Substituted quinazolin-4-one derivatives

Patent metadata

Field	Value
Publication number	US-9840498-B2
Application number	US-201414907225-A
Country	US
Kind code	B2
Filing date	Jul 24, 2014
Priority date	Jul 24, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

Provided are substituted quinazolin-4-one compounds of the formula (I) and/or pharmaceutically acceptable salts and/or solvates thereof, wherein R 1 , R 2 , R 3 , R 5 , R 6 and L are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the class I PI3K kinases.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof wherein
R 1 is
phenyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

pyridyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

1-methylpyrazol-5-yl;
2-methylthiophen-5-yl;
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted in the 1 position by methyl;
tetrahydropyran-4-yl;
piperidin-1-yl;
morpholin-4-yl;
pyrolidin-3-yl, which is unsubstituted or substituted in the 1 position by a substituent which is selected from the group consisting of methoxycarbonyl, methylsulfonyl, methyl and methylcarbonyl; or
dimethylamine;
R 2 is
C 4 -C 7 -heteroaryl, containing one nitrogen atom and additional 0, 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein C 4 -C 7 -heteroaryl is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of
C 1 -C 4 -alkyl,
C 1 -C 4 -fluoroalkyl,
hydroxy-C 1 -C 4 -alkyl,
hydroxy-C 1 -C 4 -fluoroalkyl,
C 1 -C 4 -alkoxy,
C 1 -C 4 -fluoroalkoxy,
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
C 3 -C 6 -heterocycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
cyano,
fluoro,
amino,
C 1 -C 4 -alkylamino, and
C 1 -C 4 -dialkylamino;

or
C 2 -C 5 -alkynyl, which is unsubstituted or substituted by 1-2 substituents independently selected from the group consisting of
C 1 -C 4 -fluoroalkyl,
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
C 3 -C 6 -heterocycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
C 1 -C 4 -alkoxy,
C 1 -C 4 -fluoroalkoxy,
hydroxyl,
cyano,
fluoro,
amino,
C 1 -C 4 -alkylamino, and
C 1 -C 4 -dialkylamino;

R 5 and R 6 are independently hydrogen, deuterium or fluoro;
-L-R 3 is

wherein
R 7 is methoxy, difluoromethoxy, trifluoromethoxy, hydroxy, fluoro or methylsulfonylamine; and
R 3 is

wherein
R 4 is hydrogen or amino,
R 8 is hydrogen, methyl, fluoromethyl, difluoromethyl, trideuteromethyl or amino, and
X is NH, NMe or S.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, of the formula (I′)

wherein,
R 1 is
phenyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

pyridyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

1-methylpyrazol-5-yl;
2-methylthiophen-5-yl;
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted in the 1 position by methyl;
tetrahydropyran-4-yl;
piperidin-1-yl;
morpholin-4-yl;
pyrolidin-3-yl, which is unsubstituted or substituted in the 1 position by a substituent which is selected from the group consisting of methoxycarbonyl, methylsulfonyl, methyl and methylcarbonyl; or
dimethylamine;
R 2 is C 4 -C 7 -heteroaryl, containing one nitrogen atom and additional 0, 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein C 4 -C 7 -heteroaryl is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of
C 1 -C 4 -alkyl,
C 1 -C 4 -fluoroalkyl,
hydroxy-C 1 -C 4 -alkyl,
hydroxy-C 1 -C 4 -fluoroalkyl,
C 1 -C 4 -alkoxy,
C 1 -C 4 -fluoroalkoxy,
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
C 3 -C 6 -heterocycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
cyano,
fluoro,
amino,
C 1 -C 4 -alkylamino, and
C 1 -C 4 -dialkylamino;

R 5 and R 6 are independently hydrogen, deuterium or fluoro;
-L-R 3 is

wherein
R 7 is methoxy, difluoromethoxy, trifluoromethoxy, hydroxy, fluoro or methylsulfonylamine; and
R 3 is

wherein
R 4 is hydrogen or amino,
R 8 is hydrogen, methyl, fluoromethyl, difluoromethyl, trideuteromethyl or amino, and
X is NH, NMe or S.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, of the formula (Ia)

wherein
R 1 is
phenyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

pyridyl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of
methyl, ethyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropyl, chloro and fluoro;

1-methylpyrazol-5-yl;
2-methylthiophen-5-yl;
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted in the 1 position by methyl;
tetrahydropyran-4-yl;
piperidin-1-yl;
morpholin-4-yl;
pyrolidin-3-yl, which is unsubstituted or substituted in the 1 position by a substituent which is selected from the group consisting of methoxycarbonyl, methylsulfonyl, methyl and methylcarbonyl; or
dimethylamine;
R 2 is
C 4 -C 7 -heteroaryl, containing one nitrogen atom and additional 0, 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein C 4 -C 7 -heteroaryl is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of
C 1 -C 4 -alkyl,
C 1 -C 4 -fluoroalkyl,
hydroxy-C 1 -C 4 -alkyl,
hydroxy-C 1 -C 4 -fluoroalkyl,
C 1 -C 4 -alkoxy,
C 1 -C 4 -fluoroalkoxy,
C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of methyl and fluoro,
C 3 -C 6 -heterocycloalkyl, which i

Assignees

• Novartis Ag
• Du Zhenxing
• Hintermann Samuel
• Hurth Konstanze
• Jacquier Sebastien
• Lehmann Hansjoerg
• Moebitz Henrik
• Soldermann Nicolas
• Stojanovic Aleksandar

Inventors

• Du Zhenxing
• Hintermann Samuel
• Hurth Konstanze
• Jacquier Sébastien
• Lehmann Hansjoerg
• Moebitz Henrik
• Soldermann Nicolas
• Stojanovic Aleksandar

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title