Antiviral agent

Abstract

The present invention provides an integrase inhibitor. The inventors have have found the following compound of formula (I) possessing an integrase inhibitory activity. (wherein, R C and R D taken together with the neighboring carbon atoms form a ring which may be a condensed ring, Y is hydroxy, mercapto or amino; Z is O, S or NH; R A is a group shown by (wherein, C ring is N-containing aromatic heterocycle) or the like)

1 . A method for preventing or treating a viral infectious disease in a patient, which comprises administering to the patent a therapeutically effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       (wherein, R C  and R D taken together with the neighboring carbon atoms form a ring which may be a condensed ring, Y is hydroxy, mercapto or amino; Z is O, S or NH; R A  is a group shown by  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is N-containing aromatic heterocycle, wherein at least one atom neighboring to the atom at the bonding-position is non-substituted N atom; the broken line shows the presence or absence of a bond.) or by  
       
         
           
           
               
               
           
         
       
       (wherein, X is O, S or NH; R B  is a substituent selected from substitution group A); at least one of the ring formed by R C  and R D , C ring or R B  is substituted with a group of —Z 1 —Z 2 —Z 3 —R 1  (wherein, Z 1  and Z 3  are each independently a bond, optionally substituted alkylene or optionally substituted alkenylene; Z 2  is a bond, optionally substituted alkylene, optionally substituted alkenylene, —CH(OH)—, —S-, —SO—, —SO 2 , —SO 2 NR 2 —, —NR 2 SO 2 —, —O—, —NR 2 —, —NR 2 CO—, —CONR 2 —, —C(═O)—O—, —O—C(═O) or —CO—; R 2  is hydrogen, optionally substituted alkyl optionally substituted alkenyl, optionally substituted aryl or optionally substituted heteroaryl; R 1  is optionally substituted aryl optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle); the ring formed by R C  and R D , C ring or R B  is optionally substituted with a non-interfering substituent at any possition other than that where the group of —Z 1 —Z 2 —Z 3 —R 1  (wherein, Z 1 , Z 2 , Z 3  and R 1  are the same as defined above) locates;  
       substitution groupA consists of: hydrogen, halogen, alkoxycarbonyl carboxy, alkyl, alkoxy, alkoxyalkyl nitro, hydroxy, alkenyl alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio, alkylthioalkyl, haloalkyl haloalkoxy, haloalkoxyalkyl optionally substituted cycloalkyl, optionally substituted cycloalkenyl optionally substituted heterocycle, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl carbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl alkyl, optionally substituted aryl oxy, optionally substituted heteroaryl oxy, optionally substituted aryl thio, optionally substituted heteroaryl thio, optionally substituted aralkyloxy, optionally substituted heteroaryl alkyl oxy, optionally substituted aralkylthio, optionally substituted heteroaryl alkylthio, optionally substituted aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl, optionally substituted aryl thioalkyl, optionally substituted heteroaryl thioalkyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroaryl alkylsulfonyl), its prodrug, or a pharmaceutically acceptable salt or solvate thereof, for use as an integrase inhibitor.  
     
     
         2 . A method of  claim 1  wherein the ring formed by R C  and R D  is a 5- to 6-membered ring which may contain a hetero atom(s) and be condensed with.  
     
     
         3 . A method of  claim 2  wherein the ring formed by R C  and R D  is a 5- to 6-membered ring which may contain a hetero atom(s) of O and/or N and be condensed with a benzene ring.  
     
     
         4 . A method of  claim 3  wherein the ring formed by R C  and R D  is a 5-membered ring which contains a hetero atom(s) of N.  
     
     
         5 . A method of  claim 3  wherein the ring formed by R C  and R D  is a 6-membered ring which contains a hetero atom(s) of O and is condensed with a benzene ring.  
     
     
         6 . A method of  claim 3  wherein the ring formed by R C  and R D  is a 6-membered ring which contains a hetero atom(s) of N and is condensed with a benzene ring.  
     
     
         7 . A method of  claim 3  wherein the ring formed by R C  and R D  is a 6-membered ring which contains a hetero atom(s) of O.  
     
     
         8 . A method of  claim 3  wherein the ring formed by R C  and R D  is a 6-membered ring which contains a hetero atom(s) of N.  
     
     
         9 . A method of  claim 1  wherein the ring formed by R C  and R D  is a 6-membered carbocycle.  
     
     
         10 . A method of  claim 4  which contains as an active ingredient a compound of formula (II-1)  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring, Z 1 , Z 2 , Z 3 , R 1  and the broken line is the same as  claim 1;  R 3 , R 4 , R 5  and R 19  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         11 . A method of  claim 4  which contains as an active ingredient a compound of formula (III-1)  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z, R B , Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 5 , R 6 , R 7  and R 1     9    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         12 - 13 . (Cancelled)  
     
     
         14 . A method of  claim 3  which contains as an active ingredient a compound of formula (IV-1):  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring and the broken line are the same as  claim 1;  R 8 ,R 9  and R 10  are each independently a non-interfering substituent; at least one of R E  and R F  is shown by —Z 1 —Z 2 —Z 3 —R 1  (wherein, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1)  and the other is a non-interfering substituent, or R E  and R F  taken together with the neighboring carbon atoms may form a ring shown by:  
       
         
           
           
               
               
           
         
       
       (wherein, R 1     1    to R 1     3    are each independently a non-interfering substituent, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1) , its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         15 . A method of  claim 5  which contains as an active ingredient a compound of formula(IV-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring, Z 1 , Z 2 , Z 3 ,R 1  and the broken line are the same as  claim 1;  R 8  to R 1     3    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         16 . A method of  claim 3  which contains as an active ingredient a compound of formula (V-1)  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring, Z 1 , Z 2 , Z 3 ,R 1  and the broken line are the same as  claim 1;  R 9  and R 10  are each independently a non-interfering substituent; R E  and R F  are each independently a non-interfering substituent or taken together with the neighboring carbon atoms may form a ring shown by:  
       
         
           
           
               
               
           
         
       
       (wherein, R 1     1    to R 1     4    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         17 . A method of  claim 5  which contains as an active ingredient a compound of formula (V-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring, Z 1 , Z 2 , Z 3 , R 1  and the broken line are the same as  claim 1;  R 9  to R 1     4    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         18 - 19 . (Cancelled)  
     
     
         20 . A method of  claim 3  which contains as an active ingredient a compound of formula(VII-1):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z, R B , Z 1 , Z 2 , Z 3  and R 1  are the same as claim; W 1  is —O or —N(—R G )—; R G  is a non-interfering substituent; R 6  and R 7  are each independently a non-interfering substituent; R E  and R F  are each independently a non-interfering substituent or taken together with the neighboring carbon atoms form a ring shown by  
       
         
           
           
               
               
           
         
       
       (wherein, R 1     1    to R 1     4    are each independently a non-interfering substituent)), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         21 . A method of  claim 3  which contains as an active ingredient a compound of formula(VII-2):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z, R B . Z 1 , Z 2 ,Z 3  and R 1  are the same as  claim 1;  W 1  is —O or —N(R G )—; R G  is a noninterfering substituent; R 6 , R 7 , R 1     1    to R 1     4    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         22 . A method of  claim 3  which aontains as an active ingredient a compound of formula (VII-3):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z, R B , Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  W is —O or —N(—R G ); R G  is a non-interfering substituent; R 6  and R 7  are each independently a non-interfering substituent; R E  and R F  are each independently a noninterfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         23 - 24 . (Cancelled)  
     
     
         25 . A method of  claim 8  which contains as an active ingredient a compound of formula (IX-1):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z, R B , Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 6  and R 7  are each independently a noninterfering substituent; R F  and R G  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or its solvate thereof.  
     
     
         26 . A method of  claim 8  which contains as an active ingredient a compound of formula (IX-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y, Z, C ring, Z 1 , Z 2 , Z 3 , R 1  and the broken line are the same as  claim 1;  R 9  and R 10  are each independently a non-interfering substituent; R F  and R G  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         27 - 34 . (Cancelled)  
     
     
         35 . A method of  claim 1 , wherein the non-interfering substituents are independently selected from hydrogen, halogen, alkoxycarbonyl carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, hydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio, alkylthioalkyl haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl optionally substituted heterocycle, oxo, thioxo, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkylcarbonyl alkylcarbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aralkyloxy, optionally substituted heteroarylalkyloxy, optionally substituted aralkylthio, optionally substituted heteroarylalkylthio, optionally substituted aryloxyalkyl optionally substituted heteroaryloxyalkyl optionally substituted arylthioalkyl, optionally substituted heteroarylthioalkyl optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroarylalkylsulfonyl.  
     
     
         36 - 37 . (Cancelled)  
     
     
         38 . A compound of formula(I-Q): Q—Z 1 —Z 2 —Z 3 —R 1 , its prodrug or pharmaceutically acceptable salt or solvate thereof, wherein, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  Q is shown by any one of the following formulae:  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y is hydroxy; Z is O; R 3 , R 4 , R 5  and R 19  are the same as  claim 10) ,  
       
         
           
           
               
               
           
         
       
       (wherein, X is O; Y and Z are the same as above; R 5 , R 6 ,R 7  and R 19  are the same as  claim 11;  R B  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 6 ,R 7  and R 1     9    are the same as  claim 11) ,  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 8  to R 10  are the same as  claim 14;  W 1  is the same as  claim 20;  R 16  is a non-interfering substituent),  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 8  to R 13  are the same as  claim 14;  W 1  is the same as  claim 20) ,  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 9  to R 4  is the same as  claim 16;  W 1  is the same as  claim 20) ,  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; W 1  is the same as  claim 20;  R 9  and R 10  are the same as  claim 14;  R 17  and R 18  are each independently a non-interfering substituent),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; W 1  is the same as  claim 20;  R 6  and R 7  are the same as  claim 11;  R 1     1    to R 1     4    are the same as  claim 16) ,  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; W 1  is the same as  claim 20;  R 6  and R 7  are the same as  claim 11;  R 17  and R 18  are each independently a non-interfering substituent):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 6  and R 7  are the same as  claim 11;  R 1     7    and R 1     8    are each independently a non-interfering substituent),  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 9  and R 1  are the same as  claim 14;  R 1     7    and R 18  are the same as defined above),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 5  is the same as  claim 10;  R 6  and R 7  are the same as  claim 11;  R 1     7    and R 1     8    are the same as defined above),  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 5  is the same as  claim 10;  R 9  and R 10  are the same as  claim 14;  R 17  and R 18  are the same as defined above),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 5  and R 5 ′ are the same as claim  27 ; R 6  and R 7  are the same as  claim 11) ,  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 5  and R 5 ′ are the same as claim  27 ; R 9  and R 10  are the same as claim  14 ):  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 6  and R 7  are the same as  claim 11;  R 1     7    and R 1     8    are the same as above, the broken line(---) shows the presence or absence of a bond),  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 9  and R 10  are the same as  claim 14;  R 1     7    and R 1     8    are the same as above, the broken line (---) shows the presence or absence of a bond),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 5 , R 6  and R 7  are the same as  claim 11;  R 1     7    and R 1     8    are the same as above, the broken line(---) shows the presence or absence of a bond),  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 5  is the same as  claim 10;  R 9  and R 10  are the same as  claim 14;  R 1     7    and R 1     8    are the same as above, the broken line(---) shows the presence or absence of a bond),  
       
         
           
           
               
               
           
         
       
       (wherein, X, Y, Z and R B  are the same as above; R 5 , R 6  and R 7  are the same as  claim 11;  R 18  is the same as defined above), and  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is the same as  claim 1;  Y and Z are the same as above; R 5  is the same as  claim 10;  R 9  and R 10  are the same as  claim 14;  R 18  is the same as defined above); 
 provided that excluded are compounds, wherein Z 1  is a bond, Z 2  is —O—, Z 3  is methylene, R 1  is phenyl and Q is a group of the formula:  
                     
 (wherein, R 8  to R 1     3    are hydrogens, Y is hydroxy, Z is O, W is —O—, and C ring is quinoline-2-yl) or the formula:  
                     
 wherein, R 9  and R 10  are the same as above, R 1     7    is alkyl, R 1     8    is hydrogen, Y is hydroxy, Z is O, C ring is dihydropirimne).  
 
     
     
         39 . A compound of  claim 38 , shown by formula (H-1):  
       
         
           
           
               
               
           
         
       
       (wherein, Y is hydroxy; Z is O; C ring, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 3 ,R 4 ,R 5  and R 1     9    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         40 . A compound of  claim 39 , wherein Z 1  and Z 3  are each independently a bond or alkylene; Z 2  is a bond or —O—; R 1  is optionally substituted aryl or optionally substituted heteroaryl its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         41 . A compound of  claim 39 , wherein C ring is pyrimidine-4yl or 1,3,4-oxadiazole-2yl; Z 1  is a bond; Z 2  is −0 or alkylene; Z 3  is a bond or alkylene; R 1  is aryl optionally substituted with halogen; R 3 , R 4  and R 1     9    are hydrogens; R 5  is alkyl, aralkyl, cycloalkyl, aryl or alkoxy, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         42 . A compound of  claim 38 , shown by formula (III-1):  
       
         
           
           
               
               
           
         
       
       (wherein, X is O; Y is hydroxy; Z is O; R B  is optionally substituted aryl, optionally substituted heteroaryl optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle; Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 5 , R 6 , R 7  and R 19  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         43 . A compound of  claim 39  or  42 , wherein, R 5  is hydrogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl, alkoxy, alkoxyalkyl optionally substituted ammo, hydroxyalkyl, alkenyl alkoxycarbonylalkyl or heteroarylalkyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         44 . A compound of above  42 , wherein R B  is fran-2yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         45 . A compound of above  42 , wherein R B  is aryl or fran-2yl; Z 1  and Z 3  are bonds; Z 2  is alkylene; R 1  is aryl optionally substituted with halogen; R 6 ,R 7  and R 1     9    are hydrogens; R 5  is alkyl, cycloalkyl, alkoxy, aryl optionally substituted with alkoxy, hydroxyalkyl, alkenyl aralkyl, alkoxycarbonylalkyl, or pyridine-2ylmethyl its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         46 - 51 . (Cancelled)  
     
     
         52 . A compound of  claim 38 , shown by formula (IV-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y is hydroxy; Z is O; C ring, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 8  to R 1     3    are each independently a non-interfering substituent, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         53 . A compound of  claim 52 , wherein C ring is pyridine-2-yl, 1,2,4-triazole-3-yl or imidazole-2-yl optionally substituted with alkyl; Z 1  is a bond; Z 2  is —O—; Z 3  is alkylene; R 1  is aryl optionally substituted with halogen; R 8  to R 1     3    are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         54 . A compound of  claim 38 , shown by formula (V-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y is hydroxy; Z is O; C ring, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 9  to R 1     4    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         55 . A compound of  claim 52  or  54 , wherein Z 1  and Z 3  are each independently a bond or alkylene; Z 2  is a bond or —O—; R 1  is optionally substituted aryl or optionally substituted heteroaryl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         56 . A compound of  claim 54 , wherein C ring is 1,3,4-oxadiazole-2y1; Z 1  and Z 3  are bonds; Z 2  is alkylene; R 1  is aryl optionally substituted with halogen; R 9  to R 1     4    are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         57 - 59 . (Cancelled)  
     
     
         60 . A compound of  claim 38 , shown by formula (VI-4):  
       
         
           
           
               
               
           
         
       
       (wherein, X is O; Y is hydroxy; Z is O; W 2  is —O or —NH—; R B  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle; Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 6 ,R 7 ,R 1     1    to R 1     4    are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         61 . A compound of  claim 60 , wherein R B  is fran-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         62 . A compound of  claim 60 , wherein R B  is fran-2-yl; Z 1  and Z 3  are bonds; Z 2  is alkylene; R 1  is aryl optionally substituted with halogen; R 6 ,R 7 ,R 1     1    to R 1     4    are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         63 . A compound of  claim 38 , shown by formula (VII-5):  
       
         
           
           
               
               
           
         
       
       (wherein, X is O; Y is hydroxy; Z is O; W 2  is —O or —NH—; R B  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle; Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1  R 6 ,R 7 , R E  and R F  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         64 . A compound of  claim 63 , wherein, R B  is fran-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         65 . A compound of  claim 63 , wherein, R B  is fran-2yl; Z 1  and Z 3  are bonds; Z 2  is alkylene; R 1  is aryl optionally substituted with halogen; R 6 ,R 7 , R E  and R F  are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         66 - 69 . (Cancelled)  
     
     
         70 . A compound of  claim 38 , shown by formula (IX-1):  
       
         
           
           
               
               
           
         
       
       (wherein, X is O; Y is hydroxy; Z is O; R B  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle; Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 6 ,R 7 , R F  and R G  are each independently a non-interfering substituent), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         71 - 72 . (Cancelled)  
     
     
         73 . A compound of  claim 38 , shown by formula (IX-2):  
       
         
           
           
               
               
           
         
       
       (wherein, Y is hydroxy; Z is O; C ring, Z 1 , Z 2 , Z 3  and R 1  are the same as  claim 1;  R 9 ,R 10 , R F  and R G  are each independently a non-interfering substituent, provided that when R G  is hydrogen and R F  is alkyl C ring is not dihydropirimidine), its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         74 - 89 . (Cancelled)  
     
     
         90 . A compound of  claim 38 ,  39 ,  46 ,  52 ,  54 ,  57 ,  69 ,  73 ,  77 ,  81 ,  85  or  89 , wherein C ring is optionally substituted pyridine-2-yl, optionally substituted pyrimidine-4-yl, optionally substituted 1,3,4-oxadiazole-2yl, optionally substituted 1,2,4-triazole-3yl or optionally substituted imidazole-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         91 . A compound of  claim 38 ,( 39 ),( 46 ),( 52 ),( 54 ),( 57 ),( 69 ),( 73 ),( 77 ),( 81 ),( 85 ) or ( 89 ), wherein Z 1  and Z 3  are each independently a bond or alkylene; Z 2  is a bond or —O—; R 1  is optionally substituted aryl or optionally substituted heteroaryl its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         92 . A compound of  claim 38 ,( 39 ),( 46 ),( 52 ),( 54 ),( 57 ),( 69 ),( 73 ),( 77 ),( 81 ),( 85 ) or ( 89 ), wherein C ring is pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl; Z 1  is a bond; Z 2  is —O or allylene; Z 3  is a bond or alkylene; R 1  is aryl optionally substituted with halogen R 3 ,R 4  and R 1     9    are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         93 . A compound of claim  38 ,( 39 ),( 42 ),( 46 ),( 49 ),( 52 ),( 54 ),( 57 ),( 60 ).( 63 ),( 66 ),( 69 ),( 70 ),( 73 ),( 74 ,( 77 ),( 78 ),( 81 ),( 82 ),( 85 ),( 86 ) or ( 89 ), wherein each non-interfering substituent is independently selected from hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy, alkoxy alkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio, alkylthio alkyl, haloalkyl, haloalkoxy, haloalkoxy alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, oxo, thioxo, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl carbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl optionally substituted heteroaryl alkyl, optionally substituted aryl oxy, optionally substituted heteroaryl oxy, optionally substituted aryl thio, optionally substituted heteroaryl thio, optionally substituted aralkyloxy, optionally substituted heteroaryl alkyl oxy, optionally substituted aralkylthio, optionally substituted heteroaryl alkylthio, optionally substituted aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl, optionally substituted aryl thioalkyl, optionally substituted heteroaryl thioalkyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroaryl alkylsulfonyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         94 . A compound of  claim 38 , ( 39 ), ( 42 ), ( 46 ), ( 49 ), ( 52 ), ( 54 ), ( 57 ), ( 60 ). ( 63 ), ( 66 ), ( 69 ), ( 70 ), ( 73 ), ( 74 ), ( 77 ), ( 78 ), ( 81 ), ( 82 ), ( 85 ), ( 86 ) or ( 89 ), wherein Z 1 , Z 2  and Z 3  are not bonds at the same, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         95 . A compound of  claim 94 , wherein R 1  is phenyl optionally substituted with halogen, Z 1  is a bond, Z 2  is alkylene or —O—, Z 3  is a bond or alkylene, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         96 . A compound of  claim 95 , wherein R 1  is 4-fluorophenyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         97 - 99 . (Cancelled)  
     
     
         100 . A pharmaceutical composition comprising a compound of any one of  claims 38  to  99 , its prodrug or pharmaceutically acceptable salt or solvate thereof.  
     
     
         101 - 120 . (Cancelled)  
     
     
         121 . A method for preventing or treating an integrase-mediated disease in a patient, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       (wherein, R C  and R D taken together with the neighboring carbon atoms form a ring which may be a condensed ring, Y is hydroxy, mercapto or amino; Z is O, S or NH; R A  is a group shown by  
       
         
           
           
               
               
           
         
       
       (wherein, C ring is N-containing aromatic heterocycle, wherein at least one atom neighboring to the atom at the bonding pition is non-substituted N atom; the broken line shows the presence or absence of a bond.) or by  
       
         
           
           
               
               
           
         
       
       (wherein, X is O, S or NH; R B  is a substituent selected from substitution group A); 
 at least one of the ring formed by R C  and R D , C ring or R B  is substituted with a group of —Z 1 —Z 2 —Z 3 —R 1  (wherein, Z 1  and Z 3  are each independently a bond, optionally substituted alkylene or optionally substituted alkenylene; Z 2  is a bond, optionally substituted alkylene, optionally substituted alkenylene, —CH(OH)—, —S—, —SO—,—SO 2 —, —SO 2 NR 2 —, —NR 2 SO 2 —, —O—, —NR 2 —, —NR 2 CO—, —CONR 2 —, —C(═O)—O—, —O—C(═O) or—CO—; R 2  is hydrogen, optionally substituted alkyl optionally substituted alkenyl, optionally substituted aryl or optionally substituted heteroaryl; R 1  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle);  
 the ring formed by R C  and R D , C ring or R B  is optionally substituted with a non-interfering substituent at any position other than that where the group of —Z 1 —Z 2 —Z 3 —R 1  (wherein, Z 1 , Z 2 , Z 3  and R 1  are the same as defined above) locates;  
 substitution groupA consists of: hydrogen, halogen, alkoxycarbonyl carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, alkenyl, alkynyl alkylsulfonyl, optionally substituted amino, alkylthio, alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl optionally substituted cycloalkyl optionally substituted cycloalkenyl, optionally substituted heterocycle, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl carbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl alkyl, optionally substituted aryl oxy, optionally substituted heteroaryl oxy, optionally substituted aryl thio, optionally substituted heteroaryl thio, optionally substituted aralkyloxy, optionally substituted heteroaryl alkyl oxy, optionally substituted aralkylthio, optionally substituted heteroaryl alkylthio, optionally substituted aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl, optionally substituted aryl thioalkyl, optionally substituted heteroaryl thioalkyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroaryl alkylsulfonyl), its prodrug, or a pharmaceutically acceptable salt or solvate thereof, for use as an integrase inhibitor.