HRP20191283T1 - Diaril makrocikli kao modulatori protein kinaze - Google Patents

Diaril makrocikli kao modulatori protein kinaze Download PDF

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HRP20191283T1
HRP20191283T1 HRP20191283TT HRP20191283T HRP20191283T1 HR P20191283 T1 HRP20191283 T1 HR P20191283T1 HR P20191283T T HRP20191283T T HR P20191283TT HR P20191283 T HRP20191283 T HR P20191283T HR P20191283 T1 HRP20191283 T1 HR P20191283T1
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fluoro
4alkyl
ethenopyrazolo
methyl
tetrahydro
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Jingrong Jean Cui
Yishan LI
Evan W. ROGERS
Dayong Zhai
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Turning Point Therapeutics, Inc.
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Claims (13)

1. Spoj sljedeće formule (IV): naznačen time da M je CH ili N; X1 i X1’ su neovisno -C(R1a)(R2a)-, -S-, -S(O)-, -S(O)2-,-O- ili -N(Rk’)-;
 svaki R1a i R2a je neovisno H, deuterij, C1-6alkil, C3-6cikloalkil, C6-10 aril, -C(O)ORa’, -C(O)NRa’Rb’, -NRa’Rb’, -SRa’, -S(O)Ra’, -S(O)NRa’. -S(O)2Ra’, -S(O)2NRa’ ili -ORa’ naznačen time da svaki vodikov atom u C1-6alkil je neovisno opcionalno zamijenjen deuterijem, halogenom, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, NHC(O)C1-4alkil, -N(C1-4alkil)C(O)C1-4alkilom, -NHC(O)NHC1-4alkilom, -N(C1-4alkil)C(O)NHC1-4alkilom, -NHC(O)N(C1-4alkil)2,-N(C1-4alkil)C(O)N(C1-4alkil)2 , -NHC(O)OC1-4alkilom, -N(C1-4alkil)C(O)OC1-4alkilom, -CO2H, -CO2C1-4alkilom, -CONH2, -CONH(C1-4alkil), -CON(C1-4alkil)2, -SC1-4alkil, -S(O)C1-4alkilom, -S(O)2C1-4alkilom, -S(O)NH(C1-4alkil), -S(O)2NH(C1-4alkil), -S(O)N(C1-4alkil)2, -S(O)2N(C1-4alkil)2, C3-6cycloalkilom, ili 3-do 7-članim heterocikloalkilom; R3a i R3b su svaki neovisno H, deuterij, fluoro, kloro, bromo, metil, etil, propil, izopropil, metoksi, etoksi, izopropoksi, -CN, ili -CF3; R7a je H, C1-6alkil ili 3-do 7-člani heterocikloalkil, naznačen time da svaki vodikov atom u C1-6alkil ili 3-do 7-člani heterocikloalkil je neovisno opcionalno zamijenjen deuterijem, halogenom, -CN, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, -CO2H, -CO2C1-4alkilom, -CONH2, -CONH(C1-4alkil), -CON(C1-4alkil)2, cikloalkilom, ili monocikličkim heterocikloalkilom; svaki Rk’ je neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3-do 7-člani heterocikloalkil, C6-10 aril, ili mono- ili biciklički heteroaril; naznačen time da svaki vodikov atom u C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3-do 7-člani heterocikloalkil, C6-10 aril, ili mono- ili biciklički heteroaril u Rk’ je neovisno opcionalno zamijenjen deuterijem, halogenom, C1-6alkilom, C1-6haloalkilom ili -ORa’; naznačen time da je svaki Ra’ i Rb’ neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3- do 7-člani heterocikloalkil, C6-10 aril, or heteroaril;
 svaki Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je neovisno N, NH, ili C(RX), naznačen time da je svaki Rx kada prisutan neovisno H, deuterij, halogen, C1-4alkil, -O-C1-4alkil, -OH, -NH2, -NH(C1-4alkil), -NH(fenil), -NH(heteroaril), CN, ili -CF3, s time da barem jedan od Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je N ili NH; i m’ je 2 ili 3; ili njegova farmaceutski prihvatljiva sol.
2. Spoj temeljem zahtjeva 1, naznačen time da je formula: naznačen time da M je CH ili N; X1 i X1’ su neovisno -C(R1a)(R2a)-, -S-, -S(O)-, -S(O)2-,-O- ili -N(Rk’)-;
 svaki R1a i R2a su neovisno H, deuterij, C1-6alkil, C3-6cikloalkil, C6-10aril, -C(O)ORa’, -C(O)NRa’Rb’, -NRa’Rb’, -SRa’, -S(O)Ra’, -S(O)NRa’, -S(O)2Ra’, -S(O)2NRa’ ili -ORa’ naznačen time da svaki vodikov atom u C1-6alkilu je neovisno opcionalno zamijenjen deuterijem, halogenom, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, NHC(O)C1-4alkilom, -N(C1-4alkil)C(O)C1-4alkilom, -NHC(O)NHC1-4alkilom, -N(C1-4alkil)C(O)NHC1-4alkilom, -NHC(O)N(C1-4alkil)2,-N(C1-4alkil)C(O)N(C1-4alkil)2, -NHC(O)OC1-4alkil, -N(C1-4alkil)C(O)OC1-4alkilom, -CO2H, -CO2C1-4alkilom, -CONH2, -CONH(C1-4alkil), -CON(C1-4alkil)2, -SC1-4alkilom, -S(O)C1-4alkilom, -S(O)2C-4alkilom, -S(O)NH(C1-4alkil), -S(O)2NH(C1-4alkil), -S(O)N(C1-4alkil)2, -S(O)2N(C1-4alkil)2, C3-6cikloalkilom, ili 3-do 7-članim heterocikcloalkilom; R3a i R3b su svaki neovisno H, fluoro, kloro, bromo, metil, etil, propil, izopropil, metoksi, etoksi, izopropoksiy, -CN, ili -CF3;
 R7a je H, C1-6alkil ili 3-do 7-člani heterocikloalkil, naznačen time da svaki vodikov atom u C1-6alkilu or 3-do 7-članom heterocikloalkilu je neovisno opcionalno zamijenjen halogenom, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, -CO2H, -CO2C1-4alkilom, -CONH2, - CONH(C1-4alkil), -CON(C1-4alkil)2, cikloalkilom, ili monocikličkim heterocikloalkilom; svaki Rk’ je neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3-do 7-člani heterocikoalkil, C6-10 aril, ili mono- ili biciklički heteroaril; naznačen time da svaki vodikov atom u C1-6alkilu, C2-6alkenilu, C2-6alkinilu, C3-6cikloalkilu, 3-do 7-člani heterocikloalkilu, C6-10 arilu, ili mono- ili bicikličkom heteroarilu u Rk’ je neovisno opcionalno zamijenjen deuterijem, halogenom, C1-6alkilom, C1-6haloalkilom ili -ORa’; naznačen time da svaki Ra’ i Rb’ je neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3- do 7-člani heterocikloalkil, C6-10 aril, ili heteroaril; svaki Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je neovisno N, NH, ili C(RX), naznačen time da svaki Rx kada prisutan je neovisno H, deuterij, halogen, C1-4alkil, -O-C1-4alkil, -OH, -NH2, -NH(C1-4alkil), -NH(fenil), -NH(heteroaril), CN, ili -CF3, s time da barem jedan od Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je N ili NH; i m’ je 2 ili 3; ili odabran iz skupine koja se sastoji od
i naznačen time da M je CH ili N;
 X1 i X1, su neovisno -C(R1a)(R2a)-, -S-, -S(O)-, -S(O)2-,-O- ili -N(Rk’)-;
 svaki R1a i R2a su neovisno H, deuterij, C1-6alkil, C3-6cikloalkil, C6-10 aril, -C(O)ORa’, -C(O)NRa’Rb’, -NRa’Rb’, -SRa’, -S(O)Ra’, -S(O)NRa’, -S(O)2Ra’, -S(O)2NRa’ ili -ORa’ naznačen time da svaki vodikov atom u C1-6alkilu je neovisno opcionalno zamijenjen deuterijem, halogenom, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, NHC(O)C1-4alkilom, -N(C1-4alkil)C(O)C1-4alkilom, -NHC(O)NHC1-4alkilom, -N(C1-4alkil)C(O)NHC1-4alkilom, -NHC(O)N(C1-4alkil)2,-N(C1-4alkil)C(O)N(C1-4alkil)2 , -NHC(O)OC1-4alkilom, -N(C1-4alkil)C(O)OC1-4alkilom, -CO2H, -CO2C1-4alkilom, -CONH2, -CONH(C1-4alkil), -CON(C1-4alkil)2, -SC1-4alkilom, -S(O)C1-4alkilom, -S(O)2C1-4alkilom, -S(O)NH(C1-4alkilom), -S(OhNH(C1-4alkil), -S(O)N(C1-4alkil)2, -S(O)2N(C1-4alkil)2, C3-6cikloalkilom, ili 3-do 7-člani heterocikloalkilom; R3a i R3b su svaki neovisno H, fluoro, kloro, bromo, metil, etil, propil, izopropil, metoksi, etoksi, izopropoksi, -CN, ili -CF3; R7a je H, C1-6alkil ili 3-to 7-člani heterocikloalkil, naznačen time da svaki vodikov atom u C1-6alkilu ili 3-do 7-članom heterocikloalkilu je neovisno opcionalno zamijenjen halogenom, -OH, -OC1-4alkilom, -NH2, -NH(C1-4alkil), -N(C1-4alkil)2, -CO2H, -CO2C1-4alkilom, -CONH2, - CONH(C1-4alkil), -CON(C1-4alkil)2, cikloalkilom, ili monocikličkim heterocikloalkilom; svaki Rk’ je neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3-do 7-člani heterocikloalkil, C6-10 aril, ili mono- ili biciklički heteroaril; naznačen time da svaki vodikov atom u C1-6alkilu, C2-6alkenilu, C2-6alkinilu, C3-6cikloalkilu, 3-do 7-članom heterocikloalkilu, C6-10 arilu, ili mono- ili bicikličkom heteroarilu u Rk’ je neovisno opcionalno zamijenjen deuterijem, halogenom, C1-6alkilom, C1-6haloalkilom ili -ORa’; naznačen time da svaki Ra’ i Rb’ je neovisno H, deuterij, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-6cikloalkil, 3- do 7-člani heterocikloalkil, C6-10 aryl, ili heteroaril; svaki Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je neovisno N, NH, ili C(Rx), naznačen time da je svaki Rx kad prisutan je neovisno H, deuterij, halogen, C1-4alkil, -O-C1-4alkil, -OH, -NH2, -NH(C1-4alkil), -NH(fenil), -NH(heteroaril), CN, ili -CF3, s tim da barem jedan od Z1, Z2, Z3, Z4, Z5, Z6 ili Z7 je N ili NH; i m’ je 2 ili 3; ili njegova farmaceutski prihvatljiva sol.
3. Spoj temeljem zahtjeva 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da Z1, Z4 i Z7 su N, i Z2, Z3, Z5 i Z6 su C(RX), s tim da je svaki Rx kad prisutan je H.
4. Spoj temeljem zahtjeva 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da M je CH, Z1, Z4 i Z7 su N, i Z2, Z3, Z5 i Z6 su C(RX), s tim da je svaki Rx kad prisutan je H.
5. Spoj temeljem zahtjeva 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da M je CH, Z1, Z4 i Z7 su N, Z2, Z3, Z5 i Z6 su C(RX), s tim da je svaki Rx kad prisutan je H, i X1 je -N(Rk’)-.
6. Spoj temeljem zahtjeva 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da M je CH, Z1, Z4 i Z7 su N, Z2, Z3, Z5 i Z6 su C(RX), s tim da je svaki Rx kad prisutan je H, X1 je -N(Rk’)-, i X1, je -O-.
7. Spoj temeljem zahtjeva 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da M je CH, Z1, Z4 i Z7 je N, Z2, Z3, Z5 i Z6 su C(RX), s tim da je svaki Rx kad prisutan je H, X1 je -C(R1a)(R2a)-, i X1, je -O-. 

8. Spoj temeljem bilo kojeg zahtjeva 1 do 7, ili njegova farmaceutski prihvatljiva sol, naznačen time da je Rk’ iz skupine koja se sastoji od H, metil, etil, propyl, izopropil, ciklopropil, 2-hidroksietil, 2-hidroksi-2-metil-propil, i N-metil-pirol-3-il.
9. Spoj temeljem bilo kojeg zahtjeva 1 do 8, ili njegova farmaceutski prihvatljiva sol, naznačen time da je Rk’ je H ili metil.
10. Spoj temeljem zahtjeva 1 naznačen time da je odabran iz skupine koja se sastoji od (13R)-5,13-dimethil-6,7-dihidro-13H-1,15-etenopirazol[4,3f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-11-fluoro-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol [4,3f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 11-fluoro-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-12-kloro-11-fluoro-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-12-kloro-11-fluoro-5-(2-hidroksietil)-13-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-5-(2-hidroksetil)-13-metiyl-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 2-[(13R)-12-kloro-11-fluoro-13-metil-4-okso-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-5(4H)-il]acetamid; 2-[12-kloro-11-fluoro-13-metil-4-okso-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-5(4H)-il]acetamid; (13R)-12-kloro-11-fluoro-13-metil-5-(pirolidin-2-ilmetil)-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-13-metil-5-(pirolidin-2-ilmethil)-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-12-kloro-11-fluoro-7-(hidroksimetil)-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-7-(hidroksimetil)-5,13-dimetil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13S)-11-fluoro-13-(fluorometil)-5-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 11-fluoro-13-(fluorometil)-5-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-13-ciklopropil-11-fluoro-5-metil-6,7-dihidro-13H-1,15-etenopirazol [4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 13-ciklopropil-11 -fluoro-5-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-11-fluoro-13-metil-6,7-dihidro-13H-1,15-etenopirazol [4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 11-fluoro-13-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (13R)-12-kloro-11-fluoro-13-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-13-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-6-metil-6,7-dihidro-13H-1, 15-etenoprazol[4,3- f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-7-metil-6,7-dihidro-13H-1,15-etenopirazol[4,3-f][1,10,4,8]benzodioksadiazaciklotridecin-4(5H)-one; (8R)-9-kloro-10-fluoro-8-metil-15,16-dihidro-8H-3,6-etenoimidazo[5,1-f][1,10,4,7,8]benzodioksatriazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-8-metil-15,16-dihidro-8H-3,6-etenoimidazo[5,1-f][1,10,4,7,8]benzodioksatriazaciklotridecin-17(14H)-one; (7R)-8- kloro-9-fluoro-7-metil-14,15-dihidro-2H,7H-3,5-(azenometheno)pirol[3,4-f][1,10,4,8]benzodioksadiazaciklotridecin-16(13H)-one; 8-kloro-9-fluoro-7-metil-14,15-dihidro-2H, 7H-3,5-(azenometeno)pirol[3,4- f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; (5R)-3-fluoro-5-metil-14, 15-dihidro-5H, 10H-9,7-(azenometeno)pirido[2,3-k]pirol[3,4-d][1,10,3,7]dioksadiazaciklotridecin-12(13H)-one; 3-fluoro-5-metil-14,15-dihidro-5H,10H-9,7-(azenometeno)pirido[2,3-k]pirolo[3,4-d][1,10,3,7]dioksadiazaciklotridecin-12(13H)-one; (5R)-3-fluoro-5,16-dimetil-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oksatriazaciklotridecin-12(10H)-one; 3-fluoro-5,16-dimetil-13,14,15,16-tetrahidro-5H-9,7-(azenometeno)pirido[2,3-k]pirolo[3,4-d][1,3,7,10]oksatriazaciklotridecin-12(10H)-one; (13R)-12-kloro-11-fluoro-5,13-dimetil-6,7-dihidro-2H,13H-1,15-(azenometeno)pirolo[3,4-f][1,10,4]benzodioksazaciklotridecin-4(5H)-one; 12- kloro-11-fluoro-5,13-dimetil-6,7-dihidro-2H, 13H-1,15-(azenometeno)pirolo[3,4-f][1,10,4]benzodioksazaciklotridecin-4(5H)-one; (7R)-8-kloro-9-fluoro-7,15-dimetil-14,15-dihidro-2H,7H-3,5-(azenometheno)pirazolo[3,4-f][1,10,4]benzodioksazaciklotridecin-16(13H)-one; 8-kloro-9-fluoro-7,15-dimetil-14,15-dihidro-2H,7H-3,5-(azenometeno)pirazolo[3,4-f][1,10,4]benzodioksazacilotridecin-16(13H)-one; 11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (13R)-12-kloro-11-fluoro-13,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-13,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-5,14-dimetil-6,7,13,14-tetrahidro-15,1-(azenometeno)pirazolo[4,3-f][1,4,10]benzoksadiazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-14-metil-6,7,13,14-tetrahidro-15,1-(azenometeno)pirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-(azenometeno)pirolo[3,2-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-(azenometeno)pirolo[3,2-f][1,4,10]benzoksadiazaciklotridecin-4(5H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-3,6-etenoimidazo[5,1-f][1,4,7,8,10]benzoksa- tetraazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-6,3-(azenometeno)imidazo[5,1-f][1,4,7,8,10]benzoksxatetraazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-6,3-(azenometeno)imidazo[5,1-f][1,4,7,10]benzoksatriazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-3,6-(azenometeno)pirolo[2,1-f][1,4,7,10]benzoksatriazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-3,6-(azenometeno)imidazo[2,1-f][1,4,7,10]benzoksatriazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-3,6-eteno[1,2,4]triazolo[3,4- f][1,4,7,8,10]benzoksatetraazaciklotridecin-17(14H)-one; 9-kloro-10-fluoro-7-metil-7,8,15,16-tetrahidro-6,3-(azenometeno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoksatriazaciklotridecin-17(14H)-one; 8-kloro-9-fluoro-6-metil-6,7,14,15-tetrahidro-2H-3,5-(azenometeno)pirolo[3,4-f][1,4,8,10]benzoksatriazaciklotridecin-16(13H)-one; 8-kloro-9-fluoro-6-metil-6,7,14,15-tetrahidro-2H-3,5-(azenometeno)pirazolo[3,4-f][1,4,8,10]benzoksatriazaciklotridecin-16(13H)-one; 8-kloro-9-fluoro-6-metil-6,7,14,15-tetrahidro-2H-3,5-(azenometeno)pirazolo[3,4- f][1,4,10]benzoksadiazaciklotridecin-16(13H)-one; 12-kloro-11-fluoro-5,14-dimetil-6,7,13,14-tetrahidro-2H-1,15-(azenometeno)pirolo[3,4-f][1,4,10]benzoksadiazaciklotridecin-4(5H)-one; (8R)-10-fluoro-8,16-dimetil-15, 16-dihidro-8H-3,6-etenoimidazo[5,1-f][1,10,4,7,8]benzodioksatriazaciklotridecin-17(14H)-one; 10-fluoro-8,16-dimetil-15,16-dihidro-8H-3,6-etenoimidazo[5,1-f][1,10,4,7,8]benzodioksatriazaciklotridecin-17(14H)-one; (7R)-9-fluoro-7,15-dimetil-14,15-dihydro-2H,7H-3,5-(azenometeno)pirolo[3,4-f][1,10,4,8]benzodioksadiazaciklotridecin-16(13H)-one; 9-fluoro-7,15-dimetil-14,15-dihidro-2H,7H-3,5-(azenometeno)pirolo[3,4-f][1,10,4,8]benzodioksadiazaciklotridecin-16(13H)-one; 12-kloro-11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-3,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 10-fluoro-8-metil-15,16-dihidro-8H-3,6-etenoimidazo[5,1-f][1,10,4,7,8]benzodioksatriazaciklotridecin-17(14H)-one; 10-fluoro-7-metil-7,8,15,16-tetrahidro-3,6-etenoimidazo[5,1-f][1,4,7,8,10]benzoksatetraazaciklotridecin-17(14H)-one; 14-etil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-propil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-(propan-2-il)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 14-ciklopropil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-(2-hidroksietil)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-6,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (13R)-11-fluoro-13-metil-6,7,13,14-tetrahdro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-kloro-11-fluoro-13-metil-6,7,13,14-tetrahidro-1,15-etenoprazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-metil-4-okso-4,5,6,7,13,14-heksahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecine-7-karboksiamid; 11-fluoro-7-(hidroksimetil)-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-metil-4-okso-4,5,6,7,13,14-heksahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecine-7-karboksamid; 11-fluoro-7-(hidroksimetil)-13-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-4-okso-4,5,6,7,13,14-heksahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecine-7-karboksamid; 11-fluoro-7-(hidroksimetil)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; metil 11-fluoro-4-okso-4,5,6,7,13,14-heksahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecine-13-karboksilat; 11-fluoro-4-okso-4,5,6,7,13,14-heksaidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecine-13-karboksamid; 11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f]pirido[3,2-1][1,4,8,10]oksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f]pirido[3,2-l][1,4,8,10]oksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-(propan-2-il)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f]pirido[3,2-l][1,4,8,10]oksatriazaciklotridecin-4(5H)-one; 13-ciklopropil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f]pirido[3,2-l][1,4,8,10]oksatriazaciklotridecin-4(5H)-one; 13-ciklopropil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3- f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-(propan-2-il)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-6,7-dihidro-13H-1,15-etenopirazolo[4,3-f][1,10,4,8]benzoksatiadiazaciklotridecin-4(5H)-one; 11-fluoro-6,7-dihidro-13H-1,15-etenopirazolo[4,3-f][1,10,4,8]benzoksatiadiazaciklotridecin-4(5H)-one 14,14-dioksid; 6,7-dihidro-13H-1,15-etenopirazolo[4,3-f][10,1,4,8]benzoksatiadiazaciklotridecin-4(5H)-one; 14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[3,4-f] [1,4,8,10]benzothiatriazaciklotridecin-4(5H)-one;
 13-metil-6,7,13,14-tetrahidro-1,15-etanopirazolo[4,3-f][1,4,8,10]benzotiatriazaciklotridecin-4(5H)-one;
 11-fluoro-6,7-dihidro-5H-1,15-etenopirazolo[3,4-e][11,1,2,4,8]benzoksatiatriazaciklotridecin-4(14H)-one 13,13-dioksid; 11-fluoro-14-metil-6,7-dihidro-5H-1,15-etenopirazolo[3,4-e][11,1,2,4,8]benzoksatiatriazaciklotridecin-4(14H)-one 13,13-dioksid; 12-fluoro-15-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; 12-fluoro-14-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; (14R)-12-fluoro-14-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; 11-fluoro-7,14-dimetil-4,5,6,7,13,14-heksahidro-8H-1,15-etenopirazolo[3,4-e][2,4,10]benzotriazaciklotridecin-8-one; 11-fluoro-7,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[3,4-e][7,2,4,10]benzoksatriazaciklotridecin-8(5H)-one; 11-fluoro-7,14-dimetil-4,5,6,7,13,14-heksahidro-8H-1,15-etenopirazolo[3,4-e][2,4,7,10]benzotetraazaciklotridecin-8-one; 11-fluoro-4,7,14-trimetil-4,5,6,7,13,14-heksahidro-8H-1,15-etenopirazolo[3,4-e][2,4,7,10]benzotetraazaciklotridecin-8-one; 11-fluoro-7,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[3,4-e][7,2,4,10]benzotiatriazaciklotridecin-8(5H)-one; 11-fluoro-7,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[3,4-e][7,2,4,10]benzotiatriazaciklotridecin-8(5H)-one 4,4-dioksid; 12-fluoro-8,15-dimetil-5,6,7,8,14,15-heksahidro-9H-1,16-etenopirazolo[3,4-e][7,2,4,8,11]benzotiatetraazaciklotetradecin-9-one 4,4-dioksid; 11-kloro-13-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3- f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 13-etil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 13-ciklobutil-11-fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-1[1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-metil(6,6,7,7-2H4)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-fenil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 13-(ciklopropilmetil)-11- fluoro-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (7R,14R)-12-fluoro-7-hydroksi-14-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; (7S,14R)-12-fluoro-7-hidroksi-14-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; (7R,13R)-11-fluoro-7,13-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazacidotridedn-4(5H)-one; (7S,13R)-11-fluoro-7,13-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (7R)-11-fluoro-7,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (6R)-11-fluoro-6,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-fluoro-7-hidroksi-15-metil-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]ben- zoksatriazaciklotetradecin-4-one; (7S)-11-fluoro-7,14-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-13-(hidroksimetil)-6,7,13,14-tetrahidro-1,15-ete-nopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-fluoro-14-(hidroksimetil)-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9,11]benzoksatriazaciklotetradecin-4-one; 11-fluoro-13,14-dimetil- 6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-(2-hidroksi-2-metilpropil)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f)[1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 12-fluoro-5,6,7,8,14,15-heksahidro-4H-1,16-etenopirazolo[4,3-g][1,5,9]benzoksadiazaciklotetradecin-4-one; 11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzotiatriazaciklotridecin- 4(5H)-one; 11-fluoro-14-(1-metilpirolidin-3-il)-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; 11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzotiatriazaciklotridecin-4(5H)-one 8-oksid; 11-fluoro-14-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzotiatriazaciklotridecin-4(5H)-one 8,8-dioksid; (7S)-11-fluoro-7-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8]benzoksadiazaciklotridecin-4(5H)-one; (6S,13R)-11-fluoro-6,13-dimetil-6,7,13, 14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (6R,13R)-11-fluoro-6,13-dimetil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3-f][1,4,8,10]benzoksatriazaciklotridecin-4(5H)-one; (7S,13S)-11-fluoro-13-(hidroksimetil)-7-metil-6,7,13,14-tetrahidro-1,15-etenopirazolo[4,3- f][1,4,8,10]benzoksathazaciklotridecin-4(5H)-one; i 11-fluoro-6,7-dihidro-13H-1,15-etenopirazolo[4,3-f][1,10,4,8]benzoksatiadiazaciklotridecin-4(5H)-one; ili njegova farmaceutski prihvatljiva sol.
11. Spoj temeljem zahtjeva 1 naznačen time da je formule: ili ili ili ili ili ili njegove farmaceutski prihvatljive soli.
12. Farmaceutska mješavina naznačena time da se sastoji (a) od barem jednog spoja temeljem bilo kojeg zahtjeva 1 do 11, ili njegove farmaceutski prihvatljive soli, i (b) farmaceutski prihvatljive pomoćne tvari.
13. Spoj temeljem bilo kojeg zahtjeva 1 do 11, ili njegova farmaceutski prihvatljiva sol, za uporabu u liječenju raka, boli, neuroloških bolesti, autoimunih bolesti, ili upala kod osoba koji trebaju takvo liječenje.
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