Isoquinoline compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-12378249-B2
Application number	US-202117156387-A
Country	US
Kind code	B2
Filing date	Jan 22, 2021
Priority date	Jul 24, 2018
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

Isoquinoline compounds of formula (I):

variations thereof, and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, halogen, hydroxyl, C 1-6 alkyl optionally substituted with halogen, C 3-4 cycloalkyl, or —O(C 1-6 alkyl) optionally substituted with halogen;
R 2 is (i) or (ii):
(i) a monocyclic 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; or
(ii) a polycyclic heteroaryl having the formula (a) or (b):

wherein the wavy line represents the attachment point to the parent structure,
Q is CR 20 , NR 21 , N, O or S;
T is N or CR 22 ;
Z 1 and Z 2 are independently N or C, provided at least one of Z 1 and Z 2 is C;
T 1 , T 2 and T 3 are independently N or CR 23 ;
ring A and ring B are independently a C 5-8 cycloalkyl or a 5- to 8-membered heterocycle having at least 3 ring-forming carbon atoms and 1, 2 or 3 ring-forming heteroatoms independently selected from the group consisting of N, P, O and S; wherein the C 5-8 cycloalkyl and the 5- to 8-membered heterocycle are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; and wherein two substituents of the C 5-8 cycloalkyl or the 5- to 8-membered heterocycle, where present, optionally taken together form a spiro, fused or bridged cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 or a sprio, fused or bridged heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;
R 20 , R 21 , R 22 and R 23 are each independently hydrogen or R 10 ;

R 3 is hydrogen or halogen; cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, or —OR 7 ; wherein the C 1-6 alkyl, C 3-8 cycloalkyl and 3- to 14-membered heterocyclyl of R 3 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl or halogen, cyano, —C(O)R 6 , —C(O)OR 7 , —C(O)NR 8a R 8b , —OR 7 , —OC(O)R 6 , —OC(O)NR 8a R 8b , —SR 7 , —S(O)R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8a R 8b , —P(O)R 9a R 9b , —NR 8a R 8b , —N(R 8 )C(O)R 6 , —N(R 8 )C(O)OR 7 , —N(R 8 )C(O)NR 8a R 8b , —N(R 8 )S(O) 2 R 9 , or —N(R 8 )S(O) 2 NR 8a R 8b ; wherein the-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R 4 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
R 5 is hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, —C(O)R 6 , —C(O)OR 7 , —C(O)NR 8a R 8b , —OR 7 , —OC(O)R 6 , —OC(O)NR 8a R 8b , —SR 7 , —S(O)R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8a R 8b , —P(O)R 9a R 9b , —NR 8a R 8b , —N(R 8 )C(O)R 6 , —N(R 8 )C(O)OR 7 , —N(R 8 )C(O)NR 8a R 8b , —N(R 8 )S(O) 2 R 9 , or —N(R 8 )S(O) 2 NR 8a R 8b ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R 5 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 6 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 6 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 7 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 7 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 8 is independently hydrogen or C 1-6 alkyl;
each R 8a and R 8b is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 8a and R 8b are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
or R 8a and R 8b are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;

each R 9 is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3 _ 8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 9 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 9a and R 9b is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C 1-6 alkyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 9a and R 9b are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
or R 9a and R 9b are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;

each R 10 is independently oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, —C(O)R a , —C(O)OR, —C(O)NR c R d , —OR, —OC(O)R a , —OC(O)NR c R d , —SR b , —S(O)R, —S(O) 2 R e , —S(O)(═NH)R c , —S(O) 2 NR c R d , —NR c R d , —N(R f )C(O)R a , —N(R f )C(O)OR, —N(R f )C(O)NR c R d , —N(R f )S(O) 2 R e , —N(R f )S(O) 2 NR c R d , or —P(O)R g R h ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R 10 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _ 8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _ 8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R a are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R b is independently hydrogen, C 1-6 alkyl, C 3 _ 8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3 _ 8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R b are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R c and R d is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5

Assignees

• Genentech Inc

Inventors

• Liang Jun
• Malhotra Sushant
• Mendonca Rohan V
• Rajapaksa Naomi
• Siu Michael
• Stivala Craig
• Tellis John C
• Wei Binqing
• Chan Bryan K
• Drobnick Joy Alison
• Gazzard Lewis J
• Heffron Timothy
• Jones Graham
• Lainchbury Michael
• Madin Andrew
• Seward Eileen Mary
• Cartwright Matthew W
• Gancia Emanuela
• Favor David
• Fong Kin Chiu
• Good Andrew
• Hu Yonghan

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title