US 12,377,080 B2
Allosteric EGFR inhibitors and methods of use thereof
Courtney A. Cullis, Bedford, MA (US); Krista E. Gipson, Medford, MA (US); Yongbo Hu, Winchester, MA (US); Shih-Chung Huang, Lexington, MA (US); Nathanael S. Gray, Jamaica Plain, MA (US); David A. Scott, Newton, MA (US); Thomas Gero, Stow, MA (US); David Heppner, Brookline, MA (US); Tyler Beyett, Brookline, MA (US); Ciric To, Medford, MA (US); and Michael Eck, Brookline, MA (US)
Assigned to Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Appl. No. 17/596,720
Filed by Dana-Farber Cancer Institute, Inc., Boston, MA (US)
PCT Filed Jun. 19, 2020, PCT No. PCT/US2020/038672
§ 371(c)(1), (2) Date Mar. 31, 2022,
PCT Pub. No. WO2020/257607, PCT Pub. Date Dec. 24, 2020.
Claims priority of provisional application 63/007,210, filed on Apr. 8, 2020.
Claims priority of provisional application 62/864,899, filed on Jun. 21, 2019.
Prior Publication US 2022/0378757 A1, Dec. 1, 2022
Int. Cl. C07D 471/04 (2006.01); A61K 31/437 (2006.01); A61K 31/444 (2006.01); A61K 31/496 (2006.01); A61K 31/506 (2006.01); A61K 39/395 (2006.01)
CPC A61K 31/437 (2013.01) [A61K 31/444 (2013.01); A61K 31/496 (2013.01); A61K 31/506 (2013.01); A61K 39/3955 (2013.01); C07D 471/04 (2013.01)] 20 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is aryl or 5-to 6-membered heteroaryl;
R2 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted one or two times, independently, with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, NO2, NH2, (CH2)pOH, S(O)qH, S(O)qNH2, or CN;
W and Z are each independently N, CH, CF, or C-(C1-C3 alkyl);
X and Y are each independently N, CH, or CR3;
provided that at least one of W, X, Y, or Z is N, and provided that at least one of W, X, Y, or Z is CH or CR3;
R3, for each occurrence, is halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C6-C10 aryl, 5- to 6-membered heteroaryl, or 5- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5;
R4, for each occurrence, is independently H, (CH2)0-3—(C3-C7 cycloalkyl), (CH2)0-3—(C4-C7 cycloalkenyl), (CH2)0-3—(C6-C10 aryl), (CH2)0-3-(5- to 6-membered heteroaryl), or (CH2)0-3-(5- to 7-membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5;
R5, for each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2)1-3—OH, NH2, OH, CN, (CH2)0-3—(C6-C10 aryl), (CH2)0-3-(5- to 6-membered heteroaryl), or (CH2)0-3-(5- to 7-membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, (CH2)1-2—OH, C(O)(CH2)1-2—OH, and C(O)O(C1-C6 alkyl);
n is 1 or 2;
p is 1, 2, 3, or 4; and
q is 0, 1, or 2.