Glucosylceramide synthase inhibitors

Abstract

The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer.

1 . A compound represented by the following structural formula, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is 1, 2 or 3; 
         m is 0 or 1; 
         p is 0 or 1; 
         t is 0, 1 or 2; 
         y is 1 or 2; 
         z is 0, 1 or 2; 
         E is S, O, NH, NOH, NNO 2 , NCN, NR, NOR or NSO 2 R; 
         X 1  is CR 1  when m is 1 or N when m is 0; 
         X 2  is O, —NH, —CH 2 —, SO 2 , NH—SO 2 ; CH(C 1 -C 6 )alkyl or —NR 2 ; 
         X 3  is a direct bond, O, —NH, —CH 2 —, CO, —CH(C 1 -C 6 )alkyl, SO 2 NH, —CO—NH— or —NR 3 ; 
         X 4  is a direct bond, CR 4 R 5 , CH 2 CR 4 R 5  or CH 2 —(C 1 -C 6 )alkyl-CR 4 R 5 ; 
         X 5  is a direct bond, O, S, SO 2 , CR 4 R 5 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, —O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkenyloxy, —R 7 —(C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-R 7 —, —R 7 —(C 6 -C 12 )aryl, (C 6 -C 12 )aryl-R 7 —, —R 7 —(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl-R 7 —, —R 7 —(C 2 -C 9 )heterocycloalkyl, and (C 2 -C 9 )heterocycloalkyl-R 7 —, wherein R 7  is a direct bond, O, S, SO 2 , CR 4 R 5 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, —O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkenyloxy; and further wherein when X 5  is defined as —R 7 —(C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-R 7 —, —R 7 —(C 6 -C 12 )aryl, (C 6 -C 12 )aryl-R 7 —, —R 7 —(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl-R 7 —, —R 7 —(C 2 -C 9 )heterocycloalkyl, and (C 2 -C 9 )heterocycloalkyl-R7-, wherein the (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl groups are optionally substituted by one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylenyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, O(C 3 -C 6  cycloalkyl), (C 3 -C 6 )cycloalkoxy, nitro, CN, OH, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 9 )heterocycloalkyl, R 8 R 9 N—CO— wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl or R 8  and R 9  can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl or (C 2 -C 9 )heterocycloalkyl group optionally substituted by one to three halo groups, (C 1 -C 6 )alkylsulfonyl optionally substituted by one or two groups selected from (C 1 -C 6 )alkoxy and (C 3 -C 10 )cycloalkyl; 
         (C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; and 
         (C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; 
         R is (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; 
         R 1  is H, CN, (C 1 -C 6 )alkylcarbonyl, or (C 1 -C 6 )alkyl; 
         R 2  and R 3  are each independently —H, (C 1 -C 6 )alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 6 -C 12 )aryl, halo(C 6 -C 12 )aryl, and halo(C 2 -C 9 )heteroaryl, or optionally when X 2  is —NR 2  and X 3  is —NR 3 , R 2  and R 3  may be taken together with the nitrogen atoms to which they are attached form a non-aromatic heterocyclic ring optionally substituted by with one or more substituents selected from halogen, (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 6 -C 12 )aryl, halo(C 6 -C 12 )aryl, and halo(C 2 -C 9 )heteroaryl; 
         R 4  and R 5  are independently selected from H, (C 1 -C 6 )alkyl, or taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; 
         R 6  is —H, halogen, —CN, (C 6 -C 12 )aryl, (C 6 -C 12 )aryloxy, (C 1 -C 6 )alkyloxy; 
         (C 1 -C 6 )alkyl optionally substituted by one to four halo or (C 1 -C 6 )alkyl; 
         A 1  is (C 2 -C 6 )alkynyl; (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl wherein A 1  is optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl optionally substituted by one to three halo; (C 1 -C 6 )alkenyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, nitro, CN, —OH, (C 1 -C 6 )alkyloxy optionally substituted by one to three halo; (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkylcarbonyl; 
         A 2  is H, (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl wherein A 2  is optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylenyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, O(C 3 -C 6  cycloalkyl), (C 3 -C 6 )cycloalkoxy, nitro, CN, OH, (C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 9 )heterocycloalkyl, R 8 R 9 N—CO— wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl or R 8  and R 9  can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl or (C 2 -C 9 )heterocycloalkyl group optionally substituted by one to three halo groups, (C 1 -C 6 )alkylsulfonyl optionally substituted by one or two groups selected from (C 1 -C 6 )alkoxy and (C 3 -C 10 )cycloalkyl; 
         (C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; and 
         (C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; 
         with the proviso that the sum of n+t+y+z is not greater than 6; 
         with the proviso that when p is 0; X 2  is NH—SO 2  and X 3  is NH; 
         with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2  is NH; E is O; X 3  is NH; A 2  is H and X 5  is a direct bond; A 1  is not unsubstituted phenyl, halophenyl or isopropenyl phenyl; 
         with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2  is O; E is O; X 3  is NH; A 1  is (C 6 -C 12 )aryl and X 5  is a direct bond; A 2  is H and R 4  is H then R 5  is not cyclohexyl; 
         with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2  is NH; E is O; X 3  is CH 2 ; R 4  and R 5  are both hydrogen; A 2  is H and X 5  is a direct bond; then A 1  is not unsubstituted phenyl; and 
         with the proviso that when X 3  is O, —NH, —CH 2 —, CO, —CH(C 1 -C 6 )alkyl, SO 2 NH, —CO—NH— or —NR 3 ; and X 4  is CR 4 R 5 , CH 2 CR 4 R 5  or CH 2 —(C 1 -C 6 )alkyl-CR 4 R 5 ; then A 2  must be (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl substituted with one or more substituents selected from the group consisting of, (C 2 -C 9 )heterocycloalkyl, R 8 R 9 N—CO— wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl or R 8  and R 9  can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl or (C 2 -C 9 )heterocycloalkyl group optionally substituted by one to three halo groups, (C 1 -C 6 )alkylsulfonyl optionally substituted by one or two groups selected from (C 1 -C 6 )alkoxy and (C 3 -C 10 )cycloalkyl; 
         (C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; 
         or (C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy. 
       
     
     
         2 - 246 . (canceled) 
     
     
         247 . A compound according to  claim 1 , or a pharmaceutically acceptable salt, selected from the group consisting of:
 1-azabicyclo[2.2.2]oct-3-yl[2-(2,4′-difluorobiphenyl-4-yl)propan-2-yl]carbamate;   1-azabicyclo[2.2.2]oct-3-yl{2-[4-(1,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamate;   1-azabicyclo[3.2.2]non-4-yl{1-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamate;   1-azabicyclo[2.2.2]oct-3-yl{1-[3-(4-fluorophenoxy)phenyl]cyclopropyl}carbamate;   1-azabicyclo[2.2.2]oct-3-yl{1-[4-(1,3-benzothiazol-5-yl)phenyl]cyclopropyl}carbamate;   1-azabicyclo[2.2.2]oct-3-yl[1-(4′-fluoro-3′-methoxybiphenyl-4yl)cyclopropyl]carbamate;   1-azabicyclo[2.2.2]oct-3-yl[3-(4′-fluorobiphenyl-4-yl)oxetan-3-yl]carbamate;   1-azabicyclo[2.2.2]oct-3-yl{1-[6-(4-fluorophenoxy)pyridin-2-yl]cyclopropyl}carbamate;   1-azabicyclo[2.2.2]oct-3-yl[3-(4′-fluorobiphenyl-4-yl)pentan-3-yl]carbamate;   1-azabicyclo[2.2.2]oct-3-yl{2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yl}carbamate;   1-azabicyclo[2.2.2]oct-3-yl{2-[2-(1H-pyrrol-1-yl)pyridin-4-yl]propan-2-yl}carbamate;   1-(3-ethyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]urea;   N-(1-azabicyclo[2.2.2]oct-3-yl)-N′-[1-(4′-fluorobiphenyl-4yl)cyclopropyl]ethanediamide;   1-azabicyclo[2.2.2]oct-3-yl(1-{4[(4,4difluorocyclohexyl)oxy]phenyl}cyclopropyl) carbamate;   1-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)-3-[1-(5-phenylpyridin-2-yl)cyclopropyl]urea;   1-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea;   1-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea;   1-{2-[4′-(2-methoxyethoxy)biphenyl-4-yl]propan-2-yl}-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea;   2-(1-azabicyclo[3.2.2]non-4-yl)-N-[1-(5-phenylpyridin-2-yl)cyclopropyl]acetamide;   3-(4′-fluorobiphenyl-4-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)butanamide;   N-[2-(biphenyl-4-yl)propan-2-yl]-N′-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide;   N-[2-(4′-fluorobiphenyl-4-yl)propan-2-yl]-N′-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide;   1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]propan-2-yl}urea;   1-azabicyclo[2.2.2]oct-3-yl[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamate;   1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]urea;   N-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide;   1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicyclo[3.2.2]nonan-3-yl)urea;   1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-1-azabicyclo[4.2.2]decan-4-yl)urea;   1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicyclo[4.2.2]decan-3-yl)urea; and   1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(5-methyl-1-azabicyclo[4.2.2]decan-5-yl)urea.   
     
     
         248 . (canceled) 
     
     
         249 . A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to  claim 1 , wherein the disease or disorder is cancer, a metabolic disorder or a neuropathic disease. 
     
     
         250 - 255 . (canceled) 
     
     
         256 . A method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to  claim 1 . 
     
     
         257 . (canceled) 
     
     
         258 . The method of  claim 256 , wherein the lysosomal storage disease is selected from the group consisting of Gaucher, Fabry, G M1 -gangliosidosis, G M2  Activator deficiency, Tay-Sachs and Sandhoff. 
     
     
         259 . (canceled) 
     
     
         260 . The method of  claim 256 , further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme. 
     
     
         261 - 265 . (canceled) 
     
     
         266 . The method of  claim 249  or  256 , wherein the compound is represented by the following structural formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         267 - 271 . (canceled) 
     
     
         272 . A compound according to  claim 1 , wherein m is 1; E is O; X 2  is O and X 3  is direct bond. 
     
     
         273 . A compound according to  claim 1 , wherein m is 1; E is O; X 2  is NH and X 3  is direct bond. 
     
     
         274 . A compound according to  claim 1 , wherein m is 1; E is O; X 2  is CH 2  and X 3  is direct bond. 
     
     
         275 . A compound according to  claim 1 , wherein m is 1; E is S; X 2  is NH and X 3  is direct bond. 
     
     
         276 . A compound according to  claim 1 , wherein m is 0; E is O; X 1  is NH and X 3  is direct bond. 
     
     
         277 . A compound according to  claim 1 , wherein m is 1; p is 0; X 2  is NH—SO 2  and X 3  is direct bond. 
     
     
         278 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 1; E is O; X 2  is O and X 3  is direct bond. 
     
     
         279 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 1; E is O; X 2  is NH and X 3  is direct bond. 
     
     
         280 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 1; E is O; X 2  is CH 2  and X 3  is direct bond. 
     
     
         281 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 1; E is S; X 2  is NH and X 3  is direct bond. 
     
     
         282 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 0; E is O; X 1  is NH and X 3  is direct bond. 
     
     
         283 . A compound according to  claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1  is CR 1 ; m is 1; p is 0; X 2  is NH—SO 2  and X 3  is direct bond. 
     
     
         284 . A compound according to  claim 1 , wherein X 5  is a direct bond, O, S, SO 2 , CR 4 R 5 ; (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkenyl or (C 1 -C 6 )alkenyloxy. 
     
     
         285 . A compound according to  claim 1 , wherein X 5  is —O—(C 1 -C 6 )alkyl, —R 7 —(C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-R 7 —, —R 7 —(C 6 -C 12 )aryl, (C 6 -C 12 )aryl-R 7 —, —R 7 —(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl-R 7 —, —R 7 —(C 2 -C 9 )heterocycloalkyl, and (C 2 -C 9 )heterocycloalkyl-R 7 —, wherein R 7  is a direct bond, O, S, SO 2 , CR 4 R 5 ; (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, —O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl or (C 1 -C 6 )alkenyloxy. 
     
     
         286 . A compound according to  claim 1 , wherein A 2  is H, (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl optionally substituted by one to three halo; (C 1 -C 6 )alkylenyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, O(C 3 -C 6  cycloalkyl), (C 3 -C 6 )cycloalkoxy, nitro, CN, OH, (C 1 -C 6 )alkyloxy optionally substituted by one to three halo; (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyl or (C 1 -C 6 ) haloalkyl. 
     
     
         287 . A compound according to  claim 1 , wherein A 2  is (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl wherein A 2  is substituted with one or more substituents selected from the group consisting of (C 2 -C 9 )heterocycloalkyl, R 8 R 9 N—CO— wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl or R 8  and R 9  can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl or (C 2 -C 9 )heterocycloalkyl group optionally substituted by one to three halo groups, (C 1 -C 6 )alkylsulfonyl optionally substituted by one or two groups selected from (C 1 -C 6 )alkoxy and (C 3 -C 10 )cycloalkyl;
 (C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; and 
 (C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy. 
 
     
     
         288 . A compound according to  claim 1 , wherein X 3  is O, —NH, —CH 2 —, CO, —CH(C 1 -C 6 )alkyl, SO 2 NH, —CO—NH— or NR 3 ; X 4  is CR 4 R 5 , CH 2 CR 4 R 5  or CH 2 —(C 1 -C 6 )alkyl-CR 4 R 5 ; and A 2  is (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl wherein A 2  is substituted with one or more substituents selected from the group consisting of, (C 2 -C 9 )heterocycloalkyl, R 8 R 9 N—CO— wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl or R 8  and R 9  can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl or (C 2 -C 9 )heterocycloalkyl group optionally substituted by one to three halo groups, (C 1 -C 6 )alkylsulfonyl optionally substituted by one or two groups selected from (C 1 -C 6 )alkoxy and (C 3 -C 10 )cycloalkyl;
 (C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy; 
 or (C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkoxy; or (C 3 -C 10 )cycloalkoxy optionally substituted by (C 1 -C 6 )alkoxy. 
 
     
     
         289 . A compound according to  claim 1 , wherein A 1  is phenyl. 
     
     
         290 . A compound according to  claim 1 , wherein X 5  is a direct bond. 
     
     
         291 . A compound according to  claim 1 , wherein A 2  is phenyl substituted by (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy. 
     
     
         292 . A compound according to  claim 1 , wherein n is 1; t is 0; y is 1; z is 1; X 1  is CR 1 ; m is 1; p is 1; E is 0; X 2  is O; X 3  is NH; R 1  is H; X 4  is CR 4 R 5  wherein R4 and R5 are each independently methyl; R 6  is a hydrogen; A 1  is phenyl; X 5  is a direct bond, O or CR 4 R 5  and A2 is phenyl substituted by (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy. 
     
     
         293 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         294 . A compound according to  claim 1 , wherein A 1  is piperdine optionally substituted by halo. 
     
     
         295 . A compound according to  claim 1 , wherein X 5  is pyrimidine optionally substituted by halo.