Bicyclic and Tricyclic Heteroaromatic Compounds

Abstract

Disclosed are compounds of the formula: and the pharmaceutically acceptable salts thereof, wherein W, Q, X, X 1 , Y and Z are as defined herein. These compounds bind with high selectivity and/or high affinity to the benzodiazepine site of GABA A receptors and are therefore useful in the treatment of central nervous system (CNS) diseases and as probes for the localization of GABA A receptors in tissue samples. Also disclosed are intermediates useful in the preparation of these compounds.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X represents N or CR 1 , wherein
 R 1  is hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, or amino(C 1 -C 6 )alkyl; 
 
         X 1  represents N, CH, or C 1 -C 6 alkyl; 
         Y and Z are independently hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, or amino(C 1 -C 6 )alkyl; or 
         Y and Z together form an arylene ring or a C 3 -C 8  cycloalkylene ring, each of which is optionally substituted with up to four groups R 2  independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, and amino(C 1 -C 6 )alkyl; 
         W is aryl or heteroaryl, each of which is optionally substituted with one or more groups R A , wherein each R A  is independently
 i) halogen, hydroxy, cyano, nitro, amino, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl) —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), or —SO 2 (C 1 -C 8  alkyl); 
 ii) aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, and amino(C 1 -C 6 )alkyl; 
 iii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8  alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 3  alkyl), C 3 -C 8 cycloalkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from hydroxy, oxo, halogen, C 1 -C 6 alkoxy, —CONH 2 , —CONHC 1 -C 6 alkyl, —CON(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —COOH, and —CO 2 C 1 -C 6 alkyl; or 
 iv) NR 4 R 5 , wherein R 4 , R 5  and the nitrogen to which they are attached form a monocyclic or bicyclic ring optionally containing one or more of oxo, O, S, SO, SO 2 , or NR 6  wherein R 6  is hydrogen, C 1 -C 6 alkyl, or Ar—(C 1 -C 6 alkyl) where
 Ar is aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, and amino(C 1 -C 6 )alkyl; and 
 Q is selected Formulas III, IV and V: 
 
 
       
       
         
           
           
               
               
           
         
         wherein: 
         J is N or C 1 -C 8  alkylene; and
 R 9  and R 10  are independently hydrogen, C 1 -C 8  alkyl, or Ar 1 , wherein Ar 1  is aryl or heteroaryl, each of which may be substituted with one or two of R B , where each R B  independently carries the definition of R A ; or 
 R 9 , R 10  and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring optionally containing one or more double bonds or one or more of oxo, O, S, SO, SO 2 , or N—R 8  wherein R 8  is hydrogen, C 1 -C 8  alkyl, or Ar 1 —(C 1 -C 8  alkyl); wherein Ar 1  is optionally substituted with one or two of R B , where each R B  independently carries the definition of R A ; and wherein the monocyclic or bicyclic ring is optionally substituted with C 1 -C 6  alkyl or hydroxy(C 1 -C 6 )alkyl; 
 R 11  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, C 1 -C 8  alkanoyl, aryl(C 1 -C 6 )alkyl, and aryl(C 1 -C 6 )alkanoyl; and 
 R 12  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, and C 1 -C 8  alkoxy; or 
 R 11  and R 12  together with the atoms to which they are attached form a 5-8 membered monocyclic ring which is optionally substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, or amino(C 1 -C 6 )alkyl; and 
 n is 1, 2, 3, or 4; and 
 W′
 (i) independently carries the same definition as W; 
 (ii) represents —OR where R is C 1 -C 8  alkyl or aryl(C 1 -C 6 )alkyl; or 
 (iii) is M 5  where M 5  is hydroxy, C 1 -C 8  alkyl, aryl(C 1 -C 6 )alkyl or —N(C 1 -C 4  alkyl)(C 1 -C 4  alkoxy). 
 
 
       
     
     
         2 . A compound according to  claim 1  of the formula 
       
         
           
           
               
               
           
         
         wherein each R 2 , Q, X, and X 1  are defined as in  claim 1 , and 
         W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
 halogen, hydroxy, cyano, nitro, amino, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), —SO 2 (C 1 -C 8  alkyl) and phenyl. 
 
       
     
     
         3 . A compound according to  claim 2  wherein W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
 halogen, hydroxy, cyano, nitro, amino, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), —SO 2 (C 1 -C 8  alkyl) and phenyl.   
     
     
         4 . A compound according to  claim 3 , wherein
 R 2  is independently selected at each occurrence from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;   Q is selected from the group consisting of Formulas III, IV and   
       
         
           
           
               
               
           
         
         wherein:
 J is N or C 1 -C 8  alkylene; and 
 R 9  and R 10  are independently hydrogen, C 1 -C 8  alkyl; or
 R 9 , R 10  and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO 2 , or N—R 8  wherein R 8  is hydrogen, C 1 -C 8  alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C 1 -C 6  alkyl or hydroxy(C 1 -C 6 )alkyl; 
 
 R 11  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, C 1 -C 8  alkanoyl, aryl(C 1 -C 6 )alkyl, and aryl(C 1 -C 6 )alkanoyl; and 
 R 12  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, and C 1 -C 8  alkoxy; or 
 R 11  and R 12  together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C 1 -C 6  alkyl; and 
 n is 1, 2, 3, or 4; 
 
         W′ phenyl, pyridyl, or naphthyl; and 
         W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy. 
       
     
     
         5 - 10 . (canceled) 
     
     
         11 . A compound according to  claim 1  of the formula 
       
         
           
           
               
               
           
         
         wherein R 2 , Q, X, and X 1  are as defined in  claim 1 ; 
         p is 1, 2, 3, or 4; and 
         W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
 halogen, hydroxy, cyano, nitro, amino, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), —SO 2 (C 1 -C 8  alkyl) and phenyl. 
 
       
     
     
         12 - 16 . (canceled) 
     
     
         17 . A compound according to  claim 1 , wherein
 Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl; and   W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
 halogen, hydroxy, cyano, nitro, amino, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), —SO 2 (C 1 -C 8  alkyl) and phenyl. 
   
     
     
         18 - 19 . (canceled) 
     
     
         20 . A compound according to  claim 17  wherein X 1  and X are both CH. 
     
     
         21 - 46 . (canceled) 
     
     
         47 . A compound according to  claim 1 , which is:
 (R)-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine.   
     
     
         48 . A compound according to  claim 1 , which is:
 cis-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3,5-dimethyl-piperazine.   
     
     
         49 - 53 . (canceled) 
     
     
         54 . A compound according to  claim 1 , which is:
 3-Phenyl-6-(S-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-yl-)-imidazo[5,1-a]isoquinoline.   
     
     
         55 - 68 . (canceled) 
     
     
         69 . A compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         X 1  represents N, CH, or C 1 -C 6 alkyl; 
         Y and Z are independently hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, or amino(C 1 -C 6 )alkyl, or 
         Y and Z together form an arylene ring or a C 3 -C 8  cycloalkylene ring, each of which is optionally substituted with up to four groups R 2  independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 ) alkylamino, amino(C 1 -C 6 )alkyl; 
         R is C 1 -C 6 alkyl;
 R N  is hydrogen, C 1 -C 6  alkyl, or —C(O)W where 
 
         W is aryl or heteroaryl, each of which is optionally substituted with one or more groups R A , wherein each R A  is independently
 i) halogen, hydroxy, cyano, nitro, amino, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 8  alkyl), —SO 2 N(C 1-8  alkyl)(C 1 -C 8  alkyl), —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)(C 1-8  alkyl), —N(C 1 -C 8  alkyl)CO(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl)CO 2 (C 1 -C 8  alkyl), —CONH 2 , —CONH(C 1 -C 8  alkyl), —CON(C 1 -C 8  alkyl)(C 1 -C 8  alkyl), —CO 2 (C 1 -C 8  alkyl), —S(C 1 -C 8  alkyl), —SO(C 1 -C 8  alkyl), or —SO 2 (C 1 -C 8  alkyl); 
 ii) aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, and amino(C 1 -C 6 )alkyl; 
 iii) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 3  alkyl), C 3 -C 8 cycloalkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from hydroxy, oxo, halogen, C 1 -C 6 alkoxy, —CONH 2 , —CONHC 1 -C 6 alkyl, —CON(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —COOH, and —CO 2 C 1 -C 6 alkyl; 
 iv) NR 4 R 5 , wherein R 4  and R 5  and the nitrogen to which they are attached form a monocyclic or bicyclic ring that may contain one or more of oxo, O, S, SO, SO 2 , or NR 6  (wherein R 6  is hydrogen, C 1 -C 6 alkyl, or Ar—(C 1 -C 6 alkyl) where
 Ar is aryl or heteroaryl each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C 1 -C 6 )alkylamino, and amino(C 1 -C 6 )alkyl. 
 
 
       
     
     
         70 . A compound according to  claim 69 , which has the formula 
       
         
           
           
               
               
           
         
         wherein X 1 , R, and each R 2  are as defined in  claim 69 , and R N  is hydrogen or —C(O)W. 
       
     
     
         71 . A compound according to  claim 70 , wherein R N  is hydrogen. 
     
     
         72 - 73 . (canceled) 
     
     
         74 . A compound according to  claim 1 , wherein X is CH and Q is —C(O)OR where R is C 1 -C 6  alkyl. 
     
     
         75 . A compound according to  claim 1 , wherein X 1  is CH and Q is —C(O)OR where R is C 1 -C 6  alkyl. 
     
     
         76 - 81 . (canceled) 
     
     
         82 . A compound according to  claim 1 , wherein Q is —C(O)M 5 . 
     
     
         83 . A compound according to  claim 1  of the formula 
       
         
           
           
               
               
           
         
         wherein 
         W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V 1 , V 2  and V 3 , where V 1 , V 2 , and V 3  independently represent
 halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); 
 
         R 1  and R 2  independently represent hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); 
         X is nitrogen or CR 111 , where R 111  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); and 
         R 9  and R 10  are independently hydrogen or C 1 -C 8  alkyl; or 
         R 9  and R 10  together represent a C 4 -C 6  straight chain alkylene group which together with the nitrogen atom to which R 9  and R 10  are attached form a 5- to 7-membered ring optionally containing one or two double bonds, O and/or N—R 8  where R 8  is hydrogen, C 1 -C 8  alkyl, or HAr—(C 1 -C 8 )alkyl, where HAr is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with one or two halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl). 
       
     
     
         84 . A compound according to  claim 1  of the formula 
       
         
           
           
               
               
           
         
         wherein 
         W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V 1 , V 2  and V 3 , where V 1 , V 2 , and V 3  independently represent
 halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 1 C 8  alkyl)(C 1 -C 8  alkyl); 
 
         R 1  and R 2  independently represent hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); 
         X is nitrogen or CR 111 , where R 111  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); and 
         W′ represents
 (i) phenyl optionally substituted with one, two, or three of T 1 , T 2  and T 3 , where T 1 , T 2 , and T 3  independently represent halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 8  alkoxy, —NO 2 , —CN, amino, —NH(C 1 -C 8  alkyl), or —N(C 1 -C 8  alkyl)(C 1 -C 8  alkyl); 
 (ii) —OR where R is C 1 -C 8  alkyl or aryl(C 1 -C 6 )alkyl; or 
 (iii) M 5  where M 5  is hydroxy, C 1 -C 8  alkyl, aryl(C 1 -C 6 )alkyl or —N(C 1 -C 4  alkyl)(C 1 -C 4  alkoxy). 
 
       
     
     
         85 - 89 . (canceled) 
     
     
         90 . A pharmaceutical composition comprising a compound according to  claim 1  combined with at least one pharmaceutically acceptable carrier or excipient. 
     
     
         91 . A method for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A  receptor, said method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of  claim 1 . 
     
     
         92 - 102 . (canceled)