US 11,773,096 B2
Small-molecule PI5P4K alpha/beta inhibitors and methods of treatment using same
Ya Ha, Mamaroneck, NY (US); Jonathan Ellman, Guilford, CT (US); Song Chen, New Haven, CT (US); Caroline Chandra Tjin, Boston, MA (US); Fabrizio Micheli, Verona (IT); Agostino Cianciulli, Verona (IT); and Claudia Beato, Verona (IT)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Appl. No. 17/267,488
Filed by YALE UNIVERSITY, New Haven, CT (US)
PCT Filed Aug. 9, 2019, PCT No. PCT/US2019/045894
§ 371(c)(1), (2) Date Feb. 9, 2021,
PCT Pub. No. WO2020/033823, PCT Pub. Date Feb. 13, 2020.
Claims priority of provisional application 62/717,504, filed on Aug. 10, 2018.
Prior Publication US 2021/0292326 A1, Sep. 23, 2021
Int. Cl. C07D 475/00 (2006.01)
CPC C07D 475/00 (2013.01) 13 Claims
 
1. A compound of Formula (IA) or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof:

OG Complex Work Unit Chemistry
wherein:
R is

OG Complex Work Unit Chemistry
 or heteroaryl,
wherein the heteroaryl is optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halogen, —OH, —C(═O)OH, —C(═O)C1-C6 alkyl, —C(═O)C3-C8 cycloalkyl, thiol, C1-C6 thioalkoxy, and —NR′R′,
wherein each occurrence of R′ is independently H or C1-C6 alkyl or the two R′ bound to the N combine to form 3-7 membered heterocyclyl;
R1 is selected from the group consisting of isopropyl, sec-butyl, tert-butyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, C3-C8 heterocycloalkyl,

OG Complex Work Unit Chemistry
 and C1-C6 alkyl substituted with at least one group selected from C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halogen, —OH, thiol, C1-C6 thioalkoxy, phenyl, heteroaryl, heterocyclyl, and —NR″R″,
wherein in R1 each occurrence of cycloalkyl, heteroalkyl, or heterocycloalkyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halogen, —OH, thiol, C1-C6 thioalkoxy, phenyl, heteroaryl, heterocyclyl, and —NR″R″;
each occurrence of R″ is independently H or C1-C6 alkyl or the two R″ bound to the N combine to form 3-7 membered heterocyclyl;
R2 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, and C3-C8 heterocycloalkyl;
wherein in R2 each occurrence of alkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halogen, —OH, thiol, C1-C6 thioalkoxy, phenyl, heteroaryl, heterocyclyl, and —NR′″R′″,
wherein each occurrence of R′″ is independently H or C1-C6 alkyl or the two R′″ bound to the N combine to form 3-7 membered heterocyclyl;
R3 is selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C8 cycloalkyl;
R4 is selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, —OH, —C(═O)OH, —C(═O)C1-C6 alkyl, and —C(═O)C3-C8 cycloalkyl;
R5 is selected from the group consisting of H, —OH, —C(═O)OH, —C(═O)C1-C6 alkyl, and —C(═O)C3-C8 cycloalkyl;
R6 is selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, —OH, —C(═O)OH, —C(═O)C1-C6 alkyl, and —C(═O)C3-C8 cycloalkyl;
R7 is selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C8 cycloalkyl;
R8 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, —OH, C1-C6 alkoxy, and —NR″R″; and
R9 is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, —OH, C1-C6 alkoxy, and —NR″R″,
wherein, if R9 is H, R8 is not methyl.