HRP20220319T1 - Makrociklički spojevi kao inhibitori protein kinaze - Google Patents

Makrociklički spojevi kao inhibitori protein kinaze Download PDF

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HRP20220319T1
HRP20220319T1 HRP20220319TT HRP20220319T HRP20220319T1 HR P20220319 T1 HRP20220319 T1 HR P20220319T1 HR P20220319T T HRP20220319T T HR P20220319TT HR P20220319 T HRP20220319 T HR P20220319T HR P20220319 T1 HRP20220319 T1 HR P20220319T1
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Joaquin PASTOR FERNÁNDEZ
Rosa María ÁLVAREZ ESCOBAR
Rosario Concepción RIESCO FAGUNDO
Ana Belén GARCÍA GARCÍA
Antonio RODRÍGUEZ HERGUETA
Jose Ignacio MARTÍN HERNANDO
Carmen Blanco Aparicio
David Álvaro CEBRIÁN MUÑOZ
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Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO)
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Claims (20)

1. Spoj sa formulom I, [image] pri čemu: prsten A i prsten B predstavljaju spojenu bicikličku grupu sa bilo kojom od sljedećih formula: [image] [image] pri čemu u formuli IA: W1a je CH, CF ili N; W2a je CH, CF ili N; W3a je CR4a ili N; W4a je CR5a ili N; W5a je CR6a ili N; u formuli IB: W1b je CH, CF ili N; W2b je CH, CF ili N; W3b je CR4b ili N; W4b je C ili N; W5b je CR6b ili N; W6b je C ili N; W7b je C ili N, i pri čemu kada W3b predstavlja N, W4b i W6b predstavljaju C i W5b predstavlja C ili N, tada R* je vodik (u svim ostalim slučajevima R* je izostavljeno); u formuli IC: W1c je CH, CRt1, N, NRq1, O ili S; W2c je CH, CRt2, N, NRq2, O ili S; W3c je C ili N; W4c je CR5c ili N; W5c je CR6c ili N; W6c je C ili N; u formuli ID: W1d je CH, CRt3, N, NRq3, O ili S; W2d je CH, CRt4, N, NRq4, O ili S; W3d je C ili N; W4d je CR5d ili N; W5d je C ili N; W6d je C ili N; svako Rt1, Rt2, Rt3 i Rt4 je nezavisno odabrano od halo, C1-3 alkila (npr. aciklički C1-3 alkil ili ciklopropil), 3- do 5-člane heterocikloalkil grupe, -ORs1, -CN, -N(Rs2)Rs3, -S(O)w1CH3 ili -C(O)CH3; w1 predstavlja 0, 1 ili 2; svako Rs1, Rs2 i R3s nezavisno predstavlja vodik ili C1-2 alkil; svako Rq1, Rq2, Rq3 i Rq4 je nezavisno odabrano od C1-3 alkila (npr. aciklički C1-3 alkil ili ciklopropil), 3- do 5-člane heterocikloalkil grupe ili -C(O)CH3; svako R1, R2a, R2b, R2c, R3, R4a, R5a, R6a, R4b, R6b, R5c, R6c i R5d je nezavisno odabrano od vodika ili supstituenta odabranog od halo, -CN, -C(O)N(Rf1)Rf2, -C(O)Rf3, -N(Rf4)Rf5, -C(O)ORf6, -ORf7, -OC(O)-Rf8, -S(O)w2CH3 ili C1-8 alkila (npr. aciklički C1-6 alkil ili C3-7 cikloalkil) i 3- do 8-članih heterocikloalkil grupa, od kojih su obje (tj. alkil i heterocikloalkil grupe) po izboru supstituirane sa jednim ili više supstituenata odabranih od =O i E1; w2 predstavlja 0, 1 ili 2; Rf1, Rf2, Rf4, Rf5 i Rf7 nezavisno predstavljaju vodik ili C1-6 alkil po izboru supstituiran sa jednim ili više supstituenata odabranih od =O i E2; ili Rf1 i Rf2 i/ili Rf4 i Rf5 mogu biti povezani zajedno da formiraju 4- do 8- (npr. 5- do 6-) člani prsten po izboru supstituiran sa jednim ili više supstituenata odabranih od C1-3 alkila i halo; Rf3, Rf6 i Rf8 nezavisno predstavljaju C1-6 alkil po izboru supstituiran sa jednim ili više supstituenata odabranih od =O i E2; X predstavlja direktnu vezu, -C(Ra)(Rb)-, -O-, -S-, -N(Rc)-, -N(Rd)C(O)-, -C(O)N(Re)- ili -N(Rf)-C(O)-N(Rg)-; Y predstavlja -arilen-, -heteroarilen- (pri čemu su posljednje dvije grupe po izboru supstituirane sa jednim ili više supstituenata odabranih od E3), -heterocikloalkilen- iliC1-12alkilen- (pri čemu su posljednje dvije grupe po izboru supstituirane sa jednim ili više supstituenata odabranih od =O i E4); RN predstavlja vodik ili C1-6 alkil po izboru supstituiran sa jednim ili više supstituenata odabranih od =O i E5; Z predstavlja -(Ax)1-7-, pri čemu svako Ax nezavisno predstavlja -C(Rx1)(Rx2)-, -N(Rx3)-, -C(O)-, -O-, -S-, -S(O)- ili -S(O)2-; Rx1, Rx2 i Rx3 svako nezavisno predstavlja vodik ili supstituent odabran od Ex; svako Ex nezavisno predstavlja halo, -C(O)Ry1, -N(Ry2)-C(O)-N(Ry3)(Ry4), C1-6 alkil ili heterocikloalkil (od kojih obje od posljednje dvije grupe su po izboru supstituirane sa jednim ili više halo atoma); Ry1, Ry2, Ry3 i Ry4 svako nezavisno predstavlja vodik ili C1-3 alkil po izboru supstituiran sa jednim ili više halo atoma; svako Ra, Rb, Rc, Rd, Re, Rf i Rg nezavisno predstavlja vodik ili C1-6 alkil po izboru supstituiran sa jednim ili više halo atoma; svako E1, E2, E3, E4 i E5 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi: (i) Q4; (ii) C1-12 alkil ili heterocikloalkil, od kojih su oba po izboru supstituirana sa jednim ili više supstituenata odabranih od =O i Q5; bilo koje dvije E1, E2, E3, E4 i/ili E5 grupe (na primjer na C1-12 alkil grupama, npr. kada su vezane za iste ili susjedne atome ugljika, ili, na aromatičnim grupama, kada su vezane za susjedne atome), mogu biti povezane zajedno da formiraju 3- do 12-člani prsten, koji po izboru sadrži jedno ili više (npr. jedno do tri) nezasićenja (poželjno, dvostruke veze), i pri čemu je prsten po izboru supstituiran sa jednim ili više supstituenata odabranih od =O i J1; svako Q4 i Q5 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi: halo, -CN, -N(R20)R21, -OR20, -C(=Y1)-R20, -C(=Y1)-OR20, -C(=Y1)N(R20)R21, -C(=Y1)N(R20)-O-R21a, -OC(=Y1)-R20, -OC(=Y1)-OR20, -OC(=Y1)N(R20)R21, -OS(O)2OR20, -OP(=Y1)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y1)R21, -N(R22)C(=Y1)OR21, -N(R22)C(=Y1)N(R20)R21, -NR22S(O)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y1)R20, -SC(=Y1)OR20, -SC(=Y1)N(R20)R21, -S(O)2R20, -SR20, -S(O)R20, -S(O)2OR20, C1-6 alkil ili heterocikloalkil (pri čemu su posljednje dvije grupe po izboru supstituirane sa jednim ili više supstituenata odabranih od =O i J2); svako Y1 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi, =O, =S, =NR23 ili =N-CN; svako R21a predstavlja C1-6 alkil ili heterocikloalkil (pri čemu su posljednje dvije grupe po izboru supstituirane sa jednim ili više supstituenata odabranih od J4 i =O); svako R20, R21, R22 i R23 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi, vodik, C1-6 alkil ili heterocikloalkil (pri čemu su posljednje dvije grupe po izboru supstituirane sa jednim ili više supstituenata odabranih od J4 i =O); ili bilo koji relevantan par od R20, R21 i R22, može (na primjer, kada su vezani za isti atom, susjedan atom (tj. 1,2-odnos) ili za atome koji su udaljeni dva atoma, tj. u 1,3-odnosu) biti povezan zajedno da formira (npr. zajedno sa potrebnim atomom dušika za koji mogu biti vezani) 4- do 20- (npr. 4- do 12-) člani prsten, koji po izboru sadrži jedan ili više heteroatoma (na primjer, dodatno onima koji mogu već biti prisutni, npr. (a) heteroatom(e) odabran od kisika, dušika i sumpora), koji po izboru sadrži jedno ili više nezasićenja (poželjno, dvostruke veze), i pri čemu je prsten po izboru supstituiran sa jednim ili više supstituenata odabranih od J6 i =O; svako J1, J2, J4 i J6 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi: (i) Q7; (ii) C1-6 alkil ili heterocikloalkil, od kojih su oba po izboru supstituirana sa jednim ili više supstituenata odabranih od =O i Q8; svako Q7 i Q8 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi: halo, -CN, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(O)2R50, -S(O)2N(R50)R51, -N(R52)-C(=Ya)-N(R50)R51, -S(O)2R50, -SR50, -S(O)R50, C1-6 alkil (po izboru supstituiran sa jednim ili više fluoro atoma) ili heterocikloalkil (po izboru supstituiran sa jednim ili više supstituenata odabranih od halo, -OR60 i -N(R61)R62); svako Ya nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi, =O, =S, =NR53 ili =N-CN; svako R50, R51, R52 i R53 nezavisno predstavlja, pri svakom pojavljivanju kada se ovdje koristi, vodik ili C1-6 alkil po izboru supstituiran sa jednim ili više supstituenata odabranih od fluoro, -OR60 i -N(R61)R62; ili bilo koji relevantan par od R50, R51 i R52 može (na primjer kada su vezani za isti ili susjedne atome) biti povezan zajedno da formira, 3- do 8-člani prsten, koji po izboru sadrži jedan ili više heteroatoma (na primjer, dodatno onima koji već mogu biti prisutni, heteroatome odabrane od kisika, dušika i sumpora), koji po izboru sadrže jedno ili više nezasićenja (poželjno, dvostruke veze), i pri čemu je prsten po izboru supstituiran sa jednim ili više supstituenata odabranih od =O i C1-3 alkila; R60, R61 i R62 nezavisno predstavljaju vodik ili C1-6 alkil po izboru supstituiran sa jednim ili više fluoro atoma; ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog.
2. Spoj prema patentnom zahtjevu 1, pri čemu, prsten A i prsten B predstavlja spojenu bicikličku grupu sljedeće strukture (opcionalni supstituenti nisu prikazani): [image] [image] [image] [image] [image]
3. Spoj prema patentnom zahtjevu 1 ili patentnom zahtjevu 2, pri čemu Y predstavlja arilen, heteroarilen, heterocikloalkilen ili C1-6alkilen, od kojih su sve grupe po izboru supstituirane kako je definirano ovdje, na primjer jednu od sljedećih grupa: [image] [image] [image]
4. Spoj prema patentnom zahtjevu 1, odabran od sljedećih: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
5. Spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 4, ili farmaceutski prihvatljiva sol ili solvat istog, pri čemu je spoj; [image]
6. Spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 4, ili farmaceutski prihvatljiva sol ili solvat istog, pri čemu je spoj; [image]
7. Spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 4, ili farmaceutski prihvatljiva sol ili solvat istog, pri čemu je spoj; [image]
8. Spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 4, ili farmaceutski prihvatljiva sol ili solvat istog, pri čemu je spoj; [image]
9. Spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog, za primjenu kao lijek.
10. Farmaceutska formulacija koja uključuje spoj sa formulom I, kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog, u smjesi sa farmaceutski prihvatljivim pomoćnim sredstvima, razblaživačem ili nosačem.
11. Spoj, kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog, za primjenu u liječenju bolesti u kojem je inhibicija PI3-K, kinaze PIM familije i/ili mTOR je željena i/ili potrebna.
12. Spoj za primjenu u skladu sa patentnim zahtjevom 11, pri čemu bolest je rak, imunološki poremećaj, kardiovaskularna bolest, virusna infekcija, inflamacija, poremećaj metabolizma/endokrine funkcije, neurološki poremećaj, opstruktivna bolest dišnih puteva, alergijska bolest, inflamatorna bolest, imunosupresija, poremećaj uobičajeno u vezi sa transplantacijom organa, bolest koja je u vezi sa AIDS-om, benigna hiperplazija prostate, familijarna adenomatoza, polipoza, neuro-fibromatoza, psorijaza, koštani poremećaj, ateroskleroza, proliferacija vaskularnih glatkih ćelija udružena sa aterosklerozom, plućna fibroza, artritis glomerulonefritis i postkirurška stenoza, restenoza, moždani udar, dijabetes, hepatomegalija, Alzheimerova bolest, cistična fibroza, bolest u vezi sa hormonima, imunodeficijentni poremećaj, destruktivni poremećaj kostiju, infektivna bolest, stanje udruženo sa staničnom smrti, trombinom inducirana agregacija trombocita, kronična mijelogena leukemija, bolest jetre, patološko imunološko stanje koje uključuje aktivaciju T stanica, poremećaji CNS-a, plućna arterijska hipertenzija (PAH), i druge srodne bolesti.
13. Spoj za primjenu u skladu sa patentnim zahtjevom 11, pri čemu bolest je rak odabran od karcinoma kao što su rak mokraćnog mjehura, dojke, kolona, bubrega, jetre, pluća (uključujući nesitnostanični rak i sitnostanični rak pluća), jednjaka, žučne vrećice, jajnika, gušteraće, želuca, grlića materice, tiroideje, prostate, kože, karcinom skvamoznih stanica, testisa, genitourinarnog trakta, grkljana, glioblastom, neuroblastom, keratoakantom, epidermoidni karcinom, karcinom velikih stanica, nesitnostanični karcinom pluća, sitnostanični karcinom pluća, adenokarcinom pluća, kostiju, adenom, adenokarcinom, folikularni karcinom, nediferencirani karcinom, papilarni karcinom, seminon, melanom, sarkom, karcinom mokraćnog mjehura, karcinom jetre i žučnih puteva, karcinom bubrega, mijeloidni poremećaji, limfoidni poremećaji, vlasastih stanica, bukalne šupljine i ždrijela (oralni), usana, jezika, usta, ždrijela, tankog crijeva, kolon-rektuma, debelog crijeva, rektuma, mozga i centralnog nervnog sistema, Hodgkin-ov i leukemija; hematopoetskih tumora limfoidne loze, uključujući leukemiju, akutnu limfocitnu leukemiju, akutnu limfoblastnu leukemiju, B-stanični limfom, T-stanični limfom, Hodgkin-ov limfom, ne-Hodgkin-ov limfom, limfom vlasastih stanica i Burkittov limfom; hematopoetskih tumora mijeloidne loze, uključujući akutne i kronične mijelogene leukemije, mijelodisplastični sindrom i promijelocitnu leukemiju; tumora mezenhimalnog porekla, uključujući fibrosarkom i rabdomiosarkom; tumora centralnog i perifernog živčanog sustava, uključujući astrocitom, neuroblastom, gliom i švanome; i ostalih tumora, uključujući melanom, seminom, teratokarcinom, osteosarkom, kserodermu pigmentozum, keratoksantom, tiroidni folikularni rak i Kaposijev sarkom.
14. Kombinirani proizvod koji sadrži: (A) spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 4, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog; i (B) drugi terapijski agens koji je koristan u liječenju raka i/ili proliferativne bolesti, pri čemu svaki od spojeva (A) i (B) je formuliran u smjesi sa farmaceutski prihvatljivim pomoćnim sredstvom, razblaživačem ili nosačem.
15. Kombinirani proizvod prema patentnom zahtjevu 14, pri čemu komponenta (B) je trastuzumab.
16. Kombinirani proizvod prema patentnom zahtjevu 14, pri čemu komponenta (B) je cisplatin.
17. Kombinirani proizvod prema patentnom zahtjevu 14, 15 ili 16 koji obuhvaća farmaceutsku formulaciju koja uključuje spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog, drugi terapijski agens koji je koristan u liječenju raka i/ili proliferativne bolesti, i farmaceutski prihvatljiva pomoćna sredstva, razblaživač ili nosač.
18. Kombinirani proizvod prema patentnom zahtjevu 14, 15 ili 16 koji sadrži komplet dijelova koji sadrži komponente: (a) farmaceutsku formulaciju koja uključuje spoj sa formulom I kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljiv ester, amid, solvat ili sol istog, u smjesi sa farmaceutski prihvatljivim pomoćnim sredstvima, razblaživačem ili nosačem; i (b) farmaceutsku formulaciju koja uključuje drugi terapijski agens koji je koristan u liječenju raka i/ili proliferativne bolesti u smjesi sa farmaceutski prihvatljivim pomoćnim sredstvima, razblaživačem ili nosačem, pri čemu je svaka komponenta (a) i (b) osigurana u obliku koji je pogodan za administraciju u sprezi sa ostalim.
19. Proces za pripremu spoja sa formulom I kako je definirano u patentnom zahtjevu 1, pri čemu proces obuhvaća: (i) za spojeve sa formulom I u kojima Z sadrži -C(O)N(Rx3)- ili -N(Rx3)C(O)-segment, intramolekularnu reakciju spoja sa formulom II, [image] pri čemu Z1 i Z2 nezavisno predstavlja -C(O)OH, -N(Rx3)H ili djelomični Z segment sa terminalnom -C(O)OH grupom ili terminalnom -N(Rx3)H grupom (ili derivate istog, kao što su derivati estera karboksilne kiseline), pri čemu jedno od Z1 i Z2 sadrži C(O)OH grupu (ili derivat) i drugo sadrži -N(Rx3)H grupu (ili derivat) i prsten A/prsten B, R1, R2a, R2b, R2c, R3, X i Y su kako je definirano u patentnom zahtjevu 1; (ii) spojeve sa formulom I u kojima Z sadrži -O-, -S- ili -N(Rx3)-, mogu se pripremiti pomoću reakcije spoj sa formulom III, [image] pri čemu Z3 predstavlja -OH, -N(Rx3)H ili -Lx (u kome je Lx pogodna odlazeća grupa), ili Z3 sadrži djelomični Z segment sa terminalnom -OH, -N(Rx3)H ili -Lx grupom i Z4 predstavlja Ly-, HO- ili H(Rx3)N- (po potrebi) ili djelomični Z segment sa terminalnom Ly-, HO- ili H(Rx3)N-, Ly je pogodna odlazeća grupa (i pri čemu jedno od Z3 i Z4 sadrži -OH, -SH ili -N(Rx3)H segment a drugo sadrži Lx ili Ly segment), i prsten A/prsten B, R1, R2a, R2b, R2c, R3, X i Y su kako je definirano u patentnom zahtjevu 1; (iii) spojevi sa formulom I u kojima Rx3, Ry2, Ry3 i/ili Ry4 predstavljaju po izboru supstituirani C1-6 ili C1-3 alkil, mogu se pripremiti pomoću reakcije odgovarajućeg spoja sa formulom I u kojem Rx3, Ry2, Ry3 i/ili Ry4 predstavljaju vodik, sa spojem sa formulom IV, L1-R12-14 IV pri čemu R12-14 predstavlja Rx3, Ry2, Ry3 ili Ry4 (po potrebi/zahtijevano) i L1 predstavlja pogodnu odlazeću grupu kako je definirano za Lx, ili sa spojem sa formulom V, H(O)C-R12a-14a V pri čemu R12a-14a predstavlja C1-5 ili C1-2 alkil po izboru supstituiran sa jednim ili više halo atoma; (iv) za spojeve sa formulom I koja sadrže -N(Rx3)-CH2- segment, redukciju odgovarajućeg spoja sa formulom I koje sadrži -N(Rx3)C(O)- segment.
20. Proces za pripremu: (I) farmaceutske formulacije kako je definirano u patentnom zahtjevu 10, pri čemu proces obuhvaća dovođenje u vezu spoja sa formulom I, kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljivog estera, amida, solvata ili soli istog sa farmaceutski prihvatljivim pomoćnim sredstvima, razblaživačem ili nosačem; i/ili (II) kombiniranog proizvoda kako je definirano u patentnom zahtjevu 14, 15, 16, 17 ili 18, pri čemu proces obuhvaća dovođenje u vezu spoja sa formulom I, kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili farmaceutski prihvatljivog estera, amida, solvata ili soli istog sa drugim terapijskim agensom koji je koristan u liječenju raka i/ili proliferativne bolesti, i najmanje jednog farmaceutski prihvatljivog pomoćnog sredtsva, razblaživača ili nosača.
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