Aminopyrazine compounds as HPK1 inhibitor and the use thereof

1 . A compound of Formula (I):

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

wherein:

Cy 1 is cycloalkyl, aryl, monocyclic heterocyclyl, monocyclic heteroaryl, bicyclic fused heteroaryl, or bicyclic fused heterocyclyl;

L 1 is selected from a single bond, alkylene, —O—, —NR a —, —S—, —S(O)—, —S(O) 2 —, -cycloalkylene, * 1 -O-alkylene-** 1 , * 1 -alkylene-O—** 1 , * 1 —NR c -alkylene-** 1 , * 1 -alkylene-NR c —** 1 , alkenylene, or alkynylene; wherein * 1 refers to the position attached to the Cy 1 moiety, and ** 1 refers to the position attached to the aminopyrazine moiety;

R 1 , R 2 , and R 4 at each occurrence are independently hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR a , —SO 2 R a , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a R b , —NR a COR b , —NR a CONR b R c , —NR a CO 2 R b , —NR a SONR b R c , —NR a SO 2 NR b R c , or —NR a SO 2 R b , 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 R d ,

R 3 is hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 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 R d ;

R a , R b , and R c are each independently hydrogen, deuterium, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 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 substituent R c ; or

(R a and R b ), (R b and R c ), or (R c and R a ), 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 heteroatom(s) independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R e ;

R d and R e are each independently halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR f , —SO 2 R f , —SO 2 NR f R g , —COR f , —CO 2 R f , —CONR f R g , —C(═NR f )NR g R h , —NR f R g , —NR f COR g , —NR f CONR g R h , —NR f CO 2 R f , —NR f SONR f R g , —NR f SO 2 NR g R h , or —NR f SO 2 R g , 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 substituent selected from halogen, —C 1-8 alkyl, —OR i , —NR i R j , —CO—NR i R j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R f , R g , R h , R i , and R j are each independently hydrogen, —C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m, n and t are each independently 0, 1, 2, 3 or 4; and

p and s are each independently 0, 1, 2, 3, or 4.

2 . The compound according to claim 1 , wherein L 1 is a single bond, —CR a R b —, —O—, —NR a , * 1 —CR a R b —NR c ** 1 , * 1 —O—CR a R b —** 1 , or —S—; and

a) R a , R b , and R c are each independently hydrogen, deuterium, halogen, —C 1-8 alkyl, or C 3-8 cycloalkyl, each of said —C 1-8 alkyl or C 3-8 cycloalkyl is optionally substituted with OR f ; R f is each independently hydrogen or —C 1-8 alkyl; or R a and R b together with the carbon atom to which they are attached, form a 3- to 5-membered ring; or

b) R a , R b and R c are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, pentyl, or hexyl; each of said methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, pentyl, or hexyl is optionally substituted with OH.

3 . The compound according to claim 2 , wherein:

L 1 is selected from a single bond, —O—, * 1 —CH 2 —O—** 1 , * 1 —CHCH 3 —O—** 1 , * 1 —CH 2 —NH—** 1 , * 1 —CH 2 —N(CH 3 )—** 1 , * 1 —C(CH 3 ) 2 —O—** 1 , or * 1 —CF 2 —O—** 1 ;

m is 1;

R 1 is selected from hydrogen, —C 1-8 alkyl, OR a , —NR a R b , or halogen, said —C 1-8 alkyl is optionally substituted with at least one halogen;

R a and R b are each independently hydrogen or —C 1-8 alkyl;

p is 1 and s is 1, or p is 0 and s is 2;

n is 0;

R 3 is selected from —C 1-8 alkyl or C 4-8 heterocyclyl, said —C 1-8 alkyl and C 4-8 heterocyclyl are optionally substituted with R d ;

R d is selected from —C 1-8 alkyl, —NR f R g or —CONR f R g ; and

R f and R g are each independently hydrogen or —C 1-8 alkyl.

4 . The compound according to claim 3 , wherein R 3 is selected from methyl, ethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl, or piperidinyl, said methyl, ethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl, or piperidinyl is optionally substituted with R d ; R d is selected from methyl, —NR f R g or —CONR f R g ; and R f and R g are each independently hydrogen, methyl, or butyl.

5 . The compound according to claim 1 , wherein the compound has a structure of Formula (Ia) or Formula (Ib):

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

6 . The compound according to claim 5 , wherein R 1 and R 3 are each independently selected from hydrogen, —CH 3 , OCH 3 , halogen, —NHCH 3 , —NHCH 2 CH 3 ,

CHF 2 , —CF 3 or

7 . The compound according to claim 5 , wherein the compound has a structure selected from Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ii), Formula (Ik), Formula (Il), Formula (Im), or Formula (In):

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

8 . The compound according to claim 7 , wherein the compound has a structure selected from Formula (Ic1), Formula (Ic2), Formula (Ic3), Formula (Ic4), Formula (Ic5), Formula (Ic6), Formula (Ic7), Formula (Ic8), Formula (Ic9), Formula (Ic10), Formula (Ic11), Formula (Ic12), Formula (Ic13), Formula (Ic14), Formula (Ic15), Formula (Id1), Formula (Ie1), Formula (Ih1), Formula (Ii1), Formula (Ie2), or Formula (Ik1):

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

wherein R e is hydrogen or —C 1-8 alkyl.

9 . The compound according to claim 8 , wherein:

a) Cy 1 is selected from 3- to 8-membered monocyclic heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), wherein Cy 1 is optionally substituted with —(R 4 );

b) Cy 1 is selected from oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azocanyl, azetidinyl, dihydropyridinyl, tetrahydropyridinyl, pyranyl, homopiperidinyl, homopiperazinyl, azepanyl, oxepanyl, thiepanyl, oxathianyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl, wherein Cy 1 is optionally substituted with —(R 4 );

c) Cy 1 is monocyclic or bicyclic aryl group optionally substituted with —(R 4 );

d) Cy 1 is 5- or 6-membered heteroaryl optionally substituted with —(R 4 );

e) Cy 1 is selected from pyridyl, cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, oxadiazolyl, phthalazinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrrolyl, or triazoly, wherein Cy 1 is optionally substituted with —(R 4 ) t ; or

f) Cy 1 is selected from 7 to 12-membered bicyclic fused heteroaryl or heterocyclyl comprising one or two or three heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), wherein Cy 1 is optionally substituted with —(R 4 ) t .

10 . The compound according to claim 9 , wherein:

a) Cy 1 is selected from piperidinyl, dihydropyridinyl, or pyrrolidinyl, wherein Cy 1 is optionally substituted with —(R 4 ) t ; t=0 or 1; and each R 4 is selected from hydrogen, oxo, or —C 1-8 alkyl; or

b) 2-pyridyl, 3-pyridyl, 4-pyridyl, cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thien-2-yl, thien-3-yl, triazinyl, benzothienyl, furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, phthalazinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl, wherein Cy 1 is optionally substituted with —(R 4 ) t ; or

c) Cy 1 is naphthyl or phenyl, wherein Cy 1 is optionally substituted with —(R 4 ) t ; t=0, 1, 2 or 3; each R 4 is independently selected from hydrogen, halogen, —CN, —COOR a , —OR a , —CONR a R b , —NR a R b , or —C 1-8 alkyl optionally substituted with halogen or —OR f ; and R a , R b and R f are each independently hydrogen, —C 1-8 alkyl, —C 3-6 cycloalkyl, or —C 3-6 heterocyclyl; or R a and R b , together with the nitrogen atom to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s); or

d) Cy 1 is selected from indazole, benzoimidazole, quinoline, pyridooxazine, pyrrolopyridine, isoquinoline, benzoxazine, quinoxaline, isochromene, pyranopyrazole, pyranopyridine, benzodioxole, quinazoline, benzoxazole, indole, pyrrolopyrazine, pyrrolopyrimidine, imidazopyrimidine, or thienopyridine, wherein one or two carbon-carbon double bond or carbon-nitrogen double bond is optionally hydrogenated and Cy 1 is optionally substituted with —(R 4 ) t ; t is 0, 1 or 2; each R 4 is halogen, —C 1-8 alkyl, oxo, or —OR a , said —C 1-8 alkyl is optionally substituted with halogen, hydroxy or alkoxy; and R a is hydrogen or —C 1-8 alkyl.

11 . The compound according to claim 9 , wherein

is selected from:

or

12 . The compound according to claim 9 , wherein Cy 1 is selected from

wherein Cy 1 is optionally substituted with —(R 4 ), t is 0, 1, 2 or 3, provided that chemical valency rules are met.

13 . The compound according to claim 9 , wherein Cy 1 is selected from

wherein Cy 1 is optionally substituted with —(R 4 ).

14 . The compound according to claim 1 , which is selected from;

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

15 . A pharmaceutical composition comprising the compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

16 . A method of treating cancer, comprising administering a subject in need thereof the compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17 . The compound according to claim 12 , wherein t=1 or 2; and each R 4 is independently selected from hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, oxo, —CN, —OR a , —CONR a R b , —NR a COR b , or —NR a R b , each of said —C 1-8 alkyl, —C 2-8 alkynyl, cycloalkyl or heterocyclyl is optionally substituted with at least one R d .

18 . The compound according to claim 17 , wherein:

a) each R 4 is independently —C 1-8 alkyl which is optionally substituted with at least one halogen or cyano;

b) each R 4 is independently cycloalkyl which is optionally substituted with cyano, —C 1-8 alkyl or hydroxy;

c) each R 4 is heterocyclyl which is optionally substituted with halogen or —C 1-8 alkyl;

d) each R 4 is —C 2-8 alkynyl optionally substituted with at least one R d ; R d is each independently —C 1-8 alkyl, cyclopropyl, cyclohexyl, aryl, pyridyl, pyrazlyl, or thiazolyl, —SO 2 R f or —CONR f R g , each of said —C 1-8 alkyl, cyclopropyl, cyclohexyl, aryl, pyridyl, pyrazlyl, or thiazolyl is optionally substituted with at least one substituent selected from halogen, —C 1-8 alkyl, —OR i , or —NR i R j ; and R f , R g , R i , and R j are each independently hydrogen or —C 1-8 alkyl; or

e) each R 4 is —OR a , —CONR a R b , or —NR a R b , wherein R a and R b are each independently hydrogen, cycloalkyl, aryl, heterocyclyl, or —C 1-8 alkyl which is optionally substituted with R e ; and R e is selected from cycloalkyl, aryl or heterocyclyl, each of cycloalkyl, aryl or heterocyclyl is optionally substituted with at least one —CO—NR i R j ; and R i , and R j are each independently hydrogen or —C 1-8 alkyl; or wherein R a and R b together with the nitrogen atom to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R e .