US 12,264,169 B2
Heteroaryl inhibitors of PDE4
Mark E. Gurney, Grand Rapids, MI (US); Timothy J. Hagen, Lisle, IL (US); Xuesheng Mo, Naperville, IL (US); A. Samuel Vellekoop, Altamont, NY (US); Donna L. Romero, Chesterfield, MO (US); Robert Campbell, Niskayuna, NY (US); Joel R. Walker, Schenectady, NY (US); and Lei Zhu, Schenectady, NY (US)
Assigned to Tetra Discovery Partners, Grand Rapids, MI (US)
Filed by Tetra Discovery Partners, LLC, Grand Rapids, MI (US)
Filed on Jul. 11, 2023, as Appl. No. 18/350,452.
Application 14/938,544 is a division of application No. 14/349,688, granted, now 9,221,843, issued on Dec. 29, 2015, previously published as PCT/US2013/066645, filed on Oct. 24, 2013.
Application 18/350,452 is a continuation of application No. 17/808,439, filed on Jun. 23, 2022, granted, now 11,767,334.
Application 17/808,439 is a continuation of application No. 16/781,748, filed on Feb. 4, 2020, granted, now 11,401,286, issued on Aug. 2, 2022.
Application 16/781,748 is a continuation of application No. 16/396,457, filed on Apr. 26, 2019, granted, now 10,626,129, issued on Apr. 21, 2020.
Application 16/396,457 is a continuation of application No. 16/111,700, filed on Aug. 24, 2018, granted, now 10,364,258, issued on Jul. 30, 2019.
Application 16/111,700 is a continuation of application No. 15/680,842, filed on Aug. 18, 2017, granted, now 10,093,686, issued on Oct. 9, 2018.
Application 15/680,842 is a continuation of application No. 14/938,544, filed on Nov. 11, 2015, granted, now 9,777,024, issued on Oct. 3, 2017.
Claims priority of provisional application 61/776,937, filed on Mar. 12, 2013.
Claims priority of provisional application 61/733,675, filed on Dec. 5, 2012.
Claims priority of provisional application 61/718,285, filed on Oct. 25, 2012.
Prior Publication US 2023/0348501 A1, Nov. 2, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 213/72 (2006.01); A61K 31/435 (2006.01); A61K 31/44 (2006.01); A61K 31/4418 (2006.01); A61K 31/496 (2006.01); A61K 31/505 (2006.01); A61K 31/506 (2006.01); A61K 31/517 (2006.01); A61K 31/519 (2006.01); A61K 31/53 (2006.01); A61K 31/5377 (2006.01); A61K 31/69 (2006.01); A61K 45/06 (2006.01); C07D 213/56 (2006.01); C07D 213/74 (2006.01); C07D 221/04 (2006.01); C07D 239/26 (2006.01); C07D 239/70 (2006.01); C07D 251/22 (2006.01); C07D 251/30 (2006.01); C07D 251/42 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 403/12 (2006.01); C07D 405/04 (2006.01); C07D 409/04 (2006.01); C07D 409/14 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 495/04 (2006.01); C07F 5/02 (2006.01)
CPC C07F 5/027 (2013.01) [A61K 31/435 (2013.01); A61K 31/44 (2013.01); A61K 31/4418 (2013.01); A61K 31/496 (2013.01); A61K 31/505 (2013.01); A61K 31/506 (2013.01); A61K 31/517 (2013.01); A61K 31/519 (2013.01); A61K 31/53 (2013.01); A61K 31/5377 (2013.01); A61K 31/69 (2013.01); A61K 45/06 (2013.01); C07D 213/56 (2013.01); C07D 213/72 (2013.01); C07D 213/74 (2013.01); C07D 221/04 (2013.01); C07D 239/26 (2013.01); C07D 239/70 (2013.01); C07D 251/22 (2013.01); C07D 251/30 (2013.01); C07D 251/42 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 403/12 (2013.01); C07D 405/04 (2013.01); C07D 409/04 (2013.01); C07D 409/14 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 495/04 (2013.01); C07F 5/025 (2013.01)] 31 Claims
 
1. A method for treating or reducing the symptoms of a central nervous system disease in a patient in need thereof, wherein the disease is characterized by expression of PDE4D and degradation of learning and memory ability, the method comprising the administration to the subject a compound of structural Formula XI:

OG Complex Work Unit Chemistry
and/or a salt thereof, wherein:
Y is C(R2)2;
X is chosen from CH and N;
n is an integer chosen from 0, 1 or 2;
each R2 is independently chosen from hydrogen and lower alkyl;
R3 is chosen from methyl, ethyl, trifluoromethyl, and cyclopropyl;
R4 is chosen from hydrogen and ethyl;
R5 is either benzoxaborole, or is chosen from phenyl and pyridinyl, either of which is para-substituted with a substituent of the form R8—R9—(R10)a(R10)b, and is optionally substituted with a substituent R13;
R8 is chosen from a bond and lower alkyl;
R9 is chosen from halogen, lower alkyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—, S(O)2—, B(OH)2, 5-6 membered monocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl;
(R10)a and (R10)b are each independently chosen from null, hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O lower alkyl;
R13 is chosen from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, NH2, and cyano;
R6 is chosen from 3-chlorophenyl, 5-chloro-2-thienyl, cyclopentyl optionally substituted with one or two R14, and cyclopentoxy optionally substituted with one or two R14; and
each R14 is independently chosen from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, NH2, and cyano.