WILLIAMS DAVID K (US)
GILL PATRICE (US)
DHAR T G MURALI (US)
TOKARSKI JOHN S (US)
GAVAI ASHVINIKUMAR V (US)
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Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, CLAIMS 1. A compound of Formula I: or a pharmaceutically acceptable salt, solvate, isomer, enantiomer, or tautomer thereof, wherein R1 is –OCH3, –OCH2CH3, –OCF3, –OCH2CH2OH, –OCH2CH2F, halogen, or 1-methyl- pyrazol-4-yl; A is independently H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more R2; wherein R2 is independently halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy; B is a moiety that is capable of binding a E3 ligase; L1 is independently a bond, –C1-C3 alkylenyl–, –NHCO–, –CONH–, –O–, or –NH–; L2 is independently –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–C(O)–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–C(O)-Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–Y2–, –(OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y2–, –(CH2OCH2C(O))p–(4- to 12-heterocycloalkyl)–Y2–, –(CH2OCH2C(O)NH)p–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–(CH2CH2O)p–C(O)–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–(CH2CH2O)p–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–(OCH2CH2)p–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–(OCH2CH2)p–C(O)–(OCH2CH2)p–Y2–, –(CH2OCH2)p–(heteroaryl)–Y2–, –NHC(O)–(4- to 12-heterocycloalkyl)–Y1-C(O)–Y2–, –NHC(O)–(CH2)p–(4- to 12-heterocycloalkyl)–Y1-C(O)–Y2–, –NHC(O)–(CH2)p–(4- to 12-heterocycloalkyl)–Y2–, –C(O)NH–Y1–Y2–; –(CH2)p–NH–Y1–Y2–; –C(O)NH–(CH2CH2O)p–Y2–, –C(O)–(CH2CH2O)p–Y2–, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, –(CH2OCH2)p–NR3C(O)–(CH2CH2O)p–Y2–, –(CH2)p–NR3C(O)–(CH2CH2O)p–Y2–, –(CH2OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y1–C(O)–(CH2CH2O)p–Y2–, or –(CH2OCH2)p–C(O)NH–(CH2CH2O)p–Y2–, wherein R3 is –H or –C1-C3 alkyl, Y1 is independently a bond, –C1-8 alkylenyl, 4- to 12-membered heterocycloalkyl, or –C3-C10 cycloalkyl; Y2 is independently a bond, –C1-C3 alkyl–, –(CH2)m–O–, –O–(CH2)m–(4- to 6-membered heterocycloalkyl), –(CH2)m–O–(CH2)m–NH–, –(CH2)m–NH–, –(CH2)m–NHC(O)–(CH2)mO–, –(CH2)m–C(O)NH–(CH2)m–, –(CH2)m–C3-C10 cycloalkyl–, –(CH2)m–aryl, –(CH2)m–heteroaryl–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–O–, –(CH2)m–C3-C10 cycloalkyl–C(O)NH–, or –(CH2)m–(4- to 6-membered heterocycloalkyl)–O–, X1 is CH or N; X2 is CH or N; m is independently at each occurrence an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. 2. The compound of claim 1, wherein the compound has Formula I(a): Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein Het A is 4- to 6-membered heterocycloalkyl. 3. The compound of claim 1, wherein the compound has Formula I(b): I(b) wherein Het A is 4- to 6-membered heterocycloalkyl. 4. The compound of claim 1, wherein the compound has Formula I(c): I(c) wherein Het A is 4- to 6-membered heterocycloalky. 5. The compound of claim 1, wherein the compound has Formula I(d): I(d) wherein Het A is 4- to 6-membered heterocycloalkyl. 6. The compound of claim 1, wherein the compound has Formula I(e): I(e) wherein Het A is 4- to 6-membered heterocycloalkyl. 7. The compound of claim 1, wherein the compound has Formula I(f): I(f) Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein Het A is 4- to 6-membered heterocycloalkyl. 8. The compound of claim 1, wherein the compound has Formula I(g): 9. The compound of claim 1, wherein the compound has Formula I(h): 10. The compound of any one of claims 1-9, wherein moiety B capable of binding a E3 ligase is of the structure: 11. The compound of any one of claims 1-9, wherein moiety B capable of binding a E3 ligase is of the structure: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 12. The compound of any one of claims 1-11, wherein A is of the structure: . 13. The compound of any one of claims 1-12, wherein the compound is selected from: N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6 dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1-yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[9-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1-yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[5-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[11-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[13-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[15-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butylamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[5-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentanoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl] piperazin-1-yl] methyl]-1-piperidyl]-2-oxo- ethoxy] methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexylamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexyl]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butyl]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[2-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethyl]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((1-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)-1H-1,2,3-triazol-4- yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4- piperidyl]-4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperazine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4- piperidyl]-1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperidine-4-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4- piperidyl]-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperazin-1-yl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4- piperidyl]-2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]-4-piperidyl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-apyridin-4-yl)-2-pyridyl]-4-piperidyl]- 4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]piperidine-1- carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-4-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl] piperidine- 1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]- 1-piperidyl]acetamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(1-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}azetidin-3-yl)piperazin- 1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]azetidin-3-yl}piperazin- 1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbonyl]azetidin-3-yl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[1-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azetidin-3- yl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[4-benzyl-1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)piperidin- 4-yl]-1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin- 1-yl}propanoyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)piperidin- 4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidine-1-carbonyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-1-fluorocyclopropane-1-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutane-1- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(1-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-(3-Cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4‐yl}pyridin‐2‐yl)‐4‐{[4‐(3‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐ yl}propanoyl)piperazin‐1‐yl]methyl}‐N‐(2‐methylpropyl)piperidine‐4‐carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(3- methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)spiro[3.3]heptane-2- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 6-(4-{[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)piperidin-4-yl]methyl}piperazine-1-carbonyl)-N-[3-(2,4-dioxo-1,3- diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1- carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1- carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3- yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}spiro[3.3]heptane-2- carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({9-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]-3,9- diazaspiro[5.5]undecan-3-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(9-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}-3,9- diazaspiro[5.5]undecan-3-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]carbamoyl}ethoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]amino}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]carbamoyl}ethoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(3-{4- [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3- oxopropoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-({1-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]piperidin-4- yl}methyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{[1-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4- yl]methyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(4-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}piperidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{3-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]azetidin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(3-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}azetidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4- [(methylamino)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]oxy}acetyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(9-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3- carbonyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(1- methyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7- yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7- yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(8-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]amino}octyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2- yl)propanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐yl}‐2‐oxoethyl)‐3- azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2,5‐difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2,5‐difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2,5‐difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2,5‐difluorobenzamide; (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; or N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide. 14. A compound of Formula II: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and tautomers thereof, wherein R1 is –OCH2CH3, –OCH3, –OCF3, –OCH2CH2OH, –OCH2CH2F, 1-methylpyrazol-4-yl, or halogen; A1 is independently aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R2; wherein R2 is independently halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy; B is a moiety that is capable of binding a E3 ligase; L4 is independently –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–C(O)–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–Y2–, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–Y2–, wherein Y1 is independently –C1-8 alkylenyl, 4- to 12-membered heterocycloalkyl, or – C3-C10 cycloalkyl; Y2 is independently –C1-C3 alkyl–, –(CH2)m–O–, –O–(CH2)m–(4- to 6-membered heterocycloalkyl), –(CH2)m–(4- to 6-membered heterocycloalkyl)–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–, or –(CH2)m–(4- to 6-membered heterocycloalkyl)–O–, L3 is a bond, –C1-8 alkylenyl, 4- to 8-membered heterocycloalkyl, –C3-C10 cycloalkyl, or –(4- to 8-membered heterocycloalkyl)–(CH2)m–; X1 is CH or N; X2 is CH or N; X7 is O, S, NH, or a bond; m is independently at each occurrence an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 15. The compound of claim 14, wherein the compound is selected from: 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(5‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐ yl}pentanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile; or 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S)‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}pyrazolo[1,5‐a]pyridine‐3‐carbonitrile. 16. A pharmaceutical composition comprising a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 17. A method of treating a RET mediated disorder comprising administering an effective amount of a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a patient in need thereof. 18. A compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 19. Use of a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET mediated disorder. 20. Use of a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET mediated disorder. |
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 18. N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Example 19. N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 20. N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]me thyl}piperidin-4-yl]-2,5- difluorobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]met hyl}piperidin-4-yl]-2,5- difluorobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 22 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[7-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1 -yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide Example 23 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[9-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1- yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 24 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nona noyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [0329] The title compound was prepared as a solid according to the preparation of Example 1 using 1-(6-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H ,3H)- dione and tert-butyl 9-bromononanoate in STEP H. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (br d, J=0.8 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.75 (dd, J=8.9, 2.6 Hz, 1H), 7.37 - 7.31 (m, 3H), 7.28 - 7.24 (m, 2H), 6.97 (d, J=8.9 Hz, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.29 (d, J=1.7 Hz, 1H), 5.90 (t, J=5.4 Hz, 1H), 4.23 - 4.12 (m, 4H), 3.85 (t, J=6.7 Hz, 2H), 3.80 (s, 3H), 3.45 - 3.36 (m, 4H), 3.21 - 3.11 (m, 2H), 3.09 - 3.01 (m, 2H), 2.74 - 2.66 (m, 4H), 2.48 - 2.43 (m, 3H), 2.37 - 2.29 (m, 2H), 2.26 (br t, J=7.5 Hz, 2H), 1.66 - 1.56 (m, 4H), 1.52 - 1.44 (m, 2H), 1.42 - 1.22 (m, 12H); Analytical LCMS: m/z 998.7 [M+H] + , RT = 1.459 min (UHPLC Method D). Prep-HPLC purification condition: Column: Phen Axia C185μ 30x100mm; Flow rate: 40mL/min flow rate; Mobile Phase A: 95%H2O / 5%MeCN with 0.01M NH4OAc. Mobile Phase B: 5%H2O / 95%MeCN with 0.01M NH4OAc; Gradient: 20-100%B (40 min); Elution: 23.7 – 25.5 minutes; Number of runs: 5. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 25 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl )piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide Example 26 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[5-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4 -yl]-2,5- difluorobenzamide Example 27 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[7-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4 -yl]-2,5- difluorobenzamide Example 28 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[11-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin- 4-yl]-2,5- difluorobenzamide Example 29 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[13-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin -4-yl]-2,5- difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 30 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[15-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)piperid in-4-yl]-2,5- difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 31. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]buty lamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0330] A. Tert-butyl N-(4-oxobutyl) carbamate. To a solution of tert-butyl N-(4- hydroxybutyl) carbamate (200. mg, 1.06 mmol) in DCM (10 mL) was added Dess-Martin (896.17 mg, 2.11 mmol) at 0 ºC, the mixture was stirred at rt for 1h. The reaction was purified by prep-TLC to afford tert-butyl N-(4-oxobutyl) carbamate (150 mg, 75.8% yield) as a colorless oil. [0331] B. Tert-butyl N-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl] piperazin-1-yl]butyl] carbamate. To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl) piperidine-2,6-dione (45 mg, 0.14 mmol) and tert-butyl N-(4-oxobutyl) carbamate (26 mg, 0.14 mmol) in DCM (10 mL) was added DIEA (0.05 mL, 0.27 mmol). The mixture was stirred at rt for 10 min. And then AcOH (0.02 mL, 0.27 mmol) was added, the mixture was stirred at rt for 0.5 h. Then NaBH(OAc)3 (60.0 mg, 0.27 mmol) was added at 0 ºC, the mixture was stirred at rt for 3 h. The reaction was concentrated and purified by Prep-HPLC to afford the desired product (60 mg, 87.6% yield) as an off-white solid. MS: m/z [M+H] + 500. [0332] C. 3-[5-[4-(4-aminobutyl) piperazin-1-yl]-1-oxo-isoindolin-2-yl] piperidine- 2,6-dione. To a solution of tert-butyl N-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl] piperazin-1-yl] butyl] carbamate (60 mg, 0.12 mmol) in DCM (10 mL) was added TFA (2 mL), and the mixture was stirred at rt for 4 h. It was concentrated to afford the desired product (50 mg) as an off-white solid, which was used in the next step without further purification. MS: m/z [M+H] + 400. [0333] D. Tert-butyl 2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2- pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4-piperidyl]methoxy] acetate. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(hydroxymethyl)-4- piperidyl]-2,5-difluoro-benzamide (200 mg, 0.38 mmol) in THF (5 mL) was added NaH (90.13 mg, 3.76 mmol) at 0 °C. The mixture was stirred for 0.5 h. tert-butyl 2-bromoacetate (87.9 mg, 0.45 mmol) was added at 0 °C, the reaction mixture was stirred at rt for 2 h. Water was used to quench the reaction, which was extracted with EA, combined the organic phase, dried over anhydrous sodium sulphate, filtered, and concentrated. The crude was purified by Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, prep-TLC (DCM:MeOH=20:1) to afford the desired product (220 mg, 90.6% yield) as a yellow solid. MS: m/z [M+H] + 647. [0334] E. 2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-py ridyl]-4-[(2,5- difluorobenzoyl)amino]-4-piperidyl]methoxy]acetic acid. To a solution of tert-butyl 2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2- pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4-piperidyl]methoxy] acetate (30 mg, 0.05 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 1 h. It was concentrated, and the crude was purified by Prep-HPLC to afford the desired product (15.1 mg, 54.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.69 - 8.54 (m, 2H), 8.33 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 7.76 (dd, J = 8.8, 2.6 Hz, 1H), 7.47 - 7.22 (m, 4H), 6.99 (d, J = 8.8 Hz, 1H), 4.23 - 4.12 (m, 4H), 4.05 (s, 2H), 3.74 (s, 2H), 3.29 - 3.18 (m, 2H), 2.36 - 2.32 (m, 2H), 1.70 - 1.62 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); MS: m/z: [M+H] + 591. Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 10 min, 51% B; RT=9.8 min. [0335] F. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[4- [4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazi n-1-yl]butylamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide. To a solution of 3-[5-[4-(4- aminobutyl) piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (50 mg, 0.12 mmol), 2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-py ridyl]-4-[(2,5- difluorobenzoyl)amino]-4-piperidyl]methoxy]acetic acid (40 mg, 0.07 mmol) and HATU (50 mg, 0.12 mmol) in DMF (3 mL) was added DIEA (26 mg, 0.20 mmol) at -5 °C, the mixture was stirred for 1 h and purified by Prep-HPLC to afford the titled compound (28.6 mg, 43.4% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.47 (brs, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H), 7.82 - 7.78 (m, 1H), 7.76 - 7.65 (m, 1H), 7.60 - 7.57 (m, 1H), 7.46 - 7.26 (m, 4H), 7.19 - 7.00 (m, 3H), 5.09 - 5.03 (m, 1H), 4.40 - 4.29 (m, 1H), 4.29 - 4.09 (m, 5H), 4.07 - 3.89 (m, 5H), 3.77 - 3.71 (m, 3H), 3.30 - 3.03 (m, 10H), 2.95 - 2.81 (m, 1H), 2.65 - 2.55 (m, 1H), 2.42 - 2.31 (m, 3H), 2.02 - 1.91 (m, 1H), 1.77 - 1.60 (m, 4H), 1.52 - 1.41 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); MS: m/z: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [M+H] + 972. Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B in 10 min, 35% B; RT=10.32 min. Example 32. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propan oyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide [0336] A. Tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoate. To a solution of 3-[1-oxo-6-(4-piperidyl)isoindolin-2-yl]piperidine- 2,6-dione (50 mg, 0.15 mmol), tert-butyl prop-2-enoate (39.15 mg, 0.31 mmol) in MeCN (5 mL) was added DBU (0.07 mL, 0.46 mmol). The mixture was stirred at 70 °C for 16 h. The reaction was concentrated, and the crude was purified by reversed phase column chromatography to afford the desired product (60 mg, 86.2% yield) as a white solid. MS: m/z [M+H] + 456. [0337] B. 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoic acid. To a solution of tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo- isoindolin-5-yl]-1-piperidyl]propanoate (60 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. The reaction was concentrated to afford crude product, which was used directly in the next step without further purification. MS: m/z [M+H] + 400. [0338] C. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(2- hydroxyethoxymethyl)-4-piperidyl]-2,5-difluoro-benzamide. To a solution of 2-[[1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[(2 ,5-difluorobenzoyl)amino]-4- piperidyl]methoxy]acetic acid (600 mg, 1.02 mmol) in THF (5 mL) were added ClCO2Bu-i (167.02 mg, 1.22 mmol), NMM (102.8 mg, 1.02 mmol) at -15°C. The mixture was stirred at -15 °C for 0.5 h, NaBH 4 (115.3 mg, 3.05 mmol) was added. The mixture was stirred for 2 h. It was concentrated purified by prep-TLC (DCM:MeOH=20:1) to afford the desired product (400 mg, 68.3% yield) as a white solid. MS: m/z [M+H] + 577. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0339] D. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(2- oxoethoxymethyl)-4-piperidyl]-2,5-difluoro-benzamide. To a solution of (COCl)2 (0.11 mL, 1.39 mmol) in DCM (2 mL) was added DMSO (0.2 mL, 2.77 mmol) at -78 °C, the mixture was stirred at -78 °C for 0.5 h. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-(2-hydroxyethoxymethyl)-4-piperidyl]-2,5-di fluoro-benzamide (400 mg, 0.69 mmol) in DCM (0.5 mL) was added, the mixture was stirred at -78 °C for 2 h. TEA (0.6 mL, 3.47 mmol) was added, the mixture was stirred at -78 °C for 0.5 h. Water was used to quench the reaction, extracted, dried over anhydrous sodium sulphate, filtered, concentrated to afford crude product which was used directly in the next step without further purification. MS: m/z [M+H] + 575. [0340] E. Tert-butyl 4-[2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2 - pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4-piperidyl]methoxy] ethyl]piperazine-1- carboxylate. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2- pyridyl]-4-(2-oxoethoxymethyl)-4-piperidyl]-2,5-difluoro-ben zamide (30 mg, 0.05 mmol), tert-butyl piperazine-1-carboxylate (29.17 mg, 0.16 mmol), in DCM (1 mL) was added titanium(IV) isopropoxide (29.66 mg, 0.10 mmol). The mixture was stirred at rt for 1 h. NaBH(OAc) 3 (22.13 mg, 0.10 mmol) was added at 0°C. It was stirred at rt for 6 h. The crude was purified by Prep-TLC (DCM:MeOH=20:1) to afford the desired product (28 mg, 72% yield) as a white solid. MS: m/z [M+H] + 745. [0341] F. N-[1-][5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-py ridyl]-4-(2- piperazin-1-ylethoxymethyl)-4-piperidyl]-2,5-difluoro-benzam ide.) To a solution of tert-butyl 4-[2-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2 - pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4-piperidyl]methoxy] ethyl]piperazine-1-carboxylate (30 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. It was concentrated, and the crude was purified by prep-HPLC to afford the desired product (13.2 mg, 49.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 2H), 8.68 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H), 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.45 - 7.27 (m, 4H), 7.07 (d, J = 8.9 Hz, 1H), 4.27 - 4.13 (m, 4H), 3.83 - Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 3.69 (m, 4H), 3.36 - 3.33 (m, 6H), 3.26 - 3.20 (m, 2H), 2.51 - 2.50 (m, 4H), 2.36 - 2.33 (m, 2H), 1.71 - 1.63 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H); MS: m/z: [M+H] + 645. Prep-HPLC purification condition: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10 min, 36% B; RT = 8.9 min. [0342] G. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4- [3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-pi peridyl]propanoyl]piperazin- 1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide. To a solution of N-[1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(2- piperazin-1-ylethoxymethyl)-4- piperidyl]-2,5-difluoro-benzamide (30 mg, 0.05 mmol), 3-[4-[2-(2,6-dioxo-3-piperidyl)-3- oxo-isoindolin-5-yl]-1-piperidyl]propanoic acid (18.59 mg, 0.05 mmol) in DMA (3 mL) were added HATU (26.54 mg, 0.07 mmol), DIEA (0.01 mL, 0.14 mmol). The mixture was stirred at rt for 2 h. The crude was purified by Prep-HPLC to afford the titled product (6.6 mg, 13.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.11 (s, 1H), 7.76 (dd, J = 9.0, 2.5 Hz, 1H), 7.55 - 7.52 (m, 3H), 7.40 - 7.30 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.29 - 4.26 (m, 1H), 4.24 - 4.10 (m, 4H), 3.65 (s, 2H), 3.58 - 3.55 (m, 2H), 3.40 - 3.38 (m, 4H), 3.22 - 3.16 (m, 2H), 3.00 - 2.85 (m, 3H), 2.69 - 2.55 (m, 2H), 2.51 - 2.49 (m, 3H), 2.47 - 2.40 (m, 5H), 2.39 - 2.26 (m, 5H), 2.06 - 1.98 (m, 3H), 1.78 - 1.74 (m, 2H), 1.68 - 1.59 (m, 4H), 1.38 (t, J = 7.0 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 514.1 [M+2H] 2+ , RT = 1.40 min, purity: 98.1% (Method Q); Prep HPLC purification conditions: Column: YMC-Actus Triart C18 ExRS, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 64% B in 10 min, 64% B; RT=9.35 min. Example 33. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]prop anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0343] The title compound was prepared in 21.32% overall yield as a white solid according to the preparation of Example 32 using 3-(1-oxo-6-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (50 mg, 0.15 mmol), tert-butyl prop-2-enoate in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.11 (s, 1H), 7.76 (dd, J = 8.8, 2.5 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.40 - 7.31 (m, 3H), 7.29 - 7.23 (m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.31 (m, 1H), 4.26 - 4.08 (m, 5H), 3.65 (s, 2H), 3.56 (t, J = 5.5 Hz, 2H), 3.43 - 3.39 (m, 5H), 3.26 - 3.10 (m, 6H), 2.96 - 2.87 (m, 1H), 2.64 - 2.53 (m, 7H), 2.46 - 2.26 (m, 10H), 2.01 - 1.97 (m, 1H), 1.70 - 1.55 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 514.7 [M+2H] 2+ , RT = 1.38 min, purity: 98.9% (Method Q); Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 53% B in 10 min, 53% B; RT= 10.7 min. Example 34. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]prop anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide [0344] The title compound was prepared in 10.81% overall yield as a white solid according to the preparation of Example 32 using 3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.37 - 8.17 (m, 1H), 7.87 (dd, J = 9.0, 2.5 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.45 - 7.28 (m, 4H), 7.22 - 7.08 (m, 3H), 5.05 (dd, J = 13.4, 5.1 Hz, 1H), 4.41 - 4.36 (m, 2H), 4.31 - 4.10 (m, 6H), 4.08 - 3.95 (m, 3H), 3.84 - 3.81 (m, 2H), 3.76 - 3.73 (m, 2H), 3.45 - 3.36 (m, 5H), 3.29 - 3.08 (m, 7H), 2.93 - 2.87 (m, 4H), 2.71 - 2.58 (m, 1H), 2.36 (d, J = 7.3 Hz, 2H), 2.07 - 1.93 (m, 1H), 1.73 - 1.67 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H); MS: m/z [M+2H] 2+ 514.5. Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 25% B in 15 min, 25% B; RT=16.67 min. Example 35. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[5-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pent anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide [0345] The title compound was prepared in 29.12% overall yield as a white solid according to the preparation of Example 31 using 3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione in STEP B. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.90 (dd, J = 9.0, 2.5 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.47 - 7.29 (m, 4H), 7.21 - 7.13 (m, 3H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 - 4.35 (m, 2H), 4.29 - 4.12 (m, 5H), 4.09 - 3.97 (m, 3H), 3.83 - 3.81 (m, 2H), 3.75 - 3.71 (m, 2H), 3.64 - 3.46 (m, 4H), 3.39 - 3.32 (m, 3H), 3.30 - 3.24 (m, 2H), 3.18 - 3.11 (m, 7H), 2.95 - 2.86 (m, 3H), 2.69 - 2.57 (m, 1H), 2.46 - 2.30 (m, 5H), 2.01 - 1.95 (m, 1H), 1.73 - 1.65 (m, 4H), 1.54 - 1.51 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H). Analytical LCMS ESI-MS(+) m/z 528.6 [M+2H] 2+ , RT = 1.37 min, purity: 97.5% (Method Q); Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 25% B in 20 min, 25% B; RT = 17.38 min. Example 36. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[4-[[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl] piperazin-1-yl] methyl]-1-piperidyl]-2-oxo- ethoxy] methyl]-4-piperidyl]-2,5-difluoro-benzamide [0346] The title compound was prepared in 11.5% overall yield as a white solid according to the preparation of Example 31 using 3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione in STEP B. 1 H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.47 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, (brs, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.34 – 8.33 (m, 1H), 8.20 – 8.16 (m, 1H), 7.82 – 7.78 (m, 1H), 7.76 – 7.65 (m, 1H), 7.46 – 7.26 (m, 4H), 7.19 – 7.00 (m, 3H), 5.09 – 5.03 (m, 1H), 4.42 – 4.24 (m, 3H), 4.24 – 4.02 (m, 7H), 4.02 – 3.94 (m, 2H), 3.74 – 3.68 (m, 2H), 3.33 – 3.11 (m, 7H), 3.11 – 3.01 (m, 3H), 2.69 – 2.60 (m, 1H), 2.38 – 2.28 (m, 4H), 2.14 – 2.03 (m, 1H), 2.03 – 1.92 (m, 1H), 1.82 – 1.64 (m, 4H), 1.38 (t, J = 7.0 Hz, 3H), 1.23 – 1.06 (m, 3H); Analytical LCMS ESI-MS(+) m/z 500.1 [M+2H] 2+ , RT = 1.45 min, purity: 96.9% (Method Q); Prep HPLC purification conditions: Column: XBridge Prep Phenyl OBD Column, 19x250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 40% B in 8 min, 40% B; RT=7.75 min. Example 37. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propyl ]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide [0347] A. Benzyl 4-[2-(1,3-dioxolan-2-yl)ethyl] piperazine-1-carboxylate. To a solution of benzyl piperazine-1-carboxylate (1000 mg, 4.54 mmol) and 2-(2-bromoethyl)-1,3- dioxolane (822 mg, 4.54 mmol) in DMF (20 mL) was added DIEA (1757 mg, 13.62 mmol), the mixture solution was stirred at 50 °C for overnight. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried, concentrated to afford the desired product (1200 mg, 81.2% yield), which was used in the next step without further purification. MS: m/z [M+H] + 321. [0348] B. 1-[2-(1,3-dioxolan-2-yl)ethyl]piperazine. The mixture solution of benzyl 4- [2-(1,3-dioxolan-2-yl)ethyl]piperazine-1-carboxylate (1100 mg, 3.43 mmol) in Methanol (20 mL) was purged with N 2 (3 x), and then Pd/C (365 mg, 3.43 mmol) was added, H 2 was introduced to above mixture and the resulting mixture was stirred for overnight. Upon completion, the reaction was filtered, and the filtrate was concentrated to afford 1-[2-(1,3- dioxolan-2-yl)ethyl]piperazine (500 mg, 76.9% yield) as an off white solid, which was used directly in the next step without further purification. 1 H NMR (300 MHz, Chloroform-d) δ Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 4.99 - 4.87 (m, 1H), 4.05 - 3.77 (m, 4H), 3.13 - 2.89 (m, 4H), 2.57 - 2.43 (m, 6H), 1.94 - 1.79 (m, 2H). [0349] C. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4- [2-(1,3-dioxolan-2-yl)ethyl]piperazin-1-yl]ethoxymethyl]-4-p iperidyl]-2,5-difluoro- benzamide. The mixture solution of 1-[2-(1,3-dioxolan-2-yl)ethyl]piperazine (51.86 mg, 0.2800 mmol) and N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(2- oxoethoxymethyl)-4-piperidyl]-2,5-difluoro-benzamide (160 mg, 0.2800 mmol) in DCM (40 mL) were stirred at rt for 0.5 h. The reaction was cooled down to 0 °C, then NaBH(OAc)3 (59.02 mg, 0.28 mmol) was added, and the mixture was stirred at rt for overnight. The reaction was purified by Prep-TLC to afford the desired product (50 mg, 24.1% yield) as an off white solid. MS: m/z [M+H] + 745. [0350] D. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4- (3-oxopropyl)piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-d ifluoro-benzamide. To the mixture solution N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4- [2-(1,3-dioxolan-2-yl)ethyl]piperazin-1-yl]ethoxymethyl]-4-p iperidyl]-2,5-difluoro- benzamide (60 mg, 0.08 mmol) in acetone (3 mL) was added water (3 mL), the reaction was cooled down to 0 °C, then HCl (3 mL, 39.18 mmol) was added, the reaction was stirred at rt for 4 h. The reaction was diluted with water (20 mL) and extracted with EA, the water layer was cooled down to -10 °C, pH was adjusted to 7-8 with sat.NaHCO3 solution, and extracted with EA, the organic layer was washed with brine, then dried, concentrated at 10 °C to afford the desired product (50 mg, 88.6% yield) as an off-white semi-solid, which was used directly in the next step without further purification. MS: m/z [M+H] + 701. [0351] E. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4- [3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-pi peridyl]propyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide. To a solution of N-[1-[5-(3-cyano- 6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-(3- oxopropyl)piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide (45 mg, 0.06 mmol) and 3-[1-oxo-6- (4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (25.23 mg, 0.08 mmol) in DCM (6 mL) was added DIEA (0.01 mL, 0.10 mmol), the mixture was stirred at rt for 0.5 h, then cooled down to 0 °C, NaBH(OAc) 3 (27.22 mg, 0.13 mmol) was added, the reaction was concentrated and the residue was purified by Prep-HPLC to afford the titled compound (29.9 mg, 44.3% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.93 (brs, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.09 (s, 1H), 7.76 (dd, J = 8.9, 2.6 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.37 - 7.33 (m, 3H), 7.27 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 5.14-5.08 (m, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1H), 4.44 - 4.38 (m, 1H), 4.30 - 4.12 (m, 5H), 3.65 (s, 2H), 3.55 - 3.52 (m, 2H), 3.24 - 3.15 (m, 2H), 2.95 - 2.86 (m, 3H), 2.62 - 2.56 (m, 2H), 2.47 - 2.31 (m, 6H), 2.30 - 2.25 (m, 10H), 2.04 - 1.89 (m, 3H), 1.81 - 1.51 (m, 8H), 1.38 (t, J = 6.9 Hz, 3H), 1.26 - 1.22 (m, 1H); Analytical LCMS ESI-MS(+) m/z 507.1 [M+2H] 2+ , RT = 1.51 min, purity: 96.7% (Method Q); Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 65% B in 8 min, 65% B; RT = 6.8 min. Example 38. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexy lamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide [0352] The title compound was prepared in 10.1% overall yield as a white solid according to the preparation of Example 31 using 33-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2,6-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.67 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J = 8.9, 2.6 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.42 - 7.32 (m, 3H), 7.31 - 7.24 (m, 1H), 7.19 - 7.11 (m, 2H), 7.07 - 6.98 (m, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 - 4.31 (m, 1H), 4.27 - 4.11 (m, 5H), 4.06 - 3.97 (m, 2H), 3.93 - 3.87 (m, 2H), 3.74 - 3.69 (m, 3H), 3.29 - 3.18 (m, 2H), 3.17 - 3.05 (m, 8H), 2.96 - 2.84 (m, 1H), 2.64 - 2.55 (m, 2H), 2.46 - 2.34 (m, 3H), 2.02 - 1.93 (m, 1H), 1.73 - 1.61 (m, 4H), 1.44 - 1.34 (m, 5H), 1.32 - 1.21 (m, 4H); MS: m/z: [M+H] + 1000. Prep HPLC purification conditions: Column: XBridge Prep Phenyl OBD Column, 19x250 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 32% B to 55% B in 8 min, 55% B; RT=5.65 min. Example 39. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0353] A. 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid. To a solution of 6-bromo-1-methyl-indazol-3-amine (15 g, 66.35 mmol), acrylic acid (4.78 g, 66.35 mmol) in water (3 mL) was added acetic acid (2 mL). The mixture was stirred at 105 °C for 6 h. After cooling to rt, the reaction was partitioned between 1M NaOH and MBTE which dissolved all visible solid. The aqueous layer was separated and acidified with 6N HCl, concentrated, the crude was purified by reverse column chromatography to afford the desired product (7.5 g, 37.9% yield) as an off-white solid. MS: m/z [M+H] + 298. [0354] B. 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H ,3H)- dione. To a solution of 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (100 mg, 0.34 mmol) in acetic acid (2 mL) was added urea (72.52 mg, 1.21 mmol). The mixture was stirred at 120 °C for 16 h. The crude was purified by Prep-TLC (DCM:MeOH=20:1) to afford the desired product (30 mg, 27.7% yield) as a white solid. MS: m/z [M+H] + 323. [0355] C. Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperazine-1-carboxylate. To 5 mL microwave vial, 1-(6-bromo-1-methyl- indazol-3-yl)hexahydropyrimidine-2,4-dione (100 mg, 0.31 mmol), tert-butyl piperazine-1- carboxylate (57.64 mg, 0.31 mmol), Ruphos Pd G3 (28.86 mg, 0.03 mmol), Ruphos (28.88 mg, 0.06 mmol) and Cs 2 CO 3 (301.72 mg, 0.93 mmol) were suspended in 1,4-Dioxane (1 mL). The reaction was placed under vacuum, sonicated, and backfilled with nitrogen. The mixture was stirred at 100 °C for 16 h. It was concentrated and purified by prep-TLC (DCM:MeOH=20:1) to afford the desired product (45 mg, 33.9% yield) as a yellow solid. MS: m/z [M+H] + 429. [0356] D. 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimi dine- 2,4(1H,3H)-dione. To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]piperazine-1-carboxylate (150 mg, 0.35 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 2 h. The reaction was concentrated to afford crude product which was used directly in the next step without further purification. MS: m/z [M+H] + 329. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0357] E. Tert-butyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperazin-1-yl)propanoate. To a solution of 1-(1-methyl-6-piperazin-1-yl- indazol-3-yl)hexahydropyrimidine-2,4-dione (50 mg, 0.1500 mmol), tert-butyl prop-2-enoate (39.03 mg, 0.30 mmol) in MeCN (5 mL) was added DBU (69.54 mg, 0.46 mmol). The mixture was stirred at 40 °C for 16 h. It was concentrated and purified by reversed column chromatography to afford the desired product (60 mg, 86.3% yield) as a yellow oil. MS: m/z [M+H] + 457. [0358] F. 3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperazin-1-yl)propanoic acid. To a solution of tert-butyl 3-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]propanoate (60 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 2 h. It was concentrated to afford the crude product which was used directly in the next step without further purification. MS: m/z [M+H] + 401. [0359] G. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H -indazol-6-yl)piperazin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin- 1-ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (35 mg, 0.06 mmol), 3-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]propanoic acid (23.33 mg, 0.06 mmol) in DMA (5 mL) were added HATU (33.23 mg, 0.09 mmol), and DIEA (0.01 mL, 0.17 mmol). The mixture was stirred at rt for 2 h. The crude was purified by Prep- HPLC to afford the titled compound (19.2 mg, 33.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.67 - 8.56 (m, 2H), 8.33 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.28 - 7.27 (m, 1H), 7.01 - 6.89 (m, 2H), 6.82 - 6.81 (m, 1H), 4.22 - 4.13 (m, 4H), 3.91 - 3.88 (m, 5H), 3.50 - 3.38 (m, 4H), 3.28 - 3.09 (m, 6H), 2.82 - 2.68 (m, 5H), 2.64 - 2.52 (m, 9H), 2.48 - 2.44 (m, 2H), 2.38 - 2.29 (m, 2H), 1.64 - 1.58 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI- MS(+) m/z 983.6 [M+H] + , RT = 1.84 min, purity: 96.4% (Method P); Prep-HPLC purification condition: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 50% B in 9 min, 50% B; RT=8.2 min. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 40. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(5-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide [0360] A. Tert-butyl 5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperazin-1-yl)pentanoate. To a solution of 1-(1-methyl-6-piperazin-1-yl- indazol-3-yl)hexahydropyrimidine-2,4-dione (50 mg, 0.15 mmol), tert-butyl 5-oxopentanoate (52.45 mg, 0.30 mmol) in DCM (5 mL) were added DIEA (39.28 mg, 0.30 mmol) and AcOH (18.29 mg, 0.30 mmol). The mixture was stirred at rt for 1 h. NaBH(OAc)3 (64.54 mg, 0.30 mmol) was added at 0 °C, the mixture was stirred at rt for another 2 h. The solvent was evaporated to afford the crude, which was purified by reversed column chromatography to afford the desired product (43 mg, 58.3% yield) as a yellow oil. MS: m/z [M+H] + 485. [0361] B. 5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperazin-1-yl)pentanoic acid. To a solution of tert-butyl 5-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]pentanoate (43 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL), the mixture was stirred at rt for 2 h and concentrated to afford the crude product which was used directly in the next step without further purification. MS: m/z [M+H] + 429. [0362] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H -indazol-6-yl)piperazin-1- yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin-1- ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (35 mg, 0.06 mmol), 5-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]pentanoic acid (24.97 mg, 0.06 mmol) in DMA (5 mL) were added HATU (33.23 mg, 0.09 mmol), DIEA (19.93 mg, 0.17 mmol). The mixture was stirred at rt for 2 h. The crude was purified by prep- HPLC to afford the titled compound (18.8 mg, 31.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1H), 8.16 (s, 1H), 7.75 (dd, J = 9.0, 2.5 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.38 - 7.29 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.82 - 6.80 (m, 1H), 4.20 - 4.13 (m, 4H), 3.91 - 3.83 (m, 5H), 3.43 - 3.40 (m, 4H), 3.33 - 3.31 (m, 1H), 3.25 - 3.09 (m, 6H), 2.79 - 2.67 (m, 4H), 2.52 - 2.50 (m, 4H), 2.48 - 2.46 (m, 3H), 2.36 - 2.29 (m, 6H), 1.67 - 1.43 (m, 6H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 1011.4 [M+H] + , RT = 1.84 min, purity: 97.4% (Method P); Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 48% B to 58% B in 9 min, 58% B; RT =8.32 min. Example 41. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide [0363] A. tert-butyl 7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperazin-1-yl)heptanoate. To a solution of 1-(1-methyl-6-piperazin-1-yl- indazol-3-yl)hexahydropyrimidine-2,4-dione (60 mg, 0.18 mmol), tert-butyl 7-oxoheptanoate (73.19 mg, 0.37 mmol) in DCM (1 mL) was added DIEA (47.14 mg, 0.37 mmol) and AcOH (0.02 mL, 0.37 mmol). It was stirred at rt for 1 h, and NaBH(OAc) 3 (77.45 mg, 0.37 mmol) was added at 0°C. The mixture was stirred at rt for another 2 h and purified by reversed column chromatography to afford the desired product (65 mg, 69.4% yield) as a yellow oil. MS: m/z [M+H] + 513. [0364] B. 7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperazin-1-yl)heptanoic acid. To a solution of tert-butyl 7-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]heptanoate (60 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 1 h. It was concentrated to afford the crude which was used directly in the next step without further purification. MS: m/z [M+H] + 457. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0365] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H -indazol-6-yl)piperazin-1- yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin-1- ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (35 mg, 0.06 mmol), 7-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazi n-1-yl]heptanoic acid (26.6 mg, 0.06 mmol) in DMA (5 mL) were added HATU (33.23 mg, 0.09 mmol) and DIEA (0.01 mL, 0.17 mmol). The mixture was stirred at rt for 2 h. The crude was purified by Prep- HPLC to afford the titled compound (27.4 mg, 43.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.75 (dd, J = 8.8, 2.5 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.37 - 7.32 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 7.00 - 6.88 (m, 2H), 6.81 (s, 1H), 4.26 - 4.10 (m, 4H), 3.90 - 3.84 (m, 5H), 3.42 - 3.39 (m, 4H), 3.32 - 3.30 (m, 1H), 3.24 - 3.11 (m, 6H), 2.78 - 2.67 (m, 4H), 2.52 - 2.51 (m, 4H), 2.48 - 2.45 (m, 3H), 2.34 - 2.25 (m, 6H), 1.65 - 1.56 (m, 2H), 1.50 - 1.43 (m, 4H), 1.38 (t, J = 6.9 Hz, 3H), 1.34 - 1.24 (m, 4H); Analytical LCMS ESI-MS(+) m/z 1039.6 [M+H] + , RT = 1.73 min, purity: 97.3% (Method P); Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 60% B in 8 min, 60% B; RT = 8.3 min. Example 42. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(6-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide [0366] A. Tert-butyl 6-oxohexanoate. To a solution of tert-butyl 6-hydroxyhexanoate (500 mg, 2.66 mmol) in DCM (10 mL) was added Dess-Martin Periodinane (1351 mg, 3.19 mmol) at 0°C. The mixture was stirred at rt for 2 h. The reaction was concentrated, which was purified by Prep-TLC (PE:EA=2:1) to afford product tert-butyl 6-oxohexanoate (120 mg, 24.3% yield) as a yellow oil. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0367] B. Tert-butyl 6-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)hexanoate. To a solution of 1-[1-methyl-6-(4- piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione (60 mg, 0.18 mmol), tert-butyl 6- oxohexanoate (68.27 mg, 0.37 mmol) in DCM (10 mL) were added DIEA (0.03 mL, 0.37 mmol) and AcOH (0.02 mL, 0.37 mmol). The mixture was stirred at rt for 1 h. NaBH(OAc)3 (77.69 mg, 0.37 mmol) was added under 0°C. The mixture was stirred at rt for another 2 h. It was concentrated and purified by reversed column chromatography to afford the desired product (70 mg, 76.8% yield) as a yellow oil. MS: m/z [M+H] + 498. [0368] C. 6-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperidin-1-yl)hexanoic acid. To a solution of tert-butyl 6-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piper idyl]hexanoate (60 mg, 0.12 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. The reaction was concentrated to afford crude product and used directly in the next step without further purification. MS: m/z [M+H] + 442. [0369] D. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (6-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H -indazol-6-yl)piperidin-1- yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin-1- ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (35 mg, 0.06 mmol), 6-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piper idyl]hexanoic acid (25.73 mg, 0.06 mmol) in DMA (5 mL) were added HATU (22.16 mg, 0.06 mmol), and DIEA (6.64 mg, 0.06 mmol). The mixture was stirred at rt for 2 h. The crude was purified by prep-HPLC to afford the titled compound (19.5 mg, 32.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.69 - 8.53 (m, 2H), 8.32 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 8.7, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.39 - 7.30 (m, 3H), 7.27 (s, 1H), 7.04 - 6.96 (m, 2H), 4.21 - 4.13 (m, 4H), 3.96 (s, 3H), 3.90 (t, J = 6.6 Hz, 2H), 3.41 (s, 4H), 3.16 (t, J = 12.6 Hz, 2H), 2.99 - 2.96 (m, 2H), 2.76 - 2.73 (m, 4H), 2.66 - 2.56 (m, 1H), 2.48 - 2.45 (m, 3H), 2.35 - 2.27 (m, 6H), 2.04 - 1.90 (m, 2H), 1.80 - 1.73 (m, 4H), 1.67 - 1.55 (m, 2H), 1.52 - 1.44 (m, 4H), 1.38 (t, J = 6.9 Hz, 3H), 1.33 - 1.27 (m, 3H); MS: m/z [M+H] + 1025, 96.7% purity. Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 10 min, 57% B; RT =9.4 min. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 43. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide [0370] The title compound was prepared in 21.4% overall yield as a white solid according to the preparation of Example 40 using 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione and tert-butyl 4-oxobutanoate in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H), 7.75 (dd, J = 8.9, 2.6 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.43 (s, 1H), 7.37 - 7.31 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 7.06 - 6.93 (m, 2H), 4.21 - 4.13 (m, 4H), 3.96 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.45 - 3.41 (m, 4H), 3.16 (t, J = 12.5 Hz, 2H), 2.99 - 2.95 (m, 2H), 2.80 - 2.69 (m, 4H), 2.65 - 2.59 (m, 1H), 2.56 - 2.52 (m, 1H), 2.49 - 2.47 (m, 2H), 2.35 - 2.29 (m, 6H), 2.05 - 1.92 (m, 2H), 1.84 - 1.56 (m, 8H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 996.6 [M+H] + , RT = 1.65 min, purity: 95% (Method P). Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 52% B in 10 min, 52% B; RT=9.08 min. Example 44. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluoro benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0371] A. tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)acetate. To a solution of 1-[1-methyl-6-(4-piperidyl)indazol-3- yl]hexahydropyrimidine-2,4-dione (60 mg, 0.18 mmol), tert-butyl 2-oxoacetate (47.7 mg, 0.37 mmol) in DCM (10 mL) were added DIEA (0.03 mL, 0.37 mmol), and AcOH (0.02 mL, 0.37 mmol). The mixture was stirred at rt for 1h, NaBH(OAc)3 (77.69 mg, 0.37 mmol) was added at 0 °C, the mixture was stirred at rt for another 1 h. After evaporation of the solvent, the crude was purified by reversed column chromatography to afford the desired product (60 mg, 74.2% yield) as a yellow oil. MS: m/z [M+H] + 442. [0372] B. 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperidin-1-yl)acetic acid. To a solution of tert-butyl 2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piper idyl]acetate (60 mg, 0.14 mmol) in DCM (0.50 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 1 h. The reaction was concentrated to afford crude product which was used in the next step without further purification. MS: m/z [M+H] + 386. [0373] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H -indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluoro benzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin-1-ylmethyl)- 4-piperidyl]-2,5-difluoro-benzamide (35 mg, 0.06 mmol), 2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piper idyl]acetic acid (22.46 mg, 0.06 mmol) in DMA (5 mL) were added HATU (33.23 mg, 0.09 mmol), and DIEA (0.01 mL, 0.17 mmol). The mixture was stirred at rt for 2 h. The crude was purified by prep-HPLC to afford the titled compound (17.4 mg, 30% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.76 (dd, J = 8.9, 2.6 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.43 (s, 1H), 7.38 - 7.32 (m, 3H), 7.28 (d, J = 2.5 Hz, 1H), 7.05 - 6.95 (m, 2H), 4.26 - 4.11 (m, 4H), 3.96 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.56 - 3.54 (m, 2H), 3.43 - 3.40 (m, 2H), 3.19 - 3.13 (m, 4H), 2.95 - 2.92 (m, 2H), 2.80 - 2.71 (m, 4H), 2.66 - 2.56 (m, 3H), 2.49 - 2.46 (m, 2H), 2.36 - 2.33 (m, 2H), 2.19 - 2.06 (m, 2H), 1.86 - 1.57 (m, 6H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 968.6 [M+H] + , RT = 1.36 min, purity: 96.8% (Method P); Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 10 min, 63% B; RT1=9.85 min. Example 45. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide [0374] The title compound was prepared in 21.4% overall yield as a white solid according to the preparation of Example 39 using 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.76 (dd, J = 8.8, 2.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.38 - 7.32 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 7.07 - 6.92 (m, 2H), 4.25 - 4.11 (m, 4H), 3.96 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.43 - 3.41 (m, 4H), 3.20 - 3.11 (m, 2H), 3.01 - 2.97 (m, 2H), 2.78 - 2.70 (m, 4H), 2.62 - 2.55 (m, 5H), 2.49 - 2.45 (m, 4H), 2.36 - 2.32 (m, 2H), 2.09 - 2.02 (m, 2H), 1.84 - 1.67 (m, 4H), 1.64 - 1.57 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 492.0 [M+2H] 2+ , RT = 1.90 min, purity: 98.0% (Method P); Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 57% B in 10 min, 57% B; RT=10.82 min. Example 46. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0375] The title compound was prepared in 40.7% overall yield as a white solid according to the preparation of Example 39 using 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.9, 2.5 Hz, 1H), 7.65 – 7.60 (m, 1H), 7.53 – 7.46 (m, 1H), 7.44 – 7.37 (m, 3H), 7.28 (d, J = 2.3 Hz, 1H), 7.10 – 7.01 (m, 2H), 4.33 – 4.23 (m, 2H), 4.16 (q, J = 6.9 Hz, 2H), 3.99 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.68 – 3.60 (m, 3H), 3.54 – 3.49 (m, 9H), 3.27 – 3.17 (m, 3H), 3.16 – 3.06 (s, 5H), 3.05 – 2.96 (m, 1H), 2.76 (t, J = 6.6 Hz, 2H), 2.46 – 2.39 (m, 2H), 2.16 – 2.06 (m, 2H), 2.04 – 1.89 (m, 4H), 1.79 – 1.67 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 996.6, purity: 99.1%; Prep-HPLC purification condition: Column: SunFire C18 OBD Prep Column, 19x250 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 15% B to 45% B in 6.5 min, 45% B; RT= 6.1 min. Example 47. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[1-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexy l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0376] A. 3-[5-[4-(6-azidohexyl)piperazin-1-yl]-1-oxo-isoindolin-2-yl] piperidine-2,6- dione. To the mixture of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2,6-dione (90 mg, 0.27 mmol) in MeCN (20 mL) were added 1-azido-6-bromo-hexane (170 mg, 0.82 mmol), NaI (4.11 mg, 0.03 mmol), DIPEA (0.14 mL, 0.82 mmol), the mixture was warmed up to 80 °C for overnight. The reaction was concentrated and purified by Prep-TLC to afford the desired product (90 mg, 72.4% yield) as a yellow solid. MS: m/z [M+H] + 454. [0377] B. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[1- [6-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piper azin-1-yl]hexyl]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide. Under a N2 atmosphere, to a stirred solution of 3-[5-[4-(6-azidohexyl)piperazin-1-yl]-1-oxo-isoindolin-2-yl] piperidine- 2,6-dione (72 mg, 0.16 mmol) in THF (4 mL) and H2O (2 mL) was added N-[1-[5-(3-cyano- 6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(prop-2-y noxymethyl)-4-piperidyl]-2,5- difluoro-benzamide (90 mg, 0.16 mmol) at 0 °C, a solution of CuSO 4 (13 mg, 0.08 mmol) in H2O (1 mL) was subsequently added followed by addition of a solution of sodium ascorbate (16 mg, 0.08 mmol) in H2O (1 mL), the resulting mixture was stirred at rt for overnight. The reaction was concentrated and purified by reversed phase column (0.5%TFA in water/MeCN) followed by Prep-HPLC purification to afford the titled compound (23.3 mg, 14.3% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.6 Hz, 1H), 8.11-8.09 (m, 2H), 7.75 (dd, J = 8.8, 2.6 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.42 - 7.29 (m, 3H), 7.27 (d, J = 2.1 Hz, 1H), 7.04 - 7.02 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.56 (s, 2H), 4.38 - 4.25 (m, 3H), 4.21 - 4.12 (m, 5H), 3.70 (s, 2H), 3.24 - 3.13 (m, 6H), 2.97 - 2.84 (m, 1H), 2.64 - 2.57 (m, 1H), 2.57 - 2.56 (m, H), 2.47 - 2.43 (m, 3 H), 2.35 - 2.14 (m, 5H), 2.00 -1.91 (m, 1H), 1.85 - 1.75 (m, 2H), 1.68 - 1.54 (m, 2H), 1.47 - 1.35 (m, 5H), 1.29 - 1.23 (m, 4H); MS: m/z 1024.3, purity: 99.1%. Prep-HPLC purification conditions: Column: XSelect CSH Fluoro Phenyl, 30x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 29% B in 10 min, 29% B; RT=8.83 min. Example 48. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]buty l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0378] The title compound was prepared in 36.8% overall yield as a white solid according to the preparation of Example 47 using 1-azido-4-bromo-butane in STEP A. 1 H NMR (300 MHz, DMSO-d6) δ 10.88 (brs, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.6 Hz, 1H), 8.10 - 8.11 (m, 2H), 7.75 (dd, J = 8.9, 2.6 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.38 - 7.30 (m, 3H), 7.27 (d, J = 2.1 Hz, 1H), 7.04 - 7.01 (m, 2H), 6.96 (d, J = 8.9 Hz, 1H), 5.07 - 5.01(m, 1H), 4.56 (s, 2H), 4.42 - 4.25 (m, 3H), 4.24 - 4.09 (m, 5H), 3.70 (s, 2H), 3.24 - 3.12 (m, 6H), 2.96 - 2.84 (m, 1H), 2.63 - 2.54 (m, 1H), 2.49 - 2.35 (m, 4H), 2.35 - 2.24 (m, 5H), 2.00 - 1.92 (m, 1H),1.97 -1.78 (m, 2H), 1.65 - 1.56 (m, 2H), 1.46 - 1.36 (m, 5H); Analytical LCMS ESI-MS(+) m/z 1006.2 [M+H] + , RT = 1.13 min, purity: 98.9% (Method Q); Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 50% B in 9 min, 50% B; RT =8.42 min. Example 49. B N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[2-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethy l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0379] The title compound was prepared in 5.5% overall yield as a white solid according to the preparation of Example 47 using 1-azido-2-bromo-ethane in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 8.22 - 8.18 (m, 2H), 7.97 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.42 - 7.30 (m, 4H), 7.18 - 7.11 (m, 2H), 7.07 (d, J = 9.0 Hz, 1H), 5.11 - 5.04 (m, 1H), 4.90 - 4.84 (m, 2H), 4.63 (s, 2H), 4.38 - 4.31 (m, 1H), 4.27 - 4.14 (m, 6H), 3.81 - 3.75 (m, 7H), 3.26 - 3.19 (m, 2H), 2.93 - 2.89 (m, 3H), 2.76 - 2.73 (m, 2H), 2.65 - 2.58 (m, 1H), 2.45 - 2.40 (m, 1H), 2.35 - 2.27 (m, 2H), 2.01 - 1.93 (m, 1H), 1.73 - 1.61 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H); Analytical LCMS ESI- MS(+) m/z 968.5 [M+H] + , RT = 1.27 min, purity: 97.4% (Method Q). Prep HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B in 6.3 min, 55% B; RT=5.53 min. Example 50. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-(((1-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pro pyl)-1H-1,2,3-triazol-4- yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0380] A. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4- ((prop-2-yn-1-yloxy)methyl)piperidin-4-yl)-2,5-difluorobenza mide. To a stirred solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(hydroxymethyl)-4- piperidyl]-2,5-difluoro-benzamide (500 mg, 0.94 mmol) in THF (30 mL) was added NaH (90.13 mg, 3.76 mmol) at 0 °C, and the resulting mixture was stirred at rt for 0.5 h, then 3- bromoprop-1-yne (335.07 mg, 2.82 mmol) was added, the mixture solution was stirred at rt for 48 h. The reaction was quenched by ice water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford the desired product (400 mg, 74.7% yield) as an off-white solid. MS: m/z [M+H] + 571. [0381] B. 3-(5-(4-(3-azidopropyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6- dione. To the mixture solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2,6- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, dione (80 mg, 0.24 mmol) in ACN (8 mL) was added 1-azido-3-bromo-propane (120 mg, 0.73 mmol) and DIEA (0.07 mL, 0.9700 mmol), the mixture solution was stirred at 80 °C overnight. Then 1-azido-3-bromo-propane (80 mg, 0.49 mmol), DIEA (0.04 mL, 0.49 mmol) was added at rt and stirred at 80 °C overnight. The reaction was concentrated and purified by silica gel column to afford 3-[5-[4-(3-azidopropyl)piperazin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (60 mg, 0.14 mmol, 59.8% yield) as yellow solid. MS: m/z [M-H] + 410. [0382] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-(((1- (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pipe razin-1-yl)propyl)-1H-1,2,3- triazol-4-yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenz amide. The mixture solution of 3-[5-[4-(3-azidopropyl)piperazin-1-yl]-1-oxo-isoindolin-2-yl ]piperidine-2,6-dione (60 mg, 0.15 mmol) and N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]- 4-(prop-2-ynoxymethyl)-4-piperidyl]-2,5-difluoro-benzamide (83 mg, 0.15 mmol) in THF (4 mL) and water (4 mL) was degassed under N2 for 5 times, and then cooled down to 0 °C, CuSO4 (7.0 mg, 0.04 mmol), and Sodium ascorbate (10 mg, 0.05 mmol) was added successively. The resulting mixture was stirred at rt under N 2 atmosphere for 4 h. Upon completion, the reaction was concentrated and purified by Prep-HPLC to afford the titled compound (17.3 mg, 11.7% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.58 (brs, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.14 (brs, 1H), 7.91 - 7.89 (m, 1H), 7.59 - 7.57(m, 1H), 7.37 - 7.31 (m, 4H), 7.17 - 7.11 (m, 3H), 5.06 - 5.02 (m, 1H), 4.59 (s, 2H), 4.50 - 4.46 (m, 2H), 4.39 - 3.93 (m, 8H), 3.78 - 3.68 (m, 2H), 3.65 - 3.63 (m, 2H), 3.31 - 3.02 (m, 8H), 2.94 - 2.82 (m, 1H), 2.64 - 2.56 (m, 1H), 2.31 - 3.02 (m, 5H), 2.01 - 1.93 (m, 1H), 1.69 - 1.62 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 982.5 [M+H] + , RT = 1.27 min, purity: 100% (Method Q). Prep HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B in 5.5 min, 50% B; RT = 5.53 min. Example 51 N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-piperidyl]- 4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperazine-1-carboxamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0383] A. Tert-butyl 4-(tert-butylsulfinylamino)-4-cyano-piperidine-1-carboxylate . To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) in THF (120 mL) were added Ti(OEt)4 (10.52 mL, 50.19 mmol), t-BuSONH2 (3218.57 mg, 26.6 mmol). The mixture was stirred at 70 °C for 20 h under N 2 . The red solution was cooled, TMSCN (3.45 mL, 27.6 mmol) was added, and the solution was refluxed for 3 h. It was concentrated and purified by column chromatography (PE:EA=1:1 to EA) to afford the desired product (5 g, 60.5% yield) as a white solid. MS: m/z [M+H] + 330. [0384] B. Tert-butyl 4-benzyl-4-(tert-butylsulfinylamino)piperidine-1-carboxylate . To a solution of tert-butyl 4-(tert-butylsulfinylamino)-4-cyano-piperidine-1-carboxylate (3.5 g, 10.62 mmol) in THF (40 mL) was added MgBnCl (2M in THF) (13. mL, 23.9 mmol). The reaction was placed under vacuum, sonicated and backfilled with nitrogen. The mixture was stirred at 80 °C for 5 h. It was concentrated and purified by column chromatography (PE:EA=1:2 to EA) to afford the desired (2 g, 47.7% yield) as a yellow solid. MS: m/z [M+H] + 395. [0385] C. 4-benzylpiperidin-4-amine. To the mixture solution of tert-butyl 4-benzyl-4- (tert-butylsulfinylamino) piperidine-1-carboxylate (2000 mg, 5.07 mmol) in Ethyl acetate (20 mL) was added HCl (2.0 M in EA) (539 mg, 5.07 mmol) at rt, the mixture solution was stirred at rt for 3 h. The reaction was filtered, and the filter cake was dried to afford 4- benzylpiperidin-4-amine (960 mg, 97.9% yield) as an off white solid. MS: m/z [M+H] + 191. [0386] D. 4-[6-(4-amino-4-benzyl-1-piperidyl)-3-pyridyl]-6-ethoxy-pyra zolo[1,5- a]pyridine-3-carbonitrile. To the mixture solution of 4-benzylpiperidin-4-amine (26.29 mg, 0.14 mmol) and 6-ethoxy- 4-(6-fluoro-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.11 mmol) in DMA (2 mL) was added K2CO3 (44. mg, 0.32 mmol), the mixture was stirred at 100 °C for overnight. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, The reaction was purified by Prep-HPLC to afford the desired product (13.6 mg, 27.6% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.93 (brs, 2H), 7.81 (dd, J = 8.8, 2.5 Hz, 1H), 7.43 - 7.27 (m, 6H), 7.02 (d, J = 8.8 Hz, 1H), 4.16 - 4.12 (m, 2H), 3.94 - 3.73 (m, 4H), 3.08 (s, 2H), 1.84 - 1.71 (m, 4H), 1.38 (t, J = 6.9 Hz, 3H); MS: m/z [M+H] + 453. Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 38% B in 10 min, 38% B; RT = 9.35 min. [0387] E. 4-[6-(4-benzyl-4-isocyanato-1-piperidyl)-3-pyridyl]-6-ethoxy -pyrazolo[1,5- a]pyridine-3-carbonitrile. To a stirred solution of 4-[6-(4-amino-4-benzyl-1-piperidyl)-3- pyridyl]-6-ethoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (120.0 mg, 0.27 mmol) in DCM (10 mL) were added BST (31.5 mg, 0.11 mmol) and DIPEA (0.09 mL, 0.53 mmol) at 0 °C, the mixture solution was stirred at rt for 2 h. The reaction was used for next step directly without further work-up. MS: m/z [M+H] + 479. [0388] F. Tert-butyl 4-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4- yl)-2-pyridyl]-4-piperidyl] carbamoyl]piperazine-1-carboxylate. To the mixture solution of 4-[6-(4-benzyl-4-isocyanato-1-piperidyl)-3-pyridyl]-6-ethoxy -pyrazolo[1,5-a]pyridine-3- carbonitrile (150 mg, 0.31 mmol) in DCM (5 mL) was added tert-butyl piperazine-1- carboxylate (175.14 mg, 0.94 mmol) at 0 °C, and the mixture solution was stirred at rt overnight. It was concentrated and purified by silica gel column to afford the desired product (150 mg, 72% yield) as a white solid. MS: m/z: [M+H] + 665. [0389] G. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]piperazine-1-carboxamide. To the mixture solution of tert-butyl 4-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-piperidyl] carbamoyl]piperazine-1-carboxylate (140. mg, 0.2100 mmol) in ethyl acetate (4 mL) was added HCl (g) (4 mL, 0.2100 mmol) in EtOAc, and the mixture solution was stirred at rt for 2 h. It was concentrated and purified by Prep-HPLC to afford the desired product (22 mg, yield 18.4%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.73 (brs, 2H), 8.67 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 8.9, 2.5 Hz, 1H), 7.36 - 7.24 (m, 3H), 7.28 - 7.17 (m, 1H), 7.15 - 7.05 (m, 2H), Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 7.01 (d, J = 9.0 Hz, 1H), 5.84 (s, 1H), 4.20 - 4.10 (m, 4H), 3.54 - 3.51 (m, 4H), 3.14 - 3.05 (m, 8H), 2.20 - 2.17 (m, 2H), 1.60 - 1.51 (s, 2H), 1.38 (t, J = 6.9 Hz, 3H); MS: m/z [M+H] + 565.3. Prep HPLC purification conditions: Column: XSelect CSH Fluoro Phenyl, 30x150 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 29% B in 10 min, 29% B; RT = 8.83 min. [0390] H. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-o xo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperazine-1-carboxamide. To the mixture solution of 3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propan oic acid (40 mg, 0.10 mmol), N- [4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl )-2-pyridyl]-4- piperidyl]piperazine-1-carboxamide (56.55 mg, 0.10 mmol) and HATU (57.11 mg, 0.15 mmol) was added DIEA (0.02 mL, 0.30 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction was purified by Prep-HPLC to afford the titled compound (40.7 mg, 42.9% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.34 - 7.05 (m, 6H), 6.94 (d, J = 9.0 Hz, 1H), 5.65 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.33 - 4.23 (m, 1H), 4.21 - 4.04 (m, 4H), 3.05 - 3.36 (m, 6H), 3.30 - 3.25(m, 2H), 3.15 - 2.82 (m, 7H), 2.66 - 2.51 (m, 6H), 2.48 - 2.28 (m, 1H), 2.24 - 1.94 (m, 5H), 1.83 - 1.45 (m, 6H), 1.38 (t, J = 6.9 Hz, 3H); MS: m/z: [M+H] + 946.3, purity: 99.7%. Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 46% B in 15 min, 46% B; RT=12.63 min.
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 52. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-piperidyl]- 1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperidine-4-carboxamide [0391] A. Tert-butyl 4-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4 - yl)-2-pyridyl]-4-piperidyl]carbamoyl]piperidine-1-carboxylat e. To a solution of 4-[6-(4- amino-4-benzyl-1-piperidyl)-3-pyridyl]-6-ethoxy-pyrazolo[1,5 -a]pyridine-3-carbonitrile (150 mg, 0.33 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (151.99 mg, 0.66 mmol) in DMA (8 mL) were added HATU (378.09 mg, 0.99 mmol) and DIEA (0.15 mL, 1.99 mmol). The mixture was stirred at rt for 2 h and the crude was purified by reversed phase column chromatography to afford the desired product (155 mg, 70.4% yield) as an off-white solid. MS: m/z [M+H] + 664. [0392] B. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]piperidine-4-carboxamide. To a solution of tert-butyl 4-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4 -yl)- 2-pyridyl]-4-piperidyl]carbamoyl]piperidine-1-carboxylate (30 mg, 0.05 mmol) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 1 h. It was concentrated and purified by Prep-HPLC to afford the titled compound (18.7 mg, 72.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.88 (dd, J = 9.0, 2.5 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.27 - 7.20 (m, 1H), 7.17 - 7.06 (m, 3H), 4.19 - 4.13 (m, 4H), 3.35 - 3.30 (m, 2H), 3.12 - 2.98 (m, 4H), 2.89 - 2.82 (m, 2H), 2.48 - Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 2.43 (m, 1H), 2.20 - 2.14 (m, 2H), 1.88 - 1.78 (m, 4H), 1.63 - 1.55 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H). MS: m/z: [M+H] + 564, purity: 99.3%. [0393] C. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-o xo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperidine-4-carboxamide. The title compound was prepared in 24.9% yield as a white solid according to the preparation of Example 51 using N-[4-benzyl- 1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridy l]-4-piperidyl]piperidine-4- carboxamide in STEP H. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.88 - 7.77 (m, 1H), 7.69 - 7.48 (m, 3H), 7.36 - 7.20 (m, 4H), 7.14 - 7.04 (m, 3H), 5.28 - 4.98 (m, 1H), 4.43 - 4.41 (m, 2H), 4.31 - 4.28 (m, 1H), 4.16 - 4.12 (m, 4H), 3.91 - 3.88 (m, 1H), 3.67 - 3.62 (m, 2H), 3.37 - 3.33 (m, 2H), 3.13 - 3.11 (m, 3H), 3.08 - 2.93 (m, 6H), 2.93 - 2.79 (m, 2H), 2.70 - 2.51 (m, 2H), 2.46 - 2.32 (m, 1H), 2.17 - 2.14 (m, 2H), 2.11 - 1.89 (m, 5H), 1.82 - 1.46 (m, 7H), 1.39 (t, J = 6.9 Hz, 3H); MS: m/z [M+H] + 945.3, purity: 99.7%; Prep HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 38% B in 10 min, 38% B; RT = 10 min. Example 53. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-piperidyl]- 2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl] -1- piperidyl]propanoyl]piperazin-1-yl]acetamide [0394] A. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-piperazin-1-yl-acetamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, The title compound was prepared in 44.7% overall yield as a white solid according to the preparation of N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]- 4-piperidyl]piperidine-4-carboxamide (Example 52.B) using 2-(4-tert- butoxycarbonylpiperazin-1-yl)acetic acid in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.82 - 7.69 (m, 2H), 7.35 - 7.22 (m, 4H), 7.15 - 7.11 (m, 2H), 7.02 (d, J = 9.0 Hz, 1H), 4.21 - 4.13 (m, 4H), 3.67 (s, 2H), 3.30 - 3.22 (m, 8H), 3.09 - 3.03 (m, 4H), 2.18 - 2.15 (m, 2H), 1.65 - 1.57 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); MS: m/z: [M+H] + 579, purity: 98.8%. [0395] B. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)- 3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]piperazin-1-yl]acetamide. The title compound was prepared in 27.7% yield as a white solid according to the preparation of Example 51 using N-[4-benzyl-1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-pip eridyl]-2-piperazin-1-yl- acetamide in STEP C. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.51 (m, 2H), 8.31 (d, J = 2.6 Hz, 1H), 7.88 - 7.65 (m, 1H), 7.57 - 7.47 (m, 3H), 7.38 - 7.19 (m, 4H), 7.19 - 7.07 (m, 2H), 6.95 (d, J = 8.9 Hz, 1H), 5.19 - 4.93 (m, 1H), 4.41 - 4.39 (m, 1H), 4.28 - 4.25 (m, 1H), 4.22 - 4.05 (m, 4H), 3.41 - 3.39 (m, 3H), 3.19 - 2.81 (m, 9H), 2.70 - 2.52 (m, 5H), 2.49 - 2.30 (m, 7H), 2.17 - 2.14 (m, 2H), 2.09 - 1.93 (m, 3H), 1.75 - 1.73 (m, 2H), 1.69 - 1.52 (m, 4H), 1.37 (t, J = 6.9 Hz, 3H); MS: m/z [M+H] + 960.4, purity: 99.4%. Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 48% B in 9 min, 48% B; RT = 8.53 min. Example 54. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-piperidyl]- 2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl] -1-piperidyl]propanoyl]-4- piperidyl]acetamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0396] A. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-(4-piperidyl)acetamide. The title compound was prepared in 52.9% overall yield as a white solid according to the preparation of N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]- 4-piperidyl]piperidine-4-carboxamide (Example 52.B) using 2-(1-tert-butoxycarbonyl-4- piperidyl)acetic acid in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 9.0, 2.5 Hz, 1H), 7.35 - 7.20 (m, 4H), 7.16 - 7.08 (m, 3H), 4.18 - 4.13 (m, 4H), 3.29 - 3.22 (m, 2H), 3.16 - 2.99 (m, 4H), 2.83 - 2.86 (m, 2H), 2.23 - 2.09 (m, 4H), 2.07 - 1.96 (m, 1H), 1.85 - 1.81 (m, 2H), 1.64 - 1.52 (m, 2H), 1.41 - 1.28 (m, 5H); MS: [M+H] + 578. [0397] B. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)- 3-oxo-isoindolin-5-yl]-1- piperidyl]propanoyl]-4-piperidyl]acetamide. The title compound was prepared in 18.1% yield as a white solid according to the preparation of Example 51 using N-[4-benzyl-1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-pip eridyl]-2-(4- piperidyl)acetamide in STEP C. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.30 (d, J = 2.6 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.57 - 7.46 (m, 3H), 7.38 - 7.18 (m, 5H), 7.15 - 7.08 (m, 2H), 6.95 (d, J = 9.0 Hz, 1H), 5.16 - 4.97 (m, 1H), 4.55 - 4.22 (m, 3H), 4.13 - 4.11 (m, 4H), 3.88 - 3.85 (m, 1H), 3.57 - 3.55 (m, 3H), 3.09 - 2.81 (m, 8H), 2.68 - 2.52 (m, 4H), 2.42 - 2.38 (m, 1H), 2.26 - 1.88 (m, 8H), 1.83 - 1.60 (m, 6H), 1.59 - 1.47 (m, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 2H), 1.37 (t, J = 7.0 Hz, 3H), 1.13 - 1.10 (m, 1H), 1.06 - 0.79 (m, 1H); MS: m/z [M+H] + 960.4, purity: 96.8%. Prep HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 48% B to 50% B in 10 min, 50% B; RT=9.22 min. Example 55. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-apyridin-4-y l)-2-pyridyl]-4-piperidyl]- 4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-pi peridyl]methyl]piperidine-1- carboxamide [0398] A. Tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]methyl]piperidine-1-carboxylate. To the mixture solution of 3-[1-oxo-6-(4- piperidyl)isoindolin-2-yl]piperidine-2,6-dione (60 mg, 0.18 mmol) and tert-butyl 4- formylpiperidine-1-carboxylate (80 mg, 0.37 mmol) in DCM (5 mL) was added DIEA (0.03 mL, 0.37 mmol), the mixture was stirred at rt for 5 min, AcOH (0.02 mL, 0.37 mmol) was then added, the mixture was stirred at rt for 0.5 h. The reaction mixture was cooled down to 0 °C, NaBH(OAc)3 (80 mg, 0.37 mmol) was then added, and the resulting solution was stirred at rt overnight. The reaction was concentrated and purified by Prep-HPLC to afford the desired product (60 mg, 62.4% yield) as white solid. MS: m/z [M+H] + 525. [0399] B. 3-[1-oxo-6-[1-(4-piperidylmethyl)-4-piperidyl] isoindolin-2-yl]piperidine- 2,6-dione. To the mixture solution of tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo- isoindolin-5-yl]-1-piperidyl]methyl]piperidine-1-carboxylate (55 mg, 0.10 mmol) in DCM (10 mL) was added TFA (2 mL), the mixture solution was stirred at rt for 5 h. The reaction was concentrated to afford the desired product (45 mg, quant.) as an off-white solid, which was used directly in the next step without further purification. MS: m/z [M+H] + 425. [0400] C. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-apyridin-4-y l)-2- pyridyl]-4-piperidyl]-4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo -isoindolin-5-yl]-1- piperidyl]methyl]piperidine-1-carboxamide. To the mixture solution of 4-[6-(4-benzyl-4- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, isocyanato-1-piperidyl)-3-pyridyl]-6-ethoxy-pyrazolo[1,5-a]p yridine-3-carbonitrile (33.82 mg, 0.07 mmol) in DCM (5 mL) was added 3-[1-oxo-6-[1-(4-piperidylmethyl)-4- piperidyl]isoindolin-2-yl]piperidine-2,6-dione (30 mg, 0.07 mmol) in DMF (3 mL) and DIEA (0.02 mL, 0.21 mmol) at 0 °C, and the mixture solution was stirred at rt for 6 h. The reaction was concentrated and purified by Prep-HPLC to afford the titled product (12.4 mg, 19.2% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 8.9, 2.6 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.34 - 7.17 (m, 4H), 7.14 - 7.06 (m, 2H), 6.97 - 6.90 (m, 1H), 5.40 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.41 (d, J = 17.1 Hz, 1H), 4.27 (d, J = 17.1 Hz, 1H), 4.20 - 3.95 (m, 6H), 3.15 - 3.00 (m, 4H), 3.00 - 2.83 (m, 3H), 2.72 - 2.54 (m, 4H), 2.46 - 2.30 (m, 1H), 2.29 - 2.12 (m, 4H), 2.07 - 1.92 (m, 3H), 1.83 - 1.44 (m, 9H), 1.38 (t, J = 7.0 Hz, 3H), 1.06 - 0.88 (m, 2H); MS: m/z [M+H] + 903.5, purity: 98.6%. Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30x 150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 53% B to 63% B in 9 min, 63% B; RT=8.95 min. Example 56. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-4-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin- 5-yl]-1-piperidyl] piperidine- 1-carboxamide [0401] The title compound was prepared in 41.5% overall yield as a white solid according to the preparation of Example 55 using tert-butyl 4-oxopiperidine-1-carboxylate in STEP A. 1 H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.28 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.63 - 7.55 (m, 2H), 7.55 - 7.48 (m, 1H), 7.37 - 7.25 (m, 3H), 7.28 - 7.17 (m, 1H), 7.16 - 7.07 (m, 2H), 7.06 - 6.99 (m, 1H), 5.74 (s, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.27 - 4.08 (m, 6H), 3.66 - 3.56 (m, 2H), 3.50 - 3.36 (m, 1H), 3.21 - 2.81 (m, 8H), 2.78 - 2.56 (m, 3H), 2.46 - 2.35 (m, 1H), 2.29 - 1.86 (m, 9H), 1.63 - 1.47 (m, 4H), 1.38 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 889.4 [M+H] + , RT = 1.88 min, purity: 99.6% Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, (Method Q). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10 min, 34% B; RT=10.93 min. Example 57. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindo lin-5-yl]-1-piperidyl]methyl]- 1-piperidyl]acetamide [0402] A. Ethyl 1-(2-tert-butoxy-2-oxo-ethyl) piperidine-4-carboxylate. To the mixture solution of ethyl piperidine-4-carboxylate (500 mg, 3.18 mmol) and tert-butyl 2- bromoacetate (620.35 mg, 3.18 mmol) in DCM (30 mL) was added Et3N (321.23 mg, 3.18 mmol), the mixture was stirred at 40 °C for overnight. The reaction was concentrated and purified by Prep-HPLC to afford the desired product (800 mg, 92.7% yield) as a colorless oil. MS: m/z [M+H] + 272. [0403] B. Ethoxycarbonyl-1-piperidyl)acetic acid. To the mixture solution of ethyl 1- (2-tert-butoxy-2-oxo-ethyl)piperidine-4-carboxylate (800. mg, 2.95 mmol) in DCM (20 mL) was added TFA (4 mL). It was stirred at rt for 4 h, the reaction was concentrated to afford 2-(4-ethoxycarbonyl-1-piperidyl)acetic acid (600 mg, 94.5% yield) as a yellow solid. MS: m/z [M+H] + 216. [0404] C. Ethyl 1-[2-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridi n-4-yl)- 2-pyridyl]-4-piperidyl]amino]-2-oxo-ethyl]piperidine-4-carbo xylate. To the mixture solution of 2-(4-ethoxycarbonyl-1-piperidyl) acetic acid (142.69 mg, 0.66 mmol), 4-[6-(4- amino-4-benzyl-1-piperidyl)-3-pyridyl]-6-ethoxy-pyrazolo[1,5 -a]pyridine-3-carbonitrile (200 mg, 0.44 mmol), and HATU (0.17 mL, 0.66 mmol) in DMF (6 mL) was added DIEA (171.03 mg, 1.33 mmol) at 0 °C, the mixture solution was stirred at -5 °C for 1 h. The reaction was diluted with water, extracted with EA, washed with brine, dried, and purified by silica gel column chromatography to afford the desired product (250 mg, 87.1% yield) as a white solid. MS: m/z [M+H] + 650. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0405] D. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-[4-(hydroxymethyl)-1-piperidyl]aceta mide. To the mixture solution of ethyl 1-[2-[[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2- pyridyl]-4-piperidyl] amino]-2-oxo-ethyl] piperidine-4-carboxylate (150 mg, 0.23 mmol) in THF (10 mL) was added LiBH4 (0.3 mL, 2 mmol/L, 0.6 mmol) at 0 °C, the mixture solution was stirred at 35 °C for 5 h. The reaction was quenched by dropwise addition of 10% citric acid. The resulting mixture was extracted with EtOAc, the combined organic layers were dried over sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column to afford the desired product (70 mg, 49.9% yield) as a white solid. MS: m/z [M+H] + 608. [0406] E. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2- pyridyl]-4-piperidyl]-2-(4-formyl-1-piperidyl)acetamide. To the mixture solution of N-[4- benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2 -pyridyl]-4-piperidyl]-2-[4- (hydroxymethyl)-1-piperidyl]acetamide (70 mg, 0.12 mmol) in DMSO (5 mL) was added IBX (64.5 mg, 0.23 mmol), the mixture solution was stirred at 70 °C for 3 h. The reaction was diluted with water, extracted with EtOAc (5 x), dried, concentrated to afford the desired product (20 mg, 20.1% yield) as a yellow solid. The crude was used without further purification in the next step. MS: m/z [M+H] + 606. [0407] F. N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2- pyridyl]-4-piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3- oxo-isoindolin-5-yl]-1- piperidyl]methyl]-1-piperidyl]acetamide. To the mixture solution of N-[4-benzyl-1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-pip eridyl]-2-(4-formyl-1- piperidyl)acetamide (17 mg, 0.03 mmol) and 3-[1-oxo-6-(4-piperidyl)isoindolin-2- yl]piperidine-2,6-dione (13.78 mg, 0.04 mmol) in DCM (5 mL) was added DIEA (0.15 mL, 0.06 mmol), the mixture solution was stirred at rt for 5 minutes, and then Ti(OiPr)4 (15.94 mg, 0.06 mol) was added, the mixture was stirred at rt for 0.5 h, then NaBH(OAc) 3 (11.9 mg, 0.06 mmol) was added at 0 °C, the mixture solution was stirred at rt overnight. The reaction was concentrated and purified by Prep-HPLC to afford the titled compound (6.4 mg, 24.1% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 8.8, 2.6 Hz, 1H), 7.59 - 7.49 (m, 3H), 7.36 - 7.20 (m, 4H), 7.18 - 7.09 (m, 3H), 6.97 (d, J = 8.8 Hz, 1H), 5.10 (dd, J = 13.1, 4.9 Hz, 1H), 4.48 - 4.08 (m, 8H), 3.08 - 2.73 (m, 11H), 2.69 - 2.55 (m, 2H), 2.45 - 2.33 (m, 1H), 2.21 - 2.07 (m, 5H), 2.06 - 1.91 (m, 3H), 1.81 - 1.54 (m, 8H), 1.38 (t, J = 6.9 Hz, 3H), 1.25 - 1.05 (m, 2H); MS: m/z [M+H] + 917.4, purity: 97.1%. Prep HPLC purification conditions: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 62% B to 75% B in 8 min, 75% B; RT = 6.05 min. Example 58. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)pi perazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0408] A. tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1- carboxylate. To a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1 g, 3.61 mmol), 3-bromopiperidine-2,6-dione (1.38 g, 7.21 mmol) in DMF (20 mL) was added DIEA (1.94 mL, 10.82 mmol). The mixture was stirred at 80 °C for 40 h. After cooling to rt, water was added to quench the reaction and extracted with EA, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford the desired product (1 g, 71.4% yield) as a yellow solid. MS: m/z [M+H] + 389. [0409] B. 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione. To a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carbo xylate (1 g, 2.57 mmol) in 1,4-dioxane (20 mL) was added HCl (4M in dioxane) (20 mL). The mixture was stirred at rt for 4 h. It was filtered, the filter cake was dried to afford the desired product (700 mg, 94.3% yield) as a white solid. MS: m/z: [M+H] + 289. [0410] C. Tert-butyl 3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1- yl)propanoate. To a solution of 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (100. mg, 0.35 mmol) and tert-butyl prop-2-enoate (88.9 mg, 0.69 mmol) in MeCN (5 mL) was added DBU (160.48 mg, 1.04 mmol). The mixture was stirred at rt for 16 h. The solvent was concentrated, and the residue was added water and extracted with EtOAc (3x). The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by reversed column chromatography to afford the desired product (100 mg, 69.2% yield) as a yellow oil. MS: m/z [M+H] + 417. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0411] D. 3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-y l)propanoic acid. To a solution of tert-butyl 3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]propanoate (95 mg, 0.23 mmol) in 1,4-Dioxane (2 mL) was added HCl (4M in dioxane) (2 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated to afford crude product which was used directly in the next step without further purification. MS: m/z [M+H] + 361. [0412] E. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1- yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide. To the mixture solution of 3-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]propanoic acid (30 mg, 0.08 mmol), N-[1-[5- (3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4- (piperazin-1-ylmethyl)-4- piperidyl]-2,5-difluoro-benzamide (50 mg, 0.08 mmol) and HATU (50 mg, 0.12 mmol) in DMF (3 mL) was added DIEA (0.02 mL, 0.25 mmol) at -5 °C, the mixture solution was stirred at -5 °C for 2 h. The reaction was purified by Prep-HPLC to afford the titled compound (37.2 mg, 45.9% yield) as a grey solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.74 (s, 1H), 8.69- 8.60 (m, 3H), 8.38 (s, 1H), 7.86 - 7.84 (m, 1H), 7.54 - 7.38 (m, 3H), 7.30 (s, 1H), 7.10 - 7.08 (m, 1H), 6.85 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 4.33 - 4.22 (m, 4H), 4.22 - 4.12 (m, 3H), 3.66 - 3.53 (m, 7H), 3.45 - 3.35 (m, 3H), 3.29 - 3.16 (m, 6H), 2.98 - 2.83 (m, 5H), 2.80 - 2.62 (m, 2H), 2.64 - 2.56 (m, 1H), 1.92 - 1.82 (d, m, 2H), 1.93 - 1.68 (m, 4H), 1.39 (d, J = 7.2 Hz, 3H); MS: m/z [M+H] + 943.4, purity: 97.5%. Prep HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B in 6 min, 50% B; RT=5.53 min. Example 59. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)pi perazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0413] The title compound was prepared in 12.7% overall yield as an off white solid according to the preparation of Example 58 using tert-butyl 4-(3-aminophenyl)piperazine-1- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, carboxylate in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.62 (brs, 1H), 8.69 - 8.60 (m, 3H), 8.37 (s, 1H), 7.84 - 7.82 (m, 1H), 7.49 - 7.36 (m, 3H), 7.29 (s, 1H), 7.08 - 7.06 (m, 1H), 7.00 - 6.96 (m, 1H), 6.32 (s, 1H), 6.27 - 6.23 (m, 2H), 4.35 - 4.26 (m, 4H), 4.1 - 4.16 (m, 3H), 3.77 - 3.73 (m, 3H), 3.63 - 3.59 (m, 4H), 3.45 - 3.35 (m, 3H), 3.28 - 3.12 (m, 7H), 3.00 - 2.84 (m, 5H), 2.81 - 2.65 (m, 3H), 2.42 - 2.40 (m, 1H), 2.14 - 2.05 (m, 1H), 1.93 - 1.83 (m, 1H), 1.78 - 1.68 (m, 3H), 1.39 (d, J = 7.0 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 943.5 [M+H] + , RT = 1.29 min, purity: 100% (Method Q). Prep HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: water (0.5%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 45% B in 6 min, 45% B; RT = 5.63 min. Example 60. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazi n-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide [0414] The title compound was prepared in 9.1% overall yield as a white solid according to the preparation of Example 58 using 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione in STEP C. 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.18 (s, 1H), 7.77 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 - 7.33 (m, 3H), 7.29 (d, J = 2.6 Hz, 1H), 7.07 - 6.98 (m, 3H), 6.90 (d, J = 8.9 Hz, 2H), 4.23 - 4.14 (m, 4H), 3.75 - 3.71 (m, 1H), 3.47 - 3.43 (m, 3H), 3.39 - 3.36 (m, 4H), 3.19 - 3.09 (m, 6H), 2.76 - 2.73 (m, 2H), 2.57 - 2.54 (m, 5H), 2.50 - 2.48 (m, 5H), 2.37 - 2.33 (m, 3H), 2.19 - 2.09 (m, 1H), 2.05 - 1.91 (m, 1H), 1.71 - 1.53 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H); Analytical LCMS ESI-MS(+) m/z 465.1 [M+2H] 2+ , RT = 1.48 min, purity: 98.4% (Method Q). Prep HPLC purification conditions: Column: YMC-Actus Triart C18 ExRS, 30x250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 60% B in 8 min, 60% B; RT=5.25 min. Example 61. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazi n-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide [0415] A. Tert-butyl 4-(3-bromophenyl)-4-cyanobutanoate. To a solution of 2-(3- bromophenyl)acetonitrile (2 g, 10.2 mmol), tert-butyl prop-2-enoate (1.31 g, 10.2 mmol) in Toluene (20 mL) were added K2CO3 (1.41 g, 10.2 mmol) and BTEAC (231.59 mg, 1.02 mmol). The mixture was stirred at 75 °C for 16 h. The reaction mixture was concentrated and purified by reversed column chromatography to afford the desired product (1.25 g, 37.8% yield) as a yellow oil. MS: m/z [M+H] + 324. [0416] B. Tert-butyl 4-(3-(4-(tert-butoxy)-1-cyano-4-oxobutyl)phenyl)piperazine-1 - carboxylate. To a 100 mL round bottle flask, tert-butyl 4-(3-bromophenyl)-4-cyano- butanoate (1.24 g, 3.82 mmol), tert-butyl piperazine-1-carboxylate (854.82 mg, 4.59 mmol), Pd2(dba)3 (174.98 mg, 0.19 mmol), Xphos (127.71 mg, 0.27 mmol) and Cs2CO3 (2.49 g, 7.65 mmol) were suspended in 1,4-Dioxane (30 mL). The mixture was placed under vacuum, sonicated and backfilled with nitrogen. The mixture was stirred at 90 °C for 16 h. It was filtered, concentrated, the crude was purified by column chromatography (PE:EA=1:10 to PE:EA-1:1) to afford the desired product (1.3 g, 79.1% yield) as a yellow solid. MS: m/z 471 [M+H+41] + . [0417] C. 3-(3-(piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of tert-butyl 4-[3-(4-tert-butoxy-1-cyano-4-oxo-butyl)phenyl]piperazine-1- carboxylate (1.3 g, 3.03 mmol) in DCE (20 mL) was added MsOH (872.61 mg, 9.08 mmol), Tf 2 O (0.16 mL, 0.92 mmol). The mixture was stirred at 90 °C for 4 h. It was concentrated was used directly in the next step without further purification. MS: m/z [M+H] + 274. [0418] D. Tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylat e. To a solution of 3-(3-piperazin-1-ylphenyl)piperidine-2,6-dione (1.5 g, 5.49 mmol) in DMF (30 mL) were added (Boc)2O (3.78 mL, 16.46 mmol), K2CO3 (2271.98 mg, 16.46 mmol). The mixture was stirred at rt for 4 h. Water was used to quench the reaction. Extracted with Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, EA, the organic phase was washed with brine, combined the organic phase, dried, filtered, concentrated, the crude was purified by column chromatography to afford the desired product (1 g, 48.8% yield) as a yellow solid. MS: m/z [M+H] + 374. [0419] E. 3-(3-(piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (1 g, 2.68 mmol) in 1,4-Dioxane (10 mL) was added HCl (4M in 1,4-dioxane) (10 mL). The mixture was stirred at rt for 2 h. It was filtered and dried under vacuum to afford the crude product (700 mg, 95.6% yield), which was used directly in the next step without further purification. MS: m/z [M+H] + 274. [0420] F. Tert-butyl 3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1- yl)propanoate. To a solution of 3-(3-piperazin-1-ylphenyl)piperidine-2,6-dione (100 mg, 0.37 mmol), tert-butyl prop-2-enoate (93.78 mg, 0.73 mmol) in MeCN (5 mL) was added DBU (167.09 mg, 1.1 mmol). The mixture was stirred at rt for 16 h. It was concentrated and purified by reversed phase column chromatography to afford the desired product (90 mg, 61.3% yield) as a yellow oil. MS: m/z [M+H] + 402. [0421] G. 3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propa noic acid. To a solution of tert-butyl 3-[4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]propano ate (85 mg, 0.21 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at rt for 2 h. the reaction mixture was concentrated to afford crude product, which was used directly in the next step without further purification. MS: m/z [M+H] + 346. [0422] H. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)prop anoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide. To a solution of N-[1-[5-(3-cyano-6- ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin- 1-ylmethyl)-4-piperidyl]-2,5- difluoro-benzamide (50 mg, 0.08 mmol) in DMA (3 mL) were added 3-[4-[3-(2,6-dioxo-3- piperidyl)phenyl]piperazin-1-yl]propanoic acid (28.75 mg, 0.08 mmol), HATU (47.45 mg, 0.12 mmol) and DIEA (32.21 mg, 0.25 mmol). The mixture was stirred at rt for 4 h and purified by prep-HPLC to afford the titled product (24.7 mg, 30.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.88 (s, 1H), 8.70 - 8.63 (m, 1H), 8.60 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.53 - 7.48 (m, 1H), 7.46 - 7.35 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.96 - 6.87 (m, 2H), 6.73 (d, J = 7.8 Hz, 1H), 4.31 - 4.26 (m, 2H), 4.20 - 4.14 (m, 2H), 3.92 - 3.76 (m, 3H), 3.67 - 3.61 (m, 4H), 3.44 - 3.40 (m, 2H), 3.35 - 3.12 (m, 5H), 3.04 - 2.92 (m, 4H), 2.72 - 2.62 (m, 1H), 2.52 - 2.50 (m, 8H), 2.46 - 2.44 (m, 2H), 2.28 - 2.17 (m, 1H), 2.10 - 1.93 (m, 1H), 1.84 - 1.67 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H); MS: m/z: [M+H] + 464.9, purity: 96.3%. Prep Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in 5.1 min, 50% B; RT=5.33 min. Using procedures like Examples 1-14, the following Examples 62-66 were obtained. Example 62 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(1-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}azetidin-3-yl)piperazin- 1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]azetidin-3- yl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzami de Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 64 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{1-[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbonyl]aze tidin-3-yl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide Example 65 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[1-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)azetidin-3- yl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzami de N-[4-benzyl-1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-y l}pyridin-2-yl)piperidin-4- yl]-1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H-isoindol-5-yl]piperidin-1- yl}propanoyl)piperidine-4-carboxamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 67. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0423] A. Tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate. To the mixture solution of 3-(1-oxo-6- piperazin-1-yl-isoindolin-2-yl) piperidine-2,6-dione (60 mg, 0.18 mmol) and tert-butyl 4- formylpiperidine-1-carboxylate (60 mg, 0.27 mmol) in DCM (5 mL) was added DIEA (50 mg, 0.37 mmol), the mixture solution was stirred at rt for 20 minutes, and then AcOH (25 mg, 0.37 mmol) was added and the mixture solution was stirred at rt for 0.5 h, then the reaction mixture was cooled down to 0 °C, NaBH(OAc) 3 (80 mg, 0.37 mmol) was added and the mixture was stirred at rt overnight. The reaction was concentrated and purified by flash to afford the desired product (80 mg, 83.3 % yield) as an off-white solid. MS: m/z [M+H] + 526. [0424] B. 3-(1-Oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoli n-2- yl)piperidine-2,6-dione. To the mixture solution of tert-butyl 4-[[4-[2-(2,6-dioxo-3- piperidyl)-3-oxo-isoindolin-5-yl] piperazin-1-yl] methyl] piperidine-1-carboxylate (80 mg, 0.1500 mmol) in DCM (10 mL) was added TFA (3 mL), the mixture solution was stirred at rt for 4 h. The reaction was concentrated to afford the desired product (70 mg, quant.), which was used in next step without further purification. MS: m/z [M+H] + 426. [0425] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- ((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pipera zin-1-yl)methyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide. To the mixture solution of 3-[1-oxo-6- [4-(4-piperidylmethyl)piperazin-1-yl]isoindolin-2-yl]piperid ine-2,6-dione (40 mg, 0.09 mmol) and N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-formyl-4- piperidyl]-2,5-difluoro-benzamide (50 mg, 0.0900 mmol) in DCM (5 mL) was added DIEA (0.01 mL, 0.19 mmol), and the mixture solution was stirred at rt for 2 h, then TIPT (55 mg, 0.1900 mmol) was added and the mixture solution was stirred at rt for 3 days. After cooling Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, the mixture to 0 ⁰C, NaBH(OAc)3 (40 mg, 0.19 mmol) was added, and the mixture was stirred at rt overnight. The reaction was purified by Prep-HPLC to afford the titled compound (6.9 mg, 7.8 % yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.57 – 8.54 (m, 1H), 8.35 (s, 1H), 7.86 – 7.80 (m, 1H), 7.55 – 7.46 (m, 2H), 7.45 – 7.32 (m, 3H), 7.32 – 7.25 (m, 2H), 7.10 – 7.04 (m, 1H), 5.12 – 5.03 (m, 1H), 4.42 - 4.33 (m, 1H), 4.32 – 4.19 (m, 3H), 4.18 – 4.09 (m, 2H), 3.98 – 3.84 (m, 2H), 3.76 – 3.69 (m, 5H), 3.31 - 3.06 (m, 11H), 2.95 – 2.84 (m, 1H), 2.66 – 2.57 (m, 1H), 2.46 – 2.36 (m, 3H), 2.21 – 2.12 (m, 1H), 2.05 – 1.92 (m, 3H), 1.77 – 1.69 (m, 2H), 1.63 – 1.52 (m, 2H),1.38 (t, J = 7.1 Hz, 3H). MS: m/z [M+H] + 940.4, purity: 99.0%. Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B in 5.5 min, 60% B; RT=5.54 min. Example 68. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pip eridin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0426] A. N-(4-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)-1-(5-(3-c yano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-y l)-2,5-difluorobenzamide. To a stirred solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4- formyl-4-piperidyl]-2,5-difluoro-benzamide (100 mg, 0.19 mmol) in DCM (5 mL) were added 1,4-dioxa-8-azaspiro[4.5]decane (55 mg, 0.3800 mmol) and Titanium(IV) isopropoxide (145 mg, 0.38 mmol) at rt, and the resulting mixture was stirred for 1 h. NaBH(OAc)3 (80 mg, 0.38 mmol) was added at 0 °C and the mixture was stirred at rt for 2 h. The crude was purified by prep-TLC to afford the desired product (80 mg, 64.5% yield) as a colorless oil. MS: m/z [M+H] + 658. [0427] B. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- oxopiperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzami de. The mixture solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-(1,4-dioxa-8- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, azaspiro[4.5]decan-8-ylmethyl)-4-piperidyl]-2,5-difluoro-ben zamide (35 mg, 0.05 mmol) in FA (10 mL, 0.05 mmol) was stirred at 80 °C overnight. The reaction was concentrated to afford the desired product (30 mg, 91.9 % yield) as a light brown solid, which was used in next step without further purification. MS: m/z [M+H] + 614. [0428] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperaz in-1-yl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide. To the mixture solution of N-[1-[5-(3- cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[(4-oxo-1-piperidyl)methyl]-4- piperidyl]-2,5-difluoro-benzamide (30 mg, 0.0500 mmol) and 3-(1-oxo-6-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (16 mg, 0.0500 mmol) in DCM (4 mL) was added DIEA (0.01 mL, 0.10 mmol), the mixture solution was stirred at rt for 2 h, then TIPT (30 mg, 0.10 mmol) was added, the mixture solution was stirred at rt for 3 days, then the mixture was cooled down to 0 ºC, NaBH(OAc) 3 (20 mg, 0.10 mmol) was added, the mixture solution was stirred at rt overnight. The reaction was purified by flash to afford 27 mg crude, then the mixture was purified by Prep-HPLC to afford the titled compound (6.5 mg, 14.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.63 – 8.60 (m, 1H), 8.56 – 8.53 (m, 1H), 8.36 – 8.33 (m, 1H), 7.87 – 7.80 (m, 1H), 7.55 – 7.47 (m, 2H), 7.45 – 7.32 (m, 3H), 7.31 – 7.26 (m, 1H), 7.11 – 7.05 (m, 1H), 7.08 (d, J = 9.1 Hz, 1H), 5.11 – 5.01 (m, 1H), 4.42 – 4.34 (m, 1H), 4.31 – 4.21 (m, 3H), 4.14 (q, J = 6.8 Hz, 2H), 3.84 – 3.72 (m, 13H), 3.28 – 3.15 (m, 4H), 2.92 – 2.81 (m, 1H), 2.66 – 2.57(m, 1H), 2.46 – 2.35 (m, 3H), 2.33 – 2.25 (m, 2H), 2.14 – 1.97 (m, 3H), 1.80 – 1.60 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 926.3, purity: 100%. Prep- HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 40% B in 5.5 min, 40% B; RT=5.52 min. Example 69. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0429] The title compound was prepared in 9.4% overall yield as a white solid according to the preparation of Example 67 using 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.81 (dd, J = 8.9, 2.5 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.49 - 7.34 (m, 3H), 7.25 (d, J = 2.1 Hz, 1H), 7.17 - 7.14 (m, 2H), 7.04 (d, J = 8.9 Hz, 1H), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 - 4.35 (m, 1H), 4.27 - 4.22 (m, 3H), 4.15 - 4.10 (m, 2H), 3.98 - 3.89 (m, 4H), 3.66 - 3.61 (m, 4H), 3.24 - 3.07 (m, 10H), 2.92 - 2.82 (m, 1H), 2.66 - 2.58 (m, 1H), 2.41 - 2.35 (m, 3H), 2.25 - 2.09 (m, 1H), 2.04 - 1.93 (m, 3H), 1.83 - 1.69 (m, 2H), 1.61 - 1.57 (m, 2H), 1.37 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 940.5. Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B in 5.3 min, 55% B; RT=5.63 min. Example 70. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidine-1-carbonyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0430] A. Tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperidin-1-yl)azetidine-1-carboxylate. To a solution of 3-[1-oxo-6-(4- piperidyl)isoindolin-2-yl]piperidine-2,6-dione (100 mg, 0.31 mmol) and tert-butyl 3- oxoazetidine-1-carboxylate (104.58 mg, 0.61 mmol) in DCM (10 mL) were added DIEA (78.81 mg, 0.61 mmol), Titanium(IV) isopropoxide (173.5 mg, 0.61 mmol). The mixture was stirred at rt for 1 h. NaBH(OAc) 3 (129.48 mg, 0.61 mmol) was added at 0 °C and the resulting mixture was stirred at rt for another 2 h. It was concentrated, the crude was purified by reversed phase column chromatography to afford the desired product (100 mg, 67.8% yield) as a yellow oil. MS: m/z [M+H] + 483. [0431] B. 3-(6-(1-(Azetidin-3-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6- dione. To a solution of tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]azetidine-1-carboxylate (300 mg, 0.62 mmol) in DCM (5 mL) was added TFA (2 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, mL). The mixture was stirred at rt for 1 h. The reaction was concentrated to afford product, which was used directly in the next step without further purification. [0432] C. Tert-butyl 4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperidin-1-yl)azetidine-1-carbonyl)piperidine-1-carboxyl ate. To a solution of 3-[6-[1- (azetidin-3-yl)-4-piperidyl]-1-oxo-isoindolin-2-yl]piperidin e-2,6-dione (80 mg, 0.21 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (71.94 mg, 0.31 mmol) in DMA (1 mL) were added HATU (119.3 mg, 0.31 mmol), DIEA (48. mg, 0.37 mmol). The mixture was stirred at rt for 2 h. LCMS showed the reaction was complete, the crude was purified by reversed phase column chromatography to afford the desired product (80 mg, 64.4 % yield) as a yellow oil. MS: m/z: [M+H] + 594. [0433] D. 3-(1-Oxo-6-(1-(1-(piperidine-4-carbonyl)azetidin-3-yl)piperi din-4- yl)isoindolin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl 4-[3-[4-[2-(2,6-dioxo-3- piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]azetidine-1-ca rbonyl]piperidine-1-carboxylate (95 mg, 0.16 mmol) in 1,4-Dioxane (2 mL) was added HCl (4 M in dioxane) (2 mL). The mixture was stirred at rt for 2 h. It was concentrated to afford crude product, which was used directly in the next step without further purification. MS: m/z [M+H] + 494. [0434] E. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pipe ridin-1-yl)azetidine-1- carbonyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-formyl-4-piperidyl]- 2,5-difluoro-benzamide (40 mg, 0.08 mmol), 3-[1-oxo-6-[1-[1-(piperidine-4- carbonyl)azetidin-3-yl]-4-piperidyl]isoindolin-2-yl]piperidi ne-2,6-dione (37.22 mg, 0.08 mmol) in DCM (2 mL) were added Titanium(IV) isopropoxide (42.83 mg, 0.15 mmol), DIEA (19.45 mg, 0.15 mmol). The mixture was stirred at rt for 3 days. NaBH(OAc)3 (31.97 mg, 0.15 mmol) was added at 0°C. The mixture was stirred at rt for another 16 h. It was concentrated and purified by prep-HPLC to afford the titled product (8.4 mg, 11.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.07 (s, 1H), 8.68 - 8.67 (m, 1H), 8.62 - 8.59 (m, 1H), 8.54 (s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 7.82 (dd, J = 8.7, 2.6 Hz, 1H), 7.61 - 7.40 (m, 5H), 7.28 - 7.26 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.49 - 4.43 (m, 3H), 4.36 - 4.23 (m, 3H), 4.19 - 4.12 (m, 4H), 3.76 - 3.65 (m, 8H), 3.26 - 3.13 (m, 4H), 3.07 - 2.86 (m, 4H), 2.68 - 2.59 (m, 2H), 2.47 - 2.34 (m, 3H), 2.17 - 2.11 (m, 2H), 2.05 - 1.83 (m, 6H), 1.79 - 1.71 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 1008. Prep-HPLC purification condition: Column: Column: SunFire Prep C18 OBD Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in 5.3 min, 50% B; RT=5.52 min. Example 71. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidin-1-yl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0435] The title compound was prepared in 5.1 % overall yield as a white solid according to the preparation of Example 67 using 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.59 (s, 2H), 8.36 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.49 - 7.36 (m, 3H), 7.28 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 - 4.42 (m, 1H), 4.37 - 4.23 (m, 4H), 4.19 - 4.14 (m, 3H), 3.94 - 3.87 (m, 3H), 3.79 - 3.69 (m, 7H), 3.35 - 3.30 (m, 3H), 3.24 - 3.18 (m, 3H), 2.96 - 2.87 (m, 2H), 2.79 - 2.71 (m, 1H), 2.67 - 2.55 (m, 1H), 2.47 - 2.33 (m, 3H), 2.11 - 1.96 (m, 5H), 1.91 - 1.84 (m, 2H), 1.75 - 1.67 (m, 3H), 1.39 (t, J = 7.0 Hz, 3H). MS: m/z [M+H] + 980. Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 30% B in 7 min, 30% B; RT=6.57 min. Example 72. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidin-1-yl)methyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0436] The title compound was prepared in 3.65 % overall yield as a white solid according to the preparation of Example 70 using tert-butyl 4-formylpiperidine-1-carboxylate in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.59 (s, 2H), 8.37 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.8, 2.5 Hz, 1H), 7.64 - 7.52 (m, 3H), 7.51 - 7.46 (m, 1H), 7.44 - 7.36 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.47 - 4.42 (m, 2H), 4.34 - 4.23 (m, 5H), 4.19 - 4.14 (m, 2H), 34.01 - 3.88 (m, 1H), 3.77 - 3.68 (m, 7H), 3.34 - 3.27 (m, 3H), 3.24 - 3.20 (m, 2H), 3.17 - 3.06 (m, 3H), 2.96 - 2.87 (m, 2H), 2.70 - 2.57 (m, 2H), 2.45 - 2.32 (m, 3H), 2.10 - 1.96 (m, 3H), 1.90 - 1.84 (m, 4H), 1.77 - 1.67 (m, 2H), 1.62 - 1.54 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 994. Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 28% B in 7 min, 28% B; RT = 6.75 min. Example 73. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)-1-fluorocyclopropane-1-carboxamide [0437] The title compound was prepared in 21.5% yield as a white solid according to the preparation of Example 2 using N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2- pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-1-fluoro-cycl opropanecarboxamide and 3-[4- [2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidy l]propanoic acid. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.33 (s, 1H), 7.80 – 7.74 (m, 1H), 7.61 – 7.50 (m, 4H), 7.28 (s, 1H), 7.02 – 6.93 (m, 1H), 5.17 – 5.08 (m, 1H), 4.42 (d, J = 17.0 Hz, 1H), 4.28 (d, J = 17.0 Hz, 1H), 4.21 – 4.05 (m, 4H), 3.51 – 3.40 (m, 4H), 3.20 – 2.85 (m, 6H), 2.73 – 2.55 (m, 6H), 2.47 – 2.32 (m, 7H), 2.19 – 1.96 (m, 3H), 1.87 – 1.55 (m, 7H), 1.45 – 1.34 (m, 3H), 1.34 – 1.22 (m, 2H), 1.22 – 1.13 (m, 2H). MS: m/z [M+H] + 928.5. Prep-HPLC purification condition: Column: XBridge BEH C18 OBD Prep Column, 19x250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 47% B to 57% B in 6 min, 57% B; RT=5.62 min. Example 74. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)cyc lobutane-1- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide [0438] A. Tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperidin-1-yl)cyclobutane-1-carboxylate. To the mixture solution of 3-[1-oxo-6-(4- piperidyl)isoindolin-2-yl]piperidine-2,6-dione (60 mg, 0.18 mmol) and tert-butyl 3- oxocyclobutanecarboxylate (50 mg, 0.27 mmol) in DCM (5 mL) was added DIEA (0.03 mL, 0.37 mmol), the mixture solution was stirred at rt for 5 minutes, and then TIPT (105 mg, 0.37 mmol) was added, and the mixture solution was stirred at rt for 0.5 h. After cooling to 0 °C, NaBH(OAc) 3 (80 mg, 0.37 mmol) was added, and the mixture solution was stirred at rt for 5 h, the reaction was purified by Prep-HPLC to afford the desired product (60 mg, 68 % yield) as an off-white solid. MS: m/z [M+H] + 482. [0439] B. 3-(4-(2-(2,6-Dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piper idin-1- yl)cyclobutane-1-carboxylic acid. To the mixture solution of tert-butyl 3-[4-[2-(2,6-dioxo- 3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl] cyclobutanecarboxylate (55 mg, 0.11 mmol) in DCM (10 mL) was added TFA (3 mL), the mixture solution was stirred at rt for 4 h. The reaction was concentrated to afford the desired product (45 mg, 92.6 % yield), which was used in next step without further purification. MS: m/z [M+H] + 426. [0440] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pipe ridin-1-yl)cyclobutane-1- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide. To the mixture solution of 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]cyclobutanecarboxylic acid (35 mg, 0.08 mmol), N-[1-[5-(3-cyano-6-ethoxy- pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmet hyl)-4-piperidyl]-2,5-difluoro- benzamide (50 mg, 0.08 mmol) and DIEA (0.02 mL, 0.25 mmol) in DMF, was added HATU (50 mg, 0.12 mmol) at -5 °C, the mixture solution was stirred at 0 °C for 2 h. The reaction was purified by Prep-HPLC to afford the titled compound (28.1 mg, 33.4 % yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 8.33 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, J = 8.9, 2.6 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.41 – 7.31 (m, 3H), 7.27 (d, J = 2.1 Hz, 1H), 7.01 – 6.94 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.41 (d, J = 17.1 Hz, 1H), 4.34 – 4.10 (m, 5H), 3.47 – 3.39 (m, 2H), 3.31 – 3.27 (m, 1H), 3.24 – 3.07 (m, 2H), 3.03 – 2.83 (m, 4H), 2.78 – 2.68 (m, 2H), 2.67 – 2.53 (m, 4H), 2.47 – 2.39 (m, 4H), 2.40 – 2.29 (m, 3H), 2.25 – 2.14 (m, 2H), 2.05 – 1.89 (m, 3H), 1.86 – 1.73 (m, 4H), 1.70 – 1.52 (m, 4H), 1.38 (t, J = 6.9 Hz, 3H). MS: m/z [M+H] + 1009.4. Prep-HPLC purification condition: Column: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3 . H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 12 min, 57% B; RT=10.22 min. Example 75. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(1-(1-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)aze tidin-3-yl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0441] A. 3-[6-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)-1-oxo-isoindolin- 2- yl]piperidine-2,6-dione. To a 5 microwave vial, 3-(6-bromo-1-oxo-isoindolin-2- yl)piperidine-2,6-dione (500 mg, 1.55 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (443 mg, 3.09 mmol), (DiMeIHeptCl)Pd(cinnamyl)Cl (130 mg, 0.12 mmol), Cs 2 CO 3 (2012 mg, 6.19 mmol) were suspended in 1,4-dioxane (18 mL). The reaction was placed under vacuum, sonicated and backfilled with nitrogen. The mixture was stirred at rt for 16 h. It was concentrated and purified by column chromatography to afford the desired product (430 mg, 72.1% yield) as a white solid. MS: m/z [M+H] + 386. [0442] B. 3-(1-Oxo-6-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2 ,6-dione. A mixture solution of 3-[6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-oxo-isoindolin- 2- yl]piperidine-2,6-dione (200 mg, 0.52 mmol) in formic acid (8 mL) was heated at 60 °C for 20 h. It was concentrated to afford crude product which was used in the next step without further purification. MS: m/z: [M+H] + 342. [0443] C. tert-butyl 3-(4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4-(2,5-difluorobenzamido)piperidin-4-yl)met hyl)piperazin-1- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, yl)azetidine-1-carboxylate. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5- a]pyridin-4-yl)-2-pyridyl]-4-formyl-4-piperidyl]-2,5-difluor o-benzamide (80 mg, 0.15 mmol), tert-butyl 3-piperazin-1-ylazetidine-1-carboxylate (54.59 mg, 0.23 mmol) in DCM (5 mL) was added TIPT (85.65 mg, 0.30 mmol). The mixture was stirred at rt for 16 h. NaBH(OAc)3 (63.94 mg, 0.30 mmol) was added at 0°C. The mixture was stirred at rt for another 4 h. It was purified by Prep-TLC (EA as eluent) to afford the desired product (70 mg, 61.4 % yield) as a light-yellow solid. MS: m/z [M+H] + 756. [0444] D. N-(4-((4-(azetidin-3-yl)piperazin-1-yl)methyl)-1-(5-(3-cyano -6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-y l)-2,5-difluorobenzamide. To a solution of tert-butyl 3-[4-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2 - pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4-piperidyl]methyl]p iperazin-1-yl]azetidine-1- carboxylate (70 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was added HCl (4 M in dioxane) (2 mL). The mixture was stirred at rt for 2 h. It was concentrated and used directly in the next step without further purification. MS: m/z [M+H] + 656. [0445] E. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (1-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pipe ridin-4-yl)azetidin-3- yl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzami de. To a solution of N-[4- [[4-(azetidin-3-yl)piperazin-1-yl]methyl]-1-[5-(3-cyano-6-et hoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4-piperidyl]-2,5-difluoro-benzamide (40 mg, 0.06 mmol), 3-[1-oxo-6-(4-oxo- 1-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (20.82 mg, 0.06 mmol) in DCM (3 mL) were added TIPT (34.65 mg, 0.12 mmol), DIEA (15.74 mg, 0.12 mmol). The mixture was stirred at rt for 3 days, then NaBH(OAc)3 (25.86 mg, 0.12 mmol) was added at 0°C. The mixture was stirred at rt for another 16 h. It was concentrated, the crude was purified by Prep-HPLC to afford the titled product (1.2 mg, 1.9 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.12 - 9.50 (m, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.47 - 7.40 (m, 4H), 7.29 - 7.21 (m, 3H), 7.06 - 7.03 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 - 3.99 (m, 10H), 3.93 - 3.88 (m, 2H), 3.67 - 3.51 (m, 5H), 3.26 - 3.09 (m, 3H), 3.06 - 2.81 (m, 3H), 2.79 - 2.70 (m, 3H), 2.64 - 2.55 (m, 2H), 2.43 - 2.29 (m, 4H), 2.04 - 1.90 (m, 3H), 1.74 - 1.66 (m, 2H), 1.51 - 1.33 (m, 6H). MS: m/z [M+H] + 981. Prep-HPLC purification condition: Column: Welch Utimate HS-C18, 21.2x250 mm, 7μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN(0.1% TFA); Flow rate: 30 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; RT=8.05 min. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 76. 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide [0446] To the mixture solution of 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]- 1-piperidyl]propanoic acid (20 mg, 0.05 mmol) and 1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5- a]pyridin-4-yl)-2-pyridyl]-N-isopropyl-4-(piperazin-1-ylmeth yl) piperidine-4-carboxamide (27 mg, 0.05 mmol) in DMF (3 mL) was added T 3 P (46 mg, 0.08 mmol) and DIEA (0.01 mL, 0.15 mmol), and stirred at -5 °C for 1 h, the reaction was purified by Prep-HPLC to afford the titled compound (16.9 mg, 36.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.69 – 8.63 (m, 1H), 8.59 – 8.55 (m, 1H), 8.35 – 8.31 (m, 1H), 7.88 – 7.76 (m, 2H), 7.64 – 7.51 (m, 3H), 7.29 – 7.25 (m, 1H), 7.05 – 7.00 (m, 1H), 5.15 – 5.05 (m, 1H), 4.44 (d, J = 17.0 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.05 – 3.90 (m, 3H), 3.78 – 3.61 (m, 4H), 3.39 – 3.30 (m, 5H), 3.17 – 3.06 (m, 2H), 3.04 – 2.83 (s, 11H), 2.67 – 2.57 (m, 1H), 2.45 – 2.35 (m, 1H), 2.26 – 2.15 (m, 2H), 2.12 – 1.85 (m, 5H), 1.70 – 1.56 (m, 2H), 1.39 (t, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 6H). Analytical LCMS ESI-MS(+) m/z 912.6 [M+H] + , RT = 1.13 min, purity: 95% (Method Q). Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 60% B in 6 min, 60% B; RT=5.78 min.
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 77. 1-(5-(3-Cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pro panoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide [0447] The title compound was prepared in 17.4 % overall yield as a white solid according to the preparation of Example 76 using 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione in STEP A. 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.77 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.79 (dd, J = 9.0, 2.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.22 – 7.13 (m, 2H), 6.99 (d, J = 9.0 Hz, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.09 – 3.93 (m, 5H), 3.72 – 3.59(m, 4H), 3.44 – 3.34(m, 8H), 3.34 – 3.11(m, 8H), 2.98 – 2.86 (m, 3H), 2.64 – 2.56 (m, 1H), 2.47 – 2.35 (m, 1H), 2.24 – 2.13 (m, 2H), 2.03 – 1.94 (m, 1H), 1.58 (s, 2H), 1.39 (t, J = 6.9 Hz, 3H), 1.11 (d, J = 6.6 Hz, 6H). MS: m/z [M+H] + 913.6, purity: 99.0%. Prep-HPLC purification condition: Column: SunFire C18 OBD Prep Column, 19x250 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 23% B in 8 min, 23% B; RT = 6.87 min. Example 78. 1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4 ‐yl}pyridin‐2‐yl)‐4‐{[4‐(3‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperidin‐1‐ yl}propanoyl)piperazin‐1‐yl]methyl}‐N‐(2‐methylpro pyl)piperidine‐4‐carboxamide [0448] To a stirred solution of 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1- piperidyl]propanoic acid (40 mg, 0.10 mmol) in DMF (2 mL) were added 1-[5-(3-cyano-6- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-N-isobutyl-4- (piperaz-1-ylmethyl)piperidine- 4-carboxamide (81.82 mg, 0.15 mmol), T3P (63.69 mg, 0.20 mmol) and DIEA (0.02 mL, 0.3000 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the starting material was consumed completely. The mixture was directly purified by reversed phase column to obtain the titled compound (20.1 mg, 21.63 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.85-7.70 (m, 2H), 7.55 (d, J = 12.6 Hz, 3H), 7.27 (d, J = 2.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 4.29 (d, J = 17.1 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 4.07 (d, J = 12.8 Hz, 2H), 3.16 – 2.85 (m, 8H), 2.71-2.53 (m, 7H), 2.49 – 2.33 (m, 7H), 2.25 -2.07(m, 4H), 2.05 – 1.95 (m, 1H), 1.87 -1.65 (m, 5H), 1.57-1.46 (m, 3H), 1.38 (t, J = 6.9 Hz, 3H), 0.92 (t, J = 7.1 Hz, 1H), 0.86 (d, J = 6.6 Hz, 6H). MS: m/z [M+H] + 927. Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 55% B in 5.5 min, 55% B; RT = 5.24 min. Example 79. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidine-4- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide [0449] A. Tert-butyl 1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl] piperidine-4-carboxylate. The mixture solution of 1-(6-bromo-1-methyl-indazol-3-yl) hexahydropyrimidine-2,4-dione (300 mg, 0.93 mmol), tert-butyl piperidine-4-carboxylate (260 mg, 1.39 mmol), Ruphos (45 mg, 0.09 mmol), Ruphos Pd G3 (80 mg, 0.09 mmol) and Cs2CO3 (300 mg, 0.9300 mmol) in 1,4-Dioxane (8 mL) was purged with N2 for 5 times, and the resulting mixture solution was warmed up to 100 °C and stirred overnight under N2 atmosphere. The reaction was concentrated and purified by silica gel column to afford the desired product (210 mg, 52.9% yield) as a white solid. MS: m/z [M+H] + 428. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0450] B. 1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y l] piperidine-4-carboxylic acid. To the mixture solution of tert-butyl 1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl] piperidine-4-carboxylate (200 mg, 0.47 mmol) in DCM (10 mL) was added TFA (0.04 mL, 0.47 mmol), and stirred at rt for 4 h, the reaction was concentrated to afford the desired product (200 mg, quant.). MS: m/z [M+H] + 372. [0451] C. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[4- [1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl] piperidine-4-carbonyl] piperazin-1-yl] methyl]-4-piperidyl]-2,5-difluoro-benzamide. To a solution of 1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidi ne-4-carboxylic acid (30 mg, 0.08 mmol) in DMF (3 mL) were added N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin- 4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-2,5-d ifluoro-benzamide (50 mg, 0.08 mmol), DIEA (0.02 mL, 0.24 mmol), and HATU (50 mg, 0.12 mmol). The resulting solution was stirred for 1 h and purified by Prep-HPLC to afford the titled compound (19.2 mg, 24.8 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.16 (s, 1H), 7.77 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.40 – 7.32 (m, 3H), 7.28 (d, J = 2.1 Hz, 1H), 7.02 – 2.95 (m, 1H), 6.93 – 6.89 (m, 1H), 6.84 – 6.80 (m, 1H), 4.25 – 4.13 (m, 4H), 3.93- 3.87 (m, 5H), 3.86 – 3.79 (m, 2H), 3.56 – 3.50 (m, 2H), 3.48 – 3.41 (m, 2H), 3.23 – 3.11 (m, 2H), 2.88 – 2.79 (m, 3H), 2.78 – 2.70 (m, 4H), 2.60 – 2.53 (m, 5H), 2.40 – 2.35 (m, 1H), 1.75 – 1.57 (m, 6H), 1.39 (t, J = 6.9 Hz, 3H). Analytical LCMS ESI-MS(+) m/z 954.6 [M+H] + , RT = 1.53 min, purity: 99.7% (Method P). Prep-HPLC purification condition: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 58% B in 7 min, 58% B to 71% B in 8.5 min, 71% B; RT=7.58 min.
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 80. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(3- methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperid in-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide [0452] A. 3-(6-Bromo-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dion e. To a stirred mixture of methyl 5-bromo-2-(bromomethyl)benzoate (600 mg, 1.95 mmol) and 3- amino-3-methyl-piperidine-2,6-dione (332.35 mg, 2.34 mmol) in MeCN (8 mL) was added DIEA (0.2 mL, 7.79 mmol), and the resulting mixture was stirred at 60 °C for overnight. AcOH (0. mL, 0 mmol) was added to the reaction mixture, and the above mixture was stirred for 1 h at 80°C. The suspension was filtrated, and the filter cake was dried to obtain the desired product (450 mg, 68.5% yield) as a white solid. MS: m/z [M+H] + 337. [0453] B. Tert-butyl 4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl )- 3,6-dihydropyridine-1(2H)-carboxylate. To a solution of 3-(6-bromo-1-oxo-isoindolin-2- yl)-3-methyl-piperidine-2,6-dione (430 mg, 1.28 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxyla te (591.51 mg, 1.91 mmol) and Na2CO3 (405.55 mg, 3.83 mmol) in1,4-dioxane (10 mL) and Water (1 mL) was added Pd(dppf)Cl 2 (208.3 mg, 0.26 mmol). The resulting mixture was evacuated and backfilled with N 2 for 3 times and stirred at 80 °C for 3 h. The suspension was filtrated, and the filtrate was concentrated under vacuum. The resulting residue was purified by Prep-TLC (PE/EA = 0/1) to obtain the desired product (120 mg, 21.4% yield) as a tan solid. MS: m/z [M+H] + 441. [0454] C. Tert-butyl 4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-[2-(3-methyl-2,6-dioxo-3- piperidyl)-3-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (330. mg, 0.7500 mmol)in ethanol (3 mL)was added Pd/C (330. mg, 3.1 mmol) under N2. H2 was subsequently introduced into the reaction system, and the resulting mixture was stirred at ambient temperature for 1 h. The suspension was filtrated, and the filtrate was concentrated under Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, vacuum. The resulting residue was dried to obtain the desired product (300 mg) as a white solid. MS: m/z [M-H] – 440. [0455] D. 3-Methyl-3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidi ne-2,6-dione. To a stirred solution of tert-butyl 4-[2-(3-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5- yl]piperidine-1-carboxylate (290 mg, 0.66 mmol) in 1,4-dioxane (10 mL) was added a solution of 4 M HCl in 1,4-Dioxane (10 mL), the reaction mixture was stirred for 2 h at rt. The mixture was concentrated under vacuum to afford the desired product (290 mg, 0.66 mmol) as a white solid. MS: m/z [M+H] + 342. [0456] E. Tert-butyl 3-(4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5 - yl)piperidin-1-yl)propanoate. To a stirred mixture of 3-methyl-3-[1-oxo-6-(4- piperidyl)isoindolin-2-yl]piperidine-2,6-dione (100 mg, 0.29 mmol) and tert-butyl prop-2- enoate (75.08 mg, 0.59 mmol) in MeCN (3 mL) was added DBU (178.37 mg, 1.17 mmol) at rt, the reaction mixture was stirred for 4 h. It was concentrated and purified by reversed- phase column to obtain the desired product (90 mg, 65.4% yield) as a white solid. [0457] F. 3-(4-(2-(3-Methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5 -yl)piperidin- 1-yl)propanoic acid. To a stirred solution of tert-butyl 3-[4-[2-(3-methyl-2,6-dioxo-3- piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoate (85 mg, 0.18 mmol) in DCM (5 mL) was added TFA (5 mL) at rt and stirred for 2 h. The mixture was concentrated under vacuum to obtain a crude product, which was not purified and used directly in the next step. MS: m/z [M+H] + 414. [0458] G. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4- (3-(4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin- 5-yl)piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide. To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-(piperazin- 1-ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (50 mg, 0.08 mmol) and 3-[4-[2-(3-methyl- 2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]pr opanoic acid (51.63 mg, 0.12 mmol) in DMF (2 mL) were added T 3 P (52.94 mg, 0.17 mmol) , and DIEA (0.02 mL, 0.25 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The mixture was purified by reversed phase column to obtain the titled product (18.4 mg, 22.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.35 (s, 1H), 8.67 (d, J= 2.1 Hz, 1H), 8.58 (s, 1H), 8.35 (d, J= 2.6 Hz, 1H), 7.81 (dd, J= 8.9, 2.6 Hz, 1H),7.69 – 7.35 (m, 6H), 7.28 (d, J= 2.1 Hz, 1H), 7.05 (d, J= 9.0 Hz, 1H), 4.80 – 4.60 (m, 2H), 4.26 (d, J= 13.2 Hz, 2H), 4.16 (q, J= 6.9 Hz, 2H), 3.50 – 3.45 (m, 2H), 3.36 (s, 4H), 3.21 (t, J= 12.4 Hz, 3H), 3.11 (d, J= 12.0 Hz, 3H),2.98 – 2.82 (m, 5H), 2.81 – 2.60 (m, 4H), 2.55 (t, J= 4.3 Hz, 2H), 2.42 (d, J= 12.7 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Hz, 2H), 2.04 (d, J= 13.4 Hz, 2H), 2.00 – 1.84 (m, 3H), 1.83 – 1.60 (m, 5H), 1.39 (t, J= 6.9 Hz, 3H). MS: m/z [M+H] + 996. Prep-HPLC purification condition: Column: Aeris PEPTIDE 5um XB-C18 Axia, 21.2 mm X 250 mm, 5 μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 50% B in 6.5 min, 50% B; RT=6.75 min. Example 81. (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-y l)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [0459] A. Tert-butyl (4S)-5-amino-4-(6-bromo-1-oxo-isoindolin-2-yl)-5-oxo- pentanoate. To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (1 g, 3.25 mmol), tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate, hydrochloride (775.11 mg, 3.25 mmol) in DMF (30 mL) was added DIEA (1.74 mL, 9.74 mmol). The mixture was stirred at 60 °C for 16 h. It was cooled to rt, water was used to quench the reaction, extracted with EtOAc, washed with brine, combined the organic phase, dried over anhydrous sodium sulphate, filtered, concentrated, and purified by column chromatography to afford the desired product (1.2 g, 93% yield) as a white solid. MS: m/z [M+H] + 397. [0460] B. Benzyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-3-oxo- isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. To a 30 mL microwave vial, tert- butyl (4S)-5-amino-4-(6-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentano ate (330 mg, 0.83 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate (570.24 mg, 1.66 mmol), Pd(dppf)Cl2 (67.84 mg, 0.08 mmol), Na2CO3 (264.16 mg, 2.49 mmol) were suspended in 1,4-dioxane (20 mL) and Water (2 mL). The reaction was placed under vacuum, sonicated and backfilled with nitrogen. The resulting mixture was stirred at 100 °C for 4 h. It was concentrated, the crude was purified by column chromatography (PE:EtOAc=1:1 to EtOAc) to afford the desired product (400 mg, 90% yield) as a yellow solid. MS: m/z [M+H] + 534. [0461] C. Tert-butyl (4S)-5-amino-5-oxo-4-[1-oxo-6-(4-piperidyl)isoindolin-2- yl]pentanoate. A solution of benzyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-3- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (600 mg, 1.12 mmol) in Ethanol (20 mL) was placed under vacuum, sonicated and backfilled with nitrogen. Pd/C (100 mg) was added under N 2, and the reaction was placed under vacuum, sonicated and backfilled with H2. The mixture was stirred at rt for 4 h. It was filtered, washed with EtOH, concentrated to afford crude product (400 mg, 88.6% yield) as a yellow solid. MS: m/z [M+H] + 402. [0462] D. Tert-butyl (4S)-5-amino-4-[6-[1-(3-benzyloxy-3-oxo-propyl)-4-piperidyl] - 1-oxo-isoindolin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl (4S)-5-amino-5-oxo-4- [1-oxo-6-(4-piperidyl)isoindolin-2-yl]pentanoate (200 mg, 0.50 mmol), benzyl prop-2-enoate (161.58 mg, 1 mmol) in MeCN (1 mL) was added DBU (0.22 mL, 1.49 mmol). The mixture was stirred at rt for 4 h. It was concentrated and purified by reversed phase column chromatography to afford the desired product (180 mg, 64% yield) as a yellow oil. MS: m/z [M+H] + 564. [0463] E. (S)-3-(4-(2-(1-Amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3 - oxoisoindolin-5-yl)piperidin-1-yl)propanoic acid. To a solution of tert-butyl (4S)-5-amino- 4-[6-[1-(3-benzyloxy-3-oxo-propyl)-4-piperidyl]-1-oxo-isoind olin-2-yl]-5-oxo-pentanoate (175 mg, 0.31 mmol) in Ethanol (6 mL) was added Pd/C (30 mg) under N 2 . The reaction was placed under vacuum, sonicated and backfilled with H2. The mixture was stirred at rt for 6 h. It was filtered and concentrated to afford the crude product, which was used directly in the next step without further purification. MS: m/z [M+H] + 474. [0464] F. Tert-butyl (4S)-5-amino-4-[6-[1-[3-[4-[[1-[5-(3-cyano-6-ethoxy- pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[(2,5-difluorobenz oyl)amino]-4- piperidyl]methyl]piperazin-1-yl]-3-oxo-propyl]-4-piperidyl]- 1-oxo-isoindolin-2-yl]-5- oxo-pentanoate. To a solution of N-[1-[5-(1-cyano-6-ethoxy-indolizin-8-yl)-2-pyridyl]-4- (piperazin-1-ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (80 mg, 0.13 mmol), 3-[4-[2- [(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-3-oxo-isoindoli n-5-yl]-1-piperidyl]propanoic acid (63.18 mg, 0.13 mmol) in DMA (1 mL) were added HATU (76.09 mg, 0.20 mmol), and DIEA (51.63 mg, 0.40 mmol). The mixture was stirred at rt for 2 h. The crude was purified by reversed phase column chromatography to afford the desired product (80 mg, 56.8 % yield) as an off-white solid. MS: m/z [M+H] + 1057. [0465] G. N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[4- [3-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-3-oxo-isoindolin-5-yl] -1- piperidyl]propanoyl]piperazin-1-yl]methyl]-4-piperidyl]-2,5- difluoro-benzamide. To a solution of tert-butyl (4S)-5-amino-4-[6-[1-[3-[4-[[1-[5-(3-cyano-6-ethoxy-pyrazolo [1,5- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, a]pyridin-4-yl)-2-pyridyl]-4-[(2,5-difluorobenzoyl)amino]-4- piperidyl]methyl]piperazin-1- yl]-3-oxo-propyl]-4-piperidyl]-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (70 mg, 0.07 mmol) in MeCN (6 mL) was added triphosgene (62.9 mg, 0.40 mmol). The mixture was stirred at 60 °C for 20 h. The reaction was concentrated to afford the crude, which was purified by Prep-HPLC to afford the titled compound (49.4 mg, 74.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.45 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 8.9, 2.5 Hz, 1H), 7.61 - 7.59 (m, 2H), 7.55 - 7.47 (m, 2H), 7.43 - 7.37 (m, 2H), 7.29 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 - 4.42 (m, 1H), 4.43 - 4.41 (m, 1H), 4.34 - 4.32 (m, 1H), 4.29 - 4.24 (m, 2H), 3.92 - 3.71 (m, 3H), 3.68 - 3.61(m, 6H), 3.40 - 3.35 (m, 3H), 3.24 - 3.09 (m, 6H), 2.99 - 2.88 (m, 5H), 2.65 - 2.57 (m, 1H), 2.45 - 2.38 (m, 3H), 2.11 - 1.93 (m, 5H), 1.79 - 1.68 (m, 2H), 1.37 (t, J = 6.9 Hz, 3H). Analytical LCMS ESI-MS(+) m/z 982.5 [M+H] + , RT = 1.28 min, purity: 100% (Method Q). Prep-HPLC purification condition: Column: SunFire Prep C18 OBD Column, 19x150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 50% B in 6.5 min, 50% B; RT= 5.68 min. ee% = 96.6%, Analytical SFC: CHIRALPAK IA-33.0x50mm;3um, Co-Solvent: EtOH:DCM=1:1(0.5% 2M NH 3 -MeOH). Alternatively, the titled compound was obtained by chiral separation of Example 17. Example 82 (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-y l)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide and Example 81 (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-y l)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0466] Racemic Example 17 (50.0 mg) was purified via chiral preparative SFC chromatography with the following conditions: Column: Chiralcel OJ-H, 30 mm x 250 mm, 5μm particles; Mobile Phase A: CO2; Mobile Phase B: EtOH with 0.1% NH4OH / 0.1% formic acid; Isocratic elution at 38%B over 42 min; Flow Rate: 85 mL/min; Column Temperature: 45°C. Fraction collection was triggered by UV (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation. Chiral analytical SFC was used to determine the final purity. Conditions: Column: Chiralcel OJ-H, 4.6 mm x 150 mm, 5 μm particles; Mobile Phase A: CO2; Mobile Phase B: EtOH; Temperature: 45 °C; Isocratic elution at 40 %B over 20 min; Flow: 2 mL/min; Detection: UV (220 nm) and MS (ESI +). [0467] Concentration of the appropriate (earlier eluting) fractions afforded Example 82 (16.5 mg) assigned as (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2- yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin -5-yl)piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide (Enantiomer 1). Chiral analytical SFC Tr = 8.347 min; Purity = 99% (%ee = 100%). Analytical LCMS: m/z 982.3 [M+H] + , RT = 1.232 min (UHPLC Method D). Concentration of the appropriate (later eluting) fractions afforded Example 81 (20.9 mg) assigned as (S)-N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4- (2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)-piperazin-1-yl) methyl)piperidin-4-yl)-2,5- difluorobenzamide (Enantiomer 2). Chiral analytical SFC T r = 9.583 min; Purity = 95.2% (%ee = 90.3%). Analytical LCMS: m/z 982.6 [M+H] + , RT = 1.239 min (UHPLC Method D).
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 83. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(6-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)spi ro[3.3]heptane-2- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide [0468] A solution of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-di one (20.05 mg, 0.061 mmol), N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2- yl)-4-((4-(6-oxospiro[3.3]heptane-2-carbonyl)piperazin-1-yl) methyl)piperidin-4-yl)-2,5- difluorobenzamide (45 mg, 0.061 mmol), and AcOH (6.99 µl, 0.122 mmol) in DCE (2 mL) is heated to 80 °C with stirring. After 6 h the reaction is cooled to rt and sodium triacetoxyborohydride (38.8 mg, 0.183 mmol) was added. After 16 h the reaction is evaporated under reduced pressure and dried under high vacuum. The reaction mixture is diluted with DMF:Acetic acid (1:12 mL). The crude material was purified via preparative Reverse Phase chromatography to yield the titled compound (28 mg, 40 % yield). Analytical LCMS ESI-MS(+) m/z 1049.6 [M+H] + , RT = 1.31 min, purity: 100% (Method Q). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 - 10.90 (m, 1H), 8.67 - 8.61 (m, 1H), 8.60 - 8.54 (m, 1H), 8.35 - 8.29 (m, 1H), 8.15 - 8.08 (m, 1H), 7.79 - 7.73 (m, 1H), 7.56 - 7.48 (m, 1H), 7.39 - 7.30 (m, 3H), 7.30 - 7.24 (m, 1H), 7.10 - 7.03 (m, 1H), 7.01 - 6.92 (m, 1H), 5.11 - 4.98 (m, 1H), 4.38 - 4.29 (m, 1H), 4.45 - 4.06 (m, 5H), 3.24 - 3.11 (m, 2H), 2.96 - 2.84 (m, 1H), 2.75 - 2.69 (m, 2H), 2.64 - 2.56 (m, 1H), 2.56 - 2.53 (m, 3H), 2.50 - 2.42 (m, 4H), 2.44 - 2.37 (m, 2H), 2.37 - 2.30 (m, 2H), 2.30 - 2.22 (m, 1H), 2.21 - 2.16 (m, 1H), 2.15 - 2.07 (m, 1H), 2.07 - 1.93 (m, 3H), 1.92 - 1.83 (m, 1H), 1.82 - 1.72 (m, 1H), 1.68 - 1.56 (m, 2H), 1.43 - 1.35 (m, 3H) 6 methylenes are missing due to water suppression. [0469] Examples 84-99 were prepared using procedures similar to the ones described in the aforementioned examples. Example 84 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 6-(4-{[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyr idin-2-yl)-4-(2,5- difluorobenzamido)piperidin-4-yl]methyl}piperazine-1-carbony l)-N-[3-(2,4-dioxo-1,3- diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2- carboxamide Example 85 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl} piperidin-4-yl]-2,5- difluorobenzamide Example 86 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl} piperidin-4-yl]-2,5- difluorobenzamide Example 87 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Example 88 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Example 89 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[6-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}propanoyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluo robenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 90 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9 -diazaspiro[5.5]undecan-3- yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-di fluorobenzamide Example 91 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9 -diazaspiro[5.5]undecan-3- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 92 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperi din-4-yl]-2,5- difluorobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}spir o[3.3]heptane-2- carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorob enzamide Example 94 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperid in-4-yl]-2,5- difluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperid in-4-yl]-2,5- difluorobenzamide Example 96 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({9-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]-3,9- diazaspiro[5.5]undecan-3-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide Example 97 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[6-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluo robenzamide Example 98 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(9-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}-3,9- diazaspiro[5.5]undecan-3-yl)methyl]piperidin-4-yl]-2,5-diflu orobenzamide Example 99 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0470] Examples 100-135 were prepared using procedures similar to the ones described in the aforementioned examples. Example 100 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide Example 101 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperidin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 102 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(2-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]carbamoyl} ethoxy)ethyl]piperazin-1- yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide Example 103 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 104 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(2-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1- yl}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2, 5-difluorobenzamide Example 105 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(2-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}etho xy)propanoyl]piperazin- 1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 106 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide Example 107 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 108 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]carbamoyl}ethoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piper idin-4-yl]-2,5- difluorobenzamide Example 109 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl}-3- oxopropoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl ]-2,5-difluorobenzamide Example 110 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-({1-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]piperidin-4- yl}methyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide Example 111 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acet yl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide Example 113 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{[1-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)piperidin-4- yl]methyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluoro benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 115 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide Example 116 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide Example 117 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] piperidin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(4-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} piperidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{3-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]azet idin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Example 120 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(3-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} azetidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 125 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin- 1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 126 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin- 1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 127 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4- [(methylamino)methyl]piperidin-4-yl]-2,5-difluorobenzamide Example 128 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-methylp iperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 129 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylp iperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 130 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 131 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 132 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 133 4-[6-(4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihyd ro-1H-isoindol-5- yl]oxy}acetyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)p yridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile Example 134 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-(9-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5. 5]undecane-3- carbonyl)piperidin-4-yl)-2,5-difluorobenzamide
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 135 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{4-[2-(1- methyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo l-5-yl]piperazin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0471] Examples 136-171 were prepared using procedures similar to the ones described in the aforementioned examples. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT,
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Cellular RET Degradation Assay [0472] Cellular RET degradation compound potency was determined using the bead- based luminescent amplification assay – AlphaLISA Surefire Ultra Detection Kit (Perkin- Elmer). The CCDC6-RET fusion expressing papillary thyroid carcinoma (TPC-1) cell line was selected for screening of potential degraders: Parental (TPC-1/CCDC6-RET). Cells were plated in 384 well culture plates (Greiner Bio-One) at 10,000 cells/well in 50ul/well DMEM (Fisher Scientific) with 2% FBS serum (Gibco). After cellular adhesion (4 hrs), cells were treated with compound by dispensing 25nl of serially diluted compound (1:3 dilution: 11point) directly into the cell culture wells using an Echo-655 acoustic liquid dispenser (Beckman). Low normalization wells were media only and high normalization wells were cells treated with DMSO only. Treated cell plates were placed in an incubator at 37 ⁰C and 5% CO2 for 24 hrs. At 24 hrs, cell media was removed by a FELIX automated liquid hander Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, (Analytik Jena) and 25ul of cell lysis buffer (provided in AlphaLisa kit) was added to each well. 5ul cell lysate were transferred into a 384-well microplate (Perkin Elmer) before addition of 2.5ul AlphaLISA Acceptor Bead mix. The plates were sealed and kept at room temperature for 1hr before addition of donor bead mixture. Donor bead addition was performed in the dark and incubated for >1 hr before AlphaLISA luminescence was measured on an Envision plate reader with an Alphascreen aperture at RT (excitation 680 nm, emission 615 nm). RET protein abundance (and therefore degradation) directly corresponds to luminescence intensity. [0473] Intensities were normalized relative to the average values from 16 wells containing media alone (blank-low) and 16 wells containing cells +DMSO (high). % Degradation for each well was determined using the standard equation, where % ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ = × 100. DC 50 (IC50) values for each compound tested are calculated by analyzing plots of % degradation versus compound concentration, and fitting to the standard 4-parameter logistic curve where, % ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ = ^^ ^^ ^^ ^^ ^^ ^^ + [ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^] ^^×( ^^ ^^ ^^− ^^ ^^ ^^ ^^ ^^ ^^) ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^+[ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^] ^^ . and bottom are the % degradation at infinitely large and infinitely small compound concentrations, respectively, while Halfmax is the compound concentration yielding % degradation corresponding to ½ Top-Bottom, and N is the Hill coefficient. DC50 values are calculated according to the relationship, ^^ ^^ 50 = Compound replicates were performed in independent assays. Maximum degradation (YMax) was defined as the maximal % degradation value from the 4- parameter logistic equation, as previously described. Activity Table. [0474] Each of the compounds in Table 2, was tested in one or more of the degradation assays shown above, for example, the tRET AlphaLISA Degradation Assay with the parental RET TPC-1 cell line, and was found to have activity therein. The half-maximal degradation concentration (DC 50 ) and % degradation response (Ymax) are included in Table 2. All of the compounds in Table 2 were shown to have a DC50< 1 µM and Ymax >60%, with some compounds having a DC50 value D: DC50 ≤ 2 nM, some a DC50 value C: 2 nM < DC50 ≤ 10 nM, and some a DC 50 value B: 10 nM < DC 50 ≤ 100 nM and some a DC 50 value A: 100 nM < DC 50 ≤ 2000 nM. Additionally the compounds were shown to have a RET degradation efficiency Y value >60%, with some compounds having 60% < Y ≤ 90 % (shown as *), some compounds having Y >90 % (shown as **). Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Table 2 Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC 50 1/CCDC6-RET Ymax % (nM) 2 C * 3 C ** 4 C ** 5 C ** 6 C ** 7 C ** 8 C ** 9 C ** 10 D * 11 D * 12 D ** 13 D ** 14 C * 15 C ** 16 C ** 17 C ** 18 D ** 19 C ** 20 C ** 21 B * 22 B * 23 B ** 24 B * 25 C ** 26 C ** 27 C * 28 B * 29 B ** 30 A * Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC50 1/CCDC6-RET Ymax % (nM) 31 C * 32 B * 33 C * 34 B ** 35 B ** 36 C * 37 B * 38 D ** 39 D * 40 C ** 41 D ** 42 D 43 D ** 44 D * 45 D 47 C ** 48 C ** 49 C ** 50 C * 51 B * 52 C ** 53 B * 54 A * 55 C * 56 C * 57 A * 58 D ** 59 D ** 60 D ** 61 B * Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC50 1/CCDC6-RET Ymax % (nM) 62 C * 63 C * 64 D ** 65 C * 66 D * 67 C * 69 D ** 70 D ** 71 D ** 72 B ** 74 D ** 76 B * 77 D * 78 D ** 81 D ** 82 D ** 83 D ** 84 D ** 85 D * 86 D ** 87 C ** 88 B ** 89 B ** 90 B ** 91 D * 92 C ** 93 C ** 94 C * 95 C * 96 B * Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC50 1/CCDC6-RET Ymax % (nM) 97 C * 98 C ** 99 D * 100 C ** 101 B ** 103 B ** 104 C * 105 C * 108 B * 109 B * 110 C * 111 C * 112 C ** 113 D ** 114 D * 115 B * 116 C ** 117 C ** 118 C * 119 C ** 120 D ** 121 B ** 122 C ** 123 C ** 124 D ** 125 B ** 126 A * 128 A * 129 A * 137 C ** Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC50 1/CCDC6-RET Ymax % (nM) 138 NA NA 139 B ** 140 C ** 142 A NA 143 C ** 145 C * 146 B ** 147 B * 148 C * 149 D ** 150 B ** 152 C * 153 C ** 154 B * 155 D * 156 C * 157 C ** 158 D * 159 C * 160 C ** 161 D * 162 B * 163 C * 164 C ** 165 D ** 166 C * 167 C * 168 C ** 169 B * 170 A * Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example # Cell Density TPC- Cell Density TPC- 1/CCDC6-RET DC50 1/CCDC6-RET Ymax % (nM) 171 C **
Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, EMBODIMENTS Embodiment 1. A compound of Formula I: or a pharmaceutically acceptable salt, solvate, isomer, enantiomer, or tautomer thereof, wherein R 1 is –OCH 3 , –OCH 2 CH 3 , –OCF 3 , –OCH 2 CH 2 OH, –OCH 2 CH 2 F, halogen, or 1-methyl- pyrazol-4-yl; A is independently H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more R 2 ; wherein R 2 is independently halogen, OH, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy; B is a moiety that is capable of binding a E3 ligase; L 1 is independently a bond, –C 1 -C 3 alkylenyl–, –NHCO–, –CONH–, –O–, or –NH–; L 2 is independently –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –C(O)–Y 2 –, –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–Y2–, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–C(O)–Y 1 –C(O)-Y 2 –, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –Y 2 –, –(OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y2–, –(CH2OCH2C(O))p–(4- to 12-heterocycloalkyl)–Y2–, –(CH 2 OCH 2 C(O)NH) p –Y 2 –, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –(CH 2 CH 2 O) p –C(O)–Y 2 –, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–(CH2CH2O)p–Y2–, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –(OCH 2 CH 2 ) p –Y 2 –, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –(OCH 2 CH 2 ) p –C(O)–(OCH 2 CH 2 ) p –Y 2 –, –(CH2OCH2)p–(heteroaryl)–Y2–, –NHC(O)–(4- to 12-heterocycloalkyl)–Y 1 -C(O)–Y 2 –, –NHC(O)–(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 -C(O)–Y 2 –, –NHC(O)–(CH2)p–(4- to 12-heterocycloalkyl)–Y2–, –C(O)NH–Y1–Y2–; –(CH 2 ) p –NH–Y 1 –Y 2 –; –C(O)NH–(CH2CH2O)p–Y2–, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, –C(O)–(CH2CH2O)p–Y2–, –(CH2OCH2)p–NR3C(O)–(CH2CH2O)p–Y2–, –(CH 2 ) p –NR 3 C(O)–(CH 2 CH 2 O) p –Y 2 –, –(CH2OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y1–C(O)–(CH2CH2O)p–Y2–, or –(CH2OCH2)p–C(O)NH–(CH2CH2O)p–Y2–, wherein R 3 is –H or –C 1 -C 3 alkyl, Y1 is independently a bond, –C1-8 alkylenyl, 4- to 12-membered heterocycloalkyl, or –C3-C10 cycloalkyl; Y 2 is independently a bond, –C1-C3 alkyl–, –(CH 2 ) m –O–, –O–(CH2)m–(4- to 6-membered heterocycloalkyl), –(CH2)m–O–(CH2)m–NH–, –(CH 2 ) m –NH–, –(CH 2 ) m –NHC(O)–(CH 2 ) m O–, –(CH2)m–C(O)NH–(CH2)m–, –(CH2)m–C3-C10 cycloalkyl–, –(CH 2 ) m –aryl, –(CH2)m–heteroaryl–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–, –(CH 2 ) m –(4- to 6-membered heterocycloalkyl)–C(O)–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–O–, –(CH 2 ) m –C 3 -C 10 cycloalkyl–C(O)NH–, or –(CH 2 ) m –(4- to 6-membered heterocycloalkyl)–O–, X1 is CH or N; X2 is CH or N; m is independently at each occurrence an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. Embodiment 2. The compound according to Embodiment 1, wherein the compound has Formula I(a): Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein Het A is 4- to 6-membered heterocycloalkyl. Embodiment 3. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(b): wherein Het A is 4- to 6-membered heterocycloalkyl. Embodiment 4. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(c): wherein Het A is 4- to 6-membered heterocycloalkyl. Embodiment 5. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(d): wherein Het A is 4- to 6-membered heterocycloalkyl. Embodiment 6. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(e): wherein Het A is 4- to 6-membered heterocycloalkyl. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Embodiment 7. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(f): wherein Het A is 4- to 6-membered heterocycloalkyl. Embodiment 8. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(g): Embodiment 9. The compound according to any one of the preceding embodiments, wherein the compound has Formula I(h): I(h). Embodiment 10. The compound according to any one of the preceding embodiments, wherein L1 is –CONH–. Embodiment 11. The compound according to any one of the preceding embodiments, wherein L 1 is –NHC(O)–. Embodiment 12. The compound according to any one of the preceding embodiments, wherein X 1 is CH. Embodiment 13. The compound according to any one of the preceding embodiments, wherein X2 is N. Embodiment 14. The compound according to any one of the preceding embodiments, wherein R 1 is –OCH 2 CH 3 . Embodiment 15. The compound according to any one of the preceding embodiments, wherein moiety B capable of binding a E3 ligase is of the structure: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Embodiment 16. The compound according to any one of the preceding embodiments, wherein moiety B capable of binding a E3 ligase is of the structure: , wherein A is of the structure: . Embodiment 18. The compound according to any one of the preceding embodiments, wherein the compound is selected from: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hep tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hep tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hep tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6 dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pen tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ace tyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hep tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pen tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)hep tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pen tanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)but anoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]me thyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[4-(2,6- dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]met hyl}piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[7-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1 -yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[9-({3-[(2,6- dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1- yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nona noyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(9-{[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl )piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[5-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4 -yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[7-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4 -yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[11-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin- 4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[13-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin -4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[15-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)piperid in-4-yl]-2,5- difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]buty lamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propan oyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]prop anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]prop anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[5-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pent anoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[4-[[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl] piperazin-1-yl] methyl]-1-piperidyl]-2-oxo- ethoxy] methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propyl ]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[2-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexy lamino]-2-oxo- ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(5-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(7-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(6-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperazin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluoro benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidin-1- yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluo robenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyr idyl]-4-[[1-[6-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexy l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[4-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]buty l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4-[[1-[2-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethy l]triazol-4- yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-(((1-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pro pyl)-1H-1,2,3-triazol-4- yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4- piperidyl]-4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindol in-5-yl]-1- piperidyl]propanoyl]piperazine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4- piperidyl]-1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindol in-5-yl]-1- piperidyl]propanoyl]piperidine-4-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4- piperidyl]-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoin dolin-5-yl]-1- piperidyl]propanoyl]piperazin-1-yl]acetamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4- yl)-2-pyridyl]-4- piperidyl]-2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoin dolin-5-yl]-1- piperidyl]propanoyl]-4-piperidyl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-apyridin-4-y l)-2-pyridyl]-4-piperidyl]- 4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-pi peridyl]methyl]piperidine-1- carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-4-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin- 5-yl]-1-piperidyl] piperidine- 1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a] pyridin-4-yl)-2-pyridyl]-4- piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindo lin-5-yl]-1-piperidyl]methyl]- 1-piperidyl]acetamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)pi perazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)pi perazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazi n-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(3-(2,6- dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazi n-1-yl)methyl)piperidin-4- yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(1-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}azetidin-3-yl)piperazin- 1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]azetidin-3-yl}piperazin- 1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{1-[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbonyl]aze tidin-3-yl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[1-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]oxy}acetyl)azetidin-3- yl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzami de; N-[4-benzyl-1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-y l}pyridin-2-yl)piperidin- 4-yl]-1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro -1H-isoindol-5-yl]piperidin- 1-yl}propanoyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pip eridin-1-yl)methyl)piperidin- 4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidine-1-carbonyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidin-1-yl)piperidin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-((3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)aze tidin-1-yl)methyl)piperidin- 1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)piperidin-4-yl)-1-fluorocyclopropane-1-carboxamide ; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)cyc lobutane-1- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(1-(1-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)aze tidin-3-yl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pro panoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-(3-Cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pro panoyl)piperazin-1- yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridin‐4 ‐yl}pyridin‐2‐yl)‐4‐{[4‐(3‐{4‐[2‐(2,6‐ dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperidin‐1‐ yl}propanoyl)piperazin‐1‐yl]methyl}‐N‐(2‐methylpro pyl)piperidine‐4‐carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) piperidine-4- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(3-(4-(2-(3- methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperid in-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-diflu orobenzamide; (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-y l)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-y l)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-((4-(6-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)spi ro[3.3]heptane-2- carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorob enzamide; 6-(4-{[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyr idin-2-yl)-4-(2,5- difluorobenzamido)piperidin-4-yl]methyl}piperazine-1-carbony l)-N-[3-(2,4-dioxo-1,3- diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2- carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl} piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl} piperidin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}propanoyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[6-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}propanoyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluo robenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9 -diazaspiro[5.5]undecan-3- yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-di fluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{9-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9 -diazaspiro[5.5]undecan-3- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1- yl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperi din-4-yl]-2,5- difluorobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{[3-(2,4- dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}spir o[3.3]heptane-2- carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorob enzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperid in-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(6-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridine-1- carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperid in-4-yl]-2,5- difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({9-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]-3,9- diazaspiro[5.5]undecan-3-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[6-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)-2,6- diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluo robenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(9-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}-3,9- diazaspiro[5.5]undecan-3-yl)methyl]piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)-3,9- diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperidin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]carbamoyl}ethoxy)ethyl]piperazin-1-yl}methyl)piperidin-4- yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[2-(3-{4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl}-3- oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-d ifluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(2-{4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1- yl}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2, 5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]amino}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4- yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acet yl}piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(2-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy} acetyl)piperazin-1- yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(2-{[3- (2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]carbamoyl}ethoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piper idin-4-yl]-2,5- difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{2-[2-(3-{4- [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5 -yl]piperazin-1-yl}-3- oxopropoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl ]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-({1-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbon yl]piperidin-4- yl}methyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl ]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[(1-{2-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ]acetyl}piperidin-4- yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(4-{[1-(2-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]oxy}acetyl)piperidin-4- yl]methyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] piperidin-1-yl}-3- oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluoro benzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(4-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]oxy}piperidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(3-{3-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]azet idin-1- yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-({4-[3-(3-{[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]oxy}azetidin-1- yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[9-(2-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-2-oxoethyl)-3- azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluor obenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin- 1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin- 1-yl)pyridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4- [(methylamino)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-methylp iperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylp iperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpi peridin-1-yl)pyridin-3-yl]- 6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihyd ro-1H-isoindol-5- yl]oxy}acetyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)p yridin-3-yl]-6- ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin -2-yl)-4-(9-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5. 5]undecane-3- carbonyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-{[4-(7-{4-[2-(1- methyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo l-5-yl]piperazin-1- yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-diflu orobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N- methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzami de; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dih ydro-1H-isoindol-5- yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylp iperidin-1-yl)pyridin-3- yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1- methyl-1H-indazol-7- yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1 -methyl-1H-indazol-7- yl]amino}decyl)piperidine-4-carboxamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1- methyl-1H-indazol-6- yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(8-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1- methyl-1H-indazol-6- yl]amino}octyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1 -methyl-1H-indazol-6- yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-ox o-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-ox o-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-ox o-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-ox o-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2- yl)-4-(2,5- difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-ox o-2,3-dihydro-1H- isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(3-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N-(propan-2- yl)propanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe razin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(5-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N-(propan-2- yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridi n‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6 dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperidin‐1‐yl}‐2‐oxoethyl)‐3- azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2 ,5‐difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridi n‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6 dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperidin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2 ,5‐difluorobenzamide; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridi n‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6 dioxopiperidin‐3‐yl)‐3‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperazin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2 ,5‐difluorobenzamide; N‐[1‐(5‐{3‐cyano‐6‐ethoxypyrazolo[1,5‐a]pyridi n‐4‐yl}pyridin‐2‐yl)‐4‐[9‐(2‐{4‐[2‐(2,6 dioxopiperidin‐3‐yl)‐1‐oxo‐2,3‐dihydro‐1H‐is oindol‐5‐yl]piperazin‐1‐yl}‐2‐oxoethyl)‐3‐ azaspiro[5.5]undecane‐3‐carbonyl]piperidin‐4‐yl]‐2 ,5‐difluorobenzamide; (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(7-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-y l)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyr idin-2-yl)-4-((4-(7-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-y l)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; or N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin -2-yl)-4-[(7-{4-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]pipe ridin-1-yl}-N-(propan-2- yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide. Embodiment 19. A compound of Formula II: and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and tautomers thereof, wherein R 1 is –OCH 2 CH 3 , –OCH 3 , –OCF 3 , –OCH 2 CH 2 OH, –OCH 2 CH 2 F, 1-methylpyrazol-4-yl, or halogen; A1 is independently aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 2 ; wherein R 2 is independently halogen, OH, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy; B is a moiety that is capable of binding a E3 ligase; L 4 is independently –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –C(O)–Y 2 –, –(CH 2 ) p –(4- to 12-heterocycloalkyl)–C(O)–Y 1 –Y 2 –, –(CH2)p–(4- to 12-heterocycloalkyl)–Y1–Y2–, wherein Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Y1 is independently –C1-8 alkylenyl, 4- to 12-membered heterocycloalkyl, or – C3-C10 cycloalkyl; Y 2 is independently –C1-C3 alkyl–, –(CH2)m–O–, –O–(CH 2 ) m –(4- to 6-membered heterocycloalkyl), –(CH 2 ) m –(4- to 6-membered heterocycloalkyl)–, –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–, or –(CH2)m–(4- to 6-membered heterocycloalkyl)–O–, L 3 is a bond, –C 1-8 alkylenyl, 4- to 8-membered heterocycloalkyl, –C 3 -C 10 cycloalkyl, or –(4- to 8-membered heterocycloalkyl)–(CH2)m–; X1 is CH or N; X 2 is CH or N; X7 is O, S, NH, or a bond; m is independently at each occurrence an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. Embodiment 20. The compound according to any one of the preceding embodiments, wherein the compound is selected from: 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐ 1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐ 1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐ 1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(5‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐ 1‐ yl}pentanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐ 1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperazin‐ 1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; 6‐{[1‐(3‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐ 1‐ yl}propanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile; or 6‐{[1‐(7‐{4‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐3 ‐oxo‐2,3‐dihydro‐1H‐isoindol‐5‐yl]piperidin‐ 1‐ yl}heptanoyl)piperidin‐4‐yl]methoxy}‐4‐{6‐[(1R,5S) ‐6‐[(6‐methoxypyridin‐3‐yl)methyl]‐ 3,6‐diazabicyclo[3.1.1]heptan‐3‐yl]pyridin‐3‐yl}py razolo[1,5‐a]pyridine‐3‐carbonitrile. Embodiment 21. A pharmaceutical composition comprising a compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Embodiment 22. A method of treating a RET mediated disorder comprising administering an effective amount of a compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a patient in need thereof. Embodiment 23. The method according to any one of the preceding embodiments, wherein the patient is a human. Embodiment 24. The method according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer. Embodiment 25. The method according to any one of the preceding embodiments, wherein the cancer is non-small cell lung cancer. Embodiment 26. The method according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain. Embodiment 27. The method according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET. Embodiment 28. The method according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer. Embodiment 29. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder. Embodiment 30. The compound according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Embodiment 31. The compound according to any one of the preceding embodiments, wherein the cancer is non-small cell lung cancer. Embodiment 32. The compound according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain. Embodiment 33. The compound according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET. Embodiment 34. The compound according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer. Embodiment 35. The use of a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET mediated disorder. Embodiment 36. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer. Embodiment 37. The use according to any one of the preceding embodiments, wherein the cancer is non-small cell lung cancer. Embodiment 38. The use according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain. Embodiment 39. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET. Embodiment 40. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer. Embodiment 41. The use of a compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET mediated disorder. Embodiment 42. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer. Embodiment 43. The use according to any one of the preceding embodiments wherein the cancer is non-small cell lung cancer., Embodiment 44. The use according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain. Embodiment 45. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Embodiment 46. The use according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer. Equivalents [0475] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [0476] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.