# US 9,518,066 B2 · GAK modulators

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- Number: US 9,518,066 B2
- Document ID: US9518066B2
- Status: Granted
- Kind: B2
- Application number: 14/897,259
- Filed: 2014-07-04
- Published: 2016-05-05
- Granted: 2016-12-13
- Earliest claimed: 2013-07-05
- Assignees: Katholieke Universiteit Leuven, KU LEUVEN R&D
- Applicants: Katholieke Universiteit Leuven
- Inventors: Piet Herdewijn; Steven De Jonghe; Sona Kovachova; Lei Chang; Michal Sala
- Web page: https://patentgrep.com/patent/US9518066B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

An isothiazolo[4,3-b]pyridine derivative according to claim 1, wherein R6 is selected from the group consisting of 3,4-dimethoxyphenyl; 3-thienyl; phenyl; 2-thienyl; 4-m ethoxy c arb onyl-3 -methoxy-phenyl; 4-acetoxy-3 -methoxyphenyl; 3 -acetoxy-4-methoxyphenyl; 3,5-dimethoxyphenyl; 3,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 3-methoxyphenyl; 4-methoxyphenyl; 3-furanyl; N-methylbenzamide; 2-bromo-4,5-dimethoxyphenyl; 3-methoxy-4-hydroxyphenyl and 4-amino-3-methoxyphenyl.

### Claim 3 (depends on 1)

An isothiazolo[4,3-b]pyridine derivative according to claim 1, wherein R3 is selected from the group consisting of morpholinyl, ethanolamino, thiomorpholinyl, piperidinyl, 4-piperidinone, 4-hydroxypiperidinyl, 3-hydroxypiperidinyl, n-pentanolamino, tetrahydropyranyl-4-amino, diethanolamino, 2,3-dihydroxy-propanylamino, pyrrolidinyl, methoxyethylamino, cyclopropylmethylamino, dimethylamino, diethylamino, 2,6-dimethylmorpholinyl, phenyl, pyridinyl, thienyl and ethoxy.

### Claim 4

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.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising an isothiazolo[4,3-b]pyridine derivative according to claim 1.

### Claim 6 (depends on 1)

A pharmaceutical composition for the treatment of osteosarcoma or prostate cancer in an animal comprising an isothiazolo[4,3-b]pyridine derivative according to claim 1.

### Claim 7 (depends on 1)

A pharmaceutical composition for the treatment of Parkinson's disease in an animal comprising an isothiazolo[4,3-b]pyridine derivative according to claim 1.

### Claim 8 (depends on 6)

The pharmaceutical composition according to claim 6, wherein said animal is a human being.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of an isothiazolo[4,3-b]pyridine derivative according to claim 1 and one or more pharmaceutically acceptable excipients.

### Claim 10 (depends on 1)

A method of treatment of osteosarcoma or prostate cancer in an animal, comprising the administration of a therapeutically effective amount of an isothiazolo[4,3-b]pyridine derivative according to claim 1, optionally in combination with one or more pharmaceutically acceptable excipients.

### Claim 11 (depends on 7)

The pharmaceutical composition according to claim 7, wherein said animal is a human being.

### Claim 12 (depends on 10)

The method according to claim 10, wherein said animal is a human being.