US 11,925,631 B2
Substituted 6-azabenzimidazole compounds
Gayatri Balan, Bellevue, WA (US); Mark J. Bartlett, Castro Valley, CA (US); Jayaraman Chandrasekhar, Redmond, WA (US); Julian A. Codelli, Seattle, WA (US); John H. Conway, Somerville, MA (US); Jennifer L. Cosman, Foster City, CA (US); Rao V. Kalla, Cupertino, CA (US); Musong Kim, Bellevue, WA (US); Seung H. Lee, Sammamish, WA (US); Jennifer R. Lo, Seattle, WA (US); Jennifer A. Loyer-Drew, Seattle, WA (US); Scott A. Mitchell, Kenmore, WA (US); Thao D. Perry, San Jose, CA (US); Gary B. Phillips, Issaquah, WA (US); Patrick J. Salvo, Burien, WA (US); Joshua J. Van Veldhuizen, Seattle, WA (US); Suet C. Yeung, Redmond, WA (US); and Jeff Zablocki, Los Altos, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on May 27, 2021, as Appl. No. 17/331,900.
Application 17/331,900 is a division of application No. 16/668,732, filed on Oct. 30, 2019, granted, now 11,071,730.
Claims priority of provisional application 62/753,355, filed on Oct. 31, 2018.
Prior Publication US 2023/0013585 A1, Jan. 19, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/437 (2006.01); A61K 31/444 (2006.01); A61K 31/4545 (2006.01); A61K 31/5386 (2006.01); C07D 471/04 (2006.01); C07D 519/00 (2006.01); C12Q 1/00 (2006.01)
CPC A61K 31/4545 (2013.01) [A61K 31/444 (2013.01); A61K 31/5386 (2013.01); C07D 471/04 (2013.01); C07D 519/00 (2013.01)] 37 Claims
 
1. A method of inhibiting increased HPK1 activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising of a compound of Formula I,

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
one of R1 and R2 is H, —CN, —OH, halogen, or C1-6 alkyl, and the other of R1 and R2 is H, halogen, or C1-6 alkyl, wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH and halogen, or
R1 and R2 together with the carbon to which they are attached form a C3-7 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the C3-7 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocyclyl are each optionally substituted with one R11 and are each optionally substituted with 1-3 groups independently selected from —OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, or
R1 and R2 together form ═O;
R11 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, C1-3 alkyl, and C1-3 alkoxy,
ii) —S(O)2C1-6 alkyl,
iii) —S(O)2C3-7 monocyclic cycloalkyl,
iv) C1-6 alkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, or
v) —C(O)R21;
R21 is
i) H,
ii) C3-7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C1-3 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, C1-3 alkyl, and C1-3 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, C1-3 alkyl, and C1-3 alkoxy,
v) —NH2,
vi) —NH(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C1-3 alkoxy,
vii) —N(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C1-3 alkoxy,
viii) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C3-7 monocyclic cycloalkyl, or
ix) C1-6 alkyl optionally substituted with 1-3 groups independently selected from
a) —CN,
b) —OH,
c) halogen,
d) C1-3 alkoxy,
e) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, C1-3 alkyl, and C1-3 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, C1-3 alkyl, and C1-3 alkoxy, and
g) —OC(O)C1-6 alkyl optionally substituted with one —OH;
R3 and R13 are each H, or
R3 and R13 together form ═O;
L1 is a cyclobutylene optionally substituted with 1-6 groups independently selected from —OH, halogen, C1-3 alkyl, and C1-3 alkoxy;
X is —NR15R16, wherein R15 and R16 are independently
i) H,
ii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C1-3 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, C1-3 alkyl, and C1-3 alkoxy,
iv) —C(O)C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C1-3 alkoxy, or
v) C1-6 alkyl optionally substituted with 1-6 groups independently selected from
a) —CN,
b) —OH,
c) halogen,
d) C1-3 alkoxy,
e) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C1-3 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, C1-3 alkyl, and C1-3 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 R18;
each R18 is independently
i) —CN,
ii) a halogen,
iii) —OH,
iv) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl,
v) C1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl,
vi) —COOH, or
vii) —C(O)N(R22)2, wherein each R22 is independently H or C1-6 alkyl;
X1 is N or CR17;
R4, R5, R6, R10, and R17 are each independently H, halogen, C1-3 alkyl, or C1-3 alkoxy;
R7 is
i) H,
ii) C1-6 alkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, or
iii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C1-3 alkoxy;
Z is —O—, —C(R8)2—, or —NR8—;
each R8 is independently H or C1-3 alkyl;
A is a pyridinyl, pyridonyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted with 1-4 R9;
each R9 is independently
i) halogen,
ii) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C3-7 monocyclic cycloalkyl,
iii) —NH2,
iv) —NH(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C1-3 alkoxy,
v) —N(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different, and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C1-3 alkoxy,
vi) —P(O)(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different, and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, and C1-3 alkoxy,
vii) —S(O)2C1-6 alkyl,
viii) —S(O)2N(R23)2, wherein each R23 is independently H or C1-6 alkyl,
ix) C1-6 alkyl optionally substituted with 1-3 groups independently selected from
a) —OH,
b) halogen,
c) C1-3 alkoxy,
d) C3-7 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 C1-3 alkyl, and
f) —NR20C(O)OC1-3 alkyl, wherein R20 is H or C1-3 alkyl,
x) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, C1-3 alkyl, and C1-3 alkoxy,
xi) 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 —OH, halogen, C1-3 alkyl, and C1-3 alkoxy,
xii) 4-6 membered monocyclic heterocyclyl having 1-3 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 —OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy,
xiii) —COOH,
xiv) —C(O)N(R19)2, or
xv) —C1-3 alkylC(O)N(R19)2; and
each R19 is independently
i) H,
ii) —S(O)2C1-6 alkyl,
iii) C1-6 alkyl optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl,
iv) C3-7 monocyclic cycloalkyl optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from —CN, —OH, halogen, and C1-3 alkoxy, or
v) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from —CN, —OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy.