Heterocyclic compounds as monoacylglycerol lipase inhibitors

Patent metadata

Field	Value
Publication number	US-12281124-B2
Application number	US-202318475065-A
Country	US
Kind code	B2
Filing date	Sep 26, 2023
Priority date	Aug 13, 2018
Publication date	Apr 22, 2025
Grant date	Apr 22, 2025

Abstract

The invention provides new heterocyclic compounds having the general formula (I)wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:

(i) X is C—R 3 ; m is 0; n is selected from 0, 1 and 2; L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CH 2 OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 CF 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or
(ii) X is C—R 3 ; m is 1; n is selected from 0, 1 and 2; L is selected from —O—, —OCH 2 —, —CH 2 OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 CF 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or
(iii) X is C—R 3 ; m is 1; n is selected from 0, 1 and 2; L is —(CH 2 ) p —; and A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or
(iv) X is N; m is 1; n is 1 or 2; L is —(CH 2 ) p — or —CF 2 CH 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ;
p is selected from 1, 2, and 3;
q is 0 or 1;
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is selected from hydrogen, C 1-6 -alkyl, and hydroxy-C 1-6 -alkyl;
R 3 is selected from hydrogen, halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -alkyl, and halo-C 1-6 -alkyl;
each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is independently selected from hydrogen, halogen, cyano, hydroxy, C 1-6 -alkyl, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkanoyl, halo-C 1-5 -alkyl-CH(OH)—, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, SF 5 , CH 3 SO 2 , C 3-10 -cycloalkyl, C 3-10 -cycloalkyl substituted with R 13 , 3- to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R 14 and R 15 , 5- to 14-membered heteroaryl, C 6 -C 14 -aryl, C 6 -C 14 -aryloxy, halo-C 6 -C 14 -aryl, and halo-C 6 -C 14 -aryloxy;
each of R 13 , R 14 , and R 15 is independently selected from C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogen, and hydroxy; and
R 16 and R 17 , taken together with the carbon atom to which they are attached, form a C 3-10 -cycloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia):

wherein A, L, X, m, n, R 1 , and R 2 are as defined in claim 1 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib):

wherein A, L, X, m, n, R 1 , and R 2 are as defined in claim 1 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—R 3 ; m is 0; n is selected from 0, 1, and 2; and L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 OCH 2 —; or
X is N; m and n are both 1; and L is —(CH 2 ) p —; and
p is 1 or 2;
R 2 is hydrogen or C 1-6 -alkyl; and
R 3 is selected from hydrogen, halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—R 3 ;
m and n are both 0, or m and n are both 1;
L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—;
p is 2;
R 2 is hydrogen or C 1-6 -alkyl; and
R 3 is selected from hydrogen, halogen and C 1-6 -alkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkanoyl, SF 5 , C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R 14 and R 15 , 5- to 14-membered heteroaryl, C 6 -C 14 -aryloxy, and halo-C 6 -C 14 -aryl;
R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, 3-to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C 6 -C 14 -aryl;
R 6 is hydrogen or halogen;
R 7 is selected from hydrogen, C 1-6 -alkyl, C 6 -C 14 -aryl, halo-C 6 -C 14 -aryl, halo-C 6 -C 14 -aryloxy, and halo-C 1-6 -alkyl;
R 8 is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl;
R 9 is hydrogen;
R 10 is halogen;
R 11 is halogen;
R 12 is hydrogen;
R 14 is selected from C 1-6 -alkyl, C 1-6 -alkoxy, and halogen; and
R 15 is hydrogen or halogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
(i) C 6 -C 14 -aryl substituted with R 4 , R 5 and R 6 ; and
(ii) 5- to 14-membered heteroaryl substituted with R 7 , R 8 and R 9 ;

R 4 is selected from halogen, SF 5 , C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, and 3- to 14-membered heterocycloalkyl;
R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C 6 -C 14 -aryl;
R 6 is hydrogen;
R 7 is C 1-6 -alkyl or halo-C 1-6 -alkyl;
R 8 is hydrogen or halo-C 1-6 -alkyl; and
R 9 is hydrogen.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—R 3 ;
m and n are both 1;
L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, and —CH 2 O—;
p is 1 or 2; and
R 1 is hydrogen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
(i) phenyl substituted with R 4 , R 5 , and R 6 ;
(ii) oxazolyl substituted with R 7 , R 8 , and R 9 ; and
(iii) pyridyl substituted with R 7 , R 8 , and R 9 ;

R 4 is selected from chloro, SF 5 , methyl, methoxy, —OCF 3 , —CF 3 , cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl;
R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, —CF 3 , pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl;
R 6 is hydrogen;
R 7 is tert-butyl or —CF 3 ;
R 8 is hydrogen or —CF 3 ; and
R 9 is hydrogen.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—R 3 ;
m and n are both 1;
L is selected from —O—, —OCH 2 — and —CH 2 O—;
R 1 is hydrogen;
A is phenyl substituted with R 4 , R 5 , and R 6 ;

R 4 is selected from chloro, SF 5 , methyl, methoxy, —OCF 3 , and —CF 3 ;
R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, —CF 3 ; and
R 6 is hydrogen.

11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—R 3 ;
m and n are both 0;
L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—;
A is phenyl substituted with R 4 , R 5 , and R 6 ;
p is 1 or 2;
R 1 is hydrogen;
R 4 is selected from chloro, SF 5 , methyl, methoxy, —OCF 3 , and —CF 3 ;
R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, —CF 3 ; and
R 6 is hydrogen.

12. The compound of claim 1 ,

Assignees

• Hoffmann La Roche

Inventors

• Bell Charles
• Benz Joerg
• Gobbi Luca
• Grether Uwe
• Groebke Zbinden Katrin
• Hornsperger Benoit
• Kocer Buelent
• Kroll Carsten
• Kuhn Bernd
• Lutz Marius Daniel Rinaldo
• O'Hara Fionn
• Richter Hans
• Ritter Martin
• Rombach Didier
• Kuratli Martin

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title