Isoquinolines as inhibitors of HPK1

Patent metadata

Field	Value
Publication number	US-11566003-B2
Application number	US-202016921297-A
Country	US
Kind code	B2
Filing date	Jul 6, 2020
Priority date	Mar 30, 2017
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

Isoquinoline compounds 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, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, optionally substituted amino, or optionally substituted acylamino;
R 2 is (a), (b), (c), or (d), wherein:
(a) is a 5-10 membered heteroaryl having 1-4 heteroatoms selected from O, S, and N or a 5-10 membered heterocyclyl having 1-4 heteroatoms selected from O, S, and N, wherein the 5-10 membered heteroaryl and the 5-10 membered heterocyclyl are optionally substituted with one, two, three, four or five substituents;
(b) is a C 6-10 aryl optionally substituted with one, two, three, four or five substituents;
(c) is a C 3-8 cycloalkyl optionally substituted with one, two, three, four or five substituents;
(d) is a 5-10 membered heteroaryl fused with a ring selected from the group consisting of 5- or 6-membered heteroaryl, 5-10 membered heterocyclyl, C 6-10 aryl and C 3-7 cycloalkyl, wherein the 5-10 membered heteroaryl of R 2 and the fused ring are optionally substituted with one, two, three, or four substituents;

R 3 is hydrogen, cyano, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-6 alkoxy;
R 4 is A-C(O)—;
A is C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heteroaryl, C 2-9 heterocyclyl, or —NHR g ; wherein the C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heteroaryl and C 2-9 heterocyclyl of A are each optionally substituted independently with one, two, three, four or five substituents; and
R g is C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, or C 2-9 heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of R g are each optionally substituted independently with one, two, three, four or five substituents.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5-10 membered heteroaryl having 1-4 heteroatoms selected from O, S, and N or a 5-10 membered heterocyclyl having 1-4 heteroatoms selected from O, S, and N, wherein the 5-10 membered heteroaryl and the 5-10 membered heterocyclyl are optionally substituted with one, two, three, four or five substituents.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:

each of which can be optionally substituted with one, two, three, four or five substituents.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:

each of which is optionally substituted with one, two, three, four or five substituents.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

wherein R 6 , R 7 , and R 8 are each independently selected from the group consisting of:
i. branched or linear C 1-6 alkyl or C 1-6 alkenyl, wherein said alkyl and alkenyl can each be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of hydroxyl, halogen, nitrile, amino, mono(C 1-6 alkyl)amino-, di(C 1-6 alkyl)amino-, —SO 2 R y , —S(O)NR y , —(CO)NR y R z and —NR y (CO)R z , wherein R y and R z , in each instance, is independently hydrogen or C 1-6 alkyl, wherein each alkyl can optionally be substituted with one, two, three, or four substituents independently selected from the group consisting of hydroxyl and halogen;
ii. NR y R z —C(O)—, wherein R y and R z are each independently hydrogen or C 1-6 alkyl, wherein each alkyl can optionally be substituted with one, two, three, or four substituents independently selected from the group consisting of hydroxyl and halogen;
iii. hydroxy(C 1-6 alkyl);
iv. C 1-6 alkoxy, wherein said alkoxy can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of hydroxyl and halogen;
v. C 3-9 cycloalkyl, optionally substituted C 6 aryl, optionally substituted 5-membered heteroaryl, or C 2-9 heterocyclyl;
vi. halogen;
vii. amino;
viii. cyano;
ix. —NR y C(O)R z , wherein R y and R z are each independently hydrogen or C 1-6 alkyl, wherein each alkyl can optionally be substituted with one, two, three, or four substituents independently selected from the group consisting of hydroxyl and halogen;
x. —SO 2 R′, wherein R′ is H or C 1-6 alkyl;
xi. —SO 2 NR′R″, wherein R′ and R″ are independently H or C 1-6 alkyl; and
xii. —NR′C(O)OR″, —NR′SO 2 NR″ or —NR′S(O)R″, wherein each R′ is independently H or C 1-6 alkyl and each R″ is independently C 1-6 alkyl, halo(C 1-6 alkyl) or C 6-10 aryl optionally substituted with C 1-6 alkyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

wherein R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and mono(C 1-6 alkyl)amino.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-6 alkyl; R 7 is hydrogen, amino, or mono(C 1-6 alkyl)amino; and R 8 is hydrogen, hydroxyl, or C 1-6 alkoxy.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 7 is amino.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:
i. C 3-7 cycloalkyl, C 2-9 heteroaryl, or C 2-9 heterocyclyl, wherein said cycloalkyl, heteroaryl, or heterocyclyl can each be optionally substituted with one, two, three or four of R 5 , wherein each R 5 is independently selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, halogen, cyano, hydroxyl, C 1-6 alkoxy, optionally substituted C 2-9 heteroaryl, —SO 2 R e , —NR e C(O)R f , —NR e SO 2 R f and NR e R f —C(O)—; wherein the C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-6 alkenyl of R 5 can each be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of C 1-6 alkoxy, hydroxyl, halogen, cyano, —SO 2 R e , —NR e R f , —NR e C(O)R f and —C(O)NR e R f , wherein R e and R f in each occurrence are independently selected from the gro

Assignees

• Genentech Inc

Inventors

• Chan Bryan
• Drobnick Joy
• Gazzard Lewis
• Heffron Timothy
• Liang Jun
• Malhotra Sushant
• Mendonca Rohan
• Rajapaksa Naomi
• Stivala Craig
• Tellis John
• Wang Weiru
• Wei Binqing
• Zhou Aihe
• Cartwright Matthew W
• Lainchbury Michael
• Gancia Emanuela
• SEWARD Eileen
• Madin Andrew
• Favor David
• Fong Kin Chiu
• Hu Yonghan
• Good Andrew

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D417/04

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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title