Substituted isoxazolopyridazinones and isothiazolopyridazinones and methods of use

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 and R 3 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or isotopically labelled form thereof, wherein: 
         X is O or S; 
         R 1  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and phenyl; wherein,
 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are unsubstituted, partly or completely fluorinated and/or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo; 
 C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluorine, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo; 
 phenyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, and halo; 
 
         R 2  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and —(CR a R b ) n -G 1 ; wherein,
 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are unsubstituted, partly or completely fluorinated and/or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo; 
 R a  and R b  are independently selected at each occurrence from the group consisting of hydrogen, fluorine, C 1 -C 6 alkyl, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, and phenyl; wherein
 phenyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkoxy, fluoroC 1 -C 6 alkyl, and halo; 
 
 n is 1, 2 or 3; 
 G 1  is selected from the group consisting of phenyl, bicyclicaryl, monocyclic heteroaryl, and bicyclic heteroaryl; wherein the phenyl, the bicyclicaryl, the monocyclic heteroaryl, and the bicyclic heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, halo, and hydroxy; 
 
         R 3  is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, phenylC 1 -C 6 alkyl, bicyclicaryl, bicyclicarylC 1 -C 6 alkyl, monocyclic heteroarylC 1 -C 6 alkyl, monocyclic heteroaryl, and bicyclic heteroaryl; wherein
 C 1 -C 6 alkyl is unsubstituted, partly or completely fluorinated and/or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo; 
 C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkoxy, fluorine, hydroxy, and oxo; and 
 phenyl, phenyl of phenylC 1 -C 6 alkyl, bicyclicaryl, bicyclicaryl of bicyclicarylC 1 -C 6 alkyl, monocyclic heteroaryl of monocyclic heteroarylC 1 -C 6 alkyl, monocyclic heteroaryl and bicyclic heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents R Ar , which are independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, —OR 1a , —OC(O)R 1a , —OC(O)N(R d )(R 3a ), —SR 1a , —S(O) 2 R 2a , —S(O) 2 N(R d )(R 3a ), —C(O)R 1a , —C(O)OR 1a , —C(O)N(R d )(R 3a ), —N(R d )(R 3a ), —N(R c )C(O)R 1a , —N(R c )S(O) 2 R 2a , —N(R c )C(O)O(R 1a ), —N(R c )C(O)N(R d )(R 3a ), —(CR 4a R 5a ) m —OR 1a , —(CR 4a R 5a ) m —OC(O)R 1a , —(CR 4a R 5a ) m —OC(O)N(R d )(R 3a ), —(CR 4a R 5a ) m —SR 1a , —(CR 4a R 5a ) m —S(O) 2 R 2a , —(CR 4a R 5a ) m —S(O) 2 N(R d )(R 3a ), —(CR 4a R 5a ) m —C(O)R 1a , —(CR 4a R 5a ) m —C(O)OR 1a , —(CR 4a R 5a ) m —C(O)N(R d )(R 3a ), —(CR 4a R 5a ) m —N(R d )(R 3a ), —(CR 4a R 5a ) m —N(R c )C(O)R 1a , —(CR 4a R 5a ) m —N(R c )S(O) 2 R 2a , —(CR 4a R 5a ) m —N(R c )C(O)O(R 1a ), —(CR 4a R 5a ) m —N(R c )C(O)N(R d )(R 3a ), cyanoC 1 -C 6 -alkyl and fluoroC 1 -C 6 -alkyl;
 m is 1, 2, 3, or 4; 
 R c  and R d , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl; 
 R 1a  and R 3a , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl; 
 R d  and R 3a , if present as a group N(R d )(R 3a ), may together with the nitrogen atom of N(R d )(R 3a ) also form an N-bound saturated 3 to 8 membered heterocycle, which in addition to the nitrogen atom may have 1 or 2 further heteroatoms as ring members, which are selected from O, S and N; 
 R c  and R 1a , if present as a group —N(R c )C(O)R 1a , may together with the atoms of said moiety form an N-bound saturated 3 to 8 membered heterocycle, which has an oxo group in 2-position and which in addition to the nitrogen atom may have 1 or 2 further heteroatoms as ring members, which are selected from O, S and N; and 
 R 2a , at each occurrence, is independently C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl; and 
 
 R 4a  and R 5a , at each occurrence, are each independently hydrogen, 
 fluorine, C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl, 
 
         except for the following groups of compounds and except for their pharmaceutically acceptable salts: 
         compounds of formula (I), where X is O, R 1  is methyl, R 2  is methyl, ethyl, n-butyl, unsubstituted benzyl, prop-2-ynyl, 2-(ethoxycarbonyl)ethyl or 2-carboxyethyl and R 3  is unsubstituted phenyl; 
         compounds of formula (I), where X is O, R 1  is methyl, R 2  is methyl, 2,2,2-trifluoroacetyl or unsubstituted benzyl, and R 3  is methyl; 
         compounds of formula (I), where X is O, R 1  is methyl, R 2  is ethoxycarbonylmethyl and R 3  is unsubstituted benzyl, or 4-methoxybenzyl. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein
 R 1  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 6 cycloalkyl; wherein,
 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are unsubstituted, partly or completely fluorinated and/or substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkoxy, hydroxy, and oxo; and 
 C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluorine, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo. 
   
     
     
         3 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 2 , wherein
 R 1  is selected from the group consisting of C 1 -C 6 alkyl, fluoroC 1 -C 6 alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and cyclopropyl, wherein cyclopropyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of C 1 -C 3 alkyl, fluorine, and fluoroC 1 -C 3 alkyl.   
     
     
         4 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 ; wherein R 1  is phenyl; wherein phenyl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, and halo. 
     
     
         5 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R 1  is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxymethyl, phenyl which is unsubstituted or substituted by halo. 
     
     
         6 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R 2  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl; wherein
 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are unsubstituted, partly or completely fluorinated and/or substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkoxy, hydroxy, and oxo.   
     
     
         7 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 6 , wherein,
 R 2  is C 1 -C 6 alkyl or fluoroC 1 -C 6 alkyl.   
     
     
         8 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R 2  is —(CR a R b ) n -G 1 . 
     
     
         9 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 8 ; wherein G 1  is selected from the group consisting of phenyl and monocyclic heteroaryl; wherein the phenyl and the monocyclic heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, halo, and hydroxy. 
     
     
         10 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 9 , wherein G 1  is phenyl, which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, halo, and hydroxy. 
     
     
         11 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 8 , wherein
 R a  and R b  are independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl; wherein
 phenyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, and halo; and 
   n is 1 or 2.   
     
     
         12 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 11 , wherein the moiety —(CR a R b ) n — is CH 2 , CH 2 CH 2 , CH(CH 3 ) or CH(phenyl). 
     
     
         13 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 12 , wherein the moiety —(CR a R b ) n — is CH(CH 3 ), which has predominately R-configuration. 
     
     
         14 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R 2  is selected from the group consisting of 4-chlorophenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenylmethyl, 4-methoxy-3-(trifluoromethyl)phenylmethyl, 2-fluoro-5-(trifluoromethyl)phenylmethyl, 5-chloro-2-fluorophenylmethyl, 4-chloro-2-fluorophenylmethyl, 4-chlorophenylphenylmethyl, 2,4-difluorophenylmethyl, 4-fluoro-3-(trifluoromethyl)phenylmethyl, 4-chloro-3-(trifluoromethyl)phenylmethyl, 2-fluorophenylmethyl, 4-fluorophenylmethyl, 1-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 1-(4-(trifluoromethyl)phenyl)ethyl, 4-pyridylmethyl and 3-methylbutyl. 
     
     
         15 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1  wherein
 R 3  is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; wherein
 C 1 -C 6 alkyl is unsubstituted, partly or completely fluorinated and/or substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkoxy, hydroxy, and oxo; and 
 C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluorine, fluoroC 1 -C 6 alkyl, fluoroC 1 -C 6 alkoxy, hydroxy, and oxo. 
 
 
     
     
         16 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 15 , wherein
 R 3  is C 1 -C 6 alkyl or fluoroC 1 -C 6 alkyl.   
     
     
         17 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein
 R 3  is selected from the group consisting of phenyl, phenylC 1 -C 6 alkyl, bicyclicaryl, bicyclicarylC 1 -C 6 alkyl, monocyclic heteroarylC 1 -C 6 alkyl, monocyclic heteroaryl, and bicyclic heteroaryl; wherein
 the phenyl, the phenyl of phenylC 1 -C 6 alkyl, the bicyclicaryl, the bicyclicaryl of bicyclicarylC 1 -C 6 alkyl, the monocyclic heteroaryl of monocyclic heteroarylC 1 -C 6 alkyl, the monocyclic heteroaryl and the bicyclic heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents R Ar . 
   
     
     
         18 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 17 , wherein
 R 3  is selected from the group consisting of phenyl and monocyclic heteroaryl; wherein phenyl is substituted with 1, 2, 3 or 4 substituents R Ar  and where the monocyclic heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents R Ar .   
     
     
         19 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R Ar , independently of its occurrence, is selected from the group consisting of C 1 -C 6 alkyl, halogen, —OR 1a , —S(O) 2 N(R d )(R 3a ), —C(O)R 1a , —C(O)OR 1a , —C(O)N(R d )(R 3a ), —N(R d )(R 3a ), —N(R c )C(O)R 1a , —N(R c )S(O) 2 R 2a  and fluoroC 1 -C 6 -alkyl; wherein
 R c  and R d , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl; 
 R 1a  and R 3a , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl; or 
 R d  and R 3a , if present as a group N(R d )R 3a , may together with the nitrogen atom of said moiety form an N-bound pyrrolidin, N-bound piperidin or N-bound azepan radical; and 
 R 2a , at each occurrence, is independently C 1 -C 6 alkyl, or fluoroC 1 -C 6 -alkyl. 
 
     
     
         20 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein R 3  is selected from the group consisting of methyl, ethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-aminophenyl, 3-aminophenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-carbamoylphenyl, 3-(acetylamino)phenyl, 3-(methylsulfonylamino)phenyl, 3-(aminosulfonyl)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-bis(methoxy)phenyl, 3,4-bis(methoxy)phenyl, 2,5-bis(methoxy)phenyl, 2-methoxy-5-fluorophenyl, 2-amino-5-fluorophenyl, 2-methoxy-5-carboxyphenyl, 2-methoxy-5-(trifluoromethyl)phenyl, 2-methoxy-5-(acetylamino)phenyl, 2-methoxy-3-(acetylamino)phenyl, 2-(trifluoromethoxy)-5-(acetylamino)phenyl, 2-methoxy-5-(methylsulfonylamino)phenyl,4-fluoro-3-(acetylamino)phenyl, 2-methyl-5-(acetylamino)phenyl, 2-methyl-5-hydroxyphenyl, 2-methoxy-5-(aminocarbonyl)phenyl, 3-amino-2-(aminocarbonyl)phenyl, 2-methoxy-5-(N-methylaminocarbonyl)phenyl, 2-methoxy-5-(N-ethylaminocarbonyl)phenyl, 2-methoxy-5-(N,N-dimethylaminocarbonyl)phenyl, 2-methoxy-5-(pyrrolidin-1-ylcarbonyl)phenyl, 2-methoxy-5-(pyrrolidin-2on-1-yl)phenyl, 3-methoxy-5-(N,N-dimethylaminocarbonyl)phenyl, 2-amino-5-chlorophenyl, 2-amino-5-(trifluoromethyl)phenyl, 2-amino-3,5-difluorophenyl, 2-methyl-3-(acetylamino)-4-fluorophenyl, 3-pyridyl, 5-pyrimidinyl, 2-fluoro-3-pyridyl, 2-amino-4-pyridyl, 5-fluoro-3-pyridyl, 2-chloro-3-pyridyl, indol-5-yl, 2,6-difluoropyridin-4-yl, 2-thienyl, 1-ethylpyrazol-5-yl, and 1H-pyrrolo[2,3-b]pyridine-6-yl. 
     
     
         21 . The compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 , wherein X is O. 
     
     
         22 . A compound selected from the group consisting of:
 N-(3-{5-[(1S)-1-(4-chlorophenyl)ethyl]-3-cyclopropyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)acetamide;   5-(4-chlorobenzyl)-7-(4-methoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[(1R)-1-(4-chlorophenyl)ethyl]-3-cyclopropyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)acetamide;   5-[1-(4-chlorophenyl)ethyl]-7-(2,6-difluoropyridin-4-yl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,4-dimethoxyphenyl)-3-methyl-5-(pyridin-4-ylmethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2-amino-5-chlorophenyl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(2-chloropyridin-3-yl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{5-[5-(4-chlorobenzyl)-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]-2-fluorophenyl}acetamide;   7-(2,5-dimethoxyphenyl)-5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[2-(4-chlorophenyl)ethyl]-7-(2,5-dimethoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-[2-amino-5-(trifluoromethyl)phenyl]-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(1H-indol-6-yl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-(propan-2-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2-aminophenyl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-[1-(4-chlorophenyl)ethyl]-7-(5-hydroxy-2-methylphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(2-fluoro-5-{5-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methylphenyl)acetamide;   7-(4-fluorophenyl)-3-methyl-5-[4-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(2-fluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(2,5-dimethoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(5-fluoropyridin-3-yl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(3-fluorophenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)methanesulfonamide;   5-[2-fluoro-5-(trifluoromethyl)benzyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2-methoxyphenyl)-3-methyl-5-(pyridin-4-ylmethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-3-(methoxymethyl)-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   5-[4-chloro-3-(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(2-fluoro-5-{3-methyl-4-oxo-5-[4-(trifluoromethyl)benzyl]-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-(4-fluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[(1S)-1-(4-chlorophenyl)ethyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,4-dimethoxyphenyl)-5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-2-methoxyphenyl)acetamide;   N-(3-{5-[(1R)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   N-[4-methyl-3-(3-methyl-4-oxo-5-{(1R)-1[4-(trifluoromethyl)phenyl]ethyl}1-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl)phenyl]acetamide;   5-(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-ethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,4-dimethoxyphenyl)-5-[4-fluoro-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxy-N,N-dimethylbenzamide;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)acetamide;   N-(3-{5-[(1R)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)acetamide;   N-(3-{5-[4-fluoro-3-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-(4-chlorobenzyl)-7-(3,4-difluorophenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[4-fluoro-3-(trifluoromethyl)benzyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3,7-dimethyl-5-(pyridin-4-ylmethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]-4-methoxyphenyl}acetamide;   5-[2-fluoro-5-(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-3-cyclopropyl-7-(2,5-dimethoxyphenyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,4-dimethoxyphenyl)-5-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-[3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-(trifluoromethoxy)phenyl]acetamide;   5-[4-methoxy-3-(trifluoromethyl)benzyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-3-cyclopropyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   5-(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-propyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}benzenesulfonamide;   5-[4-fluoro-3-(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)methanesulfonamide;   5-(4-chlorobenzyl)-3-methyl-7-(thiophen-2-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{3-methyl-4-oxo-5-[4-(trifluoromethyl)benzyl]-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-[(1R)-1-(4-chlorophenyl)ethyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxybenzamide;   5-[2-(4-chlorophenyl)ethyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(2-fluoro-5-{5-[4-fluoro-3-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   N-(2-fluoro-5-{5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-[1-(4-chlorophenyl)ethyl]-7-(5-fluoro-2-methoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(4-methoxy-3-{3-methyl-4-oxo-5-[4-(trifluoromethyl)benzyl]-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   2-amino-6-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}benzamide;   7-(4-fluorophenyl)-5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(2-methoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[(1S)-1-(4-chlorophenyl)ethyl]-3-cyclopropyl-7-(2,5-dimethoxyphenyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[4-chloro-3-(trifluoromethyl)benzyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   5-(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-(methoxymethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[(1S)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxybenzoic acid;   7-(4-fluorophenyl)-3-methyl-5-(pyridin-4-ylmethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[(R)-(4-chlorophenyl)(phenyl)methyl]-3,7-diethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-3-methyl-7-(2-methylphenyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2-amino-3,5-difluorophenyl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   5-[1-(4-chlorophenyl)ethyl]-7-[2-methoxy-5-(trifluoromethyl)phenyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-phenyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,5-dimethoxyphenyl)-5-[4-fluoro-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[(1S)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxy-N-methylbenzamide;   5-(4-chlorobenzyl)-7-(4-fluorophenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(3-chloro-4-fluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   7-(2-aminopyridin-3-yl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(2,4-dimethoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(5-chloro-2-fluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[(S)-(4-chlorophenyl)(phenyl)methyl]-3,7-diethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(3,5-difluorophenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-4-oxo-3-propyl-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   5-(4-chloro-2-fluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,5-dimethoxyphenyl)-3-methyl-5-(pyridin-4-ylmethyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{2-fluoro-5-[3-methyl-4-oxo-5-(pyridin-4-ylmethyl)-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   7-(2,5-dimethoxyphenyl)-3-methyl-5-[4-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-4-oxo-3-(propan-2-yl)-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   7-(2-amino-5-fluorophenyl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-[2-methoxy-5-(pyrrolidin-1-ylcarbonyl)phenyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-7-(3,4-dimethoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(2-hydroxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2-methoxyphenyl)-5-[4-methoxy-3-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   -(4-chlorobenzyl)-7-(2,5-dimethoxyphenyl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-[4-methoxy-3-(3-methyl-4-oxo-5-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl)phenyl]acetamide;   N-{3-[5-(4-chlorobenzyl)-4-oxo-3-phenyl-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   N-[4-methoxy-3-(3-methyl-4-oxo-5-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl)phenyl]acetamide;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}benzamide;   N-(4-methyl-3-{3-methyl-4-oxo-5-[4-(trifluoromethyl)benzyl]-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}phenyl)acetamide;   3,7-dimethyl-5-(3-methylbutyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-3-methyl-7-(pyridin-3-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[3-methyl-4-oxo-5-(pyridin-4-ylmethyl)-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   3-{5-[(1R)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxy-N-methylbenzamide;   N-[6-fluoro-2-methyl-3-(3-methyl-4-oxo-5-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl)phenyl]acetamide;   5-[1-(4-chlorophenyl)ethyl]-3-methyl -7-(pyrimidin-5-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-7-(1-ethyl-1H-pyrazol-5-yl)-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[1-(4-chlorophenyl)ethyl]-3-methyl-7-(1H-pyrrolo[3,2-b]pyridin-6-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-(3-{5-[(1S)-1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxyphenyl)acetamide;   7-(2-methoxyphenyl)-3-methyl-5-[4-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-4-methoxy-N-methylbenzamide;   5-(4-chlorobenzyl)-3-methyl-7-(pyridin-3-yl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3,7-dimethyl-5-[3-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(4-chlorobenzyl)-3-methyl-7-phenyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-(2,4-difluorobenzyl)-3,7-dimethyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3,7-dimethyl-5-[4-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,5-dimethoxyphenyl)-3-methyl-5-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(3-aminophenyl)-5-[1-(4-chlorophenyl)ethyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   7-(2,4-dimethoxyphenyl)-3-methyl-5-[4-(trifluoromethyl)benzyl][1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   5-[(1R)-1-(4-chlorophenyl)ethyl]-3-cyclopropyl-7-(2,5-dimethoxyphenyl)[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   N-{3-[5-(4-chlorobenzyl)-3-ethyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl]phenyl}acetamide;   7-(2,5-dimethoxyphenyl)-5-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl[1,2]oxazolo[4,5-d]pyridazin-4(5H)-one;   3-{5-[1-(4-chlorophenyl)ethyl]-3-methyl-4-oxo-4,5-dihydro[1,2]oxazolo[4,5-d]pyridazin-7-yl}-N-ethyl-4-methoxybenzamide;   the pharmaceutically acceptable salts thereof and the isotopically labelled forms thereof.   
     
     
         23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1  in combination with a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         24 . A method of selectively modulating a disorder or condition, which is selected from the group consisting of pain, substance abuse (especially in alcohol dependence), depression, spasticity, fragile X syndrome, Down's syndrome, autism, retinal ganglion cell degeneration, gastro-esophageal reflux disease (GERD), smoking cessation, addiction of narcotic agents, emesis, cough, overactive bladder, anxiety, migraine and tinnitus in a mammal comprising administering an effective amount of a compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 . 
     
     
         25 . A method of treating a condition or disorder modulated by the γ-aminobutyric acid B (GABA-B) receptor in a mammal comprising administering an effective amount of a compound or pharmaceutically acceptable salt or isotopically labelled form thereof of  claim 1 . 
     
     
         26 . The method of  claim 25 , where the condition or disorder is selected from the group consisting of pain, substance abuse (especially in alcohol dependence), depression, spasticity, fragile X syndrome, Down's syndrome, autism, retinal ganglion cell degeneration, gastro-esophageal reflux disease (GERD), smoking cessation, addiction of narcotic agents, emesis, cough, overactive bladder, anxiety, migraine and tinnitus.