US 12,281,101 B2
Bicyclic lactams and methods of use thereof
Snahel Patel, Foster City, CA (US); Gregory Hamilton, San Mateo, CA (US); Craig Stivala, Atherton, CA (US); Huifen Chen, Burlingame, CA (US); and Guiling Zhao, Palo Alto, CA (US)
Assigned to Genentech, Inc., South San Francisco, CA (US)
Filed by Genentech, Inc., South San Francisco, CA (US)
Filed on Mar. 10, 2021, as Appl. No. 17/198,238.
Application 17/198,238 is a division of application No. 15/200,058, filed on Jul. 1, 2016, granted, now 10,988,459.
Claims priority of provisional application 62/188,153, filed on Jul. 2, 2015.
Claims priority of provisional application 62/387,295, filed on Dec. 23, 2015.
Prior Publication US 2022/0348559 A1, Nov. 3, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 403/12 (2006.01); A61K 31/55 (2006.01); A61K 31/553 (2006.01); A61P 1/00 (2006.01); A61P 1/04 (2006.01); A61P 1/16 (2006.01); A61P 1/18 (2006.01); A61P 9/00 (2006.01); A61P 9/10 (2006.01); A61P 11/00 (2006.01); A61P 13/12 (2006.01); A61P 17/06 (2006.01); A61P 25/00 (2006.01); A61P 27/02 (2006.01); A61P 29/00 (2006.01); A61P 31/00 (2006.01); A61P 31/04 (2006.01); A61P 35/00 (2006.01); A61P 43/00 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 491/04 (2006.01); C07D 491/044 (2006.01); C07D 491/048 (2006.01); C07D 491/052 (2006.01); C07D 491/10 (2006.01); C07D 495/04 (2006.01); C07D 495/14 (2006.01); C07D 498/04 (2006.01); C07D 498/16 (2006.01); C07D 519/00 (2006.01)
CPC C07D 403/12 (2013.01) [C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 491/04 (2013.01); C07D 491/044 (2013.01); C07D 491/048 (2013.01); C07D 491/052 (2013.01); C07D 491/10 (2013.01); C07D 495/04 (2013.01); C07D 498/04 (2013.01); C07D 519/00 (2013.01)] 15 Claims
 
1. A compound of formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of H and unsubstituted C1-C4 alkyl;
the A ring is phenyl optionally substituted with:
(a) 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2—(C3-C6 cycloalkyl) and CH2CH2—(C3-C6 cycloalkyl);
(b) 1 substituent selected from the group consisting of C4-C6 heterocyclyl, C5-C6 heteroaryl, CH2—(C4-C6 heterocyclyl), CH2CH2—(C4-C6 heterocyclyl), CH2—(C5-C6 heteroaryl) and CH2CH2—(C5-C6 heteroaryl); and optionally a second substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; or
(c) two adjacent substituents which together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl;
X is O or CH2;
Z1 is C;
n is 1; and

OG Complex Work Unit Chemistry
is selected from the group consisting of:

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
Y is selected from the group consisting of O, S, SO and SO2;
X1, X2 and X3 are each independently N or CH, wherein 1 or 2 of X1, X2 and X3 is N;
X4 and X5 are each independently N or CH;
R5a and R5b are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, benzyl, —CH2(C3-C6 cycloalkyl) and 5 to 6 membered heteroaryl; wherein R5a and R5b together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy;
R6a and R6b are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH2(C3-C6 cycloalkyl), and 5 to 6 membered heteroaryl; wherein R6a and R6b together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy;
wherein, when R5a and R6a are each H, R5b and R6b may together form a 3 or 4 membered cycloalkyl;
and wherein only two of R5a, R5b, R6a and R6b may be other than H in each instance;
R7 is selected from the group consisting of H and unsubstituted C1-C4 alkyl;
R10 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl and benzyl; and
R11 is selected from the group consisting of H, halogen, C1-C4 alkyl and C1-C4 haloalkyl.