Modulators for amyloid beta

Abstract

The invention relates to compounds of formula wherein the substituents are as described in claim 1 . Compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

1 . A compound of general formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2  or when L is NR 8 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl for L being NR 8 , or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2  for L being C(O); 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 Z is CH or N; 
 X-Y is N—CR 4 ═CR 5 , CH—CR 4 ═N, CH—CR 4 ═CR 5  or N—NH; and wherein R 4  and R 5  form together with the corresponding carbon atoms to which they are attached optionally form an additional ring with —(CH 2 ) n , with the proviso that if X-Y is CH—CR 4 ═CR 5  or CH—CR 4 ═N, then Z is N; or 
 R 4  and R 5  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six-membered heteroaryl group wherein the rings of the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which optionally substituted by lower alkyl and hydroxy, with the proviso that R 4  also optionally is hydroxy or NR 8   2 ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; 
 m is 0 or 1; and 
 n is 3 or 4; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       2 . The compound of  claim 1  having formula I-A, 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings of the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings of the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings of the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2  or when L is NR 8 , the rings of the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl for L being NR 8 , or 
 when L is C(O), the rings of the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2  for L being C(O); 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 R 4  and R 5  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which is optionally substituted by lower alkyl and hydroxy, with the proviso that R 4  also optionally is hydroxy or NR 8   2 , 
 or wherein R 4  and R 5  together with the corresponding carbon atoms to which they are attached optionally form an additional ring with —(CH 2 ) n ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; 
 m is 0 or 1; and 
 n is 3 or 4; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       3 . The compound of  claim 2  having formula I-A-1 
     
       
         
         
             
             
         
       
     
     wherein
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group,
 wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or 
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2  or when L is NR 8 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl, or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2 ; 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 R 4  and R 5  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six-membered heteroaryl group, wherein the rings of the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which is optionally substituted by lower alkyl and hydroxy, with the proviso that R 4  also optionally is hydroxy or NR 8   2 , 
 
     or wherein R 4  and R 5  together with the corresponding carbon atoms to which they are attached form an additional ring with —(CH 2 ) n ;
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; 
 m is 0 or 1; and 
 n is 3 or 4; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       4 . The compound of  claim 3 , selected from the group consisting of 
     (4-benzyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(3,4,5-trifluoro-benzyl)-pyrimidin-2-yl]-amine; 
     [4-(3-chloro-benzyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[5-methyl-4-(1-phenyl-ethyl)-pyrimidin-2-yl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-6-(3,4,5-trifluoro-phenoxy)-pyrimidin-2-yl]-amine; 
     [4-(3,4-difluoro-phenoxy)-6-methyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(4-chloro-phenoxy)-6-methyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(2,6-dichloro-phenoxy)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-6-(2-trifluoromethyl-phenoxy)-pyrimidin-2-yl]-amine; and 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-6-(3-trifluoromethoxy-phenoxy)-pyrimidin-2-yl]-amine. 
   
   
       5 . The compound of  claim 3 , selected from the group consisting of 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-6-(3-trifluoromethyl-phenoxy)-pyrimidin-2-yl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-6-(3,3,4,4,4-pentafluoro-butoxy)-pyrimidin-2-yl]-amine; 
     {4-[1-(4-chloro-phenyl)-1-methyl-ethyl]-5-methyl-pyrimidin-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     {4-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyrimidin-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     {4-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyrimidin-2-yl}-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     ethyl 4-(4-chloro-phenyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-5-carboxylate; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine; 
     (4-benzyl-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     (4-ethoxy-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; and 
     N4-(2,2,3,3,4,4,4-heptafluoro-butyl)-N2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-6-methyl-pyrimidine-2,4-diamine. 
   
   
       6 . The compound of  claim 3 , selected from the group consisting of 
     [4-(4-chloro-phenyl)-5-(4-methoxy-benzyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-methyl-pyrimidin-2-yl)-amine; 
     (4-isopropoxy-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(4-Fluoro-phenoxy)-6-methyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(4-tert-butyl-phenoxy)-6-methyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     2-{6-ethoxy-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     N4-(3-chloro-phenyl)-N2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-6-methyl-pyrimidine-2,4-diamine; 
     N4-(4-chloro-phenyl)-N2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-6-methyl-pyrimidine-2,4-diamine; 
     N4,N4-diethyl-N2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-6-methyl-pyrimidine-2,4-diamine; and 
     1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-yl}-piperidin-4-ol. 
   
   
       7 . The compound of  claim 3 , selected from the group consisting of 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methyl-6-piperidin-1-yl-pyrimidin-2-yl)-amine; 
     2-({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-yl}-methyl-amino)-ethanol; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-piperidin-1-yl-pyrimidin-4-yl}-propan-2-ol; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-pyrrolidin-1-yl-pyrimidin-4-yl}-propan-2-ol; 
     [4-butyl-6-(4-chloro-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-phenyl-pyrimidin-2-yl)-amine; 
     5-(4,6-dimethyl-pyrimidin-2-ylamino)-2-(4-methyl-imidazol-1-yl)-benzonitrile; 
     5-[4-(4-chloro-phenyl)-pyrimidin-2-ylamino]-2-(4-methyl-imidazol-1-yl)-benzonitrile; and 
     [5-ethyl-4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. 
   
   
       8 . The compound of  claim 3 , selected from the group consisting of 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(3,4,5-trifluoro-phenyl)-pyrimidin-2-yl]-amine; 
     [4-(2,5-dichloro-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(3,4-dichloro-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(2,4-dichloro-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(4-chloro-3-methyl-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(4-chloro-phenyl)-5-propyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-methoxy-4-phenyl-pyrimidin-2-yl)-amine; 
     (4-cyclopropyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     ethyl 4-benzyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-5-carboxylate; and 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(4-methyl-pent-3-enyl)-5-phenyl-pyrimidin-2-yl]-amine. 
   
   
       9 . The compound of  claim 3 , selected from the group consisting of 
     6-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-4H-benzo[1,4]oxazin-3-one; 
     [4-(2-chloro-phenyl)-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     (4-isobutyl-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     (4,6-diethyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methyl-6-phenyl-pyrimidin-2-yl)-amine; 
     (4-furan-2-yl-6-trifluoromethyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-phenyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-amine; 
     (4,6-dimethyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     (4,6-bis-trifluoromethyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; and 
     (4-isopropyl-6-trifluoromethyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. 
   
   
       10 . The compound of  claim 3 , selected from the group consisting of 
     (4,6-diisopropyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     [4-(2-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; 
     ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-thiophen-2-yl-pyrimidine-4-carboxylate; 
     ethyl 6-Isopropyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-4-carboxylate; 
     ethyl 6-cyclopropyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-4-carboxylate; 
     ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-pyridin-2-yl-pyrimidine-4-carboxylate; 
     ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylate; 
     ethyl 6-(4-chloro-benzyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-4-carboxylate; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-yl}-propan-2-ol; and 
     2-{6-ethyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol. 
   
   
       11 . The compound of  claim 3 , selected from the group consisting of 
     2-{6-isopropyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{6-cyclopropyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{6-tert-butyl-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-thiophen-2-yl-pyrimidin-4-yl}-propan-2-ol; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-pyridin-2-yl-pyrimidin-4-yl}-propan-2-ol; 
     2-{6-(4-chloro-benzyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-[2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol; 
     1-[2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-ethanone; 
     3-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-pentan-3-ol; and 
     2-[2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(3,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-propan-2-ol. 
   
   
       12 . The compound of  claim 3 , selected from the group consisting of 
     2-{6-(2,4-dichloro-phenyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{6-(4-chloro-phenyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{6-(2-chloro-phenyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-4-yl}-propan-2-ol; 
     2-{2-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-isopropyl-pyrimidin-4-yl}-propan-2-ol; 
     2-[2-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol; 
     2-{6-dimethylamino-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-propan-2-ol; 
     1-{6-(1-hydroxy-1-methyl-ethyl)-2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-yl}-4-methyl-piperidin-4-ol; 
     1-[2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-cyclopentanol; 
     5-[4-(1-hydroxy-1-methyl-ethyl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino]-2-(4-methyl-imidazol-1-yl)-benzonitrile; and 
     2-[2-[3-methyl-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol. 
   
   
       13 . The compound of  claim 2 , wherein R 1 —Ar is 2-methyl-imidazol-1-yl, 3-methyl-[1,2,4]triazol-1-yl, thiazol-5-yl, 2-methyl-thiazol-5-yl, 2-methyl-oxazol-5-yl, 2-methyl-pyridin-4-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-[1,2,4]triazol-1-yl, [1,2,4]triazol-1-yl, 5-methyl-[1,2,4]triazol-1-yl, 1,3,4]oxadiazol-2-yl, 4-pyridin-4-yl, 2-methyl-pyridin-4-yl, 3-methyl-[1,2,4]thiadiazol-5-yl, or oxazol-5-yl. 
   
   
       14 . The compound of  claim 13 , selected from the group consisting of 
     (4-benzyl-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(3-methyl-[1,2,4]triazol-1-yl)-phenyl]-amine; 
     (4-benzyl-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(2-methyl-thiazol-5-yl)-phenyl]-amine; 
     (4-benzyl-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(2-methyl-oxazol-5-yl)-phenyl]-amine; 
     2-[2-[3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol; 
     (4,6-dimethyl-pyrimidin-2-yl)-[4-(2-methyl-pyridin-4-yl)-phenyl]-amine; and 
     (4-benzyl-6-methyl-pyrimidin-2-yl)-[4-(2-methyl-pyridin-4-yl)-phenyl]-amine. 
   
   
       15 . The compound of  claim 1  having formula I-B 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings of the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings of the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings of the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is NR 3 , the rings of the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl, or 
 when L is C(O), the rings of the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2 ; 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 R 4  is hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or is cyano, phenyl, benzyl or a five- or six-membered heteroaryl group, wherein the rings of the heteroaryl group are optionally substituted by one or more R′, or is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by lower alkyl and hydroxy, or is hydroxy or NR 8   2 ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, or phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; and 
 m is 0 or 1; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       16 . The compound of  claim 15 , selected from the group consisting of 
     (6-benzyl-2-chloro-pyrimidin-4-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 
     {6-[1-(4-chloro-phenyl)-cyclobutyl]-2-methyl-pyrimidin-4-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. 
   
   
       17 . The compound of  claim 1  having formula I-C 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or moreis lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is NR 3 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl, or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2 ; 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 R 4  is hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six membered heteroaryl group, wherein the rings of the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which is optionally substituted by lower alkyl and hydroxy or is hydroxy or NR 12 ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, or phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; and 
 m is 0 or 1; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       18 . The compound of  claim 17 , which is (2-benzyl-6-chloro-pyrimidin-4-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. 
   
   
       19 . The compound of  claim 1  having formula I-D 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is NR 3 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl, or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2 ; 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 R 4  and R 5  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six-membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which is optionally substituted by lower alkyl and hydroxy′, with the proviso that R 4  also optionally is hydroxy or NR 8   2 , or wherein R 4  and R 5  together with the corresponding carbon atoms to which they are attached form an additional ring with —(CH 2 ) n ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, or phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; 
 m is 0 or 1; and 
 n is 3 or 4; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       20 . The compound of  claim 19 , selected from the group consisting of 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-phenyl-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(4-trifluoromethoxy-phenyl)-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(3-trifluoromethoxy-phenyl)-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(4-pentafluorosulfanyl-phenyl)-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(4-trifluoromethyl-phenyl)-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(3-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridine-2,6-diamine; 
     N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-4-trifluoromethyl-N′-(4-trifluoromethyl-phenyl)-pyridine-2,6-diamine; and 
     [2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethoxy-phenylamino)-pyridin-4-yl]-methanol. 
   
   
       21 . The compound of  claim 1  having formula I-E 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group, wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is NR 8 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl, or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2 ; 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl;
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently from each other hydrogen, lower alkyl, cycloalkyl, or phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; and 
 m is 0 or 1; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       22 . The compound of  claim 21 , selected from the group consisting of 
     [5-(4-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 
     [5-(4-fluoro-benzyl)-4H-[1,2,4]triazol-3-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. 
   
   
       23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy, lower alkyl, cyano or halogen; 
 R 3  is lower alkyl, lower alkenyl, lower alkyl substituted by fluoro, (CH 2 ) 2 O-lower alkyl, (CH 2 ) 2 NR 8   2 , or is 4H-benzo[1,4]oxazin-3-one, cycloalkyl optionally substituted by hydroxy, or is heterocycloalkyl, which heterocycloalkyl is optionally substituted by hydroxy or S(O) 2 -lower alkyl, or is (CH 2 ) m -aryl or is a five- or six-membered heteroaryl group,
 wherein the rings in the heteroaryl group are optionally substituted by one or more R′ for any definition of L, or 
 when L is a bond, the rings in the heteroaryl group are optionally substituted by one or more halogen, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2 , or 
 when L is —CR 6 R 7 —, the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy, —C(O)O-lower alkyl, OC(O)-lower alkyl or C(O)NH 2  or when L is NR 8 , the rings in the heteroaryl group are optionally substituted by one or more CH 2 —C(O)O-lower alkyl for L being NR 8 , or 
 when L is C(O), the rings in the heteroaryl group are optionally substituted by one or more lower alkoxy, hydroxy or NR 8   2  for L being C(O); 
 
 R′ is halogen, lower alkyl, lower alkoxy, cyano, lower alkyl substituted by fluoro, lower alkoxy substituted by fluoro, SF 5 , or is a five-membered heteroaryl group, which is optionally substituted by lower alkyl; 
 Ar is a five-membered heteroaryl group or is pyridinyl; 
 Z is CH or N; 
 X-Y is N—CR 4 ═CR 5 CH—CR 4 ═N, CH—CR 4 ═CR 5  or N—NH; and wherein R 4  and R 5  form together with the corresponding carbon atoms to which they are attached optionally form an additional ring with —(CH 2 ) n , with the proviso that if X-Y is CH—CR 4 ═CR 5  or CH—CR 4 ═N, then Z is N; or 
 R 4  and R 5  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, C(O)O-lower alkyl, lower alkyl substituted by one or more groups selected from fluoro, hydroxy, cyano and cycloalkyl, or are cyano, phenyl, benzyl or a five- or six-membered heteroaryl group wherein the rings of the heteroaryl group are optionally substituted by one or more R′, or are cycloalkyl or heterocycloalkyl, each of which optionally substituted by lower alkyl and hydroxy, with the proviso that R 4  also optionally is hydroxy or NR 8   2 ; 
 L is a bond, —CR 6 R 7 —, —O—, —NR 8 — or —C(O)—; 
 R 6  and R 7  are each independently hydrogen, lower alkyl, cycloalkyl, phenyl or R 6  and R 7  together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group, with the proviso that R 6  also optionally is hydroxy or lower alkoxy; 
 R 8  is hydrogen or lower alkyl; 
 m is 0 or 1; and 
 n is 3 or 4; 
 
     or a pharmaceutically active acid addition salt thereof and a pharmaceutically acceptable carrier.