AU2007287353A1

AU2007287353A1 - Method for improving pharmacokinetics

Info

Publication number: AU2007287353A1
Application number: AU2007287353A
Authority: AU
Inventors: Michael Ge; Chandra J. Panchal; Jinzi J. Wu
Original assignee: Ambrilia Biopharma Inc
Current assignee: Ambrilia Biopharma Inc
Priority date: 2006-07-17
Filing date: 2007-07-16
Publication date: 2008-02-28
Also published as: WO2008023273A3; JP2010502569A; CA2657316A1; WO2008023273A8; EP2109461A2; WO2008023273A2; AU2007287353A8

Description

WO 2008/023273 PCT/IB2007/003593 1 METHOD FOR IMPROVING PHARMACOKINETICS TECHNICAL FIELD OF THE INVENTION 5 This invention relates to methods for improving the pharmacokinetics of drugs which are metabolized by cytochrome P450 monooxygenase using PPL-100 and related pharmaceutical compositions. In particular, the present invention relates to methods for improving the pharmacokinetics of HIV protease inhibitors by co-administering PPL-100 10 with such protease inhibitors. BACKGROUND OF THE INVENTION 15 Inhibitors of the HIV viral protease have been developed relatively recently and their use began only in 1996. Currently, they are considered the most effective drugs against HIV infection. Unfortunately, most current proteases inhibitors are relatively large hydrophobic molecules that possess rather low bioavailability. A high pill burden is therefore required to attain the therapeutic dose in a patient. This is a deterrent, which too often results in 20 patient non-compliance and inadequate treatment results. This situation leads to sub optimal therapeutic drug concentration that in turns leads to the development of HIV resistant strains. Consequently, there is an urgent need to improve the solubility and bioavailability of proteases inhibitors. 25 Examples of improved compounds have been developed in the form of prodrugs of aspartyl protease inhibitors such as described, for example, in U.S. patent no. 6,436,989 to Hale et al, the entire content of which is incorporated herein by reference. This patent shows a novel class of molecules characterized by favourable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. However, it is well 30 known that HIV has the ability to develop resistance to the currently available drugs. Thus, there is a need for alternative HIV protease inhibitors active towards wild-type and resistant viral strains. Thus, molecules derived from current HIV protease inhibitors showing enhanced solubility and bioavailability is desirable to fight resistant viral strains. 35 A unique class of aromatic derivatives which are inhibitors of aspartyl proteases is described in U.S. patent no. 6,632,816 to Stranix et al, the entire content of which is incorporated herein by reference. This patent includes, more particularly, N-synthetic WO 2008/023273 PCT/IB2007/003593 2 amino acid substituted L-lysine derivatives possessing potent aspartyl protease inhibitory properties. However, it would be advantageous to improve these derivatives by enhancing aqueous solubility and bioavailability in order to reduce the pill burden and to favour patient's compliance. Since it is challenging to generate active protease inhibitors, 5 specifically toward wild-type and resistant strains, the formation of derivatives of original HIV protease inhibitors such as inhibitors described in U.S. patent no. 6,632,816 to Stranix et al, known to be active toward resistant strains represents a viable route with considerable advantages. More particularly, generation of compounds and formulations with enhanced aqueous solubility, oral bioavailability, time of duration and formulation 10 properties along with other advantages is desirable in the development of an effective drug. Protease inhibitors with improved pharmacokinetics are therefore desirable. SUMMARY OF THE INVENTION 15 Lysine-based compounds with increased solubility and improved oral bioavailability are described herein and have been described in United States patent application No. 10/902,935 filed on August 2, 2004 and published on February 2, 2006 under No. 2006/0025592A1, the entire content of which is incorporated herein by reference. These 20 compounds may readily be cleaved in vivo to release an active ingredient which has an affinity for aspartyl proteases and which may act as a protease inhibitor. More particularly, the active ingredient may bind, for example, to an HIV aspartyl protease (U.S. patent no. 6,632,816) and may inhibit this enzyme. The Lysine-based compounds are also referred herein as a protease inhibitor precursor. 25 Upon in vivo physiological conditions (e.g., metabolic, enteric and/or gastrointestinal conditions, etc.) the Lysine-based compounds, allow for the release of a protease inhibitor (e.g., aspartyl protease inhibitor). The Lysine-based compounds may thus serve as means for improving the solubility and/or bioavailability of protease inhibitors and 30 therefore may reduce the pill burden and/or reduce dosages needed for inhibition. Improved treatment of HIV-infected patients and favourable patient's compliance may consequently occur. The compounds described herein may be used to inhibit the activity of cytochrome P450 35 monooxygenase (CYP450). More particularly, these compounds may be used to inhibit the activity of CYP3A4, including for example, CYP3A4/5.

WO 2008/023273 PCT/IB2007/003593 3 The compounds described herein may thus be used with drugs which are metabolized by cytochrome P450 monooxygenase in order to improve their pharmacokinetics. More particularly, these compounds may be used to improve the pharmacokinetics of drugs 5 which are metabolized by CYP3A4, including CYP3A4/5. Some of the drugs which may benefit from inhibition of CYP450, may include, for example, the immunosupressants cyclosporine, FK-506 and rapamycin, the chemotherapeutic agents taxol and taxotere, the antibiotic clarithromycin and the HIV 10 protease inhibitors, A-77003, A-80987, MK-639, VX-478, AG1343, DMP-323, XM-450, BILA2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulfony)(2-methylpropyl) amino) 1-(phenylmethyl)propyl)-3-methyl-L-valinamide), KNI-272, CGP 53437, CGP 57813 and U-1 03017). 15 Exemplary embodiments of compounds encompassed by the present invention and which may be used for inhibiting CYP450 (e.g., CYP3A4) may include, for example, a compound of formula 1: O H

CH

2

OR

1 S (CH),--N R3 X H R2 U.. R6 Y 20 pharmaceutically acceptable salts and derivatives thereof (e.g., for example, when the compound of the present invention comprises an amino group, the pharmaceutically acceptable salt may be an ammonium salt), 25 wherein n may be, for example, 3 or 4, wherein X and Y, the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -OCF 3 , 30 CN, -NO 2 , -NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 , and -CH 2 OH or X and Y together define an alkylenedioxy group selected from the group consisting of a WO 2008/023273 PCT/IB2007/003593 4 methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula OCH 2

CH

2 0-, wherein Re may be selected, for example, from the group consisting of a straight alkyl 5 group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and I to 3 carbon atoms in the alkyl part thereof, wherein R 3 may be selected, for example, from the group consisting of H, a straight alkyl 10 group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula R3a-CO-, wherein R3A may be selected, for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl-, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, tert butyl-CH 2 -, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-, 15 cyclohexyl- etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH 2 -, cyclohexyl-CH 2 -, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g. CH 3 O-, CH 3

CH

2 O-, iso-butylO-, tert-butylO- (Boc), etc.), tetrahydro-3-furanyloxy, -CH 2 OH, -CF 3 , -CH 2

CF

3 , CH 2

CH

2

CF

3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3

O

2 C-, CH 3 0 2

CCH

2 -, Acetyl 20 OCH 2

CH

2 -, HO 2

CCH

2 -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH 3

OCOH

4

CH

2 -, CH 3 NH-,

(CH

3

)

2 N-, (CH 3

CH

2

)

2 N-, (CH 3

CH

2

CH

2

)

2 N-, HOCH 2

CH

2 NH-, CH 3

OCH

2 0-, CH 3 0CH 2

CH

2 0-,

C

6

H

5

CH

2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula x 25 Y' a picolyl group selected from the group consisting of CH2

H

2 C N C,/ and N

H

2 WO 2008/023273 PCT/IB2007/003593 5 a picolyloxy group selected from the group consisting of OCH2

H

2 C N c C- O aand N

H

2 5 a substituted pyridyl group selected from the group consisting of and N 10 and a group of formula, H N 15 wherein X and Y', the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 20 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, 1, -CF 3 , -NO 2 , NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 and -CH 2 OH, wherein R 4 and R 5 , the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 25 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, WO 2008/023273 PCT/IB2007/003593 6 wherein R 2 may be selected, for example, from the group consisting of a diphenylmethyl group of formula IV CH IV 5 a naphthyl-1-CH 2 - group of formula V

CH

2 X' Y' V a naphthyl-2-CH 2 - group of formula VI

H

2 C X' Y' VI 10 a biphenylmethyl group of formula VII

H

2 C Y' X1 VII and an anthryl-9-CH 2 - group of formula VIII WO 2008/023273 PCT/IB2007/003593 7

CH

2 X' Y' VIII wherein R 1 may be H or a physiologically cleavable unit, whereby upon (in vivo) physiological conditions the compound may be converted into an active protease inhibitor. 5 For example, upon cleavage of the physiologically cleavable unit, the compound may be able to release a protease inhibitor. In accordance with the present invention, R 1 may be selected, for example, from the group consisting of (HO) 2 P(O) and (MO) 2 P(O), wherein M is an alkali metal (e.g. Na, K, Cs, etc) 10 or alkaline earth metal (Ca, Mg, etc.). Further in accordance with the present invention, R 1 may be a group of formula RIA-CO-, wherein RIA may be selected, for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, iso-propyl, butyl, 15 iso-butyl, tert-butyl, tert-butyl-CH 2 -, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and I to 3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH 2 -, cyclohexyl-CH 2 -, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g.

CH

3 O-, CH 3

CH

2 0-, iso-butylO-, tert-butylO- (Boc), etc.), -CH 2 OH, CH 3 0 2 C-, CH 3

O

2

CCH

2 -, 20 Acetyl-OCH 2

CH

2 -, HO 2

CCH

2 -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,

(CH

3

)

2

NCH

2 -, (CH 3

)

2

CHCH(NH

2 )-, HOCH 2

CH

2 NH-, CH 3

OCH

2 0-, CH 3 0CH 2

CH

2 0-, 2 pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2 quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula x' Y(/ 25 1 WO 2008/023273 PCT/IB2007/003593 8 a picolyl group selected from the group consisting of 'CH2

H

2 C and N~ a N

H

2 (2-picolyl) (3-picolyl) (4-picolyl) 5 a picolyloxy group selected from the group consisting of 0 -cH2 H2 N C and N Hz (2-picolyloxy) (3-picolyloxy) (4-picolyloxy) a substituted pyridyl group selected from the group consisting of 10 NN and N (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyridyl) and a group of formula, H N 15 K wherein X', Y', R 4 and R 5 are as defined herein. 20 The compounds mentioned herein may thus be used for improving the pharmacokinetics of drugs in the methods, pharmaceutical compositions, kits and uses described herein, WO 2008/023273 PCT/IB2007/003593 9 More particularly, the present invention relates to a pharmaceutical composition which may comprise: a) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, 5 b) a drug which may be metabolized by a cytochrome P450 monooxigenase (e.g., CYP3A4), and; c) a pharmaceutically acceptable carrier; where the compound of formula I is represented by; O H CH 2 OR 1 SI-I ,L(CHI1,-N N.R3 N H R2 R6 Y 10 wherein n may be 3 or 4, wherein X and Y, the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of I to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -OCF 3 , 15 CN, -NO 2 , -NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR4, -COOR 4 , -COR 4 , and -CH 2 OH or X and Y together may define an alkylenedioxy group which may be selected, for example, from the group consisting of a methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula -OCH 2

CH

2 0-, 20 wherein R 6 may be selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, 25 wherein R 3 may be selected, for example, from the group consisting of H, a straight alkyl group of I to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula RuA-CO-, where R3A may be selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 30 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, -CH 2 OH, -CF 3

,

WO 2008/023273 PCT/IB2007/003593 10

-CH

2

CF

3 , -CH 2

CH

2

CF

3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3

O

2 C-, CH 3 0 2

CCH

2 -, Acetyl-OCH 2

CH

2 -, HO 2 CCHr, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH 3 OC6H 4

CH

2 -,

CH

3 NH-, (CH 3

)

2 N-, (CH 3

CH

2

)

2 N-, (CH 3

CH

2

CH

2

)

2 N-, HOCH 2

CH

2 NH-, CH 3

OCH

2 0-,

CH

3

OCH

2

CH

2 0-, COH 5

CH

2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2 5 quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula . Y' 10 a picolyl group which may be selected from the group consisting of CH2 Hz C and 15 a picolyloxy group which may be selected from the group consisting of OCH2

H

2 C a C/ Cif and N H, a substituted pyridyl group which may be selected from the group consisting of 20 and

N

WO 2008/023273 PCT/IB2007/003593 11 a group of formula H N S, wherein X and Y', the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I, -CF 3 , -NO 2 , 10 NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR4, -COOR4, -COR4 and -CH 2 OH, wherein R 4 and R 5 , the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, 15 wherein R 2 may be selected from the group consisting of a diphenylmethyl group of formula IV CH XV Y 20 a naphthyl-1-CH 2 - group of formula V

CH

2 X' Y'

V

WO 2008/023273 PCT/IB2007/003593 12 a naphthyl-2-CH 2 - group of formula VI

H

2 C x' Y' VI a biphenylmethyl group of formula Vil

H

2 Y' VII 5 and an anthryl-9-CH 2 - group of formula Vill

CH

2 X ' Y ' VIII wherein R 1 may be H or a physiologically cleavable unit, whereby upon (in vivo) 10 physiological conditions the compound may be converted into an active protease inhibitor. For example, upon cleavage of the physiologically cleavable unit, the compound may be able to release a protease inhibitor. In accordance with the present invention, R, may be selected, for example, from the group 15 consisting of H, (HO) 2 P(O) and (MO) 2 P(O) (wherein M may be, for example, an alkali metal or alkaline earth metal) and a group of formula RIA-CO-, where R1A may be selected, for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group WO 2008/023273 PCT/IB2007/003593 13 having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atom, -CH 2 OH, CH 3

O

2 C-,

CH

3

O

2

CCH

2 -, Acetyl-OCH 2

CH

2 -, HO 2

CCH

2 -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4 hydroxyphenyl, (CH 3

)

2

NCH

2 -, (CH 3

)

2

CHCH(NH

2 )-, HOCH 2

CH

2 NH-, CH 3

OCH

2 O-, 5 CH 3

OCH

2

CH

2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula K. 10 a picolyl group selected from the group consisting of H2

HZ

2 C andN (2-picolyl) (3-picolyl) (4-picolyl) 15 a picolyloxy group selected from the group consisting of O CH 2

H

2 a ~C 1-1N0 and N H2 (2-picolyloxy) (3-picolyloxy) (4-picolyloxy) a substituted pyridyl group selected from the group consisting of 20 WO 2008/023273 PCT/IB2007/003593 14 xX. N - and N (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyridyl) and a group of formula, H N 5 N wherein X', Y', R 4 and R 5 are as defined herein. 10 More particularly, the present invention provides in one aspect thereof, a pharmaceutical composition which may comprise; a) a compound of formula i and pharmaceutically acceptable salts thereof, b) a drug which may be metabolized by a cytochrome P450 monooxigenase (e.g., CYP3A4), and; 15 c) a pharmaceutically acceptable carrier; where the compound of formula 11 is represented by;

CH

2 OR, SSsN. N C H N R 3 I R2 RB Y wherein n may be 3 or 4, 20 wherein X and Y, the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -OCF 3 , -CN, -NO 2 , -NR 4

R

5 , NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 , and -CH 2 OH or X and Y together may define, for 25 example, an alkylenedioxy group which may be selected from the group consisting of a WO 2008/023273 PCT/IB2007/003593 15 methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula OCH 2

CH

2 0-, wherein Re may be selected, for example, from the group consisting of a straight alkyl 5 group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R 3 may be selected, for example, from the group consisting of H, a straight alkyl 10 group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula R3A-CO-, where RaA may be selected, for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the 15 alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, CH 2 OH, -CF 3 , -CH 2

CF

3 , -CH 2

CH

2

CF

3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3

O

2 C-,

CH

3 0 2

CCH

2 -, Acetyl-OCH 2

CH

2 -, HO 2

CCH

2 -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4

CH

3 0CeH 4

CH

2 -, CH 3 NH-, (CH 3

)

2 N-, (CH 3

CH

2

)

2 N-, (CH 3

CH

2

CH

2

)

2 N-, HOCH 2

CH

2 NH-,

CH

3

OCH

2 0-, CH 3

OCH

2

CH

2 0-, C 6 HsCH 2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2 20 pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula x' 25 a picolyl group which may be selected from the group consisting of CH2 H2 and

H

2 a picolyloxy group which may be selected from the group consisting of 30 WO 2008/023273 PCT/IB2007/003593 16 O CH 2

H

2 0 C NCN N a substituted pyridyl group which may be selected from the group consisting of 5 and N N N a group of formula 10 H r 15 wherein X' and Y', the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -NO 2 , -NR 4

R

5 , NHCOR 4 , -OR 4 , -SR4, -COOR 4 , -COR 4 and -CH 2 OH, 20 wherein R4 and R 5 , the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, wherein R 2 may be selected from the group consisting of a diphenylmethyl group of 25 formula IV WO 2008/023273 PCT/IB2007/003593 17 CH a naphthyl-1-CH 2 - group of formula V CH2 X Y V a naphthyl-2-CH 2 - group of formula VI 5

H

2 C X. Y. VI a biphenylmethyl group of formula Vil

H

2 C Y' X.

VII

WO 2008/023273 PCT/IB2007/003593 18 and an anthryl-9-CH 2 - group of formula Vill

H

2 X1/ Y1 VIII wherein R 1 may be H or a physiologically cleavable unit, whereby upon physiological 5 conditions (in vivo) the compound may be converted into an active protease inhibitor. In accordance with the present invention, R, may be selected, for example, from the group consisting of H, (HO) 2 P(O) and (MO) 2 P(O) (wherein M may be an alkali metal or alkaline earth metal), and a group of formula RIA-CO-, where R1A may be selected, for example, 10 from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, -CH 2 OH, CH 3

O

2 C-, CH 3

O

2

CCH

2 -, Acetyl

OCH

2

CH

2 -, HO 2

CCH

2 -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3

)

2

NCH

2 15 , (CH 3

)

2

CHCH(NH

2 )-, HOCH 2

CH

2 NH-, CH 3 0CH 2 0-, CH 3

OCH

2

CH

2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula Y Il 20 a picolyl group which may be selected from the group consisting of WO 2008/023273 PCT/IB2007/003593 19 CH2

H

2 and N CC Nd N

H

2 (2-picolyl) (3-picolyl) (4-picolyl) a picolyloxy group which may be selected from the group consisting of CH2 H2 0and I N a C nd N

H

2 5 (2-picolyloxy) (3-picolyloxy) (4-picolyloxy) a substituted pyridyl group which may be selected from the group consisting of X, XKan Nan N (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyridyl) 10 and a group of formula, H N 15 wherein X', Y', R 4 and R 5 are as defined herein. In accordance with an embodiment of the present invention, pharmaceutical compositions 20 which comprise compounds of formula II wherein Re may be, for example, iso-butyl and n may be 3 are encompassed herewith.

WO 2008/023273 PCT/IB2007/003593 20 In accordance with an additional embodiment of the present invention, pharmaceutical compositions which comprise compounds of formula I wherein Re may be, for example, iso-butyl and n may be 4 are also encompassed herewith. 5 In a particular embodiment of the present invention, R 1 may be selected, for example, from the group consisting of H, (HO) 2 P(O) and (NaO) 2 P(O). In another particular embodiment of the present invention, R1 may be selected, for example, from the group consisting of CH 3 CO, 3-pyridyl-CO, (CH 3

)

2

NCH

2 CO and 1o (CH 3

)

2

CHCH(NH

2 )CO. In accordance with another particular embodiment of the present invention, pharmaceutical compositions which comprise compounds of formula 11 wherein R 3 may be selected, for example, from the group consisting of CH 3 CO, CH 3 O-CO, (CH 3

)

2 N-CO, 3 15 pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO are encompassed by the present invention. In accordance with an embodiment of the present invention, X may be 4-NH 2 and Y may be H or F. 20 In accordance with an embodiment of the present invention, X and Y' may both be H. In accordance with a particular embodiment of the present invention, pharmaceutical compositions which comprise compounds of formula I wherein R 2 may be selected, for 25 example, from the group consisting of a diphenylmethyl group of formula IV, a naphthyl-1

CH

2 - group of formula V, a naphthyl-2-CH 2 - group of formula VI, a biphenylmethyl group of formula VII and an anthryl-9-CH 2 - group of formula VIII are encompassed herewith. For example, R 2 may, more particularly, be selected from the group consisting of a 30 diphenylmethyl group of formula IV, a naphthyl-1-CH 2 - group of formula V, and a naphthyl 2-CH 2 - group of formula VI. In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of formula 11, wherein Re is iso-butyl, n is 4 and R 2 is a 35 diphenylmethyl group of formula IV.

WO 2008/023273 PCT/IB2007/003593 21 In accordance with an embodiment of the present invention, R 1 may be selected from the group consisting of H, (HO) 2 P(O) and (NaO) 2 P(O). In accordance with a further embodiment of the present invention, R 1 may be selected 5 from the group consisting of CH 3 CO, 3-pyridyl-CO, (CH 3

)

2

NCH

2 CO and

(CH

3

)

2

CHCH(NH

2 )CO. In accordance with an additional embodiment of the present invention, R 3 may be selected, for example, from the group consisting of CH 3 CO, CH 3 O-CO, (CH 3

)

2 N-CO, 3 10 pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO. In accordance with an embodiment of the present invention, X may be 4-NH 2 and Y may be H or F. 15 More particularly, in accordance with an embodiment thereof, the present invention provides a pharmaceutical composition which may comprise a compound of formula 11, wherein X may be, for example, 4-NH 2 , Y may be H, X' may be H, Y' may be H and R 3 may be CH 3 O-CO. 20 In accordance with a particular embodiment of the present invention, R 1 may be

(HO)

2 P(O). In accordance with another particular embodiment of the present invention, R 1 may be (NaO) 2 P(O). 25 In accordance with a further particular embodiment of the present invention, R 1 may be H. More particularly, in accordance with a further embodiment thereof, the present invention provides a pharmaceutical composition which may comprise a compound of formula 11, 30 wherein X may be 4-NH 2 , Y may be 3-F, X' may be H, Y' may be H and R 3 may be CH 3

O

Co. In accordance with a particular embodiment of the present invention, R, may be

(HO)

2 P(O). 35 WO 2008/023273 PCT/IB2007/003593 22 In accordance with another particular embodiment of the present invention, R 1 may be (NaO) 2 P(O). In accordance with a further particular embodiment of the present invention, R 1 may be H. 5 More particularly, in accordance with an additional embodiment thereof, the present invention provides a pharmaceutical composition which may comprise a compound of formula 11, wherein X is 4-NH 2 , Y is H or 3-F, X' is H, Y' is H and R 3 is CH 3 CO. 10 In accordance with a particular embodiment of the present invention, R 1 may be

(HO)

2 P(O). In accordance with another particular embodiment of the present invention, R 1 may be (NaO) 2 P(O). 15 In accordance with a further particular embodiment of the present invention, R 1 may be H. More particularly, in accordance with an embodiment thereof, the present invention further provides a pharmaceutical composition which may comprise a compound of formula 11, X 20 is 4-NH 2 , Y is H or 3-F, X' is H, Y' is H and R 3 is 4-morpholine-CO. In accordance with an embodiment of the present invention X may be 4-NH 2 , Y may be H, X' may be H, Y' may be H and R 3 may be CH 3 O-CO. 25 In accordance with a particular embodiment of the present invention R 1 may be 3-pyridyl Co. In accordance with another particular embodiment of the present invention R, may be

(CH

3

)

2

NCH

2 CO. 30 In accordance with yet another particular embodiment of the present invention R 1 may be

(CH

3

)

2

CHCH(NH

2 )CO. In accordance with an additional particular embodiment of the present invention R 1 may 35 be CH 3

CO.

WO 2008/023273 PCT/IB2007/003593 23 In an additional embodiment the present invention provides pharmaceutical compositions comprising a compound of formula 11, wherein Re is iso-butyl, n is 4, X and Y' are both H,

R

2 is Naphtyl-1-CH 2 -, X is 4-NH 2 , Y is H, R 3 is 4-morpholine-CO and R 1 may be selected, for example, from the group consisting of H, (HO) 2 P(O) and (NaO) 2 P(O). 5 In a further embodiment, the present invention provides pharmaceutical compositions comprising a compound of formula 11, wherein Re is iso-butyl, n is 4, X and Y' are both H,

R

2 is Naphtyl-2-CH 2 -, X is 4-NH 2 , Y is H, R 3 is CH 3 O-CO and R 1 may be selected, for example, from the group consisting of H, (HO) 2 P(O) and (NaO) 2 P(O). 10 More particularly, the present invention provides a pharmaceutical composition which may comrpnse; a) a compound of formula Ila 0 0 CQH 2

OR

1 N,.--(CH2)-i-N "R3 Re

R

3 I I X' Y' Ha 15 and pharmaceutically acceptable salts thereof, wherein X and Y, the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 20 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CFa, -OCF 3 , CN, -NO 2 , -NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 , and -CH 2 OH or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula OCH 2

CH

2 0-, 25 wherein X' and Y', the same or different, may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -NO 2 , NR 4

R

5 , -NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 and -CH 2

OH,

WO 2008/023273 PCT/IB2007/003593 24 wherein n, R 1 , R 3 , R 4 , R 5 and Re are as defined herein; b) a drug which may be metabolized by a cytochrome P450 monooxigenase, and; 5 c) a pharmaceutically acceptable carrier. In accordance with an embodiment of the present invention, R 1 may be selected from the group consisting of H, (HO) 2 P(O) and (MO) 2 P(O), wherein M may be an alkali metal or 10 alkaline earth metal and a group of formula RIA-CO-, RIA which may be selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atom, -CH 2 OH, CH 3

O

2 C-, CH 3

O

2

CCH

2 -, Acetyl-OCH 2

CH

2 -, Is HO 2

CCH

2 -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3

)

2

NCH

2 -,

(CH

3

)

2

CHCH(NH

2 )-, HOCH 2

CH

2 NH-, CH 3

OCH

2 0-, CH 3 0CH 2

CH

2 0-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula x' 20 111 a picolyl group selected from the group consisting of

H

2 C Cf and

H

2 (2-picolyl) (3-picolyl) (4-picolyl) 25 a picolyloxy group selected from the group consisting of WO 2008/023273 PCT/IB2007/003593 25 CH2 H2 0. and N C a N H2 (2-picolyloxy) (3-picolyloxy) (4-picolyloxy) a substituted pyridyl group selected from the group consisting of NXand N 5 (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyridyl) and a group of formula, H 10 wherein X', Y', R 4 and R 5 are as defined herein. In accordance with another embodiment of the present invention, R 6 may be iso-butyl. 15 In accordance with yet another embodiment of the present invention, n may be 4. In accordance with a further embodiment of the present invention, R 1 may be selected from the group consisting of H, (HO) 2 P(O) and (NaO) 2 P(O). 20 Further in accordance with an embodiment of the present invention, R 1 may be selected, for example, from the group consisting of CH 3 CO, 3-pyridyl-CO, (CH 3

)

2

NCH

2 CO and

(CH

3

)

2

CHCH(NH

2 )CO. 25 Also in accordance with an embodiment of the present invention, R 3 may be selected from the group consisting of CH 3 CO, CH 3 O-CO, (CH 3

)

2 N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.

WO 2008/023273 PCT/IB2007/003593 26 In accordance with another embodiment of the present invention, R 3 may be selected from the group consisting of CH 3 CO, CH 3 O-CO, (CH 3

)

2 N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO. 5 In accordance with an embodiment of the present invention, X may be 4-NH 2 and Y may be H or F. In accordance with another embodiment of the present invention, X may be 4-NH 2 and Y 10 may be H or F. Also in accordance with an embodiment of the present invention, X may be 4-NH 2 , Y may be H or 3-F, X' may be H, Y' may be H and R 3 may be CH 3 CO. 15 In accordance with another embodiment of the present invention, X may be 4-NH 2 , Y may be H or 3-F, X' may be H, Y' may be H and R 3 may be 4-morpholine-CO. In accordance with a particular embodiment of the present invention, X may be 4-NH 2 , Y may be H, X may be H, Y' may be H, R 3 may be CH 3 O-CO and R 1 may be (HO) 2 P(O), 20 (NaO) 2 P(O) or H. In accordance with another particular embodiment of the present invention, X may be 4

NH

2 , Y may be 3-F, X' may be H, Y' may be H, R 3 may be CH 3 O-CO and R 1 may be

(HO)

2 P(O), (NaO) 2 P(O) or H. 25 In accordance with a further particular embodiment of the present invention, X may be 4

NH

2 , Y may be H or 3-F, X may be H, Y' may be H, R 3 may be CH 3 CO and R 1 may be

(HO)

2 P(O), (NaO) 2 P(O) or H. 30 In accordance with another particular embodiment of the present invention, X may be 4

NH

2 , Y may be H or 3-F, X' may be H, Y' may be H and R 3 may be 4-morpholine-CO. In accordance with an additional embodiment of the present invention, X may be 4-NH 2 , Y may be H, X may be H, Y' may be H, R 3 may be CH 3 O-CO and R 1 may be 3-pyridyl-CO, 35 (CH 3

)

2

NCH

2 CO, (CH 3

)

2

CHCH(NH

2 )CO or CH 3

CO.

WO 2008/023273 PCT/IB2007/003593 27 In accordance with another embodiment of the present invention, X may be 4-NH 2 , Y may be 3-F, X' may be H, Y' may be H, R 3 may be CH 3 O-CO and R 1 may be 3-pyridyl-CO,

(CH

3

)

2

NCH

2 CO or (CH 3

)

2

CHCH(NH

2 )CO. 5 Other compounds which may be used to carry out the present invention may include, for example, a compound of formula llA;

CH

2 OR 1 S1- ',1 (CHz)f-N R3 Y N H R2

H

2 N IIA 10 wherein Y, n, R1, R 2 , R 3 , X and Y' are as defined herein. In accordance with the present invention, R, may be, for example, H, (HO) 2 P(O) or (NaO) 2 P(O). Further in accordance with the present invention, n may be 4. Y may be, for example, H. R 3 may be, for example, CH 3 O-CO. R 2 may be, for example, a 15 diphenylmethyl group of formula IV, where X and Y' may be, for example H, CH X' Y' IV Compounds of formula IIA' as well as pharmaceutically acceptable salts and derivatives thereof may be used to carry out the present invention, 20 WO 2008/023273 PCT/IB2007/003593 28 0 0 CH 2 OR, (CHz)-N N H

H

2 N I I IIA' such as, for example, compound of formula IlA' wherein R 1 is H, or (HO) 2 P(O) or, 5 compound of formula llA' wherein R, is (NaO) 2 P(O). For example, pharmaceutical compositions, methods, uses and kits encompassed by the present invention may comprise one or more of the following compounds and combination thereof; 10 -a compound of formula Ila wherein n is 4, R 1 is (HO) 2 P(O), X is 4-NH 2 , Y is H, X' is H, Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO, - a compound of formula Ila wherein n is 4, R 1 is (NaO) 2 P(O), X is 4-N H 2 , Y is H, X' is H, 15 Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO, - a compound of formula Ila wherein n is 4, R 1 is (HO) 2 P(O), X is 4-NH 2 , Y is H, X is H, Y' is H, Re is iso-butyl and R 3 is CH 3 CO, 20 - a compound of formula Ila wherein n is 4, R 1 is (HO) 2 P(O), X is 4-NH 2 , Y is 3-F, X is H, Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO, - a compound of formula Ila wherein n is 4, R 1 is CH 3 CO, X is 4-NH 2 , Y is H, X' is H, Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO, 25 - a compound of formula Ila wherein n is 4, R 1 is 3-pyridyl-CO, X is 4-NH 2 , Y is H, X' is H, Y' is H, Re is iso-butyl and R 3 is CH 3 0-CO, - a compound of formula Ila wherein n is 4, R 1 is (CH 3

)

2

NCH

2 CO, X is 4-NH 2 , Y is H, X is 30 H, Y' is H, Re is iso-butyl and R 3 is CH 3

O-CO,

WO 2008/023273 PCT/IB2007/003593 29 - a compound of formula Ila wherein n is 4, R 1 is (CH 3

)

2

CHCH(NH

2 )CO, X is 4-NH 2 , Y is H, X' is H, Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO, 5 - a compound of formula lib wherein n is 4, R 1 is (HO) 2 P(O), X is 4-NH 2 , Y is H, X' is H, Y' is H, Re is iso-butyl and R 3 is CH 3 O-CO and wherein the naphthyl group is a naphthyl-2

CH

2 group, - a compound of formula lib wherein n is 4, R 1 is (HO) 2 P(O), X is 4-NH 2 , Y is H, X is H, Y' 10 is H, RG is iso-butyl and R 3 is 4-morpholine-CO and wherein the naphthyl group is a naphthyl-1-CH 2 group, or - a combination of any of the above mentioned compounds. 15 Any compound which is a precursor of an active ingredient described herein may be used to carry out the present invention and is also encompassed by the present invention. For example, compounds being able to release or generate (either in vivo or in vitro) an active ingredient of the following formula;

CH

2 OH 0 H S N N H H2N I I 20 are encompassed by the present invention. The above identified active ingredient is identified herein as PL-100 and it is to be 25 understood herein that any precursor able to release or generate the above mentioned exemplary compound either in vivo or in vitro is encompassed by the present invention and may be used to carry out methods, pharmaceutical compositions, kits and uses described herein. 30 In addition, compounds which able to release (either in vivo or in vitro) an active ingredient of the following formula; WO 2008/023273 PCT/IB2007/003593 30

CI-

2 0H0 H 0 FS N N H2N may be used to carry out the present invention and are therefore encompassed by the 5 present invention. The above identified active ingredient is identified herein as PL-337 and it is to be understood herein that any precursor able to release or generate the above mentioned exemplary compound either in vivo or in vitro may be used to carry out the present 10 invention and is encompassed by the present invention. The present invention thus relates to the use of a compound described herein for improving the pharmacokinetics of a drug which may affected by CYP450 and more particularly, CYP3A4 (e.g., CYP3A4/5 etc.). 15 The present invention also relates to methods of treatment which may comprise admininistering to an individual in need, a compound described herein with one or more drugs which may be affected (metabolized) by CYP450 and more particularly, CYP3A4 (e.g., CYP3A4/5 etc.). As indicated herein, administration may be done at the same time 20 or at different time intervals. The compound(s) and drug(s) may be mixed together or not. The present invention further relates to the use of a compound described herein in the manufacture of a medicament for improving the pharmacokinetics of a drug which may affected by CYP450 and more particularly, CYP3A4 (e.g., CYP3A4/5 etc.). 25 The present invention further relates to the use of a compound described herein and a drug which may affected by CYP450 in the manufacture of a medicament for treating a patient in need. 30 The term "pharmaceutically effective amount" refers to an amount effective in treating, preventing or reducing the risk or probability of HIV infection or of reducing HIV burden.

WO 2008/023273 PCT/IB2007/003593 31 The term "pharmaceutically effective amount" also refers to an amount effective in treating, preventing or reducing the risk or probability of developing acquired immunodeficiency syndrome (AIDS), for delaying the apparition of AIDS, or reducing AIDS symptoms. It is also to be understood herein that a "pharmaceutically effective amount" 5 may be construed as an amount giving a desired therapeutic effect, either taken into a single or multiple doses or in any dosage or route or taken alone or in combination with other therapeutic agents. In the case of the present invention, a "pharmaceutically effective amount" may be understood as an amount having an inhibitory effect (partial or complete) on HIV (HIV-1 and HIV-2 as well as related viruses (e.g., HTLV-l and HTLV-ll, 10 and simian immunodeficiency virus (SIV))) infection cycle (e.g., inhibition of replication, reinfection, maturation, budding etc.) and on any organism which rely on aspartyl proteases for its life cycle. An inhibitory effect is to be understood herein as an effect such as a reduction in the capacity of an organism (e.g. HIV) to reproduce itself (replicate), to re-infect surrounding cells, etc, or even a complete inhibition (or elimination) of an IS organism. The terms "HIV protease" and "HIV aspartyl protease" are used interchangeably and includes, for example, the aspartyl protease encoded by the human immunodeficiency virus type I or 2. 20 The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable adjuvant" and "physiologically acceptable vehicle" refer to a non-toxic carrier or adjuvant that may be administered to a patient, together with one or more compounds of the present invention, and which does not destroy the pharmacological activity thereof. 25 The term "precursor" refers to a compound, such as a Lysine-based compound which is able to be converted into an active ingredient in vitro or in vivo. For example, the compound PL-461 is a precursor of compound PL-100 as when administered to an individual, PL-461 is converted into PL-100 in vivo (e.g., under physiological conditions). 30 The term "derivative" refers to a compound which has been chemically synthesized from an original compound. For example, when considering the chemical synthesis of PL-461, PL-461 is a derivative of PL-100. 35 The term "consisting essentially of" means that the pharmaceutical composition includes the specified materials and may include other material that does not materially affect the WO 2008/023273 PCT/IB2007/003593 32 basic characteristics of the pharmaceutical composition. Pharmaceutically acceptable derivatives of the compounds of formula I (such as compounds of formulae I, 11, Ila, lib, lic, llA and IIA') and where applicable 5 pharmaceutically acceptable salts thereof such as, for example, ammonium salts are described herein. A "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a recipient (a mammal), is capable of providing (directly or indirectly) a an active compound or an antivirally active metabolite or residue 10 thereof. It is to be understood herein that a "straight alkyl group of I to 6 carbon atoms" includes for example, methyl, ethyl, propyl, butyl, pentyl, hexyl. 15 It is to be understood herein that a "branched alkyl group of 3 to 6 carbon atoms" includes for example, without limitation, iso-butyl, tert-butyl, 2-pentyl, 3-pentyl, etc. It is to be understood herein, that a "cycloalkyl group having 3 to 6 carbon" includes for example, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclocyclohexyl (i.e., 20 CH 11 ). Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N - (ClA alkyl) 4 salts. 25 The compounds described herein contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and individual diastereoisomers. 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. 30 Pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, 35 cyclopentanepropionate, digluconate, dodecylhydrogensulfate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycollate, WO 2008/023273 PCT/IB2007/003593 33 hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2 naphthylsulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, perchlorate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, 5 tartrate, thiocyanate, tosylate, and undecanoate. Compounds which are encompassed by the present invention also envisions the quaternization of any basic nitrogen containing groups of the compounds disclosed herein. The basic nitrogen may be quaternized with any agents known to those of ordinary 10 skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such 15 quaternization. It is to be understood herein, that if a "range" or "group of substances" is mentioned with respect to a particular characteristic (e.g., temperature, concentration, time and the like) of the present invention, the present invention relates to and explicitly incorporates herein 20 each and every specific member and combination of sub-ranges or sub-groups therein whatsoever. Thus, any specified range or group is to be understood as a shorthand way of referring to each and every member of a range or group individually as well as each and every possible sub-ranges or sub-groups encompassed therein; and similarly with respect to any sub-ranges or sub-groups therein. Thus, for example, 25 - with respect to the number of carbon atoms, the mention of the range of 1 to 6 carbon atoms is to be understood herein as incorporating each and every individual number of carbon atoms as well as sub-ranges such as, for example, 1 carbon atoms, 3 carbon atoms, 4 to 6 carbon atoms, etc. - with respect to reaction time, a time of 1 minute or more is to be understood 30 as specifically incorporating herein each and every individual time, as well as sub-range, above 1 minute, such as for example 1 minute, 3 to 15 minutes, 1 minute to 20 hours, 1 to 3 hours, 16 hours, 3 hours to 20 hours etc.; - and similarly with respect to other parameters such as concentrations, elements, etc... 35 WO 2008/023273 PCT/IB2007/003593 34 It is in particular to be understood herein that the compound formulae each include each and every individual compound described thereby as well as each and every possible class or sub-group or sub-class of compounds whether such class or sub-class is defined as positively including particular compounds, as excluding particular compounds or a 5 combination thereof; for example an exclusionary definition for the formula (e.g. 1) may read as follows: "provided that when one of A and B is -COOH and the other is H, -COOH may not occupy the 4' position". It is also to be understood herein that "g" or "gm" is a reference to the gram weight unit 10 and "C", or" *C " is a reference to the Celsius temperature unit. The compounds described herein may easily be prepared using conventional techniques from readily available starting materials. The detailed descriptions of these approaches are presented, for example, in schemes 1 to 5 discussed below. 15 Scheme 1 illustrates a generic example for the preparation of the phosphate monoester ll derived from a primary alcohol (see ), a compound of HIV protease inhibitors (see example 1 (step G and H) in the experimental portion of this document for a specific example of this synthesis). 20 Note: a) R 2 and R 3 are as defined herein. The synthesis of phosphate monoester I// may use a HIV aspartyl protease inhibitor (1, 25 see U.S. patent no. 6,632,816) as the starting material. The diethyl phosphotriester I/ was obtained in good yield upon treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethylphosphate. Then, addition of trimethysilyl bromide in dichloromethane (DCM) gave compound I// in good to excellent yields.

WO 2008/023273 PCT/IB2007/003593 35 Scheme 1 0 lI EtO-P-OEt SOH Diethyl chlorophosphate, O ,O - H triethylphosphate, VNi NR 3 THF, NaH N N

H

2 N H 2 N 1) TMS-Br DCM 2) H 2 0 0 HO-P-OH O ' O H +, ' N'R N Nfl - R 3

H

2 N fit Scheme 1A represents another generic example for the preparation of the phosphate monoester IIIA derived from a primary alcohol (see IA), a compound of HIV protease 5 inhibitors. Note: a) n, X, Y, R 2 , R 3 and Re are as defined herein.

WO 2008/023273 PCT/IB2007/003593 36 Scheme 1A 11 EtO-P-OEt 1_OH 0 H Diethyl chiorophosphate, I- O OH1 0 H 0' '0 N R triethylphosphate, 0, ,,o fYN OS/ - THF, NaC H2 )5-N NCH'R3 F 11A 1A 1) TMS-Br DCM 2) H 2 0 0 It HO-P-OH 1-160 H trehlhopae 0 =O NR THFNaH2*s---(H2)-N '' X HRR Q/ R Y 111A The synthesis of phosphate monoester 111A is performed as described for the preparation of M1 (scheme 1). 5 Scheme 2 illustrates a generic example for the preparation of the phosphate monoester III, a compound of HIV protease inhibitors, with a different approach starting from (3S)-3 isobutylamino-azepan-2-one (1%0. 10 Note: a) R 2 and R 3 are as defined herein. As shown in scheme 2, the phosphate monoester derivative /11 was obtained from (3S)-3 isobutylamino-azepan-2-one (IV) in a seven-step reaction sequence. Initially, (2S)-3 15 isobutylamino-azepan-2-one (IV) was sulfonated with 4-acetamidobenzenesulfonyl chloride in the presence of triethylamnine in dichloromethane to give compound V in excellent yields. The derivative VI was obtained quantitatively upon treatment of V with di tert-butyl pyrocarbonate and OMAP in acetonitrile. The reductive ring opening with sodium borohydride in ethanol lead to key intermediates VII in good yield. The diethyl 20 phosphotriester ViII was obtained in good yield upon treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and WO 2008/023273 PCT/IB2007/003593 37 triethylphosphate. The Boc protective groups were removed upon treatment with HCI in ethanol to give compound IX quantitatively (T.W. Greene and P. G. M. Wuts, Protective groups in Organic Synthesis, 3 Edition, John Wiley & Sons, Inc. 1999). Then, coupling of the free amino group present on intermediate IX with a variety of synthetic amino acid in the presence of 1-hydroxybenzotriazole (HOBt) and 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide hydrochloride (EDAC) led to derivative H in good to excellent yields. Finally, addition of trimethysilyl bromide in dichloromethane (DCM) gave compound III in good to excellent yields.

WO 2008/023273 PCT/IB2007/003593 38 Scheme 2 H H 0 N ~TEA DCM 3h 0 AcH N AcHN IV 3 eq. di-tert-butyl pyrocarbonate DMAP cat, ACN -- OH Boc O0H N- NHBoc

NABH

4 0 0 ft-~ ~ NHoc EtOH I, BocHN BocNN VI1 Ac VI Diethyl chlorophosphate, triethylphosphate, THF, NaH 0 0 EtO-P-OEt EtO-P -OEt O 0 0 0O NNHBoc HCl, EtOH N NH2 BocHN"IC*' S H 2 N NI VIII Ix Coupling EDAC, HOBt 0 TMSBr I I EtO-P -CEt HO-P-OH HPLC E - 30-45% H H N 'R H over 2 steps 0 N'

H

2 NJO 2

H

2 NIIV NR Scheme 3 presents the transformation of a diphenylmethyl derivative; (1S,5S)-(1-{5-[(4 5 amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl) carbamic acid methyl ester (PL -100) into its fluorinated phosphate monoester sodium salt analog XI. This reaction sequence may be used to produce any other similar WO 2008/023273 PCT/IB2007/003593 39 compounds (compounds) made of unsubstituted (or substituted) diphenylmethyl, 1 naphthyl, 2-naphthyl, biphenyl and 9-anthryl groups described herein. Thus, the treatment of PL-100 with SelectfluorT" in acetonitrile gave derivative X in 38% 5 yield. The introduction of the phosphate monoester group was performed as described previously in scheme I and 2. First, the diethyl phosphotriester intermediate was obtained in good yield upon treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethylphosphate. Secondly, addition of trimethysilyl bromide in dichloromethane (DCM) gave the phosphate monoester compound in good to 10 excellent yields. The final product XI was easily obtained upon treatment of the phosphate monoester with a solution of sodium hydroxide with good yields. Scheme 3 -OH 0 H 'OH 0 H N N N Selectuor, F 'S N N ' zz 'NN MOC MeCN Ny~ N M C H H

H

2 N H 2 N I PL-100 (example 1, step F) 1) Diethylchlorophosphate, triethylphosphate, THF, NaH, 2) TMS-Br, DCM 3) NaOH 0 NaO-P-ONa 0 "00 H O O F + N'Moc ):D H

H

2 N XI 15 Scheme 4 illustrates a generic example for the transformation of a phosphotriester HI into its fluorinated analog XIII in a two-step reaction sequence. This generic example represents a second approach for the synthesis of fluorinated compounds described herein. In this case, the fluorine atom is added to the phosphotriester II instead of the primary alcohol derivative of general formula I or, more specifically, PL-100 as shown on 20 scheme 3. This alternate reaction sequence may be used to produce any other similar WO 2008/023273 PCT/IB2007/003593 40 compounds made of unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and 9-anthryl groups described herein. Note: 5 a) R 2 and R 3 are as defined herein. Briefly, treatment of derivative II with SelectfluorTM in acetonitrile gave derivative XII in good yields. Then, addition of trimethysilyl bromide in dichloromethane (DCM) gave the phosphate monoester compound XIII in good to excellent yields. If desired, the final 10 product XIII may be easily transformed into the phosphate monoester sodium salt analog as described before in scheme 3. Scheme 4 0 EtO-P-OEt O 0 H + + N'N R3

H

2 N HR 2 II Selectfluor, MeCN 0 || EtO-P-OEt 0 H NN N NR 3

H

2 N 2 F TMSBr HPLC 0 11 HO-P-OH -N N NR 0 R2

H

2 N HR 2 F X11/ WO 2008/023273 PCT/IB2007/003593 41 Scheme 5 illustrates exemplary synthesis of various ester compounds XVI described herein. The ester compounds are known to be easily cleaved in vivo by esterase enzymes and, as a result, may release the active ingredient. In this scheme R 2 is set as a diphenylmethyl group. However, this reaction sequence may be used to produce any 5 other similar compounds made of unsubstituted (or substituted) diphenylmethyl, 1 naphthyl, 2-naphthyl, biphenyl and 9-anthryl groups described herein. Note: a) RIA represents the "residue" of the acid molecule that is linked to the free primary 10 alcohol group present on intermediate XV and is as defined herein. The compounds XVI are generally obtained in a three-step reaction sequence in high yields. Esterification of (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) isobutyl-sulfamoyl]-phenyl)-carbamic acid tert-butyl ester (VI) with a variety of acid in the 15 presence of 1-hydroxybenzotriazole (HOBt) and 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide hydrochloride (EDAC) led to the desired esters XIV in excellent yields. The acetyl ester was obtained quantitatively using acetic anhydride in the presence of N,N-dimethylaminopyridine (DMAP) in dichloromethane (DCM). Cleavage of the Boc protective group was achieved quantitatively upon treatment with trifluoroacetic acid (TFA) 20 in DCM. A second coupling with (2S)-2-methoxycarbonylamino-3,3-dipheny-propionic acid is performed on the primary amino group of intermediate XVwith HOBt and EDAC to give the desired compounds XVI in good to excellent yields. If necessary, catalytic hydrogenation of a benzyloxycarbonyl group is performed using 10% palladium on carbon to give the final compound XVI.

WO 2008/023273 PCT/IB2007/003593 42 Scheme 5 R R1A

RACO

2 H NO Ho EDAC. HOBt ONHo S*I N; NHBoc; DMF, 99% S -- HO BocHNk.: or Ac 2 O, DMAP BocHN DCM, 99% ViI (R1A = CH 3 ) X/V TFA, DCM, 99% o R1A YR1A 0-1 H 0O O O H Coupling O S2 N Moc EDAC, HOBt. 20-70% S( N -- NH 2 H IHlN

H

2 N,( -12 XVI XV R2

H

2 , Pd/C R1 I H C', etc. N

NH

2

NH

2 O'r o0o 0 H N NSNO Moc H

H

2 N Y. XVi As it may be appreciated by the person skilled in the art, the above synthetic schemes are 5 not intended to be a comprehensive list of all means by which the compound described in this application may be synthesized but only represent exemplification of synthesis methods among others. Further methods will be evident to those of ordinary skill in the art. The compounds described herein may be modified by appending appropriate 10 functionalities to enhance selective biological properties. Such modifications may include those which increase biological penetration into a given biological system (e.g., blood, WO 2008/023273 PCT/IB2007/003593 43 lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. Pharmaceutical compositions of this invention comprise any of the compounds of the 5 present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles 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 10 phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, 15 polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. It is therefore understood herein that oral administration or administration by injection are encompassed by the present invention. For example, compounds of the present invention, may, for example, be orally administered in an aqueous solution. The pharmaceutical 20 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. 25 When the compounds described herein are administered in combination with a drug which may be metabolized by CYP450, they may be administered sequentially or concurrently to the patient. Administration of the compound and drug may also be separated by a suitable time interval. 30 In the description herein, the following abbreviations are used: Abbreviation Meanina Ac Acetyl AcOH Acetic acid 35 APCI Atmospheric pressure chemical ionization AIDS Acquired Immunodeficiency Syndrome WO 2008/023273 PCT/IB2007/003593 44 APV Amprenavir ATV Atazanavir AZT 3-Azido-3-deoxythymine (Zidovudine) Boc Benzyloxycarbonyl 5 t-Butyl tert-Butyl CAM Cerium ammonium molybdate DCM Dichloromethane DMAP NN-dimethylaminopyridine DMSO Dimethylsulfoxide 0 DMF Dimethylformamide DNA Deoxyribonucleic acid EDAC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate 15 EtOH Ethyl alcohol g Gram h hour HIV-1, -2 Human immunodeficiency virus type 1, type 2 HOBt 1 -Hydroxybenzotriazole 20 HPLC High performance liquid chromatography HTLV-1, -11 Human T-cell lymphotropic virus type 1, type I IL-2 Interleukin-2 IDV Indinavir Kg Kilogram 25 L Liter LC-MS Liquid chromatography-mass spectrometry LPV Lopinavir M Molar MeOH Methyl alcohol 30 mg Milligram mp Melting point min Minute Moc Methoxycarbonyl mol Mole 35 mL Milliliter mmol Millimole WO 2008/023273 PCT/IB2007/003593 45 NFV Nelfinavir - nm Nanometer nM Nanomolar po Orally 5 rEPO Recombinant erythropoietin RTV Ritonavir SQV Saquinavir TLC Thin layer chromatography 3TC 2',3'-Dideoxy-3-thiacytidine 10 TFA Trifluoroacetic acid THF Tetrahydrofuran EXAMPLES 15 This section describes the synthesis of lysine based compounds able to release an HIV aspartyl protease inhibitors as described herein. 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. This section presents the detailed synthesis of compounds no. I to 10 of this invention. 20 Exemplary synthesis schemes of the active ingredients have been disclosed in U.S. patent no. 6,632,816 to Stranix et al,. Materials and Methods-preparation of compounds 25 Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica gel E. Merck 60 F 2 54 plates and eluted with the indicated solvent systems. Preparative chromatography was performed by flash chromatography, using silica gel 60 (EM Science) with the indicated solvent systems and positive air pressure to allow proper rate 30 of elution. Detection of the compounds was carried out by exposing eluted plates (analytical or preparative) to iodine, UV light and/or treating analytical plates with a 2% solution of p-anisaldehyde in ethanol containing 3% sulfuric acid and 1% acetic acid followed by heating. Alternatively, analytical plates may be treated with a 0.3% ninhydrin solution in ethanol containing 3% acetic acid and/or a CAM solution made of 20 g 35 (NH4)BM070 24 and 8.3 g Ce(S0 4

)

2 polyhydrate in water (750 mL) containing concentrated sulfuric acid (90 mL).

WO 2008/023273 PCT/IB2007/003593 46 Preparative HPLC were performed on a Gilson apparatus equipped with a C18 column, a 215 liquid handler module and 25 mL/min capacity head pumps. The HPLC is operated with a Gilson UniPoint System Software. 5 Semi-preparative HPLC conditions for purification of test compounds: HPLC system: 2 Gilson #305-25 mL pumps, Gilson #215 liquid handler for injection and collection and a Gilson #155 UV-Vis absorbance detector, all controlled from a Gilson Unipoint V1.91 software 10 Column: Alltech (#96053) Hyperprep PEP, C-18, 100 Aa, 8 ±m, 22 x 250 mm Flow: 15 mL/min Solvents: A: H 2 0; B; CH 3 CN Gradient: 25% to 80% of B over 40 min Detector: absorbance; X: 210 & 265 nm 15 The crude material dissolved in acetonitrile to a concentration of around 50 to 80 mg / 2 mL were injected in each run. Fractions were collected in amounts of 9 mL pertaining absorbance was detected at the UV detector. 20 Unless otherwise indicated, all starting materials were purchased from a commercial source such as Aldrich Co. or Sigma Co. Melting points (mp) were determined on a Buchi 530 melting point apparatus in capillary tubes and were uncorrected. 25 Mass spectra were recorded on a Hewlett Packard LC/MSD 1100 system using APCI or electrospray sources either in negative mode or positive mode. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX-1l-500 30 equipped with a reversed or QNP probe. Samples were dissolved in deuterochloroform (CDCl 3 ), deuteroacetone (acetone-ds), deuteromethanol (CD 3 OD) or deuterodimethylsulfoxide (DMSO-ds) for data acquisition using tetramethylsilane as internal standard. Chemical shifts () are expressed in parts per million (ppm), the coupling constants (J) are expressed in hertz (Hz) whereas multiplicities are denoted as s for 35 singlet, d for doublet, 2d for two doublets, dd for doublet of doublets, t for triplet, q for quartet, quint. for quintet, m for multiplet, and br s for broad singlet.

WO 2008/023273 PCT/IB2007/003593 47 DETAILED DESCRIPTION OF THE INVENTION EXAMPLES: 5 Specific examples for the preparation of derivatives of general formula I The preparation of PL-100, PL-337 and other compounds of this class is presented in U.S. patent no. 6,632,816 to Stranix et al. The following compounds were prepared from L-lysine derivatives using the procedures 10 summarized in schemes 1, 1A, 2, 3, 4 and 5 of this invention. Example 1. Preparation of (1S,5S)-(1-(5-[(4-amino-benzenesulfonyl)-isobutyl amino]-6-phosphonooxy-hexylcarbamoyl-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-461) 15 The preparation of the title compound is based on schemes 1 and 2 of this invention. Step A. Preparation of (3S)-3-isobutylamino-azepan-2-one (V) 20 L-a-amino--caprolactam (22.0 g) was dissolved in cold dichloroethane (DCM, 200 mL). isobutyraldehyde (12.6 g) was added slowly and stirred until the heat evolved was dissipated (water forms at the surface). The cold solution was added to 46.5 g of powdered NaBH(OAc) 3 in DCM (0.5 L). AcOH (70 mL) was added to the solution. The slightly turbid mixture was stirred at 20 *C for 4 h. A 500 mL solution of 2M NaOH was 25 added slowly to the turbid mixture and the pH adjust to 11 using a concentrated NaOH solution, and then the mixture stirred for a further 20 min. After extraction, the DCM layer was dried with MgSO 4 , filtered and evaporated. The oil thus obtained crystallizes slowly on standing (27.8 g, 85%) and was used without further purification in the next step. 30 'H NMR (CDCl 3 ): 8 0.93 (d, J = 6.5, 3H), 0.97 (d, J = 6.5, 31-), 1.39 (t, J = 9.8, 1H), 1.47 (m, 1H), 1.78-1.65 (m, 21-), 2.00-1.93 (m, 2H), 2.32-2.2 (m, 2H), 2.38 (t, J= 9.7, 1H), 3.16 (m, 3H), 6.62 (s, 1H (NH)). mp 52-54 *C (hexanes). A small sample was converted to the S-methyl benzyl urea by adding the solid to a 35 solution of S-methyl benzyl isocyanate in MeCN. NMR gives 98% ee WO 2008/023273 PCT/IB2007/003593 48 Step B. Preparation of Nc-isobutyl-Na-(4-acetamidobenzenesulfonyl)-L-a amino-caprolactam (V) Na-isobutyl-L-a-amino--caprolactam (IV) (4.1 g free base) was dissolved in DCM (200 5 mL) and treated with 4.0 g triethylamine, followed by 4-acetamidobenzenesulfonyl chloride (5.2 g). A 0.1 g portion of dimethylaminopyridine was added and the mixture was stirred 5 h. The resulting thick slurry was poured into 500 mL 0.5 M HCI and shaken vigorously. The solid in the biphasic solution was filtered out and washed with cold acetone to give 7.3 g (87%) of clean product. 10 'H NMR (DMSO-de): . 0.93 (d, J = 6.0, 3H), 0.96 (d, J = 6.0, 3H), 1.39 (t, J = 12.0, 1H), 1.85-1.65 (m, 3H), 2.08-2.18 (m and s, 6H), 2.90-2.97 (m, 1H), 3.00-3.06 (m, 2H), 3.35 (dd, J = 14.2, 8.5, 1H), 4.65 (d, J = 8.7, 1H), 6.3 (s, 1H), 7.42 (d, J = 8.8, 2H), 7.6 (d, J 8.8, 2H). mp 230-233 *C (EtOH). 15 Step C. Preparation of (3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino) benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylic acid tert-butyl ester (Boc activation) (VI) 20 4.2 g of Na-isobutyl-Na-(4-acetamidobenzenesulfonyl)-L-a-amino--caprolactam (V) was suspended in 30 ml MeCN and briefly sonicated to break up any large chunks. To this white suspension was added 6.7 g (3 eq.) of di-tert-butyl pyrocarbonate in 10 mL MeCN. The suspension was stirred with a magnetic bar and a 120 mg portion of DMAP was added. The solution becomes a clear light yellow after a few minutes. TLC (EtOAc) 25 reveals 1 product Rf 0.9 (starting material Rf at 0.4). The solution is poured in distilled water 20 mL and extracted with ether, dried with Na 2

SO

4 and evaporated yielding 6.90 g. A sample was recrystallized from hexanes. 'H NMR (DMSO-de): . 0.68 (d, J = 6.0, 3H), 0.85 (d, J = 6.0, 3H), 1.39 (s, 10H), 1.47 (s, 30 9H), 1.85-1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, J = 4, 1H), 3.10-3.36 (m, 2H), 4.01 (d, J 8.0, 1 H), 4.85 (d, J = 8.7, 1 H), 7.32 (d, J = 8.8, 2H), 7.87 (d, J = 8.8, 2H). mp 123-124 *C Step D. Preparation of (1 S)-4-amino-N-(5-amino-1 -hydroxymethyl-pentyl)-N isobutyl-benzenesulfonamide (VII-deprotected) (reductive ring opening and deprotection) 35 WO 2008/023273 PCT/IB2007/003593 49 A 3.0 g portion of (3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl amino}-2-oxo-azepane-1-carboxylic acid tert-butyl ester (VI, step C) is dissolved in 40 mL EtOH followed by 750 mg NaBH 4 . Brief heating with a heat gun gives a clear solution. TLC reveals one streaky spot after 20 min (EtOAc). The solution is concentrated to a paste, 5 poured in 40 mL 1 N NaOH and extracted with ethyl acetate, the organic phase dried with NaSO 4 and evaporated to give 2.8 g of product intermediate (Vi); (1S)-{4-[(5-tert butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (VI). 10 The above product intermediate is dissolved in 5 mL EtOH and 5 mL 12 N HCI is added. Vigorous gas evolution is observed for a few minutes. After 2 h the solution is evaporated and rendered basic with concentrated KOH and extracted with EtOAc yielding 1.75 g of a white powder. is 'H NMR (DMSO-ds): . 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H), 1.57 (m, 1H),. 1.84 (m, 1H), 2.40 (t, J = 7.8, 2H), 2.75 (m, IH), 2.85 (m, 1H), 3.21 (m, 1H), 3.44 (d, J = 6.4, 2H), 5.92 (br s, 2H), 6.59 (d, J = 8.0, 2H), 7.39 (d, J = 8.0, 2H). Step E. Preparation (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic 20 acid To a solution of L-diphenylalanine (241 mg, 1.0 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na 2

CO

3 (resulting solution at pH 10) was added methoxycarbonyloxysuccinimide (carbonic acid 2,5-dioxo-pyrrolidin-1-yi ester methyl 25 ester) (180 mg, 1.1 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1 N HCl. The organic phase was dried over Na 2

SO

4 .filtered and evaporated to an oil, which solidifies to yields 30 250 mg (83%) of the desired material. This derivative was used as such in the next step. Step F. Preparation of (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6 hydroxy-hexylcarbamoyl)-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-100) 35 The title compound was prepared from (1 S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl) N-isobutyl-benzenesulfonamide (VII-deprotected) (step D) and (2S)-2- WO 2008/023273 PCT/IB2007/003593 50 methoxycarbonylamino-3,3-diphenyl-propionic acid (step E) using the coupling procedure with HOBt and EDAC described in example 3 (step D). The final product was obtained in 67% yield (121 mg). 5 LC-MS: 625.3 (M+H)*, 95% pure 'H NMR (CD 3 OD): 8 0.71-0.85 (m, 2H), 0.88 (d, J = 6.3, 5H), 0.91-0.96 (m, 2H), 1.29 1.34 (m, IH), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2.81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J = 5.0, 1H), 3.50-3.51 (m, 1H), 3.52 (s, 3H), 4.28 (d, J = 10 11.0 1H), 4.87 (d, J = 11.0, 1H), 6.69 (d, J = 8.0, 2H), 7.15-718 (m, 2H), 7.20-7.31 (m, 6H), 7.33 (d, J = 7.9, 2H), 7.47 (d, J = 7.5, 1H). 3 C NMR (CD 3 OD): 6 20.0, 20.1, 23.3, 25.4, 28.1, 28.5, 28.9, 38.1, 40.0, 51.2, 51.6, 53.1, 57.2, 57.4, 59.5, 61.9, 62.4, 112.6, 125.7, 126.2, 126.3, 127.9, 128.1,128.15, 128.2, 128.4, 128.7, 141.3, 141.9, 152.4, 155.9, 169.9, 172.5. 15 Step G. Preparation of (iS,5S)-{1-[5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6 (diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamic acid methyl ester The PL-100 compound (product of step F, 203 mg, 0.325 mmol) was dissolved in dry 20 tetrahydrofuran (3 mL) and 0.2 mL triethylphosphate under N 2 atmosphere. The mixture was stirred at this temperature for 15 min, followed by the addition of diethyl chlorophosphate (0.061 mL, 0.423 mmol). Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) was added at 0 *C. The solution was stirred for 1 h at 0 *C and 12 h at room temperature. 20 mL of Amberlite XAD-2 was added to the solution and the beads were 25 thoroughly mixed with the solvent. To the mixture was added ice water 2 mL, and the THF evaporated off. The beads were then washed with distilled water 6 times 100 mL then extracted three times with ethyl acetate (30 mL). The combined phase was evaporated and the residue was dried under high vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane (8/2), then EtOAc 100% as eluent. The yield 30 of this reaction is 152 mg 61%. LC-MS: 761.2 (M+H)*, 90% pure 'H NMR (CD 3 OD): 6 0.68-0.75 (m, 1H), 0.75-0.84 (m, 1H), 0.84-1.10 (m, 9H), 1.21-1.50 35 (m, 8H), 1.88 (m, 1H), 2.58-2.71 (m, 1H), 2.80-2.89 (m, 1H), 2.89-3.08 (m, 2H), 3.49-3.60 (s, 3H), 3.65-3.74 (m, 1H), 3.85-3.95 (m, 1H), 3.97-4.02 (m, 1H), 4.07-4.21 (m, 4H), 4.29 WO 2008/023273 PCT/IB2007/003593 51 (d, J = 10.8, 1 H), 6.71 (d, J = 8.0, 2H), 7.10-7.20 (m, 2H), 7.20-7.32 (m, 5H), 7.32-7.45 (m, 3H), 7.50 (d, J = 7.5, 2H), 7.86 (br s, 1 H). 3 1 P NMR (CD 3 OD): 6 1.62 5 Step H. Preparation of (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6 phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-461) The product of step G prepared above (152 mg) was dissolved in anhydrous 10 dichloromethane (3.0 mL). Trimethylsilyl bromide (0.5 mL) was added at 0 *C. The mixture was stirred during 1 h at this temperature and overnight at room temperature. The solvent was evaporated and 0.2 mL water was added to the residue. 3 mL EtOH was added mixed and evaporated. This step was repeated three times and the residue dried in vacuo. Yields 98 mg 70% of the title derivatives of this first example. 15 LC-MS: 705.2 (M+H)*, 95% pure 'H NMR (CD 3 0D): 6 0.65-0.73 (m, IH), 0.75-0.83 (m, IH), 0.89 (d, J = 5.6, 8H), 1.27 1.38, (m, IH), 1.42-4.55 (m, 1H), 1.82-1.94 (m, 1H), 2.57-2.68 (m, IH), 2.78-2.90 (m, 1H), 20 2.91-3.09 (m, 2H), 3.54 (s, 3H), 3.60-3.72 (m, 1H), 3.87-4.05 (m, 1H), 4.00 (m, 1H), 4.29 (d, J = 11.3, 1 H), 4.90 (d, J = 11.4, 1 H), 6.73 (d, J = 8.0, 2H), 7.13-7.22 (m, 2H), 7.22-7.33 (m, 6H), 7.33-7.45 (m, 2H), 7.51 (d, J = 7.5, 2H). 31P NMR (CD 3 0D): 6 2.80 25 Example 2. Preparation of (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl amino]-6-phosphonooxy-hexylcarbamoy)-2,2-diphenyl-ethyl) carbamic acid methyl ester sodium salt (PL-462) 30 70.7 mg of the final product of example 1 is added to 1 mL 0.1 N NaOH and diluted with 1 mL of distilled water. The Solution is then frozen and lyophilized. Yields 67.2 mg (92%) of the desired material with 95% purity. 'H NMR (CD 3 OD): 6 0.72-0.83 (m, 1H), 0.90 (d, J = 5.8, 9H), 1.26-1.38 (m, 1H), 1.53 35 1.65 (m, IH), 1.88-2.00 (m, IH), 2.60-2.70 (m, 1H), 2.79-2.89 (m, 1H), 2.98-3.00 (m, 1H), 3.00-3.08 (m, IH), 3.54 (s, 3H), 3.58-3.71 (m, 1H), 3.72-3.83 (m, 1 H), 3.84-3.95 (m, 1H), WO 2008/023273 PCT/IB2007/003593 52 4.28 (d, J = 11.1, 1H), 4.91 (d, J = 11.0, 1H), 6.70 (d, J = 7.6, 2H), 7.12-7.22 (m, 2H), 7.22-7.32 (m, 6H), 7.33-7.40 (m, 2H), 7.50 (d, J = 7.7, 2H). 31 P NMR (CDaOD): 6 3.13 5 Example 3. Preparation of (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl amino]-6-phosphonooxy-hexylcarbamoyl-2-naphthalen-2-yI-ethyl) carbamic acid methyl ester (PL-507) 10 The preparation of the title compound is based on scheme 2 of this invention. Step A. Preparation of (1 S)-(4-{([5-tert-butoxycarbonylamino-1 (diethoxyphosphoryloxymethyl)-pentyl]-isobutyl-sulfamoyl}-phenyl)-carbamic acid tert butyl ester (Vil) 15 2.00 g (3.7 mmol) (1 S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (VII) (example 1, step D) is dissolved in 0.63 mL triethylphosphate and 10 mL THF at 0 *C under inert argon atmosphere. 0.63 mL (4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2 mmol), NaH 60% in oil 20 is added in portionwise. The mixture is allowed to warm to room temperature and left to stir for 2 h (LC-MS showed completion after 1 h). To the solution is added 20 mL of Amberlite XAD-2 resin and the slurry thoroughly mixed and added to 200 mL ice water. After stirring for 15 min. the resin suspension is filtered and the resin washed several times with distilled water (500 mL). The desired product is desorbed from the resin with 25 acetone (5 X 50 mL), EtOAc (5 X 50 mL), the organic phase is then dried over Na 2

SO

4 . After evaporation of the solvent 2.66 g (89%) of clear oil is obtained. The crude product contains a fraction with two diethyl phosphates and is used as is in the next step. 'H NMR (CD 3 OD): 6 0.91 (d, J = 6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t, J = 6.9, 1OH), 1.43 30 (s, 9H), 1.53 (s, 10H), 1.90-1.97 (m, 1H), 2.88-2.96 (m, 3H), 2.96-3.04 (m, 1H), 3.81-3.90 (m, 1H), 3.91-3.99 (m, 1H), 4.01-4.14 (m, 4H), 7.61 (d, J = 8.3, 2H), 7.72 (d, J = 8.4, 2H). 31 P NMR (CD 3 OD): 6 1.59 35 Step B. Preparation of (2S)-phosphoric acid 6-amino-2-[(4-amino benzenesulfonyl)-isobutyl-amino]-hexy ester diethyl ester (IX) WO 2008/023273 PCT/IB2007/003593 53 The crude product obtained in the previous step (Vili, 2.66 g) is dissolved in 12 mL EtOH. 4 mL of HCI c. is added and heated briefly to 70 "C then left at room temperature for 3h. The solvent is evacuated and the residue triturated with 50 mL ether. The thick residue is 5 then dissolved in 3 mL ice water and the pH adjusted to 12 with 50% NaOH. The thick slurry obtained is extracted with EtOAc (3 X 50 mL) and the organic phase dried over Na 2

SO

4 . After filtration of the drying agent the organic phase is evacuated to yield 1.84 g (98%) of the desired product (IX). 10 LC-MS: 480.2 (M+H)*, 95% pure. 'H NMR (CD 3 OD): 6 0.91 (s, 6H), 1.11-1.26 (m, 3H), 1.28-1.43 (m, 8H), 1.45-1.51 (m, 1H), 1.52-1.61 (m, 1H), 1.89-1.96 (m, 1H), 2.56 (t, J = 6.7, 2H), 2.85-2.91 (m, 1H), 2.98 3.11 (m, IH), 3.79-3.99 (m, 1H), 3.94 (d, J = 5.3, 1H), 4.09-4.11 (m, 4H), 6.69 (d, J = 7.9, 15 2H), 7.50 (d, J = 7.9, 2H). 31 P NMR (CD 3 OD): 61.61 Step C. Preparation of (2S)-2-methoxycarbonylamino-3-naphthalen-2-yl 20 propionic acid (or L-Moc-2-naphthylalanine) To a solution of L-2-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na 2

CO

3 (resulting solution at pH 10) was added methoxycarbonyloxysuccinimide (187 mg, 1.1 mmol) dissolved in 5 mL. Afterwards, the 25 reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1 N HCI. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1 N HCI. The organic phase was dried over Na 2

SO

4 .filtered and evaporated to an oil, which solidifies to yields 200 mg (73%) of the desired material. This intermediate 30 (referred as the N-substituted amino acid) was used without further purification in the next step. Step D. Preparation of (1 S,5S)-(1 -{5-[(4-amino-benzenesulfonyl)-isobutyl-aminol-6 phosphonooxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamic acid methyl ester (PL 35 507) WO 2008/023273 PCT/IB2007/003593 54 100 mg L-Moc-2-naphthylalanine (step C) was activated with 100 mg EDAC and 57 mg HOBt in 1.5 mL DMF for 30 minutes. Then, 100 mg of phosphoric acid 6-amino-2-[(4 amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (step B) was added and left to stir at room temperature for 1 h. 40 mL of 1M K 2

CO

3 was added to the DMF solution 5 and left for 10 min. 50 mL of EtOAc was then added and the mixture was then agitated vigorously. Separation of the EtOAc phase was effected, followed by extraction with 5% citric acid (50 mL) once, then water (50 mL) 3 times and finally brine. The organic phase was the separated and evaporated. The residue was taken up in 50 mL DCM and re evaporated. The residue was again taken up in 50 mL DCM and 0.5 mL of TMSBr was 10 added. The solution was left overnight (16 h). The DCM was evacuated and a solution of ice cold MeOH: Water 1:1 was added, stirred briefly and evacuated. The residue was triturated with ether then dissolved in 1N NaOH. The clear solution was extracted with ether and the aqueous phase acidified with 6N HCI. The white precipitated was then collected by filtration and dried in vacuo overnight. Yields 88 mg of the title compound. 15 LC-MS: 679.8 (M+H)*, 95% pure. 'H NMR (CD 3 OD): 6 0.89-0.98 (m, 8H), 1.15 (m, 2H), 1.35 (m, 1H), 1.45 (m, 1H), 1.88 (m, 1H), 2.84 (m, 2H), 2.98 (m, 1H), 3.01 (m, 2H), 3.24 (m, 1H), 3.56.(s, 3H), 3.60 (m, 20 1H), 3.81 (m, IH), 3.99 (m, 1H), 4.39 (t, J = 6.8, 1H), 6.91 (d, J = 8.0, 2H), 7.34 (d, J= 8.0, IH), 7.45 (m, 2H), 7.58 (d, J = 8.0, 2H), 7.66 (s, 1H), 7.70-7.82 (m, 3H). 31 P NMR (CD 3 OD): 6 2.56 25 Example 4. Preparation of (2S,2S) phosphoric acid mono-(2-[(4-amino benzenesulfonyl)-isobutyl-amino]-6-{2-[(morpholine-4-carbonyl) amino]-3-naphthalen-1-yl-propionylamino}-hexyl) ester (PL-498) 30 Step A. Preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl propionic acid To a solution of L-1-naphthylalanine (215 mg, I mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na 2

CO

3 (resulting solution at pH 10) was added morpholine-4 35 carbonyl chloride (150 mg, 1.0 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with WO 2008/023273 PCT/IB2007/003593 55 ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCL. The organic phase was dried over Na 2

SO

4 , filtered and evaporated to an oil, which solidifies to yields 125 mg (38%) of the desired material. This compound was used as 5 such in the next step. Step B. Preparation of (2S,2S) Phosphoric acid mono-(2-[(4-amino benzenesulfonyl)-isobutyl-amino]-6-{2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1 -yl propionylamino)-hexyl) ester (PL-498) 10 This compound was made as for the preparation of the product of example 3 (step D) with 100 mg of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (step A of this example). The resulting precipitated residue was further purified by reverse phase preparative HPLC. Yields 41 mg of the final compound. 15 LC-MS: 734.8 (M+H)*, 95% pure. 'H NMR (CD 3 OD): 6 0.83-0.98 (m, 8H), 1.00-1.25 (m, 4H), 1.45-1.52 (m, 1H), 1.52-1.66 (m, 1H), 1.88-1.99 (m, 1H), 2.77-2.92 (m, 2H), 2.98-3.16 (m, 3H), 3.40-3.49 (m, 1H), 3.50 20 3.56 (m, 6H), 3.67-3.69 (m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.59 (t, J = 6.0, 1H), 6.75 (d, J = 8.0, 2H), 7.30-7.60 (m, 7H), 7.75 (d, J = 8.0, 1H), 7.90 (d, J= 7.8, iH), 8.23 (d, J=7.8 2H). 3 1 P NMR (CD 3 OD): 6 2.71 25 Example 5. Preparation of (2S,2S)-phosphoric acid mono-{6-(2-acetylamino-3,3 diphenyl-propionylamino)-2-[(4-amino-benzenesulfonyl)-isobutyl amino]-hexyl) ester (PL-504) 30 Step A. Preparation (2S)-2-acetylamino-3,3-diphenyl-propionic acid To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na 2

CO

3 (resulting solution at pH 10) was added acetyl chloride (0.5 35 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous WO 2008/023273 PCT/IB2007/003593 56 phase was acidified with 1N HCI. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCI. The organic phase was dried over Na 2

SO

4 .filtered and evaporated to an oil, which solidifies to yields 70 mg (60%) of the desired material. This crude intermediate was used as such in the next step. 5 Step B. Preparation of (2S,2S)-phosphoric acid mono-{6-(2-acetylamino 3,3-diphenyl-propionylamino)-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl} ester (PL-504) 10 This compound was made as for the preparation of the product of example 3 (step D) with 100 mg of (2S)-2-acetylamino-3,3-diphenyl-propionic acid (this example step A). The final product was obtained in 30% yield (30 mg). LC-MS: 689.3 (M+H)*, 95% pure. 15 'H NMR (CD 3 OD): 6 0.77-1.04 (m, 9H), 1.10-1.17 (m, 1H), 1.23-1.49 (m, 1H), 1.46-1.57 (m, 1H), 1.78 (s, 3H), 1.88-1.99 (m, IH), 2.80-2.92 (m, 2H), 2.92-3.08 (m, 2H), 3.63-3.75 (m, 1H), 3.79-3.95 (m, 1H), 4.00 (m, 1H), 4.34 (d, J = 11.3, 1H), 5.19-5.28 (m, 1H), 6.77 6.85 (m, 2H), 7.10-7.20 (m, 2H), 7.27-7.33 (m, 6H), 7.32-7.41 (m, 2H), 7.49-7.62 (m, 2H). 20 3 1 P NMR (CD 3 0D): 6 2.70 Example 6. Preparation of (1 S,5S)-(1-(5-[(4-amino-3-fluoro-benzenesulfonyl) isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl)-2,2-diphenyl 25 ethyl)-carbamic acid methyl ester (PL-515) First methodology: The preparation of the title compound is based on scheme 3 of this invention. 30 Step A. Preparation of (1-(5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6 hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (X) (PL-337) The product of example 1, step F (0.624 g, 1 mmol) is dissolved in 5 mL MeCN at 24 *C. SelectFluor 0.35 g (1 mmol) is added in one portion and stirred for 1h. I mL of water is 35 added and the solution was injected directly into a preparative reverse-phase HPLC. The product was collected and lyophilized to give 250 mg (38%) yield of a white solid.

WO 2008/023273 PCT/IB2007/003593 57 LC-MS: 643.3 (M+H)*, 99% pure. 'H NMR (MeOD): 6 0.71-0.85 (m 2H), 0.88 (d, J = 6.3, 6H), 0.91-0.96 (m, 2H), 1.21-1.29 5 (m, 1 H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, IH), 2.61-2.68 (m, 1H), 2.81-2.85 (m, 2H), 2.94 3.05 (m, 2H), 3.38-3.40 (t, J = 5, 1H), 3.49-3.52 (m, 5H), 4.28 (d, J = 10, 1H), 4.87 (d, J = 10, 1H) 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H). Step B. Preparation of (1S,5S)-{1-[5-[(4-amino-3-fluoro-benzenesulfonyl) 10 isobutyl-amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl-2,2-diphenyi-ethyl}-carbamic acid methyl ester The product of step A was phosphorylated with chlorodiethylphosphate following the procedure described in example 1, step G. Yields 157 mg, 68%. 15 LC-MS: 779.3 (M+H)*, 95% pure. 'H NMR (CD 3 OD): 6 0.82 (m, 1H), 0.92 (d, J = 6.2, 8H), 0.96 (m, 3H), 1.36 (d, J = 3.7, 6H), 1.90 (m, 1H), 2.69 (m, 1H), 2.89 (m, 1H), 2.98 (m, 2H), 3.56 (s, 3H), 3.74 (m, 1H), 20 3.93 (m, 1H), 4.03 (m, 1H), 4.12 (q, J = 7.5 and 14.8, 4H), 4.32 (d, J = 11.4, 1H), 4.92 (d, J = 11.4, 1H), 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H). 31 P NMR (CD 3 OD): 6 1.65 25 Step C. Preparation of (1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl) isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (XI) (PL-515) Deprotection was effected using the procedure described in example 1, step G. Yields 30 101 Mg. LC-MS: 723.2 (M+H)*, 95% pure. 'H NMR (CD 3 OD): 6 0.65-0.77 (m, 1H), 0.77-0.85 (m, 1H), 0.85-1.05 (m, 9H), 1.25-1.39 35 (m, 1H), 1.40-1.52 (m, IH), 1.82-1.98 (m, IH), 2.58-2.72 (m, IH), 2.82-2.92 (m, 1H), 2.92 3.05 (m, 2H), 3.54 (s, 3H), 3.64-3.75 (m, 1H), 3.80-3.92 (m, 1H), 3.91-4.04 (m, 1H), 4.29 WO 2008/023273 PCT/IB2007/003593 58 (d, J = 11.4, 1H), 7.19 (t, J = 6.6, 1H), 7.13-7.21 (m, 2H), 7.22-7.33 (m, 6H), 7.34-7.38 (m, 2H), 7.39-7.48 (m, 2H). 31 P NMR (CD 3 OD): 6 2.74 5 Second methodology: The preparation of the title compound is based on scheme 4 of this invention. Step A. Preparation (1 S,5S)-(1 -{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6 1o phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-461) (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1, step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of (2S)-phosphoric acid 6-amino-2-[(4-amino 15 benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (IX) (example 3, step B) and the mixture stirred for 3 h. 20 9 of Amberlite XAD-2 resin was then added and the beads were left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly with distilled water (400 mL) and 200 mL-of 1M NaHCQ 3 . The beads were then washed with 4 X 50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. 20 The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to yield 2.4 g (83%) of white solid after evaporation. NMR identical as in example 1, step H. 25 Step B. Preparation (1 S,5S)-{1 -[5-[(4-amino-3-fluoro-benzenesulfonyl) isobutyl-amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamic acid methyl ester (XI!) The product of step A above, (1 S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6 30 phosphonooxy hexylcarbamoyl)-2,2-diphenyl-ethyl)-carbamic acid methyl ester (0.555 g, 0.73 mmol) was dissolved in 5 mL MeCN. Selectfluor (0.26 g, 0.7 mmol) was added and the mixture stirred for 30 min. The mixture was purified by reverse phase preparative HPLC and lyophilized to yield 278 mg (48% yield) white solid. 35 1 H NMR identical as previous entry, see first methodology above.

WO 2008/023273 PCT/IB2007/003593 59 Step C. Preparation (1 S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl) isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl)-2,2-diphenyl-ethyl)-carbamic acid methyl ester (XIII, in this specific case is compound X) (PL-515) 5 The procedure make this derivative was as described in the deprotection step for the methodology above. Yields 139 mg 70% after reverse phase HPLC. 'H NMR identical as previous entry, see first methodology above. 10 Example 7. Preparation of (2S,2S)-acetic acid 2-[(4-amino-benzenesulfonyl) isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl propionylamino)-hexyl ester (PL-521) The preparation of the title derivative is based on scheme 5 of this invention. 15 Step A. Preparation of (2S)-acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexy ester (XIV, RIA = CH 3 ) To a stirred solution of (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) 20 isobutyl-sulfamoyl]-phenyl)-carbamic acid tert-butyl ester (intermediate product (VII) of example 1, step D, 97 mg, 0.18 mmol) in anhydrous CH 2

C

2 (3 mL) was added NN dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 mL, 0.18 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the organic layer was washed with water (30 mL), 25 then dried with Na 2

SO

4 and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The yield obtained was quantitative (100 mg). LC-MS: 586.2 (M+H)*, 95% pure 30 Step B. Preparation of (2S)-acetic acid 6-amino-2-[(4-amino benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV, RIA = CH 3 ) This derivative was prepared from (2S)-acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexy ester as described in WO 2008/023273 PCT/IB2007/003593 60 example 15, step B. The yellow solid (66 mg) was used for the next reaction without purification. LC-MS: 386.2 (M+H)*, 95% pure 5 Step C. Preparation of (2S,2S)-acetic acid 2-[(4-amino-benzenesulfonyl )isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexyl ester (XVI, R1A = CH 3 ) (PL-521) 10 This derivative was prepared from (2S)-acetic acid 6-amino-2-[(4-amino-benzenesulfonyl) isobutyl-amino]-hexyl ester (product of step B) as described in example 15, step B. The final product was purified by flash chromatography with a mixture of eluents hexanefethyl acetate (2/8). A yellow solid was obtained in 70% yield (70 mg). 15 LC-MS: 667.3 (M+H)*, 95% pure 1 H NMR (acetone-ds): 8 0.85-0.97 (m, 12H), 1.21-1.41 (m, 2H), 1.88-2.00 (s, 3H), 2.59 2.69 (m, 1H), 2.83-2.90 (m, 1H), 2.90-3.01 (m, 1H), 3.01-3.10 (br s, 1H), 3.45-3.60 (s, 3H), 3.70-3.80 (m, IH), 3.93-4.00 (m, 1H), 4.00-4.11 (m, 1H), 4.38-4.45 (d, J'= 11.0, 1H), 4.89 20 4.98 (t, J = 10.0, 1H), 5.43-5.58 (br s, 1H), 6.28-6.48 (d, J = 8.9, 1H), 6.72-6.83 (d, J = 8.0, 2H), 6.85-6.93 (br s, 1H), 7.12-7.22 (t, J = 7.4, 1H), 7.21-7.31 (d, J = 7.0, 4H), 7.31-7.45 (m, 5H), 7.48-7.57 (d, J = 8.0, 2H). Example 8. Preparation of (2S,2S)-nicotinic acid 2-[(4-amino-benzenesulfonyl) 25 isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl propionylamino)-hexyl ester (PL-520) Step A. Preparation of (2S)-nicotinic acid 6-tert-butoxycarbonylamino-2-[(4-tert butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexy ester (XIV, RIA = 3-pyridyl) 30 (1 S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl} carbamic acid tert-butyl ester (intermediate product (VIl) of example 1, step D, 130 mg, 0.24 mmol) was dissolved in anhydrous DMF (1 mL) and treated with 0.066 mL (0.48 mmol) of triethylamine followed by EDC (120 mg, 0.65 mmol), HOBt (88 mg, 0.65 mmol) 35 and nicotinic acid (27 mg, 0.22 mmol). The mixture was stirred overnight at room WO 2008/023273 PCT/IB2007/003593 61 temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic phase was separated and dried with Na 2

SO

4 , then evaporated to give 200 mg of crude product. This compound was purified by flash chromatography with ethyl acetate as the eluent. A clear oil was obtained in 100% yield (150 mg). 5 LC-MS: 649.3 (M+H)*, 95% pure 'H NMR (acetone-de): 6 0.90-1.14 (d, J = 5.9, 6H), 1.31-1.42 (m, 2H), 1.48 (s, 9H), 1.51 1.55 (m, 2H), 1.59 (s, 9H), 1.62-1.69 (m, IH), 1.72-1.83 (m, 1H), 3.00-3.11 (m, 2H), 3.11 10 3.17 (m, 1H), 3.19-3.27 (m, 1H), 4.15-4.24 (m, 1H), 4.35-4.44 (t, J = 9.1, 1H), 4.50-4.58 (dd, J = 4.4 and 11.5, 1H), 5.89-5.99 (br s, 1H), 7.53-7.60 (m, 1H), 7.70-7.77 (d, J = 8.2, 2H), 7.80-7.87 (d, J = 8.2, 2H), 8.24-8.31 (d, J = 7.3, 1H), 8.75-8.82 (m, 1H), 8.82-8.88 (m, 1H), 9.12-9.18 (br s, 1H). 15 Step B. Preparation of (2S)-nicotinic acid 6-amino-2-[(4-amino benzenesulfonyl)-isobutyl-amino]-hexy ester (XV, RIA = 3-pyridyl) The product of step A, (2S)-nicotinic acid 6-tert-butoxycarbonylamino-2-[(4-tert butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexy ester (150 mg, 0.23 mmol), 20 was dissolved in CH 2

CI

2 (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred during 2 hours at room temperature. The solvent was evaporated and the residue was extracted with ethyl acetate (40 mL) and NaOH 1M (40 mL) (pH = 10). The organic portion was separated, dried with Na 2

SO

4 and evaporated. The residue (100 mg) was used for the next reaction without further purification. The yield was quantitative. 25 LC-MS: 449.2 (M+H)', 95% pure Step C. Preparation of (2S,2S)-nicotinic acid 2-[(4-amino-benzenesulfonyl) isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexy ester 30 (PL-520) The product of step B, (2S)-nicotinic acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl amino]-hexyl ester (100 mg, 0.22 mmol) was dissolved in anhydrous DMF (2 mL) and treated with 0.062 mL (0.45 mmol) of triethylamine followed by EDC (100 mg, 0.56 mmol), 35 HOBt (75 mg, 0.56 mmol) and (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid WO 2008/023273 PCT/IB2007/003593 62 (56 mg, 0.19 mmol). The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic layer was separated and dried with Na 2

SO

4 , then evaporated to give 160 mg of crude oil. The residue was purified by flash chromatography with a mixture of eluents hexane/ethyl 5 acetate (2/8). The title compound was obtained as a clear oil in 20% yield (25 mg). LC-MS: 730.2 (M+H)*, 95% pure H NMR (acetone-do): 6 0.80-0.97 (m, 9H), 0.97-1.13 (m, 2H), 1.26-1.40 (m, 1H), 1.40 10 1.57 (m, 1H), 2.61-2.73 (m, 1H), 2.86-2.98 (m, 2H), 3.00-3.17 (m, 2H), 3.45-3.59 (s, 3H), 3.91-4.00 (m, 1H), 4.24-4.34 (m, 1H), 4.34-4.47 (m, 2H), 4.90-4.99 (t, J = 9.7, 1H), 6.35 6.44 (m, 1H), 6.68-6.79 (d, J = 7.9, 1H), 6.91-7.00 (br s, 1H), 7.13-7.22 (m, 2H), 7.22-7.31 (m, 3H), 7.35-7.48 (m, 4H), 7.49-7.64 (m, 2H), 7.75-7.84 (m, 1H), 8.25-8.36 (m, 1H), 8.76 8.88 (br s, 1H), 9.12-9.26 (br s, 1H). 15 Example 9. Preparation of (2S,2S)-dimethylamino-acetic acid 2-[(4-amino benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3 diphenyl-propionylamino)-hexyl ester (PL-534) 20 Step A. Preparation of (2S)-dimethylamino-acetic acid 6-tert-butoxycarbonylamino 2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XIV, R1A =

(CH

3

)

2

NCH

2 -) This title compound was obtained from (1S)-{4-[(5-tert-butoxycarbonylamino-1 25 hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl)-carbamic acid tert-butyl ester (intermediate product (Vi) of example 1, step D) as described example 15, step A using N,N-dimethylglycine. The clear oil was obtained in 100% yield (150 mg). LC-MS: 629.3 (M+H)*, 95% pure 30 'H NMR (acetone-do): 5 0.81-0.95 (d, J = 6.1, 6H), 1.18-1.30 (m, 2H), 1.32-1.43 (s, 9H), 1.43-1.52 (s, 8H), 1.52-1.62 (m, 1H), 1.93-2.00 (m, 1H), 2.19-2.29 (s, 4H), 2.69-2.80 (m, 4H), 2.90-3.05 (m, 6H), 3.60-3.65 (m, IH), 3.85-3.97 (m, 1H), 3.98-4.08 (m, IH), 4.08 4.14 (m, 1H), 5.78-5.88 (m, 1H), 7.68-7.80 (m, 3H), 8.80-8.88 (br s, 1H). 35 WO 2008/023273 PCT/IB2007/003593 63 Step B. Preparation of (2S)-dimethylamino-acetic acid 6-amino-2-[(4-amino benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV, R1A = (CH 3

)

2

NCH

2 -) The title derivative was prepared from (2S)-dimethylamino-acetic acid 6-tert 5 butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino] hexyl ester as described in example 15, step B. The final product (100 mg) was used as such in the next step. LC-MS: 429.3 (M+H)*, 90% pure 10 Step C. Preparation of (2S,2S)-dimethylamino-acetic acid 2-[(4-amino benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl propionylamino)-hexyl ester (PL-534) 15 This title compound was prepared from (2S)-dimethylamino-acetic acid 6-amino-2-[(4 amino-benzenesulfonyl)-isobutyl-amino]-hexy ester as described in example 15, step C. The crude product was purified by LC-preparative. The final compound was obtained in 10% yield (10 mg). 20 LC-MS: 710.3 (M+H)*, 92% pure 'H NMR (acetone-de): 5 0.81-0.98 (m, 12H), 1.14-1.30 (m, 2H), 1.31-1.45 (m, 1H), 2.58 2.77 (m, 2H), 2.79-2.90 (m, 2H), 3.42-3.56 (s, 3H), 3.75-3.85 (m, IH), 3.99-4.17 (m, 3H), 4.23-4.35 (m, 1H), 4.36-4.45 (m, 1H), 4.86-4.96 (m, 1H), 6.33-6.42 (m, IH), 6.74-6.83 (m, 25 1H), 6.85-6.90 (m, 1H), 7.12-7.22 (m, 3H), 7.23-7.31 (m, 4H), 7.31-7.44 (m, 5H), 7.47 7.55 (m, 1H), 7.73-7.80 (m, 1H). Example 10. Preparation of (2S,2S)-2-amino-3-methyl-butyric acid 2-[(4-amino benzenesulfonyl)-isobutyl-amino] -6-(2-methoxycarbonylamino-3,3 30 diphenyl-propionylamino)-hexyl ester (PL-530) Step A. Preparation of (2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 6-tert butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino] hexyl ester (XIV, RIA = (CH 3

)

2

CHCH(NH

2 )-) 35 WO 2008/023273 PCT/IB2007/003593 64 This title compound was obtained from (IS)-{4-[(5-tert-butoxycarbonylamino-1 hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (intermediate product (VI) of example 1, step D) as described in example 15, step A using (2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid. The crude product was purified by 5 flash chromatography eluting with a mixture of hexane/ethyl acetate (1/1). The yield obtained was 100% (150 mg). LC-MS: 777.3 (M+H)*, 95% pure 10 'H NMR (acetone-de): 8 0.80-1.00 (m, 14), 1.13-1.28 (s, 2H), 1.30-1.44 (s, 11H), 1.45 1.56 (s, 10), 1.58-1.67 (m, 1H), 2.87-3.04 (m, 4H), 3.84-3.97 (m, 1H), 3.97-4.12 (m, 2H), 4.12-4.21 (m, 1H), 4.99-5.14 (m, 2H), 5.78-5.89 (m, 1H), 6.38-6.52 (m, 1H), 7.24-7.34 (m, 1H), 7.34-7.41 (m, 2H), 7.65-7.83 (m, 4H), 8.77-8.86 (m, 1H). 15 Step B. Preparation of (2S)-benzyloxycarbonylamino-3-methyl-butyric acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexy ester (XV RIA =

(CH

3

)

2

CHCH(NH

2 )-) This derivative was prepared from (2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 20 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl amino]-hexyl ester (product of step A) as described in example 15, step B. The final compound was obtained in quantitative yield (110 mg) and used for the next step without purification. 25 LC-MS: 577.3 (M+H)*, 90% pure Step C. Preparation of (2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3 diphenyl-propionylamino)-hexyl ester 30 The title compound was obtained from (2S)-benzyloxycarbonylamino-3-methyl-butyric acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-aminol-hexyl ester (product of step B) as described in example 15, step C. The clear oil was obtained in 86% yield (120 mg). 35 LC-MS: 858.3 (M+H)*, 95% pure WO 2008/023273 PCT/IB2007/003593 65 Step D. Preparation of (2S,2S)-2-amino-3-methyl-butyric acid 2-[(4-amino benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl propionylam ino)-hexyl ester (PL-530) 5 To a stirred solution of (2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4 amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl propionylamino)-hexyl ester (step C. 120 mg, 0.14 mmol) in anhydrous THF (8 mL), under nitrogen atmosphere, was added palladium 10% wt. on activated carbon (160 mg). The 10 mixture was reacted under hydrogen atmosphere overnight, at room temperature. The solution was filtered and the palladium on carbon was washed with THF (50 mL). The solvent was evaporated and the residue (110 mg) was purified by flash chromatography using ethyl acetate as the eluent. The clear oil was obtained in 47% yield (47 mg). 15 LC-MS: 796.4 (M+H)*, 95% pure 'H NMR (acetone-d): 0 0.84-0.97 (m, 12H), 0.97-1.08 (m, 2H), 1.27-1.43 (m, 3H), 1.49 1.62 (m, 4H), 1.80-1.93 (m, 1H), 1.94-2.00 (m, 1H), 2.36-2.46 (m, 1H), 2.58-2.74 (m, 2H), 2.86-2.96 (m, 3H), 2.99-3.10 (m, 2H), 3.46-3.52 (s, 3H), 3.52-3.60 (m, 2H), 3.75-3.87 (m, 20 2H), 3.95-4.04 (m, 1H), 4.10-4.18 (m, 1H), 4.37-4.44 (m, 1H), 4.89-4.97 (m, 1H), 5.40 5.48 (m, 1H), 6.30-6.40 (m, 1H), 6.76-6.83 (d, J = 8.2, 1H), 6.87-7.03 (m, 2H), 7.14-7.22 (m, 1H), 7.23-7.34 (m, 3H), 7.35-7.45 (m, 4H), 7.50-7.56 (m, 1H), 7.57-7.65 (m, 1H). Example 11. In vitro inhibition of CYP450 25 Human Liver Microsomes Pooled human liver microsomes (from 15 donors) were purchased from In vitro Technologies, Inc., Baltimore, Maryland, USA. 30 PL-100 and Ritonavir solutions preparation Stock solution of PL-100 was prepared in methanol at 25 mM. For the CYP3A4 assay, the 25 mM stock solution was diluted with methanol to 0.25 and 0.125 mM. The 25 mM stock solution and the 0.25 and 0.125 mM solutions were diluted 250 fold for microsomal incubation to a final concentration of 200, 500 and 1000 nM. A sub-stock solution of PL 35 100 was prepared in methanol at 25 M and diluted in methanol to 2.5 and 0.25 iM and WO 2008/023273 PCT/IB2007/003593 66 further diluted 250 fold for microsomal incubation giving final concentrations of 100, 10 and inM. Stock solution of Ritonavir was prepared in methanol at 25 mM. A sub-stock solution was 5 prepared in methanol at 25 RM. This sub-stock solution was diluted in methanol to 2.5 and 0.25 pM and further diluted 250 fold for microsomal incubation giving final concentrations of 100, 10 and inM. Control incubations were performed in the presence of an equal volume of methanol. The 10 final methanol concentration in incubation mixtures was < 1%. Selective inhibitors of CYP450 were tested in parallel as a positive control. Testosterone 6p-Hydrolase (TESH) Activity The TESH activity was determined by HPLC-UV analysis following incubation of 15 microsomes with testosterone as. a substrate. Liver microsomes (at a final concentration of 0.30 mg/mI protein) were incubated for 10 minutes at 37 0 C with various concentrations of testosterone in 0.5 ml reaction mixture, containing 0.1 M phosphate buffer (pH 7.4), 1 mM EDTA, and 3mM magnesium chloride with a NADPH-generating system, PL-100, Ritonavir or Ketoconazole, at appropriate concentrations, were present in the incubation 20 medium with the probe substrate before the reaction was started by addition of NADPH generating system. The reaction was terminated with 500 pL ice-cold acetonitrile and the 6p -hydroxytestosterone formation was quantified using 6 point standard curve (range 2 to 20 nmol/mL). The analysis of 3 quality controls (LQC, MQC and HQC) was also performed. The associated enzyme activity was expressed as nmol of 6p 25 hydroxytestosterone per mg of protein per min. Data were captured with Millenium chromatographic data management and storage system (version 4.0). Michaells-Menten Kinetics EnzFitter software (Biosoft) was used for the calculation of Km, Vmax of probe substrates 30 and apparent Km', Vmax' in the presence of various concentration of PL-100, Ritonavir or selective inhibitors and Ki of PL-1 00, Ritonavir or selective inhibitors. The cytochrome P450 activities were plotted against substrate concentrations. A nonlinear regression analysis was generated for Michaelis-Menten models in the presence and absence of PL 100, Ritonavir or selective inhibitors. 35 WO 2008/023273 PCT/IB2007/003593 67 Lineweaver-Burk Plots To determine the mode of inhibition, a transformation of fitted IN values were employed to generate a linear regression of IN vs. 1/[S] using EnzFitter software. The nature of the curves was utilized as an indication of the type of inhibition. 5 Ki was calculated using the equation corresponding to the type of inhibition: No inhibitor: V= Vmax*[S]/ (Km +[S]) 1o Competitive inhibition: V= Vmax*[S] / (Km (1 +[1] / Ki) +[S]) Km'= Km* (1+[l] / Ki ) Non-competitive inhibition: V= Vmax*[S] / (Km (1+[1] / Ki ) +[S] (1+[l] / Ki)) = 15 = (Vmax / (1 +[1] / Ki )* [S]) / (Km+[S]) Vmax'= Vmax / (1+[lI] / Ki) 20 Uncompetitive inhibition: V= Vmax*[S] / (Km+[S](1+[I] / Ki)) = = (Vmax / (1+ [1] / Ki) *[S]) / (Km/(1+[I] / Ki) +[S]) Km' = Km / (1+[I] / Ki) 25 Vmax' = Vmax / (1+[1] / Ki) V: Velocity of the enzyme reaction in the presence of inhibitor Vmax: Maximal velocity 30 Vmax': Maximal velocity in the presence of inhibitor [S]: Substrate concentration [1]: Inhibitor concentration Km: dissociation constant of the enzyme-substrate complex Km': dissociaton constant of the enzyme-substrate complex in the presence of 35 inhibitor WO 2008/023273 PCT/IB2007/003593 68 Ki: dissociation constant of the enzyme-inhibitor complex HPLC methods 5 6P- hydroxytestosterone Column: C18, 4pim, 3.9 x 150 mm Detection: UV@ 254 nm Mobile phase (gradient): A: Methanol, Water, Acetonitrile (39:60:1) B: Methanol, Water, Acetonitrile (80:18:2) 10 Flow rate: 1mL/min. Data calculation and Statistical analysis Numerical data obtained during the study were subjected to calculation group mean 15 values, standard deviations, where appropriate, using Excel software (Microsoft). Enzyme kinetic parameters (Km and Vmax) and the Ki values of test articles and selective inhibitors were calculated by nonlinear regression analysis using EnzFitter software. EnzFitter software was utilized also for the fitting of the Michaelis-Menten curves and for the generation of the Lineweaver-Burk plots, from the fitted values of Michaelis-Menten 20 curves, allowing the identification of the type of inhibition were appropriate. The testosterone 6p-hydrolase activity, a selective marker for CYP3A4/5, was assessed in the presence of PL-100. With a Ki of 0.445 ± 0.050 pM (R 2 = 0.98: Figs. 1 to 4), PL-100 could be considered as a strong competitive inhibitor of human CYP3A4 although this 25 compound was approximately 13 fold less potent than Ritonavir. In agreement with litterature data, Ritonavir showed a strong competitive inhibition of CYP3A4 activity with a Ki of 0.034 ± 0.005pM (R 2 = 0.98: Figs. I and 2). 30 A Ki of 0.052 ± 0.012 pM was calculated for ketoconazole, a strong competitive inhibitor of CYP3A4 activity (R 2 = 0.99: Figs. 1 to 3). PL-100 is thus considered a strong inhibitor of CYP3A4/5, but with a Ki value 13 fold higher than Ritonavir and 8.5 fold higher than ketoconazole. 35 WO 2008/023273 PCT/IB2007/003593 69 Example 12. In vivo inhibition of CYP450 Preparation of PPL-100 mixture (40 mg/mL) An appropriable amount of test article, PPL-100, was dissolved in a mixture of 20% 5 ethanol, 50% propylene glycol, 0.1% Tween and 30% water (v/v/v/v), to obtain a concentration of 40 mg/mL. Purity of the test article was taken into account for calculation of the concentration. Preparation of Atazanavir mixture (10 mg/mL) 10 Atazanavir was dissolved in a mixture of 20% ethanol, 50% propylene glycol, 0.1% Tween and 30% water (v/v/v/v), to obtain a concentration of 10 mg/mL. Preparation of Dosing Solutions Dosing solutions were prepared shortly prior to dosing as follows: Briefly 4 mL of PPL 15 100 mixture (40 mg/mL) was mixed with 4 mL of Atazanavir mixture (10 mg/mL). Animals Sprague Dawley rats (Rattus norvegicus) aged 7 - 8 weeks at start of dosing were used for the study (Charles River Canada Inc., Montreal, PQ). Animals received Atazanavir 20 (25 mg/kg) and PPL-100 (100 mg/kg). Six female rats were used on each time point. Animals were dosed with a mixture containing Atazanavir (5 mg/mL) and PPL-100 (20 mg/mL) at a dose volume 5 mL per kg body weight. A summary of treatment is illustrated in Table A below. 25 Table A: Treatment Groups Conc. of Dose Test Route of Dosing Number of Test Article Volume animals per (mg/kg) Article administration (mglmL) (ml) group PPL-100 100 20 Oral Gavage 5 6 female Atazanavir 25 5 Blood samples were collected on 6 occasions. Rats were bled as per outline in Table B.

WO 2008/023273 PCT/IB2007/003593 70 For the purpose of collection of the samples indicated above, each rat were bled from the orbital sinus. Each blood sample (approximately 0.4 mL) was collected into a tube containing the anticoagulant K 2 EDTA. The time (actual time, in conjunction with the day and time of dosing) was recorded for each sample. Following collection, the samples was 5 inverted for approximately 10 minutes and then, the samples were centrifuged under refrigeration (2 - 8*C) for 20 minutes at 2000 rpm. The plasma obtained from each sample was recovered and stored frozen (at approximately -80 0 C) pending analysis. A the time of analysis, protein was extracted from the plasma samples and PL-1 00 (the 10 active ingredient released rom PPL-100 under physiological conditions) or atazanavir were detected by HPLC-UV-MSD (1100 series, Hewlett Packard). Table B. Bleeding Time after PPL-100 and Atazanavir Administration Group30 min 60 min 3 hrs 6 hrs 12 hrs 24 hrs PPL-100 (100 mg/kg) + F X X X X X X Atazanavir (25 mg/kg) 15 Results of this analysis presented in Fig. 5 and Fig. 6 indicate that PL-1 00 (PPL-1 00) decreases the metabolism of Atazanavir in vivo. PL-1 00 (PPL-1 00) succesfully increases the plasma concentration of Atazanavir at 24 hours. 20 Example 13. Microsomal Stability In vitro studies were conducted to demonstrate that PL-100 enhances protease inhibitors' stability in microsomes. 25 The protease inhibitors which were tested were: Atazanavir (ATV), Lopinavir (LPV), Saquinavir (SQV), Amprenavir (APV), Nelfinavir (NFV) and Indinavir (IDV). The concentration of the protease inhibitors and PL-100 was 10 pM, except for the experiment involving Atazanavir, in which Atazanavir was at concentration of 1.0 pM and 30 PL-1 00 was at a concentration of 2.0 pM.

WO 2008/023273 PCT/IB2007/003593 71 After each protease inhibitor was incubated with microsomes, the percent of parent (original protease inhibitor) remaining was measured. The measurements were conducted at time point 60 minutes. The percent of parent remaining quantifies the extent of stability of protease inhibitors, as protease inhibitors are susceptible to being 5 metabolized into daughter molecules in microsomes, decreasing the amount of the original protease inhibitor. The greater the percent of parent remaining, the greater the stability of the protease inhibitor in microsomes. The percent of parent remaining was measured for each protease inhibitor in the 10 presence or absence of PL-100. As a control, the percent of protease inhibitor remaining was also measured in the presence of Ritonavir (RTV) to compare the boosting effect between PL-100 and RTV. The results of the experiment (Figure 7) demonstrate that PL-1 00 can enhance the 15 stability of all tested protease inhibitors in microsomes. Thus, PPL-100 is a potential booster of these protease inhibitors in vivo.

Claims

1. A pharmaceutical composition comprising: a) a lysine-based compound of formula I 0 H CH 2 OR 1 O I- OL(CH2Y--N R3 XN H R2 I R2 Y or a pharmaceutically acceptable salt thereof, 5 wherein n is 3 or 4, wherein X and Y, the same or different, are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -OCF 3 , CN, -NO 2 , -NR 4 R 5 , -NHCOR4, -OR 4 , -SR 4 , -COOR 4 , -COR 4 , and -CH 2 OH or X and 10 Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula -OCH 2 CH 2 0-, wherein R is selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl 15 group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R 3 is selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula RaA-CO-, RaA being selected from 20 the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, CH 2 OH, -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, 25 CH 3 0 2 C-, CH 3 O 2 CCH 2 -, Acetyl-OCH 2 CH 2 -, HO 2 CCH 2 -, 3-hydroxyphenyl, 4 hydroxyphenyl, 4-CH 3 OCOH 4 CH 2 -, CH 3 NH-, (CH 3 ) 2 N-, (CH 3 CH 2 ) 2 N-, WO 2008/023273 PCT/IB2007/003593 73 (CH 3 CH 2 CH 2 ) 2 N-, HOCH 2 CH 2 NH-, CH 3 0CH 2 0-, CH 3 0CH 2 CH 2 0-, C 6 HsCH 2 O-, 2 pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula Y1' 5 a picolyl group selected from the group consisting of CH2 H2 C I and N c C, Nn N H 2 a picolyloxy group selected from the group consisting of CH 2 H 2 Ic d N H, a substituted pyridyl group selected from the group consisting of 10 and N 10 - N C-N N a group of formula H N K j WO 2008/023273 PCT/IB2007/003593 74 wherein X' and Y', the same or different, are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -NO 2 , NR 4 R 5 , -NHCOR 4 , -OR 4 , -SR4, -COOR 4 , -COR 4 and -CH 2 OH, 5 wherein R 4 and R 5 , the same or different, are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, wherein R 2 is selected from the group consisting of a diphenylmethyl group of formula IV CH IV 10 a naphthyl-1-CH 2 - group of formula V CH 2 x. y' V a naphthyl-2-CH 2 - group of formula VI H 2 C VI 15 a biphenylmethyl group of formula VII WO 2008/023273 PCT/IB2007/003593 75 H 2 VII and an anthryl-9-CH 2 - group of formula Vill CH2 xY' VIII 5 wherein R 1 is H or a physiologically cleavable unit; b) a drug which is affected by cytochrome P450 monooxigenase; and 10 c) a pharmaceutically acceptable carrier; wherein the ratio (w/w) of the lysine-based compound, or pharmaceutically acceptable salt thereof, to said drug which is affected by cytochrome P450 monooxigenase is between about 4:1 and about 1:1. 15 WO 2008/023273 PCT/IB2007/003593 76

2. A pharmaceutical composition according to claim 1 wherein the lysine-based compound is a compound of formula lI, CH 2 0R, S N ( H R 3 X III R2 Y 5 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1 or claim 2, wherein R 1 is selected from the group consisting of H, (HO) 2 P(O) and (MO) 2 P(O), and a group of formula RIA CO-, R1A being selected from the group consisting of a straight or branched alkyl 10 group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of I to 6 carbon atom, -CH 2 OH, CH 3 O 2 C-, CH 3 0 2 CCH 2 -, Acetyl-OCH 2 CH 2 -, HO 2 CCH 2 -, 2 hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3 ) 2 NCH 2 -, 15 (CH 3 ) 2 CHCH(NH 2 )-, HOCH 2 CH 2 NH-, CH 3 OCH 2 0-, CH 3 OCH 2 CH 2 O-, 2-pyrrolyl, 2 pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula x' 20 il a picolyl group selected from the group consisting of WO 2008/023273 PCT/IB2007/003593 77 H2 H 2 C N and H 2 (2-picolyl) (3-picolyl) (4-picolyl) a picolyloxy group selected from the group consisting of CH2 H2 CC an d N~ CC N H 2 5 (2-picolyloxy) (3-picolyloxy) (4-picolyloxy) a substituted pyridyl group selected from the group consisting of X---..- X---- X' Nand < N (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyridyl) 10 and a group of formula, H N 15 wherein M is an alkali metal or alkaline earth metal and wherein X', Y', R 4 and R 5 are as defined in claim 1. WO 2008/023273 PCT/IB2007/003593 78

4. The pharmaceutical composition of claim 1, wherein X, Y, n, R1, R2, R3, R6, X' and Y' are set forth for each of the lysine-based compounds of formula I below: EX. No V. L. (PL-#) X Y n Ro R, Re XWY OL RS i (PL-481) 4-NH 2 H 4 (HO P(O) (C*HqbCH CH:O-CO iso-but H4M S.S 2 (PL-462) 4-NH, H 4 (NaO)P(O) (CaHs)CH CatO-CO 60-b" KIH S.S 3 (PL-507) 4.NH2 H 4 (HO) 2 P(O) Napfthy§-2-CH, CH30-CO &obuy MtH SS 4 (PL-498) 4-NH, H 4 (HO)P(O) Naphthyl-1-CHa 4-nphOlifO- bo-bu2y4 HiM S.S Co 5 (PL-504) 4-Nt H 4 (HOh)P(O) (CoHbbCH CH3CO s Ho" M 8S 6 (PL-515) 4-NH, 3-F 4 (HOhP(O) (C.HO)aCH CHO-CO i ' * HH SS 7 (PL-621) 4-NH, H 4 CH 3 CO (C.Hs)CH CH3o-CO L " - $S 8 (PL-s20) 4-Nt9 " 4 3-Pyy-CO (CisCH CKO-CO *" HM S.S 9 (PL-534) 4-NH, H 4 (C%)NCHCO (C.%)CH CH30-CO o"but HIH S.S 10 (PL-530)4-NH2 H 4 (CHahjCHCH(NH1)CO(CHahCH CHA-CO iso-butyl HM S.S 11 (PL-100) 4-N% H 4 H (CHM),CH CHaO-CO o-but H/M s cpt.337)4, 3-F 4 H COHhCH CKSO-CO io-buy MiH 5

5. The pharmaceutical composition of any one of claims 1 to 4, wherein said drug which is affected by cytochrome P450 monoxigenase is selected from the group consisting of Atazanavir (ATV), Lopinavir (LPV), Saquinavir (SQV), Amprenavir (APV), Nelfinavir (NFV) and Indinavir (IDV). 10

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the ratio (w/w) of said lysine-based compound and said drug which is affected by cytochrome P450 monooxigenase is about 4:1.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein said cytochrome P450 monoxignease is CYP3A4. 15

8. A pharmaceutical combination comprising: a) a lysine-based compound of formula I CH 2 OR 1 0 SI-I ,,L(CH 2 -Yi-N R3 NXH R2 Y WO 2008/023273 PCT/IB2007/003593 79 or a pharmaceutically acceptable salt thereof, wherein n is 3 or 4, 5 wherein X and Y, the same or different, are selected from the group consisting of H, a straight alkyl group of I to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -OCF 3 , CN, -NO 2 , -NR 4 Rs, -NHCOR 4 , -OR 4 , -SR 4 , -COOR 4 , -COR 4 , and -CH 2 OH or X and Y together define an alkylenedioxy group selected from the group consisting of a 10 methylenedioxy group of formula -OCH 2 0- and an ethylenedioxy group of formula -OCH 2 CH 2 0-, wherein R6 is selected from the group consisting of a straight alkyl group of I to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl 15 group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R 3 is selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group 20 of 3 to 6 carbon atoms, and a group of formula Ra-CO-, R3A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, 25 CH 2 OH, -CF 3 , -CH 2 CF 3 . -CH 2 CH 2 CF 3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3 0 2 C-, CH 3 2CCH2-, Acetyl-OCH 2 CH 2 -, HO 2 CCH 2 -, 3-hydroxypheny, 4 hydroxyphenyl, 4-CH 3 OC 6 H 4 CH 2 -, CH 3 NH-, (CH 3 ) 2 N-, (CH 3 CH 2 ) 2 N-, (CH 3 CH 2 CH 2 ) 2 N-, HOCH 2 CH 2 NH-, CH 3 0CH 2 0-, CH 3 0CH 2 CH 2 O-, C 6 H 5 CH 2 0-, 2 pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4 30 quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula Y. WO 2008/023273 PCT/IB2007/003593 80 a picolyl group selected from the group consisting of CH2 C CI and H, 5 a picolyloxy group selected from the group consisting of 1-, 0IICH2 H 2 cIc and H 2 10 a substituted pyridyl group selected from the group consisting of X x. d N N1 aN N 15 a group of formula N rN 20 wherein X' and Y', the same or different, are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 WO 2008/023273 PCT/IB2007/003593 81 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF 3 , -NO 2 , NR 4 Rs, -NHCOR 4 , -OR 4 , -SR 4 , -COOR4, -COR4 and -CH 2 OH, wherein R 4 and R 5 , the same or different, are selected from the group consisting of 5 H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, wherein R 2 is selected from the group consisting of a diphenylmethyl group of formula IV CH X IV 10 a naphthyl-1-CH 2 - group of formula V CH 2 V 15 a naphthyl-2-CH 2 - group of formula VI H 2 C X' y' VI a biphenylmethyl group of formula VII WO 2008/023273 PCT/IB2007/003593 82 H 2 Y' VII and an anthryl-9-CH 2 - group of formula Vill CH 2 XY ' VIII 5 wherein R 1 is H or a physiologically cleavable unit; and b) a drug which is affected by cytochrome P450 monooxigenase; 10 wherein the ratio (w/w) of said lysine-based compound, or pharmaceutically acceptable salt thereof, to said drug which is affected by cytochrome P450 monooxigenase is between about 4:1 and about 1:1.

9. A pharmaceutical combination of claim 8 wherein the lysine-based compound is a 15 compound of formula 1I, O o CH 2 OR 1 0 I S (CH2 r-N-' R3 N H R X- R2 Y WO 2008/023273 PCT/IB2007/003593 83 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical combination of claim 8 or claim 9, wherein R 1 is selected from 5 the group consisting of H, (HO) 2 P(O) and (MO) 2 P(O), and a group of formula RIA CO-, RIA being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon 10 atom, -CH 2 OH, CH 3 O 2 C-, CH 3 O 2 CCH 2 -, Acetyl-OCH 2 CH 2 -, HO 2 CCH 2 -, 2 hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CHCH(NH 2 )-, HOCH 2 CH 2 NH-, CH 3 OCH 2 0-, CH 3 OCH 2 CH 2 0-, 2-pyrrolyl, 2 pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of 15 formula x a picolyl group selected from the group consisting of 20 HH C and H2 (2-picolyl) (3-picolyl) (4-picolyl) a picolyloxy group selected from the group consisting of WO 2008/023273 PCT/IB2007/003593 84 cM2 H2 C0 andN H2 (2-picolyloxy) (3-picolytoxy) (4-picolyloxy) a substituted pyridyl group selected from the group consisting of x. X' X' and N 5 (substituted 2-pyridyl) (substituted 3-pyridyl) (substituted 4-pyidyl) and a group of formula, H 10 wherein M is an alkali metal or alkaline earth metal and wherein X', Y', R 4 and R 5 are as defined in claim 8. 15

11. The pharmaceutical combination of claim 8, wherein X, Y, n, R1, R2, R3, R6, X' and Y' are set forth for each of the lysine-based compounds of formula I below: WO 2008/023273 PCT/IB2007/003593 85 D L. (PL-) X Y n R, R, R4 Ps Xr L RS I (PL-481) 4-4H 2 H 4 (HO)4(O) (C*Hs)CH CH-CO KoIbu Ss 2 (PL-482) 4-NH, H 4 (NaO),P(O) (CH)aCH CH4O-CO o WH" S.S 3 (PL-507) 4-NH, H 4 (HO)O() Nepaty-2-CM, CH,-CO MH S.S 4 (PL-498) 4-NH3 H 4 (HObP(O) Nephthyl--CH, 4-morphonin- bo-bAI HiH S.S CO 5 (PL-504) 4-N H 4 (HO)P(O) (COHahCH CH 3 CO Hb NH S.S e (PL-515) 4-NH, 3-F 4 (HO)hP(O) (C.HbhCH CH4O-CO Io-bu' HM S, 7 (PL-621) 4-NH, H 4 CHCO (C.H.)3CH CO-CO - HN S.S a (PL-520) 4-NH, H 4 3-PydIdy-CO (C.HehCH CH 2 O-CO MKH S.S 9 (PL-534) 4-NH 2 H 4 (CM)ANCKCO (CjH41C CHSO-CO WH S.S 10 (PL-630)4-NH H 4 (CHa)ZCHCH(N)4CO(Cs)hCH CHO-CO '3 ' HIH S.S 11 (PL-100)4-NH% H 4 H (UH,uC44 C4CO 40-bUtyl H/H 12 (PL-337) 4.N" 3-F 4 H CeHc)gCH C2O-CO t-u K" l

12. The pharmaceutical combination of any one of claims 8 to 11, wherein said drug which is affected by cytochrome P450 monoxigenase is selected from the group 5 consisting of Atazanavir (ATV), Lopinavir (LPV), Saquinavir (SQV), Amprenavir (APV), Nelfinavir (NFV) and Indinavir (IDV).

13. The pharmaceutical combination of any one of claims 8 to 12, wherein the ratio (w/w) of said lysine-based compound and said drug which is affected by 10 cytochrome P450 monooxigenase is about 4:1.

14. The pharmaceutical combination of any one of claims 8 to 13, wherein said cytochrome P450 monoxignease is CYP3A4.

15. The use of at least one lysine-based compound of formula I 15 0 H 2 OR, N H(CH2--N R 3 XLI R2 Y or a pharmaceutically acceptable salt thereof and a drug which is affected by cytochrome P450 monooxigenase in the manufacture of a drug for the treatment or prevention of an HIV infection or for treatment or prevention of AIDS, 20 WO 2008/023273 PCT/IB2007/003593 86 wherein n, X, Y, X', Y', R 1 , R 2 , R 3 , R 4 , Re and Re are as defined in claim 1; and wherein the ratio (w/w) of the lysine-based compound and the drug which is affected by cytochrome P450 monooxigenase is between about 4:1 and about 1:1. 5

16. A method of treating or preventing an HIV infection or of treating or preventing AIDS, the method comprising administering either the pharmaceutical composition as defined in claim 1, or the pharmaceutical combination as defined in claim 8, to 10 a mammal in need thereof.

17. A method of treating or preventing an HIV infection or of treating or preventing AIDS, which comprises administering a) a lysine-based compound of formula I 0 H 0 0 H 2 OR, j SN(C HR3 X-- R2 Y 15 wherein n, X, Y, X', Y', R 1 , R 2 , R 3 , R 4 , R 5 and Re are as defined in claim 1 or a pharmaceutically acceptable salt thereof, and b) one or more drugs which are affected by cytochrome P450 monoxigenase, 20 wherein said lysine-based compound is in an amount which is sufficient to reduce the metabolism of said one or more drugs which are affected by cytochrome P450 monoxigenase, and wherein the ratio (w/w) of said lysine based compound to said one or more drugs is between about 4:1 and about 1:1. 25

18. A method for improving the pharmacokinetics of a drug which is affected by cytochrome P450 monoxigenase, the method comprising administering to a WO 2008/023273 PCT/IB2007/003593 87 human in need thereof an amount of the lysine-based compound of formula I of claim 1 effective to inhibit cytochrome P450 monoxigenase and the drug which is affected by cytochrome P450 monoxigenase, wherein the ratio (w/w) of the lysine based compound to said drug is between about 4:1 and about 1:1.