US 11,771,684 B2
Inhibitors of dihydroceramide desaturase for treating disease
Donna L. Romero, Half Moon Bay, CA (US); John M. McCall, Half Moon Bay, CA (US); and Jeremy Blitzer, Half Moon Bay, CA (US)
Assigned to Centaurus Therapeutics, Half Moon Bay, CA (US)
Filed by Centaurus Therapeutics, Half Moon Bay, CA (US)
Filed on Sep. 17, 2021, as Appl. No. 17/477,953.
Application 17/477,953 is a continuation of application No. 16/468,637, granted, now 11,135,207, previously published as PCT/US2017/066172, filed on Dec. 13, 2017.
Claims priority of provisional application 62/433,625, filed on Dec. 13, 2016.
Prior Publication US 2022/0079926 A1, Mar. 17, 2022
Int. Cl. A61K 9/00 (2006.01); A61K 39/395 (2006.01); A61K 31/44 (2006.01); A61K 31/167 (2006.01); A61K 31/416 (2006.01); A61K 31/444 (2006.01); A61K 31/496 (2006.01); A61P 9/10 (2006.01); A61P 3/06 (2006.01); A61P 3/10 (2006.01); A61P 11/00 (2006.01); A61P 35/00 (2006.01); C07C 233/65 (2006.01); C07D 213/73 (2006.01); C07D 231/56 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01)
CPC A61K 31/44 (2013.01) [A61K 9/0053 (2013.01); A61K 31/167 (2013.01); A61K 31/416 (2013.01); A61K 31/444 (2013.01); A61K 31/496 (2013.01); A61K 39/3955 (2013.01); A61P 3/06 (2018.01); A61P 3/10 (2018.01); A61P 9/10 (2018.01); A61P 11/00 (2018.01); A61P 35/00 (2018.01); C07C 233/65 (2013.01); C07D 213/73 (2013.01); C07D 231/56 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01)] 42 Claims
 
1. A method of inhibiting dihydroceramide desaturase (Des) activity in a biological sample comprising contacting the biological sample with a compound of Formula I:

OG Complex Work Unit Chemistry
or a salt thereof, wherein:
R1a and R1b are independently selected from hydrogen, cycloalkylalkyl, aryl, and heteroaryl, and is optionally substituted with 1, 2, or 3 R2 groups, or
R1a and R1b together with the intervening atoms, form a 5-7 membered heterocyclic ring, and is optionally substituted with 1, 2, or 3 R2 groups;
at least one of R1a and R1b is not hydrogen;
X is selected from ethenyl, alkyl, aryl, biaryl, (aryl)cycloalkyl, (aryl)heterocycloalkyl, (aryl)heteroaryl, cycloalkyl, (cycloalkyl)aryl, (cycloalkyl)cycloalkyl, (cycloalkyl)heterocycloalkyl, (cycloalkyl)heteroaryl, heterocycloalkyl, (hetercycloalkyl)aryl, (heterocycloalkyl)cycloalkyl, (heterocycloalkyl)heteroaryl, (heterocycloalkyl)heterocycloalkyl, heteroaryl, (heteroaryl)aryl, (heteroaryl)cycloalkyl, (heteroaryl)heterocycloalkyl, and (heteroaryl)heteroaryl, any of which is optionally substituted with 1, 2, 3, or 4 R3 groups;
Y is selected from —CHR4—,—CHR4CHR4—, and —CR4=CR4;
each R2 is independently selected from alkyl, alkoxy, amino, cycloalkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, halogen, hydroxy, S-sulfonamido, and oxo, and is optionally substituted with 1, 2, or 3 R5
n is selected from 1, 2, 3, 4, and 5;
each R3 is independently selected from alkyl, alkoxy, cyano, haloalkyl, hydroxy, halogen, and oxo; and
each R4 is independently selected from hydrogen, alkyl, alkylamino, halo, and hydroxyl; and
each R5 is independently selected from hydroxy and alkoxy.