Isoxazolyl ether derivatives as GABAA α5 PAM

Patent metadata

Field	Value
Publication number	US-11840528-B2
Application number	US-202017119977-A
Country	US
Kind code	B2
Filing date	Dec 11, 2020
Priority date	Jun 13, 2018
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

Abstract

The invention provides novel compounds having the general formula (I) or (II)

wherein R 2 , R 3 , R 5 , R 99 , W, Y and Z are as described herein, compositions including the compounds and methods of using the compounds.

First claim

What is claimed is:

1. A compound of formula (I) or (II)

or a pharmaceutically acceptable salt thereof,
wherein
W is selected from N and CR 4 ;
Y is selected from N and CH;
Z is selected from N and CH;
R 99 is selected from C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, H, and halogen;
R 2 is selected from H, halogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, and halo-C 1-6 -alkyl;
R 3 is selected from heterocycloalkyl substituted with R 6 , R 7 and R 8 , amino substituted on the nitrogen atom by one or two substituents independently selected from R 9 and R 10 , aryl substituted with R 11 , R 12 and R 13 , and heteroaryl substituted with R 11 , R 12 and R 13 ;
R 4 is selected from H, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, and halogen;
R 5 is selected from H, C 1-6 -alkyl, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, and halogen;
R 6 , R 7 and R 8 are each independently selected from H, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, cyano, amino substituted on the nitrogen atom by one or two substituents each independently selected from R 22 and R 23 , C 3-8 -cycloalkyl, wherein the C 3-8 -cycloalkyl is substituted with R 24 , R 25 and R 26 , C 3-8 -cycloalkoxy, wherein the C 3-8 -cycloalkoxy is substituted with R 24 , R 25 and R 26 , C 3-8 -cycloalkyl-C 1-6 -alkoxy, wherein the C 3-8 -cycloalkyl-C 1-6 -alkoxy is substituted with R 24 , R 25 and R 26 , C 3-8 -cycloalkylaminocarbonyl, wherein the C 3-8 -cycloalkylaminocarbonyl is substituted with R 24 , R 25 and R 26 , C 3-8 -cycloalkylcarbonyl, wherein the C 3-8 -cycloalkylcarbonyl is substituted with R 24 , R 25 and R 26 , C 3-8 -cycloalkyl-C 1-6 -alkoxycarbonyl, wherein the C 3-8 -cycloalkyl-C 1-6 -alkoxycarbonyl is substituted with R 24 , R 25 and aryloxy substituted with R 27 , R 28 and R 29 , aryl substituted with R 27 , R 28 and R 29 ,heteroaryl substituted with R 27 , R 28 and R 29 , heteroaryloxy substituted with R 27 , R 28 and R 29 , halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, halogen, hydroxy, hydroxy-C 1-6 -alkyl, and oxo;
R 9 and R 10 are each independently selected from H, halo-C 1-6 -alkyl, C 1-6 -alkyl, heterocycloalkyl substituted with R 30 , R 31 and R 32 , heterocycloalkyl-C 1-6 -alkyl substituted with R 30 , R 31 and R 32 , hydroxy-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, and halogen;
R 11 , R 12 and R 13 are each independently selected from H, hydroxy, hydroxy-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl, cyano, aryl, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, heteroaryl, amino substituted on the nitrogen atom by one or two substituents each independently selected from R 14 and R 15 , C 3-8 -cycloalkyl-C 1-6 -alkyl, heterocycloalkyl substituted with R 16 , R 17 and R 18 , heterocycloalkoxy substituted with R 16 , R 17 and R 18 , heterocycloalkyl-C 1-6 -alkyl substituted with R 16 , R 17 and R 18 , and halogen;
R 14 and R 15 are each independently selected from H, and C 1-6 -alkyl;
R 16 , R 17 and R 18 are each independently selected from H, halogen, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 1-6 -alkyl;
R 22 and R 23 are each independently selected from H, C 1-6 -alkyl, and C 1-6 -alkylcarbonyl;
R 24 , R 25 and R 26 are each independently selected from C 1-6 -alkyl, H, C 1-6 -alkoxy, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogen, hydroxy, and oxo;
R 27 , R 28 and R 29 are each independently selected from H, C 1-6 -alkoxy, C 1-6 -alkyl, C 3-8 -cycloalkyl, and halogen; and
R 30 , R 31 and R 32 are each independently selected from H, halogen, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 1-6 -alkyl.

2. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
W is CR 4 ; Y is N;
Z is selected from N, and CH;
R 99 is H;
R 2 is methyl;
R 3 is selected from azetidinyl substituted with R 6 , R 7 and R 8 , and 5-oxa-2-azaspiro[3.5]nonanyl substituted with R 6 , R 7 and R 8 ;
R 4 is H,
R 5 is selected from methyl and fluoro; and
R 6 , R 7 and R 8 are independently selected from tert-butoxy, H, fluoro.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, C 1-6 -alkyl, C 3-8 -cycloalkyl, and halo-C 1-6 -alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from heterocycloalkyl substituted with R 6 , R 7 and R 8 , and heteroaryl substituted with R 11 , R 12 and R 13 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from
heterocycloalkyl substituted with R 6 , R 7 and R 8 , wherein heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl, 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 1-oxa-7-azaspiro[3.5]nonanyl, 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptanyl, 5-oxa-2-azaspiro[3.4]octanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 3-oxa-9-azaspiro[5.5]undecanyl, 5-oxa-2-azaspiro[3.5]nonanyl, 1-oxa-9-azaspiro[5.5]undecanyl, 5-oxa-2-azaspiro[3.6]decanyl, 2-azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2-azaspiro[3.5]nonanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1-oxa-8-azaspiro[4.5]decanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, and azetidinyl; and
heteroaryl substituted with R 6 , R 7 and R 8 , wherein heteroaryl is selected from pyridinyl, imidazo[1,2-a]pyridinyl, and pyrazolyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from C 1-6 -alkyl, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, and halogen.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 6 , R 7 and R 8 are each independently selected from H; C 1-6 -alkyl; C 1-6 -alkoxy; C 1-6 -alkoxycarbonyl; cyano; amino substituted on the nitrogen atom by one or two substituents each independently selected from R 22 and R 23 ; C 3-8 -cycloalkyl-C 1-6 -alkoxy, wherein the C 3-8 -cycloalkyl is substituted with R 24 , R 25 , and R 26 wherein R 24 , R 25 and R 26 are each independently selected from H and C 1-6 -alkyl; C 3-8 -cycloalkylaminocarbonyl, wherein the C 3-8 -cycloalkyl is, substituted with R 24 , R 25 and R 26 , wherein R 24 , R 25 and R 26 are H; C 3-8 -cycloalkylcarbonyl, wherein the C 3-8 -cycloalkyl is substituted with R 24 , R 25 and R 26 , wherein R 24 , R 25 and R 26 are each independently selected from H and C 1-6 -alkyl; C 3-8 -cycloalkyl substituted with R 24 , R 25 and R 26 , wherein R 24 , R 25 , and R 26 are each independently selected from H and C 1-6 -alkyl; C 3-8 -cycloalkoxy substituted with R 24 , R 25 and R 26 , wherein R 24 , R 25 and R 26 are each H; aryloxy, wherein the aryl is substituted with R 27 , R 28 and R 29 , wherein R 27 , R 28 and R 29 are each independently selected from H and halogen, and wherein the aryl is phenyl; aryl substituted with R 27 , R 28 and R 29 , wherein R 27 , R 28 and R 29 are each independently selected from H and alkoxy; and wherein the aryl is phenyl; heteroaryl substituted with R 27 , R 28 and R 29 , wherein R 27 , R 28 and R 29 are each independently selected from H and C 1-6 -alkyl, and wherein the heteroaryl is selected from imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridinyl and oxadiazolyl; heteroaryloxy, wherein the heter

Assignees

• Hoffmann La Roche

Inventors

• Cecere Giuseppe
• Zbinden Katrin Groebke
• Hernandez Maria-Clemencia
• Knust Henner
• Koblet Andreas
• Olivares Morales Andres Miguel
• Patiny-Adam Angélique
• Pinard Emmanuel
• Runtz-Schmitt Valerie
• Steiner Sandra

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D491/08

  Bridged systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title