US 2014/0275069 A1 · Novel inhibitor compounds of phosphodiesterase type 10A

Abstract

The present invention relates to compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof: In formula I the variables X1 is CH or N, X2 is O or S and where R1, R2, R3, R4 and Q are as defined in the claims. The compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof are inhibitors of phosphodiesterase type 10A. Thus, the invention also relates to the use of the compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof 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.

A compound of formula I

wherein
Q is O or S;
X1 is N or CH;
X2 is O or S;
R1 is a moiety Y1-Cyc1;
R2 is selected from the group consisting of hydrogen, halogen, OH, C1-C4-alkyl, trimethylsilyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C7-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated C3-C7-cycloalkyl, C3-C7-cycloalkyloxy, CN and NRx1Rx2;
Rx1 and Rx2, independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, and C3-C6-cycloalkyl;
R3 is a moiety Y3-Cyc3;
R4 is unsubstituted C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, fluorinated C3-C7-cycloalkyl, or C1-C4-alkyl which carries one or two radicals R44
R44 is selected from the group consisting of C1-C4-alkoxy, C1-C4-fluoroalkoxy, CN, OH, NRx3Rx4, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, a 3- to 10-membered saturated, C-bound mono- or bicyclic heterocyclyl, 3- to 10-membered saturated, C-bound mono- or bicyclic heterocyclyloxy, where the last four groups of radicals are unsubstituted, partially or completely fluorinated and/or carry 1, 2, or 4 radicals selected from the group consisting of OH, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-fluoroalkoxy, and where C-bound heterocyclyl and C-bound heterocyclyloxy has 1, 2, 3 or 4 heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO2 as ring members;
where Rx3 and Rx4, independently of each other, are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, and C3-C6-cycloalkyl, or NRx3Rx4 is a saturated N-bound 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 consisting of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, OH, C1-C4-alkyl and C1-C4-alkoxy;
Y1, Y3 independently of each other are selected from the group consisting of a chemical bond, CH2, O, O—CH2, O—CH(CH3), O—CH2—C(O)—NH, C(O)O, C(O), NRy, NRy—CH2, S(O)2—NRy, C(O)—NRy, S, S(O), S(O)2, C(O)—O—CH2, C(O)—NRy—CH2, 1,2-ethanediyl, 1,2-ethenediyl and 1,2-ethynediyl, where Ry is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, and C1-C4-fluoroalkylsulfonyl;
Cyc1, Cyc3 independently of each other are selected from the group consisting of phenyl, naphthyl, C3-C8-cycloalkyl, 3- 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, SO2 and N, and where the 5- or 6-membered monocyclic hetaryl and the 8- to 10-membered bicyclic hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are selected from the group consisting of O, S and N,
where C3-C8-cycloalkyl, the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC1 or one radical Y′—RC2 and 0, 1, 2, 3 or 4 radicals RC1;
where phenyl, naphthyl, the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals and the mono and bicyclic heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC3 or one radical Y′—RC2 and 0, 1, 2, 3 or 4 radicals RC3;
where
RC1 is selected from the group consisting of halogen, OH, CN, NO2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylsulfanyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, cyano-C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkylsulfonyl, C(O)Ra, Z—C(O)ORb, Z—C(O)NReRd, NRgSO2Rh, S(O)2NRcRd and Z—NReRf, where
Ra, Rh independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl and C1-C4-fluoroalkyl,
Rb, Rg independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C2-C4-alkenyl and C1-C4-fluoroalkyl,
Rc, Rd independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-fluoroalkoxy,
Re, Rf independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-fluoroalkoxy,
Z is a covalent bond or C1-C4-alkanediyl,
or two radicals RC1 which are bound at adjacent carbon atoms may form a fused 5- or 6-membered carbocyclic radical or a fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 heteroatoms as ring members, which are selected from the group consisting of O, S and N;
or two radicals RC1 which are bound at the same carbon atom may form a spiro 5- or 6-membered carbocyclic radical or a spiro 5- or 6-membered heterocyclic radical having 1 or 2 heteroatoms as ring members, which are selected from the group consisting of O, S and N,
or two radicals RC1 which are bound at the same carbon atom may form an oxygen atom,
where the fused and the spiro radicals are unsubstituted or carry 1, 2, 3 or 4 radicals RC4;
Y′ is a chemical bond, CH2, O, O—CH2, C(O), S(O)2, NRy′, NRy′—CH2 or NRy′—S(O)2, where Ry′ is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl and C1-C4-fluoroalkylsulfonyl;
RC2 is a carbocyclic or heterocyclic radical selected from the group consisting of phenyl, 3- to 7-membered saturated or partially unsaturated monocarbocyclic radicals, 3- to 7-membered saturated or partially unsaturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from the group consisting of O, S and N, and 5- or 6-membered heteroaromatic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from the group consisting of O, S and N, where the carbocyclic and the heterocyclic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC4;
RC3 is selected from the group consisting of halogen, OH, CN, NO2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylsulfanyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, cyano-C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkylsulfonyl, C(O)Ra, Z—C(O)ORb, Z—C(O)NRcRd, NRgSO2Rh, S(O)2NRcRd and Z—NReRf,
wherein Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh have the same meaning as defined above,
or two radicals RC3 which are bound at adjacent carbon atoms may form a saturated or partially unsaturated fused 5- or 6-membered carbocyclic radical or a saturated or partially unsaturated fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 heteroatoms as ring members, which are selected from the group consisting of O, S and N, where the carbocyclic and the heterocyclic radical are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC4;
RC4 is selected from the group consisting of hydrogen, halogen, OH, CN, C1-C4-alkyl, C1-C4-alkoxy, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, cyano-C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C2-C6-alkenyl, C(O)Ra, benzyl, Z—C(O)ORb, Z—C(O)NRcRd, S(O)2NRcRd and Z—NReRf, where, Z, Ra, Rb, Rc, Rd, Re and Rf are as defined above or two radicals RC4 which are bound at the same atom may form an oxygen atom;
and the N-oxides, the prodrugs, the tautomers and the hydrates thereof, and the pharmaceutically acceptable salts thereof.

30 more elements

Novel inhibitor compounds of phosphodiesterase type 10A

Life of this patent

Novel inhibitor compounds of phosphodiesterase type 10A

Life of this patent

Abstract

Claims37