MXPA00006973A

MXPA00006973A - Antivirals

Info

Publication number: MXPA00006973A
Application number: MXPA/A/2000/006973A
Authority: MX
Inventors: Christer Sahlberg; Rolf Noreen; Marita Hogberg; Per Engelhardt
Original assignee: Per Engelhardt; Hoegberg Marita; Medivir Ab; Rolf Noreen; Christer Sahlberg
Priority date: 1998-01-16
Filing date: 2000-07-14
Publication date: 2001-09-07

Abstract

Compounds of formula (I):wherein Rx is cyano or bromo;R1 is halo;R2 is C1-C3 alkyl, and pharmaceutically acceptable salts and prodrugs thereof have activity as antiretrovirals.

Description

ANTIVI RALES Technical Field This invention relates to the field of antivirals and in particular to VI H reverse transcriptase inhibitors. The invention provides novel compounds, pharmaceutical compositions comprising these compounds and methods for the inhibition of HIV using them.

BACKGROUND OF THE INVENTION Of the pharmacists who have shown clinically relevant activity in the inhibition of reverse transcriptase of VI H in the treatment of VI H, most are nucleoside analogues such as AZT, ddI, ddC and D4T. These nucleoside analogs are not as specific as desired and therefore have to be administered at relatively high dose levels. At these dose levels, nucleoside analogues tend to be rather toxic, limiting their long-term use. To overcome these problems of specificity and toxicity, several non-nucleoside inhibitors of HIV reverse transcriptase have been developed. For example, TIBO, a reverse transcriptase of Janssen, inhibits HIV at nanomolar concentrations and does not show any clinically significant toxicity. Both TIBO and non-nucleotide reverse transcriptase inhibitor nevírapina proceeded rapidly to phase I clinical trials in patients. However, it soon became apparent that these non-nucleoside inhibitors rapidly select HIV mutants in vivo that are resistant to the usual doses of the respective inhibitors. In the case of nevirapine, for example, after only four weeks of therapy, the virus isolated from the patient's serum was 1 00 times less sensitive to the drug compared to viruses isolated from untreated patients (Drug Design &Discovery 1 992 8 pp 255-263). A similar pattern emerged from other non-nucleoside RT inhibitors that have entered clinical trials, delavirdine (U-87201) from Upjohn and L-697661 from Merck, ie, that the promising in vitro activity has rapidly produced resistant HIV mutants. when it is administered in patients. Despite this disadvantage, nevirapine and delavirdine have recently been registered for clinical use, although limited to specific co-administration regimens in an attempt to delay the development of resistance. International Patent Application No. WO 95/06034 discloses a series of novel urea derivatives that exhibit good in vitro activity against the reverse transcriptase of VI H and a good inhibition of duplication of HIV in cell culture. However, the practical deployment of the compounds in WO 95/06034 is hindered by their poor pharmacokinetic performance. Additionally, as with many non-nucleoside reverse transcriptase inhibitors, the compounds presented in WO 95/06034 leave room for an improvement in the key parameter of the development of low resistance and a favorable pattern of activity against LV m utants. H generated by other antiviral regimens. A sheet by Óberg et al. at the 1995 ICAR in Santa Fe he exhibited, among other things, a racemic compound nominally within the above-mentioned WO 95/06034 and having the formula: At the beginning, the compound illustrated above was considered less interesting than thiourea variants having a phenyl ring containing methoxy / acetyl. However, it has now been discovered that an alternative substitution pattern manifests an improved resistance pattern compared to the compounds of the prior art, in conjunction with a good pharmacokinetic performance and a prolonged time with respect to resistance to the virus. The invention thus provides inhibitors that combine the superior specificity of non-nucleoside inhibitors with the clinical practicality that all inhibitors of the prior art lack.

BRIEF DESCRIPTION OF THE INVENTION According to the invention, compounds of the formula I are provided where R1 is halo; R 2 is C 1 Ca alkyl; Rx is cyano or bromine; and pharmaceutically acceptable salts and prodrugs of the same. The invention further provides pharmaceutical compositions comprising the compounds of the formula I and pharmaceutically acceptable carriers or diluents for the same. Additional aspects of the invention provide methods for the inhibition of VI H comprising the administration of a compound of formula I to a subject suffering from VI H. The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections. Under treatment conditions originated by VI H, the compounds of the formula I are preferably administered in an amount to achieve a plasma level of about 10 to 1000 nM and more preferably 1 00 to 500 nM. This corresponds to a proportion of doses, depending on the bioavailability of the formulation, in the order of 0.01 to 10 mg / kg / day, preferably 0.1 to 2 mg / kg / day. A typical dose rate for a normal adult will be from about 0.05 to 5 g per day, preferably from 0.1 to 2 g such as 500-750 mg, in units of one to four doses per day. A preferred subset of compounds within claim 1, particularly with respect to pharmacokinetics, has the structure IA: IA wherein R1 and R2 are as defined above, including pharmaceutically acceptable salts and prodrugs thereof. A further favored subset of compounds within Formula I, particularly with respect to the ease of forming prodrugs, comprises the compounds wherein Rx is bromine. Preferably R1 is chloro and more preferably fluoro. Suitable R2 groups include methyl, isopropyl, n-propyl and preferably ethyl. As described above, the cyclopropyl ring is in the cis configuration, allowing two enantiomers, 1S, 2S and 1R, 2R (respectively and denoted unconventionally 2R, 1S and 2S, 1R in SE 980016 -7 and SE 98001 1 3-4): Each of these enantiomers are potent antiretrovirals, although the different enantiomers can display very sharp differences in physiological properties. For example, the enantiomers, 1S, 2S, and 1R, 2R may show a different metabolism pattern within the P450 system. The 1S, 2S enantiomer of the compounds in which Rx is cyano is particularly preferred since it seems unique in being able to avoid the key components of the P450 system. Other retroviral agents, such as ritonavir VI H protease inhibitor, interact extensively with the P450 system, leading to an arrangement of undesirable physiological responses that include extensive alteration of the metabolism of other co-administered drugs. This is of particular interest with pharmacists administered for a chronic infection where patients can expect to take several pharmaceuticals for years, if not decades. Suitable prodrugs of the compounds of the formula I include those of the formula I I: wherein R1, R2 and Rx are as defined above, R3 is H, (CHm) nN R5R6; R4 is H, C, -C3 alkyl, (CHm) nNR5R6, (CHm) nC (= O) R5, (CHm) nOH, OR7, halo, CF3 or CN; or R3 and R4 together define a fused ring composed of 5 or 6 members having 0-2 hetero atoms and / or 0-2 unsaturated bonds and / or 0-2 substitutes; R5 is H, C1-C3 alky1, C (= O) R7, or a peptide of 1 to 4 am or acids; R6 is H, alkyl d -Ca; or R5 and R6 together define a ring composed of 5 or 6 members that have 0 or 1 additional atoms thereto and / or 0-2 unsaturated bonds and / or 0-2 substitutes; R7 is H, alkyl CrC, 2, (CHm) nN R5R6; X and its enclosing circle define a ring composed of 5 or 6 members having from 0 to 3 unsaturated bonds and / or from 0 to 3 hetero atoms selected from S, O and N; m is independently 1 or 2; n is independently 0, 1 or 2; and pharmaceutically acceptable salts thereof. The corresponding prodrugs of the compounds wherein Rx is chlorine, form a further aspect of the invention. The annular structure containing X, hereinafter referred to as the X-ring, can be saturated or have 1 -3 unsaturated bonds, including rings with an aromatic character. Preferred X rings include a cyclohexanyl or cyclohexenyl ring or more preferably a phenyl ring. Other preferred X-rings include morpholino or more preferably a pyridyl ring. Alternatively, the X-ring may define a ring composed of five members such as pentenyl or pyrrolole. Suitable fused ring systems for the X-ring in case R3 and R4 join to form a ring optionally containing hetero include ring systems of naphthyl, quinolyl, tetrahydroisoquinolyl, indolyl or benzimidazole. Suitable substitute rings for the X-ring in case R4 and R5 join to form a ring include morpholino and piperidino. These fused rings or substitutes can be optionally substituted with halo, halomethyl, amino such as (CHm) nNR5R6, C (= O) N R5R6, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C? .3 alkoxy C? _3 alkyl and the similar. The X-ring can be separated from the adjacent carbonyl element by a methylene or ethylene group which can be optionally substituted with substitutes such as halo, halomethyl, amino, amino methyl, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C1.3alkyl, C3_3alkoxy and the like. It is preferred that the X ring be adjacent to the carbonium. Preferably, the element represented by the annular system X, R3, R4 and, if present, R5-R7, has a certain basic character. This can be achieved by selecting an appropriately basic heterocycle such as the X ring, such as pyridyl or benzopyridyl. Alternatively or additionally, one or more of R3 to R7 may comprise a basic substitute such as a primary, secondary or tertiary amine, an amino acid, etc. The favored R3 and / or R4 groups include NH2, N (CH2) 2 and alkyl of NHCrC3, such as NHCH3 or NHCH2CH3. Preferably R3 is in the meta position relative to the carbonyl and its optional separator, especially when the ring containing X is phenyl or R3 is in the para position when the ring containing X is heteroaromatic, such as pyrid-3-yl. . The currently preferred value for p and / or n is zero, that is, the respective groups are absent. Preferred compounds of the invention include: (1S, 2S) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -yl) -urea, (1S, 2S) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-butyrylphenyl) -cycIopropyl] -N '- (5-cyanopyrid-2-yl) ) -urea, (1S, 2S) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) - urea, (1S, 2S) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) )-urea; (1S, 2S) -N- [c / 's-2- (2- (3-am inofen and Icarboni loxi) -6-fluoro-3-butyri [phenyl] -cyclopropyl] -N' - (5-cyanopyrid-2-yl) -u rea; (1S, 2S) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) )-urea; (1S, 2S) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyla) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) - urea; (1S, 2S) -N- [c / 's-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclic oppropyl] -N' - (5-cyan opi rid-2) -il) -urea; (1S, 2S) -N- [c / s-2- (2- (3-ethylamidophenolylcarbonyloxy) -6-f Iuoro-3-acetyl in il) -cyclopropyl] -N '- (5-cyanopyrid- 2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropy] -N '- (5-cyanopyrid-2-yl) - urea; (1S, 2S) -N- [c / s-2- (2- (3-dimethylmethanocarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyridyl) 2-yl) -urea; (1S, 2S) -N- [c.s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea; and pharmaceutically acceptable salts thereof. Other preferred compounds include (1S, 2S) -N- [c s-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fl uoro-3-propionylphenyl) -cyclopropyl] -N '- ( -cyanopyrid-2-yl) -urea; (1S, 2S) -N- [c / 's-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N' - (5-cyanopyridyl) 2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (6-met-lam-nopyrid-3-M carbonylloxy) -6-f-uoro-3-acetylphenyl) -cyclopropyl] -N ' - (5-cyanopyrid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid) -2-il) -urea; (1S, 2S) -N- [c / 's-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyriphenyl) -cyclopropyl] -N' - (5- cyanopyrid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -il) -urea; and pharmaceutically acceptable salts thereof. Other suitable compounds of the invention include: (1 R, 2 R) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1 R, 2R) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1 R, 2R) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1R, 2R) -N- [c / 's-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N' - (5-cyanopyrid-2-yl) -urea, (IR, 2R) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1 R, 2R) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1 R, 2 R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) - urea, (1R, 2R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) ) -urea, (1R, 2R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropi I] -N '- (5-cyan or pyrid-2-yl) -u rea, (1R, 2R) -N- [c s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- ( 5-cyanopyrid-2-yl) -urea, (1 R, 2R) -N- [c / 's-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1R, 2R) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) - cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, and pharmaceutically acceptable salts thereof. Other suitable compounds include; (1 R, 2R) -N- [c / s-2- (2- (6-methylamine-inopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyla) -cyclopropyl] -N '- (5-cyanopyrid- 2-yl) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -il) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-methalamide-inopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- ( 5-cyanopyrid-2-yl) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -il) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-cyanopyrid -2-l) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -il) -urea; and pharmaceutically acceptable salts thereof. Preferred compounds of the invention include (1S, 2S) -N- [cs-2- (2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- ( -bromopyrid-2-yl) -urea; (1S, 2S) -N- [c s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c.s-2- (2- (3-aminophenylcarbonyloxy) -6-fIuoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) - urea; (1S, 2S) -N- [cs-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (3-ethylamophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyridyl) 2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) )-urea; (1S, 2S) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) - urea; (1 R, 2R) -N- [c / s-2- (2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea; (1 R, 2R) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphen, incised propi I] -N '- (5-brom or pyrid-2) il) -u rea; (1 R, 2R) -N- [c / s-2- (2- (3-amhophenoxycarbonyloxy) -6-fluoro-3-acetyl in il) -cyclopropyl] -N'- (5-bromopyrid-2-yl) -urea; (1 R, 2 R) -N- [c / 's-2- (2- (3-amophenophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N' - (5-bromopyrid-2) -il) -urea; (1 R, 2 R) -N- [c / s-2- (2- (3-ethi-mofenac-Icarbonyl-oxy) -6-fluo-ro-3-propionylphenyl) -cyclopropyl] -N '- (5 -bromopyrid-2-yl) -urea; (1 R, 2R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) - urea; (1 R, 2R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) - urea; (1 R, 2 R) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenol) -cyclopropyl] -N '- (5-bromopyrid-2-yl) )-urea; (1 R, 2 R) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) - urea; (1 R, 2R) -N- [c / 's-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N' - (5-bromopyrid-2-yl) -urea; and their pharmaceutically acceptable salts. Additional preferred compounds include: (1S, 2S) -N- [c / s-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N ' - (5-bromopyrid-2-yl) -urea; (1S, 2S) -N- [c / 's-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N' - (5-bromopy) rid-2-yl) -urea; (1S, 2S) -N- [c / s-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2) -il) -urea; (1S, 2S) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenol) -cyclopropyl] -N '- (5 -bromopyrid-2-yl) -urea; (1S, 2S) -N- [c s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid- 2-yl) -urea; (1S, 2S) -N- [c / 's-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl] -N' - (5- Bromopyrid-2-yl) -urea; (1 R, 2 R) -N- [c / 's-2- (2- (6-methylaminopyrid-3-ylcarbonylloxy) -6-fluoro-3-propionylphenyl) -cycIopropyl] -N' - (5- Bromopyrid-2-yl) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-methylaminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2) -il) -urea; (1 R, 2R) -N- [c / 's-2- (2- (6-methylam-inopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylfenyl) -cyclopropyl] -N' - (5-bromopyrid -2-il) -urea; (1 R, 2 R) -N- [c s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2- il) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2) -il) -urea; (1 R, 2 R) -N- [c / s-2- (2- (6-aminopyrid-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropy] -N '- (5-bromopyrid-2) -il) -urea; and pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the formula I include salts of organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic and succinic acids, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toesulfonic acid; and inorganic acids such as hydrochloric, hydroiodic, sulfuric, phosphoric and sulfamic acids. In keeping with the usual practice of VI H inhibitors, it is advantageous to co-administer one to three additional antivirals to provide synergistic responses and to ensure complementary resistance patterns. Such additional antivirals may include AZT, ddI, ddC, D4T, 3TC, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, foscarnet, hydroxyurea, HBY 097 from Hoescht-Bayer, efavirenz, trovirdine, nevirapine, delavirdine, PFA, H2G , ABT 606, DMP-450, loviride, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX 478), nelfinavir and the like, typically at molar proportions reflecting their respective activities and bioavailabilities. In general, such a ratio will be of the order of 25: 1 to 1: 25, relative to the compound of formula I. Although it is possible for the active agent to be administered alone, it is preferable that it be present as part of a pharmaceutical formulation. Such a formulation will comprise the active agent defined above together with one or more acceptable carriers and optionally other therapeutic ingredients. The vehicle (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in the form of unit doses, for example, prolonged-release tablets and capsules and may be prepared by any method well known in the art of pharmacy. Such methods include the step of associating the active agent defined above with the vehicle. In general, the formulations are prepared by conducting in uniform and intimate association to the active agent with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations of oral administration in the present invention can be presented as discrete units such as capsules, solid capsules or tablets, each containing a predetermined amount of the active agent; as a powder or granules; as a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an emulsion of oil in water liquid or an emulsion of water in oil liquid and as a bolus, etc. With regard to compositions for oral administration (for example, tablets and capsules), the suitable term vehicle includes carriers such as common excipients, for example, binding agents, for example, rockrose, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; filling materials and vehicles, for example, corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metal stearates, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, raspberry flavoring or the like may also be used. It may be desirable to add a coloring agent to make the dosage form easily identifiable. The tablets may also be covered by methods that are well known in the art. Convenient vehicles for an oral dose include liquid formulations in the form of solutions, suspensions or emulsions, optionally encapsulated or otherwise presented in dosage unit form in a conventional manner. Flavored formulations include acacia / TWEEN / water, TWEEN / water, propylene glycol, vegetable oil (such as peanut, safflower, olive and the like) with 1-20-20% ethanol, vegetable oil / MGM from Capmul, MCM from Capmul / propylene glycol, methyl / water cellulose, vegetable oil / monoester of glycerol stearoyl, vegetable oil / mono-unsaturated fatty acid ester of g licerol and the like. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine, the active agent in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersant. The molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be covered or labeled and formulated so as to provide a slow or controlled release of the active agent. Formulations suitable for topical administration include lotions comprising the active agent in a flavored base, typically sucrose and acacia or tragacanth; pills comprising the active agent in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active agent in a suitable liquid vehicle. Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the active agent and a pharmaceutically active carrier. An exemplary topical delivery system is a transdermal patch containing the active agent. Other topical formulations include antiseptic plugs that release the active agent on the skin prior to invasive procedures such as injection or capillary blood sampling. Such plugs neutralize the VI H in the blood or serum that emanates from the invasive procedure, thus helping to prevent the transfer of HIV to health care workers through accidents with needle punctures. Such plugs may comprise a sterile surgical gauze bearing immersed in a solution of the active agent in a volatile solvent such as ethanol and individually packaged in a sealed pouch. Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa butter or a salicylate. Other vaginal presentations may be presented as tampons, creams, gels, pastes, foams or spray formulations that contain, in addition to the active agent, such vehicles known in the art as appropriate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size of, for example, in the range of 20 to 500 microns, which is administered in the manner in which it is used. takes the sniffing, that is, by rapid inhalation from a dust container held near the nose. Suitable formulations wherein the vehicle is a liquid for administration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, regulators, bacteriostases and solutes which become isotonic to the formulation with the blood of the proposed recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit dose or multiple dose containers, for example, sealed poly bags or flasks, and can be stored in a freeze-dried condition (lyophilized) that requires only the addition of the sterile liquid vehicle, eg, water for injection, immediately before use. The extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. A further aspect of the invention provides methods for the preparation of the compounds of Formula I, in particular, the cis enantiomers, which comprise the reinstallation of Curtius of a compound of the formula: followed by the coupling of a compound of the formula and deprotection, wherein R1, R2 and Rx are as defined above and PG is a hydroxy protecting group. The methods of the invention may further comprise the step of acylation with an activated compound of the formula lll: wherein R, R, X and n are as defined above but are optionally protected and R8 is hydrogen or a conventional activating group. Alternatively, the method of the invention may further comprise the alkylation step with a compound of the formula I or the: Illa where n, R3, R4 and X are as defined above, but where the substitutes of exposed amine, hydroxy, etc. , they are protected with conventional protective groups. The enantiomeric compounds of the formula I can therefore be prepared by the reaction of the following scheme: OH 'XJ The above scheme illustrates the preparation of a compound (1S, 2S) of the invention wherein Rx is cyano, R1 is F and R2 is ethyl, but the corresponding methodology is applicable to the other variants of Rx, R1 and R2. The chiral ligand indicated for the fourth step can comprise, for example, a compound of the formula: To prepare the 1R, 2R enantiomer, the chiral projected image ligand is used. Alternatively, the chiral ligand can be omitted in order to form the racemate. The prodrugs of the formula I I wherein p is 0 can be synthesized by the acylation of a compound of the formula I with an activated compound of the formula 11, Rd R «lll wherein R3, R4, X and n are as defined above but optionally protected and R8 is hydrogen or a conventional activating group. The activated compounds of Formula I include the acid halide, acid anhydride, activated acid ester or the acid in the presence of a coupling reagent such as dicyclohexylcarbodiimide. Representative activated acid derivatives include acid chloride, mixed anhydrides derived from formic and acetic acid, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, esters derived from N-hydroxysuccinamide, esters derived from N-hydroxyphthalimide, esters derived from N-hydroxy-5-norbornene-2,3-dicarboxamide, esters derived from 2,4,5-trichlorophenol and the like. Suitable optional protecting groups for the compounds of the formula I, especially any constitutive amine, include those groups proposed to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. The commonly used N-protecting groups are set forth in Greene, "Protective Groups in Organic Syntheses" (John Wiley &Sons, New York, 1981), which is incorporated herein by reference. Protecting groups of N include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyl oxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, -methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, a, a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, ben ci h id I oxycarbonyl, t-butoxycarbonyl, di iso propyl methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-m-ethoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz). The acylation is carried out under conventional esterification conditions such as DMAP and DCC in a solvent such as dimethylformamide or pyridine. Optional protecting groups can be removed with conventional techniques as discussed above in Greene, such as TFA, HCI (aqueous) / dioxane or hydrogenation in the presence of a catalyst to give the compound of the formula I I. The compounds of the formula I I, wherein p is 1, can be prepared by the reaction of a compound of the formula I 1 with iodochloromethane or dichloro / iodochloromethane mixed under conventional alkylation conditions to form a compound of the formula I: R < where n, R3, R4 and X are as defined above, but where the substitutes of exposed amine, hydroxy, etc. , they are protected with conventional protective groups. The compound of the formula Il is then preferably converted to the corresponding iodine derivative by the reaction with Nal, followed by coupling to the compound of the formula I, typically under basic conditions, such as an organic solvent containing sodium hydride.

DETD DESCRIPTION OF THE INVENTION The aspects of the invention will now be illustrated by way of example only with respect to the following non-limiting Examples and the Drawings in which: Figure 1 illustrates the rate of development of resistance against time for a compound of the invention compared to a prior art compound, as described in Biological Example 2; Figure 2 illustrates the time versus plasma levels after oral administration to rats, of a compound of the invention or a compound of the prior art, as described in Biological Example 5; Figure 3 illustrates kinetics for the reverse transcriptase of a compound of the invention as compared to a prior art compound, as tested with the surface plasmon resonance methodology, as described in Biological Example 10.

Preparation of Intermediate Compounds EXAMPLE 1 3-1,1- (Ethylenedioxy) propi II -6-f Ioro-2-methoxy benzaldehyde To a solution of 3-fluorophenol (22.4 g, 0.2 mol), pyridine (24 ml, 0.3 mol) and dichloromethane (200 ml) at room temperature was added 20 ml (0.225 mol) of propionyl chloride over a period of 5 min. The reaction was exothermic. The solution was stirred for another 30 m in. After addition of dichloromethane, the organic phase was rinsed with saturated NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo. 33.8 g (1 00%) of 3-fIuoro-1-propionyloxybenzene were obtained. This compound reacted with 33.3 g (0.25 mol) of AICI3 at 1 50 ° C for a period of 10 min. After careful careful quenching with water, the reaction mixture was extracted three times with ether. The ether phase was dried (MgSO) and evaporated to give 29.5 g (0.1 76 mol, 88%) of re-arranged product.

This intermediate compound was dissolved in 200 ml of acetone and K2CO3 (42, 0.3 mol) and Mel (25 ml, 0.4 mol) were added. The reaction mixture was heated at 40 ° C for a period of 12 h. The reaction mixture was filtered and the acetone was evaporated. The residue was dissolved in ether and the ether phase was rinsed with a 0.5 M solution of NaOH and water. It was dried (MgSO 4) and evaporation gave 31.2 g (0.1 7 mol, 86% yield for the three stages) of 4-fluoro-2-methoxypropiophenone. To a solution of 4-fluoro-2-methoxypropiophenone (31.2 g, 0.1 71 mol), ethylene glycol (0.5 ml, 0.188 mol) in benzene (300 ml) was added 1 g of p-toluenesulfonic acid. The reaction mixture flowed again in a Dean-Stark apparatus for about 12 h. After cooling, the organic phase was rinsed several times with 1 M NaOH solution, and dried (Na2SO4 and K2CO3). The solvent was evaporated and approximately 38 g of the acétalo were obtained. The purity according to capillary GC was 88% and the impurity was basically unreacted acetone. To a solution of the acetate in THF (450 ml) at -65 ° C and under nitrogen were added, dropwise, 1 28 ml (0.32 mol) of 2.5 M n-BuLi. Although the temperature was maintained at about -65 ° C, a solution of DMF (25 ml, 0.32 mol) in THF (50 ml) was added. The reaction mixture was allowed to slowly reach room temperature and according to GC no starting material was left after about 30 min. After another hour, the reaction mixture was quenched with saturated NH 4 Cl solution and extracted three times with ether. After drying (Na2SO4), the residue was purified on a column of silica gel (Merck silica gel 60, particle size 0.04-0.063 mm), levigated with EtOAc 1 and hexanes 9 to give 10 g (25%) ) of the main compound. 1H NMR (CDCl 3) d 0.85 (t, eH), 2.1 (q, 2H), 3.8-3.95 (m, 2H), 3.97 (s, 3H), 4.0-4.15 (m, 2H), 6.9 (t, 1H ), 7.7-7.8 (m, 1H), 10.4 (s, 1H).

EXAMPLE 2 3-f1, 1- (Ethylenedioxy) propyl-6-fluoro-2-methoxystyrene To a suspension of methyltriphenylphosphonium bromide (14.3 g, 40 mmol) in THF (250 ml) at room temperature and under nitrogen, 16 g. ml (40 mmol) of 2.5 M n-BuLi. To the nearly obtained solution was then added 3- [1,1- (ethylenedioxy) -propyl] -6-fluoro-2-methoxybenzaldehyde (10 g, 39.5 mmol) in THF (30 ml). The reaction mixture was then stirred at room temperature for 2 h and emptied into a mixture of hexanes and saline. The organic phase was rinsed twice with saline and once with water. After evaporation of the solvent, the residue was filtered through a tunnel filled with alumina (aluminum oxide 90 acc Brockmann from Merck) and levigated with EtOAc 1 and hexanes 9 in order to remove the triphenylphosphonium oxide formed. Evaporation of the organic solvent gave a residue which was finally purified on silica gel, eluting with EtOAc 1 and hexanes 9 to give 6.9 g (705) of the main compound with a purity of 94.5% as determined by capillary GC. 1 H NMR (250 Mhz, CDCl 3) d 0.85 (t, 3 H), 2.1 (q, 2 H), 3.8 (s, 3 H), 3.8-3.95 (m, 2 H), 4.0-4.1 (m, 2 H), 5.55- 5.65 (m, 1H), 5.95-6.05 (m, 1H), 6.7-6.85 (m, 2H), 7.3-7.4 (m, 1H).

EXAMPLE 3 (1S, 2R) -c / s-2- (6-Fluoro-2-methoxy-3-propionylphenyl) cyclopropacarboxylic acid The ethyl ester of (1S, 2R) -c / 's- acid was prepared. 2- [3- (1, 1-ethylenedioxy) ethyl-6-fluoro (2-methoxy-phenyl) -cyclopropylcarboxylic acid from 3- [1,1- (ethylenedioxy) propyl] -6-fluoro-2-methoxystyrene ( 19.4 g, 69 mmol) and ethyl diazoacetate (29 ml, 275 mmol) was obtained by using an asymmetric cyclopropagation reaction catalyzed by Cu (l) triflate (679 mg, 1.35 mmol) and the chiral ligand ([2.2 ' -sopropylidenes ((4R) -4-.erf-butyl-2-oxazoline)] (794 mg, 2.1 mmol), as generally described by Evans et al., In J. Am Chem. Soc. 1991, 113, 726- 728. After chromatography on silica gel, 9.4 g (40.5%) of the ethyl ester was obtained.The enantiomeric excess was 99% as determined by HPLC on a chiral column. The ester was dissolved in 150 ml of dioxane and 30 ml of 6M HCl was added.The reaction mixture was stirred overnight and divided into ether and saline The solvent was evaporated to give 19 g of crude product. This product was dissolved in methanol (250 ml) and water (75 ml) and 6 g (250 mmol) of LiOH were added. The reaction mixture was heated to 90 ° C for 24 h and most of the solvent was evaporated. The remaining mixture was acidified and extracted three times with dichloromethane. Evaporation of the solvent produced 11.2 g of the main compound. 1 H-NMR (250 MHz, CDCl 3) d 1.15 (t, 3 H), 1.59 (t, 2 H), 2.10-2.17 (m, 1 H), 2.22-2.32 (m, 1 H), 2.91 (q, 2 H), 3.80. (st, 3H), 6.82 (t, 1H), 7.44-7.50 (m, 1H), 11.30 (broad s, 1H).

Example 4 (1R, 2S) -cs-2- (6-fluoro-2-methoxy-3-propionylphenyl) cyclopropylcarboxylic acid This compound was prepared from 3- [1,1- (ethylenedioxy) propyl] -6-fluoro -2-methoxystyrene as described for the acid in Example 3. The chiral ligand that was used was 2,2'-isopropylidene bios [(4S) -4-.erf-butyl-2-oxazoline]. 1 H NMR (250 Mhz, CDCl 3) d 7.48 (q, 1 H), 6.84 (t, 1 H), 3.82 (s, 3 H), 2.93 (q, 2 H), 2.29 (q, 1 H), 2.14 (q, 1 H) , 1.60 (m, 2H), 1.16 (t, 3H).

Preparation of Compounds of Formula I and II Example 5 (+) N - ["cis-2- (2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl-N '- (5-cyanopyrid-2-yl) -urea A solution of 3- [1, 1- (ethylenedioxy) propyl] -6-fluoro-2-methoxystyrene (32.4 g, Example 2) and copper bromide-dimethyl sulfide complex (0.30 g) in dichloroethane (200 ml) was heated to 80 ° C under nitrogen Ethyl diazoacetate (54 ml) in dichloroethane (600 ml) was added for 7 h After the addition was complete, the heating was turned off After 16 h, the solvent was evaporated and the residue it was purified on silica gel, eluted with ethyl acetate and hexanes to give the cis-ester (6.5 g) The cis-ester (3.7 g, 10.9 mmol) was dissolved in ethanol (20 ml) and KOH was dissolved (1.8 g). g, 32.7 mmol) in water (10 ml). The solutions were combined and heated to reflux for 3 h. Water (30 ml) was added and the solution was rinsed twice with hexanes (20 ml). The water phase was cooled in an ice bath and acidified with dilute HCl. The solution was extracted three times with toluene. The toluene phase was dried (MgSO4) and evaporated to give 1.9 g of (±) c / s-2- [3- (1,1-ethylenedioxypropyl) -6-fluoro-2-methoxyphenyl] cyclopropylcarboxylic acid. Triethylamine (59 μL, 0.43 mmol) and diphenylphosphoryl azide (92 μL, 0.43 mmol) were added to a solution of the acid (120 mg, 0.39 mmol) in dry toluene. The solution was stirred at room temperature for 1 h and then heated to 120 ° C. After 1 h, 2-amino-5-cyanopyridine (51 mg, 0.43 mmol) was added. The heating was maintained for an additional 3 h. After 16 h, the solvent was evaporated, the residue was dissolved in dichloromethane (30 ml), rinsed with dilute HCl, dried (MgSO4) and evaporated to give 152 mg. This product was dissolved in dioxane and HCl (6N, 1 ml) was added. After 2 h, the mixture was evaporated, dissolved in dichloromethane (25 ml), rinsed with water (10 + 10 ml), dried (MgSO4) and evaporated to give 117 mg. The residue was purified on silica gel, eluting with ethyl acetate and hexanes to give 37 mg of 2-methoxyphenyl intermediate. A 1M solution of boron tribromide in dichloromethane (194 μL, 0.194 mmol) was added to a solution of the intermediate of 2-methoxyphenyl (37 mg, 0.097 mmol) in dichloromethane at -60 ° C. After 10 min, the cooling bath was removed and stirring continued for 2 h. The solution was diluted with dichloromethane, rinsed with dilute NaHCO3 and water, dried (MgSO4) and evaporated. The residue was recrystallized from MeCN to give 17 mg of the main compound. 1 H-NMR (250 Mhz, DMSO-d 6) d 10.7-1.16 (m 4 H), 1.41-1.50 (m, 1 H), 1.91-2.01 (m, 1 H), 3.06-3.19 (m, 3 H), 6.86 (dd) , 1H), 7.43 (d, 1H), 7.80-7.90 (m, 1H), 7.97-8.08 (m, 2H), 8.32 (d, 1H), 9.83 (s, 1H), 13.2 (d, 1H).

Example 6 (1R, 2R) -N- (c / s-2- (6-fluoro-2-h idroxy-3-propionylphenyl, -cyclopropyl) -N '- (5-cyanopyrid) 2-yl) -urea Triethylamine (0.85 mL, 6.1 mmol) and diphenylphosphoryl azide (1.72 g, 6.1 mmol) were added to a solution of the acid prepared in Example 4 (1.47 g, 5.5 mmol) in dry toluene (15 mL The solution was stirred at room temperature under argon for 30 min and then heated to 120 ° C. After 15 min, a solution of 2-amino-5-cyanopyridine (0.99 g, 8.9 mmol) in DMF ( 3 mL) and heating continued for 4 h.Toluene was evaporated and the mixture was diluted with diethyl ether (100 mL) and ethyl acetate (50 mL) and rinsed with 1M HCl, H 2 O and saline. The organic layer was dried (Na2SO4) and concentrated The residue was purified by flash column chromatography on silica gel by levigation with ethyl acetate / n-hexane 1:10 to 1: 1 to give 1.6 g (66%) of the intermediate product of 2-methoxyphenium. of 1M boron trichloride in CH2Cl2 (11.0 mL, 11.0 mmol) was added to a solution of the intermediate of 2-methoxyphenyl (1.40 g, 3.66 mmol) in CH2Cl2 (80 mL) at -72 ° C under argon. After 10 min, the cooling bath was removed and stirring continued for 1 h 15 min. The solution was diluted with CH2Cl2 and rinsed with an aqueous solution of NaHCO3, H2O and saline. The organic layer was dried (Na2SO) and concentrated. The precipitate of acetonitrile / H 2 O 1: 1 gave 0.62 g of pure master compound. The residue was concentrated and chromatography by levigation with ethyl acetate / n-hexane 1:10 to 1: 1 and ethyl acetate and then crystallization from acetonitrile gave 0.2 g of the main product. The production was 0.82 g (61%). The ee was 95% as determined by HPLC on a chiral column. [a] d22-171.2 ° (c = 0.50, CH2Cl2). 1 H NMR (250 Mhz, CDCl 3) d 13.35 (d, 1 H), 10.02 (br s, 1 H), 9.40 (br s, 1 H), 8.11 (s, 1 H), 7.71 (m, 2 H), 7.00 (m, 1H), 6.61 (t, 1H), 3.21 (m, 1H), 3.01 (q, 2H), 2.03 (m, 1H), 1.55 (m, 1H), 1.29 (m, 4H).

Example 7 (1R, 2R) -N-rcs-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl-N '- (5-cyanopyrid-2-yl) -urea A solution of the compound described in Example 6 (1.64 g, 4.4 mmol), protected 3-aminobenzoic acid with BOC (1.6 g, 6.6 mmol) and 4-dimethylaminopyridine (269 mg, 2.2 mmol) in 20 ml of dichloromethane and 10 ml of DMF at room temperature and under argon were added 1.36 g (6.6 mmol) of DCC. The reaction mixture was stirred for 24 hrs. The solvent was carefully evaporated and the residue was purified on silica gel using hexanes / ethyl acetate 1: 1 as solvent to give 2.6 g of BOC-protected main product. This product was added to 75 ml of trifluoroacetic acid at 0 ° C. The mixture was then stirred at 0 ° C for 1 hour. The solvent was carefully removed in vacuo. The residue was divided between ethyl acetate and saturated potassium carbonate. The organic phase was dried and evaporated. The residue was purified on a silica gel column using 4: 1 ethyl acetate / hexanes as eluent to give 1.03 g of the free base of the main compound. This intermediate compound was treated with 3 ml of 1M HCl in ether and 0.84 g of the main compound was achieved. The purity of HPLC was about 97%. 1H-NMR amine released (250 MHz, CDCl 3) d 1.09 (t, 3H), 1. 2-1.3 (m, 1H), 1.4-1.5 (m, 1H), 1.95-2.00 (m, 1H), 2.83 (q, 2H), 3.15-3.25 (m, 1H), 3.85 (s, 2H), 6.90 (dd, 2H), 7.09 (t, 1H), 7.20-7.27 (m, 1H), 7.44-7.46 (m, 1H), 7.56 (dd, 1H), 7.65-7.77 (m, 2H), 8.13 ( d, 1H), 9.1 (broad s, 1H), 9.6 (broad s, 1H).

Example 8 (1S.2S, -N- (cs-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- (5-cyanopyrid-2-yl) -urea Triethylamine (670 μL, 4.8 mmol) and diphenylphosphoryl azide (1.05 mL, 4.9 mmol) were added to a solution of the acid prepared in Example 3 (1.2 g, 4.5 mmol) in dry toluene (10 mL) under nitrogen. The solution was stirred at room temperature for 30 min and then heated to 120 ° C. After 15 min., a solution of 2-amino-5-cyanopyridine (0.80 g, 6.7 mmol) in dimethylformamide (1.5 ml) was added and heating continued for 4 h. The solution was diluted with diethyl ether and rinsed with 1M hydrochloric acid. The organic layer was dried (MgSO) and concentrated. The residue was purified by flash chromatography on silica gel (gradient start with n-hexane / ethyl acetate 1: 1, terminated with pure ethyl acetate) to give a non-pure 2-methoxyphenyl derivative (0.93 g). The chromatography was repeated, as described above, gave the pure 2-methoxyphenyl derivative (0.70 g, 41%). A solution of 1M boron trichloride in methylene chloride (5.5 ml, 5.5 mmol) was added to a solution of the intermediate of 2-methoxyphenyl (700 mg, 1.8 mmol) in methylene chloride at -60 ° C. After 10 min the cold bath was removed and stirring continued for 2 h. The solution was diluted with methylene chloride and rinsed with an aqueous solution of sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated and the residue was purified by flash chromatography on silica gel (gradient, n-hexane: ethyl acetate 2: 1, 1: 1, 1: 2, ethyl acetate: methanol (8: 1) giving the main compound (500 mg, 74%). [A] D22 + 165.0 ° (C = 0.5, CH2Cl2) .1H-NMR (DMSO-d6) d 1.10-1.16 (m, 4H, CH3 , CH2-cyclopropyl), 1.45 (dd, 1H, CH2-cyclopropyl), 1.96 (q, 1H, CH, cyclopropyl), 3.10-3.19 (m, 3H, CH-cyclopropyl, CH2), 6.85 (t, 1H, Ar ), 7.43 (d, 1H, Ar), 7.86-8.07 (m, 3H), 8.32 (s, 1H), 9.83 (s, 1H), 13.22 (s, 1H, Ar.OH).

Example 9 (1S, 2S) -N-rc / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl-N '- (5-cyanopyrid-2-) il) -urea Beginning with the compound described in Example 6 and by using the method described in Example 7 the main product was given as the hydrochloride salt. 1 H-NMR (250 Mhz, DMSO-d 6) d 0.94 (t, 3 H), 0.9-1.0 (m, 1 H), 1.3-1.4 (m, 1 H), 1.85-1.95 (m, 1 H), 2.91 (q, 2H), 3.05-3.15 (m, 1H), 7.4-7.5 (m, 2H), 7.6-7J (m, 1H), 7.9-8.1 (m, 5H), 8.08 (d, 1H), 9.85 (s, 1 HOUR).

Example 10 (1S, 2S) -N- (cs-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- (5-bromopyrid-2-yl) -urea Acid (1S, 2R) -c / 's-2- (6-fluoro-2-methoxy-3-propionylphenyl) -cyclopropylcarboxylic acid 83.0 g, 11.3 mmol), triethylamine (1.58 mL, 11.3 mmol) and diphenylphosphoryl azide (2.44 mL, 11.3 mL) ) were dissolved in dry toluene (8 ml) at room temperature and under an argon atmosphere. The reaction mixture was stirred at room temperature for a period of 30 min, after which the temperature was increased to 120 ° C and remained so for another 15 min. Then 2-amino-5-bromopyridine (2.08 g, 12 mmol) was added and the reaction mixture was stirred at 120 ° C for 2.5 hrs. Benzene and 1M HCl solution were added and the organic phase was evaporated. The residue was purified on silica gel using hexanes: ethyl acetate 1: 1 as the eluent. Appropriate fractions were collected and 5.0 g of (1S, 2S) -N- (c / s-2- (6-fluoro-2-hydroxy-3-propionyl-phenyl) -cyclopropyl) -N '- (5 -bromopyrid-2-yl) -urea. This compound was dissolved in dichloromethane (100 ml) and the solution was kept under argon and cooled to -65 ° C. Boron trichloride (30 ml of a 1M solution in dichloromethane, 30 mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Dichloromethane and saturated sodium bicarbonate were added. The organic phase was evaporated and the residue was purified on silica gel using 9: 1 ethyl acetate: methanol as the eluent. 1.96 g (41%) of the main compound were obtained. Analysis: Calculated: C 51.2, H 4.1, N 9.9. Found: C 51. 5, H 3.7, N 9.5. Mp: 198-199 ° C. [] D22 + 149.8 ° (c = 0.50, CH2Cl2) 1 H-NMR (250 Mhz, CDCl 3) d 1.28 (t, 3 H), 1.52-1.62 (m, 2 H), 1.94-2.05 (m, 1 H), 2.97- 3.06 (m, 2H), 3.17-3.20 (m, 1H), 6.60 (t, 1H), 6.76 (broad s, 1H), 7.57 dd, 1H), 7.67-7.72 (m, 1H), 7.83 (s broad , 1H), 8.53 (broad s, 1H), 13.32 (d, 1H).

Example 11 (1R, 2R) -N- (c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- (5-bromopyrid-2-yl) -urea performed an asymmetric cyclopropagation reaction, as described in Example 3, on the compound described in Example 2 by the use of the chiral ligand 2,2'-isopropylidenebis (4S) -4-.er.-butyl-2- oxazoline (commercially available from Aldrich). The obtained (1R, 2S) -c / s-2- (6-fluoro-2-methoxy-3-propionylphenyl) -cyclopropylcarboxylic acid was then used in a manner analogous to Example 10 to give the main compound. 1 H-NMR (250 MHz, DMSO-d 6) d 1.05-1.15 (m, 1H), 1.12 (t, 3H), 1.40-1.50 (m, 1H), 1.90 (q, 1H), 3.00-3.10 (m, 1H), 3.12 (q, 2H), 6.82 (t, 1H), 7.18 (d, 1H), 7.78 (dd, 1H), 7.88 (broad s, 1H), 7.95-8.05 (m, 1H), 9.41 ( s broad, 1H), 13.20 (s, 1H). [a] D22-158.8 ° (c = 0.50, CH2Cl2).

Example 12 (1S, 2S) -N-, cs-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-proponylphenyl) -cyclopropyl-N '- (5-bromopyrid-2-yl) - urea To a solution of the compound of Example 10 (633 mg, 1.5 mmol), protected 3-aminobenzoic acid with BOC (475 mg, 2 mmol) and 4-dimethylaminopyridine (123 mg, 1 mmol) in 20 mL of dichloromethane: DMF 1: 1 at room temperature and under argon, 415 mg (2 mmol) of DCC was added. The reaction mixture was stirred for 36 hrs. The solvent was carefully evaporated and the residue was purified on silica gel using hexanes: ethyl acetate 1: 1 as the solvent to give 811 mg of BOC-protected main product. This product was dissolved in dioxane (20 ml) and 10 ml of 6M HCl was added and the mixture was stirred overnight. The solvent was carefully removed in vacuo. The residue was treated with ethanol and ether and 255 mg of the main product was obtained as the HCl salt. The purity of HPLC was about 93%. 1 H-NMR (250 MHz, CD3OD) d 1.15 (t, 3H), 1.3-1.4 (m, 1H), 1.5-1.6 (m, 1H), 2.05-2.15 (m, 3H), 3.04 (q, 2H), 3.23-3.27 (m , 1H), 7.16 (d, 1H), 7.34 (t, 1H), 7.85-7.93 (m, 2H), 8.05 (dd, 1H), 8.19 (broad d, 1H), 8.26 (broad s, 1H), 8.35-8.37 (m, 1H), 8.42-8.46 (m, 1H).

Example 13 (1S, 2S) -N-rc / s-2- (2- (3-L-alanylamophenolylcarbonyloxy) -6-f luoro-3-propionylphenyl) -cyclopropyl-N '- (5-bromopyrid- 2-yl) -urea The starting compound, BOC protected 3-L-alanylaminobenzoic acid, was prepared from 3-aminobenzoic acid protected with TCE by the use of standard chemistry, see for example "The Peptide Synthesis Practice" of Bodanszky, 2nd Edition, Springer. This compound reacted with the compound of Example 10, as described in Example 12, to give the main product as the HCl salt. 1 H-NMR (250 MHz, liberated amine, CDCl 3) d 1.10 (t, 3H), 1.15-1.25 (m, 1H), 1.4-1.5 (m, 1H), 1.42 (d, 2H), 1.76 8s broad, 2H ), 1.88-1.97 (m, 1H), 2.84 (q, 2H), 3.1-3.2 (m, 1H), 3.59-3.67 (m, 1H), 6.78 (d, 1H), 7.09 (t, 1H), 7.85-7.93 (m, 2H), 8.08 (d, 1H), 8.11 (s, 1H), 8.29 (s broad, 1H), 9.05 (s broad, 1H), 9.70 (s broad, 1H).

Example 14 (1S, 2S) -N-. { c / s-2-r6-fluoro-3-propionyl-2- (4-pyridinylcarbonyl) phenyl-cyclopropyl, -N '- (5-bromopyrid-2-yl) urea In a manner analogous to Example 12, the product of Example 10 was condensed with isonicotinic acid to give the main product as the HCL salt. H-NMR (250 MHz, CD3OD) d 9.26 (d, 2H), 8.83 (d, 2H), 8.14 (m, 2H), 8.04 (dd, 1H), 7.39 (t, 1H), 7.10 (d, 1H) ), 3.38 (m, 1H), 3.08 (m, 2H), 2.15 (m, 1H), 1.62 (m, 1H), 1.38 (m, 1H), 1.13 (t, 3H).

Example 15 (1S.2S.-N-1c / s-2-r2- (3-dimethylam inofen-1-ylcarbonyloxy) -6-f-3-propionylphenyl-cyclopropyl} -N '- (5-bromopyrid- 2-yl) urea In a manner analogous to Example 12, the product of Example 10 was condensed with 3-dimethylaminobenzoic acid to give the main product as the HCL salt.1H-NMR (250 MHz, CD3OD) d 8.61 (s, 1H), 8.45 (d, 1H), 8.15-8.03 (m, 4H), 7.92 (t, 1H), 7.34 (t, 1H), 7.10 (d, 1H), 3.48 (s, 6H), 3.28 (m , 1H), 3.00 (m, 2H), 2.11 (m, 1H), 1.58 (m, 1H), 1.38 (m, 1H), 1.14 (t, 3H).

Example 16 (1S, 2S) -N-Fc.s-2- (2- (3-L-amnomethylbenzoyloxymethyloxy) -5-fluoro-3-propionylphenyl) -cyclopropyl-N '- (5-bromopyrid-2- il) -urea The 3-t-butoxycarbonylamidomethylbenzoic acid was treated with a solution of tetrabutyl ammonia hydroxide (1 M in MeOH) at a pH of 9 and evaporated. The residue was dissolved in dichloromethane and treated with chloroiodomethane overnight. The solution was rinsed with water and evaporated to obtain crude 3-t-butoxycarbonylaminoethylbenzoyloxymethylchloride. This material reacted with the sodium salt of Example 10 (prepared with sodium hydride in DMF) with a little sodium iodide as catalyst. After 2 hours of reaction, the solution was quenched with acetic acid and diluted with dichloromethane, rinsed with water and evaporated. The crude product was purified on silica gel by levigation with ethyl acetate / hexane 1: 2 and the pure material was treated with trifluoroacetic acid and evaporated to obtain the trifluoroacetate salt of the main compound as a solid. 1 H NMR (CDCU) d 1 .1 (t, 3 H), 1 .3-1 .5 (m, 2 H), 2.2 (q, 1 H), 2.9 (m, 2 H), 3.2 (bs, 1 H ), 4.2 (s, 2H), 5.9 (q, 2H), 6.8 (d, 2H), 7.0 (t, 1 H), 7.3-8.1 (m, 9H).

Example 17 (1S, 2S) -N- (c / 's-2- (2- (3-amino-4-methylbenzoyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl) -N' - (5- Bromopyrid-2-yl) -urea (1S, 2S) -N- (c / 's-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyrid- 2-yl) -urea of Example 10 was condensed with 3-t-butoxycarbonylamido-4-methylbenzoic acid according to the procedure in Example 12. The product was treated with trifluoroacetic acid and evaporated to obtain a trifluoroacetic salt of the main compound as a solid. 1H NMR (CDCU) d 1.1 (t, 3H), 1.3-1.5 (m, 2H), 1.9 (q, 1H), 2.4 (s, 3H), 2.9 (q, 2H), 3.1 (BS, 1H), 7.1 (t, 1H), 7.4 (d, 1H), 7.8 (m, 1H), 7.9 (m, 2H), 8.1 (s, 1H), 8.3 (s, 1H) Example 18 (1S, 2S) -N- (cs-2- (2- (3-ethylamino) -benzoyloxy) -6-fluoro-3-propyonylphenyl) -cyclopropyl) -N '- (5-bromopyrid-2- il) -urea The compound of Example 10 was condensed with 3- (N-ethyl-t-butoxycarbonylamido) benzoic acid according to the procedure in Example 12 and the product was treated with trifluoroacetic acid and evaporated to obtain a trifluoroacetic salt of the main compound as a solid. 1 H NMR (CDCl 3) d 1.1 (t, 3 H), 1.3-1.6 (m, 5 H), 2.9 (q, 2 H), 3.1 (bs, 1 H), 3.5 (q, 2 H), 7.1 (t, 1 H), 7.2 (bs, 1H), 7.6 (t, 1H), 7.7-7.8 (m, 2H), 7.9 (d, 1H), 8.1 (s, 1H), 8.2 (d, 1H), 8.4 (s, 1H) Example 19 (1S, 2S, -N- (cs-2- (2-quinolo-4-yloxy-6-fluoro-3-propionylphenyl) cyclopropyl) -N '- (5-bromopyrid-2-yl) -urea The compound of Example 10 was condensed with 4-quinolinic acid according to the procedure in Example 12 and the product was dissolved in trifluoroacetic acid and evaporated to obtain the acetic salt of the main compound as a solid.1H NMR (CDCU) d 1.1 ( t, 3H), 1.2 (m, 1H), 1.5 (m, 1H), 1.9 (m, 1H), 2.8 (q, 2H), 3.2 (bs, 1H), 6.7 (d, 1H), 7.2 (t , 1H), 7.5 (m, 1H), 7.7 (t, 1H), 7.8-8.0 (m, 2H), 8.2 (d, 1H), 8.3 (d, 1H), 8.8 (d, 1H), 9.1 ( m, 2H), 9.2 (bs, 1H) Example 20 (1S, 2S) -N- (c / s-2- (3-aminomethyl-2-methylbenzoyloxy) -fluoro-3-propionylphenyl) cyclopropyl) -N '- (5-bromopyrid-2-yl) ) -urea The compound of Example 10 was condensed with 3-t-butoxycarbonylamido-2-methylbenzoic acid according to the procedure in Example 12. The product was treated with trifluoroacetic acid and evaporated to yield the main compound as a solid. 1 H NMR (CDCl 3) d 1.1 (t, 3 H), 1.1-1.3 (m, 2 H), 1.9 (m, 1 H), 2. 5 (s, 3H), 2.9 (q, 2H), 3.1 (bs, 1H), 4.2 (s, 2H), 7.0-7.2 (m, 2H), 7.4 (d, 1H), 7.6-7.7 (m, 2H), 7.8-8.0 (m, 2H), 8.2 (bs, 2H) Example 21 (1S, 2S) -Nf c / s-2- (6-f I uoro-2- (4-aminomethyl) eni Icarboni loxi) -3-propionyl-phenyl) -cyclopropyl-N '- (5-bromopyrid- 2-yl) -urea 4 - (. E-Butyloxycarbonylamidomethyl) benzoic acid was prepared by adding 6.5 g of DCC to a solution of 4 g of 4-cyanobenzoic acid in 200 ml of MeOH. The mixture was stirred for 70 hours at room temperature, filtered to remove the precipitated dicyclohexylurea and the filtrate was concentrated in vacuo to yield 7 g of a crude product. The methyl ester was dissolved in 500 ml of MeOH and 9.6 g of CoCl2-6H2O were added. The mixture was treated per portion with NaBH4. After 5 h, the reaction mixture was concentrated and the precipitate was removed. The filtrate was acidified with 150 mL of 1M HCl (aqueous) and extracted with 2x100 mL of CH2Cl2. The acidic phase was treated with 100 ml of 25% NH3 (aqueous), extracted with 3x100 ml of CH2Cl2, dried with Na2SO4 and concentrated to give 2.64 g of brown-tone oil. The oil was dissolved in 30 ml of a dioxane / water mixture (2: 1) and treated for 20 hours with 1.5 g of NaOH (s). The solvent was removed and 40 ml of a t-butanol / water (1: 1) mixture was added. The solution was stirred 24 hours after the addition of 3.7 g of di-ferf-butyl dicarbonate, then more water was added and the mixture was extracted with 2x50 ml of hexane. The water phase was acidified (pH -1.5-20) with NaHSO4 and extracted with 3x75 ml of ether. The deposited extracts were rinsed with 50 ml of saline, dried with Na2SO4 and evaporated to yield the intermediate compound of 4 - (. E? .- butyloxycarbonyl-amidomethyl) benzoic acid as a white solid. 4 - (. Ert-Butyloxycarbonylamidomethyl) benzoic acid and (1S, 2S) -N- (c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- (5- Bromopyrid-2-yl) -urea of Example 10 were condensed and the BOC protecting group was removed by using the method described in Example 12 to obtain the main product as the hydrochloride salt. 1 H NMR (250 MHz, CDCl 3) d 0.98 (t, 3 H), 1.05-1.20 (m, 1 H), 1.31-1.49 (m, 1 H), 1.69-1.90 (m, 1 H) m 2.65 (q, 2 H), 3.33-3.49 (m, 1H), 4.31 (broad s, 2H), 7.02-7.22 (m, 2H), 7.35-7.49 (m, 1H), 7.50-7.68 (m, 2H), 7.69-7.93 (m, 2H), 8.08 (d, 1H), 8.37 (broad s, 1H).

Example 22 (1S.2SR) -N-rc / s-2- (6-fluoro-2- (N-methylindol-5-carbonyloxy) -3-proponylphenyl) -cyclopropyl-N '- (5-bromopyrid- 2-yl) -urea i) Preparation of N-methylindole-5-carboxylic acid 0.1 g of indole-5-carboxylic acid was mixed with 2 equivalents of methyltrifluoromethane sulfonate in 1 ml of DMF at room temperature. After 5 h, the solvent was evaporated and 1 H NMR: 1 H NMR (250 MHz, DMSO-d 6) d 2.76 (s, 3 H), 6.57 (broad s, 1 H), 7.46-7.50 (m, 2 H) was recorded. , 7.75 (dd, 1H), 8.23-8.29 (m, 2H), 11.56 (broad s, 1H).

I) Preparation of the main compound N-methylindole-5-carboxylic acid and (1S, 2S) -N- (cs-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- ( 5-Bromopyrid-2-yl) -urea of Example 10 was condensed by using the method described in Example 12 to obtain the main product as the hydrochloride salt. 1 H-NMR (250 MHz, CDCl 3) d 1.08 (t, 3 H), 1.15-1.25 (m, 1 H), 1.39-1.50 (m, 1 H), 1.92-2.08 (m, 1 H), 2.89 (q, 2 H) , 2.90 (s, 3H), 3.20-3.35 (m, 1H), 6.55 (broad s, 1H), 6.65 (broad d, 1H), 7.11 (t, 1H), 7.20-7.29 (m, 2H), 7.41 (dd, 1H), 7.72-7.83 (m, 2H), 7.95 (dd, 1H), 8.51 (broad s, 1H), 9.25 (broad s, 1H), 9.43 (broad s, 1H).

Example 23 (1S, 2S) -N-rcs-2- (6-f luo ro-2- (indole-4-carbonyloxy) -3-propionylphilel) -cyclopropin-N '- (5-bromopyrid-2) -ill-urea lndol-4-carboxylic acid and (1S, 2S) -N- [c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl] -N '- (5 -bromopyrid-2-yl] -urea Example 10 were condensed using the method described in Example 12 to obtain the main product as the hydrochloride salt. 1 H-NMR (250 MHz, CDCl 3) d 1.07 (t, 3 H), 1.17-1.30 (m, 1 H), 1.31-1.47 (m, 1 H), 1.90-2.10 (m, 1 H), 2.89 (q, 2 H) , 3.02-3.18 (m, 1H), 6.75 (broad d, 1H), 7.00-7.35 (m, 4H), 7.55 (dd, 1H), 7.60 (d, 1H), 7.79 (dd, 1H), 7.89 ( d, 1H), 8.10 (d, 1H), 9.27 (broad d, 2H).

Example 24 (1S, 2S, -N-rc.s-2- (6-fluoro-2- (3-amino-4-chlorophenylcarbonyloxy, -3-propionylphenyl) -cyclopropin-N '- (5-bromopyrid-2- H-urea 3-Amino-4-chlorobenzoic acid and (1S, 2S) -N- [c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl] -N '- (5 -bromopyrid-2-yl] -urea of Example 10 were condensed using the method described in the Example 12 to obtain the main product as the hydrochloride salt. 1 H-NMR (250 MHz, liberated amine, CDCl 3) d 1.10 (t, 3H), 1. 17-1.30 (m, 1H), 1.42-1.52 (m, 1H), 1.88-2.01 (m, 1H), 2.88 (q, 2H), 3. 19-3.31 (m, 1H), 4.25 (broad s, 2H), 6.80 (broad d, 1H), 7.09 (t, 1H), 7.35 (t, 1H), 7.48-7.60 (m, 2H), 7.66 ( d, 1H), 7.73-7.88 (m, 2H), 9.25 (broad s, 2H).

Example 25 (1S, 2S, -N-rc.s-2- (6-fluoro-2- (pyrid-3-ylcarbonyloxy) -3-propionylphenin-cyclopropyl-N '- (5-cyanopyrid-2-yp- urea A dry mixture of the compound of Example 8 (50 g, 0.68 mmol),? /,? / '- dicyclohexylcarbodiimide (0.168 g, 0.81 mmol), nicotinic acid (0.1 g, 0.81 mmol) and 4- (dimethylamino) pyridine (0.041 mmol). g, 0.34 mmol) was dissolved in CH2Cl2 (5 ml) and? /,? / - dimethylformamide (DMF) (2.5 ml). The mixture was then stirred at room temperature. After 20 h. The mixture was filtered and dried under vacuum, then redissolved in a minimum amount of dichloromethane and filtered. The clear solution was evaporated on silica and purified by chromatography (ethyl acetate) to give the main compound (0.168 g, 50%). An analytical sample was obtained by recrystallization from chloroform-hexane. 1 H NMR (CDCl 3): 9.89 (br s, 1 H), 9.41 (m, 1 H), 9.33 (br s, 1 H), 8.86 (dd, 1 H), 8.46 (d t, 1 H), 8.18 (d, 1 H), 7.80 (dd, 1H), 7.71 (dd, 1H), 7.49 (ddd, 1H), 7.13 (t, 1H), 6.92 (d, 1H), 3.18 (m, 1H), 2.88 (q, 2H), 1.99 (m, 1H), 1.52 (m, 1H), 1.25 (m, 1H), 1.13 (t, 3H).

Example 26 (1R, 2R) -N-rc / s-2- (6-fluoro-2- (pyrid-3-ylcarbonyloxy, -3-pro pion ilf enyl) -cycloprop.p-N '- (5- cyanopyrid-2-ip-urea A dry mixture of the compound of Example 6 (0.1 g, 0.27 mmol),? /,? / '- dicyclohexylcarbodiimide (0.067 g, 0.33 mmol) and nicotinic acid (0.037 g, 0.3 mmol) was suspended in dichloromethane (2 ml. ). A minimum of DMF was added drop by drop to obtain a reasonably clear solution. 4- (dimethylamino) pipdine (0.016 g, 0.14 mmol) was then added. The reaction mixture was stirred at room temperature. After 20 h. the solvent was evaporated in vacuo and the crude residue was dissolved in aqueous hydrochloric acid (pH 1-2) and filtered. The clear solution was then made slightly alkaline with sodium hydrogen carbonate and the precipitated product was filtered. Purification by chromatography (dichloromethane-methanol, 15: 1) gave the main compound 0.072 g (56%). 1 H NMR (CDCl 3): 9.85 (br s, 1 H), 9.42 (s, 1 H), 9.35 (br s, 1 H), 8.86 (d, 1 H), 8.47 (dt, 1 H), 8.18 (d, 1 H), 7.81 (dd, 1H), 7.71 (dd, 1H), 7.48 (dd, 1H), 7.13 (t, 1H), 6.92 (d, 1H), 3.19 (m, 1H), 2.91 (q, 2H), 1.99 (m, 1H), 1.49 (m, 1H), 1.24 (m, 1H), 1.13 (t, 3H).

Example 27 (1S, 2S) -N-fc / s-2- (2- (3- (N-ethyl, N-Boc-amino) phenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl-N'- (5-cyanopyrid-2-ill-urea) The compound of Example 8 (0.37 g, 1.0 mmol), N, N'-dicyclohexylcarbodiimide (0.25 g, 1.2 mmol), 4-dimethylaminopyridine (0.06 g, O.dmmol) and acid 3 (? / - etl1? / -butoxycarbonyl) aminobenzoic acid (0.320 g, 1. 2 mmol) (prepared by reductive amination of 3-aminobenzoic acid, followed by protection of the amino group) was dissolved in dichloromethane (8 ml) and DMF (3 ml). The mixture was then stirred at room temperature. After 18 h. the solvent was removed in vacuo and the crude product was redissolved in dichloromethane and filtered. The clear solution was evaporated on silica and chromatographed (ethiiohexane acetate, 3: 2) to give the main compound sufficiently pure (0.24 g, 39%). 1 H NMR (CDCl 3): 10.0 (br s, 2 H), 8.20 (d, 1 H), 8.06 (d, 1 H), 8. 03 (m, 1H), 7.77 (dd, 1H), 7.70 (dd, 1H), 7.48 (m, 2H), 7.10 (t, 1H), 6.95 (d, 1H), 3.71 (q, 2H), 3.14 (m, 1H), 2.90 (q, 2H), 1.95 (q, 1H), 1.44 (s, 10H), 1.2-1.09 (m, 7H).

Example 28 (1S, 2S) -N-rc / s-2- (2- (3-ethylaminophen-1-carbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl-N '- (5-cyanopyrid -2-ip-urea Trifluoroacetic acid (5 ml) was added to a stirred solution of the compound of Example 27 (0.120 mg, 019 mmol) in dichloromethane (10 ml). The mixture was left at room temperature for 1-2 h. then it was evaporated to dryness. The crude product was purified on HPLC (prep column C-18, 40% water in acetonitrile) to yield 0.045 g (30%) of the main compound as the trifluoroacetate salt. 1 H NMR (CDCl 3): 11.08 (br s, 2 H), 9.83 (br s, 1 H), 9.36 (br s, 1 H), 8.23-8.08 (m, 3 H), 7.82-7.54 (m, 4 H), 7.13 ( t, 1H), 7.02 (d, 1H), 3.42 (q, 2H), 3.20 (m, 1H), 2.83 (q, 2H), 1.94 (q, 1H), 1.46 (m, 1H), 1.34 (t , 3H), 1.24 (m, 1H), 1.06 (t, 3H).

Example 29 (1S, 2S) -N-rc / s-2- (2- (3-dimethylamine inofenyl rbon i loxi) -6-fluoro-3-propionylphenyl) -cyclopropyl-N '- ( 5-cyanopyrid-2-ill-urea The compound of Example 8 (0.1 g, 0.27 mmol), N-N'-dicyclohexylcarbodiimide (0.067 g, 0.33 mmol), 4-dimethylaminopyridine (0.016 g, 0.14 mmol) and 3-dimethylaminobenzoic acid (0.054 g, 0.39 mmol) were dissolved in dichloromethane (3 ml) and DMF (1 ml). The reaction was left at room temperature for 16 h. The solvent was then removed in vacuo and the solid was redissolved in dichloromethane and filtered. Purification by chromatography (ethyl acetate-hexane, 2: 1) followed by HPLC (column C-18, 0.1% TFA in acetonitrile) yielded the main compound as the trifluoroacetate salt 0.1 g (58%). 1 H NMR (CDCl 3): 8.38-8.23 (m, 3 H), 7.92-7.69 (m, 4 H), 7.15 (t, 1 H), 7.05 (m, 1 H), 3.32 (s, 6 H), 3.26 (m, 1 H) ), 2.89 (q, 2H), 2.02 (m, 1H), 1.55-1.27 (m, 2H), 1.10 (t, 3H).

Example 30 (S, 2S) -N-rc7s-2- (2- (3-L-valinyl) inofen-ylcarbonyl-yl) -6-fluoro-3-propionyl-phenyl) -cyclopropyl-N '- (5-cyanopipd-2) -p-urea a) 3- (N-Boc-l-va lyl) aminomethyl benzoate This intermediate compound was prepared analogously to Villaneuve & Chan, Tetrahedron Letters 1997 vol 37 6489-6492. A mixture of / V-ferf-butoxycarbonyl-L-valine (2.17 g, 10 mmol) and hexachloroacetone (1.32 g, 5 mmol) in dichloromethane (20 ml) was stirred under nitrogen and cooled to below -78 degrees C. Triphenylphosphine (2.6 g, 10 mmol) in dichloromethane (10 ml) was added dropwise and the mixture was stirred for 30 min. Methyl 3-aminobensoate (1.5 g, (10 mmol) in dichloromethane (10 ml) was then added dropwise followed by triethylamine (1 g, 10 mmol) in dichloromethane.The reaction was allowed to reach room temperature after which the The solvent was evaporated under vacuum.The residue was purified by silica chromatography (hexane-ethyl acetate, 3: 1) followed by recrystallization from ethyl acetate-hexane to give 0.7 g (28%) of the pure intermediate, depicted above. 1 H NMR (CDCl 3): 8.30 (br s, 1 H), 8.07 (d, 1 H), 7.85-7.75 (m, 2 H), 7.37 (t, 1H), 5.15 (d, 1H), 4.05 (m, 1H), 3.91 (s, 3H), 2.26 (m, 1H), 1.48 (s, 9H), 1. 03 (dd, 6H). b) 3- (N-Boc-L-valyl) aminobenzoic acid The intermediate from step a) (0.65 mg, 1.8 mmol) was suspended in methanol (6 ml) and water (2 ml). Lithium hydroxide (0.11 g, 3.9 mmol) was added and the mixture was stirred for 24 h. at room temperature. Water (10 ml) was then added and the volume reduced by half. The aqueous solution was rinsed with 10-20 ml of ethyl acetate then acidified with aqueous hydrochloric acid. Extraction with ethyl acetate (2 x 20 ml), drying and evaporation in vacuo yielded the pure intermediate, represented above 0.524 g (84%). 1H NMR (CD3OD): 8.23 (t, 1H), 7.84 (d, 1H), 7.76 (d, -1H), 7.42 (t, 1H), 6.70 (d, 1H), 4.00 (m, 1H), 2.08 (m, 1H), 1.45 (a, 9H), 1.00 (d, 6H). c) (1S, 2S) -N-rc / s-2- (2- (3-N-Boc-L-valynylaminophenylcarbonyl) -6-fluoro-3-proponylphenyl) -cyclopropyl-N '- (5 -cianopyrid-2-p-urea The compound of Example 8 (0.23 g, 0.62 mmol), N-N'-dicyclohexylcarbodiimide (0.153 g, 0.74 mmol), 4-dimethylaminopyridine (0.038 g, 0.3 mmol) and the intermediate of step b) (0.25 g, 0.74 mmol) were dissolved in dichloromethane (9 ml) and DMF (3 ml). The reaction was left at room temperature for 19 h. The solvent was then removed in vacuo and the solid was redissolved in dichloromethane and filtered. Purification by chromatography (ethyl acetate-hexane, 1: 1) gave 0.299 g (67%) of the pure N-protected main compound. 1H NMR (CD3OD): 8.56 (t, 1H), 8.27 (s, 1H), 7.98-7.82 (m, 4H), 7.53 (t, 1H), 7.23 (t, 1H), 7.10 (d, 1H), 3.98 (d, 1H), 3.09 (m, 1H), 2.90 (q, 2H), 2.06-1.93 (m, 2H), 1.44 (m, 10H), 1.18-0.94 (m, 10H). d) (1S, 2S) -N-rc / 's-2- (2- (3-L-valynylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl-N' - (5-cyanopyridyl) 2-ip-urea The N-protected compound from step c (0.16 g, 0.23 mmol) and thiophenol (0.054 g, 0.46 mmol) were dissolved in dichloromethane (6 ml) and cooled to 0 degrees. Trifluoroacetic acid (6 ml) was added and the mixture was allowed to reach room temperature and left for 1 h. Evaporation to dryness followed by chromatography (dichloromethane-methanol, 10: 1.5) gave 0.150 g (90% 9) of the main compound as the TFA salt.1H NMR (CD3OD): 8.60 (s, 1H), 8.25 (d, 1H) , 8.0-7.85 (m,, 4H), 7.53 (t, 1H), 7.21 (t, 1H), 7.09 (d, 1H), 5.0 (m, 1H), 3.12 (m, 1H), 2.96-2.87 ( m, 2H), 2.20 (m, 1H), 1.97 (m, 1H), 1.46 (m, 1H), 1.09-1.03 (m, 10H).

Example 31 (1S, 2S) -N- (c / s-2-f6-fluoro-3-propionyl-2- (6-ethylaminopyrid-3-ylcarbonyloxy) phenyl-1-cyclopropyl) -N '- (5-cyanopyrid-2-yl-urea) a) 6-ethylaminonicotinic acid This intermediate compound was prepared from 6-chloroicotinic acid and ethylamine by the same procedure, as described by Example 35 step a). 1-Butanol was replaced with ethyl acetate for extraction. Recrystallization (MeOH-CHCl3) yielded 0.53 g (50%). 1 H NMR (DMSO-d 6): 12.1 (br s, 1 H), 8.54 (d, 1 H), 7.77 (dd, 1 H), 7.15 (t, 1 H), 6.45 (dd, 1 H), 3.33 (m, 2 H) , 1.14 (t, 3H). b) (1S, 2S) -N-. { c / s-2-y6-fluoro-3-pro pion il-2- (6-ethylaminopi-3-ylcarbonyloxy) phenylcyclopropyl} -N '- (5-cyanopyrid-2-ipurea) The compound of Example 8 (0.1 g, 0.27 mmol), 6-ethylammonicotinic acid (0.084 g, 0.54 mmol),? / -? / '- dicyclohexylcarbodiimide (0.127 g, 0.62 mmol) and 4-dimethylaminopyridine (0.016 g, 0.13 mmol ) were dissolved in DMF (3 ml) and left at room temperature. After 19 h, the solvent was removed in vacuo and the residue was suspended in dichloromethane and filtered. The solvent was removed and the crude product was purified by chromatography (ethyl acetate-hexane, 2: 1) to give the main compound (0.063 g, 45%). 1 H NMR (CDCl 3): 9.85 (br s, 1 H), 9.25 (br s, 1 H), 8.91 (d, 1 H), 8.18-8.02 (m, 3 H), 7.76-7.67 (m, 2 H), 7.65 (t , 1H), 6.96 (d, 1H), 6.37 (d, 1H), 5.40 (m, 1H), 3.37 (m, 2H), 3.19 (m, 1H), 2.8 (q, 2H), 1.98 (m, 1H), 1.49 (m, 1H), 1.28 (t, 3H), 1.15 (m, 1H), 1.10 (t, 3H).

Example 32 (1S.2S) -N- (c.s-2-r6-fluoro-3-propionyl-2- (5-bromopyrid-3-ylcarbonyloxy) phenylcyclopropyl) -N '- (5-cyanopyrid-2-inurea -Bromonicotinic acid (0.065 g, 0.33 mmol), the compound of Example 8 (0.1 g, 0.27 mmol),? / -? / '-dicyclohexylcarbodumide (0.127 g, 0.62 mmol) and 4-dimethylaminopyridine (0.016 g, 0.13 mmol) ) were dissolved in dichloromethane (4 ml) and left at room temperature. After 19 h, the mixture was filtered and the solvent removed in vacuo. The crude product was purified by chromatography (ethyl acetate-hexane, 1: 1) to give the main compound (0.040 g, 27%). 1 H NMR (CDCl 3): 9.80 (br s, 1 H), 9.30 (d, 1 H), 9.17 (br s, 1 H), 8.89 (d, 1 H), 8.57 (dd, 1 H), 8.57 (dd, 1 H), 7.80 (dd, 1H), 7.70 (dd, 1H), 7.12 (t, 1H), 6.83 (d, 1H), 3.25 (m, 1H), 2.87 (q, 2H), 2.00 (q, H), 1.50 (m, 1H), 1.24 (m, 1H), 1.12 (t, 3H).

Example 33 (1S, 2S) -N- (c / s-2-r6-fluoro-3-propionyl-2- (6-aminopyrid-3-ylcarbonyloxy) phenyl-cyclopropyl) -N '- (5-cyanopyrid -2-urea a) 6-aminonicotinic acid, methyl ester 6-aminonicotinic acid (2 g, 22 mmol) was dissolved in methanol (10 ml) and sulfuric acid (0.5 ml). The solution was refluxed overnight and the solvent was evaporated in vacuo. The crude product was dissolved in water-EtOAc and made alkaline by aqueous sodium hydrogencarbonate. Extraction by EtoAc produced the pure intermediate represented above (2.3 g, 70%). 1 H NMR (DMSO-d 6): 8.51 (dd, 1H), 7.81 (dd, 1H), 6.66 (br s, 2H), 6.45 (dd, 1H), 3.77 (s, 3H). b) MetiI-6-butoxycarbonilam non icoti nato The intermediate from step a) (0.75 g, 4.9 mmol) was dissolved in THF (5 ml). Bis (trimethylsilyl) amide sodium (5 ml, 2 M in THF) was added dropwise. After stirring at room temperature for 30 min. Di-tert-butyldicarbonate (1.1 g, 5 mmol) in THF (8 ml) was added. The reaction mixture was left overnight under a nitrogen atmosphere. The solution was then evaporated in vacuo and dissolved in EtOAc (40 ml) and 0.1 M hydrochloric acid (100 ml). The layers were separated and the aqueous phase was extracted twice with EtOAc (40 ml), then made slightly alkaline with aqueous sodium hydrogencarbonate and extracted again with EtOAc (20 ml). The organic fractions were combined, dried over sodium sulfate and purified by chromatography (EtOAc-hexane, 1: 4) to give the intermediate represented above (0.5 g, 40%). 1 H NMR (CDCl 3): 8.93 (dd, 1 H), 8.62 (s, 1 H), 8.26 (dd, 1 H), 8.06 (dd, 1 H), 3.91 (s, 3 H), 1.60 (s, 9 H). c) 6-t-butoxycarbonylaminonicotinic acid The intermediate from step c) (0.4 g, 1.6 mmol) was suspended in methanol (4 ml) and water (1.25 ml). LiOH (0.1 g, 4 mmol) was added. The mixture was left at room temperature for 48 h. the clear solution was then concentrated in vacuo and dissolved in water and acidified with acetic acid (pH = 4-5). Extraction with EtOAc gave the pure intermediate represented above (0.27 g, 70%). 1 H NMR (DMSO-d 6): 9.98 (s, 1 H), 8.74 (d, 1 H), 8.18 (d, 1 H), 8.88 (d, 1 H), 1.49 (s, 9 H). d) (1S.2S) -N-. { c / s-2-, 6-fluoro-3-propionyl-2- (6-tert-butoxycarbonylaminopyrid-3-ylcarbonyloxy) phen.p-cyclopropyl) -N '- (5-cyanopyrid-2-inurea) The compound of Example 8 (0.150 g, 0.41 mmol), the intermediate of step c) (0.17 g, 0.49 mmol), N-N'-dicyclohexylcarbodiimide (0.1 g, 0.49 mmol) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol) were dissolved in DMF (2 ml). The mixture was stirred at room temperature overnight, then placed in a 50 ° oil bath for 2 h. Evaporation on silica gel and purification by chromatography afforded the main N-protected compound (0.048 g, 20%). 1 H NMR (CDCl 3 / CD 3 OD): 9.02 (s, 1 H), 8.43 (dd, 1 H), 8.22 (d, 1H), 8.10 (d, 1H), 7.81-7.75 (m, 2H), 7.15 (t, 1H), 7.08 (d, 1H), 3.15-3.05 (m, 1H), 2.90 (q, 2H), 1.96 (m, 1H), 1.56 (s, 9H), 1.50-1.40 (m, 1H), 1.25-1.09 (m, 4H).

T) (1S.2S) -N- (c / s-2-, 6-fluoro-3-propionyl-2- (6-aminopyrid-3-ylcarbonyloxy) phenylcyclopropyl.} - N '- (5-cyanopyrid- 2-illurea The intermediate compound from step d) (0.048 g, 0.08 mmol) was dissolved in dichloromethane (2 ml). Trifluoroacetic acid (1 ml) was added and the mixture was stirred for 1 h. Vacuum evaporation produced the crude master compound. This product was dissolved in ether (2 ml) and allowed to remain overnight. The white precipitates formed were separated by filtration to give the pure master compound as the trifluoroacetate salt (0.032 g., 65%). 1 H NMR (CD3OD / CDCl 3): 8.71 (d, 1H), 8.29 (dd, 1H), 8.16 (t, 1H), 8.82-7.74 (m, 2H), 7.20-7.10 (m, 2H), 6.96 (d , 1H), 3.25 (m, 1H), 2.86 (m, 2H), 1.96 (m, 1H), 1.52-1.43 (m, 1H), 1.24-1.19 (m, 1H), 1.09 (t, 3H).

Example 34 (1S, 2S) -N- (c / s-2-α6-fluoro-3-proponyl-2- (6-chloropyrid-3-ylcarbonyloxy) phenyl-cyclopropyl) -N '- (5-cyanopyrid-2) -nour The compound of Example 8 (0.15 g, 0.4 mmol), 6-chloronicotinic acid (0.076 g, 0.49 mmol),? / -? / '- dicyclohexylcarbodiimide (0.1 g, 0.49 mmol) and 4-dimethylaminopyridine (0.024 g, 0.2 mmol) ) were dissolved in dichloromethane (4 ml). The mixture was left overnight. Evaporation in vacuo, purification by chromatography (EtOAc-hexane, 1: 2) yielded the main compound (0.067 g, 32%). 1H NMR (CDCU): 9.77 (br s, 1H), 9.18 (br d, 2H), 8.39 (dd, 1H), 7.79 (dd, 1H), 7.71 (dd, 1H), 7.46 (d, 1H), 7.13 (t, 1H), 6.92 (d, 1H), 3.25 (m, 1H), 2.88 (q, 2H), 2.00-1.90 (m, 1H), 1.55-1.46 (m, 1H), 1.25-1.22 ( m, 1H), 1.11 (t, 3H).

Example 35 (1S, 2S, -N- { Cs-2-r6-fluoro-3-propionyl-2- (6-di-ethylaminopyrid-3-ylcarbonyloxy) -phen-cyclopropyl) -N '- (5-cyan opi) rid-2-ill urea a) 6-dimethylaminonicotinic acid 6-chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine (10 ml, 40% in water) were heated in a sealed pressure vessel at 130 ° C for 6 h. The solvent was then removed and the residue was absorbed in water and the pH adjusted to 4-5. Extraction with dichloromethane yielded the pure intermediate represented above (0.1 g, 20%). H NMR (CDCU): 8.87 (dd, 1H), 8.04 (dd, 1H), 6.49 (dd, 1H), 3.18 (s, 6H). b) (1S, 2S) -N-. { c / 's-2-r6-fluoro-3-propionl-2- (6-di methylamine pyrid-3-lcarbonyloxy phenylcyclopropyl.) - N' - (5-cyanopyrid-2-illurea) The compound of Example 8 (0.13 g, 0.3 mmol), the intermediate compound of step a) (0.05 g, 0.3 mmol), N-N'-dicyclohexylcarbodiimide (0.09 g, 0.4 mmol) and 4-dimethylaminopyridine (0.02 g, 0.18 mmol) were dissolved in dichloromethane (3 ml) and DMF (1 ml).

The mixture was left overnight. Evaporation under vacuum and purification by chromatography (EtOAc-hexane, 2: 1) yielded the main compound (0.06 g, 39%). 1 H NMR (CDCU): 10.10 (br s, 1 H), 9.29 (br s, 1 H), 8.18 (d, 1H), 8.12 (dd, 1H), 7.76-7.60 (m, 2H), 7.06 (t, 1H), 6.95 (d, 1H), 6.62 (d, 1H), 3.18 (m, 7H), 2.83 (q, 2H), 2.10-1.99 (m, 1H), 1.51-1.42 (m, 1H), 1. 19 (m, 1H), 1.09 (t, 3H).

Example 36 (1S, 2S) -N-rc / s-2- (6-fluoro-2-O-3-propionylphenol) -cyclopropyl-N '- (5-cyanopyrid-2-urea) -O-4-hydroxybenzoate a) 4-Benzyloxybenzoic acid To a solution of 4-hydroxybenzoic acid (6.9 g, 50 mmol) in 150 ml of DMF was added potassium tert-butoxide (12.34 g, 10 mmol) and the mixture was mixed. stirred at room temperature for one hour. Benzyl bromide (20.5 g, 1 20 mmol) was added and the mixture was stirred for two days at room temperature. The mixture was evaporated under reduced pressure and 1 00 ml of 1,4-dioxane and a solution of sodium hydroxide (6.0 g, 150 mmol) in 50 ml of water were added. The mixture was refluxed for two hours, cooled and evaporated under reduced pressure. Water was added and the mixture was acidified with acetic acid. The product was filtered, rinsed with cold water and dried. Product: 1 0.2 g = 89%. b) 4-benzyloxybenzoyl chloride To a mixture of 4-benzyloxybenzoic acid (2.28 g, 10 mmol) in 20 μl of dry dichloromethane were added five drops of DMF and 2.5 ml of thionyl chloride. The mixture was refluxed for three hours and evaporated under reduced pressure. Product: 2.45 g = 100%. c) (1S, 2H) -N-rc / s-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl-N'-22- (5-cyanopyrid-2-illurea- Q-4-hydroxy benzoate To a solution of (1 S, 2S) -N- [c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) cyclopropyl] -N '- (5-cyanopyrid -2-yl] urea (1 84 mg, 0.5 mmol) in 3 ml of DMF was added tert potassium butoxide (78.5 mg, 0.7 mmol) and the mixture was stirred for one hour at room temperature. Benzyloxybenzoylchloride (185 mg, 0.75 mmol) in 1 ml of DMF was added, 40 ml of ethyl acetate were added and the organic phase was rinsed four times with water.The solution was dried with sodium sulfate and evaporated under reduced pressure. Product was isolated by silica gel column chromatography Product: 180 mg = 62% .1H-NMR (DMSO d-6): 0.92 (m, 4H), 1.31 (m, 1H), 1.85 (m, 1H) , 2.82 (m, 2H), 3.06 (m, 1H), 5.26 (s, 2H), 7.20 (m, 2H), 7.38-8.12 (m, 11H), 8.38 (m, 1H). c) Synthesis of (1S, 2S) -N- [c / s-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl] -N '- [2- (5-cyanopyrid-2-yl] urea-O-4- hydroxybenzoate A solution of (1S, 2S) -N- [c / s-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl] -N '- [2- (5- cyanopyrid-2-yl] urea-O-4-hydroxybenzoate (170 mg, 0.29 mmol) in 15 ml of ethyl acetate and 15 ml of methanol was hydrogenated with 10% palladium in vegetable char (30 md) three times at room temperature environment and normal pressure The catalyst was filtered and rinsed with ethyl acetate and methanol and the solution was evaporated under reduced pressure The product was isolated by silica gel column chromatography Product: 100 mg = 70% 1H-NMR (DMSO d-6): 0.93 (m, 4H), 1.32 (m, 1H), 1.88 (m, 1H), 2.85 (m, 2H), 3.05 (m, 1H), 6.92 (m, 2H), 7.38 (m, 2H), 8.00 (m, 4H), 8.38 (m, 1H).

Example 37 (1S.S. 2S) -N-rc / s-2- (6-fluoro-2-O-3-propionylphenyl) -cycloprop.p-N'-r2- (5-cyan opylidylurea-O-methyl) no-4-h id roxy benzoate a) Methyl-4- (4-methoxybenzyloxy) benzoate.

To a solution of methyl 4-hydroxybenzoate (6.85 g, 45 mmol) in 80 ml of DMF was added tert potassium butoxide (5.6 g, 51 mmol) and the mixture was stirred at room temperature for one hour. 4-Methoxybenzyl chloride (8.3 g, 52 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and 200 ml of ethyl acetate was added. The organic phase was rinsed four times with water, dried with sodium sulfate and evaporated under reduced pressure. Product: 12.3g = 100%. 1 H-NMR (CDCU) 3.82 (s, 3 H), 3.88 (s, 3 H), 5.03 (s, 2 H), 6.96 (m, 4 H), 7.36 (d, 2 H), 7.98 (d, 2 H). b) 4- (4-methoxybenzyloxy) benzoic acid To a solution of methyl benzoate 4- (4-methoxybenzyloxy) (12.2 g, 44.8 mmol) in 50 ml of 1,4-dioxane was added a solution of sodium hydroxide. lithium (2.15 g, 89.6 mmol) and the mixture was stirred overnight at 60 ° C. The mixture was evaporated under reduced pressure and 5% acetic acid was added. The product was filtered, rinsed with water and dried. Product: 10.1 g = 87%. 1 H-NMR (DMSO d-6) 3.74 (s, 3 H), 5.08 (s, 3 H), 6.92 (d, 2 H), 7.06 (d, 2 H), 7.36 (d, 2 H), 7.90 (d, 2 H) c) Chloromethyl 4-4 (methoxybenzyloxy) benzoate To a solution of 4- (4-methoxybenzyloxy) benzoic acid (5.16 g, 20 mmol) in 100 ml of 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide. (14.27 g, 22 mmol) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated twice with 1,4-dioxane and twice with toluene. The dried product was dissolved in 60 ml of dichloromethane and iodochloromethane (35.3 g, 200 mmol) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Approximately 100 ml of ethyl acetate were added and the organic phase was rinsed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Product: 4.48 g = 73%. 1 H-NMR (CDCU) 3.83 (s, 3 H), 5.06 (s, 3 H), 5.94 (s, 2 H), 7.00 (m, 4 H), 7.36 (d, 2 H), 8.05 (d, 2 H). d) Iodomethyl-4- (4-methoxybenzyloxy) benzoate To a solution of cyoromethyl-4- (4-methoxybenzyloxy) benzoate (0.77 g, 2.5 mmol) in 15 ml of dry acetone was added sodium iodide (1.87 g, 12.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate / water. The organic phase was rinsed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Product: 0.86 g = 86%. 1H-NMR (CDCU) 3.84 (s, 3H), 5.05 (s, 3H), 6.14 (s, 2H), 6.98 (m, 4H), 7.36 (d, 2H), 8.00 (d, 2H). e) Benzoate of (1S, 2S) -N- [c / s-2- (6-fluoro-2-O-3-propionylphenyl) (cyclopropyl) -N '- [2- (5-cyanopyridyl) urea-O -methylene-4- (4-methoxybenzyloxy) To a solution of (1S, 2S) -N- [c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) cyclopropyl] -N'- [2- (5-cyanopyridyl) urea (368 mg, 1 mmol) in 5 ml of DMF was added a suspension of 60% sodium hydride in mineral oil (44 mg, 1.1 mol) and the mixture was stirred for one hour at room temperature. A solution of iodomethyl-4- (4-methoxybenzyoloxy) benzoate (0.84 g, 2.1 mmol) in 2 mL of THF was added and the mixture was stirred overnight at room temperature. 50 ml of ethyl acetate were added and the organic phase was rinsed four times with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Product: 525 mg = 82%. 1 H-NMR (CDCU) 0.91 (m, 3 H), 1.32 (m, 1 H), 1.60 (m, 1 H), 2.04 (m, 1 H), 2.90 (m, 2 H), 3.20 (m, 1 H), 3.82 ( s, 3H), 5.04 (s, 2H), 5.84-6.06 (m, 2H), 6.91-8.18 (m, 13H). f) (1S, 2S) -N- [c / 's-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl] -N' - [2- (5-cyanopyridyljurea-O-methylene-4 -hydroxybenzoate To a solution of (1S, 2S) -N- [c / 's-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl] -N' - [2- (5-c) benzoate Anopyridyl] urea-O-methylen-4- (4-methoxybenzyloxy (100 mg, 0.156 mmol) in 4 ml of dichloromethane was added TFA (0.5 ml) and the solution was stirred for one hour at room temperature. under reduced pressure and the product was isolated by silica gel column chromatography.

Product: 45 mg = 55%. 1 H-NMR (DMSO d-6) 0.84 (m, 3 H), 1.10 (m, 1 H), 1.48 (m, 1 H), 2.12 (m, 1 H), 2.80 (m, 2 H), 3.19 (m, 1 H) , 5.85-6.02 (m, 2H), 6.84 (m, 2H), 7.18 (m, 1H), 7.46 (m, 2H), 7.74 (m, 2H), 8.04 (m, 2H), 8.38 (m, 1H) ).

Example 39 (1S, 2S) -N- (c / s-2-f6-fluoro-3-propionyl-2- (6-methylaminopyrid-3-ylcarbonyloxy) phenylcyclopropyl) -N '- (5-cyanopyrid-2- inurea This compound was prepared from 6-methylaminonicotinic acid (0.050 g, 0.33 mmol) and the compound of Example 8 (0.1 g, 0.27 mmol) by the same procedure for Example 31. The crude product (containing the main compound and unreacted start) was purified by chromatography (ethyl acetate) to give 0.030 g (22%) of the main compound. 1 H-NMR (CDCU); 9.8 (br s, 1H), 9.25 (br s, 1H), 8.90 (d, 1H), 8.20 (d, 1H), 8.10 (m, 1H), 7.72 (m, 2H), 7.08 (t, 1H) , 6.9 (d, 1H), 6.37 (d, 1H), 3.20 (m, 1H), 2.95 (d, 3H), 2.85 (q, 2H), 1.95 (m, 1H), 1.48 (m, 1H), 1.10 (t, 3H).

Biological Example 1 Resistance Pattern The compounds of the invention were tested for antiviral activity against a number of HIV strands, including wild-type and known mutants that arise from the use of other non-nucleoside reverse transcriptase inhibitors as described in the summary of Schinazi presented in Table 1. TABLE 1 The analysis included multiple determinations with XTT in MT-4 cells (Weislow et al., J Nat Cancer I nst 1 989, vol 81 no 8, 577 et seq) including determinations in the presence of 50% human serum to indicate the contribution of linking the protein. The ED50 is presented in μg / ml. The initial data in the calculated therapeutic index (SI) are also presented, defined as the dose that produces 50% toxicity in the corresponding HIV free cells divided by the ED50. The compound of the prior art, from the 1995 ICAR Santa Fe is depicted above. It will be appreciated that the compounds of the invention, especially the enantiomers, have ED50 values that are distinctly inferior to previously known compounds, including the values against the known problematic mutants K103N and Y181C, as well as L100I and the double mutant L100I, Y181C. In addition, the indices for the enantiomers are 5 to 10 times greater than the compound of the prior art. These results should be observed in the context of HIV therapy where patients can expect to take the drug for many years, if not for the rest of their lives against resistance notoriously prone to HIV virus. In this way, a large Sl is needed to avoid cumulative toxicity, while at the same time allowing the proper dose to maintain therapeutic pressure and prevent the spontaneous generation of multiple chains of resistant HIV.

Biological Example 2 Time of resistance Las. 2 x 104 MT4 cells per well in a microtiter plate were infected with 5-10 TCID50 of HIV-1? nB. The compounds that are tested are added in concentrations around ED50, using 8 duplicates per concentration. After 6 days of incubation the RT activity was measured in 10 μl of supernatant. The following procedure was followed in subsequent passages of the cultures once a week: the viruses produced in the concentration of the test compound which shows>. 50% of the RT activity of untreated infected cells (SI C, I nicioinhibitory I Concentration) were transferred to fresh MT4 cells. 1 5 μl of supernatant from each of the 8 duplicates were transferred to the cells without the test compound (control) and to the cells with the test compound in the same concentration, and in addition two concentrations five times higher, respectively (See Table 2 below). When viral growth is allowed at the highest non-toxic concentration (5-40 μM), 2-4 parallel cavities are collected and expanded to give material for sequence analysis and transverse resistance.

TABLE 2 Allowed viral growth Production of inhibited virus 125 x SIC 125 x SIC 25 x SIC? 25 x SIC 5 x SIC 25 x SIC 5 x SIC? Without compound 25 x sic 5 x SIC? Without compound 5 x SIC SIC SIC? Without compound SIC? Without compound Step 1 Step 2 Step 3 Step 4 Step 5 Figure 1 marks the growth of viral resistance for a compound of the invention (Example 8) against time. Also marked is the corresponding curve for the compound closest to Santa Fe, mentioned above. It will be apparent that the compounds of the invention show a significantly slower development rate of resistance.

Biological Example 3 Metabolism P450 The metabolism of the compounds of the invention through the major isoforms of the human cytochrome P450 system were determined in insect cells infected with baculoviruses transfected with human cytochrome c4DNA (supersomes) P450 Gentest Corp Woburn E.U.A. Test compounds in concentrations of 0.5, 5 and 50 μM were incubated in duplicate in the presence of supersomes overexpressing several cytochrome P450 isoforms including CYP1 A2 + P450 reductase, CYP2A6 + P450 reductase, CYP2C9-Arg 144 + P450 reductase, reductase CYP2C1 9 + P450, reductase CYP2D6-Val 374 + P450 and reductase CYP3A4 + P450. The incubated ones contain a fixed concentration of cytochrome P450 (for example, 50 pmoles) and are conducted for 1 hour. The inclusion of a given isoform in the metabolism of the test compound is determined by UV HPLC chromatographically by measuring the disappearance of the parent compound. After testing the three concentrations for 7.5 minutes, the remaining% -type figures suggest that CYP3A4, 2C1 9 and 2A6 are included in the metabolism of the compound of Example 7. Similar constellations of P450 isoforms are also included in the metabolism of the Santa Fe halopyridinyl compounds of the prior art. Surprisingly, no significant p450 metabolism with any isomer was recorded for the compound of Example 8, implying that the compound is stable in vivo and that the possibility of altered metabolism of coadministered drugs is correspondingly low.

Biological Example 4 Pharmacokinetics The release of a compound of Formula I from an orally administered prodrug of Formula I I was monitored in rats. The compound of Example 7 was integrated in a propylene glycol vehicle and administered orally to uncooked Sprague Dawley rats, paired, in a dose corresponding to 0.027 μmol / kg. In the indicated time intervals, 0.2 ml of blood was collected from a catheter implanted in the canis jugularis, centrifuged and frozen for further analysis. The drug released from Formula I (Example 6) was analyzed by HPLC. The aliquots comprising 40-100 μl of each plasma sample were mixed with an equal volume of acetonitrile (10 seconds, Vibrofex). The sample was centrifuged (2 min, 14000 RPM) and 30 μl of the supernatant was injected into an HPLC system, as follows. Pre-column: RP-18, 7μm, 15 x 3.2 mm Column: Basic YMC, 3μm, 150 x 3mm Mobile phase: 60% acetonitrile in 3mM ammonium acetate, pH 6.4 Flow rate: 0.4 ml / min Detection: UV, 250 nm Table 3 In Table 3 it is clear that oral administration of the prodrugs of the Formula releases in vivo clinically significant amounts of the compounds of Formula I.

Biological Examples 5-8 i) Preparatory The rats used in the pharmacokinetic examples were male Sprague-Dawley, weighing approximately 200-250 g. The rats did not eat for at least 1 6 hours before the experiment, but had free access to water. The day before the experiment the rats were anesthetized using a mixture of Efrane®, oxygen and laughing gas. A catheter was inserted into the jugular vein. On the day of the experiment the weights of the rats were recorded. The animals were briefly anesthetized before the oral dose or iv dose injected into the back or neck was given. Each substance was administered to duplicate rats. The monkeys did not eat for 12 hours before oral administration but had free access to water. The test compound was delivered through an infant nasogastric feeding tube. After 6 hours, the monkeys received an apple. I) Preparation of the Dosage The appropriate amounts of the active ingredients described in the following examples were dissolved / suspended in a solution of propylene glycol or 10% Acacia and 1% Tween in water for oral administration. The compounds were dissolved in DMSO for intravenous administration. Ii) Blood sampling Blood samples (typically 0.6 ml for rats, 2 ml for monkeys) were taken before and at the indicated time intervals, as marked, after drug administration. The monkeys were connected from the femoral vein in tubes containing EDTA. The blood samples were centrifuged infectious agents neutralized with 1% SDS / 64 ° / 20 min and the plasma was stored at -20 ° C. iv) Bioanalysis Plasma samples were prepared as follows: 40-1,00 μl of plasma were mixed with an equal volume of acetonitrile (10 seconds, Vibrofex). The sample was centrifuged (2 min, 14000 RPM) and 30 μl of the supernatant was injected into an H PLC system, as follows. Pre-column: RP-18, 7μm, 1 5 x 3.2 mm Column: Basic Y, 3μm, 1 50 x 3mm Mobile phase: 60% acetonitrile in 3mM ammonium acetate, pH 6.4 Flow rate: 0.4 ml / min Detection: UV, 250 nm Biological Example 5 Comparison with the closest prior art compound In vivo stability and availability of the compounds of Formula I were compared to the nearest Santa Fe compound, mainly (+/-) - N- (c / s-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N '- (5-chloropyridyl-2-yl) -urea, wherein doses of 0.024 mmol / kg of the respective compounds were administered in a DMSO vehicle. Figure 2 is a graph showing the plasma levels of the respective compounds (n = 2 in each case) over time. It will be apparent that the respective curves follow a common pattern but that the compound of the invention has an AUC (0-4h) in excess of 1.5 times the AUC (0-4h) of the closest prior art compound. In other words, the compounds of the invention provide in vivo exposure greater than 50% than the previously described derivative, although this is due to a slower clearance of the compounds of the invention or a higher degree of tissue binding with the compounds. of the previous technique, etc. must still be determined.

Biological Example 6 Bioequivalence of prodrugs and parent compound The various compounds of Formula II (ie prodrugs of the compounds of Formula I) were administered to rats and the plasma levels of the parent compound of the invention (in this example, the compound of Example 1 0) were monitored over time. The vehicle was acacia at 1.0% and 1% Tween in water or propylene glycol (asterisked). The plasma level figures in Table 4 refer to individual animals.

TABLE 4 It will be apparent that the prodrugs of Formula I I release in vivo clinically relevant amounts of the compounds of Formula I in plasma. The absolute oral bioavailability (determined relative to the iv dose, as described in the preparatory section) was 28-33% for the compound of Example 37 and 27% for the animal evaluable with the compound of Example 27.

Biological Example 7 Bioavailability in different species A prodrug of the invention of Formula II (Example 12) was administered in the same dose (0.026 m mol / kg) and in the same vehicle (1% acacia and 1% Tween) in ag ua) to rats and cinomolgus monkeys. The plasma levels of the parent compound of Formula I (Example 10) were measured as a function of time.

TABLE 5 It will be apparent that the prodrugs of Formula I I release in vivo clinically relevant amounts of the compounds of Formula I. The release occurs in both rodents and primates, with significantly higher plasma levels in primates. The corresponding data for the compound of Example 28 (rat: acacia / Tween, mono: propylene glycol) are shown in Table 5A: TABLE 5A Biological Example 8 Antiviral Activity Compounds of Formula I were tested for the activity of H IV-1 against the wild-type HI VM IB and the resistant mutants, with or without the presence of 50% of human serum in the analysis of XTT-formazan, where the inhibition of cytopathogenic effects is analyzed in MT4 cells. In each case, the ED5o is indicated in μM. TABLE 6 The compounds of the formula I are thus highly active against the various H IV chains at concentrations attainable in vivo.

Biological Example 9 Antiviral Activity Compounds of the invention have also been compared to the closest prior art compound using a state of the cell culture analysis of the art, where the MT4 cells of human T cell line are grown in medium RPMI 1 640 supplemented with 100% fetal bovine serum, penicillin and streptomycin seeded in 96 m cavity platelets (2 »1 04 cells / cavity) infected with 1 0-20 TCI D50 per H IV-1 cavity N | B (wild type) or mutant virus that supports mutations of RT l ie 1 00, Cys 1 81 or Asn 1 03. Seriously diluted test compounds are added to respective cavities and the culture was incubated at 37 ° C in an atmosphere enriched with C02 and the viability of the cells is determined on day five or six with vital XTT dye. The results below show the average values of a number of determinations. The results are presented as ED50 μM. TABLE 8 The compounds of the invention have significantly improved their performance against the wild type and especially clinically important methods that arise during treatment with NNRTIs.

Biological Example 10 Binding kinetics The rate of association and dissociation of an NNRTI in the target enzyme can be analyzed directly by the surface plasmon resonance methodology, where the reverse transcriptase is immobilized on the surface of a microplate and the union or Dissociation of the putative inhibitor is monitored by observing changes in the refractive index caused by the concomitant reduction or increase in the mass of the microplate. A compound of the invention (Example 8) was compared to the closest prior art compound of Santa Fe, as depicted above. The experiments were carried out in a Biacore 2000 (Biacore AB, Uppsala, Sweden), using BIA evaluation software (see 3.0) for data evaluation. The binding of the small analyte (NN RTI) to the much longer enzyme results in binding responses in the range of 1-20-20 RU. The difference in the refractive index of volume between the regulator of operation and the sample makes it difficult to evaluate the data obtained during the injection of the sample. During the dissociation phase there is a significant change in the volume refractive index, in this way the union of the different substances has been evaluated during this phase. Immobilization: The enzyme and reference protein were immobilized by direct coupling to primary amines on a CM5 chip (Markgren et al., 1998). The antibody for Fc g (Biacore BR-1 000-57) was used as the reference protein and immobilized according to the manufacturer's instructions. The reverse transcriptaza of H IV (U nge et al., 1 990) was transferred from 3 M of (NH4) 2SO4 to 5 mM of Hepes, pH 7.6 containing 4 mM of MgCl, using 1 0K of Nanosept Centrifugal concentrators ( Pall Filtron, MA, E. U.A.). The RT quantities corresponding to 6800-9700 RU were immobilized to the detector chip. The surface of the detector is deactivated by injection of 35 ml of 0.5 M Tris pH 7.6; 4 mM MgCl 2, 0.5 M KCl. The immobilization procedure was carried out at 33 ° C. Interaction with inhibitors: Reservoir inhibitor solutions (1 mg / ml in DMSO) were dissolved in RT regulator (1.0 mM Hepes pH 7.6, 4 mM MgCl2, 0.25 mM spermine, 40 mM KCl; 0.5% Triton X-1 00, 3% DMSO, 0.5% fecal bovine serum) at a concentration of 1.0 mM. The binding of the RT substance was analyzed by injection of 200 ml of the diluted substance, the flow rate was 20 ml / min and the temperature was 25 ° C. After each injection of the substance, the system was rinsed by injection of 1 20 ml of 10% DMSO into the RT operating regulator. The results are shown in Figure 3. It is apparent that the composition of the invention and the prior art compound show different kinetics of interaction with the compound of the invention by disassociating with the lower speed, which indicates a more efficient bonding. to the enzyme References: Unge T, Ahola H, Bhikhabhai R, Backbro K, Lovgren S, Fenyo EM, Honigman A, Panet A, Gronowitz JS, Strandberg B, Expression, purification and crystallization of the HIV-1 reverse, transcriptase (RT). AI DS Res Hum Retroviruses 1 990 Nov; 6 (11): 1297- 303. Margren P-O, Hamalainen M, Danielson U H, Screening of compounds interacting with H IV-1 proteinase using optical biosensor technology. Analytical Biochem istry 1 998, vol 265, in press. Although various aspects and embodiments of the invention have been illustrated with reference to the foregoing specific examples, the comparative examples and the Figures, it will be appreciated that the invention is not limited in any way to these embodiments, but extends throughout the spirit and scope of the appended claims.

Claims

CLAIMS 1. A compound of the formula I wherein Rx is cyano or bromine; R1 is halo; R2 is CrC3 alkyl, and prodrugs and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, characterized in that R1 is fluoro.
3. A compound according to claim 1, characterized in that R2 is ethyl.
4. A compound according to claim 1, characterized in that it comprises at least 60%, preferably at least 90% of I S, 2S enantiomerically. 5. A compound according to claim 1, characterized in that Rx is cyano. 6. A compound according to claim 1, characterized in that the prodrug has the formula I I: wherein Rx, R1 and R2 are as defined above, R3 is H, (CHm) nNR5R6; R4 is H, C, -C3 alkyl, (CHm) nNR5R6, (CHm) nC (= O) R5, (CHm) nOH, OR7, halo, CF3 or CN; or R3 and R4 together define a 5 or 6 membered fused ring having 0-2 hetero atoms and / or 0-2 unsaturated bonds and / or 0-2 substituents; R5 is H, Ct-Cs alkyl, C (= O) R7 or a peptide of 1 to 4 amino acids; R6 is H, alkyl dCs; or R5 and R6 together define a 5 or 6 membered ring having 0 or 1 additional hetero atom and / or 0-2 unsaturated bonds and / or 0-2 substituents; R7 is H, 0, -0.2 alkyl, (CHm) nNR5R6; X and its surrounding circle define a ring of 5 or 6 m members that has 0 to 3 unsaturated bonds and / or 0 to 3 hetero atoms selected from S, O and N; m is independently 1 or 2; n is independently 0, 1 or 2; p is 0 or 1; and pharmaceutically acceptable salts thereof. 7. A compound according to claim 6, characterized in that the ring containing X is naphthyl, pyridyl, quinolyl or phenyl. 8. A compound according to claim 7, characterized in that the ring containing X is phenyl. 9. A compound according to claim 7, characterized in that the ring containing X is pyrid-2-yl or preferably pyrid-3-yl. 10. A compound according to claim 6, characterized in that R3 is -NH2, -NHCH3, -NHCH2CH3 or -N (CH3) 2. eleven . A compound according to claim 6, characterized in that R3 is in the meta position relative to the carbonyl group especially where the ring containing X is phenyl, or where R3 is in the para position relative to the carbonyl group, especially wherein the ring containing X is a heterocycle. 12. A compound according to claim 6, characterized in that - (CH2) n- and / or - (CH2) n- are absent, ie py / on are 0. 13. A compound according to claim 6, characterized in that Rx It's cyano. 14. A compound according to claim 6, characterized in that R1 is fluoro.
5. A compound according to claim 6, characterized in that R2 is ethyl. 1 6. A compound according to claim 6, characterized in that it comprises at least 60%, preferably at least 90% > of IS, 2S enantiomerically. 1 7. A compound according to claim 1, characterized in that it is selected from (1 S, 2S) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-propionylphenol) - cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1R, 2R) -N- [c /' s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1S, 2S) -N- [c s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea and (1 R, 2R) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '~ (5-bromopyrid-2-yl) -urea and pharmaceutically acceptable salts thereof. 1 8. A compound according to claim 1 7 denoted (1S, 2S) -N- [c / s-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl] -N '- (5- cyanopyrid-2-yl) -urea or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 1 selected from the group consisting of (1S, 2S) -N- [c / s-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropi I] -N '- (5-cyanopyrid-2-yl) -u rea, (1S, 2S) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro- 3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1 S, 2S) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) -urea, (1S, 2S) -N-. { c / s-2- [6-fluoro-3-propionyl-2- (6-methylamine inopyrid-3-ylcarbonyloxy) phenyl] cyclopropyl} -N '- (5-cyanopyrid-2-yl) urea, (1 R, 2 R) -N- [c / s-2- (2- (3-aminophenylcarbonyl) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2-yl) ) -urea, (1R, 2R) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid-2) -yl) -urea, (1R, 2R) -N- [c / s-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-cyanopyrid -2-il) -urea, (1 R, 2R) -N-. { c / s-2- [6-fluoro-3-propionyl-2- (6-methylaminopyrid-3-ylcarbonyloxy) phenyl] cyclopropyl} -N '- (5-cyanopyrid-2-yl) urea, (1S, 2S) -N- [c / s-2- (2- (3-amhophenoxycarbonyloxy) -6-fluoro-3-propionylfine I) -cyclopropyl] -N '- (5- Bromopyrid-2-yl) -urea, (1S, 2S) -N- [c / s-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- ( 5-Bromopyrid-2-yl) -urea, (1 S, 2S) -N- [c / s-2- (2- (3-dimethylamine mofen Icarbon i loxi) -6-f I uoro-3-propionylphenyl ) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea, (1S, 2S) -N-. { c / s-2- [6-fluoro-3-propionyl-2- (6-methylaminopyrid-3-ylcarbonyloxy) phenyl] cyclopropyl} -N '- (5-bromopyrid-2-yl) urea, (1 R, 2 R) -N- [c / 's-2- (2- (3-am inofen and Icarbonyl) -6-fluoro-3-propioni Ifin incid propi I] - N' - (5 -brom opi rid-2-il) -u rea, (1 R, 2 R) -N- [c / 's-2- (2- (3-eti lam inofen ilcarbonyloxy) -6-fl uoro-3- propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea, (1R, 2R) -N- [c s-2- (2- (3-dimethylamidophenylcarbonyloxy) -6-fluoro- 3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea, (1R, 2R) -N- { Cs-2- [6-fluoro-3-propionyl- 2- (6-methylaminopyrid-3-ylcarbonyloxy) phenyl] cyclopropyl} - N '- (5-bromopyrid-2-yl) urea, and pharmaceutically salts thereof 20. A compound according to claim 19 (1S) , 2S) -N- { C / s-2- [6-fluoro-3-propionl-2- (6-methylaminopyrid-3-ylcarbonyloxy) phenyl] cyclopropyl} - N '- (5-cyanopyrid-2-yl) urea and its pharmaceutically acceptable salts 21. A compound according to claim 19 (1S, 2S) -N- [c / s-2- (2- (3 -aminophenylcarbonylloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl] -N '- (5-bromopyrid-2-yl) -urea and its pharmaceutical salts amente acceptable. 22. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 21 and a pharmaceutically acceptable carrier or diluent therefor. 23. A composition according to claim 22, characterized in that it further comprises one to three additional antiviral agents. 24. A composition according to claim 23, characterized in that the additional antiviral agent is selected from the group consisting of AZT, dd l, ddC, D4T, 3TC, adefovir, adefovir dipivoxil, abacavir, bis-POC-PMPA, foscarnet, hydroxyurea, efavirenz, trovirdine, neviparin, delavirdine, PFA, H2G, ABT 606, ritonavir, saquinavir, ndinavir, amprenavir (Vertex VX 478), Mitsubishi MKC-442 and nelfinavir. 25. A compound according to any of claims 1 to 21, for use in therapy. 26. The use of a compound according to any of claims 1 to 21 in the manufacture of a medicament for the treatment or prophylaxis of H IV. 27. A method for inhibiting or preventing HIV infection comprising administering an effective amount of a compound as defined in claim 1 or 6 to a subject in need of the same. 28. A method for the preparation of a compound of Formula I comprising the compression of the Curtius reinstallation of the azide of a compound of the formula: followed by coupling with a compound of the formula and deprotection, wherein R1, R2 and Rx are as defined above and PG is a hydroxy protecting group. 29. A method according to claim 28, characterized in that it further comprises the step of a) acylating with an activated compound of the formula I 1: R Where R3, R4, X and n are as defined above but optionally protected, and R8 is hydrogen or a conventional activation group; or b) renting with a compound of the formula I l the: halo «Illa wherein n, R3, R4 and X are as defined above, but wherein the exposed amine, hydroxy substituents etc are protected with conventional protecting groups.