CA2231700C - Prodrugs of aspartyl protease inhibitors - Google Patents

Abstract

The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. This invention also relates to pharmaceutical compositions comprising these prodrugs. The prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.

Description

PRODRUGS OF' ASPARTYL PROTEASE INHIBITORS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. This invention also relates to pharmaceutical compositions comprising these prodrugs.
The prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.
BACKCiROUND OF THE INVENTION
Aspartyl protease inhibitors are considered the mosi~ effective current drug in the fight against HIV
infESCtion. These inhibitors, however, require certain phy:~icochemical properties in order to achieve good potency against the enzyme. One of these properties is high hydrophobicity. Unfortunately, this property results in poor aque~~us solubility and low oral bioavailability.
United States Patent 5,585,397 describes a class of sulfonamide compounds that are inhibitors of the aspartyl protease enzyme. These compounds illustrate the drawbacks concomitant to pharmaceutical compositions comprising hydrophobic aspartyl protease inhibitors. For example, VX-478 (4-amino-N-((2-syn,3S)-2-hydroxy-4-phenyl-2((S)-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl-N-isobutyl-benzenesulfonamide) is an aspartyl protease inhibitor cLisclosed in the '397 patent. It has a relatively low aqueous solubility. While the oral bioavailability of this inhibitor in a "solution"
formulation is excellent, the dosage of VX-478 in this form is severely limited by the amount of liquid present in the particular liquid dosage from, e.g., encapsulated into a soft gelatin capsule. A higher aqueous solubility would increase drug load per unit dosage of VX-478.
Currently, the solution formulation of VX-478 produces an upper limit of 150 mg of VX-478 in each capsule. Given a therapeutic dose of 2400 mg/day of VX-478, this formulation would require a patient to consume 16 ~~apsules per day. Such a high pill burden would lik~sly result in poor patient compliance, thus producing sub-optimal therapeutic benefit of the drug. The high pil:1 burden is also a deterrent to increasing the amount of l~he drug administered per day to a patient. Another dra~Nback of the pill burden and the concomitant patient compliance problem is in the treatment of children infected with HIV.
Furthermore, these "solution" formulations, such as the mesylate formulation, are at a saturation solubility of VX-478. This creates the real potential of havung the drug crystallize out of solution under various storage and/or shipping conditions. This, in turn, would likely result in a 1«ss of some of the oral bioavailability achi~=ved with VX-478.

One way of: overcoming these problems is to develop a standard :solid dosage form, such as a tablet or a capsule or a suspension form. Unfortunately, such solid dosage forms nave much lower oral bioavailability of the drug.
Thus, there is a need to improve the drug load per unit dosage form for aspartyl protease inhibitors.
Such an improved do~.age form would reduce the pill burden and increase patient compliance. It would also provide for the possibility of increasing the amounts of the drug administered per day to a patient.
SUMMARY OF THE INVENTION
The present invention provides novel prodrugs of a class of sulfonamide compounds that are inhibitors of aspartyl protease, in particular, HIV aspartyl protease. These prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
The present invention also provides pharmaceutical com~~ositions comprising these prodrugs and methods of tre~~ting HIV infection in mammals using these prodrugs and the pharmaceutical compositions thereof.
These prodrugs can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immi~nomodulators or vaccines, for the treatment or prophylaxis of viral infection.
It is a principal object of this invention to provide a novel class of prodrugs of sulfonamide compounds that are aspartyl protease inhibitors, and particularly, HIV a;3partyl protease inhibitors. This novel class of sulfonamides is represented by formula I:
D
H
A--(B)X N H -C H N S02 E
~ ~ 2 ~~ (I
(G)X OR D ) wherein:
A is selected from H; Ht; -R1-Ht; -R1-C1-C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, -O-Ht, -NRz-CO-N (Rz) z or -CO-N (Rz) z:
-R1-Cz-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-(~4 alkoxy, Ht, -O--Ht, -NRz-CO-N (Rz) z or -CO-N (Rz) z; or R'' each R1 is independently selected from -C(O)-, -S (O) z-, -C (O) -C (O) -, -O-C (O) -. -0-S (0) z~ -NRz-S (O) z-. -NRz_ C (O) - or -NRz-C (O) -C (O) -;
each Ht is independently selected from C3-C~
cycloalkyl; CS-C~ cyc:loalkenyl; C6-Clo aryl; or a 5-7 metribered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(Rz), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fuss=d to Q; and wherein any member of said Ht is optionally substituted with one or more substituents indf=_pendently selected from oxo, -ORz, SRz, -Rz, -N (R''') (Rz) , -Rz-OH, -CL~1, -COzRz, -C (O) -N (Rz) z -S (c7) z-N (Rz) z. -N (Rz) wC (O) -Rz, -C (O) -Rz, -S (O) n-Rz, -OCF3, -S (O ) n-Q, methylenedioxy, -N (Rz) -S (O) z (Rz) , halo, -CF3, -NO,;, Q, -OQ, -OR', -SR', -R', -N (Rz) (R') or -N (R') z;
each Rz is independently selected from H, or Cl-C4 alkyl optionally :substituted with Q;

B, when present, is -N (R2) -C (R3) 2-C (O) -;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1-(~6 alkyl, CZ-C6 al:kenyl, C3-C6 cycloalkyl or CS-C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from -OR2, -C (O) -NH-R2, -S (O) n-N (RZ) (R2) , Ht, -CN, -SR2, -COzR2, NRZ-C (O) -R2;
each n is independently 1 or 2;
G, when present, is selected from H, R' or Cz-C4 alk.~l, or, when G is Cl-C4 alkyl, G and R' are bound to one anoi~her either directly or through a Cz-C3 linker to form a hE=_terocyclic ring; or when G is not present (i.e., when x in (G)X is 0), then the nitrogen to which G is attached is bound directly to the R' group on -OR';
D and D' a:re independently selected from Q; C1-C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3, -O-~~ or Q; CZ-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3, -O-Q or Q; C3-C6 cycloalkyl, which is optionally sub:~tituted with or :Fused to Q; or CS-C6 cycloalkenyl, which is optionally ;substituted with or fused to Q;
each Q is independently selected from a 3-7 memx~ered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n or N(R2); wherein Q is optionally substituted with one or more groups seelected from oxo, -OR2, -R2, -N (Rz) 2, -N (R.2) -C (O) -R2, -RZ-OFi, -CN, -C02R2, 61009-317(S) -C (O) -N (Rz) z, halo or -CF3;
E is selected from Ht; O-Ht; -Ht-Ht; -O-R3;
-N(Rz) (R3) ; Cl-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; CZ-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or CS-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from -ORZ, -SRz.. -C (O) -NHRz, -S (O) z-NHRz, halo, -NRz-C (O) -Rz, -N (Rz) z or -CN;
each R' is independently selected from H, ZM
H O ~ Z(M) or CH2 p (R~X[N~
-f-C z -~-- x x wherein each M is independently selected from. H, Li, Na, K, Mg, Ca, Ba, -N (Rz) 4, Cl-Clz-alkyl, Cz-Clz-alkenyl, or -R6; wherein 1 to 4 -CHz radicals of the alkyl or alkenyl group, other than the -CHz that is. bound to Z, is optionally replaced by a heteroatom group selected from O, S, S (O) , S (Oz) , or N (Rz) ; and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -Rz, N (Rz) z. N (Rz) a. RzOH. -CN. -CO2Rz, -C (O) -N (Rz) z. S (O) z-N (Rz) z. N (Rz) -C (O) -Rz. C (O) Rz, -S (O) a-Rz, OCF3, -S (fl) n-R6 N (Rz) -S (O) z (Rz) , halo, -CF3, or -NOz;
M' is H, Cl-Clz-alkyl, Cz-Clz-alkenyl, or -R6;
wherein 1 to 4 -CHz radicals of the alkyl or alkenyl.group is optionally replaced by a heteroatom group sel~ct~d from O, S, S (O) , S (Oz) , or N(Rz) ; and. wherein any hydrogen 61009-317(S) in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -ORz, -Rz, -N (Rz) z, N (Rz) 3, -R20H, -CN, -C02Rz, -C (O) -N (Rz) 2, -S (O) z-N (Rz) z, -N (Rz) -C (O) -Rz, -C (O) Rz, -S (O) n-Rz, -OCF3, -S (O) n-R6, -N (Rz) -S (O) 2 (Rz) , halo, -CF3, or -NOz;
Z is -CHz-, O, S, -N (Rz) -, or, when M is not present, H, CH3, or -N(Rz)z;
Y is P or S;
X is 0 or S; and R9 is C (Rz) z, O or N (Rz) ; and wherein when Y is S, Z
is not S; and R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S (O) n or N (Rz) ; and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, O-C1-C4 alkyl or OC (0) C1-C4 alkyl .
It is also an object of this invention to provide pharmaceutical compositions comprising the sulfonamide prodrugs of formula I and methods for their use as prodrugs of HIV aspartyl protease inhibitors.
Thus, in one aspect, the present invention provides a compound of formula I.
In another aspect, the present invention provides a pharmaceutical composition, comprising a compound of the 61009-317(S) - 7a -invention and a pharmaceutically acceptable carrier, an adjuvant or a vehicle.
In another aspect, the present invention provides a pharmaceutical composition, comprising a compound of the invention in an amount effective to treat infection by a virus that is characterized by an aspartyl protease; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
In another aspect, the present invention provides use of a compound of the invention for the manufacture of a medicament for inhibiting aspartyl protease activity in a mammal.
In another aspect, the present invention provides use of a compound of the invention for inhibiting aspartyl protease activity.
In another aspect, the present invention provides use of a compound of the invention for the manufacture of a medicament for treating HIV infection in a mammal.
In another aspect, the present invention provides commercial packages comprising compounds or pharmaceutical compositions of the invention together with instructions for use for inhibiting aspartyl protease activity or treating HIV in a mammal.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:

61009-317(S) - 7b -Designation Reagent or Fragment Ac acetyl Me methyl Et ethyl - g _ Bzl benzyl Trityl triphenylmethyl Asn D- or L-asparagine Ile D- or L-isoleucine Phe D- or L-phenylalanine Val D- or L-valine Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl (carbobenzyloxy) Fmoc 9-fluorenylmethoxycarbonyl DCC dicyclohexylcarbodiimide DIC diisopropylcarbodiimide EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt 1-hydroxybenzotriazole HOSu 1-hydroxysuccinimide TFA trifluoroacetic acid DIEA diisopropylethylamine DBU 1,8-diazabicyclo(5.4.0)undec-7-ene EtOAc ethyl acetate The following terms are employed herein:
Unless expressly stated to the contrary, the terms "-S02-" and "-S(O)2-" as used herein refer to a sul:Eone or sulfone derivative (i.e., both appended groups lin)ced to the S) , and not a sulfinate ester.
For the compounds of formula I, and intE~rmediates thereof, the stereochemistry of OR' is defined relative to :D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compounds of formula XI, XV, XXII, XXIII and XXXI). If both OR' and D
res_Lde on the same side of the plane defined by the extended backbone of the compound, the stereochemistry of _ g _ OR' will be referred to as "syn". If OR' and D reside on opposite sides of that plane, the stereochemistry of OR' will be referred to as "anti".
The term "aryl", alone or in combination with any other term, refers to a carbocyclic aromatic radical containing the specified number of carbon atoms.
The term "heterocyclic" refers to a stable 5-7 membered monocycle or 8-11 membered bicyclic heterocycle which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. The heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable structure. Preferred heterocycles defined above include, for example, benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, ind~elyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyr,~zinyl, quinoxolyl, piperidinyl, morpholinyl, thi~~morpholinyl, furyl, thienyl, triazolyl, thiazolyl, i3-carholinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thi~~morpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxo~~yrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tet:rahydropyranyl, tetrahydrofuranyl, thiadiazoyl, ben:aodioxolyl, thiophenyl, tetrahydrothiophenyl and sul:Eolanyl .
The terms "HIV protease" and "HIV aspartyl prol~ease" are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
The term "pharmaceutically effective amount"
refers to an amount effective in treating HIV infection in a patient. The term "prophylactically effective amount" refers to aru amount effective in preventing HIV
infection in a patient. As used herein, the term "patient" refers to a mammal, including a human.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, malefic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in '~~he preparation of salts useful as intermediates in obt<~ining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e. g., sodium), alkaline earth metal (e. g., magnesium), ammonium and N-(C1_4 alkyl)4+ salts.

The term "thio~~arbamates" refers to compounds containing the functional group N-SOZ-O.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. The explicitly shown hydroxyl is also preferred to be syn to D, in the extended zigzag conformation between the nitrogens shown in compounds of formula I.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stab7.e compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art.
Typically, such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, d.igluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrox-yethanesulfonate, lactate, maleate, methanesulfonate, 2-nap:hthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, piv~alate, propionate, succinate, tartrate, thiocyanate, tos:ylate and undecanoate.
This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be c~uaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates inc:Luding dimethyl, diethyl, dibutyl and diamyl sulfates;
lon<3 chain halides such as decyl, lauryl, myristyl and ste~~ryl chlorides, bromides and iodides; and aralkyl halides including be:nzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The novel ;sulfonamides of this invention are tho;~e of formula I:
D
H
A (B)X N H--C H N S02 E ( I ) (G)X OR D
wherein:
A is selected from H; Ht; -R1-Ht; -R1-C1-C6 alk~~l, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N f Rz) 2 or -CO-N (R2) z;
-Rl-C2-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N(R2)2 or -CO-N(Rz)z; or R' each R1 is independently selected from -C(O)-, -S (O) z-, -C (O) -C (O) -, -O-C (O) -, -O-S (O) z. -NRz-S (O) z-, -NRz-C (O) - or -NRz-C (O) -C (O) -;
each Ht i~; independently selected from C3-C-, cycloalkyl; CS-C~ cycloalkenyl; C6-Clo aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(Rz), O, S and S(O)n; wherein said ,aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, -ORz, SRz, -Rz, -N (R'Z) (Rz) , -Rz-OH. -CN, -COzRz. -C (O) -N (Rz) z, -S (O) z-N (Rz) z ~ -N (Rz) -C (O) -Rz, -C (O) -Rz, -S (O) n-Rz, -OCF3, -S (O) n-Q, methylenedioxy, -N (Rz) -S (O) z (Rz) , halo, -CF3, -NOz, Q, -OQ, -OR', -SR', -R', -N(Rz) (R') or -N(R')z;
each Rz is independently selected from H, or Cl-C4 alkyl optionally :substituted with Q;
B, when present, is -N (Rz) -C (R3) z-C (O) -;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1-C'.6 alkyl, Cz-C6 alkenyl, C3-C6 cycloalkyl or CS-C6 cyc=Loalkenyl; wherein any member of said R3, except H, is opt_Lonally substituted with one or more substituents selected from -ORz, --C (O) -NH-Rz, -S (O) n-N (Rz) (Rz) , Ht, -CN, -SRz, -C02Rz, NR'''-C (O) -Rz;
each n is :independently 1 or 2;
G, when present, is selected from H, R' or C1-C4 alkyl, or, when G is Cl-C4 alkyl, G and R' are bound to one another either direci~ly or through a Cl-C3 linker to form a heterocyclic ring; or when G is not present (i.e., when x in (G)X is 0), then the nitrogen to which G is attached is bound directly to the R' group in -OR' with the concomitant displacement of one -ZM group from R';
D and D' are independently selected from Q; Cl-C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3, -O-Q or Q; Cz-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3, -O-Q or Q; C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or CS-C6 cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 memhered saturated, partially saturated or unsaturated carhocyclic ring system; or a 5-7 membered saturated, pari~ially saturated or unsaturated heterocyclic ring coni;aining one or more heteroatoms selected from O, N, S, S(O)n or N(Rz); wherein Q is optionally substituted with one or more groups selected from oxo, -ORz, -Rz, -N (R2) z, -N (RZ) -C (O) -R2, -Rz-OH, -CN, -C02R2, -C (O) -N (RZ) 2, halo or -CF3;
E is selected from Ht; O-Ht; Ht-Ht; -O-R3;
-N (Rz) (R3) ; C1-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C6 saturated carbocycle, which is optionally :substituted with one or more groups selected from R4 or Ht; or CS-C6 unsaturated carbocycle, which is optionally ;substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from -OR2, -SRz, -C (O) -NHR2, -S (O) 2-NHR2, halo, -NR2-C (O) -R2, -N (R2) a or -~CN;
each R' is independently selected from ZM O
-CH2 o~-Y Z(M)x °r ~ CH2 O ~(R9)XM' x II
X
wherein each M is independently selected frovm H, Li, Na, K, Mg, Ca, Ba, -N(Rz)4, C1-Clz-alkyl, Cz-Clz-alkenyl, or -R6; wherein 1 to 4 -CHz radicals of the alkyl or alkenyl group, other than the -CHz that is bound to .Z, is optionally replaced by a heteroatom group selected from O, S, S (O) , S (Oz) , or N(Rz) ; and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -Rz, N(R~)2. N(R2)s~ R20H~ -CN. -CO2Rz~ -C(O)-N(Rz)2. S(O)2 N (R~) 2 ~ N (R2) -C (O) -Rz, C (O) Rz, -S (O) n-Rz. OCF3, -S (O) n-R6 N (R' ) -S (O) z (Rz) , halo, -CF3, or -NOz;
M' is H, C1-Clz-alkyl, Cz-Clz-alkenyl, or -R6;
wherein 1 to 4 -CHz radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S (O) , S (Oz) , or N (R2) ; and wherein any hydrogen in raid alkyl, alkenyl or R6 is optionally replaced with a sub:~tituent selected from oxo, -ORz, -R2, -N (Rz) z, N (R2) 3, -R20H, -CN, -CO2Rz, -~~ (O) -N (Rz) z, -S (O) z-N (R2) z, -N (Rz) -C (O) -Rz, -C (O) Rz, -S (O) n-Rz, -OCF3, -S (O) n-R6, -N (R2) -S (O) z (Rz) , halo, -CF3, or -NOz;
Z is CHz, 0, S, N (Rz) z, or, when M is not present, H.
Y is P or .3;
X is O or 3; and R9 is C (Rz) z, O or N (Rz) ; and wherein when Y is S, ~; is not S; and R6 is a 5-E. membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(Rz);
and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, O-C1-C4 alkyl or O-C (O) -C1-C4 alkyl .
Preferably, at least one R' is selected from:

HzC O~O~N~CH O ~N' ' ~O~O~ ' ~.NJ

~.~0~ . - (L) -lysi.ne, -P03Naz, ~O~NMez , O O
~NHAc , JL ~NH , _pp3Mg.
~N - (L) -tyrosine, O
-POs (NHa) z. -CHz-OP03Naz, ~N~NHz , - H - (L) -serine, O
SO~'Naz, ~O~Me NMe2' -S03Mg, -S03 (NH4) z, O
H N
-CHz-OS03Naz, -CHz-OS03 (NH4) z, ~N~NHz O NHz O
O ~N~ ~N~
~,iO~O~OMe , NHz , ,~ , O /NHz O ~ O O
II N' acetyl , ~ , ~ , - (L) -valine, -(L)-glutamic acid, ~-(L)-aspartic acid, O O
- (L) -y-t-butyl-aspart.ic acid, ~O~ ' O
- (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, ~CF3 O H
J.~ H
H
O O ~~~OAc O H OAc O OAc H
O O O O
n n n n ~ P1~0~ NH3 + ~ P1~0~~ NMe3 + ~O~ P1~0- /
- . O- . O- . O- .
PO3F;2, P03Ca, P03-spermine, P03- (spermidine) 2 or P03- (meglamine) z.
It will be understood by those of skill in the art that component M or M' in the formulae set forth herESin will have either a covalent, a covalent/
zwii~terionic, or an ionic association with either Z or R9 depending upon the a~~tual choice for M or M'. When M or M' .is hydrogen, alkyl, alkenyl, or R6, M or M' is covalently bound to 29 or Z. If M is a mono- or bivalent metal or other charged species (i.e., NH4+), there is an ion__c interaction bel~ween M and Z and the resulting compound is a salt.
When x is 0 in (M)X, Z may be a charged species.
When that occurs, thss other M may be oppositely charged to produce a 0 net charge on the molecule.
Alternatively, the counter ion may located elsewhere in the molecule.
Except where expressly provided to the contrary, as used herein, the definitions of variables A, R1-R4, R6-R9, Ht, B, x, n, D, D' , M, Q, X, Y, Z and E are to )r>e taken as they are defined above for the compounds of formula I.

According to a preferred embodiment, the compounds of this invention are those represented by formulas XXII, XXIII: or XXXI:
H ORS D' A~N~~~N-S02-E
(XXII) /
D' H ORS
Het-(CH2~/O N~N~SOZ-E
O ~ 3 R
R3 R3' ORS D' l0 ANN NH~N-S02-E
H O (XXXI) wherein A, R3, R', Ht, D, D', x, E are as defined above for compounds of formula I. For ease of reference, the two R3 moieties present in formula XXXI have been labeled R3 a.nd R3 ~ .
For compounds of formula XXII, more preferred compounds are those wherein:
A is selected from 3-tetrahydrofuryl-O-C(O)-, 3-(1, 5-dioxane) -O-C (O) -, or 3-hydroxy-hexahydrofura [2, 3-b] -furanyl-O-C (O) -;

D' is Cl-C4 alkyl which is optionally substituted with one or more grc>ups selected from the group consisting of C3-C6 cycloalkyl, -ORz, -R3, -O-Q and Q;
E is C6-Clo aryl. optionally substituted with one or more substituents selected from oxo, -ORz, SRz, -Rz, -N (Rz) z, -Rz-OH, -CN, -COzRz, -C (O) -N (Rz) z, -S (O) z-N (Rz) z.
-N (Rz) -C (O) -Rz, -C (O) -Rz, -S (O) n-Rz, -OCF3, -S (O) n-Q.
methylenedioxy, '-N (R:z) -S (O) z (Rz) , halo, -CF3, -NOz, Q, -OQ, -OR', -SR', -R', -N (R_z) (R') or -N (R') z; or a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH3, R4, or Ht.
Ht, insofar as it is defined as part of R3, is defined as above except for the exclusion of heterocycles; and all other variables are as defined for formula I.
Even more preferred are compounds of formula XXII, wherein A is 3-tetrahydrofuryl-O-C(O)-; G is hydrogen; D' is isobutyl; E is phenyl substituted with N(R')z; each M is independently selected from H, Li, Na, K, l~Ig, Ca, Ba, C1-C4 alkyl or -N(Rz)4; and each M' is H or C1-C:4 alkyl.
Another preferred embodiment for the formula XXII compounds are those wherein:
E is a 5-membered heterocyclic ring containing one S
and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH3, 3 0 R4 , or Ht ; and all other variables are as defined for formula I.

61009-317 (S) Even more preferred are any of the formula XXII
compounds set forth above, wherein R' in -OR' is -PO(OM)2 or C (O) CH20CH2CHzOCH2CH20CH3 and both R' in -N (R') 2 are H, wherein M is H, Li, Na, K or C1-C4 alkyl; or wherein R' in -OR' is C ( O ) CH20CH2CH20CH3 , one R' in -N ( R' ) 2 i s C ( O ) CH20CH2CH20CH3 and the other is H.
The most preferred compound of formula XXII has the structure:
O O
O
O N
H

For compounds of formula XXIII, most preferred compounds are those wherein:
R3 is C1-C6 alkyl, Cz-C6 alkenyl, CS-C6 cycloalkyl, CS-C6 cycloalkenyl or a 5-6 membered saturated or unsaturated heterocycle, wherein any member of said R3 may be optionally substituted with one or more substituents selected from the group consisting of -OR2, -C (O) -NH-R2, -S (O) nN (R2) (R2) , Ht, -CN, -SR2, -C (O) 2R2 and NR2-C (O) -R2; and D' is C1-C3 alkyl or C3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, -OR2, -O-Q and Q (with all other variables being defined as above for compounds of formula I).

61009-317(S) - 20a -Even more preferred are compounds of formula XXIII
described above, wherein R7 is -PO(OM)2 or -C(O)-M'.
For compounds of formula XXXI, most preferred compounds are those wherein A is R1-Ht, each R3 is independently C1-C6 alkyl which may be optionally substituted with a substituent selected from the group consisting Of -ORz, -C (O) -NH-R2, -S (O) nN (R2) (Rz) , Ht, -CN, -SR.2, -COZRz or -NRZ-C (O) -R2; and D' is C1-C4 alkyl, which may be optionally substituted with a group selected from the group consisting of C3-C6 cycloalkyl, -OR2,' -O-Q; and E is Ht, Ht-Ht and -NR2R3.
Even more preferred are those compounds of formula XXXI described above wherein R' is -PO(OM)2 or -C (O) -M' .
TABLE I
O
OR ~ /
-- O N N ~ \
iS~O
i O O
CMF'D R7 W

/ 'O ~ ~ Np2 19 ~~
Q -NHZ
~N~
~,NMe -NHz ~0~ NMe2 t'r'M1PDR7 w ~N~NHAc H

O -~2 'N

NH

:3 -NHz ~N~NH2 H

~N~NH

H

20~~

Q -NHZ

H

20E>

O -~2 ~N NH2 ',~

O -NHz N ,,yN H2 CMl?D R7 w O -NOz NH2 ~. OBn 2 0'.3 O -NOz ~~~Me O -NHz "' p " UMe 21.L
O _ NH2 NH2 \ OH
21 a! O
-~z O~CH3 21 _~
O -NHz ~~ OOH

O -NHz ~NH2 O -NHz ~O~a~OMe 61009-317(S) CMPD g7 W

O -NHZ
~O~N~NMe2 Me O ~N -NH2 IN J

H O
~N ~ N
H
NHz H
O
~N ~ ~N
H NHz NH~

H O ~NMe ~N~N~
H

H O
~N~O~N~NMez Me H
~N O~OMe H

61009-317(S) CMPD g7 W

H O
~N~O~O~OMe H

O
~ /O
O ~CH3 ~N~ ~OMe H

/P~H
OH

/p~OH
OH

/POOH
OH

O -NHZ
/P~O NA
O Na H O
\N~O\/\O~/OwCH3 H

O O
~O\~ ~/O~ \N~O~O~O\CH3 __.

O -NOz OH

O Fi -NOz Ac0 O

'OAc T

OAc i AcOH

~a - S03H -NOz () - S03H -NHz .L

-NOZ

II p 0 ~P~
~NMe3 O

NHz I I ~

~P~
~NMe3 O

~~

O - NHz P' H

OH

CMpD R7 W
2 4 i5 O _~z '. v _OH
NHS
24'7 Q
-NHz ~O

24f3 -~z 2 4 ~a CH3 NHz -NHz ~CH3 257_ O
-NHz NHZ
2 5 ~; O
_ NHz ~' O H
NHz 2 5 .. O
O -NHz NHz OH
2 59: O
-NHz CMF'D R7 W

H -NH-CHO
25Ei O
H
N
H
NH
2 5 ;~ O
H
\ H CH3 H O
\ ~CH3 N
H
255a H O
\ N CH3 H
26C~
O
H
H CFs / CHs H CHa /~ CH3 \ N CH3 H

CH3 \N I ~H3 H

P03Ca -NHZ
26E~-.
P03Mg -NH2 /~ OtBu -NHZ

308.
-~2 4 0 2 f'$OC
H

O
403 rpOC
H

O

H
~H2 O INIH
405 NHAc H H
/N NHZ' O
406 NHAc H H
/N
N HZ
O

H
~2 O INIH

-~2 O

TABLE II
OR' ~ NOz H
,N, N~ \
is~0 O

n H C;~O~ ~O CH3 CHs H
~O~CH3 H
H~C~O
2 3 5 H,3C O NO
O / z H C~O
3 ~ \
CH3 / 'O

3 p H3C~0~ O
CH3 ~ O
TABLE III
O o ''S;o O~N N~ /
O
R'- O
W

H-P-- -NOZ

O

I I

O

OH ~ w -NO2 O

OH ~ ~- -NHZ

O

According to another embodiment, the invention provides compounds of the following formulae:

R' w. ' ~, NH
w I
O~O
, ~~= N O Q S
R' v I~
R~ N
R )X I w I V
/
(G)X

R' r .I o I/
1006 , N~z ~I~H

1009 , or R

OR' / (NH)XR' S
O
HsC CHs wherein, in compound 1005, when R' is P03M, (G)X is not H;
and wherein R1° is selected from isopropoyl or cyclopentyl; R11 is selected from NHR' or OR'; and x, R' and G are as defined above.
The prodrugs of the present invention may be synthesized using conventional synthetic techniques.
Unit=ed States patent 5,585,397 discloses the synthesis of compounds of formula:

61009-317 (S) D
H
A ~B) X f~l H ~ H ---N ~02~
(G )X OH D' wherein A, B, x, D, D', and E are as defined above.
Prodrugs of formula (I) of the present invention can be readily synthesized from the '397 compounds using conventional techniques. One of skill in the art would be well aware of conventional synthetic reagents to convert the -OH group of the '397 compounds to a desired -OR7 functionality of the present invention, wherein R7 is as defined above. The relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds.
For example, VX-478, a compound disclosed in the '397 patent, can be readily converted to the corresponding bis-phosphate ester derivative, as shown below:
I
p O q O ~ ~~~0 DCC, H3_P03 ~O~N N'S ~ ~ O N N
O I ~ pyridine, 60~C, 3h O-P-O ~NHPO H
~NHz . ~ s z H OH
Alternatively, if the monophosphate ester of VX-478 is desired, then the synthetic scheme can be readily adapted by beginning with the 4-nitrophenyl derivative of VX-478, as shown below:

61009-317(S) p ~I p ~IQ
~O DCC, H3P03 ~ ~ ,~~0\
O N N I ~ ~ O N N
O ~ pyridine, 60°C, 3h O-P-O I ~ NO
NOz H \ ~ 2 OH
i hexame~isilazane ~ ~ w I O/O
2' bis(trimethyl)peroxide O N N'S ~ ~ EtOAc, 35 psi 120°C, 2h O=p-O ~ ~ NO

HO OH
O ~ I
J~ ,O
w ~O~N N'S ~I
O=P 0 v'NH2 OH
HO
Examples of specific compounds in addition to VX-478 which may be converted to the prodrugs of this invention by similar techniques (and the syntheses of those intermediates to the compounds of the present invention) are disclosed in WO 94/05639 and WO 96/33184.
Pharmaceutically acceptable salts of the compounds of the present invention may be readily prepared using known techniques. For example, the disodium salt of the mono phosphate ester shown above can be prepared as shown below:
O w IO O w 10 O 1) 3 equiv. aq. NaHC03 ~ ~ It,O
O N N ~I ~ --~ O N N'S~
O=P'~ v 'NH2 2) Mitsubishi CHP-20 O=P-O I ~ NH
OH ~ polyaromatic resin column + /1 - 2 HO 0% to 5% CH3CN in H20 Na O O Na+
3) lyophilize The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rats=_ of excretion.
Without being bound by theory, we believe that two different mechanisms are involved in converting the prodrugs of this invention into the active drug, dept=nding upon the structure of the prodrug. The first mechanism involves the enzymatic or chemical transformation of the prodrug species into the active form. The second mechanism involves the enzymatic or chemical cleavage of a functionality on the prodrug to produce the active compound.
The chemical or enzymatic transformation can involve to transfer of a functional group (i.e., R') from one heteroatom within the molecule to another heteroatom.
This transfer is demonstrated in the chemical reactions shown below:
TFA -pH 7.6 and 61009-317(S) ~0~0 HO
TFA- H2N N S\ \ / NH pH 7.6 ' ~D"N N S\ NH
d ~ 2 o-J d .o v / 2 The cleavage mechanism is demonstrated by the reaction below where a phosphate ester-containing prodrug is converted into the active form of the drug by removal of the phosphate group.
O
H _ H _ O ~ O
These protease inhibitors and their utility as inhibitors of aspartyl proteases are described in United States Patent 5,585,397.
The prodrugs of the present invention are characterized by unexpectedly high aqueous solubility. This solubility facilitates administration of higher doses of the prodrug, resulting in a greater drug load per unit dosage.
The prodrugs of the present invention are also characterized by facile hydrolytic cleavage to release the active aspartyl protease inhibitor in vivo. The high aqueous solubility and the facile in vivo metabolism result in a greater bioavailability of the drug. As a result, the pill burden on a patient is significantly reduced.

61009-317(S) - 37a -The prodrugs of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, a prodrug of 'this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
Alternatively, the prodrugs of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time. The prodrugs may be employed in such vaccines either alone or together with other compounds of thi:~ invention in a manner consistent with the conventional utilization of protease inhibitors in vaccines. For example, a prodrug of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over- an extended period time against HIV infection. As such, the novel protease inhibitors of this invention can be administered as agents for treating or preventing HIV
infection in a mammal.
The prodrugs of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV.
By administering the compounds of this invention with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-61009-317 (S) administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Anti-HIV agents targeting such early life cycle events include, didanosine (ddI), alcitabine (ddC), d4T, zidovudine (AZT), polysulfated polysaccharides, sT4 (soluble CD4), ganciclovir, dideoxycytidine, trisodium phosphonoformate, eflor-nithine, ribavirin, acyclovir, alpha interferon and tri-menotrexate. Additionally, non-nucleoside inhibitors of reverse transcriptase, such as TIBO or nevirapine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase.
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV
replication because each component agent of the combination acts on a different site of HIV replication.
The use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. In particular, we have discovered that these prodrugs act synergistically in preventing the replication of HIV in human T cells.
Preferred combination therapies include the administration of a prodrug of this invention with AZT, ddI, ddC or d4T.
Alternatively, the prodrugs of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM .323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
We prefer administering the prodrugs of this invention as single agents or in combination with ret:roviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors. We believe that the co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inh:ibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely elirninating viral infectivity and its associated symptoms.
The prodrugs of this invention can also be adm~_nistered in combination with immunomodulators (e. g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diet:hyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO); and antibiotics (e. g., pentamidine iset:hiorate) to prevent or combat infection and disease associated with HIV infections, such as AIDS and ARC.
When the prodrugs of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of a prodrug of this invention and another therapeutic or prophylactic agent.
Although this invention focuses on the use of the prodrugs disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which dep~=nd on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, as wel:L as other AIDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, but are not limited to, HTLV-I and HTLV-II. In addition, the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl prot~eases that process endothelin precursors.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
Pharmaceutically acceptable carriers, adjuvants and veh~_cles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or elecarolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, pol~ethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invE=_ntion may be administered orally, parenterally, by inh<~lation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral adm:inistration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
Thi:~ suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3--butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conven-tionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as :Ph. Helv or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, cap:~ules, tablets, and aqueous suspensions and solutions.
In i=he case of tablets for oral use, carriers which are commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsify-ing and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added .
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is :solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical forrnulation and may be prepared as solutions in saline, emp7_oying benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about .O1 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection.
Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion.
Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95%
active compound (w/w). Preferably, such preparations coni~ain from about 20% to about 80% active compound.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the des_Lred level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required.
Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Example 1 General conditions:
(A) Analytical HPLC 0-100%B/30 min, 1.5 mL/min, A=0.1% TFA in water, B=0.1% TFA in acetonitrile.
Detection at 254 and 220 nm, C18 reverse phase Vydac, t0=.2.4 min.
(B) 1/3 v/v EtOAc/hexane (C) 1/2 v/v EtOAc/hexane (D) Analytical HPLC 0-100%B/10 min, 1.5 mL/min, A=0.1% TFA in water, B=0.1% TFA in acetonitrile.
Detection at 254 and 220 nm, C18 reverse phase Vydac, t0=2.4 min.
OpN
\ ~ O O
O
O OH O
_ O
1L - ~ O
O NH~N. _ _ V ~/ O 17 ~ / NOZ O~NH~N.S NO
~/ ~ O. 'b \ / 2 A mixture of 2.Og (3.7 mMol) of 197 and 3.Og (16 mMol) of di-p-nitrophenyl carbonate in 10 ml of dimethylformamide was treated at 25° with 4 ml (4 mMol) of P4-phosphazene base (Fluka, 1M in hexane). The mixture was stirred for 6h at 25° until all of the starting alcohol was consumed. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with 1N sodium hydroxide and brine, dried over magnesium sulfate and con~~entrated in vacuo. Titration with dichloromethane gav~= the desired mixed carbonate (1.2g cropl and 0.6g crop 2) as a fine powder. Combined yield: 69%. Rf=0.13 (1/:3 EtOAc/hexane, conditions B), Rf=0.40 (1/2 EtOAc/hexane, conditions C), tHPLC=23.83 min (A), MS(ES+) 701 (M+1) .
1H-1~TMR (CDC13 ) : 0 . 82 ( 6H, dd) , 1 . 9 (2H, m) , 2 . 15 ( 1H, m) , 2 . 8 ( 1H, m) , 3 . 0 (4H, m) , 3 . 5 (2H, m) , 3 . 6 ( 1H, m) , 3 . 8 (4H,m) , 4.3 (lH,bs) , 4.8 (lH,m) , 5.17 (2H,m) , 7.7 (7H,m) , 7 . 95 (2H, d) , 8 . 35 (4H, m) .
13C (CDC13): 155.2 152.2, 149.9, 145.6, 135.9, +129.0, +12~3.8, +128.5, +127.2, +125.4, +124.4, +121.8, +78.1, +75.8, -73.1, -66.9, -56.5, +52.7, -48.2, -35.9, -35.9, 32.6, -+26.4, +19.9, +19.8.
Example 2 OpH
O T'~~~ O MeN N
O O
/ O ~_ O
~OxNH N. - '/ ~ O O
~O'SO ~ I NOZ ~ V_OxNH N.
I NHS

To 0.208 (0.286 mM) of 198 dissolved in 3 ml of THF was added 0.11 g (1.14 mM) of 1-Methyl-piperidine and the mixture was stirred overnight at room temperature ("rl~~~). All the solvents were then evaporated and the solid residue partitioned between EtOAc and water. The volatiles were removed and, where appropriate, the residue was treated with 1:1 TFA/DCM over 30 min at rt to remove the Boc protecting group. The product was dis:~olved in 0.25 ml TFA and 1.5 ml THF. Hydrogenolysis for 10 hours in presence of 30 mg of 10~ Pd/C gave the desired compound. 'the final purification was on preparative reversed phase C18 using conditions Example 1, except that the flow rate was 18 ml/min.
C,H,.N: talc: 49.27, 5.57, 8.25, found 49.15, 5.76, 8.29 C31H,~SNSO~S1 . 1.9CF3COOH
LC/MS (ES+) 632 (M+1) 1 peak at 4.71 min Ana7_ytical HPLC (A) t=N/A min 1H: 0 . 71 (3H, d) , 0 . 74 (3H, d) , 1 . 80 (2H, m) , 2 . 03 (1H, m) , 2.63 (2H,m) , 2.74 (lH,m) , 2.82 (3H, s) , 2.92 (2H,m) , 3.20 (4H, m) , 3 . 42 (3H, m) , 3 . 62 (2H, m) , 3 . 75 ( 1H, m) , 4 . 05 (3H,m) , 4.97 (2H,m) , 6.2 (lH,bs) , 6.60 (2H,m) , 7.22 (5H,m) , 7.40 (3H,m) , 13C (DMSO): 156.4, 154.0, 153.8, 138.8, 129.6, 129.5, 128.3, 126.5, 123.7, 112.7, 74.8, 72.9, 66.7, 58.2, 54.0, 53.1., 49.3, 42.3, 40.8, 36.0, 33.3, 25.8, 20.4, 20.3 Example 3 oZN
O \ ~ O O MeiN O
o ~_ o ~'OxNH' ~ /N. - O O
~ I N02 -i ~OxNH~N.S NH

The synthesis of compound 200 from compound 198 was carried as described in Example 1, except that N,N-dimethyl-aminoethanol was used in place of di-p-nit=rophenyl carbonate .
1HNMR (acetone-d6) : 0 . 82 (6H, dd) , 1 . 83 (2H, m) , 2 . 07 (lH,,m) , 2.64 (2H,m) , 2.82 (6H, s) , 2.90 (2H,m) , 3.19 ( 1H,, m) , 3 . 38 (4H, m) , 3 . 63 (2H, m) , 3 . 76 ( 1H, m) , 4 . 17 (2YH,m) , 4.40 (lH,m) , 4.56 (lH,m) , 4.96 (lH,m) , 5.06 (lH,.m) , 6.06 (lH,d) , 6.68 (2H,d) , 7.23 (5H,m) , 7.47 (2H,, d) .
13CNMR (acetone d6): 20.2, 20.3, 27.5, 33.4, 35.6, 43.8, 50.~~, 54.2, 56.4, 58.5, 63.1, 67.4, 73.6, 76.2, 79.9, 114..2, 118.3, 127.4, 129,2, 130.1, 130.3, 139.3, 153.4, 157Ø
LC/MS : 1 peak, 621 (MH+) .
Example 4 OpN
O
AeHN H O
O O~ ~N~
O ~_ /O
~~OxNH N. O _O
~OSO ~ I NOZ -~ ~OUNH ~ 'N.
N HZ

The synthesis of compound 201 from compound 198 was carried as described in Example 1, except that N-acetyl-ethylenediamine was used in place of di-p-nit:rophenyl carbonate.
C,H,N: calc: 49.66, 5.64, 8.83, found 49.76, 5.98, 8.93 C3oH4sNsOeSi . 1.4CF3COOH.
LC/1~IS (ES+) 634 (M+1) 1 peak at 5.08 min.
Analytical HPLC(A) t=15.92 min.
1H: d-3 acetonitrile: 0.88 (6H,dd), 1.92 (3H,s), 1.94 (2H, m) , 2 . 17 ( 1H, m) , 2 . 72 (2H, m) , 2 . 96 (2H, m) , 3 . 07 (3H,m) , 3.29 (lH,m) , 3.42 (3H,m) , 3.69 (lH,m) , 3.77 (lH,,m) , 3.82 (lH,m) , 4.133 (lH,m) , 4.40 (lH,bs) , 5.05 (2H,,m) , 5.80 (lH,m) , 6.10 (lH,d) , 6.78 (2H,d) , 6.83 (lH,,bs) , 7.28 (SH,m) , 7.58 (2H,d) .
13C (d3-acetonitrile): 157.1, 157.0, 153.2, 139.6,+130.3, +130.2, +129.2, +127.2, 126.2, +114.2, +76.0, +75.4, -73.Ei, -67.4, -58.2, +54.9, -50.2, -41.6, -39.8, -35.9, -33.~6, +27.3, +23.1, +20.4, +20.2.
Example 5 O~N
\ I O HN
O~ ~N~O
O
O ~ O
~ / O
~O~NH~N1S \ / NOZ ~ ~OkNH~ ~O ~N.
v O O~ ~O~S.O ~ ~ NH2 /

The synthesis of compound 202 from compound 198 was carried as described in Example 1, except that mono N-Bc~c-piperazine was used in place of di-p-nitrophenyl carbonate.
C,H,N: calc: 48.28, 5.68, 8.41, found 48.28, 5.36, 8.28 C3pHq3N5O~S1 X 2 CF3COOH
LC/MS (ES+) 618 (M+1) 1 peak at 4.36 min.

Analytical HPLC(A) t=14.84 min.
1H: d6-DMSO: 0.72 (3H,d), 0.77 (3H,d), 1.78 (2H,m), 2.09 ( 1H, m) , 2 . 64 ( 2H, m) , 2 . 7:3 ( 1H, m) , 2 . 80 ( 1H, m) , 3 . 08 (4H, m) , 3 . 32 (2H, m) , 3 . 41 ( 1H, m) , 3 . 50 (4H, m) , 3 . 54 (lH,m), 3.63 (lH,m), 3.70 (lH,m), 3.98 (lH,m), 4.89 ( 1H, m) , 4 . 97 ( 1H, m) , 6 . 61 ( 2H, d) , 7 . 23 ( 5H, m) , 7 . 42 (3H,m) , 8.88 (2H,bs) .
13C: (DMSO): 155.7, 153..6, 153.0, 138.4, +129.1, +129.0, +128.1, +126.1, 123.2, +112.7, +75.2, +74.4, -72.5, -66.2, -56.9, +53.1, -48.8, -42.5, -40.8, -35.0, -32.2, +26.2, +20.0, +19.8.
Example 6 OyN
O \ ~ O O HZN N
o ~ o '/~ 0 OKNH ~ 'N01S0 \ / NOZ V _OxNH ~ 'N.S NH
V V V V O~ O ~ ~ 2 The synthesis of compound 203 from compound 198 was carried as described in Example 1, except that mono-N-Boc-ethylenediamine was used in place of di-p-nitrophenyl carbonate.
C,H,N: calc: 46.89, 5.29, 8.54, found 46.50, 5.51, 8.54 CzeH4INsO~S1 x 2 CF3COOH.
LC/MS (ES+) 592 (M+1) 1 peak at 4.32 min.
Analytical HPLC(A) t=14.69 min.
lH:d-6 DMSO: 0.77 (6H,d), 1.82 (2H,m), 2.06 (lH,m), 2.57 ( 2H, m) , 2 . 82 (4H, m) , 2 . 97 ( 1H, m) , 3 . 3 0 ( 5H, m) , 3 . 55 (lH,m), 3.65 (lH,m), 3.70 (lH,m), 3.95 (lH,m), 4.88 (lH,m) , 4.95 (lH,m) , 6.62 (2H,d) , 7.20 (6H,m) , 7.39 (3H,m) , 7.78 (3H,bs) .

13C (dmso): 155.9, 152.9, 138.5, 129.2, 128.9, 128.1, 126.1, 122.9, 112.7, 74.7, 74.5, 72.6, 66.2, 57.2, 53.2, 49.4, 38.8, 37.94, 35.1, 32.1, 26.3, 20.0, 19.8.
Example 7 OZN
O O~O H~N~N O
O ~ O
O~NH~N;S NO _ JOl O
\ / Z -~ O NH ~ 'N.S NH
O. O \ / s The synthesis of compound 204 from compound 198 was carried as described in Example 1, except that mono-1,3-diamino-3-N-Boc-propane was used in place of di-p-nitrophenyl carbonate.
C,H,N: calc: 49.07, 5.64, 8.89,, found 48.95, 6.00, 8.92 CZgH43N5O~S1 X 1.6 CF3COOH
LC/MS (ES+) 605 (M+1) 1 peak at 4.27 min.
Analytical HPLC(A) t=14.72 min.
1H: d-6 DMSO: 0 . 78 (6H, dd) , 1 . 64 (2H, m) , 1 . 83 (2H, m) , 2 . 03 (lH,m), 2.57 (lH,m), 2.78 (4H,m), 2.94 (lH,m), 3.03 (2H, m) , 3 . 32 (2H, m) , 3 . 58 ( 1H, m) , 3 . 63 ( 1H, m) , 3 . 73 (lH,m), 3.87 (lH,m), 4.84 (lH,m), 4.92 (lH,m), 6.61 (2H, d) , 7.22 (6H.m) , 7. 36 (1H, d) , 7.28 (2H, d) , 7 . 76 (3H, ns) .
13C (dmso): 155.8, 155.7, 138.5, +129.1, +129.0, +128.0, +126.1, 122.9, +112.7, +74.6, +74.3, -72.7, -66.2, -57.2, +53.6, -49.5, -37.4, -36.'7, -35.5, -32.1, -27.6, +26.2, +20.0, +19.8.

Example 8 OZN
\ I HyN
O H O
~, N
_ o OKNH' ~ / -N. O O
~ I NOZ ---~ ~OKNH~ ~ ~N.
V V OYSO ~ / NHZ

The synthesis o:f compound 205 from compound 198 was carried as described :in Example 1, except that 1,4-diamino-4-N-Boc-butane wars used in place of di-p-nitrophenyl carbonate.
C,H,N: talc: 48.17, 5.59, 8.26, found 48.02, 5.96, 8.24 CaoH4sNsO~S1 .2 CF3COOH
LC/MS (ES+) 620 (M+1) 1 peak at 4.36 min.
Analytical HPLC(A) t=14.93 min.
1H: d-6 DMSO: 0 . 77 (6H, dd) , 1 . 43 (4H, m) , 1 . 82 (2H, m) , 2.03 (lH,m) , 2.77 (4H,m) , 2.95 (3H,m) , 3.31 (2H,m) , 3.56 (lH,m), 3.63 (lH,m), 3.70 (lH,bq), 3.82 (lH,m), 4.85 ( 1H, m) , 4 . 92 ( 1H, m) , 6 . 62 ( 2H, d) , 7 . 2 ( 7H, m) , 7 . 3 8 (2H, d) , 7 . 72 (3H, bs) .
13C: 155.7, 152.9, +138.6, +129.1, +129.0, +128.0, +126.1, +123.0, +112.7, +74.4, +74.3, -72.7, -66.2, -57.2, +53.7, -49.7, -38.6, -38.5, -35.4, -32.1, -26.3, +26.2, -24.4, +20.1, +19.9 Example 9 O~N ~ HZN
\ I O
O N _ 'O
~O
~ o °- o ~OxNH~N.S NO Jl O
---~ O N H' ~ /N.
N HZ

The synthesis of compound 206 from compound 198 was carried as described in Example l, except that (3R)-(+)-3-Boc-aminopyrrolidine was used in place of di-p-nitrophenyl carbonate.
C,H,N: calc: 48.28, 5.36, 8.28, found 47.89, 5.53, 8.57 C30H43N5~7S1 x 2 TFA
LC/MS (ES+) 618 (M+1) 1 peak at 4.32 min.
Analytical HPLC(A) t=14.31 min.
1H and 13C NMR: complex and overlapping mixtures of rotomers.
Example 10 OZN ~ HzN
O
O CN O
O
O ~ O
' ~ / '/~O
~OxNH\~N~g- ~ I NO~ ~ V_OILNH~ ~O ~N.
O O ~O~SO ~ I NHZ

The synthesis of compound 207 from compound 198 was carried as described :in Example 1, except that (3S)-(-)-3-Boc-aminopyrrolidine was used in place of di-p-nitrophenyl carbonate.
LC/MS (ES+) 618 (M+1) 1 pesak at 4.19 min.
Analytical HPLC(A) t=14.75 min.
1H and 13C NMR: complex and overlapping mixtures of rotomers.

Example 11 Mew 02N \ ~ N
~O
O
O 9 Mew Ox NH N. O
~ NOZ ---~ ~ Ox NH ~ 'N~.~, ~~0~ ~ NH2 The synthesis of compound 308 from compound 198 was carried as described in Example 1, except that N
triphenylmethyl-N,N'-dimethylethanediamine was used in place of di-p-nitrophenyl carbonate.
1H-NMR: 0.76 (6H,dd), 1.65 (2H,m), 1.95 (lH,m), 2.07 (lH,m) , 2.7 (2H,m) , 2.75 (3H,s) , 2.95 (3H,m) , 3.45 (2H, m) , 3 . 7 (4H, m) , 4 . 2 (2H, bm) , 5 . 05 (2H, bd) , 6 . 62 (2H, d) , 7 . 2 (5H, m) , 7 . 5 (:?H, d) .
LC/MS: 1 peak, 620 (MH+).
Example 12 General Procedures Acylat ion Bno /

O OH O HEN
~O~NH~N.S - NO k O
-----~ O N H~ N;S/ NOp O O ~ I

To 200mg (.37mM) of 197 dissolved in 5ml CH2C12 was added N-CBz-L-Benzyl tyrosine 183mg (.4lmM) followed by 231 mg (1.12mM) DCC, followed by 29mg (.23mM) DMAP.
The reaction is stirred at rt for 24hr. The precipitates present were removed by filtration. The filtrate was then concentrated in vacuo. The final compound was purified on preparative reversed phase C18 using purification by HPLC C1$ Waters Delta Prep 3000 Column:
YMC-Pack ODS AA 12505-2520WT 250X20 mm I.D. S-5mm, 120A, 0-100% B over 1/2h, flow=18 ml/min, monitored at 220 nm, B=0.1% trifluoroacetic acid in acetonitrile, A=0.1%
trifluoroacetic acid in w;~ter. Analytical Column: YMC-Pack ODS AA1 2505-2520WT 250X4.6 mmI.D. S-5mm, 120A, 0-100% B at 1.5 ml/min. over 1/2 h, monitored at 220 nm, B=0.1% trifluoroacetic acid in acetonitrile, A=0.1%
trifluoroacetic acid in w<~ter.
The aqueous phase was lyophilized to give 59 mg, (16.3%) GW431896X, (U11484-72-10) tgpLC=11.71 min. , MW=966.04, LC/MS=MH+967.
Reduction of the Nitro Functionalit Meow o O O~ MeO~ ~ O

O
~O~NH~N'S NOz ~ O
\ / -w O NH~N'S NH
/ ' /

A slurry of 209 (170 mg) and 10 mg of 10% Pd.C
in 95% EtOH was flushed with hydrogen in a scintillation vial equipped with septum and a stir bar. Continuous overnight hydrogenolysis under hydrogen balloon resulted in a complete conversion. The crude preparation was then filtered off the catalyst, and purified on RP C18 HPLC
(Prep Nova-Pack C186 um, 60 A, gradient 0-100% B over 30 min. The desired product was collected and lyophilized affording a white fluffy solid (50 mg, 30.8%).

Example 13 HO
p ~O
/ O OH O Hp _ ~N
~OxNH~N;S NOz JpL O
V O O ~ ~ ~ O NH ~ 'N;Sf NHz V

Compound 211 was obtained following the acylation and reduction procedures of Example 12.
ES+ 669.2 (M+1), tHPLC=8.06 min (D), 13C NMR (DMSO)168.9, 156.9, 155.7, 153.1, 138.:1, 130.5, 129.2, 129.1, 128.1, 126.2, 124.7, 122.5, 112.8, 76.2, 74.5, 72.5, 66.1, 58.0, 53.6, 52.6, 49.2, 33.6, 32.1, 26.6, 25.3, 20Ø
tHPLC=11.71 min (D), ES+ 967 (M+1).
Example 14 i p 10 O ~_H O
O~NH N. ~ ~ O O
\~/O'SO ~ ~ NOZ -~ ~OxNH~NOS NH
O ~ ~ z 212 was obtained following the procedures of Example 12.
tHPLC= 9.45 min (D), ES+ 592.2 (M+1).
13C NMR (DMSO) 171.5, 155.8, 148.9, 137.8, 129.5, 129.3, 128.5, 126.7, 115.2, 75.2, 73.8, 73.1, 68.3, 67.0, 58.7, 57.1, 53.3, 49.2, 35.4, 32.4, 26.7, 20.1, 19.8.
1H (CDC13, 399.42 KHz) : 8 .33 (2H, d, J=8.8) , 7. 95 (2H, d, J=8.8) , 7.23 (5H, m) 5.22 (m, 2H) , 5.08 (m, 1H) , 4 . 08 (m, 1H), 3.80-3.45 (7H, m), 3.41 (3H, s), 2.98 (m, 3H), 2.66 (m, 1H), 2.57 (m, 2H), 2.10 (s, 1H), 1.93 (2H, m), 0.82 (3H, d) , 0.78 (3H, d) .
ES+ 622 (M+1), 644 (M+Na) tHPLC =10.29 min (D).
13C NMR (CDC13): 171.3, 155.5, 149.9, 145.6, 136.9, 129.2, 128.6, 128.5, 126.8, 124.4, 76.7, 75.3, 73.2, 72.9, 68.2, 66.9, 58.7, 5.5.9, 53.1, 48.3, 35.3, 32.7, 26.3, 19.9, 19.8.
Example 15 0 H0~0~0 O O H ~1'O
OxNH ~ 'N;Sr NOp _ ~ O
0 NH~N;S' NHZ
V O O ~ I

Compound 213 was obtained following the procedure of Example 12. tHPLC = 9.21 min (D); ES+ 622 (M+1) .
13C NMR (CDC13): 170.54, 156.2, 148.6, 136.8, 129.4, 129.2, 128.6, 126.6, 115.7, 76.7, 74.6, 73.2, 71.8, 70.6, 68.2, 66.9, 58.9, 57.3, 53.8, 49.4, 36.2, 33.1, 26.8, 19.8, 19.5.
Intermediate: t HPLC = 10.05 min (D); ES+= 652 (M+H) 674 ( M+Na ) .

Example 16 NHZ
,O HZN O
O OH O
~OxNH~N;S, NOp k O
~ ~/ O O ~ / --~ O NH ~ 'N.S NH
O~O~

214 was obtained following the procedure of Example 12.
ES+ 634.4 (M+1); t HPLC = 7.17 min (D).
13C (DMSO): 169.3, 155.8, 153.1, 138.0, 129.1, 129.0, 128.1, 126.3, 122.6, 112.8, 94.3, 75.6, 74.6, 72.4, 66.1, 57.8, 52.7, 52.0, 49.3, 38.4, 34.7, 32.2, 29.1, 26.6, 21.4, 20.1, 20Ø
Example 17 o nn.o~o~o~o / O O H '(O
~O NH' ~ /N. - ~~ O
~ / NO~ -~ '"OUNH . ~ 'O'S NHZ
V O ~ /

215 was obtained following the procedure of Example 12.
t HPLC = 9.12 min (D) 1H (DMSO) all signals broad: 7.38 (3H, br m), 7.20 (5H, br m), 6.62 (2H, br m), 5.15 (1H, br m), 4.92 (1H, br m), 4.00 (3H, m), 3.7-3.0 (16H, m), 2.78 (2H, m), 2.57 (3H, m), 2.04 (m, 1H), 1.78 (m, 2H), 0.77 (6H, m) 13C (DMSO) 170.6, 156.3, 153.7, 139.1, 129.8, 128.4, 126.7, 123.7, 113.3, 79.8, 79.2, 77.3, 76.1, 75.4, 75.2, 73.0, 71.9, 52.3, 51.8, 48.2, 46.7, 39.9, 38.7, 25.8, 22.6.
Intermediate:
t HPLC = 10.18 min (D); ES+ 696.3 (M+1).
Example 18 Me O MexN~N~ 10 O OH O
_ O
O~NH~N;S NO JL O
V V p O ~ I 2 ----~ O N H~ N ;S N H

216 was obtained following the procedure of Example 12.
1H-NMR: 0.97 (6H,t), 1.95 (2H,m), 2.20 (lH,m), 2.9 (2H,m), 2.96 (6H,s), 3.00 (3H,s), 3.38 (lH,m), 3.42 (3H,m) , 3.36 (lH,m) , 3.6 (2H,m) , 3.7 (6H,m) , 3.98 (2H,m) , 4.2 (2H ,dd) 5.1 (lH,bs) 5.4 (lH,m) , 6.8 (2H,d) , 7.4 , , (5H, 7 . (2H, d) .
m) , 6 LC-MS: 1 peak, (MH+).

Exams 1 a 19 N'Me N
O
O OH
Ok NH O O ~O
~~ NO z ~ OJL NH
O~ NH 2 217 was obtained following the procedure of Example 12.

1H-NMR (CDC13 ) : 0 . 78 ( 6H, dd) , 1 . 9 (2H, m) , 2 . 1 ( 1H, m) , 2 . 3 ( 3H, s ) , 2 . 9 ( 8H, m) , 2 . 9 ( 2H, m) , 3 . 15 ( 1H, m) , 3 . 3 5 ( 1H, m) , 3 . 5 (1H, m) , 3 . 75 (4H, m) , 4 . 06 (2H, s) , 4 . 15 (2H, m) , 4 . 9 (lH,dd) , 5.05 (lH,bs) , 5.2 (lH,bs) , 6.63 (2H,d) , 7.2 (5H, m) , 7 . 55 (2H, d) , 8 . 0 (2H, m) .
ESMSP: 676 (MH+).
Example 20 General Procedure for N-acylated Compounds - N
O
OH
OxNH~N_S NH O -O OH H N
O b \ I Z O~NH ~ 'N.
O
i A mixture of 0.5g (1 mMol) of (3S)-Tetrahydro-3-furfuryl-N-((1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-aminobenzenesulfonamido)propyl) carbamate, 0.4g (1.5 mMol) of Boc-(S)-3-pyridyl alanine, 0.29g (1.5 mMol) EDCI
and O.lg 4-dimethylamino pyridine in 10 ml of N,N-dimethylformamide was stirred at 25° for 12 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with 1N sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a 2 inch plug of silica gel (1:1 ethyl acetate:
hexane) to give the desired N-acylated material.
Deprotection by treatment with 50 ml of trifluoroacetic acid, followed by co-evaporation of residual acid with methanol gave the desired prodrug as a white foam (0.2g, 26~) .
H1-NMR (acetonitrile-D3 ) : 0 . 95 (6H, dd) , 2 . 0 (2H, m) , 2 . 25 (lh,m) , 2.8-3.1 (SH,m) , 3.6-4.0 (7H,m) , 4.25 (lH,m) , 4.75 (lH,m) , 5.18 (lH,m) , 5.45 (lH,m) , 7.0 (2H,d) , 7.4 (SH,m) , 7.75 (2H,d), 8.2 (lH,m), 8.8 (lH,d), 8.85 (lH,d), 9.15 (lH,s) .
LC/MS: 1 peak, 654 (MH+).
Example 21 'N
H lNr~
O
/ O OH
~O~NH~/N-S- NH '/ -O~ O OH HyN
O Q ~ I = V _pxNH ~ 'N:S N O
O p ~ I H

220 was obtained using the general procedure in Example 20.
1H-NMR (acetone-d6/ methanol-d4): 0.95 (6H,t), 2.0 (2H,m), 2.2 (lH,m), 2.90 (lH,dd), 2.95 (2H,d), 3.12 ( 1H, dd) , 3 . 4 (2H, m) , 6 ( 1H, d) , 3 . 8 ( 5H, m) , 4 . 4 (2H, bm) , 6 . 82 (2H, d) , 7.20 (1H, s) , 7 . 4 (5H, m) , 7 . 65 (2H, d) , 8 . 0 (lH,s) .
LC/MS: 1 peak, 643 (MH+).

Examgle 22 ~NMe , O OH N
° - J
~OxNH~N-S NH O O ~H
V v z C~ _ ~O~NH~N.S N O
O' b ~ I H

221 was obtained using the general procedure in Example 20.
1H-NMR (DMSO d-6 ) : 0 . 76 ( 6H, t ) , 1 . 80 (2H, m) , 2 . 10 ( 1H, m) , 3.7 (4H,m) , 3.75 (3H,s) , 3.2 (5H,m) , 3.58 (2H,s) , 3.7 (4H, m) , 4 . 97 ( 1H, bm) , 5 . 18 (1H, bs) , 6 . 7 (2H, d) , 7 . 22 (SH,m) , 7,45 (2H,d) .
LC/MS: 1 peak, 646 (MH+).
Example 23 NMei MeN
'O
O OH O
~O~NH~N-S NH O O O_H
V z C~
_OxNH ~ 'N, V V O . ~ I N~O
b~ H

222 was obtained using the general procedure in Example 20.
1HNMR (acetonitrile d-3): 1.0 (6H,t), 2.0 (2H,m), 2.2 (lH,m) , 3 . 00 (6H, s) , 3 . 02 (3H, s) , 3. 1 (4H,m) , 3 .5 (3H,m) , 3.8 (8H,m) , 4.4 (2H,s) , 5.15 (lH,bs) , 7.4 (SH,m) , 7.97 (2H, d) , 8 . 04 (2H, d) .

LC/MS: 1 peak, 692 (MH+).
Example 24 Me0 O
O OH O
~Ox NH~ N-S_ NHC O~ O OH
O U ~ I Z ~OxNH N.
H O

223 was obtained using the general procedure in Example 20.
t HPLC = 9 . 22 min (D) ; ES+ 622 (M+1 ) .
1H NMR d6-DMSO: 0.76 (6H,dd), 1.0-1.8 (l5H,m), 2.03 (lH,m) , 2.58 (2H,m) , 2.79 (2H,m) , 3.11 (lH,m) , 3.28 (3H,s), 3.3-3.5 (l2H,m), 3.94 (lH,m), 4.08 (lH,m), 4.94 (lH,m) , 5.14 (lH,m) , 6.61 (2H,d) , 7.22 (SH,m) , 7.40 (3H,m) .
13C (DMSO) 169.7, 165.9, 152.9, 138.4, 129.2, 129.1, 128.1, 126.2, 123.1, 112.8, 74.4, 74.1, 72.5, 71.2, 69.8, 66.1, 58.1, 57.1, 52.9, 47.5, 33.4, 33.2, 26.3, 24.5, 18.9, 18.8.
Example 25 OMe O
/O
O OH O
_ O /
~OxNH~N.s NH O OH , V v O O ~ I ~ O~NH~N.S N~O
V V O b ~ I H
-i 224 was obtained using the general procedure in Example 20.
Example 26 O,N-diacvlated Prodrugs The general procedure for N,O-diacylated compounds followed the protocol outlined in Example 20, above, except that a five fold excess of reagents was used relative to the starting material.
Me0' l' Me0 O
O
/ O
O OH O
O
~O~NH~N'S NH=C~ O O
~OxNH~NOS - N O
V V p ~ I H
-1 w t HPLC 9.26 min (D); ES+ 738 (M+1) 760 (M+Na).
13C (DMSO): 170.2, 169.8, 156.4, 143.4, 138.8, 129.5, 128.8, 128.5, 126.8, 119.7, 74.9, 74.2, 73.7, 71.6, 70.7, 70.3, 68.0, 67.2, 59.3, 57.6, 53.8, 49.6, 35.7, 33.8, 27.1, 20.4.

1H (DMSO): 10.1 (1H, s), 7.84 (d, 2H, J=8.5), 7.76 (d, J=8.7, 2H), 7.40 (1H, d, J=9.2), 7.22 (m, 5H), 5.14 (1H, m), 4.95 (1H, m), 4.1 (m , 8H), 3.7-3.3(m, 13H), 3.28 (s, 3H), 3.26 (s, 3H), 2.86 (m, 2H), 2.73(m, 1H), 2.59 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 0.78(m, 6H).

Example 27 0 0 \ ~ o o \
O/$ O HsPO~, DCC ~ O~\$ O
O N N ~ \ - O N N \
H
H
OH / pyridine ~
NOz ba °C, 3h O=p~0 ~NO
OH ~ z H

To a mixture of 197 (2.93 g, 5.47 mmol) and phosphorous acid (Aldrich, 2.2 equiv., 12.03 mmol, 987 mg) in 20 ml pyridine was added 1,3-dicyclohexylcarbodiimide (Aldrich, 2.1 equiv., 11.49 mmol, 2.37 g) and the reaction heated to 60 °C under nitrogen for 3h. Solvent was removed in vacuo, the residue treated with 200 ml O.1N aqueous sodium bicarbonate and stirred lh at ambient temperature. The mixture was filtered, the filtrate acidified to pH 1.5 by addition of conc. HC1 and extracted with ethyl acetate (3 x 100 ml). The combined orgnic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 3.15g (96%) of desired product 226 which was used directly in the next reaction. HPLC: Rt = 8.91 min (96%) , MS (AP+) 600.5 (M+1.) .
Example 28 0 0 \ ~ o o \
v v O~ ~O C ~ u O O
~O~N N'$ \ TMSO-OTMS ~O~N N~\$/ \
H ~ (TMS)ZNH H
O-p~0 ~ NO 120 °C, lh O-p~0 ~ ~ NO
nOH ~ z i~OH z H HO

A suspension of 226 (--5.47 mmol) in 18 ml hexamethyldisilazane was stirred at 120°C until homogeneous followed by addition of bis(trimethylsilyl) peroxide (Gelest, Inc., 2.3 equiv., 12.58 mmol, 2.24 g, 2.71 ml). After lh the mixture was cooled to ambient temperature, solvent removed in vacuo, the residue stirred with 100 ml methanol, solvent removed in vacuo, the residue stirred with 100 ml O.1N aqueous sodium bicarbonate, acidified to pH 1.5 by addition of conc.
HCl, saturated with brine and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.98 g (88%) of desired product 227, which was used directly in the next reaction. HPLC: Rt =
9.28 min (90%), MS (AP+) 616.5 (M+1).
Alternatively, 227 can be synthesized directly from 197. In this method, 197 was dissolved in pyridine (300mL). The resulting solution was concentrated in vacuo to about 150 ml at 50-55°C. The solution was then cooled under N2 to 5°C, and treated with POC13 (6.5 ml, 1.24 equiv.) over 2 minutes. The cooling bath was removed and the reaction stirred at ambient temperature for 2.5 hrs. The solution was then cooled to 5°C and water (300 ml) was added over 30 minutes.
The resulting mixture was extracted with 4-methylpentan-2-one (MIBK, 2 x 150 ml). The combined extracts were washed with 2N HC1 (2 x 250 ml). The acid washes were back extracted with MIBK (60 ml), then the combined MIBK solutions were treated with 2N HC1 (150 ml). The two phase mixture was stirred rapidly and heated to 50°C for 2 hours. The reaction mixture was cooled to 20°C, the phases were separated and the MIBK

solution was washed with brine (150 ml). The product, 227, was isolated by drying the solution with magnesium sulfate, filtering of the drying agent and concentrating in vacuo at 40°C to give the product as a pale yellow foam (31 g, 90% yield) .
Example 29 i ~ /
0 0 \ o o \
0 0, O N N'S \ -HZ,Pd/C ~ ~S \
H O N N
O EtOAc, 35 psi OrP\OH / NOy OaP\OH / NH
HO HO

A solution of 227 (2.98 g, 4.84 mmol) in 50 ml ethyl acetate was treated with 10% palladium on carbon (Aldrich, 300 mg) and put under 35 psi of hydrogen on a Parr shaker for 15h. Catalyst was removed by filtration and solvent removed in vacuo to give 2.66 g (94%) of desired product 228. HPLC: Rt = 7.23 min (92%), MS (ES+) 586.3 (M+1).
Example 30 / ~ /
0 0 \ o o \
o~ ,o ~O~N N'S \ NaHCO O~~ ~O \
H 3 ~O N N~S
H
O;P~O ~ / NH O, 'O /
~ OOH 2 Pw NHZ
O-Na HO Na -O

Solid 228 (2.66 g, 4.54 mmol) was treated with 10 ml aqueous sodium bicarbonate (Baker, 3.0 equiv., 13.63 mmol, 1.14 g) and loaded onto a resin column (Mitsubishi Kasei Corp., MCI-gel, CHP-20). Distilled water was run through until the eluent was neutral followed by product elutian with 1% acetonitrile in water. Pure fractions were pooled and lyophilized to give 918 mg of pure bis-sodium salt 229.
Alternatively, 7 g of 228 was dissolved in 100 ml of EtOAc with warming and the solution was extracted with 100 ml of aqueous 250 mM triethylammonium bicarbonate (TEABC) (2X). The aqueous extracts were combined and diluted to 1500 ml with water. This solution was applied to a 300 ml DEAE-52 column (Whatman) which was equilibrated with 50 mM TEABC. The column was washed with 8 L of 50 mM TEABC and the TEA salt was eluted with 2 L of 250 mM TEABC. The solution was evaporated en vacuo to 100 ml then lyophilized to yield the TEA salt (1.5 TEA equivalents). The TEA salt was (5.8 g) was dissolved in 200 ml water, 300 ml of 1 N HC1 was added and the mixture was extracted with EtOAc (3 x 200 ml). The ethyl acetate solution was dried with MgS04 then evaporated en vacuo to yield 4 g of the free acid.
Two grams of the free acid was dissolved in 50 ml of acetonitrile and a solution of 573 mg NaHC03 in 200 ml water was added. The mixture was lyophilized yielding 2.1 g of the bis sodium salt (compound 229).
Example 31 ~z N.S-~-NH
H OH ~ O~.Ow/'O~.Ow v 02 N,S~-NHZ ~ ~ + 230 H OH ~ O ~ 02 O~ ~ H N.S-~-NH
p~Ø/~ pw Oy ~. ~ a-w. ~l 0 . 53 g (3 . 0 mmol) 2- [2- (2-Methoxyethoxy) ethoxy]
acetic acid was added to a stirred solution of 1.2 g (3.15 mmol) HATU 0.2 g (1.47 mmol) HOAt 0.4 g (4.0 mmol) NMM in 10 ml anhydrous N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes, then 0.5 g (1 mmol) of (3S)-Tetrahydro-3-furfuryl-N-((1S,2R)-1-benzyl-2hydroxy-3-(N-isobutyl-4-aminobenzenesulfonamido)-propyl) carbamate was added to the solution in one portion. The mixture was stirred at 20°C for an hour then at 50°C for an additional 12 hours.
It was then cooled to 20°C, 50 ml of ether was added, and the solution was washed with water three times. The aqueous phase was washed with ether, and then the combined organic phases were dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain the desired Mono-(N)acylated (102 mg, 15 %) and Bis-(O, N) acylated (262 mg, 32%) compounds.
Mono-(N)-acylated: 1H-NMR(CDC13): 0.85 (dd, 6H), 1.85 (m, 2H), 2.08 (m,lH), 2.8-3.1 (m, 7H), 3.33 (s, 3H), 3.55 (m, 3H), 3.70-3.90 (m, 8H), 4.1 (s, 2H), 5.0 (d, 1H), 5.08 (s (br) , 1H) , 7.2 (m, 5H) , 7.70 (d, 2H) , 7. 80 (d, 2H) , 9.09 (s, 1H) .
MS (FAB+) : 666 (M+1) .
Bis-(O,N)-acylated: 1H-NMR(CDC13): 0.77 (m, 6H), 1.81 (m, 1H), 1.95 (m, 1H), 2.05 (m, 1H), 2.6-3.0 (m, 6H), 3.2 (m,lH), 3.332 (s, 3H), 3.338 (s, 3H), 3.5-3.8 (m, 18H), 4.1 (s, 2H), 4.14 (s, 2H), 4.17 (m, 1H), 5.05 (m, 2H), 5 .25 (s (br) , 1H) , 7 .2 (m, 5H) , 7 . 69 (d, 2H) , 7 . 78 (d 2H) , 9.06 (s, 1H) .
MS (FAB+) : 826 (M+1) , 848 (M+Na) .

Example 32 y O \ ~ IO
~O~N ,OH 1L
H
SOZ.N~ SO ,N~

\ / \
N OZ

We dissolved 0.5218 (1 mM) of 1273W94 in 5 ml THF, then cooled to -78°C under nitrogen, and added 1.56 ml (2.5 mM) of a 1.6 M solution of nBuLi in hexane.
After 20 min at -78°C, we added 105 ~.L (1.1 mM) of ethyl chlorocarbamate and warmed up the reaction to room temperature, followed by addition of another 105 ~.L of ethyl chlorocarbamate.
After stirring for additional 4 hrs, the reaction was quenched with water and the organic solvent evaporated. Part of the crude product was purified on a silica gel (Rf=0.69 (1:2 ethyl acetate: hexane)), yielding 0.1318 of the product.
C,H,N: calc: 46.06, 4.97, 5.88, found 45.90, 4.97, 5.88 C23H33NS~SS1. 2 .2 TFA
LC/MS (ES+) 594 (M+1) 1 peak at 6.96 min.
Analytical HPLC(A) t=24.57 min.
13C (CDC13): 155.8, 154.4, 149.9, 145.7, 136.8, +129.2, +128.7, +126.8, +124.2, 80.1, +76.9, -64.3, -56.2, -52.5, -48.7, -36.2, +28.1, +26.4, +20.0, +19.8, +14.3.

Example 33 I
O
NHZ ~10~0 TFA salt NOz We dissolved 0.1318 of the above ethyl carbonate in 4 ml DCM, followed by 4 ml of TFA. Solvents were then removed after 45 min at room temperature, resulting in the title compound.
1H (DMSO) : 8.37 (2H, d, J=7.2) , 8.15 (2H, m) , 8.00 (2H, d, J=7.0), 7.37 (5H, m), 5.04 (1H, d, J=6.9), 4.06 (2H, q, J=7.0), 3.82 ((1H, m), 3.35 (2H, m), 2.95 (4H, m), 1.82 (1H, m), 1.20 (3H, t, J=7.0), 0.72 (overlapping doublets, 6H, J=6.2).
LC/MS 1 peak at 4.76 min.
ES+ 497.3 (M+1) .
Example 34 O,N-Acyloxv Rearranaement I
I
C T~ ~~ Q w_ pI-1=7.6 NHZ tl~ ~ ~ p~NH ~1~H
.N~ ~ .N~
S02 SOz i TFA salt NOZ NOZ

C,H,N: calc:53.26, 6.14, 7.57, found 53.22, 6.14, 7.57 C23H33NS~SS1 X 0 . 8 TFA

LC/MS (ES+) 594 (M+1) 1 peak at 6.96 min.
Analytical HPLC(A) t=24.57 min.
1H (DMSO): 8.34 (2H, d, J=8.7), 8.02 (2H, d, J=8.0), 7.19 (5H, m), 6.98 (1H, d, J=7.2), 5.00 (1H, m), 3.83 (2H, q), 3.50 (2H, m), 3.06 (m, 2H), 2.96 (2H, m), 2.43 (1H, m), 1.97 (1H, m) , 1.02 (3H, t) , 0.84 (3H, d) , 0.82 (3H, d) .
13C (DMSO): 156.2, 150.1, 145.7, 140.0, +129.7, +129.2, +128.5, +126.3, +125.0, +71.8, -60.0, +56.2, -56.0, -51.8, -36.0, +26.3, +20.3, +20.1, +14.6.
Example 35 I
O \ ~ ~NOZ
~O~NH ~~O O \ /

\ /
NOZ

Synthesis of 235 was accomplished analogous to that set forth in Example 1.
Yield 15.2%; tHPLC=25.2 min (A).
Rf=0.54 (B) ; ES+ 687.3 (M+1) .
1H (CDC13): 8.34 (overlapping d+d, 4H), 7.97 (d, 2H, J=8.9), 7.35 (7H, m), 5.09 (1H, m), 4.56 (1H, d, J=8.4), 4.20 (1H, m) , 3.54 (1H, m) , 3.00 (3H, m) , 2.82 (1H, m) , 1, 84 (1H, m) , 1.37 (9H, s) , 0.84 (3H, d) , 0. 82 (3H, d) .

Example 36 ~O
\1 O _' O
~O~NH ~~O~O
SOZ N
NOZ

We dissolved 150 mg of 235 in 3 ml of anhydrous dioxane, added 0.35 ml of S(+)-3-OH-THF and 0.14 ml triethyl amine. The mixture was refluxed gently under nitrogen for 2 days. Conversion to 236 was quantitative.
Solvents were removed and the compound purified on silica (B) .
tHPLC=22.98 min (A); ES+ 636.2 (M+1).
1H NMR (CDC13) : 8.29 (2H, d) , 7.91 (2H, d) , 7.22 (5H, m) , 5 . 13 ( 1H, m) , 4 . 96 ( 1H, m) , 4 . 52 ( 1H, d) , 4 . 02 ( 1H, m) , 3.84 (2H, m) , 3.44 (1H, m) , 3.36 (1H, m) , 3.10 (3H, m, overlap), 2.88 (2H, m), 2.64 (1H, m), 2.14 (1H, m), 2.05 (1H, m), 1.84 (1H, m), 1.27 (9H, s), 0.78 (6H, two overl.
d) .

Example 37 Carbohydrate-Based Prodruas 1. 5-TBDMSO-pentanoic acid, EDCI HO~\~p O OH 2. AcOH I H z0 I THF
~p NH N, ~~ O .Q
NOZ " ' O NH K,~ NO
~~~0~ ~ 2 /
H OAc Ac4-GIcBr I Ag pC03 AcOJ , O
Ac0 H p H OA
H
O
O .Q
Ox N H N, ~ NOZ
/

A mixture of 0.548 (1 mMol) of (3S)-Tetrahydro-3-furfuryl-N-((1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-aminobenzenesulfonamido)propyl) carbamate, 0.468 (2 mMol) of 5-dimethyl-tert-butyosi.lyloxypentanoic acid, 0.3468 (l.8mMo1) of EDCI and 0.556mL (4 mMol) of triethylamine in 10 ml of dimethyl formamide was stirred at rt for 24h.
Another 3 mMol each of acid, EDCI and triethylamine were added and stirring was continued for an additional 96h.
A third batch of acid and EDCI was added (3 mMol each) and the mixture was stirred 72h to complete the reaction.
The reaction mixture was then diluted with ethyl acetate and extracted with 1N hydrochloric acid, saturated sodium bicarbonate and water. Evaporation of the solvent and purification on silica gel (30% ethyl acetate-hexane) gave the desired product (500mg) as a waxy solid.
LCMS: 1 peak, 772.5 (M+Na) 1H NMR (CDCL3): 0.01 (6H,s), 0.78 (6H,dd), 0.95 (9H,s), 1.4-1.8 (6H,m) , 1.9 (2H,m) , 2.05 (lH,m) , 2.3 (2H,m) , 2.65 ( 1H, m) , 2 . 95 ( 2H, m) , 3 . 22 ( 1H, m) , 3 . 4 ( 1H, m) , 3 . 6 (2H, m) , 3.75 (3H,m), 4.8 (lH,d), 5.1 (lH,bs), 5.2 (lH,bs), 7.2 (5H, m) , 7. 95 (2H, d) , 8 . 36 (2H, d) .
450mg of the 238 was dissolved in 30 ml of tetrahydrofuran and treated with 20 ml of water and 50 ml of acetic acid. The mixture was stirred at rt for 2h and evaporated. Titration with hexane gave the desired alcohol (290mg) as a white solid.
A mixture of 0.158 (0.24 mMol) of the alcohol produced above from the previous reaction, 0.205g (0.5 mMol) of tetraacetylglucosylbromide and 0.1918 (0.7 mMol) of silver carbonate in 3 ml of dichloromethane was stirred at rt for 6h. 150mg of additional glucosyl bromide and 150 mg of silver carbonate were added and the mixture was stirred at rt overnight. The mixture was loaded onto a pad of silica gel and eluted with 30%
ethylacetate-hexane to afford the desired protected carbohydrate pro-drug as a white foam (200mg).
LCMS: 1 peak, 966 (M+H).
1H-NMR (CDC13): 0.78 (6H,dd), 1.9 (2H,m), 2.00 (3H,s), 2 . 02 (3H, s) , 2 . 05 (3H, s) , 2 . 06 (3H, s) , 2 . 1 (2H,m) , 2 .3 (2H,m) , 2.7 (lH,m) , 2.94 (3H,bd) , 3.35 (2H,m) , 3.45 (2H.m) , 3.8 (SH,m) , 4.1 (3H,m) , 4.5 (lH,d) , 4.9 (lH,bs) , 4 . 95 ( 1H, t, ) , 5 . 08 (4H, m) , 2H, d) , 8 . 35 (2H, d) .

_ 77 _ Example 38 ~ I oI ~ 02 O 02 O~N N.S \ / N02 O O~H N.S \ / N02 ----.~ O~ H O
OH
~S03H

1.5 g (9.4 mmol) S03.py complex was added to a stirred solution of 1 g (1.87 mmol) of 197 in 25 mL
anhydrous tetrahydrofurane. The mixture was stirred at 20°C for 12 hours, then filtered. The filtrate was concentrated at reduced pressure, and the residue was transferred to a silica gel column and eluted with EtOAc (neat), followed by EtOAc:EtOH (4:1) to obtain 471 mg (47 %) 239 as a colorless foam.
1H-NMR(CDC13): 0.80 (m, 6H), 1.8-2.1 (m, 3H), 4.15 (s (br) , 1H) , 4 . 8 (t, 1H) , 5 . 04 (s (br) , 1H) .
MS (ES-) : 614 (M-1) .
I
0~f 02 _ o X N.S \ / N02 02 O' 'N N.S \ / NH2 O H O O O H
O
~S03H ~S03H

100 mg (0.162 mmol) 239 dissolved in 15 ml anhydrous tetrahydrofuran and 200 mg Pd/BaS04 (5%) was added to the solution. The mixture was stirred under atmospheric pressure of hydrogen for 8 hours, and then the catalyst was filtered. The filtrate was concentrated under reduced pressure then dried under vacuum (~1 Hg mm, 48 hrs.) to produce 80 mg (81 %) 240 as a colorless foam.
1H-NMR(DMSO-d6): 0.85 (dd, 6H), 0.90 (m, 1H), 2.05 (m, 2H), 2.58 (m, 3H), 2.84 (dd, 1H), 3.05 (m, 2H), 3.55-3.80 (m, 6H), 4.20 (t, 1H), 4.42 (m, 1H), 4.93 (s(br), 1H), - 78 _ 6.09 (s, 2H), 6.70 (d, 2H), 6.80 (d, 1H), 7.15-7.40 (m, 4H) , 7.51 (d, 2H) .
MS (ES-) : 584 (M-1) .
Example 39 'i i o o ~ oz .S~NO
O O N.S \ / N02 ~ O~p H N \ / 2 O
O H ~O~
C) /\P~O~NMe3 780 mg (3 mmol) 2-Chloro-1,3,2-dioxaphospholane was added to a stirred solution of 1.07 g (2 mmol) 197 and 0.7 ml (4 mmol) N,N-Diisopropylethylamine in 25 ml dichloromethane at 0°C. The mixture was allowed to warm up to room temperature and it was stirred for 2 hours.
The mixture was then cooled to 0°C and 1.5 g (9.3 mmol) bromine was added in 5 ml dichloromethane. The mixture was stirred for 1 hour at 20°C, followed by evaporation under reduced pressure. An aqueous solution (50%) of 15 ml trimethylamine was added to the residue, and the mixture was stirred at 20 °C for 12 hours.
Solvents were removed under reduced pressure and 50 ml EtOAc:EtOH (9:1) was added to the residue. The solid was filtered, washed with EtOAc:EtOH (9:1) then the filtrate was concentrated under reduced pressure. The residue was chromatographed on a 3 inch plug of silica gel using ethyl acetate (neat), then methanol (neat), as eluents to obtain 1.15 g (82 %) 241 as an off-white solid.
1H-NMR(CDC13): 0.60 (dd, 6H), 1.70 (m, 1H), 1.95 (m, 1H), 2.10 (m, 1H), 2.8-3.2 (m, 6H), 3.4 (s (br), 9H), 5.09 (s(br), 1H), 7.25 (m, 5H), 7.83 (d, 2H), 8.28 (d, 2H).

MS (ES+) : 701 (M+1) , 184 (phosphatidyl choline+) .
Example 40 a ~~ 02 _ ~I
O~N~N~S \ / NOz ~ ~Sz \ / NHz O O~ O~O H O N
~II O~ O
I~ Q+
P
Q-O/ ~O~NMe3 ~ /P~ ~NMe3 O O

250 mg Pd/C (10 %) was added to a solution of 250 mg (0.35 mmol) 241 in 10 ml methanol, and the mixture was stirred under atmospheric pressure of hydrogen for 4 hours at 20°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was then dissolved in 10 ml water and lyophilized to obtain 174 mg (74 %) 242 as white solid.
1H-NMR(DMSO-d6): 0.82 (dd, 6H), 1.80-2.00 (m, 2H), 2.10 (m, 1H), 2.80 (m, 3H), 3.00 (m, 2H), 3.2 (s (br), 9H), 4.0-4.3 (m, 4H), 4.91 (s(br), 1H), 6.08 (s(br), 2H), 6.67(d, 2H), 7.30 (m, 5H), 7.48 (d, 2H), 8.12 (d, 1H).
MS(ES+): 671 (M+1), 184 (phosphatidyl choline+).
Example 41 'I
o ~ 02 _ 2 0 O O~H N S \ / NOz O
I_ \ I 11 P O 226 OI~ v Oz OH
O~N N'S \ / NOz O H OH ~ +

O\J O N N.S \ / NOz H-P-O
O

0.175 ml (2 mmol) phosphorus trichloride was added to a stirred solution of 1.07 g (2 mmol) 197 and 0.35 ml (2 mmol) N,N-Diisopropylethylamine in 25 ml dichloromethane at 20°C. The mixture was stirred for 4 hours at 20°C, then 1 ml water was added and stirred for an additional 12 hours at 20°C. 3 g anhydrous magnesium sulfate was added to the mixture and it was stirred for 30 minutes, then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using EtOAc:Hexane (4:1), then EtOAc:EtOH
(1:1), to obtain 402 mg (48%) 226 and 427 mg (36%) 243.
226:
1H-NMR(DMSO-d6): 0.82 (dd, 6H), 1.84 (m, 1H), 1.98 (m, 1H), 2.10 (m, 1H), 2.68 (dd, 1H), 2.9-3.2 (m, 4H), 3.6-3 .8 (m, 3H) , 3 . 94 (t, 1H) , 4.30, (s (br) , 1H) , 4. 97 (s (br) , 1H) , 7 .30 (m, 5H) , 8. 14 (d, 2H) , 8.43 (d, 2H) .
MS (ES-) : 598 (M-1) .
243: (1:1 mix of diastereomers):
1H-NMR(CDC13): 0.80 (m, 6H), 1.8-2.1 (m, 4H), 2.8-3.2 (m, 6H), 3.7-3.9 (m, 4H), 4.15 (m, 1H), 4.8-5.15 (m, 2H), 5.57, 5.72 ((d,d), 1H), 7.25 (m, 5H), 7.95 (dd, 2H), 8.35 (m, 2H) .
MS (ES-) : 580 (M-1) , 598 ( (M+H20) -1) .
Example 42 o n oz o n oz O~O~N N.S ~ ~ Npz -~ ~O~N N.S ~ ~ NHz O'~r H P-O ~ H-P-O
ii a O O

The reduction was carried out as described in Example 40; (Yield: 79%) .

1H-NMR(DMSO-d6): 0.81 (dd, 6H), 1.82 (m, 1H), 1.95 (m, 1H), 2.08 (m, 1H), 2.6-3.15 (m, 6H), 3.6-3.75 (m, 3H), 4 . 03 (t, 1H) , 4 .28, (m, 1H) , 4 . 96 (s (br) , 1H) , 6. 07 (s, 2H) , 6. 65 (d, 2H) , 7 .25 (m, 5H) , 7.42 (d, 2H) .
MS (ES-) : 568 (M-1) .
Example 43 'i O ~ ~ O O ~ Oz z O O~H v N~S \ / NOz -~ O~N N'S \ / NH2 O~ H
O O
H-p=O H-P=O
OH OH

The reduction was carried out as described in Example 40; (Yield: 98 %) .
(1:1 mix of diastereomers):
1H-NMR (DMSO-d6) : 0 . 82 (m, 6H) , 1 . 75-2 . 0 (m, 2H) , 2 . 05 (m, 1H), 2.6-3.2 (m, 6H), 3.55-3.8 (m, 4H), 4.02, 4.22 (m, t, 1H), 4.75 (m, 1H), 4.90, 5.01 ((d,d), 1H), 6.12 (s, 1H), 6.68 (d, 2H), 7.30 (m, 5H), 7.49 (d, 2H).
MS (ES-) : 550 (M-1) , 568 ( (M+H20) -1) .
Example 44 Pharmacokinetics In Sprague-Dawley Rats Following Single Oral Dose In order to study the pharmacokinetics of the prodrugs of this invention, we administered single oral doses of a series of prodrugs of this invention, as well as VX-478, to male and female Sprague-Dawley rats.
Administration of molar equivalents of a series of prodrugs of this invention in a variety of pharmaceutical vehicles was tested.

Separate groups of male and female Sprague-Dawley rats (3/sex/group) received oral doses of compound 229 by oral gavage, in different vehicles at the same dose equivalent (40 mg/kg molar equivalent of VX-478).
The different vehicles for compound 229 were: 1) water;
2) 5/4/l; 3) PEG 400; 4) TPGS/PEG 400; and 5) PEG. The vehicles for VX-478 were: 1) 33% TPGS/PEG400/PEG; and 2) 12.5 % TPGS/PEG 400/PEG.
Blood samples were collected following administration at various time intervals and analyzed for the presence of both compound 229 and its metabolite, VX-478, by HPLC and MS methods. The results of this study are tabulated below (Table IV).
TABLE IV

__ .._Com ound-_..__.__._..229 .__.._...__.....___._..229_229 .__~ : x-47 _...____._.____..._.._._.
._.--__.._..229 _._._.-___ -_______.__..x.478 8 P __._ - .._..._ vehicle ~' Hz0 HzO:PG:EtOH PEG 400 TPGSIPEG33 /o ' 12.5 /o TPGSI TPGSI

5:4:1 ' 4001PGPEG 400/PEG 400IPG
PG

:_.~umberofrats_._.__.~.3_.__.._._._._.._..._-_.3.______._..._-.._.3..___.__..___._3_._.__.__._.__.__._._._.__.6______.____.-_~3 _.________._.--.__...._.__._._....____...____.___.____._-___._._.__._.....__.______._.__.__._...______._____.............__..__......_..
.._...__..._._.___.__.____.__...._._.__..__________.___._._...____...._.____._.
_..
Molar equiv. 40 PO 40 PO 40 PO 40 PO a 41 50 PO
PO

dosel478 Dose ~m9lKg) ~

....
_..._._..._...._......._._...._._._._...._........._.._.._.......
..._._._.___._.__._._.... ; 8 +
.__._....__..__.___.._.__..._.__._........_.__.__._._..
___._._._._.__...__......-___.___-.._..__.2-1.6 . 16.2 .-._____._....___ 29.6 1.8 AUC ; 11.7 4.8 , + -10.67.4 7.418 ....
_.__ -5.8 (ug*hrlml) ~
_ _ ....__....___._._...._._.___._._.__ _.__.__.__.____ 3.00.7 14.02.2 .....5.01.0_...._ .___.__._._....__._____ -_ ._.__-.____..__..__._..__.-__.__._......
Cmax(NM) 7.11.7 X3.30.6 3.10.3 ._.___..._.._.._.___.__.__._._._....._._..._...___.*...._...._._._..__._,.._._.
......____.____.__._._........_...__._......__._._._._-_ __.___.__._...._._......__.__.__.___._....._.____._..._...._._._.........._....
_...
half life (hr) 1.7 ! 3.4* 2.8* 2.8* 2.5 2.2 1.0 0.9 ....Rep_...._IV...._A
_._.;._...._...._._.._.._.__...._.___.___.______...._....__...___.._._._...____ ._...__.______._....__._._._....._.......__..__..._._.._.__._._.__._....._.....
....._..........__._._._.__.__..._..._._...._._.__..._._._._........._.__ at a vail. of 39.5t 35.8t 81.Stt ' 27.71 reference__._._.__ 25.Ot reference VX-478 90.2tt ' 57.1 tt 63.3tt ...._............__._._._.__..._...._._.__._...._.__~_._._ __....__.__....__.___...___._____._..._..._.__..___.___._..__.__ g._......_ g ...~_._.___..p _____...__.:...-.___ of VX-478.
q ___.__._.~..._____...._g ._.._.
g - a dose of 50 m / K of com ound 229 is a ual to 40 m I K

- no compound 229 was detected in plasma at 15 min. ( first data point ).

Represents the harmonic mean t Relative availability of VX-478 when compared to a 2 0 prototype clinical formulation tt Relative availability of VX-478 when compared to a prototype toxicology formulation We performed a similar study on dogs using both a solid capsule formulation of compound 229 and an ethanolic/methyl cellulose solution formulation, as compared to a TPGS-containing solution formulation of VX-478. The results from this study are presented below in Table V.
TABLE V
_., .______...__._.___., _.___._____._.___._._......._..........__..__._................._-___--_._._._._..______.____._.__ -yX.478 Com ound 229 X229 -__.-p vehicle ~._...._.._._..._.__.._......._____.____._____._.._;. solid.methyl __.22%_____._._____.__ capsule---_-.__ celluloseTPGSIPEG
in 5%

EtOHlwater4001PG
~

_._.__.__._..___.___g._ . 2 __._...__._.._._._._..._._._.._.'.. ~2 _._._._......_.._....__...._..._...._..._...._.._._...._._.__._.2 ._._....____._..._....__...- .______.___.__._._.
number of do s Molar equiv-_._._.____....._._._...._.____................~_.._9_....9~.__.._.1~.P0________ .. ~7 ._._1._...___._._.____...__..__ . dosel 478 Dose m PO -._._....__..__._7 p0 IK

-_..___..._.__..___..__...._....___._.._._._._...____.__.
:._ U~ h __~_-___-...._._ 16.7 14.2 23.5 7.4--_ - 2.7 3.2 rlml :(9 ) Cmax (Nglml)-'--~ -_..6.1+e-6.3 .-.-6.8 _- __._.__-___ 1.7 0.3 1.1 .._._.._..___, -__-- __.___ - 0.6 -_____;.Ø5 ,-1.0 Tmax ( 0.5 O.g-._.___~
F -__-._ hr) 2_3 ~

- . 60.4 ~ reference ___.__.___.__.____._._._.______._.___.__.
Relative Avail. of _ VX-478 (%) ~ 71.1 The results demonstrate that oral administration of compound 229 as an aqueous solution resulted in improved bioavailability in comparison to the other vehicles studied. Also, following administration of compound 229, none of that compound was detected in the first time point blood sample (or later samples), suggesting first pass metabolism to VX-478. Comparison of the aqueous dose of compound 229 with the two non-aqueous formulations used for VX-478 indicated equivalence in delivery as illustrated by the range found for the bioavailability.

Example 45 OH ~ N~ ~ O ~ N02 H D- I~ _ N N- w ~ N
o ~ O d' o y i We added 0.28 ml (3.0 mmol) POC13 to a stirred solution of 1.07 g (2.0 mmol) of compound 197 in 10 ml anhydrous pyridine at 5°C. The mixture was allowed to warm up to room temperature and stirred at 20°C for 3 hours. The mixture was cooled to 0°C, and quenched with 10 ml water. The solvents were removed under reduced pressure, the residue was dissolved in 100 ml ethyl acetate and washed with 20 ml 1M sodium bicarbonate solution. The organic phase was dried with anhydrous magnesium sulfate, filtered then concentrated.
Chromatographic purification (Si02, EtOAc) produce 280 mg of compound 400 (Yield = 23%).
1H-NMR(DMSO-d6): 0.86 (dd, 6H), 2.05 (m, 2H), 2.84 (d, 2H), 2.95 (dd, 1H),3.06 (m, 1H), 3.25 (dd, 1H), 3.50-3.70 (m, 4H), 4.20 (m, 1H), 4.35 (m, 1H),7.2-7.4 (m, 5H), 7.9-8. 1 (m, 2H) , 8.40 (m, 2H) .
MS (ES-) : 596 (M-1) .
OH
O ~ N02 ~ O N~
I >
°1r c~~o °lr c~~o o I~ o Compound 400 was converted to compound 401 using the standard hydrogenation method described above employing H2/PdC(10%), atmospheric pressure, 4 hours at room temperature, solvent: MeOH-H20(5:1). Yeld of 401 =
68%.
1H-NMR(DMSO-d6): 0.85 (dd, 6H), 2.0 (m, 2H), 2.6-3.1 (m, 4H), 4.15 (m, 1H),4.40 (m, 1H), 6.1 (s (br), 1H), 6.61 m (2H), 7.2-7.5 (m, 7H).
MS (ES-) : 566 (M-1) .
Example 46 H NHBoc H ~ ~ N~ ~ n N'R
N, w ~ ~ ~, w ~ ~~Cbz O,, O ~' ,O
O
350A n = 2, R = H
3508 n=3,R=H
350C n = 2 , R = -C(=NH)NHCbz We added 1.0 g (2.8) mmol Na-t-Boc-nd-Cbz-L-Ornithine was added to stirred solution of 1.2 g (3.15 mmol) HATU, 0.2 g (1.47 mmol) HOAt, 0.4 g (4.0 mmol) NMM
inl0 ml DMF. The mixture was stirred at room temperature for 2 hrs. then 0.5 g(1.0 mmol) of compound 218 was added and the solution was stirred at 50°C for 12 hours. The mixture was cooled to room temperature, 100 ml ether was added and extracted with 5x 50 ml water.
The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hexane-EtOAc (1:1) then EtOAc (neat)) to yield 410 mg (48%) of compound 350.

Compound 350 A
1H-NMR(CDC13): 0.85 (dd, 6H), 1.41 (s, 3H), 1.45 (s, 6H), 1.60 (m, 4H), 1.90 (m, 2H), 2.1 (m, 1H), 2.75-3.25 (m, 6H), 3.60-3.90 (m, 6H), 5.15 (dd, 2H),7.2-7.4 (m, lOH), 7.68 (dd, 4H).
MS (ES-) : 852 (M-1) .
MS (ES+) : 854 (M+1) .
Compound 350 B
1H-NMR(CDC13): 0.81 (dd, 6H), 1.39 (s, 9H), 1.40-2.10 (m, 9H), 2.70-3.20 (m, 8H), 3.60-3.90 (m, 6H), 4.10 (m, 1H), 4.80 (d, 1H), 5.04 (s(br), 2H), 7.1-7.3 (m, lOH), 7.61 (s, 4H) .
MS (ES-) : 866 (M-1) .
MS (ES+) : 868 (M+1) .
Compound 350 C
1H-NMR(CDC13): 0.86 (dd, 6H), 1.40 (s, 3H), 1.46 (s, 6H), 1.60-2.10 (m, 7H), 2.70-3.15 (m, 6H), 3.60 (d, 1H), 3.70-4.10 (m, 6H), 4.81 (d, 1H), 5.05-5.30(m, 7H), 7.18-7.4 (m, 17H), 7.55 (d, 2H).
MS (FAB+) : 1030 (M+1) , 1052 (M+Na) .
H
H d-I i n fvtR ~ f~tR
c~ '~
o ~c~ o ---~ o 350A n = 2, R = H
350Bn=3, R=H
350C n = 2 , R =-C(=NH)NHCbz 403 n = 3 , R = H
404 n = 2 , R = -C(=NH)NHZ
Compounds 350A, 350B and 350C were converted to Compounds 402, 403, and 404, respectively, using the standard hydrogenation method set forth above:

_ 87 -H2/PdC(10%), atmospheric pressure, 4 hours, room temperature, solvent: EtOH, Yield: 81 %.
Compound 402 1H-NMR(CDC13): 0.80 (dd, 6H), 1.38 (s, 9H), 1.8 (m, 6H), 2.10 (m, 2H), 2.75-3.30 (m, 8H), 3.50-4.00 (m, 7H), 4.55 (s(br), 1H), 7.2 (m, SH), 7.60 (d, 2H), 7.81 (d, 2H).
MS (ES+) : 720 (M+1) .
Compound 403 1H-NMR(CDC13): 0.87 (dd, 6H), 1.45 (s, 9H), 1.50-2.00 (m, 8H), 2.08 (m, 1H), 2.75-3.15 (m, 8H), 3.60 (d, 1H), 3.75-3 . 90 (m, 5H) , 4 .28 (s (br) , 1H) , 4 . 92 (d, 1H) , 5. 11 (m, 1H) , 5.27 (s (br) , 1H) , 7.28-7.35 (m, 5H) , 7. 70 (s, 4H) .
MS (ES+) : 734 (M+1) .
Compound 404 1H-NMR(CDC13): 0.80 (dd, 6H), 1.32 (s, 9H), 1.50-2.10 (m, 7H), 2.60-3.20 (m, 8H), 3.40-3.80 (m, 5H), 5.0(s(br), 1H), 7.05-7.2 (m, 5H), 7.50-7.80 (m,4H).
MS (ES+) : 762 (M+1) .
Example 47 H NHBoc HAc O~ H OH ~ ~ N~ N'R O~ H OH ~ ~ N N'R
O N N, ~ (y C bz O N _ N, ~ C bz .rS ~ ,S
O O ~ ~ O O b 350A n = 2, R = H
3508 n =3,R=H
350C n = 2 , R =-C(=NH)NHCbz ~ 351A n = 2, R = H
3518 n =3, R=H
351C n =2 , R =-C(=NH)NHCbz We added 5 ml TFA to a stirred solution of 260 mg (0.3 mmol) Compound 350A, 350B, or 350C in 20 ml chloroform. The mixture was stirred for 5 hours at room temperature, and then the solvents were removed under reduced pressure. The residue was dissolved in 20 ml dichloromethane, 2 ml (11 mmol) N,N-diisopropylethylamine and 1 ml (10 mmol) acetic anhydride was added to the reaction mixture. The solution was stirred for 1 hour, then the solvents were removed. The residue was purified by silica gel chromatography (eluant: EtOAc-EtOH(9:1)) to obtain 170 mg (71 %) of compound 351A, 351B or 351C, respectively.
Compound 351A
1H-NMR(CDC13): 0.85 (dd, 6H), 1.60 (m, 3H), 1.80-2.00 (m, 3H), 2.06 (2, 3H), 2.75 (dd, 1H), 2.80-3.20 (m, 5H), 3.60-3.90 (m, 7H), 4.85 (d, 2H), 5.10 (m, 3H), 6.46 (d, 1H), 7.25 (m, lOH), 7.67 (s, 4H), 9.30 (s, 1H).
MS (ES+) : 796 (M+1) , 818 (M+Na) .
Compound 351B
1H-NMR(CDC13): 0.80 (dd, 6H), 1.38 (m, 2H), 1.50 (m, 2H), 1.70 (m, 2H), 1.85 (m, 2H), 2.00 (s, 3H), 2.70 (dd, 1H), 2.75-3.20 (m, 7H), 3.55 (d, 1H), 3.75 (m, 6H), 4.45 (q, 1H), 4.83 (d, 1H), 4.95 (t, 1H), 5.03 (s(br), 3H), 6.46 (d, 1H), 7.20 (m, lOH), 7.61 (s, 4H), 9.29 (s, 1H).
MS (ES+) : 810 (M+1) , 832 (M+Na) .
Compound 351C
1H-NMR(CDC13): 0.85 (dd, 6H), 1.70-2.00 (m, 6H), 2.07 (s, 3H), 2.70 (dd, 1H), 2.80-3.00 (m, 3H), 3.10 (dd, 1H), 3.60 (d, 1H), 3.65-4.00 (m, 6H), 4.1(m, 1H), 4.62 (q, 1H), 4.82 (d, 1H), 5.00-5.30 (m, 5H), 7.10-7.40 (m, 15H) , 7. 55 (d, 2H) , 7 . 65 (m, 3H) 9. 18 (s (br) , 1H) , 9.45 (s (br) , 1H) , 9. 56 (s (br) , 1H) .
MS (FAB+) : 972 (M+1) , 994 (M+Na) .

H NH~c , H 0~..~ i n ~R ~ ~R
~l w ~ ~~Cbz C~'S~O -.s O
351A n=2,R=H
351Bn=3,R=H
351 C n = 2 , R = -C(=NH)NHz 405 n = 2, R = H
406 n=3,R=H
407 n = 2 , R = -C(=NH)NHZ
The conversion of compounds 351A, 351C, and 351C to 405, 406, and 407, respectively was achieved by standard hydrogenation using H2/PdC(lOs), atmospheric pressure, 4 hours at room temperature, solvent: EtOH, Yield = 46~.
Compound 405 1H-NMR(DMSO-d6): 0.85 (dd, 6H), 1.62 (m, 3H), 1.81 (m, 2H), 1.94 (s, 3H), 2.00-2.2 (m, 2H), 2.75-3.00 (m, 5H), 3.10 (m, 2H), 3.50-3.80 (m, 5H), 4.54 (m, 1H),5.00 (m, 1H), 5.11 (d, 1H), 7.2-7.4 (m, 5H), 7.80-8.00 (m, 5H), 10, 72 (s, 1H) .
MS (ES+) : 662 (M+1) .
Compound 406 1H-NMR(DMSO-d6): 0.80 (dd, 6H), 1.30-1.80 (m, 7H), 1.85 (s, 3H), 1.95-2.10 (m, 2H), 2.70 (m, 4H), 2.99 (m, 2H), 3.30 (m, 5H), 3.40-3.80 (m, 4H), 4.35 (m, 1H), 4.90 (s, 1H), 5.00 (d, 1H), 7.08-7.25 (m, 5H), 7.50 (s(br), 1H), 7.71 (d, 2H), 7.79 (d, 2H), 10.54 (s, 1H).
MS (ES+) : 676 (M+1) .
Compound 407 1H-NMR(DMSO-d6): 0.80 (dd, 6H), 1.40-1.60 (m, 4H), 1.75 (m, 2H), 1.86 (s, 3H), 2.00 (m, 2H), 2.75 (dt, 2H), 3.00 (m, 2H), 3.10 (q, 2H), 3.40-3.70 (m, 5H), 4.39 (q, 1H), 4.92 (s (br), 1H), 5.01 (d, 1H), 7.20 (m, 5H), 7.70 (d+m, 3H), 7.81 (d, 2H), 8.30 (d, 1H), 10.60 (s, 1H).
MS (ES+) : 704 (M+1) .
Example 48 QBn H / N 02 ~ O=R~ / N Oz H
N N- y I -- N N_ ' ~ I
._ O'~O ~ O'~O
I~ I
i i We added 1.0 g (7.5 mmol) methanephosphonyl dichloride to a stirred solution of 2.14 g (4.00 mmol) of compound 197 in 20 ml toluene, containing 10%
pyridine. The mixture was stirred at 100°C for 5 hours, then cooled to 40°C, 2 g (18.5 mmol) benzyl alcohol was added to the reaction, and the mixture was stirred at 20°C
for 12 hours. The solid was filtered, washed with 2 x 10 ml toluene and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel chromatography (eluants: Hexane-EtOAc (1:1), then EtOAc (neat)) to yield 550 mg (20 %) of compound 352.
1H-NMR(CDC13): 0.67 (dd, 6H), 1.53 (d, 3H), 1.70 (m, 1H), 1.90-2.10 (m, 2H), 2.65-3.20 (m, 6H), 3.55 (d, 1H), 3.80 (m, 3H), 4.10 (m, 1H), 4.70 (q, 1H), 4.90-5.20 (m, 4H), 6.37 (d, 1H), 7.2-7.4 (m, lOH), 7.90 (d, 2H), 8,30 (d, 2H) .
MS (ES+) : 704 (M+1) , 726 (M+Na) .

DH
N
~H p i N, w I --~ N, w ~, O ~ p O O
li li Compound 352 was converted to compound 408 using standard hydrogenation method: H2/PdC(10%), atmospheric pressure, 2 hours, room temperature, solvent:
MeOH; Yield: 78%.
1H-NMR(DMSO-d6): 0.84 (dd, 6H), 1.44 (d, 3H), 1.82 (m, 1H), 1.90-2.10 (m, 2H), 2.62 (m, 2H), 2.95 (m, 2H), 3.10 (d, 1H), 3.39 (d, 1H), 3.45-3.80 (m, 4H), 4.14 (t, 1H), 4.53 (m, 1H), 5.00 (s (br), 1H), 6.68 (d, 2H), 7.2-7.4 (m, 5H) , 7. 50 (d, 2H) .
MS (ES-) : 582 (M-1) .
While we have described a number of embodiments of this invention, it is apparent that our basic construc-tions may be altered to provide other embodiments which utilize the products and processes of this invention.
Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments which have been presented by way of example.

Claims (40)

1. A compound of formula I:
wherein:
A is selected from H; Ht; -R1-Ht; -R1- (C1-C6) -alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N(R2)2 or -CO-N(R2)2; -R1-(C2-C6)-alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, -O-Ht, -N(R2)-C(O)-N(R2)2 or -CO-N(R2)2; or R7;
each R1 is independently selected from -C(O)-, -S(O)2-, -C(O)-C(O)-, -O-C(O)-, -O-S(O)2, -N(R2)-S(O)2-, -N(R2)-(O)- or -N(R2)-C(O)-C(O)-;
each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, -OR2, SR2, -R2, -N(R2)2, -R2-OH, -CN, -C(O)O-R2, -C(O)-N(R2)2, -S(O)2-N(R2)2. -N(R2)-C(O)-R2. -C(O)-R2. -S(O)n-R2, -OCF3, -S(O)n-Q, methylenedioxy, -N(R2)-S(O)2-R2, halo, -CF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N(R2)(R7) or -N(R7)2;

each R2 is independently selected from H, or (C1-C4)-alkyl optionally substituted with Q;
B, when present, is -N(R2)-C(R3)2-C(O)-;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, (C1-C6) -alkyl, (C2-C6) -alkenyl, (C3-C6) -cycloalkyl or (C5-C6)-cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from -OR2, -C(O)-NH-R2, -S(O)n-N(R2)2, Ht, -CN, -SR2, -CO2R2, N(R2)-C(O)-R2;
each n is independently 1 or 2;
G, when present, is selected from H, R7 or (C1-C4) -alkyl, or, when G is (C1-C4) -alkyl, G and R7 are bound to one another either directly or through a C1-C3 linker to form a heterocyclic ring; or when G is absent, the atom to which G is attached is bound directly to the R7 group in -OR7 with the concomitant displacement of one -ZM group from R7;
D and D' are independently selected from Q;
(C1-C6)-alkyl, which is optionally substituted with one or more groups selected from (C3-C6) -cycloalkyl, -OR2, -R3, -O-Q
or Q; (C2-C4)-alkenyl, which is optionally substituted with one or more groups selected from (C3-C6) -cycloalkyl, -OR2, -R3 -O-Q or Q; (C3-C6)-cycloalkyl, which is optionally substituted with or fused to Q; or (C5-C6)-cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n or N(R2); wherein any ring in Q is optionally substituted with one or more groups selected from oxo, -OR2, -R2, -N(R2)2, -N(R2)-C(O)-R2, -R2-OH, -CN, -C(O)OR2, -C(O)-N(R2)2, halo or -CF3;
E is selected from Ht; O-Ht; -Ht-Ht; -O-R3;
-N(R2)(R3); (C1-C6) -alkyl, which is optionally substituted with one or more groups selected from R4 or Ht;
(C2-C6)-alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; (C3-C6) -saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or (C5-C6) -unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from -OR2, -SR2, -C(O)-NHR2, -S(O)2-NHR2, halo, -N(R2)-C(O)-R2, -N(R2)2 or -CN;
each R7 is independently selected from wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, (C1-C12)-alkyl, (C2-C12) -alkenyl, or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group, other than the -CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O)2, or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, N(R2)2, N(R2)3, R2OH, -CN, -C(O)OR2, -C(O)-N(R2)2, S(O)2-N(R2)2, N(R2)-C(O)-R2, C(O)R2, -S(O)n-R2, OCF3, -S(O)n-R6, N(R2)-S(O)2-R2, halo, -CF3.
or -NO2;
M' is H, (C1-C12)-alkyl, (C2-C12)-alkenyl, or -R6;
wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O)2, or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, -N(R2)2, N(R2)3, -R2OH, -CN, -CO2R2, -C(O)-N(R2)2, -S(O)2-N(R2)2, -N(R2)-C(O)-R2, -C(O)R2, -S(O)n-R2, -OCF3, -S(O)n-R6, -N(R2)-S(O)2-R2, halo, -CF3, or -NO2;
Z is -CH2-, O, S, -N(R2)-, or, when M is not present, H, CH3, or -N(R2)2;
Y is P or S;
X is O or S ; and R9 is C(R2)2, O or N(R2); and wherein when Y is S, Z
is not S; and R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, O- (C1-C4) -alkyl or O-C(O)-(C1-C4)-alkyl.

2. The compound according to claim 1, wherein at least one R7 is selected from:

- (L) -lysine, -PO3Na2, -(L)-tyrosine, , PO3Mg, -PO3(NH4)2, -CH2-OPO3Na2, , -(L)-serine, -SO3Na2, , -SO3Mg, -SO3(NH4)2, -CH2-OSO3Na2, -CH2-OSO3(NH4)2, acetyl, , -(L)-valine, - (L) -glutamic acid, - (L) -aspartic acid, - (L) -.gamma.-t-butyl-aspartic acid, , - (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, , PO3K2, PO3Ca, PO3-spermine, PO3-(spermidine)2 or PO3-(meglamine)2.

3. The compound according to claim 2, wherein said compound has formula XXII:
wherein A, D', R7 and E are as defined in claim 1.

4. The compound according to claim 3, wherein A is selected from 3-tetrahydrofuryl-O-C(O)-, 3-(1,5-dioxane)-O-C(O)-, or 3-hydroxy-hexahydrofura [2, 3-b] -furanyl-O-C(O)-;
D' is (C1-C4)-alkyl which is optionally substituted with one or more groups selected from the group consisting of (C3-C6) -cycloalkyl, -OR2, -R3, -O-Q and Q;
E is (C6-C10)-aryl optionally substituted with one or more substituents selected from oxo, -OR2, SR2, -R2, -N(R2)2, -R2-OH, -CN, -C(O)O-R2, -C(O)-N(R2)2, -S(O)2-N(R2)2, -N(R2)-C(O)-R2, -C(O)-R2, -S(O)n-R2, -OCF3, -S(O)n-Q, methylenedioxy, -N(R2)-S(O)2-R2, halo, -CF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N(R2)(R7) or -N(R7)2; or a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH3, R4, or Ht; and Ht, insofar as it is defined as part of R3, is defined as in claim 1 except for the exclusion of heterocycles.

5. The compound according to claim 4, wherein:
A is 3-tetrahydrofuryl-O-C(O)-;
G is hydrogen;
D' is isobutyl;
E is phenyl substituted with N(R7)2;
each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C1-C4 alkyl or -N(R2)4; and each M' is H or C1-C4 alkyl.

6. The compound according to claim 3, wherein:
E is a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH3, R4, or Ht.

7. The compound according to claim 3, wherein:
E is Ht substituted with N(R')2;

R7 in the -OR7 group shown in formula XXII is -PO(OM)2 or C(O)CH2OCH2CH2OCH2CH2OCH3 and both R7 in the -N(R7)2 substituent of Ht are H; or R7 in -OR7 group shown in formula XXII is C(O)CH2OCH2CH2OCH3, one R7 in the -N(R7)2 substituent of Ht is C(O)CH2OCH2CH2OCH3 and the other R7 in the -N(R7)2 substituent of Ht is H; and wherein M is H, Li, Na, K or C1-C4 alkyl.

8. The compound according to claim 3, having the structure:
wherein each M is Na or K.

9. The compound according to claim 8, wherein each M
is Na.

10. The compound according to claim 2, wherein said compound has formula XXIII:

11. The compound according to claim 10, wherein:

R3 is (C1-C6) -alkyl, (C2-C6) -alkenyl, (C5-C6) -cycloalkyl, (C5-C6) -cycloalkenyl, or a 5-6 membered saturated or unsaturated heterocycle; wherein any member of R3 is optionally substituted with one or more substituents selected from the group consisting of -OR2, -C (O) -NH-R2, -S (O) nN (R2) 2, -Ht, -CN, -SR2, -C (O) O-R2 and N (R2) -C (O) -R2; and D' is (C1-C3) -alkyl or C3 alkenyl; wherein D' is optionally substituted with one or more groups selected from (C3-C6) -cycloalkyl, -OR2, -O-Q or Q.

12. The compound according to claim 11, wherein R7 in the -OR7 group depicted in formula XXIII is -PO(OM)2 or -C (O) -M'.

13. The compound according to claim 2, wherein said compound has formula XXXI:
wherein R3' has the same meaning as R3.

14. The compound according to claim 13, wherein:

A is R1-Ht;
each R3 is independently (C1-C6) -alkyl which is optionally substituted with -OR2, -C (O) -NH-R2, -S (O) nN (R2) 2, -Ht, -CN, -SR2, -CO2R2 or -N (R2) -C (O) -R2; and D' is (C1-C4)-alkyl, which is optionally substituted with (C3-C6)-cycloalkyl, -OR2, -O-Q; and E is Ht, Ht-Ht and -N (R2) (R3).

15. The compound according to claim 14, wherein R7 in the -OR7 group depicted in formula XXXI is -PO(OM)2 or -C (O) -M'.

16. The compound according to claim 1, selected from any one of compound numbers 198 to 217, 225 to 229, 231, 237 to 242, 245 to 254, 261 to 267, or 308, depicted in Table I;
any one of compound numbers 232, 233, 235 or 236 depicted in Table II; or any one of compound numbers 243 to 244 depicted in Table III:

TABLE I

TABLE II

TABLE III

17. The compound according to claim 1 selected from:

18. The compound according to any one of claims 1-3, wherein:

A is 3-hexahydrofura[2,3-b]-furanyl-O-C(O)-;

D' is (C1-C4)-alkyl which is optionally substituted with one or more groups selected from the group consisting of (C3-C6) -cycloalkyl, -OR2, -R3, -O-Q and Q;

E is (C6-C10-aryl optionally substituted with one or more substituents selected from oxo, -OR2, SR2, -R2, -N (R2) 2, - (C1-C4) -alkyl substituted with OH and optionally substituted with Q, -CN, -C (O) O-R2, -C (O) -N (R2) 2, -S (O) 2-N (R2)2, -N (R2) -C (O) -R2, -C (O) -R2, -S (O) n-R2, -OCF3, -S (O) n-Q, methylenedioxy, -N (R2) -S (O) 2-R2, halo, -CF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N (R2) (R7) or -N (R7) 2; or a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH3, R4, or Ht; and Ht, insofar as it is defined as part of R3 is defined as in claim 1 except for the exclusion of heterocycles.

19. The compound according to claim 18, wherein:

D' is isobutyl; and E is phenyl substituted with -N(R2)2.

20. The compound according to any one of claims 1-3 having the structure:

21. The compound according to any one of claims 18-20, wherein:
each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C1-C4 alkyl or -N(R2)4; and each M' is H or C1-C4 alkyl.

22. The compound according to claim 1 or claim 3 having the structure:
wherein each M is Na or K.

23. The compound according to claim 1 or claim 3, having the structure:

24. The compound according to claim 1 or claim 3, having the structure:

25. A pharmaceutical composition, comprising a compound according to any one of claims 1 to 24 and optionally a pharmaceutically acceptable carrier, adjuvant or vehicle.

26. A pharmaceutical composition, comprising a compound according to any one of claims 1 to 24 in an amount effective to treat infection by a virus that is characterized by an aspartyl protease; and a pharmaceutically acceptable carrier, adjuvant or vehicle.

27. The pharmaceutical composition according to claim 26, wherein said virus is HIV.

28. The pharmaceutical composition according to any one of claims 25 to 27, wherein said pharmaceutical composition is formulated for oral administration.

29. The pharmaceutical composition according to any one of claims 25 to 28 further comprising one or more agents selected from an anti-viral agent, an HIV protease inhibitor other than a compound according to claim 1, and an immunostimulator.

30. The pharmaceutical composition according to claim 29, further comprising one or more agents selected from zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), 935U83, abacavir (1592U89), 524W91, saquinavir (Ro 31-8959), indinavir (MK-639, L-735,524), SC-52151, ritonavir (ABT 538, A84538), nelfinavir (AG 1343), XM 412, XM 450, CGP 53,437, tuscarasol, polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, and erythropoievin (EPO).

31. Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for inhibiting aspartyl protease activity in a mammal.

32. Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for treating HIV infection in a mammal.

33. The use according to claim 32, wherein said compound is adapted for administration with one or more additional agents selected from an anti-viral agent, an HIV
protease inhibitor other than a compound according to claim 1, and an immunostimulator, either as a part of a single dosage form or as a separate dosage form.

34. The use according to claim 33, wherein said additional agent is selected from zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), 935U83, abacavir (1592U89), 524W91, saquinavir (Ro 31-8959), indinavir (MK-639, L-735,524), SC-52151, ritonavir (ABT 538, A84538), nelfinavir (AG 1343), XM 412, XM 450, CGP 53,437, tuscarasol, polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, and erythropoietin (EPO).

35. The use according to any one of claims 32 to 34 wherein said medicament is adapted for oral administration.

36. Use of a compound according to any one of claims 1 to 24 for inhibiting aspartyl protease activity.

37. A commercial package comprising the compound according to any one of claims 1 to 24 or the pharmaceutical composition according to any one of claims 25 to 30 together with instructions for use for treating HIV in a mammal.

38. A commercial package comprising the compound according to any one of claims 1 to 24 or the pharmaceutical composition according to any one of claims 25 to 30 together with instructions for use for inhibiting aspartyl protease activity.

39. The commercial package according to claim 38 which is for use for inhibiting aspartyl protease activity in a mammal.

40. The commercial package according to claim 39 which is for use for treating HIV in a mammal.