Isoquinoline compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-12473301-B2
Application number	US-202117220307-A
Country	US
Kind code	B2
Filing date	Apr 1, 2021
Priority date	Oct 2, 2018
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

3-Carbonylaminoisoquinoline 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 3-carbonylaminoisoquinoline 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, C 1-6 haloalkyl, C 3-4 cycloalkyl, —O(C 1-6 alkyl), or —O(C 1-6 haloalkyl);
R 15 is —OR 16 , —SR 16 , —NR 17 R 18 , or D;
each R 16 is independently C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 14-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 14-membered heterocyclyl of R 16 are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
R 17 is hydrogen or C 1-6 alkyl;
R 18 is 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; C 3-10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; or C 1-6 alkyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
or R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a saturated 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;

D is

 wherein the wavy line represents the attachment point to the parent structure;
R 30 , R 31 , R 32 , R 33 and R 34 are independently hydrogen or R 10 ; or,
optionally two of R 30 , R 31 , R 32 , R 33 and R 34 taken together with the carbon atoms to which they are attached form a C 3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 or 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; provided that at least one of R 30 , R 31 , R 32 , R 33 and R 34 is other than hydrogen;
R 3 is hydrogen, 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 selected from the group consisting of:

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 saturated 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 b , —C(O)NR c R d , —OR b , —OC(O)R a , —OC(O)NR c R d , —SR b , —S(O)R e , —S(O) 2 R e , —S(O)(═NH)R e , —S(O) 2 NR c R d , —NR c R d , —N(R f )C(O)R a , —N(R f )C(O)OR b , —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 6-10 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- 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 c and R d are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
or R c and R d are taken together with the nitrogen atom to which they are attached to form a saturated 4- to 12-membered heterocyclyl optionally substituted with 1

Assignees

• Genentech Inc

Inventors

• Liang Jun
• Mendonca Rohan V
• Siu Michael
• Tellis John
• Wang Weiru
• Wei Binqing
• Chan Bryan
• Choo Edna F
• Drobnick Joy
• Gazzard Lewis J
• Heffron Timothy

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title