Heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-2022275005-A1
Application number	US-202217737656-A
Country	US
Kind code	A1
Filing date	May 5, 2022
Priority date	Sep 9, 2019
Publication date	Sep 1, 2022
Grant date	—

Abstract

The invention provides new heterocyclic compounds having the general formula (I)wherein A, B, L, X, R1, R2, R3 and R4 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

First claim

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
X is N or C—R 5 ;
L is selected from a covalent bond, —(CH 2 ) n —O—, —O—(CH 2 ) p —, and —SO 2 —;
n is an integer selected from 0, 1, 2 and 3;
p is an integer selected from 1, 2 and 3;
A is:
(i) C 6-14 -aryl substituted with R 6 , R 7 and R 8 ; or
(ii) 5-14 membered heteroaryl substituted with R 9 , R 10 and R 11 ; or

B is a bridged bicyclic heterocycle;
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
R 3 is hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, halogen or hydroxy;
R 4 is hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, halogen or hydroxy;
R 5 is hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, halogen or hydroxy; and
R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, halogen, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, SF 5 , C 1-6 -alkylsulfonyl, cyano, C 3-10 -cycloalkyl, C 6-14 -aryl, and 5-14 membered heteroaryl, wherein said C 3-10 -cycloalkyl, C 6-14 -aryl, and 5-14 membered heteroaryl are optionally substituted with 1-2 substituents selected from halogen, cyano, SF 5 C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, and halo-C 1-6 -alkoxy.

2 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

3 . The compound of formula (I) according to claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

4 . The compound of formula (I) according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

5 . The compound of formula (I) according to any one of claims 1 to 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

6 . The compound of formula (I) according to any one of claims 1 to 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

7 . The compound of formula (I) according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, and halogen.

8 . The compound of formula (I) according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halo-C 1-6 -alkyl and halogen.

9 . The compound of formula (I) according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from CF 3 , chloro, and fluoro.

10 . The compound of formula (I) according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen and halogen.

11 . The compound of formula (I) according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein R 7 is halogen.

12 . The compound of formula (I) according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein R 7 is fluoro or chloro.

13 . The compound of formula (I) according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.

14 . The compound of formula (I) according to any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, C 3-10 -cycloalkyl, and C 6-14 -aryl, wherein said C 6-14 -aryl is substituted with 1-2 substituents selected from halogen and halo-C 1-6 -alkyl.

15 . The compound of formula (I) according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen and halogen.

16 . The compound of formula (I) according to any one of claims 1 to 15 , or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.

17 . The compound of formula (I) according to any one of claims 1 to 16 , or a pharmaceutically acceptable salt thereof, wherein X is C—R 5 .

18 . The compound of formula (I) according to any one of claims 1 to 17 , or a pharmaceutically acceptable salt thereof, wherein L is selected from —(CH 2 ) n —O— and —O—(CH 2 ) p —.

19 . The compound of formula (I) according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0 and 1.

20 . The compound of formula (I) according to any one of claims 1 to 19 , or a pharmaceutically acceptable salt thereof, wherein p is 1.

21 . The compound of formula (I) according to any one of claims 1 to 20 , or a pharmaceutically acceptable salt thereof, wherein A is C 6-14 -aryl substituted with R 6 , R 7 and R 8 .

22 . The compound of formula (I) according to any one of claims 1 to 20 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with R 6 , R 7 and R 8 .

23 . The compound of formula (I) according to any one of claims 1 to 22 , or a pharmaceutically acceptable salt thereof, wherein B is a 6-14 membered bridged bicyclic heterocycle comprising 1-3 heteroatoms selected from N, S, and O.

24 . The compound of formula (I) according to any one of claims 1 to 22 , or a pharmaceutically acceptable salt thereof, wherein B is a 6-9 membered bridged bicyclic heterocycle comprising 1-2 heteroatoms selected from N and O.

25 . The compound of formula (I) according to any one of claims 1 to 22 , or a pharmaceutically acceptable salt thereof, wherein B is a 6-8 membered bridged bicyclic heterocycle comprising 1 nitrogen atom.

26 . The compound of formula (I) according to any one of claims 1 to 22 , or a pharmaceutically acceptable salt thereof, wherein B is selected from 8-azabicyclo[3.2.1]octan-8-yl (a); 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl (b); 3-azabicyclo[3.1.0]hexan-3-yl (c); and 2-azabicyclo[2.2.1]heptan-2-yl (d):

wherein a wavy line indicates the point of attachment to the carbonyl bridge bridging B to the hexahydropyrido oxazinone core of formula (I).

27 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II):

wherein:
X is N or CH;
L is selected from a covalent bond, —(CH 2 ) n —O—, —OCH 2 —, and —SO 2 —;
n is an integer selected from 0 and 1;
A is:
(i) C 6-14 -aryl substituted with R 6 and R 7 ; or
(ii) 5-14 membered heteroaryl substituted with R 9 and R 10 ; or

B is a 6-9 membered bridged bicyclic heterocycle comprising 1-2 heteroatoms selected from N and O;
R 6 is selected from hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, and halogen;
R 7 is selected from hydrogen and halogen;
R 9 is selected from hydrogen, C 3-10 -cycloalkyl, and C 6-14 -aryl, wherein said C 6-14 -aryl is substituted with 1-2 substituents selected from halogen and halo-C 1-6 -alkyl; and
R 10 is selected from hydrogen and halogen.

28 . The compound of formula (I) according to

Assignees

• Hoffmann La Roche

Inventors

• Grether Uwe
• Hornsperger Benoit
• Kroll Carsten
• Kuhn Bernd
• Lutz Marius Daniel Rinaldo
• O`Hara Fionn
• Richter Hans

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title