US 12,252,488 B2
HPK1 antagonists and uses thereof
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); William Sinko, Roslindale, MA (US); Shawn Watts, Portland, OR (US); Mark Anthony Ashwell, Carlisle, MA (US); and Byron Scott Delabarre, Arlington, MA (US)
Assigned to Nimbus Saturn, Inc., Boston, MA (US)
Filed by Nimbus Saturn, Inc., Cambridge, MA (US)
Filed on Feb. 11, 2022, as Appl. No. 17/650,732.
Claims priority of provisional application 63/148,857, filed on Feb. 12, 2021.
Prior Publication US 2023/0096641 A1, Mar. 30, 2023
Int. Cl. C07D 471/04 (2006.01); C07D 401/14 (2006.01); C07D 453/06 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 401/14 (2013.01); C07D 453/06 (2013.01); C07D 519/00 (2013.01)] 22 Claims
 
1. A compound of formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR3;
Y is N, CH or CR2; Z is N, CH or CR2; A is CH or CR2;
L is —NR—;
R1 is selected from phenyl and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of RC;
each R2 is independently selected from phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6-11 membered saturated, partially unsaturated, or unsaturated fused, bridged, or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of RD;
each R3 is independently selected from H; C1-6 aliphatic; and phenyl; each of which is substituted with s instances of RE; or R3 is halogen, —CN, or —C(O)OR;
R4 is H;
each instance of RC, RD, RE, and RF is independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —N═S(O)R2, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR2, —P(O)(R)OR, or —P(O)R2; or each instance of RC, RD, RE, and RF is independently an optionally substituted group selected from C1-6 aliphatic; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with u instances of R;
each R is independently hydrogen, —CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6-11 membered saturated or partially unsaturated bicyclic heteroocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
m is 1, 2, or 3;
n is 0, 1, or 2;
each of q, r, s, and t is independently 0, 1, 2, 3, or 4; and
u is 0, 1, 2, 3, or 4.