ME02763B - Derivati bipirazola kao inhibitori jak - Google Patents

Derivati bipirazola kao inhibitori jak

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Publication number
ME02763B
ME02763B MEP-2017-116A MEP2017116A ME02763B ME 02763 B ME02763 B ME 02763B ME P2017116 A MEP2017116 A ME P2017116A ME 02763 B ME02763 B ME 02763B
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alkyl
pharmaceutically acceptable
acceptable salt
bipyrazol
cyanomethyl
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French (fr)
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Yun-Long Li
Jincong Zhuo
Ding-Quan Qian
Song Mei
Ganfeng Cao
Yongchun Pan
Qun Li
Zhongjiang Jia
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Incyte Corp
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Claims (27)

1.Jedinjenje, koje ima Formulu I: ili neka njegova farmaceutski prihvatljiva so; gde: Cy1 je fenil, piridil, pirimidinil, pirazinil, ili piridazinil, od kojih je svaki opciono supstituisan sa 1, 2, 3, ili 4 grupe, koje se nezavisno biraju između R3, R4, R5 i R6; Y je N ili CH; R1 je C1-6 alkil, C1-6 haloalkil, C3-7 cikloalkil, C3-7 cikloalkil-C1-3 alkil, 4 - 7-mo člani heterocikloalkil, 4 – 7-mo člani heterocikloalkil-C1-3 alkil, fenil, fenil-C1-3 alkil, 5 - 6-to člani heteroaril ili 5 - 6-to člani heteroaril-C1-3 alkil, od kojih je svaki opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, hloro, C1-3 alkil, -OH, -O(C1-3 alkil), -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(C1-3 alkil), -N(C1-3 alkil)2, -C(=O)N(C1-3 alkil)2, -C(=O)NH(C1-3 alkil), -C(=O)NH2, -C(=O)O(C1-3 alkil), -S(=O)2(C1-3 alkil), -S(=O)2(C3-6 cikloalkil), -C(=O)(C3-6 cikloalkil) i -C(=O)(C1-3 alkil); R2 je H ili C1-3 alkil; pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, hloro, -OH, -O(C1-3 alkil), -CN, -CF3, -CHF2, -CH2F, NH2, -NH(C1-3 alkil) i -N(C1-3 alkil)2; ili R1 i R2, zajedno sa atomom azota za koji su vezani, formiraju neki 4-, 5- ili 6-člani heterocikloalkil prsten, koji je opciono supstituisan sa 1, 2, ili 3 substitutenta koji se nezavisno biraju između F, Cl, -OH, -O(C1-3 alkil), -CN, C1-3 alkil, C1-3 haloalkil, -NH2, -NH(C1-3 alkil), -N(C1-3 alkil)2, -CH2CN i -CH2OH; R3 je H, F, Cl, -CN, C1-3 alkil, C1-3 fluoroalkil, -O(C1-3 alkil), ili -O(C1-3 fluoroalkil); R4 je H, F, Cl, -CN, C1-3 alkil, C1-3 fluoroalkil, -O(C1-3 alkil), ili -OC(C1-3 fluoroalkil); R5 je H, F, Cl, -CN, C1-3 alkil, C1-3 fluoroalkil, -O(C1-3 alkil), ili -OC(C1-3 fluoroalkil); R6 je H, F, Cl, -CN, C1-3 alkil, C1-3 fluoroalkil, -O(C1-3 alkil), ili -OC(C1-3 fluoroalkil); R7 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, -NR17R17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b ili S(=O)2NR17aR17b, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, Cl, -CN, -CF3,-CHF2, -CH2F, -NH2, -NH(CH3), -N(CH3)2, OH, -OCH3, -OCF3, -OCHF2, i -OCH2F; R8 je H, F, Cl, C1-3 alkil, ili C1-3 haloalkil; R9 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, ciklopropil, -CN, -NH2, -NH(C1-3 alkil), ili -N(C1-3 alkil)2, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2 i OH; R10 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, ciklopropil, -CN, -NH2, -NH(C1-3 alkil), ili -N(C1-3 alkil)2, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2 i OH; R17 je C1-6 alkil, fenil ili 5 - 6-to člani heteroaril, od kojih je svaki opciono supstituisan sa 1, 2, 3 ili 4 supstituenta koji se nezavisno bira iz R27; R17a je H ili C1-3 alkil; R17b je C1-3 alkil, opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(CH3), -N(CH3)2, OH, -OCH3 i -OCF3, -OCHF2 i -OCH2F; i svaki R27 se nezavisno bira između halo, -OH, NO2, -CN, C1-3 alkil, C2-3 alkenil, C2-3 alkinil, C1-3 haloalkil, cijano-C1-3 alkil, HO-C1-3 alkil, CF3-C1-3 hidroksialkil, C1-3 alkoksi-C1-3 alkil, C3-7 cikloalkil, C1-3 alkoksi, C1-3 haloalkoksi, H2N-, (C1-3 alkil)NH-, (C1-3 alkil)2N-, HS-, C1-3 alkil-S-, C1-3 alkil-S(=O)-, C1-3 alkil-S(=O)2-, karbamil, C1-3 alkilkarbamil, di(C1-3 alkil)karbamil, karboksi, C1-3 alkil-C(=O)-, C1-4 alkoksi-C(=O)-, C1-3 alkil-C(=O)O-, C1-3 alkil-C(=O)NH-, C1-3 alkil-S(=O)2NH-, H2N-SO2-, C1-3 alkil-NH-S(=O)2-, (C1-3 alkil)2N-S(=O)2-, H2N-S(=O)2NH-, C1-3 alkil-NHS(=O)2NH-, (C1-3 alkil)2N-S(=O)2NH-, H2N-C(=O)NH-, C1-3 alkil-NHC(=O)NH- i (C1-3 alkil)2N-C(=O)NH-.
2.Jedinjenje prema Zahtevu 1, koje ima Formulu Ia: ili neka njegova farmaceutski prihvatljiva so; gde: X je N ili CR4; a W je N ili CR6.
3.Jedinjenje prema Zahtevu 1, koje ima Formulu Ia: ili neka njegova farmaceutski prihvatljiva so; gde: X je N ili CR4; W je N ili CR6; Y je N ili CH; R1 je C1-6 alkil, C1-6 haloalkil, C3-6 cikloalkil, C3-6 cikloalkil-C1-3 alkil, 4 – 6-to člani heterocikloalkil, ili 4 – 6-to člani heterocikloalkil-C1-3 alkil, od kojih je svaki opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, hloro, C1-3 alkil, -OH, -O(C1-3 alkil), -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(C1-3 alkil), -N(C1-3 alkil)2, -C(=O)N(C1-3 alkil)2, -C(=O)NH(C1-3 alkil), -C(=O)NH2, -C(=O)O(C1-3 alkil), -S(=O)2(C1-3 alkil), -S(=O)2(C3-6 cikloalkil), -C(=O)(C3-6 cikloalkil) i -C(=O)(C1-3 alkil); R2 je H ili C1-3 alkil; pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, hloro, -OH, -O(C1-3 alkil), -CN, -CF3, -CHF2, -CH2F, NH2, -NH(C1-3 alkil) i -N(C1-3 alkil)2; ili R1 i R2, zajedno sa atomom azota za koji su vezani, formiraju neki 4-, 5- ili 6-člani heterocikloalkil prsten, koji je opciono supstituisan sa 1, 2, ili 3 substitutenta koji se nezavisno biraju između fluoro, -OH, -O(C1-3 alkil), -CN, C1-3 alkil, C1-3 haloalkil, -NH2, -NH(C1-3 alkil), -N(C1-3 alkil)2 i -CH2CN; R3 je H, F, Cl, -CN, C1-3 alkil, -OCF3, -CF3, ili -O(C1-3 alkil); R4 je H, F, Cl, -CN, C1-3 alkil, ili -O(C1-3 alkil); R5 je H, F, Cl, -CN, C1-3 alkil, ili -O(C1-3 alkil); R6 je H, F, Cl, -CN, ili C1-3 alkil; R7 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, -NR17R17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b ili -S(=O)2NR17aR17b, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, Cl, -CN, -CF3,-CHF2, -CH2F, -NH2 i OH; R8 je H, F, Cl, C1-3 alkil, ili C1-3 haloalkil; R9 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, ciklopropil, -CN, -NH2, -NH(C1-3 alkil), ili -N(C1-3 alkil)2, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2 i OH; R10 je H, F, Cl, C1-3 alkil, C1-3 haloalkil, ciklopropil, -CN, -NH2, -NH(C1-3 alkil), ili -N(C1-3 alkil)2, pri čemu je pomenuti C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2 i OH; R17 je C1-6 alkil, fenil ili 5 – 6-to člani heteroaril, od kojih je svaki opciono supstituisan sa 1, 2, 3 ili 4 supstituenta koji se nezavisno biraju iz R27; R17a je H ili C1-3 alkil; R17b je C1-3 alkil opciono supstituisan sa 1, 2, ili 3 supstituenta koji se biraju između F, hloro, -CN, -CF3, -CHF2, -CH2F, -NH2 i OH, i svaki R27 se nezavisno bira između halo, -OH, NO2, -CN, C1-3 alkil, C2-3 alkenil, C2-3 alkinil, C1-3 haloalkil, cijano-C1-3 alkil, HO-C1-3 alkil, CF3-C1-3 hidroksialkil, C1-3 alkoksi-C1-3 alkil, C3-7 cikloalkil, C1-3 alkoksi, C1-3 haloalkoksi, H2N-, (C1-3 alkil)NH-, (C1-3 alkil)2N-, HS-, C1-3 alkil-S-, C1-3 alkil-S(=O)-, C1-3 alkil-S(=O)2-, karbamil, C1-3 alkilkarbamil, di(C1-3 alkil)karbamil, karboksi, C1-3 alkil-C(=O)-, C1-4 alkoksi-C(=O)-, C1-3 alki-C(=O)O-, C1-3 alkil-C(=O)NH-, C1-3 alkil-S(=O)2NH-, H2N-SO2-, C1-3 alkil-NH-S(=O)2-, (C1-3 alkil)2N-S(=O)2-, H2N-S(=O)2NH-, C1-3 alkil-NHS(=O)2NH-, (C1-3 alkil)2N-S(=O)2NH-, H2N-C(=O)NH-, C1-3 alkil-NHC(=O)NH- i (C1-3 alkil)2N-C(=O)NH-.
4.Jedinjenje prema Zahtevu 3, ili neka njegova farmaceutski prihvatljiva so, gde: R1 je C1-6 alkil, C1-6 haloalkil, C3-6 cikloalkil, ili C3-6 cikloalkil-C1-3 alkil, pri čemu je svaki pomenuti C1-6 alkil, C3-6 cikloalkil i C3-6 cikloalkil-C1-3 alkil, opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, -CF3 i metil; R2 je H ili metil; R3 je H, F, ili Cl; R4 je H ili F; R5 je H ili F; R6 je H ili F; R7 je H, metil, etil ili HO-CH2-; R8 je H ili metil; R9 je H, metil ili etil; i R10 je H, metil, etil ili HO-CH2-.
5.Jedinjenje prema bilo kom od Zahteva 2 do 4, ili neka njegova farmaceutski prihvatljiva so, gde: a) Y je N; ili b) Y je CH.
6.Jedinjenje prema bilo kom od Zahteva 2 do 5, ili neka njegova farmaceutski prihvatljiva so, gde: a) X je N; ili b) X je CR4; ili c) X je CR4, a R4 je H ili F.
7.Jedinjenje prema bilo kom od Zahteva 2 do 6, ili neka njegova farmaceutski prihvatljiva so, gde: a) W je N; ili b) W je CR6; ili c) W je CR6, a R6 je H, F, ili Cl; ili d) W je CR6, a R6 je H ili F; ili e) W je CR6, a R6 je H.
8.Jedinjenje prema bilo kom od Zahteva 2 do 7, ili neka njegova farmaceutski prihvatljiva so, gde R3 predstavlja H ili F.
9.Jedinjenje prema bilo kom od Zahteva 2 do 8, ili neka njegova farmaceutski prihvatljiva so, gde R5 predstavlja H ili F.
10.Jedinjenje prema bilo kom od Zahteva 1 do 9, ili neka njegova farmaceutski prihvatljiva so, gde: a) R2 je H ili metil; ili b) R2 je H.
11.Jedinjenje prema bilo kom od Zahteva 1 do 10, ili neka njegova farmaceutski prihvatljiva so, gde: a) R1 je C1-6 alkil, C1-6 haloalkil, C3-6 cikloalkil, ili C3-6 cikloalkil-C1-3 alkil, pri čemu je svaki od pomenutih C1-6 alkil, C3-6 cikloalkil i C3-6 cikloalkil-C1-3 alkil, opciono supstituisan sa 1, 2, ili 3 supstituenta koji se nezavisno biraju između fluoro, -CF3 i metil; ili b) R1 je izopropil, etil, 1-metilpropil, 2,2,2-trifluoro-1-metiletil, 1-ciklopropiletil, ciklopropil, 1-trifluorometilciklopropil, 1-ciklopropil-2,2,2-trifluoroetil, 2,2,2-trifluoroetil, ili 2,2-difluoroetil; ili c) R1 je izopropil, etil, 1-metilpropil, ili 2,2,2-trifluoro-1-metiletil.
12.Jedinjenje prema bilo kom od Zahteva 1 do 11, ili neka njegova farmaceutski prihvatljiva so, gde R7 predstavlja H, metil, etil, ili HO-CH2-.
13.Jedinjenje prema bilo kom od Zahteva 1 do 12, ili neka njegova farmaceutski prihvatljiva so, gde a) R8 je H ili metil; ili b) R8 je H.
14.Jedinjenje prema bilo kom od Zahteva 1 do 13, ili neka njegova farmaceutski prihvatljiva so, gde a) R9 je H, metil ili etil; ili b) R9 je H; ili c) R9 je metil.
15.Jedinjenje prema bilo kom od Zahteva 1 do 14, ili neka njegova farmaceutski prihvatljiva so, gde a) R10 je H, metil, etil, ili HO-CH2-; ili b) R10 je H; ili c) R10 je metil; ili d) R10 is etil; ili e) R10 je HO-CH2-.
16.Jedinjenje prema bilo kom od Zahteva 1-4 i 6-15, ili neka njegova farmaceutski prihvatljiva so, koje a) ima Formulu II: ili neka njegova farmaceutski prihvatljiva so; ili b) ima formulu III: ili neka njegova farmaceutski prihvatljiva so; ili c) ima formulu IV: ili neka njegova farmaceutski prihvatljiva so; ili d) ima formulu IIa: ili neka njegova farmaceutski prihvatljiva so; ili e) ima formulu IIIa: ili neka njegova farmaceutski prihvatljiva so; ili f) ima formulu IVa: ili neka njegova farmaceutski prihvatljiva so.
17.Jedinjenje prema Zahtevu 1, koje se bira između: 5-[3-(cijanometil)-3-(3’-metil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N-[(1S)-2,2,2- trifluoro-1-metiletil]pirazin-2-karboksamid; 5-[3-(cijanometil)-3-(3’-metil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N-izopropilpirazin- 2-karboksamid; 4-[3-(cijanometil)-3-(3’-metil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N- izopropilbenzamid; 4-[3-(cijanometil)-3-(3’-metil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamid; 4-[3-(1H,1’H-4,4’-bipirazol-1-il)-3-(cijanometil)azetidin-1-il]-2,5-difluoro-N-[(1S)-2,2,2- trifluoro-1-metiletil]benzamid; 5-[3-(cijanometil)-3-(3,3’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N- izopropilpirazin-2-karboksamid; 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamid; 5-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N- izopropilpirazin-2-karboksamid; 5-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N-[(1S)-2,2,2- trifluoro-1-metiletil]pirazin-2-karboksamid; 5-[3-(cijanometil)-3-(3-metil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N-izopropilpirazin- 2-karboksamid; 5-[3-(cijanometil)-3-(3’-etil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-N-[(1S)-2,2,2- trifluoro-1-metiletil]pirazin-2-karboksamid; 4-{3-(cijanometil)-3-[3’-(hidroksimetil)-1H,1’H-4,4’-bipirazol-1-il]azetidin-1-il}-2,5- difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamid; 4-{3-(cijanometil)-3-[3-(hidroksimetil)-3’-metil-1H,1’H-4,4’-bipirazol-1-il]azetidin-1-il}- 2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamid; ili neka njegova farmaceutski prihvatljiva so.
18.Jedinjenje prema Zahtevu 1, koje predstavlja 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamid, ili neka njegova farmaceutski prihvatljiva so.
19.So prema Zahtevu 1, koja se bira između: 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamidna so fosforne kiseline; 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamidna so hlorovodonične kiseline; 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamidna so bromovodonične kiseline; i 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N- [(1S)-2,2,2-trifluoro-1-metiletil]benzamidna so sumporne kiseline.
20.Kompozicija, koja sadrži neko jedinjenje ili so prema bilo kom od Zahteva 1 do 19, i neki farmaceutski prihvatljiv nosač.
21.Postupak inhibiranja aktivnosti JAK1, koji se sastoji od: a) dovođenja in vitro u kontakt JAK1 sa nekim jedinjenjem ili solju prema bilo kom od Zahteva 1 do 19; ili b) dovođenja in vitro u kontakt JAK1 sa nekim jedinjenjem ili solju prema bilo kom od Zahteva 1 do 19, pri čemu su pomenuto jedinjenje ili so selektivni prema JAK1, u poređenju sa JAK2.
22.Jedinjenje ili so prema bilo kom od Zahteva 1 do 19 za upotrebu, u nekom postupku za tretiranje neke autoimune bolesti, nekog kancera, nekog mijeloproliferativnog poremećaja, neke inflamatorne bolesti, neke bolesti resorpcije kosti ili odbacivanja transplantiranog organa.
23.Jedinjenje ili so za upotrebu prema Zahtevu 22, a pri tome a) pomenutu autoimunu bolest predstavlja neki poremećaj na koži, multipla skleroza, reumatoidni artritis, psorijatički artritis, juvenilni artritis, tip I dijabetesa, lupus, inflamatorna bolest utrobe, Crohn-ova bolest, mijastenija gravis, imunoglobulinske nefropatije, miokarditis, ili autoimuni poremećaj tiroide; ili b) pomenutu autoimunu bolest predstavlja reumatoidni artritis; ili c) pomenutu autoimunu bolest predstavlja neki poremećaj na koži; ili d) pomenutu autoimunu bolest predstavlja neki poremećaj na koži, pri čemu pomenuti poremećaj na koži predstavlja atopični dermatitis, psorijaza, senzibilizacija kože, iritacija kože, crvenilo kože, kontaktni dermatitis ili allergijska kontaktna senzibilizacija.
24.Jedinjenje ili so za upotrebu prema Zahtevu 22, što a) pomenuti kancer predstavlja neki čvrst tumor; ili b) pomenuti kancer predstavlja kancer prostate, kancer bubrega, kancer jetre, kancer dojke, kancer pluća, kancer tiroide, Kaposi-ev sarkom, Castleman-ova bolest ili kancer pankreasa; ili c) pomenuti kancer predstavlja limfom, leukemija, ili multipli mijelom.
25.Jedinjenje ili so za upotrebu prema Zahtevu 22, što a) pomenuti mijeloproliferativni poremećaj predstavlja policitemija vera (PV), esencijalna trombocitemija (ET), primarna mijelofibroza (PMF), hronična mijelogena leukemija (CML), hronična mijelomonocitna leukemija (CMML), hipereozinofilni sindrom (HES), idiopatska mijelofibroza (IMF) ili sistemska bolest mast ćelija (SMCD); ili b) pomenuti mijeloproliferativni poremećaj predstavlja mijelofibroza; ili c) pomenuti mijeloproliferativni poremećaj predstavlja primarna mijelofibroza (PMF); ili d) pomenuti mijeloproliferativni poremećaj predstavlja post policitemija vera mijelofibroza (Post-PV MF); ili e) pomenuti mijeloproliferativni poremećaj predstavlja post-esencijalna trombocitemija mijelofibroza (Post-ET MF).
26.Jedinjenje ili so za upotrebu prema bilo kom od Zahteva 1 do 19 u postupku tretiranja: a) nekog mijelodisplastičnog sindroma (MDS); ili b) nekog mijelodisplastičnog sindroma (MDS), pri čemu se pomenuti mijelodisplastični sindrom bira između refraktorne citopenije sa unilineažnom displazijom (RCUD), refraktorne anemje sa prstenastim sideroblastima (RARS), refraktorne citopenije sa multilineažnom displazijom, refraktorne anemije sa viškom blasta-1 (RAEB-1), refraktorne anemije sa viškom blasta -2 (RAEB-2), mijelodisplatičnog sindroma, neklasifikovane (MDS-U) i mijelodisplatičnog sindroma povezanog sa izolovanim del(5q).
27.Postupak za dobijanje 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamidne soli fosforne kiseline, koji se sastoji od: (a) rastvaranja 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamidne soli fosforne kiseline u metanolu, na nekoj temperaturi od 40°C do 70°C, uz formiranje primarne smeše; (b) dodavanja n-heptana ovoj primarnoj smeši, na nekoj temperaturi od 40°C do 70°C, uz formiranje sekundarne smeše; i (c) hlađenja ove sekundarne smeše, što daje 4-[3-(cijanometil)-3-(3’,5’-dimetil-1H,1’H-4,4’-bipirazol-1-il)azetidin-1-il]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-metiletil]benzamidnu so fosforne kiseline.
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