US 11,919,839 B2
Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
Kenneth W. Bair, Wellesley, MA (US); Nicholas Barczak, Waterford, CT (US); Bingsong Han, Westwood, MA (US); David R. Lancia, Jr., Boston, MA (US); Cuixian Liu, Madison, CT (US); Matthew W. Martin, Arlington, MA (US); Pui Yee Ng, Lexington, MA (US); Aleksandra Rudnitskaya, Roslindale, MA (US); Jennifer R. Thomason, Clinton, MA (US); Mary-Margaret Zablocki, Revere, MA (US); and Xiaozhang Zheng, Lexington, MA (US)
Assigned to VALO HEALTH, INC., Boston, MA (US)
Filed by Valo Health, Inc., Boston, MA (US)
Filed on Apr. 23, 2021, as Appl. No. 17/238,529.
Application 17/238,529 is a continuation of application No. 16/689,252, filed on Nov. 20, 2019, granted, now 10,988,441.
Application 16/689,252 is a continuation of application No. 16/387,937, filed on Apr. 18, 2019, granted, now 10,508,077, issued on Dec. 17, 2019.
Application 16/387,937 is a continuation of application No. 15/925,559, filed on Mar. 19, 2018, granted, now 10,266,487, issued on Apr. 23, 2019.
Application 15/925,559 is a continuation of application No. 15/688,732, filed on Aug. 28, 2017, abandoned.
Application 15/688,732 is a continuation of application No. 15/067,605, filed on Mar. 11, 2016, granted, now 9,745,253, issued on Aug. 29, 2017.
Claims priority of provisional application 62/270,371, filed on Dec. 21, 2015.
Claims priority of provisional application 62/184,335, filed on Jun. 25, 2015.
Claims priority of provisional application 62/132,895, filed on Mar. 13, 2015.
Prior Publication US 2022/0073452 A1, Mar. 10, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07C 259/06 (2006.01); A61K 31/185 (2006.01); A61K 31/277 (2006.01); A61K 31/397 (2006.01); A61K 31/4035 (2006.01); A61K 31/407 (2006.01); A61K 31/417 (2006.01); A61K 31/4184 (2006.01); A61K 31/435 (2006.01); A61K 31/438 (2006.01); A61K 31/44 (2006.01); A61K 31/4439 (2006.01); A61K 31/451 (2006.01); A61K 31/495 (2006.01); A61K 31/5377 (2006.01); C07D 207/10 (2006.01); C07D 207/267 (2006.01); C07D 209/08 (2006.01); C07D 209/42 (2006.01); C07D 209/44 (2006.01); C07D 209/46 (2006.01); C07D 211/16 (2006.01); C07D 211/58 (2006.01); C07D 213/56 (2006.01); C07D 213/65 (2006.01); C07D 213/75 (2006.01); C07D 213/81 (2006.01); C07D 215/12 (2006.01); C07D 221/20 (2006.01); C07D 231/14 (2006.01); C07D 231/18 (2006.01); C07D 233/36 (2006.01); C07D 233/38 (2006.01); C07D 233/68 (2006.01); C07D 235/14 (2006.01); C07D 235/30 (2006.01); C07D 239/20 (2006.01); C07D 239/22 (2006.01); C07D 241/08 (2006.01); C07D 241/12 (2006.01); C07D 249/18 (2006.01); C07D 257/04 (2006.01); C07D 261/18 (2006.01); C07D 277/56 (2006.01); C07D 295/155 (2006.01); C07D 295/192 (2006.01); C07D 307/68 (2006.01); C07D 317/68 (2006.01); C07D 333/70 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 405/12 (2006.01); C07D 409/04 (2006.01); C07D 409/12 (2006.01); C07D 417/04 (2006.01); C07D 417/12 (2006.01); C07D 471/04 (2006.01); C07D 471/10 (2006.01); C07D 487/04 (2006.01); C07D 487/08 (2006.01); C07D 487/10 (2006.01); C07D 491/10 (2006.01); C07D 493/08 (2006.01); C07D 495/10 (2006.01); C07D 498/04 (2006.01); C07D 513/10 (2006.01)
CPC C07C 259/06 (2013.01) [A61K 31/185 (2013.01); A61K 31/277 (2013.01); A61K 31/397 (2013.01); A61K 31/4035 (2013.01); A61K 31/407 (2013.01); A61K 31/417 (2013.01); A61K 31/4184 (2013.01); A61K 31/435 (2013.01); A61K 31/438 (2013.01); A61K 31/44 (2013.01); A61K 31/4439 (2013.01); A61K 31/451 (2013.01); A61K 31/495 (2013.01); A61K 31/5377 (2013.01); C07D 207/10 (2013.01); C07D 207/267 (2013.01); C07D 209/08 (2013.01); C07D 209/42 (2013.01); C07D 209/44 (2013.01); C07D 209/46 (2013.01); C07D 211/16 (2013.01); C07D 211/58 (2013.01); C07D 213/56 (2013.01); C07D 213/65 (2013.01); C07D 213/75 (2013.01); C07D 213/81 (2013.01); C07D 215/12 (2013.01); C07D 221/20 (2013.01); C07D 231/14 (2013.01); C07D 231/18 (2013.01); C07D 233/36 (2013.01); C07D 233/38 (2013.01); C07D 233/68 (2013.01); C07D 235/14 (2013.01); C07D 235/30 (2013.01); C07D 239/20 (2013.01); C07D 239/22 (2013.01); C07D 241/08 (2013.01); C07D 241/12 (2013.01); C07D 249/18 (2013.01); C07D 257/04 (2013.01); C07D 261/18 (2013.01); C07D 277/56 (2013.01); C07D 295/155 (2013.01); C07D 295/192 (2013.01); C07D 307/68 (2013.01); C07D 317/68 (2013.01); C07D 333/70 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 405/12 (2013.01); C07D 409/04 (2013.01); C07D 409/12 (2013.01); C07D 417/04 (2013.01); C07D 417/12 (2013.01); C07D 471/04 (2013.01); C07D 471/10 (2013.01); C07D 487/04 (2013.01); C07D 487/08 (2013.01); C07D 487/10 (2013.01); C07D 491/10 (2013.01); C07D 493/08 (2013.01); C07D 495/10 (2013.01); C07D 498/04 (2013.01); C07D 513/10 (2013.01); Y02A 50/30 (2018.01)] 20 Claims
 
1. A method of treating, inhibiting, or eliminating a disease or disorder associated with inhibition of HDAC8, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
X1, X2, X3, and X4 are each CH;
Ra is hydrogen;
Rb is —C(O)Rc;
or alternatively, Ra and Rb are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more Rd;
Rc is aryl, optionally substituted with one or more Rd or Re;
Rd is hydrogen, C1-C6 alkyl, oxo, C3-C8 cycloalkyl, or —ORe,
or two Rd when attached to the same carbon atom can form a C3-C12 spirocycle or a 3- to 12-membered spiroheterocycle;
Re is aryl; and
A is hydrogen;
with the proviso that:
when Ra is H and Rb is —C(O)Rc, then Rc cannot be phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl.