DK2705029T3 - Hidtil ukendte forbindelser som modulatorer af proteinkinaser - Google Patents

Hidtil ukendte forbindelser som modulatorer af proteinkinaser Download PDF

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DK2705029T3
DK2705029T3 DK12722989.6T DK12722989T DK2705029T3 DK 2705029 T3 DK2705029 T3 DK 2705029T3 DK 12722989 T DK12722989 T DK 12722989T DK 2705029 T3 DK2705029 T3 DK 2705029T3
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substituted
fluoro
unsubstituted
fluorophenyl
ethyl
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DK12722989.6T
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Dhanapalan Nagarathnam
Swaroop Kumar V S Vakkalanka
Meyyappan Muthuppalaniappan
Srikant Viswanadha
Govindarajulu Babu
Prashant Kashinath Bhavar
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Rhizen Pharmaceuticals S A
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Claims (23)

1. Forbindelse med formlen
(I) eller en tautomer deraf, en N-oxid deraf eller et farmaceutisk acceptabelt salt deraf, hvor hver forekomst af R er udvalgt uafhængigt fra hydroxy, halogen, carboxyl, cyano, nitro, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret cycloa I kyla I kyl, substitueret eller ikke-substitueret cycloalkenylalkyl, substitueret eller ikke-substitueret heterocyclyl, substitueret eller ikke-substitueret heterocyclylalkyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, -COORX, -C(O)RX, -C(S)RX, -C(O)NRxRy, -C(O)ONRxRy, -NRxRy, -NRxCONRxRy,-N(Rx)SORx, -N(Rx)SO2Ry, -(=NN(RX)RV), - NRxC(O)ORy, -NRxRy, -NRxC(ORy-, -NRxC(S)Ry, -NRxC(S)NRxRy, -SONRxRy-, -SO2NRxRv-, -ORx, -ORxC(O)NRxRy, -ORXC(O)ORX-, -OC(O)RX, -OC(O)NRxRy, - RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRxRy, -RxC(O)Ry, -RxOC(O)Ry, -SRX, -SORX, -SO2RX, -ONO2, hvor Rx, Ry og Rz i hver af ovenstående grupper kan være hydrogen, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl,
substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloaIkylaIkyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret heterocyclylalkyl-ring eller substitueret eller ikke-substitueret amino eller (i) to af Rx og Rv vilkårligt kan være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-14-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRZ eller S, eller (ii) to af Rx og Rv vilkårligt forbindes, så de danner en oxo (=0), thio (=S) eller imino (=NRf) (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl); R1 og R2 kan være den samme eller forskellige og er uafhængigt udvalgt fra hydrogen, halogen og substitueret eller ikke-substitueret Ci_6 alkyl, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret cycloa Ikyla Ikyl og substitueret eller ikke-substitueret heterocyclyl, eller både R1 og R2 direkte bundet til et fælles atom, kan være forbundet, så de danner en oxo-gruppe (=0) eller en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring (herunder det carbonatom, hvortil R1 og R2 er bundet), som eventuelt kan indbefatte et eller flere heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRa og S; Cy1 er udvalgt fra substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret heterocyklisk gruppe, substitueret eller ikke-substitueret aryl og substitueret eller ikke-substitueret heteroaryl; Cy2 er udvalgt fra en substitueret eller ikke-substitueret heterocyklisk gruppe, substitueret eller ikke-substitueret aryl og substitueret eller ikke-substitueret heteroaryl; Li mangler eller er udvalgt fra -(CRaRb)q-, -O-, -S(=0)q-, -NRa- eller -C(=Y)-; hver forekomst af Ra og Rb kan være den samme eller forskellige og er uafhængigt udvalgt fra hydrogen, halogen, hydroxy, cyano, substitueret eller ikke-substitueret (Ci_ 6)a I kyl, -NRcRd (hvor Rc og Rd uafhængigt er hydrogen, halogen, hydroxy, cyano, substitueret eller ikke-substitueret (Ci_6)a I kyl eller (Ci_6)alkoxy) og -ORC (hvor Rc er substitueret eller ikke-substitueret (Ci_6)a I kyl) eller Ra og Rb, når de er direkte bundet til et fælles atom, kan være forbundet, så de danner en oxo-gruppe (=0) eller danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring (inklusive det fælles atom, hvortil Ra og Rb er direkte bundet), som eventuelt kan indbefatte et eller flere heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRd (hvor Rd er hydrogen eller substitueret eller ikke-substitueret (Ci_6)aIkyl) eller S; Y er udvalgt fra O, S og NRa; og q er 0,1 eller 2, hvor betegnelsen substitueret henviser til en substitution udvalgt fra hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substitueret eller ikke-substitueret Ci-C8aIkyl, substitueret eller ikke-substitueret Ci-C8 alkoxy, substitueret eller ikke-substitueret C2-Cio alkenyl, substitueret eller ikke-substitueret C2-Ci2 alkynyl, substitueret eller ikke-substitueret C3-Ci2 cycloalkyl, substitueret eller ikke-substitueret C3-Cs cycloalkenyl, -COORX, -C(O)RX, -C(S)RX, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S02Rv, -(=N-N(Rx)Rv), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry-,-RxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy-, -SO2NRxRv-, -0Rx, -ORxC(O)NRyRz,-ORxC(O)ORy-, -OC(0)RX, -OC(O)NRxRy, -RXNRVC(O)RZ, -RxORy, -RxC(O)ORy,-RxC(O)NRyRz, -RXC(O)RX, -RxOC(0)Ry, -SRX, -SORX, -S02Rx og -0N02, hvor (i) Rx, Ry og Rz i hver af ovennævnte grupper kan være hydrogen, substitueret eller ikke-substitueret Ci-C8 alkyl, substitueret eller ikke-substitueret Ci-C8 alkoxy, substitueret eller ikke-substitueret C2-Ci0 alkenyl, substitueret eller ikke-substitueret C2-Ci2 alkynyl, substitueret eller ikke-substitueret 6β·62ο aryl, substitueret eller ikke-substitueret C6-C20 aryl(Ci-C8 alkyl), substitueret eller ikke-substitueret C3-Ci2 cycloalkyl, substitueret eller ikke-substitueret C3-Ci2 cycloalkyl(Ci-C8 alkyl), substitueret eller ikke-substitueret C3-C8 cycloalkenyl, substitueret eller ikke-substitueret amino, substitueret eller ikke-substitueret 5-14-leddet heteroaryl (hvor heteroatomerne er udvalgt fra N, O og S), substitueret eller ikke-substitueret 5-14-leddet heteroaryl(Ci-C8 alkyl) (hvor heteroatomerne er udvalgt fra N, O og S), substitueret eller ikke-substitueret 3-15-leddet heterocyklisk ring (hvor heteroatomerne er udvalgt fra N, P, O og S) eller substitueret 3-15-leddet heterocyclyl(Ci-C8 alkyl), eller to af Rx, Ry og Rz vilkårligt kan være forbundet, så de danner en substitueret eller ikke-substitueret mættet eller umættet 3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRX (Rx er hydrogen eller Ci_6 alkyl) eller S, og (ii) substituenterne i førnævnte "substituerede" grupper ikke kan substitueres yderligere.
2. Forbindelse ifølge krav 1, hvor R er uafhængigt udvalgt fra halogen, cyano, substitueret eller ikke-substitueret Ci_6 alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret C2-6 alkenyl, substitueret eller ikke-substitueret C2-6 alkynyl, substitueret eller ikke-substitueret C3_8 cycloalkyl og substitueret eller ikke-substitueret heterocyklisk gruppe; Cy1 er udvalgt fra en substitueret eller ikke-substitueret aryl og substitueret eller ikke-substitueret heteroaryl; R1 og R2 uafhængigt repræsenterer hydrogen eller substitueret eller ikke-substitueret C1-6 alkyl.; Li mangler eller er udvalgt fra S(=O)q- eller -NRa-; og Cy2 er udvalgt fra en substitueret eller ikke-substitueret heterocyklisk gruppe og substitueret eller ikke-substitueret heteroaryl.
3. Forbindelse ifølge krav 2, hvor R er fluor, methyl, methoxy eller morpholin; Cy1 er udvalgt fra
q er 0; og Li mangler eller er -NH-.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor Li-Cy2 er udvalgt fra
hvor X er CR3; og hver forekomst af R3 er uafhængigt udvalgt fra hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloaIkylaIkyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret eller ikke-substitueret heterocyclylalkyl-ring, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret guanidin, -COORX, -C(O)RX, -C(S)RX, -C(O)NRxRy, -C(O)ONRxRy, -NRyRz,-NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), - NRxC(O)ORy,-NRxRy, -NRxC(O)Ry-, -NRxC(S)Ry -NRxC(S)NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)RX, -OC(O)NRxRy,-RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RXC(O)RX, -RxOC(O)Ry, -SRX, -SORX, -SO2RX eller -ONO2, hvor Rx, Ry og Rz i hver af ovenstående grupper kan være hydrogen, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret
eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloa Ikyla I kyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret heterocyclylalkyl-ring eller substitueret eller ikke-substitueret amino, eller to af Rx, Ry og Rz vilkårligt kan være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRf eller S (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl); hver forekomst af R' og R" er uafhængigt udvalgt fra hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloa Ikyla I kyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret eller ikke-substitueret heterocyclylalkyl-ring, substitueret eller ikke-substitueret guanidin, -COORX, -C(O)RX, -C(S)Rx,-C(O)NRxRy, -C(O)ONRxRy, -NRyRz, -NRxCONRyRz, -N(Rx)SORy,-N(Rx)SO2Ry, -(=N-N(Rx)Ry), - NRxC(O)ORy, -NRxRy, -NRxC(O)Ry-,-NRxC(S)Ry-NRxC(S)NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)RX, -OC(O)NRxRy, - RxNRyC(O)Rz, -Rx-ORy,-RxC(O)ORy, -RxC(O)NRyRz, -RXC(O)RX, -RxOC(O)Ry, -SRX, -SORX, -SO2Rx,-ONO2, eller både R' og R" sammen med nitrogenatomet kan være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRf (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl) eller S; hvor Rx, Ry og Rz i hver af ovenstående grupper kan være hydrogen, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloa I kyla I kyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret heterocyclylalkyl-ring eller substitueret eller ikke-substitueret amino, eller to af Rx, Rv og Rz vilkårligt kan være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRf eller S (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl); og q er 0,1 eller 2.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor Li-Cy2 er udvalgt fra
6. Forbindelse ifølge krav 1, hvor forbindelsen har formlen (IA-1), (IA-II), (IA-III), (IA-IV), (IA-V), (ΙΑ-la), (IA-lla), (IA-llla), (ΙΑ-lb) eller (IA-llb)
eller en tautomer deraf, en N-oxid deraf eller et farmaceutisk acceptabelt salt deraf, hvor: R er udvalgt fra halogen, -ORa, CN, substitueret eller ikke-substitueret Ci_6 alkyl, substitueret eller ikke-substitueret C2-6 alkenyl, substitueret eller ikke-substitueret C2_6 alkynyl, substitueret eller ikke-substitueret C3_8 cycloalkyl og substitueret eller ikke-substitueret heterocyklisk gruppe; R1 og R2 kan være den samme eller forskellige og er uafhængigt udvalgt fra hydrogen, halogen og substitueret eller ikke-substitueret Ci_6 alkyl, eller både R1 og R2 direkte
bundet til et fælles atom, kan være forbundet, så de danner en oxo-gruppe (=0) eller kan være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring (herunder det fælles atom, hvortil R1 og R2 er direkte bundet), som eventuelt kan indbefatte et eller flere heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRa og S; Cy1 er en monocyklisk gruppe udvalgt fra substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret heterocyklisk gruppe, substitueret eller ikke-substitueret aryl og substitueret eller ikke-substitueret heteroaryl; og X, R3, R', R", Ra og q er som defineret i et hvilket som helst af kravene 1-4;
7. Forbindelse ifølge krav 1, hvor forbindelsen har formlen (IA-VI) eller (IA-VIII)
eller et farmaceutisk acceptabelt salt deraf, hvor R, R1, R2, R3 R', R" og X er som defineret i et hvilket som helst af kravene 1-6; hver forekomst af R5 er hydrogen, Ci_6 alkyl eller halogen; og p er O, 1, 2, 3, 4 eller 5.
8. Forbindelse ifølge et hvilket som helst af kravene 4, 6 eller 7, hvor R3 er hydrogen, halogen, cyano, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret heterocyclyl, substitueret eller ikke-substitueret aryl eller substitueret eller ikke-substitueret heteroaryl; hver af R' og R" er udvalgt fra hydrogen eller Ci_6 alkyl, eller -NR'R" sammen er forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet
3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRf (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl) eller S; og X er CR3, hvor R3 uafhængigt er hydrogen, halogen, hydroxyl eller NH2.
9. Forbindelse ifølge krav 8, hvor R3 er udvalgt fra
hver forekomst af X uafhængigt er CR4 eller N; X1 er O, S eller NR4; og hver forekomst af R4 er uafhængigt udvalgt fra hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloa Ikyla Ikyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret eller ikke-substitueret heterocyclylalkyl-ring, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret guanidin, -COORX, -C(O)RX, -C(S)RX, -C(O)NRxRy, -C(O)ONRxRy, -NRyRz,-NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Rv), - NRxC(O)ORy,-NRxRy, -NRxC(O)Ry-, -NRxC(S)Ry -NRxC(S)NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)RX, -OC(O)NRxRy,-RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RXC(O)RX, -RxOC(O)Ry, -SRX, -SORX, -SO2Rx eller -ONO2, hvor Rx, Ry og Rz i hver af ovenstående grupper kan være hydrogen, substitueret eller ikke-substitueret alkyl, substitueret eller ikke-substitueret alkoxy, substitueret eller ikke-substitueret alkenyl, substitueret eller ikke-substitueret alkynyl, substitueret eller ikke-substitueret aryl, substitueret eller ikke-substitueret arylalkyl, substitueret eller ikke-substitueret heteroaryl, substitueret eller ikke-substitueret heteroarylalkyl, substitueret eller ikke-substitueret cycloalkyl, substitueret eller ikke-substitueret cycloa Ikyla I kyl, substitueret eller ikke-substitueret cycloalkenyl, substitueret eller ikke-substitueret heterocyklisk ring, substitueret heterocyclylalkyl-ring eller substitueret eller ikke-substitueret amino, eller to af Rx, Ry og Rz vilkårligt kan
være forbundet, så de danner en substitueret eller ikke-substitueret, mættet eller umættet 3-10-leddet ring, som eventuelt kan indbefatte heteroatomer, der kan være de samme eller forskellige og er udvalgt fra O, NRf eller S (hvor Rf er hydrogen eller substitueret eller ikke-substitueret alkyl) eller S.
10. Forbindelse ifølge krav 8, hvor R3 er udvalgt fra
hver af R' og R" er udvalgt fra hydrogen eller methyl, eller -NR'R" sammen er udvalgt fra
og X er CR3, hvor R3 er hydrogen eller fluor.
11. Forbindelse ifølge krav 1, udvalgt fra: 2-(6-Amino-9H-purin-9-yl)methyl)-3-(3-fluorphenyl)-5-methoxy-4H-chromen-4-on; 2- ((4-Amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) methyl)- 3- (3-fluorphenyl)-5-methoxy-4H-chromen-4-on; 2-((4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-((4-amino-3-(3-fluor-5-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-((4-amino-3-(3-fluor-5-hydroxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (+)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (-)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-methyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (+)-2-(l-(4-amino-3-(3-methyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (-)-2-(l-(4-amino-3-(3-methyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(lH-pyrazol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4Hchromen-4-on; 2-(l-(6-amino-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; 2-(l-(4-amino-3-(benzofuran-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H- chromen-4-on; (+)-2-(l-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H- chromen-4-on; (-)-2-(l-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H- chromen-4-on; 2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(lH-pyrazol-4-yl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-lH-pyrazolo[3,4-d] pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-isopropyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(piperidin-4-yloxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(2-hydroxyethylamino)phenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2- (l-(4-amino-3-(3-fluor-4-(isopropylamino)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-(dimethylamino)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(2-methyl-lH-benzo[d]imidazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(4-methylpiperazin-l-yl)phenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-(dimethylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4- on; 2-(l-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H- chromen-4-on; 2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; 2-(l-(4-amino-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-ethyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(benzo[b]thiophen-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-morpholino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(dimethylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(piperidin-l-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(6-isopropoxypyridin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on 4-methylbenzensulfonat; 2-(l-(4-amino-3-(3-methyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on 4-methylbenzensulfonat; 2-(l-(4-amino-3-(4-(l-benzhydrylazetidin-3-yloxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(trifluormethoxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-(oxetan-3-yloxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(pyrrolidin-l-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3- fluorphenyl)-4H-chromen-4-on; N-(4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramid; 2-(l-(4-amino-3-(4-isobutylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3- (3-fluorphenyl)-4Hchromen-4-on; 2-(l-(4-amino-3-(4-isopropoxy-3-methylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-(5,6-dihydro-4H-l,3-oxazin-2-yl)phenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzensulfonamid; 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluor-N-isopropylbenzamid; 2-(l-(4-amino-3-(4-(5-(methylamino)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; N-(4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methansulfonamid; 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzensulfonamid; 4- (4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzensulfonamid; 2-(l-(4-amino-3-(2-isopropoxypyrimidin-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (R) /(S)-2-(l-(4-amino-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)benzensulfonamid; methyl 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-carboxylat; 2-(l-(4-amino-3-(5-methylthiophen-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; methyl 4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorbenzoat; 2-(l-(9H-purin-6-ylamino)propyl)-5-fluor-3-phenyl-4H-chromen-4-on; 2-(l-(4-amino-3-(3-hydroxyprop-l-ynyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (S) /(R)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on 4-methylbenzensulfonat; (+)-2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on 2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (R)/(S)-2-(l-(4-amino-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-(methoxymethyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(imidazo[l,2-a]pyridin-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; tert-butyl (5-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamat; 2-(l-(4-amino-3-(2,4-dimethylthiazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(5-(morpholinomethyl)thiophen-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-(5-amino-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (-)-2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2- (l-(4-amino-3-(l,3-dimethyl-lH-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; N-(4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorphenyl)isobutyramid; N-(4-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorphenyl)acetamid; 2-(l-(4-(dimethylamino)-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 5-fluor-2-(l-(3-(3-fluor-4-isopropoxyphenyl)-4-(methylamino)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; 5-fluor-2-(l-(3-(3-fluor-4-isopropoxyphenyl)-4-morpholino-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; N-(2-fluor-4-(l-(l-(5-fluor-3-(4-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4- morpholino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramid; N-(2-fluor-4-(l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramid; (S)/(R)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on sulfat; (S)/(R)- 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on ; (S)/(R)- 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on camphorsulfonat; 2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(lHpyrazol-4-yl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-phenyl-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; (S)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; (R) -2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; (S) -2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; (R) -2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-(dimethylamino)-3-(3-fluor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 5-fluor-2-(l-(3-(3-fluor-4-morpholinophenyl)-4-(methylamino)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; (S) -2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; (R)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; (S)-2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; (R) -2-(l-(4-amino-3-(4-(difluormethoxy)-3-fluorphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-fluor-3-phenyl-4H-chromen-4-on; (+)-5-fluor-2-(l-(3-(3-fluor-4-isopropoxyphenyl)-4-(methylamino)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; (-)-5-fluor-2-(l-(3-(3-fluor-4-isopropoxyphenyl)-4-(methylamino)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(6-amino-2-fluor-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(6-amino-2-fluor-9H-purin-9-yl)ethyl)-5-fluor-3-(4-fluorphenyl)-4H-chromen-4-on; 5-fluor-3-(4-fluorphenyl)-2-(l-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-on; 5-fluor-3-(4-fluorphenyl)-2-(l-(6-(4-methylpiperazin-l-yl)-9H-purin-9-yl)ethyl)-4H- chromen-4-on; 2-(l-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4- on; 2-(l-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4- on; 5-fluor-3-(3-fluorphenyl)-2-(l-(3-(3-methyl-lH-indazol-6-yl)-4-morpholino-lH- pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-chlor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (+)-2-(l-(4-amino-3-(4-isopropoxy-3-methylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (-)-2-(l-(4-amino-3-(4-isopropoxy-3-methylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (S) /(R)- 5-fluor-2-(l-(3-(3-fluor-4-isopropoxyphenyl)-4-morpholino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-chlor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 5-fluor-3-(3-fluorphenyl)-2-(l-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-on; 2- (l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 3- (3-fluorphenyl)-5-morpholino-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- 5- morpholino-3-phenyl-4H-chromen-4-on; 6- (4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-l-on; 5-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-l-on; 2-(l-(3-(4-acetyl-3-fluorphenyl)-4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5- fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 5-fluor-3-(3-fluorphenyl)-2-(l-(6-(4-methylpiperazin-l-yl)-9H-purin-9-yl)ethyl)-4H- chromen-4-on; (S)-2-(l-(4-amino-3-(3-chlor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (R) -2-(l-(4-amino-3-(3-chlor-4-morpholinophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; N-(3-(4-amino-l-(l-(5-fluor-3-(3-fluorphenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methansulfonamid; (S) -2-(l-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (R)-2-(l-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on ; 2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-(2-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(4-ethoxy-3-(trifluormethyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)propyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on; (S)-5-fluor-3-(3-fluorphenyl)-2-(l-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen- 4-on; (R) -5-fluor-3-(3-fluorphenyl)-2-(l-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen- 4-on; (S) /(R)-5-fluor-2-(l-(2-fluor-9H-purin-6-ylamino)ethyl)-3-(3-fluor phenyl)-4H-chromen- 4-on; (S)/(R)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-on; 2-(l-(9H-purin-6-ylamino)ethyl)-5-fluor-3-o-tolyl-4H-chromen-4-on; og farmaceutisk acceptable salte deraf.
12. Forbindelse ifølge krav 1, hvor forbindelsen med formlen I er 2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on og farmaceutisk acceptable salte deraf.
13. Forbindelse ifølge krav 1, hvor forbindelsen med formlen I er (+)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on eller et farmaceutisk acceptabelt salt deraf.
14. Forbindelse ifølge krav 1, hvor forbindelsen med formlen I er (-)-2-(l-(4-amino-3-(3-fluor-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl) ethyl)-5-fluor-3-(3-fluorphenyl)-4H-chromen-4-on eller et farmaceutisk acceptabelt salt deraf.
15. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 til 14 og en farmaceutisk acceptabel bærer.
16. Farmaceutisk sammensætning ifølge krav 15, der endvidere omfatter en eller flere yderligere terapeutiske midler udvalgt fra anti-cancermidler, anti-inflammatoriske midler, immunsupprimerende midler, steroider, ikke-steroide anti-inflammatoriske midler, antihistaminer, analgetika og blandinger deraf.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 til anvendelse til behandling af en PI3K-associeret sygdom eller forstyrrelse.
18. Forbindelse ifølge krav 17, der endvidere omfatter mindst ét andet anti-cancermiddel, anti-inflammatorisk middel, immunosupprimerende middel, steroid, ikke-steroidt anti-inflammatorisk middel, antihistamin, analgetikum eller en blanding deraf.
19. Forbindelse ifølge et hvilket som helst af kravene 17 eller 18, hvor den PI3K-associerede sygdom, forstyrrelse eller tilstand er en immunsystem-relateret sygdom, en sygdom eller forstyrrelse, der indebærer inflammation, cancer eller andre proliferative sygdomme, en leversygdom eller-forstyrrelse eller en nyresygdom eller-forstyrrelse.
20. Forbindelse ifølge et hvilket som helst af kravene 17 eller 18, hvor den PI3K-associerede sygdom, forstyrrelse eller tilstand er udvalgt fra inflammation, glomerulonefritis, uveitis, leversygdomme eller-forstyrrelser, nyresygdomme eller-forstyrrelser, kronisk obstruktiv lungesygdom, rheumatoid arthritis, inflammatorisk tarmsygdom, vaskulitis, dermatitis, osteoarthritis, inflammatorisk muskelsygdom, allergisk rhinitis, vaginitis, interstitiel cystitis, skleroderma, osteoporose, eksem, allogen eller xenogen transplantation, graft-afstødning, graft-versus-host-sygdom, lupus erythematosus, lungefibrose, dermatomyositis, thyroiditis, myasthenia gravis, autoimmun hæmolytisk anæmi, cystisk fibrose, kronisk recidiverende hepatitis, primær biliær cirrhose, allergisk konjunktivitis, hepatitis, atopisk dermatitis, astma, Sjogrens sygdom, organtransplantatafstødning, multipel sklerose, Guillain-Barre, autoimmun uveitis, autoimmun hæmolytisk anæmi, perniciøs anæmi, autoimmun trombocytopeni, temporal arteritis, anti-phospholipidsyndrom, vaskulitter såsom Wegeners granulomatose, Behcets sygdom, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohns sygdom, colitis, ulcerativ colitis, primær biliær cirrhose, autoimmun hepatitis, type 1 eller immunmedieret diabetes mellitus, Graves sygdom. Hashimotos thyroiditis, autoimmun ooforitis og orchitis, autoimmun binyreforstyrrelse, systemisk lupus erythematosus, polymyositis, dermatomyositis, ankyloserende spondylitis, transplantatafstødning, hudgraft-afstødning, arthritis, knoglesygdomme, der er associeret med forhøjet knogleresorption;, ileitis, Barretts syndrom, respiratorisk stresssyndrom hos voksne, kronisk obstruktiv luftvejssygdom; corneadystrofi, trachom, onchocerkiasis, sympatisk oftalmitis, endoftalmitis; gingivitis, parodontitis; tuberkulose; spedalskhed; uræmiske komplikationer, nefrose; sklerodermatitis, psoriasis, kroniske demyelinerende nervesystemsygdomme, AIDS-relateret neurodegeneration, Alzheimers sygdom, smitsom meningitis, encefalomyelitis, Parkinsons sygdom, Huntingtons sygdom, amyotrofisk lateral sklerose, viral eller autoimmun encefalitis; autoimmune forstyrrelser, immunkompleks-vaskulitis, systemisk lupus og erythematoder; systemisk lupus erythematosus (SLE); kardiomyopati, iskæmisk hjertesygdom, hyperkolesterolæmi, aterosklerose, præeklampsi; kronisk leversvigt, hjerne - og rygmarvstraume, cancer, hæmopoietiske tumorer af lymfoid afstamning, leukæmi, akut lymfocytisk leukæmi, akut lymfoblastisk leukæmi, B-celle-lymfom, T-celle-lymfom, Hodgkins lymfom, non-Hodgkin-lymfom, hairy cell-lymfom og Burketts lymfom; hæmopoietiske tumorer af myeloid afstamning, akutte myelogene leukæmier, kroniske myelogene leukæmier, myelodysplastisk syndrom, promyelocytisk leukæmi; blærekarcinom, brystkarcinom, colonkarcinom, nyrekarcinom, leverkarcinom, lungekarcinom, små-cellet lungecancer, øsofaguscancer, galdeblærecancer, ovariecancer, pancreascancer, mavecancer, cervixcancer, thyroideacancer, prostatacancer, hudcancer, pladecellekarcinom; tumorer af mesenkymal oprindelse, fibrosarkom, rhabdomyosarkom; tumorer i det centrale og perifere nervesystem, astrocytom, neuroblastom, gliom, schwannom; melanom, seminom, teratokarcinom, osteosarkom, xenoderoma pigmentosum, keratoakantom, thyroid follikelcancer og Kaposis sarkom.
21. Forbindelse ifølge krav 20, hvor den PI3K-associerede sygdom, forstyrrelse eller tilstand er udvalgt fra kronisk obstruktiv lungesygdom, astma, rheumatoid arthritis, kronisk bronkitis, inflammatorisk tarmsygdom, allergisk rhinitis, lupus erythematosus og ulcerativ colitis, hæmopoietiske tumorer af lymfoid afstamning, leukæmi, akut lymfocytisk leukæmi, akut lymfoblastisk leukæmi, B-celle-lymfom, T-celle-lymfom, Hodgkins lymfom, non-Hodgkin-lymfom, kronisk lymfocytisk leukæmi, hairy cell-lymfom og Burketts lymfom, hæmopoietiske tumorer af myeloid afstamning, akutte myelogene leukæmier, kroniske myelogene leukæmier, myelodysplastisk syndrom, promyelocytisk leukæmi eller myelomatose, som indbefatter sovende myelomatose, ikke-sekretorisk myelomatose, osteosklerotisk myelomatose, plasmacelleleukæmi, solitært plasmacytom og extramedullært plasmacytom;
22. Forbindelse ifølge et hvilket som helst af kravene 20 eller 21, hvor den PI3K-associerede sygdom, forstyrrelse eller tilstand er udvalgt fra kronisk obstruktiv lungesygdom, astma, kronisk lymfocytisk leukæmi (CLL); non-Hodgkin-lymfom (NHL); akut myeloid leukæmi (AML); myelomatose (MM), småcellet lymfocytært lymfom (SLL) og indolent non-Hodgkin-lymfom (l-NHL).
23. Forbindelse udvalgt fra formlerne (12), (14) og (15)
(12) (14) (15) hvor R, R1, R2 og Cy1 er som defineret i kravene 1-11.
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