	US 12,454,534 B2
	Pyrrolo[2,3-b]pyrazines as HPK1 inhibitor and the use thereof
Jing Li, Beijing (CN); Zhiwei Wang, Beijing (CN); and Sanjia Xu, Beijing (CN)
Assigned to BeOne Medicines I GmbH, Basel (CH)
Appl. No. 17/623,732
Filed by BEIGENE, LTD., Grand Cayman (KY)
PCT Filed Jul. 3, 2020, PCT No. PCT/CN2020/100037 § 371(c)(1), (2) Date Dec. 29, 2021, PCT Pub. No. WO2021/000925, PCT Pub. Date Jan. 7, 2021.
Claims priority of application No. PCT/CN2019/094749 (WO), filed on Jul. 4, 2019; application No. PCT/CN2019/123268 (WO), filed on Dec. 5, 2019; and application No. PCT/CN2020/089498 (WO), filed on May 9, 2020.
Prior Publication US 2022/0267333 A1, Aug. 25, 2022
Int. Cl. C07D 487/04 (2006.01); C07D 519/00 (2006.01)

CPC C07D 487/04 (2013.01) [C07D 519/00 (2013.01)]

25 Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein:

R¹and R²are each hydrogen;

n is 0, 1, 2, 3 or 4;

R³and R⁴, at each of its occurrence, are independently F, Cl, —C_1-8alkyl, cycloalkyl, heterocyclyl, —C_1-8alkyl-heterocyclyl, —C_1-8alkyl-cycloalkyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^3a, —SO₂R^3a, —SO₂NR^3aR^3b, —COR^3a, —CO²R^3a, —CONR^3aR^3b, —C(═NR^3a) NR^3bR^3c, —NR^3aR^3b, —NR^3aCOR^3b, —NR^3aCONR₃R^3c, —NR^3aCO₂R^3b, —NR^3aSONR^3bR^3c, —NR^3aSO₂NR^3bR^3c, or —NR^3aSO₂R^3b, each of said —C_1-8alkyl, cycloalkyl, heterocyclyl, or —C_1-8alkyl-heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R^3d; or R³and R⁴, when on adjacent carbon atoms of the phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituents R^3e;

or two R⁴, when on adjacent carbon atoms of the phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s);

R^3a, R^3b, and R^3care each independently hydrogen, —C_1-8alkyl, cycloalkyl, or heterocyclyl, each of said-C_1-8alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituents R^3e; or

(R^3aand R^3b), (R^3band R^3c), or (R^3cand R^3a), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituents R^3e,

R^3dand R^3eare each independently F, Cl, —C_1-8alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^3f, —SO₂R^3f, —SO₂NR³R^3g, —COR^3f, —CO₂R^3f, —CONR^3dR^3e, —C(═NR^3f) NR^3gR^3h, —NR³R^3g, —NR^3fCOR^3g, —NR³CONR^3gR^3h, —NR³CO₂R^3f, —NR^3fSONR³R^3g, —NR^3fSO₂NR^3gR^3h, or —NR³SO₂R³⁸, each of said —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from F, Cl, —C_1-8alkyl, —OR³ⁱ, —NR³ⁱR^3j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^3f, R^3g, R^3h, R³ⁱ, and R^3jare each independently hydrogen, —C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond;

R⁵at each of its occurrence, is each independently —C_1-8alkyl, cycloalkyl, —C_1-8alkyl-cycloalkyl, heterocyclyl, —COR^5a, CO₂R^5a, —CONR^5aR^5b, CH₂CONR^5aR^5b, —CH₂CH₂CONR^5aR^5b, —CH₂CH₂CH₂CONR^5aR^5bCH₂CH₂NR^5aR^5b, or —CH₂CH₂CH₂NR^5aR^5b, each of said —C_1-8alkyl, cycloalkyl, —C_1-8alkyl-cycloalkyl, or heterocyclyl, is optionally substituted with at least one substituents R^5d;

R^5aand R^5bare each independently hydrogen, —C_1-8alkyl, —C_1-8alkyl-C_1-8alkoxy, cycloalkyl, —C_1-8alkyl-heterocyclyl, —C_1-8alkyl-aryl, heterocyclyl, aryl, or heteroaryl, each of said —C_1-8alkyl, C_1-8alkyl-C_1-8alkoxy, cycloalkyl, —C_1-8alkyl-heterocyclyl, —C_1-8alkyl-aryl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R^5e; or

R^5aand R^5b, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituents R^5e;

R^5dand R^5eare each independently hydrogen, F, Cl, —C_1-8alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂—, —CF₃, —OR^5f, —SO₂R^5f, —SO₂NR^5fR^5g, —POR^5fR^5g, —COR^5f, —CO₂R^5f, —CONR^5fR^5g, —C(═NR^5h) NRSR^5g, —NRSR^5g, —NR^5fCOR^5g, —NR^5hCONR^5fR^5g, —NR^5gCO₂R^5h, —NR^5hSONR^5fR^5g, —NR^5hSO₂NR^5fR^5g, or —NR^5fSO₂R^5g, each of said —C_1-8alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from halogen, —C_1-8alkyl, —OR⁵ⁱ, —NR⁵ⁱR^5j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^5f, R^5g, R^5h, R⁵ⁱ, and R^5jare each independently hydrogen, —C_1-8alkyl, —C_1-8alkoxy, hydroxy, C_1-8alkoxy-C_1-8alkyl-, —C_2-8alkenyl, —C_2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is hydrogen, —C_1-8alkyl, —OR^6a, or —NR^6aR^6b, said —C_1-8alkyl is optionally substituted with at least one substituents R^6d;

R^6aand R^6bare each independently hydrogen or —C_1-8alkyl;

each Rod is independently F, Cl, or —OR^6f; and

R^6fis hydrogen or C_1-8alkyl.