Spiro-thiazolones

Patent metadata

Field	Value
Publication number	US-10092551-B2
Application number	US-201715591980-A
Country	US
Kind code	B2
Filing date	May 10, 2017
Priority date	Nov 14, 2014
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

Spiro-thiazolones of formula I

wherein X 1 , X 2 , X 3 , X 4 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein, which act as V1a receptor modulators, and in particular as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments for treatment of inappropriate secretion of vasopressin, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, aggressive behavior and phase shift sleep disorders, in particular jetlag.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
X 1 C—R 1 or N;
X 2 C—R 1 or N;
X 3 C—R 1 or N;
X 4 C—R 1 or N;
whereby
i) one of X 1 , X 2 , X 3 is C—R 1 and X 4 is N,
ii) each of X 1 , X 2 , X 3 and X 4 is C—R 1 ;
R 1 each separately is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 -alkyl and C 1-6 -alkoxy;
R 2 is selected from the group consisting of hydrogen and C 1-6 -alkyl;
R 3 is selected from the group consisting of hydrogen and C 1-6 -alkyl;
or R 2 and R 3 together are ═O;
R 4 is hydrogen;
R 5 is selected from the group consisting of
i) hydrogen,
ii) C 3-7 -cycloalkyl,
iii) C 3-7 -cycloalkyl substituted by one or more substituents individually selected from halogen and C 1-6 -alkyl,
iv) C 1-6 -alkyl,
v) C 1-6 -alkyl substituted by one or more substituents individually selected from amino, halogen, hydroxy, C 1-6 -alkoxy, —O—C(═O)—C 1-6 -alkyl, NH(C═O)O—C 1-6 -alkyl and —O—Si(C 1-6 -alkyl) 3 ,
vi) aryl,
vii) aryl substituted by one or more substituents individually selected from halogen and C 1-6 -alkyl,
viii) heteroaryl, and
ix) heteroaryl substituted by one or more substituents individually selected from halogen and C 1-6 -alkyl;
R 6 is selected from the group consisting of
i) C 1-6 -alkyl,
ii) C 1-6 -alkyl substituted by one or more substituents individually selected from amino, halogen, C 1-6 -alkoxy, —O—C(═O)C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , NH(C═O)O—C 1-6 -alkyl, SO 2 —C 1-6 -alkyl and —O—Si(C 1-6 -alkyl) 3 ;
iii) C 2-6 -alkenyl
iv) aryl,
v) aryl substituted by one or more substituents individually selected from halogen and C 1-6 -alkyl;
vi) C 3-9 -cycloalkyl,
vii) C 3-9 -cycloalkyl substituted by one or more substituents individually selected from —(C═O)O—C 1-6 -alkyl, oxo, C 1-6 -alkoxy and C 1-6 -alkyl;
viii) heterocyclyl,
ix) heteroaryl, and
x) heteroaryl substituted by one or more substituents individually selected from halogen, C 1-6 -alkoxy and C 1-6 -alkyl;
or R 5 and R 6 together are selected from the group consisting of
i) C 3-9 -cycloalkyl, optionally fused with one or two phenyl,
ii) C 3-9 -cycloalkyl, optionally fused with phenyl, wherein the phenyl moiety is substituted by one or more substituents individually selected from halogen, hydroxy, (C═O)O—C 1-6 -alkyl, C 1-6 -alkoxy and C 1-6 -alkyl,
iii) C 3-6 -cycloalkenyl,
iv) heterocyclyl, optionally fused with one or two phenyl, and
v) heterocyclyl, optionally fused with phenyl, wherein the heterocyclyl moiety is substituted by one or more substituents individually selected from oxo, (C═O)O—C 1-6 -alkyl and SO 2 —C 1-6 -alkyl or wherein the phenyl moiety is substituted by one or more halogen;
R 7 is hydrogen;
or R 4 and R 7 together are —(CH 2 ) n —; and
n is 2, 3 or 4;
or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein
X 1 C—R 1 or N;
X 2 C—R 1 or N;
X 3 C—R 1 ;
X 4 C—R 1 or N;
whereby
i) one of X 1 or X 2 is C—R 1 and X 4 is N, or
ii) each of X 1 , X 2 , X 3 and X 4 is C—R 1 ;

R 1 each separately is hydrogen;
R 2 is hydrogen;
R 3 is hydrogen;
or R 2 and R 3 together are ═O;
R 4 is hydrogen;
R 5 is selected from the group consisting of
i) hydrogen,
ii) C 3-7 -cycloalkyl,
iii) C 1-6 -alkyl,
iv) C 1-6 -alkyl substituted by one or more substituents individually selected from amino, halogen, hydroxy, C 1-6 -alkoxy, —O—C(═O)—C 1-6 -alkyl, NH(C═O)O—C 1-6 -alkyl and —O—Si(C 1-6 -alkyl) 3 ,
v) aryl,
vi) aryl substituted by halogen, and
vii) heteroaryl;

R 6 is selected from the group consisting of
i) C 1-6 -alkyl,
ii) C 1-6 -alkyl substituted by one or more substituents individually selected from amino, halogen, C 1-6 -alkoxy, —O—C(═O)C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , NH(C═O)O—C 1-6 -alkyl, SO 2 —C 1-6 -alkyl and —O—Si(C 1-6 -alkyl) 3 ;
iii) C 2-6 -alkenyl
iv) aryl,
v) aryl substituted by halogen,
vi) C 3-9 -cycloalkyl,
vii) heterocyclyl,
viii) heteroaryl, and
ix) heteroaryl substituted by one or more substituents individually selected from halogen, C 1-6 -alkoxy and C 1-6 -alkyl;

or R 5 and R 6 together are selected from the group consisting of
i) C 3-9 -cycloalkyl, optionally fused with one or two phenyl,
ii) C 3-9 -cycloalkyl, optionally fused with phenyl, wherein the phenyl moiety is substituted by one or more substituents individually selected from halogen, hydroxy, and C 1-6 -alkoxy,
iii) C 3-6 -cycloalkenyl,
iv) heterocyclyl, optionally fused with one or two phenyl, and
v) heterocyclyl, optionally fused with phenyl, wherein the heterocyclyl moiety is substituted by one or more substituents individually selected from halogen, oxo, (C═O)O—C 1-6 -alkyl and SO 2 —C 1-6 -alkyl or wherein the phenyl moiety is substituted by one or more halogen;

R 7 is hydrogen;
or R 4 and R 7 together are —(CH 2 ) n —; and
n is 2.

3. The compound of claim 1 , wherein
X 1 C—R 1 or N;
X 2 C—R 1 or N;
X 3 C—R 1 ;
X 4 C—R 1 or N;
whereby
i) one of X 1 , X 2 , X 3 is C—R 1 and X 4 is N, or
ii) each of X 1 , X 2 , X 3 and X 4 is C—R 1 ;

R 1 each separately is hydrogen;
R 2 is hydrogen;
R 3 is hydrogen;
or R 2 and R 3 together are ═O;
R 4 is hydrogen;
R 5 is selected from the group consisting of
i) hydrogen,
ii) C 1-6 -alkyl, and
iii) C 1-6 -alkyl substituted by one substituents individually selected from hydroxyl and C 1-6 -alkoxy;

R 6 is selected from the group consisting of
i) C 1-6 -alkyl substituted by one C 1-6 -alkoxy;
ii) aryl,
iii) aryl substituted by halogen, and
iv) heteroaryl substituted by one or two substituents individually selected from halogen and C 1-6 -alkyl; and

R 7 is hydrogen.

4. The compound of claim 1 , wherein
i) X 1 is N, X 2 is CH, X 3 is CH and X 4 is CH,
ii) X 1 is CH, X 2 is CH, X 3 is CH and X 4 is CH, or
iii) X 1 is CH, X 2 is CH, X 3 is CH and X 4 is N.

5. The compound of claim 1 , wherein
X 1 is CH, X 2 is CH, X 3 is CH and X 4 is CH.

6. The compound of claim 1 , wherein R 2 is hydrogen and R 3 is hydrogen.

7. A compound of formula I according to claim 1 , wherein R 5 is hydrogen, methyl, —CH 2 —OCH 3 , —CH 2 —OH or —CD 3 .

8. The compound of claim 1 , wherein R 6 is phenyl, halogen-phenyl, halogen-pyridinyl, methyl-pyridinyl, dimethyl-oxazolyl or —CH 2 —OCH 3 .

9. The compound of claim 1 , selected from:
(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-thiazol-4(5H)-one,
(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-2-(1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-thiazol-4(5H)-one,
1′-{(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-4-oxo-4,5-dihydro-1,3-thiazol-2-yl}-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,
(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-2-(1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-thiazol-4(5H)-one and (5Z)-5-[1-(4-chlorophenyl)ethylidene]-2-(1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-thiazol-4(5H)-one,
8-{(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-4-oxo-4,5-dihydro-1,3-thiazol-2-yl}-3′H-spiro[8-azabicyclo[3.2.1]octane-3,1′-[2]benzofuran]-3′-one,
(5E/Z)-5-[1-(4-chlorophenyl)ethylidene]-2-(1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-thiaz

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Dolente Cosimo
• Fasching Bernhard
• Runtz-Schmitt Valerie
• Schnider Patrick

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/24

  Antidepressants · CPC title