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, and for the treatment of cancer.

What is claimed: 
     
         1 . A compound represented by the following structural formula, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug 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 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 ; 
         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, (C 1 -C 6 )alkenyloxy; 
         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 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 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(C3-C6 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, (C 1 -C 6 ) haloalkyl; 
         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; and 
         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. 
       
     
     
         2 - 271 . (canceled) 
     
     
         272 . A compound according to  claim 1 , wherein the compound is a compound representing by the following structural formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 n is 1; 
 m is 1; 
 p is 1; 
 t is 0; 
 y is 1; 
 z is 1; 
 E is O; 
 X 1  is CR 1  and is directly bonded to X 2 ; 
 X 2  is O; 
 X 3  is —NH; 
 X 4  is 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, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkenyloxy; 
 R 1  is H, CN, (C 1 -C 6 )alkylcarbonyl, or (C 1 -C 6 )alkyl; 
 R 4  and R 5  are each independently (C 1 -C 6 )alkyl; 
 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 thiophene, thiazole, isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyrimidine, pyridazine, indole, benzotriazole, benzopyrazole, benzimidazole, benzofuran, benzoxazole or benzisoxazole, each of which 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; and 
 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(C3-C6 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, (C 1 -C 6 ) haloalkyl. 
 
     
     
         273 . 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, the method comprising the step of administering to the subject an effective amount of a compound according to  claim 1 . 
     
     
         274 . 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, the method comprising the step of administering to the subject an effective amount of a compound represented by the following structural formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 n is 1; 
 m is 1; 
 p is 1; 
 t is 0; 
 y is 1; 
 z is 1; 
 E is O; 
 X 1  is CR 1  and is directly bonded to X 2 ; 
 X 2  is O; 
 X 3  is —NH; 
 X 4  is 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, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkenyloxy; 
 R 1  is H, CN, (C 1 -C 6 )alkylcarbonyl, or (C 1 -C 6 )alkyl; 
 R 4  and R 5  are each independently (C 1 -C 6 )alkyl; 
 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 thiophene, thiazole, isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyrimidine, pyridazine, indole, benzotriazole, benzopyrazole, benzimidazole, benzofuran, benzoxazole or benzisoxazole, each of which 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; and 
 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(C3-C6 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, (C 1 -C 6 ) haloalkyl. 
 
     
     
         275 . The method according to  claim 274 , wherein R 4  and R 5  are each methyl. 
     
     
         276 . The method according to  claim 274 , wherein R 6  is H. 
     
     
         277 . The method according to  claim 274 , X 5  is a direct bond 
     
     
         278 . The method according to  claim 274 , X 5  is a CR 4 R 5 . 
     
     
         279 . The method according to  claim 278 , wherein R 4  and R 5  are each methyl. 
     
     
         280 . The method according to  claim 274 , wherein A 2  is (C 6 -C 12 )aryl. 
     
     
         281 . The method according to  claim 274 , wherein A 2  is (C 2 -C 9 )heteroaryl. 
     
     
         282 . The method according to  claim 281 , wherein A 2  is pyridine. 
     
     
         283 . The method according to  claim 274 , wherein A 2  is (C 2 -C 9 )heterocycloalkyl. 
     
     
         284 . The method according to  claim 283 , wherein A 2  is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyh 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or octahydro-1H-indolyl. 
     
     
         285 . The method according to  claim 274 , wherein A 2  is benzo(C 2 -C 9 )heterocycloalkyl. 
     
     
         286 . The method according to  claim 285 , wherein A 2  is 2,3-dihydrobenzo[b][1,4]dioxine or 2,2-difluorobenzo[d][1,3]dioxole. 
     
     
         287 . The method according to  claim 274 , where R 1  is hydrogen or methyl. 
     
     
         288 . The method according to  claim 274 , wherein A 1  is (C 3 -C 10 )cycloalkyl. 
     
     
         289 . The method according to  claim 274 , wherein A 2  is (C 3 -C 10 )cycloalkyl. 
     
     
         290 . The method according to  claim 274 , wherein the compound is represented by the following structural formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         291 . The method according to  claim 274 , wherein the compound is represented by the following structural formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         292 . The method according to  claim 274 , wherein the disease or disorder is selected from the group consisting of cancer, a metabolic disorder, a neuropathic disease, Alzheimer's disease and Parkinson's disease. 
     
     
         293 . The method according to  claim 292 , wherein the disease or disorder is a metabolic disorder which is a lysosomal storage disease. 
     
     
         294 . The method according to  claim 292 , wherein the lysosomal storage disease is Gaucher, Fabry, G M1 -gangliosidosis, G M2  Activator deficiency, Tay-Sachs or Sandhoff disease. 
     
     
         295 . The method according to  claim 274 , wherein the disease or disorder is selected from renal hypertrophy, renal hyperplasia, diabetic nephropathy, and polycystic kidney disease. 
     
     
         296 . The method according to  claims 295 , wherein the disease or disorder is polycystic kidney disease. 
     
     
         297 . A pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         298 . A pharmaceutical composition comprising a compound according to  claim 272 . 
     
     
         299 . A method for inducing decreased glucosylceramide synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effect amount of a compound according to  claim 1 . 
     
     
         300 . 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 . 
     
     
         301 . The method of  claim 300 , further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme. 
     
     
         302 . A method of reducing glucosylceramide synthase (GCS) activity in a subject diagnosed as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to  claim 1 , either alone or as a combination therapy with an enzyme replacement therapy. 
     
     
         303 . A method of reducing accumulation of a GCS-derived material in a subject diagnosed as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to  claim 1 , either alone or as a combination therapy with an enzyme replacement therapy.