Inhibitor compounds of phosphodiesterase type 10A

Patent metadata

Field	Value
Publication number	US-9790203-B2
Application number	US-201314087680-A
Country	US
Kind code	B2
Filing date	Nov 22, 2013
Priority date	Nov 26, 2012
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention relates to compounds which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.

First claim

We claim:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof;
where in form (I) the moiety of the formula Het1/2

is selected from the following radicals Het1/2a to Het1/2q:

where R b is hydrogen or has one of the meanings given for R;
Het 2 is phenyl or a 5- or 6-membered monocyclic hetaryl, which has one heteroatom, selected from the group consisting of O, S and N as a ring member and optionally one or two further heteroatoms or heteroatom moieties independently selected from the group consisting of O, S, N and N—R 1a as ring members, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry, independently of each other, 1, 2 or 3, radicals R 1 ;
Cyc is selected from the group consisting of
i. monocyclic 5-membered hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from the group consisting of O, S and N as ring members, which is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R 2 , or
monocyclic 6-membered hetaryl, which is selected from the group consisting of 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, and 3-pyridazinyl, where the monocyclic 6-membered hetaryl is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R 2 ,

ii. fused 8-, 9- or 10-membered bicyclic hetaryl having one heteroatom selected from the group consisting of O, S and N and optionally 1, 2 or 3 nitrogen atoms as ring members, where the fused bicyclic hetaryl is selected from the group consisting of 3-isoquinolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, pyrrolo[2,3-b]pyridine-6-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl, and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the fused bicyclic hetaryl is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R 2 ,
iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from the group consisting of O, S and N as ring members, which in addition to monocyclic hetaryl, may carry 1, 2 or 3 identical or different substituents R 2a , and
iv. C 5 -C 8 -cycloalkyl or saturated or partially unsaturated, 5- to 10-membered heteromonocyclic or heterobicyclic radical, having 1, 2 or 3 heteroatoms or heteroatom moieties independently selected from the group consisting of O, S, S═O, S(═O) 2 , N and N—R 1a as ring members, and which may carry 1, 2 or 3 identical or different substituents R 2b ;

Ar is a radical of the following formula

wherein
X 1 is N or C—R x1 ;
X 2 is N or C—R x2 ;
X 3 is N or C—R x3 ;
X 4 is N or C—R x4 ;
provided that 0, 1 or 2 of X 1 , X 2 , X 3 and X 4 are N;
and where R x1 , R x2 , R x3 , R x4 , independently of each other, are hydrogen or have one of the meanings given for R 3 ;
R is selected from the group consisting of halogen, CN, NR 13 R 14 , C(O)NR 13 R 14 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, trimethylsilyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfonyl, fluorinated C 1 -C 6 -alkylsulfanyl, fluorinated C 1 -C 6 -alkylsulfonyl, C 1 -C 4 -alkyl-OR 11 , C 1 -C 4 -alkyl-SR 12 , C 1 -C 4 -alkyl-NR 13 R 14 , C 1 -C 6 -alkoxy, OC 1 -C 4 -alkyl-OR 11 , OC 1 -C 4 -alkyl-SR 12 , OC 1 -C 4 -alkyl-NR 13 R 14 , C 2 -C 6 -alkenyloxy, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 3 -C 6 -cycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, where the cycloalkyl moiety in the last two radicals is unsubstituted, partially or completely fluorinated, or substituted by 1, 2 or 3 methyl groups;
R a is selected from the group consisting of hydrogen, C(O)NR 13 R 14 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, trimethylsilyl, C 1 -C 4 -alkyl-OR 11 , C 1 -C 4 -alkyl-SR 12 , C 1 -C 4 -alkyl-NR 13 R 14 , C 1 -C 6 -fluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 3 -C 6 -cycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, where the cycloalkyl moiety in the last two radicals is unsubstituted, partially or completely fluorinated, or substituted by 1, 2 or 3 methyl groups;
two radicals R or the radical R together with the radical R a , if attached to adjacent ring atoms, may also form a linear C 3 -C 5 -alkanediyl, wherein 1 or 2 CH 2 moieties can be replaced by C═O, O, S, S(═O), S(═O) 2 or NR′, and where alkanediyl is unsubstituted or may carry 1 or 2 radicals independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy;
R 1 is attached to a carbon atom of Het 2 and selected from the group consisting of halogen, CN, NR 13 R 14 , C(O)NR 13 R 14 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, trimethylsilyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfonyl, fluorinated C 1 -C 6 -alkylsulfanyl, fluorinated C 1 -C 6 -alkylsulfonyl, C 1 -C 4 -alkyl-OR 11 , C 1 -C 4 -alkyl-SR 12 , C 1 -C 4 -alkyl-NR 13 R 14 , C 1 -C 6 -alkoxy, OC 1 -C 4 -alkyl-OR 11 , OC 1 -C 4 -alkyl-SR 12 , OC 1 -C 4 -alkyl-NR 13 R 14 , C 2 -C 6 -alkenyloxy, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 3 -C 6 -cycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, where the cycloalkyl moiety in the last two radicals is unsubstituted, partially or completely fluorinated, or substituted by 1, 2 or 3 methyl groups;
R 1a is selected from the group consisting of hydrogen, C(O)NR 13 R 14 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, trimethylsilyl, C 1 -C 4 -alkyl-OR 11 , C 1 -C 4 -alkyl-SR 12 , C 1 -C 4 -alkyl-NR 13 R 14 , C 1 -C 6 -fluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 3 -C 6 -cycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, where the cycloalkyl moiety in the last two radicals is unsubstituted, partially or completely fluorinated, or substituted by 1, 2 or 3 methyl groups;
R 2 is selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, OH, hydroxy-C 1 -C 4 -alkyl, O—C 3 -C 6 -cycloalkyl, benzyloxy, C(O)O—(C 1 -C 4 -alkyl), O—(C 1 -C 4 -alkyl)-CO 2 H, NR 23 R 24 , C(O)NR 23 R 24 , C 1 -C 4 -alkyl-NR 23 R 24 , —NR 25 —C(O)—NR 23 R 24 , NR 25 —C(O)O—(C 1 -C 4 -alkyl), —NR 25 —SO 2 —R 22 , phenyl, CN, —SF 5 , —OSF 5 , —SO 2 R 22 , —SR 22 , trimethylsilyl and C 3 -C 6 -cycloalkyl, where the cycloalkyl moiety in the last radical is unsubstituted, partially or completely fluorinated, or substituted by 1, 2 or 3 methyl groups, or two radicals R 2 , which are bound to adjacent ring atoms may also form a linear C 3 -C 5 -alkanediyl, wherein 1 or 2 CH 2 moieties can be replaced by C═O, O, S, S(═O), S(═O) 2 or NR′, and where alkanediyl is unsubstituted or may carry 1 or 2 radicals independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy;
R 2a has one of the meanings given for R 2 or one radical R 2a may also be a 5- or 6-membered hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from the group consisting of O, S and N as ring members, where hetaryl is unsubstituted or may carry 1, 2 or 3 radicals independently selected from the group consisting of halogen, OH, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
R 2b is selected from the group consisting of halogen, C 1 -C 4 -alkyl,

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Geneste Hervé
• Turner Sean Colm
• Ochse Michael
• Drescher Karla
• Black Lawrence A
• Jantos Katja

Classifications

• A61P43/00

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

• A61P25/22

  Anxiolytics · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title