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Priority claimed from US08/899,242external-prioritypatent/US6124289A/en
Priority claimed from PCT/US1997/013072external-prioritypatent/WO1998003510A1/en
Publication of SI9720045ApublicationCriticalpatent/SI9720045A/en
Publication of SI9720045BpublicationCriticalpatent/SI9720045B/en
Corticotropin releasing factor (CRF) antagonists of formula (I) or (II) and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
Claims (5)
-1- -1- Sl 9720045 Nasiov: AZOLOTRIAZINI IN PIRIMIDINI Patentni zahtevki 1. [1,5-a]-Pirazolo-1,3,5-triazini s formulo(1)-1- -1- Sl 9720045 Nasiov: AZOLOTRIAZINES AND PYRIMIDINES Claims 1. [1,5-a] -Pyrazolo-1,3,5-triazines of formula (1)(1) kjer Arje fenil, piridil ali 2,3-dihidrobenzofuranil, vsak (Ar) opcijsko substituiran z 1 do 4 R4 substituenti; R1 je neodvisno izbran vsakič izmed H, C1-C4 alkila, C2-C4 alkenila, C2-C4 alkinila, halo, CN, C1-C4 haloalkila, C1-C-12 hidroksialkila, C2-C-12 alkoksialkila, C2-C10 cianoalkila, C3-C6 cikloalkila, C4-C10 cikloalkilajkila, NR9R10, Ci-C4alkil-N R9R10, NR9CO R10, OR11, SH ali S(0)nR12; ' R2 je izbran izmed H, C-1-C4 alkila, C2-C4 alkenila, C2-C4 alkinila, C3-C6cikloalkila, C4-C-10 cikloalkilalkila, C1-C4 hidroksialkila, halo, CN, -NR6R7, NR9COR10, -NR6S(0)nR7, S(0)nNR6R7, CrC4 haloalkila, -OR7, SH ali -S(0)nR12; -2- R3 je NR6aR7a; R4 je neodvisno izbran vsakič izmed : C-i-C-io aikila, C2-Cio alkenila, C2-C10 alkinila, C3-Ce cikloalkila, C4-C12 cikloalkilalkila, NO2, halo, CN, C1-C4 haloalkila, N R6R7, NR8COR7, NR8C02R7, COR7, OR7, CONR6R7, CO(NOR9)R7, C02R7, ali S(0)nR7, kjer je vsak tak C1-C10 alkil, C2-C10 alkenil, C2-Ci0 alkinil, C3-C6 cikloalkil in C4-C12 cikloalkilalkil opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed CrC4 aikila, N02, halo, CN, NR6R7, NR8COR7, NR8C02R7, COR7 OR7, CONR6R7, C02R7, CO(NOR9)R7, ali S(0)nR7; R6 in R7, R6a in R7a so neodvisno izbrani vsakič izmed : •H, • C-i-C-io aikila, C3-C10 alkenila, C3-C10 alkinila, C-i-C-io haloalkila z 1-10 halogeni, C2-C8alkoksialkila, C3-C6 cikloalkila, C4-C-12 cikloalkilalkila, C5-C10 cikloalkenila, ali C6-C14 cikloalkenilalkfla, kjer je vsakTipcijskcrsubstituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C-1-C6 aikila, C3-C6 cikloalkila, halo, C-|-C4 haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, NRsCONR16R15, NR8C02R13, NR16R15, CONR16R15, arila, heteroarila ali heterociklila, • arila, aril(C-|-C4 aikila), heteroarila, heteroaril(C-|-C4 aikila), heterociklila ali heterociklil(C-|-C4 aikila); alternativno, NR6R7 in NR6aR7a sta neodvisno piperidinska, pirolidinska, piperazinska, N-metilpiperazinska, morfolinska ali tiomorfolinska skupina, vsaka opcijsko substituirana z 1 do 3 C-1-C4 alkilnimi skupinami; R8 je neodvisno izbran vsakič izmed H ali C-1-C4 aikila; R in R sta neodvisno izbrana vsakič izmed H, C1-C4 aikila, ali C3-C6 cikloalkila; R11 je izbran izmed H, C1-C4 aikila, C1-C4 haloalkila, ali C3-C6 cikloalkila; R12 je C1-C4 alkil ali C1-C4 haloalkil; -3- R13 je izbran izmed C-1-C4 aikila, C1-C4 haloalkila, C2-C8 alkoksialkila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, arila, aril(C-|-C4 aikila)-, heteroarila ali heteroaril(Ci-C4 aikila)-; R14 je izbran izmed C-i-C-io aikila, C3-C10alkenila, C3-Cioalkinila, C3-C8 cikloalkila, ali C4-C12 cikloalkilalkila, vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed Ci-C6 aikila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02Ri5, NR16R15, CONR16R15, in C-j-Ce alkiltio, CrC6 alkilsulfinila in Ci-Cgalkilsulfonila; R15 in R16 sta neodvisno izbrana vsakič izmed H, CrCe aikila, C3-Cio cikloalkila, C4-C16 cikloalkilalkila, razen da pri S(0)nR15, R15 ne more biti H; aril je fenil ali naftil, vsak opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed C1-C6 aikila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR15, COR15, C02R15, OC(O) R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15 in CONR16R15; heteroaril je piridil, pirimidinil, triazinil, furanil, piranil, kinolinil, izokinolinil, tienil, imidazolil, tiazolil, indolil, pirolil, oksazolil, benzofuranil, benzotienil, benzotiazolil, izoksazolil, pirazolil, 2,3-dihidrobenzotienil ali 2,3-dihidrobenzofuranil, vsak opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed C1-C6 aikila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR15, -COR15, C02R15, C0(0)R15, NR8COR15, N(COR15)2, nr8conr16r15, nr8co2r15, NR16R15 in CONR16R15; heterociklil je nasičen ali delno nasičen heteroaril, opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed Ci-Cq aikila, C3-C6 cikloalkila, halo, CrC4 haloalkila, ciano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NRsC02 R15, NR15R16, in CONR16R15; n je neodvisno vsakič 0, 1 ali 2, pod pogojem, da: (1) kadar je R1 metil ali etil, R2 je H, in R3 je NH(n-C4H9) ali N(C2H5)2, tedaj Ar ni nesubstituiran fenil ali m-metilfenil; in (2) kadar je R2 H, in je Ar piridil, in je R3 NR6aR7a, tedaj R6a in R7a nista H ali alkil, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 2. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 1, kjer je Ar fenil, piridil ali 2,3-dihidrobenzofuranil, vsak (Ar) je substituiran z 1 do 4 R4 substituenti, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 3. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 1 ali 2, kjer je Ar fenil ali piridil, vsak (Ar) je opcijsko substituiran z 1 do 4 R4 substituenti, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 4. [1,5-a]-Pirazolo-1,3,5-triazini po enem izmed zahtevkov 1 do 3, kjer sta R1 in R2 neodvisno izbrana izmed H, C1.4 alkila, C3-C6 cikloalkila, C4-C10 cikloalkilalkila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 5. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 4, kjer sta R in R neodvisno izbrana izmed H ali C-|.4 alkila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). -5- 6. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 4, kjer sta R1 in R2 neodvisno izbrana izmed C1.4 alkila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 7. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 4, kjer je R1 metil, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 8. [1,5-a]-Pirazolo-1,3,5-triazini po kateremkoli izmed zahtevkov 1 do 7, kjer je R6a neodvisno izbran izmed: •H, • C1-C10 alkila, C3-C10 alkenila, C3-C10 alkinila, C1-C10 haloalkila z 1-10 halogeni, C2-C8 alkoksialkila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, C5-C10 cikloalkenila, ali C6-C14 cikloalkenilalkila, vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C-|-Cs alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR13, CO R15, C02 R15, OC(O) R13, NR8CO R15 N(CO R15)2, NR8CONR16R15, NR8C02 R13, NR16R15, C0NR16R15, arila, heteroarila ali heterociklila, • aril, aril(Ci-C4 alkil)-, heteroaril, heteroaril(Č-|-C4 alkil)-, heterociklil ali heterociklil(C-i-C4 alkil)-; in R7a je neodvisno izbran vsakič izmed: • H, • C5-C10 alkila, C3-C10 alkenila, C3-C10 alkinila, Ci-C10 haloalkila z 1-10 halogeni, C2-C8 alkoksialkila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, C5-C10 cikloalkenila, ali C6-C14 cikloalkenilalkila, vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C-i-Ce alkila, C3-Ce cikloalkila, halo, C1-C4 haloalkila, ciano, -6- OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15, arila, heteroarila ali heterociklila, • arila, aril(CrC6 alkila)-, heteroarila, heteroaril(C-|-C4 alkila)-, heterociklila ali heterociklil(Ci-C4 alkila)-; alternativno sta NR6R7 in NR6aR7a neodvisno piperidin, pirolidin, piperazin, N-metilpiperazin, morfolin ali tiomorfolin, vsak opcijsko substituiran z 1 do 3 C-1-C4 alkilnimi skupinami, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 9. [1,5-a]-Pirazolo-1,3,5-triazini po kateremkoli izmed zahtevkov 1 do 7, kjer je R6a izbran izmed: •H, • C1-C10 alkila, C3-C10 alkenila, C3-C10 alkinila, C-i-C-io haloalkila z 1-10 halogeni, C2-Cs alkoksialkila, C3-C6 cikloalkila, C4-Ci2 cikloalkilalkila, C5-C10 cikloalkenila, ali C6-C-14 cikloalkenilalkila, vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranega vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02 R13, NR16R15, CONR16R15, arila, heteroarila ali heterociklila, • arila, aril(C-|-C4 alkila)-, heteroarila, heteroaril(Ci-C4 alkila)-, heterociklila ali heterociklil(Ci-C4 alkila)-; R7a je izbran izmed: C1-C4 alkila in vsak tak C1-C4 alkil je substituiran z 1-3 substituenti, neodvisno izbranih vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, -7- NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15, arila, heteroarila ali heterociklila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 10. [1,5-a]-Pirazolo-1,3,5-triazini po kateremkoli izmed zahtevkov 1 do 7, kjer R6a je H, R je izbran izmed : • C1-C4 alkila in vsak tak C-1-C4 alkil je substituiran z 1-3 substituenti, neodvisno izbranih vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15, arila, heteroarila ali heterociklila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 11. [1,5-a]-Pirazolo-1,3,5-triazini po kateremkoli izmed zahtevkov 1 do 7, kjer sta R6a in R7a neodvisno H ali C1-C-10 alkil, pri čemer je vsak tak C1-C10 alkil opcijsko substituiran z 1-3 substituenti, neodvisno izbranih vsakič izmed C-i-Ce alkila, C3-C6 cikloalkila, halo, CrC4 haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR6COR15, N(COR15)2i r8conr16r15, nr8co2r13, nr16r15, CONR16R15, arila, heteroarila ali heterociklila, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). -8- 12. [1,5-a]-PirazoIo-1,3,5-triazini po kateremkoli izmed zahtevkov 1 do 7, kjer sta R6a in R7a neodvisno H ali C1-C10 alkil, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 13. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 1 s formulo (50)(1) wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each (Ar) optionally substituted with 1 to 4 R 4 substituents; R 1 is independently selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, C 1 -C 4 haloalkyl, C 1 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 2 -C 10 cyanoalkyl , C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4alkyl-N R9R10, NR9CO R10, OR11, SH or S (O) nR12; 1 R 2 is selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 10 cycloalkylalkyl, C 1 -C 4 hydroxyalkyl, halo, CN, -NR 6 R 7, NR 9 COR 10, - NR6S (O) nR7, S (O) nNR6R7, C1-C4 haloalkyl, -OR7, SH or -S (O) nR12; -2- R3 is NR6aR7a; R 4 is independently selected from each: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 12 cycloalkylalkyl, NO 2, halo, CN, C 1 -C 4 haloalkyl, N R 6 R 7, NR 8 COR 7, NR 8 COR7, OR7, CONR6R7, CO (NOR9) R7, CO2R7, or S (O) nR7, each of which is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents independently selected each from C 1 -C 4 alkyl, NO 2, halo, CN, NR 6 R 7, NR 8 COR 7, NR 8 CO 2 R 7, COR 7 OR 7, CONR 6 R 7, CO 2 R 7, CO (NOR 9) R 7, or S (O) n R 7; R6 and R7, R6a and R7a are each independently selected from: • H, • C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8alkoxyalkyl, C3-C6 cycloalkyl , C4-C-12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each of which is Typically substituted with 1 to 3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C- C4 haloalkyl, cyano, OR15, SH, S (O) nR13, COR15, CO2R15, OC (O) R13, NR8COR15, N (COR15) 2, NR5CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine groups, each optionally substituted with 1 to 3 C1-C4-C4 alkyl groups; R 8 is independently selected from H or C 1 -C 4 alkyl; R and R are each independently selected from H, C1-C4 alkyl, or C3-C6 cycloalkyl; R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 3 -C 6 cycloalkyl; R12 is C1-C4 alkyl or C1-C4 haloalkyl; -3- R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl (C1-C4 alkyl) -, heteroaryl or heteroaryl (C1-C4 alkyl) -; R14 is selected from C1-C10 alkyl, C3-C10alkenyl, C3-C10alkynyl, C3-C8 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl , halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, COR15, CO2R15, 0C (0) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8C02R15, NR16R15, CONR16R15, and Cj alkylthio, C1-C6 alkylsulfinyl and C1-C6alkylsulfonyl; R 15 and R 16 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 16 cycloalkylalkyl, except that for S (O) n R 15, R 15 cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, COR15, CO2R15, OC (O) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2R15, NR16R15 and CONR16R15; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl-pyrrolidinyl, pyrazolizylbenzoyl each optionally substituted with 1 to 5 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, -COR15, CO2R15, C0 (0 ) R15, NR8COR15, N (COR15) 2, nr8conr16r15, nr8co2r15, NR16R15 and CONR16R15; heterocyclyl is saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents independently selected each from C1-Cq alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, COR15, CO2R15 , OC (O) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2 R15, NR15R16, and CONR16R15; n is independently 0, 1 or 2 independently, provided that: (1) when R 1 is methyl or ethyl, R 2 is H, and R 3 is NH (n-C 4 H 9) or N (C 2 H 5) 2, then Ar is not unsubstituted phenyl or m-methylphenyl; and (2) when R 2 is H, and Ar is pyridyl, and R 3 is NR 6a R 7a, then R 6a and R 7a are not H or alkyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof ( pro-drugs). The [1,5-a] -pyrazolo-1,3,5-triazines of claim 1, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each (Ar) being substituted with 1 to 4 R 4 substituents, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and their pharmaceutically acceptable salts or pro-drugs. [1,5-a] -Pyrazolo-1,3,5-triazines according to claim 1 or 2, wherein Ar is phenyl or pyridyl, each (Ar) is optionally substituted with 1 to 4 R 4 substituents, and geometric isomers thereof , stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to one of Claims 1 to 3, wherein R 1 and R 2 are independently selected from H, C 1-4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 10 cycloalkylalkyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to claim 4, wherein R and R are independently selected from H or C 1-4 alkyl, and their geometric isomers, stereoisomeric forms, or mixtures stereoisomeric forms, and pharmaceutically acceptable salts or pro-drugs thereof. -5- 6. [1,5-a] -Pyrazolo-1,3,5-triazines according to claim 4, wherein R 1 and R 2 are independently selected from C 1-4 alkyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or pro-drugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to claim 4, wherein R 1 is methyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof ( pro-drugs). [1,5-a] -Pyrazolo-1,3,5-triazines according to any one of claims 1 to 7, wherein R 6a is independently selected from: • H, • C 1 -C 10 alkyl, C 3 -C 10 alkenyl, C 3- C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 independently substituents each of C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR 15, SH, S (O) n R 13, CO R 15, CO 2 R 15, OC (O) R 13, NR 8 CO R 15 N R15) 2, NR8CONR16R15, NR8CO2 R13, NR16R15, C0NR16R15, aryl, heteroaryl or heterocyclyl, • aryl, aryl (C1-C4 alkyl) -, heteroaryl, heteroaryl (C1-C4 alkyl) -, heterocyclyl or heterocyclyl C4 alkyl) -; and R7a is independently selected from each of: • H, • C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, -6- OR15, SH, S (O) nR13, COR15, CO2R15, 0C (0) R13, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, • aryl, aryl (C1-C6 alkyl) heteroaryl, heteroaryl (C 1 -C 4 alkyl) -, heterocyclyl or heterocyclyl (C 1 -C 4 alkyl) -; alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C-1-C4 alkyl groups, and their geometric isomers, stereoisomeric forms, or mixtures thereof, and stereois pharmaceutically acceptable salts or pro-drugs. [1,5-a] -Pyrazolo-1,3,5-triazines according to any one of claims 1 to 7, wherein R 6a is selected from: • H, • C 1 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents, independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR13, COR15, CO2R15, OC (O) R13, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2 R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, • aryl, aryl (C1-C4 alkyl) -, heteroaryl, heteroaryl (C1-C4 alkyl) -, heterocyclyl or heterocyclyl (C1-C4 alkyl) ; R7a is selected from: C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH , S (O) nR13, COR15, CO2R15, 0C (0) R13, NR8COR15, N (COR15) 2, -7- NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and geometric isomers thereof, stereo or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to any one of claims 1 to 7, wherein R 6a is H, R is selected from: • C 1 -C 4 alkyl and each such C 1 -C 4 alkyl is substituted with 1-3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR13, COR15, CO2R15, OC (0) R13, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof . [1,5-a] -Pyrazolo-1,3,5-triazines according to any one of claims 1 to 7, wherein R 6a and R 7a are independently H or C 1 -C 10 alkyl, each of which is C 1 -C 10 alkyl optionally substituted with 1-3 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR13, COR15, CO2R15, OC (O) R13, NR6COR15, N (COR15) 2i r8conr16r15, nr8co2r13, nr16r15, CONR16R15, aryl, heteroaryl or heterocyclyl, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. -8- 12. [1,5-a] -Pyrazolo-1,3,5-triazines according to any one of claims 1 to 7, wherein R 6a and R 7a are independently H or C 1 -C 10 alkyl, and their geometric isomers, stereoisomeric forms , or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to claim 1 of formula (50)(50) kjer je spojina izbrana iz skupine, ki obstaja iz: • spojine s formulo (50), kjer R3 pomeni -NHCH(n-Pr)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)(n-Bu), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(n-Bu), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(CH2OMe), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4eje H; -9- • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Et)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Me)(Ph), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(n-Pr)2, R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(n-Pr), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni-N(CH2CH20Me)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni-NHCH(Et)(CH20Me), R4a je Me, R4b je H, R4c je Me, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; -10- • spojine s formulo (50), kjer R3 pomeni -N(CH2CN)2, R4a je Me, R4b je H, R4cje Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni-NHCH(Me)(CH20Me), R4a je Me, R4b je H, R4c je Me, R4djeH in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(n-Pr)(CH2C-Pr), R4a je Me, R4b je H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni-NHCH(Me)(CH2N(Me)2), R4a je Me, R4b je H, R4c je Me, R4djeHin R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Me, R4b je H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -N(n-Pr)(CH2CH2CN), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(n-Bu)(CH2CN), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(CH2OMe), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -Ν(ΟΗ2ΟΗ2ΟΜβ)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2OMe)2, R4a je Br, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(CH2OMe), R4a je Br, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; -11- • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Et)2, R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2CH20Me)(CH20Me)2, R4a je Me, R4b je H, R4cje Me, R4d je H in R4eje Me; • spojine s formulo (50), kjer R3 pomeni morfolino, R4a je Me, R4b je H, R4c je Me, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Br, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Br, R4b je H, R4c je OMe, R4djeH in R4ejeH; • spojine s formulo (50), kjer R3 pomeni-N(Et)2, R4aje Br, R4bje H, R4cje OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NH(c-Pr), R4a je Me, R4b je H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni-NHCH(CH20Me)2, R4a je CN, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je Me; • spojine s formulo (50), kjer R3 pomeni -NCH(CH20Me)2, R4a je Me, R4b je H, R4c je Br, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)(CH2CH20Me), R4a je Me, R4b je H, R4c je Br, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)2, R4a je Me, R4b je H, R4c je OMe, R4d je Me in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH2OMe)2, R4a je Me, R4b je H, R4c je OMe, R4d je Me in R4e je H; -12- • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4c je OMe, R4d je Me in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Me, R4b je H, R4c je OMe, R4d je Me in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2OMe)2, R4a je Cl, R4b je H, R4c je Me, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(CH2OMe), R4a je Cl, R4bje H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH2OMe)2, R4a je Cl, R4b je H, R4cje Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2OMe)(CH2CH2OMe), R4a je Cl, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Me, R4b je H, R4c je OMe, R4d je Me in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2OMe)(CH2CH2OMe), R4a je Cl, R4b je H, R4c je Cl, R4dje H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4c je Br, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH2OMe)2, R4a je Me, R4b je H, R4c je Br, R4djeH in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NH(CH2OMe)(CH2-i-Pr), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; -13- • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Me, R4b je H, R4c je H, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Me, R4b je H, R4c je NMe2, R4dje H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)(n-Pr), R4aje Me, R4bje H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni-NHCH(CH20Et)(Et), R4a je Me, R4bje H, R4c je Me, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20Me)(CH2CH20Me), R4a je Me, R4b je H, R4c je NMe2, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni —N(Et)2, R4a je Me, R4b je H, R4cje Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4cje Cl, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Me, R4b je H, R4c je Cl, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH2OMe)2, R4a je Me, R4b je H, R4c je Cl, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Me, R4b je H, R4c je · R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Cl, R4b je H, R4cje Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni-NHCH(Et)2, R4a je Cl, R4b je H, R4c je Me, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je H, R4c je NMe2, R4d je H in R4eje H; -14- • spojine s formulo (50), kjer R3 pomeni (S)-NHCH(CH20Me)(CH2CH20Me), R4aje Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni —NHCH(CH20Me)(CH2CH20Me), R4a je Me, R4b je H, R4c je Me, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni (S)-NHCH(CH20Me)(CH2CH20Me), R4a je Me, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni —NHCH(CH20Me)(CH2CH20Me), R4a je Me, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Me, R4b je H, R4c je Cl, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NH(Et)(CH2CN), R4a je Me, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Me, R4b je Me, R4cje OMe, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)(CH2CH20H), R4a je Cl, R4b je H, R4c je Cl, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Me, R4b je Me, R4c je OMe, R4d je H in R4eje H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Me, R4b je Me, R4c je OMe, R4djeHinR4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(CH2C-Pr)(n-Pr), R4a je Me, R4b je H, R4c je Cl, R4djeH in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Me, R4b je Me, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)2, R4a je Cl, R4b je H, R4c je OMe, R4d je H in R4e je H; -15- • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Cl, R4b je H, R4c je OMe, R4d je H in R4ejeH; • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Cl, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(Et)(CH20Me), R4a je Cl, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(Et)2, R4a je Cl, R4bje H, R4c je CN, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -N(c-Pr)(CH2CH2CN), R4a je Cl, R4b je H, R4c je OMe, R4d je H in R4e je H; • spojine s formulo (50), kjer R3 pomeni -NHCH(CH20H)2, R4a je Cl, R4b je H, R4cje Cl, R4d je H in R4e je H; in • spojine s formulo (50), kjer R3 pomeni -N(CH2CH20Me)2, R4a je Me, R4b je H, R4c je OMe, R4d je H in R4e je H; in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 14. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 1, kjer Ar je 2-kloro-5-fluoro-metoksifenil; R1 in R2 sta metil; in R3jeNHCH(Et)2; in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 15. [1,5-a]-Pirazolo-1,3,5-triazini s formulo (1) -16-(50) wherein the compound is selected from the group consisting of: • a compound of formula (50) wherein R 3 is -NHCH (n-Pr) 2, R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (Et) (n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (Et) (n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) (CH 2 OMe), R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; -9- • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (Et) 2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OEt) 2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (Me) (Ph), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (n-Pr) 2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) (n-Pr), R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NCHCH (Et) (CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; Compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; -10- • compounds of formula (50), wherein R3 is -N (CH2CN) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NCHCH (Me) (CH2OMe), R4a is Me, R4b is H, R4c is Me, R4 is H and R4 is H; • compounds of formula (50) wherein R3 is -N (n-Pr) (CH2C-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NCHCH (Me) (CH 2 N (Me) 2), R 4a is Me, R 4b is H, R 4c is Me, R 4 is H and R 4 is H; • compounds of formula (50) wherein R3 is -N (c-Pr) (CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -N (n-Pr) (CH 2 CH 2 CN), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -N (n-Bu) (CH 2 CN), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) (CH 2 OMe), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is Me; Compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is Me; • compounds of formula (50) wherein R3 is -Ν (ΟΗ2ΟΗ2ΟΜβ) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) (CH 2 OMe), R 4a is Br, R 4b is H, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is Me; -11- • compounds of formula (50) wherein R3 is -NHCH (CH2OEt) 2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; • compounds of formula (50) wherein R 3 is -NHCH (CH 2 CH 2 OMe) (CH 2 OMe) 2, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is Me; • compounds of formula (50) wherein R 3 is morpholino, R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Br, R 4b is H, R 4c is OMe, R 4 is H and R 4 is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Br, R 4b is H, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -NH (c-Pr), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -NCHCH (CH2OMe) 2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is Me; • compounds of formula (50) wherein R3 is -NCH (CH2OMe) 2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H; • compounds of formula (50) wherein R 3 is -N (CH 2 CH 2 OMe) 2, R 4a is Me, R 4b is H, R 4c is OMe, R 4d is Me and R 4e is H; -12- • compounds of formula (50), wherein R3 is -NHCH (Et) 2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H; Compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is H, R 4c is OMe, R 4d is Me and R 4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (Et) (CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; Compounds of formula (50) wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Me, R 4b is H, R 4c is OMe, R 4d is Me and R 4e is H; • compounds of formula (50) wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is (S) -NHCH (CH2OMe) (CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4 is H and R4e is H; Compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is H, R 4c is Br, R 4d is H and R 4 is H; • compounds of formula (50) wherein R 3 is -N (CH 2 CH 2 OMe) 2, R 4a is Me, R 4b is H, R 4c is Br, R 4 is H and R 4 is H; • compounds of formula (50) wherein R3 is -NH (CH2OMe) (CH2-i-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; -13- • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is H, R4c is H, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is H, R4c is NMe2, R4 is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (n-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NCHCH (CH 2 OEt) (Et), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) 2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is H, R 4c is · R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Cl, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; Compounds of formula (50) wherein R 3 is -NCHCH (Et) 2, R 4a is Cl, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; Compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is H, R 4c is NMe 2, R 4d is H and R 4e is H; -14- • compounds of formula (50) wherein R3 is (S) -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50), wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is (S) -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50), wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Me, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -NH (Et) (CH 2 CN), R 4a is Me, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; Compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Me, R 4b is Me, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) (CH2CH2OH), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; • compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Me, R 4b is Me, R 4c is OMe, R 4 is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (CH2C-Pr) (n-Pr), R4a is Me, R4b is H, R4c is Cl, R4 is H and R4 is H; • compounds of formula (50) wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Me, R 4b is Me, R 4c is OMe, R 4d is H and R 4e is H; Compounds of formula (50) wherein R 3 is -NHCH (Et) 2, R 4a is Cl, R 4b is H, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Cl, R 4b is H, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; • compounds of formula (50) wherein R3 is -NHCH (Et) (CH2OMe), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; Compounds of formula (50) wherein R 3 is -N (Et) 2, R 4a is Cl, R 4b is H, R 4c is CN, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -N (c-Pr) (CH 2 CH 2 CN), R 4a is Cl, R 4b is H, R 4c is OMe, R 4d is H and R 4e is H; • compounds of formula (50) wherein R 3 is -NHCH (CH 2 OH) 2, R 4a is Cl, R 4b is H, R 4c is Cl, R 4d is H and R 4e is H; and • compounds of formula (50) wherein R3 is -N (CH2CH2OMe) 2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or pro-drugs thereof. The [1,5-a] -pyrazolo-1,3,5-triazines of claim 1, wherein Ar is 2-chloro-5-fluoro-methoxyphenyl; R1 and R2 are methyl; and R 3 is NHCH (Et) 2; and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or pro-drugs thereof. 15. [1,5-a] -Pyrazolo-1,3,5-triazines of formula (1) -16-kjer Arje fenil, piridil ali 2,3-dihidrobenzofuranil, vsak (Ar) opcijsko substituiran z 1 do 4 R4 substituenti; 1 2 R in R sta neodvisno izbrana vsakič izmed C1-C4 aikila; R3 je NR6aR7a; R4 je neodvisno izbran vsakič izmed: C-i-C-ιο aikila, C2-C10 alkenila, C2-C10 alkinila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, NO2, halo, CN, C1-C4 haloalkila, NR6R7, NR8COR7, NR8C02R7, COR7, OR7, CONR6R7, CO(NOR9)R7, C02R7, ali S(0)nR7, kjer je vsak tak C1-C10 alkil, C2-C-10 alkenil, C2-C10 alkinil, C3-C6 cikloalkil in C4-C12 cikloalkilalkil opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C1-C4 aikila, N02, halo, CN, NR6R7, NR8COR7, NR8C02R7, COR7 OR7, CONR6R7, C02R7, CO(NOR9)R7, ali S(0)nR7; R6 in R7, R6a in R7a so neodvisno izbrani vsakič izmed: • H, l • C-1-C10 aikila, C3-C10 alkenila, C3-C10 alkinila, C1-C10 haloalkila z 1-10 halogeni, C2-C8 alkoksialkila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, C5-C-10 cikloalkenila, ali C6-C-14 cikloalkenilalkila, kjer je vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C-1-C6 aikila, C3-C6 cikloalkila, halo, C1-C4 -17- haloalkila, ciano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15 N(COR15)2, NR8CONR16R15 NR8C02R13, NR16R15, CONR16R15 arila, heteroarila ali heterociklila, • arila, aril(C-|-C4 alkila), heteroarila, heteroaril(Ci-C4 alkila), heterociklila ali heterociklil(Ci-C4 alkila); alternativno, NRSR7 in NR6aR7a sta neodvisno piperidinska, pirolidinska, piperazinska, N-metilpiperazinska, morfolinska ali tiomorfolinska skupina, vsaka opcijsko substituirana z 1 do 3 C1-C4 alkilnimi skupinami; R8 je neodvisno izbran vsakič izmed H ali C-1-C4 alkila; R in R sta neodvisno izbrana vsakič izmed H, C1-C4 alkila, ali C3-C6 cikloalkila; R11 je izbran izmed H, C-1-C4 alkila, C1-C4 haloalkila, ali C3-C6 cikloalkila; R12 je C-1-C4 alkil ali C-1-C4 haloalkil; R13 je izbran izmed C-1-C4 alkila, C1-C4 haloalkila, C2-Ca alkoksialkila, C3-C6 cikloalkila, C4-C12 cikloalkilalkila, arila, aril(C1-C4 alkila)-, heteroarila ali heteroaril(C-i-C4 alkila)-; R14 je izbran izmed C1-C10 alkila, C3-C-ioalkenila, C3-Cioalkinila, Cs-Cscikloalkila, ali C4-Ci2 cikloalkilalkila, vsak opcijsko substituiran z 1 do 3 substituenti, neodvisno izbranih vsakič izmed C-1-C6 alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02Ri5, NR16R15, CONR16R15 in CVC6 alkiltio, CrC6 alkilsulfinila in C1-C6 alkilsulfonila; R15 in R16 sta neodvisno izbrana vsakič izmed H, C1-C6 alkila, C3-C10 cikloalkila, C4-C16 cikloalkilalkila, razen da pri S(0)nR , R ne more biti H; aril je fenil ali naftil, vsak opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, C1-C4 haloalkila, ciano, OR15, SH, S(0)nR15, COR15, C02R15, OC(O) R15, NR8COR15, N(COR15)2, NR8CONR16R15, NRsC02R15, NR16R15 in CONR16R15; -18- heteroaril je piridil, pirimidinil, triazinil, furanil, piranil, kinolinil, izokinolinil, tienil, imidazolil, tiazolil, indolil, pirolil, oksazolil, benzofuranil, benzotienil, benzotiazolil, izoksazolil, pirazolil, 2,3-dihidrobenzotienil ali 2,3-dihidrobenzofuranil, vsak opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, Ci-C4haloalkila, ciano, OR15, SH, S(0)nR15, -COR15, C02R15, C0(0)R15, NR8COR15 N(COR15)2i nr8conr16r15, nr8co2r15, NR16R15 in CONR16R15; heterociklil je nasičen ali delno nasičen heteroaril, opcijsko substituiran z 1 do 5 substituenti, neodvisno izbranih vsakič izmed C1-C6 alkila, C3-C6 cikloalkila, halo, Ci-C4 haloalkila, ciano, OR15 SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR15R16, in CONR16R15; n je neodvisno vsakič 0, 1 ali 2, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 16. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 15, kjer 4 Arje fenil, piridil ali 2,3-dihidrobenzofuranil, vsak (Ar) je substituiran z 1 do 4 R substituenti, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). 17. [1,5-a]-Pirazolo-1,3,5-triazini po zahtevku 15 ali 16, kjer Arje fenil ali piridil, vsak (Ar) je opcijsko substituiran z 1 do 4 R4 substituenti, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs). -19- 18. [1,5-a]-Pirazolo-1,3,5-triazini po enem izmed zahtevkov 15 do 17, kjer sta R6a in R7a neodvisno H ali C-i-C-ιο alkil, in njihovi geometrični izomeri, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs).wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each (Ar) optionally substituted with 1 to 4 R 4 substituents; 1 2 R and R are each independently selected from C1-C4 alkyl; R3 is NR6aR7a; R4 is independently selected from each of: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7R, , OR7, CONR6R7, CO (NOR9) R7, CO2R7, or S (O) nR7, each of which is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO (NOR9) R7, or S (O) nR7; R6 and R7, R6a and R7a are each independently selected from: • H, 1 • C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C-10 cycloalkenyl, or C6-C-14 cycloalkenylalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected each from C-1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 -17-haloalkyl, cyano, OR15, SH, S (O) nR13, COR15, CO2R15, OC (O) R13, NR8COR15 N (COR15) 2, NR8CONR16R15 NR8CO2R13, NR16R15, and heteroR16R or heterocyclyl, • aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); alternatively, NRSR7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine groups, each optionally substituted with 1 to 3 C1-C4 alkyl groups; R 8 is independently selected from H or C 1 -C 4 alkyl; R and R are each independently selected from H, C1-C4 alkyl, or C3-C6 cycloalkyl; R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 3 -C 6 cycloalkyl; R12 is C-1-C4 alkyl or C-1-C4 haloalkyl; R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C1 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl (C1-C4 alkyl) -, heteroaryl or heteroaryl ) -; R14 is selected from C1-C10 alkyl, C3-C10alkenyl, C3-C10alkynyl, C3-C8cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C1-1-C6 alkyl each, C3 -C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, COR15, CO2R15, OC (O) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2R15, NR16R15, CON alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl; R 15 and R 16 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 16 cycloalkylalkyl, except that for S (O) n R, R cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (O) nR15, COR15, CO2R15, OC (O) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR5CO2R15, NR16R15 and CONR16R15; -18- heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl -dihydrobenzofuranyl, each optionally substituted with 1 to 5 substituents independently selected each from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4haloalkyl, cyano, OR15, SH, S (O) nR15, -COR15, CO2R15, C0 (0) R15, NR8COR15 N (COR15) 2i nr8conr16r15, nr8co2r15, NR16R15 and CONR16R15; heterocyclyl is saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15 SH, S (O) nR15, COR15, CO2R15, OC (O) R15, NR8COR15, N (COR15) 2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15; n is independently 0, 1, or 2 independently, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or pro-drugs thereof. The [1,5-a] -pyrazolo-1,3,5-triazines of claim 15, wherein 4 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each (Ar) being substituted with 1 to 4 R substituents, and their geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and their pharmaceutically acceptable salts or pro-drugs. The [1,5-a] -pyrazolo-1,3,5-triazines according to claim 15 or 16, wherein Ar is phenyl or pyridyl, each (Ar) being optionally substituted with 1 to 4 R 4 substituents, and geometric isomers thereof, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof. [1,5-a] -Pyrazolo-1,3,5-triazines according to one of Claims 15 to 17, wherein R 6a and R 7a are independently H or C 1 -C 10 alkyl, and their geometric isomers, stereoisomeric forms , or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts or prodrugs thereof.19. Farmacevtski sestavek, ki obsega [1,5-aj-pirazolo-1,3,5-triazin s formulo (1) po enem izmed zahtevkov 1 do 18 ali njegove geometrične izomere, stereoizomerne oblike, ali zmesi stereoizomernih oblik, in njihove farmacevtsko sprejemljive soli ali predzdravilne oblike (pro-drugs).A pharmaceutical composition comprising [1,5-aj-pyrazolo-1,3,5-triazine of formula (1) according to one of claims 1 to 18 or a geometric isomer, stereoisomeric form, or mixture of stereoisomeric forms thereof, and pharmaceutically acceptable salts or pro-drugs.20. Uporaba [1,5-a]-pirazolo-1,3,5-triazina s formulo (1) po kateremkoli izmed zahtevkov 1 do 18 ali njegovih geometričnih izomerov, stereoizomernih oblik, ali zmesi stereoizomernih oblik, in njegovih farmacevtsko sprejemljivih soli ali predzdravilnih oblik (pro-drugs), za pripravo zdravila za zdravljenje afektivnih motenj, anksioznosti, depresije, glavobola, sindroma iritabilnega kolona, post-travmatske stresne motnje, supranuklearne paralize, supresije imunosti, Alzheimerjeve bolezni, gastrointestinalnih bolezni, nervozne anoreksije ali drugih motenj prehranjevanja, zasvojenosti z drogami, simptomov pri odvajanju od drog ali alkohola, vnetnih bolezni, kardiovaskularnih ali srčno pogojenih bolezni, problemov pri oploditvi, infekcij z virusom humane imunske pomanjkljivosti, hemoragičnega stresa, debelosti, neplodnosti, travme glave in hrbtenjače, epilepsije, kapi, razjed (ulkusov), amiotrofične lateralne skleroze, ali hipoglikemije.Use of [1,5-a] pyrazolo-1,3,5-triazine of formula (1) according to any one of claims 1 to 18 or its geometric isomers, stereoisomeric forms, or mixtures of stereoisomeric forms, and pharmaceutically acceptable salts thereof or prodrugs, for the preparation of a medicament for the treatment of affective disorders, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other disorders diet, drug addiction, withdrawal symptoms, inflammatory diseases, cardiovascular or cardiovascular disease, fertilization problems, human immunodeficiency virus infections, haemorrhagic stress, obesity, infertility, head and spinal cord trauma, epilepsy, stroke ulcers, amyotrophic lateral sclerosis, or hypoglycemia.21. Uporaba po zahtevku 20, za zdravljenje afektivnih motenj, anksioznosti, depresije, sindroma iritabilnega kolona, post-travmatske stresne motnje, supranuklearne paralize, supresije imunosti, Alzheimerjeve bolezni, gastrointestinalnih bolezni, nervozne anoreksije ali drugih motenj prehranjevanja, zasvojenosti z drogami, simptomov pri odvajanju od drog ali alkohola, vnetnih bolezni ali problemov pri oploditvi. -20-Use according to claim 20, for the treatment of affective disorders, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction in withdrawal from drugs or alcohol, inflammatory diseases, or problems with fertilization. -20-22. Uporaba po zahtevku 21, za zdravljenje anksioznosti.Use according to claim 21, for the treatment of anxiety.
SI9720045A1996-07-241997-07-23Azolo triazines and pyrimidines
SI9720045B
(en)
4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) pyrazolo-[1,5-a]-1,3, 5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands.
Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and the use thereof as adenosine receptor ligands, process for their preparation and pharmaceutical compositions containing them
Triazolopyrimidine derivatives which are angiotensin ii receptor antagonists, processes for preparing them and pharmaceutical compositions containing them
2, 4-Diamino-5-benzylpyrimidines as antibacterial agents. 4. 6-Substituted trimethoprim derivatives from phenolic Mannich intermediates. Application to the synthesis of trimethoprim and 3, 5-dialkylbenzyl analogs