HRP20202058T1 - Pirazolo[1,5-a]pirimidini korisni kao inhibitori atr kinaze za liječenje karcinoma - Google Patents

Pirazolo[1,5-a]pirimidini korisni kao inhibitori atr kinaze za liječenje karcinoma Download PDF

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HRP20202058T1
HRP20202058T1 HRP20202058TT HRP20202058T HRP20202058T1 HR P20202058 T1 HRP20202058 T1 HR P20202058T1 HR P20202058T T HRP20202058T T HR P20202058TT HR P20202058 T HRP20202058 T HR P20202058T HR P20202058 T1 HRP20202058 T1 HR P20202058T1
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independently selected
cancer
optionally
ring
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Nadia AHMAD
Dean Boyall
Jean-Damien Charrier
Chris Davis
Rebecca Davis
Steven Durrant
Gorka ETXEBARRIA I JARDI
Damien Fraysse
Juan-Miguel Jimenez
David Kay
Ronald Knegtel
Donald Middleton
Michael ODONNELL
Maninder PANESAR
Francoise Pierard
Joanne Pinder
David Shaw
Pierre-Henri Storck
John Studley
Heather Twin
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Vertex Pharmaceuticals Inc.
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Claims (33)

1. Spoj koji ima formulu I: [image] ili njegovu farmaceutski prihvatljivu sol, naznačen time, da: R1 je neovisno odabran od -C(J1)2CN, halo, -(L)k-W ili M; R9 je neovisno odabran od H, -C(J1)2CN, halo, -(L)k-W ili M; J1 je neovisno odabran od H ili C1-2alkila; ili dva pojavljivanja J1, zajedno s atomom ugljika za kojeg su vezani, tvore 3-4-eročlani po izboru supstituirani karbociklički prsten; k je 0 ili 1; M i L su C1-8alifatski spoj u kojem su do tri metilenske jedinice po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-, svaki M i L1 je po izboru supstituiran s 0-3 pojavljivanja JLM; JLM je neovisno odabran od halo, -CN ili C1-4alifatskog lanca u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; W je neovisno odabran od 3-7-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog monocikličkog prstena koji ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski biciklički prsten koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; u kojem je W po izboru supstituiran s 0-5 pojavljivanja JW; JW je neovisno odabran od -CN, halo, -CF3; C1-4alifatski spoj u kojem su do dvije metilenske jedinice po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; ili 3-6-eročlanim nearomatskim prstenom koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; R2 je neovisno odabran od H; halo; -CN; NH2; C1-2alkila po izboru supstituiranog s 0-3 pojavljivanja fluora; ili C1-3alifatskim lancem u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n; R3 je neovisno odabran od H; halo; C1-4alkilom po izboru supstituiranim s 1-3 pojavljivanja halo; C3-4cikloalkil; 3-4-eročlani heterociklil; -CN; ili C1-3alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lnaca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n; R4 je neovisno odabran od Q1 ili C1-10alifatskog lanca u kojem su do četiri metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; svaki R4 je po izboru supstituiran s 0-5 pojavljivanja JQ; ili R3 i R4, uzeti zajedno s atomima za koje su vezani, tvore 5-6-eročlani aromatski ili nearomatski prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; prsten formiran od R3 i R4 je po izboru supstituiran s 0-3 pojavljivanja JZ; Q1 je neovisno odabran od 3-7-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog monocikličkog prstena, 3-7-eročlani prsten ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog bicikličkog prstena koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; JZ je neovisno odabran od C1-6alifatskog spoja, =O, halo ili →O; JQ je neovisno odabran od -CN; halo; =O; Q2; ili C1-8alifatskog lanca u kojem su do tri metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; svako pojavljivanje JQ je po izboru supstitirano s 0-3 pojavljivanja JR; ili dva pojavljivanja JQ na istom atomu, uzeti zajedno s atomom za kojeg su vezani, tvore 3-6-eročlani prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; pri čemu je prsten koji je formiran putem dva pojavljivanja JQ po izboru supstituiran s 0-3 pojavljivanja JX; ili dva pojavljivanja JQ, zajedno s Q1, tvore 6-10-eročlani zasićeni ili djeomično nezasićeni premošteni prstenski sustav; Q2 je neovisno odabran od 3-7-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog monocikličkog prstena koji ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog bicikličkog prstena koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; JR je neovisno odabran od -CN; halo; =O; →O; Q3; ili C1-6alifatskog lanca u kojem su do tri metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; svaki JR je po izboru supstituiran s 0-3 pojavljivanja JT; ili dva pojavljivanja JR na istom atomu, zajedno s atomom za zakojeg su vezani, tvore 3-6-eročlani prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; u kojem prsten koji je formiran s dva pojavljivanja JR po izboru supstituiran s 0-3 pojavljivanja JX; ili dva pojavljivanja JR, zajedno s Q2, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prstenski sustav; Q3 je 3-7-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski monociklički prsten koji ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski biciklički prsten koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; JX je neovisno odabran od-CN; =O; halo; ili C1-4alifatskog lanca u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; JT je neovisno odabran od halo, -CN; →O; =O; -OH; C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n-; ili 3-6-eročlani nearomatski prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; svako pojavljivanje JT je po izboru supstituirano s 0-3 pojavljivanja JM; ili dva pojavljivanja JT na istom atomu, zajedno s atomom za kojeg su vezani, tvore 3-6-eročlani presten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; ili dva pojavljivanja JT, zajedno s Q3, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prstenski sustav; JM je neovisno odabran od halo ili C1-6alifatskog spoja; n je 0, 1 ili 2; i R je neovisno odabran od H ili C1-4alifatskog spoja.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da (I) R9 je H; ili: u kojem je (II) R9 je M; po izboru kada M je C1-8alifatski spoj u kojem su do tri metilenske jedinice po izboru zamijenjene s -O- ili -NR-; po izboru i kada je, M je C1-4alkil, -(C1-4alkil)O(C1-3alifatski spoj), -(C1-3alkil)OH, -O(C1-4alkil)N(C1-2alkil)2, -NH(C1-4alkil) ili -(C1-4alkil)NH(C1-4alkil); po izboru i kada je M je C1-4alkil.
3. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-2, naznačeno time, da R9 je -(L1)k-W; po izboru: u kojem (I) k je 0; ili: u kojem (II) k je 1; po izboru gdje L je C1-8alifatski spoj u kojem su do tri metilenske jedinice po izboru zamijenjene s -O- ili -NR-; po izboru i kada L je -O-, -O(C1-4alifatski spoj)- ili -NR(C1-3alkil)-.
4. Spoj u skladu s patentnim zahtjevom 1, naznačeno time, da (I) W je 3-7-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski monociklički prsten koji ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru u kojem W je 3-7-eročlani heterociklil, po izboru i kada je W neovisno odabran od pirolidinila, piperidinila, piperazinila, oksetanila ili azetidinila; ili: u kojem (II) W je 7-12-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski biciklički prsten koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora.
5. Spoj u skladu s patentnim zahtjevom 3 ili patentnim zahtjevom 4, naznačeno time, da (I) JW je odabran od C1-3alkila ili CF3; ili: u kojem (II) dva pojavljivanja JW na istom atomu, zajedno s atomom za kojeg su vezani, tvore 3-6-eročlani prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru kada je prsten formiran putem dva pojavljivanja JW na istom atomu je oksetanil.
6. Spojevi u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačeno time, u kojem (I) R1 je fluor; ili: u kojem (II) R1 je -CH2CN, -C(CH3)2CN ili -CH(C1-2alkil)CN; ili: u kojem (III) R1 je kloro.
7. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 6, naznačeno time, R2 je neovisno odabran od -CF3, -NH(C1-2alkil), klor ili H; po izboru: u kojem (I) R2 je H; ili: u kojem (II) R2 je -kloro.
8. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačeno time, R3 je neovisno odabran od H, kloro, fluoro, CHF2, -CN, ciklopropila ili C1-4alkil; po izboru: u kojem R3 je neovisno odabran od H, kloro ili fluoro; po izboru i u kojem: gdje (I) R3 je H; ili: gdje (II) R3 je kloro; ili: gdje (III) R3 je fluoro.
9. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 8, naznačeno time, da R4 je neovisno odabran od: -O-; [image] ili -CH2-R7 , u kojem: -O- je supstituiran s jednim JQ; Prsten A je neovisno odabran od 3-7-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog monocikličkog prstena koji ima 1-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog bicikličkog prstena koji ima 1-5 heteroatoma odabrana od kisika, dušika ili sumpora; Prsten B je neovisno odabran od 3-7-eročlanog potpuno zasićenog, djelomično nezasićenog ili aromatskog monocikličkog prstena koji ima 0-3 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski biciklički prsten koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; R6 je H; R7 je neovisno odabran od H ili C1-8alifatskog lanca u kojem su do tri metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -S-, -C(O)- ili -S(O)n-; i p je 0 ili 1.
10. Spoj u skladu s patentnim zahtjevom 9, naznačeno time, da R4 je -O-: po izboru: u kojem (I) JQ je neovisno odabran od -(C1-4alkil), -(C1-4alkil)N(C1-4alkil)2,-(C1-3alkil)O(C1-2alkil)N(C1-3alkil)2, (C1-4alkil)OH, -(C1-4alkil)NH2 ili -(C1-4alkil)O(C1-4alkil); ili: u kojem (II) JQ je Q2; po izboru: u kojem (i) Q2 je 3-7-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski monociklički prsten koji ima 0-3 heteroatoma odabrana od kisika, sumpora ili dušika; po izboru: u kojem je Q2 neovisno odabran od 5-6-eročlanog arila, 5-6-eročlanog heteroarila, 4-6-eročlanog cikloalifatski spoj ili 3-7-eročlani heterociklil; po izboru i u kojem je: (a) Q2 je neovisno odabran od 4-7-eročlanog cikloalifatskog ili 3-7-eročlanog heterociklila; po izboru u kojem Q2 je 3-7-eročlani heterociklil; po izboru i kada je: Q2 neovisno odabran od pirolidinila, piperidinila, azepanila, pirazolidinila, izoksazolidinila, oksazolidinila, tiazolidinila, imidazolidinila, piperazinila, morfolinila, tiomorfolinila, 1,3-oksazinanila, 1,3-tiazinanila, dihidropiridinila, dihidroimidazolila, 1,3-tetrahidropirimidinila, dihidropirimidinila, 1,4-diazepanila, 1,4-oksazepanila, 1,4-tiazepanila, tetrahidrotiopiranila, tetrahidrofuranila, tetrahidropiranila, azetidinila i oksetanila; po izboru i u kojem je Q2 neovisno odabran od tetrahidrotiopiranila, pirolidinila, piperidinila, piperazinila, tetrahidrofuranila, tetrahidropiranila ili azetidinila; ili: u kojem (b) Q2 je 5-6-eročlani heteroaril; po izboru u kojem je Q2 neovisno odabran od imidazolila, pirolila, piridinila, pirazinila, pirimidinila, pirazolila, 1,2,3-triazolila ili 1,2,4-triazolila; po izboru i kada Q2 je piridinil; ili: u kojem (c) Q2 je 4-6-eročlani cikloalifatski spoj; po izboru u kojem je Q2 je neovisno odabran od ciklobutila ili cikloheksila; ili: u kojem (d) Q2 je fenil; ili: u kojem (ii) Q2 je 7-12-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski biciklički prsten koji ima 0-5 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru u kojem Q2 je 6,7-dihidro-5H-pirolo[1,2-a]imidazol.
11. Spoj u skladu s bilo kojim od patentnih zahtjeva 9 i 10, naznačeno time, da su neovisno odabrani od: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
12. Spoj u skladu s patentnim zahtjevom 9, naznačeno time, da R4 je: [image] po izboru u kojem Prsten A je 3-7-eročlani potpuno zasićeni, djelomično nezasićeni ili aromatski monociklički prsten koji ima 1-3 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru i kada (I) Prsten A je 3-7-eročlani heterociklil; po izbrou u kojem je Prsten A neovisno odabran od pirolidinila, piperidinila, azepanila, pirazolidinila, izoksazolidinila, oksazolidinila, tiazolidinila, imidazolidinila, piperazinila, morfolinila, tiomorfolinila, 1,3-oksazinanila, 1,3-tiazinanila, dihidropiridinila, dihidroimidazolila, 1,3-tetrahidropirimidinila, dihidropirimidinila, 1,4-diazepanila, 1,4-oksazepanila, 1,4-tiazepanila i azetidinila; po izboru i kada je Prsten A neovisno odabran od piperidinila, piperazinila, 1,4-diazepanila, tiomorfolinila, pirolidinila, azepanila, morfolinila; po izboru I kada Prsten A je neovisno odabran od piperazinila ili piperidinila; ili: u kojem (II) Prsten A je 5-eročlani heteroaril; po izboru u kojem je Prsten A neovisno odabran od pirolila, imidazolila, pirazolila, 1,2,3-triazolila ili 1,2,4-triazolila; po izboru i kada je Prsten A eovisno odabran od pirazolila ili imidazolila.
13. Spoj u skladu s patentnim zahtjevom 9, naznačeno time, da ima formulu I-A-1: [image] u kojem: R5 je odabran od C1-4alifatskog spoja, 3-6-eročlanog cikloalkila ili 3-6-eročlanog heterociklila koji ima 1-2 heteroatoma odabrana od kisika ili sumpora; R8 je odabran od H ili C1-3 alkila; ili R5 i R8, zajedno s atomima za koje su vezani, tvore 5-6-eročlani ne-aromatski prsten koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru: u kojem (I) R1 je fluoro; po izboru u kojem R5 je C1-4alifatski spoj; po izboru I kada R5 je neovisno odabran od metila ili etila; ili: u kojem (II) R5 je 3-6-eročlani cikloalkil; po izboru u kojem R5 je ciklopropil; ili: u kojem (III) R5 je 3-6-eročlani heterociklil koji ima 1-2 heteroatoma odabrana od kisika ili sumpora; po izboru u kojem R5 je tetrahidrofuranil ili oksitanil; ili: u kojem (IV) R5 i R6, uzeti zajedno s atomima za koje su vezani, tvore 5-6-eročlani nearomatski prsten koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru: u kojem (i) prsten formiram s R5 i R6 je peteročlani prsten; ili: u kojem (ii) prsten formiram s R5 i R6 je šesteročlani prsten.
14. Spoj u skladu s bilo kojim od patentnih zahtjeva 12 i 13, naznačeno time, da su neovisno odabrani od: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
15. Spoj u skladu s patentnim zahtjevom 9, naznačeno time, da R4 je: [image] po izboru: u kojem p je 1; po izboru i još uz to: u kojem Prsten B je 3-7-eročlani cikloalifatski ili heterociklil prsten koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; po izboru još uz to: u kojem Prsten B je neovisno odabran od ciklopropila, ciklobutila, ciklopentila, cikloheksila, cikloheptila, pirolidinila, piperidinila, azepanila, pirazolidinila, izoksazolidinila, oksazolidinila, tiazolidinila, imidazolidinila, piperazinila, morfolinila, tiomorfolinila, 1,3-oksazinanila, 1,3-tiazinanila, dihidropiridinila, dihidroimidazolila, 1,3-tetrahidropirimidinila, dihidropirimidinila, 1,4-diazepanila, 1,4-oksazepanila, 1,4-tiazepanila, 1,2,3,6-tetrahidropiridina i azetidinila; po izboru još uz to: u kojem Prsten B je piperidinil.
16. Spoj u skladu s patentnim zahtjevom 1, naznačeno time, da je neovisno odabran od: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
17. Farmaceutski pripravak, naznačeno time, da sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 16 i farmaceutski prihvatljivi nosač.
18. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, ili farmaceutski pripravak prema zahtjevu 17, naznačeno time, da je za uporabu u liječenju pacijenata od karcinoma.
19. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, ili farmaceutski pripravak prema zahtjevu 17, za uporabu u skladu s patentnim zahtjevom 18, naznačeno time, da nadalje sadrži primjenu na rečenog pacijenta dodatnog terapijskog sredstva neovisno odabranog od sredstva za oštećenje DNK; u kojem je rečeno dodatno terapijsko sredstvo prikladno za bolest koja se liječi; i rečeno dodatno terapijsko sredstvo se daje zajedno s rečenim spojem u obliku jedne doze ili posebno od rečenog spoja kao dio višestrukog oblika doziranja; po izboru: u kojem je (I) navedeno sredstvo koje oštećuje DNK odabrano od liječenja kemoterapijom ili zračenjem; proizvoljno pri čemu je sredstvo za oštećenje DNK sredstvo za alkiranje odabrano od Temozolomida; ili: u kojem se (II) navedeno sredstvo koje oštećuje DNK neovisno bira između ionizirajućeg zračenja, radiomimetičkog neokarzinostatina, sredstva za platiniranje, inhibitora Topo I, inhibitora Topo II, antimetabolita, alkilirajućeg sredstva, alkil sulfonata ili antibiotika; proizvoljno u kojem se (i) navedeno sredstvo za oštećivanje DNK neovisno bira između ionizirajućeg zračenja, sredstva za platinizaciju, inhibitora Topo I, inhibitora Topo II ili antibiotika; ili: u kojem se (ii) spomenuto sredstvo za oštećivanje DNK neovisno bira između ionizirajućeg zračenja, sredstva za platiniranje i Topo I inhibitora, Topo II inhibitora, antimetabolita, alkilirajućeg sredstva ili alkil sulfonata; po želji: u kojem se (a) navedeno sredstvo za platiniranje neovisno bira između Cisplatina, Oksaliplatina, Karboplatina, Nedaplatina, Lobaplatin, triplatin tetranitrata, pikoplatina, satraplatina, ProLindaca i Aroplatina; rečeni inhibitor Topo I odabran je od Camptothecina, Topotecana, Irinotecan / SN38, Rubitecana i Belotecana; spomenuti inhibitor Topo II odabran je između Etopozida, Daunorubicina, Doxorubicina, Aclarubicina, Epirubicina, Idarubicina, Amrubicina, Pirarubicina, Valrubicina, Zorubicina i Tenipozida; spomenuti antimetabolit je odabran između Aminopterina, Metotreksata, Pemetrekseda, Raltitrekseda, Pentostatina, kladribina, klofarabina, fludarabina, tioguanina, merkaptopurina, fluorouracila, kapecitabina, tegafura, Carmofura, Floxuridina, Cytarabina, Gemcitabina, Azacitidina i Hydroxyuree; odabrano je spomenuto alkilirajuće sredstvo od Mekloretamina, Ciklofosfamida, Ifosfamida, Trofosfamida, Chlorambucila, Melphalana, Prednimustina, Bendamustina, Uramustina, Estramustina, Karmustina, Lomustina, Semustina, Fotemustina, Nimustina, Ranimustina, Streptozocina, Busulfana, Mannosulfana, Treosulfana, Karbokina, ThioTEPA, triazikina, trietilenmelamina, Prokarbazina, Dakarbazina, Temozolomida, Altretamina, Mitobronitola, Aktinomicina, Bleomicina, Mitomicina i Plicamycin; po izobru: u kojem je (aa) navedeno sredstvo za platiniranje neovisno odabrano između Cisplatina, Oksaliplatina, Karboplatina, Nedaplatina ili Satraplatina; navedeni inhibitor Topo I odabran je između kamptotecina, topotekana, irinotekana / SN38, rubitekana; rečeni Topo II inhibitor odabran od Etoposida; rečeni antimetabolit je odabran od metotreksata, pemetrekseda, Thioguanina, Fludarabina, Cladribina, Cytarabina, gemcitabina, 6-Mercaptopurina ili 5-Fluorouracila; rečeno alkilirajuće sredstvo je odabrano od dušične gorušice, nitrosouree, triazena, alkil sulfonata, prokarbazina ili aziridina; i spomenuti antibiotik odabran je iz obitelji Hydroxyurea, Anthracyclines, Anthracenediones ili Streptomyces; ili: pri čemu se (bb) navedeno sredstvo za oštećivanje DNK neovisno bira između sredstva za platinizaciju ili ionizirajućeg zračenja; proizvoljno gdje je dodatno terapijsko sredstvo Gemcitabin, a karcinom je rak gušterače; ili: pri čemu je (cc) kemoradijacija gemcitabin i zračenje; ili: pri čemu (b) je antimetabolit gemcitabin; ili: pri čemu (c) sredstvo koje oštećuje DNK je ionizirajuće zračenje; ili: pri čemu (d) sredstvo za oštećivanje DNK je sredstvo za platiniranje neovisno odabrano između Cisplatina ili Carboplatina; ili: pri čemu je (e) sredstvo koje oštećuje DNK inhibitor Topo II odabran između Etopozida; ili: pri čemu se (f) sredstvo za oštećivanje DNK neovisno bira između jednog ili više od sljedećeg: Cisplatin, Carboplatin, gemcitabin, etopozid, temozolomid ili ionizirajuće zračenje; po izboru pri čemu dodatna terapijska sredstva biraju između jednog ili više od sljedećeg: gemcitabin, cisplatin ili karboplatin i etopozid.
20. Spoj ili njegova prihvatljiva farmaceutska sol u skladu s bilo kojim od patentnih zahtjeva 1 do 16 ili farmaceutski pripravak u skladu s patentnim zahtjevom 17 za uporabu u skladu s patentnim zahtjevom 18 ili patentnim zahtjevom 19, naznačeno time, da je rečeni karcinom solidni tumor odabran od sljedećih tipova karcinoma: oralnog: usne šupljine, ustiju, jezika, ustiju, ždrijela; srčanog: sarkoma (angiosarkom, fibrosarkom, rabdomiosarkom, liposarkom), miksom, rabdomiom, fibrom, lipom i teratom; plućnog: bronhogeni karcinom (skvamozni ili epidermoidni, nediferencirane male stanice, nediferencirane velike stanice, adenokarcinom), alveolarni (bronhiolarni) karcinom, bronhijalni adenom, sarkom, limfom, hondromatozni hamartom, mezoteliom; gastrointestinalnog: jednjak (skvamozni karcinom, grkljan, adenokarcinom, leiomiosarkom, limfom), želuca (karcinom, limfom, leiomiosarkom), gušterača (duktalni adenokarcinom, insulinom, glukagonom, gastrinom, karcinoidni tumori, tanki čvor, vipoma karcinom, limfom, karcinoidni tumori, Karposijev sarkom, leiomiom, hemangiom, lipom, neurofibroma, fibroma), debelo crijevo ili debelo crijevo (adenokarcinom, tubularni adenom, vilozni adenom, hamartom, leiomiom), debelo crijevo, debelo crijevo-rektum, kolorektal; rektum, genitourinarnog trakta: bubrega (adenokarcinom, Wilmov tumor [nefroblastom], limfom), mokraćnog mjehura i mokraćne cijevi (skvamozni karcinom, karcinom prijelaznih stanica, adenokarcinom), prostate (adenokarcinom, sarkom), testisa (seminom, teratom, embrionalni karcinom, teratokarcinom, horiokarcinom, sarkom, karcinom intersticijskih stanica, fibroma, fibroadenom, adenomatoidni tumori, lipomi); jetara: hepatom (hepatocelularni karcinom), kolangiokarcinom, hepatoblastom, angiosarkom, hepatocelularni adenom, hemangiom, bilijarni prolazi; kostiju: osteogeni sarkom (osteosarkom), fibrosarkom, maligni fibrozni histiocitom, hondrosarkom, Ewingov sarkom, maligni limfom (sarkom retikulumskih stanica), multipli mijelom, kordom malignog tumora gigantskih stanica, osteohronfroma (osteokartilagični kostondomagijski kostomandomagijski kostomandomagijski kosto-bronhomagijski kosto-bronhomagijski kosto-bronhomagijski kosto-magni kostoni bronhomani bronhomani kosti tumori osteoma i divovskih stanica; živčanog sustava: lubanja (osteom, hemangiom, granulom, ksantom, osteitis deformans), moždane ovojnice (meningiom, meningiosarkom, gliomatoza), mozga (astrocitom, meduloblastom, gliom, ependimom, germinom [pinealoma], glioblaligoma genomblastomoma multiformni glioblastomahnom, multiformni glioblastomahnom, glioblastomahnom, glioblastomahnom, glioblastomahnom, glioblastodomom, glioblastodomom. kongenitalni tumori), neurofibrom leđne moždine, meningiom, gliom, sarkom); ginekološkog/ženskog: maternice (karcinom endometrija), cerviksa (karcinom vrata maternice, predtumorska cervikalna displazija), jajnici (karcinom jajnika [serozni cistadenokarcinom, mucinozni cistadenokarcinom, nerazvrstani karcinom], tumori granulosatekalnih stanica, tumori staničnih ćelija Sertoli-Leydig, disgerminom, zloćudni teratva disgerminom, maligni teratva skvamozni karcinom, intraepitelni karcinom, adenokarcinom, fibrosarkom, melanom), vagina (bistrocelularni karcinom, skvamozni karcinom, botrioidni sarkom (embrionalni rabdomiosarkom), jajovodne cijevi (karcinom), dojka; kože: karcinom maligne stanice, karcinom skvamoznih stanica, Karposijev sarkom, keratoakantom, molekularni displastični nevusi, lipomi, angiomi, dermatofibromi, keloidi, psorijaza, štitnjača: papilarni karcinom štitnjače, folikularni karcinom štitnjače; medularni karcinom štitnjače, multipla endokrina neoplazija tip 2A, multipla endokrina vrsta rak štitnjače, feokromocitom, paragangliom i nadbubrežne žlijezde: neuroblastom: po izboru: pri čemu se spomenuti rak bira između karcinoma pluća ili gušterače; po izboru: pri čemu je spomenuti rak rak pluća; po izboru: pri čemu je rak pluća karcinom pluća malih stanica ili rak pluća ne-malih stanica; po izboru: pri čemu (I) rak pluća je rak pluća malih stanica, a dodatna terapijska sredstva su cisplatin i etopozid; ili gdje je (II) rak pluća ne-malih stanica, a dodatna terapijska sredstva su gemcitabin i cisplatin; po izboru: pri čemu (i) je karcinom pluća rak nemalih stanica skvamozni karcinom pluća malih stanica ili: pri čemu (ii) je terapija karcinomom gemcitabin i zračenje.
21. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16 ili farmaceutski pripravak u skladu s patentnim zahtjevom 17 za uporabu u skladu s patentnim zahtjevom 18 ili patentnim zahtjevom 19, naznačeno time, da je (I) navedeni karcinom odabran od raka pluća, raka glave i vrata, raka gušterače, želuca ili mozga; ili: pri čemu je (II) navedeni karcinom odabran od raka pluća ne-malih stanica, raka pluća malih stanica, raka gušterače, raka žuči, raka glave i vrata, raka mokraćnog mjehura, raka debelog crijeva, glioblastoma, raka jednjaka, raka dojke, hepatocelularnog karcinoma ili raka jajnika; proizvoljno pri čemu je karcinom rak dojke, a dodatno terapijsko sredstvo je cisplatin; po izboru pri čemu je karcinom trostruko negativni rak dojke.
22. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, u kombinaciji s dodatnim terapijskim sredstvom odabranim od Gemcitabina, terapije zračenjem ili Gemcitabina i terapije zračenjem zajedno, naznačeno time, da je za uporabu u liječenju raka gušterače.
23. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačeno time, da se koristi u liječenju koje povećava osjetljivost stanica raka gušterače na terapiju karcinoma odabranu između kemoterapije ili zračenja; po izboru: pri čemu je (I) kemoterapija gemcitabin; ili: gdje je (II) terapija karcinoma gemcitabin; ili: pri čemu je (III) terapija karcinoma zračenje.
24. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, ili farmaceutski pripravak u skladu s patentnim zahtjevom 17, naznačeno time, da u kombinaciji s gemcitabinom (100 nM) i / ili zračenjem (6 Gy) je za uporabu u liječenju koji inhibira fosforilaciju Chk1 (Ser 345) u stanici raka gušterače.
25. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačeno time, da se koristi u tretmanu koji senzibilizira stanice raka gušterače na terapiju zračenjem u kombinaciji s terapijom zračenja.
26. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačeno time, da se koristi u liječenju koje sadrži (I) radiosenzibilizirajuće hipoksične stanice raka gušterače u kombinaciji s terapijom zračenja; ili: sadrži (II) senzibilizirajuće hipoksične stanice raka gušterače u kombinaciji s terapijom zračenja.
27. Spoj za uporabu, ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 25 ili 26, naznačeno time, da navedena stanica raka je PSN-1, MiaPaCa-2 ili PancM stanica raka.
28. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 1 do 16, naznačeno time, da se koristi u liječenju karcinoma koji tretman obuhvaća narušavanje kontrolnih točaka staničnog ciklusa izazvanu oštećenjem u kombinaciji s terapijom zračenjem i / ili gemcitabin.
29. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 1 do 16, naznačeno time, da se koristi u liječenju karcinoma gušterače, tretmanom koji uključuje inhibiranje popravka oštećenja DNK homolognom rekombinacijom u stanici raka gušterače u kombinaciji s terapijom zračenjem i / ili gemcitabinom.
30. Spoj za uporabu ili njegov farmaceutski derivat, u skladu s patentnim zahtjevima 26 do 29, naznačeno time, što se spoj daje u stanicu raka gušterače; proizvoljno pri čemu su stanice raka gušterače izvedene iz stanične linije stanica gušterače koje su odabrane od PSN-1, MiaPaCa-2 ili Panc-1 stanica.
31. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 1 do 16, naznačeno time, da se koristi u liječenju karcinoma, pri čemu tretman obuhvaća (I) liječenje raka pluća ne-malih stanica u kombinaciji s jednim ili više sljedećih dodatnih terapijskih sredstava: Cisplatin ili Karboplatin, Etopozid i ionizirajuće zračenje; ili: (II) promicanje stanične smrti u stanicama raka; ili: (III) sprječavanje popravka stanica od oštećenja DNK; ili: (IV) inhibiranje ATR u biološkom uzorku koji obuhvaća korak kontaktiranja spoja prema bilo kojem od zahtjeva 1 do 3 do 31 s navedenim biološkim uzorkom; proizvoljno pri čemu je navedeni biološki uzorak stanica; ili: (V) senzibilizacija stanica na agense koji oštećuju DNK.
32. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva od 1 do 16 ili farmaceutski pripravak prema zahtjevu 17, za uporabu prema zahtjevima 19 do 31, naznačeno time, što je (I) navedena stanica je stanica raka koja ima nedostatke na signalnim kaskada ATM-a; po želji: pri čemu (i) je navedeni nedostatak promijenjena ekspresija ili aktivnost jednog ili više od sljedećeg: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP ili SMC1; ili: pri čemu (ii) je navedeni nedostatak izmijenjena ekspresija ili aktivnost jednog ili više od sljedećeg: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 ili H2AX; ili: pri čemu (II) je spomenuta stanica stanica raka koja eksprimira onkogene koji oštećuju DNK; proizvoljno pri čemu navedena stanica raka ima promijenjenu ekspresiju ili aktivnost jednog ili više od sljedećeg: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, ciklin E, ciklin A i Rb; ili: pri čemu (III) spomenuti rak, stanica raka ili stanica ima nedostatak u temeljnom proteinu za popravak ekscizije; proizvoljno gdje je temeljni protein za popravak ekscizije UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNK glikozilaze); APE1, APEX2 (AP endonukleaze); LIG1, LIG3 (DNK ligaze I i III); XRCC1 (dodatak LIG3); PNK, PNKP (polinukleotid kinaza i fosfataza); PARP1, PARP2 (polimeraze (ADP-riboza)); PolB, PolG (polimeraze); FEN1 (endonukleaza) ili Aprataxin; po izboru, pri čemu temeljni protein za popravak ekscizije je PARP1, PARP2 ili PolB; po izboru pri čemu je temeljni protein za popravak ekscizije PARP1 ili PARP2.
33. Spoj ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 16 ili farmaceutski pripravak prema zahtjevu 17 za uporabu prema zahtjevima 19 do 32, naznačeno time, da nadalje obuhvaća davanje pacijentu navedenog dodatnog terapijskog sredstva u kojem spomenuto sredstvo inhibira ili modulira temeljni protein za popravak ekscizije; proizvoljno gdje je temeljni protein za popravak ekscizije odabran od UNG, SMUG1, MBD4, TDG, OGG1, MYH NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNK glikozilaze); APE1, APEX2 (AP endonukleaze); LIG1, LIG3 (DNK ligaze I i III); XRCC1 (dodatak LIG3); PNK, PNKP (polinukleotid kinaza i fosfataza); PARP1, PARP2 (Poli (ADP-riboza) polimeraze); PolB, PolG (polimeraze); FEN1 (endonukleaza) ili Aprataxin; po želji pri čemu je temeljni protein za popravak ekscizije odabran između PARP1, PARP2 ili PolB; po izboru, pri čemu su proteini za popravak osnovne ekscizije odabrani od PARP1 ili PARP2; po izboru pri čemu je navedeno sredstvo odabrano iz Olapariba (poznat i kao AZD2281 ili KU-0059436), Inipariba (poznat i kao BSI-201 ili SAR240550), Velipariba (poznat i kao ABT-888), Rucaparib (poznat i kao PF-01367338), CEP-9722, INO-1001, MK-4827, E7016, BMN673 ili AZD2461.
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