HPK1 inhibitors, preparation method and application thereof

A compound of Formula Y or Z, or a pharmaceutically acceptable salt thereof,

• wherein:
• A is CH;
• Ar is an optionally substituted phenyl or an optionally substituted 5 or 6-membered heteroaryl selected from thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl,
• wherein:
• (i) the optionally substituted 5 or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100, —NR101R102, —C(═O)—R103, —NR101—C(═O)—R103, —NR101—SO2—R104, —SO2—R104, —NR101—POR105R106, —POR105R106, —SR107, halogen, and —CN,
• wherein each R100 is independently selected from hydrogen, an oxygen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• each R101 or R102 is independently selected from hydrogen, a nitrogen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• each R103 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
• each R104 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
• each R105 or R106 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
• each R107 is independently selected from hydrogen, a thiol protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents each independently selected from 1) C1-7 alkyl optionally substituted with 1-3 substituents each independently selected from halogen, oxo, —OH or protected OH, optionally substituted C1-4 alkoxy, —NH2 or protected NH2, —N(C0-4 alkyl)(C0-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 4-8 membered heterocyclyl;
• 2) halogen;
• 3) —OH or protected OH;
• 4) optionally substituted C1-4 alkoxy;
• 5) —NH2 or protected NH2;
• 6) —N(C0-4 alkyl)(C0-4 alkyl), wherein the alkyl is optionally substituted;
• 7) optionally substituted C3-6 cycloalkyl;
• 8) optionally substituted phenyl;
• 9) optionally substituted 5- or 6-membered heteroaryl;
• and 10) optionally substituted 4-8 membered heterocyclyl;
• or
• (ii) when applicable, two adjacent substituents of the optionally substituted 5 or 6-membered heteroaryl form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring;
• L is a linker of formula J1-J2-J3, wherein each of J1, J2, and J3 is independently null, O, S, SO, SO2, C═O, NH, optionally substituted C1-4 alkylene, provided that L does not contain O—O, O—N, S—S, N—S, O—S, or N—N bond, and at most one of J1, J2, and J3 is SO, SO2, or C═O;
• ring B is an aryl or heteroaryl ring;
• n is 0, 1, 2, or 3, as valance permits,
• each RA is independently selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, CN, OH, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, wherein when applicable, two adjacent RA can form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring,
• RB and RC are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or RB and RC together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl,
• RD is hydrogen, optionally substituted C1-5 alkyl, optionally substituted C3-10 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl,
• wherein the triple bond in Formula Y or Z is meta to the linker L;
• and
• wherein unless otherwise indicated,
• (A) the above optionally substituted non-aromatic group is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, —OH, oxo (as applicable), C1-7 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C1-7 alkyl and C1-4 alkoxy;
• and
• (B) the above optionally substituted aromatic group is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, —OH, —CN, C1-7 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C1-7 alkyl and C1-4 alkoxy.