HK1036280B - Antivirals - Google Patents

Description

Antiviral medicine

Technical Field

The present invention relates to the field of antiviral drugs and in particular to HIV reverse transcriptase inhibitors. The present invention provides novel compounds, pharmaceutical compositions containing these compounds and methods of using them for the inhibition of HIV.

Background

Among the drugs that have shown clinically relevant activity in the treatment of HIV in the inhibition of HIV reverse transcriptase are most nucleoside analogs such as AZT, ddl, ddC and D4T. These nucleoside analogues are not as specific as desired and therefore have to be administered at relatively high dosage levels. At these dosage levels, nucleoside analogs cause considerable toxicity, limiting their long-term use.

To overcome these specificity and toxicity problems, a number of non-nucleoside inhibitors of the HIV reverse transcriptase have been developed. For example, TIBO, a reverse transcriptase inhibitor from the company popson, inhibits HIV at nanomolar concentrations and does not exhibit clinically significant toxicity. Both TIBO and the non-nucleoside reverse transcriptase inhibitor nevirapine rapidly undergo patient phase II clinical trials. However, it has become apparent shortly that these non-nucleoside inhibitors rapidly select in vivo their HIV mutants against the usual dose of the respective inhibitor. For example, in the case of nevirapine, the virus isolated from the patient's serum was 100-fold less sensitive to the Drug than the virus isolated from untreated patients only after four weeks of treatment (Drug Design & Discovery 19928, page 255-263). A similar pattern has emerged for other non-nucleoside RT inhibitors that have entered clinical trials, namely that L-697661 from Merck and delavirdine (U-87201) from Protek, which are active in vitro, have rapidly generated mutants against HIV when administered to patients. Nevirapine and delavirdine, which have the above disadvantages, have recently been registered for clinical use, although limited to specific combination regimens in an attempt to delay the development of drug resistance.

International patent application No. WO 95/06034 describes a series of novel urea derivatives which exhibit good in vitro anti-HIV reverse transcriptase activity and good inhibition of HIV replication in cell culture. However, the practical use of the compounds described in WO 95/06034 is hampered by their poor pharmacokinetic performance. Furthermore, like many non-nucleoside reverse transcriptase inhibitors, the compounds in WO 95/06034 leave room for improvement in key parameters of slow drug resistance development and in a good model of anti-HIV mutant activity resulting from other antiviral regimens.

* berg, equal to 1995 on ICAR held by Santa Fe, specifically discloses the above mentioned racemic compound in WO 95/06034 and having the formula

At this time, the above-described compounds are considered to have a smaller meaning than the variant of thiourea containing a benzene ring with methoxy/acetyl groups. However, we have now found additional substitution patterns which demonstrate an improved resistance pattern compared to prior art compounds with good pharmacokinetic properties and a prolonged period of viral resistance. Thus, the present invention provides inhibitors that combine the superior specificity of non-nucleoside inhibitors with the lack of clinical utility of all prior art inhibitors.

Brief description of the invention

The present invention provides compounds of formula I:

wherein

R¹Is halogen;

R²is C₁-C₃An alkyl group;

R^xis cyano or bromo;

and pharmaceutically acceptable salts and prodrugs thereof.

The present invention further provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent therefor. In a further aspect of the invention, there is provided a method of inhibiting HIV which comprises administering to a patient suffering from HIV a compound of formula I. The invention also extends to the use of a compound of formula I in therapy, for example in the manufacture of a medicament for the treatment of HIV infection.

In the treatment of HIV-induced diseases, the compound of formula I is preferably administered in an amount to achieve a plasma level of about 10 to 1000nM and more preferably 100 to 500 nM. This corresponds to a dosage ratio of 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day, depending on the bioavailability of the preparation. Typical dosage rates for normal adults will be about 0.05 to 5g per day, preferably one to four dosage units per day, 0.1 to 2g, e.g. 500-750 mg.

A preferred subset of compounds in claim 1 with particular regard to pharmacokinetics has the structure IA:

wherein R is¹And R²As defined above, including pharmaceutically acceptable salts and prodrugs thereof.

In formula I, another advantageous subset of compounds that are particularly susceptible to forming prodrugs include those wherein R^xA compound which is bromine.

R¹Preferably chlorine and more preferably fluorine. Suitable R²The groups include methyl, isopropyl, n-propyl and preferably ethyl.

As mentioned above, the cyclopropyl ring exists in a cis configuration, allowing the presence of two enantiomers, 1S, 2S and 1R, 2R (2R, 1S and 2S, 1R in SE 980016-7 and SE 9800113-4, respectively and unconventionally):

each of these enantiomers is a potent antiretroviral drug, although the different enantiomers can exhibit subtle differences in physiological properties. For example, the 1S, 2S and 1R, 2R enantiomers can exhibit different patterns of metabolism in the P450 system. Wherein R is^xThe 1S, 2S enantiomer of the compound being cyano is particularly preferred because it uniquely exhibits the ability to avoid key components in the P450 system. Other retroviral drugs such as the HIV protease inhibitor ritonavir interact extensively with the P450 system, resulting in a number of undesirable physiological responses including extensive alterations in the metabolism of other co-administered drugs. This is particularly relevant for drugs administered for chronic infections when patients expect to take multiple agents for many years, if not decades.

Suitable prodrugs of compounds of formula I include those of formula II:

wherein

R¹、R²And R^xAs defined above, the above-mentioned,

R³is H, (CH)_m)_nNR⁵R⁶；

R⁴Is H, C₁-C₃Alkyl group, (CH)_m)_nNR⁵R⁶、(CH_m)_nC(＝O)R⁵、(CH_m)_nOH、OR⁷Halogen, CF₃Or CN; or

R³And R⁴Together are defined as a 5 or 6 membered fused ring having 0-2 heteroatoms and/or 0-2 unsaturated bonds and/or 0-2 substituents;

R⁵is H, C₁-C₃Alkyl, C (═ O) R⁷Or a peptide of 1 to 4 amino acids;

R⁶is H, C₁-C₃An alkyl group; or R⁵And R⁶Together are defined as a 5-or 6-membered ring having 0 or 1 additional heteroatoms and/or 0-2 unsaturated bonds and/or 0-2 substituents;

R⁷is H, C₁-C₁₂Alkyl group, (CH)_m)_nNR⁵R⁶；

X and the rings comprising it are defined as 5 or 6 membered rings having 0 to 3 unsaturated bonds and/or 0 to 3 heteroatoms selected from S, O and N;

m is independently 1 or 2;

n is independently 0, 1 or 2;

and pharmaceutically acceptable salts thereof.

Wherein R is^xThe corresponding prodrug of a compound which is chlorine forms a further aspect of the invention.

The X-containing ring structure, referred to hereinafter as the X-ring, may be saturated or have 1-3 unsaturated bonds, including rings with aromatic character. Preferred X-rings include a cyclohexyl ring or a cyclohexene ring or more preferably a benzene ring. Other preferred X-rings include morpholino or more preferably pyridine rings. Alternatively, the X-ring may be defined as a five-membered ring such as a pentenyl or pyrrolyl group.

At R³And R⁴Where the bonds form a ring containing optional heteroatoms, suitable fused ring systems for the X-ring include naphthyl, quinolinyl, tetrahydroisoquinolinyl, indolyl or benzimidazole ring systems. At R⁴And R⁵Where the bond forms a ring, suitable substituent rings for the X-ring include morpholino and piperidino. These fused or substituted rings may be substituted with halogen, halomethyl, amino groups such as (CH)_m)_nNR⁵R⁶、C(＝O)NR⁵R⁶Hydroxy, hydroxymethyl, carboxy, carboxymethyl, C_1-3Alkyl radical, C_1-3Alkoxy, and the like are optionally substituted.

The X-ring may be separated from the adjacent carbonyl moiety by a methylene or ethylene group, which may be substituted by substituents such as halogen, halomethyl, amino, aminomethyl, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C_1-3Alkyl radical, C_1-3Alkoxy, and the like are optionally substituted. Preferably the X-ring is adjacent to the carbonyl group.

From X-ring systems, R³、R⁴And R if present⁵-R⁷The moiety shown preferably has a somewhat basic character. This can be achieved by selecting a suitable basic heterocyclic ring as the X-ring, for example pyridyl or benzopyridyl. Or, R³To R⁷One or more of which may contain basic substituents such as primary, secondary or tertiary amines, amino acids, and the like.

Advantageous R³And/or R⁴The radicals comprising NH₂、N(CH₂)₂And NHC_1-3Alkyl radicals such as NHCH₃Or NHCH₂CH₃。R³Preferably in meta position relative to the carbonyl group and optional spacer groups thereof, especially when the ring containing X is phenyl or when containingWhen the ring of X is a heteroaromatic ring, e.g. pyridin-3-yl, R³Is in the para position. It is generally preferred that p and/or n have a value of zero, i.e. the respective group is absent.

Preferred compounds of the invention include: (1S, 2S) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Other preferred compounds include: (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Other suitable compounds of the invention include: (1R, 2R) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Other suitable compounds include: (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include: (1S, 2S) -N- [ cis-2- (2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N '- (5-bromopyridin-2-yl) -urea, (1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N '- (5-bromopyridin-2-yl) -urea, (1R, 2R) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea Urea; (1R, 2R) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Further preferred compounds include: (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1S, 2S) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-methylaminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-butyrylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; (1R, 2R) -N- [ cis-2- (2- (6-aminopyridin-3-ylcarbonyloxy) -6-fluoro-3-acetylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea; and pharmaceutically acceptable salts thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula I include organic carboxylates such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic and succinic acids, salts of organic sulphonic acids such as methanesulphonic, ethanesulphonic, benzenesulphonic, p-chlorobenzenesulphonic and p-toluenesulphonic acids; and include inorganic acids such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, and sulfamates.

In keeping with the usual practice of using HIV inhibitors, it is advantageous to co-administer one to three additional antiviral drugs to provide a synergistic response and ensure a complementary resistance pattern. Such additional antiviral agents may include AZT, ddI, ddC, D4T, 3TC, abacavir, adefovir dipivoxil, bis-POC-PMPA, foscarnet, hydroxyurea, Hurst-Bayer HBY097, efavirenz, trovirdine, Nevirapine, delavirdine, PFA, H2G, ABT606, DMP-450, loviride, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX478), nelfinavir, and the like, typically administered in molar ratios responsive to their respective activities and bioavailabilities. In general, such a ratio is from 25: 1 to 1: 25 relative to the compound of the formula I.

Although it is possible for the active agent to be administered alone, it is preferably present as part of a pharmaceutical formulation. Such formulations will include the active agents defined above together with one or more acceptable carriers and optionally include other therapeutic ingredients. The carrier must be acceptable in terms of compatibility with the other ingredients of the formulation and not deleterious to the recipient.

Such formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and transdermal) administration. The formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and may be prepared by any of the methods well known in the art of pharmacy.

Such a method comprises the step of bringing together the active agent as defined above and said carrier. The formulations are generally prepared by uniformly and intimately bringing into association the active agent with liquid carriers or solid carriers for powders or both, and then, if necessary, shaping the product.

The formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent, as powders or granules, as solutions or suspensions of the active agent in water-soluble or non-water-soluble liquids or as oil-in-water or water-in-oil liquid emulsions and as boluses (bolus) and the like.

With respect to compositions for oral administration (e.g., tablets and capsules), the term suitable carrier includes vehicles such as common excipients for example binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers such as 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 fluids, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, and the like can also be used. The addition of a colorant may be required to make the dosage form readily discernible. Tablets may also be coated by methods well known in the art.

Suitable carriers for oral administration include liquid preparations in the form of solutions, suspensions or emulsions, optionally encapsulated in conventional manner or in unit dosage forms. Advantageous formulations include acacia/tween/water, propylene glycol, vegetable oils with 10-20% ethanol (e.g. peanut oil, safflower oil, olive oil, etc.), vegetable oils/Capmul MGM, Capmul MCM/propylene glycol, methyl cellulose/water, vegetable oils/stearoyl monoglycerides, vegetable oils/monounsaturated fatty acid glycerides, etc.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may 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, surfactant or dispersing agent. Molded tablets may be prepared by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and formulated so as to provide slow or controlled release of the active agent.

Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth, pastilles comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia, and mouthwashes comprising the active agent in a suitable liquid carrier.

Formulations suitable for topical administration to the skin include those which may be presented as ointments, creams, gels, and pastes containing 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 swabs that release the active agent onto the skin prior to invasive procedures such as syringe or capillary blood sampling. Such swabs neutralize HIV in the blood or serum shed from the invasive process, thereby helping to prevent accidental transfer of HIV through the needle to a healthy care worker. Such swabs may comprise sterile surgical gauze pads soaked in a solution of the active agent in a volatile solvent, such as ethanol, and individually packaged in sealed sachets.

Formulations for rectal or vaginal administration may be presented as suppositories and pessaries with suitable bases including, for example, cocoa butter or salicylates. Other vaginal formulations can be presented as tampons, creams, gels, pastes, foams or sprays containing in addition to the active agent such carriers as are known in the art to be appropriate.

Formulations suitable for nasal administration in which the carrier is a solid include a coarse powder having a particle volume, for example in the range 20 to 500 microns, which is administered in a manner in which snuff is taken, i.e. by rapid inhalation from the powder container held up to the nose. Formulations wherein the carrier is a liquid suitable 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 aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, antimicrobials and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (freeze-dried) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

In another aspect the invention provides a process for the preparation of a compound of formula I, especially the cis isomer, which process comprises a curtius rearrangement of a compound of formula:

followed by coupling and deprotection of a compound of the formula wherein R¹、R²And R^xAs defined above and PG is a hydroxyl protecting group:

the process of the invention additionally comprises the step of acylation with an activated compound of formula III:

wherein R is³、R⁴X and n are as defined above but are optionally protected, and R⁸Hydrogen or a conventional activating group. Alternatively, the process of the invention may additionally comprise the step of alkylation with a compound of formula IIIa:

wherein n and R³、R⁴And X is as defined above, but the exposed amine, hydroxyl, etc. substituents are protected with conventional protecting groups.

Accordingly, the enantiomeric compound of formula I can be prepared by the following reaction scheme:

the above scheme illustrates where R^xIs cyano, R¹Is F and R²Preparation of the (1S, 2S) compounds of the invention which are ethyl, but the corresponding processes are suitable for other R^x、R¹And R²A variant of (a). The chiral ligands suitable for use in the fourth step may include, for example, compounds of the formula:

to prepare the 1R, 2R enantiomers, a mirror image chiral ligand is used. Or the chiral ligand may be omitted in order to form the racemate.

Prodrugs of formula II wherein p is 0 can be synthesized by acylating a compound of formula I with an activated compound of formula III,

wherein R is³、R⁴X and n are as defined above but are optionally protected, and R⁸Hydrogen or a conventional activating group.

Activated compounds of formula III include acid halides, anhydrides, esters of activated acids or the acids in the presence of coupling agents such as dicyclohexyl-carbodiimide. Representative activated acid derivatives include acid chlorides, mixed anhydrides derived from formic and acetic acids, anhydrides derived from alkoxycarbonyl halides such as isobutoxycarbonyl chloride 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 formula III, particularly amines of any substituent, include those intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthesis. Commonly used N protecting groups are disclosed in Greene, "protecting groups in organic Synthesis" (John Wiley & Sons, New York, 1981), which is incorporated herein by reference. The N-protecting group includes acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl such as benzenesulfonyl, p-toluenesulfonyl and the like, and carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, and the like, 2, 2, 2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc.; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Advantageous N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-Butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).

The acylation reaction is carried out using conventional esterification conditions such as DMAP and DCC in a solvent such as dimethylformamide or pyridine. The optional protecting group can be removed by conventional techniques as discussed in general in Greene above, e.g., TFA, HCl (aq)/dioxane or hydrogenation in the presence of a catalyst to provide the compound of formula II.

Compounds of formula II wherein p is 1 can be prepared by the following method: reacting the compound of formula III with iodochloromethane or mixed dichloromethane/iodochloromethane under conventional alkylation conditions to form the compound of formula IIIa:

wherein n and R³、R⁴And X is as defined above, but the exposed amine, hydroxyl, etc. substituents are protected with conventional protecting groups. The compound of formula IIIa is then preferably converted to the corresponding iodo derivative by reaction with NaI and subsequently coupled with the compound of formula I, typically under basic conditions, for example in an organic solvent containing sodium hydride.

Detailed Description

These aspects of the invention will now be elucidated by way of example only with reference to the following non-limiting examples and figures, in which;

FIG. 1 depicts the rate of drug resistance development versus time for compounds of the invention as compared to prior art compounds as described in biological example 2.

Figure 2 depicts the time to plasma levels of a compound of the invention or a prior art compound as described in biological example 5 after oral administration to rats.

FIG. 3 depicts the binding kinetics of reverse transcriptase for compounds of the invention compared to prior art compounds as determined by surface plasmon resonance as described in biological example 10.

Preparation of intermediates

Example 1

3- [1, 1- (ethylenedioxy) propyl ] -6-fluoro-2-methoxybenzaldehyde

To a solution of 3-fluorophenol (22.4g, 0.2mol), pyridine (24ml, 0.3mol) and dichloromethane (200ml) was added 20ml (0.225mol) propionyl chloride at room temperature over 5 minutes. The reaction is exothermic. The solution was stirred for an additional 30 minutes. After addition of dichloromethane, saturated NaHCO was added₃The solution and water wash the organic phase over MgSO₄Dried and concentrated in vacuo. 33.8g (100%) of 3-fluoro-1-propionyloxybenzene are obtained. This compound was reacted with 33.3g (0.25mol) AlCl at 150 DEG C₃The reaction was carried out for 10 minutes. After careful quenching with water, the reaction mixture was extracted three times with diethyl ether. Drying (MgSO)₄) The ether phase was evaporated to give 29.5g (0.176mol, 88%) of the rearrangement product. This intermediate was dissolved in 200ml acetone and K₂CO₃(42, 0.3mol) and MeI (25ml, 0.4mol) was added. The reaction mixture was heated at 40 ℃ for 12 hours. The reaction mixture was filtered and the acetone was evaporated. The residue was dissolved in ether and the ether phase was washed with 0.5m naoh solution and water. Drying (MgSO)₄) And evaporated to give 31.2g (0.17mol, 86% yield in three steps) of 4-fluoro-2-methoxyphenylethyl ketone.

To a solution of 4-fluoro-2-methoxyphenylethyl ketone (31.2g, 0.171mol), ethylene glycol (10.5ml, 0.188mol) in benzene (300ml) was added 1g of p-toluenesulfonic acid. The reaction mixture was refluxed in a dean-Stark apparatus for about 12 hours. After cooling, the organic phase is washed several times with 1M NaOH solution and dried (Na)₂SO₄And K₂CO₃). The solvent was evaporated and about 38g of acetal was obtained. According to capillary GC, the purity was 88% and the impurities were essentially unreacted ketone. To a solution of the acetal in THF (450ml) at-65 ℃ under a nitrogen atmosphere was added dropwise 128ml (0.32mol) of 2.5M n-butyllithium. While maintaining the temperature at about-65 ℃, a solution of DMF (25ml, 0.32mol) in THF (50ml) was added. The reaction mixture was allowed to slowly reach room temperature and left the starting material after about 30 minutes according to GC. After another 1 hour, the reaction mixture was saturated with NH₄The Cl solution was quenched and extracted three times with ether. Drying (Na)₂SO₄) The residue was then purified on a silica gel column (from Merck silica gel 60, particle size 0.04-0.063mm), eluting with EtOAc1 and hexane 9, to give 10g (25%) of the title compound.¹H NMR(CDCl₃)δ0.85(t，3H)，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- [1, l- (ethylenedioxy) propyl ] -6-fluoro-2-methoxystyrene

To a suspension of methyltriphenylphosphonium bromide (14.3g, 40mmol) in THF (250ml) at room temperature under a nitrogen atmosphere was added 16ml (40mmol) of 2.5M n-butyllithium. Then, 3- [1, 1- (ethylenedioxy) propyl group in THF (30ml) was added to the resulting solution]-6-fluoro-2-methoxybenzaldehyde (10g, 39.5 mmol). The reaction mixture was then stirred at room temperature for 2 hours and poured into a mixture of hexane and brine. The organic phase was washed twice with brine and once with water. After evaporation of the solvent, the residue was filtered through a funnel filled with alumina (alumina 90acc. brockmann from merck) and eluted with EtOAc1 and hexane 9 to facilitate removal of the triphenylphosphonium oxide formed. Evaporation of the organic solvent gave a residue which was finally purified on a silica gel column eluting with EtOAc1 and hexanes 9 to give 6.9g (70%) of the title compound with 94.5% purity as determined by capillary GC.¹H NMR(250MHz，CDCl₃)δ0.85(t，3H)，2.1(q，2H)，3.8(s，3H)，3.8-3.95(m，2H)，4.0-4.1(m，2H)，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) -cis-2- (6-fluoro-2-methoxy-3-propionylphenyl) cyclopropylcarboxylic acid

Copper (I) trifluoromethanesulfonate (679mg, 1.35mmol) and a chiral ligand were used as generally described by Evans et al in J.Am.chem.Soc.1991, 113, 726-728Body ([2, 2' -isopropylidene bis ((4R) -4-tert-butyl-2-oxazoline)](794mg, 2.7mmol) from 3- [1, 1- (ethylenedioxy) propyl]-6-fluoro-2-methoxystyrene (19.4g, 69mmol) and ethyl diazoacetate (29ml, 275mmol) to prepare ethyl (1S, 2R) -cis-2- [3- (1, 1-ethylenedioxy) ethyl-6-fluoro (2-methoxy-phenyl) cyclopropylcarboxylate. After chromatography on silica gel, 9.4g (40.5%) of the ethyl ester are obtained. The enantiomeric excess was 99% as determined by HPLC on a chiral column. The ester was dissolved in 150ml dioxane and 30ml 6M HCl was added. The reaction mixture was stirred overnight and partitioned between ether and brine. Evaporation of the solvent gave 19g of crude product. The product was dissolved in methanol (250ml) and water (75ml) and 6g (250mmol) of LiOH was added. The reaction mixture was heated to 90 ℃ for 24 hours and most of the solvent was evaporated. The remaining mixture was acidified and extracted three times with dichloromethane. Evaporation of the solvent gave 11.2g of the title compound.¹H NMR(250MHz，CDCl₃) δ 1.15(t, 3H), 1.59(t, 2H), 2.10-2.17(m, 1H), 2.22-2.32(m, 1H), 2.91(q, 2H), 3.80(st, 3H), 6.82(t, 1H), 7.44-7.50(m, 1H), 11.30 (width s, 1H).

Example 4

(1R, 2S) -cis-2- (6-fluoro-2-methoxy-3-propionylphenyl) cyclopropylcarboxylic acid

From 3- [1, 1- (ethylenedioxy) propyl ] as described for the acid in example 3]-6-fluoro-2-methoxystyrene. The chiral ligand used was 2, 2' -isopropylidenebis ((4S) -4-tert-butyl-2-oxazoline).¹H NMR(250Mhz，CDCl₃)δ7.48(q，1H)，6.84(t，1H)，3.82(s，3H)，2.93(q，2H)，2.29(q，1H)，2.14(q，1H)，1.60(m，2H)，1.16(t，3H)。

Preparation of Compounds of formulae I and II

Example 5

(±) N- [ cis-2- (2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

A solution of 3- [1, 1- (ethylenedioxy) propyl ] -6-fluoro-2-methoxystyrene (32.4g, example 2) and copper bromide-dimethylsulfide complex (0.30g) in dichloroethane (200ml) was heated to 80 ℃ under a nitrogen atmosphere. Ethyl diazoacetate (54ml) in dichloroethane (600ml) was added over 7 hours. After the addition was complete, the heating was terminated. After 16 h, the solvent was evaporated and the residue was purified on silica gel, eluting with ethyl acetate and hexane, to give the cis-ester (6.5 g).

The cis-ester (3.7g, 10.9mmol) was dissolved in ethanol (20ml) and KOH (1.8g, 32.7mmol) was dissolved in water (10 ml). The solutions were combined and heated to reflux for 3 hours. Water (30ml) was added and the solution was washed twice with hexane (20 ml). The aqueous phase was cooled on an ice bath and acidified with dilute HCl. The solution was extracted three times with toluene. Drying (MgSO)₄) The toluene phase was evaporated to give 1.9g of (. + -.) -cis-2- [3- (1, 1-ethylenedioxypropyl) -6-fluoro-2-methoxyphenyl]Cyclopropyl carboxylic acid.

Triethylamine (59. mu.l, 0.43mmol) and diphenylphosphoryl azide (92. mu.l, 0.43mmol) were added to a solution of the acid (120mg, 0.39mmol) in dry toluene. The solution was stirred at room temperature for 1 hour and then heated to 120 ℃. After 1h, 2-amino-5-cyanopyridine (51mg, 0.43mmol) was added. Heating was maintained for another 3 hours. After 16 h, the solvent was evaporated, the residue was dissolved in dichloromethane (30ml) and washed with dilute HCl, dried (MgSO)₄) And evaporated to give 152 mg. The product was dissolved in dioxane and HCl (6N, 1ml) was added. After 2 hours, the mixture was evaporated, dissolved in dichloromethane (25ml), washed with water (10+10ml) and dried (MgSO)₄) And evaporated to give 117 mg. The residue was purified on silica gel, eluting with ethyl acetate and hexanes, to give 37mg of the 2-methoxyphenyl intermediate product.

A1M solution of boron tribromide in dichloromethane (194 μ l, 0.194mmol) was added to a solution of the 2-methoxyphenyl intermediate (37mg, 0.097mmol) in dichloromethane at-60 ℃. After 10 minutes, withdrawThe cooling bath was removed and stirring was continued for 2 hours. The solution was diluted with dichloromethane and diluted NaHCO₃And washed with water and dried (MgSO)₄) And evaporated. The residue was recrystallized from MeCN to yield 17mg of the title compound.¹H NMR(250MHz，DMSO-d₆)δ1.07-1.16(m，4H)，1.41-1.50(m，1H)，1.91-2.01(m，1H)，3.06-3.19(m，3H)，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- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-cyanopyridin-2-yl) -urea

Triethylamine (0.85mL, 6.1mmol) and diphenylphosphoryl azide (1.72g, 6.1mmol) were added to a solution of the acid prepared in example 4 (1.47g, 5.5mmol) in dry toluene (15 mL). The solution was stirred at room temperature for 30 minutes under argon atmosphere and then heated to 120 ℃. After 15 min, a solution of 2-amino-5-cyanopyridine (0.99g, 8.9mmol) in DMF (3mL) was added. Heating was continued for 4 hours. Toluene was evaporated, the mixture diluted with ether (100mL) and ethyl acetate (50mL) and washed with 1M HCl, H₂O and brine wash. Drying (Na)₂SO₄) The organic layer was concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-hexane 1: 10 to 1: 1 to give 1.6g (66%) of the 2-methoxyphenyl intermediate.

Boron trichloride in CH at-72 ℃ under argon₂Cl₂To the 1M solution (11.0mL, 11.0mmol) of the 2-methoxyphenyl intermediate (1.40g, 3.66mmol) in CH₂Cl₂(80 mL). After 10 minutes, the cooling bath was removed and stirring was continued for 1 hour 15 minutes. The solution is prepared from CH₂Cl₂Diluted and treated with NaHCO₃Aqueous solution, H₂O and brine wash. Drying (NaSO)₄) The organic layer was concentrated. From acetonitrile/H₂Precipitation of O1: 1 gave 0.62g of the pure title compound. Concentrating the residue andchromatography eluting with ethyl acetate/n-hexane 1: 10 to 1: 1 and ethyl acetate followed by crystallization from acetonitrile gave 0.2g of the title product. The yield was 0.82g (61%). The ee was 95% as determined by HPLC on a chiral column. [ alpha ] to]_d ²²-171.2°(c＝0.50，CH₂Cl₂)。¹H N-MR(250Mhz，CDCl₃)δ13.35(d，1H)，10.02(br s，1H)，9.40(br s，1H)，8.11(s，1H)，7.71(m，2H)，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- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

To a solution of the compound described in example 6 (1.64g, 4.4mmol), BOC-protected 3-aminobenzoic acid (1.6g, 6.6mmol) and 4-dimethylaminopyridine (269mg, 2.2mmol) in 20ml dichloromethane and 10ml DMF was added 1.36g (6.6mmol) DCC at room temperature under an argon atmosphere. The reaction mixture was stirred for 24 hours. The solvent was carefully evaporated and the residue was purified on silica gel using hexane/ethyl acetate 1: 1 as solvent to give 2.6g of the BOC-protected title product. The product was added to 75ml of trifluoroacetic acid at 0 ℃. The mixture was then stirred at 0 ℃ for 1 hour. The solvent was carefully removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium carbonate. The organic phase was dried and evaporated. The residue was purified on a silica gel column using ethyl acetate/hexane 4: 1 as eluent to give 1.03g of the title compound as the free base. The intermediate was treated with 3ml of 1M HCl in ether and 0.84g of the title compound was obtained. HPLC purity was about 97%.¹H NMR liberated amine (250MHz, CDCl)₃) δ 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 (width)s, 1H), 9.6 (width s, 1H).

Example 8

(1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-cyanopyridin-2-yl) -urea

Triethylamine (670. mu.l, 4.8mmol) and diphenylphosphoryl azide (1.05ml, 4.9mmol) were added to a solution of the acid prepared in example 3 (1.2g, 4.5mmol) in dry toluene (10ml) under nitrogen. The solution was stirred at room temperature for 30 minutes and then heated to 120 ℃. After 15 minutes, a solution of 2-amino-5-cyanopyridine (0.80g, 6.7mmol) in dimethylformamide (1.5ml) was added and heating was continued for 4 hours. The solution was diluted with ether and washed with 1M hydrochloric acid. Drying (MgSO)₄) The organic layer was concentrated. The residue was purified by flash chromatography on silica gel (gradient elution, starting with n-hexane/ethyl acetate 1: 1, run with pure ethyl acetate) to give a slightly impure 2-methoxyphenyl derivative (0.93 g). The chromatography was repeated as described above to give the pure 2-methoxyphenyl derivative (0.70g, 41%).

A1M solution of boron trichloride in dichloromethane (5.5ml, 5.5mmol) was added to a solution of the 2-methoxyphenyl intermediate (700mg, 1.8mmol) in dichloromethane at-60 ℃. After 10 minutes, the cooling bath was removed and stirring was continued for 2 hours. The solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate. Drying (MgSO)₄) The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (gradient, n-hexane: ethyl acetate 2: 1, 1: 2, Ethyl acetate methanol (8: 1) purification afforded the title compound (500mg, 74%). [ alpha ] to]_D ²²+165.0°(C＝0.5，CH₂Cl₂)。¹H NMR(DMSO-d₆)δ1.10-1.16(m，4H，CH₃，CH₂Cyclopropyl), 1.45(dd, 1H, CH)₂Cyclopropyl), 1.96(q, 1H, CH-cyclopropyl), 3.10-3.19(m, 3H, CH-cyclopropyl, CH)₂)，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- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

Starting from the compound described in example 6 and using the method described in example 7, the title product was obtained as the hydrochloride salt.¹H NMR(250MHz，DMSO-d₆)δ0.94(t，3H)，0.9-1.0(m，1H)，1.3-1.4(m，1H)，1.85-1.95(m，1H)，2.91(q，2H)，3.05-3.15(m，1H)，7.4-7.5(m，2H)，7.6-7.7(m，1H)，7.9-8.1(m，5H)，8.08(d，1H)，9.85(s，1H)。

Example 10

(1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

(1S, 2R) -cis-2- (6-fluoro-2-methoxy-3-propionylphenyl) cyclopropylcarboxylic acid (3.0g, 11.3mmol), triethylamine (1.58ml, 11.3mmol) and diphenylphosphoryl azide (2.44ml, 11.3mmol) were dissolved in dry toluene (8ml) at room temperature under argon. The reaction mixture was stirred at room temperature for 30 minutes, after which the temperature was raised to 120 ℃ and maintained for another 15 minutes. Then, 2-amino-5-bromopyridine (2.08g, 12mmol) was added and the reaction mixture was stirred at 120 ℃ for 2.5 hours. Benzene and 1M HCl solution were added and the organic phase was evaporated. The residue was purified on silica gel using hexane/ethyl acetate 1: 1 as eluent. The appropriate fractions were collected and 5.0g of (1S, 2S) -N- (cis-2- (6-fluoro-2-methoxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea was obtained. The compound was dissolved in dichloromethane (100ml), the solution was kept under argon and cooled to-65 ℃. Boron trichloride (30ml of a 1M solution in dichloromethane, 30mmol) 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 ethyl acetate methanol 9: 1 as eluentA compound (I) is provided. 1.96g (41%) of the title compound are obtained. And (3) analysis: calculated values: c51.2, H4.1, N9.9. Measured value: c51.5, H3.7, N9.5. And Mp: 198 ℃ and 199 ℃. [ alpha ] to]_D ²²+149.8°(c＝0.50，CH₂Cl₂)。¹H NMR(250MHz，CDCl₃) δ 1.28(t, 3H), 1.52-1.62(m, 2H), 1.94-2.05(m, 1H), 2.97-3.06(m, 2H), 3.17-3.20(m, 1H), 6.60(t, 1H), 6.76 (width s, 1H), 7.57(dd, 1H), 7.67-7.72(m, 1H), 7.83 (width s, 1H), 8.53 (width s, 1H), 13.32(d, 1H).

Example 11

(1R, 2R) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

The compound described in example 2 was subjected to asymmetric cyclopropanation using the chiral ligand 2, 2' -isopropylidenebis (4S) -4-tert-butyl-2-oxazoline (available from Aldrich) as described in example 3. The resulting (1R, 2S) -cis-2- (6-fluoro-2-methoxy-3-propionylphenyl) cyclopropylcarboxylic acid was then used in analogy to example 10 to give the title compound.¹H NMR(250MHz，DMSO-d₆) δ 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 (width s, 1H), 7.95-8.05(m, 1H), 9.41 (width s, 1H), 13.20(s, 1H). [ alpha ] to]_D ²²-153.8°(c＝0.50，CH₂Cl₂)。

Example 12

(1S, 2S) -N- [ cis-2- (2- (3-aminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

To a solution of the compound from example 10 (633mg, 1.5mmol), BOC-protected 3-aminobenzoic acid (475mg, 2mmol) and 4-dimethylaminopyridine (123mg, 1mmol) in 20ml dichloromethane: DMF 1: 1 was added 415mg (2mmol) of DCC at room temperature under argon. The reaction mixture was stirred for 36 hours. Carefully steamingThe residue was purified on silica gel using hexane: ethyl acetate 1: 1 as solvent to give 811mg of BOC-protected title product. This product was dissolved in dioxane (20ml) and 10ml 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 diethyl ether to give 255mg of the title product as HCl salt. The HPLC purity was about 93%.¹H-NMR(250MHz，CD₃OD) δ 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 (wide d, 1H), 8.26 (wide s, 1H), 8.35-8.37(m, 1H), 8.42-8.46(m, 1H).

Example 13

(1S, 2S) -N- [ cis-2- (2- (3-L-alanylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

See, e.g., Bodanszky's "practice of peptide Synthesis" second edition, Springer, using standard chemical methods to prepare the starting compound BOC-protected 3-L-alanoylaminobenzoic acid from TCE-protected 3-aminobenzoic acid. This compound was reacted with the compound of example 10 as described in example 12 to give the title product as HCl salt.¹H-NMR (250MHz, liberated amine, CDCl)₃) δ 1.10(t, 3H), 1.15-1.25(m, 1H), 1.4-1.5(m, 1H), 1.42(d, 2H), 1.76 (width s, 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 (width s, 1H), 9.05 (width s, 1H), 9.70 (width s, 1H).

Example 14

(1S, 2S) -N- { cis-2- [ 6-fluoro-3-propionyl-2- (4-pyridylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-bromopyridin-2-yl) urea

The product of example 10 was condensed with isonicotinic acid in a similar manner to example 12 to give the title product as the HCl salt。¹H-NMR(250MHz，CD₃OD)δ9.26(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- { cis-2- [2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl ] cyclopropyl } -N' - (5-bromopyridin-2-yl) urea

The product of example 10 was condensed with 3-dimethylaminobenzoic acid in analogy to example 12 to give the title product as the HCl salt.¹H-NMR(250MHz，CD₃OD)δ8.61(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- [ cis-2- (2- (3-aminomethylbenzoyloxymethyloxy) -5-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

3-tert-Butoxycarbonylaminomethylbenzoic acid was treated with tetrabutylammonium hydroxide solution (1M in MeOH) to pH9 and evaporated. The residue was dissolved in dichloromethane and treated with chloroiodomethane overnight. The solution was washed with water and evaporated to give crude 3-tert-butoxycarbonylamidomethylbenzoyloxymethyl chloride. This material was reacted with the sodium salt of example 10 (prepared with sodium hydride in DMF) using a small amount of sodium iodide as catalyst. After 2 hours reaction, the solution was quenched with acetic acid and diluted with dichloromethane, washed with water and evaporated. The crude product was purified on silica gel eluting with ethyl acetate/hexane 1: 2 and the pure material was treated with trifluoroacetic acid and evaporated to give the trifluoroacetate salt of the title compound as a solid.¹H-NMR(CDCl₃)δ1.1(t，3H)，1.3-1.5(m，2H)，2.2(q，1H)，2.9(m，2H)，3.2(bs，1H)，4.2(s，2H)，5.9(q，2H)，6.8(d，2H)，7.0(t，1H)，7.3-8.1(m，9H)。

Example 17

(1S, 2S) -N- (cis-2- (2- (3-amino-4-methylbenzoyloxy) -6-fluoro-3-propionylphenyl) cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

(1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea from example 10 was condensed with 3-tert-butoxycarbonylamido-4-methylbenzoic acid according to the procedure in example 12. The product was treated with trifluoroacetic acid and evaporated to give the trifluoroacetate salt of the title compound as a solid.¹H-NMR(CDCl₃)δ1.1(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- (cis-2- (2- (3-ethylaminobenzoyloxy) -6-fluoro-3-propionylphenyl) cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

The compound of example 10 was condensed with 3- (N-ethyl-tert-butoxycarbonylamido) benzoic acid and the product was treated with trifluoroacetic acid and evaporated as in example 12 to give the trifluoroacetate salt of the title compound as a solid.¹H NMR(CDCl₃)δ1.1(t，3H)，1.3-1.6(m，5H)，2.9(q，2H)，3.1(bs，1H)，3.5(q，2H)，7.1(t，1H)，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- (cis-2- (2-quinolo-4-yloxy-6-fluoro-3-propionylphenyl) cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

The compound of example 10 was condensed with 4-quinolinic acid according to the procedure of example 12, and the product was dissolved in trifluoroacetic acid and evaporated to give a solidThe acetate salt of the title compound of (1).¹H NMR(CDCl₃)δ1.1(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- (cis-2- (3-aminomethyl-2-methylbenzoyloxy) -fluoro-3-propionylphenyl) cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea

The compound of example 10 was condensed with 3-tert-butoxycarbonylamido-2-methylbenzoic acid according to the procedure of example 12. The product was treated with trifluoroacetic acid and evaporated to give the title compound as a solid.¹H NMR(CDCl₃)δ1.1(t，3H)，1.1-1.3(m，2H)，1.9(m，1H)，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) -N- [ cis-2- (6-fluoro-2- (4-aminomethylphenylcarbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

4- (tert-Butoxycarbonylaminomethyl) benzoic acid was prepared by adding 6.5g DCC to a solution of 4g 4-cyanobenzoic acid in 200ml MeOH. The mixture was stirred at room temperature for 70 hours, the precipitated dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuo to give 7g of crude product. The methyl ester was dissolved in 500ml MeOH and 9.6g CoCl was added₂ 6H₂And O. Mixing the mixture with NaBH₄And (5) performing treatment in a grading manner. After 5 hours the reaction mixture was concentrated and the precipitate was removed. The filtrate was acidified with 150ml of 1M HCl (aq.) and with 2X 100ml of CH₂Cl₂And (4) extracting. The acidic aqueous phase was dissolved in 100ml of 25% NH₃(aq.) treatment with 3X 100ml CH₂Cl₂Extracted with Na₂SO₄Dried and concentrated to give 2.64gBrown oil.

The oil was dissolved in 30ml of dioxane/water mixture (2: 1) and treated with 1.5g NaOH(s) for 20 hours. The solvent was removed and 40ml of tert-butanol/water mixture (1: 1) were added. After addition of 3.7g of di-tert-butyl dicarbonate the solution is stirred for 24 hours, then more water is added and the mixture is extracted with 2X 50ml of hexane. Mixing the aqueous phase with NaHSO₄Acidified (pH 1.5-2.0) and extracted with 3X 75ml of diethyl ether. The combined extracts were washed with 50ml brine, washed with Na₂SO₄Drying and evaporation gave 4- (tert-butoxycarbonylamidomethyl) benzoic acid as an intermediate as a white solid.

4- (tert-Butoxycarbonylaminomethyl) benzoic acid and (1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea from example 10 were condensed and the BOC-protecting group was removed using the method described in example 12 to give the title product as the hydrochloride salt.¹H-NMR(250MHz，CDCl₃) δ 0.98(t, 3H), 1.05-1.20(m, 1H), 1.31-1.49(m, 1H), 1.69-1.90(m, 1H), 2.65(q, 2H), 3.33-3.49(m, 1H), 4.31 (width s, 2H), 7.02-7.22(m, 2H), 7.35-7.49(m, 1H), 7.50-7.68(m, 2H), 7.69-7.83(m, 2H), 8.08(d, 1H), 8.37 (width s, 1H).

Example 22

(1S, 2SR) -N- [ cis-2- (6-fluoro-2- (N-methylindole-5-carbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

i) Preparation of N-methylindole-5-carboxylic acid

0.1g of indole-5-carboxylic acid is mixed with 2 equivalents of methyl trifluoromethanesulfonate in 1ml of DMF at room temperature. After 5 hours the solvent was evaporated and recorded¹H-NMR：¹H-NMR(250MHz，DMSO-d₆) δ 2.76(s, 3H), 6.57 (width s, 1H), 7.46-7.50(m, 2H), 7.75(dd, 1H), 8.23-8.29(m, 2H), 11.56 (width s, 1H).

ii) preparation of the title Compound

N-methylindole-5-carboxylic acid and (1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea from example 10 were condensed using the method described in example 12 to give the title product as the hydrochloride salt.¹H-NMR(250MHz，CDCl₃) δ 1.08(t, 3H), 1.15-1.25(m, 1H), 1.39-1.50(m, 1H), 1.92-2.08(m, 1H), 2.89(q, 2H), 2.90(s, 3H), 3.20-3.35(m, 1H), 6.55 (wide s, 1H), 6.65 (wide 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 (wide s, 1H), 9.25 (wide s, 1H), 9.43 (wide s, 1H).

Example 23

(1S, 2S) -N- [ cis-2- (6-fluoro-2- (indole-4-carbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

Indole-4-carboxylic acid and (1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea from example 10 were condensed using the method described in example 12 to give the title product as the hydrochloride salt.¹H-NMR(250MHz，CDCl₃) δ 1.07(t, 3H), 1.17-1.30(m, 1H), 1.31-1.47(m, 1H), 1.90-2.10(m, 1H), 2.89(q, 2H), 3.02-3.18(m, 1H), 6.75 (width 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 (width d, 2H).

Example 24

(1S, 2S) -N- [ cis-2- (6-fluoro-2- (3-amino-4-chlorophenylcarbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea

Using the procedure described in example 12, 3-amino-4-chlorobenzoic acid and (1S, 2S) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-bromopyridin-2-yl) -urea from example 10 were condensed to give the title product as the hydrochloride salt.¹H-NMR (250MHz, liberated amine, CDCl)₃)δ1.10(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 (width s, 2H), 6.80 (width 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 (width s, 2H).

Example 25

(1S, 2S) -N- [ cis-2- (6-fluoro-2- (pyridin-3-ylcarbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

A dry mixture of the compound from example 8 (50g, 0.68mmol), N' -dicyclohexylcarbodiimide (0.168g, 0.81mmol), nicotinic acid (0.1g, 0.81mmol) and 4- (dimethylamino) pyridine (0.041g, 0.34mmol) was dissolved in CH₂Cl₂(5ml) and N, N-Dimethylformamide (DMF) (2.5 ml). The mixture was then stirred at room temperature. After 20 hours, the mixture was filtered and dried in vacuo, then redissolved in a minimal amount of dichloromethane and filtered. The clear solution was evaporated on silica gel and purified by chromatography (ethyl acetate) to give the title compound (0.168g, 50%). Analytical samples were obtained by recrystallization from chloroform-hexane.¹H NMR(CDCl₃)：9.89(br s，1H)，9.41(m，1H)，9.33(br s，1H)，8.86(dd，1H)，8.46(dt，1H)，8.18(d，1H)，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- [ cis-2- (6-fluoro-2- (pyridin-3-ylcarbonyloxy) -3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

A dry mixture of the compound from example 6 (0.1g, 0.27mmol), N' -dicyclohexylcarbodiimide (0.067g, 0.33mmol) and nicotinic acid (0.037g, 0.3mmol) was suspended in dichloromethane (2 ml). Minimal DMF was added dropwise to obtain a fairly clear solution. 4- (dimethylamino) pyridine (0.016g, 0.14mmol) was then added. The reaction mixture was stirred at room temperature. After 20 hours, the solvent was evaporated in vacuo and the crude residue was dissolved in aqueous hydrochloric acid (pH1-2) and filtered. The clear solution was then made slightly basic with sodium bicarbonate and the precipitated product was filtered. Purification by chromatography (dichloromethane-methanol, 15: 1) gave 0.072g (56%) of the title compound.¹H NMR(CDCl₃)：9.85(br s，1H)，9.42(s，1H)，9.35(br s，1H)，8.86(d，1H)，8.47(dt，1H)，8.18(d，1H)，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- [ cis-2- (2- (3- (N-ethyl, N-Boc-amino) phenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

The compound from example 8 (0.37g, 1.0mmol), N' -dicyclohexylcarbodiimide (0.25g, 1.2mmol), 4-dimethylaminopyridine (0.06g, 0.5mmol) and 3- (N-ethyl-N-butoxycarbonyl) aminobenzoic acid (0.320g, 1.2mmol) (prepared by reductive amination of 3-aminobenzoic acid followed by protection of the amino group) were dissolved in dichloromethane (8ml) and DMF (3 ml). The mixture was then stirred at room temperature. After 18 hours, the solvent was removed in vacuo and the crude product was redissolved in dichloromethane and filtered. The clear solution was evaporated on silica gel and purified by chromatography (ethyl acetate-hexanes, 3: 2) to give the title compound (0.24g, 39%) sufficiently pure.¹H NMR(CDCl₃)：10.0(br s，2H)，8.20(d，1H)，8.06(d，1H)，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- [ cis-2- (2- (3-ethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

Trifluoroacetic acid (5ml) was added to a stirred solution of the compound from example 27 (0.120mg, 0.19mmol) in dichloromethane (10 ml). The mixture was left at room temperature for 1-2 hours. Then evaporated to dryness. The crude product was purified on HPLC (preparative C-18 column, 40% water in acetonitrile) to give 0.045g (30%) of the title compound as trifluoroacetate salt.¹H NMR(CDCl₃)：11.08(br s，2H)，9.83(br s，1H)，9.36(br s，1H)，8.23-8.08(m，3H)，7.82-7.54(m，4H)，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- [ cis-2- (2- (3-dimethylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

The compound from example 8 (0.1g, 0.27mmol), N' -dicyclohexylcarbodiimide (0.067g, 0.33mmol), 4-dimethylaminopyridine (0.016g, 0.14mmol) and 3-dimethylaminobenzoic acid (0.054g, 0.39mmol) were dissolved in dichloromethane(3ml) and DMF (1 ml). The reaction was left at room temperature for 16 hours. The solvent was then removed in vacuo and the solid was redissolved in dichloromethane and filtered. Purification by chromatography (ethyl acetate-hexanes, 2: 1) followed by HPLC (C-18 column, 0.1% TFA in acetonitrile) gave 0.1g (58%) of the title compound as the trifluoroacetate salt.¹H NMR(CDCl₃)：8.38-8.23(m，3H)，7.92-7.69(m，4H)，7.15(t，1H)，7.05(m，1H)，3.32(s，6H)，3.26(m，1H)，2.89(q，2H)，2.02(m，1H)，1.55-1.27(m，2H)，1.10(t，3H)。

Example 30

(1S, 2S) -N- [ cis-2- (2- (3-L-valylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

a)3- (N-Boc-L-valyl) aminomethylbenzoic acid ester

This intermediate is prepared analogously to the method of Villaneuve and Chan, tetrahedron letters 1997, Vol.37, pp.6489-6492. A mixture of N-tert-butoxycarbonyl-L-valine (2.17g, 10mmol) and hexachloroacetone (1.32g, 5mmol) in dichloromethane (20ml) was stirred and cooled to-78 deg.C under a nitrogen atmosphere. Triphenylphosphine (2.6g, 10mmol) in dichloromethane (10ml) was added dropwise and the mixture stirred for 30 min. Methyl 3-aminobenzoate (1.5g, 10mmol) in dichloromethane (10ml) was then added dropwise followed by triethylamine (1g, 10mmol) in dichloromethane. The reaction was then allowed to reach room temperature, after which the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 3: 1) followed by recrystallization from ethyl acetate-hexane to give 0.7g (28%) of the pure intermediate described above.¹H NMR(CDCl₃)：8.30(br s，1H)，8.07(d，1H)，7.85-7.75(m，2H)，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 (0.65mg, 1.8mmol) of step a) was suspended in methanol (6ml) and water (2 ml). Lithium hydroxide (0.11g, 3.9mmol) was added and the mixture was stirred at room temperature for 24 hours. Then water (10ml) was added and the volume was reduced to half. The aqueous solution was washed with 10-20ml of ethyl acetate and then acidified with aqueous hydrochloric acid. Extraction with ethyl acetate (2X 20ml), drying and evaporation in vacuo gave 0.524g (84%) of the pure intermediate described above.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- [ cis-2- (2- (3-N-Boc-L-valylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

The compound from example 8 (0.23g, 0.62mmol), N' -dicyclohexylcarbodiimide (0.153g, 0.74mmol), 4-dimethylaminopyridine (0.038g, 0.3mmol) and step b) intermediate (0.25g, 0.74mmol) were dissolved in dichloromethane (9ml) and DMF (3 ml). The reaction was left at room temperature for 19 hours. The solvent was removed in vacuo and the solid was redissolved in dichloromethane and filtered. Purification by chromatography (ethyl acetate-hexanes, 1: 1) gave 0.029g (67%) of the pure N-protected title 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- [ cis-2- (2- (3-L-valylaminophenylcarbonyloxy) -6-fluoro-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) -urea

The N-protected compound of step c) (0.16g, 0.23mmol) and thiophenol (0.054g, 0.46mmol) were dissolved in dichloromethane (6ml) and cooled to 0 ℃. Trifluoroacetic acid (6ml) was added and the mixture was brought to room temperature and left for 1 hour. Evaporation to dryness followed by chromatography (dichloromethane-methanol, 10: 1.5) gave 0.150g (90%) of the title compound as 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- { cis-2- [ 6-fluoro-3-propionyl-2- (6-ethylaminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

a) 6-Ethylaminonicotinic acid

This intermediate was prepared from 6-chloronicotinic acid and ethylamine by the same method as described in example 35, step a). 1-butanol was used instead of ethyl acetate for extraction. Heavy loadCrystallization (MeOH-CHCl)₃) Yield 0.53g (50%).¹H NMR(DMSO-d₆)：12.1(br s，1H)，8.54(d，1H)，7.77(dd，1H)，7.15(t，1H)，6.45(dd，1H)，3.33(m，2H)，1.14(t，3H)。

b) (1S, 2S) -N- { cis-2- [ 6-fluoro-3-propionyl-2- (6-ethylaminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

The compound from example 8 (0.1g, 0.27mmol), 6-ethylaminonicotinic acid (0.084g, 0.54mmol), N' -dicyclohexylcarbodiimide (0.127g, 0.62mmol) and 4-dimethylaminopyridine (0.016g, 0.13mmol) were dissolved in DMF (3ml) and left at ambient temperature. After 19 hours, 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-hexanes, 2: 1) to give the title compound (0.063g, 45%).¹H NMR(CDCl₃)：9.85(br s，1H)，9.25(br s，1H)，8.91(d，1H)，8.18-8.02(m，3H)，7.76-7.67(m，2H)，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- { cis-2- [ 6-fluoro-3-propionyl-2- (5-bromopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

5-Bromonicotinic acid (0.065g, 0.33mmol), the compound of example 8 (0.1g, 0.27mmol), N' -dicyclohexylcarbodiimide (0.127g, 0.62mmol) and 4-dimethylaminopyridine (0.016g, 0.13mmol) were dissolved in dichloropyridineMethane (4ml) and left at ambient temperature. After 19 hours, the mixture was filtered and the solvent was removed in vacuo. The crude product was purified by chromatography (ethyl acetate-hexanes, 1: 1) to give the title compound (0.040g, 27%).¹H NMR(CDCl₃)：9.80(br s，1H)，9.30(d，1H)，9.17(br s，1H)，8.89(d，1H)，8.57(dd，1H)，8.57(dd，1H)，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- { cis-2- [ 6-fluoro-3-propionyl-2- (6-aminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

a) 6-Aminonicotinic acid methyl ester

6-Aminonicotinic acid (2g, 22mmol) was dissolved in methanol (10ml) 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 basified with aqueous sodium bicarbonate. Extraction by EtoAc gave the pure intermediate described above (2.3g, 70%).¹H NMR(DMSO-d₆)：8.51(dd，1H)，7.81(dd，1H)，6.66(br s，2H)，6.45(dd，1H)，3.77(s，3H)。

b) 6-Butoxycarbonylamino-nicotinic acid methyl ester

The intermediate (0.75g, 4.9mmol) from step a) was dissolved in THF (5 ml). Adding dropwiseSodium (trimethylsilyl) amide (5ml, 2M in THF). Stirred at room temperature for 30 minutes. Di-tert-butyl dicarbonate (1.1g, 5mmol) in THF (8ml) was added. The reaction mixture was left overnight under nitrogen atmosphere. The solution was then evaporated in vacuo and dissolved in EtOAc (40ml) and 0.1M hydrochloric acid (100 ml). The layers were separated and the aqueous phase was extracted twice with EtOAc (40mL) and then slightly basified with aqueous sodium bicarbonate and extracted once more with EtOAc (20 mL). The organic fractions were combined, dried over sodium sulfate and purified by chromatography (EtOAc-hexanes, 1:4) to give the pure intermediate described above (0.5g, 40%).¹H NMR(CDCl₃)：8.93(dd，1H)，8.62(s，1H)，8.26(dd，1H)，8.06(dd，1H)，3.91(s，3H)，1.60(s，9H)。

c) 6-tert-butoxycarbonylamino nicotinic acid

The intermediate (0.4g, 1.6mmol) from step c) was suspended in methanol (4ml) and water (1.25 ml). LiOH (0.1g, 4mmol) was added. The slurry was left to stand at room temperature for 48 hours. The clear solution was then concentrated in vacuo and dissolved in water and acidified with acetic acid (pH 4-5). Extraction with EtOAc afforded the pure intermediate described above (0.27g, 70%).¹H NMR(DMSO-d₆)：9.98(s，1H)，8.74(d，1H)，8.18(d，1H)，8.88(d，1H)，1.49(s，9H)。

d) (1S, 2S) -N- { cis-2- [ 6-fluoro-3-propionyl-2- (6-tert-butoxycarbonylamino-pyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

The compound from example 8 (0.150g, 0.41mmol), the intermediate from step c) (0.17g, 0.49mmol), N' -dicyclohexylcarbodiimide (0.1g, 0.49mmol) and 4-dimethylaminopyridine were combined(0.06g, 0.49mmol) was dissolved in DMF (2 ml). The mixture was stirred at room temperature overnight and then placed in a 50 ℃ oil bath for 2 hours. Evaporation on silica gel and purification by chromatography gave the N-protected title compound (0.048g, 20%).¹H NMR(CDCl₃/CD₃OD)：9.02(s，1H)，8.43(dd，1H)，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)。

e) (1S, 2S) -N- { cis-2- [ 6-fluoro-3-propionyl-2- (6-aminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

The intermediate of step d) (0.048g, 0.08mmol) was dissolved in dichloromethane (2 ml). Trifluoroacetic acid (1ml) was added and the mixture was stirred for 1 hour. Evaporation in vacuo gave the crude title compound. The product was dissolved in diethyl ether (2ml) and left overnight. The white precipitate formed was filtered off to give the pure title compound as the trifluoroacetate salt (0.032g, 65%).¹H NMR(CD₃OD/CDCl₃)：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- { cis-2- [ 6-fluoro-3-propionyl-2- (6-chloropyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

The compound (0.15g, 0.4mmol) of example 8, 6-chloronicotinic acid (0.076g, 0.49mmol) were addedl), N' -dicyclohexylcarbodiimide (0.1g, 0.49mmol) and 4-dimethylaminopyridine (0.024g, 0.2mmol) were dissolved in dichloromethane (4 ml). The mixture was left overnight, evaporated in vacuo and purified by chromatography (EtOAc-hexane, 1: 2) to give the title compound (0.067g, 32%).¹H NMR(CDCl₃)：9.77(br s，1H)，9.18(br d，2H)，8.39(dd，1H)，8.14，7.79(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- { cis-2- [ 6-fluoro-3-propionyl-2- (6-dimethylaminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

a) 6-dimethylaminobenzoic acid

6-Chloronicotinic acid (0.5g, 3.17mmol) and dimethylamine (10ml, 40% in water) were heated in a sealed pressure vessel for 6 hours at 130 deg.C. The solvent was then removed and the residue was extracted with water and adjusted to pH 4-5. Extraction with dichloromethane yielded the pure intermediate described above (0.1g, 20%).¹H NMR(CDCl₃)：8.87(dd，1H)，8.04(dd，1H)，6.49(dd，1H)，3.18(s，6H)。

b) (1S, 2S) -N- { cis-2- [ 6-fluoro-3-propionyl-2- (6-dimethylaminopyridin-3-ylcarbonyloxy) phenyl ] cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

The compound from example 8 (0.13g, 0.3mmol), the intermediate from step a) (0.05g, 0.3mmol), N' -dicyclohexylcarbodiimide (0.09g, 0.4mmol)) And 4-dimethylaminopyridine (0.02g, 0.18mmol) in dichloromethane (3ml) and DMF (1 ml). The mixture was left overnight, evaporated in vacuo and purified by chromatography (EtOAc-hexane, 2: 1) to give the title compound (0.06g, 39%).¹H NMR(CDCl₃)：10.10(br s，1H)，9.29(br s，1H)，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- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) -cyclopropyl ] -N' - (5-cyanopyridin-2-yl) urea-O-4-hydroxybenzoate

a) 4-Benzyloxybenzoic acid

To a solution of 4-hydroxybenzoic acid (6.9g, 50mmole) in 150ml of DMF was added potassium tert-butoxide (12.34g, 110mmole) and the mixture was stirred at room temperature for one hour. Benzyl bromide (20.5g, 120mmole) was added and the mixture was stirred at room temperature for two days. The mixture is evaporated under reduced pressure and 100ml of a solution of 1, 4-dioxane and sodium hydroxide (6.0g, 150mmole) in 50ml of water are 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, washed with cold water and dried. Yield: 10.2 g-89%.

b) 4-Benzyloxybenzoyl chloride

To a mixture of 4-benzyloxybenzoic acid (2.28g, 10mmole) in 20ml dry dichloromethane were added 5 drops of DMF and 2.5ml of thionyl chloride. The mixture was refluxed for three hours and evaporated under reduced pressure. Yield: 2.45g to 100%.

c) (1S, 2H) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl ] -N' - [2- (5-cyanopyridin-2-yl) urea-O-4-benzyloxybenzoate

To (1S, 2S) -N- [ cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) cyclopropyl]To a solution of-N' - (5-cyanopyridin-2-yl) urea (184mg, 0.5mmole) in 3ml of DMF was added potassium tert-butoxide (78.5mg, 0.7mmole), and the mixture was stirred at room temperature for one hour. A solution of 4-benzyloxybenzoyl chloride (185mg, 0.75mmole) in 1ml of DMF was added and the mixture was stirred at room temperature overnight. 40ml of ethyl acetate are added and the organic phase is washed four times with water. The solution was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 180mg ═ 62%.¹H-NMR(DMSOδ-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)。

d) Synthesis of (1S, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl ] -N' - (5-cyanopyridin-2-yl) ] urea-O-4-hydroxybenzoate

At room temperature and normal pressure, (1S, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl]A solution of (E) -N' - (5-cyanopyridin-2-yl) urea-O-4-benzyloxybenzoate (170mg, 0.29mmole) in 15ml of ethyl acetate and 15ml of methanol was hydrogenated three times with 10% palladium on charcoal (30 mg). The catalyst was filtered and washed with ethyl acetate and methanol, and the solution was evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 100mg ═ 70%.¹H-NMR(DMSOδ-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, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) -cyclopropyl ] -N' - [2- (5-cyanopyridyl) ] urea-O-methylene-4-hydroxybenzoate

a)4- (4-Methoxybenzyloxy) benzoic acid methyl ester

To a solution of methyl 4-hydroxybenzoate (6.85g, 45mmole) in 80ml of DMF was added potassium tert-butoxide (5.6g, 51mmole) and the mixture was stirred at room temperature for one hour. 4-methoxybenzyl chloride (8.3g, 52mmole) was added and the mixture was left at room temperatureThe mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and 200ml of ethyl acetate were added. The organic phase was washed four times with water, dried over sodium sulfate and evaporated under reduced pressure. Yield: 12.3g to 100%.¹H-NMR(CDCl₃)：3.82(s，3H)，3.88(s，3H)，5.03(s，2H)，6.96(m，4H)，7.36(d，2H)，7.98(d，2H)。

b)4- (4-methoxybenzyloxy) benzoic acid

To a solution of methyl 4- (4-methoxybenzyloxy) benzoate (12.2g, 44.8mmole) in 50ml of 1, 4-dioxane was added a solution of lithium hydroxide (2.15g, 89.6mmole) and the mixture was stirred at 60 ℃ overnight. The mixture was evaporated under reduced pressure and 5% acetic acid was added. The product was filtered, washed with water and dried. Yield: 10.1 g-87%.¹H-NMR(DMSOδ-6)：3.74(s，3H)，5.08(s，2H)，6.92(d，2H)，7.06(d，2H)，7.36(d，2H)，7.90(d，2H)。

c)4- (4-methoxybenzyloxy) benzoic acid chloromethyl ester

To a solution of 4- (4-methoxybenzyloxy) benzoic acid (5.16g, 20mmole) in 100ml of 1, 4-dioxane was added a 40% tetrabutylammonium hydroxide solution (14.27g, 22mmole) and the mixture was stirred at room temperature for 2 hours. 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 60ml of dichloromethane and iodochloromethane (35.3g, 200mmole) was added. The solution was stirred at room temperature for two days and evaporated under reduced pressure. About 100ml of ethyl acetate were added and the organic phase was washed twice with water. Dried over sodium sulfate and evaporated under reduced pressure. The product was purified by silica gel column chromatography. Yield: 4.48 g-73%.¹H-NMR(CDCl₃)：3.83(s，3H)，5.06(s，2H)，5.94(s，2H)，7.00(m，4H)，7.36(d，2H)，8.05(d，2H)。

d)4- (4-methoxybenzyloxy) benzoic acid iodomethyl ester

To a solution of 4- (4-methoxybenzyloxy) benzoic acid chloromethyl ester (0.77g, 2.5mmole) in 15ml dry acetone was added sodium iodide (1.87g, 12.5mmole) and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and extracted with ethyl acetate/water. The organic phase was washed with 5% sodium thiosulfate solution, dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.86 g-86%.

¹H-NMR(CDCl₃)：3.84(s，3H)，5.05(s，2H)，6.14(s，2H)，6.98(m，4H)，7.36(d，2H)，8.00(d，2H)。

e) (1S, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl ] -N' - [2- (5-cyanopyridyl) urea-O-methylene-4- (4-methoxybenzyloxy) benzoate

To (1S, 2S) -N- [ cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) cyclopropyl]-N' - [2- (5-cyanopyridyl) urea (368mg, 1mmole) in 5ml of DMF was added a suspension of 60% sodium hydride in mineral oil (44mg, 1.1mmole) and the mixture was stirred at room temperature for one hour. A solution of iodomethyl 4- (4-methoxybenzyloxy) benzoate (0.84g, 2.1mmole) in 2ml of THF was added and the mixture was stirred at room temperature overnight. 50ml of ethyl acetate are added and the organic phase is washed four times with water, dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: and 525 mg-82%.¹H-NMR(CDCl₃)：0.91(m，3H)，1.32(m，1H)，1.60(m，1H)，2.04(m，1H)，2.90(m，2H)，3.20(m，1H)，3.82(s，3H)，5.04(s，2H)，5.84-6.06(m，2H)，6.91-8.18(m，13H)。

f) (1S, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl ] -N' - [2- (5-cyanopyridyl) ] urea-O-methylene-4-hydroxybenzoate

To (1S, 2S) -N- [ cis-2- (6-fluoro-2-O-3-propionylphenyl) cyclopropyl]-N' - [2- (5-cyanopyridyl) urea-O-methylene-4- (4-methoxybenzyloxy) benzoate (100mg, 0.156mmole) in 4ml of dichloromethane was added TFA (0.5ml) and the solution was stirred at room temperature for one hour. Evaporating the solution under reduced pressureAnd separating the product by silica gel column chromatography. Yield: 45mg ═ 55%.¹H-NMR(DMSOδ-6)：0.84(m，3H)，1.10(m，1H)，1.48(m，1H)，2.12(m，1H)，2.80(m，2H)，3.19(m，1H)，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- { cis-2- [ 6-fluoro-3-propionyl-2- (6-methylaminopyridin-3-ylcarbonyloxy)

Phenyl ] -cyclopropyl } -N' - (5-cyanopyridin-2-yl) urea

This compound was prepared from 6-methylaminonicotinic acid (0.050g, 0.33mmol) and the compound of example 8 (0.1g, 0.27mmol) by the same method as in example 31. The crude product (containing the title compound and unreacted starting materials) was purified by chromatography (ethyl acetate) to yield 0.030g (22%) of the title compound.¹H.NMR(CDCl₃)：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 model

The compounds of the invention were tested for antiviral activity against a variety of HIV strains, including wild-type and mutants known to occur using other non-nucleoside reverse transcriptase inhibitors as described in the review by Schinazi et al, International antiviral News, Vol.4, No. 6, pp.95-107 (1996). The results are presented in table 1.

TABLE 1

HIV strain	Example 5	Example 6	Example 8	Prior Art*
					Wild type	0.0012+/-0.0004	0.0008+/-0.0004	0.0007+/-0.0002	0.0056+/-0.004
Wild type 50% serum	0.01+/-0.009	0.006+/-0.003	0.007+/-0.001	0.023+/-0.011
					K103N	0.05+/-0.04	0.017+/-0.008	0.037+/-0.007	0.13+/-0.060
K103N 50% serum	0.38+/-0.31	0.17+/-0.07	0.39+/-0.31	0.9+/-0.6
					Y181C	0.017+/-0.018	0.006+/-0.002	0.006+/-0.001	0.13+/-0.02
Y181C 50% serum	0.10+/-0.06	0.08+/-0.05	0.08+/-0.06	0.13+/-0.07
					Y188L	0.13+/-0.07	0.08+/-0.06	0.06+/-0.02	0.17+/-0.03
Y188L 50% serum	1.5+/-0.9	0.9+/-0.05	1.0+/-0.05	1.9+/-1.5
					L100I，Y181C	ND	ND	0.34+/-0.06	1.0
L100I	ND	ND	0.009+/-0.001	0.026+/-0.009
					SI	＞41 600	22 500	87 000	5 900
SI 50% serum	ND	8 830	4 285	800

The assay includes a variety of assays induced by XTT in MT-4 cells (Weislow et al, J Nat Cancer Inst 1989, Vol.81, No. 8, p.577, etc.), which includes assays that demonstrate an effect on protein binding in the presence of 50% human serum. ED (electronic device)₅₀Presented in μ g/ml. Raw data based on calculated therapeutic index (SI) are also presented, defined at the dose corresponding to 50% toxicity in non-HIV cells divided by the ED₅₀. The prior art compounds from said 1995 ICARSanta Fe are described above.

It is evident that the compounds of the invention, in particular the enantiomers, have a significantly lower ED than the compounds known hitherto₅₀Values, including against known undefined mutants K103N and Y181C and L100I and bisValues for the heavy mutant L100I, Y181C. Furthermore, the therapeutic index of the enantiomers is 5 to 10 times higher than that of the compounds of the prior art. These results will be observed in the context of HIV therapy, and patients can expect long-term medication even if the rest of their life is not significantly resistant to the well-known proviral HIV. Therefore, large SI is needed to avoid accumulating toxicity while properly dosing to maintain therapeutic pressure and prevent spontaneous development of resistance to HIV strains.

Biological example 2

Time and resistance

On microtiter plates, 5-10 TCID₅₀HIV-1 of_IIIBInfection 2X 10 per well⁴MT4 cells. Using 8 pairs per concentration, at approximately ED₅₀To the concentration of test compound. After 6 days of incubation the RT activity in 10. mu.l of supernatant was measured.

After subsequent weekly culture passages, the following procedure was performed: viruses produced at concentrations of test compound (SIC, initial inhibitory concentration) that showed > 50% of the RT activity of untreated infected cells were passaged to fresh MT4 cells. 15 μ l of supernatant from each of the eight pairs of assays was transferred to cells without test compound (control) and cells containing the same concentration of test compound, and two others had five times higher concentrations, respectively. (see table 2 below).

When the virus was allowed to grow at the highest non-toxic concentration (5-40 μ M), 2-4 parallel wells were collected and expanded to give material for analysis of results and cross-mode resistance.

TABLE 2

Allowing viral growth

Inhibited virus production

125×SIC

125×SIC 25×SIC→

25×SIC 5×SIC

25×SIC 5×SIC→ No compound

25×SIC 5×SIC→ No compound

5×SIC SIC

SIC→ No compound

SIC→ No compound

Passage (pass)1 passage 2 passage 3 passage 4 passage 5

FIG. 1 depicts the growth of virus resistance versus time for the compound of the invention (example 8). The corresponding curves for the recent Santa Fe compounds mentioned above are also depicted. It is apparent that the compounds of the invention show a significantly lower rate of resistance development.

Biological example 3

P450 metabolism

Metabolism of the compounds of the invention through the major isoforms of the human cytochrome system P450 was determined in insect cells infected with baculovirus transfected with human cytochrome P450 cDNA (supersomes) Gentest company Woburn USA.

The test compounds were incubated in duplicate in the presence of a supramer overexpressing multiple cytochrome P450 isoforms including CYP 1a 2+ P450 reductase, CYP2a6+ P450 reductase, CYP2C9-Arg 144+ P450 reductase, CYP2C19+ P450 reductase, CYP2D6-Val 374+ P450 reductase and CYP3a4+ P450 reductase at concentrations of 0.5, 5 and 50 μ M. The incubation is carried out for 1 hour or more with a fixed concentration (e.g., 50 picomoles) of cytochrome P450. The given isoform involved in the metabolism of the test compound is determined by UV HPLC chromatography measuring the disappearance of the parent compound.

After testing the three concentrations for 7.5 minutes, the percent life retention plots suggest that CYP3a4, 1a2, 2C19, and 2a6 are involved in the metabolism of the compound of example 7. The P450 isoforms of similar conformation are also involved in the metabolism of Santa Fe halopyridyl compounds of the prior art.

Surprisingly, for the compound of example 8, no significant P450 metabolism with any isomer was recorded, suggesting that the compound is stable in vivo and the potential for metabolic interference of co-administered drugs is correspondingly low.

Biological example 4

Pharmacokinetics

The release of the compound of formula I from orally administered prodrug of formula II in rats was monitored. The compound of example 7 was dissolved in propylene glycol vehicle and administered orally to paired fasted male Sprague-Dawley rats at a dose corresponding to 0.027 mmol/kg. At the indicated time intervals, 0.2ml of blood was collected from the catheter implanted in the jugular vein of canis, centrifuged and frozen for later analysis. The released drug of formula I (example 6) was tested by HPLC. Aliquots containing 40-100. mu.l of each plasma sample were mixed with an equal volume of acetonitrile (10 sec, Vibroflex). The samples were centrifuged (2 min, 14000 RPM) and 30 μ Ι of supernatant was injected into the HPLC system as follows.

Pre-column: RP-18, 7. mu.M, 15X 3.2mm

Column: YMC substrate, 3. mu.M, 150X 3mm

Mobile phase: 60% acetonitrile in 3mM ammonium acetate, pH6.4

Flow rate: 0.4ml/min

And (3) detection: UV, 250nm

TABLE 3

Time (min)	Plasma levels (μ g/ml) of parent Compound
		30	0.24，0.35
60	0.18，0.28
		120	0.13，0.17
240	0.07，0.12
		360	0.05，0.07

In table 3, it is clear that orally administered prodrugs of formula II release clinically significant amounts of the compound of formula I in vivo.

Biological examples 5 to 8

i) Preparation of

The rats used in the pharmacokinetic example were male Sprague-Dawley rats weighing approximately 200-250 g. Prior to the experiment, the rats fasted for at least 16 hours, but had free access to water. The day before the experiment, the rats were anesthetized with a mixture of Efrane *, laughing gas and oxygen. The catheter was inserted into the jugular vein of the rat. On the day of the experiment, the body weight of the rats was recorded. The animals were briefly anesthetized prior to oral administration of a drug or intravenous injection into the back of the neck. Two rats were given each substance.

Prior to oral administration, monkeys fasted for 12 hours, but had free access to water. The test compounds were administered via infant nasogastric feeding tubes. After 6 hours, the monkeys received apples.

ii) preparation of the dose

An appropriate amount of the active ingredient described in the following examples was dissolved/suspended in propylene glycol solution or a solution of 10% gum arabic and 1% tween in water for oral administration. Compounds were dissolved in DMSO for intravenous administration.

iii) blood sample Collection

Before drug administration, blood samples (rats typically 0.6ml, monkeys 2ml) were collected and taken at the indicated time intervals after drug administration (as shown in the figure) as before. Monkey blood was tapped from the femoral vein into tubes containing EDTA. Blood samples were centrifuged, infected drugs were neutralized with 1% SDS/64 °/20 min and plasma was stored at-20 ℃.

iv) biological analysis

Plasma samples were prepared as follows: 40-100. mu.l of plasma was mixed with an equal volume of acetonitrile (10 sec, Vibrodex). The samples were centrifuged (2 min, 14000 RPM) and 30 μ Ι of supernatant was injected into the HPLC system as follows.

Pre-column: RP-18, 7. mu.M, 15X 3.2mm

Column: YMC substrate, 3. mu.M, 150X 3mm

Mobile phase: 60% acetonitrile in 3mM ammonium acetate, pH6.4

Flow rate: 0.4ml/min

And (3) detection: UV, 250nm

Biological example 5

Comparison with the closest prior art Compounds

The in vivo stability and efficacy of the compound of formula I was compared to the closest Santa Fe compound, namely (+/-) -N- (cis-2- (6-fluoro-2-hydroxy-3-propionylphenyl) -cyclopropyl) -N' - (5-chloropyridin-2-yl) -urea, to administer a dose of 0.024mmol/kg of each of the compounds in DMSO vehicle. Figure 2 is a graph of the plasma levels of the compounds described over time (n-2 in each case). It is evident that the curves follow a conventional pattern, but that the compounds of the invention have an AUC (0-4 hr) that is 1.5 times greater than the AUC (0-4 hr) of the closest prior art compound. In other words, the compounds of the present invention provide greater than 50% in vivo contact than the previously described derivatives, whether due to slower clearance of the compounds of the present invention over the prior art compounds or a higher degree of tissue binding has also been determined.

Biological example 6

Bioequivalence of prodrugs to parent Compounds

A variety of compounds of formula II (i.e., prodrugs of compounds of formula I) were administered to rats and plasma levels of the parent compound of the invention (in this example, the compound of example 10) were monitored throughout. The solvent is 10% of Arabic gum and 1% of Tween (plus asterisk) in water or propylene glycol. The plasma level data in table 4 refer to individual animals.

TABLE 4

Compound (I)	Dosage (mmol/kg)	Time (min)	Plasma levels (μ g/ml) of parent Compound
							Example 12	0.053	306090120180240330420	0.20.20.30.20.30.3	0.30.40.40.50.40.4	0.060.120.100.110.080.080.05	0.110.200.200.230.240.150.12
Example 12	0.026	3060120180240330420	0.090.100.090.080.06	0.050.070.080.080.050.030.02
							Example 22	0.026	3060120180240360	0.050.040.030.02＜0.02	0.080.110.080.070.04＜0.02
Example 14	0.053	3060120180240360	0.100.150.270.350.350.24	0.080.080.070.090.090.12
							Example 18	0.053	3060120180240360	0.120.150.150.230.120.08	0.030.030.070.140.160.08

Example 23	0.053	3060120180240360	0.140.220.360.440.350.14	0.320.490.490.320.270.14
							Example 17	0.053	3060120180240360	0.050.070.060.070.070.04	0.050.050.140.200.170.12
Example 29	0.027*	3060120240360	0.2580.2680.1280.051＜0.03	0.031＜0.03＜0.03＜0.03＜0.03
							Example 37	0.027*	3060120240360	0.2340.2730.1110.0560.054	0.1370.1890.1330.0450.056

It is apparent that the prodrug of formula II releases clinically relevant amounts of the compound of formula I into the blood in vivo. The absolute oral bioavailability (measured relative to the iv dose, as described in the preparation section) was 28-33% for the compound of example 37 and 27% for the animals evaluated to take the compound of example 27.

Biological example 7

Bioavailability in different species

The prodrug of formula II of the present invention (example 12) was administered to rats and cynomolgus monkeys at the same dose (0.026mmol/kg) and in the same vehicle (10% acacia and 1% tween in water). Plasma levels of the parent compound of formula I (example 10) were measured as a function of time.

TABLE 5

Species (II)	Time (min)	Plasma levels (μ g/ml) of parent Compound
				Rat	3060120180240330420	0.090.100.090.080.06	0.050.070.080.080.05
Monkey	459018024036060024 hours	0.080.201.00.720.380.130.03	0.040.260.550.540.390.100.03

It is apparent that the prodrug of formula II releases a clinically relevant amount of the compound of formula I in vivo. Release occurs both in rodents and primates, where significantly higher plasma levels are present.

The corresponding data for the compound of example 28 (rat: acacia/tween, monkey: propylene glycol) are shown in table 5A:

TABLE 5A

Species (II)	Time (min)	Plasma levels (μ g/ml) of parent Compound
				Rat	3060120240360	0.0330.0390.0660.039＜0.03	0.0460.0840.1230.034＜0.03
Monkey	3090180240540	0.1080.1590.062＜0.030.036	＜0.030.0980.0500.0600.070

Biological example 8

Antiviral activity

In the XTT A * test, compounds of formula I were tested for resistance to wild-type HIV in the presence and absence of 50% human serum_IIIBAnd HIV-1 activity of resistance mutants, in which inhibition of the cytopathic effect is tested in MT4 cells, ED in each case₅₀Indicated in μ M.

TABLE 6

HIV strain	Example 10	Example 1050% serum	Example 11	Example 1150% serum
					Wild type	0.01	0.06	0.009	0.05
L100I	0.05	0.33	0.09	0.95
					K103N	0.38	2.4	0.09	2.0
Y181C	0.09	0.4	0.07	3.3

At concentrations attainable in vivo, the compounds of formula I are highly active against a variety of HIV strains.

Biological example 9

Antiviral activity

The compounds of the invention were also compared to the closest prior art compounds using a prior art cell culture assay in which human T cell line MT4 cells were seeded into 96-well microdropletsFixed plate (2, 10)⁴Cells/well) were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum, penicillin, and streptomycin, with HIV-1 per well_IIIB(wild type) or mutant viruses 10-20 TCID loaded with RT Ile 100, Cys 181 or Asn 103 mutations₅₀And (4) infection. Test compounds, serially diluted, were added to the respective wells and the cultures were incubated at 37 ℃ in CO-rich medium₂And cell viability was determined with XTT vital dye on day five or day six. The results show the average of the following various assays. The results are expressed as ED₅₀μM。

TABLE 8

Examples	Wild type	Wild type 50% serum	Ile100	Cys181	Asn103
						Santa Fe of the prior art	0.027	nd	0.220	0.340	0.350
Example 10	0.012	0.056	0.053	0.095	0.358
						Example 11	0.008	0.058	0.100	0.069	0.080
Example 8	0.003	0.019	0.021	0.019	0.086
						Example 6	0.002	0.016	0.064	0.018	0.046

The compounds of the invention have significantly improved performance against wild-type and in particular against clinically important mutants that occur during treatment with NNRTIs.

Biological example 10

Binding kinetics

The binding and dissociation rates of NNRTIs on the target enzyme can be tested directly by surface plasmon resonance methods, in which reverse transcriptase is immobilized on the surface of the slug and binding or dissociation of a putative inhibitor is monitored by observing changes in refractive index caused by an increase or decrease in mass that accompanies the slug. As described above, the compound of the invention (example 8) was compared with the closest prior art compound from Santa Fe. The experiments were performed on a Biacore 2000(Biacore AB, Uppsala, sweden) using BIA evaluation software (version 3.0) for evaluating the data. Binding of the small analyte (NNRTI) to the much larger enzyme results in a binding response in the range of 10-20 RU. The difference in overall refractive index between the flowing buffer and the sample makes it difficult to evaluate the data obtained during injection of the sample. During the dissociation phase there is no significant change in the overall refractive index, so the binding of different species has been evaluated in this phase.

Fixing: the enzyme and control protein were immobilized on CM5 patches by direct coupling to primary amines (Markgren et al, 1998). Antibodies to Fcg (Biacore BR-1000-57) were used as control proteins and were fixed according to the manufacturer's instructions. HIV reverse transcriptase (Unge et al, 1990) was purified from 3M (NH) using a Nanosept centrifugal concentrator 10K (Pall Filtron, MA, U.S.A.)₄)₂SO₄Transfer to a medium containing 4mM MgCl₂5mM Hepes, pH 7.6. RT corresponding to the amount of 6800-9700 RU was immobilized on the sensor chip. By injection of 35ml of 0.5M Tris pH7.6, 4mM MgCl₂0.5M KCl passivates the sensor surface. The immobilization process was carried out at 33 ℃.

Interaction with inhibitors: stock solutions of the inhibitors (1mg/ml in DMSO) were dissolved in RT flow buffer (10mM Hepes pH7.6, 4mM MgCl₂0.25mM spermine, 40mM KCl, 0.5% Triton X-100, 3% DMSO, 0.5% fetal bovine serum) to achieve a concentration of 10 mM. Binding of the substance to RT was analysed by injecting 200ml of the diluted substance at a flow rate of 20ml/min and a temperature of 25 ℃. Flow at RT by injection after each injection of substance120ml of 10% DMSO in buffer (c) washes the system.

The results are depicted in fig. 3. It is evident that the compounds of the invention and the compounds of the prior art show different kinetics of interaction, with the lowest dissociation rate, indicating that they bind more efficiently to the enzyme.

Reference documents:

expression, purification and crystallization of Unge T, Ahola H, Bhikhabhai R, Backbro K, Lovgren S, Fenyo EM, Honigman A, Panet A, Gronowitz JS, Strandberg B, HIV-1 Reverse Transcriptase (RT). AIDS Res Hum Retroviruses 1990 month 11; 6(11): 1297-303. Markgren P-O, Hamalainen M, Danielson UH, screened compounds that interact with HIV-1 protease using optical biosensor technology. Analytical Biochemistry1998, volume 265. (in printing).

While various aspects and embodiments of the present invention have been illustrated by reference to the above specific examples, comparative examples and figures, it will be understood that the invention is not in any way limited to these embodiments, but extends within the spirit and scope of the appended claims.

Claims (10)

1. A compound of formula I:

wherein

R^xIs cyano or bromo;

R¹is halogen;

R²is C₁-C₃An alkyl group;

and pharmaceutically acceptable salts and prodrugs thereof.

2. The compound of claim 1, wherein R¹Is fluorine.

3. The compound of claim 1, wherein R²Is ethyl.

4. The compound of claim 1 comprising at least 60% of the 1S, 2S enantiomeric form.

5. The compound of claim 1 comprising at least 90% of the 1S, 2S enantiomeric form.

6. The compound of claim 1, wherein R^xIs cyano.

7. The compound of claim 1 selected from the group consisting of (1S, 2S) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N ' - (5-cyanopyridin-2-yl) -urea, (1R, 2R) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N ' - (5-cyanopyridin-2-yl) -urea, (1S, 2S) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N ' - (5-bromopyridin-2-yl) -urea and (1R, 2R) -N- [ cis-2- (6-fluoro, 2-hydroxy, 3-propionylphenyl) -cyclopropyl ] -N' - (5-bromopyridin-2-yl) -urea and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent therefor.

9. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of HIV.

10. A process for the preparation of a compound of formula I, comprising curtius rearrangement of an azide of the compound of formula:

followed by coupling and deprotection with a compound of the formula:

wherein R is¹、R²And R^xAs defined above and PG is a hydroxyl protecting group.