US 11,840,528 B2
Isoxazolyl ether derivatives as GABAA α5 PAM
Giuseppe Cecere, Basel (CH); Katrin Groebke Zbinden, Oberwil BL (CH); Maria-Clemencia Hernandez, Delémont (CH); Henner Knust, Rheinfelden (DE); Andreas Koblet, Elsau ZH (CH); Andres Miguel Olivares Morales, Basel (CH); Angélique Patiny-Adam, Kembs (FR); Emmanuel Pinard, Linsdorf (FR); Valerie Runtz-Schmitt, Rixheim (FR); and Sandra Steiner, Sursee (CH)
Assigned to Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed by Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed on Dec. 11, 2020, as Appl. No. 17/119,977.
Application 17/119,977 is a continuation of application No. PCT/EP2019/065129, filed on Jun. 11, 2019.
Claims priority of application No. 18177522 (EP), filed on Jun. 13, 2018; and application No. 18177825 (EP), filed on Jun. 14, 2018.
Prior Publication US 2021/0094945 A1, Apr. 1, 2021
Int. Cl. C07D 413/14 (2006.01); C07D 487/04 (2006.01); C07D 487/10 (2006.01); C07D 491/08 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01)
CPC C07D 413/14 (2013.01) [C07D 487/04 (2013.01); C07D 487/10 (2013.01); C07D 491/08 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01)] 15 Claims
 
1. A compound of formula (I) or (II)

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein
W is selected from N and CR4;
Y is selected from N and CH;
Z is selected from N and CH;
R99 is selected from C1-6-alkyl, C1-6-alkoxy, halo-C1-6-alkoxy, hydroxy-C1-6-alkyl, C3-8-cycloalkyl, H, and halogen;
R2 is selected from H, halogen, C1-6-alkyl, C3-8-cycloalkyl, and halo-C1-6-alkyl;
R3 is selected from heterocycloalkyl substituted with R6, R7 and R8, amino substituted on the nitrogen atom by one or two substituents independently selected from R9 and R10, aryl substituted with R11, R12 and R13, and heteroaryl substituted with R11, R12 and R13;
R4 is selected from H, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, and halogen;
R5 is selected from H, C1-6-alkyl, C3-8-cycloalkyl, halo-C1-6-alkyl, and halogen;
R6, R7 and R8 are each independently selected from H, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxycarbonyl, cyano, amino substituted on the nitrogen atom by one or two substituents each independently selected from R22 and R23, C3-8-cycloalkyl, wherein the C3-8-cycloalkyl is substituted with R24, R25 and R26, C3-8-cycloalkoxy, wherein the C3-8-cycloalkoxy is substituted with R24, R25 and R26, C3-8-cycloalkyl-C1-6-alkoxy, wherein the C3-8-cycloalkyl-C1-6-alkoxy is substituted with R24, R25 and R26, C3-8-cycloalkylaminocarbonyl, wherein the C3-8-cycloalkylaminocarbonyl is substituted with R24, R25 and R26, C3-8-cycloalkylcarbonyl, wherein the C3-8-cycloalkylcarbonyl is substituted with R24, R25 and R26, C3-8-cycloalkyl-C1-6-alkoxycarbonyl, wherein the C3-8-cycloalkyl-C1-6-alkoxycarbonyl is substituted with R24, R25 and aryloxy substituted with R27, R28 and R29, aryl substituted with R27, R28 and R29,heteroaryl substituted with R27, R28 and R29, heteroaryloxy substituted with R27, R28 and R29, halo-C1-6-alkoxy, halo-C1-6-alkyl, halogen, hydroxy, hydroxy-C1-6-alkyl, and oxo;
R9 and R10 are each independently selected from H, halo-C1-6-alkyl, C1-6-alkyl, heterocycloalkyl substituted with R30, R31 and R32, heterocycloalkyl-C1-6-alkyl substituted with R30, R31 and R32, hydroxy-C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, and halogen;
R11, R12 and R13 are each independently selected from H, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkyl, cyano, aryl, C3-8-cycloalkyl, halo-C1-6-alkyl, halo-C1-6-alkoxy, heteroaryl, amino substituted on the nitrogen atom by one or two substituents each independently selected from R14 and R15, C3-8-cycloalkyl-C1-6-alkyl, heterocycloalkyl substituted with R16, R17 and R18, heterocycloalkoxy substituted with R16, R17 and R18, heterocycloalkyl-C1-6-alkyl substituted with R16, R17 and R18, and halogen;
R14 and R15 are each independently selected from H, and C1-6-alkyl;
R16, R17 and R18 are each independently selected from H, halogen, C1-6-alkoxy, C3-8-cycloalkyl, C1-6-alkyl;
R22 and R23 are each independently selected from H, C1-6-alkyl, and C1-6-alkylcarbonyl;
R24, R25 and R26 are each independently selected from C1-6-alkyl, H, C1-6-alkoxy, C3-8-cycloalkyl, halo-C1-6-alkyl, halo-C1-6-alkoxy, halogen, hydroxy, and oxo;
R27, R28 and R29 are each independently selected from H, C1-6-alkoxy, C1-6-alkyl, C3-8-cycloalkyl, and halogen; and
R30, R31 and R32 are each independently selected from H, halogen, C1-6-alkoxy, C3-8-cycloalkyl, C1-6-alkyl.