Tetrahydropyrazolo [3,4-b] azepine derivatives and their use as allosteric modulators of metabotropic glutamate receptors

Patent metadata

Field	Value
Publication number	US-9765091-B2
Application number	US-201113809581-A
Country	US
Kind code	B2
Filing date	Jul 11, 2011
Priority date	Jul 14, 2010
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention relates to novel compounds of Formula (I), wherein M, A and Y are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR 4 ”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR 4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR 4 is involved.

First claim

The invention claimed is:

1. A compound of Formula (I),

a pharmaceutically acceptable acid or base addition salt, a stereochemically isomeric form or an N-oxide form thereof, wherein
M is a an optionally substituted heteroaryl;
A is NH or O;
Y is —CR 3 R 4 —NR 5 —;
R 1 , R 2 , R 3 or R 4 are each independently selected from the group of hydrogen, halogen, —CN, —CF 3 or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —O—(C 0 -C 6 )alkyl, —N—((C 0 -C 6 )alkyl) 2 , —(C 1 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 1 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 ; or optionally, any
two radicals of R (R 1 , R 2 , R 3 or R 4 ) are taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; and
R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylene-(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-(C 3 -C 7 )halocycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —(C 2 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 2 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 .

2. A compound according to claim 1 of Formula (II),

a pharmaceutically acceptable acid or base addition salt, a stereochemically isomeric form, or an N-oxide form thereof.

3. A compound according to claim 2 of Formula (III),

wherein,
R 1 , R 2 , R 3 or R 4 are each independently selected from the group of hydrogen, halogen, —CN, —CF 3 or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —O—(C 0 -C 6 )alkyl, —N—((C 0 -C 6 )alkyl) 2 , —(C 1 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 1 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 ; or optionally, any
two radicals of R (R 1 , R 2 , R 3 or R 4 ) are taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; and
R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylene-(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-(C 3 -C 7 )halocycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —(C 1 -C 6 )alkylene-(C 3 -C 7 )cycloalkyl, —(C 2 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 2 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 .

4. A compound according to claim 2 of Formula (III),

wherein,
R 1 , R 2 , R 3 or R 4 are each independently selected from the group of hydrogen, halogen, —CN, —CF 3 or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —O—(C 0 -C 6 )alkyl, —N—((C 0 -C 6 )alkyl) 2 , —(C 1 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 1 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 ; or optionally, any
two radicals of R (R 1 , R 2 , R 3 or R 4 ) are taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; and
R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylene-(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-(C 3 -C 7 )halocycloalkyl, aryl, heteroaryl, heterocycle, —(C 1 -C 6 )alkylene-aryl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-heterocycle, —(C 2 -C 6 )alkyl-O—(C 0 -C 6 )alkyl, or —(C 2 -C 6 )alkyl-N—((C 0 -C 6 )alkyl) 2 .

5. A compound according to claim 3 or claim 4 of Formula (III) wherein,
M is an optionally substituted pyridinyl, pyrimidinyl, thiadiazolyl, triazinyl, thiazolyl or oxadiazolyl;
R 1 , R 2 , R 3 or R 4 are each independently selected from the group of hydrogen and an optionally substituted —(C 1 -C 6 )alkyl; and
R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of methyl, ethyl, isopropyl, cyclobutyl, methyl-ethylene-O-methyl, tetrahydrofuranyl, methylene-amide, methylene-trifluoromethyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-cyclopentyl, methylene-cyclohexyl, methylene-phenyl, methylene-tetrahydrofuranyl, methylene-pyrazolyl, methylene-isoxazolyl, methylene-oxazolyl, methylene-triazolyl, methylene-thiazolyl, methylene-pyrrolyl, methylene-imidazolyl, methylene-pyridinyl, methylene-pyrimidinyl, methylene-piperidinyl, ethylene-OH, ethylene-O-methyl, ethylene-O-isopropyl, ethylene-methylamine, ethylene-sulfonyl-methyl, ethylene-trifluoromethyl, ethylene-phenyl, ethylene-pyridinyl, ethylene-cyclopropyl or propylene-O-methyl.

6. A compound according to claim 3 or claim 4 of Formula (III) wherein,
M is selected from the group of pyridinyl, pyrimidinyl, thiadiazolyl or triazinyl or optionally each are substituted by hydrogen, methyl, fluoro, chloro, methoxy, amino, hydroxyl, methylenehydroxy or fluoromethylene;
R 1 , R 2 , R 3 or R 4 are each independently selected from the group of hydrogen or an optionally substituted —(C 1 -C 6 )alkyl; and
R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of methyl, ethyl, isopropyl, cyclobutyl, methyl-ethylene-O-methyl, tetrahydrofuranyl, methylene-amide, methylene-trifluoromethyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-cyclopentyl, methylene-cyclohexyl, methylene-phenyl, methylene-tetrahydrofuranyl, methylene-pyrazolyl, methylene-isoxazolyl, methylene-oxazolyl, methylene-triazolyl, methylene-thiazolyl, methylene-pyrrolyl, methylene-imidazolyl, methylene-pyridinyl, methylene-pyrimidinyl, methylene-piperidinyl, ethylene-OH, ethylene-O-methyl, ethylene-O-isopropyl, ethylene-methylamine, ethylene-sulfonyl-methyl, ethylene-trifluoromethyl, ethylene-phenyl, ethylene-pyridinyl, ethylene-cyclopropyl or propylene-O-methyl.

7. A compound as in any one of the claims 1 - 4 , which can exist as optical isomers, wherein said compound is either the racemic mixture or one or both of the individual optical isomers.

8. A compound according to claim 1 , wherein said compound is selected from:
6-Methyl-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d] azepin-2-amine,
N-(5-Fluoropyrimidin-2-yl)-6-methyl-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d] azepin-2-amine,
6-Ethyl-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d] azepin-2-amine,
6-(Cyclopropylmethyl)-N-(5-fluoropyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b] thiazolo[4,5-d]azepin-2-amine,
6-Isopropyl-N-(4-methylpyrimidin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2-amine,
N-(5-Fluoropyrimidin-2-yl)-6-isopropyl-4,5,6,8-tetrahydropyrazolo[3,4-b]thiazolo[4,5-d]azepin-2

Assignees

• Bolea Christelle
• Celanire Sylvain
• Tang Lam
• Liverton Nigel J
• Jones Philip
• Addex Pharmaceuticals Sa
• Merck Sharp & Dohme

Inventors

• Bolea Christelle
• Celanire Sylvain
• Tang Lam
• Liverton Nigel J
• Jones Philip

Classifications

• 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title