Novel inhibitor compounds of phosphodiesterase type 10a

Abstract

The present invention relates to novel carboxamide compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating or controlling 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.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is C—R 1 , 
         X 2  is N or C—R 2 , 
         X 3  is N or C—R 3 , 
         X 4  is C—R 4 , 
         provided that 0, 1 or 2 of the moieties X 1 , X 2 , X 3  or X 4  is N; 
         A is selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 5a  and CR 5 R 6 ; 
         Het is selected from the group consisting of
 i. 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. fused 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 H, 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 consisting of O, N, S, SO and SO 2  as ring members and which may carry 1, 2, 3, 4, 5 or 6 C 1 -C 4 -alkyl substituents; 
 
         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  and NR x1 R x2 -C 1 -C 4 -alkoxy; 
         R 2 , R 3  independently of each other, are 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 4  is Y-Cyc; 
         R 5 , R 6  independently of each other are selected from the group consisting of hydrogen, OH, halogen, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl or the radicals R 5 , R 6  together with the carbon atom to which they are bound form a carbonyl group or 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 the group consisting of fluorine and methyl; 
         R 5a  is selected from the group consisting of from 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, optionally substituted by 1, 2 or 3 methyl groups, fluorinated C 3 -C 6 -cycloalkyl, phenyl, benzyl, 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, and 5- or 6-membered hetarylmethyl having 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, where the rings in the last four mentioned radicals are unsubstituted or carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy; 
         R 7 , R 8 , R 9 , R 10  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 the group consisting of fluorine and methyl or either the radicals R 7 , R 8  or the radicals R 9 , R 10  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 the group consisting of fluorine and methyl; 
         Y is 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, or 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 is a radical selected from the group consisting of 4- to 8-membered saturated or partially unsaturated monocarbocyclic radicals, 7- to 10-membered saturated or partially unsaturated bicarbocyclic radicals, 4- to 8-membered saturated or partially unsaturated heteromonocyclic radicals, saturated or partially unsaturated 7- to 10 membered heterobicyclic radicals, 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,
 where the saturated or partially unsaturated mono- and bicarbocyclic radicals, the heteromonocyclic and heterobicyclic radicals and the mono and bicyclic heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R C1  or one radical Y′—R C2  and 0, 1, 2, 3 or 4 radicals R C1 ; where 
 R C1  is selected from the group consisting of hydrogen, halogen, OH, CN, NO 2 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, cyano-C 1 -C 4 -alky, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 1 -C 4 -alkylsulfonyl, C(O)R a , Z—C(O)OR b , Z—C(O)NR c R d , S(O) 2 NR c R d  and Z—NR e R f , where
 R a  is selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -fluoroalkyl, 
 R b  is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 1 -C 4 -fluoroalkyl, 
 R c , R d  is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy, 
 R e , R f  is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy, 
 Z is a covalent bond or C 1 -C 4 -alkandiyl, 
 or two radicals R C1  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 R C1  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 R C1  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 R C3 ; 
 
 Y′ is a chemical bond, CH 2 , O, O—CH 2 , S(O) 2 , NR Y ′, NR y ′—CH 2  or NR y ′—S(O) 2 , 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; 
 R C2  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 radical is unsubstituted or carries 1, 2, 3, 4 or 5 radicals R C3 ; 
 R C3  is selected from the group consisting of hydrogen, halogen, OH, CN, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl , cyano-C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 2 -C 6 -alkenyl, C(O)R a , Z—C(O)OR b , Z—C(O)NR c R d , S(O) 2 NR c R d  and Z—NR e R f , where, Z, R a , R b , R c , R d , R e  and R f  are as defined above or two radicals R C3  which are bound at the same atom may form an oxygen atom; 
 
         or an N-oxide, prodrug, tautomer, or hydrate thereof; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , where X 2  is C—R 2  and X 3  is C—R 3 . 
     
     
         4 .- 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , where R 1 , R 2  and R 3 , if present, are selected, independently of each other, from the group consisting of hydrogen, fluorine, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl. 
     
     
         8 .- 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , where A is a radical CR 5 R 6 . 
     
     
         12 . The compound of  claim 1 , which is of the formula (I-A) 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , where R 4  is a radical Y-Cyc and X 1  is C—R 1 , where R 1  is selected from the group consisting of hydrogen, fluorine, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl. 
     
     
         14 . The compound of  claim 11 , where R 5  and R 6  are, independently of each other, selected from the group consisting of hydrogen, fluorine and methyl. 
     
     
         15 . The compound of  claim 1 , where Het is selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from the group consisting of O, S and N as ring member;
 where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x .   
     
     
         16 . The compound of  claim 15 , where Het has at least one imino-nitrogen as ring member, which located in the position adjacent to carbon atom bound to the group CR 9 R 10 . 
     
     
         17 . The compound of  claim 15 , where Het is selected from the group consisting of 2-benzofuryl, 2-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, benzothiazolyl, imidazo[1,2-a]pyridine-2-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 aforementioned radicals may carry 1, 2 or 3 radicals selected from fluorine, chlorine, C 1 -C 4 -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl. 
     
     
         18 . The compound of  claim 1 , where R 7  and R 8  are, independent from each other selected from the group consisting of hydrogen and fluorine. 
     
     
         19 . The compound of  claim 1 , which is of the formulae (I-Aa) or (I-Ab) 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , which is of the formula (I-Ac) 
       
         
           
           
               
               
           
         
         where Q is S or N—CH 3 ; and R xx  is hydrogen, fluorine or CH 3    
       
     
     
         21 . The compound of  claim 1 , which is of the formula (I-Ad) 
       
         
           
           
               
               
           
         
         where q is 0 or 1; and R x  is selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, which is optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl. 
       
     
     
         22 . The compound of  claim 19 , where R 1  is selected from the group consisting of hydrogen, fluorine, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl. 
     
     
         23 . The compound of  claim 19 , where R 5  and R 6  are, independently of each other, selected from the group consisting of hydrogen, fluorine and methyl. 
     
     
         24 . The compound of  claim 1 , where Y is selected from the group consisting o chemical bond, O and NH. 
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 1 , where Cyc is a saturated 4-, 5-, 6-, 7- or 8-membered heteromonocycle or a saturated 7-, 8-, 9- or 10-membered heterobicycle, where the heteromonocycle and the heterobicycle have one nitrogen or oxygen atom as ring member and may have one further heteroatom or heteroatom group as ring member, which is selected from the group consisting of O, S, S(═O), S(═O) 2  and N, where the saturated heteromonocycle and the saturated heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R C1  or one radical Y′—R C2  and 0, 1, 2, 3 or 4 radicals R C1 . 
     
     
         27 . The compound of  claim 1 , where Y-Cyc is selected from the group consisting of 1-piperidinyl, 4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl, 2-oxa-6-azaspiro-[3,4]octyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino, 1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino. 
     
     
         28 . - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , where R 9  and R 10  are, independent from each other, selected from the group consisting of hydrogen and fluorine. 
     
     
         31 . The compound of  claim 1 , which is selected from the group consisting of
 7-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-Piperazin-1-yl-2-(2-quinolin-2-yl-dihydro-isoindol-1-one,   7-(3,8-Diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(4-Pyridin-4-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[1,4]Oxazepan-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(7-nitro-3,4-dihydroisoquinolin-2 (1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one,   7-(7-amino-3,4-dihydroisoquinolin-2 (1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one,   4-Chloro-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide,   4-Isopropyl-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide,   2-[2-(6-Fluoro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   2-[2-(6-Methoxy-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   2-[2-(4-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   2-[2-(8-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-Morpholino-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one,   7-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[8-(Morpholine-4-sulfonyl)-3 4-dihydro-1H-isoquinolin-2-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1-Oxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(2-Oxa-6-aza-spiro[3,5]non-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3-Amino-azetidin-1-yl) -2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(5,5-Difluoro-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl-)2,3-dihydro-isoindol-1-one,   7-(4,4-Difluoro-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(Azetidin-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[(3S,4S)-4-(2-Fluoro-4-trifluoromethoxy-phenyl)-3-methyl-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-(2-Quinolin-2-yl-ethyl)-7-thiomorpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[4-(4-Ethyl-piperazin-1-yl)piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-(2-Quinolin-2-yl-ethyl)-7-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-2,3-dihydro-isoindol-1-one,   7-(4-Pyridin-3-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3-Amino-4-methyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol -1-one,   2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(1,1-dioxothiomorpholin-4-yl)-2,3-dihydro-isoindol-1-one,   7-[(1S,4S)-5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(4-Methyl-piperazin-1-ylmethyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-Morpholin-4-ylmethyl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one   7-(1,1-Dioxo-thiomorpholin-4-yl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihydro-isoindol-1-one,   7-(1,1-Dioxo-thiomorpholin-4-yl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1,1-Dioxo-tetrahydrothiophen-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(4-Pyrrolidin-1-yl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-[1,4′]Bipiperidinyl-1′-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1S,5S)-3,6-Diaza-bicyclo[3.2.0]hept-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3dihydro-isoindol-1-one,   7-(3aR,7aS)-Octahydro-pyrrolo-[3,2-c]pyridin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-((R)-3-Amino-pyrrolidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(2-Methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(2-Dimethylaminomethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-Morpholin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(4-Methyl-piperazin-1-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl.)-2,3-dihydro-isoindol-1-one,   4-Methoxy-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   4-(1,1-Dioxothiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione,   7-(2-Ethyl -morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(4-methyl-piperazin-1-yl)-2,3-dihydro-isoindol-1-one,   7-(2,6-Dimethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one,   4-Methoxy-7-(4-methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   2-(2-Benzothiazol-2-yl-ethyl)-7-morpholin4-yl-2,3-dihydro-isoindol-1-one,   2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)4-methoxy-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   4-Methoxy-7-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione,   7-(Oxetan-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   4-(Oxetan-3-ylamino)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one,   7-(2-Ethyl-6-methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-(Octahydro-[1,5]naphthyridin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, 4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-(2-Methoxymethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-Morpholin-4-yl-2-[2-(1-propyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihydro-isoindol-1-one,   2-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2 3-dihydro-isoindol-1-one,   2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-(3aS,8aR)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   7-(3aS,8aS)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,   2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-(oxetan-3-ylamino)-2,3-dihydro-isoindol-1-one, and   4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   or an N-oxide, prodrug, tautomer, or hydrate thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         32 . The compound of  claim 1 , which is selected from the group consisting of
 4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(oxetan-3-ylamino)-2,3-dihydro-isoindol-1-one,   4-Fluoro-7-(oxetan-3-ylamino)-2-[2-(2-quinolyl-ethyl]isoindolin-1-one,   4-Fluoro 7-morpholino-2-[2-(2 quinolyl)ethyl]isoindolin 1 one,   2-[2-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one,   7-Morpholino-2-(2-quinoxalin-2-ylethyl)isoindolin-1-one,   4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)-7-(oxetan-3-ylamino)isoindolin-1-one, and   7-Morpholino--2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-1-one,   or an N-oxide, prodrug, tautomer or hydrate thereof; or a pharmaceutically acceptable salt thereof.   
     
     
         33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising at least one compound of  claim 1  and at least one excipient. 
     
     
         35 .- 44 . (canceled) 
     
     
         45 . A method for treating a medical disorder, selected from neurological and psychiatric disorders which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound of  claim 1  to a subject in need thereof. 
     
     
         46 . The compound of  claim 1 , which is 4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one, an N-oxide, a tautomer, a hydrate; or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The method of  claim 45 , where the medical disorder is a CNS disorder. 
     
     
         48 . The method of  claim 45 , where the medical disorder is selected from the group consisting of schizophrenia, bipolar disorders, depression, cognitive dysfunction associated with Alzheimer's disease, diet-induced obesity Huntington's disease and anxiety.