It relates moreover to the use of such compounds for treating HIV- related diseases.

Furthermore it relates to a process for the preparation of these compounds.

It is known that some pyrimidinone and pyridinone derivatives inhibit HIV reverse transcriptase.

In particular, derivatives from 1- [ (2-hydroxyethoxy) methyl]-6- (phenylthio) thymine (HEPT) are well known for their HIV1 reverse transcriptase inhibitory properties.

European Patent Application EP-0 462 800 (Merck and Company Inc.) discloses pyridinones being substituted on position 3 with an aryl or heterocyclic group, linked to the pyridinone ring through a chain.

Unfortunately, strains resistant to these compounds appeared.

Thus, their use in therapeutical treatments is questionable.

4-aryl-thio-pyridinones have been more recently disclosed by DOLLE et al. (1995, J. Med. Chem., 38,4679-4686), and in the corresponding PCT Patent Application WO 97/05 113.

However, their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains.

The most active thio pyridinones disclosed therein have a 50% inhibitory concentration of virus multiplication (IC5o) for nevirapine resistant strains of about 260 nM.

The inventors have found a new pyridinone derivative family which show better HIV inhibitory properties.

They have moreover found a new process for obtaining these compounds.

The present invention relates to compounds having the following general formula 1.

FORMULA (I) wherein -Q represents-NR1R2 or-RoNR1R2 wherein: *Ro represents Cl-6 alkanediyl; * R, and R2 each independently represent C1-6alkyl or C3-6alkenyl; said C1-6alkyl and C36alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkylthio, aryloxy, arylthio, amino, mono-or di (C1-4alkyl) amino and aryl; or * Ri and R2 taken together may form a bivalent radical-Ri-R2- wherein-R1-R2-represents-(CH2) 2-O-(CH2) 2-,-(CH2) 2-NR7-(CH2) 2, -(CH2)n,whereinR7represents-(CH2)2-CH(NHR7)-(CH2)2-or hydrogen or C1-4alkyl and n represents 2,3,4,5 or 6; -R3 represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl, -R4 and R5 each independently represent hydrogen, C1-6alkyl, C3-6alkenyl, C1-4alkoxy, C1-4alkyloxy, C1-4alkyl, amino, mono-or di (C14alkyl) amino, formyl, C1 4alkylcarbonyl, carboxyl, C14 alkyloxycarbonyl, or C1-4alkyl-

aminocarbonyi ; wherein C16alkyl and C36alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkyl thio, aryloxy, arylthio, amino, mono-or di (C1 4alkyl) amino and aryl; or -R4 and R5 taken together form a bivalent radical of formula-R4- <BR> <BR> <BR> R5-wherein-R4-R5-represents-CH=CH-CH=CH-or- (CH2) t-, wherein t represents 3 or 4 ; -R6 represents hydrogen, hydroxy, C1-4alkyloxy, C1-6alkyl, C3-6alkenyl, aryl, C1-4alkyl, amino, mono-or di (C1 4alkyl) amino or alkylaryl ; -Y represents O or S; -X represents a radical of formula : - (CH2) p- - (CH2) q-Z- (CH2) r-or-CO- wherein p represents 1,2,3,4 or 5; q represents 0,1,2,3,4 or 5; r represents 0,1,2 or 3; -Z represents NRB, C (= O), CHOH, CHNRgRg; CF2, O, S or CH=CH; wherein R8 and Rg each independently represent hydrogen or C1-4 alkyl; or N-oxides, stereochemically isomeric forms or a pharmaceutically acceptable addition salts thereof.

As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-4-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl. ethyl, propyl, butyl and the like; C1 6alkyl is meant to include Ci- 4alkyl and the higher homologues thereof containing 5 to 6 carbon atoms such as, for example, pentyl, hexyl or the like; C36alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom

of said C3-6alkenyl being connected to a nitrogen atom preferably is saturated ; C1 6alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term « C (=O) » refers to a carbonyl group.

Aryl is phenyl or phenyl substituted with one, two or three substituents selected from C1 4alkyl, C1 4alkyloxy, haio and trifluoromethyl, Preferred compounds according to the present invention are those in which X represents-CH2-or C (= O) and R3 represents a phenyl group, substituted with two methyl groups, and the most preferred of them are those wherein R3 represents a phenyl group substituted, in each meta position, with two methyl groups.

Preferably, in the compounds according to the present invention, Ri and R2 represent each a methyl group, R4 represents an ethyl group, R5 represents a methyl group and/or R6 represents a hydrogen atom.

The most preferred compound of this invention is the 3- dimethylamino-4- (3, 5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2 (1 H)-one.

The compounds in which X is-CH2-, R3 represents a phenyl group optionally substituted, Y represents O and R6 represents a hydrogen atom can be obtained by the general process represented on figure 1.

This first process comprises the following steps: a) reacting a pyridine (2), substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a Ci-Ce alkyllithium, resulting in a lithiated derivate (3) of the said pyridine. b) transforming the lithiated derivate (3) into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide.

c) obtaining the pyridinone (4) by reacting the organocopper reagent with optionally substituted benzyl halide. d) hydrolysing the protected pyridinone (4) and obtaining the deprotected pyridinone (5). e) substituting the 3-amine group of the pyridinone (5) and obtaining the pyridinone (6).

This first process is summarized in the reaction Scheme I hereinafter: SCHEMEI

In this process R10 and RI, represent independently Ci-Cg atkyt. tn a preferred embodiment, R10 is a methyl group and RI, is a tert-butyl group.

The C1-C6 alkyllithium, reacted with the pyridine (2) can be a n- butyllithium.

The optionally substituted benzyl halide used in the step c) is preferably benzyl bromide.

The hydrolysis of the protected pyridinone (4), resulting in its deprotection, is advantageously obtained by adding hydrochloric acid to the pyridinone (4) and refluxing the mixture.

In a preferred embodiment, the amino group in position 3 of the pyridinone ring, deprotected during the step (d) is substituted by alkylation, by the Eschweiler-Clarke reaction.

Compounds wherein X represents -(CH2)q-Z-(CH2)r-, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a similar process.

Compounds wherein X represents C (= O), or-CH2-, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a second process.

In this second process, the lithiated derivative (3) is reacted with an optionally substituted benzaldehyde, resulting in the intermediates of formula (7).

The intermediate (7) is oxidized to intermediate (8).

The intermediate (8) is thereafter deprotected by hydrolysis, as in the first process, resulting in the pyridinone (9) of general formula 1.

This second process is summarized in the reaction scheme 11 hereinafter.

Reaction II

Preferably the oxidation of the intermediate (7) is performed in the presence of manganese dioxide.

The intermediate (7) can also be transformed into corresponding ester (10) wherein R12 represents a Cl-C4 alkyl group whose hydrogenolysis provides pyridinone (4) in better yields. Preferably, the ester (10) wherein R12 is CH3 is prepared by treatment of intermediate (7) with acetic anhydride.

Subsequently hydrogenolysis is performed under hydrogen atmosphere and in the presence of a catalyst, especially 30% paladized charcoal. This process is summarized in the reaction scheme III Reaction scheme III

Other compounds of general formula 1, and wherein X is (CH2) p or (CH2) q-Z- (CH2) r or C (=O), and R3 is other than phenyl and R6 is other than hydrogen can be obtained by these processes, appropriately adapted by the man skilled in the art.

The compounds according to the present invention, in which X is S can be obtained by the process described in the article of DOLLE et al.

(1995, previously cited) or in the corresponding patent application WO 97/05 113, the contents of which are included in the present application.

The compounds can also be obtained by other processes known by the man skilled in the art.

The present invention relates moreover to the. intermediates of the processes hereabove disclosed. In particular it relates to the lithiated derivative of formula (3).

The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, and in particular HIV-1 reverse transcriptase and the prevention or treatment of infection by the human immuno deficiency virus (HIV) and of HIV-related diseases, such as AIDS.

For these purposes, the compounds of the present invention may be administered orally, parenterally (including sub-cutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tectoniques), by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.

Thus, another object of the present invention is a method, and a pharmaceutical composition for treating HIV related diseases, HIV infection, and in particular AIDS.

The invention relates also to these compounds for use as medecine and to their use for the manufacture of a medecine for the treatment of HIV related diseases, HIV infection, and in particular AIDS.

These pharmaceutical compositions may be in the form of orally- administrable suspensions or tablets, nasal sprays, sterile injectable preparations, or suppositories.

The present invention is illustrated without being limited by the following examples.

EXAMPLES: EXAMPLE 1 Preparation of 3-dimethylamino-4-(3. 5-dim thylbenzyl)-5-ethyl-6- methylpyridin-2 (1 H)-one.

1) 5-Ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine.

This compound has been prepared as indicated by DOLLE et al.

(1997, Tetrahedron, vol. 53, n°37,12.505-12.524). The content of this article is hereby incorporated by reference.

3,68g of 3-Amino-5-ethyl-2-methoxy-6-methylpyridine (22,14 mmol), obtained as indicated by HOFFMAN et al. (1993, J. Med. Chem., 36, 953-966), was dissolved in a mixture of dichloromethane (260 ml) and triethylamine (3.39 ml). The mixture was cooled at 0°C and 3.00 ml of trimethylacetyl chloride was added dropwise. The solution was stirred at 0°C for 15 min. and then washed with 100 ml water. The aqueous layer was extracted with 3 x 200 mi dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluant to provide the 5-ethyl-2-methoxy-6-methyl-3- pivaloylaminopyridine 96%). Elemental analysis calculated for C14H22N202; C, 67.17. H, 8.86; N, 11.19; O, 12.78; found: C, 67.11; H, 8.56; N, 10.91; 0,12.67.

2) 4-(3, 5-Dimethylbenzyl)-5-ethyl-2-methoxv-6-methyl-3-pivaloylami- nopyridine.

i) By lithiation of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine: 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine and 3,5- dimethylbenzyl bromide were dried in the presence of phosphorus pentoxide under vacuum at room temperature during 24 hours. Copper iodide (Cull) was dried in the presence of phosphorus pentoxide under vacuum at 50°C for 24 hours. 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (1.06g) and freshly distille tetramethylethylenediamine (TMEDA) (2.24 mL) were dissolved in dry tetrahydrofuran (THF) (26 mL) and the mixture was cooled at-78°C under a nitrogen atmosphere. n-Butyllithium (1.6 M in hexane, 9.26 mL) was added dropwise. The mixture was stirred for 1 hour at O°C.

Cull: dimethyl sulfide complex, prepared by adding dimethylsulfide (14 mL) to a suspension of copper iodide (2.82g) in dry THF (52 ml) at- 78°C under N2 atmosphere, was then added dropwise to the mixture at- 78°C. The mixture was stirred at O°C for 30 min and cooled again at-78°C to allow the addition of 3,5-dimethylbenzyl bromide (3.81g) dissolved in THF (4 mL). The resulting mixture was stirred at O°C for 3 hours and at room temperature for 12 hours. 16 mL of water and 20 mL of 28% aqueous ammonium hydroxide were added. The aqueous layer was extracted with 3 x 80 mL of ether. The combined organic layers were washed with 40 mL of brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using cyclohexane-ethyl acetate (1: 0 to 8: 2) as eluant giving 4- (3,5- dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopy ridine (577 mg, 37%) mp 138-139°C. ii) By hydrogenolysis of + (5-ethvl-2-methoxy-6-methyl-3- Pivaloylaminopyridin-4-yl)-(3, 5-dimethvlphenyl)-methvl(3, 5-dimethvlphenyl)-methvl acetate.

(+,-) (5-Ethyl-2-methoxy-6-methyl-3-nivaloylaminopvridin-4-yl)-< ;BR> (3§5-dimethylphenyl)-methylacetate.

8.34g of (+,-)- (3,5-dimethylphenyl)- (5-ethyi-2-methoxy-6-methyl-3- pivaloylaminopyridin-4-yl)-methanol, prepared as described below, was dissolved in pyridine (200 mL) and added to acetic anhydride (10.24 mL), and the solution was stirred for 1.5 h at room temperature and for 60 h at 60°C. An additional 10.24 mL of acetic anhydride (108.51 mmol) was added and heating was continued at 60°C for 24 h. The pyridine was evaporated under reduced pressure and the residue was taken up in 500 mL of ethyl acetate. The organic layer was washed with 170 mL of an aqueous saturated sodium bicarbonate solution, 170 mL of water and 170 mL of brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using dichloromethane- ethanol (1: 0 to 95: 5) to give the titled compound (8.78g, 95%) mp 70-71 °C.

A mixture of this compound (850 mg) and Pd-C (30%, 850mg) in acetic acid-water-dioxane (42.5 mL, 2: 1: 2, v/v/v) was stirred at room temperature for 24 hours under 10 atm of hydrogen. The catalyst was removed by filtration and washed with ethanol. The solvent of the combined filtrates was evaporated under reduced pressure giving 4- (3,5- dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopy ridine (726 mg, 99%) which was identical to the compound as prepared in example 1.2. i).

3) 3-Amino-4- (3, 5-dimethvlbenzyl)-5-ethyl-6-methylpyridin-2 (1H)-one.

3M aqueous hydrochloric acid (150 mL) was added to a suspension of 4- (3, 5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3- pivaloylaminopyridine (2.36 g) in water (300 mL). The mixture was refluxed

for 3.5 h and then stirred at room temperature for 12 h. The solution was basified by adding concentrated ammonium hydroxyde and was extracted with 3 x 800 mL ethyl acetate. The combined organic. layers were washed with 110 mL brine, dried over magnesium sulfate and concentrated under reduced pressure giving 3-amino-4- (3, 5-dimethylbenzyl)-5-ethyl-6- methylpyridin-2 (1H)-one. (1.79g, 100%). mp 204-205°C.

4) 3-Dimethylamino-4-(3, 5-dimethvibenzyl)-5-ethyl-6-methylpyridin-2- (1 H)-one.

To a stirred solution of 3-amino-4- (3, 5-dimethylbenzyl)-5-ethyl-6- methylpyridin-2 (1H)-one (200 mg) and 37% of aqueous formaldehyde (0.60 mL) in 5 mL of acetonitrile was added 139 mg of sodium cyanoborohydride. Glacial acetic acid (0.07 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. An addition 0.07 mL of glacial acetic acid was added, and stirring was continued for 30 minutes. The solvent was evaporated and 15 mL ether were added to the resulting residue. The organic layer was washed with 3 x 30 mL 1 N aqueous potassium hydroxide and 3 mL brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-dimethylamino-4- (3,5- dimethylbenzyl)-5-ethyl-6-methylpyridin-2 (1H)-one (200 mg, 91%) mp 229- 230°C.

EXAMPLE 2: H Biological activity of the compound according to example 1.

1. Material and Methods The antiviral activity, the expression and purification of the recombinant HIV-RT enzyme, the reverse transcriptase activities and the inhibition of RT were evaluated as described in WO 97/05 113.

The retrovirucidal effect and the reverse transcription were measured as described hereinafter.

1.1. Retrovirucidal effect.

HIV-1 viral suspensions were obtained by coculture of MT4 cells and H9 cells chronically infected by HIV-Ia aj isolate. 200, ul of a cell supernatant containing viral particles (HIV-ILai : 100 TCID50) were incubated at room temperature with various concentrations of different inhibitors. After 3 hours, virions were washed through 0.02pm anopore membrane in 1.5 mL Vectaspin tube (Whatman) for 10 minutes at 5 000 g. Each of the three subsequent washes was performed in the same conditions after the viral concentrate was refilled with 500 uL of RPMI medium. Then, the viral concentrate was readjusted to the initial volume with RPMI plus 10% foetal calf serum (FCS). The residual infectivity was assayed on P4 cells as described by CHARNEAU et al.. (1994, J. Mol. Biol., 241,651-662). Briefly, P4 cells were plated using 100 uL of DMEM medium plus 10% FCS in 96 plate multi-wells at 20 x 105 cells per mL. After overnight incubation at 37°C, the supernatant was discarded and the viral preparation (200 uL) was added. One day later the wells were washed three times in PBS. Each well was refilled with 200 uL of a reaction buffer containing 50 mM Tris-HCI pH 8.5,100 mM 2-mercaptoethanol, 0.05% Triton X-100 and 5 mM 4- methylumbelliferyl ß-D-galactopyranoside (MUG). After 3 hours at 37°C, the level of the reaction was measured in a fluorescence microplate reader.

1.2) Reverse transcription.

The plasmid pAV4 containing the 50-997 HIV-1 nucleotide fragment (MAL strain) in pSP64, under the control of the bacteriophage T7 promoter was a kind gift from Dr. J. L. DARLIX (INSERM-Lyon, France). E. coli HB 101 recA-was used for plasmid amplification. After digestion of this clone with Pstl and in vitro transcription using T7 RNA polymerase, a HIV-1 genomic RNA fragment starting at position +50 of the MAL sequence was obtained. In vitro transcription using T7 RNA polymerase as performed as follows. Three ug of linearized plasmid DNA were transcribed in 100 uL of 40 mM Tris-HCI pH 8.0,8 mM MgCtz, 10 mM spermidine, 25 mM NaCI, 10 mM dithiothreitol, 0.5 mM of each ribonucleoside triphosphate, with 100 units of T7 RNA polymerase and in the presence of 20 units of human placenta ribonuclease inhibitor, for 2 hours at 37°C. After treatment with 12 units of Rnase-free Dnase I (for 10 minutes at 37°C), the RNA transcripts were extracted with 1 volume of phenol/chloroformlisoamyl alcohol (24: 24: 1) and with chloroform and precipitated in 2.5 volumes of ethanol and 0.3 M ammonium acetate (pH 5.5).

Reverse transcription was performed in a total volume of 50 uL containing 50 mM Tris-HCI pH 8.0,6 mM MgCI2,2 mM dithiothreitol, 12 mM NaCI, 150 nM HIV-1 RNA, and either 200 nM of a synthetic oligodeoxynucleotide primer (18-mer ODN) complementary to the PBS of HIV-1 RNA, or 200 nM tRNALYs3. When the 18-mer ODN was used as primer, incubation was carried out at 37°C with the template and 300 nM RT. After 30 minutes, 10 u Ci [a-32P] dGTP (3000 Ci/mmol) and 0.1 mM of each dNTP were added and the incubation proceeded for 30 minutes at 37°C. With tRNALYs3 as primer, the same conditions were used except that tRNA and RNA were prehybridized by heating for 2 minutes at 90°C and then slowly cooled. Samples were extracted with phenol-chloroform and

collecte by ethanol precipitation. Reaction products were analyzed on 8% polyacrylamide-TBE (90 mM Tris pH 8.3,90 mM borate, 2 mM EDTA)-7 M urea gels.

RESULTS The antiviral activity of the compounds according to example 1 has been tested on various strains.

On HIV-LAI wild type this compound shows the following activities: IC50 = 0,2nM; CC50 > 105 nM (S. I. > 33.333).

On an HIV-1 novirapine resistant strain the activities of the compound of example 1 are as follows: IC50 > 104nM CC50 > 104nM The compound of example 1 has been also tested on various HIV strains and primary cell cultures. The table 1 illustrates the activity of this compound on these strains.

The retrovirucidal effect of the compound according to example 1 has been tested. Table 2 illustrates this effect at various doses of this compound.

The IC50 of the compound of example 1 for the inhibition of the reverse transcriptase is 20 nM.

TABLE 1-Anti HIV-1 activity of the compound of example 1 on various HIV strains and primary cell cultures ICSOyM) ICC5o (nM)

Compound HIV-1 IIIIB HIV-1 HIV-1 IIIB HIV-2 D HIV-1 Bal/ /MT4 AZTres./PBMC 194 Mono/macro- /MT4/PBMC phages Example 1 2.41>1000 0.2/>1000 0.58/>1000 >1000/> 0.004/>1000 1000 TABLE 2: Inhibition of infectivity of the compound of example 1 Dosage of compound of example 1 % inhibition of infectivity 10 nM 26% 100 nM 46% 1 pm 83% 99%10µm

EXAMPLE 3: Other 3- (amino- or aminoalkyl) Pyridinone derivatives and their retrovirucidal activity against two different HIV-1 strains.

3.1 Compounds: Further compounds according to the general formula (I) (compounds n°1-25,27-108,110-125,127-145 and 147-203) as well as four intermediate compounds used for synthesis (compounds n°26,109,126 and 146) have been synthesized and are listed in table 3 below.

The meaning of each of the groups Y, Q and R3-R6 is defined for every exemplified pyridinone derivative.

3.2 RETROVIRUCIDAL EFFECT The retrovirucidal effect of each pyridinone derivative listed in table 3 has been assayed according to the teachings of example 2, excepted that the anti-viral effect has been tested on the two following HIV-1 strains: a) HIV-1 strain IIIB (see example 2); b) HIV-1 strain 103 N which is a mutant strain bearing a point mutation in the reverse transcriptase gene leading to an enzyme wherein the initial Lys-103 residue is replaced for a Asn residue.

HIV-1 103N strain exhibits resistance to the reverse transcriptase inhibitor TIBO R82913 (BALZARINI J. et al. 1993, Virology, 192 : 246-253).

The HIV-1 103 N strain has also been described by SAHLBERG et al., (1998, Antiviral Res., 37 (3): ASS) and BALZARINI etal. (1996, Antimicrobial Agents and Chemotherapy, 40 (6): 1454-1466).

The results are expressed as ploc50 (ploc50 = - log IC50), of every of <BR> <BR> <BR> <BR> compound as regards to each of the HIV-1 strains IIIB and 103N. Thus, the ploc50 value of compound n°1 as regards to HIV-1 IIIB being 7,6999, the IC50 can be directly deduced as being equal to 10-76999M.

Such high retrovirucidal activities had never been observed previously when using prior art reverse transcriptase inhibitors.

Consequently, the novel pyridinone derivatives according to the present invention are of a high therapeutical value against HIV related diseases, particularly against HIV-1 related diseases.

TABLE 3 HIV1 pIC50 T jRB R4 |RS 66 X ; 1 A 1 O NH2 Chemistry 4 Et Me H 7.699 6.671 O 2 o N H. s Et Me H 6. 6t 2 6.64 30 NMe2 3, 5-Di Et Me H 8. 004 7. 438 u Xi \/ k Ak 4 0;. s E Et Me H 5.094 <4 5o NH2 3,5-Dimethylbenzyi Et Me H 6.261 5.636 ou 60NH2Chemistry 52EtMeH5. 795 5.026 | 7 O NH2 Chemistry 58 Et Me H <4 <4 toNH24-Methybenzy ! EtMeH4. 3734. 39 T 9 O NH2 3-Methylbenzyl Et Me H 5. 373 5. 103 10 NMe2 Chemistry 82 Et Me H 6.241 4.389 Yxj 1 l _ NMe2 3, 5-Dimethylbenr/l Et Me Me 7.215 6.094 2 12 0NEt23. S-Dimethybenzy) Et Me H 8. 022 6.363 L 13 o siMe2 3 Methylbenryl Et Me H 8. 824 7.622 ; y 14 o qMe2 2-Methylbenzyl Et ue H 7.676 5. 849 2x 15 O NH2 3, 5-Dimethylbenryl H H H <4. 17 4.138 I 16 6 0 NMe2 3, 5-Dimethylbenry H H H 5.061 4.401 JL 17 0 N (n-Pr) 2 3,5-Dimethyibenryl Et Me H 6.285 4.379 0318 0 NMe2 4-Methylbenryl Et Me H 6.454 4. 895 _ Sj t4475.94719 O NMe2 3, 4-Dimethylbenryl Et Me H 7. 2 O NMe2 2, 3-Dimelhylbenryl Et Me H 6. 926 5.585 21 0 NMe2 Benzy) B Me H 8. 409 6. 65 2). i 22 O NMe2 3, 5-Dimethylbenryi Et Me Benzyl 4.603 <4 ""° Jjk 23 o NMe2 l iD 2 Et Me Chemistry 163 5. 254 e4 --- - AJk 24 O Chemistry 165 3. 5-Dimethylbenryl Et Me H 4. 262 <4 N Y i i 25 O Chemistry 171 3.5-Dimethylbenzyl Et Me H <4 4. 259 0 0)"- IF NU 26 o Chemistry 177 3, Et Me, 27 o NH2 Me Et H 5.949 5.098 i 28 Et H 8.032 6.943 / 2 9 o NHCH2Ph 3, 5-Dimelhylbenzyl Et Me H 6.555 5.496 n i Xr' 3 O Piperidin-1yl 3, 5-Dimethylbenryi Et Me H 6. 214 4. 224 31 0NH22. 4-Dimothy) benzy ! aMeH<4<4 310 NH2 2,4-Dimethylbenryl Et Me H <4 <4 J 32 O NH2 3, 5-Oimethylbenryl Me Me H 6. 104 <5 2). 330 NMe2 Me Me H 8.42 6.286 34 O NMe2 2. 4-Dimethylbenryl Et Me H 5. 019 <4 0 35 0NMe23. 5-Dimethy) benzoy ! EtMeH8.585 7.987 36 o si-Morpholino 3 8'Me H 6 763 e4 37 O qMe2 s Et Me H 6 796 5.729 F"aF F \ F 38 0NMe23. 5-Di) ! uorobenzy) EtMeH8. 155 7. 402 cri 39 O NH2 3-Chlorobenryl Et Me H 5 4. 751 4 O NMe2 3-Chlorobenryl Et Me H 8. 585 7412 IF 41 _ NH2 3-Fluorobenzyl Me H 5131 4 473 enzyl 42 O NMe2 3Fluorobenryl Et Me H 8. 569 7. 18 / 43 O NMe2 Chemistry 280 Et Me H 7.377 6. 422 i1 N 44 O NMe2 Chemistry 286 Et Me H 7.889 6.355 X 45 O NMe2 3, 5-Dimethylbenryl EI Me Et 5. 519 4. 095 460 NHME-3, 5-Dirt Et Me H 8. 119 7.034 XN 47 O Chemistry 303 3, 5-Dimethylbenryl Et Me H 7.767 6.968 ou 48 O NMe2 Chemistry 310 Et Me H 8 6. 711 49 0 4H2 Chemistry 316 Et Me H <4 <5 F F F F 50 0 NH2 3-Thnuoromethy ! benzyi EtMe H <5 <5 1 510 NMe2 Chemistry334 Et Me H 5. 384 <5 FIF F F F 52 o qH2 4-Tniluoromethylbenryl Et Me H <4 <5 /' F F F F F 530 NMe2 4-Tdtluoramethylbenzyl El Me H 5.828 <5 54 O NH2 4-Chbrobenryl Et Me H <4 <5 cl 55 O NMe2 4-Chiorobenryi Et Me H 6. 651 560 Chemistry 363 3 Et Me H 8.194 7.11 F F F 57 O NMe2 3-Tdtluoromethylbenryl Et Me H 8. 086 6.414 1 1 1 5 O NH2 2. 4, 6-Tdmethylbenryl Et Me H <4 <5 1 5 9 o NMe2 2,4,6-Trimethylbenryl Et Me H 5.029 <5 6 O NMe2 3-Bromobenryl Et Me H 8.444 7.001 61 o Chemistry 393 3, 5-Dimethylbenryl Et Me H 7.693 5.922 zizi 62o Chemistry 399 Et Me H 6.604 5.305 /i 63 0NMe23. 5-Dimethy ! benzytMe n-Pr H 7.029 6.334 J 64 o NHC (=O)-iPr 3, 5-Dimelhyibenzyl El Me H ci 65 o NMe2 z Et Me H 8.284 6.405 N'IS V 66 O NMe2 Chemistry 430 Et Me H 7.588 5.72 N"ZZ" XN 67o Chemistry 435 Et Me IH 6.804 4.955 H AJk O \ 68 Chemistry 441 Et Me H 69 o NH (n-Bu) 3, 5-Dimethylbenzyl Et Me H 6.891 5.655 \ 70 o NMe2 3, 5-Dimethylbenzyl Chemistry 45 Me H 7.752 7.159 \ 710 NMe2 3, 5-Dimethylbenryl n-Pr Me H 7. 777 777 049 HO Xi 72 o Chemistry 465 3, 5-Dimethylbenzyl Et Me H 7. 079 <4 _ Oo 73 o NH2 Chemistry 472 Et Me H 8.027 6.92 / 74 o NH2 Chemistry 478 Et Me H <4 <4 k N 75 o NMe2 Chemistry 490 Et Me H 5.252 4.132 ( 76 o NH2 3, 5-Dimethylbenzyl H i-Am H <5.494 <4 A-_ 77 O NMe2 3. 5-Dimethylbenryl H i-Am H 5.827 <4 po 78 0Chemistry 5073. 5-Dimethybenzy ! EtMeH8.678 7.128 1 xi1' 79o Chemistry 513 3 Et-Me H 6.987 5.47 80o NH2 Chemistry 520 Et Me H <4 <4 e 81 D NHEt Et Ue H 7.866 6.444 H XN i 82o Chemistry 531 3, 5-Din Et Me H 7.735 5.813 83 O NH2 Chemistry 538 Et Me H <4. 033 <4 N'IN v \ 8rJ O NH2 3-Methylbenzyi Me Me H 4. 954 <4 --v- 860 NMe2 3-Methyl Me Me H 7.863 5.936 X _ 87 o NH2 3 Et vie H 6.46 5.653 N'ion 88 O fVMe2 Chemistry 568 Et Me H <4 89 O NH2 3, 5-Dimethylbenryl H n-Bu H 6.237 9 O NMe2 3. 5-Dimethylbenryl H n-Bu H 6.359 91 0 NH2 3-Methyll (CH2) 4 CH2) 4 H 5.73 92 0NMe23-Methy) benzy ! CH2) 4 H 7.807 0 93 O NMe2 3-Methylbenzoyl Et Me H 8.721 0 i 94 O 4H2 Mets Me Me H 5 t53 0 95 O NEt2 3-Methylbenzoyt Et Me H 8.268 0 )0 96 O NMe2 3-Methylbenzoyl Me Me H 7. 824 6. 37 97 0NH2Chemistfy 622aMeH<4<4 \ 980 NH2 3-Ethyl Et Me H 5. 358 4. 978 A 99 O NMe2 B t Me H 8 569 6.718 i 100 NH2 3. 5-Din H Ime H 871 <4 /I 1010 NMe2 3, 5-Dimethylbenryi H Me H 6.341 4.25 f1 /N \ po652aMeH 4. 369<4 /I 1030NH2Chemistty 658EtMeH5.747 \ 104 O NMe2 Chen Et Me H 8 7.058 i 105 O NH2) 3 s, 1 H H 4 943 106 O NMe2 3, 5-Dimethylbenryl CI H H 7. 063 0 i 107 2 (CH2) 4 (CH2) 4 H 7.231 O 10810 NMe2 3-Methy'Me'Et H 7. 005 H j XN II °Jk 100Chemistry 699 3.5-Dimethylbenryl H OMe H OH 1100NMe2Chemistry 706EtMeH 7. 783 u 1 0 J 111 0 NH2 Chemistry 712 Et Me H <4 0 1 0 J 112 NMe2 Chemistry 718 Et Me H 6.394 6 : D 113 O NH2 Chemistry 724 Et Me H 5.273 -ICI 3fN/\ 0 114 O Chemistry 729 Chemistry 730 Et Me H v t i 115 O NMe2 3-Methylbenzoyl Ef Me Chemistry 745 <4.307 po i 116 o NMe2 Chemistry 748 Et Me H 6 627 117 O CH2NMe2 3-Methylbenzyl (CH2) 4 (CH2) 4 H <4. 139 I 118 0NH23. 5-Dimethy) benzy ! Met-Pr H4.042 2). 1190 NMe2 Me i-Pr H 6. 114 ou 1 2C 0 NH2 3-Methoxybenzyl Et Me H 5 033 --a- 1210 NMe2 3Methoxybenryi Et Me H 8.469 6.948 ou 122 3 NMe2}-OHbenzyl Et Me H 7. t 96 OH 123 O Chemistry 789 3, 5-Dimethylbenryl Et Me H 8.444 6.918 T "0" 1240NH2Chemistry 796EtMeH 4.389 \ 125 _ NHCHO 3-Methylbenzyl Et Me H 0 i 126 c NHCHO 3-Methylbem yl Et Me ri o i 127 O NMe2 Chemistry 814 Et Me H 4.174 1 0 \ OH 12$ O NMe2 Chemistry 820 Et Me H 7.848 XNO// 129 0 Chemistry 825 3, 5-Dimethylbenzyl Et Me H 8.398 7.057 ou "o" 130 O NH2 Chemistry 832 Et Me H <4 T 1310 NH2 3-Methylbenzyl (CH2) 3 (CH2) 3 H 5. 799 \ y 32 O NMe2 3-Methyibenzyl (CH2) 3 (CH2) 3 H 7.863 /N I \ / 13310 NMe2 Chemistry Et Me H 4. 94 0 ou 134 O NH2 Chemistry 856 Et Me H 4.056 oui J 135 O NMe2 Chemistry 862 Et Me H 6.688 XN i i ' 136 O 3Methylbenzyl Et Me H 9 6.996 \ 137S NMe2 Et Me H 7.658 0 138 S NMe2 3, 5-Dimethylbenzoyi Et Me H 8.215 7.401 F F F 139 O NHMe 3-Tritluoromethylbenzyl Et Me H 6.908 0 F F F 14010 NH2 3-Tritluoromethylbenzoyl Et Me--H 5.766 I o o-J 141 O NH2 Chemistry 898 Et Ma H 4. 642 6 142 O NH2 3-Methylbenzoyl (CH2) 3 (CH2) 3 H 4. 889 _ O i o 143 8 NMe2 Chemistry 910 Et Me i 7 421 I kNo i I 144 O Chemistry 915 3-Methylbenzyl Et Me H 6.446 'OH XN OH 145 0Chemistry 9213-MethybenzytEtMeH8. 42 6.028 0 I 0 yak n eNH 04 146o Chemistry 927 Chemistry 928 Et Me H 1 o Wjo 147o NMe2 Chemistry 934 Et Me H 7 721 O X 148 o NMe2 3-Methylbenzoyi (CH2) 3 (CH2) 3 H 7.863 vs 149 o Me2 Chemistry 946 Et Me H 8 959 7.883 0 I o ; FOj 150 o H2 Chemistry 952 Et Me H 4 881 y 952 Xi 0 ou 151 0 NMe2 Chemistry958 Et Me H 7. 845 2 152 O NMe2 3, 5-Dimethylbenryl Et Me Ph 4.21 0 153 O NMe2 3, 5-Dimethylbenryi Et Me NH2 6.749 XNOH 154 O Chemistry 981 3-Methylbenryl Et Me H 8.009 6.262 I 'kj 155 o Chemistry987 i-Methylbenzyl Et Me H 7.514 156 o NH2 Chemistry 994 Et Me H 4 934 I W 157 O NMe2 Chemistry 1000 Et Me H 6.413 Y 158 o NMe2 s Et Me H 8 041 6.625 -S 159 _ NH2 ms 12 Et Me H 7 011 xi I 61, 1"F rii F F 161 0 Chemistry 1023 3-Tritluoromethylbenryl Et Me H 7. 821 5. 814 '1) o 162 O NMe2 Chemistry 1030 Et Me H 6. 418 5. 026 I HN 163 O NMe2 Chemistry 1036 Et Me H 5.596 4. 236 I kj. 164oChemistry 10413-MethyibenzytaMeH7. 818 6.505 OH 1650NMe2Chemistry 1048EtMeH 4.354 <4 I s ^/ 166 O NMe2 Chemistry 1054 Et Me H 5.693 4.518 I "n ZON 167 O NMe2 Chemistry 1060 Et Me H 6.338 5.828 0 po 168 0NH2Chemistry 1066EtMeH4. 525 4. 806 0 ° 1690 NMe2 Chemistry 1072 Et Me H 7. 101 5.771 x, o s A 170 0NMe2Chemistry 1078EtMeH8. 553 553 224 HN N "il N 171 0 NMe2 Chemistry 1084 Et Me H 5. 895 4.74 i 2 z wme w 73 O NMe2 3, 5-Dimethylbenryl (CH2) 4 (CH2) 4 H 8. 086 6. 469 170NMe23.5-Dimethy! benzy) (CH2) 4 (CH2) 4 H8.086 6.469 6ber er 1740NMe23-BromobenzoyiEt Me H 8.921 7. 68 0 I 0 175 o Chemistry 1107 wn Et Me H 8. 92t 7.717 NU 6. 176 o NMe2 « Et Me H 8.432 6.436 0 177 o NH2 SJ Et Me H 5. t 06 <4 0 vs 178 O NMe2 Chemistry 1126 Et Me H 7. 873 6.461 0 I 179 o NHMe 3-Bromobenzoyl Et Me H 8.42 7.182 zou X Ow j 180 o Chemistry 1137 3-Methylbenzyi Et Me H 5.988 / 181 0NMe2Chemistry 1150EtMeH7. 928 0 F F F F 182 o NH2 Chemistry 1156 Et Me H 5.933 0 1 F F F F 180NMe2Chemistry 1162EtMe H8. 481 // O Br 184oChemistry 11673-Bromobenzy) EtMeH 8.523 6.804 Jkr XN/ e 1850Chemist) y11733-Bromobenzoy ! EtMeH 8. 745 7.433 1 0 jS Br 186 o NH2 is Et Me H 5 78t fus Br Br 187 0 NMe2 Chemistry 1186 Et Me H 8. 481 7.006 xi ^S ber 188 0NH2Chemistry 1192EtMeH7.063 C CI aci 1 89 o NH2 3, 5 Dichlorobenzyl Et Me H 6 40t a fgo o NH2 t u t vte H 7 757 ci,'Cl 1910 NMe2 3, 5-Dichlorobenryl Et Me H 8. 097 7. 553 0 192 O NMe2 3 N D ch4wLz t vie H 8 699 8 319 vs ex 1930 NMe2 Chemistry 1222 Et Me H 8. 481 7. 245 0 ex er 194 o NH2 Chemistry 1228 Et Me H 4.665 zizi --o"rjj 195 o Chemistry 1233 13-Methy Et Me H 8.569 6.52 o 0 1960 NMe2 Chemistry 1240 Et Me H 6.411 Jy A 197 O NH2 Chemistry 1246 Et Me H 7.307 sY 198 0 NH2 Chemistry 1252 Me H H 4.457 Xl o/\ W92419 9 O Chemistry 1257 3-Methylbenzyl Et Me H 7. xl ov 23 0 w 200 o Chemistry 1263 Benzyl Et Me H 8. 42 5.95 A 201 o NMe2 Chemistry 1276 Et Me H 8.585 7.231 tzBr22 0 NH2 2-Bromobenryl Et Me H 5. 715 /er 203 o NMe2 2-Bromobenzyl Et Me H 6 161