Bifunctional degraders of hematopoietic progenitor kinase and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-11739101-B2
Application number	US-202117308879-A
Country	US
Kind code	B2
Filing date	May 5, 2021
Priority date	May 6, 2020
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

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

First claim

The invention claimed is:

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 fr

Assignees

• Nurix Therapeutics Inc
• Gilead Sciences Inc

Inventors

• Shunatona Hunter P
• Shearn-Nance Galen Paul
• Mitchell Scott A
• Buell John

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/05

  Dipeptides · CPC title