Pyrrolo[2,3-b]pyrazines as HPK1 inhibitor and the use thereof

Patent metadata

Field	Value
Publication number	US-12454534-B2
Application number	US-202017623732-A
Country	US
Kind code	B2
Filing date	Jul 3, 2020
Priority date	Jul 4, 2019
Publication date	Oct 28, 2025
Grant date	Oct 28, 2025

Abstract

Disclosed herein is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein:
R 1 and R 2 are each hydrogen;
n is 0, 1, 2, 3 or 4;
R 3 and R 4 , at each of its occurrence, are independently F, Cl, —C 1-8 alkyl, cycloalkyl, heterocyclyl, —C 1-8 alkyl-heterocyclyl, —C 1-8 alkyl-cycloalkyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 3a , —SO 2 R 3a , —SO 2 NR 3a R 3b , —COR 3a , —CO 2 R 3a , —CONR 3a R 3b , —C(═NR 3a ) NR 3b R 3c , —NR 3a R 3b , —NR 3a COR 3b , —NR 3a CONR 3 R 3c , —NR 3a CO 2 R 3b , —NR 3a SONR 3b R 3c , —NR 3a SO 2 NR 3b R 3c , or —NR 3a SO 2 R 3b , each of said —C 1-8 alkyl, cycloalkyl, heterocyclyl, or —C 1-8 alkyl-heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R 3d ; or R 3 and R 4 , 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 R 4 , 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 3c are each independently hydrogen, —C 1-8 alkyl, cycloalkyl, or heterocyclyl, each of said-C 1-8 alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituents R 3e ; or
(R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and 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 3d and R 3e are each independently F, Cl, —C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 3f , —SO 2 R 3f , —SO 2 NR 3 R 3g , —COR 3f , —CO 2 R 3f , —CONR 3d R 3e , —C(═NR 3f ) NR 3g R 3h , —NR 3 R 3g , —NR 3f COR 3g , —NR 3 CONR 3g R 3h , —NR 3 CO 2 R 3f , —NR 3f SONR 3 R 3g , —NR 3f SO 2 NR 3g R 3h , or —NR 3 SO 2 R 38 , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from F, Cl, —C 1-8 alkyl, —OR 3i , —NR 3i R 3j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, —C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L 1 is a single bond;

R 5 at each of its occurrence, is each independently —C 1-8 alkyl, cycloalkyl, —C 1-8 alkyl-cycloalkyl, heterocyclyl, —COR 5a , CO 2 R 5a , —CONR 5a R 5b , CH 2 CONR 5a R 5b , —CH 2 CH 2 CONR 5a R 5b , —CH 2 CH 2 CH 2 CONR 5a R 5b CH 2 CH 2 NR 5a R 5b , or —CH 2 CH 2 CH 2 NR 5a R 5b , each of said —C 1-8 alkyl, cycloalkyl, —C 1-8 alkyl-cycloalkyl, or heterocyclyl, is optionally substituted with at least one substituents R 5d ;
R 5a and R 5b are each independently hydrogen, —C 1-8 alkyl, —C 1-8 alkyl-C 1-8 alkoxy, cycloalkyl, —C 1-8 alkyl-heterocyclyl, —C 1-8 alkyl-aryl, heterocyclyl, aryl, or heteroaryl, each of said —C 1-8 alkyl, C 1-8 alkyl-C 1-8 alkoxy, cycloalkyl, —C 1-8 alkyl-heterocyclyl, —C 1-8 alkyl-aryl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R 5e ; or
R 5a and 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 5d and R 5e are each independently hydrogen, F, Cl, —C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 —, —CF 3 , —OR 5f , —SO 2 R 5f , —SO 2 NR 5f R 5g , —POR 5f R 5g , —COR 5f , —CO 2 R 5f , —CONR 5f R 5g , —C(═NR 5h ) NRSR 5g , —NRSR 5g , —NR 5f COR 5g , —NR 5h CONR 5f R 5g , —NR 5g CO 2 R 5h , —NR 5h SONR 5f R 5g , —NR 5h SO 2 NR 5f R 5g , or —NR 5f SO 2 R 5g , each of said —C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from halogen, —C 1-8 alkyl, —OR 5i , —NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 5f , R 5g , R 5h , R 5i , and R 5j are each independently hydrogen, —C 1-8 alkyl, —C 1-8 alkoxy, hydroxy, C 1-8 alkoxy-C 1-8 alkyl-, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 6 is hydrogen, —C 1-8 alkyl, —OR 6a , or —NR 6a R 6b , said —C 1-8 alkyl is optionally substituted with at least one substituents R 6d ;
R 6a and R 6b are each independently hydrogen or —C 1-8 alkyl;
each Rod is independently F, Cl, or —OR 6f ; and
R 6f is hydrogen or C 1-8 alkyl.

2. The compound of claim 1 , wherein:
a) R 3 is —C 1-8 alkyl, —C 1-8 alkyl-heterocyclyl or —C 1-8 alkyl-cycloalkyl, wherein said —C 1-8 alkyl, —C 1-8 alkyl-heterocyclyl or —C 1-8 alkyl-cycloalkyl is optionally substituted with at least one substituent R 3d ; R 3d is independently selected from —C 1-8 alkyl or —OR 3f ; R 3f is each independently hydrogen, —C 1-8 alkyl; or
b) R 3 is —CONR 3a R 3b , R 3a and R 3b are each independently hydrogen or —C 1-8 alkyl, each of said —C 1-8 alkyl is substituted with at least one substituent selected from hydrogen, —OR 3f , CN, or 4-to-7 membered heterocyclyl comprising 1 or 2 heteroatoms selected from nitrogen or oxygen; and R 3f is hydrogen or —C 1-8 alkyl; or
c) R 3 is —CONR 3a R 3b or —NR 3a R 3b ; R 3a and R 3b together with the nitrogen atom to which they are attached forms a 4- to 12-membered ring comprising 1 or 2 additional nitrogen or oxygen heteroatoms as ring members, said ring is optionally substituted with at least one substituent R 3e ; R 3e each is selected from oxo, —C 1-8 alkyl, —OR 3f , or —NR 3f R 3g , said —C 1-8 alkyl is optionally substituted with at least one halogen; and wherein R 3f and R 3g are each independently hydrogen, or —C 1-8 alkyl; or
d) R 3 is selected from

3. The compound of claim 2 , wherein R 3 is selected from

4. The compound of claim 1 , wherein n is 0, 1 or 2; R 4 is selected from F halogen, —C 1-8 alkyl, CN, —OR 3a or —NR 3a CONR 3b R 3c , said-C 1-8 alkyl is optionally substituted with at least one substituent R 3d , R 3a , R 3b and R 3c are each independently hydrogen or —C 1-8 alkyl; and R 3d is each independently F, Cl, or —C 1-8 alkyl.

5. The compound of claim 4 , wherein:
a) n is 1; R 4 is selected from —C 1-8 alkyl, F, CN, OR 3a or —NR 3a CONR 3b R 3c , said —C 1-8 alkyl is optionally substituted with at least one substituent R 3d , R 3a , R 3b and R 3c are each independently hydrogen or —C 1-8 alkyl; and R 3d is each independently F, Cl, or —C 1-8 alkyl; or
b) n is 2; and R 4 is F; or

Assignees

• Beigene Ltd
• Beone Medicines I Gmbh

Inventors

• Li Jing
• Wang Zhiwei
• Xu Sanjia

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title