Isoxazolyl ether derivatives as gaba a alpha5 pam

Patent metadata

Field	Value
Publication number	US-2022411415-A1
Application number	US-202117378410-A
Country	US
Kind code	A1
Filing date	Jul 16, 2021
Priority date	Dec 8, 2016
Publication date	Dec 29, 2022
Grant date	—

Abstract

Compounds having the formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z are as described herein, compositions including the compounds and methods of using the compounds.

First claim

1 . A method for treatment of prophylaxis of a disease mediated by GABA A α5 receptor, the method comprising administering, to a subject in need thereof, an effective amount of a compound of formula (I)

wherein
X is selected from
i) N, and
ii) CH;

Y is selected from
i) N, and
ii) CR 10 ;

Z is selected from
i) N, and
ii) CR 11 ;

R 1 is selected from
i) C 1-6 -alkyl,
ii) halo-C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) halo-C 1-6 -alkoxy,
v) hydroxy-C 1-6 -alkyl,
vi) C 3-8 -cycloalkyl,
vii) halogen, and
viii) amino substituted on the nitrogen atom by one or two substituents independently selected from
a. H,
b. C 1-6 -alkyl, and
c. C 3-8 -cycloalkyl;

R 2 is selected from
i) H, and
ii) halogen;

R 3 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl,
iv) hydroxy-C 1-6 -alkyl, and
v) halo-C 1-6 -alkyl;

R 4 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 3-8 -cycloalkyl, and
v) halogen;

R 5 is H;
R 6 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl substituted with R 7 , R 8 and R 9 ,
iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 ,
v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl,
vi) cyano-C 1-6 -alkyl,
vii) hydroxy-C 1-6 -alkyl,
viii) dihydroxy-C 1-6 -alkyl,
ix) halo-C 1-6 -alkyl,
x) heterocycloalkyl substituted with R 7 , R 8 and R 9 , and
xi) heterocycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 ;

R 7 , R 8 and R 9 are independently selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 1-6 -alkoxyalkyl,
v) C 1-6 -alkoxycarbonyl,
vi) cyano,
vii) C 3-8 -cycloalkoxy,
viii) C 3-8 -cycloalkyl,
ix) halo-C 1-6 -alkoxy,
x) halo-C 1-6 -alkyl,
xi) halogen,
xii) hydroxy,
xiii) hydroxy-C 1-6 -alkyl, and
xiv) oxo;

R 10 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 3-8 -cycloalkyl, and
v) halogen;

R 11 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 3-8 -cycloalkyl, and
v) halogen;

or R 5 and R 10 together form —(CH 2 ) n —;
or R 5 and R 11 together form —(CH 2 ) n —;
or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R 7 , R 8 and R 9 ;
n is selected from 1 and 2;
or pharmaceutically acceptable salts.

2 . The method of claim 1 , wherein
X is selected from
i) N, and
ii) CH;
Y is selected from
i) N, and
ii) CR 10 ;
Z is selected from
i) N, and
ii) CR 11 ;
R 1 is selected from
i) C 1-6 -alkyl,
ii) halo-C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 3-8 -cycloalkyl,
v) halogen, and
vi) amino substituted on the nitrogen atom by two independently selected C 1-6 -alkyl;
R 2 is selected from
i) H,
ii) halogen;
R 3 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl, and
iv) halo-C 1-6 -alkyl;
R 4 is selected from
i) H, and
ii) C 1-6 -alkyl;
R 5 is H; R 6 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. C 1-6 -alkoxy,
d. C 1-6 -alkoxyalkyl,
e. C 1-6 -alkoxycarbonyl,
f. cyano,
g. C 3-8 -cycloalkoxy,
h. halo-C 1-6 -alkoxy,
i. halo-C 1-6 -alkyl,
j. halogen,
k. hydroxy, and
l. hydroxy-C 1-6 -alkyl;

iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and B 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. C 1-6 -alkoxy,
d. C 1-6 -alkoxyalkyl,
e. C 1-6 -alkoxycarbonyl,
f. cyano,
g. C 3-8 -cycloalkoxy,
h. halo-C 1-6 -alkoxy,
i. halo-C 1-6 -alkyl,
j. halogen,
k. hydroxy, and
l. hydroxy-C 1-6 -alkyl;

v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl,
vi) cyano-C 1-6 -alkyl,
vii) dihydroxy-C 1-6 -alkyl,
viii) halo-C 1-6 -alkyl,
ix) heterocycloalkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. hydroxy, and
d. oxo;

 and wherein the heterocycloalkyl is selected from
a. oxetanyl,
b. tetrahydrofuranyl,
c. tetrahydropyranyl,
d. oxepanyl,
e. oxabicyclo[2.2.1]heptanyl,
f. oxaspiro[3.3]heptanyl,
g. azetidinyl,
h. tetrahydrothiophenyl, and
i. tetrahydrothiopyranyl; and

x) oxetanyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. hydroxy;

R 10 is selected from
i) H, and
ii) halogen;
R 11 is selected from
i) H,
ii) C 1-6 -alkyl, and
iii) C 1-6 -alkoxy;
or R 5 and R 10 together form —(CH 2 ) n —; or R 5 and R 11 together form —(CH 2 ) n —; or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from  a. H,  b. C 1-6 -alkyl,  c. C 1-6 -alkoxy,  d. cyano,  e. halogen,  f. hydroxy, and  g. oxo; and wherein the heterocycloalkyl is selected from  a. azetidinyl,  b. pyrrolidinyl,  c. piperidinyl,  d. morpholinyl,  e. thiomorpholinyl,  f. oxaazabicyclo[3.1.1]heptanyl,  g. oxaazabicyclo[2.2.1]heptanyl,  h. azaspiro[3.3]heptanyl,  i. oxaazaspiro[3.3]heptanyl,  j. thiaazaspiro[3.3]heptanyl; n is 1; or pharmaceutically acceptable salts.

3 . The method of claim 1 , wherein
X is selected from
i) N, and
ii) CH;
Y is selected from
i) N, and
ii) CR 10 ;
Z is selected from
i) N, and
ii) CR 11 ;
R 1 is selected from
i) C 1-6 -alkyl,
ii) halo-C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) C 3-8 -cycloalkyl,
v) halogen, and
vi) amino substituted on the nitrogen atom by two independently selected C 1-6 -alkyl;
R 2 is selected from
i) H,
ii) halogen;
R 3 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl, and
iv) halo-C 1-6 -alkyl;
R 4 is selected from
i) H, and
ii) C 1-6 -alkyl;
R 5 is H; R 6 is selected from
i) H,
ii) C 1-6 -alkyl,
iii) C 3-8 -cycloalkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. C 1-6 -alkoxy,
d. C 1-6 -alkoxyalkyl,
e. C 1-6 -alkoxycarbonyl,
f. cyano,
g. C 3-8 -cycloalkoxy,
h. halo-C 1-6 -alkoxy,
i. halo-C 1-6 -alkyl,
j. halogen,
k. hydroxy, and
l. hydroxy-C 1-6 -alkyl;

iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. C 1-6 -alkoxy,
d. C 1-6 -alkoxyalkyl,
e. C 1-6 -alkoxycarbonyl,
f. cyano,
g. C 3-8 -cycloalkoxy,
h. halo-C 1-6 -alkoxy,
i. halo-C 1-6 -alkyl,
j. halogen,
k. hydroxy, and
l. hydroxy-C 1-6 -alkyl;

v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl,
vi) cyano-C 1-6 -alkyl,
vii) dihydroxy-C 1-6 -alkyl,
viii) halo-C 1-6 -alkyl,
ix) heterocycloalkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. C 1-6 -alkyl,
c. hydroxy, and
d. oxo;

 and wherein the heterocycloalkyl is selected from
a. oxetanyl,
b. tetrahydrofuranyl,
c. tetrahydropyranyl,
d. oxepanyl,
e. oxabicyclo[2.2.1]heptanyl,
f. oxaspiro[3.3]heptanyl,
g. azetidinyl,
h. tetrahydrothiophenyl, and
i. tetrahydrothiopyranyl; and

x) oxetanyl-C 1-6 -alkyl substituted with R 7 , R 8 and R 9 , wherein R 7 , R 8 and R 9 are independently selected from
a. H,
b. hydroxy;

R 10 is selected from
i) H, and
ii) halogen;
R 11 is selected from
i) H,
ii) C 1-6 -alkyl, an

Assignees

• Hoffmann La Roche

Inventors

• Buettelmann Bernd
• Cecere Giuseppe
• Fasching Bernhard
• Groebke Zbinden Katrin
• Hernandez Maria-Clemencia
• Knust Henner
• Koblet Andreas
• Pinard Emmanuel
• Thomas Andrew

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D495/06

  Peri-condensed systems · CPC title

• C07D493/08

  Bridged systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title