Inhibitor compounds of phosphodiesterase type 10A

摘要

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 Het, A, X, Y, Z, R1, R2, R3, R4, R5 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.

主权项

1. A method for treating a medical disorder, selected from the group consisting of schizophrenia, cognitive dysfunction associated with schizophrenia, a bipolar disorder, depression, cognitive dysfunction associated with Alzheimer's disease, diet-induced obesity, Huntington's disease, and anxiety which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound of formula (I) to a subject in need thereof: wherein X is CRx1Rx2 or C(O), where
Rx1 and Rx2, independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl, or the radicals Rx1 and Rx2, 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, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents independently selected from the group consisting of fluorine and methyl; Y is CRy1Ry2 or C(O), where
Ry1 and Ry2, independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl, or the radicals Ry1 and Ry2, 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, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents independently selected from the group consisting of fluorine and methyl;provided that one or both of X and Y is/are C(O); A is O, [C(R6,R7)]k with k=1 or 2, OC(R6,R7), C(R8)═C(R9) or C≡C; Het is independently selected from the group consisting of
i. monocyclic 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, which is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents Ra,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 unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents Ra, andiii. 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 Raa, and where hetaryl is unsubstituted or carries 1, 2 or 3 radicals Ra;Ra is independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-cycloalkyl, cyclopropyl substituted by 1, 2 or 3 methyl groups, fluorinated C3-C6-cycloalkyl, O—C3-C6-cycloalkyl, benzyloxy, C(O)O—(C1-C4-alkyl), O—(C1-C4-alkyl)-CO2H, C1-C4-alkyl-OR11, C1-C4-alkyl-SR12, C1-C4-alkyl-NR13R14, C1-C6-alkoxy, OC1-C4-alkyl-OR11, OC1-C4-alkyl-SR12, OC1-C4-alkyl-NR13R14, NR13R14, C(O)NR13R14, C1-C4-alkyl-NR13R14, —NR15—C(O)—NR13R14, NR15—C(O)O—(C1-C4-alkyl), —NR15—SO2—R12, CN, —SF5, —OSF5, —SO2R12, —SR12 and trimethylsilyl, or
two radicals Ra, which are bound to adjacent ring atoms may also form linear C3-C5-alkanediyl, wherein 1 or 2 CH2 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, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, and C1-C4-fluoroalkoxy;Raa has one of the meanings given for Ra or one radical Raa may also be phenyl or a 5- or 6-membered hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom independently selected from the group consisting of O, S and N as ring members, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 radicals independently selected from the group consisting of halogen, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy; Q is O or S; Z is independently selected from the group consisting of a chemical bond, CH2, O, O—CH2, C(O)O, C(O), NRz, NRz—CH2, S(O)2—NRz, C(O)—NRz, S, S(O), S(O)2, C(O)—O—CH2, C(O)—NRz—CH2, 1,2-ethanediyl, 1,2-ethenediyl and 1,2-ethynediyl, where Rz is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, and C1-C4-fluoroalkylsulfonyl; R1 is independently 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 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 independently 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)Rh, Z′—C(O)ORb, Z′—C(O)NRcRd, NRgSO2Rh, S(O)2NRcRd and Z′—NReRf, where
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-hydroxyalkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy and C1-C4-fluoroalkoxy,Rh is independently selected from the group consisting of C1-C4-alkyl and C1-C4-fluoroalkyl,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 independently 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 independently 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 independently 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 independently 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 independently 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;RC3 is independently 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)Rh, Z′—C(O)ORb, Z′—C(O)NRcRd, NRgSO2Rh, S(O)2NRcRd and Z′—NReRf,
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 independently 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 independently selected from the group consisting of 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)Rh, benzyl, Z′—C(O)ORb, Z′—C(O)NRcRd, S(O) 2NRcRd and Z′—NReRf, or two radicals RC4 which are bound at the same atom may form an oxygen atom, R2 is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkyl-CN, C1-C4-alkyl-OR21, C1-C4-alkyl-SR22, C1-C4-alkyl-NR23R24, C1-C6-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-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, phenyl, phenyl-C1-C4-alkyl, 5- or 6-membered hetaryl and 5- or 6-membered hetaryl-C1-C4-alkyl, where hetaryl has 1 heteroatom selected from the group consisting of O, S and N as ring member and 0, 1 or 2 further N atoms as ring members, and wherein phenyl and hetaryl in the last four mentioned radicals are unsubstituted or carry 1 or 2 radicals independently selected from the group consisting of 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)Rh, benzyl, Z′—C(O)ORb, Z′—C(O)NRcRd, S(O)2NRcRd and Z′—NReRf; R3 is independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-cycloalkyl, cyclopropyl substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, OH, hydroxy-C1-C4-alkyl, O—C3-C6-cycloalkyl, benzyloxy, C(O)O—(C1-C4-alkyl), O—(C1-C4-alkyl)-CO2H, C1-C4-alkyl-OR3′, C1-C4-alkyl-SR32, C1-C4-alkyl-NR33R34, OC1-C4-alkyl-OR11, OC1-C4-alkyl-SR32, OC1-C4-alkyl-NR33R34, NR33R34, C(O)NR33R34, C1-C4-alkyl-NR33R34, —NR35—C(O)—NR33R34,
NR35—C(O)O—(C1-C4-alkyl), —NR35—SO2—R32, phenyl, CN, —SF5, —OSF5, —SO2R32, —SR32 and trimethylsilyl; R4, R5 independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, and C3-C6-cycloalkyl, or the radicals R4, R5 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, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine and methyl; R6, R7 independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, and C3-C6-cycloalkyl, or the radicals R6, R7 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, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine and methyl; R8, R9 independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl and C1-C4-fluoroalkyl, the moiety C(R4,R5)-A may also form a moiety C(R8)═C(R9), C≡C, C(R8)═C(R9)—C(R6,R7) or C≡C—C(R6,R7), the moiety C(R4,R5)-A may also form a cyclopropane-1,2-diyl or cyclopropane-1,2-diyl-C(R6,R7), where the cyclopropane-1,2-diyl moiety is unsubstituted or carries 1 or 2 radicals independently selected from the group consisting of halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-fluoroalkoxy; and where R11, R12, R21, R22, R31 and R32 independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, and C3-C6-cycloalkyl-C1-C4-alkyl, where R11 may also be selected from the group consisting of C1-C4-alkylsulfonyl and C1-C4-fluoroalkylsulfonyl; R13, R14 independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4-alkyl, or
R13 and R14 together with the N atom to which they are attached form a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups independently 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 C1-C4-alkyl substituents; R23, R24, R33 and R34 have one of the meanings given for R13, R14; R15, R35 independently of each other are selected from the group consisting hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4-alkyl; and R′ is hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C4-alkyl; an N-oxide thereof, a prodrug thereof, a tautomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.