US 11,787,768 B2
Tetrahydroquinoline-based bromodomain inhibitors
R. Kip Guy, Lexington, KY (US); P Jake Slavish, Memphis, TN (US); William Robert Shadrick, Collierville, TN (US); Brandon M. Young, Germantown, TN (US); Vincent A. Boyd, Tyler, TX (US); Nagakumar Bharatham, Bangalore (IN); Jeanine E. Price, Germantown, TN (US); and Anang Shelat, Memphis, TN (US)
Assigned to ST. JUDE CHILDREN'S RESEARCH HOSPITAL, Memphis, TN (US)
Filed by St. Jude Children's Research Hospital, Memphis, TN (US)
Filed on Mar. 4, 2021, as Appl. No. 17/192,683.
Application 17/192,683 is a continuation of application No. 16/468,657, granted, now 11,028,051, previously published as PCT/US2017/065705, filed on Dec. 12, 2017.
Claims priority of provisional application 62/433,597, filed on Dec. 13, 2016.
Prior Publication US 2021/0188777 A1, Jun. 24, 2021
Int. Cl. C07D 215/42 (2006.01); C07D 215/44 (2006.01); C07D 215/46 (2006.01); C07D 401/10 (2006.01); C07D 401/12 (2006.01); C07D 405/10 (2006.01); C07D 405/12 (2006.01); C07D 409/10 (2006.01); C07D 413/12 (2006.01)
CPC C07D 215/42 (2013.01) [C07D 215/44 (2013.01); C07D 215/46 (2013.01); C07D 401/10 (2013.01); C07D 401/12 (2013.01); C07D 405/10 (2013.01); C07D 405/12 (2013.01); C07D 409/10 (2013.01); C07D 413/12 (2013.01)] 20 Claims
 
1. A compound having a structure represented by a formula:

OG Complex Work Unit Chemistry
wherein R1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 deuterated alkyl;
wherein R2 is C1-C4 alkyl;
wherein R4a is selected from hydrogen, C1-C4 alkyl, and amine protecting group;
wherein R4b is selected from —(CH2)nCy1, —(CH2)oAr2, and amine protecting group;
wherein each of n and o, when present, is selected from 0, 1, 2, and 3;
wherein Cy1, when present, is selected from cycloalkyl, five-membered heterocycle, and six-membered heterocycle and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar2, when present, is selected from aryl and 5- to 12-membered heteroaryl and is substituted with 0-4 R5 groups independently selected from halogen, —OH, —CN, —NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 aminoalkyl, C3-C6 cycloalkyl, —COR21, —CO2R21, —CONR22aR22b, (CH2)qNR22aR22b, —SO2NR22aR22b, —NR23C(O)R24, —NR23(CH2)q(C3-C6 cycloalkyl), —NR23(CH2)q(heterocycloalkyl), and 3- to 5-membered heterocycloalkyl;
wherein q, when present, is selected from 0, 1, 2, 3, and 4;
wherein each occurrence of R21, when present, is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, —COR30, —(C1-C4 alkyl)OC(O)(C1-C4 alkyl), and —(C1-C6 alkyl)NHC(O)A;
wherein A has a structure:

OG Complex Work Unit Chemistry
wherein each occurrence of R30, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
wherein each occurrence of each of R22a and R22b, when present, is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and —COR30;
wherein R23, when present, is selected from hydrogen and C1-C4 alkyl;
wherein R24, when present, is selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-4 alkylamino(C1-C4 alkyl), (C1-C4)(C1-C4) dialkylamino(C1-C4 alkyl), —(CH2)r(C3-C6 cycloalkyl), and —(CH2)r(C3-C6 heterocycloalkyl);
wherein r, when present, is selected from 0, 1, 2, and 3;
wherein Ar3 is:

OG Complex Work Unit Chemistry
wherein R7, when present, is selected from hydrogen, C1-C4 alkyl, and aryl substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
provided that when R7 is hydrogen or methyl, then R4b is not amine protecting group, and
provided that when o is 0, then Ar2 is substituted with at least one non-hydrogen group,
or a pharmaceutically acceptable salt thereof.