Piperidine Derivatives Useful As Ccr5

Europäisches Patentamt & (19) European Patent Office

Office européen des brevets (11) EP 1 421 075 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 401/04 (2006.01) A61P 31/18 (2006.01) 07.06.2006 Bulletin 2006/23 A61K 31/435 (2006.01)

(21) Application number: 02766142.0 (86) International application number: PCT/US2002/027389 (22) Date of filing: 28.08.2002 (87) International publication number: WO 2003/020716 (13.03.2003 Gazette 2003/11)

(54) PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS FOR THE TREATMENT OF HIV PIPERIDIN DERIVATE ALS CCR5 REZEPTOR ANTAGONISTEN ZUR BEHANDLUNG VON HIV DERIVES DE LA PIPERIDINE UTILISES COMME ANTAGONISTES DU CCR5 POUR LE TRAITEMENT DU SIDA

(84) Designated Contracting States: (74) Representative: Adams, Harvey Vaughan John et AT BE BG CH CY CZ DE DK EE ES FI FR GB GR al IE IT LI LU MC NL PT SE SK TR Mathys & Squire Designated Extension States: 120 Holborn AL LT LV MK RO SI London EC1N 2SQ (GB)

(30) Priority: 29.08.2001 US 315683 P (56) References cited: EP-A- 0 151 824 EP-A- 0 855 999 (43) Date of publication of application: WO-A-01/30348 WO-A-01/77101 26.05.2004 Bulletin 2004/22 WO-A-97/24324 WO-A-98/01425 WO-A-02/081449 US-A- 5 952 349 (73) Proprietor: SCHERING CORPORATION Kenilworth, NJ 07033-0530 (US) • PALANI, A. ET AL.: "Discovery of 4-[(Z)-(4- Bromophenyl)-(ethoxyimino)methyl ]-1’-[(2,4- (72) Inventors: dimethyl-3-pyridinyl)carbonyl]- 4’-methyl-1,4’- • PALANI, Anandan bipiperidine N-Oxide (SCH 351125): An Orally Bridgewater, NJ 08807 (US) Bioavailable Human CCR5 Antagonist for the • MILLER, Michael, W. Treatment of HIV Infection" JOURNAL OF Westfield, NJ 07090 (US) MEDICINAL CHEMISTRY, vol. 44, no. 21, 11 • SCOTT, Jack, D. October 2001 (2001-10-11), pages 3339-3342, Springfield, NJ 07081 (US) XP002220286

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 421 075 B1

Printed by Jouve, 75001 PARIS (FR) EP 1 421 075 B1

Description

CROSS REFERENCE TO RELATED APPLICATION

5 [0001] This application claims priority to U.S. Provisional Application 60/315683, filed August 29, 2001.

FIELD OF INVENTION

[0002] The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical 10 compositions containing the compound of this invention, and methods of treatment using the inventive compounds. The invention also relates to the use of a combination of the compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of the compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, 15 allergies or multiple sclerosis.

BACKGROUND OF INVENTION

[0003] The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), 20 is unquestioned. While recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus. [0004] It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and 25 other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists. [0005] CCR5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheu- 30 matoid arthritis, atopic dermatitis, psoriasis, asthma and allergies. Inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. [0006] Other piperidine derivatives, which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer’s disease, are disclosed in US patents 5,883,096, 6,037,352, 5,889,006, 5,952,349, and 5,977,138. 35 [0007] A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203 (1998) disclose current clinical treat- ments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy ("HAART"). HAART involves various combinations of nucleoside reverse transcriptase inhibitors ("NRTI"), non- nucleoside reverse transcriptase inhibitors ("NNRTI") and HIV protease inhibitors ("PI"). In compliant drug- naive patients, HAART is effective in reducing mortality and the progression of HIV-1 to AIDS. However, these multidrug therapies do 40 not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.

SUMMARY OF THE INVENTION

45 [0008] The present invention provides a novel class of compounds as antagonists of the CCR5 receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, and uses in the treatment, prevention or amelioration of one or more diseases associated with the CCR5 receptor. [0009] One aspect of the invention relates to a compound having the general structure shown in Formula 1:

2 EP 1 421 075 B1

or a pharmaceutically acceptable salt or solvate thereof; wherein: 15 R1 is

R2 is selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroarylalkyl, alkylketone, arylketone, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, cycloalkylalkyl, alkylsulfonyl, arylsulfonyl, alkoxyalkyl, or amide; 35 R3 is selected from the group consisting of aryl, 6- membered heteroaryl, fluorenyl; and diphenylmethyl, 6 membered heteroaryl-N-oxide,

45 wherein said aryl, fluorenyl, diphenyl or heteroaryl is optionally substituted with 1-4 substituents which can be the same or different and are independently selected from the group consisting of R11, R12. R13, R14 and R15; R4 is 1-3 substituents selected from the group consisting of H, halo, alkyl, haloalkyl, alkoxy, cycloalkyl, cycloheter- 7 oalkyl, amide, CF3, OCF3, aryl, heteroaryl, -XR , -C(O)C3-C8cycloalkyl, -C(O)C3-C8cycloheteroalkyl, -(C1-C6)alkyl- 21 22 20 21 22 8 8 N(R )SO2R , -(C1-C6)alkyl-C(O)NR R , -CN, -CO2H, -CO2R , R -aryl(C1-C6)alkyl-, R -heteroaryl(C1-C6) 50 8 21 22 21 22 alkyl-, -C(O)-(C1-C6)alkyl, R -aryl-C(O)-, -C(O)NR R , -C(O)NH2, -C(O)N(H)OH, -(C1-C6)alkyl-N(R )C(O)R , 21 22 -(C1-C6)alkyl-N(R )CO2R , 21 21 22 21 22 21 22 -(C1-C6)alkyl-N(R )C(O)NR R , -(C1-C6)alkyl-NR R , -(C1-C6)alkyl-NH2, (C1-C6)alkyl, -SO2NR R and 21 22 4 -SO2NR R , wherein R can be the same or different and is independently selected when there is more than one R4 present; 55 5 8 8 R is selected from the group consisting of H, arylalkyl, (C1-C6)alkyl, R -aryl(C1-C6)alkyl-, R -heteroaryl(C1-C6) 8 alkyl-, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-aryl, R -aryl-SO2-, -C(O)-(C1-C6)alkyl, -C(O)-(C4-C6)cy- 8 21 22 21 22 cloalkyl, R -aryl-C(O)-, -C(O)NR R , and -SO2NR R ; 6 R is H, -(C1-C6)alkyl, or -(C1-C6)haloalkyl;

3 EP 1 421 075 B1

R7 is selected from the group consisting of aryl, substituted aryl, heteroaryl, alkyl, haloalkyl and cycloalkyl; 8 R is 1, 2 or 3 substituents selected from the group consisting of H, halo, (C 1-C6)alkyl, (C1-C6)alkoxy, -CF3, -OCF3, 8 CH3C(O)-, -CN, CH 3SO2-, CF 3SO2- and -NH 2, wherein R can be the same or different and is independently selected when there are more than one R8 present; 5 R9, R10 and B can be the same or different and are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, and -(C1-C6)haloalkyl: 11 12 R and R can be the same or different and are each independently selected from the group consisting of (C 1-C6) 19 20 alkyl, -(C1-C6)haloalkyl, halogen, -NR R , -OH, CF3, -OCH3, -O-acyl, and -OCF3; 13 11 R is selected from the group consisting of hydrogen, R , H, phenyl, -NO 2, -CN, -CH 2F, -CHF 2, -CHO, -CH=NOR 19, 10 pyridyl-N-oxide, pyrimidinyl, pyrazinyl, N (R20)CONR20R21, -NHCONH(chloro-(C 1-C6)alkyl), -NHCONH((C 3-C10)-cycloalkyl(C1-C6)alkyl), -NHCO(C1-C6)alkyl, -NHCOCF3, -NHCOCF3, -NHSO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, 22 22 22 -N(SO2CF3)2, -NHCO2(C1-C6)alkyl, (C3-C10)cycloalkyl, -SR , -SOR , -SO2R , -SO2NH(C1-C6 alkyl), -OSO2 19 20 (C1-C6)alkyl, -OSO2CF3, hydroxy(C1-C6)alkyl, -CONR R , -CON(CH2CH2-O-CH3)2, -OCONH(C1-C6)alkyl, -CO2R19, -Si(CH3)3 and -B(OC(CH3)2)2; 15 14 15 R is selected from the group consisting of (C1-C6)alkyl, -(C1-C6)haloalkyl -NH2 and R -phenyl; 15 R is 1-3 substituents selected from the group consisting of hydrogen,1 -C (C6)alkyl, -(C1-C6)haloalkyl, -CF3, 20 15 -CO2R , -CN, (C1-C6)alkoxy and halogen; wherein R can be the same or different and is independently selected when there are more than one R15 present; R16 and R17 can each be the same or different and are each independently selected from the group consisting of 20 hydrogen and (C1-C6)alkyl, or 16 17 R and R together are a C2-C5 alkylene group and with the carbon to which they are attached from a spiro ring of 3 to 6 carbon atoms; R19, R20 and R21 can each be the same or different and are each independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6)cycloalkyl; 25 22 R is selected from the group consisting of (C1-C6)alkyl, -(C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C2-C6)alkylene, (C3-C6)cycloalkyl, aryl and aryl(C1-C6)alkyl-; A is selected from the group consisting of (C1-C6)alkyl, and (C2-C6) alkenyl. M is aryl or heteroaryl optionally substituted with R4; Q is CH or N; and 30 X is selected from the group consisting of CH2, SO2, SO, S, and O, with the following proviso:

1 2 when R is phenyl, pyridyl, thiophenyl or naphthyl, R cannot be H, -(C1-C6)alkyl or -C(O)-(C1-C6)alkyl.

[0010] Another aspect of the invention relates to a pharmaceutical composition for treatment of HIV comprising one 35 or more compounds of formula I. [0011] Yet another aspect of the invention relates to the use of one or more compounds of the invention in the manufacture of a pharmaceutical composition for treating Human Immunodeficiency Virus. A further aspect of the invention relates to the use of one or more compounds of the invention in the manufacture of a pharmaceutical composition for treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel 40 disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis. [0012] Still another aspect of this invention relates to the use of one or more compounds of the invention in the manufacture of a pharmaceutical composition for treating Human Immuno- deficiency Virus wherein said treatment further comprises administering the one or more compounds of the invention in combination with one or more antiviral or other agents useful in the treatment. A further aspect of this invention relates to the use of one or more compounds of the 45 invention in the manufacture of a pharmaceutical composition for treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma or allergies wherein said treatment further comprises administering the one or more compounds of the invention in combination with one or more antiviral or other agents useful in the treatment. [0013] The CCR5 and antiviral or other agents which are components of the combination can be administered in a 50 single dosage or administered separately. A kit comprising separate dosage forms of the actives is also contemplated.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention relates to a compound having the general structure shown in Formula I: 55

4 EP 1 421 075 B1

15 or a pharmaceutically acceptable salt or solvate thereof; wherein:

wherein R1, R2, R3, R9, R10, A and B are defined as above.

[0015] When R1 is 20

Q is preferably CH or N, and R2 is preferably alkyl, aryl or benzyl. 30 4 [0016] When R1 is M-R , R2 is preferably benzyl, phenyl or cyclopropylmethly. [0017] As used herein, the following terms are used as defined below unless otherwise indicated. [0018] "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to about 6 carbon atoms in the chain. Branched alkyl means that one or more lower alkyl groups 35 such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Preferred alkyl groups in the present invention are lower alkyl groups. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, n- pentyl, heptyl, nonyl, decyl, trifluoromethyl and cyclopropylmethyl. [0019] "Halo" means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred 40 are fluoro and chloro. [0020] "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine. [0021] "Haloalkyl" or "halogenated alkyl" means alkyl having one or more halo atom substituents. Preferably, the haloalkyl is a haloalkyl. Non-limiting examples include -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -CH2-CH2F, 45 -CH2CHF2, -CH2CF3 and -CF2CF3. [0022] "Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylamino, arylamino, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, aralkyloxy, 50 acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroar- alkylthio, cycloalkyl, cycloalkenyl, Y1Y2N-, Y1Y2N-alkyl-, Y1Y2NC(O)- and Y1Y2NSO2-, wherein Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. [0023] "Cycloalkyl" means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon 55 atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Non- limiting examples of suitable multicyclic cycloalkyls include 1- decalinyl, norbomenyl, adamantyl and the like.

5 EP 1 421 075 B1

[0024] "Cycloheteroalkyl" means a non- aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms, wherein the cycloheteroaryl has 1 or 2 heteroatoms independently selected from O S or N, said heteroatom(s) interrupting a carbocyclic ring structure provided that the rings do not contain adjacent oxygen and/or sulfur atoms. The cycloheteroalkyl can be optionally 5 substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. [0025] "Aryl" means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 ring carbon atoms, preferably 6 to 10 ring carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. 10 [0026] "Heteroaryl" represents cyclic aromatic groups of 5 or 6 ring atoms or bicyclic groups of 11 to 12 ring atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. Preferred heteroaryls contain 5 to 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as 15 defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2- pyridyl, 3-pyridyl and 4- pyridyl. Useful 6- membered heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like and the N-oxides thereof. Useful 5-membered heteroaryl rings include furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl and the like. Useful bicyclic groups include benzo- fused ring sys- 20 tems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzoth- ienyl, indolyl and the like. [0027] Amide is represented by RCONH 2 wherein one or both of the hydrogen atoms in RCONH 2 can be substituted by an alkyl group and alkyl has the same meaning as defined above. [0028] Arylalkyl or aralkyl represents a moiety containing an aryl group linked to the main group or ring via an alkyl. 25 [0029] Alkylketone represents a moiety containing an alkyl group linked to the main group or ring via a ketone. [0030] Arylketone represents a moiety containing an aryl group linked to the main group or ring via a ketone. [0031] Alkylaryl represents a moiety containing an alkyl linked to the main group or ring via an aryl group. [0032] Heteroarylalkyl represents a moiety containing a heteroaryl group linked to the main group or ring via an alkyl. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. 30 [0033] The term "solvate" as used herein means an aggregate that consists of a solute ion or molecule with one or more solvent molecules, for example, a hydrate containing such ions. [0034] As used herein, the terms "composition" and "formulation are intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients. 35 [0035] "Patient" includes mammals and other animals. [0036] "Mammal" includes humans and other mammalian animals. [0037] The term "therapeutically effective amount" is intended to mean an amount of a therapeutic agent of the compound of formula I that will have an effect on a tissue, system, animal or patient that is being sought by the administrator (such as a researcher, doctor or veterinarian), which includes alleviation of the symptoms of the condition or disease 40 being treated and the prevention, slowing or halting of progression of the disease or condition, for example, the inflammatory, immunomodulatory or respiratory diseases discussed herein. [0038] Prodrugsand solvatesof the compounds of the invention are also contemplated withinthe scopeof this invention. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt 45 and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella,Pro- drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. [0039] The compounds of formula I can form salts, solvates and prodrugs which are also within the scope of this 50 invention. Reference to a compound of formula I herein is understood to include reference to salts, solvates and prodrugs thereof, unless otherwise indicated. [0040] The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to a 55 carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates

6 EP 1 421 075 B1

or in an aqueous medium followed by lyophilization. [0041] Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, ben- zenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, hep- 5 tanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropion- ates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical 10 compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; and Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York). These disclosures are incorporated herein by reference thereto. [0042] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) 15 such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N- methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. 20 benzyl and phenethyl bromides), and others. [0043] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. [0044] Compounds of formula I, and salts and solvates and prodrugs thereof, may exist in their tautomeric form (for 25 example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. [0045] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are 30 contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the 35 inventive compounds. [0046] The term "nucleoside and nucleotide reverse transcriptase inhibitors" ("NRTI" s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV- 1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1.RNA into proviral HIV-1 DNA. [0047] Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo- Well- 40 come Inc., Research Triangle, NC 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, NJ 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, NJ 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, NJ 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, NC 27709; abacavir (1592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo-Wellcome Re- 45 search Triangle, NC 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, CA 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP- 0358154 and EP- 0736533 and under development by Bristol- Myers Squibb, Princeton, NJ 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH- 10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V, 4A7, Canada; emitricitabine [(-)-FTC] licensed from Emory University under Emory Univ. 50 U.S. Patent No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, NC 27707; beta-L- FD4 (also called beta-L-D4C and named beta-L-2’, 3’-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceu- ticals, New Haven CT 06511; DAPD, the purine nucleoside, (-)-beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, NC 27707; and lodenosine (FddA), 9-(2,3-dideoxy-2=fluoro-b- D-threo-pentofuranosyl)adenine, an acid stable purine- based 55 reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Consho- hoken, PA 19428. [0048] The term "non-nucleoside reverse transcriptase inhibitors" ("NNRTI"s) as used herein means non- nucleosides that inhibit the activity of HIV-1 reverse transcriptase.

7 EP 1 421 075 B1

[0049] Typical suitable NNRTis include nevirapine (BI- RG-587) available under the VIRAMUNE tradename from Boe- hringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, OH 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co., Bridgewater NJ 08807; efavirenz (DMP- 266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Phar- 5 maceutical Co., Wilmington, DE 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Phar- macia and Upjohn, Bridgewater NJ 08807; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)- thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonate disclosed in WO 96 /10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenyl- methyl)-(2,4(1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Phar- 10 maceuticals, Durham, NC 27707; and (+)-calanolide A (NSC- 675451) and B, coumarin derivatives disclosed in NIH U.S. Patent No. 5,489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-Invest as an orally administrable product. [0050] The term "protease inhibitor" ("PI") as used herein means inhibitors of the HIV- 1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual 15 functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN(available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron). [0051] Typical suitable Pls include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, NJ 07110-1199; 20 ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, IL 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck & Co., Inc., West Point, PA 19486-0004; nelfnavir (AG- 1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; amprenavir (141W94), tradename AGENERASE, a nonpeptide protease inhibitor under development by Vertex Pharmaceu- ticals, Inc., Cambridge, MA 02139-4211 and available from Glaxo- Wellcome, Research Triangle, NC under an expanded 25 access program; lasinavir (BMS- 234475) available from Bristol- Myers Squibb, Princeton, NJ 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol- Myers Squibb, Princeton, NJ 08543, as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott , Abbott Park, IL 60064; and AG- 1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron 30 Pharmaceuticals, Inc., LaJolla CA 92037-1020. [0052] Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T- cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL- 2 is disclosed in Ajinomoto 35 EP-0142268 , Takeda EP-0176299, and Chiron U. S. Patent Nos. RE 33653, 4530787, 4569790, 4604377, 4748234, 4752585, and 4949314, and is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, CA 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL- 12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, NJ 07110-1199 and American 40 Home Prodocts, Madison, NJ 07940; a dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide,disclosed in U.S. Patent No.5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg /day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI’s to HIV-1 positive patients refractory to a triple combination therapy; use of 45 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV -1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042 , Israel. Ribavirin, 1- β-D-ribofuranosyl-1H-1,2,4- triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, CA; its manufacture and formulation are described in U.S. Patent No. 4,211,771. [0053] The term "anti-HIV-1 therapy" as used herein means any anti- HIV-1 drug found useful for treating HIV- 1 infec- 50 tions in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one Pl, a second Pl, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from NNRTls and Pls. Typical suitable HAART - multidrug combination therapies include: 55 (a) triple combination therapies such as two NRTIs and one PI ; or (b) two NRTIs and one NNRTI ; and (c) quadruple combination therapies such as two NRTIs, one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination

8 EP 1 421 075 B1

therapy; the use of two NRTIs and one PI is prefered unless there is intolerance to Pls. Drug compliance is essential. The CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug,e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:

5 ANTI-HIV-1 MULTI DRUG COMBINATION THERAPIES

A Triple Combination Therapies

[0054] 10 1. Two NRTIs1 + one PI2 2. Two NRTIs1 + one NNRTI3

B. Quadruple Combination Therapies4 15 [0055] Two NRTIs + one PI + a second PI or one NNRTI

C. ALTERNATIVES:5

20 [0056]

Two NRTI1 One NRTI5 + one PI2 Two Pls6 + one NRTI7 or NNRTI3 25 One PI2 + one NRTI7 + one NNRTI3

FOOTNOTES TO TABLE

[0057] 30 1. One of the following: zidovudine + lamivudine; zidovudine + didanosine; stavudine + lamivudine; stavudine + didanosine; zidovudine + zalcitabine 2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules. 3. Nevirapine or delavirdine. 35 4. See A-M. Vandamne et al Antiviral Chemistry & Chemotherapy 9:187 at p. 193-197 and Figures 1 + 2. 5. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients. 6. Most data obtained with saquinavir and ritonavir (each 400 mg bid). 40 7. Zidovudine, stavudine or didanosine.

[0058] Specific examples of compounds of the present invention include, but are not limited to, compounds wherein R1, R2 and R3 are as defined in the following table:

9 EP 1 421 075 B1

10 EP 1 421 075 B1

11 EP 1 421 075 B1

12 EP 1 421 075 B1

13 EP 1 421 075 B1

14 EP 1 421 075 B1

15 EP 1 421 075 B1

16 EP 1 421 075 B1

17 EP 1 421 075 B1

18 EP 1 421 075 B1

[0059] Preferred compounds from TABLE I above are shown below in TABLE IA: 50

19 EP 1 421 075 B1

20 EP 1 421 075 B1

21 EP 1 421 075 B1

22 EP 1 421 075 B1

[0060] Even more preferably, the compounds of the present invention are represented by the following formulae:

23 EP 1 421 075 B1

24 EP 1 421 075 B1

35 [0061] The compound of the present invention, also referred to herein as the inventive compound, is particularly useful as a CCR5 antagonist. [0062] Compounds of the invention can be made by the procedures known in the art, for example by the procedures described in the following reaction schemes, by the methods described in the examples below, and by using the methods described in US patents 5,883,096; 6,037,352; 5,889,006; 5,952,349; and 5,977,138. 40 [0063] The following solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); trifluoroacetic acid(TFA); trifluoroacetic anhydride(TFAA); 1-hydroxy- benzotriazole (HOBT); m- chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); tert-butoxycarbonyl (BOC); 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU); dimethylsulfoxide (DMSO); p-toluene sulfonic acid (p-TSA); potassium bis(trimethylsilyl)-amide (KHMDA); 45 4-dimethylaminopryidine (DMAP); N,N,N-diiospropylethylamine (DIPEA); and 1-(3-dimethyl-aminopropyl)-3-ethyl car- bodiimide hydrochloride (EDCI). RT is room temperature.

25 EP 1 421 075 B1

2 3 5 [0064] Compounds of formula IA wherein X is CH2 or N, R is alkyl, aryl, or benzyl, and R and R is as defined in the summary of the invention are prepared according to Scheme A.

40 [0065] For the synthesis of compounds of formula IA, 4-hydroxy- piperidine 1 and N- Boc-4-piperidone 2 are sequentially treated with titanium isopropoxide and diethyl aluminum cyanide to furnish the cyano-amine 3. The cyano-amine 3 is treated with methyl magnesium bromide to furnish the methylated derivative 4. The piperidinol 4 is oxidized to the ketone 5 by swern oxididation. The Boc group in 5 is removed by treatment with an acid such as TFA, and the free amine is coupled with acid such as R3CO2H using standard conditions to furnish the keto-amide 6. The keto-amide 8 is reacted 45 with a substituted 4-amino piperidine 7 in the presence of sodium triacetoxy borohydride to give the amine 8. The free 2 amine in 8 can be functionalized either by reductive amination (RCHO/Na (AcO)3BH) or alkylation (NaH or Cs 2CO3/R X) to furnish compounds of formula IA.

26 EP 1 421 075 B1

[0066] Compounds of formula IIA where R2, R3, R4, and M are as defined are prepared according to Schemes B, C and D as follows.

25 [0067] The keto-amide 5 is reacted with an amine 10 in the presence of sodium triacetoxyborohydride to furnish the 2 functionalized amine 11. The amine 11 can be alkylated either with NaH, Cs 2CO3/R X or Na(AcO)3BH/RCHO to furnish the tertiary amine 12. The Boc group in 12 can be removed with an acid such as HCI or TFA, and the resulting piperidine can be coupled to acids to furnish compounds of formula IB.

27 EP 1 421 075 B1

2 [0068] N-Boc-4-piperidone 2 is reacted with and amine (R NH2) in the presence of Na (AcO)3BH to furnish the amine 13. The amine 13 can be reacted with either aryl or heteroaryl halides/triflates under palladium catalysis or Cu(OAc)2/ 35 4 (R M)3Bi to furnish the arylated amines 14. The Boc group in 14 can be removed, and the second piperidine ring can be added according to the procedure previously discussed ( Scheme 1; Steps 1 and 2) to furnish the piperidine 15. The Boc group in 15 is removed with an acid such as TFA or HCL, and the amine is coupled to an acid represented by R3CO2H to furnish the compounds of formula IB.

[0069] The functionalized amine 11 can be reacted according to procedures outlined above in Scheme C to furnish compounds of formula IB.

28 EP 1 421 075 B1

[0070] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, 5 talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington’s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. [0071] Liquid form preparations include solutions, suspensions and emulsions. An example of this includes, but is not 10 limited to, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. [0072] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. 15 [0073] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. [0074] The compound of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. 20 [0075] The compounds of this invention may also be deliverable subcutaneously. [0076] Preferably the compound is administered orally. [0077] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing a therapeutically effective amount of the compound having formula 1. [0078] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 10 mg to 25 about 500 mg, preferably from about 25 mg to about 300 mg, more preferably from about 50 mg to about 250 mg, and most preferably from about 55 mg to about 200 mg, according to the particular application. [0079] The actual dosage of the inventive compound employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions 30 during the day as required. [0080] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 100 mg/day to about 300 mg/day, preferably 150 mg/day 35 to 250 mg/day, more preferably about 200 mg/day, in two to four divided doses. [0081] The doses and dosage regimens of the NRTIs, NNRTIs, Pls and other agents used in combination with the compounds of this invention will be determined by the attending clinician inview of the approved doses and dosage regimens in the package inserts or as set forth in the protocols, taking into consideration the age, sex and condition of the patient and the severity of the condition treated. 40 [0082] In a preferred embodiment, the compound of the present invention can be used to treat Human Immunodefi- ciency Virus by administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds having formula I, preferably in combination with one or more pharmaceutically acceptable carriers. One or more, preferably one to four, antiviral agents useful in anti- HIV-1 therapy can be used in combination with the compound of the present invention. The antiviral agent or agents can be combined with one or more compounds of the present 45 invention in a single dosage form, or the one or more compounds of the present invention and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms. [0083] The antiviral agents contemplated for use in combination with the compound of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications. Specific examples of antiviral 50 agents include, but are not limited to, zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir, BCH- 10652, emitricitabine, beta- L-FD4, DAPD, Iodenosine, nevirapine, delaviridine, efavirenz, PNU- 142721, AG-1549, MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP- 450, BMS- 2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, lL-2, IL-12, pentafuside, Yissum No. 11607 and AG-1549. In particular, the combinations known as HAART are contemplated for use in combination with the compound of this 55 invention. [0084] For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

29 EP 1 421 075 B1

[0085] Another aspect of the invention provides a method of treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of formula I, preferably in combination with one or more pharmaceutically acceptable carriers. 5 In another embodiment, the method for treating solid organ transplant rejection, graft v. host disease, rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis further comprises administering one or more other agents useful in the treatment of said diseases in combination with one or more compounds of formula I. [0086] Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the compound of the present invention 10 are as follows:

solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin- 10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids; inflammatory bowel disease: IL-10 (see US 5,368,854), steroids and azulfidine; 15 rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; multiple sclerosis: interferon-beta, interferon-alpha, and steroids.

[0087] Another aspect of the invention relates to a kit comprising in separate containers in a single package pharmaceutical composition for use in combination to treat Human Immunodeficiency Virus. In one container, a pharmaceutical 20 composition comprises one or more compounds of formula I in one or more pharmaceutically acceptable carriers, and in separate containers, one or more pharmaceutical compositions comprising an effective amount of one or more antiviral agents or other agents useful in the treatment of Human Immunodeficiency Virus in one or more pharmaceutically acceptable carriers. [0088] The goal of the HIV-1 therapy of the present invention is to reduce the HIV- 1-RNA viral load below the detectable 25 limit. The "detectable limit of HIV-1-RNA" in the context of the present invention means that there are fewer than about 200 to fewer than about 50 copies of HIV-1-RNA per ml of plasma of the patient as measured by quantitative, multi- cycle reverse transcriptase PCR methodology. HIV- 1-RNA is preferably measured in the present invention by the methodology of Amplicor -1 Monitor 1.5 (available from Roche Diagnsotics) or of Nuclisens HIV-1 QT -1. [0089] The following assays can be used to determine the CCR5 inhibitory and antagonistic activity of the compounds 30 of the invention.

CCR5 Membrane Binding Assay:

[0090] A high throughput screen utilizing a CCR5 membrane binding assay identifies inhibitors of RANTES binding. 35 This assay utilizes membranes prepared from NIH 3T3 cells expressing the human CCR5 chemokine receptor which have the ability to bind to RANTES, a natural ligand for the receptor. Using a 96-well plate format, membrane preparations are incubated with 125I-RANTES in the presence or absence of compound for one hour. Compounds are serially diluted over a wide range of 0.001ug/ml to 1 ug/ml and tested in triplicates. Reaction cocktails are harvested through glass fiber filters, and washed thoroughly. Total counts for replicates are averaged and data reported as the concentration required 40 to inhibit 50 percent of total 125I-RANTES binding. Compounds with potent activity in the membrane binding assay are further characterized in seconday cell-based HIV-1 entry and replication assays.

HIV-1 Entry Assay:

45 [0091] Replication defective HIV-1 reporter virions are generated by cotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (which has been modified by mutation of the envelope gene and introduction of a luciferase reporter plasmid) along with a plasmid encoding one of several HIV-1 envelope genes as described by Connor et al, Virology, 206 (1995), p. 935-944. Following transfection of the two plasmids by calcium phosphate precipitation, the viral supernatants are harvested on day 3 and a functional viral titer determined. These stocks are then used to infect U87 cells 50 stably expressing CD4 and the chemokine receptor CCR5 which have been preincubated with or without test compound. Infections are carried out for 2 hours at 37 °C, the cells washed and media replaced with fresh media containing compound. The cells are incubated for 3 days, lysed and luciferase activity determined. Results are reported as the concentration of compound required to inhibit 50% of the luciferase activity in the control cultures.

55 HIV-1 Replication Assay:

[0092] This assay uses primary peripheral blood mononuclear cells or the stable U87- CCR5 cell line to determine the effect of anti-CCR5 compounds to block infection of primary HIV-1 strains. The primary lymphocytes are purified from

30 EP 1 421 075 B1

normal healthy donors and stimulated in vitro with PHA and IL-2 three days prior to infection. Using a 96-well plate format, cells are pretreated with drug for 1 hour at 37 °C and subsequently infected with an M-tropic HIV-1 isolates. Following infection, the cells are washed to remove residual inoculum and cultured in the presence of compound for 4 days. Culture supernatants are harvested and viral replication measured by determination of viral p24 antigen concen- 5 tration.

Calcium Flux Assay:

[0093] Cells expressing the HIV coreceptor CCR5 are loaded with calcium sensitive dyes prior to addition of compound 10 or the natural CCR5 ligand. Compounds with agonist properties will induce a calcium flux signal in the cell, while the compounds of this invention are identified as compounds which do not induce signaling by themselves but are capable of blocking signaling by the natural ligand RANTES.

GTP S Binding Assay (secondary membrane binding assay): 15 [0094] A GTP S binding assay measures receptor activation by CCR5 ligands. This assay measures the binding of 35S labeled-GTP to receptor coupled G-proteins that occurs as a result of receptor activation by an appropriate ligand. In this assay, the CCR5 ligand, RANTES, is incubated with membranes from CCR5 expressing cells and binding to the receptor activation (or binding) is determined by assaying for bound35S label. The assay quantitatively determines if 20 compounds exhibit agonist characteristics by inducing activation of the receptor or alternatively antagonist properties by measuring inhibition of RANTES binding in a competitive or non-competitive fashion.

Chemotaxis Assay:

25 [0095] The chemotaxis assay is a functional assay which characterizes the agonist vs. antagonist properties of the test compounds. The assay measures the ability of a non- adherent murine cell line expressing human CCR5 (BaF-550) to migrate across a membrane in response to either test compounds or natural ligands (i.e., RANTES, MIP-1β). Cells migrate across the permeable membrane towards compounds with agonist activity. Compounds that are antagonists not only fail to induce chemotaxis, but are also capable of inhibiting cell migration in response to known CCR5 ligands. 30 Luciferase Replication Assay:

[0096] Plasmids encoding the full length genome of HIV-1 pNL-4-Luc with the gp 120 V-3 loop replaced by the Bgl II fragment of HIV- 1 ADA, YU- 2 or HxB (ADA- Luc-FL, YU-2-Luc-FL and HxB-Luc-FL) are obtained from Dr. Susan Pontow 35 (Washington University, St. Louis MO). Replication-competent luciferase reporter virus stocks are generated by transfection of plasmids into 293T cells using Superfect (Qiagen) or Mirus transfection reagents. Viral stocks are collected 48 hours following transfection and titered for luciferase production on U-87-CCR5 or CXCR4 cells. U87-CD4-CCR5 cells (104/well) are plated in 96-well cell culture plates and incubated overnight. Media is removed and replaced with 50 Pl of fresh culture media (DMEM, 10% FCS) and 50 Pl of compound diluted in culture medium. Cells are incubated with 40 compound at 37°C for 1 hour. The resultant supernatant is removed and replaced with P 20l of media containing compound and infected with an equal volume of diluted or undiluted virus stock at 37 °C for 3-4 hours. The cells are washed once with DMEM, and 200 Pl of media containing compound is added. The cultures are incubated for 3 days, the cells lysed in luciferase lysis buffer (Promega, Madison, WI) and transferred to Immulon plates (Dynex Technologies; Chantilly VA). An equal volume of luciferase substrate (Promega, Madison WI) is added to lysates and the plates read 45 immediately in a Wallac Luminometer. Fifty and ninety percent inhibitory concentrations are determined using GraphPad PRISM software. [0097] Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. 50 Example 1:

[0098]

31 EP 1 421 075 B1

15 Step 1

[0099] 4-Hydroxy-piperidine (1.0 g, 9.9 mmol) and N- Boc-4-piperidone (1.97 g, 9.9 mmol), and Ti (OiPr)4 (3.2 mL, 10.9 mmol) were taken up in CH2Cl2 and stirred at rt for19 h. To this solution; 24 mL of Et2AlCN (1.0 M in toluene) were added. The resulting solution was stirred at rt for 24 h. The solution was cooled and quenched with sat. NaHCO3. The 20 mixture was diluted with EtOAc and filtered through a plug of Celite. The filter cake was rinsed with EtOAc and 2HO. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration through Celite and concentration gave a cyanide compound (2.84 g, 93 %) as a solid.

25 Step 2

[0100] The cyanidecompound fromstep 1 (2.84g, 9.2 mmol) was takenup in THF andcooled to 0°C. Methyl magnesium bromide (15 mL of 3.0 M in diethyl ether) was added to the solution at 0°C. The solution was warmed to rt and stirred at that temperature for 16 h. The solution was cooled to 0°C and quenched with 1 N NaOH (aq.). The mixture was filtered 30 through a plug of Celite. The Celite was rinsed with EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration through Celite and concentration gave an alcohol (2.5 g, 90 %) as an oil.

Step 3 35

[0101] DMSO (0.9 mL, 12.6 mmol) was taken up in CH2Cl2 and cooled to -40°C (CO2/CH3CN). Oxalyl chloride (1.1 mL, 12.6 mmol) was added dropwise to the solution at -40°C. The solution was stirred at that temperature for 20 minutes. The alcohol from step 2 (2.5 g, 8.39 mmol) in CH2Cl2 was added to the solution at -40°C. The resulting solution was stirred at that temperature for 30 minutes. Triethyl amine (3.5 mL, 25.2 mmol) was added to the solution at -40°C, and 40 the resulting slurry was warmed to rt. After 30 minutes, the solution was diluted with CH2Cl2 and washed with 1 N NaOH(aq.). The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (2/1 EtOAc/ hexanes, SiO2) gave 2.15 grams (87 %) of a ketone as an oil that slowly solidified.

45 Step 4

[0102] Boc-piperidine (2.0 g, 6.7 mmol) was taken up in CH 2Cl2 and TFA (7 mL) was added. The solution was stirred at rt for 1h. The solution was concentrated. The resulting salt was taken up in H 2O and basified with NaOH. The solution was extracted with CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried 50 (Na2SO4), filtered, and concentrated to furnish 1.1 g (85 %) of deprotected piperidine. [0103] The deprotected piperidine 1.1 g (5.6 mmol), EDCI hydrochloride (1.6 g), HOBT (1.2 g), diisoproplyethylamine (1.8 g), and 4,6-dimethyl-3-pyrimidine carboxylic acid (1.1 g) were taken up in CH2Cl2 and stirred at rt for 16 h. The solution was diluted with CH2Cl2 and washed with 1 N NaOH(aq.). The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Filtration through Celite and concentration gave 0.94 g (51 %) of 55 amide as a foam.

32 EP 1 421 075 B1

Step 5:

[0104] The amide from step 4 (0.94 g, 2.8 mmol), 4-amino-N-benzyl piperidine (0.5 g), Na(AcO)3BH (0.84 g), and HOAc (0.26 g) were taken up in CH2Cl2 and stirred at rt for 2 h. The solution was diluted with CH2Cl2 and washed with 5 1 N NaOH(aq.). The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Filtration through Celite and concentration gave an oil. Purification via flash chromatography (gradient: CH2Cl2-2 % [7 N NH3 in MeOH] in CH2Cl2-4 % [7 N NH3 in MeOH][in CH2Cl2, SiO2) gave 1.2 g (84 %) of amine as an oil. MS (FAB) 505.4 (MH+).

10 Step 6

[0105] The amine from step 5 (0.10 g, 0.20 mmol), benzaldehyde (0.06 g), and Na(AcO)3BH (0.12 g) were taken up in CH2Cl2 and stirred at rt for 15 h. More benzaldehyde (0.06 g) and Na (AcO)3BH (0.12 g) were added to the reaction. The reaction was stirred for an additional 15 h. The solution was diluted with CH2Cl2 and washed with 1 N NaOH(aq.). 15 The aqueous layer was extracted with CH 2Cl2. The combined organic layers were dried over Na 2SO4. Filtration through Celite and concentration gave an oil. Purification via preparative layer chromatography (7 % [7 N NH 3 in MeOH in CH 2Cl2, + SiO2) gave 0.025 g (21 %) of the product shown above in this example. MS (FAB) 595.5 (MH ). [0106] The compounds shown below in Table 2 were prepared in a similar fashion as outlined above. The compounds shown below in Table 2 were prepared in a similar fashion as oulined above for Example 1. 20 Table 2 # Structure HIV Replication (luciferase) IC50 HRMS found (MH+) nM

25 1 0.1 679.3197

2 0.8 583.3428 35

3 32 643.3185

50 4 1.7 595.4115

33 EP 1 421 075 B1

Table continued # Structure HIV Replication (luciferase) IC50 HRMS found (MH+) nM

5 5 2.1 679.3184

6 0.9 679.3181

20 7 3 609.3598

40 [0107] This series concentrates on when M = aryl or hetero-aryl. Most preferred are when R2 is benzyl, phenyl, and cyclopropylmethyl.

Example 2 45 [0108]

34 EP 1 421 075 B1

15 Step 1

[0109] 4-Bromo aniline (8.3 g, 48 mmol), N-Boc-4-piperidone (8.0 g, 40 mmol), Na(AcO)3BH (12.7 g, 60 mmol), and AcOH (3.5 mL, 60 mmol) were taken up in CH 2Cl2 and stirred at 25 °C (17 h). The solution was diluted with CH 2Cl2 and quenched with 1 N NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried 20 (Na2SO4), filtered and concentrated. Purification via recrystallization (CH 2Cl2/hexanes) gave 10.2 g (72%) of an amine product.

Step 2

25 [0110] The amine (1.5 g, 4.22 mmol), benzyl bromide (0.74 mL, 6.3 mmol), NaH (250 mg of a 60 wt% dispersion in oil), and Kl (350 mg, 2.11) were taken up in DME and stirred at 100 °C (18h). The solution was cooled and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration followed by purification via flash chromatography (4/1 hexanes/Et2O, SiO2) gave 528 mg (28 %) of a benzyl amine product. 30 Step 3

[0111] The benzyl amine product from step 2 and 4.0 M HCl in dioxane (5 mL) were taken up in MeOH, and the solution was stirred at 25 °C for 18 hours. The solution was concentrated. The residue was partitioned between CH 2Cl2 35 and 1 N NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried with Na2SO4. Filtration and concentration gave 314 mg (77 %) of a free amine product.

Step 4

40 [0112] The free amine product from step 3 was treated sequentially with 1) N- Boc-4-piperidone (181 mg, 0.91 mmol) /Ti(OiPr)4(0.32 mL, 1.1 mmol) and 2) EtAICN (1.1 mL of a 1.0 M solution in toluene) according to the conditions described above in Step 1 of Example 1. After work-up, 500 mg (Quant.) of a cyano-amine was obtained.

Step 5 45

[0113] The cyano-amine from step 4 was treated with MeMgBr (1.5 mL of a 3.0 M solution in Et2O) according to the conditions described above in Step 2 of Example 1. Purification via preparative thin-layer chromatography (2/1 hexanes/ EtOAc, SiO2) gave 344 mg (70 %) of the amine as a colorless oil.

50 Step 6

[0114] The amine from step 5 and 4.0 M HCI in dioxane (4 mL) were taken up in MeOH and stirred at 25 °C for 17 hours. The solution was concentrated. The HCl salt of the deprotected amine was used as is in the next step.

55 Step 7

[0115] The HCl salt from step 6, EDCI hydrochloride (169 mg, 0.88 mmol), HOBT (119 mg, 0.88 mmol), and iPr 2NEt (1.5 mL, 8.8 mmol), and 4,6-dimethyl-3-pyrimidine carboxylic acid (134 mg, 0.88 mmol) were taken up in CH3CN and

35 EP 1 421 075 B1

stirred at 25° C for 20 hours. The solution was concentrated. The residue was partitioned between EtOAc and 1 N NaOH. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine and dried with Na2SO4. Filtration and concentration followed by purification via preparative, thin-layer chromatography (30/1 CH2Cl2/ 7 N NH3, SiO2) gave 172 mg (68%) of Compound 8. The amide was taken up in EtOAc and was precipitated as the HCl 5 salt upon addition of 2.0M HCl in Et 2O. m.p.(HCl salt) : 168-170 C. HRMS (MH+) calc’d for 576.2338; Found: 576.2331. The following compounds were prepared via similar procedures:

Table 3 Example Structure HIV Replication HRMS found (MH+) 10 (luciferase) IC50 nM 9 3 498.3233

20 10 0.5 566.3099

30 11 0.2 582.3064

12 0.2 532.2850

13 0.2 567.3063

36 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 14 0.1 516.3034

15 10 673.3375 15

16 0.5 658.3377 658.3377

17 0.1 576.2331

18 0.1 532.2832

37 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 19 0.5 594.2235

15 20 0.2 566.3116

21 1 554.3849 25

22 0.2 540.3713

23 0.1 624.2203

38 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 24 0.2 582.3067

25 0.1 534.3053 15

26 0.3 566.2460

27 0.1 550.2753

28 0.22 590.2500

39 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 29 0.1 562.2959

30 0.26 578.2314 15

31 0.44 516.3151

32 1.7 566.2464

33 0.53 528.3349

40 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 34 10 634.2993

35 2 600.2712 15

36 0.1 534.3040

37 0.1 528.3348

38 3 646.2207

41 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 39 0.1 512.3383

40 <0.1 542.3489 15

41 <0.1 526.3541

42 0.8 516.3142

43 2 590.3502

42 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 44 0.1 523.3180

15 45 0.9 538.3765

46 2 578.3603 25

47 0.05 619.3441

48 0.8 709.3915

43 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 49 0.4 583.3756

50 1 576.2998 15

51 0.32 583.2961

52 1 629.2440

53 0.6 549.3349

44 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 54 0.6 625.3853

55 3.5 541.3663 15

56 0.2 645.3600 25

35 57 0.4 687.3323

45 58 2 582.3459

45 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 59 4 542.3118

15 60 27 542.3136

25 61 0.5 541.3283

35 62 4 611.3705

63 6 597.3910 45

46 EP 1 421 075 B1

Table continued Example Structure HIV Replication HRMS found (MH+) (luciferase) IC50 nM

5 64 4 557.3230

15 65 2 617.3610

25 66 1 631.3769

35 67 6 585.3561

45 68 2 581.3598

47 EP 1 421 075 B1

Example 3

[0116]

20 Step 1

[0117] 3-Amino-6(trifluoromethyl)pyridine (1.0 g, 6.2 mmol), N- Boc-4-piperidone (1.5 g, 7.4 mmol), Na (AcO)3BH (2.0 g, 9.3 mmol), and AcOH (0.35 mL, 6.2 mmol) were taken up in 1,2- dichloroethane and stirred at 55 °C for 17 hours. The solution was diluted with CH2Cl2 and quenched with 1 N NaOH. The aqueous layer was extracted with CH2Cl2. The 25 combined organic layers were dried (Na2SO4), filtered and concentrated to furnish a yellow oil. The residue was resub- jected to the reaction conditions for 20 hours. After workup, a yellow oil was obtained. The amine product was purified via recrystallization (CH2Cl2/hexanes) to give 1.6 g (75%) of the amine.

Step 2 30

[0118] The amine from step 1 (500 mg, 1.45 mmol), Ph3Bi (1.28 g, 2.9 mmol), Cu(OAc)2 (530 mg, 2.9 mmol), and Et3N (0.40 mL, 2.9 mmol) were taken up in toluene and heated at 90 °C for18 hours. More Ph 3Bi, Cu(OAc)2, and Et3N were added, and the reaction was stirred at 90 °C (48 h). The solution was filtered through Celite and concentrated. Purification via flash chromatography (3/1 hexanes/ EtOAc, SiO 2) gave 352 mg (58%) of the diphenyl amine as a colorless 35 oil.

Steps 3,4,5,6 and 7

[0119] The Boc amine from step 2 was converted into the pyrimidine amide following steps 3-7 described above in 40 Example 2AD. Purification via preparative thin layer chromatography (3/1 hexanes/ acetone, SiO2) gave 49 mg of Com- pound 69. HRMS (MH+) calc’d for 553.2903: Found, 553.2907. m.p.(HCl): 189-193 C. IC50 = 0.11nm The following compounds were prepared via similar procedures:

Table 4 45 Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) IC50 nM

50 70 1 568.2905

48 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 71 0.6 563.2143

15 72 0.3 484.3080

25 73 0.3 518.2695

74 10 462.3235 35

75 38 512.3396

49 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 76 0.2 553.2912

15 77 7 485.3033

25 78 1 519.2632

79 1 502.2989 35

80 2 499.3180

50 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 81 3 659.3199

15 82 0.1 644.3220

25 83 0.05 644.3226

84 10 590.3490 35

85 2 504.3696

51 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 86 75 499.3193

15 87 0.1 56202194

25 88 5 577.2297

89 0.8 577.2286 35

90 3.4 499.3180

52 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 91 0.12 548.2795

15 92 4.1 552.2293

25 93 0.21 502.2975

94 1 514.3178 35

95 2 632.2051

53 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 96 0.3 498.3226

15 97 0.3 579.2271

25 98 2 582.2808

99 0.3 528.3343 35

100 0.1 512.3386

54 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 101 0.1 520.2890

15 102 0.3 514.3178

25 103 2 546.2297

104 3 502.2975 35

105 5 576.3334

55 EP 1 421 075 B1

Table continued Example SCH Structure HIV HRMS found Replication (MH+) (luciferase) 5 IC50 nM 106 1 504.3696

15 107 1 610.2057

25 Example 4

[0120]

Step 1 45

[0121] The ketone 5 (5.0 g, 16.9 mmol), benzyl amine (1.67 mL, 15.3 mmol), Na(AcO)3BH (3.89 g, 18.4 mmol), and AcOH (1.1 mL, 18.4 mL) were taken up in CH 2Cl2 and stirred at 25 °C for 18 hours. The solution was diluted with CH 2Cl2 and quenched with 1 N NaOH. The aqueous layer was extracted with CH 2Cl2. The combined organic layers were dried (Na2SO4). Filtration and concentration followed by purification via flash chromatography (20/1 CH 2Cl2/7 N NH 3 in MeOH, 50 SiO2) gave 5.79 g (97%) of an amine product.

Step 2

[0122] The amine from step 1 (200 mg, 0.52 mmol), 4-bromo-pyridine HCl (202 mg, 1.04 mmol), Pd(OAc)2 (23 mg, 55 0.1 mmol), P(tBu)3 (84 mg, 0.42 mmol), and NaOtBu (200 mg, 2.1 mmol) were taken up in toluene and heated at 110 °C for 17 hours. The solution was cooled and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried in Na2SO4. Filtration and concentration

56 EP 1 421 075 B1

followed by purification via preparative thin-layer chromatography (30/1 CH2Cl2/7N NH3 in MeOH SiO2) gave 129 mg (54%) of an amino-pyridine product.

Steps 3 and 4 5 [0123] The Boc amine from step 2 is treated according to the procedures described above in steps 6 and 7 in Example 2. Purification via preparative thin-layer chromatography (30/1 CH2Cl2/7 N NH3 in MeOH, SiO2) gave 95 mg (68 %) of an amide product (Compound 108). The amide was taken up in EtOAc and was precipitated as the HCl salt upon additionof 2.0M HCI in Et 2O. m.p. (HCI salt) : 182-189C. HRMS (MH+) calc’d for 499.3185; Found: 499.3181. IC 50 = 0.8nm 10 The following compound was prepared via similar procedures:

Table 5 Example Structure HIV Replication (luciferase) IC50 HRMS found (MH+) nM 15 109 0.3 499.3180

25 Example 5

[0124]

Step1

[0125] 8-Amino quinoline (1.0g, 6.9 mmol), ketone 5 (3.08g, 10.4 mmol), AcOH (1.11mL, 19.3 mmol), and Na (AcO)3BH 45 (2.9g, 10.4 mmol) were taken up in 30 mL ClCH2CH2Cl and stirred at 25°C for 16hours. The solution was diluted with CH2Cl2 and quenched with 1M NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified via flash chromatography (gradient 2:1 -1:1 hexanes/EtOAc) to afford 2.66 g (91%) of an aniline product.

50 Step 2

[0126] The aniline (85mg, 0.20 mmol), propanal (23mg, 0.4 mmol), and Na (AcO)3BH were taken up in CH 2Cl2 (2 mL). The solution was allowed to stir at 25°C for 16 hours. The solution was diluted with CH 2Cl2 and quenched with 1M NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and 55 concentrated to afford 100 mg of a tertiary amine. The product was used without further purification.

57 EP 1 421 075 B1

Step 3

[0127] The Boc carbamate and 4.0 M HCI in dioxane (2 mL) were taken up in MeOH (4 mL) and the solution was stirred at 25°C for 3 hours. The solution was concentrated. The HCl salt of the deprotected amine produced here here 5 was used as is in the next step.

Step 4

[0128] The HCl salt from step 3, EDCI hydrochloride (61 mg, 0.032 mmol), HOBt (43mg, 0.032 mmol), iPr 2Net (0.365 10 mL, 2.1 mmol), and 4,6-dimethyl-3-pyrimidine carboxylic acid (49 mg, 0.32 mmol) were taken up in MeCN (2 mL) and stirred at 25°C for 24 hours. The solution was concentrated. The residue was parttioned between EtOAc and 1 N NaOH. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. Purification via preparative, thin-layer chromagotraphy (95/5 CH2Cl2/MeOH) gave 60 mg (57%) of an amide product (Compound 110). The amide was taken up in EtOAc and was precipitated as the HCl 15 salt upon addition of 2.0 M HCl in Et2O. m.p. (HCl salt): 181°C (decomposition). HRMS (MH+) calc’d 501.3342; found: 501.3349. IC50 = 23nm

Example 6

20 [0129]

Step 1 35 [0130] 8-amino quinoline (4.5g, 31.3 mmol), N-chlorosuccinimide (4.80g, 36 mmol) was taken up in iPrOH (50mL) at 60°C. The mixture was heated to reflux and stirred for 20 min. The solution was cooled to 25°C and concentrated to 1/3 original volume. The mixture was partitioned between CH 2Cl2 and water. The aqueous layer was extracted with CH 2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by 40 flash chromatography (5:1 hexanes/ EtOAc) to afford 1.90 g (34%) of a 8-amino-4-chloroquinoline product.

Step 2

[0131] The quinoline (1.28 g, 7.2 mmol) (3.18g, 10.7 mmol), AcOH (1.16 mL, 20.1 mmol), and Na(AcO)3BH (3.05g, 45 14.4 mmol) were taken up in 30 mL ClCH 2CH2Cl and stirred at 25°C for 16 hours. The solution was diluted with CH 2Cl2 and quenched with 1M NaOH. The aqueous layer was extracted with CH 2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified via flash chromatography (2: 1 hexanes/EtOAc) to afford 2.0 g (61%) of the quinoline as a yellow oil/foam.

50 Step 3

[0132] The quinoline from step 2(144mg, 031 mmol), methyl iodide (67mg, 0.47 mmol), and cesium carbonate (153 mg, 0.47 mmol) was taken up in DMF (3 mL) in a sealed tube and heated to 100°C for 24 hours. The mixture was cooled to 25 °C and diluted with EtOAc. The organic layer was washed with water followed by brine. The organic layer was 55 dried over Na 2SO4, filtered, and concentrated. The crude product was purified via preparative, thin- layer chromagotraphy (2:1 hexanes/EtOAc) to afford 14 mg (10%) of a methylated amine product.

58 EP 1 421 075 B1

Step 4

[0133] The product of step 3 was treated as described above for Example 5 (steps 3 and 4) to furnish the crude pyrimidine amide. Purification via preparative, thin-layer chromagotraphy (99:1 95/5 CH2Cl2/MeOH:7 N NH3 in MeOH) 5 gave 8 mg (53%) of Compound 111. The amide was taken up in EtOAc and was precipitated as the HCl salt upon addition of 2.0 M HCl in Et2O. m.p. (HCl salt): 164-167°C (decomposition). HRMS (MH+) calc’d 507.2639; found: 507.2634.

Example 7 10 [0134]

Step 1 30

[0135] Compound 108 (10.5 grams) and TFA (20 mL) were taken up in CH 2Cl2 and stirred at 25 C for 12 hours. The solution was concentrated, and the residue was partitioned beween CH2Cl2 and 1 N NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4). Filtration and concentration gave an amine product. 35 Step 2

[0136] The amine from step 1, 4,6-dimethyl-3- pyrimidine carboxylic acid (6 g), EDCI (8.6 g), and iPr 2NEt (7.8 g) were taken up in CH3CN and stirred at 25 °C for 10 hours. The solution was concentrated, and the residue was partitioned 40 beween EtOAc and 1 N NaOH. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine and dried (Na 2SO4). Purification via flash chromatography (3%- 5% MeOH in CH 2Cl2, SiO2) gave 4.9 grams of a pyrimidine-ketone product.

Step 3 45

[0137] The ketone from step 2 (1.65 g, 4.99 mmol), Na(OAc)3BH (2.1 g), AcOH (1 g), and (+/-)-3-amino-N-Boc- piperidine (1 g) were taken up in CH2Cl2 and stirred at 25 °C for 48 hours. The solution was diluted with CH2Cl2 and washed with 1 N NaOH. The aqueous layer was extracted with CH 2Cl2. The combinedorganic layers were dried (Na 2SO4). Filtration and concentration followed by purification via flash chromatography (3%- 10% 7N NH 3 in MeOH/CH 2Cl2, SiO2) 50 gave 1.7 g (66%) of an amine product.

Step 4

[0138] The amine from step 3 (400 mg), benzyl bromide (0.2 mL), Cs 2CO3 (1 g), and Kl (10 mg) were heated in DMF 55 at 100 C for 12 hours. The solution was partitioned between EtOAc and water. The aqueous layer was exracted with EtOAc. The combined organic layers were washed with brine and dried (Na 2SO4). Filtration and concentration followed by purification via flash chromatography (3% MeOH in CH2Cl2, SiO2) gave 300 mg of a benzyl amine product.

59 EP 1 421 075 B1

Step 5

[0139] The amine from step 4 (300 mg) and 4.0M HCl in dioxane (10 mL) were taken up in MeOH and stirred at 25 °C for 10 hours. The solution was concentrated. The residue was partitioned between CH2Cl2. The aqueous layer was 5 extracted with CH2Cl2. The combined organic layers were dried (Na 2SO4). Filtration and concentration gave 200 mg of a deprotected amine product.

Step 6

10 [0140] The amine from step 5 (100 mg) and cyclopropylsulfonyl chloride (50 mg) were partitioned between CH2Cl2 and 1 N NaOH. The mixture was stirred vigorously at 25 °C for2 h. The layers were separated and the aqueous layer was extracted with CH 2CI2. The combined organic layers were dried with Na 2SO4. Filtration and concentration followed by purification via preparative thin-layer chromatography (9 % MeOH in CH2Cl2, SiO2) gave 50 mg of amide product (Compound 112). The amide was taken up in EtOAc and was precipitated as the HCl salt upon addition of 2.0M HCl in 15 Et2O. m.p.(HCl salt) : 190-195 °C. HRMS (MH+) calc’d for 609.3587; Found: 609.3578. IC50 = 30nm The following compound was prepared via similar procedures:

Table 6 Example Structure HIV Replication (luciferase) IC50 HRMS found (MH+) 20 nM 113 40 583.3422

Claims

35 1. A compound represented by the structural formula I

50 or a phamnaceutically acceptable salt or solvate thereof; wherein:

R1 is

60 EP 1 421 075 B1

15 R2 is selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroarylalkyl, alkylketone, arylketone, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, cycloalkylalkyl, alkylsulfonyl, arylsulfonyl, alkoxyalkyl, or amide; R3 is selected from the group consisting of aryl, 6-membered heteroaryl, fluorenyl; and diphenylmethyl, 6 membered heteroaryl-N-oxide, 20

wherein said aryl, fluorenyl, diphenyl or heteroaryl is optionally substituted with 1-4 substituents which can be the same or different and are independently selected from the group consisting of R11, R12, R13, R14 and R15; 30 R4 is 1-3 substituents selected from the group consisting of H, halo, alkyl, haloalkyl, alkoxy, cycloalkyl, cy- 7 cloheteroalkyl, amide, CF3, OCF3, aryl, heteroaryl, -XR , -C(O)C3-C8cycloalkyl, -C(O)C3-C8cycloheteroalkyl, 21 22 20 21 22 8 -(C1-C6)alkyl-N(R )SO2R , -(C1-C6)alkyl-C(O)NR R , -CN, -CO2H, -CO2R , R8-aryl(C1-C6)alkyl-, R -het- 8 21 22 eroaryl(C1-C6)alkyl-, -C(O)-(C1-C6)alkyl, R -aryl-C(O)-, -C(O)NR R , -C(O)NH2, -C(O)N(H)OH, -(C1-C6)alkyl 21 22 21 22 21 21 22 21 22 N(R )C(O)R , -(C1-C6)alkyl-N(R )CO2R , -(C1-C6)alkyl-N(R )C(O)NR R , -(C1-C6)alkyl-NR R , 35 21 22 21 22 4 -(C1-C6)alkyl-NH2, (C1-C6)alkylSO2NR R and -SO2NR R , wherein R can be the same or different and is independently selected when there is more than one R4 present; 5 8 8 R is selected from the group consisting of H, arylalkyl, (C 1-C6)alkyl, R -aryl(C1-C6)alkyl-, R -heteroaryl(C1-C6) 8 alkyl-, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-aryl, R -aryl-SO2-, -C(O)-(C1-C6)alkyl, -C(O)-(C4-C6) 8 21 22 21 22 cycloalkyl, R -aryl-C(O)-, -C(O)NR R , and -SO2NR R ; 40 6 R is H, -(C1-C6)alkyl, or -(C1-C6)haloalkyl; R7 is selected from the group consisting of aryl, substituted aryl, heteroaryl, alkyl, haloalkyl and cycloalkyl; 8 R is 1, 2 or 3 substituents selected from the group consisting of H, halo, (C1-C6)alkyl, (C1-C6)alkoxy, -CF3, 8 -OCF3, CH3C(O)-, -CN, CH3SO2-, CF3SO2- and -NH2. wherein R can be the same or different and is independently selected when there are more than one R8 present; 45 R9, R10 and B can be the same or different and are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, and -(C1-C6)haloalkyl; R11 and R12 can be the same or different and are each independently selected from the group consisting of 19 20 (C1-C6)alkyl, -(C1-C6)haloalkyl, halogen, -NR R , -OH, CF3, -OCH3, -O-acyl, and -OCF3; 13 11 R is selected from the group consisting of hydrogen, R, H, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, 50 -CH=NOR19, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, N(R20)CONR20R21, -NHCONH(chloro-(C1-C6)alkyl),- NH- CONH((C3-C10)-cycloalkyl(C1-C6)alkyl), -NHCO(C1-C6)alkyl, -NHCOCF3, -NHCOCF3, -NHSO2N((C1-C6) 22 22 22 alkyl)2, -NHSO2(C1-C6)alkyl, -N(SO2CF3)2, -NHCO2(C1-C6)alkyl, (C3-C10)cycloalkyl, -SR , -SOR , -SO2R , 19 20 -SO2NH(C1-C6 alkyl), -OSO2(C1-C6)alkyl, -OSO2CF3, hydroxy(C1-C6)alkyl, -CONR R , -CON(CH2CH2O- CH3)2, -OCONH(C1-C6)alkyl, -CO2R19, -Si(CH3)3 and -B(OC(CH3)2)2: 55 14 15 R is selected from the group consisting of (C1-C6)alkyl, -(C1-C6)haloalkyl -NH2 and R -phenyl; 15 R is 1-3 substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, -(C1-C6)haloalkyl, -CF3, 20 15 -CO2R , -CN, (C1-C6)alkoxy and halogen; wherein R can be the same or different and is independently selected when there are more than one R15 present;

61 EP 1 421 075 B1

R16 and R17 can each be the same or different and are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or 16 17 R and R together are a C2-C5 alkylene group and with the carbon to which they are attached from a spiro ring of 3 to 6 carbon atoms; 5 R19, R20 and R21 can each be the same or different and are each independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6)cycloalkyl; 22 R is selected from the group consisting of 1 (C-C6)alkyl, -(C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C2-C6) alkylene, (C3-C6)cycloalkyl, aryl and aryl(C1-C6)alkyl-; A is selected from the group consisting of (C1-C6)alkyl, and (C2-C6) alkenyl. 10 M is aryl or heteroaryl optionally substituted with R4; Q is CH or N; and X is selected from the group consisting of CH2, SO2, SO, S, and O, with the following proviso:

1 2 when R is phenyl, pyridyl, thiophenyl or naphthyl, R cannot be H, -(C1-C6)alkyl or -C(O)-(C1-C6)alkyl; 15 and wherein unless otherwise indicated;

"alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising 1 to 20 carbon atoms in the chain; 20 "halo" means fluoro, chloro, bromo or iodo groups; "haloalkyl" means alkyl having one or more halo atom substituents; "cycloalkyl" means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms; "cycloheteroalkyl" means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring 25 carbon atoms, wherein the cycloheteroalkyl has 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom (s) interrupting a carbocyclic ring structure provided that the rings do not contain adjacent oxygen and/or sulfur atoms; "aryl" means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 ring carbon atoms; "heteroaryl" represents cyclic aromatic groups of 5 or 6 ring atoms or bicyclic groups of 11 to 12 ring atoms 30 having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalised pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms; "arylalkyl" or "aralkyl"represents a moietycontaining an alkyl linkedto the main groupor ring viaan aryl group; "heteroarylalkyl" represents a moiety containing a heteroaryl group linked to the main group or ring via an 35 alkyl.

2. A compound having the structural formula I according to claim 1 wherein R9, R10 and B are H, and R1, R2 and R3 are as defined in the following table:

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10 3. A compound according to claim 2 wherein R1, R2 and R3 each represent:

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40 4. A compound according to claim 3 represented by the structural formulae:

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55 5. A pharmaceutical composition comprising one or more compounds of claim 1.

6. A pharmaceutical composition comprising one or more compounds of claim 4.

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7. The pharmaceutical composition according to claim 5 further comprising one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 6 further comprising one or more pharmaceutically acceptable 5 carriers.

9. The pharmaceutical composition according to claim 5, wherein said pharmaceutical composition contains a therapeutically acceptable amount of said one or more compounds.

10 10. The pharmaceutical composition according to claim 6, wherein said pharmaceutical composition contains a therapeutically acceptable amount of said one or more compounds.

11. Use of one or more compounds according to claim 1 in the manufacture of a pharmaceutical composition for treating Human Immunodeficiency Virus. 15 12. Use of one or more compounds according to claim 4 in the manufacture of a pharmaceutical composition for treating Human Immunodeficiency Virus.

13. The use of claim 11 wherein said treatment further comprises administering said one or more compounds in com- 20 bination with one or more pharmaceutically acceptable carriers.

14. The use of claim 11 wherein said treatment further comprises administering one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus in combination with said one or more compounds according to claim 1. 25 15. The use of claim 14 wherein said antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

16. The use of claim 14 wherein said antiviral agent is selected from the group consisting of zidovudine, lamivudine, 30 zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4. DAPD, lodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 11607 and AG-1549.

35 17. Use of one or more compounds of claim 1 in the manufacture of a pharmaceutical composition for treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.

18. The use of claim 17 for treating solid organ transplant rejection, graft v. host disease, rheumatoid arthritis, inflam- 40 matory bowel disease or multiple sclerosis wherein said treatment as further comprises administering said one or more compounds in combination with one or more pharmaceutically acceptable carriers.

19. The use of claim 17 for treating solid organ transplant rejection, graft v. host disease, rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis wherein said treatment further comprises administering one or more 45 other agents useful in the treatment of said diseases in combination with said one or more compounds of claim 1.

20. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Human Immunodeficiency Virus which comprises in one container a phamnaceutical composition comprising one or more compounds of claim 1 in one or more pharmaceutically acceptable carriers, and in separate container, 50 one or more pharmaceutical compositions comprising one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus in one or more pharmaceutically acceptable carriers.

21. One or more compounds of claim 1 for use in medicine.

55 22. One or more compounds of claim 4 for use in medecine.

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Patentansprüche

1. Verbindung mit der Strukturformel I

oder ein pharmazeutisch annehmbares Salz oder Solvat davon, worin R1

ist; R2 ist ausgewählt aus der Gruppe bestehend aus H, Alkyl, Aryl, Arylalkyl, Heteroarylalkyl, Alkylketon, Arylketon, Alkyl, Halogenalkyl, Cycloalkyl, Cycloheteroalkyl, Cycloalkylalkyl, Alkylsulfonyl, Arylsulfonyl, Alkoxyalkyl oder Amid; 40 R3 ist ausgewählt aus der Gruppe bestehend aus Aryl, 6-gliedrigem Heteroaryl, Fluorenyl und Diphenylmethyl, 6- gliedrigem Heteroaryl-N-oxid,

50 wobei das Aryl, Fluörenyl, Diphenyl oder Heteroaryl gegebenenfalls mit 1 bis 4 Substituenten substituiert ist, die gleich oder.verschieden sein können und unabhängig ausgewählt sind aus der Gruppe bestehend aus R11, R12, R13, R14 und R15; R4 ist 1 bis 3 Substituenten ausgewählt aus der Gruppe bestehend aus H, Halogen, Alkyl, Halogenalkyl, Alkoxy, 55 7 Cycloalkyl, Cycloheteroalkyl, Amid, CF3, OCF3, Aryl, Heteroaryl, -XR , -C(O)C3-C8-Cycloalkyl, -C(O)C3-C8-Cyclo- 21 22 20 21 22 8 heteroalkyl, -(C1-C6)-Alkyl-N(R )SO2R ,-(C1-C6)-Alkyl-C(O)NR R , -CN, -CO2H, -CO2R , R -Aryl(C1-C6)-Al- 8- 8 21 22 kyl-, R Heteroaryl (C1-C6) -Alkyl-, -C(O)-(C1-C6)-Alkyl, R -Aryl-C(O)-, -C(O)NR R , -C(O)NH2, -C(O)N(H)OH, 21 22 21 22 21 21 22 -(C1-C6)-Alkyl-N(R ) C(O)R , -(C1-C6)-Alkyl-N(R )CO2R , -(C1-C6)-Alkyl-N(R )C(O)NR R ,-(C1-C6)-Alkyl-

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21 22 21 22 21 22 4 NR R ,-(C1-C6)-Alkyl-NH2, (C1-C6) -AlkylSO2NR R und -SO 2NR R , wobei R gleich oder verschieden sein kann und unabhängig ausgewählt ist, wenn mehr als ein R4 vorhanden ist; 5 8 8 R ist ausgewählt aus der Gruppe bestehend aus H, Arylalkyl, (C1-C6) -Alkyl, R -Aryl (C1-C6) -Alkyl-, R -Hete- 8 roaryl-(C1-C6) -Alkyl-, -SO2(C1-C6)-Alkyl, -SO2-(C3-C6)-Cycloalkyl, -SO2-Aryl, R -Aryl-SO2-, -C(O)-(C1-C6)-Alkyl, 5 8 21 22 21 22 -C(O)-(C4-C6) -Cycloalkyl, R -Aryl-C(O)-, -C(O)NR R und -SO2NR R ; 6 R ist H, -(C1-C6)-Alkyl oder -(C1-C6)-Haloalkyl; R7 ist ausgewählt aus der Gruppe bestehend aus Aryl, substituiertem Aryl, Heteroaryl, Alkyl, Halogenalkyl und Cycloalkyl; 8 R ist 1, 2 oder 3 Substituenten, die ausgewählt sind aus der Gruppe bestehend aus H, Halogen, (C1-C6)-Alkyl, 10 8 (C1-C6)-Alkoxy, -CF3, -OCF3, CH3C(O)-, -CN, CH 3SO2-, CF3SO2- und -NH 2, wobei R gleich oder verschieden sein kann und unabhängig ausgewählt ist, wenn mehr als ein R8 vorhanden ist; R9, R10 und B können gleich oder verschieden sein und sind jeweils unabhängig ausgewählt aus der Gruppe bestehend aus Wasserstoff, (C1-C6) -Alkyl und - (C1-C6) -Halogenalkyl; R11 und R 12können gleich oder verschieden sein und sind jeweils unabhängig ausgewählt aus der Gruppe bestehend 15 19 20 aus (C1-C6) -Alkyl, - (C1-C6) -Halogenalkyl, Halogen, -NR R , -OH, CF3, -OCH3, -0-Acyl und -OCF3; 13 11 R ist ausgewählt aus der Gruppe bestehend, aus Wasserstoff, R , H, Phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR19, Pyridyl-N-oxid, Pyrimidinyl, Pyrazinyl, (R20 N)CONR20R21, -NHCONH (Chlor-(C1-C6)-Alkyl), -NHCONH((C3-C10)-Cycloalkyl 1 (C-C6) -Alkyl), -NHCO1 -C6)-Alkyl, (C -NHCOCF3, -NHCOCF3, -NHSO2N((C1-C6)-Alkyl)2, -NHSO2(C1-C6)-Alkyl, -N (SO2CF3) 2, -NHCO2(C1-C6) -Alkyl, (C3-C10) -Cycloalkyl, 20 22 22 22 -SR , -SOR , -SO2R , -SO2NH(C1-C6)-Alkyl), -OSO2 (C1-C6) -Alkyl, -OSO2CF3, Hydroxy (C1-C6) -Alkyl, 19 20 -CONR R , -CON (CH2CH2-O-CH3)2, -OCONH (C1-C6) -Alkyl; -CO2R19, -Si(CH3)3 und -B(OC(CH3)2)2; 14 15 R ist ausgewählt aus der Gruppe bestehend aus (C1-C6)-Alkyl, -(C1-C6) -Halogenalkyl, -NH2 und R -Phenyl; 15 R ist 1 bis 3 Substituenten ausgewählt aus der Gruppe bestehend aus Wasserstoff, 1(C-C6) -Alkyl, - (C1-C6) 20 15 -Halogenalkyl, -CF3, -CO2R , -CN, (C1-C6) -Alkoxy und Halogen, wobei R gleich oder verschieden sein kann 25 und unabhängig ausgewählt ist, wenn mehr als ein R15 vorhanden ist; R16 und R 17können gleich oder verschieden sein und sind jeweils unabhängig ausgewählt aus der Gruppe bestehend aus Wasserstoff und (C1-C6)-Alkyl oder 16 17 R und R sind zusammen eine C 2-C5-Alkylengruppe und bilden mit dem Kohlenstoff, an den sie gebunden sind, einen Spiroring mit 3 bis 6 Kohlenstoffatomen; 30 R19, R20 und R21 können jeweils gleich oder verschieden sein und sind jeweils unabhängig ausgewählt aus der Gruppe bestehend aus H, (C1-C6)-Alkyl und -(C3-C6)-Cycloalkyl; 22 R ist ausgewählt aus der Gruppe bestehend aus1-C 6 (C)-Alkyl, -(C1-C6)-Haloalkyl, (C2-C6)Hydroxyalkyl, (C2-C6)-Alkylen, (C3-C6)-Cycloalkyl, Aryl und -Aryl (C1-C6) -alkyl-; A ist ausgewählt aus der Gruppe bestehend aus (C1-C6)-Alkyl und (C2-C6)-Alkenyl; 35 M ist Aryl öder Heteroaryl, gegebenenfalls mit R4 substituiert; Q ist CH oder N; und X ist ausgewählt aus der Gruppe bestehend aus CH2, SO2, SO, S und O mit der folgenden Maßgabe:

1 2 wenn R Phenyl, Pyridyl, Thiophenyl oder Naphthyl ist, kann R nicht H, -(C 1-C6)-Alkyl oder -C (O)-(C1-C6)-Alkyl 40 sein;

und wenn nicht anders angegeben ist, gilt:

"Alkyl" bedeutet eine aliphatische Kohlenwasserstoffgruppe, die geradkettig oder verzweigt sein kann und 1 45 bis 20 Kohlenstoffatome in der Kette enthält; "Halo" bedeutet Fluor-, Chlor-, Brom- oder Iodgruppen; "Halogenalkyl" bedeutet Alkyl mit einem oder mehreren Halogenatomsubstituenten; "Cycloalkyl" bedeutet ein nicht-aromatisches, mono- oder multicyclisches kondensiertes Ringsystem, das 3 bis 10 Ringkohlenstoffatome enthält; 50 "Cycloheteroalkyl" bedeutet ein nicht-aromatisches, mono- oder multicyclisches kondensiertes Ringsystem, das 3 bis 10 Ringkohlenstoffatome enthält, wobei das Cycloheteroalkyl 1 oder 2 Heteroatome unabhängig ausgewählt aus O, S oder N aufweist, wobei das Heteroatom/die Heteroatome eine carbocyclische Ringstruktur unterbricht bzw. unterbrechen, mit der Maßgabe, dass die Ringe keine benachbarten Sauerstoff- und/oder Schwefelatome enthalten; 55 "Aryl" bedeutet ein aromatisches monocyclisches oder multicyclisches Ringsystem, das 6 bis 14 Ringkohlen- stoffatome enthält; "Heteroaryl" bedeutet cyclische aromatische Gruppen mit 5 oder 6 Ringatomen oder bicyclische Gruppen mit 11 bis 12 Ringatomen mit einem oder zwei Heteroatomen, die unabhängig ausgewählt sind aus O, S oder N,

81 EP 1 421 075 B1

wobei das Heteroatom/die Heteroatome eine carbocyclische Ringstruktur unterbricht/unterbrechen und eine ausreichende Anzahl delokalisierter n-Elektronen hat/haben, um aromatischen Charakter zu liefern, mit der Maßgabe, dass die Ringe keine benachbarten Sauerstoff- und/oder Schwefelatome enthalten; "Arylalkyl" oder "Aralkyl" bedeutet eine Einheit, die ein Alkyl enthält, das über eine Arylgruppe an die Hauptgruppe 5 oder den Ring gebunden ist; "Heteroarylalkyl" bedeutet eine Einheit, die eine Heteroarylgruppe enthält, die über ein Alkyl an die Hauptgruppe oder den Ring gebunden ist.

2. Verbindung mit der Strukturformel I nach Anspruch 1, wobei R9, R10 und B H sind und R1, R2 und R3 wie in der 10 folgenden Tabelle definiert sind

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3. Verbindung nach Anspruch 2, wobei R1, R2 und R3 jeweils für die Folgenden stehen:

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4. Verbindung nach Anspruch 3 mit den Strukturformeln:

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5. Pharmazeutische Zusammensetzung, die eine oder mehrere Verbindungen gemäß Anspruch 1 enthält.

30 6. Pharmazeutische Zusammensetzung, die eine oder mehrere Verbindungen gemäß Anspruch 4 enthält.

7. Pharmazeutische Zusammensetzung nach Anspruch 5, die ferner einen oder mehrere pharmazeutisch annehmbare Träger enthält.

35 8. Pharmazeutische Zusammensetzung nach Anspruch 6, die ferner einen oder mehrere pharmazeutisch annehmbare Träger enthält.

9. Pharmazeutische Zusammensetzung nach Anspruch 5, wobei die pharmazeutische Zusammensetzung eine the- rapeutisch annehmbare Menge, der einen oder mehreren Verbindungen enthält. 40 10. Pharmazeutische Zusammensetzung nach Anspruch 6, wobei die pharmazeutische Zusammensetzung eine the- rapeutisch annehmbare Menge der einen oder mehreren Verbindungen enthält.

11. Verwendung von einer oder mehreren Verbindungen nach Anspruch 1 zur Herstellung einer pharmazeutischen 45 Zusammensetzung zur Behandlung des menschlichen Immunschwächevirus.

12. Verwendung von einer oder mehreren Verbindungen nach Anspruch 4 zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung des menschlichen Immunschwächevirus.

50 13. Verwendung nach Anspruch 11, wobei die Behandlung ferner die Verabreichung von einer oder mehreren Verbin- dungen in Kombination mit, einem oder mehreren pharmazeutisch annehmbaren Trägern beinhaltet.

14. Verwendung nach Anspruch 11, wobei die Behandlung ferner die Verabreichung von einem oder mehreren antivi- ralen oder anderen Mitteln, die zur Behandlung des menschlichen Immunschwächevirus brauchbar sind, in Kom- 55 bination mit einer oder mehreren Verbindungen gemäß Anspruch 1 beinhaltet.

15. Verwendung nach Anspruch 14, bei der das antivirale Mittel ausgewählt ist aus der Gruppe bestehend aus Nukleosid- reverse-Transkriptase-Inhibitoren, Nicht-Nukleosidreverse-Transkriptase-Inhibitoren und Protease-Inhibitoren.

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16. Verwendung nach Anspruch 14, wobei das antivirale Mittel ausgewählt ist aus der Gruppe bestehend aus Zidovudin, Lamivudin, Zalcitabin, Didanosin, Stavudin, Abacavir, Adefovir, Dipivoxil, Lobucavir, BCH- 10652, Emitricitabin, beta- L-FD4, DAPD, Lodenosin, Nevirapin, Delaviridin, Efavirenz, PNU-142721, AG-1549, MKC-442, (+)-Calanolide A und B, Saquinavir, Indinavir, Ritonavir, Nelfinavir, Lasinavir, DMP-450, BMS-2322623, ABT-378, Amprenavir, Hy- 5 droxyharnstoff, Ribavirin, IL-2, IL-12, Pentafusid, Yissum Nr. 11607 und AG-1549.

17. Verwendung von einer oder mehreren Verbindungen nach Anspruch 1 zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von Abstoßung solider Organtransplantate, Graft- versus-Host-Erkrankung, Ar- thritis, rheumatoider Arthritis, entzündlicher Darmerkrankung, atopischer Dermatitis, Psoriasis, Asthma, Allergien 10 oder multipler Sklerose.

18. Verwendung nach Anspruch 17 zur Behandlung von Abstoßung solider Organtransplantate, Graft-versus-Host- Erkrankung, rheumatoider Arthritis, entzündlicher Darmerkrankung oder multipler Sklerose, wobei die Behandlung ferner die Verabreichung von einer oder mehreren Verbindungen in Kombination mit einem oder mehreren phar- 15 mazeutisch annehmbaren Trägern beinhaltet.

19. Verwendung nach Anspruch 17 zur Behandlung von Abstoßung solider Organtransplantate, Graft-versus-Host- Erkrankung, rheumatoider Arthritis, entzündlicher Darmerkrankung oder multipler Sklerose, wobei die Behandlung ferner die Verabreichung von einem oder mehreren Mitteln, die zur Behandlung der Erkrankungen brauchbar sind, 20 in Kombination mit einer oder mehreren Verbindungen gemäß Anspruch,;1 beinhaltet.

20. Kit, der in separaten Behältern in einer einzelnen Verpackung pharmazeutische Zusammensetzungen zur Verwen- dung in Kombination zur Behandlung von menschlichem Immunschwächevirus enthält, und der in einem Behälter eine pharmazeutische Zusammensetzung enthält, die eine oder mehrere Verbindungen gemäß Anspruch 1 in einem 25 oder mehreren pharmazeutisch annehmbaren Trägern enthält, und der in einem separaten Behälter eine oder mehrere pharmazeutische Zusammensetzungen enthält, die ein oder mehrere antivirale oder andere Mittel, die zur Behandlung von menschlichem Immunschwächevirus brauchbar sind, in einem oder mehreren pharmazeutisch annehmbaren Trägern enthalten.

30 21. Eine oder mehrere Verbindungen nach Anspruch 1 zur medizinischen Verwendung.

22. Eine oder mehrere Verbindungen nach Anspruch 4 zur medizinischen Verwendung.

35 Revendications

1. Composé représenté par la formule développée I

50 ou sel ou produit d’addition de solvant pharmacologiquement admissible de ce composé ; dans laquelle formule, R1 représente

101 EP 1 421 075 B1

15 R2 est choisi parmi un élément de l’ensemble formé par un atome d’hydrogène, et des groupes alkyle, aryle, arylalkyle, hétéroarylalkyle, alkylcétone, arylcétone, halogénoalkyle, cycloalkyle, cyclohétéroalkyle, cycloalkylalkyle, alkylsulfonyle, arylsulfonyle, alcoxyalkyle, et amide ; R3 est choisi parmi un élément de l’ensemble formé par des groupes aryle, hétéroaryle à 6 chaînons, fluorényle, diphénylméthyle, hétéroaryl-N-oxyde à 6 chaînons, 20

ledit groupe aryle, fluorényle, diphényle ou hétéroaryle pouvant éventuellement porter 1 à 4 substituants qui peuvent être identiques ou différents et être indépendamment choisis parmi un élément de l’ensemble formé par les groupes R11, R12, R13, R14 et R15; 40 R4 représente 1 à 3 substituants choisis parmi un atome d’hydrogène, un atome d’halogène et des groupes alkyle, 7 halogénoalkyle, alcoxy, cycloalkyle, cyclohétéroalkyle, amide, CF 3, OCF3, aryle, hétéroaryle, -XR , -C(O)(cycloalk- 21 22 yle en C3-C8), -C(O)(cyclohétéroalkyle en C3-C8), -(alkyle en C1-C6)-N(R )SO2R , -(alkyle en C1-C6)-C(O) 20 21 22 8 8- NR R , -CN, -CO 2H, -CO 2R , R -aryl-(alkyle en C 1-C6)-, R hétéroaryl-(alkyle en C 1-C6), -C(O)-(alkyle en C 1-C6), 8 21 22 21 22 R -aryl-C(O)-, -C(O)NR R , -C(O)NH2, -C(O)N(H)OH, -(alkyle en C1-C6)-N(R )C(O)R , -(alkyle en C1-C6)-N 45 21 22 21 21 22 21 22 (R )CO2R , -(alkyle en C 1-C6)-N(R )C(O)NR R , -(alkyle en C 1-C6)-NR R , -(alkyle en C 1-C6)-NH2, -(alkyle 21 22 21 22 4 en C1-C6)-SO2NR R et -SO2NR R , les substituants R pouvant être identiques ou différents et étant choisis indépendamment lorsque plus d’un substituant R4 est présent ; R5 est choisi parmi un élément de l’ensemble formé par un atome d’hydrogène et des groupes arylalkyle, alkyle en 8 8 C1-C6, R -aryl-(alkyle en C1-C6)-, R -hétéroaryl-(alkyle en C1-C6)-, -SO2-(alkyle en C1-C6), -SO2-(cycloalkyle en 50 8 8 C3-C6), -SO2-aryle, R -aryl-SO2-, -C(O)-(alkyle en C1-C6), -C(O)-(cycloalkyle en C4-C6), R -aryl-C(O)-, -C(O) 21 22 21 22 NR R , et -SO2NR R ; 6 R représente un atome d’hydrogène, un groupe alkyle en C1-C6 ou un groupe halogénoalkyle en C1-C6; R7 est choisi parmi un élément de l’ensemble formé par des groupes aryle, aryle portant un ou plusieurs substituants, hétéroaryle, alkyle, halogénoalkyle et cycloalkyle ; 55 R8 représente 1, 2 ou 3 substituants choisis parmi un atome d’hydrogène, un atome d’halogène et des groupes 8 alkyle en C1-C6, alcoxy en C1-C6, -CF3, -OCF3, CH3C(O)-, -CN, CH3SO2-, CF3SO2- et -NH2, les substituants R pouvant être identiques ou différents et étant choisis indépendamment lorsque plus d’un substituant R 8 est présent ; R9, R10 et B peuvent être identiques ou différents et sont indépendamment choisis parmi un élément de l’ensemble

102 EP 1 421 075 B1

formé par un atome d’hydrogène, un groupe alkyle en C1-C6, et un groupe halogénoalkyle en C1-C6 ; R11 et R 12 peuvent être identiques ou différents et sont indépendamment choisis parmi un atome d’halogène et des 19 20 groupes alkyle en C1-C6, halogénoalkyle en C1-C6, -NR R , -OH, -CF3, -OCH3, -O-acyle, et -OCF3 ; 13 11 R est choisi parmi un élément de l’ensemble formé par un atome d’hydrogène et des groupes R , phényle, -NO 2, 5 19 20 20 21 -CN, -CH2F, -CHF2, -CHO, -CH=NOR , pyridyl-N-oxyde, pyrimidinyle, pyrazinyle, N(R )CONR R , -NHCONH (chloro-(alkyle en C 1-C6)), NHCONH(cycloalkyle en C 3-C10)-(alkyle en C 1-C6), -NHCO (alkyle en C 1-C6), -NHCOCF 3, -NHSO2N(alkyle en C1-C6)2, -NHSO2(alkyle en C1-C6), -N(SO2CF3)2, -NHCO2(alkyle en C1-C6), cycloalkyle en 22 22 22 C3-C10, -SR , -SOR , -SO2R , -SO2NH(alkyle en C1-C6), -OSO2(alkyle en C1-C6), -OSO2CF3, hydroxy(alkyle 19 20 19 en C1-C6), -CONR R , -CON(CH2CH2-O-CH3)2, -OCONH(alkyle en 1 C-C6), -CO2R , -Si(CH3)3 et -B(OC 10 (CH3)2)2 ; 14 R est choisi parmi un élément de l’ensemble formé par des groupes alkyle en1-C 6 C, -(halogénoalkyle en 15 C1-C6)-NH2 et R -phényle ; R15 représente 1 à 3 substituants choisis parmi un atome d’hydrogène, un atome d’halogène et des groupes alkyle 20 15 en C1-C6, halogénoalkyle en C1-C6, -CF3, -CO2R , CN, alcoxy en C1-C6 ; les substituants R pouvant être iden- 15 tiques ou différents et étant choisis indépendamment lorsque plus d’un substituant R15 est présent ; R16 et R17 peuvent être identiques ou différents et sont choisis indépendamment parmi un atome d’hydrogène ou un groupe alkyle en C1-C6, ou 16 17 R et R forment ensemble un groupe alkylène en C2-C5, ou bien ils constituent un cycle spiro comportant 3 à 6 atomes de carbone avec l’atome de carbone auquel ils sont liés ; 20 R19, R20 et R21 peuvent être identiques ou différents et sont choisis indépendamment parmi un atome d’hydrogène, un groupe alkyle en C1-C6 et un groupe cycloalkyle en C3-C6 ; 22 R est choisi parmi un élément de l’ensemble formé par des groupes alkyle en C1-C6, halogénoalkyle en C1-C6, hydroxyalkyle en C2-C6, alkylène en C2-C6, cycloalkyle en C3-C6, aryle et aryl-(alkyle en C1-C6); A est choisi parmi un élément de l’ensemble formé par des groupes alkyle en C1-C6 et alcényle en C2-C6, 25 M représente un groupe aryle ou hétéroaryle portant éventuellement un substituant R4 ; Q représente CH ou N ; et X est choisi parmi un élément de l’ensemble formé par CH2, SO2, SO, S et O, à la condition suivante :

lorsque R1 représente un groupe phényle, pyridyle, thiophényle ou naphtyle, R2 ne peut pas représenter un atome d’hydrogène, un groupe alkyle en C1-C6 ou un groupe -C(O)-(alkyle en C1-C6); 30 et sauf indication contraire ; le terme « alkyle » signifie un groupe hydrocarboné aliphatique qui peut être linéaire ou ramifié et dont la chaîne comporte 1 à 20 atomes de carbone ; le terme « halogène » signifie un atome de fluor, de chlore, de brome ou d’iode ; 35 le terme «halogénoalkyle» signifie un groupe alkyle portant un ou plusieurs substituants de type atome d’halogène ; le terme « cycloalkyle » signifie un système monocyclique ou multicyclique à cycles condensés non aromatique comportant 3 à 10 atomes de carbone cycliques ; le terme « cyclohétéroalkyle » signifie un système monocyclique ou multicyclique à cycles condensés non aromatique comportant 3 à 10 atomes de carbone cycliques, lequel groupe cyclohétéroalkyle possède 1 ou 2 hétéroatomes 40 indépendamment choisis parmi un atome d’oxygène, un atome de soufre ou un atome d’azote, lesdits hétéroatomes interrompant une structure de type cycle carboné, sous réserve que les cycles ne renferment pas d’atomes d’oxygène et/ou de soufre adjacents ; le terme « aryle » signifie un système monocyclique ou multicyclique aromatique comportant 6 à 14 atomes de carbone cycliques ; 45 le terme « hétéroaryle » représente des groupes cycliques aromatiques comportant 5 ou 6 atomes cycliques, ou des groupes bicycliques comportant 11 à 12 atomes cycliques dont 1 ou 2 hétéroatomes qui sont indépendamment choisis parmi un atome d’oxygène, un atome de soufre ou un atome d’azote, lesdits hétéroatomes interrompant une structure de type cycle carboné et dont le nombre d’électrons π délocalisés est suffisant pour fournir un caractère aromatique, sous réserve que les cycles ne renferment pas d’atomes d’oxygène et/ou de soufre adjacents ; 50 un groupe « arylalkyle » ou « aralkyle » représente un fragment qui renferme un groupe alkyle lié au groupe principal ou au cycle principal par l’intermédiaire d’un groupe aryle ; un groupe « hétéroarylalkyle » représente un fragment qui renferme un groupe hétéroaryle lié au groupe-principal ou au cycle principal par l’intermédiaire d’un groupe alkyle.

55 2. Composé de formule développée I selon la revendication 1, dans lequel R9, R10 et B représentent un atome d’hy- drogène, et R1, R2 et R3 ont les significations indiquées dans le tableau suivant :

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3. Composé selon la revendication 2 dans lequel R1, R2 et R3 représentent chacun :

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4. Composé selon la revendication 3, représenté par les formules développées : 25

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119 EP 1 421 075 B1

5. Composition pharmaceutique comprenant un ou plusieurs composés selon la revendication 1. 35 6. Composition pharmaceutique comprenant un ou plusieurs composés selon la revendication 4.

7. Composition pharmaceutique selon la revendication 5, comprenant en outre un ou plusieurs véhicules pharmacologiquement admissibles. 40 8. Composition pharmaceutique selon la revendication 6, comprenant en outre un ou plusieurs véhicules pharmacologiquement admissibles.

9. Composition pharmaceutique selon la revendication 5, laquelle composition pharmaceutique contient une quantité 45 à effet thérapeutique d’un ou de plusieurs desdits composés.

10. Composition pharmaceutique selon la revendication 6, laquelle composition pharmaceutique contient une quantité à effet thérapeutique d’un ou de plusieurs desdits composés.

50 11. Utilisation d’un ou de plusieurs composés selon la revendication 1 dans la fabrication d’une composition pharmaceutique permettant de traiter le Virus de l’Immunodéficience Humaine.

12. Utilisation d’un ou de plusieurs composés selon la revendication 4 dans la fabrication d’une composition pharmaceutique permettant de traiter le Virus de l’Immunodéficience Humaine. 55 13. Utilisation selon la revendication 11, dans laquelle ledit traitement comprend en outre l’administration d’un ou de plusieurs desdits composés en combinaison avec un ou plusieurs véhicules pharmacologiquement admissibles.

120 EP 1 421 075 B1

14. Utilisation selon la revendication 11, dans laquelle ledit traitement comprend en outre l’administration d’un ou de plusieurs agents antiviraux ou d’autres agents utilisables dans le traitement du Virus de l’Immunodéficience Humaine en combinaison avec un ou plusieurs desdits composés selon la revendication 1.

5 15. Utilisation selon la revendication 14, dans laquelle ledit agent antiviral est choisi parmi un élément de l’ensemble formé par des inhibiteurs nucléosidiques de la transcriptase inverse, des inhibiteurs non nucléosidiques de la transcriptase inverse et des inhibiteurs de protéase.

16. Utilisation selon la revendication 14, dans laquelle ledit agent antiviral est choisi parmi un élément de l’ensemble 10 formé par la zidovudine, la lamivudine, la zalcitabine, la didanosine, la stavudine, l’abacavir, l’adéfovir dipivoxil, le lobucavir, le BCH-10652, l’émitricitabine, le béta-L-FD4, le DAPD, la lodénosine, la névirapine, la délaviridine, l’éfavirenz, le PNU- 142721, l’AG-1549, le MKC-442, le (+)-calanolide A et le (+)-calanolide B, le saquinavir, l’indinavir, le ritonavir, le nelfinavir, le lasinavir, le DMP- 450, le BMS-2322623, l’ATB-378, l’amprénavir, l’hydroxyurée, la riba- virine, l’IL-2, l’IL-12, le pentafuside et l’Yissum N° 11607. 15 17. Utilisation d’un ou de plusieurs composés selon la revendication 1 dans la fabrication d’une composition pharmaceutique permettant de traiter le rejet de greffe d’organes, la réaction du greffon contre l’hôte, l’arthrite, la polyarthrite rhumatoïde, l’affection abdominale inflammatoire, la dermatite atopique, le psoriasis, l’asthme, des allergies ou la sclérose en plaques. 20 18. Utilisation selon la revendication 17 permettant de traiter le rejet de greffe d’organes, la réaction du greffon contre l’hôte, la polyarthrite rhumatoïde, l’affection abdominale inflammatoire ou la sclérose en plaques, lequel traitement comprend en outre l’administration d’un ou de plusieurs desdits composés en combinaison avec un ou plusieurs véhicules pharmacologiquement admissibles. 25 19. Utilisation selon la revendication 17 permettant de traiter le rejet de greffe d’organes, la réaction du greffon contre l’hôte, la polyarthrite rhumatoïde, l’affection abdominale inflammatoire ou la sclérose en plaques, lequel traitement comprend en outre l’administration d’un ou de plusieurs autres agents utilisables dans le traitement desdites maladies en combinaison avec un ou plusieurs desdits composés selon la revendication 1. 30 20. Kit comportant dans des récipients séparés, dans un seul emballage, des compositions pharmaceutiques destinées à être utilisées en combinaison afin de traiter le Virus de l’Immunodéficience Humaine, dont un récipient comporte une composition pharmaceutique comprenant un ou plusieurs composés selon la revendication 1 dans un ou plusieurs véhicules pharmacologiquement admissibles, et dont un récipient séparé comporte une ou plusieurs com- 35 positions pharmaceutiques comprenant un ou plusieurs agents antiviraux ou un ou plusieurs autres agents utilisables dans le traitement du Virus de l’ Immunodéficience Humaine dans un ou plusieurs véhicules pharmacologiquement admissibles.

21. Un ou plusieurs composés selon la revendication 1 destinés à être utilisés dans un médicament. 40 22. Un ou plusieurs composés selon la revendication 4 destinés à être utilisés dans un médicament.

121