TW200817349A - Process for the preparation of retroviral protease inhibiting compounds - Google Patents

Abstract

The present invention provides a method for preparing the compound of formula:

Description

200817349 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, HI V infection, a method of making the compound and the synthetic intermediate used in the method. [Prior Art] Retroviruses are viruses that reverse transcription and record enzymes 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 leukemia in humans' as well as bovine and 13 leukemia viruses, 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 200817349 = Reducer! . Angiotensin! Further steps are cut by the egg from the enzyme vascular 1 ace, forming a hypoallergenic vasoconstrictor, an inhibitor of known resveratrol and weaving can reduce hypertension in the living Zhao. Retrovirus: A protease inhibitor that will provide a disease caused by a retrovirus. The genome of a retrovirus that encodes a protease is a proteolytic process that causes a multiprotein precursor such as the PM and g gene products.

Ο Reason. See WeUink, Arch. Vir. 1.Ml (1988). Retroviral proteases most commonly add gag precursors to nuclear proteins, and also process precursors to reverse transcriptase and retroviral proteases. In addition, retroviral proteases are sequence specific. See Pearl, Nature's Acacia (1987) 〇 ' For the collection of infectious virions, it is necessary to correctly process the precursor polyprotein from the retrovirus's protein aphid. It has been shown that in the living spoon dog, Ai produces a protease-incomplete virus, resulting in a lack of infectivity... nuclear. The production of forms. See Crawf〇rd, j. Virol. 53^ 899 (1985), Katoh et al., Vir〇1〇gy (1985). Therefore, the inhibition of proteases in reverse transcripts provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987). A treatment of ill-infected diseases usually involves the administration of a viral DNA. a compound. Current treatments for AIDS involve the administration of, for example, 3 - $nitro-3, deoxythymidine (AZT), 2,3,-dideoxycytidine (DDC), dideoxyinosine (DDI), Compounds such as d4T and 3TC, and the speculative sex caused by immunosuppression caused by HIV infection

O:\106\106749.DOC 200817349 Dyed compounds. In the treatment and/or reversal of the disease, none of the AIDS therapies have been shown to be fully effective. 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, the HIV protease inhibitors ntonavir and saquinavir0 indinavir have been approved for the treatment of HIV infection in the United States. However, there is a continuing need to improve HIV protease inhibitors.

SUMMARY OF THE INVENTION According to the present invention, there is a compound of formula I:

Wherein Ri and R2 are each selected from the group consisting of a low carbon number alkyl group, a cycloalkyl group, and an aryl group;

R3 is a low-number burnt group, a burnt group or a cycloalkyl group; R4 is an aryl group or a heterocyclic ring; R5 is

O:\106\106749.DOC 200817349

ϋ

e)

X

g)

O:\106\106749.DOC -10- 200817349 ο

i) HO 〇 where n is 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 〇, s or NH, and Y is -CHy, _〇_, _s_ or -N ( R6)·, wherein R6 is hydrogen, lower alkyl, decyl, cycloalkylalkyl, aryl or aralkyl, Y, is -CH2- or -N(RV')- 'where R0 " is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkylaryl or aralkyl, Y' is -N(R6,)-, wherein R6 is hydrogen, lower carbon number, % An alkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and 2 is fluorene, 3 or NH; and Ο 1^ is a) -〇-, b) -S-, c) -N(R7)- Wherein R? is hydrogen, lower alkyl, cycloalkyl or cycloalkylalkyl, d) -0-alkyl-, e) alkyl-f) _S (〇M alkyl)

O:\106\106749.DOC -11 - 200817349 g) -s(o)2-alkyl-, h)-N(R7)-alkylene-, wherein R7 is as defined above, i) - Alkyl-Ο-, j)-alkyl-S-, k)alkyl-N(R7)-, wherein R7 is as defined above, l) alkyl, or m) alkenyl; Or a pharmaceutically acceptable salt, ester or drug precursor thereof. Fl

Preferred compounds are those wherein Ri and R2 are aralkyl groups, R3 is a lower alkyl group, R4 is an aryl group, and 115 is X.

, .^N

, (CH2)nV

X

VS (CH2)m b)

X \ C)

Z

O:\106\106749.DOC 200817349

X r% Λ d) (CHzJm, or e) χό -R6·· Ο where X, Υ, Υ, Υ", Ζ, R6", η, 111, and m, as defined by F 々IJ above, and 1^ is a compound of formula I which is an alkyl group. More preferred compounds are those wherein R#R2 is benzyl, or Ri is a lower carbon number, R3 is a lower carbon number, and R4 is a) a phenyl substituted with two low carbon numbers. Optionally, a third substituent selected from the group consisting of: a carbon group, a hydroxyl group, an amine group, and a halogen, or b) a two-carbon group substituted with a lower ratio of a bite base or a spray Base, and optionally substituted with a second substituent selected from the group consisting of a lower alkyl group, a hydroxyl group, an amine group and a halogen, R5 is

X Λ

Y (CH2)r a)

Where η is 1 or 2' X is Ο or S, and γ is _ch2 or -NH-X Y (CH2)m b) O:\106\106749.DOC -13 - 200817349

Where m is 1 or 2, X is Ο, Υ is -CH2- and Ζ is Ο X

c) where m* is 1, X is Ο, Z is 〇 and γ is -NH-, X Υ" Ο d)

Where m' is 1, X is 〇, 丫" is and γ, is, or X e) tr n - r6 · · Formula I where X is 〇 and R6" is hydrogen and Ο L! is -O-CH2 - Compound. Further preferred compounds are those wherein 1 and & are benzyl, or & benzyl and the core is isopropyl 'R3 is a lower carbon alkyl group, which is 2,6-didecylphenyl, which may optionally Substituted by a third substituent selected from the group consisting of a lower alkyl group and a halogen, r5 is X(CH2)nV a)

O:\106\106749.DOC -14- 200817349 where η is 1 or 2, X is Ο or S, and 丫 is -(:1|2 or -ΝΗ-

Z b)

X Ο ·, ζ c) ί_Γ where 11^ is 1, X is Ο, ζ is 〇 and Υ is -ΝΗ_,

X γ” d) or

Where m' is 1, X is 0, γ" is and Y is _nH· X Ο \Αν·

And R. a group, R 3 is a lower alkyl group, and & is 2,6-dimethylphenyl, which may be optionally substituted with a third substituent selected from the group consisting of a lower alkyl group and a _ element.

O:\106\106749.DOC * 15- X200817349 R5 is Υ (CH2)n- a)

Where η is 1 or 2' X is Ο or S, and Y&_Ch2*_nh· X Ο

TL b) (CH2)m. where m' is 1, X is 0, Z is O and γ is -Nh_,

Y" (CH2)r \ c) or where m is 1, X is Ο, Y, is -NH- and Y is -NH- Ο d) where X is 〇 and R / is nitrogen and 1^ is -0-(: 112- of the compound of formula I. The most excellent compound is one in which 1 and R2 are fluorenyl, or R1 is fluorenyl and R2 is isopropyl, R3 is a lower carbon number, and R4 is 2. 6-dimethylphenyl, which may optionally be taken from a third substituent selected from the group consisting of a lower alkyl group and a halogen: O: \106\106749.DOC -16- 200817349

Generation, heart is X \ /

(CH2)nJ wherein η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH-, and 1^ is -0-(:112- of the compound of formula I. 0 Excellent and best Examples of compounds of formula I are selected from the group consisting of: (2S,3S,5S)-2-(2,6-diamidinophenoxyethyl)amino-3-hydroxy-5-[2S-(l- Tetrahydro-pyrimidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexanhydride; (2S,3S,5S)-2-(2,6-dimercaptophenoxy Ethyl)amino-3-hydroxy-5-(2 8-(1-imidazolidin-2-one)-3,3-dimethylbutanyl)amino-1,6-diphenylhexane (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)amino-3-hydroxyindole-5-(2 8-(1-imidazolidin-2-sulfinium) (3S,3S,5S)-2-(2,4,6-trimercaptophenoxy) anthracene -3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutenyl)amino-1,6-diphenylhexan; (2S,3S,5S)-2 -(4-Fluoro-2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amine Base-1,6-diphenylhexan; O:\106\106749.DOC 17 200817349 (2S,3S,5S)-2-(2,6-two Nonylphenoxyethyl hydrazino)amino-3-hydroxy-5-(2S-(l-pyrrolidin-2-one)-3-methylbutanyl)amino-1,6-diphenylhexan (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-pyrrolidine-2,5-dione) -3-methylbutylidene)amino-1,6-diphenylhexanhydride; (2 8,3 8,5 8)-2-(trans-3-(2,6-didecylphenyl) Propylene fluorenyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one)-3-methylbutenyl)amino-1,6-diphenylhexane; (2 8,3 8,5 8)-2-(3-(2,6-Dimercaptophenyl)propanyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2- Keto)-3-methylbutylidene)amino-1,6.diphenylhexanhydride; (2S,3S,5S)-2-(2,6-dimercaptophenoxyethyl)amino- 3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3indolylbutenyl)amino-1,6-diphenyl hexane; (2S,3S,5S )-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydropyrimidin-2-one)-3 (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5- (2S-(1- Hydropyrimidin-2-one)-3-mercaptobutyl hydrazino)amino-1-phenyl-6-methylheptane; ♦ (2S,3S,5S)-2-(2,6-dimethylbenzene Oxidyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3-indolylbutenyl)amino-1-phenyl-6- Heptoheptane; and O:\106\106749.DOC -18 - 200817349 (28,3^-(2,6-dimethylphenoxyethyl)amino)_3_pyridyl-5·(2δ· (4. aza- 4,5-dehydro-dioxa-2-yl)- 3 -methylbutyryl)amino-1,6-diphenylhexan; or a pharmaceutically acceptable salt thereof, Ester or drug precursor. An extremely excellent compound of formula I is (2S,3S 9 η < , , A, 5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2S- (l-tetrahydropyrimidinium 9 oxime-2-one)-3_methylbutylidene feeyl-1,6-monophenylhexanone; or a pharmaceutically acceptable salt, ester or drug thereof Precursor. Ο 丙酮 Acetone, acetonitrile and the like), then add the solution to the water to prepare it. Preferably, (28,35,58)_2-(2,6-dimercaptophenoxyethyl)amino-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-2-one) ) _3_methylbutenyl]amine group In some cases, it is preferred to be able to prepare (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl fluorenyl)amine as an amorphous solid. Base_3_ _美-5-[2S-(1_tetrahydro(tetra)_2-keto)_3-methylbutanyl]amino-], 6-diyl hexane (or its pharmaceutically acceptable salt, vinegar Or drug precursors). This type of amorphous solid can be obtained by (2S, 3S, called 2-(2,6-dimethylphenoxyethyl)amino-3-carbyl_5_[28_(1_tetrahydro Bite _2 _ _ _ _ _ _ _ methyl butyl ketone] Amino-1,6 · diphenyl hexanone dissolved in organic solvents (such as ethanol, isopropanol, -1,6-phenylene The alkane is dissolved in ethanol (from about 2 to about 4 ml/g) and the ethanolic solution is added to water (from about 1 Torr to about 1 cc/g) and stirred to provide an amorphous (28) ,38,5;5)_2_(2,6-dimethylphenoxyethyl)amino-3-hydroxy_5_[2S-(l-tetrahydropyrimidin-2-yl)-3 -mercaptobutyl fluorenyl Amino-1,6-diphenyl hexane. Other specific embodiments of the invention include HIV protease inhibiting compounds,

O:\106\106749.DOC -19- 200817349 It includes substituents of formula II:

Rs 〇 wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; R5 is Ο

O:\106\106749.DOC -20- 200817349

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-21-200817349 N(R6)...wherein R6" is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, y%_n(R6,)_, wherein R6 is hydrogen, low Preferred are compounds having a C number alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and Z is a hydrazone, S or NH 〇 is an HIV protease inhibitory compound containing a substituent of the formula II, in Formula II R3 is a low carbon number alkyl group, and R5 is \

Ο

(CH2)m· d) or O:\106\106749.DOC -22- X 200817349 \Α·Latch 6·, e) Γ

Wherein X, Υ, Υ', Υ", Ζ, R6'', η, m and m' are as defined above. A more preferred compound is an HIV protease inhibitory compound containing a substituent of formula II, in formula II R3 is a lower alkyl group and R5 is X

(CH2)nV a)

Where η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH-X Υ / (CH2)m ο b)

Where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο, X Υ c) iCH2W where m' is 1, X is 0, Z is 〇 and Y is -NH-O:\106\ 106749.DOC •23 - 200817349 χ ·,· d) (CH2)r where m' is 1, X is Ο, Yf' is -ΝΗ- and Υ' is -ΝΗ-, or

X Ο 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 Ο or S, and Y is -CH2*-NH-,

X i—(CH2)m

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

X

Where m' is 1, X is 0, Z is O and Y is -NH-, O:\106\106749.DOC -24- 200817349

XA Υ" d) (CH2)r where m' is 1, X is 〇, γ, is _NHjY, is _νη_, or

X n-r6·. Ο e) wherein X is 0 and R 6" is hydrogen. The most preferred compound is a formula; [Ϊ Ϊ substituent v v protease inhibitor compound 'in formula II, R 3 is isopropyl, And r5 is

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

b) where m is 1, X is Ο, Z is 〇 and Y is -NH-X ^ , γ, ·

XA C) (CH2)r O:\106\106749.DOC -25 - 200817349

Where m is 1, X is 〇, Y, is -NH- and Y is -NH_, or X

Wherein X is hydrazine and R6" is hydrogen. The most excellent compound is an HIV protease inhibiting compound containing a substituent of the formula π. In the formula II, R3 is an isopropyl group, and

〇 where η is 1 or 2, X is 〇 or SJ_Y is -CH2 or. Examples of such HI V protease inhibiting compounds include: cis-N-tert-butyl-decahydro-2_[2(r)-hydroxy-heart phenyl-3 (SH2S_(i·tetrahydropyridin-2-one) -3v-mercaptosyl)aminobutyl]-(4aS,8aS)_isoindoline-3(S)-carboxamide; cis-N-tert-butyl-decahydrohydroxy_4^ -3(S)-(2S-(1-tetrahydropyridine.2-keto)-3-mercaptobutyl)aminobutyl]-(4aS,8aS)·isoquinoline_3(S)_carboxylate Indoleamine; and 'amino-N-((2 ipsilateral, 3S)-2-hydroxy-4-phenyl-3-(2S-(l.tetrahydropyrimidin-2-Siqyl)-3-indenyl) Butyrylamino)butyl)isobutyl-benzenesulfonamide; and analogs thereof; or a pharmaceutically acceptable salt thereof. Such an HIV protease inhibiting compound containing a substituent of formula II can be

O:\106\106749.DOC -26- 200817349 Suitable for having an amine group (-ΝΗ2 or -NHR*, wherein R* is a lower alkyl group), a hydroxyl group (-OH) or a thiol group (-SH) The intermediate or precursor is prepared by coupling to a compound of formula II or a salt thereof or an activated ester derivative thereof:

Il Ο wherein R 3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and R 5 is

X \ / (CH2)n"

b)

X

c)

X d) O:\106\106749.DOC -27- 200817349

Where η is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 0, S or NH, and Y is -CH2-, -0-, -S- or -N (R6 - wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y'' is -CH2- or -N(R6n)-, wherein R6" is Hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y' is -N(R6')-, wherein R6' is hydrogen, low carbon number-28-

O:\106\106749.DOC 200817349 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,

Wherein R3 is a lower alkyl group and R5 is X \ / (CH2)n^ Ο

Wherein X, γ, γ', γ", z, R6", η, m and mf are as defined above. O:\106\106749.DOC -29- 200817349 A more preferred compound is a compound of formula III or an activated ester derivative thereof,

Where r3 is a lower alkyl group and r5 is X

Y (CH2)n^ a)

Where η is 1 or 2, X is Ο or S, and Y is -CH24-NH-X Ο m b)

Wherein m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο X c) (CH2)m· where mfgl, X is 0, Z is 0, and Y is -NH-, 〇

X Υ,· d)

Where m' is 1, X is Ο, Y" is -ΝΗ· and Y' is -NH-, or X

Wherein X is 0 and R6n is hydrogen. O:\106\106749.DOC -30- 200817349 A more preferred compound is a compound of formula III or an activated ester derivative thereof,

Wherein R3 is isopropyl and R5 is X

Y (CH2)n- a)

Where η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH-X Ο Ο Υ / (CH2)r b)

Where m is 1 or 2, X is 0, Y is -CH2- and Z is 〇, X

c)

Where m' is 1, X is Ο, Z is Ο, and Y is -NH_ X \ d) where m1 is 1, X is Ο, YΠ is -NH- and Υ1 is -ΝΗ-, or

Wherein X is 0 and R6" is hydrogen. O:\106\106749.DOC -31 - 200817349 The most preferred compound is a compound of formula III or an activated ester derivative thereof.

Where R3 is isopropyl and R5 is X (CH2)n"

Y a)

Where η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH_ X Ο Υ

b) (CH2w where m' is 1, X is Ο, Z is O, and Y is -NH-X Y" c) (CH2)r

O

Where m' is 1, X is Ο, Y" is -NH- and Y' is -NH-, or X*n-r6.·d)

Wherein X is O and R6n is hydrogen. The most excellent compound is where R3 is isopropyl and R5 is X.

Wide (CH2)nV

YO:\106\106749.DOC -32-200817349 A compound of formula m or an activated derivative thereof wherein / or 2, χ is 0 or S, and hydrazine is -CH2 or - ΝΗ a compound of the invention Includes asymmetrically substituted carbon atoms. d Fruit sounds means that all stereoisomers of the compounds of the invention are included in the invention: a mixture of racemic mixtures, diastereoisomers, and single diastereoisomers of the compounds of the invention.

Ο "s" and "R" Configuration-words as in IUPAC 1974 Recommendations (IV), Fundamental Stereochemistry, Pure Appi

Chem. (1976) 45, 13-30. As used herein, the term "Ν-protecting group" or "Ν_protected" means those groups that attempt to protect the ice terminal of an amino acid or peptide, or to protect the amine group from being synthesized in a private manner. The desired reaction. In Greene and Wuts, "Protective Groups In Organic Synthesis" (John Wiley & Sons, New York (1991)), the commonly used N-protecting group is disclosed. This is incorporated herein by reference. The protecting group includes a fluorenyl group such as a fluorenyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a trimethyl ethenyl group, a second-butyl acetyl group, a 2-meryl group. Base, 2-anthracene, trifluoroethenyl, dioxetyl, @太醯基, o-nitrophenoxyethenyl, butyl ketone, benzamidine, 4-chlorobenzene Sulfhydryl, 4-bromobenzoinyl, 4-nitrobenzhydryl and the like; sulfonyl, such as phenyl fluorenyl, p-nonyl fluorenyl and the like; amine decanoic acid a group formed, such as benzyloxycarbonyl, p-chloroproxenyl, p-oxime benzyloxycarbonyl, p-nitroxyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromofluorenylcarbonyl, 3, 4-two Oxyloxycarbonylcarbonyl, 3,5-dimethoxybenzyloxy, 2,4-dimethoxyfluorenylcarbonyl, 4-methoxyindoleoxycarbonyl, 2-nitro-4,5_O :\106\106749.DOC -33 - 200817349 Dimethoxy-oxyxyl group, 3,4,5·trimethoxy-Yi oxygen county, Bu (p-biphenyl-1-methylethoxyl group, α,α_Dimethyl_3,5·dimethoxyloxymethyl, diphenylmethoxymethyl, tert-butoxymethyl, diisopropylmethoxyoxy, isopropoxy a group, an ethoxy group, an anthracene group, a dipropoxyl group, a 2,2,2-trichloroethoxycarbonyl group, a phenoxycarbonyl group, a 4-nitrophenoxycarbonyl group, a benzyl group 9-methoxy group, a cyclopentyloxycarbonyl group, an adamantyloxycarbonyl group, a cyclohexyloxycarbonyl group, a phenylthiocarbonyl group, and the like; an alkyl group such as an anthracenyl group, a trityl group, a fluorenyloxymethyl group, and a oxime thereof; a group, such as a trimethyl sulphide group and the like. Preferred oxime-protecting groups are a fluorenyl group, an ethyl fluorenyl group, a benzamyl group, a trimethyl ethane group, a third-butyl acetyl group, Phenylxanthyl, aryl, third-butoxyl (b〇c) and ethoxylated (Cbz). As used herein, activated ester derived The term "," means fluorenyl halide, such as decyl chloride, and activated esters include, but are not limited to, formic acid and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides, such as isobutoxycarbonyl gas. And its analogues, a group of hydroxy amber succinimide-derived esters, n- hydrazine hydroxy quinone-derived esters, N-hydroxybenzotriazole-derived esters, N-hydroxy-5-norbornene _ 2,3-dicarboxyguanamine-derived esters, 2,4,5-trichlorophenol-derived esters, thiophenol-derived esters, propylphosphonic acid-derived anhydrides, and the like. As used herein, 'alkyl fluorenyl,' means κ] 9(:(〇)/, wherein Ri9 is lower alkyl. Field is used herein to extend the alkenyl group, the term And means a 4-shell group derived from a straight or branched hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon biguanide. Examples of an extended alkenyl group include _CH=CH-, _CH2CH= CH/, a 34-

O:\106\106749.DOC 200817349 -C(CH3)=CH-, -CH2CH=CHCH2- and the like. As used herein, "alkoxy" and "thioalkoxy", as used herein, mean R15〇- and R15S_, respectively, wherein Ri5 is lower alkyl. - When used herein, "alkane" Oxidyloxy, as used herein, means r22〇_R23〇_, wherein R22 is lower alkyl as defined above, and R23 is alkyl. Representative examples of alkoxyalk include Anthracene methoxy, ethoxymethoxy, second-butoxymethoxy and the like. When used herein, the term "alkoxyalkyl" means alkoxy addition. In the case of a lower alkyl group, the term "alkoxycarbonyl" is used herein to mean R20c(o)_, wherein R20 is alkoxy. When used herein, "alkylamine The term "base" means _NHR, where Ri6 is a lower alkyl group. When the term "alkylaminocarbonyl" is used herein, it means R21C(0)_, where 21 is an alkylamine group. When used herein, the term "alkylene" refers to the removal of two hydrogen atoms derived from a straight or branched chain containing from a hydrazine to a carbon atom. Saturated hydrocarbon Divalent groups such as methylene (-CHr), ethyl (_CH2CH2), 1, 1-ethyl (-CH=CH3), 1,3-propyl (_CH2CH2CH2), 2, 2 Dimethyl propyl (-CH2C(CH3)2CH2-), and analogs thereof. As used herein, the term "amine carbonyl" means _c(0)nh2. . As used herein, the term "aryl" means 'a carbocyclic ring system containing 6 to 12 carbon atoms or a bicyclic ring system' and has one or two aromatic rings including, but not limited to, benzene. Base 'mercapto group, tetrahydro tea base, gas sulfhydryl group, imprint base and the like

O:\106\106749.DOC 200817349. The aryl group may be unsubstituted or may be selected from one, two or three, respectively, lower alkyl, halogen, alkyl halide, alkoxy, silk, alkoxycarbonyl, thioalkoxy. Substituents such as an amine group, an alkylamino group, a dialkylamino group, an amine carbonyl group, a decyl group, a nitro group, a carboxaldehyde group, a carboxyl group and a hydroxyl group are substituted. When "aryl"" 51 is used herein, the aryl group defined before the reduction is appended to a lower alkyl group such as a benzyl group and the like. As used herein, the term "ring-burning" means having 3 to 8 carbon atoms.

The aliphatic ring system of hydrazine includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. When "cycloalkylalkyl" is used herein, it is meant that the cycloalkyl group is appended to a lower alkyl group, including but not limited to cyclohexylmethyl. As used herein, the second compound amine term means a servant wherein R1 6 and R! 7 are each selected from a lower carbon number. When the term "di-alkolyl" is used herein, it means R22c(〇)_, where R22 means dialkylamino. When used herein, the term "fun" means ur , _m_F. When "toothing an oxy group,", is used herein, means "Ο., which is a halogenated alkyl group. When a decyl group is used herein, it is meant that a lower number of chlorine atoms or a plurality of chlorine atoms are replaced by dentate, such as a gas methyl group, a chloroethyl group, a trifluoromethyl group, and the like. As used herein, "heterocycle" means any 3 or a ring of a ring containing a hetero atom selected from the group consisting of oxygen, nitrogen and melon; or ._. v ^ a hetero atom of a mouse, oxygen and sulfur 5_, 6_ or 7_ member ring, or contain

O:\106\106749.DOC -36- Ο Ο 200817349 4 nitrogen ring of 5' member ring; and includes -, _, an oxygen atom; a sulfur atom solid - or two nitrogen atoms; - oxygen Atom η from nitrogen and - a sulfur atom '·- a nitrogen and placed on one of the two ... placed on the two helium atoms; in the non-adjacent position J 1 oxygen and a sulfur 屌 ^. , ',, in no Two sulphur atoms in adjacent positions, two sulfur atoms in the position of the target ^... The melon atom, two non-adjacent nitrogen atoms and - a sulfur atom and an oxygen atom 5-, 6 - or 7_ member ring. 5-Bei% has 0-2 雔, and < j π. + Again... and the shell has 0-3 double bonds. It may be understood that any one of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (for example, a +dyl) quinal group, an isocentric forest group, a tetrahydro (tetra)yl group, a benzoindole bistetrahydrofuran or Benzotetraphenyl and its analogs. Heterocycles include azetidinyl "bido" bilorinyl" bismuthyl" vaso-based, pyridinoline pyrazolidine, imidazolyl , imidazolinyl, imidazolidinyl, pyridyl, /, hydropyridyl, hexahydropyridyl, pyridinyl, hexahydropyrryl, pyrimidinyl, hydrazine, carbazolyl, oxazolidinyl, Isoxazolyl, isoxazolidinyl, morpholinyl, pyrazolyl, thiazolidinyl, isoxazolyl, isoxazolidinyl, fluorenyl, porphyrin, isoquinolinyl, benzimidazole Benzo, benzo-p-oxazolyl, benzoxazolyl, furyl, porphinyl, tetrahydrofuranyl, tetrahydron-butenyl, P-plug. sputum-based, iso-P-sodium, three-dimensional , Sijunji, X. Sitru, 'di-salyl, ρ-sodium, ρ, succinyl, pyrimidine and benzoxanthene. Heterocycles also include

O:\106\106749.DOC -37- 200817349 A compound in which X* is -CH2-, -ΝΗ- or -Ο-, γ* is _c(0)_ or [<(ΙΙ")2_] ν where R" is hydrogen or Cl_C4 alkyl, and 〃 is j, 2 or 3, and redundancy * is -〇_4-NH-, like 1,3-benzodioxo, hydrazine, 'benzo Dioxonyl and its analogs.

杂环 Heterocycles may be unsubstituted or may be selected from one, two, three or four, respectively, including hydroxy, halo, oxo (=〇), alkylimido (R*N=, where R * is a lower alkyl group), an amine group, an alkylamino group, a dialkylamino group, an alkoxy group, an alkoxy group, an alkoxy group, an alkyl group, a aryl group, an aryl group, an aryl group, a COOH group, Substituents of S〇3H and a lower alkyl group are substituted. Further, the nitrogen contained in the heterocyclic ring may be N·protected. When the term "hydroxyalkyl" is used herein, it is meant that a lower alkyl group is attached to the fluorenyl group. The term "lower alkyl" as used herein, is intended to mean a straight or branched alkyl group having up to 6 carbon atoms, including but not limited to methyl, ethyl, and -propyl, iso-propyl, n-butyl, iso-butyl, second butyl, tert-butyl, n-pentyl, m-butyl, 2,2-dibutyl, Methyl amyl, 2,2-dimercaptopropyl, n-hexyl and the like. When a "thio-based alkyl group is used herein, it is meant that a thioalkyloxy group is attached to a lower alkyl group. The formula "chelon" of the present invention can be prepared as shown in the scheme 。_ιν. As outlined in Scheme 1, the standard peptide coupling reagent and method can intermediate the intermediate i and (wherein ΡΘΝ_protecting group , for example, the third _ Dinglian 'for example in hydrazine, benzotriazine and carbonization such as dicyclohexyl:: (DCC) or Ν-ethyl Ν, · dimethylaminopropyl carbodiimide (10) from) and

O:\106\106749.DOC -38 - 200817349 In the presence of a diimine such as a quinone, 1 is reacted with 1 to obtain 1. Alternatively, a salt of the intermediate i or a derivative of an activated ester (e.g., a sulfhydryl group) may be reacted with the intermediate 1 by reacting a carboxylic acid with sulfinium chloride. The a substance 1 was deprotected from N-protection to give the compound 4. In the N-deprotection of i, where ρι (especially where P) is a third-butoxycarbonyl group) is an acid-labile N-protecting group which leads to the formation of impurities due to the sulfhydryl group RrL^C^ O) - the result of shifting from the amine group to the hydroxyl group. The formation of the impurities can be reduced or eliminated by performing the following de-shading action: (1) using trifluoroacetic acid in methylene chloride, or (7) using concentrated chloric acid in indole acetic acid at about room temperature (from about 2 mole equivalents to about 6 mole equivalents, preferably from about 2 mole equivalents to about 4 mole equivalents). A preferred method of N-deprotection comprises catalyzing a compound (wherein Ρ is a third-butoxycarbonyl group) in acetonitrile at a temperature of from about 〇C to about 5 C (from about 2 to about 1 liter liter) / per gram of compound y with concentrated hydrochloric acid (from about 10 to about 20 mole equivalents). The compound or its activated anthracene derivative can then be coupled to the compound to give a compound of formula j ( That is, 6). 展示 Show another method in the plan. You can couple compound 2 (where ? 2 is a group of sulfhydryl groups, such as oxime oxycarbonyl) to the compound, or its activated ester 彳' (For example, mercapto chloride can be prepared by reacting a carboxylic acid with sulfite gas), and can be obtained by deprotecting the compound! The compound can be derived from the compound 1 or its activated ester. Coupling to give a compound of formula j (i.e., D. Scheme IIB shows another preferred method wherein it is in an inert solvent (e.g., ethyl acetate, dimethylformamide, THF, acetonitrile, isopropyl acetate) Ester or toluene and its analogues, at temperatures ranging from about 〇 to about 5 〇 Next, make O:\106\106749.DOC -39- 200817349 protected amino alcohol (10) is hydrogen and h is a small protecting group, or W4 is N_ 蒦 蒦 佺 疋 3 P3 and P4 are sulfhydryl groups) And with a carboxylic acid S or a salt thereof or an activated ester derivative (for example, sulfhydryl gas) from about i to about 丨·3 molar

• f is prepared by reacting (iv) with acetic acid gas or with sulfite gas in toluene/DMF • and its analogues, from about h〇 to about 4〇莫耳当ΐ (preferably from about 25 to about 3.5 moles of organic amine base (e.g., imidazole, hydrazine methylimidazole, 2-methylimidazole, 2-isopropylimidazole, arylmethyl 0 imidazole, 4 _nitroimidazole, pyridine, hydrazine, hydrazine-dimethylaminopyridine, i, 2, 'triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and the like), or The reaction of 攸, ,, tl 1 to force 2 0 in the presence of an inorganic test (for example, sodium carbonate or hydrogencarbonate steel and/or a hydrazine) gives a compound Zhao. A preferred organic amine test includes Imidazole and 1,2,4_triazine. Deamination of hydrazine (for example, using hydrogen and hydrogenation catalysts, or Pd/C and formate salts (such as ammonium formate and its analogues), or pd/c And formic acid and its analogs) provide 2. It is advantageous to catalyze the compound 2 by utilizing the catalysis of an organic carboxylic acid such as s_pyroglutamic acid, Q succinic acid or fumaric acid and the like. A preferred organic carboxylic acid is s_pyramine. The compound of the compound (or the organic carboxylate of Compound 2) and from about 1 Torr to about 13 molar equivalents of formic acid 1 or its activated ester. Derivatives (e.g., aryl chloride) at (1) from about 4 to about 8 mole equivalents (preferably from about 5 to about 7 mole equivalents) of inorganic tests (e.g., NaHC03, Na2C03, KHC03, K2C03, In the presence of NaOH or KOH and its analogs, in an inert solvent (eg 1:1 succinic acid / water, or isopropyl acetate / water, or benzene / water or THF / water and the like) In the reaction, the reaction is carried out at about room temperature, or (2) in an amount of from about ι·〇 to about 4 〇Mo:\106\106749.DOC -40-200817349 (equivalently from about 2· 5 to about 3.5 moles of organic amine test (eg imidazole, 1-mercaptoimidazole, 2-hydrazinoimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole'pyridine , Ν, Ν _: methylaminopyridine, I,] triazole, succinct, 3-m, triethylamine or hydrazine methyl phenanthrene and its analogues, in the presence of an inert solvent (eg acetic acid B) Ester, isopropyl acetate, thf, toluene, B , Dimethylformamide and the like), the reaction is carried out at a temperature of from about 〇.〇 to 5〇 c, and to provide compound 6.

In a preferred embodiment of the invention (shown in the scheme), the intermediate compound i has the chemical formula of the compound M (the heart is like the definition of the compound of the formula z and is preferably isopropyl). Various methods shown in m can be planned to prepare the compound μ. In one method, the amino acid u (in the form of a free slow acid acid acylate (ie, a low carbon number sulphuric acid vinegar)) is converted by reaction with an appropriate chlorinated acid vinegar. It is a urethane urethane U (R, a phenyl group substituted with a phenyl group, a lower alkyl group, a phenyl group substituted with a phenyl group, a nitro group substituted phenyl group, a trifluoromethyl phenyl group and the like). The urethane is intended to be associated with an amine u or an acid addition salt thereof from about 1 Torr to about 1.5 moles (Q is a cleavage group such as C1).

Br, I or a sulfonate such as methanesulfonate, trifluorosulfonate, p-toluenesulfonate, besylate and the like) in an inert solvent (eg thf, methyl third-butyl) In ether, dimethoxyethane, THF/water, dimethoxyethane/water, toluene or heptane and the like, in tests from about 25 to the amount (eg Li〇H, Na〇H) The reaction is carried out in the presence of Li2C〇-^ sodium phenoxide and the like to provide urea. The urea 11 can be isolated and made in an inert solvent (e.g., THF, dimethoxyethane, methyl second-butane, methyl or heptane, and the like), from about 2 Torr.

O:\106\106749.DOC -41 * 200817349 A base present in an amount equivalent to about 5·molar equivalents (for example, potassium tert-butoxide, hydrogenated steel, potassium hydride or ruthenium pyridine and the like) Further reaction, or conversion of 旌i to cyclic urea. If the amino acid ester of Liao is the starting material, the ester is further hydrolyzed to provide the carboxylic acid. Or by using amino acid 11 (in the form of a free carboxylic acid or a carboxylic acid vinegar) in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane and In the analog), the isocyanate 11CQ in the presence of a base and from about 1 Torr to about i 5 ^ molar equivalent is a cleavage group such as CM, Br or I, or a sulfonate such as methane sulfonate. The acid salt, trifluorosulfonate, p-toluenesulfonate, besylate and the like are reacted to convert it to urea. Alternatively, by means of an amino acid (in the form of a free carboxylic acid or a carboxylic acid ester) in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane and In the analog thereof, in the presence of a base (for example, NaH or potassium tributoxide and the like) in an amount of from about 1 Torr to about 4 moles, and from about 约 to about 约. 5 molar equivalents of amines or their N-protected derivatives (Q is a cleavage group, such as a, BntI, or a retinidate, such as a sulphate, a trifluorosulfonate, a pair The tosylate, the besylate and the like are reacted to convert it to the diamine u. If you use a protected ^^• protected organism, you need N-deprotection. The diamine is equivalent to the carbonyl group (for example, phosgene, a few groups of dimizone and its analogs, wherein Q, and Q) are excipients, such as CM, Br, Bu·〇·low carbon money base, (4) Or a (d) group and analogs thereof, in an inert solvent (for example, THF, dimethoxyethane, methyl tri-butyl, toluene or heptane and the like), from about 2 Torr to about 4 〇 Mo: the presence of the amount of the test (NaH or third potassium oxo and its analogs);

O:\106\106749.DOC -42- 200817349 The reaction carried out gave cyclourea I. If the amino acid ester of Liao is the starting material, the ester is hydrolyzed to provide the carboxylic acid I. Alternatively, as shown in Scheme IV, the compound jj_ (freely acid or • Wei l ® day (ie, low carbon number) can be used according to J. Am. Chem. Soc. 72, 2599 (1950) ) reacting with acrylonitrile to obtain an aminonitrile cluster. Alternatively, 21 may be provided by replacing acrylonitrile with 3" chloropropionitrile. The N-protection of the aminonitrile cluster is like the urethane (Rso is a lower alkyl or phenyl or haloalkyl (eg 2-chloroethyl, 2-◎ bromoethyl and the like) and the like , using standard conditions (eg, amine' with a suitably pure gasified formate (ClC(O)OR30, where R3 is a lower alkyl, phenyl, haloalkyl, and the like), Or in an inert solvent (such as water, THF and the like) - in inorganic tests (such as Na〇H, K0H, K2C03 and their analogues) or organic bases (such as alkylamines or dialkylamines and the like) The reaction in the presence of an analog thereof and the like) provides the compound j^. 19 in the presence of a catalyst (such as Ni-Al alloy (alkaline) or bismuth (neutral or basic) or 扒〇2 (acidic) and its analogs) in an inert solvent (such as water or Hydrogenation in methanol or ethylene glycol or THF and its analogs provides cyclic urea over. 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, at a level of from about 1 Torr to about 5 moles. The compound is hydrogenated to provide cyclic urea in the presence of a test such as KOH or NaOH or LiOH or an organic amine test and the like. If the amino acid ester of II is the starting material, the ester is then hydrolyzed to provide the carboxylic acid u. Alternatively, the diamine provided by the hydrogenation of the compound (as described above for the compound O. chinensis) is converted to the compound 如同 as previously described. If the amino acid of II is a starting material, the ester is hydrolyzed to provide the carboxylic acid i oxime. O:\106\106749.DOC -43- 200817349 Plan i

Ο

O:\106\106749.DOC

5

-44- 200817349

Plan IIA

Rs

O:\106\106749.DOC -45- 6 200817349

Plan IIB

O:\106\106749.DOC -46- 6 200817349

Plan III Ο

RMO(0)C-HN

O:\106\106749.DOC -47- 200817349 Plan ιν

I钊I V

Nh2 co2h co2h

R3 15

o r3 10 A key intermediate for the preparation of the compounds of the invention, comprising a compound of formula III and a compound of formula IV as described above:

O:\106\106749.DOC -48- 200817349 or a salt thereof, wherein Ρ3 and Ρ4 are respectively selected from hydrogen or oxime-protecting group; and R i and R 2 are respectively selected from the group consisting of a low carbon number group and a cycloalkyl group. And an aryl group; R3 is a lower alkyl group, a hydroxyalkyl group or a cycloalkylalkyl group; and R5 is

Ο

e) (CH2W O:\106\106749.DOC -49- 200817349

\Λ vr ^n-r6 i) where n is 1, 2 or 3, m is 1, 2 or 3, m is 1 or 2, X is 〇, S or NH ' Y is _Ch2-, -〇- , -s- or -N(R6)_, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, γ" is _Ch2_ or -N(R0 "), wherein R6" is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y, is -Ν(Ιν)-, wherein & is hydrogen, A compound having a lower carbon number, a cycloalkyl group, a (iv) group, an aryl group or a aryl group, and 2 is preferably a ruthenium, 8 or NH oxime, wherein Ρ#Ρ4 is hydrogen or Henry, and R#R2 is aryl. Hyun base, I is a low carbon number alkyl group, and 5 is

O:\106\106749.DOC -50- X 200817349 , person \ / (CH2)n^

X

Wherein X, Y, Y', Y", Z, R6n, η, m and m' are as defined above for the compound of formula IV. More preferred compounds are those wherein 1^ and 112 and thiol, or the heart is 芊The base 112 is a lower alkyl group, R3 is a lower alkyl group, and R5 is O:\106\106749.DOC -51 - 200817349 Ο

And Y is -CH2 or -NH-,

b) where η is 1 or 2 and X is Ο or S,

Where m' is 1, X is 0, Z is 〇 and γ is _NH

X

A compound of formula IV wherein X is deuterium and RV' is hydrogen. Further preferred compounds are those wherein R] and R2 and benzyl, or the core is fluorenyl and R is isopropyl, R3 is lower alkyl, and R5 is O:\106\106749.DOC -52- 200817349 ,Λ(CH2)n^ a)

Where η is 1 or 2, X is 0 or S, and γ is -ch2 or -NH-, X(CH2)m b) Ο where m is 1 or 2, X is 0, Y is -CH2- and Z is Ο

c) where is 1, X is Ο, Z is 〇 and γ is -NH-,

Y,· (CH2)m· \ d) where m' is Bu X is Ο, Y" is -NH- and Y,4-NH-, or

A compound of formula IV wherein X is deuterium and R6" is hydrogen. The most preferred compound is 11 and R2 and benzyl, or 1 is an indenyl group and R2 is an isopropyl group, R3 is a lower alkyl group, and R5 is O:\106\106749.DOC-53-

X 200817349

a) where η is 1 or 2, X is Ο or S, and Υ is ·ί:Η2 or -ΝΗ-,

Where is 1, X is 〇, Ζ is Ο and Υ is -ΝΗ-,

X

Where m' is 1, X is ο, Υ" is -ΝΗ- and Υ, is -ΝΗ-, or Ο d)

X

Or a compound of formula IV wherein Ri is fluorenyl and 112 wherein X is deuterium and R6" is hydrogen. The most preferred compounds are those wherein R1 and R2 are aryl, isopropyl, R3 is lower alkyl, and R5 for

Wherein η is 1 or 2, X is hydrazine or S, and Y is -CH2 or a compound of formula IV. O:\106\106749.DOC -54- 200817349 The salt is an organic salt, especially #(8)-pyroglutamine. A preferred acid salt of the compound of formula IV. [Embodiment] Further examples of the preparation of the present invention are provided by the following examples. " Example 1 Ethyl)amino-3-hydroxy-propenyl]amino-1,6-diphenylanthracene (2S,3S,5SH2,6-dimethylphenoxy-5-[28- (1-Mini-salt_2__yl)_3_methylethaneΑ·Ν,Ν-subunit_(L)-Phenylalanine is intended to contain L_phenylalanine (10) kg '975 Mo Ear), a solution of potassium carbonate (445 kg '3220 mol), water (675 liters), ethanol (10 liters) and word base chlorine (4) 5 kg, 3275 mol), heated to 卯 5 〇 1 〇 _ 24 hours . The reaction mixture was cooled to 6 Torr: and the aqueous layer below was removed. Heptane (850 liters) and water (385 liters) were added to the organics, stirred and separated. The organics were then rinsed once with a water/methanol mixture (150 liters / 15 liters liters). 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, 305 0, 3 03 0, 1730, 1495, 145 0,1160 cm NMR (300 MHz, CDC13) 5 7·5-7·0 (m, 20H), 5.3 (d5 1H , J = 13.5 Hz), 5·2 (d, 1H, J = 13.5 Hz), 4.0 (d5 2H, J = 15 Hz), 3_8 (t, 2H, J = 8.4 Hz), 3·6 (d, 2H, J=15 Hz), 3.2 (dd, lH, J = 8.4, 14 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- 200817349 126.2, 66.0, 62.3, 54.3, 35·6. [〇: ]d -79〇(c = 〇·9, DMF). Β·(4S)-4-(N,N-Diamylamino)_3_oxo-5-phenyl-pentanenitrile under nitrogen, will be contained in 520 ml of tetrahydrofuran and 42 ml of acetonitrile. The product (ie: ^) (about (10) Moer> solution cold _ to -40 C. The second solution in a 850 ml tetrazole containing amination of sodium (4) knife, 1.25 m) cooling To -4 〇 it. Slowly add 75 ml of acetonitrile to the sodium azide solution and stir the resulting solution for 15 minutes at _4 (rc). Then slowly add the azide/acetonitrile solution to benzyl at -40 °C. In the ester solution, stir the mixed solution at -40 C for an hour, then stop it with 255〇ml of 25% (body weight/body weight) citric acid solution. Allow the resulting slurry to warm to ambient temperature' The organic matter was separated, and then the organic matter was washed with 35 ml of a 25% (w/v) sodium chloride solution, and further diluted with 9 ml of heptane, and then chlorinated with 900 ml of 5% (w/v). The organic solution was washed three times with sodium solution, washed twice with 900 ml of a 1 M aqueous solution of methanol, rinsed once with 9 ml of a 15% methanol aqueous solution, and then rinsed with 900 ml of a 20% aqueous methanol solution. Once, the organic matter was dried and the resulting material was dissolved in 7 ml of hot ethanol. When cooled at room temperature, the desired product precipitated. Filtration gave the desired product from L-phenylpropylamine. The yield in acid is 59%. IR (CHCl3) 3090, 3 05 0, 3 03 0, 22 5 0, 173 5,1600, 1490,1450,1370,1300,1215 cm-1,4 NMR (CDC13) 5 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, 10·5 0 Hz), 3.2 (dd, 1H, J = ΐ〇·5, 13·5 Hz), 3·〇 (dd, 1H, J = 4.0, O:\106\106749.DOC -56- 200817349 13.5^^), 3.0 (d, 1Η, J= 19.5#^}j 13c NMr (3〇〇^#, CDCl3) <5 197.0, 138.4, 138 〇, l29 5, i29 〇, i28 8 128.6,127.8, 126.4,68.6, 54.8, 30.0, 28.4 〇[ a ]D -96»(c = 〇_5, DMF). c. (5S)-2-Amino-5·(Ν,Ν-dibenzylamino)_4_oxodiphenylhexene- 2-sparse

Add the gasification word base (378 kg 'in Dingshao 2Μ, 7〇8 mol) to -5 C, in nitrile product (9 〇 kg, 244 mol) of the example (3) in tetrahydrofuran (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 rinsed with 1% sodium sulphate (235 kg) and the solid was dried. The product was again dried from ethanol (289 liters) and then dissolved in acetonitrile (58 1 liter) at 80 °C. After cooling to room temperature, the mixture was stirred for 12 hours. The resulting product was transferred and dehydrated in a vacuum oven at 3 ° C to give about 95 kg of the desired product. Melting point ιοί]〇21,IR (CDC13) 3630, 3500, 3 1 10, 3060, 3030, 2230,1620,1595, 1520, 1495, 1450 cm·\ 4 NMR (300 MHz, CDC13) d 9.8 (br s , 1H), 7.2 (m, 20H), 5·1 (s, 1H), 4.9 (br s5 1H) 5 3·8 (d, 2H, J = 14.7 Hz), 3.6 (d, 2H, J =14.7) Hertz), 3.5 (m, 3H), 3.2 (dd, 1H, J = 7.5, 14.4 Hz), 3.0 (dd5 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- 200817349 [α ]D -147. (c = 0.5, 125.6, 96.9, 66.5, 54.3, 42·3, 32·4 DMF) 〇-2-(N,N-dibenzylamino)_3_ hydroxy",^2D· (2S,3S,5S -5-Aminophenylhexanone 0 will be cooled in a suspension of tetrahydrofuran (157 gram of sodium citrate (6.6 kg, 175 m)) below Ρ Ρ to below 〇 ± 5C Slowly add 甲烷 methanesulfonate • u • A, 433 mol)' and maintain the temperature at 0 during the addition - below... Once the addition is done, 'slowly water (6 liters, 333 servants) The solution of the product of Example 1C (20 kg, 43 mol u, Wu Dou) and tetrafurfuran (6 1 liter)

The liquid is added ' while maintaining the temperature in the enthalpy during the addition. 〇The following. The mixture was mixed at 0 ± 5 C for at least 9 hours. > ϋ) In a separate flask, sodium borohydride (6 6 kg, 175 mol) and tetrahydroanthracene were added. South (157 liters). After cooling to _5 ± 5 t, triacetate (24.8 kg, 218 mol) was added while maintaining the temperature at 15. 〇The following. The solution is stirred at 15 ± 5 ° C, and then added to the reaction mixture obtained in the step ,, keeping the temperature below 2 (rc.) at 2 〇 ± 5 搅拌 under stirring until the reaction is completed. The solution was cooled to 丨〇 ± 5 < t and quenched with 3 n Na 〇 H (195 kg). After stirring with the third butyl butyl ether (162 liters), the organic layer was separated and Rinse 5 NaOH (200 kg) once, rinse once with 20% w/v aqueous ammonium chloride (195 kg), and rinse twice with 25% aqueous sodium chloride (160 kg). Dry the organics to give an oil. For the desired product, use it directly in the next step. IR (CHC13) 35 10, 3400, 3 1 10, 3060, 3030, 1630, cm · ι

1H NMR (300 megahertz, CDCl3) 5 7·2 (m5 20H), 4.1 (d2H O:\106\106749.DOC -58- 200817349 J = 13.5 Hz),, 3.65 (m, 1H), 3.5 ( d, 2H, J = 13.5 Hz), 3·1 (m, 2H), 2.8 (m, 1H), 2.65 (m5 3H), 1.55 (m, 1H), 1.30 (m, 1H), 13CNMR (3 00) Megahertz, CDC13) (5 140·8, 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· (28,38,58)_2-(]>^-dibenzylamino)-3-hydroxy-5-(tris-butoxymethylamino)-1,6-diphenyl Base burned BOC anhydride (65 kg '373 m) and 1% potassium carbonate (550 kg) were added to MTBE (1096 liters) [2 8,3 8,5 8]-2-team 1 a solution of benzylamino-3-hydroxy-5-aminodiphenylhexane (about 5 kg, 226 mol). Stir the mixture until the reaction is complete (about 1 hour). Remove the bottom layer and use water. (665 liters) of organic matter was washed. The solution was then dried to give the desired product as an oil. 300 Hz -1,4 NMR (CDC13) 1.4 s (s, 9H), 1.58 (s, 2H), 2.45- 2.85 (m, 4 H), 3.05 (m5 1H), 3·38 (d, 2Η), 3·6 (m, 1Η), 3·79 (m, 1Η), 3·87 (d, 2Η), 4.35 (s, 1H) ), 4.85 (s, broad, 1H), 7.0-7.38 (m, 20H). Fl·(2S,3S,5S)_2_Amino-3-transyl-5-(tris-butoxy [2S53S,5S]-2-N,N-diamidino-3-hydroxy-5-third, amino)-l,6-diphenylhexane under stirring in methanol (350 ml) · A solution of butoxycarbonylamino-L6-diphenylhexane (12 g '21.3 mmol) into ammonium formate (8 〇 5 g, us mmol, 6.0 eq.) and 10% palladium on carbon (2.4 g). Stir the solution for 3 hours under rc and nitrogen, then at 751 for 12 hours. Add additional ammonium formate (6 g) and 1 〇❹. palladium on carbon (1·5) g), and 1 ml of glacial acetic acid.

O:\106\106749.DOC -59- 200817349

The return machine was completed within 2 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite. The filter cake was rinsed with decyl alcohol (75 mL) and the combined filtrate was concentrated under reduced pressure. The residue was taken up in 1N EtOAc (3 mL) and taken to dichloromethane. • Rinse the mixed organic layer with brine (250 mL) and dehydrate with 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% methanol in dichloromethane) can be accomplished by flash chromatography. 300 megahertz lHNMMCDCl3) 5 (1)), 1.70 (m, 1H), 2 2 〇 (s, wide, 2H), 厶 52 (10), called, 2.76-2.95 (m, 4H) 5 3 5 〇 (m, 1H ), 3 95 (m, 1H), 4 8 〇 (4) wide, 1H), 7·15-7·30 (m, 10H). F_2·(2S,3S,5S)-2-amino-3-hydroxy-5-tris-butoxycarbonylamino•1,6-diphenylhexane succinate 5% palladium on carbon (24 kg A methanol-based slurry (285 ml) was added to [28,38,58]-2&quot; in the methanol (437 liters), and the dibenzylamino-3-hydroxy-5-tris-butoxycarbonylamine • Diphenyl hexane (approx. 127 kg, 225 mol) • In solution. A solution of ammonium citrate (84 liters, 1332 moles) in methanol (361 liters) was added thereto. The solution was heated to 75 ° C for 6-12 hours and then cooled to /JHL and mixed from the reaction using a filter paper coated with a filter aid (diatomaceous earth). The solid was filtered and the methanol was removed from the reaction mixture using heat and vacuum (up to 7 Torr.). The residue was dissolved in isopropyl acetate (44 〇〇g), heated (40 C) and then Rinse with 10% sodium carbonate solution (725 kg) and finally with water (665 liters). Both rinse steps were carried out under 4 Torr and the product of O:\106\106749.DOC •60· 200817349 was stored in In solution, use heat (up to 7 (rc) to remove solvent in vacuum. Then add isopropanol (475 liters) and strip to remove residual solvent. Add isopropanol (1200 liters) to the residue And stirring until it is homogenized. A solution of succinic acid (15_4 〇 kg) in isopropanol (12 liters liter) is added to the solution. The solution sleeve is heated to 70 〇c for dissolution. All the solids were then allowed to cool slowly to room temperature and stirred for 6 hours. Then the solution was filtered to give the desired product as a white solid (55-80 kg). Melting point: 145-146 ° C. 4 NMR: (Me2SO-d6, 300 MHz) (5 0.97 (d, 3H, IPA), 1.2 0 (s5 9H),1·57 (t,2H), 2.20 (s,2H,succinic acid), 2·55 (m,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 (m5 10H) 〇HNMR (CD3OD, 300 megabytes) Hertz) (51·11 (d, 3H, J = 7 Hz, IPA), 1.29 (s5 9H), 1·70 (m, 2H), 2.47 (s5 2H, broken (five) acid) 5 2.65 (m5 2H), 2.85 (m, 2H), 3.22 (m, 1H), 3·64 (m, 1H), 3.84 (m, 1H), 7.05-7.35 (m, 10H). G· 2,6-xyleneoxyacetic acid The ethyl ester was added to ethyl acetate (18.2 ml, 164 mmol) and cesium carbonate (58 g, 176 amol) to 2 in dioxane (600 ml), and bisphenol (8 〇)克, 6 6 I Mo) in the trough solution. The reaction mixture was heated to reflux for 18 h, cooled to room temperature, filtered and concentrated in vacuo. Purified by column chromatography (5% to 20) % diethyl ether in hexane) to give the desired compound (8 〇〇 / 〇). 300 megahertz bNMMCDCh) 5 1.35 (t, J == 7.5 Hz), 2·30 (s, 6 Η) 5 4.31 ( Q5 J = 7.5 Hz, 2 Η), 4.40 (s, 2 Η) 5 7.0 (m, 3Η). O:\106\106749.DOC -61 - 200817349 Η· 2,6-diphenoxyacetic acid 5.3 g of lithium hydroxide was added to methanol (17 〇 ml) and water (56 house) at 〇 ° C </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was acidified with EtOAc (EtOAc) (EtOAc) The organic layer was dried and concentrated to give a white solid (4 EtOAc, EtOAc). 300 MHz 4 NMR (CDC13) 5 2.30 (s, 6Η), 4.48 (s, 2Η) 7.0 (m, 3H) 〇I· (2S'3S, 5S)_2_(2,6-diphenoxy B Amidinosylamino-3-carbamoyl-tert-oxycarbonylaminodiphenylhexane The amine from the example if was coupled with the acid from Example 1H using a standard EDAC coupling procedure to give the desired Compound (78%). 3 〇〇 MHz Hz H nmr (CDC13) (J 1.40 (s5 9H) 5 1.65 (m? 3H) 5 2.18 (s5 6H), 2.78 (m, 2H), 2.98 (d, J = 9 Hz, 2H) , 3.75 (m, 1H), 3.90 (m5 1H), 4.15 (m, 1H), 4.20 (s, 2H), 4.60 (m, 1H), 7.0 (m, 3H), 7.25 (m, 10H). :(M=H)+ = 547. J· 2-...(Ethyloxy)amino-Ethylene 1.34 ml of oxalic acid chloride was added dropwise at -78 ° C to 1.45 ml of 20 ml CH2C12 In a solution of DMSO. After 15 minutes at -78 ° C, a solution of N-Cbz-aminoethanol in 40 ml CH ^ CU was added. At -78 ° C for 15 min and 0 ° C for 2 min. Thereafter, the solution was cooled to -78 ° C, and diethylamine (6 · 14 Torr: liter) was added dropwise. The solution was stirred at -78 ° C for 30 minutes, and poured into 50 liters of ice cold. The mixture was extracted with 1% hydr. Concentration in vacuo. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (CDCI3) δ 4.17 (d, J = 6 Hz, 2 Η), 5·15 (s' 2Η)' 5·40 (br s, ιη), 7·36 (m, 5 Η), 9.66 (s ,1Η). Mass Spectrum: (Μ+ΝΗ4)+ = 211. Κ· Ν-(芊 芊 methoxycarbonylaminoethyl methionine methyl methionate hydrogenate (0·72 g, 4·29 毫Mole), sodium acetate (〇.7^g, 8.58耄mol) and cyanosilver hydride (0.54g, 8.58mmol) to the aldehyde in the sample · 829 g, 4.29 mmoles. The mixture was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (1 mL) and sat. The mixture was washed with EtOAc (EtOAc) (EtOAc) (EtOAc) The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) = 3 Hz, 3H), 0.94 (d, J = 3 Hz, 3H), ΐ·9〇(m,1H), 2.55 (m, 1H), 2.80 (m,1H), 2.98 (d, J = 6 Hz, 1H), 3·20 (m, m), 3 3 〇(m,1H), 3 7l (s, 3H), 5·1〇(s, 2H), 5 27 (br s, m), 7 37 (m, 5H). Mass Spectrometry···(M+H)+ - 309 〇L· 2S-(1-Micyridone-based methylbutanoic acid methyl ester removes Cbz-protection of the compound in the example by hydrogenolysis, and The crude product is treated with carbonyl diimidazole in equivalent to CH2C12 to give the desired compound (64o/o), 300 Hz. HNMR (CDCl3) (5 0·95 (d)

O:\106\106749.DOC -63- 200817349 J = 7·5 Hz), 〇·98 (d5 J = 7·5 Hz, 3H), 2.15 (m, 1 Η), 3·47 (m, 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)+ = 201. Μ· 2S-(1·imidazolidin-2-one)-3-mercaptobutyric acid Add lithium hydroxide monohydrate (20 equivalents) to 2·5 ml of water and 5 liters of liter at 0 C In the solution of the compound of Example 1L (151 mg, 0.75 mmol) in oxyhexacyclohexane. Here. The solution was stirred under stirring for 15 hours and at room temperature for 1 hour. Acidified with IN HC1 to Et0Ac (1 〇〇 ml + 2 χ 5 〇

</ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 3 〇〇 megahertz NMR (DMSO-d6) 5 0·85 (d5 J = 12 Hz, 3H), 0.92 (d, J = 12 Hz, 3H), 2·〇5 (m, 1H), 3.25 ( m, 2H), 3.30 (m, 1H) 5 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·(28,38,58)-2-(2,6-dioxaphenoxyethyl)amino-3-hydroxy-5-amino-1,6-diphenylhexyl in 4.5 g Self-contained in the compound of π. Add 40 ml each of trifluoroacetic acid. The solution was left at room temperature for j hours. The solution was concentrated in vacuo to give the desired compound (100%). 3 〇〇 megahertz lH nmr (CDCl3) 5 1.48 (m? 1H)? 1.62 (m5 1H)5 2.05 (m? m)5 2.24 (s? 6H)5 2.50 (m,1H), 2.80 (m,1H ),3·0·3·10 (m,4H), 3.90 (d, J = 10 Hz, 1H), 4.17 (m5 1H), 4.26 (ABq, J is 3·5 Hz, 2H), 7.0 (m , 3H), 7.10 (m, 2H), 7.30 (m, 7H) 5 7.41 (d5 J = 10 Hz, 1H). Mass spectrum: (m+H)+ = 447. O:\106\106749.DOC -64- 200817349 22 A2)·2# xylyleneoxyethyl)amino-3-carbyl hexane 'H2-residue) winter methyl-butyl aryl Amino-M-diphenyl

J was coupled to the desired compound (80) from the amine compound of Example 1N using a standard coupling procedure [aminopropyl in DMF]. %). 300 dead Hertz 4 NMR (CDC13) (5 0.83 (d5 J = 3H)? 0.86 (d? J = 6Hj 3H)5 Ο (m? 2h)5 2.16 (m? iH)? 2.18 (s5 6H)5 2.76 ( m? 2H)5 2.97 (d, J = 7.5 Hz, 2H), 3"4 (m, 2H), 3.30 (m, 2H), 3.70 (d, J = Buchs, 1H), 3.75 (m , ih), 4.20 (m, 4H), 4·50 (br s, 1H), 6·7〇 (d, J = 7.5 Hz, 1H), 7·〇(m, 3H), 7 25 (m, 1〇H). Mass Spectrum: (M+H)+ = 615. Example 2 (2S,3S,5S)-2-(2,6-Methyloxyethyl)amino-3-hydroxy-5- [2S-(l-tetrahydropyrimidine_2-ketomethylbutanyl)amine β1,6-diphenyl Q- hexane A· 2S-(1_tetrahydro, acyl-2-keto)-3- Methyl butyric acid • The procedure described in Examples 11 to 1M was used, but N-Cbz-aminoethanol in Example 1J was replaced with N-Cbz-3-aminopropanol to give the desired compound. 300 MHz Towel NMR (DMSO-d3) 5 0·82 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H), 1.77 (m, 2H), 2.10 (m, 1H) 5 3.10- 3.23 (m5 4H), 4.42 (d, J = 10.5 Hz, 1H), 6.37 (br s5 1H). Mass spectrum: (M+H)+ = 201. Β· (28,38,58)-2- (2,6-xyloxyethenyl) Benzyl-3-hydroxy OA106\106749.DOC -65- 200817349 5 [2S-(1-tetrahydro-n-nose 2-keto)-3-methylbutenyl]amine _^,6-diphenylhexanone utilization The standard procedure (EDAC in DMF) was such that the amine compound from Example 1N was coupled with the acid from Example 2A to give the desired compound (7 %). 3 赫 赫 赫 赫 赫 赫 赫 赫 赫 赫 赫 赫(d, J ==4 5#|S 3H), 〇·83 (d, J = 4.5 Hz, 3H), 1·50 (m, 1H), 1.65-1.72 (m, 6H), 2.2 〇 (s ,6H),2·68 (m,1H),2.82 (m,2H)5 3·〇(d,j = 7.5 Hz, Η), 3·〇5 (m,4H), 3.77 (s, Ih), 4.07 (d, J = 4.5 Hz, 1H), 4·2 〇 (m, 4H), 4.50 (br s, 1H), 6.78 (br d, 1H), 7.0 (m, 3H), 7· 25 (m, lOH). Mass Spectrum: (M+H)+ = 629. Example 3 Xylyloxyethyl)amino-3_carbamic-5-[2S-(3-oxazolidin-2-one)-3-methylbutanyl]aminodiphenylhexane A· 2S-(3-oxazolidine-2-one)-3-methylbutyric acid methyl hydrazine in a solution of hydrazine hydrazide hydrochloride (7.6 mmol), added to ethanol A solution of ethylene oxide (1.5 equivalents). The solution was maintained under it for 0.5 hours and then at room temperature for 18 hours at which time 0. 01 equivalents of BF3·EhO were 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 taken in EtOAc and cooled to EtOAc. To this solution was added 12 equivalents of triethylamine and 1 〇 ϊ ϊ diphosgene. After 1 hour, the solvent was removed in vacuo and the residue was washed with water (30 ml), and extracted with &lt;3&gt; (3 χ 5 mM), dehydrated and concentrated. The crude product was obtained by hydrazine column chromatography (5% EtOAc / EtOAc (EtOAc): EtOAc: EtOAc: Hertz 1h NMR (CDC13) 6 〇·98 (d, J = 4.0 Hz, 3H), 1.0 (d, J = 4·〇 Hertz, 3H), 2·16 (m, 1H), 3.60 (m, 2H) ,3·73 (s,3H),4·20 (d, • J = 10 Hz, m), 4·37 (m5 2H), mass spectrum: (m+H)+ = 202. Β· 2S-(3 -oxazolidin-2-one)-3-methyl-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 NMR (DMSO- Dj 6 0.90 q (d, J = 6 Hz, 3H), 〇·95 (d, J = 6 Hz, 3H), 2.1 (m, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 3.88 (d, J = 9 Hz, 1H), 4.30 (m5 2H), 13.0 (br, s5 1H). Mass spectrum: (M+NH4)+ = 205. C· (28,38,58)-2-( 2,6-xyloxyethenyl)amino-3-3-hydroxy-5-[2S-(3-oxazolidin-2-one)-3-indolylbutanyl]amino-16-diphenyl The hexane was coupled with the acid from Example 3B using a standard coupling procedure (EDAC in DMF). To the desired compound. 300 megahertz q !H NMR (CDC13) accounted for 0.83 (d, J = 4.5 Hz, 3H), 〇·87 (d5 J = 4·5 Hz, 3H), 1.75 (m, 1H) , 2· 10 (m, 1H), 2.20 (s, 6H), 2.65 (m5 1H) 5 2.85 (m, 1H), 3.0 (m5 3H), 3.30 (m5 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). Mass Spectrum: (M +H)+ = 616. Example 4 (28,38,58)_2_[(311,338,6311)_bis-tetrahydrofuranyloxy]amino-3-hydroxy-5-[2S-(3-indolyl- 1-Imidazolidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexan O:\106\106749.DOC -67- 200817349 A· 2S-(3-methyl Methyl-1-pyrazin-2-one-3-methylbutanoate 150 mg of the compound from Example 1L in 4.5 ml of DMF was added to 45 mg in 0.5 ml of DMF (60 % oil dispersion) in sodium hydride suspension. At room temperature for 20 minutes, (1.5 equivalents, 0.07 ml) of methyl iodide was added. The reaction was completed in 1 hour. The reaction was quenched with saturated aq. EtOAc (EtOAc) (EtOAc) The crude product was purified by EtOAc EtOAc (EtOAc) 300 CI . megahertz 4 NMR (CDC13) δ 0·95 (d, J = 6 Hz, 3 Η), 0·97 (d, J = 6 Hz, 3H), 2.15 (m, 1H), 2.80 (s, 3H), 3.32 (m, 3H) 5 3.60 (m, 1H), 3.70 (s5 3H), 4.25 (d, J = 10.5 Hz, 1H). Mass spectrometry: (M+H)+ = 215 〇Β· 2S-(3-methyl-1-miquid 2 keto)-3-methylbutyric acid using the procedure described in Example 1M, Hydrolysis of the methyl ester from Example 4A gave the desired compound. 300 MHz NMR (DMSO-d6) 5 Q 0·85 (d, J = 6 Hz, 3H) 5 0.92 (d, J = ό Hertz, 3H), 2·05 (m, 1H), 2·65 ( s, 3H), 3·25 (m, 3H), 3·42 (m, 1H), 3.90 (d, J = 10 Hz, 1H). Mass spectrum: (M+H)+ = 201. C·(3R,3aS,6aR)-bis-tetrahydrofuro drink_(4_nitrophenyl) acid salt, diethylamine (0.263⁄4 liter, 1.85 millimolar) and chloroantimonic acid Phenyl ester (341 mg ' 1.69 mmol) was added to 3R-hydroxy-(3aS,6aR)-bis-tetrahydrofuran in 1 mL of ch2c12 [j· Med chem 37, 2506-2508 (1994)] (2003⁄4) Gram, 1.54 millimoles) in solution. The solution was kept at room temperature for 3 days, diluted with CH.sub.2Cl.sub.2 (100 mL) and washed with sat. NaHC.sub.3::::::::::::::: The organic layer was dehydrated and concentrated in vacuo. Purification by silica gel column chromatography 5% EtOAc/EtOAc (EtOAc) 300 MHz iH NMR (CDC13) 5 2.0 (m?l H)? 2.20 • (m? 1H)5 3.18 (m5 1H), 4.0 (m? 3H)? 4.17 (m? iH)5 5.27 (m5

1H), 5·80 (d5 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-[(311,3, 631〇-bis-tetrahydrofuranyloxy)amine^-3-hydroxy 4-(tri-butoxycarbonyl)amino- 1,6-Diphenylhexane The compound from Example 1F (130 mg, 0.34 mmol) was added to the carbonate from Example 4C in 3.4 mL of DMF (1 mg, 〇·34) In a solution of millimolar). The solution was kept at room temperature overnight and then concentrated in vacuo. The crude product was purified by column chromatography (2% to 5% MeOH/CH2C12) to give desired Compound (93%). 300 MHz NMR (CDC13) δ 1·4 〇 (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 (m5 10H). Mass Spectrum: (M+NH4)+ = 558 〇Ε·(2S,3S,5S)-2-[(3R,3aS,6aR)-bis-tetrahydrofluorenyloxy]amino-3-hydroxy-5-amino-1,6-diphenyl 5 ml of trifluoroacetic acid was added to a solution of the compound of Example 4D (170 mg, 0.31 mmol) from 5 ml of trifluoroacetic acid. After 25 hours, the solvent was removed in vacuo. The residue was dissolved in 1 mL of EtOAc and washed with EtOAc EtOAc EtOAc EtOAc EtOAc \106\106749.DOC -69- 200817349 1.27-1.60 (m,4H),1.75 (m5 2H), 2.47 (m,1H), 2.80 (m5 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, l〇H). Mass Spectrum: (M+H)+ = 441. F· (2S,3S,5S)-2-[(3R,3aS,6aR)-bis-tetrahydrofuranyloxy Amino-3-carbyl-5-[2S-(3-methyl-1-imidate-2-mercapto)-3-methylbutanyl]amino],6-diphenylhexane Standard coupling procedure (EDAC in DMF), from Example 4B

The C. I carboxylic acid was coupled with the amine compound from Example 4E to give the desired compound. 300 MHz ^ NMMCDCh) 5 0.82 (d, J = 3 Hz, 3H), 〇 · 85 (d, J = Hertz, 3H), 1.65 (m, 1H), 2 · 77 (s5 3H), 2.85 (m , 3H), 3.17 (m, 2H), 3.47 (m5 1H), 3.60 (m, 2H), 3.75 (m, 1H), 3.87 (m, 1H), 4.0 (m, 1H), 4.20 (m, 1H) ), 5.05 (m, 2H), 5.68 (d, J = 6 Hz, 1H), 6.45 (br d5 J = 7.5 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (m+H)+ = 623. 〇Example 5 (28,38,58)-2-[(31^,338,6纽11)-bis-tetrahydrofuranyloxy]amino-3-hydroxy-5_[2S-(1-imidazole pyridine_2_ Ketomethylmethylbutylidene]aminodiphenylhexanhydride The amine compound from Example 4E was coupled with the carboxylic acid from Example 1M using standard coupling procedures (EDAC/DMF) to afford the desired compound. 300 megahertz ^ NMMCDcw 5 〇.85 (d, J = 7 Hz, 311), 0.88 (d, J = Hertz, 3H), i 7 〇 (m, 2 Η), 2 18 (m, 1H), 2 8 〇(m,3Η), 2.95 (m,1Η), 3.20 (m,4Η), 3.60 (m5 3Η), 3.75 (m,2Η),4·0

O:\106\106749.DOC -70- 200817349 (m,1Η),4·20 (m,1Η),4·45 (s lm &lt; 1Λ ,

... (5 1H), 5·10 (m5 2H), 5·67 (d J

=6 Hz, 111), 6.60 ((1,:^75 (, J 铋, 1H), 7.20 (m, i〇H). Mass Spectrum: (M+H)+ = 609. 夕夕y 6 (2S ,3S,5S)-2-[(N_((( ^ 唆 ) ) ) ) ) ) ) ) ) ) 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 终 - - - - - - - - - 2-methylmercaptoacetate

Ο cooled to 0 ° C, equipped with the first = π, "potassium butoxide (0.5 m, 500 ml of 1 Μ solution in THF) and 500 亳 也, the three-neck 2 liter round bottom of the house liter of anhydrous THF In the flask, chlorinated ethyl acetate (0.5 mol, q ancient 53.53⁄4 liter) and ethyl formate (〇·5 mo) in 2 liters of THF were added dropwise from the addition of leakage + within 3 hours. A solution of the ear, 40.4 ml). After the addition was used as 6 ^ ^ ▲ 1 卞 70%, the reaction mixture was stirred for 1 hour' and allowed to stand overnight. The resulting solid was diluted with diethyl ether and in an ice bath. The mixture was cooled in. The pH was reduced to about 3 knives using 6NHCH, and the organic phase was separated, and the layer was washed three times with diethyl ether. The mixed ether was partially dehydrated with NaS 〇 4 and concentrated in vacuo. The compound was intended to be stored at -30 C and used without further purification. B. Odor-5-oleic acid ethyl ester was added to a round bottom flask with 250 ml of anhydrous acetone, 7.5 g (0·123 mol). Thiocarbamide and 18.54 g (0.123 mol) of 1 chloro-2-carboxylacetic acid B. The reaction was heated to reflux for 2 h. In addition to the solvent, the residue was purified by chromatography (SiO 2 , 6 cm 〇.d. column, 100% CHC13, Rf = 0.25) to give 6 g (60%) of pale yellow oil. NMR (CDCI3) 5 1.39 (t, J = 7 Hz, 3H), 4.38 (q, j = 7 O: \106\106749.DOC -71 - 200817349 Hz, 2H), 8.50 (s, 1H) , 8.95 (s, 1H) C. 5-(hydroxyindenyl)carbazole in a pre-cooled (ice bath), three-necked 500 containing lithium aluminum hydride (2.89 g, 76 mmol) in 250 ml of THF In a milliliter flask, ethyl phthalate-5-propionate (11.82 g, 7 5 · 6 8 houser) was added dropwise in 100 ml of THF over a period of 5 hours to avoid excessive foaming. Stirring the reaction For an additional 1 hour, carefully treat with 2.9 ml of water, 2.9 ml of 15% NaOH and 8.7 ml of water. Filter the solid salts and set the filtrate to one side. The crude salt was heated to reflux for 3 minutes. The resulting mixture was filtered and the two filtrates were combined, dried over Na 2 s 4 and concentrated in vacuo. The product was purified by chromatography. In Elution with 0%-2%-4% methanol in the imitation gave the desired compound, Rf _ 〇.3 (4° / 〇methanol in chloroform), which solidified upon standing, yield 75 〇 / 〇 nmR (CDC13) δ 4·92 (s, 2Η), 7.78 (s, 1Η), 8.77 (s, 1Η). Mass spectrometry: (Μ+Η)+ = 116° D·((5^塞zolyl)methyl)-4-(4-nitrophenyl)carbonate 3.11 g (27 m) in 100 ml of dichloromethane The solution of 5-(hydroxymethyl)p-serazole and excess hydrazinoline was cooled to 〇 and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After stirring for 1 hour, the reaction mixture was diluted with CHC13, successively washed with in HCl, saturated aqueous NaHC03, and saturated brine, dried over EtOAc, and concentrated in vacuo. The residue was purified by silica gel chromatography (Si </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; To produce products. NMR (CDC13) accounted for 5.53 (s, 2Η), O:\106\106749.DOC -72- 200817349 7·39 (dt, J = 9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt5) J = 9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ = 281. Ε·(2S,3S,5S)-5-Amino-2-(indolyl-((5-pyrazolyl)methoxycarbonyl)amino)-3-hydroxy-i,6-diphenylhexane From the procedure of Example 4D, the amine compound from Example 1F was coupled with the carbonate from Example 6D, followed by removal of the Boc-protecting group using tfA/CH2C12 to give the desired compound. 300 MHz NMR (CDC1J 5 ◎ m·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 q5 1H), 3.81 (br d5 J = 10 Hz, 1H), 5.28 (s, 2H), 5.34 (br d, J = 9 Hertz, 1H), 7.07 (br d, J = 7 Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s5 1H), 8.80 (s5 1H). Mass Spectrum: (M+H)+ = 426. F·(2S,3S,5S)-2-[(N-((5-carbazolyl)methoxycarbonyl)amino)_5_((2S-(1-imidazolidin-2-one)-3- Methyl butyl hydrazino)amino) hydroxy-1,6-diphenyl hexane oxime using a standard procedure (EDAC in DMF) to give the amide from Example 6E to the carboxylic acid of Example 1M Acid coupling 'to give the desired compound (52./〇). 300 MHz 丨HNMR(CDCl3) 5 〇82 (d,j = 75 Hz, 3H), 0.85 (d, J = 7.5 Hz, 3H), 1.65 (m, 2H), 2.15 (m, 1H), 1H), 3.30 (m, 2H); 3.60 (m5 3H)5 3.80 (m, 1H), 4.I6 (m, 1H), 4.4〇 (s , 1H), 5.16 (d, J = 9 Hz, 1H), 5.24 (s, 2H), 6 6 〇 (d, = 9 Hz, 1H), 7 2 〇 (m, 1 〇 H), 7 83 (s, 1H), 8 8 〇 (s. ie mass spectrum: (M+H) + = 594. O:\106\106749.DOC -73- 200817349 Example 7 (2S, 3S, 5S)-2-(N-((5-喽 篡 篡 λ m ^ U 哩 曱 曱 曱 曱 曱 曱 曱 羰 羰 -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- m m m m m m m m m m m m Amino-1,6-diphenylhexane A. 2S-(1- miso bite_2, yl)_3,3-dimethylbutyric acid using the procedure interpolated in the example umM, but with l • The third _butyl-leucine methyl ester instead of L-proline methyl ester &amp; T knows 'to obtain the desired compound. 300

MH Hertz NMR (DMSO-d6) ^ l rw nTT, 6) 0 !·〇(s? 9H), 3.22 (t5 J = 7.5 Hz, 2H), 3·55 (q, J = 7.5 Hz, 1H) , 3 65 (q,; = 7 5 Hz, 1H), 4·14 (s, 1H), 6_40 (s, 1H), 12 62 (br s, 1H). Mass Spectrum: (M+H)+ = 201 〇Β·(2S,3S,5S)-2-(N-((5-oxazolylmethoxycarbonyl)amino)hydroxy-5-(2 S-(l -imidin-2-one)-3,3-dimethylbutylidene)amino-j/•diphenylhexan

The amine compound from Example 6E was coupled with the carboxylic acid from Example 7A using standard procedures (EDAC in DMF) to afford the desired compound (77%). 300 MHz 1H NMR (CDCl3) 5l·0 (S59H), l·68(m, 2H)5 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 (d, J = 7.5 Hz, 1H), 5.25 (ABq, 1H), 6.50 (d, J = 7 Hz, 1H), 7.20 (m5 10H), 7.83 (s5 1H), 8.80 (s, 1H). Mass spectrum: (m+H)+ = 609. Example 8 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)- 3,3-Dimethylbutanyl)amine·^Bu 2 O:\106\106749.DOC -74- 200817349 Phenylhexane using standard procedure (ED AC in D MF) will be obtained from Example 1N The amine compound was coupled with the formic acid from Example 7 A to give the desired compound (80%). 300 MHz 1H NMR (CDC13) δ 1.0 (s5 9H)? 2.18 (s? 6H), 2·68 (m, 1H), 2·80 (m, 1H), 2.98 (m, 3H), 3.10 (m, 1H), 3.27 (q, J = 7 Hz, 1H), 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-methylbutanyl)amino-1,6-diphenylhexane A. 2S-(1-imidazolidin-2-sulfinyl)-3-methylbutyric acid is similar to that used in Example 1J The procedure described in 1M, but replacing 1,1-carbonyl-diimidazole with 1,1-thiocarbonyldiimidazole, gave the desired compound. 300 MHz NMR (DMSO-d6) 5 0.87 (d, J = 6 Hz, 3H), 0·96 (d, J = 6 Hz, 3H), 2.11 (m, 1H), 3·45 (m, 2H), 3.62 (m, 1H), 3·80 (q, 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_ylamino-5-(28-(1-weijun bite-2-sulfur Alkyl-1,6-diphenylhexane Amino-1,6-diphenylhexane The amino group compound from Example 1 was obtained from Example 9 using standard procedures (EDAC in DMF). The carboxylic acid was coupled to give the desired compound O: \106\106749.DOC -75 - 200817349 (53%). 300 MHz NMR (CDC13) 5 0·82 (d, J = 6 Hz, 3H), 0.93 (d, J = 6 Hz, 3H), 1.75 (m, 1H), 2.20 (s, 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 = Hz, ih), 3.78 (m, 1H) , 4·22 (m, 4H), 4·56 (d, J = 1〇·5 Hz, ih), 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-methylbutylidene)amino-1,6-diphenylhexane oxime · 2,6-dimethyl-4-nitrophenoxyacetic acid ethyl acetate slowly 50 ml of trifluoroacetic acid It was added to a solution of 10.5 g (54.63⁄4 mol) of 2,6-xyloxyacetic acid ethyl acetate 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 di- methane. 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 ethyl (2,6-dimethyl-4-nitrophenoxyacetate) as a pale yellow column. 300 MHz NMR (CDC13) 1 1.34 (3H, t, J = 7.5 Hz), 2·39 (6H, s) 5 4.3 1 (2H, q5 J = 7.5 Hz), 7·93 (2H, s ). Β·2,6-Dimethyl-4-nitrophenoxyacetic acid 1 ml of 3 Ν sodium hydroxide was added to 0.962 g of 10 ml methanol. O:\106\106749.DOC -76- 200817349 (4.06 House Moer) in a solution of 2,6• dimethyl + nitrophenoxyacetic acid ethyl acetate. After stirring the reaction mixture for 30 minutes at room temperature, acidify with 3 Ν HCl and distribute it between water and di-methane, rinse the mixed organic extract with brine and dehydrate with anhydrous sodium sulfate. Evaporate to dryness under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&gt;&gt; 300 MHz iH nmr (d3-DMSO) 5 2·35 (6H, s), 4.55 (2H, s), 7.97 (2H, s), 13·02 (1H, br). 0 C·(2S,3S,5S)-2-(Third-butoxy)amino-3-3-hydroxy-5-(2S-(l-imidazolidinone)-3(methylbutylidene)amino group 4,6-diphenylhexane using standard procedures (EDAC in DMF), (2S, 3S, 5S)-2-(third &quot;butoxy-Ik-based)amino-3-yl-5 -Amino-1,6-diphenylhexanone was coupled with a carboxylic acid from Example 1 to give the desired compound (%). 3〇〇 megahertz 4 NMR (CDC13) (5 〇·83 (d, J = 6 Hz, 3H), 0.87 (d, J = 6 Hz, 3H), 1·40 (s, 9H), 1.70 (m, 2H), 2.16 (m, 1H), 2.58-2.80 "I (m, 4H), 3·10-3·30 (m, 4H), 3.65 (m, 2H), 4.20 (m, 1H) , 4·38 (s, 1H), 4.83 (d, J = Hertz, 1H), 6.53 (d, J = 9 Hz, 1H), 7.20 (m, l〇H). Mass Spectrum: (M+H)+ = 553. D. (2S,3S,5S)-2-Amino-3-hydroxy-5-(2S-(l-imidazolidin-2-oneyl)-3-methylbutanyl)amino-1 6,6-Diphenylhexane The compound from Example 10C was removed from the Boc-protecting group by standard procedures (TFA/CH2C12) to give the desired product. 300 MHz NMR (CDC13) 5 〇·87 (d , J = 6 Hz, 3H), 0.90 (d, J = 6 Hz 5 3H) 5 1.33 (dd, J = 4.5, 9.0 Hz, 1H), 2.18 (m5 1H), 2·50 (m, O:\ 106\106749.DOC -77- 200817349 1H), 2.80 (m, 5H), 3.20 (m, 4H), 3·72 (d, Bu 1 〇 Hertz, 1H), 4·30 (m, 1H), 4.50 (s, 1H), 6.67 (d, j = 7 Hz, ΐΗ), 7·20 (m, 10H). Mass spectrum: (M+H)+ = 453. Ε· (2S,3S,5S)-2- (4-nitro-2,6-xylyleneoxyl) Mercapto)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-yl)decylbutenyl)aminodiphenylhexane is obtained using standard procedures (EDAC in DMF) Example The amine compound of 丨〇D was coupled with the carboxylic acid from Example 10B to give the desired compound. 300 ' megahertz 1H NMR (CDC13) occupies 0.83 0^ = 7 Hz, 3 Η), 〇·86 (d, J = 7 Hz, 3 Η), 1.70 (m, 3 Η), 2.18 (m, 2 Η), 2.28 (S, 6 Η), 2.75 (m, 3H), 2.95-3.3 0 (m, 6H), 3.67 (d, J=i〇.^||,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, l〇H), 7.92 (s, 2H). Mass spectrum: (M+H)+ = 660 o F·(2S,3S,5S)-2-(4-amino-2,6-xyloxyethoxy)amino p-3-hydroxy-5 -(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amino q,6-diphenylhexane A solution of 69 mg of the compound from Example 1 〇E was added to 7 mg of 10% Pd/C suspension in 5 ml of methanol. Intensively mix under hydrogen pressure • The reaction mixture (attach a hydrogen-filled balloon to the three-way stopcock). After the hour, the reaction was confirmed by TLC analysis; the catalyst was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by EtOAc (2% to 5% MeOH / CH.sub.2) to afford the desired compound (65%). 3〇〇 megahertz 1111^]^11 (CDC13) 6 0.82 (d, J = Hertz, 3H), 0.87 (d5 J = 6 Hz, O: \106\106749.DOC • 78- 200817349 3H), 1.70 ( m, 2H), 2·10 (s, 6H), 2.15 (m5 2H), 2·72 (m, 2H), 2·97 (d, J = 7.5 Hz, 2H), 3.08 (m5 1H), 3.15 (m, 1H), 3·3〇(m5 2H), 3.45 (br s, 2H)5 3.66 (d, J is called Hertz, ih), 3.72 (m, 1H), 3.90 (d, J = 3 Hz) ,1H),4·1〇-4·2〇(m,4H),4.30 (s, 1H)5 6.33 (s,2H),6.57 (d,J = 9 Hz, ih)5 7·20 (m , 10H). Mass spectrometer··(Μ+Η〇+ = 630 〇Example 11 (2S,3S,5S)-2-(2,4,6-Trimethyloxyethoxy)aminol--5-(2 S- (l-Imidazolidin-2-one)-3-methylbutanyl)amino-i,6-diphenylhexaneΑ·2,4,6-trimethyloxyacetic acid was obtained from Examples 1G and 1H. Procedure, but replacing 2,6-xylenol with 2,4,6-tricresol to give the desired compound. 300 MHz NMR (CDC13) 5 2·25 (s, 9H), 4.43 (s5 2H ), 6.84 (s, 2H). Mass Spectrum: (M+H)+ = 195 ° B· (28,38,58)_2-(2,4,6-trimethyloxyethoxy)amino-3 -Hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amino-1,6-diphenylhexane will be obtained using standard procedures (EDAC in DMF) The amine compound from Example 10D was coupled with the carboxylic acid from Example 11A to give the desired compound (51%). 300 MHz NMR (CDCI3) (5 〇.82 (d, J = 6 Hz 5 3H) , 〇·8 5 (d, J = 6 Hz, 3H), 1.70 (m, 4H), 2.13 (s, 6H), 2.25 (s, 3H), 2.75 (m5 2H), 2.97 (d5 J = 7 Hz, 1H), 3.13 (m, 2H), 3.28 (m, 2H), 3·68 (d, J = 10 Hz, ih), 3.72 (m5 1H), 4.16 O:\1 06\106749.DOC •79- 200817349 (m,4H), 4.40 (brS,1H), 6.67 (d,; = 8 Hz, m), 68 〇 (s, 2H), 7.20 (m, 10H). :(m+H)+ = 629. Example 12 (2s,3s,5s)-2-(4-Fluoro-2,6-xyloxyethoxymethyl)amino-3_hydroxy-5-(2S -(1-Imidazolidinone fluorenyl decyl)aminodiphenylhexane, A. 4-^-2,6-monodecyloxyacetate Ο Ο Using the procedures from Examples 1G and 1Η, but with 4_Fluoro-2,6-xylenol instead of 2,6-dimethyl hydrazine to give the desired compound. 3〇〇 megahertz 1h nmr (CD3CD) 5 2.26(S,6H), 4.37(s,2H ), 6 73 (d, j = 9 Hz, 2H). Mass Spectrum: M+ = 198. B. (2S,3S,5S)-2-(4,2,6-dioxaphenoxyethyl)amine The hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutenyl)aminophenylhexane will be obtained from the amine compound of Example 10D and the carboxylic acid couple from Example nA. Combine to get the desired compound. 300 MHz NMR (CD(:l3) 〇.S3 (d, Ι = 6#^53Η), 0.86 (d, J = 6# ^ } , Η), 1.72 (m, 2Η), 2.15 (s, 6Η), 2.2〇(m,1Η), 2.76 (m,2η), 2 % (d 】=7 Hz, 2Η), 3.12 (m, 2Η), 3.30 (m, 2Η), 3 67 (d, 】 =ι〇赫兹, 1Η), 3.72 (m,1Η), 4.13 (ABq, J = 8 9 Hz, 2Η), 4 2〇 (called 2Η), 4.37 (s,1Η),6·64 (d,J = 9 Hz, 1 Η), 6 7 〇 (4); = Hertz, 2 Η), 7.20 (m, 10 Η). Mass spectrum ··(Μ+Η)+ = 633. Example 13 (28,38,58)-2-(4,6-dimethyl-biting _5-oxyethyl)amino group _3_ via O:\106\106749.DOC -80- 200817349 -5-(2S-(l-imidin-2-one)-3-mercaptobutyl)amino-indole-6-diphenylhexaneΑ·4,6-dimethylpyrimidine-5 -oxyacetic acid 'utilizes the procedure from Examples 1G and 1H, but replaces 2,6 with 5-based _4,6-dimethyl-rhodium (according to Chem. Ben 93, page 1998, I960) _ 曱 曱 'Get the desired compound. 300 MHz iH NMR (DMS 〇 _d6) ^ 2.45 (s, 6H), 4.55 (s, 2H), 8.50 (s, 1H). Mass spectrum: μ+ = 1 83. 〇B·(2S,3S,5S)-2_(4,6-Dimethylpyrimidin-4-ethoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one) Base -3 -methylbutanyl)amino 4,^ Diphenylhexane The amine compound from Example 10D was coupled with the carboxylic acid from Example 13A to give the desired compound. 300 MHz NMR (CDC13) (5 0.82 (d, J = 6 Hz, 3H), 0.85 (d5 J = 6 Hz, 3H), 1·70 (m, 2 Η), 2.15 (m, 1 Η), 2· 40 (s,6Η), 2.75 (m,2Η), 2.97 (d, J = 7 Hz, 2H), 3.12 (m, 2H), 3.30 (m, 2H), 3.66 (d, J = 10 Hz, I ) 1H), 3·74 (m, 1H), 3.88 (d, J = Hertz, 1H), 4 2〇4H), 6.62 (d, J = 9 Hz, 1H), 7.0 (d, J = 9 Hz) , between 7.20 (m, 10H), 8.70 (s, 1H). Mass Spectrum: (M+H) + = 617. Example 14 (28, 38, 58) -2- (2, 4- dimethylpyridine _ 3-methoxyethyl)amino-3_hydroxy-5-(2S-(l-imidazolidin-2-one)-3,3-dimethylbutanyl)amino-i,6-diphenyl Hexane A·2.4-monomethyl p is a procedure derived from the examples 1G and 1H, but with 2,4-dimethylhydroxy O:\106\106749.DOC -81 - 200817349 leaves Bite (prepared according to J. Med. Chem. 35, page 3667-3671, 1992)

Instead of 2,6 - one, get the desired compound. 3 0〇 megahertz 1 η NMR (DMSO-d6) 5 2.26 (s, 3H), 2.42 (s, 3H), 4.44 (S, 2H), 7.08 (d, J = 5 Hz, ih), 8.07 (d, J = 5 Hz, 1H). Mass spectrometer··(m+h)+= 182 〇Β·(28,38,58)-2-(2,4-dimethylpyridin-3-oxethoxyethyl)amino-3-hydroxy (the first Tri-butoxycarbonyl)amino q,6-diphenylhexane The amine compound from Example i〇f was coupled with the carboxylic acid from Example 14A using standard procedures (EDAC in DMF). The compound you want. 3 〇〇 megahertz NMR (CDC13) ^ 1.40 (s, 9H), 1.70 (m, 2H), 2.18 (s, 3H), 2.40 (s, 3H), 2.77 (m, 2H), 2·98 (d5 J = 7 Hz, 2H), 3.75-3.95 (m, 3H), 4.20 (s, 2H), 4.22 (m, 1H), 4.60 (br d, 1H), 7.0 (d, J = 5 Hz, 1H) , 7.10 (m, 3H), 7.25 (m5 7H), 8.16 (d5 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 NMR (CDC13) (5 1 · 45 (m, 1H), 1.62 (m, 1H), 2.23 (s, 3H), 2·45 (s5 3H), 2.50 (m, 1H), 2.80 (m5 1H), 3.0 (m, 2H), 3.12 (m, 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) 5 7.30 (m5 8H), 8.17 (d, J = 5 Hz, 1H). Mass spectrum: (M+H)+ = 448. D · (28,38,58)-2-(2,4-Dimethylpyridin-3-yloxyethyl)amino group O:\106\106749.DOC -82 - 200817349 -3-carbyl-5 -(2S-(l- miso-2-mercapto)-3,3-dimercaptobutyl)amino-1,6-diphenylhexane using standard procedures (EDAC in DMF) The amine-based compound from Example 14C was coupled with the carboxylic acid from Example 7A to give the desired compound. 3 00 MHz NMR (CDC13) (5 1 · 〇 (s, 9H), 1.70 (m, 3H), 2.18 (s, 3H), 2.42 (s, 3H), 2.75 (m5 2H), 3·0 (m, 4H) 5 3.30 (m, 1H), 3.55 (m5 1H), 3.80 (m, 1H) ), 4·05 (s, 1H), 4.20 (m, 4H), 4.60 (s, 1H), 6.70 (d, J = 7 Hz, 1H), 6.97 (d, J = 5 Hz, 1H), 7 ·15 (m, 3H), 7.25 (m, 7H), 8 17 (d, J = Hertz, ih) Mass Spectrum (M+H) + = 630. Example 15 (28,38,58)-2-(2,4-Dimethylpyridin-3-yloxy B Mercapto)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)aminodiphenylhexane using standard procedures (EDAC in DMF) The amine ί I compound from Example 14C was coupled with the carboxylic acid from Example 1 to give the desired compound. 3 〇〇 mega red] H NMR (CDC13) 5 0.82 (d, J = Hertz, 3 Η) , 0.86 (d5 J = 6 Hz, 3H), 1.75 (m, 3H) 5 2.15 (m, 1H), 2.18 (s, 3H), 2.40 (s, 3H), 2.75 (m, 2H), 2.97 (d5 J = 7.5 Hz, 2H), 3.20 • (m, 4H), 3.70 (d5 J = 10 Hz, 1H), 3.75 (m, 1H), 4.20 (m, 6H), 4.52 (s5 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, l〇H), 8.17 (d, J = 4.5 Hz, 1H). Mass spectrum: (m+H)+ = 616. Example 16 O:\106\106749.DOC -83- 200817349 (28,38,58)-2_(2,6-dimethylthiophenoxyethyl)amino-3-3-hydroxy-5_(2S- (1-Imidazolidinone)_3_methylbutanyl)amino-1,6-diphenylhexane A. 2,6-Dimethylthiophenoxyacetic acid using procedures from Examples 1G and 1Η However, 2,6-xylenol was replaced by 2,6-dimethylthiophenol to obtain the desired compound. 300 MHz 4 NMR (CDC13) ά 2·56 (s, 6 Η), 3.40 (s, 2 Η), 7.10 (m, 3 Η). Mass spectrometry: M+ = 197 〇Β· (28,38,58)-2-(2,6-dimercaptothiophenoxy)amino-3-hydroxy-5-(2S-(l-imi) The carboxylic acid from Example 16A was coupled with the amine compound from Example 1〇13, arylidene-2-keto)-3-methylbutanyl)amino-; 1,6-diphenylhexane. The desired compound is obtained. 300 MHz iH NMR (CDC13) (5 0.82 (d5 J = Hertz, 3H), 〇 · 86 (d, J := 6 Hz, 3H), 2.15 (m, 1H), 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

Mass spectrum: (M+H)+ = 631. Example 17

It has been added to 30% CH2C12 Α· 臭 醯 醯 缬 缬 将 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,

O: \106\106749.DOC -84- 200817349 A solution of 1.08 g (8.4 mmol) of L-proline methyl ester was cooled to hydrazine. 〇 Then add gram (8.4 mmol) of 4 -> Smelly Stuff. The solution was mixed at 0 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 (EtOAc) 300 MHz 4 NMR (CDC13) (5 . 0·92 (d, J = 6 Hz, 3H), 0·96 (d, J = 6 Hz, 3H), 2.20 (m, p 3H), 2.46 (m, 2H), 3.50 (m, 2H), 3.76 (s, 3H), 4.58 (dd, J = 4.7 Hz, 1H), 5.97 (br d, J = 7 Hz, 1H). Mass Spectrum: (M+ H) + = 297. B. 2S, 1-pyrrolidin-2-one)-3-methylbutanoic acid L49 g (5.3 mmol) of the compound from Example 17A in a mixture of DMF/CH2C12 The solution was cooled to 〇〇c and ❹^'gram equivalent of 60% sodium hydride in mineral oil was added. Slowly warm the mixture back to the chamber /JDL and smear it. The mixture was poured into saturated ammonium chloride and extracted with EtOAc EtOAc (EtOAc). Use hydrogen as in Example 1H

Oxidation hydrolyzes the crude product to give the desired compound. 3〇〇 megahertz】H NMR (CDCI3) δ 0.96 (d5 J = 7# ^ ? 3Η)5 1.06 (d? J = 7# ' 3H), 2·10 2H), 2·40 (m, 1H) , 2.5 0 (t, J = 7 Hz, 2H), 3.56 (m, 2H), 4·14 (d, j = 1 Hz, ih). Mass spectrometry: (m+h)+ 186 〇C (28'38'58)_2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy (2S (1 p ratio slightly bite- 2__ylmethylbutylidene)amino-i,6-diphenylhexane

O:\106\106749.DOC-85-200817349 The formic acid from Example 17B was coupled with the amine from Example 1N using standard procedures (ED AC in DMF) to give the desired compound. 3〇〇 MHz Hertz NMR (CDC13) 5 0·77 (d, J = 7 Hz, 3 Η) 5 〇·83 (d, j = 7 Hz, 3H), 1·75 (m5 3H), 2.10 (m , 1H), 2.20 (s, 6Η), 2·25 (m, 1H), 2.65 (m, 1H), 2.85 (m5 1H), 3.0 (d, J = 7 Hz, 2H), 3.20 • (m, 1H), 3.77 (m, 2H), 3.88 (d5 J = l〇 Hertz, 1H), 4·20 (m, t 3H), 6·30 (d, J = 7 Hz, 1H), 6.98 (m, 3H), 7.20 (m5 10H). Mass spectrum··(M+H)+ = 614.实例 Example 18 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethenyl)amine keto-5-(28-(1-pyrrolidine-2,5-dione) 1, 3-methylbutanyl)amino-l,6-diphenylhexane A·2S-(1-pyrrolidine-2,5-dione)_3-methylbutyrate decyl ester 1 equivalent The succinic anhydride was added to a solution of 7 mg (3 · 38 mmol) of benzyl L-leumenate in 6 ml of gas. 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-diamine amino group ρ was added. The solution was left at room temperature for 3 days. After standard treatment, the crude product was purified by a seper column chromatography to give the desired product (3H), 1·12 (d, J = 7 Hz, 3 Η), 2·7 〇 (m, 1 〇). ), 2·71 (s, 4H), 4·45 (d5 J = 9 Hz, 1H), 5.15 (s, 2H), 7.30 (m, 5H). Β· 2S-(lw than pyridin-2,5-dione)-3-methylbutyric acid

O:\106\106749.DOC •86- 200817349 0.245 g of the product from Example A8A and 3 〇mg of 1〇 in a 5 ml of methanol under intense hydrogen pressure (a balloon filled with hydrogen) A mixture of % palladium carbon for 1 hour. The catalyst was filtered off and the solvent was removed under vacuum to give 168 mg of desired compound. 300 MHz NMR (CDC1J (5 ο Μ (d, J = 6 Hz 5 3 Η), 1.13 (d5 J = 6 Hz, 3 Η), 2·65 (m, m), • 2·80 (s5 4 Η), 4.45 (d, J = 8 Hz, 1 Η). Mass spectrum: (Μ+Η)+ = 2〇〇. • C· (28,38,58)-2-(2,6-dimethylphenoxyacetamidine Amino group _3_hydroxy 0 -5-(2S-(1 〇pyrrolidine-2,5-dione)-3-methylbutanyl)amino-1,6-diphenylhexane The standard procedure (EDAC in DMF) coupled the carboxylic acid from Example B8B with the amine of Example IN to give the desired product (75%). 3 〇〇 megahertz 1H NMR (CDCM Λ n τ —......一

(' s,5s) 2 (anti-3_(2,6-diphenylene) propylene)amino-3_light-S-(2S-(1·tetrahydroneptin-2-, base ) _3 曱 醯 醯 ) ) ) ) ) ) 胺 以 以 一 一 一 一 一 一 一 一 一 Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw Sw 2-Hydroxybenzoyl alcohol oxidation, NMR (CDC13) (5 2.62 (s5 Hz, 1H), 10.63 (s, iH). The desired compound was obtained. 300 MHz s, 6H), 7.10 (m, 2H) ), 7.33 (t, J = 7. Mass spectrometer··(M+H)+ = 135

O:\106\106749.DOC '87 - 200817349 Β·Reverse-3-(2,6-xylyl) methacrylate Add 36 gram of sodium nitride (60% in oil) to 15 ml of THF In a solution of trimethyl acetate (149 mg, 0.82 mmol). After 15 minutes, '100 mg of the compound from Example 丨9a was taken in 2 ml of THF. After 2 hours, the reaction was carefully stopped and extracted with ethyl acetate (7 〇 - house liter) to dehydrate and concentrate. Purification of the crude product by EtOAc (hexanes / EtOAc 95:5) gave the desired compound (π%). 3〇〇〇 megahertz 4 NMR (CDC13) 5 2.35 (s, 6H), 3.82 (s5 3H), 6.07 (d, J = 16 Hz, 1H), 7·10 (m5 3H), 7.85 (d5 J = 16 Hz, 1H). Mass spectrum: (M+NH4)+ = 191. C·trans-3-(2,6-dimethylphenyl)acrylic acid

The formazan 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 iH NMR (CDC13) 6 2.3 8 (s, 6H), 6·13 (d, J = 16 Hz, 1H), 7.10 (m, 3H), 7.96 (d5 J = 16 Hz, 1H) . Mass spectrum: (M+H)+ = 194. QD·(2S,3S,5S)_2-(anti-winter (2,6-diphenylene)propenyl)amino-3-hydroxy-5-(second-butoxycarbonyl)amine β1,6 _Diphenylhexane • The carboxylic acid from Example 19C was coupled with the amine from Example 1F using standard procedure (EDAC/DMF) to afford the desired compound (84%). 3 〇〇 Hz NMR (CDC13) δ 1.40 (s, 9 Η), 1.68 (m, 1 Η), 2.34 (s, 6H), 2.75 (m, 2H), 2·96 (nv2H), 3.72 (m, 1H) ), 3.85 (m, 1H), 4.08 (m, 2H), 4.60 (m, 1H), 5.88 (d, J = 10 Hz, ih) 5 5·94 (d, J = 16 Hz, 1H), 7.10 (m, 5H) 5 7.25 (m, 8H), 7.72 (d5 J = 16 Hz, 1H). Mass spectrum: (M+H)+ = 543. O:\106\106749.DOC -88 - 200817349 Ε·(2S,3S,5S)-2-(trans-3_(2,6-diphenylene)propenyl)amino-3-hydroxy-5 -(2S-(l-tetrahydropyrimidinyl) 3-mercaptopropyl)amino-1,6-diphenylhexane was removed from the Boc-protecting group of the compound from Example 19D (TFA/CHei2) And the resulting amine was coupled with the carboxylic acid from Example 2A using the standard procedure (EDAC/DMF) to give the desired compound (73%). 300 M Hz 1H NMR (CDCl3) 5 0.82 (d , J = 6 Hz, 3H), 0.87 (d, J 0 = 6 Hz, 3H), i·50 (m, 1H), 1.70 (m, 2H), 2.20 (m, 1H), 2.33 (s, 6H) ), 2.68 (m, 1H), 2.78 (m, 1H), 2.85 (m, 1H), 3.05 (m, 5H), 3.73 (m5 1H), 4.17 (m, 1H) 5 4.30 (d, J = 3 Hertz, ih), 4.60 (s, 1H), 5.95 (d, J = 15 Hz, 1H), 6·〇 (d, j = 9 Hz, m), 6.80 (d, J = 7 Hz, 1H), 7.25 (m, 13H), 7·70 (d5 J := 15 Hz, 1H). Mass spectrum: (M+H)+ = 625. Example 20 (2S,3S,5S)-2-(3-(2, 6-dimethylphenyl)propanyl)amine j via quinone-5-(2S_(1-tetrahydropyrimidinyl)-3-methylbutanyl)amine 4,diphenyl The benzyl hexane 3-(2,6-dimethylphenyl) propionate is vigorously stirred under hydrogen pressure (balloon pressure) in 400 ml of 25 ml of sterol and 4 ml of 10% Pd/C. A solution of the compound from Example 19 was carried out for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the desired product (98%). 00 MHz NMR (CDCl3) 5 2 35 (§, New), 2 45 (m, 2 Η), 2.98 (m, 2 Η), 3.22 (s, 3 Η), 7.02 (s, 3 Η). Mass Spectrum: (Μ+Η)+ = 210 〇

O:\106\106749.DOC -89&gt; 200817349 Β· 3-(2,6-dimethylphenyl)propionic acid is neutralized with hydrazine by hydrolysis of the oxime ester obtained from the example 20 ,, &gt; Compound (93%). 3 megahertz (CDC13) accounts for 6 (s' 6Η)' 2.50 (m, 2 Η), 3 〇 (m, 2 Η), 7 〇 3 (s, 3 Η). Mass spectrometry: (Μ+ΝΗ4)+ '196. (2S,3S,5S)-2_(3_(2,6c-tolyl)propanyl)amino group I was used in the standard of the use of keto (t-butoxy)amino-π-diphenylhexane The coupling procedure (EDAC/DMF) coupled the amine from Example -20 of the carboxylic acid from Example 1F to give the desired compound. Megahertz 4 NMR (CDC13) δ 1.40 (S? 9H)? 1.55 ( M5 2H)5 2.20 (m5 2H)? 2.3 0 (s,6H), 2.74 (m,2H),2.8 5 (m,4H), 3.66 (m,1H),3.82 (m,1H),3.95 (m , 2H)5 4.57 (br d,1H), 5.66 (d, J = 9 Hz, 1H), 7_0 (s, 3H), 7.22 (m5 10H). Mass Spectrum: (m+H)+ = 545. (28 '38,5卟2-(3_(2,6-Dimethylphenyl)propanyl)amino-3-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one) 3-methyl Butyl) Aminodiphenyl-II-hexane The compound Boc-protected thiol group from Example 2〇c was removed using trifluoroacetic acid in CHCh and the resulting amine was obtained using standard coupling procedures (EDAC/DMF). Coupling with the carboxylic acid from Example 2A gave the desired compound. 3 〇〇 Hz H NMR (CDCl3) 5 0.82 (d5 J = 6 Hz, 3H), 0.86 (d, J = 6 Hz, 3H)5 1·55 (m5 2H),1·65 (m,1H),1·70 (s, 3H), 2·20 (m, 3H), 2.30 (s5 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) 5 4·63 (s, m), 5.75 (d, J = 7 Hz, 1H), 6.76 (d, J = 7 Hz) ,ih),7.0 (m5 3H), 7.20

O:\106\106749.DOC -90- 200817349 (m,10H). Mass spectrum: (M+H)+ = 627. Example 21 (28,38,58)-2-(2,6-Dimethyl-4-methylphenoxyethenyl)amino-3-carbyl-5-(2S-(l-tetrahydropyrimidine) 2-keto)-3-methylbutanyl)amine q,6-diphenylhexanin A. 2,6-dimethyl-4-tris-butyldimethyloxyalkoxyphenol will be 200 Pd/C (20%) of gram was added to a solution of 2.5 g (14 7 ^ mmol) of 2,6-dimethylphenylhydrazine in 53⁄4 liters of methanol. The reaction mixture was stirred overnight under hydrogen at i atmosphere. The Pd/c was moved up on the chopped algae soil, and the solvent was evaporated to dryness under reduced pressure to obtain 2.0 g (100%) of 2,6-dimercaptodihydrophenylhydrazine as a pale yellow oil. At 0C, the serial will be 1.2 grams (17. 6 millimoles) _. Sit and add 2·2 g (14·7 mmol) of second-butyl dimethyl sulphur base gas to 2.0 g (14.73⁄4 mol) of 2·6 -2 in 10 ml of methylene chloride. In the solution of methyl dihydrophenyl hydrazine. After the completion of the reaction, it was partitioned between dichloromethane and a 1:1 mixture of hydrogen hydrazine and brine according to the instructions of butyl b. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatography using 5% acetic acid: ethyl acetate: hexane afforded 18 g (49%) of 2,6-dimethyl-4-tris-butyl-di- decyloxyphenol as a white solid. 3〇〇 megahertz lH NMR (CDC13) 5 0.16 (s5 6H)? 0.98 (s? 9H)? 2.19 (s5 6H)5 4.22 (s, 1H), 6.48 (s, 2H). Mass spectrum: (m+H)+ = 253. Β·2,6-Dimethyl-4-tris-butyldimethyloxyalkyloxyphenoxyacetate with 2.0 g (1.43 mmol) of potassium carbonate and 83 〇 microliters (7 5 mmol) Ear) Ethyl bromide to treat 18 g (71 mmol Mo: \106\106749.DOC Λ 200817349 ears) in 2 ml of dimethylformamide 2,6-dimethyl-4-second a solution of butyl-monodecyloxyphenol. 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 rinsed with diluted brine, dehydrated with sulphuric acid, filtered and evaporated in vacuo. Chromatography with 5% ethyl acetate:hexane afforded 2 〇3 g (85%). 2,6-dimethyl-4-tris-butyldimethyl decyloxy Phenoxy! Ethyl acetate. 300 MHz NMR (CDC13) 5 〇·17 (s,6H), 〇〇·97 (S,9H), L33 A 3H, Bu 6·3 Hz), 2·22 (s,6H),4 3〇 (q, 2H, J = 6.3 Hz), 4·35 (s, 2H), 6.57 (s, 2H). Mass Spectrum: (m+h) + =356 ° C· 2,6-Dimethyl-4-Phenylphenoxyacetic acid 4 ml of 3N sodium hydroxide was added to 2 〇 3 g in i 〇 ml of methanol ( 6 〇 mmol of a solution of 2,6-dimethyltris-butyl-dimethyl methoxy methoxy phenoxyacetate. 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 i hours and then partitioned between water and dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Triturated with hexane to give 910 mg (77%) of white solid

2,6-monomethyl-4-hydroxyphenoxyacetic acid. 300 MHz NMR (CD3〇D) 5 2·18 (s, 6Η) 5 4·31 (s5 2H), 6.41 (s, 2H). Mass spectrometer··(Μ+Η)+ = 214 〇D· (2S,3S,5S)_2_(2,6-dimethyl-4-hydroxyphenoxyethyl)amino hydroxy _5 gas third-butyl Oxycarbonyl)amino-1,6-diphenylhexane is obtained from the carboxylic acid of Example 21 using a standard coupling procedure () 〇 〇 〇: /〇^/1?)

O:\106\106749.DOC-92-200817349 Coupling with an amine known as κ IF gives the desired compound. Megahertz a NMR (CDC13) 5 1.40 (S? 9H)? 1.68 (m5 2H)5 2.07 (s? 6H)? 2.77 (d, J-6 Hess, 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· 1 0·7 · 30 (m, 1 〇 H). E*(28'38'58)-2-(2,6-Dimethyl-4-carbonylphenoxyethyl)amino-3-hydroxy-5-(2S-(;U tetrahydropyrimidine_2 _keto)3methylbutylidene)amino-1,6-diphenylhexane

The B〇c_ protecting group from the compound of Example 21D was removed using TFA/CH2C12, and the obtained amine was coupled with the carboxylic acid from Example 2A using a proprietary calibration procedure (EDAC/DMF). The desired compound. 3〇〇 megahertz] H NMR (CDC13) 6 0.78 (d, J = 5 Hz, 3H), 0.81 (d5 J = 5 Hz, 3H)? 1.47 (m? 1H)? 2.03 (s5 6H)5 2.18 ( M3 1H)5 2.62 (m5 1H)! 2.80 (m,2H),3·05 (m,6H), 3.78 (m,1H),4·12 (m,6H),4.3 7 (m,1H), 4.71 (s, lH), 6.47 (s, 2H) 5 6.94 (br d, 1H), 7.20 (m, 10H). Mass spectrometry: (M+H broad = 645. 'Example 22 (2S, 3S, 5S)-2-(cis (earth)-;^ dioxo-2-isopropyltetrahydro] phenoxy)amino- 3-hydroxy-5-(2S-(l-tetrahydropyrimidinyl)_3_methylbutanyl)amino-1,6-diphenylhexane A·cis (±)_2-isopropyl perylene Hydrogen pcephene Sodium ethoxide (16.75 g, 0.246 mol) was carefully added in several portions to a solution of ethyl 3-mercaptopropionate (27.25 ml, 〇·246 mol) in 200 ml of ethanol. The resulting suspension was then cooled to _2 (rc, and 2-bromoisovalerate in 50 ml of ethanol was added dropwise over 2 hours to O:\106\106749.DOC-93-200817349 (50 g , 0.239 mol) After the addition was completed, the reaction was warmed to ambient temperature and stirred for 3 hours. The mixture was poured into 600 ml of ethyl acetate and 6 ml of saturated ΝΗβΙ. The ester layer was extracted with ethyl acetate (2 X 200 liters). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. 〇〇ml of A* benzene and add B Sodium (16.75 g, 0.246 mol). The reaction mixture was heated to reflux for 6 h then cooled to room temperature then poured into ice-cooled 1N JJC1 (235 mL) and ethyl acetate (3 χ ι5) 〇ml) extraction. The combined organic layers were dried over sodium sulfate, filtered and concentrated to an oil, which was used directly in the next step without further purification. The crude product was added to 500 ml of aqueous 10% sulfuric acid. The resulting mixture was heated to reflux for several hours, then cooled to room temperature and neutralized with 6 EtOAc NaH. and extracted with ethyl acetate (3×300 mL). Concentration in vacuo gave a dark-colored oil. The crude product was purified by vacuum distillation at 75-80 C (g). 3 〇〇 megahertz NMR (CDC13) 5 0.93 (d, J = 9 Hz, 3H),1·〇3 (d5 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) To a solution of 125 ml of CH2C12$S above, was stirred at 0 ° C. The reaction mixture was allowed to warm to room temperature and then quenched by the addition of IN HCl (255 mL). Diethyl ether (3 χ ι 5 〇 ml) was taken to the reaction mixture' and the scaly solution of O:\106\106749.DOC-94-200817349 was washed with saturated sodium bicarbonate and brine, and dehydrated with magnesium sulfate. The solution was concentrated in vacuo and the obtained oil was purified eluting with EtOAc EtOAc 3 〇〇 megahertz bNMRNDClO 5 l.03 (d5j = 7 Hz, 3 Η), 1·08 (d, J = 7 Hz, 3 Η), 1.80 (d, J = 9 Hz, 1 Η), 1·90 (m5 2Η), 2.24 (m, 1H), 2.90-3.10 (m, 3H), 4·36 (m5 1H). Mass spectrometry: (M+H)+ • = 147 〇^ B· cis (earth)_2-(isopropyl exembyl)-2-(2-p aryl) carbonate 〇 diisopropylethylamine (4·65 ml, 26.7 mmol) and dipyridyl)

Stone ruthenium (5.42 g ' 25.12⁄4 mol) was added to the product from Shell Example 22A (2.29 g &lt; 15.7 mmol) in 4 mL of CH2CI2. After a period of room temperature, the reaction mixture was diluted with chloroform, 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/hexane) to give the desired compound. 3〇〇 megahertz iH NMR (CDC13) (5 1.05 (d5 J = 7 Hz, 3H), 1·〇8 (d, J = 7 Hz, 〇3Η), i·90 (m, 1Η), 2· 05 (m, 2Η), 2.58 (dd, J = 6, 15 Hz, 2H), 3·10 (m, 2Η), 3·28 j = 3, 12 Hz, ih), 5 47 (five), • 1H) , 7.12 (m, 1H), 7·27 (m, 1H), 7.80 (m, 1H), 8.41 (m, 1H). Mass spectrum: (M+H)+ = 268. C·(2S,3S,5S)-2-(cis(±)-2-isopropyl-3-tetrahydrothienyloxy)amino-3-hydroxy-5-(tris-butoxycarbonyl)amine Base_M_diphenylhexane The amine from Example 1F (791 mg, 2.06 mmol) was added to the compound from Example 22B (5 mg, 187 mmol) in 5 mL CH.sub.2. / Valley liquid. Stir the reaction at room temperature until all the examples are exhausted

O:\106\106749.DOC -95- 200817349 22B until σ. The reaction mixture was diluted with chloroform and washed with (4) succinic acid, sat. EtOAc, brine, and then evaporated and evaporated. The crude product was purified by hydrazine column chromatography (... CH.sub.2) to give the desired compound (n%). 3(10) megahertz lH NMR (CDC13) 〇·83]·05 (m,6H), L40 (s, 9H), 1.90 (m,3H), 2·20 (m5 1H), 2·75 (m5 2H) ,2·85 (m,4H), 2.95-3.15 (m? 3H)5 3.67^3.90 (m5 4H)? 4.55 (m? 1H)? 5.10 (m5 1H), 5.30 (m,1H), 7.10-7.26 (m5 10H). Mass Spectrum: (M+H)+ = 557. D·(2S,3S,5S)-2·(cis(:1:)-1,1 dioxo-2-isopropyl-_3_tetrahydropyrimenyloxy)amino-3-hydroxy (p. Tri-butoxycarbonyl)amino q,6-diphenylhexane Potassium peroxodisulfate formulation (0xone) (839 mg, 137 mmol) and sodium bicarbonate (152 mg, ι·82 mmol) ) A solution of the compound from Example 22C (523 mg, 〇·91 mmol) in 1 ml of acetone and 5 ml of water was added. The solution was stirred for 2 hours. At this time, a white sediment appeared. The reaction was quenched with aqueous bisulfite, extracted with ethyl acetate (2×1 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (2% MeOH/EtOAc) to afford 422 mg. 300 MHz NMR CCD Ch) δ 1.20 (m5 6H) 1·40 (s5 9H), 1·60 (m, 4H), 2.10-2.32 (m, 4H), 2·67 (m, 2H), 2.75 (m, 2H), 2.85 (m, 2H), 3.15 (m5 2H), 3·7 (Μ·9〇(m, 3H) 4.56 (m, 1H), 5.30 (m5 2H), 7.10-7.30 (m5 l〇H ) 〇E· (2S,3S,5S)_2-(cis(±)-l,l-dioxo-2-isopropyl-3_tetrahydro phenoxy)amino-3-hydroxy-5- (2S-(l-tetrahydropyrimidinyl)_3_methylτ-yl)amino-1,6-diphenylhexane O:\106\106749.DOC -96- 200817349 Using TFA/CH/l2 shift The Boc-protecting group of the compound from Example 22D was obtained and the obtained amine was coupled with the carboxylic acid from Example 2A to give the desired compound (82%). 00 MHz 4 &gt; 13)5 0.82 (1115611), 1.0-1.20 (m, 6H), 1.60 (m, 2H), 2.07 (m, 1H), 2.25 (m, 2H), 2·65_3·20 (m, 12Η), 3 · 70 (m, 1H), 3.90 (m, 1H), 4.10-4.20 (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, 10H). Mass Spectrum: (M+H)+ = 671. Example 23 (2S,3S,5S)-2-(2,6·Dimethylphenoxyethyl) Amine _3-hydroxy-5-(2 S-(l-dihydropyrimidine_2,4-dione)_3_methylbutanyl)amino 4,6·diphenylhexaneΑ·N-(2-ethoxypropene醯*)_n, -(1S_methoxycarbonyl-2-methylpropyl)urea 3.90 g (0.026 mol) of silver cyanate was added to 1.74 g (0.013 mol) of 2-ethoxypropene in 18 ml of toluene. The mixture was heated to reflux for 0.75 hours. The mixture was allowed to warm to room temperature and the precipitate was allowed to settle. The supernatant (9.6 mL) was recovered and 18 ml of anhydrous DMF and 5 ml of hydrazine were added. Cool to _15. (: 45 minutes, and leave in the refrigerator overnight. Loose solvent in vacuum ' and purify the residue by 矽 管 column chromatography (2% Me 〇 H / CH 2 Cl 2)' to get 1.59 g The desired compound (90.2%). 300 MHz H NMR (CDC13) accounted for 0.96 (d, J = 7 Hz, 3H), 1.0 (d, J = 7 Hz, 3H), 1.37 (t5 J = 7.5 Hz, 3Η), 2·25 (m, 1Η), 3·74 (s, 3H), 3.97 (q, J = 7.5 Hz, 2H), 4.42 (dd, J = 4.5, 8.0 Hz, 1H), 5.25 (d5 J = 12 Hz, 1H), 7.68 (d5 J = 12 Hz, 1H), 8.55 (s, 1H), 9.10 (d, J = 8 Hz, 1H). Mass spectrum: (M+H) + two 273. O:\106\106749.DOC -97- 200817349 Β· 2S-(1-dihydropyrimidin-2,4-dione)-3-mercaptobutyric 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 crystalljjjjjjjjjjj 300 MHz NMR (CDC13) 5 1 ·〇6 (d, J = 7 Hz, 3H), 1.13 (d5 J = 7 Hz, 3H), 2.25 (m, 1H), 5.04 (d, J = l〇 Hertz, 1H), 5.74 (d, J = 7 Hz, 1H), 7·50 (d, J = 10 Hz, 1H), 8 43 〇 (s5 1H) 〇C· (28,38,58)-2 -(2,6-dimethylphenoxyethyl)amino-3-3-hydroxy-5-(2S-(1-dihydropyrimidin-2,4-dione)-3-methylbutenyl)amino i,6-Diphenylhexane 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. 3〇〇 megahertz 1H NMR (CDC13) 5 0.81 (d, J = 7 Hz, 3H), 0.92 (d, J = Q 7 Hz, 3H), 2.18 (s5 6H), 2·23 (m, 1H) , 2.63 (m, 1H), 2·85 (m, 1H), 3·0 (m, 2H), 3·78 (m, 1H), 4·20 (m, 4H), 4·58 (d, J = 10 Hz, 1H), 5.68 (dd, J = 1.5, 7.5 Hz, 1H), 7·〇-7_25 (m, 13H), 7.50 (d, J = 7.5 Hz, 1H) 5 9·50 (s , 1H). Mass spectrum··(M+H)+ = 640. Example 24 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-2-one) Another preparation method of _3_methylbutydenyl]aminodiphenylhexanol O:\106\106749.DOC -98- 200817349 Α· 2,6-dimethylphenoxyacetic acid

Ο 2,6-dioxol (102·8 g, 0.842 mol) and emulsified Bfee (159.6 g, 1.68 mol) in 1000 ml of Η2〇, plus 3 liters with mechanical mixing and water - A 3-neck round bottom flask in a cold condenser. 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 Na〇I1 solution (67.2 g, 莫68 mol in 200 ml water) were added to the reaction mixture. After 19 hours, additional chlorinated acetic acid (39·8 g, 〇·42 mol) and NaOH solution (316 g, 莫84 mol in 1 mL of water) were added to the reaction mixture and continued. Reflux until the starting phenol is consumed. The reaction flask was cooled in an ice water bath and acidified to pH Η 1 with concentrated HCl to cause formation of a precipitate. The resulting slurry was stirred in an ice bath for an hour and then filtered. The solid was dissolved in hot (100%) water and allowed to cool to crystallize the product into a white plate with a melting point = 136-137. (:, yield = 78.8 g, 52%, oxime oxoethyl)amino-3-hydroxy-5·(tris-butoxycarbonylaminodiphenylhexane, grass chloroform (36.3 ml, 〇.42 mol) added to the 2,6-dimethylphenoxyacetic acid (5 gram ' 〇 28 mol) in 5 (10) ml of toluene, followed by 5 drops of DMF and at room temperature Mix for 3 minutes, then remove the toluene on the gasifier... and remove the residual army in the vacuum. The 2,6-dimethylphenoxylate is a yellow-brown oil.

100% 〇 A tri-butoxycarbonylamino-j,6_ will [2S,3S,5S]-2-amino-3-hydroxy

O:\106\106749.DOC -99- 200817349 Monophenylhexane χ·5 succinate (111.9 g, 0.25 m) was placed in a 2 liter, erected round neck flask with mechanical stirring. Add NaHC03 (106 g ' 1.26 mol), 600 ml of h2 oxime and 6 ml of EtOAc and stir vigorously until all the solids were dissolved (丨5 min). Stirring was slowed and 2,6-dimercaptophenoxy oxime and EtOAc (100 mL) were added in a narrow stream via a funnel. After stirring for 30 minutes, the starting material (HPLC fractionation) was depleted and the layers were separated. The layers were extracted with EtOAc (EtOAc) and EtOAc (EtOAc) EtOAc (EtOAc) C·(28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3-3-hydroxyt-butylcarbonylamino)-1,6-diphenylhexane (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)aminohydroxy-5-(second-butoxycarbonylamino)-;[,6•diphenyl Hexane (i75i gram, 〇·32 Mo) and 500 ml of CH2C12 were stirred. CF3c〇2H (249 mA Q liter, 3.2 mM) was added and stirred for 20-25 minutes, then the reaction mixture was poured into a sep. funnel containing 10003⁄4 liters of water and 200 ml of CH2C12. Shake carefully. Swing the resulting mixture and separate the layers. Rinse the organic layer again with 5 ml of water, rinse with 3 χ 500 ml of NaHc 〇 3, and finally rinse with 5 〇〇 ml • saline. The organic solution was dehydrated with MgS 4 , filtered and concentrated to give a gold-colored oil, which was then taken up to a foam, and 3 liters of diethyl ether was added to the crude product and shaken vigorously to dissolve. The solid began to crystallize within a few minutes 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. Filtration O:\106\106749.DOC -100- 200817349 The solid was air dried to give 115 g of the desired product as white needles, yield 81%. A solution of HC1/diethyl ether was added to the filtrate to precipitate the residual product as a HCl salt. The slightly reddish solid was collected by filtration, and the solid was carefully kept in N2 while being moistened with diethyl ether. * At the time of dehydration, the amine salt was transferred to a separatory funnel and extracted with (: Ι 2 2 (: 12 and NaHCCh (aqueous)). The organic layer was washed with brine, covered with ton (10), dehydrated, concentrated and By way of treatment, an additional 15 grams of the desired product was obtained with a total yield of 91%. D. N-carbonylbenzyloxy-3-aminopropanol In a 12 liter 3-neck round bottom flask, isopropyl acetate was added ( 6. 5 liters. Cool the solvent to the crucible in an ice water bath and add 3-aminoacetone (1.14 kg, 15.1 mol, 2.15 equivalents) at a time. In this rapidly stirred solution, Benzyl phthalate (1.2 〇 kg, 'Mor, 1. 〇 equivalent) was added dropwise over 2 hours while maintaining the internal temperature of the flask at 1 (rc to 15 〇c). After the completion of the action, the reaction mixture was allowed to stir for an additional 〇·3 hours between 10 ° C and 15 °, after which time water (3.5 liters) was added once and then the solution was dispensed and an additional 2 X 3 · 5 liters of water was rinsed and the organic layer was dehydrated with potassium carbonate and concentrated to give a solid which was then dissolved in isopropyl acetate. And, by adding the compound to heptane, it was precipitated from the solution. The solid was filtered under nitrogen to give the desired product as a colorless solid. Ε· Ν- Benzyl benzyloxy-3-aminopropanal 335 ml of dimethyl sulfoxide and 9 liters of dioxane and cooled to -48

O:\106\106749.DOC -101 - 200817349 C. 3 13 ml of grass cockroach was added over 25 minutes to maintain the temperature below -40 °C. Cool to -48 ° C and add 5 gram of N-Cbz-3-amino-1-propanol dissolved in } liters of dichloromethane to maintain the temperature below _4 (rc. at _45 ° Stir for an additional 1 hour at C. Add 1325 ml of diethylamine at a rate that maintains the temperature below _ 4 〇t. Allow the mixture to warm back after stirring for an additional 15 minutes at _4 (^c) To _30. (:, then add 2·5 liters of 20% potassium dihydrogen phosphate containing water. Stir for 1 hour, then separate the layers, rinse with salt water

有机 Wash the organic layer and dehydrate it with magnesium sulfate. The resulting aldehyde was retained in a solution at -20 ° C until needed. Methyl F. N-(N-(benzyloxycarbonylamino)propyl) decanoate The crude product of Example 24E (not chromatographed) was added to a 5 liter 3-neck round bottom flask (115 g, 0· 555 mol, h〇 equivalent), followed by water (4 mL) and methanol (1600 mL). The reaction mixture was maintained at 25 throughout the course of the reaction. (: After the solution became homogenized, add (s) _ methyl hydrazide hydrogenate (9 〇 · 2 g, 〇 · 538 m, 〇 · 97 equivalents) at a time, and then quickly add people in order Sodium acetate trihydrate (151 g, 1.11 mol, 2·〇 equivalent) and sodium cyanoborohydride (73. 2 g, 117 mol, 21 eq.) allowed to stir the reaction mixture at ambient temperature 〇·5 Hour and concentrate in vacuo to remove all methanol present. In this solution, saturated aqueous sodium carbonate (400 ml) was added and the mixture was extracted with isopropyl acetate (1 liter). (2 X 4003⁄4 L) The organic layer was washed, dried over sodium sulfate and concentrated, and 150 g of crude product was obtained and dissolved in isopropyl acetate (3 ml) and hexane (2400 ml). Anhydrous HC is foamed therein, and an oily solid is dissolved in the solution. The liquid other than the solid is discarded and dissolved.

O:\106\106749.DOC •102- 200817349 Decomposed in dioxane (3 liters). The solution was washed with water (600 ml) and saturated aqueous sodium bicarbonate (600 ml) and dried over sodium sulfate. Concentrate in vacuo to give 105 g (yield: 59%) of desired product as pale yellow oil. G. N-(3-Amino)propyl proguanilate The product of Example 24F (120 g, 〇·372 mol) and decyl alcohol (1 liter) were added to a 3 liter flask. The solution was allowed to stand for 1 hour in the presence of Raney nickel (180 g). After the Raney nickel was removed by filtration, Pd(〇H) 2 (24 g) was added, ◎ and the solution was allowed to stir under a hydrogen pressure of 60 psig for 12 hours. 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 (12 ml) was added to the oil, and the solution was again concentrated in vacuo to give the desired product. H. Tetrahydropyrimidine _3-keto)_3_methylbutyrate methyl ester The crude product of Example 24G (150 g, 〇·8 mol) was added to a 5 liter 3 neck round bottom flask with a stir bar. And dioxane (3·2 liters). Carbonyldiimidazole (232 g, 1.44 mol, 1.8 eq.) was added in portions slowly over 25 min. 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 〇〇 ml). The organic layer was dried over sodium sulfate and concentrated to give 126 g (yel. I. tetrahydropyrimidine 2 - keto) _3_methylbutyrate methyl ester in a 12 liter 3-neck round bottom flask with a stir bar, add Example 24H to O: \106\106749.DOC -103 - 200817349 Product (126 g, 〇·588 mol), water (13 liters) mhf (39 liters). The Yuanluo solution was cooled to an ice bath, and lithium hydroxide monohydrate (74 g 丨·76 mol, 3.0 eq.) was added in one portion and rapidly stirred. Allowed. The solution was stirred under reflux for 14 hours. It was then acidified to pH 11 by slowly adding 5 % aqueous phosphoric acid and the butyl was removed in vacuo. The liquid phase was rinsed with isopropyl acetate (2 liters) and then the layer was extracted by slowly adding 35% aqueous 11 (:1 to </ RTI> </ RTI> </ RTI> <RTIgt; The combined organic layers were concentrated to give the desired product (1···················· Stirring was continued until 5 mL of solvent was evaporated. The solution was cooled to hydrazine (yield and filtered to give 92 g (75%) of pure desired product.

Je (2S,3S,5S)-2-(2,6^ T-phenoxyethyl)amino-3-hydroxy-5-[2S-(l-tetrapyrimidin-2-one)-3 -Methylbutylidene] Aminodiphenylhexane In a 2 liter 3-neck round bottom flask, mix Example 24C (1 gram, 〇22 moles), product of Example 241 (44.8 gram, 0.22 mole) And 750 ml of DMF and the mixture was cooled in an ice/water bath. HOBT (90.9 g, 0.67 mol) EDAC (86 g '0.45 mol) and triethylamine (62.53⁄4 liter, 0.45 mol) were added and the ice bath was removed, allowing the reaction mixture to stir and warm to room Warm for 5 hours. The reaction was diluted with 1000 ml of IPAC and quenched with 1 mL of water. The mixture was shaken and separated, and the layer was extracted with i X 400 ml of IPAC, and the organic matter was washed with 1 X 400 ml of 10% HCl, 1 X 500 ml of NaHC03, diluted with 100 liters of hexane, and then with 4 X of 500 ml of water. 1 X 5〇〇O:\106\106749.DOC - 104- 200817349 The house was rinsed with brine, dehydrated with MgS 4 , filtered and concentrated to give the desired product as a white foam. Example 25 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)aminohydroxy-5_[2S-(l-w-hydropyrimidin-2,4-dione-based) Isobutyryl]aminodiphenylhexane, Α·曱oxycarbonyl)ethyl phthalic acid third-butyl ester 9.0 ml of decyl acrylate was added to 1 mM methanol. In the solution of acid second butyl ester. The solution was heated to reflux overnight. An additional 0.9 grams of millimethyl acrylate was added and reflux was continued for 24 hours. The solvent was purified in vacuo, and the crude material was purified eluting eluting eluting eluting eluting eluting 3 〇〇 megahertz] HNMR (CDCl3) $ 0.91 (d, J = 3 5 Hz, 3 Η), 〇 93 (d, J = 3.5 Hz, 3 Η), 1.47 (s, 9 Η), 1.85 (m, 1 Η) , 2.47 (t, J = 7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J: = 6 Hz 21, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (m+H)+ = 260. Β· N-(2-Resinylamino)ethyl lysine III _ 酉 酉 将 在 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 The solution was obtained from the solution of the product of Example 25. After the correction clock, 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 liters of 1117 was added, followed by O:\106\W6749.DOC-105-200817349 and 1.43 ml of concentrated ammonium hydroxide. The reaction was allowed to proceed overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate&apos; and washed with sodium bicarbonate, brine and evaporated from anhydrous sodium sulfate. After the dehydrating agent was filtered off, the filtrate was concentrated in vacuo and purified eluting EtOAc EtOAc EtOAc 300 MHz 4 NMR (CDC13) 5 〇·95 (d, J = 7 Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 1·48 (s5 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 s5 1H). Mass spectrum: (M+H)+ = 245. C. 2S-(1_tetrahydropyrimidin-2,4·dione)-3-methylbutyric acid tert-butyl ester 0.92 g of a solution obtained from the product of Example 25B in 10 mL of THF And 1.83 g of carboxydiimidazole (CDI) was refluxed for 26 hours. Then 1.83 g of CDI was added and the solution was again refluxed for 72 hours. The solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate, washed with water, saturated sodium hydrogen carbonate, dilute hydrogen acid and then brine. 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 CH2C12) to afford to afford 54 g (52%) of desired compound. 300 MHz 4 NMR (CDC13) 5 0.96 (d, J = 7 Hz, 3H), 1.05 (d, J = 7 Hz, 3H), 1·48 (s, 9H), 2·20 (m, 1H) , 2.66 (m, 2H), 3.43 (m, 1H), 3.75 (m5 1H), 4·63 (d, J = 9 Hz, ih) 5 7.35 (br s, 1H). Mass spectrum: (m+H)+ = 271. D· : 2S-(1-tetrahydropyrimidine_2,4-dione)_3_methylbutyric acid was stirred at 5 ° C in 5 ml of trifluoroacetic acid · 53 g of compound from Example 25C The solution was 1.25 hours. The solvent was evaporated in vacuo, purified and purified eluting elut elut elut elut elut eluting eluting 300 MHz NMR (DMSO-d6) 5 0·86 (d, J = 7 Hz, 3H), 0.97 (d5 J = 7 Hz, 3H), 2.15 (m5 1H), 3.40 (m, 4H), 4.39 ( d, J = 10 Hz, 1H). Mass spectrometry: (M+H)+ = 2 1 5 o E·(28,38,58)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2S -(l-tetrahydropyrimidin-2, aryldione)-3_methylbutanyl]aminodiphenylhexane The amine compound from the example in was obtained using a standard coupling procedure (EDAC in DMF) Coupling with the acid from Example 25) gave the desired compound (68%). 300 MHz 111&gt;^]仙〇^&lt;:13) (5 0.83 ((1, Bu 7 Hz 5 3H), 0·88 (d, J = 7 Hz, 3H) 5 le8 〇 (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) , 3.65 (d, J = 5 Hz, 1H), 3·83 (m, 1H), 4·2 〇 (m, 5H), 6.18 (d, J 9 Hz, ih) 5 7·〇-7· 38 (m5 14H). Mass Spectrum··(m+H)+ = 643 ° Example 26 (2S,3S,5S)-2-(2,6·difylphenoxyethyl)amino-3_hydroxyl -5-丨2S-(4-azatetrahydropyrimidin-2-yl)_3_methylbutanyl]amino-1,6-diphenylhexaneΑ·N(l)_third-butoxy carbonyl-N(2)-allyl hydrazine Add 19.0 g of potassium carbonate to a solution of ΐ8·ι8 g of the third-butoxycarbonyl protected ruthenium in 5 ml of acetonitrile, followed by the addition of η·9 ml of allyl The reaction mixture was heated to reflux for a total of 3 hours, filtered and concentrated in vacuo.

O:\106\106749.DOC -107- 200817349 Contraction. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. After concentrating in vacuo, the crude product was purified by EtOAc EtOAc EtOAc EtOAc 3 〇〇 megahertz iH nmR (CDC13) 5 1.45 (s, 9H), 3.46 (m, 2H), 4.0 (br s, 1H), 5.10 (m, 2H), 5·83 (m, 1H), 6 · 0 (br s, 1H). Mass spectrum: (M+H)+ = 173. Β·N(l)-Third-butoxycarbonyl*_N(2)-allyl_N(2)-benzyloxycarbonyl hydrazine Adds 4.69 g of oxacarbonyloxysuccinimide to 15 4.8 grams of solution from the compound of Example 26A in ml of dMF. 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. The crude product obtained after concentration was purified by silica gel column chromatography (20% to 5% EtOAc in hexane) to afford 5.27 g of the desired compound. 300 MHz WNMRfDClO ά 丄 43 (brs, 9H), 4.15 (br s? 2H)5 5.18 (s5 2H)5 5.20 (m5 2H)? 5.82 (m? 1H)? 6.39 (br s,1H), 7.36 ( m, 5H). Mass spectrum: (m+H)+ = 307. C·N(l)-Second-butoxy-yl-n(2)-methylaminomethyl-n(2)-benzyloxy-based hydrazine using an anhydrous ice/acetone bath in 1 ml of methanol A solution of 6.5 g of the compound from Example 26 was cooled. Let the ozone bubble in it for a few hours until it continues to light blue. Air was passed through the solution for 1 minute, then 15.6 ml of dimethyl sulfide was added and the reaction mixture was allowed to gradually warm to room temperature. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and rinsed with water then rinsed several times with brine. The organic layer was dehydrated with anhydrous sulphuric acid &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& 300 megahertz] H NMR (CDC13) occupied i shoulder (b&quot;,9Η), 4·35 (m,2Η),5·20 (s,2Η)5 6·65 (br s,1Η), 7.36 (s , 5Η), 9·70 (br s, 1H). Mass spectrum: (m+NH4)+ = 326. D· Ν·[2&lt;&quot;(Ν_(2)-卞Oxycarbonyl-N-(l)-tris-butoxycarbonylindenyl]ethyl-L-proline methyl ester 3.55 g L-缬Methylamine hydrochloride was added to a solution of 7.2 g of the compound from Example 26C in 1 mL of methanol followed by 3.48 g of sodium acetate and 1.33 g of sodium cyanoborohydride. The reaction mixture was stirred and the mixture was concentrated and concentrated in vacuo. EtOAc was purified eluting eluting Hertz iHNMR (CDC13) 5 0.90 (d, J = 6 Hz, 6H), 1.43 (br s, 9H), 1.87 (m, 1H), 2.60-3.0 (m5 4H), 3.72 (s, 3H), 5· 18 (s, 2H), 7·3 7 (m, 5H). Mass spectrum: (m + H) + = 424. Ε · 2S-[4_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Methyl 3-methylbutanoate A solution of 2.4 g of a compound from Example 6D in 2 ml of HCl and dioxane was stirred under argon at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated in vacuo. The crude product was dissolved in 28 mL of CHAH, and s. The solution was left at room temperature for 48 hours. The solvent was removed and the desired compound was obtained from EtOAc (EtOAc:EtOAc:EtOAc: 300 MHz iH NMR (CDCl3) 5 0.90 (d, J = 7 Hz, 3H), O: \106\106749.DOC -109- 200817349 0.98 (d, J = 7 Hz, 3 Η) 5 2·ΐ7 (m, 1Η), 3.34 (m, 1Η), 3.61 (m, 2H), 3.72 (s, 3H), 3.98 (m, 1H), 4.71 (d5 J = i〇 Hertz, ih) 5 5.20 (s, 2H ), 6.72 (br s, 1H), 7.38 (m, 5H). Mass spectrum: (M+h)+ = 350. F· 2S-(4-benzyloxycarbonyl aza-i-tetrahydropyrimidin-2-yl)_3_mercaptobutyric acid

In aqueous dioxane, 0.78 g of the compound from Example 26E was hydrolyzed using hydrogen chloride to give the desired compound. 3 〇〇 megahertz lH

NMR NMR (CDC13) 5 0.85 (d, J = 7 Hz, 3 Η) 5 1·04 (d, J = 7 Hz, 3H), 2.40 (m, 1H), 3.40 (m, 1H), 3.50 (m, 1H), 3.8 〇 (m, 2H), 3.95 (d, J = 10 Hz, 1H), 5.2 〇 (s, 2H), 7 3 〇 (s, iH), 7.36 (s, 5H). Mass spectrum: (m+H)+ = 336. G·(28,38,58)-2-(2,6-Dimercaptophenoxyethyl)amino-3_hydroxy-5-[2S-(benzyloxycarbonyl aza j-tetrahydropyrimidine _ 2-keto)indolylbutyryl] Amino-1,6-diphenylhexanhydride Aminolation from (iv) was carried out using a standard coupling procedure (EDAC/DMF) to give the desired compound (36%). 〇·72 (d, J = 7 Hz, 3H), coupled with acid from Example 26F, 300 MHz 4 NMR (CDC13) 3 0.83 (d, J = 7 Hz, 3H), 2 20 ( s 6m 〇a / Λ (S,6H),2·65 (m,1H),2·83 (m, 1H)5 3.0-3.10 (m5 4H)5 3.90 (m 1H) 6 ,,(1)),6.65 (m,1H),7 〇_7·35 (m, 1 8H) ° % B^a · (M+H)+ = 754 〇H· (2S,3S,5S)-2-(2,6- 2--5_[2S-(4-aza-1-tetrazole-1,6-diphenylhexanemethylphenoxyethyl)amino-3-hydroxy-2-indenyl)-3 _Methylbutanyl group] Amino group using 10 ° /. Palladium carbon as a catalyst,

By hydrogenolysis will be obtained from the example 26G

O:\W6\W6749.DOC -1J0- 200817349 The compound Μ oxygen (4) protecting group is removed, ^ think mm. · Megahertz iHNMR (CDCl3H 0.83 (d, 45 Hz, 3H), 〇86 (U = 4.5 Hz, SHUW 1 Η), 2.2 () ΜΗ). —, 1H), 2.67 2.90 (m, 2H), 3.〇(^ 1H)j 3&gt;8〇1H, 4.2〇(m,3H),6.72(m,1H),7.〇(m5 2H), 7 2〇(m, qing. quality • · (M+H)+ = 630 ° Example 27 〇(2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino (1 - tetra-argon (tetra) 2 - keto) _3 · methyl butyl ketone] Amino phenyl phenyl hydrazine heptane A. (2S, 3S, 5S) _2 amino group (third - Butylated arylamino)-1-phenyl-6-methylheptane according to the procedure described in Example 1A to Example 1F], but in Example ic, chloropropyl magnesium was substituted for isopropyl chloride. Magnesium, get the desired compound. 300 MHz f (CDci3H ^ Qing, Bu 7 Fu 〇〇 · 92 J = !.43 (S5 9^^.50-1.80 (m, 4 Η)? 2-55 (m, 1H)5 2.90 (m5 lH), 3.0 (m, 1H)5 3.54 (m, 2H), 4.62 (m, 1H), 7·30 (m, 5H). Mass spectrometer··(μ+ή)+ = 337 8.(28'38,58)|(2,6-Dimethylphenoxyethyl)amino]-based _5-(tris-butoxymethylamino)+phenyl _6· Methylglycolate The amine compound from Example 27 was coupled to the acid of Example 1 using a standard EDAC coupling procedure to give the desired compound. Heart: MR (CDC13) 6 0·85 (d, J = 7 Hz, 3 Η), 〇 9 〇 (d : ” 赫 ^ 3H)? 1.43 (s? 9H)? l.7 〇 (m? 2H) 2.20 (s? 6H)5 3.03 (d? j ^

O:\106\106749.DOC &gt;111- 200817349 8 Hz 5 2H), 3.42 (m, 1H), 3.80 (m, ih) 5 4.20 (m, 2H), 4.22 (s, 2H), 4.55 ( m, 1H), 7.0 (m, 3H), 7·3 〇 (m, 5H). Mass Spectrum: (M+H)+ = 499 〇C·(28,3§,58)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-amino- 1-Phenyl-6-methylheptane • The desired compound was obtained by the procedure of Example 1N using 'the third-butoxycarbonyl protecting group from the compound of Example 27B was removed'. 3 megahertz! H NMr 〇(CDC13) 5 〇·9〇(d, Bu 3 Hz, 3H), 〇94 (d, J = 3 Hz, 3H), 1.60 (m, 4H), 2.20 (s5 6H), 2.85 (m, 2H), 3.0 (m, 1H), 3.85 (m, 1H), 4.20 (m5 2H), 7.0 (m, 2H), 7.35 (m5 6H). Mass spectrum: (M+H)+ == 399. D·(28'38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-2-one) _3_曱基丁醢基]Aminophenyl-6-methylheptane The amine oxime compound from Example 27C was coupled with the acid from Example 2A using standard coupling procedures (EDAC/DMF) to give the desired compound of. 3 〇〇 炫 H H NMR (CDC13) 5 〇·88 (m5 12H), 1.67 (m, 2H), 1.90 (m, 1H) 5 2.20 (s, 6H) 5 3.0 (d, J = 8 Hz, 2H ), 3·22 (m, 4H), 3.67 (m, 1H), 3·77 (m, 1H), 4·20 (s, 2H), 4.40 (m, 1H), 4·76 (m, 1H) ), 7·0 (m, 3H), 7·30 (m5 5H). Mass Spectrum: (M+H)+ = 581 ° Example 28 (2S'3S'SS)_2-(2,6-Dimercaptophenoxyethyl)amino-3-hydroxy-5-[2S-(l- Tetrahydropyrimidine_2,4-dione)_3_mercaptobutyl]aminobenzene

O:\106\106749.DOC-112-200817349 _6-methylheptane The amine-based compound from Example 27C was coupled with the acid from Example 25D using a standard coupling procedure (EDAC/DMF). The desired compound is obtained. 3〇〇 megahertz] HNMR (CDCl3) 5 〇.83 (d, J = 7 Hz, 6h) 〇92 (t, J 7 Hz, 6H), 1.73 (m, 2H), 2.18 (s, 6H) ), 2.30 (m, 1H), 2-62 (m, 2H), 3.03 (m, 2H), 3.45 (m5 1H), .3.55 (m, 1H)5 4.72 (m, 2H), 4.20 (m, 4H), "ο (br d,] = 9 Hz, ih), 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-1hydroxy-5-[2S-(l-hexahydropyrazine-2,3-dione ) 夂 夂 夂 夂 夂 夂 胺 胺 胺 胺 胺 胺 胺 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 The hydrazine diimidazole was added to a solution of 0.77 g of N-( +oxy-Ik-based fe-)-ethyl acenamate in 20 ml of toluene and 1 ml of acetonitrile. The reaction mixture was kept at 50. 24 hours at ° C, and add 2 g of oxazolidine diimidazole. The reaction mixture was kept at 5 (rc for another 72 hours. Evaporate the solvent in vacuo) and by means of Shixi rubber column chromatography (1 〇% Et〇Ac, purified in CH^ci2) to give the desired compound. 3 〇 Hz NMR (CDC13) 5 0.95 (d, J = 7 Hz, 3H), 1·〇3 (d, J = 7 Hz, 3H), 2.20 (m, 1H), 3.60 (m, 1H), 3.73 3,3,5,5,5 5H) Mass Spectrum: (M+H)+ = 380. O:\106\106749.DOC -113 - 200817349 Β· 2S-(1-hexahydropyrazine-2,3-dione)-3-A ^ ▲ Τ Τ Τ 甲酯 虱 虱 虱 虱 ' 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用.· MHz 4H NMR (CDC13) 5 0.95 (4^7 du from 7 Hz, 3H), 1.03 (d, J = 7 Hz, 3H), 2 2 〇 ( 1H) 3 5 〇) vm5 3H)? 3.74 (s ? 3H), 3.83 (m, 1H), 5.0 (d, J = l〇 Hertz, 1H), 7 3 (W, „, 八/·(bl« s,m) 〇 mass spectrum: (M+H) + = 229 〇

C. (4) Mail--from dimethyl phenoxyethyl ketone to keto-carbyl-5-[2S-(l-hexahydroindole_2,3_dione)_3_methylbutanyl]amine- A kiln was used to hydrolyze the vinegar from Example 29B and the resulting acid was coupled to the amine compound from Example m using standard EDAC coupling procedures to give the desired compound. 3〇〇 megahertz lH NMR (cdcij 〇·82 (d5 J = 6 Hz, 3 Η), 〇·85 (d, j := 6 Hz, 3H), 18 〇 (10), 2H), 2.18 (m? 1H ) 5 2.20 (s5 6H)? 2.65 (m? iH)? 2.82-3.0 (m5 4H)5 3.30 (m? 3H)? 3.70 (m? iH)? 3.82 (m? lH)5 4.22 (m5 3H)5 4.54 (d, J = l 〇 Hertz, 1H), 6·30 (br, s, 1H), 6 65 gamma d, 1H), 7.0-7.30 (m, 13H). Mass spectrum: (m+h)+ = 643. Example 30 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)amino-3_hydroxy-S-[2S-(4-aza-4,5-dehydrogenation) Pyrimidine_2-keto)_3_methylbutanyl]amino-1,6-diphenylhexanin A·2S-〇4-aza M,5-dehydropyrimidine_2__yl)_3_fluorenyl Butyric acid from the hydrolysis product mixture of Example 26F, in column chromatography O:\106\I06749.DOC *· 114- 200817349

The desired product was isolated after MeOH/5G / EtOAc (m.p. 300 MHz iH NMR (CD3OD) 5 〇·93 (d, J = 7 Hz, 3H), 1·〇4 (d, J = 7 Hz, 3H), 2·20 (m, 1H), 3.92 (dd,j = 15, 3 Hz, ih) 5 4.0 (dd, J = 15, 3 Hz, 1H), 4.50 (d, J = 10 Hz, 1H), 6.95 (t, J = 3 Hz, 1H) . Mass spectrum··(m+H)+ = 334. Ο Ο ^•(28,38,58)-2-(2,6-diamidinophenoxyethyl)amino-3_ylamino-5-[2S-(4-aza-4,5 -dehydro-1-pyrimidin-2-one)-3-methylbutanyl]aminodiphenylhexane The compound obtained from the example iN was passed through a standard example using a standard coupling procedure (EDAC/DMF). The acid coupling of 30A gives the desired compound. 3 〇〇 Hz NMR (CDC13) d 0.80 (d, j = 7 Hz, 3 Η), 〇·85 (d, J - 7 Hz, 3 Η) 5 1·75 (m, 2 Η), 2.15 (m, 1 Η) ),2·20 (s,6Η), 2.62 (m5l H), 2.85 (m? 1H)3 3.02 (m5 2H)5 3.55 (m5 2H)? 3.80 (m,1H), 4.20 (m,4H), 6.38 (br d,1H), 6.72 (t, J = 3 Hz, out), 7.0 (m, 3H), 7.22 (m, 10H), 7.63 (s5 1H). Mass spectrum: (m+H)+ = 628 〇 Example 31 cis-N-tert-butyl·decahydro-2-[2(R)_hydroxy_4_phenyl-3(S)_(2S_(1_four Hydropyrimidin-2-one)-3-methylbutanyl)aminobutyl b (4,8)_isojunolin-3(S)-carboxamide can be prepared using standard coupling procedures (in DMF) EDAC) by the product of Example 2 A with cis-N-tert-butyl-decahydro-2-[2(R)-hydroxyphenyl-3(s)-aminobutyl: R4aS, 8aS - Isoquinoline-3(S)-carboxamide (disclosed in U.S. Patent No. W09426749 and U.S. Pat. No. 23, 1993, issued on March 23, 1993, U.S. Patent No. 0:\106\106749.DOC-115-200817349 5, The title compound was prepared by coupling in 196, 438, which is incorporated herein by reference. Example 32 cis-t-butyl-decahydro-2_[2(R)-hydroxy-4-phenylthio-3(8)-(28-(1-tetrahydropyrimidin-2-one)-3- Methylbutenyl)aminobutyl]-(4aS,8aS&gt;isojun-3-(S)-carboxamide can be prepared by standard coupling procedure (EDAC in DMF) by using the product of Example 2a ◎ cis-N-tert-butyl-decahydro-2_[2(R)_hydroxy-phenylphenylthio-3(S)-aminobutyl]-(4aS,8aS)-isoindoline-3 (S _ Carboxylamine (disclosed in PCT Patent Application No. W〇95/〇9843, published on April 13th, and US Patent No. 5,484,926, issued on January 16, 2016, The title compound was prepared by coupling as described herein. Example 33 4-Amino-N-((2 cis,3S)-2-hydroxyphenyl_3_(2-heart (1-tetrahydropyrimidin-2-one) Benzyl-3-methylbutyrylamido)butyl)-N-isobutyl-benzenesulfonamide A standard coupling procedure (EDAC in DMF) can be used by using the product of Example 2 and 4-amine. -N-((2cis,3S)-2-hydroxyphenyl-3-amino)-butyl)isobutyl-benzenesulfonamide (disclosed in the patent application filed on March 17, 1994) In WO94/05639, it is incorporated herein by coupling, Preparation of the title compound. ) · Alternative preparation of (2S,3S,5S)-2-(2,6-:methylphenoxyethylamino-3-hydroxy-s-aminodiphenylhexane The method is provided with a mechanical stirrer, a degree probe, a dropping funnel and a dropping funnel.

0: \106\106749.DOC -116- 200817349 In a 1 liter 3-neck flask of anhydrous nitrogen line, 30.0 g (54.87 mmol) of the product of Example II and 120 ml of acetonitrile were charged. The resulting slurry was cooled to 〇_5〇c, and 54.1 g (549 mmol) of 37% aqueous hydrochloric acid was slowly added, maintaining the internal temperature not exceeding +5 during the addition. (3. Grant the reaction mixture in 〇-5. 〇 and periodically take the sample by HPLC (zorbax column, - mobile phase = 1:1 acetonitrile / 0·1 ° / 〇 aqueous phosphoric acid, flow rate = Analyze the consumption of the starting material at 1.25 ml/min.). ^ The reaction was completed after stirring for 3 hours. The reaction was carried out by slowly adding 105 ml of 20% aqueous sodium hydroxide. The internal temperature was again maintained at +5 ° C during the addition. Once the reaction mixture was confirmed to be basic, the solution was warmed to room temperature. Ethyl acetate (18 mL) was added. After stirring, the lower liquid phase was separated and discarded, and then the organic phase was washed once with 10 ml of 10% aqueous sodium chloride. The title compound was obtained from 12 ml / g of 1:2 ethyl acetate / Geng Shaozhong, Shishijing (yield 80-85%) Q. 另一·Another preparation of (2S,3S,5S)-2-(2,6-dimethyl ethoxyethoxyethyl)amino-3 -Hydroxy-5-amino-1,6-diphenylhexane method The product of Example II was added to a round bottom 3-neck 1 liter flask containing a mechanical tax drop rod and thermometer. 51.6 g, 0.095 mol) and 100 ml of glacial acetic acid. Add 35% aqueous HCl (1 〇 5 ml, 0.103 mol) to the resulting suspension. Allow the solution to stir for 3 hours under &amp; At this point, add an additional 1 0.5 ml of 35% aqueous HC. After an additional 5 hours, the reaction flask was immersed in an ice bath and NaOH was added at a rate to maintain the internal temperature of the flask below 30 °C. Solution (16 ml, 〇·198 mM). Add O:\106\106749.DOC •117- 200817349 water (200 ml) and extract the mixture with 4 x 200 ml of isopropyl acetate. 2.5 M NaOH (2 x 20 mL), 1 mL of H.sub.2 H.sub.sub.sub.sub. 95% purity. The product can be purified in one step by dissolving the product in 2 ml of isopropanol, heating in a steam bath, allowing to cool to 〇-5 ° C and stirring to yield 32.2 g (76). %) desired product, melting point = 131. 〇. _ Example 35 〇 Alternative preparation 2S-1 Method for (1-tetrahydrogenate 2-keto)-3-methylbutyric acid Α·N-phenoxyl-yl-lysine can be applied according to US Patent Application No. 28, 1996 The procedure disclosed in U.S. Patent Application Serial No. 08/08/67, No. 893, which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety, in In the reactor of the cooler, pH probe and thermocouple, add lithium gasification (15·6 g, 386 mol), L·proline (26 〇 〇, 222 mol), neutral 矾Soil (8.1 kg, 150 mesh, Aldrich) and 156 kg of distilled water. Mix this uneven mixture and cool to _ 14. 〇 +5 °c. The pH was adjusted to 1〇1 with ίο% aqueous lithium hydroxide. Pre-cooled (-20 ° C) gasified phenyl formate (36. 6 kg, 234 mol) was added while maintaining the temperature below -9 ° C, and during the reaction with continuous addition of 1% water Lithium hydroxide was used to control the pH (the pH was maintained in the range of 9·5 to 1 〇·5, and the target was 10.0). The reaction was stirred at about -14 ° C for 2 hours. The reaction mixture was transferred through Shixiazhu soil and the filter cake was rinsed with 42 kg of distilled water. Methyl third-butyl

O:\106\106749.DOC -118- 200817349 Ether (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. Is the stirred two-phase solution adjusted to 25% (w/w) sulfuric acid? 11 value 18_2〇. The toluene layer was concentrated to no more than 40 C, to about 12 liters, filtered (3 gram kilograms of benzene washed), and then concentrated to about 12 liters at no more than 40 tons. 44.2 kg of heptane was added to the resulting solution, and the resulting solution was heated to 40 C ± 10 ° C for 15 minutes. Remove the heat source, seed the solution, and stir the instrument. The product was crystallized on the wall of the reactor and resuspended in 8 Torr of toluene, concentrated to about 13 liters at not more than 50 t: and then added 45. 2 kg of heptane. The resulting solution was then heated to 4 Torr. 〇±1〇 It is at least 15 minutes, then 2 〇. (: The following / hour rate is cooled to 18 ^ ± 5 C. After not less than 12 hours, the resulting white silt is cooled to j4 C ± 5 C ' and stirred for more than 3 hours. Filtering the white slurry And rinsing the solid with 4 丨 kg of 1-1 of a benzene/g. The solid product was dehydrated under no more than 5 Torr to give the desired product (47·8 kg) as a white powder. 2S-(1-tetrahydropyrimidin-2-yl)-3-methylbutyric acid N-phenoxycarbonyl-L-proline (25 g, 0.106 mol) and 3 in THF (250 mL) a mixture of chloropropylamine hydrochloride (15.2 g, 〇116 mol) was cooled to fc. Sodium hydroxide (12,7 g, 0.31 8 mol) was added to the stirring suspension. After about 35 minutes, A slow exotherm occurred to 1 ° C. The reaction was stirred for 2 hours below 10 ° C. To the third potassium butoxide in 125 ml of THF was added over a period of 10 minutes (29·6 g, ο·%5) Mohr), followed by rinsing with 2 liters of THF. During the addition, the temperature of the reaction mixture was allowed to rise to 20 V. The reaction mixture was stirred at room temperature for 19 hours. O:\W6\W6749. DOC -Π9- 200817349 The reaction mixture was quenched with 200 ml of distilled water, then acidified to pH 9 with 26.2 g of concentrated hydrogen acid, keeping the temperature below 30 ° C. The liquid layer was separated and an additional 125 It was rinsed with THF. Ethanol 3A (75 ml) was added to the separated liquid layer, and the mixture was acidified to pH &lt;3 with 12.3 g of concentrated hydrochloric acid, keeping the temperature below 25 ° C. (250 ml-liter and 150 ml) extract the mixture that has been acidified twice. On a rotary evaporator, the mixed organic layer is evaporated to anhydrous at a temperature below 50 ° C. 0 to 2 5 liters of acetic acid The residual solid was washed with ethyl acetate, and the residual solid was dissolved in 150 ml of ethanol 3A at reflux temperature and filtered through a 5 g pad of Darco-G60 coated with a filter aid, followed by 5 ml of hot ethanol. The filtrate was evaporated to dryness on a rotary evaporator 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. 2 hours. Collect solids by transition and take 2〇 Evaporate cold ethyl acetate (5-8. 〇 rinse. At 40: (: after 72 hours of dehydration, the desired product was obtained as a white solid (15·6 g, 74 〇/〇). Q Example 36 Preparation of 2S-(1-tetrahydropyrimidin-2-one)_3_methylbutyric acid phenoxycarbonyl-L-proline (250 g, ι·05 mol; according to June 28, 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 content The mixture in it was cooled to 2 it. Sodium hydroxide (127 grams, 32 moles) was added to the stirring suspension. After about 45 minutes, a rapid exotherm occurred to 1 〇 &lt; 3 (:.), the reaction was stirred for 2 hours, and additional 3 chloropropylamine (1 gram, 〇〇 8 moles) was added. And hold O:\106\106749.DOC -120- 200817349 and continue to mix for 1 hour. Then add 30-butan potassium potassium (296 g, 2·6 mol) in 丨25 liters of THF within 30 minutes. The solution was then rinsed with 1 mL of THF. During the addition, the temperature of the reaction mixture was allowed to rise by 1% to 20 C'. The reaction mixture was stirred at room temperature for 12-16 hours. The reaction mixture was quenched and cooled to 12, then acidified to pH 9 with 258 g (2.6 mol) of concentrated hydrochloric acid. The temperature was kept below 30 C. The liquid layer was separated. Ethanol 3a 0 (625 house liters) was added to the liquid layer and the mixture was acidified to pH &lt; 3 ' with a concentration of 116 g (1.2 mol) of concentrated hydrochloric acid. The acidified mixture was treated with acetic acid. Extracted twice (2.5 liters and 1.5 liters). On a rotary evaporator, mix organic at temperatures below 50 °C. The layer was evaporated to dryness. The residue was repeatedly dried by distillation with ethyl acetate (4 X 1 liter). The residual solid was dissolved in 75 ml of methanol and decolorized with carbon (1 g)

Darc(R)-G60(R) treatment, overnight at room temperature. Carbon is removed by passing through the diatomaceous earth. The filtered CJ solution was decanted to dryness at a temperature below 5 Torr &lt; t on a rotary evaporator. Ethyl acetate (1.5 liters) was added to the residue and divided by about 5 Torr in a rotary evaporator. The suspension was cooled to below 1 (C) for several hours. The solid was collected by filtration and washed with 2 X 100 mL cold ethyl acetate (5-8t). After dehydration at 5 ° C for 72 hours, the desired product was obtained. Example 37 Another method for preparing 2S-(i-tetrahydropyrimidin-2-one)-3-methylbutyric acid Α·(S)·(一)_Ν·carboxymethyl-N(y5)cyanoethylproline In a 5 liter 3-neck flask with mechanical stirrups, add (8) salicylate

O:\106\106749.DOC -121 - 200817349 (m", i.45 mol) and water 145 ml. The solution was cooled to 0 C in an ice water bath, and a solution of the work-equivalent KOH (93 g of 88% solid K?H) in 18 ml of water was added dropwise over 20 minutes. After the addition was completed, acrylonitrile h〇 (95·5 ml) was added dropwise and vigorously mixed while maintaining the internal temperature of the flask below 5 cC. Allow to stir between 〇_yc • This solution is 4.5 hours. Water (6 ml) was added and a pH meter was inserted into the solution. The vaporized formazan formazan 1.0 equivalent (112 ml) was added dropwise while maintaining the pH of the solution between 9.5 and 1 〇·5 using p: 1 〇 ° / 〇 aqueous KOH. This addition was carried out within 0.5 hours. The solution was then Islized to pH 2 with a concentration of 11:1 and phosphoric acid, and then extracted with 2 liters of isopropyl acetate. The organic layer was concentrated under vacuum to give 201 g (60%) of colorless oil. It will solidify upon standing. Melting point 65-66 ° C. The optical rotation of the sodium lanthanum line at -25 ° C is -0.44 (c = 4.3, ethanol). IR (cm-1, CDCl3) 2960, 174 〇, m 〇, 147(). NMR (300 MHz, CDCl3); TMS, 〇〇〇) ppm 〇% (4) 3H, J = 7 Hz), L07 (d, 3H, j = 6 Hz), 2.16-2.36 (m , 1H), Q 2·62-2·86 (m, 2H), 3.62 (t, 2H, J = 7.5 Hz), 3.77 (s5 1·2Η rotating body), 3.82 (s, 1.8H, rotating body) , 4.15-4.30 (m, 1H), 9.76-9.96 (brs, lH). Ms (CDI/NH3) 246, 185, 146, 125. FABhrms: Calculated value for (m+H)+ · 229.1 188 ; Experimental value: 229.1 185 〇Β· 2S_(1-tetrahydropyrimidin-2-one)-3_methylbutyric acid in a 2 liter pressure bottle The product of Example 37A (190 g, 0.833 mol), water (900 mL) and K0H (3 eq. At the ambient temperature, 75 g of a nickel-aluminum alloy (in-situ type) was added to the solution. Note that this is in the form of activation without O:\106\106749.DOC-122-200817349. The solution was sealed in a pressure bomb and placed under a hydrogen pressure of 6 psi. The resulting solution was heated to i 〇〇. . 4 hours. After cooling the solution to ambient temperature, it was filtered, rinsed with 9 mL of dioxane = followed by acidification to pH 1. The aqueous/liquid mixture was extracted with 2 X 900 ml of dichloromethane. The combined organic layers were concentrated to give 12 g of crude material, which was crystallised in isopropyl acetate to afford 70 g of the title compound. Example 38 0 Alternative Preparation of (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-indole 28·(1_tetrahydropyrimidine_2 _keto)_3_methylbutylidene]Amino-1,6-diphenylhexanin method Α-1· 2S-(1-tetrahydropyrimidin-2-yl)_3_methylbutane oxime 2S -(l-rahydropyrimidin-2-yl)methylbutyric acid (17.6 g, 87·9 mmol) was slurried in THF (240 mL) and cooled to &lt;5&gt; Thionite chloride (14.3 g, 120 mmol) was added over 5 minutes (exothermic). The slurry was stirred at 2 ° C for 70 minutes until the completion of *HPLC (the sample was quenched in methanol). The THF was removed by rotary vaporization; heptane (90 mL) was added and removed by rotary vaporization to give a damp solid mass. This material was slurried in DMF (85 mL). Α·2·Another method for preparing 2S-(1-tetrahydropyrimidin-2-one)-3_fluorenyl fluorene gas

2S-(1-Tetrahydropyrimidin-2-one)-3-methylbutyric acid (39 6 g, 198 mmol) was slurried in THF (590 mL) and cooled. Thionite chloride (28.3 g, 238 mmol exotherm) was added within 5 minutes. The slurry was stirred at 2 ° C for 2 hours. The THF was removed on a rotary evaporator; THF O:\106\106749.DOC -123 - 200817349 wet solid block was added. (200 ml) and removed on a rotary evaporator to obtain a moisture which allowed the material to form a slurry in DMF (225 mL).

(28,38,58)-2 ratio]^dibenzylamino-3-cyanopyrimidin-2-one)-3-methylbutanyl]amino group _]L,6_diphenyl Ethylene ( 28,38,58)-2-&gt;1,&gt;^-dihanylamino-3-transyl-5-amino-16-benzoic acid (about 83 millimolar; February 13, 1996曰Applying US $2,491,253, incorporated herein by reference) and imidazole (82 g, 〇Ο 120 mmol) dissolved in ethyl acetate (350 ml, KF &lt; 〇i%) * and cooled to 2 °C. The product of the slurry formed in Example 38A4 was added (exothermic, maximum temperature was 1 Torr. 〇, then rinsed with DMF (15 mL). The reaction was stirred and started to be ice-cold, then allowed to slowly warm to room temperature. Stirring was continued overnight. The reaction was quenched with 100 mL of water and stirred for 3 min. The organic layer was separated and washed with 3 X 125 mL of 5% NaCI. The crop is condensed into a viscous sugar, 62 g. The HPLC purity is about 85% (Shangfeng District). The isomer content is about n.2% CIMS (NH3) m/z 647 (M+H)+ NMR (300 megahertz, CDCl3) δ 7 35-7 1〇(m,1〇H), 7.13-7.06 (m3 1H)5 6.87 (br d3 1H)5 5.22 (br s5 1H)5 4.28 (d5 1H ) 4.20-4.05 (m5 iH)? 3.95 (d? 2H)? 3.65^3.56 (m? 1H)5 3.37 (d,2H),3.12-2.89 (m,5H),2.83-2.53 (m,4H) , 2.23-2.08 (m,1H),1.74-1.40 (m,4H)5 0.87-0.75 (m,6H). C NMR (75 MHz, CDC13) ά 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, 4 0.5,

O:\106\106749.DOC -124- 200817349 40.0, 39.7, 31.5, 25.4, 21.6, 19.5, 18.6. B-2. Another preparation (28,38,58)_2喟, engraved dibenzylamino _3_hydroxy 5 [2S (1-tetraqi' hexane-2-ketomethylbutanyl)amine 1-6 benzene The method of base-burning will be (2S,3S,5S)-2-N,N-di-arylamino-3-trans group, 5m,6.diphenylhexane (about 180 millimolar; 1996 2 U.S. Patent No. 5,491,253, the entire disclosure of which is hereby incorporated by reference in its entirety in 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 all And cooled to 1 C. The slurry formed product of Example 38A-2 was slowly added over 30 minutes (exothermic, maximum temperature 6 ° C), then rinsed with ethyl acetate (225 mL). The reaction was stirred for 1.5 hours, then allowed to slowly warm to about 27 ° C and stirred for about 20 hours. The reaction was quenched with a dilute solution of HC1 (36.75 grams of concentrated HCl in 225 ml of water) and stirred. After 20 minutes, the mixture of the two phases was filtered and rinsed with EtOAc (EtOAc). The organic layer was separated and washed with &lt;RTI ID=0.0&gt;&gt; % NaCl 2 X 225 ml of 5% NaHC〇3 rinse. Concentrate the organic solution by rotary vaporization to obtain the desired product as a viscous syrup. C·(28,38,58)-2-amino-3-hydroxy-5 -[28-(1-tetrahydro-choke-2-one)-3-methylbutanyl]amino-1,6-diphenylhexane The crude product of Example 38 (about 83 mmol) was dissolved. In methanol (260 ml), add Pd/C (50% moist Pearleman's catalyst, 1 〇·4 g wet weight) and ammonium formate (15.1 g, 239 mmol) and warm the mixture to 50 ° C. After 2.5 hours, the reaction was completed by TLC. The mixture was cooled to O:\106\106749.DOC-125-200817349 to 35 c, and the catalyst was removed by filtration through diatomaceous earth, followed by Washing with a scalp (referred to as ML). Concentrate the mixed filtrate on a rotary evaporator. Dissolve the residue in dioxane (150 ml) and warm it. Oxygen hexacyclohexane is removed on a rotary evaporator. 60 g of a yellow oil was obtained. HPLC purity was about 88.2% (same peak) 'isomer content ^ 7.9% (however, one isomer was not isolated from the main peak). CIMS (NH3) m/ z 46 7 (M+H)+ 4 NMR (300 MHz, CD3OD) (5 7·35-7·10 (m, 10H), 4.40-4.20 (m, 1H), 4.25 (d, 1H), 3.68 镰3.57 (m,1H), 3.20-3.09 (m,2H),3.08-2.90 (m,3H),2.90-2.74 (m,2H), 2.65-2.49 (m? 2H)5 2.20-2.04 (m? 1H) 1.92-1.78 (m3 1H)? 1.78-1.60 (m, 2H), 1·6 (Μ·45 (m, 1H), 0.88-0.77 (m, 6H) 13C NMR (75 MHz, CD3OD) 5 1 71 ·3,1 58.4,140·5, 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 4 NMR (300 MHz, CD3OD) ^ 7.35-7.13 (m, 10H), 5.35 (s5 1H), 4.40-4.23 (m, 2H), 3.60-3.52 (m, 1H), 3.25-2.65 (m,8H), 2.58-2.45 (dd,1H), 2.30-2.10 (m,1H), 1.90-1.65 (m,3H),1.65-1.50 (m,1H),0.91 (d,3H),〇 · 84 (d, 3H) 13C NMR (75 MHz, CDC13) 5 171 · 2,1 56.6, 139.1, 138.5, 129.3, 129.2, 128.5, 128.2, 126.3, 126.0, 71.6, 63.1 (br)5 56·3 , 48.7, 41.6, 41.0, 40.6, 40.0, 39.6, 25.5, 21·7, O:\106\106749.DOC -126- 200817349 19·7, 18· 7 D· (2S,3S,5S)-2_Amino-3-hydroxy_5-[2S-(l_tetrahydropyrimidin-2-one)-3-methylbutanyl]amine q,'diphenyl The charred glutamate was dissolved in the crude product of Example 38C in dioxane (37 mL, KF == 0.07% moisture). S-pyroglutamic acid (10. 3 g, 80 mmol) was added and the suspension was warmed to 50 C to give a clear solution. After 1 hour of soaking, the solution was sown with a small amount of product salt crystals. Slowly sink the salt. The slurry was slowly cooled and stirred at room temperature overnight. The product was isolated by filtration and washed with dioxane (1 mL). The wet cake weight is Uq grams. The product was dehydrated by purging with nitrogen in a vacuum supply phase of 6 ° C. Produces 3 $ · 2 g of gray-white powder. HPLC purity &gt; 98% (peak zone includes pyroglutamic acid). The isomer 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 (M+H on test)+, 147 (M+NH4 on pyroguanidine)+, 130 (on coke m+H)+ IR (Kbr) of glutamic acid 1586, 1655, 1682 cm NMR (400 MHz, DMSO-d6) (5 7.62 (s5 1H)5 7.54 (d5 1H), 7.32-7.06 (m, 10H ), 6.33 (s, 1H), 4.26 (d, 1H), 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 (m5 2H), 2.92-2.70 (m, 5H), 2.53-2.43 (m? 1H), 2.26-2.14 (m5 1H)? 2.13-1.99 (m5 2H) 1.99-1.87 (m? 2H)5 1.72-1.61 (m? 2H)5 1.61-1.49 (m? 1H)5 O:\106\106749.DOC -127- 200817349 1.46-1.35 (m,1Η),0·70 (d , 3H), 0·64 (d, 3H). I3C 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 ο 4 NMR (300 MHz, CD3OD) δ 7.32-7.03 (m, 10H), 4.23-4.12 (m,1H), 4.12 (d, 1H), 3.98 (dd5 1H), 3.71-3.63 (m, 1H)? 3.46-3.37 (m? 1H)? 3.11-2.98 (m5 2 H)? 2.97-2.80 (m5 4H)5 2.70-2.59 (m? 1H)5 2.49-2.38 (m5 1H), 2.38-2.12 (m5 3H)? 2.07-1.92 (m? 2H)? 1.75-1.63 (m 2H)5 1.63- 1.50 (m? 1H), 1.45-1.32 (m, 1H), 0.74-0.65 (m, 6H). 13C NMR (75 MHz, CD3OD) δ 1 8 1 ·0,1 79.6,17 1.6, 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) (5 7.30-6.97 (m, 10H), 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 (m5 3H)? 1.68-1.56 (m? 1H)5 1.52- 1.37 (m? 1H)? 1.32-1.18 (m,1H), 0.60-0.52 (m,6H). 13C NMR (75 MHz, D20 ) 5 181·6,180.1,171.0, 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- 200817349 Ε· (28,38,58)-2-(2,6-Dimethylphenoxyacetamidine Amino-3-carbyl-5-[2S-(l-tetrahydropyrimidin-2-one)-3-methylbutanyl]amino-if diphenylhexane to give the product of the shell 1H ( 7.26 g, 40.3 mmoles in ethyl acetate (22 A slurry was formed in ML), and sulphur sulphur gas (5·75 g, 48·3 mmol) was added, followed by a drop of DMF. The mixture was warmed to 50 ° C and stirred for 5 hours. The obtained mercapto chloride solution was cooled to 22 ° C and applied to the subsequent coupling reaction. 0 The product of Example 38D was mixed in a flask (20 g, 31.7 mmol, corrected for dioxane content) Sodium bicarbonate (16.5 g, 197 mmol), ethyl acetate (150 mL) and water (15 mL) and stirred until the product of Example 38D had dissolved (some salts remained insoluble). A solution of the above-prepared decyl chloride was added over 5 minutes, followed by rinsing with ethyl acetate (5 mL). The addition is mildly exothermic (maximum temperature is 23r). The mixture was stirred overnight. The organic layer was separated and washed with 5% sodium bicarbonate (1 mL) and water (1 mL). Remove the solvent on the rotary evaporator. The residue was dissolved in EtOAc EtOAc (EtOAc)EtOAc. The solvent was removed from the mixed filtrate on a rotary evaporator. The residue was dissolved in hot ethyl acetate (m.sub.5 mL). The slurry was cooled and stirred at 2 〇 23 t for an hour. The product was collected by filtration and washed with l/i (v/v) ethyl acetate/heptane (30 ml). At 70. (: The product was dehydrated under a vacuum oven, I to 1 8.8 g of the desired product as a white powder. Example 39 Preparation of amorphous (28,38,58)-2-(2,6-dimethylphenoxyethyl) Amidino) O:\106\106749.DOC -129- 200817349 -夂Hydroxy-5-[2S-(1-tetrahydropyrimidinyl)-3-mercaptobutyl]amino-1,6-diphenyl Hexane A· The product of Example 38E (2.5 g) was dissolved in 8 mL of absolute ethanol. The solution was slowly added dropwise to 25 liters of liters of hydrazine, and stirred vigorously. The solid was continuously stirred for 5 minutes and the solid was collected by filtration. Vacuum dehydration at 50 ° C for 12 hours gave 2.32 g of the desired product as an amorphous solid. 2.5 g) was dissolved in 6 ml of absolute ethanol. The solution was slowly added dropwise to 3 ml of cold water and vigorously scrambled. A white solid appeared. Stirring was continued for 2 minutes and filtered. The solid was collected and vacuum-dehydrated at 50 ° C for 12 hours to obtain 2,24 g of the desired product as an amorphous solid. C. The product of Example 38 (〇·5 Dissolved in 8 ml of isopropanol. The solution was slowly added dropwise to 1 ml of cold water and vigorously scrambled. A white solid appeared. Stirring was continued for 2 min and filtered. The solid was collected by air-drying to give the desired product as an amorphous solid of 48 g. 〇································· The solution was slowly added dropwise to 1 mL of 1 Torr of 15 cc of cold water and stirred vigorously. A white solid appeared. Stirring was continued for 1 〇ίί ' and the solid was collected by filtration. 46 g of the desired product in the form of an amorphous solid. Ε· The product of Example 38 (5 g) was dissolved in 2 ml of acetonitrile. The solution was added dropwise to 丨〇〇ml 1 〇 丨 5 It is in cold water and stirred vigorously. A white solid appears. Stirring is continued for 2 minutes and collected by filtration.

O:\106\106749.DOC -130- 200817349 The solid. Air dried to give 0 46 g of the desired product as an amorphous solid. Example 40 N-(3-Actylpropylaminocarbonyl&gt; Methyl prolinate added 3-chloropropyl isocyanate (〇·31 ml, 3.〇 mmol) to thf (1〇 pen L) a slurry of L-methyl carbamide hydrogenate (〇·5 g, 3 〇 mmol) and triethylamine (0.42 ml, 3·〇 mmol). Stir at room temperature. The reaction was quenched for 4 hours, then quenched with aqueous sodium bicarbonate. The reaction mixture which had been quenched was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product. Example 41 (2S, 3S,5S)_2_(2,6·Dimethylphenoxyethyl)amino-3_hydroxy-5-[2S-(l-tetrahydro-4-hydroxy-pyrimidin-2-yl)_3_ Methylbutanyl]amino-1,6-diphenylhexane A solution of the product of Example 25E in dichloromethane was reacted with sodium borohydride to give the desired product. Q Example 42 (2S, 3S, 5S )-2-(2,6-dimethylphenoxyethyl)amino-3_hydroxy_5_[2S-(1-tetrahydro-6-hydroxy-pyrimidin-2-one oxime methyl fluorenyl) Amino-1,6-diphenylhexanone rc, will have been completed on the base group of the ethyl oxime moiety in % (5M M' 6.0 microcurie) (2S, 3S, 5S)_2_(n-methylphenoxyethyl)amino-3-carbyl-5-[2S_(1_tetrahydro_6_pyridyl m嗣3) _3_methylbutylidene] Amino-1,6-diphenylhexine 3 〇〇 ml culture with rat liver microsomes (0.5 mg/ml microsomal protein) and NADpH_produce O:\ I06\106749.DOC-131 - 200817349 The system was incubated for 60 minutes. The metabolic reaction was stopped by the addition of 300 ml of acetonitrile. The supernatant obtained after centrifugation at 3 RPM for 10 minutes in vacuo was evaporated to dryness. Reconstitute the residue in 2 mL of HPLC mobile phase. Separate the desired product at ambient temperature using a Bechman Ultrasphere 5 micron 10 X 150 mm C18 tube_column connected with an Alltech Ultrasphere 5 micron C18 cartridge protection column. Using a linear gradient of 25-55% acetonitrile in a buffer solution (25 mM ammonium acetate, adjusted to pH of formic acid to 4·8) at a flow rate of 2.8 ml/separation as a column Eluate. Fluorescence generation assay for screening inhibitors of HIV protease can determine the compounds of the invention by the following methods Inhibition of potency. The compound of the invention was dissolved in DMSO and a small aliquot was dissolved in DMSO to a desired concentration of the final concentration for the test at 6 x 50 mm for a total volume of 300 ml. The reaction was carried out in a test tube. The final concentration of each component in the reaction buffer solution was: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.53⁄4 g/ml bovine serum albumin, 13 # M fluorescence generation. 〇 Enzyme, 2% (v/v) dimethyl sulfoxide, pH 4.5. After the addition of the inhibitor, the reaction mixture was placed on a scaffold of a fluorometer compartment and incubated for several minutes at 3 ° c. Start by adding a small aliquot of ice-cold mv protease. Fluorescence intensity (excitation 34 〇 nm, emission 49 〇 nm) was recorded as a function of time. The reaction rate was determined in the first 6 to 8 minutes. The observed rate is proportional to the number of moles of enzyme being cleaved per unit time. The percent inhibition is 100 χ (1 - (the rate at which the inhibitor is present) / (the rate at which the inhibitor is absent. Fluorescence is produced by the enzyme. · Dabc汴Gabajerca AsnU. Ile-Val-Gln-EDANS, where DABCYL is slightly Dimethylamino 'phenyl)

O:\106\106749.DOC-132· 200817349 Azobenzoic acid, Gaba=r-aminobutyric acid, and EDANS = 5-((2-aminoethyl)amino)-indole-1-sulfonic 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 - 200817349 Antiviral activity The anti-mv activity of the compounds of the invention can be determined on MT4 cells according to the following procedure. The HivmB-free cell supernatant (using a known 5 〇% tissue culture infectious dose (tciD5 must be pre-frozen) was used to infect MT4 cells for one hour at a multiplicity of infection (M〇I) of 0·003. After infection, wash the cells twice to remove residual virus, resuspend in the medium, and seed together with various semi-log dilutions of the compound at a dose of 1 x 1 〇 4 cells per well at 96_ The wells were cultured on the plate. Uninfected cells were included in the toxicity and cell control groups. RpMI 16 (Gibc(R)) with l 〇y. fetal calf serum was used as the medium. Various concentrations of human serum were added to the medium. (sigma) 50%, 25%, and 12.5%, giving a final concentration of 60%, 35%, and 22.5% total serum. All assay plates were incubated in the incubator for 5 days at 37 ° C. In all wells Add MTT (Sigma, 5 mg/ml in PBS) for 25 hours at 25 μL per well, and add 20% SDS with 〇·〇2Ν HC1 in water in an amount of 50 μL per well. To dissolve the cells. To completely dissolve, culture the Q plate overnight at 570/650 nm. The strengths were read on a microtiter plate reader to determine the optical density (OD) of the cells. The original data was analyzed for percent inhibition by the following formula: OD·test well-OD·virus control group xlOO OD cell control group- The OD virus control group relied on the midpoint potency equation (Chou, 1975, Proc. Int. Cong.

Phamac〇i. Sixth Edition, p. 619) Calculates the 50% effective concentration (EC50) and determines the potency of the compound. 50% lethal concentration (LC5〇) was calculated using uninfected MT4 cells 〇0:\106\106749.DOC -134- 200817349 Under these conditions, the following data were obtained (n=4 repeated determination): Table 2 Example Compound IC5G (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 56 30B 0.003 18 O: \106\106749.DOC-135-200817349 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: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, disulfate, butyrate, camphor Acid salt, camphor sulfonate, digluconate, cyclopentyl propionate, dodecyl sulfate, ethane sulfonate, grape heptanoic acid salt, glycerol phosphate, hemisulfate, Heptanoate, hexanoate, fumarate, hydrogenate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (glyme) lactate, maleate , methanesulfonic acid 'salt, nicotinic acid salt, yttrium salt, oxalate, pamoate, pectate ester, persulphate, 3-phenylpropionate, picrate , pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. It is also possible to use, for example, lower alkyl groups such as methyl ethyl propyl and butyl chloride, bromine and moth; dialkyl sulphate such as dinonyl sulphate, diethyl sulphate, dibutyl sulphate and dipentane Esters, long chain halides such as decyl, dodecyl, tetradecyl and stearic acid chloride, bromine and iodine, aryl Q alkyl halides such as benzyl bromide and phenethyl bromide and others The formulation quaternizes 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, maleic acid, succinic acid and citric acid. Organic acid. Other salts include those formed with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases. Preferred salts of the compounds of the invention include hydrochlorides; decane sulfonates, sulfonates, phosphonates and isethionates. O: \106\106749.DOC -136· 200817349 The compounds of the invention may also be used in the form of esters. Particular examples of such esters include those in which the mesogenic groups in the compounds of the present invention have been thiolated with the following residues: N-protected or unprotected amino acid residues, phosphoric acid functions, half a succinate residue, a hydrazino residue of the formula R*C(〇), or R*C(S)_, wherein R* is hydrogen, lower alkyl, haloalkyl, alkoxy, • sulfur Alkoxy, alkoxyalkyl, thioalkoxyalkyl or ialkoxy, or of the formula Ra_C(Rb)(Rd)-C(0)• or Ra-C(Rb)(Rd)-C a sulfhydryl residue of (S)-, wherein Rb and Rd are each independently selected from hydrogen or a lower alkyl group, and 1 is -N(Re)(Rf), 〇Re or -SRe, wherein R&gt;Rf are each selected from a hydrogen, a lower alkyl group and an il alkyl group, or an amine-fluorenyl residue of the formula r18gNH(ch2)2-NHCH2C(0)- or Rm 丽(CH2)2〇CH2C(〇), wherein Rl8G is hydrogen, Lower carbon alkyl, aralkyl, cycloalkylalkyl, alkanealkyl, benzhydryl or a-amine fluorenyl. Amino acid esters of particular interest are glycine and lysine; however, other amino acid residues may be used, including those wherein the amine sulfhydryl group is -CCCOCI^NRmoRw, wherein (1) is independently selected from hydrogen and The low enthalpy number is a base or a group is a nitrogen contained in a heterocyclic ring. These esters serve as drug precursors for the compounds of the invention and increase the solubility of these materials in the gastrointestinal tract. These esters may also increase the solubility of the compound for intravenous administration. Other pharmaceutical precursors include those in which a hydroxy group on a compound of the invention is functionalized with a substituent of _CH(Rg)0c(0)R181 or -CH(Rg)OC(S)Rm, wherein Rm is a lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy group, and Rg is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminecarbonyl, alkylamino Carbonyl or dialkylaminocarbonyl. According to the procedure of SchreibeT O:\106\106749.DOC -137- 200817349 (Tetrahedron Lett. 1983 2d _ ^, 24, 2363), hunting for ozone in the methanol relative to the deer methacrylic acid vinegar This drug precursor is prepared by decomposition followed by treatment with acetic acid liver. The compound of the present invention is obtained by metabolizing the ruthenium of the present invention in vivo from &gt; The preparation of the drug precursor vinegar is carried out by reacting an amine sulfhydryl group, a thiol group, a half lysyl group or a thiol derivative as described above for activating the compound 6 of the present invention. The resulting product is then deprotected to give: oxime, precursor esters. The pharmaceutical precursor vinegar of the invention can also:

By the hydroxyl group and the (10) leuco) acetalization of the acetylation of the S chain, or the condensation of the base with the activated acid: followed by the esterification of the intermediate hemiacetal Prepared. The compounds of the invention may be used to inhibit retrovirus proteases, particularly proteases in vitro or in vivo (especially in drinking milk animals, especially in humans). The compounds of the invention may also be used to inhibit reversal of viruses, particularly human immunodeficiency virus (HIV), in vivo. The compound of the present invention ◎ can also be used for the treatment or prevention of diseases caused by retroviruses, particularly acquired immunosuppression syndrome, or HIV infection in humans or other mammals. The total dose per dose administered to a human or other mammal in a single or divided dose may be, for example, from 0.001 to 300 mg per kilogram of body weight per day, more commonly (U to 20 mg per kilogram of body weight per day). The dosage unit composition may contain a fraction of this amount to prepare a daily dose. The mixture is mixed with the carrier material to produce a single dosage form which will be administered depending on the host to be treated and the particular administration. Ways to change: 里O:\106\106749.DOC -138- 200817349 ο and 'will understand the unique dosage for any particular patient based on various factors, including the activity of the particular compound used, the annual private,,: :,:: general health status, sex, diet, time of administration, route of administration, rate of excretion, composition of the drug, and severity of the disease being treated. The compound of the present invention may be in the form of a dosage unit formulation, including a non-toxic pharmacy The desired carrier, adjuvant m " Ο Ο ::: parenteral administration, sublingual, by inhalation spray, rectal or topical technique. Topical administration It may involve the use of transdermal administration, such as a thin or ionic electroosmotic device. When parenteral L words are used herein, the tablets include subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Injectable articles For example, sterile injectable aqueous solutions may be formulated according to the known art, using suitable eight or humectants and suspending agents, including: suspensions. Sterile injectable preparations may also be in non-toxic parenteral. A sterile injectable solution or suspension in a diluent or solvent, such as a solution in = propylene glycol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic chlorination can be used. Sodium solution. In addition, sterile fixed oils have traditionally been used as a solvent or suspending medium. For this purpose, 'any mild solid oil can be used, including monoglyceride or = oil vinegar. Fatty acids, such as oleic acid, are used in the preparation of injectables. The suppository used for rectal administration can be obtained by administering the drug with a suitable non-irritating excipient such as cocoa butter and polyethylidene. The diol is mixed to prepare: it solidifies at room temperature, but liquefies at rectal temperature and thus will melt and release to the drug in the rectum.

O:\106\106749.DOC -139- 200817349 Solid dosage forms for oral use can be used in capsules, ingots, indigo, powders and granules. In such solid dosage forms, the active compound 混合 can be mixed with at least one inert diluent such as sucrose, lactose or starch/, guaranium f 4 U neck. The quinones may also include additional materials other than inert diluents, as in conventional practice, such as lubricants such as stearic acid. In the case of capsules, lozenges and pills, the dosage form; it may also contain a buffer. Tablets and pills can be additionally prepared with an enteric film

液体 Liquid dosage forms for oral use, including wind-acceptable milk cuts, solutions, suspensions, syrups, and sitin, containing inert diluents such as water commonly used in the art. Such compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents' and sweeteners&apos; flavorings and flavorings. 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 dish fats or other waxy 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 both natural and synthetic phospholipids and phospholipids (lecithin). Methods of forming vesicles are well known in the art. See, for example, Prescott, eds., Methods in Cell Biology, Book XIV, Academic Press, New York, Ν·Υ· (1976), page 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-140-200817349

Al-Razzak, S. Ghosh and R. Gao, filed an application for the name of Pharmaceutical Composition, which is incorporated herein by reference.较佳 较佳 A preferred dosage form of the compound of the invention comprises a compound of formula I in an amount of from about 1% to about 50%, preferably from about 5% to about 30% by weight of the total solution. And (b) a solution of polyoxyl 35 castor oil present in an amount of from about 〇% to about 20%, preferably from about 5% to about 1% by weight, based on the total solution, in the presence of pharmacy The acceptable organic solvent comprises (1) from about 2% to about 99% by weight of the total solution (preferably from about 30% to about 70%; more preferably from about 4%) % to about 65%) the amount of oleic acid present, or (ϋ) (ι), based on the weight of the total solution, from about 20% to about 99% (about 30% to about 70% compared to 疋k; Preferably, from about 4% to about 65%) of the oilfee present, and (2) from about 〇% to (preferably about 10%) by weight of the total solution of ethanol or Mixture of Propylene Glycol or Mixtures In a more preferred embodiment of the invention, the solution is encapsulated in a soft, flexible gelatin capsule (SEC), or a hard gelatin capsule. The preferred compositions of the invention, including (a) based on the weight of the total solution, Large, scoop 3〇% Luli exists in the formula! Compound, and (8) according to the weight of the total solution, in a large spoon of ίο / 〇 己 己 己 己 35 35 35 35 35 35 35 35 35 35 In the organic* agent, it comprises (1) a mixture of oleic acid ' and (2) in an amount of about 50% by weight of the total solution, based on the weight of the total solution, in an amount of about (10). In a preferred embodiment, the solution is encapsulated in a soft and flexible gelatin capsule (SEC), or a hard gelatin capsule, and the 兮·,,交,,,, and the seven people are y'', 匕έ from the weight of the total solution, from about 0.01% to about 0. 08% (preferably according to the weight of the total amount of gluten)

O:\106\106749.DOC • 141 · 200817349 0 · 01 % to about 0 · 0 5 %) Contains an antioxidant (preferably βητ (butylated hydroxytoluene)). Examples of such compositions and methods for their preparation are provided below. Ingredients Weight ❶ /. Example 2B compound (free base) Ethanol (USP, 200 standard strength) Polyoxyl 35 castor oil (Cremophor® EL) \ 〇 Oleic acid, 6321, NF ca

Butylated hydroxytoluene (BHT), NF Preparation of the above composition: 0.01 吹 Purge the mixing tank with nitrogen. Oleic acid (499·9 g) and ethanol (100 g) were mixed in the tank. Butylated hydroxytoluene (cardiac) was placed in the tank and mixed until the solution was clear. The compound of Example 2 (3 g) was slowly charged into the tank and mixed until the solution was clear. In the tank, oxime 35 castor oil (1 gram) was added and mixed. The resulting solution was filled into a soft and flexible capsule (0.33 g solution/SEC) to give a dose of 1 mg of the compound of Example 2B/SEC, or 667667 g/SEC. 200 mg of the compound of Example 2B / SEC dose. While the compound of the present invention is administered as the sole active pharmaceutical preparation, it may also be used in combination with one or more immunomodulators, antiviral agents, other anti-infective agents or vaccines. Other anti-caries agents that can be administered in combination with the compounds of the invention include 721, cold interferon, polymannide acetate, reverse transcriptase inhibitors (eg, dideoxycytidine (ddc; zalcitabine) )), dideoxygen: y: (ddI; dida letter (dida_n〇sine)),

O:\106\106749.DOC -142- 200817349 BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) , DP-AZT, FLT (fluorothymidine nucleus: y:), BCH-189, 5-halogen-3匕p-detoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT) ), nevirapine, delviridine, MSA-300, trovirdine and its analogues, non-nucleoside reverse transcriptase inhibitors (eg R82193, L-697, 661, BI-RG-587 (荇菲拉平), a protease inhibitor of retrovirus (eg Γ HIV protease inhibitors such as ritonavir, Ro 3 1-8959 (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)-benzoinyl-4(S)-hydroxy-5-( 1-(4-(3-pyridine) Mercapto)-2(S)-N^th-butyl-butyl-carbamicin)-hexahydropyridyl 11 well base))-pentyl decylamine (MK-639; Indinavir (i Ndinavir)),5(S)-Boc-q Amino-4(s)-hydroxy-6-phenyl-2(R)-benzoindolyl-(L)-proline-(L) -Phenylalanine-morpholin-4-ylguanamine, 1-oxoethoxyethyl-callo-methylthio-alanine-(2S,3S)-3-amino-2-hydroxy-4-butanyl-1 , 3-thiazolidine-4-tris-butylamine (ie 1-oxoethoxymethyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5·isoindolineoxy Ethyl-/3-methylsulfanyl-alanine-(2S,3S)-3-amino-2-hydroxy-4-butanyl-l,3-p-oxazolidine-4-tri-butylhydrazine Amine (also known as iQ〇a-Mta-Apns-Thz-NHtBu) and its analogues), 1 卩 化合物 compounds (1^, 697, 639, 1182150, 11-87201 and their analogues), HIV integrase inhibitors (Zintevir and its similar O:\106\106749.DOC-143 - 200817349), TAT inhibitors (such as RO-24-7429 and its analogues), trisodium phosphinate, HPA- 23, eflonithine, peptide T, reticulose (nuclear phosphoprotein), ansamycin (ansamycin) LM 427, trimetrexate, UA00 1, trinitrogen Ribavirin, alpha interferon, oxetano Cin), eautonol-G, cyclbut-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, vidarabine, famciclovir, plate Penciclovir, acyclovir, ganciclovir, castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, gold Hypericin, oxacin, 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, diethyldithiocarbamate, interleukin-2, alpha-interferon, muscle pranobex, methionine brain phenanthrene, cell wall thiol- Tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, interferon, 7 interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, α 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- 200817349 High immunity of 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, gp 120 (recombinant), Env2-3 (gp 120), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (gpl60), immune-Ag (gpl60), HGP-30, 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 Ansaraceae LM 427, 嘌呤-free nucleic acid, ABPP, AI-721, carrisyn, AS-101, avarol, azimexon, colchicine, compound Q, CS-85 , N-ethinyl cysteine, (2-oxooxazolidine-4-carboxyindole), D-penicillin, diphenyl carbazide, EL-10, erythropoietin, fusiform Acid, dextran, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-Oxol, and other p-quinolone (q/uinolone) Antibiotics, ruber polysaccharides, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, hexyl Pentofylline, pentoxifylline, peptide T, pineapple extract, polydextrose acetate, reticulin, retrogen, ribavirin, ribozymes ), RS-47, Sdc-28, strontium tungstate, THA, thymic fluid factor, thymopentin, thymosin fragment 5, thymosin α 1, thymostimulin, UA00 1, urine 17 ϋ定定核, Vitamin B 12 and wobemugos. Other formulations which can be used in combination with the compounds of the present invention are antifungal agents, such as O:\106\106749.DOC-145 - 200817349 Amphomycin (amphotericin) B, clotrimazole, flucytosine, fluconaz〇le, itraconazole, ketoconazole and mold And other analogs. Other preparations which can be used in combination with the compound of the present invention are antibacterial agents, such as amino acid sulfate, amikacin, azithromycin, citalopar ( Ciprofloxacin), tosufloxacin, Clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, Rampampin, sulphate and TLC G-65 and their analogues. Other formulations which can be used in admixture with the compounds of the invention are anti-neoplastic agents such as interferon alpha, COMP (cyclophosphamide, vincristine, amine saxophone and dehydrocortisone), etoposide ( Etoposide), mBACOD (amine oxime, porphyrin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP (dehydrocortisone, amine A) Dish (w/ leucovin rescue), doxorubicin, cyclopamine, taxol (tax〇i), chlorpyrifos / mechlorethamine, vincristine, dehydrogenation Procacal and procarbaZine), vincristine, vinblastine, angiostatin, polypentasulfate, platelet factor 4 and SP-PG and their analogs. 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, ritalin, lithium, elavil, phenytoin, Carbamazipine, slow

O:\106\106749.DOC -146- 200817349 Mexitetine, heparin and arabinose taste and their analogues. Other preparations which can be used in combination with the compound of the present invention are anti-protozoal agents, such as albendazole, azithromycin, caromycin, clindamycin, corticosteroids, and azide. Alkali (dapsone), DIMP, Aflonini, 566C80, fansidar, furazolid〇ne, L,671,329, letrazuril, 甲石肖° Metronidazole), paromomycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, growth Inhibitors of Hormone Release, Spiramycin, Sulfadiazine, Triterpenoids, TMP/SMX, Trimetrexate, and WR 6026 and Their Analogues Among the compounds for inhibiting or treating HIV or AIDS mixed with the compound of the invention, preferred are reverse transcriptase inhibitors, especially AZT (easy to determine), ddl (didanodine), ddC (shaxitaxel), d4T (Stadling), 3TC (Lami), Philippine, Defi Ruding, Chufiding PMEA, bis -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-)2(8)-&gt;^-(tris-butylcarbonylamine) - hexahydropyridinyl))-pentane decylamine (also known as indinavir) and related compounds, O:\106\106749.DOC -147- 200817349 Uncovered in Europe, announced on May 12, 1993 U.S. Patent No. 5,413,999, issued toK.S. Patent No. 5,413,999, the disclosure of which is incorporated herein by reference. _4•Phenyl 3(S) [[N-(2-quinolinylcarbonyl)-L_aspartate]amino]butyl M4aS,8aS)-isoindoline-3(S) _ Carboxamide (also known as saquinafil) and related compounds, which are disclosed in U.S. Patent No. 5,196,438, issued on Mar. For reference; 5(8)·b〇c·amino 4(S)1kyl-6-phenyl-2(R)-benzylmethylhexyl _(L)_proline _([) phenylalanine - morpholin-4-yl decylamine and related compounds, disclosed in European Patent Application No. 532,466, issued March 17, 1993, the disclosure of which is incorporated herein by reference in its entirety · thiol-alanine _(2S,3S)_3_amino-2-hydroxy-4-butanyl-i,3-oxazolidine·4_third-butyl decylamine (also known as 荇 荇 荇Mercapto-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5-isoquinolinyloxyethyl-/S-methylthio-alanine 2S,3S)_3_aminohydroxy Dingsing-1,3-severing bite-4-third 'butyl decylamine (also known as lQoa-Mta-Apns-Thz-NHtBu) and related compounds, revealing European patent applications published on June 17, 1992 Clause 49, 667, and Chem. Pharm· Bull·狃 (8) 2251 (1992), which is incorporated herein by reference in its entirety; [18-[111*(化*),28*]]-; ^[3-[[[(1,1-Diethylethyl)amino]]yl](2-mercaptopropyl)amino]-2-hydroxy]-(phenylhydrazinyl)propyl]-2_[( 2-quinolinylcarbonyl)amino]butanediamine (also known as SC-52151) and related PCT Patent Application No. W092/08701, issued May 29, 1992, and PCT Patent Application No. W093/23,368, filed on Nov. 25, 1993, which is incorporated herein by reference. ; O:\106\106749.DOC -148- 200817349

OH

Nh2 //W 〇 O (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.

o

(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-149-200817349 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.

( </ RTI> </ RTI> <RTIgt;

(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- 200817349

(i.e., BILA 1096 BS) and related compounds are disclosed in the European Patent Application No. 560,268, filed on Sep. 15, 1993, which is incorporated herein by reference in its entirety;

(i.e., U-140 690) and related compounds are disclosed in the pCT patent application No. W095/30670, issued Nov. 16, 1995, which is incorporated herein by reference in its entirety in Acceptable salt. Ο 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 combinations are also particularly useful for inhibiting or treating ΗΙν infection in humans. When a compound of the invention is used in such a combination, the compounds of the invention may be administered in the same or different times in separate dosage forms, or they may be formulated. A single composition containing two compounds. When administered in combination with the compounds of the present invention, the law of Turner has improved the chemical properties of the present invention (i.e., increased half-life, increased time to increase plasma traces, increased blood levels). The preferred dosage forms of the law are: (4) y, the liquid dosage form used in the y service, as disclosed in US Patent No. 5,484,801 of January 1, 1996 Combine this as a tea test, (b) a rubberized solid or

O:\106\106749.DOC -151 - 200817349 Semi-solid dosage form, as in the US patents filed on March 23, 1995, PCT Patent Application No. WO95/07696 and March 13, 1995 The sequence disclosed in Serial No. 08/4(), the disclosure of which is hereby incorporated by reference in its entirety in its entirety in the the the the the the the U.S. Patent No. 5,559,158, the disclosure of which is incorporated herein by reference.其他 Other examples of preferred dosage forms of the law are disclosed in U.S. Patent Application Serial No. 08/754,390, to Lipad, La.

An application for the name of Al-Razzak, S. Ghosh and R. Gao, entitled Pharmaceutical Composition, is incorporated herein by reference. A preferred composition of the law of Ternate is comprised of (a) from the weight of the total solution, from about 1% to about 30%, preferably from about 5% to about 25%, of the ruthenium. Phenanthrene, and (b) a solution of polyoxyl oleene oil present in an amount of from about 〇% to about 2% by weight (preferably from about 5% to about 10%) by weight of the total solution. In a pharmaceutically acceptable organic solvent, which comprises (1) from about 15% to about 99% by weight of the total solution (preferably from about 3% to about 7%, more preferably The oleic acid present in the amount of from about 40% to about 65%), or (ii) hydrazine, is from about 15% to about 99% by weight of the total solution, preferably from about 3% to about More preferably, 70%, more preferably from about 4% to about 65%) of the oleic acid, and (2) from about 〇% to about 12% by weight of the total solution. /. (preferably about 1%) a mixture of ethanol or propylene glycol or a mixture thereof contained therein. In a preferred embodiment of the invention, the solution is encapsulated into a soft, flexible, capsule (SEC), or hard gelatin capsule, and the solution may also comprise

O:\106\106749.DOC -152- 200817349 The weight of the solution is from about 0.01% to about 8% (preferably from about 0.01% to about 0. 05% by weight of the total solution) The antioxidant is present (preferably ΒΗΤ (butylated hydroxytoluene)). Examples of such compositions and methods for their preparation are provided below. Weight% 20 10 5 65 0.01 Ingredients Lutneufi (free base) Ethanol (USP, 200 standard strength) Ο

Polyoxy 3 5 says Cremophor® EL Oleic acid, 6321, NF-butylated hydroxy benzene (BHT), NF Preparation of the above composition: The mixed water tank was purged with nitrogen. In the tank, oleic acid (649·9 g) and ethanol (1 g) were mixed. The mixture was warmed to approximately 33 ° C (29_37 it) and maintained at this temperature. Butylated hydroxytoluene (〇1 g) was charged into the tank and mixed until the solution was clear. Lawnerafil (2 gram) 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 (20-30 ° C). The resulting solution was filled into a soft and flexible T-capsule (0.5 g solution/SEC) to give 1 mg of timidine/SEc, or 1.0 g/SEC, to give 200 mg of Nafi/SEc dose. Ingredients .« Λ/% by weight Lutneufi (free base) 2〇 Ethanol (USP, 200 standard strength) 1〇 Polyoxyl 35 castor oil (Cremophor 81〇 O:\106\106749.DOC 153 - 200817349

Oleic acid, 6321, NF ου Butylated hydroxy benzene (ΒΗΤ), NF 〇 〇1 Preparation of the above composition: The mixed water tank was purged with nitrogen. In the tank, oleic acid (599·9 g) and ethanol (1 g) were mixed. The mixture is warmed to about m (29_37 〇) and the stomach is kept at this temperature. Butylated hydroxyindole (0.1 g) was charged into the tank and mixed until the solution was clear. Lawnerafil (200 g) was slowly charged 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 (20-3 CTC). The resulting solution was filled into a soft and flexible capsule (0.5 g solution/SEC) to give a dose of 1 gram of law Tenapee/SEC, or 1.0 g/SEC, to give 200 mg of law Tenaf /SE(:Dose. An example of a preferred single dosage form comprising a compound of the law and is disclosed in U.S. Patent Application Serial No. 8/754,39, filed on November 21, 1996, to Lipan The name of LA. Al-Razzak 5 S. Ghosh and R. Gao is hereby incorporated by reference in its entirety by reference in its entirety in its entirety in its entirety in its entirety in The composition comprises, by weight of (a) &amp; total solution, from the range of from about 1% to about 3% (preferably, from about 5% to about 25%) of the ruthenium, and The weight of the total solution is from about 1% to about 5% (preferably from about to about 5%) of the mixture of formulas present, and by weight of the total solution, about ίο% a solution of a polyoxyl 35 castor oil present in a pharmaceutically acceptable organic solvent, which comprises (i) by weight of the total solution, from about

O:\106\106749.DOC -154- 200817349 10% to about 88% (preferably from about 4% to about 65%) in the presence of oleic acid, and (ii) by weight of the total solution a mixture of ethanol present at a level of about 1%. 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抗1% to about 8% (preferably from about 1% to about 5% by weight of the total solution) of antioxidants (preferably BHT (butyl) Hydroxy benzene.

实例 Examples of such compositions and methods for their preparation are provided below. Ingredient% by weight Lunafifene (free test) 5 Example 2B compound (free base) 30 Ethanol (USP, 200 standard strength) 10 Oxygen 35 rabbit sesame oil (Cremophoi^ EL) 10 Oleic acid, 6321, NF 45 Baseted hydroxyindole benzene (BHT), NF 0.01 component weight % law phenanthrene (free test) 15 example compound (free base) 15 ethanol (USP, 200 standard strength) 10 polyoxy 3 5 castor oil (Cremophor ® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxymethyl stupid (BHT), NF 0.01 O: \106\106749.DOC -155- 200817349 Ingredient% by weight Luitaffi (free base) 15 shells 2B compound (free test) 15 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (cremoph〇r® EL) 5 Oleic acid, 6321, NF 55 Butylated hydroxy benzene (BHT), NF 0.01 Preparation of the above composition:

吹 Purge the mixing tank with nitrogen. Oleic acid (549·9 g) and ethanol (100 g) were mixed in the tank. Butylated hydroxytoluene (01 g) was charged to the tank and mixed until the solution was clear. Lawnerafil (150 g) was slowly loaded into the tank and mixed until the solution was clear. The compound of Example 2]8 (15 g) was placed in the tank and mixed until the solution was clear. In the tank, oxime 3 5 castor oil (1 gram) was added and mixed. The resulting solution was loaded into a soft and flexible capsule (1 G solution/sec) to give a dose of 15 mg/sec of each of the compound of the law of phenanthrene and the compound of Example 2B. Weight % 15 5 10 10 Ingredients Lunafifene (free test) Example 2B compound (free base) Ethanol (USP, 200 standard strength) Oxygen 35 says sesame oil (Cremophor® EL) 60 0.01

Oleic acid, 6321, NF-butylated hydroxytoluene (BHT), NF is administered to humans or other mammalian hosts in a single- or separate dose. O:\106\106749.DOC -156- 200817349 Tenafee The total daily dose administered with the compound of the present invention may be, for example, a content of from about 0.001 to 300 mg per kg of body weight per day, more commonly from 0.1 to 10 grams of gramataf. Dosage unit compositions may contain a fraction of such amounts to produce a dose per amp. In the composition comprising a mixture of the law of Terinafine and the compound of Example 2 B, the ratio (weight/weight) of the compound of the formula and the compound of Example 2B is from about 1:16 to about 5:1 (preferably). It is between about 1:6 and about 3:1). Ο

In other preferred combinations, the compounds of the invention are combined with a tertnaphene and one or more gastric reverse transcriptase inhibitors (preferably one or more selected from the group consisting of azt (easy U) ddl (Didano) Ding), ddc (沙西塔必), d4T (斯塔 / 疋) # 3TC (Lami + Ding) compounds are administered. Such combinations are particularly useful for inhibiting or treating human (IV) infections. The combination of the inventive compound and the law of the tranexin, and or the plurality of reverse transcriptase inhibitors, may be used in the form of separate preparations, with the same or no number of times, or by modulating them to contain two Or a combination of a plurality of compounds. A particularly preferred therapeutic combination comprises a compound of formula I (especially the compound of Example 23) admixed with ruthenium, azt and azide. It will be appreciated that A mixture of phlegm and sputum, which is used to inhibit, treat or prevent AIDS or HIV infection, is not limited to those listed above, but includes, in principle, any preparation that can be used to cure or prevent aids or mv infection. 'In the case of mixed administration, the treatment of Nanxun M yv β ^ can be In the same or a different number of times the number of separately administered compositions or in the form of a single compound ,, and to the therapeutic agent to the Fo., Good opening of formula wood ,,, Bian

O:\106\106749.DOC-157-200817349 The main description of the present invention is not intended to limit the invention to the disclosed compounds. Attempts to incorporate such modifications and variations within the scope and nature of the invention are defined in the obvious range of 5'. ,, the application for the appendix 〇

O:\106\106749.DOC -158-

Claims (1)

200817349 X. Patent application scope: 1. A method for preparing a compound of formula I or a pharmaceutically acceptable sleeping or brewing type thereof, I Ο Ο R5 The method comprises formulating a compound of the formula: R5 is reacted with a compound of the formula: or a salt thereof or an activated ester derivative: R' into c wherein Ri and R2 are each selected from alkyl, c3-c8 cycloalkyl c"c6 alkyl and c6-c12 aryl c a group consisting of -c6 alkyl; R3 is CVC6 alkyl, hydroxy CVC6 alkyl or c3-c8 cycloalkyl CrC6 alkyl; is CpC12 aryl or contains one or more selected from 0, N and S Atomic C3-C7 heterocycle; R5 is X human ΟΗ • NT V, \" a) (CH2)n" b) • Λ\-L ζ 123853.doc 200817349 R6 h) i) 〇1ί , OH or N-Re where n 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-, - 0-, -S- or -N(R6)-, wherein R6 is hydrogen, CVC6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl CVC6 alkyl, C6-C12 aryl or C6-C12 aryl A CVC6 alkyl group, Y" is -CH2- or -N(R6n)-, wherein R6" is hydrogen, (VC6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl (VC6 alkyl, C6-) C12 aryl or C6-C12 aryl CVC6 alkyl, Y· is _N(R6')-, wherein 123853.doc -2- 200817349 R6' is hydrogen, (^_(:6 alkyl, c3_Cj alkyl, a C3-C8 cycloalkyl CVC6 alkyl group, a C6-C12 aryl group or a c6-c12 aryl CVC6 alkyl group, and Z is 0, S or NH; and L] is selected from the group consisting of: a) _ Ο - ' b b b b b b b b b b b b b b b b b b b d) - 0- Ci-Ci 〇 烧 - ' e) -S-Ci_Ci 〇 烧 -, f). Alkyl, g) -S(0)2-Ci-C! 〇 烧 -, h) -N(R7)-Ci-C10 alkylene-, wherein r7 is as defined above, i) -CVCw alkyl-〇-, Q j) -CVCw alkyl-s-, k) -Ci-Ci〇---(R7)-, where r7 is as defined above, l) -CVCh ) alkyl, and Π 1) - C 2 &quot; C 1 〇 stretching base. 2. A method of preparing a compound of formula I or a pharmaceutically acceptable salt, ester or prodrug thereof, 123853.doc 200817349 The method comprises formulating a compound of the formula: Reaction with a compound of the formula: or a salt thereof or an activated ester derivative: 0 Li OH Ο Wherein R#R2 is respectively selected from the group consisting of a Cl-C6 alkyl group, a c3-c8 cycloalkyl crc6 alkyl group and a CVCu aryl CVC6 alkyl group; a calcinyl group, a hydroxyCl-C6 alkyl group or a c3-c8 cycloalkyl group; CVC6 alkyl; R4 is c6-c12 aryl; Wherein η is 1, 2 or 3, X is 0, S or NH, and y is -〇- or -n(R6)-, wherein &amp; is hydrogen, C"C6 alkyl, c3_C8 cycloalkyl, C3_C8 ring An alkylCl-C6 alkyl group, a c6_Cu aryl group or a C6_C12 aryl Ci_c6 alkyl group, and Li is selected from the group consisting of: a) -0-, b)_s·, c) N(R7)-, wherein R7 is gas, C]_C6 alkyl group, q core ring alkyl group or C3-C8 cycloalkyl CVC6 alkyl group, AO-CrCio stretching group _, OS-Ci-Cio stretching group _, 0 stretching group·, 123853.doc 200817349 alkyl-alkylene-i) -CrCw alkyl-hydrazine-, j) •&quot;CrC^o extended alkyl-S-, JO-Ci-Cio alkyl-n (r7 - l) -CVCio extended alkyl, and m) -C2-C1Q extended alkenyl. Q 3. The method of claim 2, wherein Ri and ^ are / aryl Ci-C6 alkyl, R3 is Cl-C6 alkyl, R 2... 4 two L6-cl2 笑 A and Li alkyl-. 暴 ' 4 · The method of claim 2, wherein r, R is benzyl and R 2 is isopropyl The base 3 is c 2 is a fluorenyl group or a substituted 2,6-dimethylphenyl group, and the substituent is selected from the group consisting of arbitrarily and halogen, and L1 is a hepta-CH 1 C6 alkane. Base -, c horse 1 or 2 , χ is 〇 or s, and Υ is -CH2j_NH_. Spoon ^ Q 5 · As in the method of claim 2, η M force 忐 where Ri and R 2 are benzyl, R 3 is Ci_C6 alkyl, R 4 is 2, 6-»_ A, T, a *f storm base, L is -〇-CH2-, n is 1 or 2'x is 0 or s, aY is _. 6. A preparation of a compound of formula I or J :药风^ ^ ^ ^ Baliang is an acceptable method for the salt, ester or ,, πr3 where R? is as defined above, where R7 is as defined above, and the method includes the compound of the formula ·· ο 义义 12 123853.doc 200817349 Reacting with a compound of the formula: or a salt thereof or an activated ester derivative: r3 hV^5 中心 its center and heart are respectively selected from CVC6 alkyl, c3-c8 cycloalkyl Ci_c6 alkyl and CVC 2 aryl CrG alkane a group consisting of 基; Ο 3 is CVC6 alkyl, hydroxy-Cl-C6 alkyl or C3_C8 cycloalkyl Ci_c6 alkyl; R4 is C^-C!2 aryl or contains one or more selected from 〇, N And the C3-C7 heterocycle of the hetero atom of S; .in a), (CH2)n 123853.doc b) c) d) e) •Λ z ΪUz, ΪLX YI (CH2)m yX, (ch2) towel· -6- 200817349 〇 Λ Y&quot; I /Y· (CH2)m. v. li r6 where n is 1, 2 or 3, m is 1, 2 or 3, m, is 1 or 2, X is 0, s or NH, and Y is -CH2-, -〇-, -s- or -N(R6)-, wherein R6 is hydrogen, CVC, alkyl, &lt;^-〇: 8-cycloalkyl, c3-C8 cycloalkyl (^(:6 alkyl, C6-C12 aryl or C6-) C12 aryl CrQ alkyl, γ" is -CH2- or -N(R6,,)-, wherein R6 is a gas, eve: 6 yard, cvc8m alkyl, C3-C8 cycloalkyl Cl-C6 alkyl , °VC12 aryl or C6_Ci2 aryl Ci_C6 alkyl, γ, is _Nd,) _, wherein R6 is hydrogen, (VC6 alkyl, (^(^cycloalkyl, C3_C8 cycloalkyl Ci_c &amp; base 'C6_c12 An aryl or c6_Ci2 aryl c group, and NH; and L! is selected from the group consisting of: a) -0-, b), c) -N(R7)·, wherein 7 is Li-C6 alkane , c3-C8 cycloalkyl or 123853.doc 200817349 C3-C8 cycloalkyl (VC6 alkyl, d) - 〇-cvc1 () alkyl-, e) alkyl-'. alkyl-, ghWCOrCVCi. Alkyl-, alkylene-, wherein R7 is as defined above, O-Ci-Ch alkyl--0-, j)-CkCm alkyl-S-, k^CrCio stretching- N(R7)- 'wherein R7 is as defined above, i) -CrCn alkylene, and m)-C2-C1Q stretching base. A method of preparing a compound of formula I or a pharmaceutically acceptable salt, ester or prodrug thereof, The method comprises formulating a compound of the formula: Reacts with a compound of the formula: or a salt thereof or an activated ester derivative: Wherein R1 and R2 are each selected from the group consisting of CrC6 alkyl, c3-c8 cycloalkyl CVC6 123853.doc 200817349 alkyl and aryl cvc6 alkyl; R3 is CVC6 alkyl, hydroxyCl_c6 alkyl or c3_c8 cycloalkyl Ci_c6 alkyl; R4 is C6-C12 aryl; λΛ R5 is (CH2)nj/ 'where η is 1, 2 or 3, X is Ο, S or 丽, and y is 〇υ(ιι6)-, wherein R6 is hydrogen, Ci_C6 alkyl, alkyl, C3-C8% alkyl Cl_C6 alkyl, C6_Ci2 aryl or q-Cu arylalkyl, and Li is selected from the group consisting of: a) -〇 -, b) a S·, c) -N(R7)-, wherein r7 is hydrogen, Ci_C6 alkyl, cycloalkyl or C3-C8 cycloalkyl CVC6 alkyl, AO-CVCio alkyl-, e) -S-CVCmalkylene-, 0-S(O)-CVC1()alkyl-, 8)-8(0)2-0^-(^0-alkyl-, h)-N (R7)_Ci-C10 alkylene-, wherein r7 is as defined above, i) -CVCioalkyl-indole-, j)-Cl_ClQ-alkyl-S-' kXi-Cn)alkyl-N (R7)-, wherein r7 is as defined above, U-CVCw alkylene, and Hl)-C2-C1() extended alkenyl. 123853.doc -9- 200817349 8. The method of claim 7, wherein the I-aryl C "C6 alkyl group, 1 is a CVC6 alkyl group, R4 is and L! is -O-Ci-Cio stretching group." The method of item 7, wherein R and 1 are benzyl and R 2 is isopropyl, and 113 is (VC6 alkyl substituted 2,6-dimethylphenyl, the substituent is selected from the group consisting of halogen The group formed, L! is -0-CH2-, η is 1 or S, and Υ is -CH2- or -ΝΗ-. 10. The method of claim 7, wherein R! stone R3 is CVC6 Alkyl, R4 is 2,6-didecylphenyl, I η is 1 or 2, X is hydrazine or S, and Y is -NH_ 11. A compound comprising a substituent of the formula R3 wherein R3 is Ci_C6 An alkyl group, a Ci_C6 alkyl group or a C3-C alkyl group, and R5 is a ^R2% C6~C1 2 c6-c12 aryl group, r2 is a benzyl group, or ^R4 is as the case may be (VC6 alkyl or 2, X is Ο l R2 is benzyl, which is -O-CH2- 5 cycloalkyl C 1 - C 6 123853.doc -10- 200817349 d) e) f) g) ^(CH2)m. ?if \n^^N-r6. h) R6laoh or i) where n is 1, 2 or 3, m is 1, 2 or 3, mf is 1 or 2, X is 0, S or NH, and Y is -CH2-, -Ο-, -S- or -N ( R6)-, wherein R6 is fluorene, CVC6 alkyl, C3-C〇f, alkyl, C3-C8 cycloalkyl CVQ alkyl, C6-C12 aryl or C6-C12 aryl CVC6 alkyl, Y" is -CH2- or -N(R6")-, wherein R6" is hydrogen, CVC6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl CVC6 alkyl, C6-C12 aryl or C6-C12 aryl CVC6 alkyl, Y' is -N(R6')-, wherein R6' is hydrogen, CVC6 alkyl, c3-c8 cycloalkyl, c3-c8 cycloalkyl CVC6 alkyl, C6-C12 aryl or C6- C12 aryl CVC6 alkyl, and Z is hydrazine, S or NH. 123853.doc • 11 - 200817349 , person \ / 12. For example, the compound of claim 11 wherein R5 is, η is 1, 2 or 3 , X is 0, S or NH, and Y is -Ο- or -N(R6)-, wherein R6 is 氲, CVC6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl CVC6 alkyl, C6 A compound of the formula 12, wherein 113 is a Ci-G alkyl group. Alkyl, η is 1 or 2 X is Ο or S, and Y is -CH2- or -NH-. 15. A compound of claim 14 wherein Y is -NH-. 123853.doc 12- 200817349 VII. Designation of representative drawings: The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 〇 123853.doc