HRP20200016T1 - Amidno supstituirani tiazoli kao modulatori rorgamat - Google Patents

Amidno supstituirani tiazoli kao modulatori rorgamat Download PDF

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HRP20200016T1
HRP20200016T1 HRP20200016TT HRP20200016T HRP20200016T1 HR P20200016 T1 HRP20200016 T1 HR P20200016T1 HR P20200016T T HRP20200016T T HR P20200016TT HR P20200016 T HRP20200016 T HR P20200016T HR P20200016 T1 HRP20200016 T1 HR P20200016T1
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alkyl
optionally substituted
group
fluorine atoms
morpholinyl
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Hariharan Venkatesan
Virginia TANIS
Maud Urbanski
Aihua Wang
David A. Kummer
Christoph Steeneck
Christian Gege
Olaf Kinzel
Gerald Kleymann
Thomas Hoffmann
Steven Goldberg
Anne M. Fourie
Xiaohua XUE
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Janssen Pharmaceutica Nv
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Claims (15)

1. Spoj Formule I: pri čemu: Ⓐ je fenil, piridil, pirimidil, pirazinil, ili piridazil; R1 je Cl, -CN, H, F, OC(1-4)alkil, OCHF2, OCF3, C(1-4)alkil, Br, I, ili ciklopropil; pri čemu spomenuti C(1-4)alkil je opcionalno supstituiran sa do šest atoma fluora; R2 je F, Cl, -CN, H, OC(1-4)alkil, OCHF2, OCF3, ciklopropil, ili C(1-4)alkil; pri čemu spomenuti C(1-4)alkil je opcionalno supstituiran sa do pet atoma fluora, i spomenuti ciklopropil je opcionalno supstituiran sa OH, CH3, CF3, i do pet atoma fluora; ili R1 i R2 mogu zajedno sa prstenom A za koji su vezani oblikovatisistem spojenih prstena izabranih iz grupe koja obuhvaća naftalenil, tetrahidronaftalenil, izokinolinil, kinolinil, 2,3-dihidro-1H-indenil, kromanil, izokromanil, i naftiridinil; pri čemu spomenuti naftalenil, tetrahidronaftalenil, izokinolinil, kinolinil, 2,3-dihidro-1H-indenil, kromanil, izokromanil, i naftiridinil mogu opcionalno biti supstituirani sa do tri supstituenata nezavisno izabranih iz grupe koja obuhvaća F, OC(1-3)alkil ili C(1-3)alkil pri čemu spomenuti OC(1-3)alkil i C(1-3) alkil je opcionalno supstituiran sa do pet atoma fluora (uključujući CHF2, CH2F, CF3, i CH3; pod uvjetomuvjet da R2 ne mora biti H ukoliko R1 je H; R3 je tiadiazolil, oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, tetrazolil, 1,2,4-oksadiazol-5(4H)-on-3-il, piridil, tiazolil, pirimidil, piridazil, pirazil, imidazolil, pirolil, furanil, ili fenil; pri čemu spomenuti tiadiazolil, oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, piridil, tiazolil, pirimidil, piridazil, pirazil, imidazolil, pirolil, furanil, ili fenil je opcionalno supstituiran sa R4, i dalje opcionalno supstituiran sa jednim supstituentom izabranim iz grupe koja obuhvaća F, CH3, CF3, i ciklopropil; R4 je H, C(1-6)alkilSO2C(1-6)alkil, C(O)NH2, C(1-6)alkil, -CN, C(3-6)cikloalkil, NH2, NH(C(1-6)alkil), N(C(1-6)alkil)2, NHCO(C(1-6)alkil), N(C(1-6)alkil)CO(C(1-6)alkil), NHSO2(C(1-6)alkil), N(C(1-6)alkil)SO2(C(1-6)alkil), O(C(1-6)alkil), C(O)NH2, CONH(C(1-6)alkil), CON(C(1-6)alkil)2, SO2NH2, SO2NH(C(1-6)alkil), SO2NH(COC(1-6)alkil), ili SO2N(C(1-6)alkil)2; pri čemu spomenuti C(1-6)alkil ili C(3-6)cikloalkil je opcionalno nezavisno supstituiran sa do šest atoma fluora, CF3, CO2H, OH, -CN, C(O)NH2, NH2, OCH3, OCHF2, OCF3, -(CKS2)m-, ili N(CH3)2; m je 2, 3, 4, ili 5; X je H, ili F; gdje je svako pojavljivanje X u jednoj molekuli nezavisno definirano; A1 je H, ili C(1-4)alkil; pri čemu spomenuti C(1-4)alkil je opcionalno supstituiran sa do šest atoma fluora, Cl, -CN, OCH3, OCHF2, ili OCF3; A2 je C(1-6)alkil, C(0-2)alkil-C(3-6)cikloalkil, CH2-C6H4-C(O)NH2, -C6H4-F, CH2-CCH, ili CH2-CC-CH3; pri čemu spomenuti C(1-6)alkil, i spomenuti C(0-2)alkil-C(3-6)cikloalkil su opcionalno supstituirani sa do šest atoma fluora, Cl, -CN, OCH3, OCHF2, ili OCF3; ili A1 i A2 mogu zajedno s dušikomdušik za koji su vezani oblikovati prsten izabran iz grupe koja se sastoji iz: tiomorfolinil, piperidinil, pirolidinil, piperazinil, morfolinil, azetidinil, i aziridinil; pri čemu spomenuti piperidinil, pirolidinil, piperazinil, morfolinil, azetidinil, i aziridinil su opcionalno supstituirani sa CF3, CH2CH2F, C(1-2)alkil, C(3-6)cikloalkil, -CN, OH, CH2OH, CH2F, F, Cl, OCH3, OCHF2, OCF3, -(CX2)nO(CX2)n-, ili -(CX2)n-, i do tri dodatna supstituenta izabrana iz grupe koja se sastoji iz CH3 i F; n je nezavisno 0, 1, 2, 3, ili 4; X je H, ili F; gdje svako pojavljivanje X u jednoj molekuli je nezavisno definirano; R5 je SO2NA3A4, CONA3A4, NA3A4, OCH2C(CF3)2OH, C(3-6)cikloalkil, ili C(1-6)alkil; pri čemu spomenuti C(3-6)cikloalkil i spomenuti C(1-6)alkil su opcionalno supstituirani sa OH, Cl, -CN, H, OCH3, OCHF2, OCF3, ili NA3A4, dalje opcionalno supstituirane sa -CH2CH2- koji je vezan za isti ugljikov atom, i do sedam atoma fluora; A3 je H, ili C(1-4)alkil; pri čemu spomenuti C(1-4)alkil je opcionalno supstituiran sa OH, Cl, -CN, OCH3, OCHF2, ili OCF3; i do šet atoma fluora; A4 je H, C(1-6)alkil, C(3-6)cikloalkil, ili C(3-6)heterocikloalkil; pri čemu spomenuti C(1-6)alkil je opcionalno supstituiran sa ciklopropil, morfolinil, OH, OCH3, C(O)NH2, Cl, -CN, OCHF2, OCF3 i dodatno supstituiran sa do tri atoma fluora; i gdje spomenuti C(3-6)cikloalkil, i C(3-6)heterocikloalkil su opcionalno supstituirani sa CF3, CH3, -CN, C(O)NH2, i do tri atoma fluora; ili A3 i A4 mogu zajedno sa dušikomdušik za koji su vezani oblikovatiprsten izabran iz grupe koja obuhvaća piperidinil, morfolinil, piperazinil, pirolidinil, aziridinil, i azetidinil gdje spomenuti piperidinil, morfolinil, piperazinil, pirolidinil, aziridinil, i azetidinil su opcionalno supstituirani sa do četiri grupe koje su izabrane iz grupe koja obuhvaća CF3, OH, CH3, CH2F, i CHF2; i dalje opcionalno supstituirani sa do četiri grupe izabrane iz grupe koja obuhvaća CF3, OH, CH3, CH2F, i CHF2; i dalje opcionalno supstituirani sa do šest atoma fluora; i njegove farmaceutski prihvatljive soli.
2. Spoj prema zahtjevu 1, pri čemu: R1 je Cl, -CN, H, F, OCH3, OCHF2, OCF3, C(1-2)alkil, Br, ili I; pri čemu spomenuti C(1-2)alkil je opcionalno supstituiran sa pet atoma fluora; R2 je F, Cl, -CN, H, OCH3, OCHF2, OCF3, ciklopropil ili C(1-2)alkil; pri čemu spomenuti C(1-2)alkil je opcionalno supstituiran sa do pet atoma fluora, i spomenuti ciklopropil je opcionalno supstituiran sa OH, CH3, CF3, i do pet atoma fluora; ili R1 i R2 mogu zajedno sa fenilom za koji su vezani oblikovatisistem spojenog prstena koji je izabran iz grupe koja obuhvaća naftalenil, tetrahidronaftalenil, izokinolinil, kinolinil, i kromanil; pod uvjetom da R2 može ne bitiH ukoliko R1 je H; R3 je oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, tetrazolil, 1,2,4-oksadiazol-5(4H)-on-3-il, piridil, tiazolil, pirimidil, piridazil, pirazil, imidazolil, ili pirolil; pri čemu spomenuti oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, piridil, tiazolil, pirimidil, piridazil, pirazil, imidazolil, ili pirolil je opcionalno supstituiran sa R4, i spomenuti triazolil može dodatno bitisupstituiran sa jednim supstituentom izabranim iz grupe koja obuhvaća CH3 i ciklopropil; R4 je H, CH2SO2CH3, C(O)NH2, C(1-4)alkil, ili -CN; pri čemu spomenuti C(1-4)alkil je opcionalno supstituiran sa do šest atoma fluora, CO2H, OH, ili -CN; A1 je H, ili C(1-3)alkil; pri čemu spomenuti C(1-3)alkil je opcionalno supstituiran sa do pet atoma fluora, Cl, -CN, OCH3, OCHF2, ili OCF3; A2 je C(1-4)alkil, C(0-2)alkil-C(3-6)cikloalkil, CH2-C6H4-C(O)NH2, -C6H4-F, CH2-CCH, ili CH2-CC-CH3; pri čemu spomenuti C(1-4)alkil, i spomenuti C(0-2)alkil-C(3-6)cikloalkil su opcionalno supstituirani sa do tri atoma fluora, Cl, -CN, OCH3, OCHF2, ili OCF3; ili A1 i A2 mogu zajedno sa dušikom za koji su vezani oblikovatiprsten izabran iz grupe koja obuhvaća:
tiomorfolinil, piperidinil, pirolidinil, piperazinil, morfolinil, azetidinil, i aziridinil; pri čemu spomenuti piperidinil, pirolidinil, piperazinil, morfolinil, azetidinil, i aziridinil u opcionalno supstituirani sa CF3, CH2CH2F, C(1-2)alkil, C(3-6)cikloalkil, -CN, OH, CH2OH, CH2F, F, Cl, OCH3, OCHF2, OCF3, -(CX2)nO(CX2)n-, ili -(CX2)n-, i do tri dodatna supstituenta koja su izabrana iz grupe koja obuhvaća CH3 i F; R5 je SO2NA3A4, OCH2C(CF3)2OH, ili C(1-6)alkil; pri čemu spomenuti C(1-6)alkil je opcionalno supstituiran sa OH, Cl, -CN, H, OCH3, OCHF2, ili OCF3; i do šest atoma fluora; A4 je C(1-6)alkil, C(3-6)cikloalkil, oksetanil, ili tetrahidrofuranil; pri čemu spomenuti C(1-6)alkil je opcionalno supstituiran sa ciklopropil, morfolinil, OH, OCH3, ili C(O)NH2, i dodatno je supstituiran sa do tri atoma fluora; i pri čemu spomenuti C(3-6)cikloalkil, oksetanil, i tetrahidrofuranil su opcionalno supstituirani sa CF3, CH3, -CN, ili C(O)NH2; ili A3 i A4 mogu zajedno sa dušikom za koji su vezani oblikovatiprsten izabran iz grupe koja obuhvaća piperidinil, morfolinil, piperazinil, i pirolidinil, pri čemu spomenuti piperidinil, morfolinil, i piperazinil su opcionalno supstituirani sa do četiri metil grupe i do šest atoma fluora; i njihove farmaceutski prihvatljive soli.
3. Spoj prema zahtjevu 2, pri čemu: R1 je Cl, -CN, H, F, OCH3, OCHF2, OCF3, ili C(1-2)alkil; pri čemu spomenuti C(1-2)alkil je opcionalno supstituiran sa do pet atoma fluora; R2 je F, Cl, -CN, CHF2, CF3, CH3, ili H; ili R1 i R2 mogu zajedno sa fenilom za koji su vezani oblikovatisistem spojenih prstena koji je izabran iz grupe koja obuhvaća naftalenil, tetrahidronaftalenil, izokinolinil, kinolinil, i kromanil; pod uvjetom da R2 ne mora bitiH ukoliko R1 je H; R3 je oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, tetrazolil, 1,2,4-oksadiazol-5(4H)-on-3-il, piridil, tiazolil, pirimidil, piridazil, ili pirazil; pri čemu spomenuti oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, piridil, tiazolil, pirimidil, piridazil, ili pirazil je opcionalno supstituiran sa R4, i spomenuti triazolil može dodatno bitisupstituiran sa jednim supstituentom koji je izabran iz grupe koja obuhvaća CH3 i ciklopropil; R4 je H, CH2SO2CH3, C(O)NH2, CH2C(CH3)2CO2H, CH2C(CH3)2CN, C(0-1)alkilC(CH3)2OH, -CN, ili C(1-2)alkil; pri čemu spomenuti C(1-2)alkil je opcionalno supstituiran sa do pet atoma fluora; A1 je H, ili C(1-3)alkil; pri čemu spomenuti C(1-3)alkil je opcionalno supstituiran sa do pet atoma fluora; A2je C(1-4)alkil, C(0-2)alkil-C(3-6)cikloalkil, CH2-C6H4-C(O)NH2, -C6H4-F, CH2-CCH, CH2-CC-CH3, ili CH2CH2-CN; pri čemu spomenuti C(1-4)alkil, i spomenuti C(0-2)alkil-C(3-6)cikloalkil su opcionalno supstituirani sa do tri atoma fluora; ili A1 i A2 mogu zajedno sa dušikom za koji su vezani oblikovatiprsten koji je izabran iz grupe koja obuhvaća:
tiomorfolinil, piperidinil, pirolidinil, piperazinil, i morfolinil; pri čemu spomenuti piperidinil, pirolidinil, piperazinil, i morfolinil su opcionalno supstituirani sa CF3, CH2CH2F, C(1-2)alkil, -CN, OH, CH2OH, CH2F, ili F, i do tri dodatna supstituenta izabrana iz grupe koja obuhvaća CH3 i F; R5 je SO2NA3A4, OCH2C(CF3)2OH, ili C(1-6)alkil; pri čemu spomenuti C(1-6)alkil je opcionalno supstituiran sa jednom OH grupom i do šest atoma fluora; A3 je H, ili C(1-4)alkil; A4 je C(1-6)alkil, ciklopropil, ciklobutil, oksetanil, ili tetrahidrofuranil; pri čemu spomenuti C(1-6) alkil je opcionalno supstituiran sa ciklopropil, morfolinil, OH, OCH3, ili C(O)NH2, i dodatno supstituiran sa do tri atoma fluora; i gdje spomenuti ciklopropil ciklobutil, oksetanil, i tetrahidrofuranil su opcionalno supstituirani sa CF3, CH3, -CN, ili C(O)NH2; ili A3 i A4 mogu zajedno sa dušikom za koji su vezani oblikovatiprsten koji je izabran iz grupe koja obuhvaća piperidinil, morfolinil, piperazinil, i pirolidinil, pri čemu spomenuti piperidinil, morfolinil, i piperazinil su opcionalno supstituirani sa jednom ili dve metil grupe i do tri atoma fluora; i njihove farmaceutski prihvatljive soli.
4. Spoj prema zahtjevu 3, pri čemu R1 je Cl, CHF2, CF3, CH3, CH2CH3, -CN, H, F, OCH3, OCHF2, ili OCF3; R2 je F, Cl, CHF2, CF3, CH3, ili H; ili R1 i R2 mogu zajedno sa fenilom za koji su vezani oblikovatispojeni sistem prstena koji je izabran iz grupe koja obuhvaća naftalenil, tetrahidronaftalenil, izokinolinil, i kromanil; pod uvjetuvjetom da R2 ne mora biti H ukoliko R1 je H; R3 je oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, tetrazolil, 1,2,4-oksadiazol-5(4H)-on-3-il, piridil, ili tiazolil, pri čemu spomenuti oksadiazolil, izoksadiazolil, oksazolil, izoksazolil, triazolil, piridil, ili tiazolil je opcionalno supstituiran sa R4, i spomenuti triazolil može dodatno biti supstituiran sa jednim supstituentom koji je izabran iz grupe koja obuhvaća CH3 i ciklopropil; R4 je H, CH2SO2CH3, C(O)NH2, CH3, CH2C(CH3)2CO2H, CH2C(CH3)2CN, C(0-1)alkilC(CH3)2OH, A1 je H, C(1-3)alkil, ili CH2CH2F; A2 je C(2-4)alkil, CH2-ciklopentil, CH2CH2-ciklopropil, C(3-4)cikloalkil, CH2-C6H4-C(O)NH2, -C6H4-F, CH2-CCH, CH2CH2-CN, CH2-CC-CH3; gdje spomenuti C(3-4)cikloalkil je opcionalno supstituiran sa jednim atomom fluora i spomenuti C(2-4)alkil je opcionalno supstituiran sa do tri atoma fluora; ili A1 i A2 mogu zajedno sa dušikom za koji su vezani oblikovati prsten izabran iz grupe koja obuhvaća:
tiomorfolinil, piperidinil, pirolidinil, i morfolinil; gdje spomenuti piperidinil, pirolidinil, i morfolinil su opcionalno supstituirani sa CF3, CH2CH2F, C(1-2)alkil, -CN, OH, CH2OH, ili CH2F i do tri dodatna supstituenta izabrana iz grupe koja obuhvaća CH3 i F; R5 je SO2NA3A4, CH2C(CF3)2OH, OCH2C(CF3)2OH, ili C(CF3)2OH; A3 je H, CH3, ili C(1-4)alkil; A4 je C(1-6)alkil,
C(CH3)2CH2OCH3, C(CH3)2CH2OH, C(CH3)2CH2-morfolinil, C(CH3)2CH2CH2OH, C(CH3)2CH2C(O)NH2, ili CH2C(CH3)2OH; gdje spomenuti C(1-6)alkil je opcionalno supstituiran sa do tri atoma fluora; ili A3 i A4 mogu zajedno sa dušikom za koji su vezani oblikovati prsten izabran iz grupe koja obuhvaća i njegove farmaceutski prihvatljive soli.
5. Spoj prema zahtjevu 4, gdje:
R1 je H, Cl, CHF2, CF3, CH3, F, OCHF2, ili OCF3; R2 je F, Cl, CHF2, CF3, CH3, ili H; ili R1 i R2 mogu zajedno sa fenilom za koji su vezani oblikovati spojeni sistem prstena izabran iz grupe koja obuhvaća naftalenil, i kromanil; pod uvjetuvjetom da R2 može ne biti H ukoliko R1 je H; R3 je
piridil, ili pirimidil, gdje spomenuti piridil ili pirimidil je opcionalno supstituiran sa R4; A1 je CH3, CH2CH3; A2 je CH2CH2CH3, CH(CH3)2, CH2CH3, ili CH2CF3; ili A1 i A2 mogu zajedno sa dušikom za koji su vezani oblikovati prsten izabran iz grupe koja obuhvaća:
A3 je H, ili CH3; A4 je CH2CF3, ili C(CH3)2CF3; i njihove farmaceutski prihvatljive soli.
6. Spoj prema zahtjevu 5 izabran iz grupe koja obuhvaća:
i njegove farmaceutski prihvatljive soli.
7. Spoj prema zahtjevu 4 izabran iz grupe koja obuhvaća:
i njihove farmaceutski prihvatljive soli.
8. Farmaceutski sastav, koji obuhvaća spoj prema zahtjevu 1 i njegov farmaceutski prihvatljiv nosač.
9. Farmaceutski sastav dobiven miješanjem spoja prema zahtjevu 1 i farmaceutski prihvatljivog nosača.
10. Postupak za dobivanje farmaceutskog sastava koji obuhvaća miješanje spoja prema zahtjevu 1 i farmaceutski prihvatljivog nosača.
11. Spoj prema zahtjevu 1 za upotrebu u postupku liječenja subjekta koji pati od ili mu je postavljena dijagnoza upalnog sindroma, poremećaja ili bolesti posredovanog sa RORyt.
12. Spoj za upotrebu prema zahtjevu 11, gdje je bolest izabrana iz grupe koja obuhvaća: upalne bolesti crijeva, reumatoidni artitis, psorijazu, kronični opstruktivni poremećaj pluća, psorijazni artritis, ankilozirajući spondilitis, neutrofilnu astmu, astmu koja je rezistentna na steroide, multiplu sklerozu, i sistemski eritematozni lupus.
13. Spoj za upotrebu prema zahtjevu 12, gdje je bolest psorijaza, psorijazni artritis ili reumatoidni artritis.
14. Spoj za upotrebu prema zahtjevu 12, gdje je upalna bolest crijeva ulcerozni kolitis ili Crohnova bolest.
15. Spoj prema zahtjevu 1 ili njegov sastav ili lijek u kombinaciji s jednim ili više anti-inflamatornim tvarima ili imunosupresivnim tvarima za upotrebu u postupku za liječenje subjekta koji pati od ili ima dijagnozu sindroma, poremećaja ili bolesti izabranog iz grupe koja obuhvaća: reumatoidni artritis, i psorijazu.
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