IP Library › Granted Patent US 11,739,101

Granted Patent B2

US 11,739,101 · App. 17/308,879 · Granted Aug 29, 2023

Bifunctional degraders of hematopoietic progenitor kinase and therapeutic uses thereof

Inventors: Hunter P. Shunatona (San Francisco, CA); Galen Paul Shearn-Nance (San Francisco, CA); Scott A. Mitchell (Foster City, CA); John Buell (San Francisco, CA)

Assignees: Nurix Therapeutics, Inc.; Gilead Sciences, Inc.

C07D519/00

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Quick Facts

Patent No.: US 11,739,101
App. No.: 17/308,879
Granted: Aug 29, 2023
Kind: B2

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Abstract

The present disclosure provides bifunctional compounds as HPK1 degraders via ubiquitin proteosome pathway, and method for treating diseases modulated by HPK1.

Claims (365)

1. A compound having the following structure (I):

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, 4, 5, or 6;

A is a C 3-7 monocyclic cycloalkyl ring or a 4-6 membered monocyclic heterocyclyl ring having 1 or 2 heteroatoms independently selected from N, O, and S;

L is a linker moiety having a length of 2-24 continuously covalently bonded atoms selected from the group consisting of C, O, N and S;

LHM is a ligase harness moiety;

R 11 is

i) selected from the group consisting of —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy; or

ii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,

iii) —S(O) 2 C 1-6 alkyl,

iv) —S(O) 2 C 3-7 monocyclic cycloalkyl,

v) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or

vi) —C(O)R 21 ;

each R 12 is independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;

R 21 is

i) H,

ii) C 3-7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,

iii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,

iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

v) —NH 2 ,

vi) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy,

vii) —N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy,

viii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl, or

ix) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from

a) —CN,

b) —OH,

c) halogen,

d) C 1-3 alkoxy,

e) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

f) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy, and

g) —OC(O)C 1-6 alkyl optionally substituted with one —OH;

R 3 and R 13 are each H, or

R 3 and R 13 together form ═O;

X is —NR 15 R 16 , wherein R 15 and R 16 are independently

i) H,

ii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

iii) 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,

iv) —C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy, or

v) C 1-6 alkyl optionally substituted with 1-6 groups independently selected from

a) —CN,

b) —OH,

c) halogen,

d) C 1-3 alkoxy,

e) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and

f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5 R 18 ;

each R 18 is independently

i) —CN,

ii) a halogen,

iii) —OH,

iv) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

v) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

vi) —COOH, or

vii) —C(O)N(R 22 ) 2 , wherein each R 22 is independently H or C 1-6 alkyl;

X 1 is N or CR 17 ;

R 4 , R 5 , R 6 , R 10 and R 17 are each independently H, halogen, C 1-3 alkyl, or C 1-3 alkoxy;

R 7 is

i) H,

ii) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or

iii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;

Z is —O—, —C(R 8 ) 2 —, or —NR 8 —;

each R 8 is independently H or C 1-3 alkyl;

R 9a , R 9b , R 9c , R 9d , and R 9e are independently

i) H,

ii) halogen,

iii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl,

iv) —NH 2 ,

v) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,

vi) —N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different, and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,

vii) —P(O)(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different, and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,

viii) —S(O) 2 C 1-6 alkyl,

ix) —S(O) 2 N(R 23 ) 2 , wherein each R 23 is independently H or C 1-6 alkyl,

x) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from

a) —OH,

b) halogen,

c) C 1-3 alkoxy,

d) C 3-7 monocyclic cycloalkyl,

e) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C 1-3 alkyl, and

f) —NR 20 C(O)OC 1-3 alkyl, wherein R 20 is H or C 1-3 alkyl,

xi) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

xii) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

xiii) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,

xiv) —COOH,

xv) —C(O)N(R 19 ) 2 , or

xvi) —C 1-3 alkylene-C(O)N(R 19 ) 2 ,

wherein one or more of R 9a , R 9b , R 9c , R 9d , and R 9e is —C(O)N(R 19 ) 2 or —C 1-3 alkylene-C(O)N(R 19 ) 2 ; and

each R 19 is independently

i) H,

ii) —S(O) 2 C 1-6 alkyl,

iii) C 1-6 alkyl optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

iv) C 3-7 monocyclic cycloalkyl optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, C 1-6 alkyl, and C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy, or

v) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy.

2. The compound of claim 1 wherein, Z is NH, X 1 is CH, R 6 is H, and the compound has a structure of Formula (Ia):

3. The compound of claim 1 wherein the compound has a structure of Formula (Ib):

4. The compound of claim 3 wherein R 3 and R 13 together form ═O.

5. The compound of claim 3 wherein X is piperdinyl.

6. The compound of claim 3 wherein n is 0 and m is 0.

7. The compound of claim 3 ,

wherein

each R 9a , R 9b , R 9c , R 9d , and R 9e is independently H, halogen, C 1-6 alkyl, or —C(O)N(R 19 ) 2 , wherein R 19 is C 1-6 alkyl;

R 4 , R 5 and R 10 are each H; and

R 7 is C 1-6 alkyl.

8. The compound of claim/wherein the compound has a structure of Formula (Ic):

9. The compound of claim 1 , wherein L is

wherein,

t is 0, 1, 2, 3, 4, 5, 6, or 7;

q is 0, 1, 2, 3, 4, 5, 6, or 7;

L 1 is a direct bond, —C(O)NH—, or —C(O)—; and

L 2 is —C(O)NH—, —O—, or —NH—.

10. The compound of claim 9 , wherein L has one of the following structures:

11. The compound of claim 1 , wherein L is

wherein,

w is 1, 2, or 3;

v is 1 or 2;

p is 1, 2, 3, 4, or 5;

Y 1 is a direct bond, —(CH 2 ) p —, or —O—;

Y 2 is a direct bond, —(CH 2 ) p —, —C(O)—, or —C(O)—CH 2 —,

X 3 and X 4 are independently N or C(R), wherein R is H or C 1-3 alkyl;

L 4 is a direct bond, —NH—, —NHC(O)—, or

12. The compound of claim 11 , wherein L has one of the following structures:

13. The compound of claim 1 , wherein L is any one of the following structures:

14. The compound of claim 1 , wherein the LHM targets CRBN and has a structure of Formula (Id):

wherein,

W is —C(R g )— or —N—;

Z 1 is —C(O)—, —C(S)—, —C(NR g )—, —C(R g ) 2 —, —C(R g ) 2 —C(O)—, —C(O)—N(R g )—, —CR g ═CR g —, —C(R g )═N—, —C(R g ) 2 —C(S)—, or —C(R g ) 2 —C(R g ) 2 —;

q is 0, 1 or 2;

R g is hydrogen or C 1-6 alkyl; and

R a is C 1-6 alkyl, halo, halo C 1-6 alkyl, —N(R g ) 2 , CN, nitro, —O—C 1-4 alkyl, or hydroxyl.

15. The compound of claim 14 wherein the LHM has one of the following structures:

16. The compound of claim 1 wherein the LHM targets VHL and has a structure of Formula (Ie) or (If):

wherein,

p is 0 or 1;

R j is 5-6 member heteroaryl optionally substituted with 1 to 3 R k ,

each R k is independently halo, oxo, —CN, —OH, C 1-6 alkyl, C 3-8 cycloalkyl, or —O—C 1-6 alkyl;

each R e is independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;

R g is hydrogen or C 1-6 alkyl;

R b is hydrogen or hydroxyl; and

R c is —C(O)R f , wherein R f is C 1-6 alkyl or C 3-8 cycloalkyl, each being optionally substituted with halo or —CN.

17. The compound of claim 16 wherein the LHM has one of the following structures:

18. The compound of claim 16 wherein the LHM has one of the following structures:

19. The compound of claim 1 selected from the group consisting of:

5-((6-(1′-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

(2S,4R)—N-(2-((10-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-10-oxodecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(11-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

(2S,4R)—N-(2-(2-(2-(2-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-3-oxopropoxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

5-((6-(1′-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

(2S,4R)—N-(2-((8-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-8-oxooctyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(2-(4-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-3-oxopropyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(2-(4-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-2-oxoethyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(1-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-2-oxoethyl)piperidin-4-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(1-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-3-oxopropyl)piperidin-4-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

5-{[6-(1′-{2-[4-(3-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}propyl)piperazin-1-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[2-(2-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[2-(4-{2-[(3RS)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-4-yl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[(3RS)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidine-4-carbonyl)pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1′-[1-[(1s,4s)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-[(6-{1′-[2-(7-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-2-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{2-[(3S)-1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]pyrrolidin-3-yl}methyl)piperidin-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1′-[1-[(1s,3s)-3-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclobutanecarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-{[6-(1′-{2-[(3S)-1-{[1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}pyrrolidin-3-yl]methyl}piperidin-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-({6-[1′-(1-{2-[(3S)-1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-3-yl]acetyl}pyrrolidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)methyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[2-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)acetyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-({6-[1′-(1-{[1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}pyrrolidin-3-yl]methyl}azetidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[2-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)methyl]pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidine-4-carbonyl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidine-4-carbonyl)pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidine-4-carbonyl)piperidine-4-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[2-(7-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-2-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[23-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)-3,6,9,12,15,18,21-heptaoxatricosan-1-yl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-({6-[1′-(2-{4-[4-({[2-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)ethyl]carbamoyl}methyl)phenyl]piperazin-1-yl}acetyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-7-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-2-oxoethyl)-7-azaspiro[3.5]nonane-2-carboxamide;

(2S,4R)-1-[(2S)-2-(2-{4-[4-(2-{6-[4-({2-fluoro-4-methyl-5-[(propan-2-yl)carbamoyl]phenyl}amino)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}-2-oxoethyl)phenyl]piperazin-1-yl}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;

(2S,4R)-1-((2S)-2-(2-(3-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-1′-yl)-3-oxopropyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

5-[(6-{1′-[1-{1-[2-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)acetyl]piperidine-4-carbonyl}pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1′-[(1s,4s)-4-[4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)piperidine-1-carbonyl]cyclohexanecarbonyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[(1r,4r)-4-[4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)piperidine-1-carbonyl]cyclohexanecarbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[(3R)-1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-[(6-{1′-[3-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[(3R)-1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-vi)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperidine-4-carbonyl)piperidin-4-yl 6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridin-6-yl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidine]-1′-carboxylate;

4-fluoro-2-methyl-5-{[6-(2-oxo-1′-{2-[(3S)-1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]pyrrolidin-3-yl]acetyl}-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-{[6-(2-oxo-1′-{2-[(3R)-1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]pyrrolidin-3-yl]acetyl}-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-N-(propan-2-yl)benzamide;

5-[(6-{1′-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}sulfonyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-{[6-(2-oxo-1′-{1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexanecarbonyl]piperidine-4-carbonyl}-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-({6-[1′-(4-{methyl[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}cyclohexyl]carbamoyl}benzoyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl}amino)-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1′-[(1s,4s)-4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino}piperidine-1-carbonyl)cyclohexanecarbonyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-{[6-(1′-{4-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidin-4-yl)oxy]benzoyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{4-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-4-yl)oxy]benzoyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[i-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}methyl)piperidin-4-yl]-1H-pyrazole-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-{[6-(2-oxo-1′-{1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}(methyl)amino)cyclohexanecarbonyl]piperidine-4-carbonyl}-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[(3R)-1-[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-{[6-(1′-{1-[4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)piperidine-1-carbonyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[(3R)-1-[4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)piperidine-1-carbonyl]pyrrolidine-3-carbonyl-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-({6-[2-oxo-1′-(1-{[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexyl]methyl}-1H-pyrazole-4-carbonyl)-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl}amino)-N-(propan-2-yl)benzamide;

5-[(6-{1′-[2-chloro-4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperazine-1-carbonyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-2-methylpiperazine-1-carbonyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

4-fluoro-2-methyl-5-[(6-{2-oxo-1′-[(3R)-1-{[(1r,4r)-4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)cyclohexyl]methyl}pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-N-(propan-2-yl)benzamide;

5-[(6-{1′-[1-(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl}-3-isopropylimidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-N-isopropyl-2-methylbenzamide;

5-[(6-{1′-[4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}piperidine-1-carbonyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-[(6-{1′-[4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}piperidine-1-carbonyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-{[6-(1′-{4-[4-({2-[2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}methyl)piperidine-1-carbonyl]benzoyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide;

5-((6-(1′-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)benzoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-((1s,4S)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)cyclohexane-1-carbonyl)-2-oxo-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(2-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)acetyl)-2-oxo-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-((3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carbonyl)-2-oxo-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-((3R)-1-(2-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)acetyl)pyrrolidine-3-carbonyl)-2-oxo-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)nicotinoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)pyrazine-2-carbonyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)nicotinoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-((3R)-1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)pyrazine-2-carbonyl)pyrrolidine-3-carbonyl)-2-oxo-1-((is,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-((6-(1′-((3S)-1-((1r,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carbonyl)-2-oxo-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-[(6-{1′-[4-(1-{[(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}ethyl)carbamoyl]methyl}piperidin-4-yl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl}-3-isopropylimidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-N-isopropyl-2-methylbenzamide;

N-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}ethyl)-5-[(4-{[6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridin-6-yl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-1′-yl]carbonyl}piperidin-1-yl)methyl]pyridine-2-carboxamide;

5-[(6-{1′-[2-(4-{4-[(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}ethyl)carbamoyl]phenyl}piperidin-1-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl}-3-isopropylimidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-N-isopropyl-2-methylbenzamide;

5-[(6-{1′-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}methyl)benzoyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl}-3-isopropylimidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-N-isopropyl-2-methylbenzamide;

5-[(6-{1′-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl}phenyl)methyl]-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl}-3-isopropylimidazo[4,5-c]pyridin-4-yl)amino]-4-fluoro-N-isopropyl-2-methylbenzamide;

5-({6-[1′-(4-{3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]benzoyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl]-3-isopropylimidazo[4,5-c]pyridin-4-yl}amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

5-{[6-(1′-{[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}methyl)phenyl]methyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl)-3-isopropylimidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-N-isopropyl-2-methylbenzamide;

5-({6-[1′-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperazine-1-carbonyl}benzoyl)-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl]-3-isopropylimidazo[4,5-c]pyridin-4-yl}amino)-4-fluoro-N-isopropyl-2-methylbenzamide;

4-fluoro-N-isopropyl-5-[(3-isopropyl-6-{2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]-1′-[(1s,4s)-4-[4-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-4-yl}oxy)piperidine-1-carbonyl]cyclohexanecarbonyl]spiro[indole-3,4′-piperidin]-6-yl}imidazo[4,5-c]pyridin-4-yl)amino]-2-methylbenzamide; and

5-{[6-(1′-{4-[(1-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperidin-4-yl)(methyl)amino]benzoyl}-2-oxo-1-[(1s,3s)-3-(piperidin-1-yl)cyclobutyl]spiro[indole-3,4′-piperidin]-6-yl)-3-isopropylimidazo[4,5-c]pyridin-4-yl]amino}-4-fluoro-N-isopropyl-2-methylbenzamide.

20. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

21. A method of treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

22. A method of increasing T-cell activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

23. A method of treating cancer associated with HPK1 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

24. A method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof, wherein the cancer is associated with HPK1 activity, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

25. A method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

26. A method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

27. A compound having a structure of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3, 4, 5, or 6;

B is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S;

L is a linker moiety having a length of 2-24 continuously covalently-bonded atoms selected from the group consisting of C, O, N and S;

LHM is a ligase harness moiety;

one of R 1 and R 2 is H, —CN, —OH, halogen, or C 1-6 alkyl, and the other of R 1 and R 2 is H, halogen, or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH and halogen, or

R 1 and R 2 together with the carbon to which they are attached form a C 3-7 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the C 3-7 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocyclyl are each optionally substituted with one R 11 and are each optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy, or

R 1 and R 2 together form ═O;

R 11 is

i) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,

i) —S(O) 2 C 1-6 alkyl,

ii) —S(O) 2 C 3-7 monocyclic cycloalkyl,

iii) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or

iv) —C(O)R 21 ;

R 21 is

i) H,

v) —NH 2 ,

vi) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy,

viii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl, or

ix) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from

a) —CN,

b) —OH,

c) halogen,

d) C 1-3 alkoxy,

e) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

g) —OC(O)C 1-6 alkyl optionally substituted with one —OH;

R 3 and R 13 are each H, or

R 3 and R 13 together form ═O;

each R 12 is independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;

each R 18 is independently

i) —CN,

ii) a halogen,

iii) —OH,

iv) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

v) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

vi) —COOH, or

vii) —C(O)N(R 22 ) 2 , wherein each R 22 is independently H or C 1-6 alkyl;

X 1 is N or CR 17 ;

R 4 , R 5 , R 6 , R 10 and R 17 are each independently H, halogen, C 1-3 alkyl, or C 1-3 alkoxy;

R 7 is

i) H,

ii) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or

iii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;

Z is —O—, —C(R′) 2 —, or —NR 8 —;

each R 8 is independently H or C 1-3 alkyl;

R 9a , R 9b , R 9c , R 9d , and R 9e are independently

i) H,

ii) halogen,

iii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl,

iv) —NH 2 ,

v) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,

viii) —S(O) 2 C 1-6 alkyl,

ix) —S(O) 2 N(R 23 ) 2 , wherein each R 23 is independently H or C 1-6 alkyl,

x) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from

a) —OH,

b) halogen,

c) C 1-3 alkoxy,

d) C 3-7 monocyclic cycloalkyl,

f) —NR 20 C(O)OC 1-3 alkyl, wherein R 20 is H or C 1-3 alkyl,

xi) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,

xiv) —COOH,

xv) —C(O)N(R 19 ) 2 , or

xvi) —C 1-3 alkylene-C(O)N(R 19 ) 2 ,

wherein one or more of R 9a , R 9b , R 9c , R 9d , and R 9e is —C(O)N(R 19 ) 2 or —C 1-3 alkylene-C(O)N(R 19 ) 2 ; and

each R 19 is independently

i) H,

ii) —S(O) 2 C 1-6 alkyl,

iii) C 1-6 alkyl optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,

28. The compound of claim 27 wherein, Z is NH, X 1 is CH, R 6 is H, and the compound has a structure of Formula (IIa):

29. The compound of claim 28 wherein the compound has a structure of Formula (IIb):

30. The compound of claim 29 , wherein

each R 9a , R 9b , R 9c , R 9d , and R 9e is independently H, halogen, C 1-6 alkyl, or —C(O)N(R 19 ) 2 ; wherein R 19 is C 1-6 alkyl;

R 4 , R 5 and R 10 are each H; and

R 7 is C 1-6 alkyl.

31. The compound of claim 29 , wherein R 3 and R 13 together form ═O; and R 1 and R 2 together with the carbon to which they are attached form a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, and wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with one R 11 .

32. The compound of claim 29 wherein the compound has a structure of Formula (IIc):

33. The compound of claim 32 , wherein L is

wherein,

t is 0, 1, 2, 3, 4, 5, 6, or 7;

q is 0, 1, 2, 3, 4, 5, 6, or 7;

L 1 is a direct bond, —C(O)NH—, or —C(O)—; and

L 2 is —C(O)NH—, —O—, or —NH—.

34. The compound of claim 33 wherein t is 0, q is 5 or 7, L 1 is —C(O)NH—, and L 2 is —O—, or —NH—.

35. The compound of claim 27 wherein the LHM targets VHL and has a structure of Formula (If):

wherein,

p is 0 or 1;

R j is 5-6 member heteroaryl optionally substituted with 1 to 3 R k ,

each R k is independently halo, oxo, —CN, —OH, C 1-6 alkyl, C 3-8 cycloalkyl, or —O—C 1-6 alkyl;

each R e is independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;

R g is hydrogen or C 1-6 alkyl;

R b is hydrogen or hydroxyl;

R c is —C(O)R f , wherein R f is C 1-6 alkyl or C 3-8 cycloalkyl, each being optionally substituted with halo or —CN.

36. The compound of claim 35 wherein the LHM has one of the following structures:

37. The compound of claim 28 wherein the LHM targets CRBN and has a structure of Formula (Id)

wherein,

W is —C(R g )— or —N—;

q is 0, 1 or 2;

R g is hydrogen or C 1-6 alkyl; and

R a is C 1-6 alkyl, halo, halo C 1-6 alkyl, —N(R g ) 2 , CN, nitro, hydroxyl, or —O—C 1-4 alkyl.

38. The compound of claim 37 wherein W is —CH—; and Z 1 is —C(O)—, —CH 2 —, —CH 2 —C(O)—, or —CH═CH—.

39. The compound of claim 38 wherein the LHM has one of the following structures.

40. The compound of claim 27 selected from the group consisting of

(3R)-1-((1s,3S)-3-(1′-acetyl-6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidin]-1-yl)cyclobutyl)-N-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)nonyl)piperidine-3-carboxamide;

(R)-1-((1s,3S)-3-(1′-acetyl-6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidin]-1-yl)cyclobutyl)-N-(7-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)heptyl)piperidine-3-carboxamide; and

(R)-1-((1s,3S)-3-(1′-acetyl-6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidin]-1-yl)cyclobutyl)-N-(9-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)nonyl)piperidine-3-carboxamide.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2023

From: SHUNATONA, HUNTER P.; SHEARN-NANCE, GALEN PAUL; BUELL, JOHN

To: NURIX THERAPEUTICS, INC.

Reel/Frame 063689/0614 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2023

From: MITCHELL, SCOTT A.

To: GILEAD SCIENCES, INC.

Reel/Frame 063689/0625 →

Continuity (2)

Provisional Application 63021045 · May 6, 2020

Related Publication 20210355140A1 · Nov 18, 2021