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Patentnummer NO/EP3468966
Europeisk (EP) publiserings nummer EP3468966
EP levert
EP søknadsnummer 17739383.2
EP meddelt
Prioritet 2016.06.10, US 201662348496 P
Sakstype Europeisk
Løpedag
Utløpsdato
Allment tilgjengelig
Validert i Norge
Innehaver Vitae Pharmaceuticals, LLC (US)
Oppfinner CACATIAN, Salvacion (US) .... se mer/flere nedenfor
Fullmektig ZACCO NORWAY AS (NO)
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Patentkrav1. En forbindelse med formel I:eller et farmasøytisk akseptabelt salt derav, hvor:A, B, D og E er hver uavhengig valgt fra -C(RA1)(RA2)-, -C(RA1)(RA2)-C(RA1)(RA2)-, -C(RA1)(RA2)-O-, -C(RA1)(RA2)-NRA3-, -C(=O)-, -C(RA1)(RA2)-C(=O)-, og -N=C(NH2)-hvor ikke mer enn en av A, B, D og E er -C(RA1)(RA2)-O-, -C(RA1)(RA2)-NRA3-, -C(RA1)(RA2)-C(=O)-, -C(=O)-, eller -N=C(NH2)-;U er N eller CRU, hvor RU er H, halo, CN, OH, C1-4 alkyl, C1-4 alkoksy, amino, C1-4 alkylamino, eller C2-8 dialkylamino;W er N eller CRW, hvor RW er H, halo, CN, OH, C1-4 alkyl, C1-4 alkoksy, amino, C1-4 alkylamino, eller C2-8 dialkylamino;X er N eller CRX, hvor RX er H, halo, CN, OH, C1-4 alkyl, C1-4 alkoksy, amino, C1-4 alkylamino, eller C2-8 dialkylamino, hvor hvis X er N, atomet av L som er direkte bundet til X er et annet enn N, O eller S;L er valgt fra -C1-6 alkylen- og -(C1-4 alkylen)a-Q-(C1-4 alkylen)b-, hvor C1-6 alkylengruppe og hvilken som helst C1-4 alkylengruppe av -(C1-4 alkylen)a-Q-(C1-4 alkylen)b- gruppen er eventuelt substituert med 1, 2 eller 3 substituenter som er uavhengig valgt fra halo, CN, OH, C1-3 alkyl, C1-3 alkoksy, C1-3 haloalkyl, C1-3 haloalkoksy, amino, C1-3 alkylamino, og di(C1-3 alkyl)amino;Q er -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NRq1-, -C(=O)O-, -OC(=O)NRq1-,-NRq1-, -NRq1C(=O)O-, -NRq1C(=O)NRq1-, -S(=O)2NRq1-, -C(=NRq2)-, eller -C(=NRq2)-NRq1-, hvor hver Rq1 er uavhengig valgt fra H eller C1-6 alkyl, og hvor hver Rq2 er uavhengig valgt fra H, C1-6 alkyl, og CN; Cy er en koblings-C6-14 aryl, C3-18 sykloalkyl-, 5-16-leddet heteroaryl- eller 4-18-leddet heterosykloalkylgruppe, som hver er eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra RCy;hver RCy er uavhengig valgt fra halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 sykloalkyl, 5-10-leddet heteroaryl, 4-10-leddet heterosykloalkyl, CN,NO2, ORa1 SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 og S(O)2NRc1Rd1, hvor nevnte C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 sykloalkyl, 5-10-leddet heteroaryl og 4-10-leddet heterosykloalkyl er hver eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra CN,NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, og S(O)2NRc1Rd1;R1 er H, Cy1, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN,NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2 og S(O)2NRc2Rd2, hvor nevnte C1-6 alkyl, C2-6 alkenyl og C2-6 alkynyl er hver eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra halo, CN,NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, og S(O)2NRc2Rd2;Y er O, S,CRY1RY2 eller NRY3, hvor RY1, RY2og RY3 er hver uavhengig valgt fra H og C1-4 alkyl;Z er Cy2, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN,NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, S(O)2NRc3Rd3og P(O)Rc3Rd3 hvor C1-6 alkyl, C2-6 alkenyl og C2-6 alkynyl er hver eventuelt substituert med 1, 2, 3 eller 4substituenter som er uavhengig valgt fra Cy2, halo, CN,NO2, CN,NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, og S(O)2NRc3Rd3;hver R2 og R3 er uavhengig valgt fra H, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN,NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, og S(O)2NRc4Rd4, hvor nevnte C1-6 alkyl, C2-6 alkenyl og C2-6 alkynyl er hver eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra halogen, CN,NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, og S(O)2NRc4Rd4;hver RA1 er uavhengig valgt fra H, halo, C1-4 alkyl, C1-4 alkoksy, C1-4 haloalkyl, C1-4 haloalkoksy, amino, C1-4 alkylamino, C2-8 dialkylamino, CN,NO2og OH;hver RA2 er uavhengig valgt fra H, halo, C1-4 alkyl, C1-4 alkoksy, C1-4 haloalkyl, C1-4 haloalkoksy, amino, C1-4 alkylamino, C2-8 dialkylamino, CN,NO2og OH;hver RA3 er uavhengig valgt fra H, C1-4 alkyl, C1-4 alkoksy, C1-4 haloalkyl, C(O)Rz, og C(O)ORz, hvor nevnte C1-4 alkyl er eventuelt substituert med fenyl, C1-4 alkoksy, C1-4 haloalkoksy, CN,NO2, eller OH;Rz er H, C1-4 alkyl, eller fenyl;hver Cy1 er uavhengig valgt fra C6-14 aryl, C3-18 sykloalkyl, 5-16 leddet heteroaryl og 4-18 leddet heterosykloalkyl, som hver er eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra RCy1;hver Cy2 er uavhengig valgt fra C6-14 aryl, C3-18 sykloalkyl, 5-16 leddet heteroaryl og 4-18 leddet heterosykloalkyl, som hver er eventuelt substituert med 1, 2, 3 eller 4 substituenter uavhengig valgt fra RCy2;hver RCy1 og RCy2 er uavhengig valgt fra halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, fenyl, C3-7 sykloalkyl, 5-6-leddet heteroaryl og 4-7-leddet heterosykloalkyl, CN,NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, og S(O)2NRc5Rd5, hvor nevnte C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, fenyl, C3-7 sykloalkyl, 5-6-leddet heteroaryl og 4-7-leddet heterosykloalkyl er hver eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra CN,NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, og S(O)2NRc5Rd5;hver Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5og Rd5 er uavhengig valgt fra H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 sykloalkyl, 5-10-leddet heteroaryl, 4-10-leddet heterosykloalkyl, C6-10 aryl-C1-6 alkyl, C3-10 sykloalkyl-C1-6 alkyl, (5-10-leddet heteroaryl)-C1-6 alkyl, og (4-10-leddet heterosykloalkyl)-C1-6 alkyl, hvor nevnte C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 sykloalkyl, 5-10-leddet heteroaryl, 4-10-leddet heterosykloalkyl, C6-10 aryl-C1-6 alkyl, C3-10 sykloalky-C1-6 alkyl, (5-10-leddet heteroaryl)-C1-6 alkyl, og (4-10-leddet heterosykloalkyl)-C1-6 alkyl er hver eventuelt substituert med 1, 2, 3, 4 eller 5 substituenter som er uavhengig valgt fra Rg;hver Re1, Re2, Re3, Re4 og Re5 er uavhengig valgt fra H, C1-4 alkyl, og CN;hver Rg er uavhengig valgt fra gruppen bestående av OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoksy, C1-6 haloalkoksy, cyano-C1-3 alkyl, HO-C1-3 alkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, tiol, C1-6 alkyltio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, karboksy, aminokarbonyl, C1-6 alkylkarbonyl og C1-6 alkoksykarbonyl;n er 0 eller 1;m er 0 eller 1;p er 0, 1, 2 eller 3;q er 0, 1 eller 2;a er 0 eller 1; ogb er 0 eller 1,hvor en hvilken som helst sykloalkyl- eller heterosykloalkylgruppe eventuelt er ytterligere substituert med 1 eller 2 okso-grupper. 2. Forbindelsen ifølge krav 1, eller et farmasøytisk akseptabelt salt derav, hvor i) Y er O, eller ii) Y er NRY3,og/eller i) U er N, eller ii) U er CRU,og/eller i) W er N, eller ii) W er CRWog/eller i) X er N, eller ii) X er CRXog/eller i) A, B, D og E er hver uavhengig valgt fra -C(RA1)(RA2)-, og -C(RA1)(RA2)-C(RA1)(RA2)-, eller ii) A, B, D og E er hver uavhengig valgt fra -CH2- og -CH2-CH2-.3. Forbindelsen ifølge krav 1 eller krav 2, eller et farmasøytisk akseptabelt salt derav, hvor:i) spirodelen er representert ved formelen nedenfor:hvor e og f indikerer festepunkter til resten av molekylet, og er valgt fra:ellerii) spirodelen er representert ved formelen nedenfor:hvor e og f indikerer festepunkter til resten av molekylet, og er valgt fra: 4. Forbindelsen ifølge et hvilket som helst av kravene 1 til 3, eller et farmasøytisk akseptabelt salt derav, hvori) L er valgt fra -C1-6 alkylen- som er eventuelt substituert med 1, 2 eller 3 substituenter som er uavhengig valgt fra halo, CN, OH, C1-3 alkyl, C1-3 alkoksy, C1-3 haloalkyl, C1-3 haloalkoksy, amino, C1-3 alkylamino, og di(C1-3 alkyl)amino, ellerii) L er valgt fra metylen, etylen og -CH2-CH(OH)-, elleriii) L er metylen, elleriv) L er valgt fra -(C1-4 alkylen)a-Q-(C1-4 alkylen)b-, hvor hvilken som helst C1-4 alkylengruppe av de N-(C1-4 alkylen)a-Q-(C1-4 alkylen)b- gruppen er eventuelt substituert med 1, 2 eller 3 substituenter som er uavhengig valgt fra halo, CN, OH, C1-3 alkyl, C1-3 alkoksy, C1-3 haloalkyl, C1-3 haloalkoksy, amino, C1-3 alkylamino, og di(C1-3 alkyl)amino, ellerv) L er valgt fra -C(O)-CH2-, -C(O)-CH2-CH2-, C(O), -NH-CH2-, NH, -C(O)-CH(NH2)-, -NH-CH(CH3)-, -N(CH3)-C(O)-, N(CH3)-CH2-, -CH2-CH2-O-, og -C(O)-NH-.5. Forbindelsen ifølge et hvilket som helst av kravene 1 til 4, eller et farmasøytisk akseptabelt salt derav, hvori) Cy er et koblingsfenyl, C3-18 sykloalkyl-, 5-10-leddet heteroaryl- eller 4-9-leddet heterosykloalkylgruppe, som hver er eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra RCy, ellerii) Cy er et koblingsfenyl, C3-18 sykloalkyl-, 5-10-leddet heteroaryl- eller 4-9-leddet heterosykloalkylgruppe, som hver er eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra RCy, eller iii) Cy er en koblingsgruppe som har formelen:hver av disse er eventuelt substituert med 1, 2, 3 eller 4 substituenter som er uavhengig valgt fra RCy, elleriv) Cy er en koblingsgruppe som har formelen:v) Z er Cy2 eller C(O)NRc3Rd3.6. Forbindelsen ifølge et hvilket som helst av kravene 1 til 5, eller et farmasøytisk akseptabelt salt derav, hvori) n er 0, eller ii) n er 1,og/eller i) m er 0 eller ii) m er 1,og/eller i) p er 0 eller ii) p er 1,og/eller i) q er 0 eller ii) q er 1.7. Forbindelsen ifølge et hvilket som helst av kravene 1 og 3 til 6, eller et farmasøytisk akseptabelt salt derav, som hari) formel IIa, IIb, IIIa eller IIIb: ellerii) formel IVa, IVb, IVc, IVd, IVe eller IVf:8. Forbindelsen ifølge krav 1, hvor forbindelsen er valgt fra:5-fluor-N,N-diisopropyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;N-etyl-5-fluor-N-isopropyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-2-((4-(7-((1-(2-hydroksyetyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;N-etyl-5-fluor-2-((4-(7-((1-(2-hydroksyetyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N-isopropylbenzamid; 5-fluor-N-(2-hydroksyetyl)-N-isopropyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(7-(((1s,4s)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-((7-(5-(2-(amino(syklopentyl)metyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(2-(syklopentyl(dimetylamino)metyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;N-(syklopentyl(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)metyl) acetamid;6-((7-(5-(4-fluor-2-(1-hydroksy-2-metylpropyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3,3-dimetylindolin-2-on;6-((7-(5-(4-fluor-2-isobutyrylfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3-metyl-2-oksoindolin-3-karbonitril;5-fluor-2-((4-(6-(3-(4-fluorfenyl)propanoyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;5-((7-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-3-okso-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;N-(4-fluor-2-(5-isopropyl-3-metylisoksazol-4-yl)fenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amin;4-(5-fluor-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)fenyl)-5-isopropyl-3-metylisoksazol;N-(5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amin; 5-fluor-2-((4-(2-(2-hydroksy-2-metylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamid;5-((7-(5-(2-(dimetylfosforyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-N-(4-fluorbenzyl)-5-oksa-2-azaspiro[3.4]oktan-7-amin;4-(((2-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-5-oksa-2-azaspiro[3.4]oktan-7-yl)amino)metyl)benzonitril;7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-N-(4-fluorbenzyl)-1-oksa-7-azaspiro[4.4]nonan-3-amin;5-fluor-N-isopropyl-N-metyl-2-((4-(7-(((1r,4r)-4-(metylkarbamoyl)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;2-((4-(7-amino-7-(4-cyanobensyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-2-((4-(7-hydroksy-8-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;2-((4-(7-amino-8-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-2-((4-(8-(4-fluorbenzyl)-7-(2-hydroksyetyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;6-((7-(5-(2-klor-4-fluorfenoksy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2-yl)metyl)-1-metyl-1H-benzo[d]imidazol-2(3H)-on;5-((7-(3-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(2-(3-syklopropyl-1-metyl-6-okso-1,6-dihydropyridin-2-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on; N-(5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-amin;2-(5-((4’,5-difluor-2’-(2-fluorpropan-2-yl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan;5-fluor-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzensulfonamid;5-((7-(5-(4-fluor-2-(2-metoksybutan-2-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-(3-hydroksypentan-3-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)-N-metylsyklopropankarboksamid;5-((7-(5-(4-fluor-2-(3-hydroksy-3-metylbutyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;metyl 2-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)syklopropankarboksylat;2-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)-N-metylsyklopropankarboksamid;6-((2-(5-(2-klor-4-fluorfenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]oktan-6-yl)metyl)-3,3-dimetylindolin-2-on;2-(6-(5-(2-klor-4-fluorfenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-karbonyl)-2,3-dihydro-1H-inden-5-sulfonamid;5-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pynmidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on; 2-syklopropyl-5'-fluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;2-syklopropyl-5'-fluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karboksamid;2-syklopropyl-5'-fluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karboksylsyre;2-syklopropyl-5'-fluor-N,N-dimetyl-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karboksamid;5-((7-(2-klor-5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-((4,5-difluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5'-fluor-2-metyl-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;5-((7-(5-((2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5-((7-(5-((5-fluor-2’-(trifluormetyl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5'-fluor-2,6-dimetyl-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;2-syklopropyl-3’, 5'-difluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;5-((7-(5-(4-fluor-2-(2-isopropyl-1H-imidazol-1-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on; 5-((7-(5-(2-(syklopropylmetoksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H -benzo[d]imidazol-2-on;etyl 2-(7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)tiazol-4-karboksylat;2-(7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)tiazol-4-karboksylsyre;2-(7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-metyltiazol-4-karboksamid;2-(7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N,N-dimetyltiazol-4-karboksamid;7-benzyl-2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan;5-((7-(5-((5-fluor-2’-(1-hydroksyetyl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5-fluor-N-isopropyl-N-metyl-2-((4-(7-(3-(2-oksooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N-isopropyl-N-metyl-2-((4-(7-(4-(2-oksooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-((7-(5-((5-fluor-2’-(2-hydroksypropan-2-yl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidiN-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;2-(1,4-dioksaspiro[4.5]dekan-8-ylmetyl)-6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan;4-((6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)metyl)sykloheksanol;2-syklopropyl-5'-fluor-2’-((4-(6-((4-hydroksysykloheksyl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;2-(5-((5-fluor-2’-(1-metoksyetyl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan; 5-(5-fluor-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)fenyl)-2,3-dihydro-1H-inden-2-amin;5-((7-(5-((5-fluor-2’-(1-hydroksypropan-2-yl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidiN-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;5-((7-(5-(4-fluor-2-(morfolinometyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d]imidazol-2(3H)-on;1-(7-(5-((2'-etyl-5-fluor-[1,1'-bifenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-metylpropan-2-ol;1-((6-(5-(4-fluor-2-(1-isopropyl-3-(trifluormetyl)-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)metyl)sykloheksan-1-ol;N-(2-amino-2-oksoetyl)-N-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;N-(5-fluor-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl) propan-2-sulfonamid;tert-butyl 7-(5-(4-fluor-2-(N-metylisobutyramido)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-karboksylat;N-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)-N-metylisobutyramid;5-((7-(5-(4-fluor-2-isobutylfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazo1-2-on;2-(3-((2'-etyl-5-fluor-[1,1'-bifenyl]-2-yl)metyl)pyridin-4-yl)-6-((tetrahydro-2H-pyran-4-yl))metyl)-2,6-diazaspiro[3.3]heptan;N-((1r,4r)-4-((2-(5-(2-(3-syklopropyl-1-metyl-6-okso-1,6-dihydropyridin-2-yl)-4-fluorfenoksy)pyrimidiN-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)-2,2,2-trifluoracetamid;N-(4-((2-(5-(2-(3-syklopropyl-1-metyl-6-okso-1,6-dihydropyridin-2-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)metansulfonamid; 5-((7-(5-(2-(3-syklopropyl-1-metyl-6-okso-1,6-dihydropyridin-2-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1-(2-hydroksyetyl)-1H-benzo[d]imidazol-2(3H)-on;(1r,4r)-4-(2-(6-(5-(2-(2-syklopropylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksan-1-amin;tert-butyl((1r,4r)-4-(((2-(5-(4-fluor-2-(isopropyl(metyl) karbamoyl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptaN-6-yl)amino)metyl)sykloheksyl)karbamat;tert-butyl((1r,4r)-4-((2-(5-(2-(N-etylisobutyramido)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)karbamat;metyl((1r,4r)-4-((2-(5-(2-(N-etylisobutyramido)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)karbamat;N-etyl-N-(5-fluor-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;2-((4-(6-(2-((1r,4r)-4-(3,3-dimetylbutanamido)sykloheksyl)etyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;tert-butyl((1r,4r)-4-(2-(6-(5-(2-(2-syklopropylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl)karbamat;5-fluor-2-((4-(7-(2-hydroksy-2-metylpropyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;2-((4-(7-((3-cyano-3-metyl-2-oksoindolin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;metyletyl(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)karbamat;5-fluor-2-((4-(7-((1-(2-hydroksyetyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N-isopropyl-N-metylbenzamid;5-fluor-N-isopropyl-N-metyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid; 5-fluor-N-isopropyl-N-metyl-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;tert-butyl((1r,4r)-4-((2-(5-(4-fluor-2-(isopropyl(metyl)karbamoyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)karbamat;metyl((1r,4r)-4-((2-(5-(4-fluor-2-(isopropyl(metyl)karbamoyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)karbamat;N-(tert-butyl)-2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.4]oktan-6-amin;2-((4-(7-(((1r,4r)-4-(3,3-dimetylureido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-2-((4-(7-((4-hydroksysykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;5-fluor-2-((4-(6-((4-hydroksysykloheksyl)metyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;2-((4-(7-((1,4-dioksaspiro[4,5]dekan-8-yl)metyl)-2,7-diazaspiro[3,5]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-N,N-diisopropyl-2-((4-(7-((tetrahydro-2H-pyran-4-yl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(6-neopentyl-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)benzamid;2-((4-(6-(syklopropylmetyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;2-((4-(6-(6-cyano-1,2,3,4-tetrahydronaftalen-2-yl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-N,N-diisopropyl-2-((4-(6-(2-((1r,4r)-4-pivalamidosykloheksyl)etyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid; N-(2-((4-(6-(sykloheksylmetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-5-fluorfenyl)-N-etylisobutyramid;N-etyl-5-fluor-N-isopropyl-2-((4-(7-((1-metyl-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;2-(5-(2-(syklopentyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)metyl)-2,7-diazaspiro[4.4]nonan;2-(5-(2-syklopropoksy-4-fluorfenoksy)pyrimidin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)metyl)-2,7-diazaspiro[4.4]nonan;N-etyl-N-(5-fluor-2-((4-(7-((tetrahydro-2H-pyran-4-yl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;5-fluor-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid;2-((4-(6-(2-(4-cyanofenyl) acetyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;5-fluor-2-((4-(6-(6-fluor-1,2,3,4-tetrahydronaftalen-2-yl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-N,N-diisopropylbenzamid;tert-butyl((1r,4r)-4-(2-(6-(5-(2-(diisopropylcarbamoyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl)karbamat;2-((4-(6-(2-(4-cyanofenyl) acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N,N-diisopropylbenzamid;N-etyl-N-(5-fluor-2-((4-(6-(5-(metylsulfonyl)-2,3-dihydro-1H-inden-2-karbonyl)-2,6diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;3-(((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)metyl)bisyklo[1.1.1]pentan-1-karbonitril;N-etyl-N-(5-fluor-2-((4-(6-(2-(4-(metylsulfonyl)fenyl) acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid; N-(2-((4-(6-(5-brom-2,3-dihydro-1H-inden-2-karbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-5-fluorfenyl)-N-etylisobutyramid;N-etyl-N-(5-fluor-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;N-syklopropyl-5-fluor-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;2-((4-(7-((1-(2-acetamidoetyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-((4-(7-((1-(2-(dimetylamino)etyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-((4-(7-((3-cyano-3-metyl-2-oksoindolin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;5-((7-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)-2-metylpyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-((4-(2-(2-(4-cyanofenyl) acetyl)-2,6-diazaspiro[3.4]oktan-6-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-((4-(7-((1-etyl-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;5-fluor-N-isopropyl-2-((4-(7-((1-(2-metoksyetyl)-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-N-metylbenzamid;4-(2-(6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]oktan-2-yl)-2-oksoetyl)benzonitril;5-((7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1-(2-metoksyetyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on; 1-(6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(6-metoksypyridin-3-yl)ethan-1-on;6-(2-(6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oksoetyl)-3,3-dimetylindolin-2-on;tert-butyl((1r,4r)-4-(2-(6-(5-(4-fluor-2-(isopropyl(metyl) karbamoyl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl)karbamat;5-((7-(5-(4-fluor-2-((isopropyl(metyl)amino)metyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;N-etyl-N-(5-fluor-2-((4-(6-isobutyl-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;N-(2-((4-(6-((4,4-difluorsykloheksyl)metyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-5-fluorfenyl)-N-etylisobutyramid;tert-butyl((1r,4r)-4-(2-(6-(5-(4-fluor-2-(N-metylisobutyramido)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl)karbamat;2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-7-(6-fluor-3,4-dihydroisokinolin-2(1H)-yl)-5-oxa-2-azaspiro[3.4]oktan;4-(((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)metyl)-1-metylsykloheksan-1-karbonitril;4-(1-((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)etyl)benzonitril;5-fluor-N-isopropyl-N-metyl-2-((4-(7-(4-(2-oksooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;N-((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl) acetamid;metyl(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)(isopropyl)karbamat; 2-((4-(7-((1H-indazol-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-((4-(7-((3-cyano-1H-indazol-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;tert-butyl((1r,4r)-4-((7-(5-(2-(syklopentyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)sykloheksyl)karbamat;4-((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)-1-metylsykloheksankarbonitril;4-(2-(2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]oktan-6-yl)-2-oksoetyl)benzonitril;5-((7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1-metyl-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-syklopropyl-5'-fluor-2’-((4-(6-((4-hydroksysykloheksyl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;4-(((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)metyl)benzonitril;5-((7-(5-(2-(2,5-dimetylpyrrolidin-1-karbonyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-(pyrrolidin-1-karbonyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-(morfolin-4-karbonyl)fenoksy)pyrimidin-4-yl)-2,7-diaza spiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;N-etyl-N-(5-fluor-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-N-(4-fluorbenzyl)-1-oksa-7-azaspiro[4.4]nonan-3-amin;N-(2-((4-(6-(sykloheksylmetyl)-2,6-diazaspiro[3.4]oktan-2-yl)pyrimidin-5-yl)oksy)-5-fluorfenyl)-N-etylisobutyramid; N-benzyl-2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]oktan-7-amin;5-((7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-((5-fluor-2’-(prop-1-en-2-yl)-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-(5-(4-fluor-2-(2-isopropoksypyridin-3-yl)fenoksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan;5-fluor-N-isopropyl-N-metyl-2-((4-(7-((1-metyl-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;etyl(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)(metyl)karbamat;N-syklopropyl-5-fluor-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)-N-fenylbenzamid;2-((4-(6-(sykloheksylmetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-(5-(2-(syklopentyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan;2-syklopropyl-5'-fluor-2’-((4-(7-((2-okso-2,3-dihydrobenso[d]oksazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;metyl(3-((7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)fenyl)karbamat;2'-((4-(7-((1H-benzo[d][1,2,3]triazol-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-2-syklopropyl-5'-fluor-[1,1'-bifenyl]-4-karbonitril; N-(2-klor-4-((7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)fenyl) acetamid;N,N-dietyl-5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N-isopropyl-N-metyl-2-((4-(7-((2-okso-2,3-dihydrobenso[d]oksazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;N-(tert-butyl)-5-fluor-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;1-(7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-metylpropaN-2-ol;2-(5-(2-(2-syklopropylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan;6-((7-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3,3-dimetylindolin-2-on;6-((7-(5-(2-(2-syklopropylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3,3-dimetylindolin-2-on;5-((7-(5-(2-(2-syklopropylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;4-(((2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]oktan-7-yl)(metyl)amino)metyl)benzonitril;6-((7-(5-(4-fluor-2-(2,2,2-trifluoroetoksy)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3,3-dimetylindolin-2-on;5-fluor-N-isopropyl-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;N-(sykloheksylmetyl)-2-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]oktan-7-amin; N-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)-N-(2-hydroksyetyl)isobutyramid;N-etyl-N-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)isobutyramid;N-(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)-N-(2,2,2-trifluoretyl)isobutyramid;N-((1r,4r)-4-((7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidiN-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)sykloheksyl) acetamid;tert-butyl((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)etyl)sykloheksyl)karbamat;5-((7-(5-(4-fluor-2-(5-isopropyltiazol-4-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;N-((1s,4s)-4-((7-(5-((4'-cyano-2'-syklopropyl-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidiN-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)sykloheksyl) acetamid;2-syklopropyl-2’-((4-(7-((1-etyl-2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5'-fluor-[1,1'-bifenyl]-4-karbonitril;3-((7-(5-(2-(syklopentyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-indol-6-karbonitril;6-((7-(5-(2-(syklopentyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-3,3-dimetylindolin-2-en;2-((4-(7-((6-cyano-1H-indol-3-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2-syklopropyl-5'-fluor-2’-((4-(7-(4-(2-oksopyrrolidin-1-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril; 2-syklopropyl-5'-fluor-2’-((4-(7-((2-oksoindolin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;6-((7-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-benzo[d][1,2,3]triazol;2-syklopropyl-3’,5'-difluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;3-((7-(5-(2-(syklopropylmetoksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-indol-6-karboksamid;3-((7-(5-(2-(syklopropylmetoksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1H-indol-6-karbonitril;2-((4-(7-((3,3-dimetyl-2-oksoindolin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid;2'-((4-(6-(4-cyanofenetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-2-syklopropyl-5'-fluor-[1,1’-bifenyl]-4-karbonitril;2-syklopropyl-5'-fluor-2’-((4-(7-((2-oksoindolin-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;2-syklopropyl-2’-((4-(7-((3,3-dimetyl-2-oksoindolin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-5'-fluor-[1,1'-bifenyl]-4-karbonitril;2-amino-2-sykloheksyl-l-(7-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)etanon;metyl(5-fluor-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)fenyl)(metyl)karbamat;5-((7-(5-(2-(benzyloksy)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H -benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-metoksyfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on; 5-fluor-N-isopropyl-N-metyl-2-((4-(7-((3-okso-3,4-dihydro-2H-benzo[b][1,4]oksazin-6-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-((7-(5-(4-fluor-2-(2-metylpyrrolidin-1-karbonyl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(2-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-karbonyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on; 1,1-difluoretyl)-5-fluor-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-syklopropyl-5'-fluor-2’-((4-(6-((4-hydroksytetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;2-syklopropyl-5'-fluor-2’-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;5-fluor-N-isopropyl-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-((7-(5-(4-fluor-2-(1-isopropyl-3-(trifluormetyl)-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-(2-isopropyl-5-oksopyrrolidin-1-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;(1r,4r)-4-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)sykloheksan-1-amin;tert-butyl((1r,4r)-4-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)sykloheksyl)karbamat;N-(4-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)fenyl)acetamid;5-fluor-N-isopropyl-N-metyl-2-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)benzensulfonamid; etyl-5'-fluor-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-2-karboksylat;5-((7-(5-(4-fluor-2-(4-isopropyltiazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-fluor-N-isopropyl-N-metyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid;5'-fluor-2-metyl-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-4-karbonitril;4-(2-(6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oksoetyl)benzonitril;4-(2-(6-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oksoetyl)benzonitril;1-(6-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-(metylsulfonyl)fenyl)ethan-1-on;5'-fluor-2-metyl-2’-((4-(7-((2-okso-2,3-dihydro-1H-benzo[d]imidazol-5-yl)metyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-[1,1'-bifenyl]-3-karbonitril;2-((3,3-difluorsykloheksyl)metyl)-6-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan;2-((3,3-difluorsykloheksyl)metyl)-6-(5-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenoksy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan;4-(((2-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]oktan-7-yl)amino)metyl)benzonitril;5-((7-(5-(2-(2-etylpyridin-3-yl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-isopentylfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;5-((7-(5-(4-fluor-2-isobutylfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on; 5-((7-(5-(4-fluor-2-(1-isopropyl-1H-pyrazol-5-yl)fenoksy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl))metyl)-2,6-diazaspiro[3.3]heptan;N-etyl-5-fluor-N-isopropyl-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid;5-fluor-N,N-diisopropyl-2-((4-(6-(metyl(tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oksy)benzamid;tert-butyl((1r,4r)-4-((7-(5-((2-(diisopropylcarbamoyl)-4-fluorfenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)metyl)sykloheksyl)karbamat;1-((6-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)amino)pyrimidin-4-yl)-2,6-diaza spiro[3.3]heptan-2-yl)metyl)sykloheksan-1-ol;5-((7-(5-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;N-(4-fluor-2-(4-isopropylpyrimidin-5-yl)fenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)metyl)-2,6-diazaspiro[3.3]heptaN-2-yl)pyrimidin-5-amin;N-(5-fluor-2'-isopropoksy-[1,1'-bifenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-amin;N-(5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-amin;N-(2'-etyl-5-fluor-[1,1'-bifenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-amin;5-fluor-N,N-diisopropyl-2-((4-(2-(4-(metylsulfonamido)sykloheksyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)benzamid; 5-((7-(3-((5-fluor-2'-isopropyl-[1,1'-bifenyl]-2-yl)oksy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)metyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on;2'-((4-(7-amino-7-benzyl-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oksy)-2-syklopropyl-5'-fluor-[1,1'-bifenyl]-4-karbonitril;tert-butyl((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorfenoksy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)metyl)sykloheksyl)karbamat;2-((4-(3-(4-acetamidobensyl)-2-amino-4-okso-1,3,7-triazaspiro[4.4]ikke-1-en-7-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropyl-N-metylbenzamid; ogN-etyl-2-((4-(7-(((1r,4r)-4-(etylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropylbenzamid;eller et farmasøytisk akseptabelt salt derav.9. Forbindelsen ifølge krav 1, som eri) 5-fluor-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(metylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)benzamid, eller et farmasøytisk akseptabelt salt derav, ellerii)N-etyl-2-((4-(7-(((1r,4r)-4-(etylsulfonamido)sykloheksyl)metyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oksy)-5-fluor-N-isopropylbenzamid, eller et farmasøytisk akseptabelt salt derav.10. Et farmasøytisk akseptabelt salt av forbindelsen ifølge krav 9, som eri) et bis-metansulfonsyresalt,ii) et bis-saltsyresalt, elleriii) et sesquifumarsyresalt.11. En krystallinsk form av saltet ifølge krav 10, som eri) i det vesentlige vannfri, eller ii) hydratisert eller solvatisert, eventuelt hvor den krystallinske formen er et monohydrat.12. En farmasøytisk sammensetning som omfatter en forbindelse, et farmasøytisk akseptabelt salt eller en krystallinsk form ifølge et hvilket som helst av de foregående kravene og i det minste en farmasøytisk akseptabel bærer.13. Forbindelsen, det farmasøytisk akseptable saltet, saltet eller den krystallinske formen ifølge et hvilket som helst av kravene 1-11 eller sammensetningen ifølge krav 12 for bruk ved behandling av kreft. for eksempel hvor kreften er: i) en hematologisk kreft, ii) leukemi, iii) lymfom eller iv) der kreften er blandet avstammingsleukemi (MLL), MLL-relatert leukemi, MLL-assosiert leukemi, MLL-positiv leukemi, MLL-indusert leukemi, omorganisert blandet avstammingsleukemi (MLL-r), leukemi som er assosiert med en MLL-omorganisering eller en omorganisering av MLL gen, akutt leukemi, kronisk leukemi, indolent leukemi, lymfoblastisk leukemi, lymfocytisk leukemi, myeloid leukemi, myelogen leukemi, barndomsleukemi, akutt lymfocytisk leukemi (ALL), akutt myeloid leukemi (AML), akutt myelogen leukemi, akutt ikke-lymfocytisk leukemi, kronisk lymfocytisk leukemi (CLL), kronisk myelogen leukemi (CML), terapirelatert leukemi, myelodysplastisk syndrom (MDS), myeloproliferativ sykdom (MPD), myeloproliferativ neoplasi (MPN), plasmacelle neoplasma, multippelt myelom, myelodysplasi, kutan T-celle lymfom, lymfoid neoplasm, AIDS-relatert lymfom, thymom, thymuskarsinom, mykos fungus, Alibert-Bazin syndrom, granulom fungus, Sézary syndrom, hårcelleleukemi, T-celle prolymfocytisk leukemi (T-PLL), stor granulær lymfocytisk leukemi, meningeal leukemi, leukemi leptomeningitt, leukemisk meningitt, multippel myelom, Hodgkins lymfom, ikke Hodgkins lymfom (ondartet lymfom) eller Waldenstroms makroglobulinemi.14. Forbindelsen, det farmasøytisk akseptable saltet eller den krystallinske formen ifølge et hvilket som helst av kravene 1-11 eller sammensetningen ifølge krav 12 for bruk i behandlingen av insulinresistens, pre-diabetes, diabetes eller risiko for diabetes.15. Forbindelsen, det farmasøytisk akseptable saltet eller den krystallinske formen ifølge et hvilket som helst av kravene 1-11 eller sammensetningen ifølge krav 12 for bruk i behandlingen av hyperglykemi.
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Innehaver i EP:
Vitae Pharmaceuticals, LLC
5 Giralda Farms Madison, NJ 07940 US

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CACATIAN, Salvacion
169 Front St. Conshohocken, Pennsylvania 19428 US
CLAREMON, David, A.
1508 Aidenn Lair Road Maple Glen, Pennsylvania 19002 US
DILLARD, Lawrence, Wayne
496 Kings Road Yardley, Pennsylvania 19067 US
DONG, Chengguo
96 Arthur Avenue Staten Island, New York 10305 US
FAN, Yi
40 Bittersweet Drive Doylestown, Pennsylvania 18901 US
JIA, Lanqi
22 Beaver Hill Road Horsham, Pennsylvania 19044 US
LOTESTA, Stephen, D.
99 Jennifer Lane Burlington, New Jersey 08016 US
MARCUS, Andrew
122 Locust Lane Media, Pennsylvania 19063 US
MORALES-RAMOS, Angel
1549 Sylvan Drive Blue Bell, Pennsylvania 19422 US
SINGH, Suresh, B.
4 Adams Road Kendall Park, New Jersey 08824 US
VENKATRAMAN, Shankar
114 Country Lane Lansdale, Pennsylvania 19446 US
YUAN, Jing
537 Candlemaker Way Lansdale, Pennsylvania 19446 US
ZHUANG, Linghang
3135 Fox Drive Chalfont, Pennsylvania 18914 US
PARENT, Stephan, D.
1200 Fawn Ridge Dr. West Lafayette, Indiana 47906 US
HOUSTON, Travis, L.
3240 Hendrickson Ln Lafayette, Indiana 47905 US
ZHENG, Yajun
712 Marlin Ave Nr. 3 Foster City California 94404 US

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Fullmektig i Norge:
ZACCO NORWAY AS
Postboks 488 0213 OSLO NO ( OSLO kommune, Oslo fylke )

Org.nummer: 982702887
Din referanse: V9953NO00
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Kilde: Brønnøysundregistrene
Fullmektig i EP:
Cooley (UK) LLP
22 Bishopsgate London EC2N 4BQ GB

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2016.06.10, US 201662348496 P

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A. SHI ET AL: "Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia", BLOOD, vol. 120, no. 23, 29 November 2012 (2012-11-29), pages 4461-4469, XP055245187, US ISSN: 0006-4971, DOI: 10.1182/blood-2012-05-429274 (B1)

WO-A1-2015/191701 (B1)

WO-A1-2014/164543 (B1)

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