Naphthyridines as inhibitors of HPK1

Patent metadata

Field	Value
Publication number	US-10407424-B2
Application number	US-201815942321-A
Country	US
Kind code	B2
Filing date	Mar 30, 2018
Priority date	Mar 30, 2017
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

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 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 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 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, C1-6 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 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, 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)-, 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 compound of claim 1 , wherein R 1 is an optionally substituted C 2-9 heteroaryl or C 2-9 heterocyclyl.

3. The compound of claim 2 , wherein R 1 is selected from the group consisting of:

each of which is optionally substituted.

4. The compound of claim 2 , wherein R 1 is selected from the group consisting of:

each of which is optionally substituted.

5. The compound of claim 4 , wherein R 1 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, C 1-6 alkenyl, C 1-6 alkenylene, and C 3-9 cycloalkyl, wherein said alkyl, alkenyl, alkenylene, and cycloalkyl are optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halogen, —CHF 2 , —CF 3 , amino, di(C 1-6 alkyl)amino, mono(C 1-6 alkyl)amino, cyano, C 3-7 cycloalkyl, C 1-6 alkoxy, —S(O)R′, —SO 2 R′, —SO 2 NR′R″, —C(O)NR′R″, and —NR′C(O)R″, wherein R′ and R″ are independently H or C 1-6 alkyl;
ii. NR a R b —C(O)—, wherein, R a and R b are each independently hydrogen or C 1-6 alkyl, wherein said alkyl can optionally be substituted with hydroxyl, halogen, —CHF 2 , or —CF 3 ;
iii. C 1-6 alkoxy;
iv. halogen;
v. cyano;
vi. hydroxyl;
vii. amino;
viii. di(C 1-6 alkyl)amino;
ix. mono(C 1-6 alkyl)amino;
x. —NR c C(O)R d , wherein R c and R d are independently H or C 1-6 alkyl;
xi. —CF 3 ;
xii. —CHF 2 ;
xiii. —SO 2 R′, wherein R′ is H or C 1-6 alkyl;
xiv. —SO 2 NR′R″, wherein R′ and R″ are independently H or C 1-6 alkyl;
xv. —C(O)NR c R d ; wherein R c and R d are independently H or C 1-6 alkyl;
xvi. —C(O)OR e ; wherein R e is H, C 1-6 alkyl, or CH 2 -aryl;
xvii. C 3-5 heterocyclyl, C 6-10 aryl, —(C 1-6 alkyl)(C 6-10 aryl), or C 2-9 heteroaryl, wherein said heterocyclyl, aryl, or heteroaryl can be optionally substituted with C 1-6 alkyl, C 6-10 aryl, or —C(O)OR e ; wherein R e is H, C 1-6 alkyl, or CH 2 -aryl;
xviii. —O—(C 2-9 heteroaryl);
xix. —NR′S(O) k′ R″, wherein k′ is 1 or 2 and R′ and R″ are independently H or C 1-6 alkyl;
wherein the C 6-10 aryl, C 2-9 heteroaryl or C 2-9 heterocyclyl of R 1 together with two of R 6 , R 7 , and R 8 can form a bicyclic; and
wherein a carbon embedded in said aryl, heteroaryl or heterocyclyl taken together with an oxygen to which it is bound can form a carbonyl.

6. The compound of claim 5 , wherein R 1 is:

7. The compound of claim 6 , wherein R 1 is:

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61K31/551

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

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring 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

• A61K31/4725

  containing further heterocyclic rings · CPC title