US 12,110,278 B2
Selective JAK2 pseudokinase ligands and methods of use
William L. Jorgensen, Deep River, CT (US); and Joseph Schlessinger, Woodbridge, CT (US)
Assigned to Yale University, New Haven, CT (US)
Filed by YALE UNIVERSITY, New Haven, CT (US)
Filed on Oct. 13, 2021, as Appl. No. 17/500,622.
Claims priority of provisional application 63/091,001, filed on Oct. 13, 2020.
Prior Publication US 2022/0112166 A1, Apr. 14, 2022
Int. Cl. C07D 249/14 (2006.01); A61K 31/4196 (2006.01); A61K 31/4245 (2006.01); A61K 31/4439 (2006.01); A61K 45/06 (2006.01); C07D 401/12 (2006.01); C07D 405/12 (2006.01); C07D 413/12 (2006.01)
CPC C07D 249/14 (2013.01) [A61K 31/4196 (2013.01); A61K 31/4245 (2013.01); A61K 31/4439 (2013.01); A61K 45/06 (2013.01); C07D 401/12 (2013.01); C07D 405/12 (2013.01); C07D 413/12 (2013.01)] 21 Claims
 
1. A compound of Formula Ia, or a pharmaceutically acceptable salt or tautomer thereof:

OG Complex Work Unit Chemistry
wherein:
X is N;
A′ is independently selected from the group consisting of F, Cl, Br, I, OC(═O)N(R)2, CN, NO2, CF3, OCF3, (C1-C6)hydrocarbyl, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R, N(R)C(═O)N(R)2, and C(═NH)N(R)2,
wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C6-C6)hydrocarbyl; or
wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can combine with the nitrogen atom or atoms to form a heterocyclyl;
R2 is:

OG Complex Work Unit Chemistry
wherein:
each of Z1, Z2, Z3, Z4, and Z5 is C-A2, provided at least one of Z1 and Z5 is CH;
each occurrence of A2 is independently selected from the group consisting of

OG Complex Work Unit Chemistry
 F, Cl, Br, I, OR, OC(═O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, C2-6 alkenyl-COOR, C2-6 alkenyl-CONR2, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R, N(R)C(═O)N(R)2, and C(═NH)N(R)2,
provided at least one occurrence of A2 is not hydrogen;
wherein zero, one, or two A2 can be independently

OG Complex Work Unit Chemistry
 wherein Y, Z, and Q are each independently C—R5 or N, wherein each R5 is independently selected from the group consisting of H, F, Cl, Br, I, OR, OC(═O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2 N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R, N(R)C(═O)N(R)2, and C(═NH)N(R)2;
wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C6-C6)hydrocarbyl; and
m is 1, 2, 3, 4, or 5.