HRP20190853T1 - Cot modulatori i postupci za njihovu upotrebu - Google Patents

Cot modulatori i postupci za njihovu upotrebu Download PDF

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Publication number
HRP20190853T1
HRP20190853T1 HRP20190853TT HRP20190853T HRP20190853T1 HR P20190853 T1 HRP20190853 T1 HR P20190853T1 HR P20190853T T HRP20190853T T HR P20190853TT HR P20190853 T HRP20190853 T HR P20190853T HR P20190853 T1 HRP20190853 T1 HR P20190853T1
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Croatia
Prior art keywords
alkyl
heterocyclyl
heteroaryl
cycloalkyl
aryl
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HRP20190853TT
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English (en)
Inventor
Elizabeth M. Bacon
Gayatri BALAN
Chien-Hung Chou
Christopher T. Clark
Jeromy J. Cottell
Musong Kim
Thorstens A. KIRSCHBERG
John O. Link
Gary Phillips
Scott D. Schroeder
Neil H. Squires
Kirk L. Stevens
James G. Taylor
William J. Watkins
Nathan E. Wright
Sheila M. Zipfel
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Gilead Sciences, Inc.
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Publication of HRP20190853T1 publication Critical patent/HRP20190853T1/hr

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Claims (21)

1. Spoj formule I: gdje R1 je vodik, -O-R7, -N(R8)(R9), -C(O)-R7, -S(O)2-R7, -C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, heterociklil, aril, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, heterociklil, aril, i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z1; R2 je vodik, -C(O)-R7, -C(O)O-R7, -C(O)N(R7)2, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z2; ili R1 i R2 zajedno sa dušikom za koji su vezani obrazuju heterociklil ili heteroaril, gdje svaki heterociklil ili heteroaril je opcionalno supstituiran sa jedan do četiri Z2; R3 je heterociklil ili heteroaril, gdje svaki heterociklil ili heteroaril je opcionalno supstituiran sa jedan do četiri Z3; R4 je heterociklil ili heteroaril, gdje svaki heterociklil ili heteroaril je opcionalno supstituiran sa jedan do četiri Z4; R5 je vodik, halo, -CN, -NO2, -O-R7, -N(R8)(R9), -S(O)-R7, -S(O)2R7, -S(O)2N(R7)2, -C(O)R7, -OC(O)-R7, -C(O)O-R7, -OC(O)O-R7, -OC(O)N(R10)(R11), -C(O)N(R7)2, -N(R7)C(O)(R7), C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-9 alkiltio, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-9 alkiltio, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z5; R6 je vodik, -C(O)-R7, -C(O)O-R7, -C(O)N(R7)2, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z6; svaki R7 je nezavisno vodik, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z7; R8 i R9 u svakom javljanju su nezavisno vodik, -S(O)2R10, -C(O)-R10, -C(O)O-R10, -C(O)N(R10)(R11), C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril može biti opcionalno supstituiran sa jednim do četiri Z8; R10 i R11 u svakom javljanju su nezavisno vodik, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril, gdje svaki C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril opcionalno je supstituiran sa jedan do četiri Z1b; svaki Z1, Z2, Z3, Z4, Z5, Z6, Z7, i Z8 je nezavisno vodik, okso, halo, -NO2, -N3, -CN, tiokso, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, C1-8 haloalkil, aril, heteroaril, heterociklil, -O-R12, -C(O)-R12, -C(O)O-R12, -C(O)-N(R13)(R14), -N(R13)(R14), -N(R13)2(R14)+, -N(R12)C(O)-R12, -N(R12)C(O)O-R12, -N(R12)C(O)N(R13)(R14), -N(R12)S(O)2(R12), -NR12S(O)2N(R13)(R14), -NR12S(O)2O(R12), -OC(O)R12, -OC(O)-N(R13)(R14), -P(O)(OR12)2, -OP(O)(OR12)2, -CH2P(O)(OR12)2,-OCH2P(O)(OR12)2, -C(O)OCH2P(O)(OR12)2, -P(O)(R12)(OR12), -OP(O)(R12)(OR12), -CH2P(O)(R12)(OR12), -OCH2P(O)(R12)(OR12), -C(O)OCH2P(O)(R12)(OR12), -P(O)(N(R12)2)2, -OP(O)(N(R12)2)2, -CH2P(O)(N(R12)2)2, -OCH2P(O)(N(R12)2)2, -C(O)OCH2P(O)(N(R12)2)2, -P(O)(N(R12)2)(OR12), -OP(O)(N(R12)2)(OR12), -CH2P(O)(N(R12)2)(OR12), -OCH2P(O)(N(R12)2)(OR12), -C(O)OCH2P(O)(N(R12)2)(OR12), -P(O)(R12)(N(R12)2), -OP(O)(R12)(N(R12)2), -CH2P(O)(R12)(N(R12)2), -OCH2P(O)(R12)(N(R12)2), -C(O)OCH2P(O)(R12)(N(R12)2), -Si(R12)3, -S-R12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 ili -S(O)2N(R13)(R14); gdje bilo koji alkil, alkenil, alkinil, cikloalkil, haloalkil, aril, heteroaril ili heterociklil je opcionalno supstituiran sa jedan do četiri Z1a grupe; svaki Z1a je nezavisno okso, halo, tiokso, -NO2, -CN, -N3, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, C1-8 haloalkil, aril, heteroaril, heterociklil, -O-R12, -C(O)R12, -C(O)O-R12, -C(O)N(R13)(R14), -N(R13)(R14), -N(R13)2(R14)+, -N(R12)-C(O)R12, -N(R12)C(O)O(R12), -N(R12)C(O)N(R13)(R14), -N(R12)S(O)2(R12), -N(R12)S(O)2-N(R13)(R14), -N(R12)S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R13)(R14), -Si(R12)3, -SR12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 ili -S(O)2N(R13)(R14); gdje bilo koji alkil, alkenil, alkinil, cikloalkil, aril, heteroaril ili heterociklil je opcionalno supstituiran sa jedan do četiri Z1b grupe; svaki R12 je nezavisno vodik, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, aril, heteroaril ili heterociklil, gdje bilo koji alkil, alkenil, alkinil, cikloalkil, aril, heteroaril ili heterociklil je opcionalno supstituiran sa jedan do četiri Z1b grupe; R13 i R14 u svakom javljanju su svaki nezavisno vodik, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, aril, heteroaril ili heterociklil; gdje bilo koji alkil, alkenil, alkinil, cikloalkil, aril, heteroaril ili heterociklil je opcionalno supstituiran sa jedan do četiri Z1b grupe, ili R13 i R14 zajedno sa dušikom za koji su vezani obrazuju heterociklil, gdje spomenuti heterociklil je opcionalno supstituiran sa jedan do četiri Z1b grupe; svaki R15 je nezavisno halo, -CN, -NO2, -O-R7, -N(R8)(R9), -S(O)-R7, -S(O)2R7, -S(O)2N(R7)2, -C(O)R7, -OC(O)-R7, -C(O)O-R7,-OC(O)O-R7, -OC(O)N(R10)(R11), -C(O)N(R7)2, -N(R7)C(O)(R7), C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C1-9 alkiltio, C1-6 haloalkil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; i svaki Z1b je nezavisno okso, tiokso, hidroksi, halo, -NO2, -N3, -CN, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, C1-8 haloalkil, aril, heteroaril, heterociklil, -O(C1-9 alkil), -O(C2-6 alkenil), -O(C2-6 alkinil), -O(C3-15 cikloalkil), -O(C1-8 haloalkil), -O(aril), -O(heteroaril), -O(heterociklil), -NH2, -NH(C1-9 alkil), -NH(C2-6 alkenil), -NH(C2-6 alkinil), -NH(C3-15 cikloalkil), -NH(C1-8 haloalkil), -NH(aril), -NH(heteroaril), -NH(heterociklil), -N(C1-9 alkil)2, -N(C2-6 alkenil)2, -N(C2-6 alkinil)2, -N(C3-15 cikloalkil)2, -N(C1-8 haloalkil)2, -N(aril)2, -N(heteroaril)2, -N(heterociklil)2, -N(C1-9 alkil)(C2-6 alkenil), -N(C1-9 alkil)(C2-6 alkinil), -N(C1-9 alkil)(C3-15 cikloalkil), -N(C1-9 alkil)(C1-8 haloalkil), -N(C1-9 alkil)(aril),-N(C1-9 alkil)(heteroaril),-N(C1-9 alkil)(heterociklil), -C(O)(C1-9 alkil), -C(O)(C2-6 alkenil), -C(O)(C2-6 alkinil), -C(O)(C3-15 cikloalkil), -C(O)(C1-8 haloalkil), -C(O)(aril), -C(O)(heteroaril), -C(O)(heterociklil), -C(O)O(C1-9 alkil), -C(O)O(C2-6 alkenil), -C(O)O(C2-6 alkinil), -C(O)O(C3-15 cikloalkil), -C(O)O(C1-8 haloalkil), -C(O)O(aril), -C(O)O(heteroaril), -C(O)O(heterociklil), -C(O)NH2, -C(O)NH(C1-9 alkil), -C(O)NH(C2-6 alkenil), -C(O)NH(C2-6 alkinil), -C(O)NH(C3-15 cikloalkil), -C(O)NH(C1-8 haloalkil), -C(O)NH(aril), -C(O)NH(heteroaril), -C(O)NH(heterociklil), -C(O)N(C1-9 alkil)2, -C(O)N(C2-6 alkenil)2, -C(O)N(C2-6 alkinil)2, -C(O)N(C3-15 cikloalkil)2, -C(O)N(C1-8 haloalkil)2, -C(O)N(aril)2, -C(O)N(heteroaril)2, -C(O)N(heterociklil)2, -NHC(O)(C1-9 alkil), -NHC(O)(C2-6 alkenil), -NHC(O)(C2-6 alkinil), -NHC(O)(C3-15 cikloalkil), -NHC(O)(C1-8 haloalkil), -NHC(O)(aril), -NHC(O)(heteroaril), -NHC(O)(heterociklil), -NHC(O)O(C1-9 alkil), -NHC(O)O(C2-6 alkenil), -NHC(O)O(C2-6 alkinil), -NHC(O)O(C3-15 cikloalkil), -NHC(O)O(C1-8 haloalkil), -NHC(O)O(aril), -NHC(O)O(heteroaril), -NHC(O)O(heterociklil), -NHC(O)NH(C1-9 alkil), -NHC(O)NH(C2-6 alkenil), -NHC(O)NH(C2-6 alkinil), -NHC(O)NH(C3-15 cikloalkil), -NHC(O)NH(C1-8 haloalkil), -NHC(O)NH(aril), -NHC(O)NH(heteroaril), -NHC(O)NH(heterociklil), -SH, -S(C1-9 alkil), -S(C2-6 alkenil), -S(C2-6 alkinil), -S(C3-15 cikloalkil), -S(C1-8 haloalkil), -S(aril), -S(heteroaril), -S(heterociklil), -NHS(O)(C1-9 alkil), -N(C1-9 alkil)S(O)(C1-9 alkil), -S(O)N(C1-9 alkil)2, -S(O)(C1-9 alkil), -S(O)(NH)(C1-9 alkil), -S(O)(C2-6 alkenil), -S(O)(C2-6 alkinil), -S(O)(C3-15 cikloalkil), -S(O)(C1-8 haloalkil), -S(O)(aril), -S(O)(heteroaril), -S(O)(heterociklil), -S(O)2(C1-9 alkil), -S(O)2(C2-6 alkenil), -S(O)2(C2-6 alkinil), -S(O)2(C3-15 cikloalkil), -S(O)2(C1-8 haloalkil), -S(O)2(aril), -S(O)2(heteroaril), -S(O)2(heterociklil), -S(O)2NH(C1-9 alkil), ili -S(O)2N(C1-9 alkil)2; gdje bilo koji alkil, cikloalkil, aril, heteroaril, ili heterociklil je opcionalno supstituiran sa jedan do četiri halo, C1-9 alkil, C1-8 haloalkil, -OH, -NH2, -NH(C1-9 alkil), -NH(C3-15 cikloalkil), -NH(C1-8 haloalkil), -NH(aril), -NH(heteroaril), -NH(heterociklil), -N(C1-9 alkil)2, -N(C3-15 cikloalkil)2, -NHC(O)(C3-15 cikloalkil), -NHC(O)(C1-8 haloalkil), -NHC(O)(aril), -NHC(O)(heteroaril), -NHC(O)(heterociklil), -NHC(O)O(C1-9 alkil), -NHC(O)O(C2-6 alkinil), -NHC(O)O(C3-15 cikloalkil), -NHC(O)O(C1-8 haloalkil), -NHC(O)O(aril), -NHC(O)O(heteroaril), -NHC(O)O(heterociklil), -NHC(O)NH(C1-9 alkil), -S(O)(NH)(C1-9 alkil), S(O)2(C1-9 alkil), -S(O)2(C3-15 cikloalkil), -S(O)2(C1-8 haloalkil), -S(O)2(aril), -S(O)2(heteroaril), -S(O)2(heterociklil), -S(O)2NH(C1-9 alkil), -S(O)2N(C1-9 alkil)2, -O(C3-15 cikloalkil), -O(C1-8 haloalkil), -O(aril), -O(heteroaril), -O(heterociklil), ili -O(C1-9 alkil); m je 0,1, ili 2; ili njegova farmaceutski prihvatljiva sol, stereoizomer, smjesa stereoizomera, ili deuteriziranih analoga.
2. Spoj prema zahtjevu 1, gdje (a) R2 je vodik i/ili m je 0, ili njegova farmaceutski prihvatljiva sol; (b) spoj ima formulu IIA: gdje R1, R3, R4, R5 i R6 su ako što je definirano u zahtjevu 1, ili njegova farmaceutski prihvatljiva sol; ili (c) spoj ima formulu IIIA: gdje R1, R4, R5, R6 i Z3 su kao što je definirano u zahtjevu 1, W, X i Y su svaki nezavisno N ili C; i n je 1, 2, ili 3; ili njegova farmaceutski prihvatljiva sol, stereoizomer, smjesa steroizomera ili deuterizirani analog.
3. Spoj prema zahtjevu 1 ili 2, gdje (i) R5 je vodik, halo, -CN, O-R7, -S(O)-R7, -S(O)2R7, -S(O)2N(R7)2, -C(O)R7, -C(O)N(R7)2, C1-9 alkil, C2-6 alkenil, C2-6 alkinil, C3-15 cikloalkil, aril, heterociklil, ili heteroaril; i heteroaril može biti opcionalno supstituiran sa jednim do četiri Z5, ili njegova farmaceutski prihvatljiva sol , ili R5 je vodik, halo, -CN, -C(O)R7, -O-R7, -S(O)2R7 ili heteroaril, ili njegova farmaceutski prihvatljiva sol; i/ili (ii) R6 je vodik, ili njegova farmaceutski prihvatljiva sol; i/ili (iii) R1 je -O-R7, C1-9 alkil, C3-15 cikloalkil, heterociklil, aril, ili heteroaril; i spomenuti C1-9 alkil, C3-15 cikloalkil, heterociklil, aril, ili heteroaril može biti opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranih iz grupe koju čine halo, -CN, -O-R12, -S(O)2R12, C1-9 alkil, C1-9 haloalkil, C3-15 cikloalkil, heterociklil, i aril, gdje spomenuti C3-15 cikloalkil može biti opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranih iz grupe koju čine C1-9 alkil, i C1-9 haloalkil, ili njihove farmaceutski prihvatljive soli, ili R1 je C1-9 alkil, opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabranih iz grupe koju čine halo, -CN, -O-R12, -S(O)2R12, C3-15 cikloalkil, heterociklil, i aril, gdje spomenuti C3-15 cikloalkil ili heterociklil može biti opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranih iz grupe koju čine C1-9 alkil, i C1-9 haloalkil, ili njihove farmaceutski prihvatljive soli, ili R1 je C3-15 cikloalkil, heterociklil ili heteroaril, gdje spomenuti C3-15 cikloalkil, heterociklil ili heteroaril je opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabranih iz grupe koju čine halo, -CN, -O-R12, C1-9 alkil, i aril, ili njihove farmaceutski prihvatljive soli, ili R1 je heterociklil ili heteroaril, gdje spomenuti heterociklil ili heteroaril je opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabranih iz grupe koju čine halo, i C1-9 alkil, ili njihova farmaceutski prihvatljiva sol, ili R1 je aril, opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabranih iz grupe koju čine halo, -CN, -O-R7, C1-9 alkil, i aril, ili njihove farmaceutski prihvatljive soli, ili R1 je aril, opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabranih iz grupe koju čine halo, -O-R7, i C1-9 alkil, ili njihove farmaceutski prihvatljive soli;.
4. Spoj prema zahtjevu 2(c), gdje (1) W je N, X is N-Z3, i Y je C-Z3, ili njegova farmaceutski prihvatljiva sol; i/ili (2) Z3 je vodik ili C1-9 alkil opcionalno supstituirano sa jednim do četiri supstituenata nezavisno izbarnih iz grupe koju čine -CN, halo, -O-R12, -C(O)OR12, -OC(O)-R12, -N(R13)(R14), -N(R13)2(R14)+, -C(O)N(R12)-S(O)2R12, C1-9 alkil, heterociklil, aril, i heteroaril, ili njihove farmaceutski prihvatljive soli, ili Z3 je C3-15 cikloalkil, heterociklil, aril, ili heteroaril; i spomenuti C3-15 cikloalkil, heterociklil, aril, ili heteroaril može biti opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranih iz grupe koju čine -CN, halo, -OR12, -C(O)-R12, -C(O)O-R12, -OC(O)-R12, -N(R13)(R14), -N(R13)2(R14)+, C1-9 alkil, C1-8 haloalkil, C1-8 hidroksialkil, C3-15 cikloalkil, heterociklil, i heteroaril, ili njihove farmaceutski prihvatljive soli;.
5. Spoj prema zahtjevu 1, koji ima formulu VIIIA: gdje Z3, R1, R4, R5 i R6 su kao što je definirano u zahtjevu 1, i Z9 je vodik, halo, -CN, ili -O-R12; ili njegova farmaceutski prihvatljiva sol, steroizomer, smjesa steroizomera ili deuterizirani analog.
6. Spoj prema zahtjevu 5, gdje: Z3 je vodik, C1-9 alkil, C3-15 cikloalkil, heterociklil, aril, ili heteroaril; gdje spomenuti C1-9 alkil, C3-15 cikloalkil, ili heterociklil može biti opcionalno supstituiran sa jednim do četiri substituenta nezavisno izabran iz grupe koju čine okso, -CN, halo, -O-R12, -C(O)-R12, -C(O)O-R12, -OC(O)-R12, -C(O)-N(R13)(R14), -N(R12)S(O)2(R12), -N(R13)(R14), -N(R13)2(R14)+, -C(O)N(R12)-S(O)2R12, C1-9 alkil, C1-8 haloalkil, C1-8 hidroksialkil, C3-15 cikloalkil, aril, heterociklil, i heteroaril; Z9 je vodik; R1 je C1-9 alkil, C3-15 cikloalkil, heterociklil, aril, ili heteroaril; gdje spomenuti C1-9 alkil, heterociklil, aril, ili heteroaril mogu biti opcionalno supstituirani sa jednim do tri supstituenta nezavisno izabranih iz grupe koju čine halo, -CN, -O-R12, -S(O)2R12, C1-9 alkil, C1-9 haloalkil, heterociklil, i aril, gdje spomenuti C3-15 cikloalkil može biti opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranih iz grupe koju čine C1-9 alkil, i C1-9 haloalkil; R4 je heterociklil ili heteroaril; gdje spomenuti heterociklil ili heteroaril je opcionalno supstituiran sa jedan do tri supstituenta nezavisno izabrana iz grupe koju čine -CN, halo, -O-R12, -C(O)-R12, -N(R13)(R14), C1-9 alkil, C1-9 haloalkil, i heterociklil; R5 je -CN, halo, -O-R7 ili -S(O)2R7; R6 je vodik; svaki R7 je nezavisno vodik ili C1-9 alkil; gdje spomenuti C1-9 alkil mogu biti opcionalno supstituirani sa jednim do tri supstituenta nezavisno izabranih iz grupe koju čine hidroksil, halo, -O(C1-9 alkil) i aril; svaki R12 je nezavisno vodik, C1-9 alkil ili heterociklil; gdje spomenuti C1-9 alkil mogu biti opcionalno supstituirani sa jednim do tri supstituenta nezavisno izabranih iz grupe koju čine hidroksil, halo, -O(C1-9 alkil) i aril; i svaki R13 i R14 je nezavisno vodik ili C1-9 alkil; gdje spomenuti C1-9 alkil mogu biti opcionalno supstituirani sa jednim do tri supstituenta nezavisno izabranih iz grupe koju čine hidroksil, halo, -O(C1-9 alkil) i aril; ili njegova farmaceutski prihvatljiva sol, steroizomer, smjesa stereoizomera.
7. Spoj prema zahtjevu 6, gdje Z3 je C3-15 cikloalkil opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranim iz grupe koju čine -CN, halo, -C(O)-R12, -OC(O)-R12, -C(O)N(R13)(R14), C1-9 alkil, C1-8 haloalkil, C1-8 hidroksialkil, C3-15 cikloalkil, i heteroaril, ili njihove farmaceutski prihvatljive soli, ili Z3 je heterociklil opcionalno supstituiran sa jednim do četiri supstituenta nezavisno izabranim iz grupe koju čine -O-R12, -C(O)O-R12, C1-9 alkil, C1-8 haloalkil, C1-8 hidroksialkil, i heterociklil, ili njihove farmaceutski prihvatljive soli;.
8. Spoj prema zahtjevu 5 ili 6, gdje R5 je cijano ili halo, ili njegova farmaceutski prihvatljiva sol; ili R6 je vodik, ili njihove farmaceutski prihvatljive soli;.
9. Spoj prema bilo kojem od prethodnih zahtjeva, gdje (i) R4 je heterociklil ili heteroaril; i spomenuti heterociklil ili heteroaril je opcionalno supstituiran sa jednim do tri supstituenta nezavisno izabranim iz grupe koju čine -CN, halo, -O-R12, -C(O)-R12, -N(R13)(R14), C1-9 alkil, C1-9 haloalkil, i heterociklil, ili njegova farmaceutski prihvatljiva sol; (ii) R4 je heteroaril opcionalno supstituiran sa jednim ili tri supstituenta nezavisno izabranim sa jednim do tri supstituenta nezavisno izabranim iz iz grupe koju čine -CN, halo, -O-R12, -C(O)-R12, -N(R13)(R14), C1-9 alkil, C1-9 haloalkil, i heterociklil, ili njegova farmaceutski prihvatljiva sol; (iii) R4 je heterociklil opcionalno supstituiran sa jednim ili tri supstituenta nezavisno izabranih iz grupe koju čine -CN, halo, -O-R12, -C(O)-R12, -N(R13)(R14), C1-9 alkil, C1-9 haloalkil, i heterociklil, ili njegova farmaceutski prihvatljiva sol; (iv)
i q je 0, 1, 2, 3 ili 4; (v) R4 je i q je 0, 1, 2, 3 ili 4, ili njegova farmaceutski prihvatljiva sol; (vi) R4 je ili njegova farmaceutski prihvatljiva sol; gdje svaki Z4 od (iv) do (vi) može biti nezavisno izabran iz grupe koju čine -CN, halo, -O-R12, -C(O)-R12, -N(R13)(R14), C1-9 alkil, C1-9 haloalkil, i heterociklil, ili njegova farmaceutski prihvatljiva sol; (vii) R4 je
10. Spoj prema zahtjevu 1 izabrano iz Tabele 1, ili njegova farmaceutski prihvatljiva sol.
11. Sastav koji sadrži spoj prema bilo kojem od zahtjeva 1-10 i farmaceutski prihvatljiv nosač.
12. Spoj prema zahtjevu 1 ili sastav prema zahtjevu 11, gdje spoj ima formulu ili njegova farmaceutski prihvatljiva sol.
13. Spoj prema zahtjevu 1 ili sastav prema zahtjevu 11, gdje spoj ima formulu ;. ili njegova farmaceutski prihvatljiva sol.
14. Spoj prema zahtjevu 1 ili sastav prema zahtjevu 11, gdje spoj ima formulu ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema zahtjevu 1 ili sastav prema zahtjevu 11, gdje spoj ima formulu ili njegova farmaceutski prihvatljiva sol.
16. Spoj prema zahtjevu 1 ili kompozicija prema zahtjevu 11, gdje spoj ima jednu od sljedećih formula: ili njihova farmaceutski prihvatljiva sol.
17. Sastav koji sadrži smjesu steroizomera spoja formule I prema zahtjevu 1: gdje smjesa sadrži spojeve formule IA i IB u odnosu od bar oko 3:1: gdje m, R1, R2, R3, R4, R5, R6 i R15 su kao što je definirano u zahtjevu 1.
18. Sastav koji sadrži spoj ili sastav prema bilo kojem od zahtjeva 1-17 i dodato antiinflamatorno sredstvo, gdje je spomenuto dodatno anti-inflamatorno sredstvo poželjno α4β7 inhibitor, steroid, MMP9 antitijelo, S1P1 agonist, TNF biološko sredstvo, ili bilo koja njihova kombinacija.
19. Spoj prema bilo kojem od zahtjeva 1-10 i 12-16 za upotrebu u terapiji.
20. Spoj ili sastav prema bilo kojem od zahtjeva 1-17 za upotrebu u postupku liječenja bolesti ili stanja u kojima posreduje ’cancer Osaka thyroid’ (Cot) kod humanog pacijenta kome je to potrebno, gdje je bolest ili stanje poželjno izabrano iz grupe koju čine: (A) rak; (B) dijabetes; (C) inflamatorna bolest kao što je inflamatorna bolest crijeva (IBD); (D) čvrsti tumor izabran iz grupe koju čine rak gušterače, rak mjehura, kolorektalni rak, rak grudi, rak prostate, rak bubrega, hepatocelularni rak, rak grudi, rak jajnika, rak cerviksa, rak želuca, ezofagusni rak, rak glave i vrata, melanom, neuroendokrini rakovi, rakovi CNS, tumori mozga (npr., glioma, anaplastični oligodendrogliom, glioblastom multiforme kod odraslih, i anaplastični astrocitom kod odraslih), rak kostiju, ili sarkom mekog tkiva; (E) dijabetes tipa 1 i tipa 2, gestacijski dijabetes, predijabetes, otpornost na inzulin, metabolički sindrom, oštećena glikemija natašte i poremećena tolerancija glukoze; (F) sistemski eritemski lupus (SLE), mijastenija gravis, reumatoidni artritis (RA), akutni diseminirani encefalomijelitis, idiopatska trombocitopenija purpura, multiple skleroza (MS), inflamatorna bolest crijeva (IBD), sepsa, psorijaza, Sjögrenov sindrom, autoimuna hemolitička anemija, astma, ili kronična obstruktivna bolest pluća (COPD), ankilozni spondilitis, akutni giht i ankilozni spondilits, reaktivni artritis, monoartikularni artritis, osteoartritis, gihtični artritis, juvenilni artritis, juvenilni početak reumatoidnog artritisa, juvenilni reumatoidni artritis ili psorijatični artritis (G) raznovrsni kolitis, ishemijski kolitis, infektivni kolitis, kemijski kolitis, mikroskopski kolitis (uključujući kolageni kolitis i limfocitni kolitis), atipični kolitis, pseudomembranozni kolitis, fulminantni kolitis, autistički enterokolitis, neodređeni kolitis, Behçetova bolest, gastroduodenalni CD, jejunoileitis, ileitis, ileokolitis, Crohnovi (granulomatozni) kolitis, sindrom iritiranih crijeva, mukozitis, radiacijski inducirani enteritis, sindrom kratkih crijeva, celijakija, čir želuca, divertikulitis, poučitis, proktitis, i kronična dijareja; (H) alkoholini hepatitis; (I) sistemski lupus eritematosus (SLE), lupus nefritis, autoimuni poremećaji u vezi sa lupusom ili ostali ili simptomi SLE; gdje simptomi sistemskog lupus eritematozusa uključuju bol u zglobovima, oticanje zglobova, artritis, umor, gubitak kose, rane u ustima, natekle limfne čvorove, osjetljivost na sunce, osip na koži, glavobolje, ukočenost, peckanje, napade, probleme sa vidom, promjene ličnosti, abdomenalnu bol, muka, povraćanje, abnormalni srčani ritam, iskašljavanje krvi i teškoće pri disanju, depigmentaciju kože i Raynaud-ov fenomen.
21. Upotreba spoja ili sastava prema bilo kojem od zahtjeva 1-17 u proizvodnji lijeka.
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