Bicyclic quinazolinone derivatives

Patent metadata

Field	Value
Publication number	US-10676446-B2
Application number	US-201715728894-A
Country	US
Kind code	B2
Filing date	Oct 10, 2017
Priority date	Apr 10, 2015
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

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

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , A 1 , A 2 , A 3 , n and m are as described herein.

First claim

The invention claimed is:

1. A compound of formula (I)

(I) wherein R 1 is hydroxycycloalkyl, alkoxy, haloalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkyl, haloalkyl, alkyl sulfonyl, haloalkyl sulfonyl, aminosulfonylalkyl, cyanoalkyl, nitratealkyl, substituted cycloalkyl, substituted cycloalkylalkyl, hydroxyalkyl, dihydroxyalkyl, substituted heteroaryl, substituted heterocycloalkyl or substituted aryl, wherein substituted cycl oalkyl, substituted cycloalkylcycloalkylalkyl, substituted heteroaryl, substituted heterocycloalkyl and substituted aryl are substituted with one to three substituents selected from H, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxy, halogen and cyano;
R 2 and R 3 are independently selected from H, alkyl and cycloalkyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl;
A l is —CH—, —C(OH)— or —N—;
A 2 is —C(O)—, —C(O)CH 2 —, —CH 2 —, —NR 11 C(O)—, —NR 11 C(O)CH 2 —, or —S(O) 2 —;
A 3 is —CR 8 — or —N—;
one of R 4 and R 5 is H or alkyl and the other is H, alkoxyalkyl, alkoxycarbonylalkyl, haloalkoxycarbonylalkyl, alkyl, haloalkyl, carb oxyalkyl, cycloalkyl or substituted aminocarbonyl alkyl, wherein substituted aminocarbonyl alkyl is substituted on the nitrogen atom by two substituents independently selected from H, alkyl, cycloalkyl and substituted phenyl, wherein substituted phenyl is substituted with one to three substituents independently selected from H, alkyl, haloalkyl and cycloalkyl;
or R 4 and R 5 together with the nitrogen and carbon atoms to which they are attached form a heterocycloalkyl;
R 6 is H or alkyl;
R 7 , R 8 and R 9 are independently H, alkyl, cycloalkyl, halogen or cyano;
R 10 is substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with one to three sub stituents selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, nitro, cyano, alkylsulfonyl, haloalkylsulfonyl and pentafluoro- λ 6 -sulfanyl;
R 11 is H, alkyl or cycloalkyl;
R 12 and R 13 are both H or R 12 and R 13 together form —(CH 2 ) p —;
R 14 is H, alkyl or hydroxy; and
n, m and p are independently zero, 1 or 2;
or a pharmaceutically acceptable salt thereof

2. A compound according to claim 1 , wherein R 1 is alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, alkyl, haloalkyl, alkyl sulfonyl, haloalkylsulfonyl, aminosulfonylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, hydroxyalkyl, dihydroxyalkyl, substituted heteroaryl, substituted heterocycloalkyl or substituted aryl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted heteroaryl, substituted heterocycloalkyl and substituted aryl are substituted with one to three substituents selected from H, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxy, halogen and cyano;
R 2 and R 3 are independently selected from H, alkyl and cycloalkyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl;
A 1 is —CH— or —N—;
A 2 is —C(O)—, —C(O)CH 2 —, —CH 2 —, —NR 11 C(O)—, —NR 11 C(O)CH 2 —, or —S(O) 2 —;
one of R 4 and R 5 is H or alkyl and the other is H, alkoxycarbonylalkyl, haloalkoxycarbonylalkyl, alkyl, haloalkyl, carboxyalkyl, cycloalkyl or substituted aminocarbonylalkyl, wherein substituted aminocarbonylalkyl is substituted on the nitrogen atom by two sub stituents independently selected from H, alkyl, cycloalkyl and substituted phenyl, wherein substituted phenyl is substituted with one to three substituents independently selected from H, alkyl, haloalkyl and cycloalkyl;
or R 4 and R 5 together with the nitrogen and carbon atoms to which they are attached form a heterocycloalkyl;
R 6 is H or alkyl;
R 7 , R 8 and R 9 are independently H, alkyl, cycloalkyl, halogen or cyano;
R 10 is substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with one to three substituents selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, nitro, cyano, alkylsulfonyl, haloalkylsulfonyl and pentafluoro-λ 6 -sulfanyl;
R 11 is H, alkyl or cycloalkyl;
R 12 and R 13 are both H or R 12 and R 13 together form —(CH 2 ) p —;
R 14 is H, alkyl or hydroxy; and
n, m and p are independently zero, 1 or 2;
or a pharmaceutically acceptable salt thereof

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxycycloalkyl, alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkyl sulfonyl, aminosulfonyl alkyl, cyanoalkyl, nitratealkyl, substituted cycloalkyl, substituted cycloalkylalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, substituted heteroaryl, substituted heterocycloalkyl or substituted aryl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted heteroaryl, substituted heterocycloalkyl and substituted aryl are substituted with one to three substituents selected from H, amino, alkyl, haloalkyl, alkoxy, alkylcarbonyl, carboxy and halogen.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, aminosulfonyl alkyl, substituted cycloalkyl, substituted cycloalkylalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, substituted heteroaryl, substituted heterocycloalkyl or substituted aryl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted heteroaryl, substituted heterocycloalkyl and substituted aryl are substituted with one to three substituents selected from H, amino, alkyl, haloalkyl, alkoxy, alkylcarbonyl, carboxy and halogen.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, aminosulfonylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, substituted furanyl, substituted oxazolyl, substituted isoxazolyl, substituted imidazolyl, substituted pyrrolyl, substituted pyridinyl, substituted oxetanyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted dioxanyl, substituted azetidinyl, substituted morpholinyl or substituted phenyl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted furanyl, substituted oxazolyl, substituted isoxazolyl, substituted imidazolyl, substituted pyrrolyl, substituted pyridinyl, substituted oxetanyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted di oxanyl, substituted azetidinyl, substituted morpholinyl and substituted phenyl are substituted with one to three substituents selected from H, amino, alkyl, haloalkyl, alkoxy, alkylcarbonyl, carboxy and halogen.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, aminosulfonylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, substituted furanyl, substituted oxazolyl, substituted isoxazolyl, substituted imidazolyl, substituted pyrrolyl, substituted pyridinyl, substituted oxetanyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted azetidinyl, substituted morpholinyl or substituted phenyl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted furanyl, substituted oxazolyl, substituted isoxazolyl, substituted imidazolyl, substituted pyrrolyl, substituted pyridinyl, substituted oxetanyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted azetidinyl, substituted morpholinyl and substi

Assignees

• Hoffmann La Roche

Inventors

• Hert Jerome
• Hunziker Daniel
• Kuratli Christoph
• Martin Rainer E
• Mattei Patrizio
• Satz Alexander Lee

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/90 Primary

  with acyclic radicals attached in position 2 or 3 · CPC title