US 12,466,841 B2
Substituted pyrrolo[3,4-c]pyridines as HPK1 antagonists
Neelu Kaila, Lexington, MA (US); Ian Linney, Saffron Walden (GB); Stuart Ward, Saffron Walden (GB); Grant Wishart, Saffron Walden (GB); Benjamin Whittaker, Saffron Walden (GB); Alexandre Cote, West New York, NJ (US); Jeremy Robert Greenwood, Brooklyn, NY (US); and Abba Leffler, Bronx, NY (US)
Assigned to Nimbus Saturn, Inc., Boston, MA (US)
Filed by Nimbus Saturn, Inc., Boston, MA (US)
Filed on Dec. 12, 2023, as Appl. No. 18/536,817.
Application 18/536,817 is a division of application No. 17/656,924, filed on Mar. 29, 2022, granted, now 12,071,442.
Claims priority of provisional application 63/182,313, filed on Apr. 30, 2021.
Claims priority of provisional application 63/167,455, filed on Mar. 29, 2021.
Prior Publication US 2024/0190895 A1, Jun. 13, 2024
Int. Cl. A61K 31/437 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 519/00 (2013.01) [C07D 487/04 (2013.01)] 24 Claims
 
1. A method for inhibiting hematopoietic progenitor kinase 1 (HPK1) activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer 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- 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 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- 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 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)NR2, S(NR)(O)R, S(O)2R, 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, and 8- to 10-membered heteroaryl is independently substituted with r independently selected R substituents and s independently selected RD substituents;
each R is independently H, halogen, CN, 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;
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 substituents, 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 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)NR2, S(NR)(O)R, S(O)2R, or S(O)2NR2;
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.