US 9,540,384 B2Granted

Pyrrolidino heterocycles

AssigneeHoffmann-La Roche Inc.

InventorsAlexander Flohr, Katrin Groebke Zbinden, Matthias Koerner, Christian Lerner

Life of this patent

Estimating the term…

Abstract

The invention relates to compounds of formula I wherein A1, A2, A3, B, R1, R2, R3 and R4 are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit PDE10A and can be used as medicaments.

Claims6

Dependent claims

A compound of formula (I)

wherein
A1, A2 and A3 are C;
B is C1-C4-alkylene, C2-C4-alkenylene, —O—C1-C4 alkyl or —NH—C1-C4alkyl;
R1 and R2 together with the nitrogen atom to which they are attached, form a azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl or pyrazolidinyl ring which can be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C7-alkyl, C1-C7-hydroxyalkyl, C1-C7 alkoxy, C1-C7-haloalkyl, hydroxyl and oxo;
R3 is selected from the group consisting of:
R8, R9 and R10 are independently selected from hydrogen, C1-C7 alkyl or NR5R6;
R11 is selected from hydrogen, halogen, C1-C7 alkyl or C1-C7 alkoxy;
R12 is selected from hydrogen or C1-C7 alkyl;
R13 is selected from hydrogen, C1-C7-alkyl optionally substituted by halogen, C3-C8 cycloalkyl, or —C(O)—NH2;
R4 is selected from hydrogen, C1-C7-alkyl or C3-C8-cycloalkyl;
R5 and R6 are independently selected from hydrogen or C1-C7-alkyl, or R5 and R6 together with the nitrogen atom to which they are attached, form a heterocycloalkyl which can be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C7-alkyl, C1-C7-hydroxyalkyl, C1-C7 alkoxy, C1-C7-haloalkyl and oxo;
or
a pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof.

10 more elements

A compound selected from the group consisting of:

(E)-2-[2-(4-Methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-quinoline,
(E)-4-(6-(2-(4-methoxy-3,5-dimethylpyridin-2-yl)vinyl)pyridin-2-yl)morpholine,
(E)-4-methoxy-3,5-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)vinyl)pyridine,
4-methoxy-3,5-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)pyridine,
2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-6-(pyrrolidin-1-yl)pyridine,
4-(6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)pyridin-2-yl)morpholine,
2,3,5-trimethyl-6-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)pyrazine,
2-methyl-3-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)quinoxaline,
2-Methyl-3-[(E)-2-(6-pyrrolidin-1-yl-pyridin-2-yl)-vinyl]-quinoxaline,
2-Methyl-3-[2-(6-pyrrolidin-1-yl-pyridin-2-yl)-ethyl]-quinoxaline,
2-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethyl]-6-pyrrolidin-1-yl-pyridine,
4-(6-chloro-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)quinazolin-4-yl)morpholine,
2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-6-(pyrazolidin-1-yl)pyrazine,
2-methyl-3-((6-(piperidin-1-yl)pyridin-2-yl)methoxy)quinoxaline,
4-(2-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)quinazolin-4-yl)morpholine,
6-chloro-N,N-dimethyl-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)quinazolin-4-amine,
4-(1-methyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine,
(E)-4-(6-chloro-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)vinyl)quinazolin-4-yl)morpholine,
4-(6-chloro-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4-yl)morpholine,
4-(2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4-yl)morpholine,
6-chloro-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)-4-(tetrahydro-2H-pyran-4-yloxy)quinazoline,
4-[2-(2H-Pyrazol-3-yl)-6-(6-pyrrolidin-1-yl-pyridin-2-ylmethoxy)-pyrimidin-4-yl]-morpholine,
4-(2-(pyridin-3-yl)-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)pyrimidin-4-yl)morpholine,
(E)-(1-(6-(2-(6-chloro-4-(dimethylamino)quinazolin-2-yl)vinyl)pyridin-2-yl)pyrrolidin-3-yl)methanol,
5-chloro-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4(3H)-one,
6-chloro-5-methoxy-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4(3H)-one,
7,8-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)-1H-purin-6(7H)-one,
6-chloro-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4(3H)-one,
2-(2-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-yl)ethyl)-N,N-dimethylquinazolin-4-amine,
1-(6-(2-(6-chloro-4-(dimethylamino)quinazolin-2-yl)ethyl)pyridin-2-yl)pyrrolidin-3-ol,
1-(6-(2-(4-(dimethylamino)quinazolin-2-yl)ethyl)pyridin-2-yl)pyrrolidin-3-ol,
(1-(6-(2-(6-chloro-4-(dimethylamino)quinazolin-2-yl)ethyl)pyridin-2-yl)pyrrolidin-3-yl)methanol,
(1-(6-(2-(4-(dimethylamino)quinazolin-2-yl)ethyl)pyridin-2-yl)pyrrolidin-3-yl)methanol,
(E)-6-chloro-N,N-dimethyl-2-(2-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)vinyl)quinazolin-4-amine,
(E)-1-(6-(2-(6-chloro-4-(dimethylamino)quinazolin-2-yl)vinyl)pyridin-2-yl)pyrrolidin-2-one,
8-methyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4(3H)-one,
6-chloro-N,N-dimethyl-2-(2-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)ethyl)quinazolin-4-amine,
(E)-5,8-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine,
2,3-dimethyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine,
5,8-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyrazine,
5,7-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyrazin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
(E)-5,7-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
5,7-Dimethyl-2-[2-(6-pyrrolidin-1-yl-pyridin-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine,
2,3-dimethyl-6-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)imidazo[1,2-b]pyridazine,
(E)-5,8-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyrazin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine,
5,8-dimethyl-2-(2-(6-(pyrrolidin-1-yl)pyrazin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyrazine,
2-ethyl-3-methyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine,
2,3-dimethyl-5-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)pyrazolo[1,5-a]pyrimidine,
2-methyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine,
2-cyclopropyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine,
3-methyl-6-((6-(pyrrolidin-1-yl)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine-2-carboxamide,
3-methyl-N-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-amine, and,
2,3-dimethyl-5-(2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine;
or
a pharmaceutically acceptable salt thereof.

52 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/554,484Filed 26 Nov 2014 · continuation
Priority: EP 1216995830 May 2012
Published: US 2015/0087644 A126 Mar 2015
Granted: 10 Jan 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system

Family

PCT/EP2013/060833Parent of this continuation · filed 27 May 2013
US 2015/0087644 A1Pre-grant publication · published 26 Mar 2015
US 9,540,384 B2This patent

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

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Abstract

Facts

Application

14/554,484Filed 26 Nov 2014 · continuation

Priority

EP 1216995830 May 2012

Published

US 2015/0087644 A126 Mar 2015

Granted

10 Jan 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system