Substituted 6-azabenzimidazole compounds

Patent metadata

Field	Value
Publication number	US-11071730-B2
Application number	US-201916668732-A
Country	US
Kind code	B2
Filing date	Oct 30, 2019
Priority date	Oct 31, 2018
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

The present disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.

First claim

What is claimed is:

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof,
wherein:
one of R 1 and R 2 is H, —CN, —OH, halogen, or C 1-6 alkyl, and the other of R 1 and R 2 is H, halogen, or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH and halogen, or
R 1 and R 2 together with the carbon to which they are attached form a C 3-7 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the C 3-7 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocyclyl are each optionally substituted with one R 11 and are each optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy, or
R 1 and R 2 together form ═O;
R 11 is
i) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,
ii) —S(O) 2 C 1-6 alkyl,
iii) —S(O) 2 C 3-7 monocyclic cycloalkyl,
iv) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or
v) —C(O)R 21 ;

R 21 is
i) H,
ii) C 3-7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,
iii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,
iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,
v) —NH 2 ,
vi) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy,
vii) —N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy,
viii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl, or
ix) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from
a) —CN,
b) —OH,
c) halogen,
d) C 1-3 alkoxy,
e) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,
f) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy, and
g) —OC(O)C 1-6 alkyl optionally substituted with one —OH;

R 3 and R 13 are each H, or
R 3 and R 13 together form ═O;
L 1 is a cyclobutylene optionally substituted with 1-6 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;
X is —NR 15 R 16 , wherein R 15 and R 16 are independently
i) H,
ii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy,
iii) 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy,
iv) —C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C 1-3 alkoxy, or
v) C 1-6 alkyl optionally substituted with 1-6 groups independently selected from
a) —CN,
b) —OH,
c) halogen,
d) C 1-3 alkoxy,
e) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and
f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C 1-3 alkyl, and C 1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5 R 18 ;
each R 18 is independently
i) —CN,
ii) a halogen,
iii) —OH,
iv) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,
v) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl,
vi) —COOH, or
vii) —C(O)N(R 22 ) 2 , wherein each R 22 is independently H or C 1-6 alkyl;

X 1 is N or CR 17 ;
R 4 , R 5 , R 6 , R 10 , and R 17 are each independently H, halogen, C 1-3 alkyl, or C 1-3 alkoxy;
R 7 is
i) H,
ii) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkoxy, and C 3-7 monocyclic cycloalkyl, or
iii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 1-3 alkoxy;

Z is —O—, —C(R 8 ) 2 —, or —NR 8 —;
each R 8 is independently H or C 1-3 alkyl;
A is a pyridinyl, pyridonyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted with 1-4 R 9 ;
each R 9 is independently
i) halogen,
ii) C 1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, and C 3-7 monocyclic cycloalkyl,
iii) —NH 2 ,
iv) —NH(C 1-6 alkyl), wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,
v) —N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different, and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,
vi) —P(O)(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl can be the same or different, and wherein each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C 1-3 alkoxy,
vii) —S(O) 2 C 1-6 alkyl,
viii) —S(O) 2 N(R 23 ) 2 , wherein each R 23 is independently H or C 1-6 alkyl,
ix) C 1-6 alkyl optionally substituted with 1-3 groups independently selected from
a) —OH,
b) halogen,
c) C 1-3 alkoxy,
d) C 3-7 monocyclic cycloalkyl,
e) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C 1-3 alkyl, and
f) —NR 20 C(O)OC 1-3 alkyl, wherein R 20 is H or C 1-3 alkyl,

x) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C 1-3 alkyl, an

Assignees

• Gilead Sciences Inc

Inventors

• Balan Gayatri
• Bartlett Mark J
• Chandrasekhar Jayaraman
• Codelli Julian A
• Conway John H
• Cosman Jennifer L
• Kalla Rao V
• Kim Musong
• Lee Seung H
• Lo Jennifer R
• Loyer-Drew Jennifer A
• Mitchell Scott A
• Perry Thao D
• Phillips Gary B
• Salvo Patrick J
• Van Veldhuizen Joshua J
• Yeung Suet C
• Zablocki Jeff

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P31/18

  for HIV · CPC title

• A61K31/444

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

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title