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FI3609888T3 - Farnesoid x -reseptorin agonisteja ja niiden käyttötapoja - Google Patents

Farnesoid x -reseptorin agonisteja ja niiden käyttötapoja

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Publication number
FI3609888T3
FI3609888T3 FIEP18768017.8T FI18768017T FI3609888T3 FI 3609888 T3 FI3609888 T3 FI 3609888T3 FI 18768017 T FI18768017 T FI 18768017T FI 3609888 T3 FI3609888 T3 FI 3609888T3
Authority
FI
Finland
Prior art keywords
substituted
unsubstituted
alkyl
trans
cyclohexyl
Prior art date
Application number
FIEP18768017.8T
Other languages
English (en)
Inventor
Nicholas D Smith
Steven P Govek
Johnny Y Nagasawa
Karensa L Douglas
Andiliy G Lai
Original Assignee
Lilly Co Eli
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Filing date
Publication date
Application filed by Lilly Co Eli filed Critical Lilly Co Eli
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Publication of FI3609888T3 publication Critical patent/FI3609888T3/fi

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Claims (16)

1 EP3 609 888 PATENTTIVAATIMUKSET
1. Yhdiste, jolla on kaavan (III) mukainen rakenne tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti: O Rom R RI N x4 x? S x1 x R10 LE OA =X A R ”x3 N RB R'n Kaava (Ill) jossa A = De Te / N (R$), on (R'n : X! on CH tai N; R! on H, D, halogeeni, -CN, -OH, -N(R'5)2, -NR15S(=O)2(C1-C4-alkyyli), - OC(=0)(C1-C4-alkyyli), -CO2H, -CO2(C1-C4-alkyyli), -C(=O)N(R'5)2, - NR'5C(=O)(C1-C4-alkyyli), -NR'5C(=O0)O(C1-C4-alkyyli), -OC(=O)N(R!5)2, - NR'5C(=O)N(R!'5)2, C1-C4-alkyyli, C2-C4-alkenyyli, C2-C4-alkynyyli, C1-C4-alkoksi, C1-C4-deuteroalkyyli, C1-C4-deuteroalkoksi, C1-C4-fluorialkyyli, C1-C4-fluorialkoksi, C1-C4-heteroalkyyli tai substituoitu tai substituoimaton monosyklinen C2-Cs- heterosykloalkyyli; X? on CR? tai N; R? on H, D, halogeeni, -CN, -OH, -N(R'5)2, -NR15S(=O)2(C1-C4-alkyyli), - OC(=0)(C1-C4-alkyyli), -CO2H, -CO2(C1-C4-alkyyli), -C(=O)N(R'5)2, - NR'5C(=O)(C1-C4-alkyyli), -NR'5C(=0)O(C1-C4-alkyyli), -OC(=O)N(R!5)2, - NR'5C(=O)N(R!'5)2, C1-C4-alkyyli, C2-C4-alkenyyli, C2-C4-alkynyyli, C1-C4-alkoksi,
2 EP3 609 888 C1-C4-deuteroalkyyli, C1-C4-deuteroalkoksi, C1-C4-fluorialkyyli, C1-C4-fluorialkoksi tai C1-C4-heteroalkyyli;
tai R! ja R? muodostavat yhdessä välissä olevien atomien kanssa substituoidun tai substituoimattoman fuusioituneen 5-jäsenisen renkaan, jossa on
0-3 N-atomia ja 0-2 O- tai S-atomia renkaassa;
X3 on CR? tai N;
R? on H, D, halogeeni, -CN, -OH, -N(R'5)2, -NR15S(=O)2(C1-C4-alkyyli), - OC(=0)(C1-C4-alkyyli), -CO2H, -CO2(C1-C4-alkyyli), -C(=O)N(R'5)2, - NR'5C(=O)(C1-Ca4-alkyyli), C1-C4-alkyyli, C2-C4-alkenyyli, C2-C4-alkynyyli, C1-C4-
alkoksi, C1-C4-deuteroalkyyli, C1-C4-deuteroalkoksi, C1-Ca-fluorialkyyli, C1-C4- fluorialkoksi tai C1-C4-heteroalkyyli;
kukin X on itsenäisesti CH tai N;
R on H, D, F tai -CH3;
R> on H, D, F tai -CH3;
tai R? ja R* muodostavat yhdessä sillan, joka on -CH>- tai -CH2CHz-; kukin R$ on itsenäisesti H, D, F, -OH tai -CHs;
m on O, 1 tai 2;
R7 on H, D, halogeeni, -CN, -OH, C1-C4-alkyyli, C1-C4-alkoksi, C1-C4- deuteroalkyyli, C1-C4-deuteroalkoksi, C1-Ca-fluorialkyyli, C1-C4-fluorialkoksi tai C1-
C<-heteroalkyyli;
R8 on H, D, C1-Ce-alkyyli, C1-Ce-deuteroalkyyli, C1-Ce-fluorialkyyli, C1-Ce- heteroalkyyli, -C(=O)(C1-C4-alkyyli), -CO2(C1-C4-alkyyli), -C(=0)N(R!)2, - S(=0)2(C1-C4-alkyyli), -S(=0)2N(R'®),, substituoitu tai substituoimaton C3-Ce- sykloalkyyli tai substituoitu tai substituoimaton monosyklinen C2-Ce-
heterosykloalkyyli, substituoitu tai substituoimaton fenyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli;
3 EP3 609 888
R'9 on -CH2OH, -CH2CH2OH, C1-Ce-heteroalkyyli, -CO2H, -C(=0)R"4, - C(=O)OR'4, -OC(=O)R'4, -OC(=O)OR!% tetratsolyyli, imidatsoli, -S(=O)2N(R??)2, - NR'5S(=O)2R'!4, -C(=O)NR'5S(=O)2R!4, -S(=O),NR'5C(=O)R'4, -CH2N(R?), - NR'SC(=0)R"4, -C(=O)N(R!2)2, -NR15C(=O)OR!'4%, -OC(=O)N(R!%)2, -
NR'5C(=O)N(R!%)>, -C(=NH)NH2, -NHC(=NH)NH>, -C(=O)NHC(=NH)NH,, -
S(=O)20H tai -OP(=0)(0OR'®);
tai R'9 on -L2-L3-L4-R"3;
L? on poissa, substituoitu tai substituoimaton C1-Ce-alkyleeni tai substituoitu tai substituoimaton C1-Ce-heteroalkyleeni;
L3 on poissa, -O-, -S-, -S(=O)-, -S(=O)2., -NR'5-, -C(=O)-, -C(=O)NR'5-, - NR'5C(=O)-, -C(=0)O-, -OC(=0)-, -OC(=O)NR!'5-, -NR15C(=O)NR'S-, - NR15C(=O)0-, -OP(=O)(OR'5)O- tai -(OCH2CH2)r-, r on 1 tai 2;
L on substituoitu tai substituoimaton C1-Ce-alkyleeni tai substituoitu tai substituoimaton C1-Ce-heteroalkyleeni;
R'3 on H, -CN, -OH, -N(R!2)2, -NR15S(=O),R!4, -S(=0)2N(R"'?),, -SR!?, - S(=0)R™, -S(=O)2R'%, -SO3H, -OP(=O0)(OR'5)2, -C(=O)R'1%, -OC(=O)R'%, -CO2H, - CO2R'%, -OC(=0)OR™, -NR'5C(=O)R!4, -C(=O)N(R!2)0, -NR'5C(=O)OR!'4%, - OC(=O)N(R!2)2, substituoitu tai substituoimaton C1-Ce-alkyyli, substituoitu tai substituoimaton C1-Ce-alkoksi, substituoitu tai substituoimaton C1-Ce-heteroalkyyli,
— substituoitu tai substituoimaton C3-Ce-sykloalkyyli, substituoitu tai substituoimaton Co-Ce-heterosykloalkyyli, substituoitu tai substituoimaton fenyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli;
kukin R'? on itsenäisesti H, C1-Cs-alkyyli, C1-C4-deuteroalkyyli, C1-C4- fluorialkyyli, C1-C4-heteroalkyyli, substituoitu tai substituoimaton C3-Ce-sykloalkyyli,
—substituoitu tai substituoimaton C2-Ce-heterosykloalkyyli, substituoitu tai substituoimaton fenyyli, substituoitu tai substituoimaton bentsyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli;
R'4 on C1-C4-alkyyli, C1-C4-deuteroalkyyli, C1-Cs-fluorialkyyli, C1-C4- heteroalkyyli, substituoitu tai substituoimaton C3-Ce-sykloalkyyli, substituoitu tai
— substituoimaton C2-Ce-heterosykloalkyyli, substituoitu tai substituoimaton fenyyli,
4 EP3 609 888 substituoitu tai substituoimaton bentsyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli; R'5 on H tai substituoitu tai substituoimaton C1-Ce-alkyyli; kukin R'6 on itsenäisesti H, D, halogeeni, -CN, -OH, -N(R!5)2, - NR'5S(=O)x(C1-C4-alkyyli), -S(C1-C4-alkyyli), -S(=0)x(C1-C4-alkyyli), -C(=0)(C1-C4- alkyyli), -OC(=O)/(C1-C4-alkyyli), -CO2H, -CO2(C1-C4-alkyyli), -NR'SC(=O)(C1-Ca- alkyyli), -C(=O)N(R!5)2, -NR'5C(=O0)O(C1-C4-alkyyli), -OC(=O)N(R!)2, C1-C4- alkyyli, C2-C4-alkenyyli, C2-C4-alkynyyli, C1-C4-alkoksi, C1-C4-deuteroalkyyli, C1-C4- deuteroalkoksi, C1-Ca4-fluorialkyyli, C1-Cas-fluorialkoksi, C1-C4-heteroalkyyli, substituoitu tai substituoimaton C3-Ce-sykloalkyyli, substituoitu tai substituoimaton monosyklinen C2-Ce-heterosykloalkyyli, substituoitu tai substituoimaton fenyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli; ja n on O, 1 tai 2; jolloin ”substituoitu”-termi tarkoittaa, että viitattu ryhmä on substituoitu yhdellä tai useammalla substituentilla, jotka on valittu itsenäisesti ryhmistä D, halogeeni, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-Cs-alkyyli), - C(=O)NH>, -C(=O)NH(C1-C4-alkyyli), -C(=O)N(C1-C4-alkyyli)2, -S(=O)2NH2, - S(=O)2NH(C1-C4-alkyyli), -S(=0)2N(C1-C4-alkyyli)2, C1-C4-alkyyli, Ca-Ce- sykloalkyyli, C1-C4-fluorialkyyli, C1-C4-heteroalkyyli, C1-C4-alkoksi, C1-C4- — fluorialkoksi, -SC1-Cas-alkyyli, -S(=0)C1-C4-alkyyli ja -S(=0)2C1-Caalkyyli.
2. Patenttivaatimuksen 1 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jolloin R? on H; R> on H; tai R? ja R* muodostavat yhdessä sillan, joka on -CH2CH>2-.
3. Patenttivaatimuksen 2 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa
EP3 609 888 yhdisteellä on kaavan (IV) tai sen farmaseuttisesti hyväksyttävän suola tai solvaatin mukainen rakenne: wf N n X? Ww x? N° x! N R10 Ä X? RV "x? PT R! R? (R) Kaava (IV).
4. Patenttivaatimuksen 2 mukainen yhdiste tai sen farmaseuttisesti 5 hyväksyttävä suola tai solvaatti, jossa yhdisteellä on kaavan (V) mukainen rakenne tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti: (RÅ) ] Ka 4 ON x S R10 Ax A R! R? (R'), Kaava (V).
5. Minkä tahansa patenttivaatimuksen 1—4 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa R'9 on -CH2OH, -CH2CH2OH, C1-Ce-heteroalkyyli, -CO2H, -C(=0)R"4, - C(=0)OR™, -OC(=O)R'4, -OC(=0)OR'* -NR'5S(=O),R!%, -CH2N(R!%)2, - NR'5C(=O)R!4 -C(=O)N(R!2)2, -NR'5C(=O)OR'4, -OC(=O)N(R!2)2, - NR'5C(=O)N(R!2)2, -S(=O),OH tai -OP(=O)(OR')2; tai R!9 on -L2-L3-L4-R'3: L? on poissa, -CH2-, -CH2CH2z-, -CH20CH2-, -CH2SCH> - tai -CH2NHCH>2-;
6 EP3 609 888 L3 on poissa, -O-, -S-, -S(=O)-, -S(=O)2., -NH-, -C(=O)-, -C(=O)NH-, - NHC(=O)-, -C(=O)O-, -OC(=0)-, -OC(=0)O-, -OC(=O)NH-, -NHC(=O)NH-, - NHC(=0)0-, -OP(=O)(OR'15)O- tai -(OCH2CH?2)r-, r on 1 tai 2; [4 on -CHo-, -CH2CH>-, -CH(CH3)-, -CH2CH(OH)-, -CH(CH2OH)-, - CH(CH2OH)CH>-, -CH>CH2CH2o-, -CH2CH(OH)CH>-, -CH2CH(CH3)-, -CH2OCH>-, - CH2OCH2CH>-, -CH2CH2OCH>-, -CH2CH20OCH2CH2-, -CH2SCH2-, -CH2SCH2CH>-, -CH2NHCH>-tai -CH-NHCH2CH>-.
6. Minkä tahansa patenttivaatimuksen 1-5 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa R' on -CH2OH, C1-Ce-heteroalkyyli, -CO2H, -NR'5C(=O)R!'%, - C(=0)N(R'2)2, -NR'5C(=O)OR!4 tai -OC(=O)N(R!2)2; tai R'9 on -L2-L3-L4-R"3; L? on poissa tai -CH2-; L3 on poissa, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)NH- tai - NHC(=0)0-; L# on -CH2-, -CH2CH2-, -CH(CH2OH)CH>-, -CH2CH2CHo- tai - CH2CH(OH)CH>-; ja R'3 on H, -CN, -OH, -N(R'2);, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - CHCH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2OH, -CH2OCH3, -CH2OCH>CH3, - CH2CH2OH, -CH2CH2OCH3, -CH2CH20CH2CHs, -CH2NH2, -CHNHCH3, - CH2N(CH3)2, -CO2H, -C(=O)NHCH3, -OC(=0)NHCH3s, NHC(=O)CH3, NHC(=O0)OCH3, NHS(=O)2CH3, SO2CH3, substituoitu tai substituoimaton syklopropyyli, substituoitu tai substituoimaton syklobutyyli, substituoitu tai substituoimaton syklopentyyli, substituoitu tai substituoimaton sykloheksyyli, —substituoitu tai substituoimaton fenyyli tai substituoitu tai substituoimaton monosyklinen heteroaryyli.
7. Minkä tahansa patenttivaatimuksen 1-6 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa
7 EP3 609 888
X? on CR?
X3 on CR? tai N;
kukin X? on CH; tai kukin X* on N; tai yksi X* on N ja toinen X* on CH;
R! on H, D, F, CI, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O0)2CH3, -
OC(=O)(CH3) -CO2H, -COCH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, - OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF>, -CF3, -CH2CF3, -OCH>F, -OCHF>, - OCF3, -OCH2CF3, -CH2OH, -CH20CH3,-CH20CH2CH3, -CH2NH2,-CH2NHCH tai - CH2N(CH3)2;
R? on H, D, F, CI, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O0)2CH3, - OC(=O)(CH3), -CO2H, -CO2CHs, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, - OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF>, -CF3, -CH2CF3, -OCH>F, -OCHF>, - OCF3, -OCH2CF3, -CH2OH, -CH20CH3,-CH20CH2CH3, -CH2NH2,-CH2NHCH tai -
CH2N(CH3)2;
tai R! ja R? muodostavat yhdessä välissä olevien atomien kanssa substituoidun tai substituoimattoman fuusioituneen 5-jäsenisen renkaan, jossa on 0—3 N-atomia ja 0-2 O- tai S-atomia renkaassa, joka on substituoitu tai substituoimaton dihydrofuranyyli, substituoitu tai substituoimaton dioksolyyli,
— substituoitu tai substituoimaton furanyyli, substituoitu tai substituoimaton tienyyli, substituoitu tai substituoimaton pyrrolyyli, substituoitu tai substituoimaton oksatsolyyli, substituoitu tai substituoimaton tiatsolyyli, substituoitu tai substituoimaton imidatsolyyli, substituoitu tai substituoimaton pyratsolyyli, substituoitu tai substituoimaton triatsolyyli, substituoitu tai substituoimaton isoksatsolyyli tai substituoitu tai substituoimaton isotiatsolyyli;
R? on H, D, F, CI, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, - OC(=O)(CH3), -CO2H, -CO2CHs, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, - OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF>, -CF3, -CH2CF3, -OCH>F, -OCHF>, -
8 EP3 609 888 OCF3, -OCH2CF3, -CH2OH, -CH2OCH3,-CHOCH>2CH3, -CH2NH2,-CH2NHCH3 tai - CH2N(CH3)2.
8. Minkä tahansa patenttivaatimuksen 1—7 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa R! on H, D, F, CI, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - OCH3, -OCH2CH3, -CD3, -OCD3, -CH>F, -CHF>2, -CF3, -CH2CF3, -OCH2F, -OCHF>, -OCF3 tai -OCH2CF3; R? on H, D, F, CI, -CHs, -CH2CH3, -OCH3, -OCH>CH3, -CD3, -OCDs3, - CH2F, -CHF>, -CF3, -OCH2F, -OCHF>, -OCF3 tai -OCH2CF3; R on H, D, F, CI, -CH3, -OCHs, -CD3, -OCD3, -CH2F, -CHF>, -CF3, - CH2CF3, -OCH2F, -OCHF> tai -OCF3.
9. Minkä tahansa patenttivaatimuksen 1—7 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa R! on -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF>, -OCF3 tai -OCH2CF3 R? on H, D, F, CI, -CHs, -CD3, -CH2F, -CHF tai -CF3; R3 on H;
10. Minkä tahansa patenttivaatimuksen 1-9 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa 4 NA Ri NV NS YTV 2X4 N Po on R! RÖV RTF OR! TF] JI LT JA N N RY ON R! PT tai R! N .
11. Minkä tahansa patenttivaatimuksen 1-10 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa
9 EP3 609 888 R8 on H, D, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH(CH3)CH2CH3, -CH2CH(CHs)2, -C(CH3)3, -CD3, -CH2F, -CHF2, -CF3, -CH2CF3, - CHFCH3, -CH2CH2F, -CH2CH2OH, -CHCH20CH3, -CH2CH2NH>2,-CH>CH2NHCH3, -CH2CH2N(CH3)2, -C(=O)CH3, -C(=O0)CH2CH3, -C(=O)CH(CH3)2, -CO2CH3, - CO2CH2CH3, -COCH(CH3)2, -C(=O)NHCH3, -S(=0)2CHs, -S(=0)2NHCH3, substituoitu tai substituoimaton syklopropyyli, substituoitu tai substituoimaton syklobutyyli, substituoitu tai substituoimaton syklopentyyli, substituoitu tai substituoimaton sykloheksyyli, substituoitu tai substituoimaton oksetanyyli, substituoitu tai substituoimaton tetrahydrofuranyyli, substituoitu tai substituoimaton tetrahydropyranyyli tai substituoitu tai substituoimaton tetrahydrotiopyranyyli; ja kukin R'5 on itsenäisesti on H, D, F, CI, -CN, -OH, -NH2, -NH(CH3), - N(CH3)2, -NHS(=O)2CH3, -S(=O0)2CH3, -C(=0)CHs, -OC(=0)CHs, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH>2CH3, - CH2CH(CH3)2, -C(CH3)3, -CH=CH>, -CH=CHCH3, -C=CH, -CECCH3, - C=CCH2CH3, -OCHs, -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF>, -CF3, -CH2CF3, -OCH2F, -OCHF>, -OCF3, -OCH2CF3, -CH2OH, -CH2CH20H, -CHOCH3, -CH2OCH2CH3, -CH2NH>2,-CH2NHCH3 tai -CH2N(CH3)2, substituoitu tai substituoimaton syklopropyyli, substituoitu tai substituoimaton syklobutyyli, substituoitu tai substituoimaton syklopentyyli, substituoitu tai substituoimaton — sykloheksyyli, substituoitu tai substituoimaton atsiridinyyli, substituoitu tai substituoimaton atsetidinyyli, substituoitu tai substituoimaton pyrrolidinyyli, substituoitu tai substituoimaton piperidinyyli, substituoitu tai substituoimaton tetrahydrofuranyyli, substituoitu tai substituoimaton tetrahydropyranyyli, substituoitu tai substituoimaton tetrahydrotiopyranyyli, substituoitu tai substituoimaton morfolinyyli, substituoitu tai substituoimaton tiomorfolinyyli tai substituoitu tai substituoimaton piperatsinyyli.
12. Minkä tahansa patenttivaatimuksen 1-10 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti, jossa R8 on -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CD3, -CH2F, -CHF2, -CF3, -CH2CF3, - CHFCH3, -CH2CH2F, -CH2CH2OH, -CHCH20CH3, -CH2CH2NH>2,-CH>CH2NHCH3, -CH2CH>2N(CH3)2, substituoitu tai substituoimaton syklopropyyli, substituoitu tai
10 EP3 609 888 substituoimaton syklobutyyli, substituoitu tai substituoimaton syklopentyyli, substituoitu tai substituoimaton sykloheksyyli, substituoitu tai substituoimaton oksetanyyli, substituoitu tai substituoimaton tetrahydrofuranyyli tai substituoitu tai substituoimaton tetrahydropyranyyli; ja kukin R'® on itsenäisesti H, D, F, CI, -CH3, -CH2CH3, -CD3, -CH2F, -CHF>2, -CF3 tai -CH2CF3.
13. Patenttivaatimuksen 1 mukainen yhdiste, joka on trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksyylimetyyli- karbamaatti; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksyylikarbamaatti; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksyyli- metyylikarbonaatti; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksyyli(2- hydroksietyyli)karbamaatti; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksyyli(2- metoksietyyli)karbamaatti; trans-N-(3-(1-syklopropyyli-1 H-pyratsol-4-yyli)fenyyli)-4-(hydroksimetyyli)- N-((trans-4-(4-metoksi-3-metyylifenyyli)sykloheksyyli)metyyli)sykloheksaani- karboksamidi; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4-metoksi- 3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksaanikarboksyyli- happo;
11 EP3 609 888 trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(6- (dimetyyliamino)pyridin-3-yyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksaani- karboksyylihappo; trans-4-(((trans-4-(3-kloori-4-metoksifenyyli)sykloheksyyli)metyyli)(3-(1- syklopropyyli-1H-pyratsol-4-yyli)fenyyli)karbamoyyli)sykloheksaani- karboksyylihappo; trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(3-fluoro-1- metyyli-1H-indatsol-5-yyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksaani- karboksyylihappo;
trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((4-(4-metoksi-3- metyylifenyyli)bisyklo[2.2.2]oktan-1-yyli)metyyli)karbamoyyli)sykloheksaani- karboksyylihappo;
trans-metyyli 4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(4- metoksi-3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksaani-
karboksylaatti;
trans-metyyli 4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((trans-4-(6- (dimetyyliamino)pyridin-3-yyli)sykloheksyyli)metyyli)karbamoyyli)sykloheksaani- karboksylaatti;
metyyli(trans-4-((3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)((frans-4-(4-
metoksi-3-metyylifenyyli)sykloheksyyli)metyyli)karbamoyyli)syklo- heksyyli)karbamaatti;
trans-4-asetamido-N-(3-(1-syklopropyyli-1H-pyratsol-4-yyli)fenyyli)-N- ((trans-4-(4-metoksi-3-metyylifenyyli)sykloheksyyli)metyyli)syklo- heksaanikarboksamidi;
trans-N-(3-(1-syklopropyyli-1 H-pyratsol-4-yyli)fenyyli)-N-((trans-4-(4- metoksi-3-metyylifenyyli)sykloheksyyli)metyyli)-4-(metyylisulfonamido)syklo- heksaanikarboksamidi tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti.
12 EP3 609 888
14. Lääkekoostumus, joka käsittää minkä tahansa patenttivaatimuksen 1—13 mukaista yhdistettä tai sen farmaseuttisesti hyväksyttävää suolaa tai solvaattia ja ainakin yhtä farmaseuttisesti hyväksyttävää apuainetta.
15. Minkä tahansa patenttivaatimuksen 1-13 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti käytettäväksi menetelmässä, jolla hoidetaan tai estetään nisäkkään maksasairautta tai -hairiétilaa; maksafibroosia nisäkkäällä; maksatulehdusta nisäkkäällä tai nisäkkään ruoansulatuskanavan sairautta tai häiriötilaa.
16. Yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai solvaatti käytettäväksi patenttivaatimuksen 15 mukaisesti, jolloin maksasairaus tai -häiriötila on primaarinen sappikirroosi, primaarinen sklerosoiva sappitietulehdus, kolestaasi, ei-alkoholiperäinen steatohepatiitti (NASH), ei-alkoholiperäinen rasvamaksa (NAFLD), rasvamaksa (steatoosi), kirroosi, alkoholiperäinen maksatulehdus, intrahepaattinen kolestaasi tai ekstrahepaattinen kolestaasi; maksafibroosi ilmenee nisäkkäällä, jolla on diagnosoitu hepatiitti C -virus (HCV), ei-alkoholiperäinen steatohepatiitti (NASH), primaarinen sklerosoiva — sappitietulehdus (PSC), kirroosi, Wilsonin tauti, hepatiitti B -virus (HBV), HIV:hen liittyvä steatohepatiitti ja kirroosi, krooninen virushepatiitti, ei-alkoholiperäinen rasvamaksa (NAFLD), alkoholiperäinen steatohepatiitti (ASH), primaarinen sappikirroosi (PBC) tai sappikirroosi; maksatulehdus ilmenee nisäkkäällä, jolla on diagnosoitu hepatiitti C -virus (HCV), ei-alkoholiperäinen steatohepatiitti (NASH), primaarinen sklerosoiva sappitietulehdus (PSC), kirroosi, Wilsonin tauti, hepatiitti B -virus (HBV), HIV:hen liittyvä steatohepatiitti ja kirroosi, krooninen virushepatiitti, ei-alkoholiperäinen
13 EP3 609 888 rasvamaksa (NAFLD), alkoholiperäinen steatohepatiitti (ASH), primaarinen sappikirroosi (PBC) tai sappikirroosi; tai maksatulehdus ilmenee nisäkkäällä, jolla on diagnosoitu tulehduksellinen suolistosairaus; tai maksatulehdus liittyy ruoansulatuskanavan tulehdukseen; ja ruoansulatuskanavan sairaus tai häiriötila on nekrotisoiva enterokoliitti, gastriitti, haavainen paksusuolitulehdus, Crohnin tauti, tulehduksellinen suolistosairaus, ärtyvän suolen oireyhtymä, gastroenteriitti, sädehoidon aiheuttama enteriitti, pseudomembranoottinen paksusuolitulehdus, kemoterapian aiheuttama enteriitti, gastroesofageaalinen refluksitauti (GERD), mahahaava, haavaan liittymätön dyspepsia (NUD), keliakia, suoliston keliakia, leikkauksen jälkeinen tulehdus, mahalaukun karsinogeneesi, käänteishyljintäreaktio tai mikä tahansa näiden yhdistelmä.
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