US 8,785,628 B2Granted

Triazine derivatives as kinase inhibitors

AssigneeUCB Pharma S.A.

InventorsDaniel Rees Allen, Roland Bürli, Alan Findlay Haughan, Jonathan David MacDonald, Mizio Matteucci, David John Nash, Andrew Pate Owens, Gilles Raphy, Elizabeth Anne Saville-Stones, Andrew Sharpe

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Abstract

A series of substituted [1,3,5]triazin-2-yl derivatives, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

Claims12

Dependent claims

A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein
E represents an optionally substituted straight or branched C1-3 alkylene chain;
Q represents oxygen, sulfur, N—R6 or a covalent bond;
the ring comprising M represents an optionally substituted saturated five-, six- or seven-membered monocyclic ring containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;
W represents C—R7 or N;
R1, R2 and R3 independently represent hydrogen, halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, aryl(C1-6)alkyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di(C1-6)alkyl-amino, C2-6 alkylcarbonylamino, C2-6alkoxycarbonylamino, C1-6alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl or di(C1-6)alkylaminosulfonyl;
R4 and R5 independently represent C1-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
or hydrogen, halogen, trifluoromethyl, —ORa, —SRa, —SORa, —SO2Ra, —NRbRc, —NRcCORd, —NRcCO2Rd, —NRcSO2Re, —CORd, —CO2Rd, —CONRbRc or —SO2NRbRc;
R6 represents hydrogen or C1-6 alkyl;
R7 represents hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy;
Ra represents C1-6 alkyl, difluoromethyl or trifluoromethyl;
Rb represents hydrogen or trifluoromethyl;
or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
Rc represents hydrogen, C1-6 alkyl or C3-7 cycloalkyl;
Rd represents hydrogen or C1-6 alkyl;
and
Re represents C1-6 alkyl.

14 more elements

A compound selected from the group consisting of

6-Methyl-N-{(S)-1-[8-methyl-2-(morpholin-4-yl)quinolin-3-yl]ethyl}1-[1,3,5]triazine-2,4-diamine,
6-Methyl-N-{(S)-1-[8-methyl-2-(pyrrolidin-1-yl)quinolin-3-yl]ethyl}1-[1,3,5]triazine-2,4-diamine,
4-{3-[(S)-1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}-piperazin-2-one,
N2-[(S)-1-{8-Chloro-2-[(S)-3-methylmorpholin-4-yl]quinolin-3-yl}ethyl]-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(S)-3-methylmorpholin-4-yl]quinolin-3-yl}ethyl]-6-methyl-[1,3,5]triazine-2,4-diamine,
N-[(S)-1-{3-[(S)-1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}pyrrolidin-3-yl]acetamide,
(S)-6-Methyl-N2-{1[-8-methyl-2-(thiomorpholin-4-yl)quinolin-3-yl]ethyl}-[1,3,5]triazine-2,4-diamine,
(S)-6-Methyl-N2-{1-1-[8-chloro-2-(1,1-dioxothiomorpholin-4-yl)quinolin-3-yl]ethyl}-[1,3,5]triazine-2,4-diamine,
(S)-N-(1-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperidin-4-yl)methanesulfonamide,
(S)-N-(1-{3-[1-(4Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}-piperidin-4-yl)methanesulfonamide,
(S)-1(4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)ethanone,
(S)-1-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)ethanone,
(S)-4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}piperazin-2-one,
(S)-4-{3-[1-(4-Amino[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-2-one,
(S)-4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-2-one,
(S)-4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-2-one,
(S)-4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methyl-quinolin-2-yl}piperazin-2-one,
N-{(1S)-1-[8-Chloro-2-(pyrrolidin-1-yl)quinolin-3-yl]ethyl}-[1,3,5]triazine-2,4-diamine,
N-{(1S)-1-[8-Chloro-2-(morpholin-4-yl)quinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
(3R)-1-(3-{(1S)-1-[(4-Amino-[1,3,5 ]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)pyrrolidin-3-ol,
(3R)-1-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)aminol]ethyl}-8-chloro-quinolin-2-yl)pyrrolidin-3-ol,
(3S)-1-(3-{(1S)-1-[(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)pyrrolidin-3-ol,
(3S)-1-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)pyrrolidin-3-ol,
1-(3-{(1S)-1-1-[(4-Amino-[1,3,5]triazin-2-yl)aminol]ethyl}-8-chloroquinolin-2-yl)-[1,4]-diazepan-5-one,
1-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)-[1,4]diazepan-5-one,
4-(3-{(1S)-1-[(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)-1-methylpiperazin-2-one,
4-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)-1-methylpiperazin-2-one,
1-(3-{(1S)-1-[(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-8-chloroquinolin-2-yl)-imidazolidin-2-one,
(S)-(4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}piperazin-1-yl)(cyclopropyl)methanone,
(S)-4-(8-Chloro-3-{1-[4-(methylamino)-[1,3,5]triazin-2-ylamino]ethyl}quinolin-2-yl)piperazin-2-one,
1-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-8-methylquinolin-2-yl)-[1,4]diazepan-5-one,
1-(3-{(1S)-1-[(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-8-methylquinolin-2-yl)-[1,4]-diazepan-5-one,
6-Methyl-N-{(1S)-1-[8-methyl-2-(piperazin-1-yl)quinolin-3-yl]ethyl}-[1,3,5]triazine-2,4-diamine,
(S)-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)(cyclopropyl)methanone,
(S)-(4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)(cyclopropyl)methanone,
(S)-2-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}piperazin-1-yl)-N,N-dimethylacetamide,
(S)-2(4-{3-[1-(4Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}piperazin-1-yl)-1-(morpholin-4-yl)ethanone,
(S)-N2-(1-{8-Chloro-2-[4-(methylsulfonyl)piperazin-1-yl]quinolin-3-yl}ethyl)-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-Ethyl 2-(4-{3-[1-(4-amino-6-methyl-[1,3 ,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)acetate,
(S)-2(4-{3-[1-(4Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)-N,N-dimethylacetamide,
(S)-N2-(4-Methoxybenzyl)-6-methyl-N4-{1-[8-methyl-2-(pyrrolidin-1-yl)quinolin-3-yl]-ethyl}-[1,3,5]triazine-2,4-diamine,
(S)-4-(3-{1-[4-(4-Methoxybenzylamino)-6-methyl-[1,3,5]triazin-2-ylamino]ethyl}-8-methylquinolin-2-yl)piperazin-2-one,
N-{(1S)-1-[7-Fluoro-2-(pyrrolidin-1-yl)quinolin-3-yl]ethyl}-[1,3,5]triazine-2,4-diamine
N-[1-(3-{(1S)-1-[-(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-7-fluoroquinolin-2-yl)-piperidin-4-yl]-acetamide,
N-{(1S)-1-[7-Fluoro-2-(pyrrolidin-1-yl)quinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
N-[-1-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-7-fluoroquinolin-2-yl)piperidin-4-yl]acetamide,
1-[4-(3-{(1S)-1-[(4-Amino-6-methyl-[1,3,5]triazin-2-yl)amino]ethyl}-7-fluoroquinolin-2-yl)piperazin-1-yl]ethanone,
1-[4-(3-{(1S)-1-[(4-Amino-[1,3,5]triazin-2-yl)amino]ethyl}-7-fluoroquinolin-2-yl-piperazin-l-yl-]ethanone,
4-{[8-Methyl-2-(pyrrolidin-1-yl)quinolin-3-yl]methoxy}-[1,3,5]triazin-2-amine,
4-{[8-Methyl-2-(morpholin-4-yl)quinolin-3-yl]methoxy}-[1,3,5]triazin-2-amine,
4-{3-[(4-Amino-[1,3,5]triazin-2-ylamino)methyl]-8-methylquinolin-2-yl}piperazin-2-one,
4-{3-[(4-Amino-6-methyl-[-1,3,5]triazin-2-ylamino)methyl]-8-methylquinolin-2-yl}-piperazin-2-one,
(S)-1-(4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-methylquinolin-2-yl}-piperazin-1-yl)ethanone,
4-{3-[(4-Amino-[1,3,5]triazin-2-yloxy)methyl]-8-methylquinolin-2yl}piperazin-2-one
4-{3-[(4-Amino-6-methyl-[1,3,5]-triazin-2-yloxy)methyl]-8-methylquinolin-2-yl}-piperazin-2-one,
(S)-4-(8-Chloro-3-{1-[4-(dimethylamino)-[1,3,5]triazin-2-ylamino]ethyl}quinolin-2-yl)piperazin-2-one,
(S)-N2-{1-[8-Chloro-2-(3,3-difluoropyrrolidin-1-yl)quinolin-3-yl]-lethyl}-[1,3,5]-1triazine-2,4-diamine,
(S)-N2-{1-[8-Chloro-2-(3 ,3-difluoropyrrolidin-1-yl)quinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(R)-3-fluoropyrrolidin-1-yl]quinolin-3-yl}ethyl]-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(R)-3-fluoropyrrolidin-1-yl]quinolin-3-yl}ethyl]-6-methyl-[1,3,5]1triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(S)-3-fluoropyrrolidin-1-yl]quinolin-3-yl}ethyl]-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-Ethyl 2(4-{3-[-1-(4amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)acetate,
(S)-4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}-N,N-dimethylpiperazine-1-carboxamide,
(S)-1-(4-{3-[1-(4Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}-[1,4]diazepan-1-yl)ethanone,
(S)-4-(7-Fluoro-8-methyl-3-{1-[4-(methylamino)-[1,3,5]triazin-2-ylamino]ethyl}-quinolin-2-yl)piperazin-2-one,
(S)-N2-{1-[7-Fluoro-8-methyl-2-(pyrrolidin-1-yl)quinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-2-[4-(8-Chloro-3-{1-[4-(methylamino)-[1,3,5]triazin-2-ylamino]ethyl}quinolin-2-yl)piperazin-1-yl]ethanol,
(S)-2-(4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)ethanol,
(S)-2-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)ethanol,
(S)-1-(4-{3-[1-(4Amino-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)-2-hydroxyethanone,
(S)-Ethyl 2-[4-(8-chloro-3-{1-[4-(methylamino)-[1,3,5]triazin-2-ylamino]ethyl}quinolin-2-yl)piperazin-1-yl]acetate,
(S)-2-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperazin-1-yl)acetic acid,
(S)-2-[4-(8-Chloro-3-{1-[4-(methylamino)-[1,3,5]triazin-2-ylamino]ethyl}quinolin-2-yl)piperazin-1-yl]acetic acid,
N-{[(R)-1-{3-[(S)-1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloro-quinolin-2-yl}pyrrolidin-3-yl]methyl}acetamide,
(S)-1-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methyl-quinolin-2-yl}piperidine-4-carboxamide,
(S)-1-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperidine-4-carboxamide,
(S)-N2-(1-{7-Fluoro-8-methyl-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]quinolin-3-yl}ethyl)-6-methyl-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{2-[(3S,5R)-3,5-Dimethylpiperazin-1-yl]-7-fluoro-8-methylquinolin-3-yl}ethyl]-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-N2-{1-[7-Fluoro-2-(4-isopropylpiperazin-1-yl)-8-methylquinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-1-(4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)-2,2-dimethylpropan-1-one,
(S)-4-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-bromoquinolin-2-yl}piperazin-2-one,
(S)-4-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-5-fluoro-8-methyl-quinolin-2-yl}piperazin-2-one,
N-[(R)-1-{3-[(S)-1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}pyrrolidin-3-yl]acetamide,
N-[(R)-1-{3-[(S)-1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}pyrrolidin-3-yl]acetamide,
(S)-N -(1-{3-[1-(4-Amino-6-methyl-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}piperidin-4-yl)acetamide,
(S)-N-(1-{3-[1-(4-Amino-[1,3,5]triazin-2-ylamino)ethyl]-8-chloroquinolin-2-yl}-piperidin-4-yl)acetamide,
(S)-N2-{1-[8-chloro-2-([1,4]oxazepan-4-yl)quinolin-3-yl]ethyl}-6-methyl-[1,3,5]triazine-2,4-diamine,
(S)-Methyl 4-{3-[1-(4-amino-[1,3,5]triazin-2-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazine-1-carboxylate,
N2-[(S)-1-{8-chloro-2-[(R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-3-yl}ethyl]-6-methyl-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-3-yl}ethyl]-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-3-yl}ethyl]-[1,3,5]triazine-2,4-diamine,
N2-[(S)-1-{8-Chloro-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-3-yl}ethyl]-6-methyl-[1,3,5]triazine-2,4-diamine,
4-{3-[(4-Amino-[1,3,5]triazin-2-ylamino)methyl]-8-chloroquinolin-2-yl}piperazin-2-one,
and N-oxides, and pharmaceutically acceptable salts and solvates of any of the above compounds.

91 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/254,964Filed 2 Mar 2010
Priority: GB 0903949.66 Mar 2009
Published: US 2012/0053167 A11 Mar 2012
Granted: 22 Jul 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

US 2012/0053167 A1Pre-grant publication · published 1 Mar 2012
US 8,785,628 B2This patent

From the US filing history. Foreign family members aren’t listed.

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