US 9,518,066 B2Granted

GAK modulators

AssigneeKatholieke Universiteit Leuven, KU LEUVEN R&D

InventorsPiet Herdewijn, Steven De Jonghe, Sona Kovachova, Lei Chang, Michal Sala

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Abstract

The present invention relates to a class of novel isothiazolo[4,3-b]pyridine derivatives and a method for their preparation, as well as to pharmaceutical compositions comprising one or more of said isothiazolo[4,3-b]pyridine derivatives and one or more pharmaceutically acceptable excipients. The present invention further relates to the use of said novel isothiazolo[4,3-b]pyridine derivatives as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, cell-proliferative and neurodegenerative diseases.

Claims12

Dependent claims

An isothiazolo[4,3-b]pyridine derivative having the general formula I:

wherein
R3 is selected from the group consisting of halogen, amino, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, (mono- or di-) C1-12 alkylamino, (mono- or di-) C2-12 alkenylamino, (mono- or di-) C2-12 alkynylamino, monoarylamino;
diarylamino;
(mono- or di-) C3-10 cycloalkylamino, C3-10 cycloalkylC1-4 alkylamino, (mono- or di-) C3-10 cycloalkenylamino, (mono- or di-) hydroxy C1-7 alkylamino, (mono- or di-) C1-4 alkylarylamino, (mono- or di-) arylC1-4 alkylamino, mercapto C1-7 alkyl, C1-7 alkoxy, C1-4 alkoxyC1-4 alkylamino, alkoxyaryl, C3-10 cycloalkoxy, heterocyclic-substituted alkylamino, heterocyclic-sub stituted arylamino, heterocyclic amino, hydroxy-alkylamino, mercaptoalkylamino, hydroxypiperidinyl, aryl and heteroaryl groups, and, wherein said morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo C1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C1-7 alkoxy, and, wherein one or more carbon atoms in any ring group may be replaced with —C(═O)—;
R6 is selected from the group consisting of halogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo C1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C1-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino;
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.

3 more elements

An isothiazolo[4,3-b]pyridine derivative selected from the group consisting of:

3-morpholino-6-phenyl-isothiazolo[4,3-b]pyridine;
3-morpholino-6-(4-fluoro-phenyl)-isothiazolo[4,3-b]pyridine;
3-morpholino-6-(3-pyridyl))-isothiazolo[4,3-b]pyridine;
3-morpholino-6-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine;
3-morpholino-6-(3-thienyl)-isothiazolo[4,3-b]pyridine;
3-ethanolamino-6-(3-pyridyl)-isothiazolo[4,3-b]pyridine;
3-ethanolamino-6-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine;
3-ethanolamino-6-(3-thienyl)-isothiazolo[4,3-b]pyridine;
3-ethanolamino-6-(3-phenyl)-isothiazolo[4,3-b]pyridine;
3-methoxy-6-phenyl-isothiazolo[4,3-b]pyridine;
3-methoxy-6-(4-fluoro-phenyl)-isothiazolo[4,3-b]pyridine;
3-methoxy-6-(3-pyridyl)-isothiazolo[4,3-b]pyridine;
3-methoxy-6-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine;
3-methoxy-6-(3-thienyl)-isothiazolo[4,3-b]pyridine;
3-(N-Me-piperazinyl)-6-phenyl-isothiazolo[4,3-b]pyridine;
3-(N-Me-piperazinyl)-6-(3-pyridyl)-isothiazolo[4,3-b]pyridine;
3-(N-Me-piperazinyl)-6-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine;
3-(N-Me-piperazinyl)-6-(3-thienyl)-isothiazolo[4,3-b]pyridine;
3-(N-Me-piperazinyl)-6-(4-fluorophenyl)-isothiazolo[4,3-b]pyridine;
3-amino-6-phenyl-isothiazolo[4,3-b]pyridine;
3-amino-6-(3-pyridyl)-isothiazolo[4,3-b]pyridine;
3-amino-6-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine;
3-amino-6-(4-fluorophenyl)-isothiazolo[4,3-b]pyridine;
3-amino-6-(3-thienyl)-isothiazolo[4,3-b]pyridine;
4-(6-(Thiophen-2-yl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
4-(6-(2,5-Dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
4-(6-(2,4-Dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
Methyl 2-methoxy-4-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)benzoate;
2-Methoxy-4-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)phenyl acetate;
4-(6-(3,5-Dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
4-(6-(3,4,5-Trimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
2-Methoxy-4-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)aniline;
4-(6-(Benzo[d][1,3]dioxol-5-yl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
4-(6-(Furan-3-yl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
Methyl 4-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)benzoate;
N-Methyl-4-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)benzamide;
6-bromo-3-(piperidin-1-yl)isothiazolo[4,3-b]pyridine;
6-bromo-3-thiomorpholinoisothiazolo[4,3-b]pyridine;
3-morpholino-6-aryl-isothiazolo[4,3-b]pyridines;
6-(3,4-dimethoxyphenyl)-3-(piperidin-1-yl)isothiazolo[4,3-b]pyridine;
6-(3,4-dimethoxyphenyl)-3-thiomorpholinoisothiazolo[4,3-b]pyridine;
3-bromo-6-(2-bromo-4,5-dimethoxyphenyl)isothiazolo[4,3-b]pyridine;
4-(6-(2-bromo-4,5-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholin;
4-(6-(3-methoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
2-methoxy-5-(3-morpholinoisothiazolo[4,3-b]pyridin-6-yl)phenyl acetate;
4-(6-(4-methoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)morpholine;
1-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)piperidin-4-one;
1-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)piperidin-4-ol;
5-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-ylamino)pentan-1-ol;
1-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)piperidin-3-ol;
6-(3,4-dimethoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)isothiazolo[4,3-b]pyridin-3-amine;
2,2′-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-ylazanediyl)diethanol;
3-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-ylamino)propane-1,2-diol;
ethyl-4-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-ylamino)piperidine-1-carboxylate;
6-(3,4-dimethoxyphenyl)-3-(pyrrolidin-1-yl)isothiazolo[4,3-b]pyridine;
6-(3,4-dimethoxyphenyl)-N-phenethylisothiazolo[4,3-b]pyridin-3-amine;
6-(3,4-dimethoxyphenyl)-N-(2-methoxyethyl)isothiazolo[4,3-b]pyridin-3-amine;
N-(cyclopropylmethyl)-6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-amine;
6-(3,4-dimethoxyphenyl)-N,N-dimethylisothiazolo[4,3-b]pyridin-3-amine;
6-(3,4-dimethoxyphenyl)-N,N-diethylisothiazolo[4,3-b]pyridin-3-amine;
(2R,6S)-4-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridin-3-yl)-2,6-dimethylmorpholine;
8-(6-(3,4-dimethoxyphenyl)isothiazolo[4,3 -b]pyridin-3 -yl)- 1,4-dioxa-8-azaspiro[4.5]decane;
6-(3,4-dimethoxyphenyl)-3-phenylisothiazolo[4,3-b]pyridine;
6-(3,4-dimethoxyphenyl)-3-(pyridin-4-yl)isothiazolo[4,3-b]pyridine;
6-(3,4-dimethoxyphenyl)-3-(thiophen-3-yl)isothiazolo[4,3-b]pyridine;
6-(3,4-dimethoxyphenyl)isothiazolo[4,3-b]pyridine;
6-(2-bromo-4,5-dimethoxyphenyl)-3-(4-methylpiperidin-1-yl)isothiazolo[4,3-b]pyridine;
and
6-(2-bromo-4,5-dimethoxyphenyl)-3-ethoxyisothiazolo[4,3-b]pyridine.

66 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/897,259Filed 4 Jul 2014
Priority: GB 1312059.75 Jul 2013
Published: US 2016/0122364 A15 May 2016
Granted: 13 Dec 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
C07D
Heterocyclic compounds

Family

US 2016/0122364 A1Pre-grant publication · published 5 May 2016
US 9,518,066 B2This patent

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

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