Bifunctional compounds capable of degrading androgen receptors

Abstract

A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: X1 is CH or N; p is 0, 1 or 2; where: each R1 is a substituent on any C atom and is independently selected from F, Cl, C1-3alkyl and C1-3 alkoxy, wherein said C1-3alkyl and C1-3alkoxy may be independently optionally substituted by one or more F; RN is selected from H and Me; n is 0, 1 or 2; m is 0 or 1; Q1 is CH or N; when n & m are both other than 0, Q2 is CH or N; when n & m are both 0, Q2 is CH; when n is 0 or 1, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is CH, Q3 is CH or O; R2a and R2b are substituents on the same or different C atoms other than at Q1 or Q2, each independently selected from H, F and C1-3alkyl, or R2a & R2b together form a -(CH2)r- group where r is 1, 2 or 3; Q4 is a single bond or -NR4C(=O); R4 is H or Me; 0, 1 or 2 of Y1, Y2, Y3, Y4 & Y5 is / are N, and are otherwise C; each R3 is a substituent on any C atom at Y1, Y2, Y3, Y4 & Y5, and is independently selected from F, Cl, CN, C1-3,alkyl and C1-3 alkoxy. wherein said C1-3 alkyl and C1-3 alkoxy may be independently optionally substituted by one or more F; q is 0, 1 or 2; wherein Linker is attached at any available C atom at Y4 & Y5; Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment 'a' and 'b' and a length of from 5 to 26 atoms between 'a' and 'b'; wherein said framework may include one or more straight and / or branched chains and / or rings and is optionally substituted on any available C atom(s) by one or more F; and W is an E3 ubiquitin ligase cereblon binder unit.

Description

HKP2620563 Invention Title: Bifunctional Compound Capable of Degrading Androgen Receptors This disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1 is CH or N; p is 0, 1, or 2; wherein: each R1 is a substituent on any C atom and is independently selected from F, Cl, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl and C1-3 alkoxy may be independently substituted by one or more Fs optionally; RN is selected from H and Me; n is 0, 1, or 2; m is 0 or 1; Q1 is CH or N; when n and m are not 0, Q2 is CH or N; when n and m are both 0, Q2 is CH; when n is 0 or 1, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is N, Q2 ... When Q3 is CH, Q3 is CH or O; R2a and R2b are substituents on the same or different C atoms other than Q1 or Q2, each of which is independently selected from H, F, and C1-3 alkyl, or R2a and R2b together form a -(CH2)r- group, where r is 1, 2, or 3; Q4 is a single bond or -NR4C (=O); R4 is H or Me; 0, 1, or 2 of Y1, Y2, Y3, Y4, and Y5 is N, otherwise it is C; each R3 is a substituent on any C atom of Y1, Y2, Y3, Y4, and Y5, and is independently selected from F, Cl, CN, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl and C1-3 alkoxy may be independently optionally substituted by one or more F; q is 0, 1 Or 2; wherein the linker is attached to any available C atom at Y4 and Y5; the linker is a saturated or partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has a length of 5 to 26 atoms between the linking endpoints 'a' and 'b' and between 'a' and 'b'; wherein the framework may include one or more straight chains and / or branches and / or rings, and is optionally substituted with one or more F atoms at any available C atom; and W is an E3 ubiquitin ligase cereblon binding unit. Abstract

Claims

CLAIMS 1. A compound of Formula (I):wherein: X1is CH or N; p is 0, 1 or 2; where: each R1is a substituent on any C atom and is independently selected from F, Cl, C1-3alkyl and C1-3alkoxy, wherein said C1-3alkyl and C1-3alkoxy may be independently optionally substituted by one or more F; RNis selected from H and Me; n is 0, 1 or 2; m is 0 or 1; Q1is CH or N; when n & m are both other than 0, Q2is CH or N; when n & m are both 0, Q2 is CH;when n is 0 or 1, Q3is CH; when n is 2 and Q2is N, Q3is CH; when n is 2 and Q2is CH, Q3is CH or O; R2aand R2bare substituents on the same or different C atoms other than at Q1or Q2, each independently selected from H, F and C1-3alkyl, or R2a& R2btogether form a -(CH2)r- group where r is 1, 2 or 3; Q4is a single bond or -NR4C(=O); R4is H or Me; 0, 1 or 2 of Y1, Y2, Y3, Y4& Y5is / are N, and are otherwise C; each R3is a substituent on any C atom at Y1, Y2, Y3, Y4& Y5, and is independently selected from F, Cl, CN, C1-3alkyl and C1-3alkoxy, wherein said C1-3alkyl and C1-3alkoxy may be independently optionally substituted by one or more F;q is 0, 1 or 2; wherein Linker is attached at any available C atom at Y4& Y5; Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a length of from 5 to 26 atoms between ‘a’ and ‘b’; wherein said framework may include one or more straight and / or branched chains and / or rings and is optionally substituted on any available C atom(s) by one or more F; and W is an E3 ubiquitin ligase cereblon binder unit.

2. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 1 or claim 2 wherein the Linker is a saturated or partially unsaturated framework and: (a) comprises C and H atoms and at least two heteroatoms; or (b) comprises C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine; or (c) includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having from 4 to 12 ring atoms, or a A1-CH2-CH2-A2unit where A1and A2are each independently selected from N and O.

3. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to either claim 1 or claim 2 wherein the Linker has the Formula: ‘a’ -QA-QB-QC- ‘b’ wherein: ‘a’ and ‘b’ represent the end points of attachment; QAis -G-QH- or -G-(C1-5alkylene)-; QBis a direct bond, -QB1-QB2-QB3- or C1-3alkylene optionally substituted by one or more F (e.g.1 or 2); where: QB1& QB3each independently represent a direct bond or C1-2alkylene; QB2is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJis H or C1-3alkyl; QCis -QH-G- or -(C1-5alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, -C(=O)- or -N(RG)- where RGis H or C1-3alkyl; each QHis independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QBand QCare selected so that the Linker does not contain any N-N or N-O bonds.

4. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 3 wherein: (a) QBis a direct bond, -CH2- or -CH2CH2-; and / or(b) QCis -QH-G- or -(C1-2alkylene)-G-; and / or (c) each QHis independently selected from piperazin-1,4-diyl, azetidin-1,3-diyl, piperidin-1,4-diyl, 1,4- diazepan-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-1,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3,6-dihydro-2H-pyridin-1,4-diyl, morpholin-2,3-diyl, 2- azaspiro[3.5]nonan-2,7-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.

5. A PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (Ia): whed in claim 1.

6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein W is W2 which is AZ is: ent bond or a double covalent bond;1 of XA2, XB2, XC2& XD2is C and covalently bound to YN; 0, 1 or 2 of XA2, XB2, XC2, XD2, XE2& XF2is / are N,where XE2& XF2are not both N, and are otherwise C;1 or 2 of XG2, XH2& XJ2is / are N; and are otherwise C; each RAAis a substituent on any available C or N atom of Z – in each case independently selected from RAA1optionally substituted by one or more RAA2; where RAAis further selected from RAA2when RAAis a substituent on an available C atom of ZA; each RAA1is independently C1-4alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxyC1-3alkyl, carboxyC1-3alkyl, C5-7carbocyclyl or a 4-6 membered heterocyclyl; each RAA2is independently selected from F, Cl, Br, CN, NH2, C1-3alkyl, O(C1-3alkyl), NH(C1-3alkyl) and N(C1-3alkyl)2; wherein said C1-3alkyls are optionally substituted by one or more F; v is 0, 1 or 2; YNis 2,4-dioxohexahydropyrimidin-1-yl.

7. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein 1 of XA2& XB2is C and covalently bound to Y and the other of XA2& XB2is C; 0 or 1 of XC2& XD2is N and is / are otherwise C; 1 of XG2& XJ2is N and the other of XG2& XJ2is C; and XH2, XE2& XF2are all C.

8. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein W is W2-1 wherein:XKand XLare either N-linker and CH, N-linker and CMe or NMe and C-linker respectively; 1 of XMand XOis C-2,4-dioxohexahydropyrimidin-1-yl (YN); 0 or 1 of XMand XNis C-F; XNmay be N if XMis not C-F; the remainder of XN, XMand XOare CH; and XPis CH or CMe.

9. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein W is W1 which is: –Z–(RA)h where Z is:wherein:represents a single covalent bond or a double covalent bond; 0, 1 or 2 of XA, XB, XC, XD, XE& XFis / are N, where XE& XFare not both N, and are otherwise C; 1 of XG, XH& XJis C(O); 1 of XG, XH& XJis N–(2,6-dioxopiperidin-3-yl) (Y); and 1 of XG, XH& XJis selected from C(RT)2, -CH2CH2-, C(O), N(C1- 3alkyl), -O- and -N=, wherein each RTis selected from H, F, Me or together with the carbon of C(RT)2forms a cycloprop-1,1-diyl group; where XG, XH& XJare selected such that there are not two C(O) groups present at adjacent positions, and that the N-(2,6-dioxopiperidin-3-yl) is not at an adjacent position to either N(C1-3alkyl) or O; each RAis independently a substituent on any available C atom at XA, XB, XCor XDselected from F, Cl, C1-3alkyl, C1-3alkoxy wherein said C1-3alkyl and C1-3alkoxy is independently optionally substituted by one or more F; h is 0, 1 or 2; and wherein the Linker is attached to any C atom at XA, XB, XCor XD.

10. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein W is W3 which is: –ZBwhere ZBis:XE3is selected from C(=O) and CRE1RE2, where RE1and RE2are independendently selected from the group consisting of H and C1-3alkyl, or RE1and RE2taken together with the carbons to be they are attached form a C3-6 cycloalkane ring; Y is N–(2,6-dioxopiperidin-3-yl); All of XA3, XB3, XC3and XD3are C; one pair of XA3and XB3, XB3and XC3and XC3and XD3form a five or six membered fully unsaturated or partially unsaturated N containg heterocylic ring, which is attached to the ‘b’ end of the Linker via a N atom; the others of XA3, XB3, XC3and XD3bear a group RB, where each RBis selected from H, F, Cl, C1-3alkyl and C1-3alkoxy.

11. The compound or pharmaceutically acceptable salt thereof, according to any preceding claim wherein RNis H, and p is 0 or 1, R1is selected from Cl, F and Me, and R1, if present, is bound para to Q1.

12. The compound or pharmaceutically acceptable salt thereof, according to any preceding claim wherein X1is N.

13. The compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 37wherein Q1is N, Q2is CH and Q3is CH, and n and m are 1 and 1 or 2 and 0 respectively.

14. The compound or pharmaceutically acceptable salt thereof, according to any preceding claim wherein R2aand R2bare both H.

15. The compound or pharmaceutically acceptable salt thereof, according to any preceding claim wherein: (a) Q4is a single bond; or (b) Q4is a NR4C(=O) and R4is H.

16. The compound or pharmaceutically acceptable salt thereof according to any preceding claim wherein Y1, Y2, Y3, Y4& Y5are all C.

17. The compound or pharmaceutically acceptable salt thereof according to any preceding claim wherein q is 0 or 1 and R3(when present) is a substituent on any C atom at Y1, Y2, Y3, Y4& Y5which is F.

18. The compound or pharmaceutically acceptable salt thereof according to any preceding claim wherein Linker is attached at Y5.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein:X1is N; p is 1; RNis H; n is 2; m is 0; R2aand R2bare both H; Q4is a single bond; Y1, Y2, Y3and Y4are all CH; Y5is C and has the Linker attached; and q is 0.

20. The compound according to claim 1, selected from: 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile;4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]phenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indol-2-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile;7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R* )-2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H- isoindol-5-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S* )-2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H- isoindol-5-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R *)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5- yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S *)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5- yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 7-(4-{4-[4-({1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4- yl}methyl)piperazin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 7-[(3S)-3-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin- 1-yl]phenyl}piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile; 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile;4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin- 6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin- 6-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-6-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}butoxy)phenyl]piperidin-1-yl}-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile;4-Chloro-7-[4-(4-{4-[(4-{2-[(3R*)-2,6-dioxopiperidin-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S*)-2,6-dioxopiperidin-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin- 6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3R*)-2,6-dioxopiperidin-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3S*)-2,6-dioxopiperidin-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-4-methyl-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-1-yl}-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}butoxy)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}butoxy)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3- carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile;7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}butoxy)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl)-1H-indole-3-carbonitrile;4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridazin-3-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidin-1-yl]pyridazin-3-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R*)-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S*)-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyrazin-2-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidin-1-yl]pyrazin-2-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-[4-(4-{4-[(4-{[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4- yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile;7-[4-(4-{4-[(4-{[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4- yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol- 4-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-1H-indole-3- carbonitrile; 7-[(3S)-3-(4-{4-[(4-{[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4- yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(1H)-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(1H)-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-1H-indazole-3-carbonitrile; 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(1H)-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 7-{(3R*)-1-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-3-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{(3S*)-1-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-3-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{(3R*)-1-[3-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-3-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{(3S*)-1-[3-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperidin-3-yl}-4-methyl-1H-indole-3-carbonitrile; 7-[(3R*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-4-methyl-1H-indole-3-carbonitrile; 7-[(3S*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indol-2-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-6-yl]piperazin-1-yl}piperidin-1-yl)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}ethyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3- carbonitrile; 4-Chloro-7-(4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}propyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3- carbonitrile;7-(4-{4-[4-({4-[5-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[(3S*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[(3R*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S*)-1-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-3-yl]-1H-indole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]piperazin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R*)-1-{4-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-4-yl}methyl)piperidin-4-yl]phenyl}piperidin-3-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S*)-1-{4-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]phenyl}piperidin-3-yl]-1H-indole-3-carbonitrile;4-Chloro-7-[(3R*)-1-{4-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperidin-4-yl}methyl)piperidin-4-yl]phenyl}piperidin-3-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-[(3S*)-1-{4-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl]piperidin-4-yl}methyl)piperidin-4-yl]phenyl}piperidin-3-yl]-1H-indole-3- carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-[4-(4-{[1-({1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4- yl}methyl)piperidin-4-yl]oxy}phenyl)piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diazinan-1-yl)-7-methyl-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-2- yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-{4-[(1-{4-[(3S)-1-(4-chloro-3-cyano-1H-indol-7-yl)piperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-1-yl}-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide; 4-{4-[(1-{4-[1-(3-Cyano-4-fluoro-1H-indol-7-yl)piperidin-4-yl]phenyl}piperidin-4- yl)methyl]piperazin-1-yl}-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide; 4-{4-[(1-{4-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide;7-[4-(4-{[4-({1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4- yl}methyl)piperazin-1-yl]methyl}phenyl)piperidin-1-yl]-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridin-3-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidin-1-yl]pyridin-3-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}piperidin-1-yl)phenyl]piperidin-1-yl}-1H-indole-3-carbonitrile; 4-Chloro-7-[4-(4-{4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl][1,4'-bipiperidin]-1'- yl}phenyl)piperidin-1-yl]-1H-indole-3-carbonitrile; 4-chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1-methyl-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{3-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-2-methyl-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S*)-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridin-3-yl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R*)-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyridin-3-yl}piperidin-1-yl]-1H-indole-3-carbonitrile;4-Chloro-7-[(2S*)-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}morpholin-4-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(2R*)-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}morpholin-4-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(2S*)-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}morpholin-4-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(2R*)-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}morpholin-4-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(3R*)-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridazin-3-yl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S*)-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyridazin-3-yl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-2-methyl-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)piperidin-1-yl]pyrimidin-5-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{2-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]pyrimidin-5-yl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)morpholin-4-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile;4-Chloro-7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)morpholin-4-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 7-(4-{4-[7-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)-2-azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[7-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin- 1-yl}methyl)-2-azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[7-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)-2-azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[7-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)- 2-azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indol-2-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 7-[(3S)-3-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-4-fluoro-1H-indazole-3-carbonitrile; 7-[(3S)-3-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin- 1-yl]phenyl}piperidin-1-yl]-4-fluoro-1H-indazole-3-carbonitrile; 7-(4-{4-[7-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)-2- azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile;4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indol-2- yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indole-3-carbonitrile; 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indol-2- yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indol-2- yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl]-1H-indazole-3-carbonitrile; 7-(4-{4-[4-({4-[6-(2,4-Dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indol-2-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indazole-3-carbonitrile; 7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-2-methyl-1H-indol-1-yl]piperidin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)-2- azaspiro[3.5]nonan-2-yl]phenyl}piperidin-1-yl)-1H-indole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indazole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin- 6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indazole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indazole-3-carbonitrile; 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-1H-indazole-3-carbonitrile;7-(4-{4-[4-({4-[4-(2,4-Dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]phenyl}piperidin-1-yl)-4-fluoro-1H-indazole-3-carbonitrile; 7-{4-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-4-methyl-1H-indazole-3-carbonitrile; 7-(4-{4-[4-({4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-4-methyl-1H-indazole-3-carbonitrile; 7-{(3S*)-3-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]pyrrolidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; 7-{(3R*)-3-[4-(4-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}butoxy)phenyl]pyrrolidin-1-yl}-4-methyl-1H-indole-3-carbonitrile; N-[1-(4-Chloro-3-cyano-1H-indazol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)- 1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[5-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-chloro-3-cyano-1~{H}-indol-7-yl)-4-piperidyl]-4-[4-[[4-[4-[(2,6-dioxo-3- piperidyl)carbamoyl]-3-fluoro-phenyl]piperazin-1-yl]methyl]-1-piperidyl]-2-fluoro-benzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-(4-{[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo- 3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl]methyl}piperidin-1-yl)-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide;N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1- methyl-1H-indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-2-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan- 1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]benzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluoro-6-methylbenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-3-methylbenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-3-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan- 1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]benzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}piperidin-1-yl)pyridine-2-carboxamide;N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(4-Chloro-3-cyano-1H-indazol-7-yl)piperidin-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)- 1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(3-Cyano-4-methyl-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(3-Cyano-4-methyl-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]benzamide; N-[4-(4-Chloro-3-cyano-1H-indol-7-yl)cyclohexyl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-fluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2,6-difluorobenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H-indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyrazine-2-carboxamide;N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyrimidine-2-carboxamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2-methylbenzamide; N-[1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-4-yl]-6-[4-({4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1H- indol-1-yl]piperidin-1-yl}methyl)piperidin-1-yl]pyridazine-3-carboxamide; N-[(3R*)-1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; and N-[(3S*)-1-(4-Chloro-3-cyano-1H-indol-7-yl)piperidin-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridine-2-carboxamide; or pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (Ia), or a pharmaceutically acceptable salt thereof according to one of claims 1-20, in association with a pharmaceutically acceptable excipient.

22. The compound of Formula (I) or PROTAC of Formula (Ia), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-20, for use in a method of treatment of the human or animal body by therapy.

23. A compound of Formula (I) or PROTAC of Formula (Ia), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-20, for use as an anti-invasive agent in the containment and / or treatment of solid tumour disease.

24. Use of a compound of Formula (I) or PROTAC of Formula (Ia), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-20, for the manufacture of a medicament for use as an anti- invasive agent in the containment and / or treatment of solid tumour disease.

25. A method for producing an anti-invasive effect by the containment and / or treatment of solid tumour disease, in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (Ia), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-20.