Substituted furo[3,2-c]pyridines, thieno[3,2-c]pyridines, thieno[2,3-d]pyridazines and pyrido[3,4-d]pyridazines as phosphodiesterase type 10A inhibitors

Patent metadata

Field	Value
Publication number	US-9657034-B2
Application number	US-201614997997-A
Country	US
Kind code	B2
Filing date	Jan 18, 2016
Priority date	Nov 9, 2011
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The present invention relates to novel compounds of the formula I 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.

wherein
Q is O or S, X 1 is N or CH, X 2 is N or C—R 7 ; X 3 is O, S—X 4 ═C(R 8 )—, where C(R 8 ) is bound to the carbon atom which carries R 2 , or —X 5 ═C(R 9 )—, where X 5 is bound to the carbon atom which carries R 2 ; X 4 is N or C—R 9 ; X 5 is N;
Het is selected from optionally substituted phenyl, monocyclic hetaryl and fused bicyclic hetaryl;
R 1 is selected inter alia from hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, the moiety Y 1 -Cyc 1 ;
R 2 is selected inter alia from hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, etc;
A represents one of the following groups A 1 , A 2 , A 3 , A 4 or A 5 :

where * indicates the points of attachment to Het and to the nitrogen atom, respectively;
and where R 3 to R 9 , R 3e , R 3f , A′, Y 1 and Cyc 1 are defined in the claims.

First claim

We claim:

1. A compound of formula (I)

wherein
Q is O or S;
when X 1 is CH, X 3 is O or S;
when X 1 is N, X 3 is S or —X 5 ═C(R 9 )—, where X 5 is bound to the carbon atom which carries R 2 ;
X 2 is C—R 7 ;
X 5 is N;
Het is selected from the group consisting of
i. 5- or 6-membered monocyclic hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, which is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R x ,
ii. 8- to 10-membered bicyclic hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, benzothienyl or benzofuryl, where bicyclic hetaryl, benzothienyl and benzofuryl are, independently of each other, unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R x , and
iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, which in addition to monocyclic hetaryl, may carry 1, 2 or 3 identical or different substituents R x ,
where
R x is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, 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, N(R x1 )(R x2 ), C(O)N(R x1 )(R x2 ), C 1 -C 4 -alkyl-N(R x1 )(R x2 ), —NR x3 —C(O)—N(R x1 )(R x2 ), NR x3 —C(O)O—(C 1 -C 4 -alkyl), —N(R x3 )—SO 2 —R x4 , phenyl, CN, —SF 5 , —OSF 5 , —SO 2 R x4 , —SR x4 and trimethylsilyl, where R x1 , R x2 , R x3 , and R x4 , independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl and C 3 -C 6 -cycloalkyl or R x1 and R x2 form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C 1 -C 4 -alkyl; or two radicals R x which are bound at adjacent carbon atoms may form a fused 5- or 6-membered saturated carbocyclic radical or a fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N;

R 1 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NR x1 R x2 , NR x1 R x2 —C 1 -C 4 -alkoxy and the moiety Y 1 -Cyc 1 ;
R 2 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN and NR x1 R x2 ;
A is selected from the group consisting of (A 1 ), (A 2 ), (A 3 ), (A 4 ) and (A 5 ):

 where * indicates the points of attachment to Het and to the nitrogen atom, respectively,
R 3 , R 4 , R 5 , and R 6 independently of each other are selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, and C 3 -C 6 -cycloalkyl, or the radicals together with the carbon atoms to which they are bound form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from fluoro and methyl or either the radicals R 3 and R 4 or the radicals R 5 and R 6 together with the carbon atom to which they are bound form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from fluoro and methyl;
A′ is selected from the group consisting of O, NR 3a , CR 3b R 3c and linear C 2 -C 3 -alkanediyl, where one of the CH 2 -moieties of C 2 -C 3 -alkanediyl may be replaced by oxygen or NR 3a , and where 1, 2, 3, or 4 of the hydrogen atoms of C 2 -C 3 -alkanediyl may be replaced by a radical R 3d , where
R 3a is hydrogen or C 1 -C 4 -alkyl,
R 3b and R 3c independently of each other are selected from the group consisting of hydrogen, halogen, and C 1 -C 4 -alkyl or R 3b and R 3c together form C 2 -C 3 -alkanediyl;
R 3d is selected from the group consisting of halogen and C 1 -C 4 -alkyl;

R 3e and R 3f independently of each other are selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
R 7 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NR x1 R x2 ; NR x1 R x2 —C 1 -C 4 -alkoxy and Y 2 -Cyc 2 ;
R 8 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN and NR x1 R x2 ;
R 9 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NR x1 R x2 , NR x1 R x2 —C 1 -C 4 -alkoxy and Y 3 -Cyc 3 ;
Y 1 , Y 2 and Y 3 independently of each other are selected from the group consisting of a chemical bond, CH 2 , O, O—CH 2 , NR y , NR y —CH 2 , NR y —S(O) 2 , S, S(O), S(O) 2 , 1,2-ethandiyl, 1,2-ethendiyl and 1,2-ethyndiyl, where R y is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -fluoroalkylsulfonyl;
Cyc 1 , Cyc 2 and Cyc 3 independently of each other are selected from the group consisting of phenyl, naphthyl, 4- to 8-membered saturated or partially unsaturated heteromonocyclic radicals, saturated or partially unsaturated 7- to 10 membered heterobicyclic radicals, 5- or 6-membered monocyclic hetaryl, and 8- to 10 membered bicyclic hetaryl, where the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals have 1, 2, 3 or 4 heteroatoms or heteroatom containing groups as ring members, which are selected from the group consisting of O, S, SO, SO 2 and N, and where the 5- or 6-membered monocyclic hetaryl and the 8- t

Assignees

• Abbvie Deutschland
• Abbvie Inc
• Abbvie Deuschland Gmbh & Co Kg

Inventors

• Geneste Hervé
• Ochse Michael
• Drescher Karla
• Turner Sean
• Behl Berthold
• Laplanche Loic
• Dinges Jürgen
• Jakob Clarissa
• BLACK Lawrence
• Jantos Katja

Classifications

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/14

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · 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