HRP20100378T1 - Spojevi triazolopirazina učinkoviti za tretman degenerativnih i upalnih bolesti - Google Patents

Spojevi triazolopirazina učinkoviti za tretman degenerativnih i upalnih bolesti Download PDF

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HRP20100378T1
HRP20100378T1 HR20100378T HRP20100378T HRP20100378T1 HR P20100378 T1 HRP20100378 T1 HR P20100378T1 HR 20100378 T HR20100378 T HR 20100378T HR P20100378 T HRP20100378 T HR P20100378T HR P20100378 T1 HRP20100378 T1 HR P20100378T1
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triazolo
pyrazin
pyrazol
piperazin
ylamino
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James Inglis Andrews Martin
Edwards Paul
Stuart Chambers Mark
Schmidt Wolfgang
Andrew Clase Juha
Bar Gregory
Louise Hirst Kim
Macleod Angus
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Galapagos N.V.
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Abstract

Spoj prema formuli III: naznačen time, da R1 je H ili supstituirani ili nesupstituirani alkil; a svaki od R8 i R9 je nezavisno odabran iz supstituiranog ili nesupstituiranog cikloalkila, supstituiranog ili nesupstituiranog heterocikloalkila, supstituiranog ili nesupstituiranog arila, supstituiranog ili nesupstituiranog heteroarila; ili njegova farmaceutski prihvatljiva sol, njegov solvat; i njegovi stereoizomeri, izotopični oblici i njegovi tautomeri. Patent sadrži još 36 patentnih zahtjeva.

Claims (37)

1. Spoj prema formuli III: [image] naznačen time, da R1 je H ili supstituirani ili nesupstituirani alkil; a svaki od R8 i R9 je nezavisno odabran iz supstituiranog ili nesupstituiranog cikloalkila, supstituiranog ili nesupstituiranog heterocikloalkila, supstituiranog ili nesupstituiranog arila, supstituiranog ili nesupstituiranog heteroarila; ili njegova farmaceutski prihvatljiva sol, njegov solvat; i njegovi stereoizomeri, izotopični oblici i njegovi tautomeri.
2. Spoj prema zahtjevu 1, naznačen time, da R8 je odabran iz supstituiranog ili nesupstituiranog ciklopentila, cikloheksila, supstituiranog ili nesupstituiranog fenila, supstituiranog ili nesupstituiranog piridila, supstituiranog ili nesupstituiranog pirimidina i supstituiranog ili nesupstituiranog pirazina, supstituiranog ili nesupstituiranog pirola, supstituiranog ili nesupstituiranog pirazola i supstituiranog ili nesupstituiranog imidazola.
3. Spoj prema zahtjevu 1, naznačen time, da je R8 odabran iz supstituiranog fenila, supstituiranog piridila i supstituiranog pirimidina; a supstitucija je -L-R8d; gdje L je odabran iz veze, alkilena, heteroalkilena, -O-, -N(R8e)-, -CO-, -CO2-, -SO-, -SO2-, -CON(R8e)-, -SO2N(R8e)-, -N(R8e)CO-, -N(R8e)SO2-, -N(R8e)CON(R8e)-, -N(R8e)SO2N(R8e)-; a R8d je odabran iz supstituiranog ili nesupstituiranog alkila, supstituiranog ili nesupstituiranog cikloalkila, supstituiranog ili nesupstituiranog arila, supstituiranog ili nesupstituiranog heterocikloalkila, supstituiranog ili nesupstituiranog heteroarila, supstituiranog ili nesupstituiranog amino, supstituiranog ili nesupstituiranog aralkila, supstituiranog ili nesupstituiranog heteroarilalkila i supstituiranog ili nesupstituiranog aminoalkila; a R8e je odabran iz H, supstituiranog ili nesupstituiranog alkila supstituiranog ili nesupstituiranog cikloalkila.
4. Spoj prema zahtjevu 1, naznačen time, da R8 je [image] gdje L i R8d su kao što je definirano u zahtjevu 3; indeks n je odabran iz brojeva od 1-4; a svaki R8a je nezavisno odabran iz vodika, supstituiranog ili nesupstituiranog alkila, alkoksi, cijano i halo.
5. Spoj prema zahtjevu 4, naznačen time, da L je veza, -O-, -CO-, -CON(R8e)- ili - N(R8e)CO-; R8d je odabran iz supstituiranog ili nesupstituiranog alkila, supstituiranog ili nesupstituiranog cikloalkila, supstituiranog ili nesupstituiranog arila, supstituiranog ili nesupstituiranog heterocikloalkila, supstituiranog ili nesupstituiranog heteroarila, supstituiranog ili nesupstituiranog aralkila, supstituiranog ili nesupstituiranog heteroarilalkila i supstituiranog ili nesupstituiranog aminoalkila; a R8e je odabran iz H, supstituiranog ili nesupstituiranog alkila.
6. Spoj prema zahtjevu 4, naznačen time, da L je veza, -CO-, -O(CH2)m1-, -CON(H)(CH2)m1- ili - NHCO-; indeks m1 je odabran iz brojeva od 1-4; a R8d je [image] a gdje je prsten P supstituirani ili nesupstituirani heterocikloalkil.
7. Spoj prema zahtjevu 1, naznačen time, da je navedeni spoj u skladu sa formulom IVa, IVb, IVc ili IVd: [image] a gdje su L i prsten P kao što je definirano u zahtjevu 6; indeks n je odabran iz brojeva od 1-4; svaki R8a je nezavisno odabran iz vodika, supstituiranog ili nesupstituiranog alkila, alkoksi, cijano i halo; a R9 je nezavisno odabran iz supstituiranog ili nesupstituiranog arila i heteroarila; ili njegova farmaceutski prihvatljiva sol, njegov solvat; i njegovi stereoizomeri, izotopični oblici i njegovi tautomeri.
8. Spoj prema zahtjevu 7, naznačen time, da L je veza.
9. Spoj prema zahtjevu 7, naznačen time, da L je -NHCO- ili -CONH-.
10. Spoj prema zahtjevu 7, naznačen time, da L je -OCH2-CH2- ili -NHCH2-CH2-.
11. Spoj prema bilo kojem od zahtjeva od 6-10, naznačen time, da prsten P je supstituirani ili nesupstituirani piperidin, morfolin ili piperazin.
12. Spoj prema zahtjevu 1, naznačen time, da je navedeni spoj u skladu sa formulom Va, Vb, Vc, Vd, Ve ili Vf: [image] [image] a gdje R9 je kako je definirano u zahtjevu 1 i R8b je vodik, supstituirani ili nesupstituirani alkil ili supstituirani ili nesupstituirani cikloalkil.
13. Spoj prema zahtjevu 1, naznačen time, da je R9 odabran iz supstituiranog ili nesupstituiranog arila.
14. Spoj prema zahtjevu 1, naznačen time, da je R9 odabran iz supstituiranog ili nesupstituiranog heteroarila.
15. Spoj prema zahtjevu 1, naznačen time, da je R9 odabran iz supstituiranog ili nesupstituiranog fenila, piridila, indolila, izoindolila, pirolila, furanila, tienila, pirazolila, oksazolila i tiazolila.
16. Spoj prema bilo kojem od zahtjeva od 1-15, naznačen time, da R9 je [image] a svaki od A1, A2 i A3 je nezavisno odabran iz S, O, N, NR9a i CR9a; i svaki od R9a je nezavisno H ili supstituirani ili nesupstituirani alkil; a R9b je CONH2, CONHMe ili CN.
17. Spoj prema bilo kojem od zahtjeva od 1-15, naznačen time, da R9 je [image]
18. Spoj prema bilo kojem od zahtjeva od 1-15, naznačen time, da R9 je [image] [image]
19. Spoj prema bilo kojem od zahtjeva od 1-15, naznačen time, da R9 je [image] a gdje je indeks m odabran iz brojeva od 1- svaki R9d je nezavisno H, supstituirani ili nesupstituirani alkil ili halo.
20. Spoj prema bilo kojem od zahtjeva od 1-15, naznačen time, da R9 je [image] a gdje je indeks m odabran iz brojeva od 1-4 i svaki R9d je nezavisno H, supstituirani ili nesupstituirani alkil ili halo.
21. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je u skladu sa formulom VIIIa, VIIIb, VIIIc, VIIId, VIIIe ili VIIIf: [image] [image] a R8b je vodik, supstituirani ili nesupstituirani alkil ili supstituirani ili nesupstituirani cikloalkil.
22. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je u skladu sa formulom IXa, IXb, IXc, IXd, IXe ili IXf: [image] [image] a R8b je vodik, supstituirani ili nesupstituirani alkil ili supstituirani ili nesupstituirani cikloalkil.
23. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je u skladu sa formulom Xa, Xb, Xc, Xd, Xe ili Xf: [image] [image] a R8b je vodik, supstituirani ili nesupstituirani alkil ili supstituirani ili nesupstituirani cikloalkil.
24. Spoj prema bilo kojem od zahtjeva 12 ili 21-23, naznačen time, da R8b je H.
25. Spoj prema bilo kojem od zahtjeva 12 ili 21-23, naznačen time, da R8b je cikloalkil.
26. Spoj prema bilo kojem od zahtjeva 12 ili 21-23, naznačen time, da R8b je ciklopropil.
27. Spoj prema bilo kojem od zahtjeva 12 ili 21-23, naznačen time, da R8b je supstituirani ili nesupstituirani alkil.
28. Spoj prema bilo kojem od zahtjeva 12 ili 21-23, naznačen time, da R8b je Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF3, CH2CF3, CH2CONH2 ili ciklopropilmetil.
29. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je u skladu sa formulom XIIa, XIIb, XIIc ili XIId: [image]
30. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je u skladu sa formulom XVa, XVb ili XVc: [image] a L je veza, -CO- ili -O-CH2-CH2-; dok prsten P je [image] a R8b je H, Me, i-Pr, t-Bu, CH2CONH2 ciklopropilmetil ili CH2CF3.
31. Spoj prema zahtjevu 30, naznačen time, da L je veza, a prsten P je [image]
32. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj je odabran iz slijedećih spojeva (4-Morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [4-(4-Metil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 4-{8-[4-(4-Metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-benzamid; 4-{8-[4-(4-Metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-1H-piridin-2-on; 4-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-benzamid; Amid 4-{8-[4-(4-metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; 2-Fluoro-4-{8-[4-(4-metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-benzamid; 3-Fluoro-4-{8-[4-(4-metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-benzamid; Amid 5-{8-[4-(4-metil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; 3-Fluoro-4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-benzamid; 2-Fluoro-4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-benzamid; [5-(5-Metil-1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-(4-morfolin-4-il-fenil)-amin; Amid 5-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; 2,6-Difluoro-4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-benzamid; Amid 4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; [4-(4-Metil-piperazin-1-il)-fenil]-[5-(5-metil-1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; (3-Fluoro-4-morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; (3-Kloro-4-morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [4-(2-Morfolin-4-il-etoksi)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; Amid 4-{8-[4-(2-morfolin-4-il-etoksi)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; Amid 5-{8-[4-(2-morfolin-4-il-etoksi)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; (4-Morfolin-4-il-fenil)-[5-(2H-pirazol-3-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; Amid 4-{8-[4-((2R,6S)-2,6-dimetil-morfolin-4-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; (4-Morfolin-4-il-3-trifluorometil-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 2,6-Difluoro-4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-benzamid; Amid 4-[8-(4-piperazin-1-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; Amid 4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; Amid 5-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-furan-3-karboksilne kiseline; Amid 5-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-furan-3-karboksilne kiseline; [5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-[4-((2S,5R)-2,4,5-trimetil-piperazin-1-il)-fenil]-amin; Amid 4-{8-[4-((2S,5R)-2,4,5-trimetil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; 5-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; Amid 4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-furan-2-karboksilne kiseline; 6-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-3,4-dihidro-2H-izokinolin-1-on; 5-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; {2-Morfolin-4-il-5-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanol; [4-(4-Izopropil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 6-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-3,4-dihidro-1H-kinolin-2-on; (4-Piperazin-1-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; (6-Morfolin-4-il-piridin-3-il)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [6-(4-Ciklopropilmetil-piperazin-1-il)-piridin-3-il]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [6-(4-Izopropil-piperazin-1-il)-piridin-3-il]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-{6-[4-(2,2,2-trifluoro-etil)-piperazin-1-il]-piridin-3-il}-amin; [5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-{4-[4-(2,2,2-trifluoro-etil)-piperazin-1-il]-fenil}-amin; [4-(4-Ciklopropilmetil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; Amid 4-[8-(6-morfolin-4-il-piridin-3-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; (5-Benzo[b]tiofen-3-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-(4-morfolin-4-il-fenil)-amin; (5-Benzo[b]tiofen-3-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-[4-(4-izopropil-piperazin-1-il)-fenil]-amin; (4-Morfolin-4-il-fenil)-(5-tiofen-3-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-amin; [4-(4-Izopropil-piperazin-1-il)-fenil]-(5-tiofen-3-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-amin; [5-(5-Etil-1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-(4-morfolin-4-il-fenil)-amin; 6-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-1,1-diokso-1,2-dihidro-1λ6-benzo[d]izotiazol-3-on; Amid 4-{8-[6-(4-ciklopropilmetil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; Amid 4-{8-[6-(4-izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; Amid 4-(8-{6-[4-(2,2,2-trifluoro-etil)-piperazin-1-il]-piridin-3-ilamino}-[1,2,4]triazolo[1,5-a]pirazin-5-il)-tiofen-2-karboksilne kiseline; Amid 4-(8-{4-[4-(2,2,2-trifluoro-etil)-piperazin-1-il]-fenilamino}-[1,2,4]triazolo[1,5-a]pirazin-5-il)-tiofen-2-karboksilne kiseline; Amid 4-{8-[4-(4-ciklopropilmetil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; [4-(4-Ciklopropil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [6-(4-Ciklopropil-piperazin-1-il)-piridin-3-il]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; Amid 4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiazole-2-karboksilne kiseline; Amid 4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiazole-2-karboksilne kiseline; Amid 4-(8-{4-[1-(2,2,2-trifluoro-etil)-piperidin-4-il]-fenilamino}-[1,2,4]triazolo[1,5-a]pirazin-5-il)-tiofen-2-karboksilne kiseline; [5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-{4-[1-(2,2,2-trifluoro-etil)-piperidin-4-il]-fenil}-amin; 5-{8-[4-(2-Morfolin-4-il-etoksi)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; (5-Benzotiazol-6-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-(4-morfolin-4-il-fenil)-amin; (2-Fluoro-4-morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; (2-Kloro-4-morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 1-{5-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-il}-etanon; {4-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2H-pirazol-3-il}-metanol; 6-{4-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-fenil}-4,5-dihidro-2H-piridazin-3-on; (5-Benzo[1,2,5]oksadiazol-5-il-[1,2,4]triazolo[1,5-a]pirazin-8-il)-(4-morfolin-4-il-fenil)-amin; Metil amid 4-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiazole-2-karboksilne kiseline; Metil amid 4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiazol-2-karboksilne kiseline; 5-[8-(2-Fluoro-4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; 5-[8-(2-Kloro-4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; 5-{8-[2-Kloro-4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; [5-(2-Amino-pirimidin-5-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-(4-morfolin-4-il-fenil)-amin; 5-{8-[6-(4-Izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; Amid 3-[8-(4-morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-benzo[b]tiofen-7-karboksilne kiseline; Amid 3-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-benzo[b]tiofen-7-karboksilne kiseline; {4-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-piridin-2-il}-metanol; (4-{8-[4-(4-Izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-piridin-2-il)-metanol; [4-(1-Izopropil-piperidin-4-il)-fenil]-[5-(1H-piazol-4-il)-[1,2,4]triazolo[1,5-a]piazin-8-il]-amin; {5-[4-(2-Amino-tiazol-4-il)-fenil]-[1,2,4]triazolo[1,5-a]pirazin-8-il}-(4-morfolin-4-il-fenil)-amin; Amid 4-{8-[6-(4-izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-furan-2-karboksilne kiseline; 5-[8-(6-Morfolin-4-il-piridin-3-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; Amid 4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-furan-2-karboksilne kiseline; Amid 4-{8-[4-(1-izopropil-piperidin-4-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-tiofen-2-karboksilne kiseline; (4-{8-[6-(4-Izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-piridin-2-il)-metanol; [5-(2-Fluorometil-piridin-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-[4-(4-izopropil-piperazin-1-il)-fenil]-amin; 5-{8-[4-(1-Izopropil-piperidin-4-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; [5-(1H-Indazol-6-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-(4-morfolin-4-il-fenil)-amin; Amid 4-[8-(6-morfolin-4-il-piridin-3-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-furan-2-karboksilne kiseline; Amid 4-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-5-metil-tiofen-2-karboksilne kiseline; Amid 4-{8-[6-(4-izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-5-metil-tiofen-2-karboksilne kiseline; 4-{8-[4-(4-Izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; 4-{8-[6-(4-Izopropil-piperazin-1-il)-piridin-3-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3 -dihidro-izoindol-1-on; 5-[8-(2-Morfolin-4-il-pirimidin-5-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; 1-{4-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-piperazin-2-on; 5-{8-[2-(4-Izopropil-piperazin-1-il)-pirimidin-5-ilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; 5-{8-[4-(4-tert-Butil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; [4-(4-tert-Butil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; [5-(1H-Indazol-5-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-(4-morfolin-4-il-fenil)-amin; 5-{8-[4-(2-Okso-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; [5-(1H-Indazol-6-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-[4-(4-izopropil-piperazin-1-il)-fenil]-amin; [6-(4-Izopropil-piperazin-1-il)-piridin-3-il]-(5-{(E)-1-[4-metilen-2,4-dihidro-pirazol-(3E)-ilidenmetil]-propenil}-[1,2,4]triazolo[1,5-a]pirazin-8-il)-amin; 7-Fluoro-5-{8-[4-(4-izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; 6-{8-[4-(4-Izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; (3-Metilaminometil-4-morfolin-4-il-fenil)-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 2-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-5,6-dihidro-furo[2,3-c]pirol-4-on; 5-{8-[4-(4-Izopropil-2-okso-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-2,3-dihidro-izoindol-1-on; 2-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-4,5-dihidro-tieno[2,3-c]pirol-6-on; 5-{8-[4-(4-Izopropil-piperazin-1-il)-fenilamino]-[1,2,4]triazolo[1,5-a]pirazin-5-il}-3,3-dimetil-2,3-dihidro-izoindol-1-on; 5-(8-Cikloheksilamino-[1,2,4]triazolo[1,5-a]pirazin-5-il)-2,3-dihidro-izoindol-1-on; 5-[8-(Tetrahidro-piran-4-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on; [4-(4-tert-Butil-piperazin-1-il)-fenil]-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-il]-amin; 2-[8-(4-Morfolin-4-il-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-4,5-dihidro-tieno[2,3-c]pirol-6-on; i 5-[8-(4-Fluoro-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-2,3-dihidro-izoindol-1-on.
33. Spoj prema zahtjevu 1, naznačen time, da je navedeni spoj odabran iz slijedećih spojeva: 4-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-N-piridin-3-ilmetil-benzamid; 4-[5-(2-Okso-1,2-dihidro-piridin-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-N-piridin-3-ilmetil-benzamid; 2-Metoksi-N-(6-metil-piridin-3-ilmetil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; Amid 4-(8-{3-metoksi-4-[(6-metil-piridin-3-ilmetil)-karbamoil]-fenilamino}-[1,2,4]triazolo[1,5-a]pirazin-5-il)-tiofen-2-karboksilne kiseline; N-Benzil-2-metoksi-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Benzil-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; 3-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-N-piridin-2-ilmetil-benzamid; N,N-Dietil-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; {3-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-pirolidin-1-ilmetanon; (4-Izopropil-piperazin-1-il)-{3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; 3-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Etil-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Cikloheksilmetil-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-(4-Hidroksi-benzil)-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; Amid 4-[8-(4-benzilkarbamoil-3-metoksi-fenilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; Amid 4-[8-(6-benzoilamino-piridin-3-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline; N-Benzil-N-metil-3-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-{5-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-piridin-2-il}-benzamid; Metil amid 1-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzoil}-piperidin-4-karboksilne kiseline; 4-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-N-(2-piridin-4-il-etil)-benzamid; (4-Etil-piperazin-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-(1-Etil-pirolidin-2-ilmetil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; (2,5-Dihidro-pirol-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; [4-(2-Etoksi-etil)-piperazin-1-il]-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-Ciklopropilmetil-4-[5-(1H-pirazol-4-il)-[1,2,4]-triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Metil-N-(1-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzoil}-pirolidin-3-il)-acetamid; [4-(4-Fluoro-benzil)-piperazin-1-il]-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; (4-Fenil-piperazin-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; ((S)-2-Metoksimetil-pirolidin-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-((R)-1-Benzil-pirolidin-3-il)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; {4-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-(4-piridin-2-il-piperazin-1-il)-metanon; N-(1-Metoksimetil-propil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; [4-(2-Metoksi-etil)-piperazin-1-il]-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-[2-(4-Hidroksi-fenil)-etil]-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; (4-sec-Butil-piperazin-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-[4-(4-Metil-piperazin-1-il)-fenil]-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; Etil ester (benzil-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzoil}-amino)-octene kiseline; N-Izopropil-2-(4-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzoil}-piperazin-1-il)-acetamid; N-(2-Metoksi-etil)-N-metil-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Etil-N-(2-metoksi-etil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; 4-[5-(1H-Pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-N-(tetrahidro-furan-2-ilmetil)-benzamid; (3,6-Dihidro-2H-piridin-1-il)-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-(2-Metilsulfanil-etil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-(2,2-Dimetil-[1,3]dioksolan-4-ilmetil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-(2-Diizopropilamino-etil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-((S)-1-Etil-pirolidin-2-ilmetil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; N-Izobutil-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; [1,4']Bipiperidinil-1'-il-{4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-fenil}-metanon; N-(2-Hidroksi-etil)-4-[5-(1H-pirazol-4-il)-[1,2,4]triazolo[1,5-a]pirazin-8-ilamino]-benzamid; i Amid 4-[8-(6-fenilacetilamino-piridin-3-ilamino)-[1,2,4]triazolo[1,5-a]pirazin-5-il]-tiofen-2-karboksilne kiseline.
34. Farmaceutski pripravak, naznačen time, da sadrži farmaceutski prihvatljiv nosač i farmaceutski učinkovitu količinu spoja prema bilo kojem od zahtjeva od 1 do 33.
35. Uporaba spoja prema bilo kojem od zahtjeva od 1 do 33, naznačena time, da se navedeni spoj koristi u proizvodnji lijeka za tretman ili profilaksu stanja koje se odlikuje sa degradacijom ECM.
36. Uporaba spoja prema bilo kojem od zahtjeva od 1 do 33, naznačena time, da se navedeni spoj koristi u proizvodnji lijeka za tretman ili profilaksu stanja koje je odabrano iz bolesti koje uključuju upalne bolesti.
37. Uporaba spoja prema zahtjevu 36, naznačena time, da je navedena bolest reumatoidni artritis.
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