, J = 4.5 Hz, 3 Η), 0·83 (d, J = 4.5 Hz, 3H), 1·50 (m5 1H), 1.65-1.72 (m, 6H) , 2.20 (s, 6H), 2.68 (m, 1H), 2.82 (m, 2H), 3.0 (d, J = 7.5 Hz, 1H), 3·05 (m, 4H), 3.77 (s, 1H) ), 4.07 (d, J = 4·5 Hz, iH), 4·20 (m, 4H), 4.50 (br s, 1H), 6.78 (br d, 1H), 7.0 (m5 3H), 7 · 25 (m, l〇H). Mass Spectrum··(M+H)+ = 629. Example 3 (2S,3S,5S)-2-(2,6-Dioxaphenoxyethenyl)amino-carbyl-5-[2S-(3-oxazolidine-2-one)- 3-methylbutylidene]aminodiphenylhexane A·2S-(3-oxazolidine-2-one)-3-methylbutyrate oxime ester in L-proline methyl ester hydrochloride ( A solution of ethylene oxide in ethanol (1.5 eq.) was added to the solution of 7.6 mmol. The solution was maintained at 〇 5 hours, and then at room temperature for 18 hours, at which time 1 equivalent of BF3 · EhO was added. Fresh ethylene oxide is bubbled directly in the solution for 3 to 4 minutes. After 8 hours the solution was concentrated to dryness and the residue was dissolved in CH.sub.2. To this solution was added 12 equivalents of triethylamine and 1 +/- dioxin. After 1 hour, the solvent was removed in vacuo and the residue was washed with water (30 ml), and extracted with CH2Cl2 (3 χ 5 mM), dehydrated and concentrated. Pure by gel column chromatography (5% Et〇Ac/CH2Ci2)

O:\106\106749.DOC -66- 1292752 The crude product was obtained to give the desired compound (42%, 2 steps). 3 〇〇 MHz Hz H NMR (CDCl3) δ 〇.98 (d, J = 4 〇 Hertz, 3H) i 〇 (dj = 4 〇 Hertz, 3H), 2.16 (m, 1H), 3.60 (m, 2H) ), 3·73 (s, 3H), 4.20 (d, J 1 〇 赫, 1H), 4.37 (m, 2H), mass spectrum: (m+h)+ = 202. 2S-(3-oxazolidine-2-one)-3-mercapto-butyric acid The oxime ester from Example 3 A was hydrolyzed using the procedure described in Example 1M to give the desired compound. 300 MHz iH NMR (DMSO-d6) (5 0.90 (d5 J = 6 Hz, 3H), 0.95 (d, J = 6 Hz, 3H), 2·1 (m, 1H), 3·55 (m, 1H) ), 3.70 (m, 1H), 3·88 (d, J = 9 Hz, ih) 5 4.30 (m, 2H), 13.0 (br, s, 1H). Mass Spectrum: (M+NH4)+ = 205. C·(2S,3S,5S)-2-(2,6c T-phenoxyethyl)amino-3-hydroxy-5-[2S-(3-oxazolidine-2-one)-3 - mercaptobutyryl]amino 4,6-diphenylhexane The amine from Example 1N was coupled with the acid from Example 3B using standard coupling procedures (EDAC in DMF) to give the desired compound. 300 MHz NMR (CDC13) 5 0.83 (d, J = 4·5 Hz, 3H), 0.87 (d, J = 4-5 Hz, 3H), 1.75 (m, 1H), 2·10 ( M5 1H), 2.20 (s, 6H), 2·65 (m, 1H), 2·85 (m, 1H), 3.0 (m, 3H), 3.30 (m, 1H), 3.60 (m, 2H), 3·77 (m,1H),4·20 (m,4H),6·25 (br d,J = 6 Hz, 1H), 7·〇(m,3H), 7.25 (m,10H). :(M+H)+ = 616. Example 4 (2S,3S,5S)-2](3R,3aS,6aR)_bis-tetrahydrofuranyloxy]amino-3-hydroxy-5-[2S-(3 -methyl-1-imidazolidin-2-one)-3-methylbutanyl Amino-1,6-^-phenylhexanyl O:\106\106749.DOC 67· 1292752 A· 2S-(3-methyl-1-imidazolidin-2-one)-3-methyl Methyl butyrate A solution of 150 mg of the compound from Example 1L in 4.5 mL of DMF was added to a 45 mg (60% oil dispersion) sodium hydride suspension in 0.5 mL DMF. After 20 minutes, (1.5 eq., 0.07 mL) of methyl iodide was added. The reaction was completed in 1 hour. The reaction was quenched with saturated NH4C1 solution and extracted with diethyl ether (1 mL, 50 mL) It was dehydrated and concentrated in vacuo. EtOAc was purified eluted elut elut elut elut elut elut elut elut J = 6 Hz, 3 Η), 0·97 (d, J = 6 Hz, 3H), 2·15 (m5 1H), 2.80 (s, 3H), 3.32 (m, 3H), 3.60 (m, 1H) , 3·70 (s, 3H), 4.25 (d, J = 10.5 Hz, 1H). Mass spectrum: (M+H)+ = 215. Β· 2S-(3-methyl-1-imidazolidin-2-one)-3-methylbutanoic acid was hydrolyzed from the methyl ester of Example 4 a using the procedure described in Example 1 得到compound of. 300 MHz 4 NMR (DMSO-d6) 6 0.85 (d, J = 6 Hz, 3H), 0.92 (d, J = 6 Hz, 3H), 2.05 (m, 1H), 2·65 (s, 3H) , 3·25 (m5 3H), 3·42 (m, 1H), 3.90 (d, J = 10 Hz, 1H). Mass spectrum: (M+H)+ = 201. C·(3R,3aS,6aR)-bis-tetrahydrofuran-(4-nitrophenyl)carbonate triethylamine (0.26 ml, 1.85 mmol) and benzoic acid to 4 choline ester (34 i mg, 1.69 mmol) added to 3R_hydroxy-(3aS,6aR)-bis-tetrahydrofuran in 10 ml of CH2Cl2 [J· Med·Chem. 3弋25〇6_25()8 (1994)] (200 mg, ί·54 mmol) in solution. The solution was kept at room temperature for 3 days, diluted with CH.sub.2Cl.sub.2 (100 mL). The organic layer was dehydrated and concentrated in vacuo. Purification by silica gel column chromatography 5% EtOAc/EtOAc (EtOAc) 3 00 MHz Η NMR (CDC13) 5 2·0 (m, l H), 2.20 (m, 1H), 3.18 (m5 1H), 4.0 (m, 3H), 4.17 (m, 1H), 5.27 ( m, 1H), 5·80 (d, J = 6 Hz), 7.40 (d, J = 7.5 Hz, 2H), 8.30 (d, J = 7.5 Hz, 2H). Mass spectrum: (M+NH4)+ = 313. D·(28,38,58)-2-[(3 shell, 338,631〇-bis-tetrahydrofuranoxy)amino-3-hydroxy-5-(tris-butoxycarbonyl)amino-l ,6-diphenylhexane

The compound from Example 1F (130 mg, 0.34 mmol) was added to a solution of the carbonate from Example 4C (100 mg, < The solution was kept at room temperature overnight and then concentrated in vacuo. The crude material was purified by silica gel column chromatography (2% to 5% MeOH / CH2 C12) to give the desired compound. 3 〇〇 megahertz 4 NMR (CDC13) δ 1.40 (s, 9 Η), 1.64 (m, 3 Η), 2.76 (m, 2 Η), 2.87 (m, 2H), 3.66-4.0 (m, 7H), 4.53 ( m, 1H), 5.06 (m, 2H), 5.68 (d, J = 6 Hz, 1H), 7·10_7·28 (m, 10H).质言昝:(M+NH4)+ = 558 〇Ε· (2S,3S,5S)-2-[(3R,3aS,6aR)_bis-tetrazirfuryloxy]amino-3-hydroxy-5 -Amino-1,6-diphenylhexane 5 ml of trifluoroacetic acid was added to a solution of the compound of Example 4D (170 mg, 〇 31 mmol) from 5 ml of ch2C12. After 25 hours, the solvent was removed in vacuo. The residue was dissolved in 1 mL of EtOAc (EtOAc) (EtOAc) elute 300 MHz 4 NMR (CDC13) 5 O:\106\106749.DOC •69- 1292752 L27-1.60 (m,4H),1.75 (m,2H),2.47 (m,1Η),2·80 (m, 1H), 2·88 (m, 2H), 3.0 (m, 2H), 3.80 (m, 4H), 4.0 (m, 1H), 5.10 (m, 1H), 5·30 (d, J = 10.5 Hz) , 1H), 5.70 (d, J = 6 Hz, 1H), 7-05-7.25 (m, 10H). Mass spectrum··(M+H)+ = 441. F·(28,38,58)-2-[(311,338,631〇-bis-tetrahydrofuranyloxy)amino group via-5-[2S-(3-methyl-1-imidazolidin-2-one) -3-methylbutanyl]amino-1,6-diphenylhexane using standard coupling procedures (EDAC in DMF) such that the formic acid from Example 4B and the amine compound from Example 4E To obtain the desired compound. 300 MHz iHNMR (CDCi3) 5 〇.82 (d, J = 3 Hz, 3H), 0.85 (d, J = Hertz, 3H) 5 1.65 (m, 1H), 2.77 ( s, 3H), 2·85 (m, 3Η), 3·17 (m5 2Η), 3·47 (m, 1Η), 3.60 (m, 2Η), 3·75 (m, 1Η), 3·87 (ηι, 1H), 4.0 (m, 1H), 4.20 (m, 1H), 5.05 (m, 2H), 5.68 (d, J = 6 Hz, ih), 6.45 (br d, J = 7.5 Hz, 1H ), 7.20 (m, 10H). Mass Spectrum: (M+H)+ = 623. Example 5 (2§'38,58)-2-[(311,338,631〇-bis-tetrahydrofuranyloxy)amine Amino--5-[2S-(1-imidazolidin-2-ylenylmethylbutanyl)amine 4, "Diphenyl has been burned using a standard coupling procedure (EDAC/DMF) to give an amine from Example 4E The base compound was coupled with the carboxylic acid from Example 1M to give the desired compound. lHNMR (CDCl3) accounts for 85.85 (d, J = 7 Hz, 3 Η), 〇·88 (d, Buchs, 3 Η), 1·70 (m, 2 Η) 5 2.18 (m, 1 Η), 2· 8〇(m,3Η), 2.95 (m,1Η), 3.20 (m,4Η),3·6〇(m,3Η),3 75 (m,2Η),4〇

O:\106\106749.DOC -70- 1292752 (m, 1H)? 4.20 (m, ΙΗ^ λ ac /

), 4·45 (s, 1H), 5_10 (m, 2H), 5.67 (d, J 2 6 Hz, 1H) 5 6·60 (d τ — ” < from # , (9), J — 7·5 Hertz, 1H), 7·20 (m, i〇H). Mass Spectrum: (M+H)+ = 609. Example 6 (2, 58) -2 嚷 嚷 嚷 )) methoxy) amide -5-((2S-(l-Mispin-2-one)-3-methylbutyryl)amino group via ", heart diphenyl hexane A · 2- gas-2-A Ethyl mercaptoacetate in the cold part to 0C, with a third _butoxy potassium (〇·5 mol, 5 〇〇 ml of a 1 Μ bath in THF) and 5 〇〇 ml of anhydrous THF three neck 2 Ethyl acetate (0.5 mol, 53.5 ml) and ethyl formate (〇·5) in 2 liters were added dropwise from the addition funnel in a liter round bottom flask. Mol, 40.4 ml) solution. After completion of the addition, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. The pH was lowered to about 3. The organic phase was separated and the layer was washed three times with diethyl ether. The mixed ether portion was dried over NaSCU and concentrated in vacuo. The crude desired compound was stored at -30 ° C and used without further purification. B. Pyrazole-5-carboxylic acid ethyl ester was added to a round bottom flask with 250 ml of anhydrous acetone, 7.5 g (0.123). Mole) thiocarbamide and 18.54 g (0.123 mol) of ethyl 2-chloro-2-methyl decylacetate. The reaction was heated to reflux for 2 h. solvent was removed in vacuo and purified by chromatography The residue was purified by EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) , J = 7 Hz, 3 Η), 4.38 (q5 J = 7 O: \106\106749.DOC • 71- 1292752 Hertz, 2H), 8·50 (s, 1Η), 8.95 (s5 1H). C 5-(Hydroxymethyl)pyrazole in a three-neck 500 ml flask containing pre-cooled (ice bath), lithium aluminum hydride (2.89 g, 76 mmol) in 250 mL THF, within 1.5 hours Ethyl pyrimide-5-carboxylate (11.82 g, 75.68 mmol) in 100 ml of THF was added dropwise to avoid excessive foaming. The reaction was stirred for an additional 1 hour with 2.9 ml of water, 2 · 9 ml of 15% NaOH and 8 7 ml of water was carefully treated. The solid salts were filtered and the filtrate was set aside. The crude salt was heated to reflux for 30 minutes in 1 mL of ethyl acetate. The resulting mixture was filtered and the two filtrates were combined, dried over Na 2 SO 4 and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 0% to 2% to 4% decyl alcohol in chloroform to give the desired compound, Rf 〇·3 (40/nonol in chloroform) It solidifies upon standing and yields 75. /〇. NMR (CDC13) 5 4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass Spectrum: (M+H)+ = 116 〇D·((5_ρ塞zolyl)methyl)-4-(4-nitrophenyl)carbonate 31.1 g in 100 ml of dichloromethane (27 A solution of 5-(hydroxymethyl)-inhibited and excess Ν-methyl?4 in millimolar is cooled to hydrazine. 〇, and treated with 8·2 g (4 1 house Moer) gas formic acid 4-n-nitrobenzene. After 1 hour of mixing, the reaction mixture was diluted with CHCI3, continuously with 1 N, saturated water.

NaHC03, washed with saturated brine, dehydrated with NaS〇4 and concentrated in the air. The residue was purified by silica gel chromatography (Si2, 1-2% MeOH/CHC13, Rf = 0·5 in 4% KleOH/CHCl3) to yield 5·9 g (78 〇/〇). The desired product. NMR (CDCI3) 5 53 (s 2Η) O:\106\106749.DOC -72- 1292752 7·39 (dt, J = 9, 3 Hz, 2H), 8.01 (s, 1Η), 8·29 (dt , J = 9, 3 Hz, 2H), 8.90 (S, 1H). Mass spectrum: (m+h)+ = 281. Ε·(2S,3S,5S)iamino-2-(N_((5-p)-methoxy)amino)-3-hydroxy-i,6-diphenylhexane The procedure of Example 4D was such that the amine compound from Example 11 was coupled with the carbonate to be obtained from Example 6D, followed by removal of the B oxime group using TFA/CH 2 Cl 2 to give the desired compound. 3 megahertz! H NMR (CDd) accounts for 13-1.6 (m, 2H), 2·40 (dd, J = 14, 8 Hz, 1H), 2·78 (dd, J = 5 Hz, 1H), 2_88 (d, J) = 7 Hz, 2H), 3·01 (m, 1H), 3·72 (br q, 1H), 3.81 (br d, J = l〇 Hertz, 1H), 5·28 (s, 2H), 5 34 (br d,;= 9 Hz, 1H), 7·07 (br d, J = 7 Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s, 1H), 8·80 (s, 1H). Mass spectrum: (m+H)+ = 426. F·(2S,3S,5S)-2-[(N-((5- p)-methoxy)methoxy)amino)-5-((2 S-(l- 嗤 嗤 bit-2-纲))-3-methylbutylidene)amino)_3_transyl-1,6-diphenylhexane using standard procedures (EDAC in DMF), such that the amine compound from Example 6E is derived from The carboxylic acid of Example 1M was coupled to give the desired compound (52%). 300 MHz 4 NMR (CDC13) 5 0.82 (d, J = 7.5 Hz, 3H), 〇·85 (d, j = 7.5 Hz, 3H), (m, 2H), 2 15 (m, 1H) , 2·7〇(m,3H), 2.85 (d, 7.5 Hz, 2Η), 3·08 (m,1H), 3.18 (m, 1H), 3.30 (m, 2H), 3.60 (m, 3H) ,3·80 (m5 1H), 4.16 (m5 1H), 4·40 (s5 1H), 5.16 (d, J = 9 Hz, 1H), 5.24 (s, 2H), 6.60 (d, J = 9 Hz) , 1H), 7.20 (m, 10H), 7.83 (s5 1H) 5 8·80 (s, 1H). Mass spectrum (M+H)+ = 594. O:\106\106749.DOC -73- 1292752 Example 7 (2S,3S,5S)-2_(N-((5-thiazolyl)methoxycarbonyl)amino)_3_hydroxy-5-(2S-( L-imidazolidin-2-yl)-3,3-dimercaptobutyl)amino-l,6-diphenylhexane A· 2S-(1-imidazolidin-2-one)-3, 3-Dimethylbutyric acid was carried out using the procedure described in Examples 1J to 1M, but replacing L-proline methyl ester with L-tris-butyl-leucine methyl ester to give the desired compound. 300 MHz 4 NMR (DMSO-d6) δ 1 ·0 (s, 9 Η), 3.22 (t, J = 7.5 Hz, 2H), 3·55 (q, J = 7.5 Hz, 1H), 3.65 (q , J = 7.5 Hz, 1H), 4.14 (s, 1H), 6·40 (s, 1H), 12.62 (br s, 1H). Mass Spectrum: (M+H)+ = 201. Β·(2S,3S,5S)-2-(N-((5-pyrazolyl)-methoxycarbonyl)amino)-3-hydroxy-5-(2S_(l-imidazolidin-2-one) -3,3-Dimethylbutanyl)amino-1,6-diphenylhexane The amino group compound from Example 6E was combined with the carboxy group from Example 7 A using standard procedures (EDAC in DMF). Acid coupling gave the desired compound (77%). 300 MHz 1H NMR (CDC13) δ 1.0 (s5 9H) 5 1.68 (m5 2H), 2.60-2.80 (m, 3H), 2.85 (d, J = 7.5 Hz, 1H), 3·10 (m, 1H) ), 3.30 (m, 1H), 3.50 (m, 1H), 4.56 (s, 1H), 5·15 (d5 J = 7.5 Hz, 1H), 5.25 (ABq, 1H), 6.50 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7·83 (s5 1H) 5 8.80 (s, 1H). Mass spectrum: (M+H)+ = 609. Example 8 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)- 3,3-Dimethylbutanyl)amino-1,6-diO:\106\106749.DOC -74- 1292752 Phenylhexane The amine from Example IN was obtained using standard procedures (EDAC in DMF) The base compound was coupled with the carboxylic acid from Example 7 A to give the desired compound (80%). 300 MHz 4 NMR (CDC13) δ 1 ·0 (s, 9Η), 2· 1 8 (s, 6Η), 2.68 (m, 1Η), 2.80 (m, 1Η), 2·98 (m, 3Η) ,3·10 (m,1Η), 3.27 (q,J = 7 Hz, ih), 3.53 (m,1H), 3.77 (m,1H), 4.0 (s, 1H), 4.20 (m,4H), 6.72 (m, 1H), 7.0 (m, 3H), 7.10-7.25 (m, l〇H). Mass Spectrum: (M+H)+ = 629. Example 9 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S_(l-imidazolidin-2-sulfinyl) -3-methylbutyryl)amino-1,6-diphenylhexane A·2S-(1-imidazolidin-2-sulfinyl)-3-methylbutanoic acid was similarly used in Examples 1J to 1M The procedure described in the above, but replacing 1,1-carbonyl-diimidazole with 1,1-thiocarbyldiimidazole gives the desired compound. 3〇〇 megahertz NMR (DMSO-d6) δ 0.87 (d, J = 6 Hz, 3H), 〇·9ό (d, J = 6 Hz, 3H), 2.11 (m, 1H), 3.45 (m, 2H), 3.62 (m, 1H), 3·80 (q5 j = 9 Hz, 1H), 4·80 (d, j = 10 Hz, 1H), 8·30 (s, 1H), 12·75 ( Br s, 1H). Β·(28,38,58)-2-(2,6-Dimercaptophenoxyethyl)amino-3-hydroxyimidazolidin-2-sulfinyl)-3-methylbutanyl)amine Base-1,6-diphenylhexanhydride The amine compound from Example 1N was coupled with the carboxylic acid from Example 9A using standard procedures (EDAC in DMF) to give the desired compound-75-

O:\106\1.06749.DOC © 1292752 (53%). 3 00 MHz 1H NMR (CDCl3) 5 0·82 (d, J = 6 Hz, 3H), 0·93 (d, J = 6 Hz, 3H), 1.75 (m5 1H), 2.20 (s5 6H), 2.65 (m,1H), 2.84 (m,1H), 3.0 (m,3H),3·25 (m,1H), 3.40 (m, 2H),3·54 (d,J=hertz,ih),3 · 78 (m, 1H), 4.22 (m, 4H), 4.56 (d, J = 10.5 Hz, 1H), 5.65 (s, 1H), 6.60 (d, J = Hertz, 1H), 7·0 (m , 3H), 7.25 (m, 10H). Mass spectrum: (M+H)+ = 631. Example 10 (2S,3S,5S)-2_(4_Amino-2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3-methylbutanyl)amino-1,6-diphenylhexane A. Ethyl 2,6-dimethyl-4-nitrophenoxyacetate slowly 50 ml of trifluoroacetic acid It was added to a solution of 10.5 g (54.6 mmol) of ethyl 2,6-xyloxyacetate and 7.5 g (109 mmol) of sodium nitrite in 1 mL of di-methane. After the addition, the reaction mixture became a solid. An additional 35 ml of trifluoroacetic acid was added. After the reaction mixture was stirred at room temperature for 3 hours, it was carefully partitioned between a saturated sodium hydrogen carbonate solution and dioxane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was recrystallized from 30% ethyl acetate and hexane to yield 4.75 g (yield: 36%) of ethylamine 2,6-dimethyl-4-bromophenoxyacetate. 300 MHz NMR (CDC13) δ 1 ·34 (3Η, t5 J = 7.5 Hz), 2.39 (6H, s), 4·31 (2H, q, J = 7.5 Hz), 7.93 (2H, s ). Β·2,6-Dimethyl-4-nitrophenoxyacetic acid, adding 13⁄4: liter of 3 Torr of sodium hydroxide to 0962 g of 1 mM methanol O:\106\106749.DOC -76-1292752 (4.06 mmol) in a solution of 2,6-dimethyl-4-nitrophenoxyacetic acid ethyl acetate. After stirring the reaction mixture for 30 minutes at room temperature, it was acidified with 3N HCl and partitioned between water and dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure afforded EtOAc (EtOAc: EtOAc) 300 MHz NMR (d3-DMSO) δ 2·35 (6H, s) 5 4·55 (2Η, s), 7.97 (2Η, s), 13·02 (1Η, br). C·(2S,3S,5S)-2-(Third-butoxycarbonyl)aminohydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amine- i,6-Diphenylhexane (2S,3S,5S)-2-(Thr-Butoxycarbonyl)amino-3-hydroxy-5-amino group using standard procedures (EDAC in DMF) -1,6-Diphenylhexane was coupled with the carboxylic acid from Example 1M to give the desired compound (1%). 3 〇〇 Hz ι NMR (CDCI3) δ 0.83 (d, J = 6 Hz, 3 Η), 0.87 (d, J = 6 Hz, 3H), 1·40 (s, 9H), 1.70 (m, 2H) , 2.16 (m, 1H), 2·58-2·80 (m, 4H) 3 3.10-3.30 (m, 4H), 3.65 (m, 2H), 4.20 (m5 1H), 4·38 (s, 1H) ), 4.83 (d, J = Hertz, 1H), 6.53 (d5 J = 9 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M+H)+ = 553. D·(2S,3S,5S)-2-amino-3-carbyl-5-(2S-(l-miso-2·indolyl)-3-mercaptobutyl)amino-1,6- The compound from Example 10C was removed from the Boc-protecting group by diphenylhexane by standard procedures (TFA/CH2C12) to give the desired product. 300 MHz NMR (CDCI3) 5 0.87 (d, J = 6 Hz, 3H), 0.90 (d, J =: 6 Hz, 3H), 1.33 (dd, J = 4.5, 9.0 Hz, 1H), 2.18 (m , 1H), 2·50 (m, O:\106\106749.DOC -77-129272 1H), 2.80 (m, 5H), 3·20 (m, 4H), 3.72 (d, J = 10 Hz, 1H), 4·3〇(m,1H), 4.50 (s,1H), 6.67 (d, J = 7 Hz 5 1H), 7.20 (m, 1〇H). Mass spectrum··(m+H)+ = 453. Ε·(2S,3S,5S)-2-(4-nitro-2,6-xyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3-methylbutanyl)amino-1,6-monohexanone The amine based compound from Example 10D and the carboxylic acid couple from Example 10B were obtained using standard procedures (EDAC in DMF). Combine to get the desired compound. 3 〇〇 megahertz NMR (CDC13) 5 0.83 (d, J = 7 Hz, 3H), 0·86 (d, J = 7 Hz, 3 Η), 1·70 (m, 3 Η), 2·18 (m , 2Η), 2.28 (s, 6Η), 2·75 (m, 3H), 2.95-3.30 (m, 6H), 3.67 (d, J = 10.5 Hz, 1H), 3·75 (m, 1H), 3·82 (d, J = 4 Hz, 1H), 4.25 (m, 5H), 6.55 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7.92 (s, 2H). Mass spectrometry: (M+H)+ = 660 〇

Fe (2S,3S,5S)_2-(4-Amino-2,6-xyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one) -3-methylbutylidene)amino-indole, "diphenylhexane. A solution of 69 housek from the compound of the example ι〇Ε was added to 7⁄4 g of 10 〇/〇Pd/ in 5 ml of methanol. In the suspension of C. The reaction mixture was vigorously stirred under a hydrogen pressure (the hydrogen-filled balloon was attached to the three-way stopcock). After 1 hour, the reaction was confirmed by TLC analysis; the catalyst was filtered off and vacuumed. The concentrated filtrate was purified by hydrazine gel chromatography (2% to 5% Me 〇H / ci^Cl2) to give the desired compound (65%). 3 〇〇 megahertz 1hnmr (CDC13) 5 〇·82 (d, J = Hertz, 3H), 〇87 (d, J = 6 Hz, O: \106\106749.DOC -78- 1292752 3Η), 1·70 (m, 2H), 2·1 〇(s,6H), 2.15 (m,2H), 2.72 (m,2H), 2·97 (d,j = 7 5 Hz, 2H), 3.08 (m, 1H), 3·15 (m, 1H) ),3·30 (m,2H),3 45 (br s5 2H),3·66 (d,J == l〇 Hertz, 1H), 3.72 (m, 1H), 3.90 (d, J 2 3 Hz , 1H), 4.10-4.20 (m, 4H), 4.30 (s 1H), 6.33 (s, 2H), 6.57 (d, J = 9 Hz, 1H), 7.20 (m5 10H) Mass Spectrum: (M+H) + 630. Example 11 (2S, 3S, 5S)-2 -(2,4,6-trimethyloxyethoxymethyl)amino-3-hydroxy-5-(2S-(i-imidazolidin-2-yl)-3-methylbutanyl)amino-1 , 6-diphenylhexane oxime 2,4,6-trimethylbenzene acetoxy acetic acid using the procedures obtained from Examples 1G and 1 H, but replacing 2,6, dimethyl with 2,4,6-trimethyl酴, the desired compound is obtained. 300 MHz 4 NMR (CDC13) ^ 2.25 (s, 9H), 4·43 (s, 2H), 6.84 (s5 2H). Mass Spectrum: (M+H)+ = 195 ° B. (28,38,58)-2-(2,4,6-Trimethyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one) -3-Methylbutanyl)amino-1,6-diphenylhexane The amine compound from Example 1D was coupled to the carboxylic acid from Example 11A using standard procedures (EDAC in DMF). , to obtain the desired compound (51%). 300 megahertz] H NMR (CDC13) 〇·82 (d, J = 6 Hz, 3H), 〇·85 (d, J = 6 Hz, 3H), 1.70 (m5 4H), 2.13 (s, 6H), 2·25 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7 Hz, 1H), 3· 13 (m, 2H), 3.28 (m, 2H), 3.68 (d, J = 10 Hz, ih), 3.72 (m, 1H), 4.16 O: \106\106749.DOC -79- 1292752 (m, 4H ), 4 40 · (br s, 1H), 6.67 (d, J = 8 Hz, 1H) 5 6.80 (s, 2H)' 7 9rw v 5 • (m, 1〇H). Mass spectrum: (m+H)+ = 629. Example 12) 2 (4_Den-2,6-xyloxyethenyl)amino group via group -5-j§ /-I shouting _ _ imizidine 2 keto keto 3 曱 曱 醯 ) ) Aminodiphenyl A·fluoro-2,6-dioxaphenoxyacetic acid is used in the procedures of Examples 10 and 1^, but 4-fluoro-2,6-diinol is used instead of 2 6- , 'One f' to get the desired compound. 3 〇〇 megahertz iH nmr (CD3CD>i Λ •26 (s,6Η), 4.37 (s,2Η), 6.73 (d, J = 9 Hz, 2H). Mass spectrum: M+ = 198. , Β· (2S ,3S,5S)_2-(4-Fluoro-2,6-xyloxyethenyl)aminohydroxy 4-(2S-(l-imidazolidin-2-yl)-3-methylbutenyl)amine The amine compound from Example 10D was coupled to the desired compound from the carboxylic acid from Example 12A. 300 MHz NMR (CDC13) 5 0·83 (d, J = 6 Hz, 3H), 〇 · 86 (d, J = 6 Hz, 3H), ! 72 (m, 2H), 2·15 (s, 6H), 2.20 (m5 1H), 2.76 (m, 2H) ), 2·98 (d J = 7 Hz, 2H), 3" 2 (m, 2H), 3.30 (m, 2H) 5 3·67 (d, j = 1 〇 Hz, 1H), 3·72 ( m,1H), 4.13 (ABq, J = 8·9 Hz, 2H), 4·2〇(m, 2H), 4.37 (s, 1H), 6·64 (d, J = 9 Hz, 1H), 6·7〇(d,j=hertz, 2H), 7.20 (m, 10H). Mass spectrum: (m+H)+ = 633. Example 13 (28,38,58)-2-(4,6-II Methylpyrimidin-5-oxyethylidene)amino-3-hydroxyO:\106\106749.DOC 8〇1292752 s-(2S-(1-imidazolidin-2-one)-3- Methylbutenyl)amino-1 , 6-diphenylhexane oxime 4,6-dimethylpyrimidin-5-oxyacetic acid using the procedure from Example 1G and 1 ,, but with 5-hydroxy-4,6-dimethyl spray (According to Chem. Ber. 93, page 1998, prepared in 1960) instead of 2,6-dimethyl </ br> to obtain the desired compound. 300 MHz NMR (DMSO-d6) δ 2·45 (s, 6 Η), 4.55 (s, 2Η), 8.50 (s, 1Η). Mass Spectrum: Μ+ = 183. Β· (28,38,58)_2-(4,6-Dimethylpyrimidin-5-oxyethyl)amine Benzyl-3-transyl- 5^2S-(1-imidazolidinonemethylbutanyl)aminodiphenylhexane. The amine compound from Example 10D was coupled with the carboxylic acid from Example 13A. Desired compound. 300 MHz 4 NMR (CDC13) 5 0.82 (d5 J = 6 Hz, 3H), 0·85 (d, J = 6 Hz, 3H), 1.70 (m, 2H), 2·15 ( m,1H),2·40 (s,6H),2.75 (m,2H),2.97 (d,J = 7 Hz, 2H), 3·12 (m, 2H), 3.30 (m, 2H), 3.66 (d, J = 10 Hz, 1H), 3.74 (m, ih), 3.88 (d, J = Hertz, iH), 4.20 (m, 4H), 6·62 (d, J = 9 Hz, 1H ), 7.0 (d, J = 9 Hz, m), 7.20 (m, l〇H), 8.70 (s, 1H). Mass Spectrum: (M+H)+ = 617. Example 14 (28,38,58)-2-(2,4-Dimercaptopyridine-3-methoxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3,3-dimethylbutanyl)amine-based hexyl burned A. 2.4-dimethylpyridyl-3-oxyacetic acid using the procedures from Examples 1G and 1H, but with 2,4 _Dimethyl-3_hydroxy O:\106\106749.DOC -81 - 1292752 Leaf acridine (prepared according to J. Med. Chem. 35, 3667-3671, 1992) to replace 2,6-dimethyl Phenol gives the desired compound. 3〇〇 megahertz iH NMR (DMSO_d6) δ 2.26 (s? 3H)? 2.42 (s? 3H)5 4.44 (s5 2H), 7.08 (d, J = 5 Hz, 1H), 8.07 (d, J = 5 Hertz, 1H). Mass spectrometry: (M+H)+ = 182 ° B·(28,38,58)-2-(2,4-dimethylpyridine-3-methoxyethenyl)amino-3-carbyl-5 -(T-Butoxycarbonyl)amino-u-diphenylhexane The amine compound from Example 10F was coupled with the carboxylic acid from Example 14A using standard procedures (EDAC in DMF). The compound you want. 300 MHz NMR (CDC13) δ 1.40 (s, 9 Η), 1·70 (m, 2 Η), 2.18 (s, 3H), 2.40 (s, 3H), 2.77 (m, 2H), 2·98 (d , J = 7 Hz, 2H), 3.75-3.95 (m, 3H), 4.20 (s, 2H), 4.22 (m5 1H), 4.60 (br d, 1H), 7.0 (d, J = 5 Hz, 1H) , 7.10 (m, 3H), 7.25 (m, 7H), 8.16 (d, J = 5 Hz, 1H). Mass spectrum: (M+H)+ = 548. C·(28,38,58)-2-(2,4-dimethylpyridin-3-yloxyethyl)amino-3-hydroxy-5-amino-1,6-diphenyl The alkane was subjected to the removal of the Boc-protecting group from the compound from Example 14B using standard procedures (TFA/CH2C12) to afford the desired compound. 300 MHz 4 NMR (CDC13) δ 1.45 (m, 1 Η), 1·62 (m, 1 Η), 2·23 (s5 3 Η), 2·45 (s, 3H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0 (m5 2H), 3·12 (m5 1H), 3.90 (m, 1H), 4·18 (m, 1H), 4.25 (ABq, J = 9, 12 Hz, 2H), 6·98 (d, J = 5 Hz, 1H), 7.10 (m, 2H), 7.30 (m, 8H), 8.17 (d5 J = 5 Hz, 1H). Mass spectrum··(M+H)+ = 448. D·(28,38,58)-2-(2,4-dimethylpyridin-3-ethoxyethyl)amino group O:\106\106749.DOC -82 - 1292752 -3-base group_ 5-(2S-(1-Imidazolidinone) 3,6-diphenylhexane The amine group from Example 14C was obtained using standard procedures (EDAC in DMF). The compound was coupled with the carboxylic acid from Example 7A to give the desired compound. 3 NMR (CDC13) δ 1.0 (s, 9 Η), 1.70 (m, 3 Η), 2·18 (s, 3H) , 2.42 (s, 3H), 2.75 (m, 2H) 5 3·0 (m, 4H), 3.30 (m, 1H), 3.55 (m, 1H), 3.80 (m, 1H), 4.05 (s, 1H) ), 4.20 (m, 4H), 4.60 (s, ih) 5 6.70 (d, J = 7 Hz, 1H), 6.97 (d, J = 5 Hz, 1H), 7.15 (m, 3H), 7.25 (m5) 7H), 8.17 (d5 J = Hertz, 1H). Mass spectrum · (M+H) + = 630. Example 15 (28, 38, 58) -2- (2,4_ dimethyl outside |; bite-3 -oxyethyl aryl)amino-3-carbyl-5-(2S-(l-imidazolidin-2-oxoninoindolyl)amine 4, "diphenylhexane using standard procedures (in DMF) EDAC) The amine-based compound from Example 14C was coupled with the carboxylic acid from Example 1M to give the desired compound. Megahertz 4 NMR (CDC13) 5 0.82 (d, J = Hertz, 3H), 0·86 (d, J = 6 Hz, 3 Η), 1.75 (m, 3 Η) 5 2.15 (m, 1 Η), 2.18 (s , 3Η), 2.40 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3·20 (m, 4Η), 3.70 (d5 J = 10 Hz, 1Η) ), 3.75 (m, 1Η), 4.20 (m5 6H), 4.52 (s, 1H), 3.75 (m, 1H), 4·20 (m, 6H), 4·52 (s, 1H), 6.80 (d , J = 7 Hz, 1H), 6.96 (d, J = 4.5 Hz, 1H), 7·20 (m, 10H), 8.17 (d, J = 4.5 Hz, 1H). Mass Spectrum: (M+H)+ = 616. Example 16 O:\106\106749.DOC -83- 1292752 (28,38,58)-2-(2,6-Dimethylthiophenoxyethyl)amino-3-3-hydroxyl S-(2S-(l-imidazolidin-2-yl)-3-methylbutanyl)amino-1&gt;6-diphenylhexane oxime·2,6-dimethylthiophenoxyacetic acid Using the procedure from Examples 1G and 1Η, but replacing 2,6-xylenol with 2,6-dimethylthiophenol, the desired compound was obtained. 300 MHz 4 NMR (CDC13) δ 2.5 6 (s, 6 Η), 3.40 (s, 2 Η), 7.10 (m, 3 Η). Mass spectrometry: M+ = 197 〇®·(28,38,58)-2-(2,6-dimethylthiophenoxyethyl)amino _3_ benzyl-5-(2S-(l-imidazole) Pyridin-2-one)-3-methylbutanyl)amino}; i,6-diphenyl was calcined. The carboxylic acid from Example 16 was coupled with the amine compound from Example 10D. compound of. 3〇〇 megahertz iH NMR (CDC13) 5 〇·82 (d5 J = Hertz, 3H), 0.86 (d, J = 6 Hz, 3H), 2.15 (m, old), 2.52 (s, 6H), 2.70 (m, 4H), 3.10 (m, 2H), 3·30 (m, 4H), 3.60 (m, 2H), 4.0 (m, 1H), 4.10 (m, 1H), 4.22 (s, 1H), 6.39 (d, J = 7 Hz, 1H), 6.58 (d, J = 9 Hz, 1H), 7.20 (m, 13H). Mass spectrum: (M+H)+ = 631. Example 17 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-1hydroxy-5-(2S-(l-pyrrolidin-2-one)_3_A Isobutyl]aminophenyldiphenylhexane oxime 4-methylbromobutyryl chloroglycolate 1.36 ml (16.8 mmol) of pyridine was added to 3 mM CH2Cl2

O:\106\106749.DOC -84 - 1292752 in a solution of 1.08 g (8.4 m mmol) of L-proline methyl ester, cooled to 〇 ° C and then added 1.55 g (8.4 mmol) ) The heart of bromobutane chloride. The solution was stirred at 〇 ° C for 40 minutes and at room temperature for 1 hour. The solution was washed with saturated NaHC03, brine and dried over anhydrous Na2SO. The crude product was purified by EtOAc EtOAc (EtOAc) elute 300 MHz 4 NMR (CDC13) 5 0.92 (d, J = 6 Hz, 3H), 〇·96 (d5 J = 6 Hz, 3H), 2.20 (m, 3H), 2.46 (m, 2H), 3.50 ( M5 2H), 3·76 (s5 3H), 4.58 (dd, J = 4·7 Hz, 1H), 5.97 (br d, J = 7 Hz, 1H). Mass spectrometry: (M+H)+ = 297 〇Β· 2S-(1-pyrrolidin-2-yl)-3-mercaptobutyric acid i.49 g in a mixture of DMF/CH^Cl2 (5· A solution of 3 mmol of the compound from Example 17A was cooled to hydrazine. 〇, and add 234 234 g equivalent) 60% sodium hydride in mineral oil. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was poured into a saturated chlorinated mixture and extracted with ethyl acetate, dried and concentrated in vacuo. The crude product was hydrolyzed using lithium hydroxide as in Example 1H to give the desired compound. 300 MHz NMR (CDC13) 5 0.96 (d, J = 7 Hz, 3H), 1.06 (d, J = 7 Hz, 3H) 5 2·10 (m, 2H), 2.40 (m, 1H), 2.50 (t, J = 7 Hz, 2H), 3.56 (m, 2H), 4·14 (d, J = l 〇 Hertz, m). Mass spectrum: (m+H)+ = 186. C·(2S,3S,5S)-2-(2,6.T-phenoxyethyl)amino-3_hydroxy_5_(2S-(1-pyrrolidine-;2-keto)_3_曱 醯 醯 )) amino-β1,6-diphenylhexan O:\106\106749.DOC •85- 1292752 The carboxylic acid from Example 17B was obtained from Example 1N using standard procedures (EDAC in DMF). The amine is coupled to give the desired compound. 300 MHz NMR (CDCls) 5 〇·77 (d5 J = 7 Hz, 3H), 0.83 (d, J = 7 Hz, 3H) 5 1.75 (m, 3H), 2·10 (m, 1H), 2 ·20 (s5 6H), 2.25 (m, iH), 2.65 (m, 1H), 2·85 (m, 1H), 3·0 (d, J = 7 Hz, 2H), 3.20 (m, 1H) ,3·77 (m,2H),3·88 (d,J = 10 Hz, 1H), 4.20 (m, 3H), 6·30 (d, J = 7 Hz, 1H), 6.98 (m5 3H) , 7.20 (m, 10H). Mass spectrum: (M+H)+ = 614. Example 18 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-pyrrolidine-2,5-dione) Ethyl 3-methylbutylidene)amino-1,6-diphenylhexane A·2S-(1-pyrrolidine-2,5-dione)-3-methylbutyrate decyl ester 1 Equivalent succinic anhydride was added to a solution of 700 mg (3.38 mmol) of L-validine phthalate in 6 ml of chloroform. After 1 hour at room temperature, the solvent was removed in vacuo and the residue was dissolved in 20 mL DMF. To the solution were added 0.52 g of hydrazine-hydroxybenzotriazole, 0.68 g of EDAC and 0.52 ml of triethylamine. After 24 hours at room temperature, 20 mg of 4-dimethylaminopyridinyl group was added. The solution was left at room temperature for 3 days. After the standard work, the crude product was purified by chromatography eluting with silica gel column chromatography to afford the desired product (26%). 300 MHz NMR (CDC13) 5 〇·84 (d, J = 7 Hz, 3H), 1.12 (d, J = 7 Hz, 3H), 2.70 (m, 1 Η), 2·71 (s, 4H), 4.45 (d, J = 9 Hz, 1H), 5·15 (s, 2H), 7.30 (m, 5H). Β· 2S-(1-pyrrolidine-2,5-dione)-3-methylbutyric acid

O:\106\106749.DOC •86- (ί 1292752 under hydrogen pressure (ball filled with helium)' vigorously stirred 0.245 g in 5 〇 ml of sterol from the product of Example 8 和 and 3 〇 A mixture of 1 in gram of palladium on carbon was used for 1 hour. The catalyst was filtered off and the solvent was removed under vacuum to give 168 </ RTI> desired compound. 300 MHz NMR 丨CDCI1J 3 (d, J = 6 Hz, 3 Η) , 1.13 (d, J = 6 Hz, 3 Η), 2·65 (m, 1 Η), 2·8 〇 (s, 4 Η), 4.45 (d, J = 8 Hz, 1 Η). Mass spectrum: (μ+η ) + = 200. C· (2S,3S,5S)-2_(2,6^methylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-pyrrolidine_2,5) The carboxylic acid from Example 18B was coupled with the amine from Example 1N using standard procedures (EDAC in DMF) using a standard procedure (EDAC in DMF). The desired product (75%) was obtained. 300 MHz 1H NMR (CDC13) 5 0.70 (d, J = 4 Hz, 3H), 0.72 (d, J = 4 Hz, 3H), 1.70 (m, 1H), 2.20 (s,6H), 2.45 (m,2H), 2.60 (s,4H), 2.80 (m5 2H), 3.0 (m,2H),3·76 (m,lH),4·20 (m, 6H) ), 7.0 (m5 3H), 7·20 (m, 10H) Mass Spectrum: (M+H)+ = 628. Example 19 (2S,3S,5S)-2-(trans_3_(2,6-dimethylphenyl)propenyl)amino-3-hydroxy-5- (2S-(l-tetrahydropyrimidin-2-one)-3-mercaptobutyryl)aminodiphenylhexane A. 2,6-dimethylbenzaldehyde by standard Swern oxidation Procedure (Grass Chlorine/DMSO) oxidize 2,6-dimercaptophenyl alcohol to give the desired compound. 300 MHz iH NMR (CDC13) δ 2.62 (s, 6 Η), 7.10 (m, 2 Η), 7·33 (t, J = 7 Hz, 1H), 10.63 (s, 1H). Mass spectrum: (M+H)+ = 135 O:\106\106749.DOC -87- 1292752 Β· 反_3_(2 , 6-dimethylphenyl) decyl acrylate. 36 mg of sodium hydride (60% in oil) was added to a solution of phosphonic acid tridecyl acetate (149 mg, 0.82 mmol) in 15 ml of THF. After a minute, 100 mg of the compound from Example 19A was taken in 2 ml of THF. After 2 hours, the reaction was quenched carefully, extracted with ethyl acetate (70 mL), dried and concentrated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) 300 MHz NMR (CDC13) δ 2.35 (s, 6Η), 3.82 (s, 3Η), 6·07 (d, J = 16 Hz, 1H), 7.10 (m, 3H), 7.85 (d, J = 16 Hertz, 1H). Mass spectrum··(M+NH4)+ = 191. C. Trans-3_(2,6-diphenylphenyl)acrylic acid The oxime ester from Example 丨〇B was hydrolyzed using lithium hydroxide in a mixture of methanol and water to give the desired compound (84%). 300 MHz 4 NMR (CDC13) δ 2.38 (s5 6Η), 6·13 (d, J = 16 Hz, 1 Η), 7·10 (m, 3H), 7.96 (d, J = 16 Hz, 1H). Mass spectrum: (M+H)+ = 194. D·(28,38,58)-2-(trans-3-(2,6-dimethylphenyl)propenyl)amino-3-carbyl-5-(second-butoxymethyl)amine The carboxylic acid from Example 19C was coupled with the amine from Example 1F using the standard procedure (EDAC/DMF) to afford the desired compound (84%). 300 megahertz]H NMR (CDC13) δ 1·40 (s5 9Η), 1.68 (m5 1Η), 2·34 (s5 6H), 2.75 (m5 2H), 2.96 (m5 2H), 3.72 (m, 1H) , 3·85 (m, 1H), 4.08 (m, 2H), 4.60 (m, 1H), 5.88 (d, J = 10 Hz, 1H), 5.94 (d, J = 16 Hz, 1H), 7.10 ( m, 5H), 7.25 (m, 8H), 7.72 (d, J = 16 Hz, 1H). Mass spectrum: (M+H)+ = 543. O:\106\106749.DOC -88· 1292752 Ε· (2 S,3S,5 S)-2-(trans-3-(2,6-dimethylphenyl)propanyl)amino-3- Hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one)-3-methylpropenyl)amino-1,6-diphenylhexane

The Boc-protecting group (TFA/CH2Ch) from the compound from Example 19D was removed, and the obtained amine was coupled with the carboxylic acid from Example 2A using standard procedures (EDAC/DMF) to give the desired compound (73). %). 300 MHz 1H NMR (CDC13) 5 〇·82 (d, J = 6 Hz, 3H), 〇·87 (d, J = 6 Hz, 3H), 1.50 (m5 1H), 1.70 (m, 2H), 2.20 (m5 1H), 2·33 (s, 6H), 2.68 (m, 1H), 2·78 (m, 1H), 2·85 (m, 1H), 3·〇5 (m, 5H), 3.73 (m,1H),4·17 (m,1H), 4.30 (d,J = 3 Hz, 1H), 4.60 (s,1H), 5.95 (d, J = 15 Hz, 1H), 6·0 (d, J = 9 Hz, ih), 6.80 (d, J = 7 Hz, 1H), 7.25 (m, 13H), 7.70 (d, J = 15 Hz, 1H). Mass spectrum: (M+H)+ = 625. Example 20 (2S,3S,5S)_2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one) )-3-methylbutanyl)amino-1,6-diphenylhexane A. Methyl 3-(2,6-dimethylphenyl)propionate is vigorously stirred under hydrogen pressure (balloon pressure) A solution of 400 mg of the compound from Example 19B in 25 ml of methanol and 40 ml of 10% Pd/C was used for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the desired product (98%). 3 00 MHz 4 NMR (CDC13) 5 2.35 (s, 6H), 2·45 (m, 2 Η), 2.98 (m, 2 Η), 3.22 (s, 3 Η), 7.02 (s, 3 Η). Mass spectrometry: (M+H)+ = 210 0 O:\106\106749.DOC -89- 1292752 Β·^(2,6-diphenylene)propionic acid in formazan and water, and lithium hydroxide The oxime ester from Example 20A was hydrolyzed to the desired compound (93%). 3 〇〇 megahertz lH nmr (Cdc13) 5 2·36 (s, 6H), 2.50 (m, 2H), 3.0 (m, 2H), 7.03 (s, 3H). Mass spectrometry: (M+NH4), 196. C·(28,38,58)_2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy(tris-butoxycarbonyl)amino-1,6-diphenyl The carboxylic acid from Example 20B was coupled with the amine from Example 1F using a standard coupling procedure (EDAC/DMF) to give the desired compound. 3〇〇MHz Hertz NMR (CDC13) δ 1.40 (s? 9Η)5 1.55 (m5 2Η)5 2.20 (m5 2Η)? 2.30 (s,6Η), 2.74 (m,2Η), 2.85 (m,4Η) ,3·66 (m,1Η),3·82 (m,1H),3·95 (m5 2H),4.57 (br d5 1H),5.66 (d5 J =9 Hz, 1H),7.0 (s,3H ), 7·22 (m, 10H). Mass spectrum: (M+H)+ = 545. D·(28,38,58)-2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-one) 3-methylbutylidene)amino-u-diphenylhexane The compound B〇c-protecting group from Example 2〇c was removed using trifluoroacetic acid in CHCh and using standard coupling procedures ( EDAC/DMF) The resulting amine was coupled with the carboxylic acid from Example 2A to give the desired compound. 3〇〇 megahertz 4 NMR (CDC13) accounted for 0.82 (d, J = 6 Hz, 3H), 0.86 (d, J = 6 Hz, 3H), 1.55 (m5 2H), 1.65 (m, 1H), 1.70 ( s, 3H), 2.20 (m5 3H), 2·30 (s, 6H), 2.65 (m, 1H), 2.75 (m, 1H), 2·86 (m, 5H), 3.10 (m, 3H), 3·68 (m, 1H), 4.10 (m, 4H), 4.63 (s5 1H), 5.75 (d, J = 7 Hz, 1H), 6.76 (d, J = 7 Hz 5 1H), 7.0 (m, 3H), 7.20 -90·

O:\106\106749.DOC 8 1292752 (m, 10H). Mass spectrum: (M+H)+ = 627. Example 21 (2S,3S,5S)-2-(2,6-Dimethyl-4-methylphenoxyethyl)amino-3-carbyl-5-(2S-(l-tetrahydropyrimidine) -2-keto)-3-indolyl decyl)amino-1,6-diphenylhexane oxime 2,6-dimethyl-4_tris-butyl dimethyl decyloxyphenol will be 200 Mg of Pd/C (20%) was added to a solution of 2.5 g (14.7 mmol) of 2,6-dimethylphenylhydrazine in 5 ml of methanol. The reaction mixture was stirred overnight under 1 atmosphere of hydrogen. The Pd/C was removed on a pad of diatomaceous earth and the solvent was evaporated to dryness under reduced pressure to give 2.0 g (100%) of 2,6-dimethyldihydrophenylhydrazine as a pale yellow oil. 1.2 g (17·6 mmol) of imidazole and 2.2 g (14.7 mTorr) of tri-butyldimethylcarbazine were continuously added to 1 ml of di-methane in 0 ° C at 0 ° C.

2.0 g (14.7 mmol) of a solution of 2.6-dimercaptodihydrophenylhydrazine. After the completion of the reaction according to the instruction of TLC, it was partitioned between dioxane and a 1:1 mixture of 3 Torr of hydrogen chloride and brine. The organic layer was washed with brine, dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure. Chromatography using 5% ethyl acetate:hexane gave 18 g (yield: 49%) of 2,6-didecyl-4-tris-butyl dimethyl methoxy phenol. 3〇〇 megahertz Vh NMR (CDC13) 5 〇·16 (s,6H), 0.98 (s,9H),2·19 (s,6H), 4·22 (s' 1Η),6·48 (s5 2Η). Mass spectrum: (Μ+Η)+ = 253. Β·2,6-Dimethyl-4-tris-butyldimethyloxyalkyloxyphenoxyacetate with 2·0 g (1.43 耄 mol) potassium carbonate and 83 〇 microliters (7.5 mM Treatment of 18 g (71 mmol Mo:\106\106749.DOC •91-1292752 ears) 2,6-dimethyl-4 in 5 ml of dimethyl decylamine by bromoacetic acid ethyl acetate a solution of a second-butyldioxyloxyphenol. The resulting solution was heated to 70 ° C for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and 3N hydrogen chloride. The combined organic layers were washed with diluted brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Using 5% acetonitrile to purify the gel to obtain 2 · 〇 3 g (85 %) of 2,6-dimethyl-4-tris-butyl dimethyl矽 alkoxyphenoxyacetam. 300 MHz Thermal NMR (CDCI3) (5 017 (s 6H) 〇·97 (s5 9H), 1·33 (t, 3H, J = 6.3 Hz), 2.22 (s, 6H), 4.30 (q, 2H) , J = 6·3 Hz), 4.35 (s, 2H), 6·57 (s, 2H). Mass Spectrum: (M+H)+ = 3 5 6 0 C· 2,6-Dimethylhydroxyphenoxy Acetic acid

Add 4 ml of 3N sodium hydroxide to 2 〇 3 g (6 〇 莫 耳) 2,6-dimethyl-4-tris-butyl dimethyl decyloxyphenoxyl in 1 mL of methanol In a solution of ethyl acetate. After the reaction mixture was stirred at room temperature for 3 minutes, it was acidified with 3NHC1. The reaction was allowed to stir for an additional 1 hour and then partitioned between water and dichloromethane. The combined organic extracts were rinsed with brine and dehydrated with anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. It was triturated with hexane to give 910 mg (77%) of 2,6-dimethyl-4-hydroxyphenoxyacetic acid as a white solid. 300 megahertz h NMR (CD3〇D) (5 2.18 (S5 6H), 4.31 (s, 2H), 6.41 (s, 2H). Mass spectrum: (M+H)+ = 214. D· (2S, 3S , 5S) 2 - (2, 6 'methyl I phenoxyphenoxy) amino group via 5--5 (tris-butoxycarbonyl) amine group L1, diphenyl hexane using standard coupling Procedure (EDAC/DMF), carboxylic acid from Example 21C

O:\106\106749.DOC 1292752 is coupled with an amine from Example IF to give the desired compound. 3 〇〇 Hz ι NMR (CDC13) 5 1.40 (s, 9H), 1.68 (m, 2H), 2.07 (s5 6H), 2·77 (d, J = 6 Hz, 2H), 2·98 (m , 2H), 3.74 (m, 1H), 3.90 (m, 1H), 4.10 (m, 3H), 4.58 (m, 1H), 5.20 (m, 1H), 6.44 (s, 2H), 7·10- 7·30 (m5 10H). Ε·(28,38,58)-2-(2,6-Dimethyl-4-carbonylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidine_2 -keto)methylbutenyl)amino-1,6-diphenylhexane_ Boc_protection of the compound from Example 21D was removed using TFA/CH2C12

The resulting amine was coupled with the carboxylic acid from Example 2A using standard coupling procedures (EDAC/DMF) to give the desired compound. 3 〇〇 Hz H NMR (CDC13) (5 0.78 (d, J = 5 Hz, 3H), 0·81 (d, J = 5 Hz, 3H), 1·47 (m, 1H), 2· 03 (s,6H), 2.18 (m,1H), 2.62 (m5 1H), 2.80 (m,2H),3·05 (m,6H), 3.78 (m5 1H),4·12 (m5 6H), 4.37 (m,1H), 4.71 (s,1H), 6.47 (s,2H),6·94 (br d,1H),7·20 (m, 10H). Mass Spectrum: (M+H)+ = 645 ® Example 22 (2S,3S,5S)_2_pK(±)-l,l-·One gas-2-isopropyl-3-tetrazine p-secenyloxy)amino-3-carbyl-5- (2S-(l-tetrahydropurine·2-keto)·3-methylbutanyl)amino-1,6-diphenylhexane oxime. cis(±)-2-isopropyl-3- Hydroxytetrahydropyrimidine Sodium ethoxide (16.75 g, 0.246 mol) was carefully added in several portions to a solution of ethyl 3-mercaptopropionate (27.25 mL, 0.246 mol) in 200 mL of ethanol. The resulting suspension was then cooled to -20 ° C and 2 - bromoisovalerate in 5 mL of ethanol was added dropwise over 2 hours at O: \ 106 \ 106 749. DOC - 93 - 1292752 (5 〇克,〇.239 摩尔)° After the addition was completed, the reaction was warmed to ambient temperature and allowed to mix for 3 hours. The mixture was poured into 600 ml of ethyl acetate and 6 ml of saturated ΝΗαΐ. The ethyl acetate layer was removed and the layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, dried and concentrated in vacuo to give an orange oil. The oil was dissolved in 500 ml of toluene and sodium ethoxide (16.75 g, 〇·246 mol) was added. The reaction mixture was heated to reflux for 6 hr then cooled to EtOAc EtOAc EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The crude product was added to 5 mL of aqueous 10% sulfuric acid, and the resulting mixture was heated to reflux for several hours, then cooled to room temperature and neutralized with 6 Ν sodium hydroxide and then ethyl acetate (3 X 300) ML) extracted. The combined organic layers were dried, filtered and concentrated in vacuo to give a dark oil. The crude product (ketone) was purified by vacuum distillation at 75-80 °C. 300 MHz 4 NMR (CDC13) 5 0.93 (d, J = 9 Hz, 3H), 1·03 (d, J = 9 Hz, 3H), 2·32 (m, 1H), 2.55-2.70 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 3.38 (d, J = 4 Hz, 1H). Mass spectrum: (M+H)+ = 145. Diisobutylaluminum hydride (86 ml, 1 M in THF) was added dropwise to a solution of the above-mentioned ketone in 125 ml of CH2C12 at 0 °C. The reaction mixture was allowed to warm to room temperature and then quenched by the addition of IN HCl (2 55 mL). The reaction mixture was extracted with diethyl ether (3.times.150 mL). EtOAc (EtOAc) The solution was concentrated in vacuo and the obtained oil was purified eluting with EtOAc EtOAc 300 MHz NMR (CDC13) 5 1·〇3 (d, J = 7 Hz, 3H), 1.08 (d, J = 7 Hz, 3H), 1·80 (d, J = 9 Hz, 1H), 1.90 (m, 2H), 2.24 (m, 1H), 2.90-3.10 (m, 3H), 4.36 (m, 1H). Mass spectrometer··(M+H)+ =147 〇B· cis(±)-2-(isopropyl-3-sulfenyl)-2-(2-pyridyl)carbonate diisopropylethylamine (4.65 ml, 26.7 mmol) and bis-(2-pyridyl) carbonate (5.42 g, 25.1 mmol) were added to the product from Example 22A in 40 mL CH2C12 (2·29 g, 15 · 7 millimoles). After 18 hours at room temperature, the reaction mixture was diluted with a gas-like mixture and washed successively with 1% citric acid, saturated sodium hydrogen carbonate, brine, and then dried over sodium sulfate; filtered and concentrated in vacuo. The crude product was purified by hydrazine column chromatography (2% EtOAc/hexanes) to afford the desired compound. 3 〇〇 megahertz NMR (CDC13) δ 1·〇5· (d, J = 7 Hz, 3 Η), 1.08 (d5 J = 7 Hz, 3H), 1·90 (m, 1H), 2.05 (m, 2H), 2.58 (dd, J = 6, 15 Hz, 2H), 3·1〇(m, 2H), 3·28 (dd5 J = 3, 12 Hz, 1H), 5·47 (m, 1H) , 7.12 (m, 1H), 7·27 (m, 1H), 7·80 (m, 1H), 8.41 (m5 1H). Mass Spectrum: = 268. C·(2S,3S,5S&gt;-2_(cis(±)·2-isopropyl-3-tetrahydropyrimenyloxy)amino-3-3-ylamino-5-(tri-butoxycarbonyl) Amino-1,6-diphenylhexane The amine from Example 1F (791 mg, 2.06 mmol) was added to the compound from Example mb in 5 mL of CHAl2 (5 mg, [π] In a solution of millimolar. Stir the reaction at room temperature until all the examples are exhausted

O:\106\106749.DOC -95-1292752 The compound of 22B. The reaction mixture was diluted with hydrazine chloroform and washed with (10) succinic acid, saturated sodium bicarbonate, brine and then dehydrated with sodium sulfate: filtered and concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc) 3(10) megahertz NMR (CDC13) 5 0.83_L05 (m, 6H), 14〇9H), 1·90 (m, 3H), 2·20 (m, 1H), 2·75 (m, 2H), 2.85 (m,4H), 2.95-3.15 (m,3H), 3.67-3.90 (m,4H),4·55 (m,iH),5·1〇(m, 1H), 5.30 (m5 1H), 7.10 -7.26 (m, l〇H). Mass Spectrum: (M+H)+ = 557. D·(2S,3S,5S)-2-(cis(±)-l,i-dioxo-2_isopropyl_3_tetrahydrothienyloxy)amino-3-carbyl_5_(third -butoxycarbonyl)amine, 6-diphenyl hexanide potassium peroxodisulphate (〇x〇ne) (839 mg, 1.37 mmol) and sodium bicarbonate (152 mg, 1.82 mmol) plus To a solution of the compound from Example 22C (523 mg, 0.91 mmol) in 1 mL of acetone and EtOAc. The resulting solution was stirred for 2 hours at which time a white precipitate appeared. The reaction was quenched with aqueous sodium hydrogen sulphate and extracted with EtOAc (EtOAc (EtOAc). The crude product was purified by silica gel column chromatography (2% MeOH / EtOAc) to afford 422 mg. 300 MHz 4 NMR (CDC13) 5 1.20 (m, 6H) 1.40 (s, 9H), 1·60 (m, 4H), 2.10-2.32 (m, 4H), 2·67 (m5 2H), 2.75 ( m, 2H), 2.85 (m, 2H), 3.15 (m, 2H), 3.70-3.90 (m, 3H) 4.56 (m, 1H), 5.30 (m, 2H), 7.10-7.30 (m, l〇H ). Ε·(2S,3S,5S)-2-(cis(±)-l,l_dioxo-2-isopropyl_3_tetrahydrothiophenoxy)amino-3-hydroxy-5-(2S- (l-tetrahydropyrimidin-2-one)_3-methylbutanyl)amino-1,6-diphenylhexane O:\106\106749.DOC -96- 1292752 Removal from TIA/CH2C12 The B〇c_ protecting group of the compound of 22D, and the obtained amine was coupled with the carboxylic acid from Example 2A to give the desired compound (820/o). 3 00 MHz 1H NMR (CDCl3) 5 0.82 (m, 6 l·l) 1·(Μ·20 (m, 6H), 1.60 (m, 2H), 2.07 (m, 1H), 2.25 (m5 2H), 2 ·65-3·20 (m,12H),3·70 (m,1H),3·90 (m,1H),4.1〇-4·2〇(m,2H),5.07 (m,1H), 5.37 (m,1H),5·87-5·98 (m,1H), 6.95-7.05 (m,1H), 7.20 (m,i〇H). Mass Spectrum: (m+H)+ = 671. 23 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-1hydroxy-5-(2S-(l-dihydropyrimidine_2,4-dione) _3_Methylbutylidene) Amino-p-phenylene oxime·N-(2-ethoxypropenylmethoxycarbonylpropyl)urea 3.90 g (0.02 6 mol) of silver cyanate is added to 1.74 g (0.013 mol) of 2-ethoxypropenyl chloride in 18 ml of toluene. The mixture was heated to reflux for 0.77 hours. The mixture was allowed to warm to room temperature and allowed to precipitate. The supernatant (9.6 ml) was recovered, and 18 ml of anhydrous DMF* 5 pen #Et2 加入 was added, and the cold portion was -15 ° C for 45 minutes, and left in the refrigerator overnight. Evaporate in the true two granules, and By gel column chromatography (2% Me〇H/CH2C12), 1.59 g of the desired compound (9 〇 2%). 3 〇〇 Hz H NMR (CDC13) δ G.96 (d5 I = 7 Hz, 3H), i 〇 (d, j = 7 Her paper, 311), 1.37〇, 1 = 7.5 Hz, 311), 2 25 (111, 111), 3.74 (8, 3H), 3.97 (q5 J = 7.5 Hz, 2H), 4·42 (10), j = 4 5, 8 〇 Hertz, 1H), 5·25 (d, J = 12 Hz, 1H), 7·68 (d, j = i2 Hertz, 1H), 8·55 (s, 1H), 9.10 (d, j = 8 Hz, 1H). Mass spectrum··(M+H)+ = 273.

O:\106\106749.DOC -97- 1292752 Β· 2S-(1-dihydropyrimidin-2,4-dione)-3-methylbutyric acid 174 mg (0.64) in 10 ml of 2N sulfuric acid A solution of the compound from Example 23A was refluxed for 2 hours, cooled to room temperature and left in the refrigerator overnight. The mixture was concentrated, and the residue was crystalljjjjjjjjjjjj 300 MHz NMR (CDC13) 5 1.06 (d, J = 7 Hz, 3H), 1.13 (d, J = 7 Hz, 3H), 2.25 (m, 1H), 5·04 (d, J = 1〇) Hertz, 1H)5 5·74 (d, J = 7 Hz, 1H), 7·50 (d5 J = 10 Hz, ιΗ), 8 43 (s5 1H) 〇C· (28,38,58)-2 -(2,6-dimethylphenoxyethyl)amino-3-3-ylamino-5-(2S-(l-dihydropyrimidin-2,4-dione)-3-methylbutanyl) Aminodiphenylhexane The carboxylic acid from Example 23B was coupled with the amine from Example 1N using standard coupling procedures (EDAC in DMF) to afford the desired compound. 300 MHz 1H NMR (CDC13) 5 0.81 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3H), 2.18 (s, 6H), 2·23 (m, 1H), 2 · 63 (m, 1H), 2_85 (m, 1H), 3·0 (m, 2H), 3.78 (m, 1H), 4·20 (m5 4H), 4·58 (d5 J = 10 Hz, 1H ) 5 5.68 (dd, J = 1.5, 7.5 Hz, 1H), 7·0_7·25 (m, 13H), 7.50 (d, J = 7.5 Hz, 1H), 9·50 (s, 1H). Mass Spectrum: (M+H)+ = 640 ° Example 24 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-( Another preparation method of l-tetrahydropyrimidin-2-one)-3-methylbutanyl]amino-i,6-diphenylhexane O:\106\106749.DOC -98- 1292752 Α· 2 , 6-Dimercaptophenoxyacetic acid will be added to 3-liter of 2,6-xylenol (102.8 g, 0.842 mol) and chlorinated acetic acid (159.6 g, 1.68 mol) in 1000 ml of hydrazine 20 Mechanically stirred and water-cooled condenser in a 3-neck round bottom flask. A solution of NaH (134·9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via an addition funnel and heated to reflux. After 2 hours. Additional chlorinated acetic acid (79. 4 g, 〇·84 mol) and NaOH solution (67. 2 g, 168 mol in 2 mL of water) were added to the reaction mixture. After 19 hours, additional chlorinated acetic acid (39.8 g, 〇·42 mol) and NaOH solution (33.6 g, 8484 mol in 1 mL of water) were added to the reaction mixture and reflux was continued. 'Until the starting phenol is exhausted. The reaction flask was cooled in an ice water bath and acidified to pH = 1 with concentrated HCl to cause formation of a precipitate. The resulting slurry was stirred in an ice bath for 1 hour and then filtered. The solid was dissolved in hot (100 C) water and then allowed to cool to crystallize the product into a white plate. Hyun = 136-137::, yield = 78.8 g, 52%, Β· (28, 38, 58) -2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(tris-butoxycarbonylamino)-1,6-diphenylhexane 36.3 ml, 〇·42 mol) was added to a slurry of 2,6-dimethylphenoxyacetic acid (50 g, 〇·28 mol) in 5 ml of decylbenzene, followed by 5 drops. DMF and stir at room temperature for 3 minutes, then at 55. Leave it for 15 hours. The toluene was removed on a helium-transformer and the residual volatiles were removed in vacuo to afford 2,6-dimethylphenoxyethylamine chloride, 55 g, 100%. [2S,3S,5S]-2-Amino-3-hydroxy-5-tris-butoxycarbonylamino 丨,6_O:\106\106749.DOC -99-1292752 0.5 succinate (U 1.9 g, 〇 25 mol) was placed in a 2 liter 3-neck round bottom flask with mechanical stirring. Add NaHC03 (1 〇 6 g ' 1.26 mol), 600 ml H20 and 600 ml EtOAc and stir vigorously until all the solids were dissolved (丨5 min). Stirring was slowed and 2,6-dimethylphenoxyacetam and Et〇Ac (1 mL) were added via a funnel in a narrow stream. After 30 minutes of scramble, the starting material (HpLC analysis) was depleted and the layers were separated. The layers were extracted with EtOAc. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj C·(28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(tris-butylcarbonylaminodiphenylhexane mixed ( 28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-(tris-butoxycarbonylamino)-indole, 6-diphenyl Hexane (1751 g, 〇.32 mol) and 500 ml of CH2C12, and stirred. Add cf3C02H (249 ml '3.2 mol) and stir for 20-25 minutes, then pour the reaction mixture into 1000 ml Water and 200 ml CH2C12 separatory funnel. Carefully shake the resulting mixture and separate the layers. Rinse the organic layer again with 5 mL of water. Then rinse with 3 X 500 mL NaHC03 and finally rinse with 500 mL of saline. The organic solution was dehydrated with MgS04, filtered and concentrated to give a golden oil, which was then taken up into a blister, and 3 liters of diethyl ether was added to the crude product and shaken vigorously to dissolve. The solid began to crystallize within a minute' and the mixture became viscous. Sufficient diethyl ether was added to stir the mixture and the mixture was stirred at room temperature for 1 hour. O:\106\106749.DOC -100- 1292752 The solid was air-dried to give 115 g of the desired product as white needles with a yield of 81%. A solution of HC 1 / diethyl ether was added to the filtrate to give a residual product. Precipitate in the form of H (:1 salt). By collecting a slightly reddish solid by filtration, carefully keep the solid in %, while moistening with ether. At the time of dehydration, the amine salt Transfer to a separatory funnel and extract with NaHC〇3 (aqueous). Wash the organic layer with brine, dehydrate with MgS〇4, concentrate and treat in the above manner to give an additional 15 g of desired product. The yield was 91%. D. N-carbonylbenzyloxy-3-aminopropanol In a 12 liter 3-neck round bottom flask, isopropyl acetate (6.5 liter) was added. The solvent was cooled in an ice water bath. To: (:, and add 3_amino-indole-acetone (1.14 kg, 15 mol), 2.15 equivalents at a time. In this rapidly stirred solution, add decyl chloroformate dropwise over 2 hours. (1·2〇 kg, fork Moer, 1.0 equivalent), while maintaining the internal temperature of the flask (7) it to ^ Yizhi After the completion of the addition, allow the reaction mixture to be stirred for an additional 〇·3 hours between 〇 and 15 ,, after which time water (3.5 liters) is added once and then the solution is dispensed. Rinse with an additional 2 X 3 · 5 liters of water. The organic layer was dehydrated with potassium carbonate and concentrated to give a solid which was taken in an excess of isopropyl acetate. The alkane was precipitated from the solution. The solid was filtered under nitrogen to give 12 g (yield: 82%) of desired product as colorless solid. Ε· Ν-carbonylbenzyloxy-3-aminopropene mixed 335 ml of dimethyl sulfoxide and 9 liters of dichloromethane, and cooled to _48

O:\106\106749.DOC • 101 - Ϊ292752 t. 313 ml of grass _ was added over 25 minutes to maintain the temperature below -40 t &gt; cooled to -48 ° C and 5 g of N-Cbz-3-amino group dissolved in i liters of methylene chloride was added - 1-propanol in order to maintain the temperature below _4 〇. Hey. Stir for an additional i hours at _45 °c. 1325 ml of triethylamine was added at a rate capable of maintaining the temperature below _4 〇t. After an additional 15 minutes of _40t:, the mixture was allowed to warm to -3 Torr, and then 2 5 liters of 2% water-containing potassium dihydrogen phosphate was added. After stirring for a few hours, the layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. The resulting aldehyde was retained at _2 Torr. In a solution of 〇 until needed. Methyl F. N-(N-(indolylcarbonyl-3-amino)propyl) decanoate The crude product of Example 24E (not chromatographed) was added to a 5 liter 3-neck round bottom flask (1) 5 g , 0.555 mol, u equivalent), followed by water (4 mL) and methanol (ml). The reaction mixture was maintained at 25 throughout the course of the reaction. (: After the solution became homogenized, (s)_glycine methyl acetate hydrochloride (90.2 g, 0.538 mol, 〇97 equivalent) was added in one portion, followed by rapid addition of sodium acetate trihydrate 按51 in order.克, ln 莫, 2. 〇 equivalent) and cyano hydride (73.2 g '117 m, 21 eq. allowed to stir the reaction mixture at room temperature for 5 hours and concentrated in vacuo to remove All methanol was present. In this solution, saturated aqueous sodium bicarbonate (400 ml) was added, and the mixture was extracted with isopropyl acetate (1 liter). The organic layer was washed with water (2×400 ml) and covered with The sodium sulfate was dehydrated and concentrated, and 150 g of a crude product was dissolved in isopropyl acetate (3 ml) and hept (2400 ml). Anhydrous HCi was foamed therein and in the solution An oily solid precipitates out. Discard the liquid other than the solid and dissolve it.

O:\106\I06749.DOC 1292752 is dissolved in monochloromethane (3 liters). The solution was washed with water (6 Ο 0 ^: liter) and saturated aqueous sodium hydrogen carbonate (600 mL) and dried over sodium sulfate. Concentration in vacuo gave 105 g (yield: 59%) of desired product as pale yellow oil. G. Ν-(3-Amino)propyl proguanilate The product of Example 24F (120 g, 0.372 mol) and methanol (1 liter) were placed in a 3 liter flask. The solution was allowed to mix for 1 hour in the presence of Raney nickel (18 g). After the Raney nickel was removed by filtration, pd(0H)2 (24 g) was added, and the solution was allowed to mix for 20 hours under a hydrogen pressure of 60 pounds per square inch. The solution was purged with nitrogen and again at an additional 1 hour under a pressure of 60 psig of hydrogen. The solution was filtered and concentrated to give 63 g of oil (90%). Toluene (120 ml) was added to the oil, and the solution was concentrated again in vacuo to give the desired product. H. 2S-(1-tetrahydropyrimidine-3-yl)-3-methylbutanoate was added to a 5 liter 3-neck round bottom flask with a stir bar. , 0.8 moles) and dioxane (3.2 liters). Carbonyldiimidazole (232 g, 1.44 mol, 1.8 equivalents) was added in portions slowly over 25 minutes. The solution was allowed to stir at ambient temperature for 40 hours. Water (200 ml) was added over 1 hour and carefully stirred until no more gas was produced. A solution of 35% HCl was slowly added to the stirring solution until the solution became acidic. The solution was then dispensed and rinsed with water (2 x 3 00 mL). The organic layer was dehydrated with sodium sulfate and concentrated to give 12 6 g (yield: 74%) of desired product. I. 2S-(l_rahydropyrimidin-2-yl)-3-mercaptobutyrate was added to a 12 liter 3-neck round bottom flask with a stir bar, and the addition of Example 24H to O:\106\106749. DOC -103 - 1292752 product (126 g '〇·588 mol), water (ι_3 liter) and THF (3.9 liter). The solution was cooled to 〇〇c in an ice bath, and lithium hydroxide monohydrate (74 g &lt;RTIgt;&lt;/RTI&gt;&gt; Allowed. The solution was mixed for 14 hours. It was then acidified to pH 11 by slowly adding 5 % aqueous phosphoric acid and thf was removed in vacuo. The liquid phase was rinsed with isopropyl acetate (2 liters) and then acidified by slowly adding 35% aqueous HCu $ pH. The layer was then extracted with ethyl acetate (5 χ 2·2 liter). The mixed organic layer was concentrated to give the desired product (1 g, 5 g) as a white solid. The compound was then purified by the addition of isopropyl acetate (500 ml) and ethanol (15 ml), and the solution was boiled and stirred rapidly until 5 ml of solvent was evaporated. The solution was cooled to hydrazine. (^ and filtered to give 92 g (75%) of pure desired product. J·(28,38,58)-2_(2,6-dimethylphenoxyethyl)amino-3-hydroxyl -5-[2S-(l-tetrahydropyrimidin-2-one]&gt;-3-methylbutanyl]amino-: i,6-diphenylhexane in a 2 liter 3-neck round bottom flask, Mix Example 24C (100 g, 0.22 mol), product of Example 241 (44.8 g, 0.22 Mo) and 750 mL of DMF, and cool the mixture in ice/water bath. Add HOBT (90.9 g, 〇·67 mol) EDAC (86 g, 0.45 mol) and triethylamine (62.5 ml, 〇·45 mol), and removed the ice bath, allowed to stir the reaction mixture, and warmed to room temperature for 5 hours. The reaction was diluted with 1000 ml of IPAC and quenched with 1 00 ml of water. The mixture was shaken and separated, extracted with 1 X 400 ml of IPAC, rinsed with 1 X 400 ml of 10% HCl, 1 X 500 ml of NaHC03 The organic matter was diluted with 100 ml of hexane, then washed with 4×500 ml of water, 1 χ 5〇〇O:\106\106749.DOC -104- 1292752, diluted with saline, dehydrated with MgS04, filtered and concentrated to give White foamy product. Example 25 (2S,3S,5S)_2-(2,6-Dimethylphenoxyethyl fluorenyl)amino _3_ carbyl-5_[2S-(1·tetrahydropyrimidin-2,4-dione 3-methylbutylidene]amino-1,6-diphenylhexane oxime N-(2-methoxycarbonyl)ethyl-L-proline acid tert-butyl ester 9.0 ml of acrylic acid The ester was added to a solution of 173 g of the third-butyl phthalate in 1 ml of methanol. The solution was heated to reflux overnight. An additional 0.9 g of methyl acrylate was added and reflux was continued. The crude product was purified by evaporating the solvent in vacuo <RTI ID=0.0>(</RTI> </RTI> <RTIgt; 3 〇〇 Hz! H NMR (CDC13) 5 0.91 (d, J = 3.5 Hz, 3 Η), 0.93 (d, J = 3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J = 7 Hz, 2H), 2.68 (m, 1H), 2.81 (d5 J = 6 Hz, 1H), 2·95 (m, 1H), 3.68 (s, 3H). :(m+H)+ = 260. Β· N-(2-carboylamino)ethyl lysine 3 -butyric acid will be added to 10.15 ml of water · 415 g of lithium hydroxide monohydrate To 5 ml 1.86 g of the solution from the product of Example 25 was obtained in THF. After 4 minutes, 10.8 ml of IN HC1 was added. The reaction mixture was evaporated to dryness and anhydrous EtOAc was evaporated. The residue was dissolved in 25 ml of acetonitrile and EtOAc (EtOAc) EtOAc. To the solution was added 2.02 g of hydrazine, Ν'-disuccinimide carbonate. The reaction mixture was stirred for 3.5 hours. The solvent was removed in vacuo and 9 mL of 1111? was added, followed by O:\106\106749.DOC -105-1292752 and 1.43 mL of concentrated ammonium hydroxide. The reaction was allowed to proceed overnight. The reaction was partitioned and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate and brine, and then evaporated from anhydrous sodium sulfate. After filtering off the dehydrating agent, the filtrate was concentrated in vacuo and purified by EtOAc EtOAc EtOAc EtOAc 300 MHz iH NMR (CDC13) 5 0.95 (d, j = 7 Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 1.93 (m, 1H), 2·37 ( m, 2H), 2·65 (m, 1H), 2.95 (m, 2H), 5·30 (br s, 1H), 7·85 (br s, 1H). Mass spectrum: (M+H)+ = 245. C. 2S-(1-tetrahydropyrimidin-2,4-dione)-3-methylbutanoic acid tert-butyl ester 0.92 g of a solution obtained from the product of Example 25B in 1 ml of THF and 1.83 Carboxydimethylimidazole (CDI) was refluxed for 26 hours. Then, 83 g of CDI was added, and the solution was again refluxed for 72 hours. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate washed with water, sat. NaHCO? The organic layer was dried, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (2% to 5% MeOH in CH2 C12) to afford 0.54 g (52%) of desired compound. 300 MHz NMR (CDC13) 5 0·96 (d, J = 7 Hz 5 3H), 1.05 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 2.20 (m, 1H), 2.66 (m, 2H), 3·43 (m5 1H), 3.75 (m, 1H), 4.63 (d5 J = 9 Hz, 1H), 7·35 (br s, 1H). Mass spectrum: (M+H)+ = 271. D. 2S-(1-tetraapyrimidine-2,4-dione)-3-methylbutyric acid 0.53 g of a solution of the compound from Example 25C, stirred in 5 mL of trifluoroacetic acid at EtOAc. hour. The solvent was evaporated in vacuo, purified and purified eluting with EtOAc EtOAc EtOAc EtOAc 300 MHz NMR (DMSO-d6) δ 0·86 (d, J = 7 Hz, 3 Η), 0.97 (d, J = 7 Hz, 3 Η), 2.15 (m, 1H), 3·40 (m, 4H) ), 4.39 (d, J = 10 Hz, 1H). Mass spectrometry: (M+H)+ =215 ° Ε·(28,38,58)-2_(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2s-(i -tetrahydropyrimidine j,4·diketomethylbutanyl]amino-l6_diphenylhexane The amine compound from Example in was obtained from Example 25D using a standard coupling procedure (EDAC in DMF). The acid is coupled to give the desired compound (68%). 300 MHz Hz 111 ((:0(::13)(5〇83((1,:[:==7 Hertz, 3H), 0.88 ( D5 J = 7 Hz, 3H), uo (m, 2H), 2 2 〇 (s, 6H), 2 4 〇 (m, 1H), 2.58 (m, 1H), 2.80 (m, 1H), 2.92 ( m,1H),3.05 (m, 3H)5 3.65 (d,J = 5 Hz, 1H), 3·83 (m,1H), 4 2〇(m,5H), 6_18 (d, J = 9 Hz , ih), 7.0-7.38 (m5 14H). Mass Spectrum: (M+H)+ = 643 〇 Example 26 (2S,3S,5S)-2-(2,6·Dimercaptophenoxyethyl)amine 3-Hydroxy-5-[2S-(4-aza-4•tetrahydropyrimidinyl)_3methylbutyryl]amino-1,6-diphenylhexaneΑ·N(l)-third- Butoxycarbonyl is added to a solution of m. Focus nX119t # The reaction mixture was heated to reflux for 3 hours in total, and concentrated in vacuo to a transition

O:\106\106749.DOC •107- 1292752 Shrink. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. After concentrating in vacuo, the crude material was purified by EtOAc EtOAc (EtOAc) 3 〇〇 megahertz iH nmr (CDC1J occupies 1.45 (s, 9H), 3.46 (m, 2H), 4.0 (br s, 1H), 5.10 (m, 2H), 5.83 (m5 1H), 6.0 (br s,1H). Mass Spectrum: (m+H)+ = 173. Β·N(l)-Second-butoxycarbonyl _]^(2)_Dilyl 4 (2 benzyloxycarbonyl hydrazine will be 4.69 g The oxocarbonyloxysuccinimide was added to a solution of 4·8 g of the compound of Example 6 6 in 15 ml. The reaction mixture was stirred at room temperature for 72 hours, and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. EtOAc EtOAc EtOAc The crude product obtained after concentration is purified to give 5.27 g of the desired compound. 300 megahertz, hnmrkdcd 5 _l43 (brs, 9H), 415 (br s, 2H), 5.18 (s, 2H), 5 · 20 (m, 2H), 5.82 (m, 1H), 6.39 (br s, 1H), 7·36 (m5 5H). Mass spectrometer··(M+H)+ = 307. C· N(l)- The third _butoxycarbonyl-N(2)-methylidylmethyl_N(2)_Yu Oxygen-based moon well is treated with an anhydrous ice/acrylic bath. Kede The solution of the compound of Example 26 was cooled. The ozone was bubbled therein for 1.75 hours until it continued to light blue. Air was passed through the solution for a minute, then 15.6 liters of dimethyl sulfide was added, and the reaction mixture was allowed. Gradually warm to room temperature overnight. Evaporate the solvent in vacuo, and dissolve the residue in ethyl acetate, rinse with water, then rinse several times with brine, with anhydrous sulfuric acid O:\106\106749.DOC -108- 1292752 The organic layer is dehydrated, (iv) and concentrated in vacuo to give 72 g of the desired compound. 300 MHz NMR (CDCl3) 3 on shoulder gamma 9H), 4-35 (m, 2H), 5.20 (s, 2H), 6.65 (br s, 1H), 7.36 (s, 5H), 9.70 (br s, 1H). Mass spectrometer··(M+NH4)+ =: 326. D· N-[2_( N-(2)-oxime oxycarbonyl-N-(l)-tris-butoxycarbonylindenyl]ethyl amide methyl ester 3.55 g of methyl L-proline hydrochloride was added to 1 〇〇 7.2 g of a solution of the compound from Example 26C in MeOH was added, followed by 'μg sodium acetate and 1.33 g of cyano hydride. The reaction mixture was passed at room temperature. The mixture was filtered and Concentrated. By silica gel column chromatography (2% MeOH in ChCh) affording crude product was 5. 8 g of the desired compound. 300 MHz iH NMR (CDCl3) d 〇9〇 ((1,; = 6 Hz, 6H), 1.43 (br s, 9H), 1.87 (m, 1H), 2·6 (Μ·0 (m, 4H), 3.72 (s, 3Η), 5.18 (s, 2Η), 7.37 (m, 5Η). Mass Spectrum: (Μ+Η)+ = 424. Ε· 2S-[4-Benzyloxycarbonyl azatetrahydropyrimidine Methyl keto)_3_methylbutanoate was stirred at ambient temperature under stirring in a solution of 2.4 g of the compound from Example 26D in 20 ml of HCl and dioxane for 1 hour. The solvent was evaporated and the residue was washed with EtOAc EtOAc (EtOAc) The carbonyl carbodiimidazole was left at room temperature for 48 hours. The solvent was removed and purified by column chromatography (10% to 30% EtOAc in CH2 C12) 300 MHz NMR (CDC13) (5 0.90 (d, J = 7 Hz, 3 Η), O:\106\106749.DOC -109- 1292752 〇·98 (d, J = 7 Hz, 3h), 2.17 (m ,1Η),3·34 (m,1Η),3·61 (m, 2H), 3.72 (s,3H),3·98 (m,1H),4.71 (d, J = 10 Hz, 1H), 5.20 (s, 2H), 6.72 (br s, 1H), 7.38 (m, 5H). Mass Spectrum: (M+H)+ = 350 ° F· 2S-(4 -Benzyloxycarbonyl azatetrahydropyrimidinyl)-3_methylbutyric acid In aqueous dioxane, 0.78 g of the compound from Example 26E was hydrolyzed using lithium hydroxide to give 〇·35 g. Compound: 3 〇〇 megahertz lH NMR (CDCl3) 6 〇·85 (d, J = 7 Hz 5 3H), 1.04 (d5 J = 7 Hz, 3H), 2·40 (m, out), 3.40 (m,1H), 3.50 (m,1H), 3.80 (m, 2H),3·95 (d,J is called Hertz, 1H), 5 2〇(s,2H),7 3〇(s,m ), 7·36 (s, 5H). Mass Spectrum··(M+H)+ = 336. G·(28'38,58)-2_(2,6-Dimethylphenoxyethyl)amino _3_Hydroxy-5-[2S-(lower oxycarbonylazatetrahydropyrimidine-2-ketoben-3-methylbutyryl) fe-l-1,6-monophenyl has been burned using standard coupling procedure (EDAC) /DMF) An acid-coupled oxime from Example ... was obtained from the acid coupling of Example 26F to give the desired compound (36%). 3(d) Hertz iHNMR (CDa3H G 72 (d, Bu 7 Hz, 3 Η), 0.83 (d? J = 7# , 3H) 5 2.20 (s5 6H) 5 2.65 (m5 1H) 5 2.83 (m5 )' -10 (m ,4H)5 3.90 (m? 1H)5 6.65 (m5 1H)3 7.0-7.35 (m,18H). Mass Spectrum: (M+H)+== 764. (2S'3S'5S)_2-(2, 6_: f-phenoxyethyl oxime) amine group j. hydroxy _5_[2S-(4-azatetrahydropyrimidin-2-one)_3_methylbutanyl]amino-indole-diphenyl The hexane utilizes 10 〇 /. | bar carbon as a catalyst, borrowed

Hydrogenolysis will be derived from Example 26G

O:\106\106749. The deoxyl base protecting group of the compound of DOC 1292752 is removed to give the desired compound. 3 〇〇 Hz NMR (CDC13) δ 〇 · 83 (d, J = 4·5 Hz, 3 Η), 0.86 (d, J = 4.5 Hz, 3 Η), 1·80 (m, 1 Η), 2.20 (s ,6Η), 2.58 (m, 1Η), 2·67 (m, 1Η), 2·90 (m, 2Η), 3.0 (m, 1Η), 3 8〇 (m, 1Η), 4.20 (m, 3Η) ), 6·72 (m, 1Η), 7.0 (m, 2Η), 7·20 (m, 11Η). Mass spectrum: (M+H)+ = 630. Example 27 (2S,3S,5S)-2»(2,6-Dimercaptophenoxyethyl)amino-3-3-ylamino-5-[2S-(l-tetrahydropyrimidin-2-yl) -3-methylbutenyl]aminophenylmethylheptane A·(2S,3S,5S)-2-amino-3-carbyl-5-(tris-butoxyamino)_1 _Phenyl-6-methylheptane was subjected to the procedure described in Example 1A to Example 1F-1, but in Example 1C, propylmagnesium chloride was replaced by vaporized fluorenyl magnesium to give the desired compound. 300 MHz iH NMR (CDC13) 5 〇.88 (d, J = 7 Hz, 3H), 〇·92 (d5 J = 7 Hz, 3H), 1.43 (s, 9H), 1.50-1·80 ( m, 4H), 2·55 (m, 1H), 2.90 (m, 1H), 3.0 (m, 1H), 3·54 (m, 2H), (62 (m, 1H), 7.30 (m, 5H) Mass spectrometry: (m+h)+ = 337. Β· (28,38,58)_2-(2,6-dimethylphenoxyethyl)amino-3_hydroxy-5- (third - Butoxycarbonylamino) β1_phenyl-6-methylheptane The amine compound from Example 27 was coupled with the acid from Example 1 using standard EDAC coupling procedures to give the desired compound. 3 〇〇 Hz a NMR (CDC13) 5 0.85 (d, J = 7 Hz, 3 Η), 〇 9 〇 (d : = 7 Hz, 3H), 1.43 (s5 9H), 1.7 〇 (m, 2H), 2.20 (s, 6H), 3·〇3 (d5 J 1

O:\106\106749.DOC -111· 1292752 8 Hz, 2H), 3·4 1 “ (10), 1H), 3.80 (m, 1H), 4·20 (m5 2H), 4·22 〇, ZH) , 4.55 (m (M+H)+= 499.' ), 7·0 (m, 3H), 7.30 (m, 5H). Mass Spectrum: c· (2S,3S,SS)<~ ^ _5_Amino 1-Cage#·(2,6-Dimethylphenoxyethyl)amino-3-hydroxymethylheptane The third-but of the compound from Example 27B was subjected to the procedure of Example 1N for oxycarbonyl protection. Base removal, ~1

ΓΓηηι λ ^ , passed to the desired compound. 300 MHz] H NMR

Cl3) 3 0 9 , ld, J = 3 Hz, 3H), 0·94 (d, J = 3 Hz, 3H), 1·60 (m, 4H) ^ Λ 2·20 (s, 6H), 2.85 (m, 2H), 3.0 (m, 1H), 3·85 (m, 1H), 4.2fw _ (m, 2H), 7·0 (m, 2H), 7.35 (m, 6H). Mass spectrum: (m+h), 399. (,S'sS)-2-(2,6-dimethylphenoxyethyl hydrazino)aminol hydroxy 5 [2S-(1-tetrahydro'唆j嗣yl)-glycolylmethyl fluorenyl _ _ fluorenyl The heptane was coupled with the acid of Example 27C from the acid of Example 2C using standard coupling procedures (EDAC/DMF) to afford the desired compound. 3〇〇NMR (CDCI3) 5 0.88 (m, i2H)? 1.67 (m? 2H)? 1·90 (m,1H), 2.20 (s,6H),3·0 (d, J = 8 Hz, 2H ),3 22 (m, 4H)5 3.67 (m5 1H)5 3.77 (m5 1H)5 4.20 (Sj 2H)5 4.40 (m5 1H)5 4·76 (m,1H), 7.0 (m,3H), 7.30 (m, 5H). Mass Spectrum: (m+h)+ = 581 〇 Example 28 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)aminol 5-[2s-(i_tetrahydro) Pyrimidine_2, "diketo 3-3-methylbutanyl]aminobenzene

O:\106\106749.DOC -112- 1292752 hexa-methylheptane 2 The amine group from Example 27C was combined using standard coupling procedures (EDAC/DMF): with the acid couple from Example 25D Combine to get the desired compound. 300 dead Hertz 4_Yang (:13) 5 G.83 (dj = 7 Hz, 6H), 〇92 J = 7# || , 6H), 1&gt;73 (m, 2H), 2.18 (s, 6H) , 2.3〇(m, 1H), 2-62 (m, 2H), 3.03 (m5 2H), 3.45 (m, lH), .3.55 (m, m), 4.72 (' 2H), 4.20 (m, 4H) ), 6.40 (br d, J = 9 Hz, m), 7 〇 (m, 3H), 7·30 (m, 5H), 7.62 (br s, 1H). Mass spectrum: (M+H)+ = 595. Example 29 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5_[2s-(i-hexahydropyrazine j, % diketone &gt;3_Methylbutyryl]Aminodiphenylhexa Burn A· 2S_(4·Benzyloxycarbonyl-1_hexahydropyrazine-2,3-dione)-i,6-methylbutyrate The ester was added to a solution of 7777 g of N-(benzyloxycarbonylamino)-ethyl_L_valerium phthalate in 2 mL of toluene and 1 mL of acetonitrile in 2 mL of toluene and 1 mL of acetonitrile. The reaction mixture was kept at 50 ° C for 24 hours, and 2 g of oxazolidine diimidazole was added. The reaction mixture was kept at 5 (rc for another 72 hours). The solvent was evaporated in vacuo and passed through a silicone tube. Column chromatography (1% Et0Ae in CH2C12) was used to purify the crude product to give the desired compound. 3 〇〇 Hz NMR (CDC13) 5 0.95 (d, J = 7 Hz, 3H), [03 (d , j = 7 Hz, 3H) 5 2·20 (m5 1H), 3.60 (m, 1H), 3.73 (s, 3H), 3.85 (m, 1H), 4.0 (m, 1H), 4.10 (m, 1H) ), 4.90 (d, J = 10 Hz, ih), 5.36 (s, 2H), 7.20 (m, 5H). Mass Spectrum: (M+H)+ = 380. -113-

O:\106\106749.DOC 1292752 Β· Μ·^1·hexahydropyrazole ** well, 2,3-dione)-3-methylbutyric acid methyl ester by virtue of '10% Pd /C as a catalyst, the oxiranyl protecting group from the compound of Example 29 was removed to give the desired compound. Then megahertz Wnmmcdcu 5 〇.95 (d, J = 7 Hz, 3η) ι 〇3 (d, J = 7 Hz, 3 Η), 2.20 (m, 1 Η), 3.50 (m, 3 Η), 3 74 (s , 3Η), 3.83 (m, 1H), 5.0 (d, J = l〇 Hertz, 1H), 7·3〇 (br s, 1H). Mass spectrum: (M+H)+ = 229. C·(28,38,58)_2_(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-[2S-(l-hexahydropyrazine-2,3-dione The methyl ester from Example 29B was hydrolyzed using the procedure of Example 1M and the resulting acid was combined with the amine from Example 1N using standard EDAC coupling procedures. The compound is coupled to give the desired compound. 3〇〇 megahertz iH NMR (CDCl3) accounts for 0.82 (d, J = 6 Hz, 3H), 〇·85 (d, j = 6 Hz, 3H),! 8〇(m, 2H), 2·18 (m, 1H), 2.20 (s, 6H), 2.65 (m, 1H), 2.82-3.0 (m, 4H), 3.30 (m5 3H), 3.70 (m, 1H), 3·82 (m, 1H), 4 22 (m, 3H), 4.54 (d, J = 10 Hz, 1H), 6.30 (br, s, 1H), 6.65 (br d, 1H), 7.0 -7.30 (m, 13H). Mass spectrum: (M+H)+ = 643. Example 30 (2S,3S,5S)_2_(2,6-Dimethylphenoxyethyl)amino-hydroxy-5-[2S-(4-aza-4,5-dehydro-r_噃Pyridin-2-ketoben-3-methylbutylidene]amino-1,6-diphenylhexane A·2S-(4-azadehydro-1-pyrimidin-2-one)-3_A From the hydrolyzate mixture of Example 26F, in the column chromatography (5 〇 / 〇 O: \ 106 \ 106749. DOC - 114 - 1292752

MeOH/5% Ac〇H, after CH2Clj), the desired product was isolated, yielding 12.5%. 300 MHz iH nmR (CD3OD) 5 〇·93 (d, J = 7 Hz, 3H), 1·〇4 (d5 J = 7 Hz, 3H), 2·20 (m, 1 Η), 3.92 ( Dd,j = 15, 3 Hz, 1H), 4 〇(10), j = 15, 3 Hz, 1H), 4·5〇(d,]=1〇Hz, 1H), 6.95 (t, J = 3 Hz , 1H). Mass spectrum: (M+H)+ = 334. Β·(28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-[2S-(4-aza-4,5-dehydrogenation 1-pyrimidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexane The compound obtained from the example in is obtained from a standard coupling procedure (EDAC/DMF). The acid coupling of Example 30A gave the desired compound (7 %). 3〇〇 megahertz hNMRWDClD 5 0.80 (d, J = 7 Hz, 3 Η), 0·85 (d5 J = 7 Hz, 3 Η), 1.75 (m5 2 Η), 2.15 (m, 1 Η), 2.20 (s, 6 Η) ), 2.62 (m, l H), 2.85 (m, 1H), 3.02 (m, 2H), 3.55 (m, 2H), 3.80 (m, 1H), 4.20 (m, 4H), 6.38 (br d, 1H), 6.72 (t, J = 3 Hz, iH), 7.0 (m, 3H), 7.22 (m, 10H), 7.63 (s, 1H). Mass spectrum: (M+H)+ = 628 o Example 31 cis-N-tert-butyl-deca-argon_2_[2(R)-hydroxy_4_phenyl-3(s)_(2S-(l- Tetrahydropyrimidin-2-keto)-3-mercaptobutyryl)aminobutyl bromide (4aS,8aS)-isoindoline-3(S)-carboxamide can be prepared using standard coupling procedures (in DMF) EDAC) by the product of Example 2A with cis-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-aminobutyl]-(4aS,8aS -isoindoline-3(S)-carboxamide (expressed in PCT Patent Application No. W09426749 and March 23, 1993, U.S. Patent No. 0: \106\106749.DOC -115-1282952 5,196,438 The title compound was prepared by coupling the two together for reference. Example 32 cis-N_T-butyl-decahydro-2]2 (R-hydroxyl-phenylphenylthio-3〇(28-(1-tetrahydropyrimidin-2-one)-3-methyl) Butyl) Aminobutyl J-(4aS,8aS)-isoquinoline-3(S)-carboxamide can be prepared by standard coupling procedure (EDAC in DMF) by using the product of Example 2A with cis- N-tert-butyl-decahydro-2_[2(R)-hydroxyphenylthio-3(S)-aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxyindole Amine (disclosed in PCT Patent Application No. WO 95/A No. 9843, issued Apr. 13, 1995, and U.S. Patent No. 5,484,926, issued Jan. Coupling to prepare the title compound. Example 33 4-Amino-((2 cis,3S)-24-yl}phenyl small (10) ♦tetrahydropyrimidin y yl)-3-methylbutyrylamino)butyl Isobutyl-benzenesulfonamide can be subjected to standard coupling procedures (product of eda in DMF and 4-W(tetra)yl-4·phenyl-3.amino)-butyl)-indole-isobutyl·benzene Sulfonamide (disclosed in ρ^τ Patent Application No. W〇94/05639, published on Mar. Method for preparing (28,38,58)-2-(2,6-dimethylphenoxyethyl fluorenyl) amino-based hexanyl oxime with mechanical stir-mix, j_KemS degree probe, drip Add funnel and

O:\106\106749.DOC 1292752 A 1 liter 3 neck flask of anhydrous nitrogen line was charged with 3 gram (54.87 millimoles) of the product of Example II and 12 liters of acetonitrile. The resulting slurry was cooled to and slowly added 54.1 grams (549 millimoles) of 37% aqueous hydrogen acid to maintain the internal temperature no more than +5 during the addition. The reaction mixture was stirred under 〇-5, and the sample was periodically taken out by HPLC (Zorbax column, mobile phase = 1:1 acetonitrile / hydrazine. 1% aqueous phosphoric acid, flow rate = 1.5 ml / min, at 2 Torr) Detection at 5 nm) Analyze the consumption of starting materials. The reaction was completed after stirring for 3 hours. The reaction was quenched by the slow addition of 1 〇 5 ml of 20% aqueous sodium hydroxide. The internal temperature is again maintained no more than +51 during the addition. Once the pH of the reaction mixture was confirmed to be inferior, the solution was warmed to room temperature. Ethyl acetate (丨 8 mL) was added and mixed, and after the sedimentation, the lower liquid phase was separated and discarded. The organic phase was then rinsed once with 105 ml of 1% aqueous sodium hydride. The title compound was crystallized from 12 mL/g of 1:2 ethyl acetate / hexane (yield 80-85%). B. Another preparation of (28,38,58)-2-(2,6-dimethylphenoxyethyl) felyl-3-yl-5-amino-1,6-diphenyl Method of Burning The product of Example II (51.6 g, 0.095 mol) and 1 ml of glacial acetic acid were added to a 3-liter 1 liter flask with a mechanically disturbed rod and thermometer. To the resulting suspension, 35% aqueous HCl (10. 5 ml, 0.103 mol) was added in one portion. The solution was allowed to stir for 3 hours under N2 pressure, at which time an additional 10.5 mL of 35% aqueous HCM was added. The reaction flask was immersed in an ice bath after an additional 15 hours, and a NaOH solution (16 ml, 0.; i98 mol) was added at a rate to maintain the internal temperature of the crucible below 30 °C. Add O:\106\W6749.DOC. Π7-Γ5 1292752 water (2003⁄4 liters) and extract the mixture with 4 χ 200 ml of isopropyl acetate. The combined organic layers were washed with aq. EtOAc (EtOAc) (EtOAc) Ηριχ is more than %% pure. The product can be purified in one step by dissolving the product in 200 ml of isopropanol, heating in a steam bath, allowing to cool to 0-5X: and stirring to yield 32.2 g (76%) of desired product. 131t:. Example 35 Another method for preparing 2S-1 (1-tetrahydropyrimidin-2-one oxime methylbutyric acid) Α·N-phenoxycarbonyl hydrazine-proline acid can be applied for according to the US patent filed on June 28, 1996. The procedure disclosed in U.S. Patent Application Serial No. 08/08/671,893, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the the Lithium chloride (15·6 g, 386 mol), L-proline (26.0 kg, 222 mol), neutral alumina in the reaction state of the sub, cooler, pH probe and thermocouple (8" kg, 15 〇 mesh, AldHch) and 156 kg of distilled water. Stir this uneven mixture and cool to - soil $. (: ίο% aqueous lithium hydroxide will be 13] 9 [value adjustment To 1〇1. Pre-cooled (-20C) phenyl chloroformate (36·6 kg, 234 mol) was added while maintaining the temperature below -9 °C, and continuously added 1 在 during the reaction. % aqueous lithium niobate to control the pH (maintain the pH in the range of 9.5 to 1 〇·5, the target is 10.0). Stir the reaction for 2 hours at about -14 C. Pass through the diatomaceous earth The reaction mixture was filtered, and washed with distilled water with 42 kg of filter cake with methyl tertiary - butyl

O:\106\106749.DOC -118- 1292752 (65 kg) The aqueous filtrate was extracted to remove residual phenol. The liquid phase was then cooled to 0-5 ° C and mixed with 200 kg of toluene. The stirred two-phase solution was adjusted to 1) 11 value 1.8_2. 利用 using 25% (w/w) sulfuric acid. The toluene layer was concentrated at no more than 40 C, to about 120 liters, filtered (30 kg of toluene washed) and then concentrated again to about 12 liters at no more than 4 °C. 44.2 kg of heptane was added to the resulting solution, and the resulting solution was heated to 40 C ± 1 (TC for 15 minutes. The heat source was removed, the solution was sown, and stirred overnight. The product crystallized on the wall of the reactor, Resuspended in 8 kg of toluene, concentrated to about 13 liters at not more than 50 ° C, then added 45.2 kg of heptane. The resulting solution was then heated to 4 (rc ± 1 〇t) : at least 15 minutes, then cool to 18 ° C ± 5 C at a rate of less than 20 ° C / hour. After not less than 12 hours, the resulting white slurry is cooled to 14 ° C ± 5 ° C, Stir for more than 3 hours. Filter the white slurry and rinse the solid with 41 kg of 1:1 toluene/heptane. Dehydrate the solid product under no more than 5 rc to give the desired product as a white powder. (47·8 kg) Β· 2 S-(l-tetrahydropiped-2-one)-3-methylbutyric acid N-phenoxycarbonyl decanoic acid in THF (250 ml) 25 g, 〇·1〇6 mol) and a mixture of 3-chloropropylamine hydrochloride (15. 2 g, 〇116 mol) were cooled to 2 ° C. Add to the stirred suspension Sodium hydroxide (127 g, 0.31 8 mol). After about 35 minutes, a slow exotherm occurred to 1 C. The reaction was stirred for 2 hours below 10 C. Add in 1 2 5 within 1 min. The third potassium butoxide (2.96 g, 〇·265 mol) in THF was washed with 2 liters of THF. During the addition, the temperature of the reaction mixture was allowed to rise to 20 °. C. The reaction mixture was stirred at room temperature for 19 hours. O:\106\106749.DOC -119- 1292752 The reaction mixture was quenched with 200 ml of distilled water and then acidified with 26 2 g of HCl. pH 9, keeping the temperature below 30 ° C. The liquid layer was separated and rinsed with an additional 125 ml of THF. Ethanol 3A (75 ml) was added to the separated liquid layer, and 12.3 g of concentrated hydrochloric acid was added. The mixture was acidified to pH &lt; 3, keeping the temperature below 25 ° C. The acidified mixture was extracted twice with ethyl acetate (250 mL and 150 mL). On a rotary evaporator, at a temperature below 50 ° C. The combined organic layers were evaporated to dryness. The residual solid was washed with ethyl acetate (250 mL) The residual solid was dissolved in 150 ml of ethanol 3A at reflux temperature and filtered through a 5 g pad of Darc(R)-G60 coated with a filter aid, followed by rinsing with 5 ml of hot ethanol. The filtrate was evaporated to dryness at a temperature below 50 ° C. Ethyl acetate (75 mL) was added to the residue and refluxed for 3 min. The suspension was cooled to below 10 ° C for 2 hours. The solid was collected by filtration and washed with 2 mL of ice cold ethyl acetate (5-8. 〇 rinse. After dehydration at 4 ° C for 72 hours, the desired product was obtained as a white solid (15·6 g, 74%). Example 36 Another preparation of 2S-(1-tetrahydropyrimidine-; 2-ketopropyl 3-methylbutanoic acid phenoxycarbonyl decanoic acid (25 g, 1 〇 5 mol; according to June 1996) The procedure disclosed in U.S. Patent Application Serial No. 8/671,893, the entire disclosure of which is incorporated herein by reference in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire content • Mix the mixture in 5 liters to 2 ° C. Add sodium hydroxide (127 g, 3.2 mol) to the stirring suspension. After about 45 minutes, a rapid exotherm occurs to 1 〇{t Stir the reaction for 2 hours under 丨巧艺. Add additional 3 chloropropylamine (1 gram, 〇〇 8 mole) and hold

O:\106\106749.DOC

(D '120- 1292752, mix for 1 hour. Then add a solution of potassium butoxide (296 g, 2.6 m) in 1 · 2 $ liters of thf within 3 , minutes, followed by 1 〇〇 Flushing with THF. During the addition, the temperature of the reaction mixture was allowed to rise to 20 ° C, and the reaction mixture was stirred at room temperature for 12-16 hours. The reaction mixture was quenched by steaming 2 g of crane water. And cooled to 12. 〇, and then acidified to 258 [9] with 258 g (2.6 mol) of concentrated hydrogen acid. 9. Keep the temperature below 30 C. Separate the liquid layer. Add in the separated liquid layer. Ethanol 3 a (625 liters) and acidified to a pH of &lt;3 with 116 grams (1.2 moles) of hydrazine acid, maintaining the temperature below 25 art. The acidified mixture was treated with acetamidine acetate (2.5 Extraction twice and 1.5 liters. The mixed organic layer was evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. Distilled with vinegar 曰 曰 S (4 X 1 liter) , the residual solid was repeatedly dehydrated. The residual solid was dissolved in 75 ml of methanol and decolorized. Carbon (1 gram

Treatment with DarC〇-G60 pad) overnight at room temperature. Remove cockroaches by filtering through diatomaceous earth. On a rotary evaporator, below 5 〇. The filtrate was evaporated to dryness at a temperature of hydrazine. Ethyl acetate (1.5 liters) was added to the residue and about 5 mL was removed on a square-turn converter. The suspension was cooled to below 1 hour &gt; 1 hour. The solid was collected by filtration and washed with 2 mL of cold ethyl acetate (5.sup.5). After dehydration at 50t for 72 hours, the desired product was obtained. Example 37 Preparation of 2S-(1-4- Method for Hydropyrimidinyl)-3-methylbutyric acid 曱· Carboxymethyl-N(n)cyanoethylproline in a 5 liter 3-neck flask with mechanical stirrer, added (s)_ Proline

O:\106\106749.DOC -121 - 1292752 (170.1 g,: [·45 mol) and water 145 ml. The solution was cooled to 〇C in an ice water bath and a solution of the equivalent hydrazine (93 g of 88% solid K 〇H) in 18 liters of water was added dropwise over 20 minutes. After the completion of the addition, acrylonitrile 1 〇 (95·5 ml) was added dropwise and vigorously stirred while maintaining the internal temperature of the flask at 5 t: or less. The solution was allowed to stir between 4.5 hours. Water (6 ml) was added and a pH meter was inserted into the solution. Methyl chloroformate 1 〇 equivalent (112 ml) was added dropwise while maintaining the enthalpy of the solution between 9.5 and 10.5 with 10% aqueous hydrazine. This addition is carried out within 5 hours. The solution was then acidified to pH 2 with concentrated HCl and phosphoric acid and then extracted with 2 liters of isopropyl acetate. The organic layer was concentrated under vacuum to give 201 g (yield: 60%) of colorless oil which solidified upon standing. 65-66 ° C melting point. The optical rotation sodium D line at -25 ° C was -0.44 (c = 4.3, ethanol). IR (cm-1, CDC13) 2960, 1740, 1710, 1470. 1H NMR (3 00 megahertz, CDCl3); ((5TMS, 0·00) pPm0·93 (d,

3H, J = 7 Hz), 1.07 (d5 3H, J = 6 Hz), 2.16-2.36 (m, 1H), 2·62-2·86 (m, 2H), 3.62 (t, 2H, J = 7.5) Hertz), 3·77 (s5 1.2H rotating body), 3·82 (s5 1·8Η, rotating body), 4·15_4·30 (m5 1Η), 9.76-9.96 (brs, 1Η)〇ms (CDI/ NH3) 246, 185, 146, 125. FABhrms: Calculated for (M+H)+: 229.1 188; Experimental value: 229.1 185 ° Β· 2S-(1-tetrahydropyrimidin-2-one)·3-mercaptobutyric acid in a 2 liter pressure bottle The product of Example 37 (190 g, 0.833 mol), water (900 ml) and hydrazine (3 eq., 140 g) were added. At the ambient temperature, 75 g of a nickel-aluminum alloy (in-situ type) was added to the solution. Note that this is not activated by O:\106\106749.DOC -122-1292752. The solution was sealed in a pressure bomb and placed under a pressure of 60 psig of hydrogen. The resulting solution was heated to 100. (3 4 hours. After cooling the solution to ambient temperature, it was filtered, rinsed with 900 ml of dichloromethane) and then acidified to pH 1. The aqueous solution was extracted with 2 X 900 ml of di-methane. Concentration gave 12 g of crude product which was crystallised in EtOAc to afford 7 g of the title compound. Dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimidin-2-yl)-3-ylmethylbutanyl]amino-1,6-diphenyl Method A-1·2S-(1-tetrahydropyrimidinone-based polymethylbutazone is used to make 2S-(1-tetrahydropyrimidin-2-one)_3&lt;_methylbutyric acid (17·6 g) , 87·9 mmoles) formed a slurry in THF (240 mL) and cooled to &lt;5. 〇. Add sulphur sulphur gas (14.3 g, 12 〇 millimolar) within 5 minutes (exothermic The slurry was stirred at 2 Torr &lt;t for 70 minutes until *HpLC was known to be complete (the sample was stopped in methanol). THF was removed by rotary vaporization; heptane was added (9 liters of pen liters) )' and removed by rotary vaporization, getting wet Block. This material was slurried in DMF (85 ml). Α···Another method for preparing 2S-(1-tetrahydropyrimidin-3-yl 3-methylbutane chloride to make 2S-(1- Tetrahydro-acridin-2-(one)-3-ylbutyric acid (39·6 g, 198 mmol) was slurried in THF (5903⁄4 L) and cooled to. Add sulphur in 5 min. Helium (28.3 g, 238 mmol) (exothermic). Stir the slurry for 2 hours at 2 Torr. Remove τΗρ from the rotary evaporator:

O:\106\106749.DOC -123- 1292752 Solid block. (200 ml) and removed on a rotary evaporator to obtain a wet slurry of the material in DMF (225 mL). Β_1·(2S,3S,5S) rhyme, N-di-aryl amino group j via _s_[2s_g_tetrahydropyrimidin-2-one)-3-methylbutanyl]aminodiphenylethane (2S , 3S,5S)-2-N,N-di-arylamino-3,ylamino",6-diphenylhexane (approximately 83 millimolar; US patent application filed on February 13, 1996) 5,491,253, which is incorporated herein by reference) and imidazole (8.2 g, 120 mmol) dissolved in ethyl acetate (35 mM, Κ]ρ &lt;〇·ι%) and cooled to 2 °C. The product of Form 38A4 which had formed a slurry (exothermic, maximum temperature of 10 °C) was added, followed by rinsing with DMF (15 mL). The reaction was stirred and started to be ice-cold, then allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched with 100 ml of water and stirred for 30 minutes. The organic layer was separated and washed with 3 X 125 mL of 5% NaCl. The organic solution was filtered and concentrated on a rotary evaporator to a thick syrup, 62 g. The HPLC purity was approximately 85% (peak zone). The isomer content is about 11.2%. CIMS (NH3) m/z 647 (Μ+Η)+. NMR (300 MHz, CDC13) δ 7.35-7.10 (m, 1 〇Η), 7.13-7.06 (m, 1H), 6.87 (br d, 1H), 5.22 (br s5 1H), 4·28 (d, 1H), 4.20-4.05 (m, 1H), 3.95 (d, 2H), 3.65-3.56 (m, 1H), 3.37 (d, 2H) 5 3.12-2.89 (m, 5H), 2.83-2.53 (m, 4H)? 2.23-2.08 (m, 1H), 1.74-1.40 (m, 4H), 0.87-0.75 (m5 6H). 3C NMR (75 MHz, CDC13) 5 170.0, 156.6, 140.2, 139.1, 138.4, 129.3, 129.1, 128.9, 128.4, 128.3, 127·1, 126.0, 125.8, 69.1, 64.0, 63.1 (br), 54.2, 49.2, 41.2, 40.5, O:\106\106749.DOC -124- 1292752 40.0, 39·7, 31.5, 25.4, 21.6, 19.5, 18.6. Β-2·Another preparation (28,38,58)_2_]^,]^dibenzylamino _3_hydroxy 5 [2 S (1_tetrahydro, ketone)-3-methylbutanyl]amine The method of 6-diphenylhexanal is (28,3 8,5 8)-2-&gt;1,;^-dibenzylamino-3-hydroxy-5-amino-1,6-diphenyl Hexane (approximately 180 millimoles; U.S. Patent No. 5,491,253, filed on Feb. 13, 1996, which is incorporated herein by reference) Dissolved in ethyl acetate (675 mL, KF &lt; 1%) and cooled to 1 C. The slurry of the Example 3 8 A-2 was slowly added over 30 minutes (exothermic, maximum temperature 6 ° C) and then rinsed with ethyl acetate (225 mL). The reaction was stirred for 1.5 hours in an ice-cold environment, then allowed to slowly warm to about 27 ° C and stirred for about 20 hours. The reaction was stopped with a dilute solution of HC1 (36.75 g of concentrated HCl in 225 ml of water) and stirred for 20 minutes. The mixture of the two phases was washed with 1 ml of ethyl acetate. The organic layer was separated and washed with 3 X 125 mL 5% NaCI. The organic layer was separated and washed with 3 X 225 mL 5% NaCl and 2 X 225 liters 5% NaHC03. The organic solution was concentrated by rotary vaporization to obtain the desired product as a viscous syrup. C·(2S,3S,5S)-2-Amino-3-hydroxy-5-[2S_(l-tetrahydropyrimidin-2-one]&gt;-3-methylbutanyl]amino-1,6- Diphenylhexane The crude product of Example 38B (about 83 mmol) was dissolved in methanol (260 mL). Pd/C (50% moist Pearlemanfs catalyst, 1 〇 4 g wet weight) and citric acid were added. Ammonium (15.1 g, 239 mmol), and the mixture was warmed to 50 ° C. After 2.5 hours, the reaction was completed by TLC. The mixture was cooled to O:\106\106749.DOC - 125- 1292752 to 35 ° C ' and remove the catalyst by filtration through diatomaceous earth, followed by washing with methanol (250 ml). The mixed filtrate was concentrated on a rotary evaporator. The residue was dissolved in dioxane (15 〇 ml) and warm. Remove the dioxane on a rotary evaporator to obtain 60 g of yellow oil. HPLC purity is about 88.2% (Nanfeng District) 'isomer content> 7.9 9% (however No isomer was isolated from the main peak. CIMS (NH3) m/z 467 (M+H)+ 4 NMR (300 MHz, CD3OD) δ 7:35-7.10 (m,1〇Η) , 4.40-4.20 (m,ιη)5 4.25 (d,1Η), 3.68-3.57 ( m,1Η), 3.20·3·09 (m,2H), 3.08-2.90 (m,3H), 2.90-2.74 (m,2H), 2.65-2.49 (m,2H), 2.20-2.04 (m,1H) ), 1.92-1.78 (m, 1H), 1.78-1.60 (m5 2H)3 1.60-1.45 (m5 1H), 0.88-0.77 (m5 6H) 13C NMR (75 megahertz, CD3OD) 5 17L3,158·4, 140.5, 139.8, 130·6, 130.4, 129.5, 129·3, 127.3, 127.0, 71.5, 63.9, 57.1, 49·1, 41.8, 41.6, 41·4, 40.7, 40.5, 26.9, 22.5, 20.0, 18.9 】 Η NMR (300 MHz, CD3〇d) accounted for 7 35 7 13 (m, 1〇Η), 5·35 (s, 1Η), 4·4 (Μ·23 (m, 2Η), 3.60.3.52 ( m,1Η), 3·25-2·65 (m,8H), 2.58-2.45 (dd,1H), 2.30-2.10 (πι,1H), 1.90-1.65 (m,3H),1.65-1.50 (m , 1H), 0.91 (d, 3H), 0.84 (d, 3H) 13C NMR (75 MHz, CDC13) 5 ι71·2, 156.6, 139.1, 138.5, 129.3, 129.2, 128.5, 128.2, 126.3, 126.0, 71.6 , 63·1 (br), 56.3, 48.7, 41·65 41.0, 40.6, Houyi, 39.6, 25·5, 21.7, O:\106\106749.DOC -126- 1292752 19.7, 18.7 D· (2S, 3S,5S)-2-Amino-3-hydroxy-5-[2S_(1-tetrahydropyrimidin-2-yl)-3-methylbutenyl]amine- 1,6-Diphenylhexane (s-pyroglutamine) The crude product of Example 38C was dissolved in dioxane (37 mL, KF == 〇·〇 7% moisture). S-pyroglutamic acid (1 〇·3 g, 8 〇 mmol) was added, and the suspension was warmed to 50 ° C to give a clear solution. After stirring for a few hours, the solution was sown with a small amount of product salt crystals. The salt is slowly precipitated. The slurry was slowly cooled and stirred at room temperature overnight. The product was isolated by filtration and washed with dioxane (100 mL). The wet cake weighs 12 grams. The product was dewatered by purging with nitrogen in a vacuum oven at 6 °C. Produced 35. 2 grams of grayish white powder. HPLC purity &gt; 98% (peak zone includes pyroglutamic acid). The isotactic content is about 1% (however, one isomer is not separated from the main peak).

Melting point 135-141°C

[a]D25 = -21.9〇(c=2.55 CH3OH) CIMS (NH3) m/z 467 (for m+H) +, I47 (for M+NH4 of pyroglutamic acid)+, 13 0 (About M+H)+ IR(Kbr) of pyroglutamic acid 1586, 1655, 1682 cm-1 4 NMR (400 MHz, DMSO-d6) (5 7.62 (s5 ιΗ) 7 54 (d,1H),7· 32-7·06 (m,10H),6.33 (s,1H),4·26 (d,lH)5 4.11-3.99 (m,1H),3.82 (dd,1H),3·57-3·48 (m,1H) 3.27-3.19 (m,1H), 3.08-2.95 (m,2H), 2.92-2.70 (m,5H) 2.53-2.43 (m,1H), 2.26-2.14 (m,1H),2.13 -1.99 (m 2H) 1.99-1.87 (m,2H),1.72-1.61 (m,2H),1.61-1.49 (m ipj) O:\106\106749.DOC -127· 1292752 1.46-1.35 (m,1H ), 0.70 (d, 3H), 0·64 (d, 3H). 13C NMR (100 MHz, DMSO-d6) δ 176.9, 176·1, 169.2, 155.5, 138.8, 137.7, 129.3, 128.3, 127.8, 126.4, 125.5, 66.9, 61.5, 56.9, 55.3, 46.8, 40·2, 39.6, 39.4, 38.8, 37.4, 29.8, 25.4, 25.3, 21.6, 19.6, 18.7 ° 4 NMR (300 MHz, CD3OD) 5 7.32- 7.03 (m,10H), 4β23-4·12 (m,1H),4·12 (d,1H),3.98 (dd,1H),3.71-3.63 (m, 1H), 3.46-3.37 (m,1H) ) , 3.11-2.98 (m, 2H), 2·97-2·80 (m5 4H), 2.70-2.59 (m, 1H), 2.49-2.38 (m, 1H), 2.38-2.12 (m, 3H), 2.07 -1.92 (m, 2H), 1.75-1.63 (m, 2H), 1.63-1.50 (m, 1H), 1·45·1·32 (m, 1H), 0.74-0.65 (m, 6H). 13C NMR (75 MHz, CD3OD) δ 181.0, 179.6? 171.65 158.4, 139.5, 137·3, 130.5, 130.0, 129.4, 128.3, 127·2, 68.1, 64.0, 59·6, 57·7, 48.8, 41.7, 41.1 , 40.7, 40·6, 37.9, 31.1, 26.9, 26.9, 22.5, 20.1, 18.9 ° 4 NMR (300 MHz, D20) δ 7.30-6.97 (m, 10 Η), 4.16-4.03 (m, 1H), 3.99 -3.91 (m, 2H), 3.71-3.63 (m, 1H), 3.43-3.35 (m, 1H), 3.00-2.68 (m, 6H), 2.40-2.13 (m, 5H), 1.88-1.72 (m, 3H), 1.68-1.56 (m, 1H), 1.52-1.37 (m, 1H), 1.32-1.18 (m, 1H), 0.60-0.52 (m, 6H). 13C NMR (75 MHz, D20) δ 1 8 1.6, 1 80· 1, 171 · 0, 157.3, 137.9, 135.2, 129.3, 129.2, 129.1, 128·4, 127.6, 126.4, 67.3, 62.6, 58.2, 56.7 , 47.5,40·1,39.4,39.2,38.7, 35.7, 29.6, 25.3, 25.2, 20.5, 18.5, 17.6 ° O:\106\106749.DOC -128- 1292752 Ε· (28,38,58)-2 -(2,6-diamidinophenoxyethyl)amino-3-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-l keto)-indolylmethylbutanyl]aminodiphenyl The product of Example 1H (7.26 g, 40·3 mmol) was slurried in ethyl acetate (22 mL) and sulphur sulphur chloride (5·75 g, 48·3 mmol) was added. Then add a drop of DMF. The mixture was warmed to 5 (rc and stirred for 5 hours. The resulting hydrazine-based gas solution was cooled to 22t and applied to the subsequent coupling reaction. The product of Example 38D was mixed in a flask (20 g, 31.7 mmol) Ears, corrected for dioxane content), sodium bicarbonate (16.5 g, 197 mmol), ethyl acetate (150 ml) and water (150 ml), and stirred until the product of the example has dissolved So far (some salts remain insoluble). A solution of the above-prepared decyl chloride was added over 5 minutes, followed by rinsing with ethyl acetate (5 mL). The addition was mildly exothermic (maximum temperature 23 t). The mixture was separated overnight. The organic layer was separated and washed with 5% sodium hydrogen carbonate (1 mL) and water (1 mL). The solvent was removed on a rotary evaporator. The residue was dissolved in ethyl acetate (100) In ML), filter and rinse with ethyl acetate (5 mL). Remove the solvent from the mixed mash on a square tweezer. Dissolve the residue in hot ethyl acetate (105 ml) In 'and add geng (1 〇 5 ml); The material began to crystallize rapidly. The slurry was cooled and disturbed for 5 hours at 2 〇 _ 2 3 ° C. The product was collected by filtration and burned with 1/1 (v/v) ethyl acetate/g ( 30 ml) rinse. The product was dehydrated in a vacuum oven at 70 ° C to give 18.8 g of the desired product as a white powder. Example 39 Preparation of amorphous (28, 38, 58) -2- (2, 6 - 2 Nonylphenoxyethyl)amino group O:\106\106749.DOC -129- 1292752 -3-hydroxy-5-[2 S-(l-tetrahydropyrimidin-2-one)-3-methyl The product of Example 38E (2.5 g) was dissolved in 8 ml of absolute ethanol. The solution was slowly added dropwise to 250 ml of 9 ° C. In cold water, stirring vigorously. A white solid appeared immediately. Stirring was continued for 15 minutes, and the solid was collected by filtration, and dehydrated under vacuum at 50 ° C for 12 hours to obtain 2 32 g of the desired product as an amorphous solid. B. The product of Example 38E (2.5 g) was dissolved in 6 mL of anhydrous ethanol. The solution was slowly added dropwise to 31 ml of cold water at 7-9 ° C and vigorously stirred. Solid Stirring was continued for 2 minutes, and the solid was collected by filtration, and dehydrated under vacuum for 5 hours at 5 Torr: to obtain 2,24 g of the desired product as an amorphous solid. C. The product of Example 38 (0·5) (g) dissolved in 8 ml of isopropanol. The bath was slowly added dropwise to 丨〇〇ml 1 (M5 ° C in cold water and stirred vigorously. A white solid appeared. Stirring continuously 2 〇 The solid was collected by filtration and dried to give 0.48 g of the desired product as an amorphous solid: D. The product of Example 38E (0.5 g) was dissolved in 8 ml of acetone and EtOAc (2 ml). The solution was slowly added dropwise to 1 〇〇 ml of 1 〇 _ 1 $ of cold water' and vigorously mixed. A white solid appeared. Continue to search for ^ 〇 minutes and collect the solid by sputum. It was air-dried to obtain the desired product of 46 g of amorphous solid. E. The product of Example 38E (0.5 g) was dissolved in 2 mL of EtOAc. The solution was slowly added dropwise to 100 ml of 1 〇 of cold water and stirred vigorously to "see a white solid. Continue to give up for 2 minutes and collect by sputum.

O:\106\106749.DOC 1292752 έ海solid. It was air-dried to obtain the desired product of 0.46 g of an amorphous solid. Example 40 Gas propylaminocarbonyl &gt; methyl methionate 3-chloropropyl isocyanate (0.3 mM, 3 〇 millimolar) was added to L-缬 in thF (10 liters) Methyl aminate hydrochloride (〇·5 g, 3 〇 mmol) and a slurry of three-month-old female (0.423⁄4 liter, 3.0 mmol). The reaction mixture was stirred at room temperature for 4 hours and then quenched by the addition of aqueous sodium hydrogen carbonate. The reaction mixture which had been discontinued was extracted with ethyl acetate. The organic layer was separated, dehydrated and evaporated to give the desired product. Example 41 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)amino-hydroxy-5-[2S-(l-tetrahydro-4-hydroxypyrimidine_2_ Keto)]3-methylbutylidene]amino-1,6-diphenylhexane The solution of the product of Example 25E in dichloromethane was reacted with sodium borohydride to give the desired product. Λ (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy] •5-[2S-(l-tetrahydro-6-carbyl)唆_2•keto)_3_indenyl]amine 3 -1,6-diphenylhexane at 371, will have been completed on the carbonyl group of the ethyl thiol moiety &quot; (50_ '6.0 microcurie' labeled (28, 38, 5 outer 2_(2,6-dimethylphenoxy 2 fluorenyl)amino-3-carbyl-5-[2S.(1. tetrahydro winter 3(10) ml culture of __哺_2·嗣基 X methylbutylidene]amino-1'6-diphenylhexanide, and; rat liver microsomes (0.5 mg/ml microsomal protein) and Reed IV _Production / O:\106\106749.DOC -131- 1292752 The system was incubated for 6 minutes. The metabolic reaction was stopped by adding 300 ml of acetonitrile. The supernatant obtained after centrifugation at 3000 RPM for 1 minute in a vacuum The liquid was evaporated to dryness. The residue was reconstituted in 2 mL of HPLC mobile phase. Bechman Ultrasphere 5 micron 10 x 150 mm C18 column was used at ambient temperature with Alltech Ultrasphere 5 micron C18 cartridge protection column. Separation of the product. Use at a flow rate of 2 · 8 liters / separation in 5 7 minutes A linear gradient of 25-55% acetonitrile in a buffer solution (25 mM ammonium acetate, pH adjusted to 4.8 with citric acid) was used as a column eluent. Fluorescence generation analysis of inhibitors for screening HIV proteases can be performed by The method determines the inhibitory potency of the compounds of the invention. The compound of the invention is dissolved in DMSO and a small aliquot is dissolved in DMSO to 1 fold to determine the desired final concentration. The reaction is at 6 χ 5 〇. Millimeter, in a total volume of 300 ml test tube. The final concentration of each wound in the reaction buffer solution: 125 mM sodium acetate, 1 Μ sodium chloride, 5 mM dithiothreitol, 0.5 mg / ml bovine serum albumin , 13 fluorescein produced by enzyme, 2% (v/v) dimethyl hydrazine, ρ Η 4 · 5. After the addition of the inhibitor, the reaction mixture was placed on the scaffold of the luminometer compartment and at 3 〇 Incubate for several minutes at ° c. Start by adding a small aliquot of ice-cold mv protease. Record the fluorescence intensity (excitation 340 nm, emission 49 〇 nm) as a function of time. The first 6 to 8 minutes to determine the reaction Rate. observed rate, with unit time The number of moles of the enzyme to be cut is directly proportional. The percentage of inhibition is 100 χ (1-(the rate of inhibitor presence) / (the rate of lack of inhibitor). Fluorescence generates enzymes ·· Dabcyi_Gaba_Ser_G〗 n_Asn 〇_ Ile-Val-Gln-EDANS, where DABCYL=heart (heart dimethylamino 'phenyl)

O:\106\106749.DOC -132· 1292752 Azobenzoic acid, Gaba=r-aminobutyric acid, and EDANS = 5-((2-aminoethyl)amino)-na-1-supply acid. Table 1 Example Compound Percent Inhibitor Concentration (nanomol) 1P 92.6 0.5 2B 93.2 0.5 3C 86.9 0.5 4F 49.7 0.5 5 80.8 0.5 6F 61.4 0.5 7B 67.1 0.5 8 55.6 0.5 9B 62.6 0.5 10F 81.0 0.5 11B 91.1 0.5 12B 76.8 0.5 13B 56.2 1.0 14D 52.7 0.5 15 48 0.5 17C 87.2 0.5 18C 57.8 0.5 19E 68.5 0.5 22E 71.8 0.5 23C 86.0 0.5 25E 100 0.5 26H 94.6 0.5 27D 92.9 0.5 28 86.6 0.5 29C 72.6 0.5 30B 91.0 0.5 O:\106\106749 .DOC -133- 1292752 Antiviral Activity The anti-HIV activity of the compounds of the invention can be determined on MT4 cells according to the following procedure. MT4 cells were infected for one hour at a multiplicity of infection (MOI) of 0.003 using a supernatant containing no cells of hivIIIB (pre-frozen at a known 50% tissue culture infectious dose (tcid5G)). After one hour of infection, the cells were washed twice to remove residual virus, resuspended in culture medium, and seeded in 96-well with various semi-log dilutions of compound at a dose of 1 X 104 cells per well. Tissue culture on the plate. Uninfected cells were included in the toxicity and cell control groups. RPM with 10〇/fetal bovine serum was used; 164〇 (Gibc〇) was used as the medium. Various concentrations of human serum (Sigma) at 50%, 25%, and 12.5% were added to the medium to give final concentrations of 60%, 35%, and 22.5% total serum. All assay plates were incubated in the incubator for 5 days at 37 °C. MTT (Sigma, 5 mg/ml in PBS) was added to 25 μl of each well in all wells and cultured for 4 hours. 20% SDS with 〇〇2N in water HCl was added in an amount of 50 microliters per well to lyse the cells. For complete dissolution, the plates were incubated overnight and read at the 570/650 nm wavelength to determine the optical density (Q D·) of the cells on the microtiter plate reader. The original data were analyzed for percent inhibition by the following formula: OD·test well-〇.D·virus control group χ1〇〇Ο · D · cell control group 〇·d · virus control group bad midpoint potency equation (Chou, 1975, Proc. Int. Cong Pharmacol. Sixth Edition, p. 619) Calculate the 50% effective concentration (EC50) to determine the potency of the compound. 50% lethal concentration (LC50) was calculated using uninfected MT4 cells 〇O:\106\106749.DOC -134- 1292752 Under these conditions, the following data were obtained (n=4 repeat determination): Table 2 Examples of compounds IC5〇(μΜ,0% plasma) LC5〇(μΜ) 1P 0.01 41.32 2B 0.016 17.78 3C 0.025 49.5 4F 0.101 &gt;100 5 0.368 &gt;100 6F 0.193 &gt;100 7B 0.204 &gt;100 8 0.019 17.78 9B 0.272 19.33 10F 0.047 91.97 11B 0.19 18.16 12B 0.093 19.11 14D 0.053 &gt;100 15 0.119 &gt;100 17C 0.051 18.96 18C 0.329 19.1 19E 0.395 17.95 20D 0.283 24.08 25E 0.012 22.88 26H 0.015 33.0 27D 0.03 56.23 28 0.011 72.2 29C 0.427 5 6 30B 0.003 18 O :\106\106749.DOC -135 - 1292752 The compounds of the invention may be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to, the following acetates, adipates, alginates, citrates, aspartates, benzoates, besylate, disulfates, butyrates, Camphorate, camphor sulfonate, digluconate, cyclopentate propionate, dodecyl sulfate, beta acid salt, grape heptanoate, glycerol phosphate, hemisulfate, g Acidate 'hexanoate, fumarate, hydrogenate, nitrogen desert, chloro moth, domain ethane sulfonate (metrate) lactate, cis-butan, salt, terminal Acid salt, acid salt, oxalate salt, pimamate dipeptidate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, number Axate, tartrate, sulphate, p-toluene and decanoate. It is also possible to use, for example, a low carbon number base, such as methyl, ethyl, propyl and butyl gases, indifferent arsenic; sulphuric acid dialkyl vinegar, like guar 酉夂 g, g ethyl ester, two Butane vinegar and dipentyl vinegar, long-chain complexes, such as fluorenyl, dodecyl, tetradecyl and stearic acid chlorides, and aralkyl, arylalkyl halides such as bromine and phenethyl bromide And other formulations quaternize the basic nitrogen-containing groups. Thereby, water or oil-soluble or dispersible products are obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and such as oxalic acid, cis-butane diacid, succinic acid and citric acid. a class of organic acids. Other salts include metals that are associated with metal or soil tests, such as sodium, potassium, or hexagrams, or with organic tests. Preferred salts of the compounds of the invention include hydrochlorides; methanesulfonates, sulphates, phosphonates and ethyl sulphates.

O: \106\106749.DOC -136- 1292752 The compounds of the invention may also be used in the form of i. Specific examples of such esters include those in which the hydroxyl group in the compound of the present invention has been thiolated with the following residues: protected or unprotected amino acid residues, phosphoric acid functions, hemisuccinates a residue, a fluorenyl residue of the formula R*C(0)- or R*C(S)-, wherein R* is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkyloxy , alkoxyalkyl, thioalkoxyalkyl or !|alkoxy, or of the formula Ra_C(Rb)(Rd)_C(〇)- or Ra-C(Rb)(Rd)-C(S)- a thiol residue, wherein Rb*Rd is independently selected from hydrogen or a lower alkyl group, and the core is -N(Re)(Rf), 〇Re or -SRe, wherein Re and Rf are each selected from hydrogen, low a number of alkyl and _alkyl groups, or an amine-fluorenyl residue of the formula Ri8gNH(CH2)2-NHCH2c(〇)- or R180NH(CH2)2〇CH2C(〇)-, wherein R18〇 is hydrogen, low carbon number An alkyl group, an aralkyl group, a cycloalkyl group, a chain decyl group, a benzepyl group or an a-amino group. Amino acids of particular interest are glycine and lysine; however, other amino acid residues may be used, including those wherein the amine group is ^(COCI^NR^Rmi, where r· and The nitrogen contained in the heterocycle is formed by adding a group selected from hydrogen and a low stone inverse alkyl group, or the group _NR2〇〇R2〇1. These esters serve as drug precursors for the compounds of the present invention, and The solubility of these substances is increased in the gastrointestinal tract. These esters may also increase the solubility of the compound for intravenous administration. Other drug precursors include a hydroxyl group in the compound of the present invention, using _CH(Rg)0C(0)R181 or a compound in which a substituent of -CH(Rg)OC(S)R181 is functionalized, wherein Rm is a lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy group and Rg It is hydrogen, a low carbon number base, a halogen group, an oxygenated prison base, an amine group, an amine base or a dialkylamino group. According to the Schreiber procedure O:\106\106749.DOC-137 - 1292752 (Tetrahedron Lett. 1983, 24 α , ^, 2363), the wrong person decomposes the corresponding methyl acrylate in methanol, 7 μ + ... liver secret operation by acetic anhydride, prepared, made

Drug-like precursors. S The drug precursor of the present invention is metabolized in vivo to obtain a compound of the present invention. The pharmaceutical precursor vinegar is prepared by subjecting the compound of the present invention to an activated amine sulfhydryl group, a phosphonium group, a semi-anthracene group or a thiol-like biological reaction as described above. The resulting product is then deprotected to give the phase, the drug precursor vinegar. The drug precursor of the present invention (4) is also intended to be: by the alkylation of a base group and a (fossil-based) ester, and by the use of a thiol-transfer of the double-branched base, or the base and activated The diestering of the acid is followed by the esterification of the intermediate hemiacetal. The compounds of the present invention can be used to inhibit retrovirus proteases, particularly HIV proteases in vitro or in vivo (especially in mammals, especially in the class), and the compounds of the invention can also be used to inhibit in vivo. Retroviral 毋 'In particular, human immunodeficiency virus (Ηιν) β The compounds of the invention may also be used to treat or prevent diseases caused by retroviruses, particularly acquired immunosuppression syndrome' or in humans or other mammals. HIV infection. For a single or a knife, the total amount of each dose administered to a human or other mammal can be, for example, from G. Thanks to the amount of milligrams per kilogram of body weight per day. The more common is G1$. / per kg body weight per day. Dosage unit. The object 3 has a fraction of the sample content to prepare the daily dose. The level of active ingredient may be combined with the carrier materials to produce a single dosage form which will vary depending upon the host to be treated and the particular mode of administration.

O:\106\106749.DOC 1292752 Understand the basis for the use of any specific patient, the specificity, age, weight, and general health of the specific compound used. Gender, diet, time of administration, route of administration, rate, composition of the drug, and severity of the disease being treated. Capsules: &amp; Compounds can be in the form of dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles which are pharmaceutically acceptable, for the purpose of: parenteral administration, sublingual, by inhalation Spray, rectal or topical medicine. Topical administration may also involve the use of transdermal administration, such as a transdermal patch = iontophoresis device. When the intestine-word is used herein, it includes subcutaneous, intra-venous, intramuscular, intrasternal injection or infusion techniques. The sterilizable injectable aqueous or oleaginous suspension can be formulated, for example, according to known techniques, using appropriate scoring w or wet fullness and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, a solution in 1,3 - propylene glycol. Among the acceptable vehicles and solvents, φ water, Ringer's solution and isotonic sodium vapor solution can be used. In addition, sterile fixed oils have conventionally been employed as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including monoglyceride or glycerin. Furthermore, it has been found that fatty acids such as oleic acid are used in the preparation of injectables. A suppository for use in a medicament for rectal administration may be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which cures under hang λ but at rectal temperature Liquefaction, and thus will melt and release in the rectum.

O:\W6\W6749.DOC -139- 1292752 Solid dosage forms for oral use can include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound can be combined with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also include additional materials other than inert diluents, as in conventional practice, such as a lubricant such as magnesium stearate. In the case of capsules, _ and pills, the dosage form may also contain a buffer. The agent and the pill can be additionally prepared as an enteric film. Liquid dosage forms for oral use may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water conventionally employed in the art. Such compositions may also contain adjuvants such as moisturizers, emulsifying and suspending agents, as well as sweetening, flavoring, and flavoring agents. The compounds of the invention may also be administered in the form of vesicles. As is well known in the art, vesicles are typically derived from phospholipids or other lipid materials. The vesicles are formed by dispersing the mono- or multi-layer hydrated liquid crystal in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming vesicles can be used. The composition of the present invention in the form of vesicles may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic vesicles and phospholipids (lecithin). Methods of forming vesicles are well known in the art. See for example

Edited by Prescott, Methods in Cell Biology, Book XIV, Academic Press, New York, Ν_Υ· (1976), p. 33 below. Some preferred dosage forms of the compounds of the present invention are disclosed in U.S. Patent Application Serial No. 08/754,390, issued November 21, 1996, to Lipari, L.A.O:\106\106749.DOC-140-1292752

An application is made by Al-Razzak, S. Ghosh and R. Ga., entitled Pharmaceutical Composition, which is incorporated herein by reference. Preferred dosage forms of the compounds of the invention include (4) a compound of formula I in an amount of from about 1% to about 5% by weight, preferably from about 5% to about 3% by weight, based on the total solution, And (b) in the presence of a weight of the total solution, in a solution of from about 〇% to about 20%, preferably from about 5% to about 丨〇%, of the polyoxy 3 10,000 sesame oil present in the presence of pharmacy The acceptable organic solvent comprises (1) from about 2% by weight to about 99% by weight of the total solution (preferably from about 30 〇/〇 to about 70 〇/〇, preferably). Is oleic acid present in an amount from about 4% to about 65%), or (ii) (1) from about 2% to about 99% by weight of the total solution (more than ^^^^300/o^ J ^ 70〇/〇; ^ ^ ^ ^ ^ „ 4〇0/〇ilJ ^ 65〇/〇)^ ^ The presence of oil I, and (2) from the weight of the total solution, from about 〇% to i2 % (preferably 疋, force 10 / 〇) contains a mixture of ethanol or propylene glycol or a mixture thereof. In a more preferred embodiment of the invention, the solution is encapsulated in a soft and flexible gelatin capsule ( In SEC), or in hard gelatin capsules. The best composition of the invention, package (4) based on the weight of the total solution, a compound of the formula ί, which is present in an amount of about 鄕, and (b) a solution of the polyoxyl 35 castor oil in the presence of 10% by weight of the total solution, The pharmaceutically acceptable organic solvent comprises (1) oleic acid ' and (2) in an amount of about 50 M by weight of the total solution, and 10% by weight of the total solution, and about 100% of the ethanol present in a. Mixture. In a preferred embodiment of the invention, the linger is encapsulated in a soft and flexible gelatin capsule (10)q, or more in a gelatin capsule&apos; and the solution is also included as a weight of the total solution to ,,, spoon, 0.01% to about 〇·08% (preferably based on the weight of the total solution, from about

O: \106\106749.DOC -141 - 1292752 Ο · 01 % to about Ο · Ο 5 %) The presence of an antioxidant (preferably bht (butylated hydroxytoluene)). Examples of such compositions and methods for their preparation are provided below. Ingredient% by weight Example 2B compound (free base) 30 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixed water tank was purged with nitrogen. Oleic acid (499·9 g) and ethanol (100 g) were mixed in the tank. Butylated hydroxytoluene (〇克) was charged into the tank and mixed until the solution was clear. The compound of Example 2B (3 g) was slowly charged into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (1 g) was added to the tank and mixed. The resulting solution was filled into a soft and flexible capsule (〇·333 g solution/SEC) to give a dose of 1 mg of the compound of Example 2B/SEC, or 0.667 g/SEC, to give 200 mg of Example 2B. The dose of compound / SEC. While the compound of the present invention is administered as the sole active pharmaceutical preparation, it can also be used in combination with one or more immunomodulators, anti-viral agents, other anti-infective agents or vaccines. Other antiviral agents that can be administered in combination with the compounds of the invention, including AL_72, interferon, polymannose acetate, reverse transcriptase inhibitors (eg, dideoxycytosine ruthenium (ddc; zalcitabine)) , dideoxyinosine (ddI; dida_n〇sine),

O:\106\106749.DOC -142- 1292752 BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) , DP-AZT, FLT (fluorothymidine #), BCH-189, 5-halogen-3, · sputum-dideoxycytosine quinone, PMEA, bis-POMPMEA, zidovudine (AZT) 'Nevirapine, delviridine, MSA-300, trovirdine and its analogues), non-nuclear reverse transcriptase inhibitors (eg R82193, L-697, 661, BI) -RG-5 87 (荇菲拉平), a protease inhibitor of retrovirus (eg HIV protease inhibitors such as ritonavir, Ro 31-8959 (saquinavir), SC -52151, VX-478, AG 1343 (nelfinavir), BMS 186, 318, SC-55389a, BILA 1096 BS, DMP-323, DMP-450, KNI-227, KNI-272, U-140690, N-(2(R)-hydroxy-1(S)-hydroindenyl)-2(R)-benzyl-4(S)-radio-5-(1-(4-(3 -p ratio) σ定methyl)-2(S)-Nf-Third-Butyl-Wilylamine)-hexa-nitrogen oxime base))-pentyl decylamine (MK-639; Indina (indinavir)), 5(S)_Boc-amino-4(s)-hydroxy-6-phenyl-2(R)-benzylglycidyl-(L)-proline-(L)- Phenylalanine-morpholin-4-ylguanamine, 1-oxoethoxyethyl-/5-decylthio-alanine-(2S,3S)-3-amino-2-hydroxy-4-butanyl-1 , 3-pyrazolidine-4-t-butyl decylamine (also known as 1-naphthyloxyethyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5-isoporphyrinoxy Ethyl thiol-cold-methylthio-alanine-(2S,3S)-3-amino-2-hydroxy-4-butenyl-1,3-pyrazolidine-4-tris-butyl decylamine (ie iQoa-Mta-Apns-Thz-NHtBu) and its analogues), HEPT compounds (L, 697, 639, R82150, U-87201E and their analogues), HIV integrase inhibitors (Zintevir) and It is similar to O:\106\106749.DOC -143- 1292752), TAT inhibitors (such as RO-24-7429 and its analogues), tris-phosphonocarboxylate, HPA-23, Aphrodite ( Eflonithine), peptide T, reticulose (nuclear prion protein), ansamycin ALS 427, trimetrexate, UA001, ribavirin, interference Oxetanocin Oplotox-G, cyclobut-G, sekbat-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, L-693, 989, BV ara-U , CMV three antibodies, FIAC, HOE-602, HPMPC, MSL-109, Tl-23, trifluridine (trifluridine), vidarabine (vidarbine), fexiciclovir, panxicofi (penciclovir), acyclovir, ganciclovir, castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, hypericin (hypericin), oxacin myristic acid, dextran sulfate, and pentosan polysulfate. An immunomodulatory agent that can be administered in combination with a compound of the present invention, including bropirimine, Ampligen, anti-human interferon alpha antibody, colony stimulating factor, CL246, 738, Imreg-1, Imreg -2, diethyldithioamino decanoate, interleukin-2, alpha-interferon, inosine pranobex, glucosinolate phenanthrene, cell wall thiol Tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, interferon, interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha Interferon immunoglobulin, IGF-1, anti-Leu-3A, autologous inoculation, biostimulation, in vitro photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G -CSF, GM-CSF, hyperthermia, O:\106\106749.DOC -144- 1292752 High immunity to isopinosine, IVIG, HIVIG, passive immunotherapy and white vaccine. Other anti-infective agents which may be administered in admixture with the compounds of the present invention include guanidinium isothioate. Any of a variety of HIV or AIDS vaccines (eg, gpl20 (recombinant), Env2-3 (gpl20), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (gpl60), immune-Ag (gpl60) ), HGP-3 0, HIV-immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with the compound of the present invention. Other preparations which can be used in combination with the compound of the present invention are ansamycin LM 427, sputum-free nucleic acid, ABPP, AI-721, carrisyn, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-Ethylcysteine, (2-oxooxazolidin-4-carboxyindole), D-penicillin, diphenyl carbazide, EL-10, erythropoietin, fusidic acid , dextran, HPA-23, human growth hormone, hydroxchloroquine, iscador, L_ oxalox and other quinolone antibiotics Polysaccharides, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, hexyl Pentofylline, pentoxifylline, peptide T, pineapple extract, polyglycol acetate, reticulum, retrogen, triazide, ribozymes ), RS-47, Sdc-28, shisha, THA, thymic fluid factor, thymopentin, thymosin fragment 5, thymosin α 1, thymostimulin, UA00 1, urinary tract Mouth saponin, vitamin B 12 and wobemugos 0 Other preparations which can be used in combination with the compound of the present invention are antifungal agents, such as O:\106\106749.DOC-145-1292752 Amphotericin (amphotericin) B, clotrimazole, 5-fluorocell, flucytosine, fluconazole, itraconazole, ketoconazole And nystatin and its analogs. Other preparations which can be used in combination with the compound of the present invention are antibacterial agents such as ammonium sulphate, amikacin, azithromycin, xipro Ciprofloxacin, tesulosin (tosuf) Loxacin), clarithromycin, clofazimine, ethambutol, isoniazid, ppyrazinamide, rifabutidine Rifabutin), rifampin, streptomycin and TLC G_65 and analogs thereof. Other formulations which can be used in admixture with the compounds of the present invention are anti-biological agents such as interferon alpha, COMP (cyclophosphamide, vincristine, amine saxophone and dehydrocortisone), scorpion scorpion ( Etoposide), mB ACOD (amino sputum, broccoli, doxorubicin, cyclosporin, vinca citrate and dexamethasone), PRO-MACE/MOPP (dehydrocortisone, amine) A dish (w/ leucovin rescue), doxorubicin, cyclamate, taxol, mechlorethamine, new test, dehydrogenation Pine and procarbazine, Changchunxin, vinca, angiostatin, pentosan polysulfate, platelet factor 4 and SP-PG and their analogues. Other preparations which can be used in combination with the compounds of the present invention are medicaments for the treatment of neurological diseases, such as peptide T, ritann, lithium, elavil, diphenylacetamidine (phenyt〇in). ), carbamazipine, slow

O:\106\106749.DOC 1292752 Mexitetine, heparin and arabinose and their analogues. Other preparations which can be used in admixture with the compounds of the invention are anti-protozoal agents, such as albendazole, azithromycin, caromycin, clindamycin, corticosteroids, ammonia Da (dapsone), DIMP, Aflonini, 566C80, fansidar, furazolid〇ne, L,671,329, Lei σ 瑞 瑞 (letrazuril), 甲石肖Metronidazole, paromomycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine , inhibitor of growth hormone release, spiramycin, sulfadiazine, trioxazole diamine. Determination, TMP/SMX, trimetrexate and WR 6026 and analogs thereof. In the preparation for inhibiting or treating HIV or AIDS mixed with the compound of the present invention, a reverse transcriptase inhibitor is preferred, especially AZT (easy to get set), ddl (Didanodine), ddC (shaxita must), d4T (Stadend), 3TC (Lami set), 荇Fiilaping, Diffy Ruding, Chu Fei Ding, PMEA, dual-POMPMEA and MSA-300. Other preferred formulations for inhibiting or treating HIV or AIDS, in combination with a compound of the invention, in particular ABT-538 (Rhinenafi) and related compounds, disclose U.S. Patent No. 5,541, issued July 30, 1996, No. 206, and U.S. Patent No. 5,491,253, issued toK.S. (R)-Benzyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-trihydropyridinyl)-pentane Indoleamine (also known as Indinavir) and related compounds, O:\106\106749.DOC -147- 1292752, discloses European Patent Application No. 541168 and May 9, 1995, published on May 12, 1993. U.S. Patent No. 5,413,999, issued toK. _[[N-(2_ oxalinyl)-L-aspartate oxime]amino]butyl]-(4aS,8aS)-isoindoline-3(S)-carboxamide ( That is, Shaquinafi) and related compounds, which are disclosed in US Pat. No. 5,196,438, issued March 23, 1993, incorporated herein by reference. ;5(s)_B〇c_Amino-4(S)-ylamino-6-phenyl-2(R)-benzoindolyl-(l)-physic acid-(l)-amphetamine酸-?11 lin-4-ylamine and related compounds are disclosed in European Patent Application No. 532,466, issued March 17, 1993, which is incorporated herein by reference in its entirety in -/5 -Methylthio-alanine _(2S,3S)-3-amino-2-hydroxy-4-butenyl-1,3-pyrazolidine-4-tris-butylamine (also known as ^ Nitoxyethyl-Mta-(2S,3 S)-AHPB A-Thz-NH-tBu), 5-iso-p-decyloxyethyl-fluorenyl-methylthio-alanine-(2S, 3S)-3-Amino-2-hydroxy-4-butanyl-1,3-p-Secret-4-III-butyl decylamine (also known as iQoa-Mta-Apns-Thz-NHtBu) and related Compounds are disclosed in European Patent Application No. 490,667, issued Jun. 17, 1992, and in Chem. Pharm. Bull. (8) 2251 (1992), incorporated herein by reference. 1R*(R*),2S*]]-NM3-[[[(1 山 曱 曱 ) ) ) ) ) ] ] ] ] ] ] ] ] ] ] 曱 曱 曱 曱Propyl]_2·[(2_junolinylcarbonyl)amino]butanediamine (also known as SC-52151) and related PCT Patent Application No. W092/08701, filed on May 29, 1992, and hereby incorporated herein by reference, in ; O:\106\106749.DOC -148- 1292752

(i.e., VX-478) and related compounds are disclosed in PCT Patent Application No. WO94/05639, the entire disclosure of which is incorporated herein by reference.

(ie DMP-323) or

(i.e., DMP-450) and related compounds are disclosed in PCT Patent Application No. WO 93/07128, filed on Apr. 15, 1993, which is hereby incorporated by reference.

(ie, AG1343 (inner Philippine)), O:\106\106749.DOC -149- 1292752 Revealing PCT Patent Application No. WO95/09843, published on April 13, 1995, and January 16, 1996 U.S. Patent No. 5,484,926, the disclosure of which is incorporated herein by reference.

(i.e., BMS 186, 318), which is hereby incorporated by reference in its entirety in its entirety in its entirety the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire

(ie SC-55389a) Revealed at the Second National Conference on Human Retroviruses and Related Infections (Washington, D.C., January 29-February 2, 1995) 88 sessions;

O:\106\106749.DOC-150-1292752 (also known as BILA 1096 BS) and related compounds, which are incorporated herein by reference in its European Patent Application No. 56-268, filed on Sep. For reference; and

(i.e., U-140 690) and related compounds are disclosed in PCT Patent Application No. W095/30, 670, filed Jan. Acceptable salt. In the most preferred combination, the compound of the invention is administered in combination with a tertna phenanthrene. Such combinations are particularly useful for inhibiting human HIV protease. Such a combination is also particularly useful for inhibiting or treating HIV infection in humans. When the compound of the present invention is used in such a combination, the compounds of the present invention may be administered in the form of separate doses, in the same or different number of times, or they may be formulated into a single composition containing the two compounds.

No. 1f, which is incorporated herein by reference, for use as a liquid test, liquid dosage for oral administration, Patent No. 5,484,801 ~ '(b) encapsulated solid or

O:\106\106749.DOC -151 - 1292752 The semi-solid dosage form, as disclosed in PCT Patent Application No. WO95/07696, filed on March 23, 1995, and the US patent filed on March 13, 1995 PCT Patent Application No. WO95/09614, the entire disclosure of which is incorporated herein by reference in its entirety, in its entirety, in its entirety, in And U.S. Patent No. 5,559,158, the disclosure of which is incorporated herein by reference. Further examples of the preferred dosage forms of the law of Turner Philip are disclosed in U.S. Patent Application Serial No. 8/754,396, filed on November 21, 1996, at 1 &lt;1&lt;1&gt; The application for the name of Razzak, S. Ghosh and R. Gao, entitled Pharmaceutical Composition, is hereby incorporated by reference. A preferred composition of the law of Tertena contains rhodium phenanthrene in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the total solution. And (b) a solution of polyoxy 35 castor oil present in an amount of from about 0% to about 20%, preferably from about 5% to about 10% by weight of the total solution, in pharmacy In an acceptable organic solvent, it comprises (1) from about 15% to about 99% by weight of the total solution, preferably from about 30% to about 70%; more preferably from about 40% to about 65. The oleic acid present in the amount of %), or (ii) (l) is from about 15% to about 99% by weight of the total solution (preferably from about 30% to about 70%); more preferably The oleic acid is present in an amount from about 40% to about 65%), and (2) is present in an amount of from about 0% to about 12%, preferably about 10% by weight of the total solution. A mixture of ethanol or propylene glycol or a mixture thereof. In a preferred embodiment of the invention, the solution is encapsulated into a soft, flexible gelatin capsule (SEC), or a hard gelatin capsule, and the solution may also contain a total of O:\106\106749.DOC -152- 1292752 The weight of the solution is present in an amount from about 0. 01% to about 0.08% (preferably from about 0. 01% to about 0. 05% by weight of the total solution). Antioxidant: (preferably ΒΗΤ (butylated hydroxy benzene)). Examples of such compositions and methods for their preparation are provided below. Ingredient% by weight Lunafifene (free base) 20 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 5 Oleic acid, 6321, NF 65 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixed water tank was purged with nitrogen. In the tank, oleic acid (649·9 g) and yeast (1 g) were mixed. The mixture was warmed to about m (mi) and held at this temperature. Butylated hydroxytoluene (01 g) was charged to the tank and mixed until the solution was clear. Lawnerafil (200 g) was slowly loaded into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (50 g) was added to the tank and mixed. The heating was interrupted and the solution was allowed to cool to ambient temperature (20-3 0 ° C). The resulting solution was filled into a soft and flexible capsule (0.5 g solution/SEC) to give ι 〇〇 特 纳 纳 纳 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Philippine / seC dose. Lawnerife (free test) 2 〇 ethanol (USP, 200 standard strength) 1 〇 polyoxy 35 castor oil (Cremophor® EL) j〇O: \106\106749.DOC -153 . 1292752 oleic acid, 6321, NF 6 〇butylated hydroxy benzene (ΒΗΤ), NF 0.01 Preparation of the above composition··

Purge the mixing tank with nitrogen. Oleic acid (599.9 g) and ethanol (100 g) were mixed in the tank. The mixture was warmed to about 33 ° C (29-37 ° C) and maintained at this temperature. Butylated hydroxyindole (01 g) was charged to the tank and mixed until the solution was clear. Lawnerafil (200 g) was slowly loaded into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The heating was interrupted and the solution was allowed to cool to ambient temperature (20-30 ° C). The resulting solution was filled into a soft and flexible capsule (〇·5 g solution/SEC) to give a dose of 1 gram of law Tenapee/SEC or '1.0 g/SEC to give 200 mg Nafie/SEC dose. An example of a preferred single dosage form comprising a compound of the genital phenanthrene and a compound of the formula I is disclosed in U.S. Patent Application Serial No. 08/754,39, filed on May 21, 1996, to Lipari, LA Al-Razzak, S. The name of Ghosh and R. Gao is called Shen, called Pharmaceutical Composition, which is incorporated herein by reference. Preferred compositions comprising a single dosage form of a law of tumfene and a formula include (a) from about 1% to about (preferably from about 5% to about 25%) by weight of the total solution. a mixture of the content of the formula (IV), and a mixture of the compound of the formula I in a weight ratio of from about 1% to about 5% (preferably from about 约 to about (10)%) of the total solution (b) a solution of polyoxyl 35 castor oil present in the mashed/spooned 10/〇3, based on the weight of the total solution, in a pharmaceutically acceptable organic solvent, including (1) by weight of the total solution, From about -154-

O:\106\106749.DOC

1292752 10% to about 8 8% (preferably from about 40% to about 65%) in the presence of oleic acid' and (ii) a mixture of ethanol present at a level of about 10% by weight of the total solution . In a preferred embodiment of the invention, the solution is encapsulated into a soft, flexible gelatin capsule (SEC), or a hard gelatin capsule, and the solution may also comprise, by weight of the total solution, from about 〇〇1% to about 〇.〇8〇/〇 (preferably, based on the weight of the total solution, from about 〇·〇丨% to about 〇, the antioxidant is present (preferably BHT (butyl) Examples of such compositions and methods for their preparation are provided below. Ingredient % by weight Lunfifin (free base) 5 Example 2B compound (free base) 30 Ethanol (USP, 200 standard strength) 10 Polyoxy 3 5 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 45 Butylated hydroxy benzene (BHT), NF 0.01 Ingredient % Lutneufi (free base) 15 Example 2B compound (Free base) 15 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxy benzene (BHT), NF 0.01 O: \106 \106749.DOC -155- 1292752 Ingredient Weight % Lunafifi (free base) 15 Examples 2B compound (free base) 15 ethanol (USP, 200 standard strength) 10 polyoxyl 35 castor oil (Cremophor® EL) 5 oleic acid, 6321, NF 55 butylated hydroxytoluene (BHT), NF 0.01 combination Preparation of the mixture: Purge the mixing tank with nitrogen. Mix oleic acid (549.9 g) and ethanol (100 g) in the tank. Put the butylated hydroxy benzene ((丨克) into the tank, and Mix until the solution is clear. Lawnerafil (丨5 gram) is slowly charged into the tank and mixed until the solution is clear. The compound of Example 2B (15 gram) is slowly loaded. In the tank, and mix until the solution is clear. Add polyoxy 3 5 castor oil (1 gram) to the tank and mix it. Fill the resulting solution into a soft and flexible capsule 〇·〇 In grams of solution / SEC), a dose of 150 mg / SEC of each of the compound of the law of the phenanthrene and the compound of Example 2B was obtained. Ingredient % by weight of the ruthenium phenanthrene (free test) 15 Example 2B of the compound (free base) 5 ethanol (USP, 200 standard strength) 10 polyoxyl 35 castor oil (Cremophor® EL) 10 oil , 6321, NF 60 Butylated hydroxyindole (BHT), NF 0.01 is administered to humans or other mammals in a single or separate dose. *O:\106\106749.DOC -156· I292752 Turner The total daily dose of phenanthrene (administered with the compound of the present invention) may be, for example, from about 0.001 to 300 mg per kg of body weight per day, the more common 疋 0 · 1 to 1 〇 mg of law Tenaf . Dosage unit compositions can contain a fraction of the dosage of such agents to produce a dosage per amp. In the composition comprising a mixture of the law of tertnaphene and the compound of Example 2B, the ratio of the compound of the law of the Tenerife and the compound of Example 23 (weight/weight) ranges from about 1:16 to about 5:1 (preferably It is between about ι:6 and about 3:丨). In other preferred combinations, the compounds of the invention are combined with a tertnaphene and one or more reverse transcriptase inhibitors (preferably one or more selected from the group consisting of AZT (easy to get 疋), ddl (di Danodin), ddC (Shasita), d4T (Star 4) and 3TC (Lamidine) are administered together. Such combinations are particularly useful for inhibiting or treating HIV infection in humans. When used in such combinations, the compound of the invention and the law of tumnafe, and one or more reverse transcriptional apron inhibitors' may be administered in the form of separate formulations, administered in the same or different times, or they may be administered It is prepared into a composition containing two or more compounds. A particularly preferred combination of treatments comprises a compound of formula 1 (particularly the compound of Example 2B) mixed with tertnafi, αζτ and 3tc. Formulations which can be combined with the compounds of the present invention for inhibiting, treating or preventing tick infections are not limited to those listed above, but in principle include any which can be used to treat or prevent MDS or HIV infection. When administered in combination, the therapeutic agent can be formulated into separate compositions administered in the same number or different numbers, or the test therapeutic agent can be administered in the form of a mono-composition.

O:\106\106749.DOC -157 · 1292752

The foregoing is a subject of the invention and is not intended to limit the invention to the disclosed compounds. The person and the person who changed the spoon--the map will be obvious to the artist. The obvious scope of the invention is 1 + 13 within the scope of the invention and within the genus, it is defined in the appendix of the patent application .曱°月专

O:\106\106749.DOC -158-

Claims (1)

96. -· ^ Chinese patent application scope replacement (September 96) X. Patent application scope: 1. A compound of the following formula: HO-C .1 wherein 113 is a Cu alkyl group; R5 is '(CH2)n", where n is 1, 2 or 3, X is -Ο- or -S-, and Y is •CH2-, -0-, -S- or -N(R6)-, Wherein R6 is hydrogen or Cw alkyl; or a salt thereof. 2. A compound according to the first aspect of the patent application, which is 2S-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, or a salt thereof. 3. Preparation of (28,38,58)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane or A method of the salt thereof, which comprises (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-tris-butoxycarbonylamino- 1,6-Diphenylhexane is reacted with trifluoroacetic acid in dichloromethane, with aqueous hydrochloric acid in acetonitrile or with aqueous hydrochloric acid in acetic acid. 4. A method of preparing a compound of the formula: or a salt thereof: 〇 «3 wherein R3 is Ci_6 alkyl and Q is a cleavage group, the method comprising (a) a compound of the formula: or a salt thereof: 106749-960929.doc, .1292752 Co2h H2N wherein R3 is as defined above and reacts with a compound of the formula: CfeC=N Q Wherein Q is as defined above; or (b) a compound of the formula: or a salt thereof: RM0-&lt;0)C-HN C02H wherein R3 is as defined above, and R" is phenyl, Cm alkyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl or trifluoromethylphenyl, reacted with a compound of the formula: Q is as defined above. 5. According to the method of claim 4, the center is (:: "alkyl and q is chlorine. 6. According to the method of claim 4, wherein &amp; is isopropyl And q is chlorine 106749-960929.doc