US 10,376,497 B2
Anti-fibrotic pyridinones
Brad O. Buckman, Oakland, CA (US); John Beamond Nicholas, Redwood City, CA (US); Johnnie Y. Ramphal, Union City, CA (US); Kumaraswamy Emayan, Albany, CA (US); and Scott D. Seiwert, Seattle, WA (US)
Assigned to INTERMUNE, INC., South San Francisco, CA (US)
Filed by INTERMUNE, INC., South San Francisco, CA (US)
Filed on Apr. 20, 2017, as Appl. No. 15/492,828.
Application 15/492,828 is a division of application No. 15/162,214, filed on May 23, 2016, granted, now 9,675,593.
Application 15/162,214 is a division of application No. 14/043,121, filed on Oct. 1, 2013, granted, now 9,359,379.
Claims priority of provisional application 61/872,157, filed on Aug. 30, 2013.
Claims priority of provisional application 61/777,499, filed on Mar. 12, 2013.
Claims priority of provisional application 61/709,075, filed on Oct. 2, 2012.
Prior Publication US 2018/0064692 A1, Mar. 8, 2018
Int. Cl. C07D 213/02 (2006.01); A61K 31/437 (2006.01); C07D 513/04 (2006.01); C07D 495/04 (2006.01); C07D 211/86 (2006.01); C07D 401/04 (2006.01); C07D 221/04 (2006.01); C07D 471/04 (2006.01); C07D 498/04 (2006.01); C07D 295/125 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 223/10 (2006.01); C07D 405/04 (2006.01); C07D 409/14 (2006.01); C07D 413/04 (2006.01); C07D 417/04 (2006.01); C07D 213/64 (2006.01); C07D 217/24 (2006.01); A61K 9/00 (2006.01)
CPC A61K 31/437 (2013.01) [A61K 9/007 (2013.01); C07D 211/86 (2013.01); C07D 213/64 (2013.01); C07D 217/24 (2013.01); C07D 221/04 (2013.01); C07D 223/10 (2013.01); C07D 295/125 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 405/04 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/04 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07D 471/04 (2013.01); C07D 495/04 (2013.01); C07D 498/04 (2013.01); C07D 513/04 (2013.01)] 37 Claims
 
1. A compound having the structure of formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein
R1 is 5-10 membered heteroaryl optionally substituted with one or more R4;
R2 is selected from the group consisting of halogen, —CN, —OR5, —SR5, —NR6R7, and —C(O)R8;
R3 is selected from the group consisting of hydrogen, phenyl, —(CH2)n-(5-10 membered heteroaryl), —(CH2)n—(C3-10 carbocyclyl), and —(CH2)n-(3-10 membered heterocyclyl), each optionally substituted with one or more R9;
each R4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R8, —SO2R16, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl optionally substituted with one or more R11, C7-14 aralkyl optionally substituted with one or more R11, 5-10 membered heteroaryl optionally substituted with one or more R11, or independently two geminal R4 together are oxo;
each R5 is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-8 alkoxyalkyl, C6-10 aryl optionally substituted with one or more R11, C7-14 aralkyl optionally substituted with one or more R11, and —(CH2)n-(3-10 membered heterocyclyl) optionally substituted with one or more R10;
R6 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R11, C7-14 aralkyl optionally substituted with one or more R11, (5-10 membered heteroaryl)alkyl optionally substituted with one or more R11, —C(O)R8, and —C(O)OR5;
R7 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R1, C7-14 aralkyl optionally substituted with one or more R11, (5-10 membered heteroaryl)alkyl optionally substituted with one or more R11, —C(O)R8, and —C(O)OR5;
or R6 and R7 together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl optionally substituted with one or more R10;
each R8 is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R1, C7-14 aralkyl optionally substituted with one or more R11, —NR12R13, and —OR5;
each R9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkylthio, optionally substituted C2-8 alkoxyalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C6-10 aryl, —OR5, —NR14R15, —C(O)R8, —SO2R16, —CN, and —NO2;
each R10 is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, or independently two geminal R10 together are oxo;
each R11 is independently selected from the group consisting of halogen, —CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, —O—(CH2)n—C1-8 alkoxy, —C(O)R8, and optionally substituted C1-6 alkoxy;
each R12 is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R11, and C7-14 aralkyl optionally substituted with one or more R11;
each R13 is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R11, and C7-14 aralkyl optionally substituted with one or more R11;
R14 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, and —C(O)R8;
R15 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, and —C(O)R8;
each R16 is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C6-10 aryl optionally substituted with one or more R11, C7-14 aralkyl optionally substituted with one or more R11, —NR12R13, and —OR5;
Z is selected from oxygen and sulfur;
each n is independently an integer from 0 to 4; and
the bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond, provided that
when R3 is H, then R1 is selected from C6-10 aryl optionally substituted with one or more R4, or 5-10 membered heteroaryl optionally substituted with one or more R4;
when R3 is a phenyl; R2 is OR5 or NR6R7; then R1 is not triazolyl;
when R3 is 4-methyl phenyl, R2 is morpholinyl, and Z is O; then R1 is not methyl; and
when R3 is 4-methyl phenyl, R2 is —N(CH3)2, Z is O; then R1 is not methyl.