Naphthyridines as inhibitors of HPK1

Patent metadata

Field	Value
Publication number	US-11034692-B1
Application number	US-201916542129-A
Country	US
Kind code	B1
Filing date	Aug 15, 2019
Priority date	Mar 30, 2017
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

Naphthyridine 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 naphthyridine compounds.

First claim

The invention claimed is:

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

or a pharmaceutically acceptable salt thereof, wherein,
R 1 is C 2-9 heteroaryl, C 2-9 heterocyclyl, C 6-10 aryl, C 3-9 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C≡C—(C 2-9 heteroaryl), —C≡C—(C 6-10 aryl), —CH(R j′ )—O—(C 2-9 heteroaryl), —CH(R j′ )—O—(C 2-9 ) heterocyclyl), —CH(R j′ )—O—(C 6-10 aryl), —CH(R j′ )—O—(C 3-9 cycloalkyl), —CH(R j′ )—O—(C 1-6 alkyl), —C(O)N(R j′ )(C 2-9 heteroaryl), —C(O)N(R j′ )(C 2-9 heterocyclyl), —C(O)NR 24 R 25 , —C(O)OR 26 , —C(═NR 29 )R 27 , —C(═NR 29 )NR 24 R 25 , —C(═NOR 29 )R 27 , cyano, hydrogen, halogen, —NR 24 R 25 , —NR 28 C(O)R 27 , —NR 28 C(O)NR 24 R 25 , —NR 28 C(O)OR 26 , —NR 28 S(O)R 29 ; —NR 28 SO 2 R 29 , —NR 28 SO 2 NR 24 R 25 , —OR 26 , —OC(O)R 27 , —OC(O)NR 24 R 25 , —S(O)R 29 ; —SO 2 R 29 , or —SO 2 NR 24 R 25 ;
wherein the C 2-9 heteroaryl and C 2-9 heterocyclyl of R 1 independently have 1-4 heteroatoms selected from O, S and N; and wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of R 1 are optionally substituted independently with one, two, three, four or live substituents;
wherein the C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl or C 2-9 heterocyclyl of R 1 together with two of said substituents can form a bicyclic which is optionally substituted;
wherein a carbon embedded in said cycloalkyl, aryl, heteroaryl or heterocyclyl taken together with an oxygen to which it is bound can form a carbonyl;
each R j′ is independently hydrogen or optionally substituted C 1-6 alkyl;
each R 24 and R 25 is independently hydrogen or optionally substituted C 1-6 alkyl; or R 24 and R 25 are taken together with the nitrogen atom to which they are attached to form a C 3-7 heterocyclyl optionally substituted with one to four substituents;
each R 26 , R 27 and R 28 is independently hydrogen or optionally substituted C 1-6 alkyl;
each R 29 is independently optionally substituted C 1-6 alkyl;
R 1′ is hydrogen, C 1-6 alkyl, alkenyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, or halogen, wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl can be optionally substituted with one, two, three, four or five substituents; provided at least one of R 1 and R 1′ is other than hydrogen;
R 2 is A-C(O)— or D;
A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 2-9 heterocyclyl, (C 3-7 cycloalkyl)-(C 1-6 alkylene)-, (C 6-10 aryl)-(C 1-6 alkylene)-, (C 2-9 heteroaryl)-(C 1-6 alkylene)-, (C 2-9 heterocyclyl)-(C 1-6 alkylene)-, —NR g R h or —OR h ;
wherein the C 1-6 alkyl, C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of A are optionally substituted independently with one, two, three, four or five substituents;
R g is H or C 1-6 alkyl optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halogen, cyano, amino, di(C 1-6 alkyl)amino, mono(C 1-6 alkyl)amino; —CHF 2 , and —CF 3 ;
R h is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl C 2-9 heteroaryl, €2-9 heterocyclyl (C 3-7 cycloalkyl)-(C 1-6 alkylene)-, (C 6-10 aryl)-(C 1-6 alkylene)-, (C 2-9 heteroaryl)(C 1-6 alkylene)-, or (C 2-9 heterocyclyl)-(C 1-6 alkylene)-;
wherein the C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of R h are optionally substituted independently with one, two, three, four or five substituents;

D is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 2-9 heterocyclyl, (C 3-7 cycloalkyl)-(C 1-6 alkylene)-, (C 6-10 aryl)-(C 1-6 alkylene)-, (C 2-9 heteroaryl)-(C 1-6 alkylene)-, (C 2-9 heterocyclyl)-(C 1-6 alkylene)-, or (C 3-7 cycloalkyl)-S(O) 2 —;
wherein the C 2-9 heteroaryl and C 2-9 heterocyclyl of D independently have 1-4 heteroatoms selected from O, S and N; and wherein the C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of D are optionally substituted independently with one, two, three, four or five substituents,
wherein two of the substituents attached to different atoms are taken together with the atoms to which they attached to form a bicyclic or tricyclic, wherein said bicyclic or tricyclic is optionally substituted, and wherein a carbon embedded in said heteroaryl or heterocyclyl taken together with an oxygen to which it is bound can form a carbonyl;

and R 2′ is H or optionally substituted C 1-6 alkyl.

2. The method of claim 1 , wherein said subject has cancer.

3. 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,
R 1 is C 2-9 heteroaryl, C 2-9 heterocyclyl, C 6-10 aryl, C 3-9 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C≡C—(C 2-9 heteroaryl), —C≡C—(C 6-10 aryl), —CH(R j′ )—O—(C 2-9 heteroaryl), —CH(R j′ )—O—(C 2-9 heterocyclyl), —CH(R j′ )—O—(C 6-10 aryl), —CH(R 1 )—O—(C 3-9 cycloalkyl), —CH(R j′ )—(O)—(C 1-6 alkyl), —C(O)N(R j′ )(C 2-9 heteroaryl), —C(O)N(R j′ )(C 2-9 heterocyclyl), —C(O)NR 24 R 25 , —C(O)OR 26 , —C(═NR 29 )R 27 , —C(═NR 29 )NR 24 R 25 , —C(═NOR 29 )R 27 , cyano, hydrogen, halogen, —NR 24 R 25 , —NR 28 C(O)R 27 , —NR 28 C(O)NR 24 R 25 , —NR 28 C(O)OR 26 , —NR 28 S(O)R 29 ; —NR 28 SO 2 R 29 , —NR 28 SO 2 NR 24 R 25 , —OR 26 , —OC(O)R 27 , —OC(O)NR 24 R 25 , —S(O)R 29 ; —SO 2 R 29 , or —SO 2 NR 24 R 25 ;
wherein the C 2-9 heteroaryl and C 2-9 heterocyclyl of R 1 independently have 1-4 heteroatoms selected from O, S and N; and wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl of R 1 are optionally substituted independently with one, two, three, four or five substituents;
wherein the C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl or C 2-9 heterocyclyl of R 1 together with two of said substituents can form a bicyclic which is optionally substituted;
wherein a carbon embedded in said cycloalkyl, aryl, heteroaryl or heterocyclyl taken together with an oxygen to winch it is bound can form a carbonyl;
each R j′ is independently hydrogen or optionally substituted C 1-6 alkyl;
each R 24 and R 25 is independently hydrogen or optionally substituted C 1-6 alkyl; or R 24 and R 25 are taken together with the nitrogen atom to which they are attached to form a C 3-7 heterocyclyl optionally substituted with one to four substituents;
each R 26 , R 27 and R 28 is independently hydrogen or optionally substituted C 1-6 alkyl;
each R 29 is independently optionally substituted C 1-6 alkyl;
R 1′ is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, or halogen, wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl can be optionally substituted with one, two, three, four or five substituents; provided at least one of R 1 and R 1′ is other than hydrogen;
R 2 is A-C(O)— or D;
A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 2-9 heterocyclyl, (C 3-7 cycloalkyl)-(C 1-6 alkylene)-, (C 6-10 aryl)-(C 1-6 alkylene)-, (C 2-9 heteroaryl)-(C 1-6 alkylene)-, (C 2-9 heterocyclyl)-(C 1-6 alkylene)-, —NR g R h or —OR h ;
wherein the C 1-6 alkyl, C 3-9 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 2-9 heterocyclyl o

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title