SUBSTITUTED PYRROLO[3,4-c]PYRIDINES AS HPK1 ANTAGONISTS

A method of treating an HPK1-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein:
• X is —NR—;
• R1 is a 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
• wherein the 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;
• wherein the 8- to 10-membered heterocyclyl is bicyclic and saturated or partially unsaturated;
• wherein the 5- to 6-membered heteroaryl is monocyclic;
• wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein the 8- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein the 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected RC substituents;
• R2 is a 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 6- to 11-membered cyclyl, phenyl, or 5- to 6-membered heteroaryl;
• wherein the 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;
• wherein the 6- to 11-membered cyclyl is (a) bicyclic, (b) fused, bridged, or spirocyclic, and (c) saturated, partially unsaturated, or fully unsaturated;
• wherein the 5- or 6-membered heteroaryl is monocyclic;
• wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the-group consisting of N, O, and S;
• wherein the 6- to 11-membered cyclyl contains 0, 1, 2, or 3 heteroatoms independently selected from the-group consisting of N, O, and S;
• wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein the 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 6- to 11-membered cyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected RC substituents;
• each R3 is independently H or C1-6 aliphatic, wherein the C1-6 aliphatic is substituted with s independently selected RD substituents;
• each RC is independently halogen, CN, NO2, C1-6 aliphatic, C(O)R, C(O)NR2, C(O)NROR, C(O)OR, NR2, NRC(NR)NR2, NRCN, NRC(O)R, NRC(O)NR2, NRC(O)OR, NRNR2, NRS(O)R, NRS(O)2R, NRS(O)2NR2, N═S(O)R2, OR, OC(O)R, OC(O)NR2, ═O, P(O)R2, P(O)RNR2, P(O)ROR, SR, S(O)R, S(O)2R, S(NR)(O)R, S(O)NR2, S(O)2NR2, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 11-membered cyclyl, 6- to 11-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl;
• wherein each 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is independently monocyclic and saturated or partially unsaturated;
• wherein each 5- to 8-membered cyclyl is independently (a) bicyclic, (b) bridged, and (c) saturated or partially unsaturated;
• wherein each 6- to 11-membered cyclyl is independently spirocyclic and saturated or partially unsaturated;
• wherein each 6- to 11-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;
• wherein each 5- or 6-membered heteroaryl is independently monocyclic;
• wherein each 8- to 10-membered heteroaryl is independently bicyclic;
• wherein each 3- to 7-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, P, Si, and S;
• wherein each 5- to 8-membered cyclyl and 6- to 11-membered cyclyl independently contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein each 6- to 11-membered heterocyclyl independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein each 5- or 6-membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein each 8- to 10-membered heteroaryl independently contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein each C1-6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 11-membered cyclyl, 6- to 11-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl is independently substituted with r independently selected R substituents and s independently selected RD substituents;
• each RD is independently halogen, CN, NO2, C(O)R, C(O)NR2, C(O)NROR, C(O)OR NR2, NRC(NR)NR2, NRCN, NRC(O)R, NRC(O)NR2, NRC(O)OR, NRNR2, NRS(O)R, NRS(O)2R, NRS(O)2NR2, N═S(O)R2, OR, OC(O)R, OC(O)NR2, ═O, P(O)R2, P(O)RNR2, P(O)ROR SR, S(O)R, S(O)2R, S(NR)(O)R, S(O)NR2, S(O)2NR2;
• each R is independently hydrogen, —CN, halogen, C1-6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 10-membered cyclyl, 6- to 11-membered heterocyclyl, 7- to 12-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl;
• wherein each 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is independently monocyclic and saturated or partially unsaturated;
• wherein each 5- to 8-membered cyclyl is independently (a) bicyclic, (b) bridged, and (c) saturated or partially unsaturated;
• wherein each 6- to 10-membered cyclyl is independently spirocyclic and saturated or partially unsaturated;
• wherein each 6- to 11-membered heterocyclyl and 7- to 12-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;
• wherein each 5- or 6-membered heteroaryl is independently monocyclic;
• wherein each 8- to 10-membered heteroaryl is independently bicyclic;
• wherein each 3- to 7-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein each 5- to 8-membered cyclyl and 6- to 10-membered cyclyl independently contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
• wherein each 6- to 11-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein each 7- to 12-membered heterocyclyl, 5- or 6-membered heteroaryl, and 8- to 10-membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein each C1-6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 10-membered cyclyl, 6- to 11-membered heterocyclyl, 7- to 12-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl is independently substituted with s independently selected RD substituents;
• or
• any two R groups, together with the nitrogen heteroatom to which they are attached, independently forms a 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, or 8- to 10-membered heteroaryl;
• wherein each 4- to 7-membered heterocyclyl is independently monocyclic and saturated, partially unsaturated, or fully saturated;
• wherein each 7- to 12-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;
• wherein each 8- to 10-membered heteroaryl is independently bicyclic;
• wherein each 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, and 8- to 10-membered heteroaryl optionally and independently contains 1, 2, or 3 additional heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein each 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, and 8- to 10-membered heteroaryl is independently substituted with s independently selected RD substituents;
• each q is independently 0, 1, 2, 3, or 4;
• r is 0, 1, 2, 3, or 4;
• and
• s is 0, 1,2,3, or 4.