HRP20220581T1 - Spojevi korisni kao inhibitori atr kinaze - Google Patents

Spojevi korisni kao inhibitori atr kinaze Download PDF

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HRP20220581T1
HRP20220581T1 HRP20220581TT HRP20220581T HRP20220581T1 HR P20220581 T1 HRP20220581 T1 HR P20220581T1 HR P20220581T T HRP20220581T T HR P20220581TT HR P20220581 T HRP20220581 T HR P20220581T HR P20220581 T1 HRP20220581 T1 HR P20220581T1
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4alkyl
image
alkyl
4aliphatic
optionally substituted
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HRP20220581TT
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Jean-Damien Charrier
Steven Durrant
David Kay
Ronald Knegtel
Somhairle Maccormick
Michael Mortimore
Michael O'donnell
Joanne Pinder
Alistair Rutherford
Anisa Nizarali Virani
Stephen Young
Philip Michael Reaper
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Vertex Pharmaceuticals Incorporated
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Claims (22)

1. Spoj formule IA: [image] ili njegova farmaceutski prihvatljiva sol; naznačen time, da Y je C1-C10alifatski lanac u kojem su po izboru zamijenjene do tri metilenske jedinice alifatskog lanca s O, NR0, S, C(O) ili S(O)2; Prsten A je heteroarilni prsten s 5 članova odabran između [image] J3 je H ili C1-4alkil pri čemu 1 metilenska jedinica alkilne skupine može po izboru biti zamijenjena s O, NH, N(C1-4alkil), ili S i po izboru supstituirana s 1 do 3 halo; Q je monociklički aromatski prsten s 5 do 6 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; ili biciklički aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; R5 je H; monociklički potpuno zasićeni, djelomično nezasićeni ili aromatski prsten s 3 do 7 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; biciklički potpuno zasićeni, djelomično nezasićeni ili aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika, ili sumpora; R5 je po izboru supstituiran s 1 do 5 J5 skupina; L je C1-4alkil lanac u kojem su-dvije metilenske jedinice alkilnog lanca po izboru zamijenjene s O, NR6, S, -C(O)-, -SO- ili -SO2-; R0 je H ili C1-C6alkil pri čemu se jedna metilenska jedinica alkilnog lanca može po izboru zamijeniti s O, NH, N(C1-4alkil), ili S; R1 je H ili C1-C6alkil; R2 je H, C1-C6alkil, -(C2-C6alkil)-Z ili ciklički prsten s 4 do 8 članova koji sadržava 0 do 2 atoma dušika; pri čemu je navedeni prsten vezan preko ugljikovog atoma i po izboru je supstituiran s jednom pojavom JZ; ili R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između kisika, dušika ili sumpora; pri čemu je navedeni heterociklički prsten po izboru zamijenjen s jednim pojavljivanjem JZ1; JZ1 je halo, CN, C1-C8alifat, -(X)t-CN ili -(X)R-Z; pri čemu se navedene-dvije metilenske jedinice navedenog C1-C8alifata mogu po izboru zamijeniti s O, NR, S, P(O), C(O), S(O) ili S(O)2; pri čemu je navedeni C1-C8alifat po izboru supstituiran s halo, CN ili NO2; X je C1-C4alkil; svaki t, r i m je neovisno 0 ili 1; Z je -NR3R4; R3 je H ili C1-C2alkil; R4 je H ili C1-C6 alkil; ili R3 i R4, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između kisika, dušika ili sumpora; pri čemu je navedeni prsten po izboru supstituiran s jednom pojavom JZ; R6 je H, ili C1-C6alkil; JZ je neovisno NH2, NH(C1-4alifat), N(C1-4alifat)2, halogen, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO(C1-4alifat), CO2(C1-4alifat), O(haloC1-4alifat) ili haloC1-4alifat; J5 je halo, okso, CN, NO2, X1-R ili -(X1)p-Q4; X1 je C1-10alifat; pri čemu su 1 do 3 metilenske jedinice navedenog C1-10alifata po izboru zamijenjene s -NR’-, -O-, -S-, C(=NR’), C(O), S(O)2 ili S(O); pri čemu je X1 po izboru i neovisno supstituiran s 1 do 4 pojavljivanja od NH2, NH(C1-4alifat), N(C1-4alifat)2, halogenom, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO2(C1-4alifat), C(O)NH2, C(O)NH(C1-4alifat), C(O)N(C1-4alifat)2, SO(C1-4alifat), SO2(C1-4alifat), SO2NH(C1-4alifat), SO2NH(C1-4alifat), NHC(O)(C1-4alifat), N(C1-4alifat)C(O)(C1-4alifat), pri čemu je navedeni C1-4alifat po izboru supstituiran s 1 do 3 pojavljivanja halo; Q4 je zasićeni ili nezasićeni monociklički prsten s 3 do 8 članova koji ima 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora, ili zasićenog ili nezasićenog bicikličkog prstena s 8 do 10 članova koji ima 0 do 6 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; svaki Q4 je po izboru supstituiran s 1 do 5 JQ4; JQ4 je halo, CN ili C1-4alkil pri čemu su do 2 metilenske jedinice po izboru zamijenjene s O, NR*, S, C(O), S(O), ili S(O)2; R je H ili C1-4alkil pri čemu je navedeni C1-4alkil po izboru supstituiran s 1 do 4 halo; J2 je halo; CN; aromatski ili nearomatski monociklički prsten s 5 do 6 članova koji ima 0 do 3 heteroatoma odabrana između kisika, dušika ili sumpora; ili C1-10alifatska skupina u kojoj su do 2 metilenske jedinice po izboru zamijenjene s O, NR’’, C(O), S, S(O) ili S(O)2; pri čemu je navedena C1-10alifatska skupina po izboru supstituirana s 1 do 3 halo ili CN; i navedeni monociklički prsten je po izboru supstituiran s 1 do 3 pojavljivanja halo; CN; C3-6cikloalkil; heterociklil s 3 do 7 članova koji sadržava 0 do 2 heteroatoma odabrana između kisika, dušika, ili sumpora; ili C1-4alkil pri čemu je do jedna metilenska jedinica alkilnog lanca po izboru zamijenjena s O, NR’’, ili S; i pri čemu je navedeni C1-4alkil po izboru supstituiran s 1 do 3 halo; q je 0, 1 ili 2; p je 0 ili 1; i R’, R’’, i R* su svaki neovisno H, C1-4alkil ili je odsutan; pri čemu je navedeni C1-4alkil po izboru supstituiran sa 1 do 4halo.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da Y je C1-C6alifatski lanac u kojem je jedna metilenska jedinica alkilnog lanca po izboru zamijenjena s C(O) ili -NR0-; R5 je monociklički potpuno zasićen, djelomično nezasićen ili aromatski prsten s 3 do 7 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; ili biciklički, potpuno zasićen, djelomično nezasićeni ili aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika, ili sumpora; R5 je po izboru supstituiran s 1 do 5 J5 skupina; JZ1 je -(X)t-CN, C1-C6alkil ili -(X)R-Z; X1 je C1-10alifat; pri čemu su 1 do 3 metilenske jedinice navedenog C1-10alifata po izboru zamijenjene s -NR’-, -O-, -S-, C(O), S(O)2 ili S(O); pri čemu je X1 po izboru i neovisno supstituiran s 1 do 4pojavljivanja NH2, NH(C1-4alifat), N(C1-4alifat)2, halogen, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO2(C1-4alifat), C(O)NH2, C(O)NH(C1-4alifat), C(O)N(C1-4alifat)2, SO(C1-4alifat), SO2(C1-4alifat), SO2NH(C1-4alifat), SO2NH(C1-4alifat), NHC(O)(C1-4alifat), N(C1-4alifat)C(O)(C1-4alifat), pri čemu je navedeni C1-4alifat po izboru supstituiran s 1 do 3 pojavljivanja halo.
3. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 2, naznačen time, da je Y NH; R5 je monociklički aril ili heteroarilni prsten s 5 do 6 članova koji ima 0 do 3 heteroatoma neovisno odabrana između dušika, kisika ili sumpora, R5 je po izboru kondenziran na aromatični prsten s 5 do 6 članova koji sadržava 0 do 2 heteroatoma odabrana između N, O ili S; svaki R5 je po izboru supstituiran s 1 do 5 J5 skupina; L je -C(O)- ili -SO2-; R1 je H, ili C1-C6alkil; R2 je -(C2-C6alkil)-Z ili ciklički prsten s 4 do 8 članova koji sadržava 0 do 2 atoma dušika; pri čemu je navedeni prsten vezan preko atoma ugljika i po izboru je supstituiran s jednom pojavom JZ; ili R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 atoma dušika; pri čemu je navedeni heterociklički prsten po izboru supstituiran s jednom pojavom JZ1; JZ1 je -(X)t-CN, C1-C6alkil ili -(X)r-Z; R3 je H ili C1-C2alkil; R4 je H ili C1-C6 alkil; ili R3 i R4, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između kisika, dušika ili sumpora; pri čemu je navedeni prsten po izboru supstituiran s jednom pojavom JZ; J5 je halogen, NO2, CN, O(haloC1-4alifat), haloC1-4alifat ili C1-6alifatska skupina u kojoj se do 2 metilenske jedinice se po izboru zamjenjuju s C(O), O ili NR’; i J2 je halo, C1-C2alkil po izboru supstituiran s 1 do 3 fluora, ili CN; na primjer, pri čemu je L -C(O)-, m je 0, a R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 atoma dušika; na primjer, pri čemu je navedeni heterociklil pirolidinil, piperidinil, piperazinil, azepanil ili 1,4-diazepanil.
4. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da je m 0, q je 0, a -L-NR1R2 je C(O)pirolidinil, C(O)piperidinil, C(O)piperazinil, C(O)azepanil, C(O) 1,4-diazepanil, C(O)NH-piperidinil, C(O)NHCH2CH2-pirolidinil, C(O)NHCH2CH2-piperidinil, CON(CH3)CH2CH2N(CH3)2, pri čemu je navedeni pirolidinil, piperidinil, piperazinil, azepanil ili 1,4-diazepanil po izboru supstituiran s C1-4alkil ili N(C1-4alkil)2.
5. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da je J2 halo, CN, fenil, oksazolil ili C1-6alifatska skupina pri čemu su do 2 metilenske jedinice po izboru zamijenjene s O, NR’’, C(O), S, S(O) ili S(O)2; navedena C1-6alifatska skupina je po izboru supstituirana s 1 do 3 fluora ili CN.
6. Spoj u skladu s patentnim zahtjevom 1 ili 2 koji ima formulu IIA: [image] naznačen time, da Prsten A je heteroarilni prsten s 5 članova odabran između [image] Y je C1-C4alkilni lanac pri čemu je jedna metilenska jedinica alkilnog lanca po izboru zamijenjena s -NR0-; Q je monociklički aromatski prsten s 5 do 6 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; ili biciklički aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; R5 je monociklički aril ili heteroarilni prsten s 5 do 6 članova koji ima 0 do 3 heteroatoma neovisno odabrana između dušika, kisika ili sumpora, R5 je po izboru kondenziran na aromatični prsten s 5 do 6 članova koji sadržava 0 do 2 heteroatoma odabrana između N, O ili S; svaki R5 je po izboru supstituiran s 1 do 5 J5 skupina; L je -C(O)- ili -SO2-; R1 je H, ili C1-C6alkil; R0 je H ili C1-C6 alkil; R2 je C1-C6alkil, -(C2-C6alkil)-Z ili ciklički prsten s 4 do 8 članova koji sadržava 0 do 2 atoma dušika; pri čemu je navedeni prsten vezan preko ugljikovog atoma i po izboru je supstituiran s jednom pojavom JZ; ili R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između dušika, sumpora ili kisika; pri čemu je navedeni heterociklički prsten po izboru zamijenjen s jednim pojavljivanjem JZ1; JZ1 je (X)t-CN, C1-C6alkil ili -(X)r-Z; X je C1-C4alkil; svaki t, r i m je neovisno 0 ili 1; Z je -NR3R4; R3 je H ili C1-C2alkil; R4 je H ili C1-C6 alkil; ili R3 i R4, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između kisika, dušika ili sumpora; pri čemu je navedeni prsten po izboru supstituiran s jednom pojavom JZ; JZ je NH2, NH(C1-4alifat), N(C1-4alifat)2, halogen, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO(C1-4alifat), CO2(C1-4alifat), O(haloC1-4alifat) ili haloC1-4alifat; J5 je halogen, NO2, CN, O(haloC1-4alifatska), haloC1-4alifatska ili C1-6alifatska grupa u kojoj su do 2 metilenske jedinice po izboru zamijenjene s C(O), O ili NR’; J2 je halo; CN; fenil; oksazolil; ili C1-6alifatska skupina u kojoj su do 2 metilenske jedinice po izboru zamijenjene s O, NR’’, C(O), S, S(O) ili S(O)2; navedena C1-6alifatska skupina je po izboru supstituirana s 1 do 3 fluora ili CN; R’ i R’’ su svaki neovisno H ili C1-C4 alkil; q je 0, 1 ili 2, p je 0 ili 1; na primjer pri čemu je Q fenil ili piridil, na primjer, pri čemu je spoj odabran između sljedećeg: Tablica IIA-2 (1. dio) [image] Tablica IIA-2 (2. dio) [image] [image]
7. Spoj u skladu s patentnim zahtjevom 1 koji ima formulu IA': [image] ili njegova farmaceutski prihvatljiva sol; naznačen time, da Y je C1-C4alkilni lanac pri čemu je jedna metilenska jedinica alkilnog lanca po izboru zamijenjena s -NR0-; G je O ili S; Q je monociklički aromatski prsten s 5 do 6 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; ili biciklički aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; R5 je monociklički potpuno zasićen, djelomično nezasićen ili aromatski prsten s 3 do 7 članova koji sadržava 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; ili biciklički potpuno zasićen, djelomično nezasićeni ili aromatski prsten s 8 do 10 članova koji sadržava 0 do 6 heteroatoma neovisno odabrana između dušika, kisika, ili sumpor; R5 je po izboru supstituiran s 1 do 5 J5 skupina; L je C1-4alkilni lanac u kojem su do dvije metilenske jedinice alkilnog lanca po izboru zamijenjene s O, NR6, S, -C(O)-, -SO- ili -SO2-; R0 je H ili C1-C6 alkil; R1 je H ili C1-C6alkil; R2 je H, C1-C6alkil, -(C2-C6alkil)-Z ili ciklički prsten s 4 do 8 članova koji sadržava 0 do 2 atoma dušika; pri čemu je navedeni prsten vezan preko ugljikovog atoma i po izboru je supstituiran s jednom pojavom JZ; ili R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između dušika, sumpora ili kisika; pri čemu je navedeni heterociklički prsten po izboru zamijenjen s jednim pojavljivanjem JZ1; JZ1 je -(X)t-CN, C1-C6alkil ili -(X)R-Z; X je C1-C4alkil; svaki t, r i m je neovisno 0 ili 1; Z je -NR3R4; R3 je H ili C1-C2alkil; R4 je H ili C1-C6 alkil; ili R3 i R4, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između kisika, dušika ili sumpora; pri čemu je navedeni prsten po izboru supstituiran s jednom pojavom JZ; R6 je H, ili C1-C6alkil; JZ je neovisno NH2, NH(C1-4alifat), N(C1-4alifat)2, halogen, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO(C1-4alifat), CO2(C1-4alifat), O(haloC1-4alifat) ili haloC1-4alifat; J5 je halo, okso, CN, NO2, X1-R ili -(X1)p-Q4, X1 je C1-10alifat; pri čemu su 1 do 3 metilenske jedinice navedenog C1-10alifata po izboru zamijenjene s -NR’-, -O-, -S-, C(O), S(O)2 ili S(O); pri čemu je X1 po izboru i neovisno supstituiran s 1 do 4pojavljivanja NH2, NH(C1-4alifat), N(C1-4alifat)2, halogen, C1-4alifat, OH, O(C1-4alifat), NO2, CN, CO2H, CO2(C1-4alifat), C(O)NH2, C(O)NH(C1-4alifat), C(O)N(C1-4alifat)2, SO(C1-4alifat), SO2(C1-4alifat), SO2NH(C1-4alifat), SO2NH(C1-4alifat), NHC(O)(C1-4alifat), N(C1-4alifat)C(O)(C1-4alifat), pri čemu je navedeni C1-4alifat po izboru supstituiran s 1 do 3 pojavljivanja halo; Q4 je zasićeni ili nezasićeni monociklički prsten s 3 do 8 članova koji ima 0 do 4 heteroatoma neovisno odabrana između dušika, kisika ili sumpora, ili zasićeni ili nezasićeni biciklički prsten s 8 do 10 članova koji ima 0 do 6 heteroatoma neovisno odabrana između dušika, kisika ili sumpora; svaki Q4 je po izboru supstituiran s 1 do 5 JQ4; JQ4 je halo, CN ili C1-4alkil pri čemu su do 2 metilenske jedinice po izboru zamijenjene s O, NR*, S, C(O), S(O), ili S(O)2; R je H ili C1-4alkil pri čemu je navedeni C1-4alkil po izboru supstituiran s 1 do 4halo; J2 je halo; CN; aromatski ili nearomatski monociklički prsten s 5 do 6 članova koji ima 0 do 3 heteroatoma odabrana između kisika, dušika ili sumpora; ili C1-10alifatska skupina u kojoj su do 2 metilenske jedinice po izboru zamijenjene s O, NR’’, C(O), S, S(O) ili S(O)2; pri čemu je navedena C1-10alifatska skupina po izboru supstituirana s 1 do 3 halo ili CN; i navedeni monociklički prsten je po izboru supstituiran s 1 do 3 halo; CN; C3-6cikloalkil; s 3 do 7 članova heterociklil koji sadržava 0 do 2 heteroatoma odabrana između kisika, dušika ili sumpora ili C1-4alkila pri čemu je do jedna metilenska jedinica alkilnog lanca po izboru zamijenjena s O, NR’’ ili S; q je 0, 1 ili 2, p je 0 ili 1; i R’, R’’, i R* su svaki neovisno H, C1-4alkil ili je odsutan; pri čemu je navedeni C1-4alkil po izboru supstituiran s 1 do 4halo; na primjer pri čemu je J5 halo, CN, fenil, oksazolil ili C1-6alifatska skupina pri čemu su do 2 metilenske jedinice po izboru zamijenjene s O, NR’, C(O), S, S(O) ili S(O)2; navedena C1-6alifatska skupina je po izboru supstituirana s 1 do 3 fluora ili CN.
8. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da je Q fenil ili piridil, i a) pri čemu je barem još jedna metilenska jedinica C1-6alifatske skupine po izboru zamijenjena heteroatomom odabranim iz skupine koju čine O, NR’’ i S; b) pri čemu je Q supstituiran s jednim ili dva J2, pri čemu je J2 C1-6alifatska skupina u kojoj se do 2 metilenske jedinice po izboru zamjenjuju s O ili NR’’; na primjer, pri čemu je J2 -OCH3, -OCH2CH2N(CH3)2, -NHCH2CH2N(CH3)2 ili piperazinil; ili c) pri čemu je Q supstituiran na para položaju sa -SO2(C1-4alkil), -SO2(C1-4alkil)N(C1-4alkil)2, C(O)N(C1-4alkil)2, C(O)(1,4-diazepanil), CO(azepanil), C(O)(piperazinil) ili C(O)(piperidinil); ili, pri čemu je Q po izboru supstituiran u para položaju s J2, pri čemu je J2 -SO2(C1-4alkil), -SO2(C3-6cikloalkil), -SO2(3-6 članova heterociklil), -SO2(C1-4alkil)N(C1-4alkil)2, -C(O)(C1-4alkil), -(C1-4alkil)N(C1-4alkil)2, ili -NHC(O)(Ci_4alkil); ili d) pri čemu je Q po izboru supstituiran u orto položaju s J2, pri čemu je J2 C1-4alkil, -C≡C-(C1-4alkil), CH=CH2, CH=CHF, O(C1-4alkil), NH(C1-4alkil), N(C1-4alkil)2, -(C1-4alkil)OH, -(C1-4alkil)O(C1-4alkil), -(C1-4alkil)NH2, -(C1-4alkil)NH(C1-4alkil), -(C1-4alkil)N(C1-4alkil)2, -(C1-4alkil)CN, CO(C1-4alkil), CON(C1-4alkil)2, C(O)O(C1-4alkil), S(C1-4alkil), -S-(C1-4alkil)NH2, S(O)(C1-4alkil)NH2, S(O )2(C1-4alkil)OH, S(O)(C1-4alkil)NHC(O)O(t-butil), NHS(O)2(C1-4alkil), halo ili CN; na primjer, pri čemu je J2 CH2CH2OH, SCH(CH3)2, -C≡CCH3, halo, CN, CON(CH3)2, CH2CN, S(O)CH2CH2NH2, SCH2CH2NH2, C(O)OCH3, CH2N(CH3)2, S(O)CH2CH2NHBOC, N(CH3)2, NHSO2CH3, CH=CHF, CH2OCH3, CH=CH2, SCH2CH3 ili -CH=CH; ili e) pri čemu je Q po izboru supstituiran u meta položaju s J2 pri čemu je J2 C1-4alkil, C1-4alkoksi, halo, haloC1-4alkil, haloC1-4alkoksil, CN, SO2(C1-4alkil), NHSO2(C1-4alkil), C(O)(C1-4alkil), C(O)NH2, NHC(O)(C1-4alkil), -(C1-4alkil)-OH, -(C1-4alkil)-O(C1-4alkil), -(C1-4alkil)-NH2, -(C1-4alkil)-N (C1-4alkil)2, ili -(C1-4alkil)NH(C1-4alkil); ili f) pri čemu je Q fenil; i Q je po izboru supstituiran u orto položaju s jednim J2, pri čemu je J2 C1-C4alkil, NH2, NHC(O)CH3, O(C1-C4alkil), CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, CN, CH2C(O)NH2, OH, OCF3, CF3, CHF2, -CH=CHF, NHC(O)CH3, C(O)CH3, C(O)NH2, SCH3, S(O)CH3, S(O)CH2CH3, SO2CH(CH3)2, -C≡CH2, oksazolil, ili fenil; na primjer, pri čemu je Q supstituiran u orto položaju s J2, pri čemu je J2 CH2OH, CHF2, S(O)CH3, ili S(O)CH2CH3.
9. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da p je 1; na primjer pri čemu je Q fenil, piridil ili naftil; na primjer pri čemu je navedeni piridil 3-piridil ili 4-piridil.
10. Spoj u skladu s patentnim zahtjevom 9, naznačen time, da L je -C(O)- ili -SO2-; na primjer pri čemu R1 i R2, zajedno s atomom na koji su vezani, tvore heterociklički prsten s 4 do 8 članova koji sadržava 1 do 2 heteroatoma odabrana između dušika, sumpora ili kisika; na primjer pri čemu je navedeni heterociklički prsten odabran između pirolidinila, piperidinila, piperazinila, morfolinila, 1,4-diazepanila, ili 1,4-oksazepanila; na primjer pri čemu je navedeni heterociklički prsten po izboru supstituiran s halo, CN, C1-6alifatičnim, haloC1-6alifatm, -C(O)O(C1-6alifat), C(O)H, C(O)(C1-6alifat), P(O)(OC1-4alkil)2, NH(C1-6alifat) ili N(C1-6alifat)2.
11. Spoj u skladu s patentnim zahtjevom 6 ili patentnim zahtjevom 7, naznačen time, da je m 0, a R5 je tienil, tiazolil, furanil, pirolidinil, azetidinil, piperidinil, piperazinil, morfolinil, piridinonil, piridil, tetrahidropiridinil, tetrahidroizokinolinil, 1,4-diazepanil, azabiciklo[2.2.1]heptanil ili fenil; na primjer pri čemu je R5 fenil, piperidinil ili tienil; na primjer pri čemu je Q po izboru supstituiran u para položaju sa -SO2(C1-4alkil), -SO2(C1-4alkil)N(C1-4alkil)2, C(O)N(C1-4alkil)2, C(O)(1,4-diazepanil), C(O)(piperazinil) ili C(O)(piperidinil); na primjer pri čemu je R5 po izboru supstituiran s 1 do 2 J5 grupe, pri čemu je J5 odabran između halo, CN, NO2, X1-R ili -(X1)p-Q4; p je 0-1; X1 je C1-10alifat pri čemu su 1 do 3 metilenske jedinice navedenog C1-6alifata po izboru zamijenjene s -NR’-, -O-, -S-, C(=NH)-, C(O), S(O)2 ili S(O); R je H; i Q4 je monociklički prsten s 3 do 6 članova koji sadržava 0 do 2 heteroatoma odabrana između O ili N, pri čemu je X1 po izboru supstituiran s 1 do 3 pojavljivanja halo ili CN; na primjer pri čemu je J5 C1-10alifat lanac pri čemu su 1 do 2 metilenske jedinice X1 zamijenjene s -O- ili-NR’-; na primjer pri čemu je R5 piperidinil po izboru supstituiran s NH2 ili -(C1-4alkil)NH2; na primjer pri čemu je R5 tienil po izboru supstituiran sa CN, C1-6alkil, -(C1-4alkil)NH2, -(C1-4alkil)NH(C1-6alkil), -(C1-4alkil)N(C1-6alkil)2, O(C1-6alkil), pirolidinil, pri čemu je navedeni alkil po izboru supstituiran s 1 do 3 halo; na primjer pri čemu je Q4 po izboru supstituirani cikloalkilni prsten s 3 do 6 članova; na primjer pri čemu je Q4 po izboru supstituirani heterociklički prsten s 3 do 6 članova odabran između pirolidinila, azetidinila ili tienil; na primjer pri čemu je J5 halo, C1-6alkil, NO2, CN, C1-6alkil, -CH=CH2, OH, OCH3, OCH2CH3, OCH(CH3)2, NH2, CH2NH2, CH2OH, CH(CH3)NHCH3, C(CH3)2NH2, CH2CH2NH2, CH2CH2OH, CH2NHCH3, CH2N(CH3)2, CH(CH3)NH2, CH(CH3)NHC(O)O(CH3)3, CH2NHC(CH3)2, CH2NHCH2CHF2, CH2NHCH2CH(CH3)OH, CH2NHCH2C(CH3)2OH, CH2NHCH2CH(OH)-ciklopropil, CH2NHCH2CH2N(CH3)2, CH2NHCH(CH2CH3)3, CH2NHCH3, CH2NHCH2CH3, CH2NHCH2CH2CH3, CH2NH-ciklopropil, CH2NHCH2CH2OH, CH2NHCH2CH2OCH3, CH2NHCH2CH2OCH2CH2OH, azetidinil, pirolidinil, CF3, C(=NH)NH2, C(=NH)NH(CH3), tienil, CH2NH-ciklopropil, CH2NH(CH2OH)3, OCH2CH2OH, OCH2CH2CH2OH, OCH2CH2NHC(O)OC(CH3)3, CH2NHC(O)O(CH3)3 ili CH2OC(O)CH3.
12. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 2, koji ima formulu IA-iii: [image] naznačen time, da Prsten A je [image] ili [image] , J5o je H, F, Cl, C1-4alifat, O(C1-3alifat) ili OH; J5p je [image] J5p1 je H, C1-4alifat, oksetanil, tetrahidrofuranil, tetrahidropiranil; pri čemu je J5p1 po izboru supstituiran s 1 do 2 pojave OH ili halo; J5p2 je H, metil, etil, CH2F, CF3 ili CH2OH; J2o je H, CN ili SO2CH3; J2m je H, F, Cl ili metil; J2p je -SO2(C1-6alkil), -SO2(C3-6cikloalkil), -SO2(heterociklil s 4 do 6 članova), -SO2(C1-4alkil)N(C1-4alkil)2, ili -SO2(C1-4alkil)-(heterociklil s 4 do 6 članova), pri čemu navedeni heterociklil sadržava 1 heteroatom odabran između kisika, dušika ili sumpora; i pri čemu je navedeni J2p po izboru supstituiran s 1 do 3 pojave halo, OH ili O(C1-4alkil).
13. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je odabran između sljedećeg: Tablica IA-1 [image] Tablica IA-2 [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]
14. Spoj, naznačen time, da je odabran između sljedećeg: [image]
15. Farmaceutski pripravak, naznačen time, da sadržava spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 14 i farmaceutski prihvatljiv nosač.
16. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 14, ili njegova farmaceutski prihvatljiva sol, ili njegov farmaceutski pripravak, u skladu s patentnim zahtjevom 15, naznačen time, da se upotrebljava u liječenju raka kod pacijenata.
17. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 14, ili farmaceutski pripravak iz patentnog zahtjeva 15, za uporabu u skladu s patentnim zahtjevom 16, naznačen time, da upotreba podrazumijeva dodatno terapeutsko sredstvo odabrano između agensa koji oštećuje DNA; pri čemu je navedeno dodatno terapeutsko sredstvo prikladno za bolest koja se liječi; i navedeno dodatno terapeutsko sredstvo se primjenjuje zajedno sa navedenim spojem kao pojedinačni oblik doze ili odvojeno od navedenog spoja kao dio višestrukog oblika doziranja; na primjer, pri čemu je navedeno sredstvo koje oštećuje DNA odabrano za kemoterapiju ili liječenje zračenjem; na primjer, pri čemu je navedeno sredstvo koje oštećuje DNA odabrano između ionizirajućeg zračenja, radiomimetičkog neokarzinostatina, sredstva za platiniranje, inhibitora topo I, inhibitora topo II, antimetabolita, sredstva za alkiliranje, alkil sulfonata, antimetabolita ili antibiotika; na primjer, pri čemu je navedeno sredstvo koje oštećuje DNA odabrano između ionizirajućeg zračenja, sredstva za platiniranje, inhibitora topo I, inhibitora topo II ili antibiotika; na primjer, pri čemu je navedeno sredstvo za platiniranje odabrano između cisplatina, oksaliplatina, karboplatina, nedaplatina ili satraplatina; navedeni inhibitor topo I je odabran između kamptotecina, topotekana, irinotekana/SN38, rubitekana; navedeni inhibitor topo II je odabran između etopozida; navedeni antimetabolit je odabran između metotreksata, pemetrekseda, tioguanina, fludarabina, kladribina, citarabina, gemcitabina, 6-merkaptopurina ili 5-fluorouracila; navedeno alkilirajuće sredstvo je odabrano između dušikovih iperita, nitrozourea, triazena, alkil sulfonata, prokarbazina ili aziridina; i navedeni antibiotik je odabran iz obitelji Hydroxyurea, Anthracyclines, Anthracenediones ili Streptomyces.
18. Spoj ili pripravak za upotrebu u skladu s patentnim zahtjevom 16, naznačen time, da upotreba nadalje sadržava sredstvo koje oštećuje DNA, pri čemu je navedeno sredstvo koje oštećuje DNA sredstvo za platiniranje ili ionizirajuće zračenje; na primjer, pri čemu je navedeno sredstvo za platiniranje odabrano između cisplatina, oksaliplatina, karboplatina, nedaplatina, lobaplatina, triplatin tetranitrata, picoplatina, satraplatina, ProLindaca i aroplatina; navedeni inhibitor topo I je odabran između kamptotecina, topotekana, irinotekana/SN38, rubitekana i belotekana; navedeni inhibitor topo II je odabran između etopozida, daunorubicina, doksorubicina, aklarubicina, epirubicina, idarubicina, amrubicina, pirarubicina, valrubicina, zorubicina i teniposida; navedeni antimetabolit je odabran između aminopterina, metotreksata, pemetrekseda, raltitreksada, pentostatina, kladribina, klofarabina, fludarabina, tioguanina, merkaptopurina, fluorouracila, kapecitabina, tegafura, karmofura, floksuridina, citarabina, gecitabidina, citarabina, gecitabidina; navedeno alkilirajuće sredstvo odabrano je između mekloretamina, ciklofosfamida, ifosfamida, trofosfamida, klorambucila, melfalana, prednimustina, bendamustina, uramustina, estramustina, karmustina, lomustina, semustina, fotemustina, nimustina, ranimustina, streptozocina manosulfana, treosulfana, karboquona, tioTEPA, triaziquona, trietilenmelamina, prokarbazina, dekarbazina, temozolomida, altretamina, mitobronitola, aktinomicina, bleomicina, mitomicina i plikamicina.
19. Spoj ili pripravak za uporabu u skladu s patentnim zahtjevom 16 ili 18, ili patentnim zahtjevom 17, kada ovisi o patentnom zahtjevu 16, naznačen time, da je navedeni rak čvrsti tumor odabran od sljedećih karcinoma: Oralni: usna šupljina, usna, jezik, usta, ždrijelo; Srčani: sarkom (angiosarkom, fibrosarkom, rabdomiosarkom, liposarkom), miksom, rabdomiom, fibrom, lipom i teratom; Pluća: bronhogeni karcinom (skvamozni ili epidermoidni, nediferencirani mali stanični, nediferencirani veliki stanični, adenokarcinom), alveolarni (bronhiolarni) karcinom, bronhijalni adenom, sarkom, limfom, hondromatski hamartom, mezoteliom; Gastrointestinalni: jednjak (karcinom skvamoznih stanica, grkljan, adenokarcinom, leiomiosarkom, limfom), želudac (karcinom, limfom, leiomiosarkom), gušterača (duktalni adenokarcinom, inzulinom, glukagonom, gastrinom, karcinoidni tumor, vipom), tanko crijevo (adenokarcinom, limfom, karcinoidni tumori, Karposijev sarkom, leiomiom, hemangiom, lipom, neurofibrom, fibrom), debelo crijevo (adenokarcinom, tubularni adenom, vilozni adenom, hamartom, leiomiom), debelo crijevo, debelo crijevo-rektum, kolorektalni; rektum, Genitourinarni trakt: bubrezi (adenokarcinom, Wilmov tumor [nefroblastom], limfom), mokraćni mjehur i uretra (karcinom skvamoznih stanica, karcinom prijelaznih stanica, adenokarcinom), prostata (adenokarcinom, sarkom), testisa (seminom, teratom, embrionalni karcinom, teratokarcinom, koriokarcinom, sarkom, karcinom intersticijskih stanica, fibrom, fibroadenom, adenomatoidni tumori, lipom); Jetra: hepatom (hepatocelularni karcinom), kolangiokarcinom, hepatoblastom, angiosarkom, hepatocelularni adenom, hemangiom, bilijarni prolazi; Kosti: osteogeni sarkom (osteosarkom), fibrosarkom, maligni fibrozni histiocitom, hondrosarkom, Ewingov sarkom, maligni limfom (sarkom retikulumskih stanica), multipli mijelom, maligni tumor divovskih stanica, hordom, osteohronfrom (osteokartilaginozna egzostoza), benigni hondrom, hondroblastom, hondromiksofibrom, osteoidni osteom i tumori divovskih stanica; Živčani sustav: lubanja (osteom, hemangiom, granulom, ksantom, osteitis deformans), moždana ovojnica (meningiom, meningiosarkom, gliomatoza), mozak (astrocitom, meduloblastom, gliom, ependimom, germinom [pinealom], multiformni glioblastom, oligodendrogliom, švanom, retinoblastom, kongenitalni tumori), neurofibrom leđne moždine, meningiom, gliom, sarkom); Ginekološki: maternica (endometrijski karcinom), cerviks (karcinom vrata maternice, predtumorska cervikalna displazija), jajnici (karcinom jajnika [serozni cistadenokarcinom, mucinozni cistadenokarcinom, neklasificirani karcinom], tumori granuloza-tekalnih stanica, tumori Sertoli-Leydigovih stanica, disgerminom, maligni teratom), vulva (karcinom skvamoznih stanica, intraepitelni karcinom, adenokarcinom, fibrosarkom, melanom), vagina (karcinom bistrih stanica, karcinom skvamoznih stanica, botrioidni sarkom (embrionalni rabdomiosarkom), karcinom jajovoda; grudi; Koža: maligni melanom, karcinom bazalnih stanica, karcinom skvamoznih stanica, Karposijev sarkom, keratoakantom, madeži displastičnih mrlja, lipom, angiom, dermatofibrom, keloidi, psorijaza, Štitnjača: papilarni karcinom štitnjače, folikularni karcinom štitnjače; medularni karcinom štitnjače, multipla endokrina neoplazija tip 2A, multipla endokrina neoplazija tip 2B, obiteljski medularni karcinom štitnjače, feokromocitom, paragangliom; i Nadbubrežne žlijezde: neuroblastom.
20. Spoj ili pripravak za uporabu u skladu s patentnim zahtjevom 16 ili 19, naznačen time, da je navedeni rak odabran između raka pluća, raka glave i vrata, raka gušterače, raka želuca i raka mozga.
21. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 da 14, ili njegova farmaceutski prihvatljiva kompozicija, naznačen time, da se koristi za promicanje stanične smrti u stanicama raka, sprječavanju popravka stanica od oštećenja DNA ili preosjetljivosti stanica na sredstva koja oštećuju DNA.
22. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 14, za uporabu u skladu s patentnim zahtjevom 21, naznačen time, da a) navedena stanica je stanica raka koja ima defekte u ATM signalnoj kaskadi; na primjer pri čemu je navedeni defekt promijenjena ekspresija ili aktivnost jednog ili više od sljedećeg: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 ili H2AX; ili 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 b) navedena stanica je stanica raka koja eksprimira onkogene koji oštećuju DNA.
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