Azaindoles as inhibitors of HPK1

Patent metadata

Field	Value
Publication number	US-11944606-B2
Application number	US-202117178021-A
Country	US
Kind code	B2
Filing date	Feb 17, 2021
Priority date	Mar 15, 2017
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

Azaindole compounds and their use as inhibitors of HPK1 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 azaindole compounds.

First claim

We claim:

1. A method for inhibiting HPK1 comprising contacting HPK1 with an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein,
G 1 is N or C—R x1 ;
G 2 is N or C—R x2 ;
G 3 is N or C—R x3 ;
G 4 is N or C—R x4 ;
wherein, 0, 1 or 2 of G 1 , G 2 , G 3 , and G 4 is N;
R x1 , R x2 , R x3 and R x4 , if present, in each instance, is independently selected from the group consisting of hydrogen, halo, C 6 -C 20 aryl optionally substituted with one or two R 1a , C 1 -C 20 heteroaryl optionally substituted with one or two R 1a , —CONR 6 R 7 , —NR 6 R 7 , and —N(R 8 )—CO(R 9 ), provided that at least one of R x1 , R x2 , R x3 and R x4 is other than hydrogen;
wherein, R 6 and R 7 taken together with the N to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 6 and R 7 are independently hydrogen or alkyl;
wherein, R 8 and R 9 taken together with the N or the carbonyl to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 8 and R 9 are independently hydrogen or alkyl;
wherein, in each instance, R 1a is independently taken together with the carbon to which it is bound to form a carbonyl; or R 1a is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;

R 1 is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;
R 2 is alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SOR 5 , or cycloalkyl; and
R 3 and R 4 , in each instance, is independently hydrogen, alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SOR 5 , or cycloalkyl;
wherein R 5 , in each instance, is independently an unsubstituted alkyl; provided that R 1 and R 4 are not both hydrogen.

2. The method of claim 1 , wherein the compound of Formula I is of the Formula Ia:

3. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. A method for enhancing an immune response in a subject in need thereof comprising administering to said subject an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein,
G 1 is N or C—R x1 ;
G 2 is N or C—R x2 ;
G 3 is N or C—R x3 ;
G 4 is N or C—R x4 ;
wherein, 0, 1 or 2 of G 1 , G 2 , G 3 , and G 4 is N;
R x1 , R x2 , R x3 and R x4 , if present, in each instance, is independently selected from the group consisting of hydrogen, halo, C 6 -C 20 aryl optionally substituted with one or two R 1a , C 1 -C 20 heteroaryl optionally substituted with one or two R 1a , —CONR 6 R 7 , —NR 6 R 7 , and —N(R 8 )—CO(R 9 ), provided that at least one of R x1 , R x2 , R x3 and R x4 is other than hydrogen;
wherein, R 6 and R 7 taken together with the N to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 6 and R 7 are independently hydrogen or alkyl;
wherein, R 8 and R 9 taken together with the N or the carbonyl to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 8 and R 9 are independently hydrogen or alkyl;
wherein, in each instance, R 1a is independently taken together with the carbon to which it is bound to form a carbonyl; or R 1a is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;

R 1 is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;
R 2 is alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SO 2 R 5 , or cycloalkyl; and
R 3 and R 4 , in each instance, is independently hydrogen, alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SO 2 R 5 , or cycloalkyl;
wherein R 5 , in each instance, is independently an unsubstituted alkyl; provided that R 1 and R 4 are not both hydrogen.

5. The method of claim 4 , wherein the compound of Formula I is of the Formula Ia:

6. The method of claim 4 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7. A method for treating a HPK1-dependent disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein,
G 1 is N or C—R x1 ;
G 2 is N or C—R x2 ;
G 3 is N or C—R x3 ;
G 4 is N or C—R x4 ;
wherein, 0, 1 or 2 of G 1 , G 2 , G 3 , and G 4 is N;
R x4 , R x2 , R x3 and R x4 , if present, in each instance, is independently selected from the group consisting of hydrogen, halo, C 6 -C 20 aryl optionally substituted with one or two R 1a C 1 -C 20 heteroaryl optionally substituted with one or two R 1a , —CONR 6 R 7 , —NR 6 R 7 , and —N(R 8 )—CO(R 9 ), provided that at least one of R x4 , R x2 , R x3 and R x4A is other than hydrogen;
wherein, R 6 and R 7 taken together with the N to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 6 and R 7 are independently hydrogen or alkyl;
wherein, R 8 and R 9 taken together with the N or the carbonyl to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 8 and R 9 are independently hydrogen or alkyl;
wherein, in each instance, R 1a is independently taken together with the carbon to which it is bound to form a carbonyl; or R 1a is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;

R 1 is hydrog

Assignees

• Genentech Inc

Inventors

• Heffron Timothy
• Malhotra Sushant
• Wei Binqing
• Chan Bryan
• Gazzard Lewis
• Gancia Emanuela
• Lainchbury Michael
• Madin Andrew
• SEWARD Eileen
• Hu Yonghan

Classifications

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/5377

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