Claims for Patent: 8,080,551

Summary for Patent: 8,080,551

Title:	HIV inhibiting pyrimidines derivatives
Abstract:	HIV replication inhibitors having formula (I) defined herein are disclosed. Pharmaceutical compositions containing the HIV replication inhibitors; the use of the HIV replication inhibitors in the treatment of HIV; and processes for preparing the HIV replication inhibitors are also disclosed.
Inventor(s):	Jérôme Emile Georges Guillemont, Patrice Palandijian, Marc René De Jonge, Lucien Maria Henricus Koymans, Hendrik Maarten Vinkers, Frederik Frans Desiré Daeyaert, Jan Heeres, Koen Jeanne Alfons Van Aken, Paulus Joannes Lewi, Paul Adriaan Jan Janssen
Assignee:	Janssen Pharmaceutica NV
Application Number:	US11/474,855
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,080,551
Patent Claims:	1. A compound of the following formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, or a stereochemically isomeric form thereof, wherein R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, or C1-6alkylcarbonyloxy; or C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl; R2′is halo, C1-6alkyl, trihalomethyl, cyano, aminocarbonyl, or C1-6alkyl substituted with cyano or aminocarbonyl; each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or —C(═O)R6, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6, or a radical of formula wherein each A1 independently is N, CH or CR6; and A2 is NH, O, S or NR6; n′ is 0, 1, 2, 3 or 4; X1 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl—, or —C1-4alkanediyl—X2—; X2 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, or —S(═O)p—; R3 is NHR13; NR13R14; —C(═O)—NHR13; —C(═O)—NR13R14; —C(═O)—R15; —CH═N—NH—C(═O)—R16; C1-6alkyl substituted with NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyl substituted with two or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyl substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O) —NR9R10, —C(═O)—C1-6alkyl or R7 and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C1-4alkanediyl; C1-6alkyl substituted with hydroxy and a second substituent selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; —C(═N—O—R8)—C1-4alkyl; R7 or —X3R7; with R9a representing hydroxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl, —CH(═NR11) or R7, wherein each of the aforementioned C1-6alkyl groups in the definition of R9a may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6,—C(═NH)R6, R7; and wherein R9a may also be taken together with R10 to form a bivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) or (d-6) as defined for R9 and R10. X3 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, or —C(═N—OR8)—C1-4alkanediyl-; with X2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, or —S(═O)p—; and with X2b being —NH—NH—, —N═N—, —C(═O)—, —S—, or —S(═O)p—; R4 is halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino, or R7; m is 0, 1, 2, 3 or 4; R5 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl or C1-6alkylcarbonyloxy; or C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl; R6 is C1-4alkyl, amino, mono- or di(C1-4alkyl)amino, or polyhaloC1-4alkyl; R7is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3—R7a, and R7a—C1-4alkyl; R7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8); R8 is hydrogen, C1-4alkyl, aryl, or arylC1-4alkyl; R9 and R10 each independently are hydrogen; hydroxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl; —CH(═NR11); or R7; wherein each of the aforementioned C1-6alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di (C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6,—C(═NH)R6, and R7; or R9 and R10 may be taken together to form a bivalent radical of formula —CH2—CH2—CH2—CH2— (d-1), —CH2—CH2—CH2—CH2—CH2— (d-2), —CH2—CH2—O—CH2—CH2— (d-3), —CH2—CH2—S—CH2—CH2— (d-4), —CH2—CH2—NR12—CH2—CH2— (d-5), —CH2—CH═CH—CH2— (d-6); R11 is cyano; C1-4alkyl optionally substituted with C1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino or aminocarbonyl; C1-4alkylcarbonyl; C1-4alkyloxycarbonyl; aminocarbonyl; or mono- or di(C1-4alkyl)aminocarbonyl; R12 is hydrogen or C1-4alkyl; R13 and R14 each independently are C1-6alkyl optionally substituted with cyano or aminocarbonyl, C2-6alkenyl optionally substituted with cyano or aminocarbonyl, or C2-6alkynyl optionally substituted with cyano or aminocarbonyl; R15is C1-6alkyl substituted with cyano or aminocarbonyl; R16 is C1-6alkyl optionally substituted with cyano or aminocarbonyl, or R7; p is 1 or 2; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7, and —X3—R7. 2. A compound according to claim 1 wherein R3 is C1-6alkyl substituted with two or more substituents selected from cyano, aminocarbonyl, NR9R10 or R7; C1-6alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR9R10 or R7 and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C1-4alkanediyl; C1-6alkyl substituted with hydroxy and a second substituent selected from cyano, aminocarbonyl, NR9R10 or R7; C1-6alkyloxyC1-6alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR9R10 or R7; C2-6alkenyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR9R10 or R7; C2-6alkynyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR9R10 or R7; —C(═N—O—R )—C1-4alkyl; R7 or —X3—R7; R4 is halo, hydroxy, C1-6a1kyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino; R7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)C1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7a, —X3—R7a, and R7a—C1-4alkyl; R7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalo C1-6alkyl, polyhalo C1-6alkyloxy or aminocarbonyl; R9 and R10 each independently are hydrogen; hydroxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl, and R7, wherein each of the aforementioned C1-6alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxy C1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6,—C(═NH)R6, and R7. 3. A compound according to claim 1 wherein R2′ is cyano, aminocarbonyl, or C1-6alkyl substituted with cyano or aminocarbonyl. 4. A pharmaceutical composition comprising as an active ingredient a compound as claimed in claim 1. 5. A process for preparing a pharmaceutical composition according to claim 4, comprising mixing a therapeutically effective amount of said compound with a pharmaceutically acceptable carrier. 6. A pharmaceutical composition according to claim 4, further comprising a pharmaceutically acceptable carrier. 7. A compound according to claim 1 wherein R3 is —CH═N—NH—C(═O)—R16; C1-6alkyl substituted with NR9R10, —C(═O)—NR9aR10, —C(═O)—C1-6alkyl or R7; C1-6alkyl substituted with two or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyl substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7 and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C1-4alkanediyl; C1-6alkyl substituted with hydroxy and a second substituent selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; —C(═N—O—R8)—C1-4alkyl; R7 or —X3—R7; with R9a representing hydroxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl, —CH(═NR11) or R7, wherein each of the aforementioned C1-6alkyl groups in the definition of R9a may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6,—C(═NH)R6, R7; and wherein R9a may also be taken together with R10 to form a bivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) or (d-6) as defined for R9 and R10. 8. A compound according to claim 1 wherein R3 is C2-6alkenyl substituted with cyano. 9. A compound according to claim 1 wherein R3 is R7; C1-6alkyl substituted with cyano and R7; C2-6alkenyl substituted with cyano and R7; C1-6alkyl substituted with R7; —C(═N—O—R8)—C1-4alkyl; C1-6alkyl substituted with hydroxy and a second substituent selected from cyano or R7. 10. A compound according to claim 1 wherein R3 is R7, NR13R14, —C(═O)R15, —CH═N—NH—C(═O)R16, —C(═O)NHR13, —C(═O)NR13R14, —C(═N—OR8)—C1-4alkyl, C1-6alkyl substituted with cyano, C1-6alkyl substituted twice with cyano, C1-6alkyl substituted with NR9R10, C1-6alkyl substituted with hydroxy and cyano, C1-6alkyl substituted with hydroxy and R7, C1-6alkyloxy C1-6alkyl, C1-6alkyloxy C1-6alkyl substituted with cyano, C2-6alkenyl substituted with R7, C2-6alkenyl substituted with cyano, C2-6alkenyl substituted twice with cyano, C2-6alkenyl substituted with cyano and R7, C2-6alkenyl substituted with cyano and —C(═O)—C1-6alkyl, C2-6alkenyl substituted with cyano and halo, C2-6alkenyl substituted with —C(═O)—NR9R10, C2-6alkenyl substituted with halo, C2-6alkenyl substituted twice with halo or C2-6alkenyl substituted with NR9R10. 11. A compound according to claim 1 wherein R2′ is cyano or aminocarbonyl. 12. A compound according to claim 1 wherein R2′ is cyano. 13. A compound according to claim 1 wherein X3 is —C(═O)—, —CH2—C(═O)—, or —C(═N—OR8)—C1-4alkanediyl-. 14. A compound according to claim 1 wherein n′ is 0. 15. A compound according to claim 1 wherein m is 2. 16. A compound according to claim 1 wherein R4 is C1-6alkyl; nitro; amino; halo; C1-6alkyloxy or R7. 17. A compound according to claim 1 wherein R4 is C1-6alkyl. 18. A compound according to claim 1 wherein R4 is methyl. 19. A compound according to claim 1 wherein X1 is NH or O. 20. A compound according to claim 1 wherein X1 is NH. 21. A compound according to claim 1 wherein R1 is hydrogen or C1-4alkyl. 22. A compound according to claim 1 wherein R1 is hydrogen. 23. A pharmaceutical composition according to claim 4 wherein the compound as claimed in claim 1 is in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. 24. A composition according to claim 23 wherein the surface modifier is a non-ionic or anionic surfactant. 25. A solid dispersion comprising: (a) a compound according to claim 1; and (b) one or more pharmaceutically acceptable water-soluble polymers. 26. A solid dispersion according to claim 25 wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPa·s when dissolved at 20 C. in an aqueous solution at 2% (w/v). 27. A solid dispersion according to claim 25 wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 700 mPa·s when dissolved at 20 C. in an aqueous solution at 2% (w/v). 28. A solid dispersion according to claim 25 wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 100 mPa·s when dissolved at 20 C. in an aqueous solution at 2% (w/v). 29. A solid dispersion according to claim 25 wherein the water-soluble polymer is selected from alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- and polysaccharides, alginic acid or alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinylalcohol and polyvinylpyrrolidone, polyalkylene oxides, copolymers of ethylene oxide and propylene oxide, cyclodextrins. 30. A solid dispersion according to claim 25 wherein the water-soluble polymer is hydroxypropyl methylcellulose. 31. A solid dispersion according to claim 25 wherein the ratio of components (a):(b) varies between 1/100 to 100/1. 32. A solid dispersion according to claim 25 wherein the ratio of components (a):(b) varies between 1/10 to 10/1. 33. A solid dispersion according to claim 25 wherein the ratio of components (a):(b) varies between 1/5 to 5/1. 34. A solid dispersion according to claim 25 which is in the form of a solid solution comprising (a) and (b). 35. A particle consisting of a solid dispersion according to claim 25. 36. A particle according to claim 35 wherein the particle has a particle size of less than 600 μm. 37. A particle according to claim 35 wherein the particle has a particle size of less than 400 μm. 38. A particle according to claim 35 wherein the particle has a particle size of less than 125 μm. 39. A process for preparing a solid dispersion according to claim 35 comprising the steps of dissolving the two components (a) and (b) in an appropriate solvent and spraying the resulting solution through the nozzle of a spray dryer followed by evaporating the solvent from the resulting droplets at elevated temperatures.