HPK1 inhibitor, preparation method therefor and use thereof

1 . A compound with a structure as shown as general formula (1), or isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

in formula (1):

“*” denotes a chiral center;

n is an integer of 0, 1, 2 or 3;

X is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

Y is —O—, —NH— or —N(C 1-3 alkyl)-;

when each R is linked to a different carbon atom, each R is independently H or C 1-3 alkyl; when two R are simultaneously linked to the same carbon atom, the two R may independently be H or C 1-3 alkyl or form a carbon group (C═O) with a carbon atom linked thereto;

R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, hydroxy-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy-substituted C 1-6 alkyl or cyano-substituted C 1-6 alkyl;

A is the following group:

 and wherein “**” denotes a position linking to a group B;

B is C 6-10 aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl consists of at least 1 carbon atom and 1-4 heteroatoms selected from the group consisting of N, O and S; wherein the N or S atom may be oxidized; wherein ring carbon atoms of the 5-10 membered heteroaryl may be optionally substituted with oxygen to form a carbonyl group (C═O); and the C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1-5 substituents independently selected from R 2 ;

R 2 is independently halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-3 alkoxy-substituted C 1-6 alkyl, C 1-3 haloalkoxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, OR 3 , SR 3 , C(O)R 3 , S(O)R 3 , S(O) 2 R 3 , C(O)OR 3 , OC(O)R 3 , NR 4 R 5 , P(O)R 4 R 5 , C(O)NR 4 R 5 , OC(O)NR 4 R 5 , —C 1-6 alkyl-NR 4 R 5 , —O—C 1-6 alkyl-NR 4 R 5 , —C 1-6 alkyl-OR 3 , —O—C 1-6 alkyl-R 3 , -hydroxy-substituted C 1-6 alkyl-R 3 , —NR 6 C(O)R 3 , —NR 6 S(O) 2 R 3 , —NR 6 CO—C 1-3 alkyl-R 3 or —NR 6 CO—C 1-3 alkyl-NR 4 R 5 ;

or two adjacent R 2 substituents on ring B, together with atoms linked thereto, form a fused 4-7 membered heterocycloalkyl or C 3-7 cycloalkyl, wherein the fused 4-7 membered heterocycloalkyl contains at least 1 carbon atom and 1-4 heteroatoms selected from the group consisting of N, O and S; wherein the N or S atom may be oxidized; wherein ring carbon atoms of the fused 4-7 membered heterocycloalkyl may be optionally substituted with oxygen to form a carbonyl group (C═O); and the fused 4-7 membered heterocycloalkyl or the C 3-7 cycloalkyl is optionally substituted with 1-5 substituents independently selected from R 7 ;

each R 3 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-7 membered heteroaryl, cyano-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-3 alkoxy-substituted C 1-6 alkyl or C 1-3 haloalkoxy-substituted C 1-6 alkyl;

each of R 4 and R 5 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, cyano-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-3 alkoxy-substituted C 1-6 alkyl or C 1-3 haloalkoxy-substituted C 1-6 alkyl, C 6-10 aryl-substituted C 1-6 alkyl or 5-10 membered heteroaryl-substituted C 1-6 alkyl, or R 4 and R 5 , together with an N atom, form 4-12 membered heterocycloalkyl, the 4-12 membered heterocycloalkyl optionally being substituted with 1-5 substituents independently selected from R 7 ;

each R 6 is H or C 1-3 alkyl;

each R 7 is OH, CN, NH 2 , NHMe, NMe 2 , C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy.

2 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), X is H, F, Cl, Me, Et, CF 3 , isopropyl or cyclopropyl.

3 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), Y is —O—, —NH—, —N(Me)- or —N(Et)-.

4 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), R is H or Me.

5 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), R 1 is H, Me, Et

6 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), B is

R 2 is independently H, CH 3 , F, Cl, OCH 3 , CF 3 , CN, CONH 2 ,

NHSO 2 CH 3 , NHCOCH 3 , PO(CH 3 ) 2 , SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCH 3 , CH 2 NHCH 3 , CH 2 NHCH 2 CH 3 ,

CH(CH 3 )NHCH 3 , CH 2 CN, CH 2 OCH 3 ,

NHCOCH 2 N(CH 3 ) 2 ,

OCON(CH 3 ) 2 ,

OCH 2 CH 2 CH 2 NH 2 , OCH 2 CH 2 CH 2 N(CH 3 ) 2 ,

and m is an integer of 0, 1, 2 or 3.

7 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), B is

8 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein in general formula (1), B is

9 . The compound, or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 , wherein the compound has one of the following structures:

10 . A pharmaceutical composition, comprising a pharmaceutically acceptable excipient or carrier, and the compound or the isomers, the crystalline forms, the pharmaceutically acceptable salts, the hydrates or the solvates thereof according to claim 1 as an active ingredient.