Substituted fused pyrimidine compounds
The present invention discloses substituted fused pyrimidine compounds of formula (I), their tautomers, polymorphs, stereoisomers, solvates, pharmaceutically acceptable salts, or pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by adenosine receptor (AR) activity. The compounds of the present invention are useful in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by antagonism of the adenosine receptor, such as asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation, reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinal tract disorders, and/or autoimmune diseases.
1. A compound of formula I
or its tautomers, stereoisomers, or a pharmaceutically acceptable salts thereof, wherein
Y is selected from the group consisting of N or CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, or aryl;
R 1 is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein one or more methylene groups are optionally replaced by hetero atoms or group selected from the group consisting of —O—, —S(O)p-, —N(R a )—, and —C(O) provided that the heteroatom is not adjacent to N in the ring; p is selected from 0, 1 or 2;
wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, —S(O) 2 NR a R a , —NR a S(O) 2 R a , or —S(O) p R a ;
R 2 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;
wherein heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O) p R d ;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
wherein alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyd, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O) p R d ;
X is optionally substituted heteroarylene;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of O, —S(O) p —, —N(R b )—, and —C(O)—;
wherein alkylene, alkenylene, and alkynylene are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano and —S(O) p R d ;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R a is independently selected from the group consisting of hydrogen and alkyl;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R c is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl;
R d is selected from the group consisting alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
2. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein
Y is N;
R 1 is selected from a group consisting of alkyl, alkenyl and alkynyl wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, or carboxyalkyl;
R 2 is selected from the group consisting of heterocyclyl, heterocyclyalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;
wherein heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
wherein alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano and —S(O) p R d ;
X is optionally substituted heteroarylene;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of O, —S(O) p —, —N(R b )—, and —C(O)—;
wherein alkylene, alkenylene, and alkynylene are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano and —S(O) p R d ;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R a is independently selected from the group consisting of hydrogen and alkyl;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R c is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
3. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein
Y is CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, and aryl;
R 1 is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, or carboxyalkyl;
R 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, and —NR b R b ;
wherein alkyl, alkenyl, alkynyl, alkoxy and R b are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl or cycloalkenyl;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
X is optionally substituted heteroarylene;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of O, —S(O) p , —N(R b )—, and —C(O)—;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
4. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein
Y is N or CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, and aryl;
R 1 is selected from the group consisting of alkyl, alkenyl and alkynyl;
R 2 is selected from the group consisting of heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy;
wherein heterocyclyl, heterocyclyloxy, heteroaryl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl or cycloalkenyl;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
X is an optionally substituted phenyl;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of O, —S(O) p —, —N(R b )—, and —C(O)—;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
5. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or a pharmaceutically acceptable salts thereof, wherein
Y is N or CR; R is selected from the group consisting of H, hydroxyl, alkoxy, alkyl, and aryl;
R 1 is selected from the group consisting of alkyl, alkenyl and alkynyl;
wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, aminocarbonylamino, hydroxyamino, alkoxyamino or nitro;
R 2 is selected from the group consisting of heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy;
wherein heterocyclyl, heterocyclyloxy, heteroaryl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy, —S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R 3 is selected from a group consisting of hydrogen, alkyl, alkenyl, and alkynyl,
wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino or nitro;
X is optionally substituted heteroarylene;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene or (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from O, —S(O) p —, —N(R b )—, and —C(O)—;
wherein alkylene, alkenylene, and alkynylene are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino or nitro;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R c is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
6. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein X is
7. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein B is unsubstituted or substituted and is
8. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein A is
9. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein
Y is N or CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, and aryl;
R 1 is alkyl wherein alkyl is unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, cyano, halogen, hydroxy, carboxy, carboxyalkyl or nitro;
R 2 is selected from the group consisting of heterocyclyl and heteroaryl;
wherein heteroaryl and heterocyclyl are unsubstituted or substituted independently with alkyl, alkoxy, acyl, acyloxy, nitro, amino, hydroxyamino, alkoxyamino, aminocarbonylamino, cyano, halogen, hydroxy, hydroxyalkyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, aminocarbonyl, cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl or heteroaryloxy;
R 3 is selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl;
wherein alkyl, aryl and arylalkyl are unsubstituted or substituted independently with alkyl, acyl, acylamino, acyloxy, amino, cyano, halogen, hydroxy, carboxy, alkylcarboxy or carboxyalkyl;
X is optionally substituted heteroarylene;
A is selected from the group consisting of a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of O, —S(O) p —, —N(R b )—, or —C(O)—;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R c ;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R c is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
10. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein
Y is N;
R 1 is an alkyl, wherein one or more methylene groups are replaced by hetero atoms or groups such as —O—, —S(O)p-, —N(R a )—, or —C(O) provided that the heteroatom is not adjacent to N in the ring; p is 0, 1 or 2;
wherein alkyl is unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, aminocarbonylamino, hydroxyamino, alkoxyamino, —S(O) 2 NR a R a , —NR a S(O) 2 R a , or —S(O) p R a ;
R 2 is selected from the group consisting heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;
wherein heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO 3 H, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R 3 is selected from the group consisting of hydrogen, alkyl and arylalkyl;
X is an optionally substituted heteroarylene;
A is selected from the group consisting of (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene group, wherein 1 to 4 methylene groups are optionally replaced by groups independently selected from the groups consisting of O, —S(O) p —, —N(R b )—, and —C(O)—;
wherein alkylene, alkenylene, and alkynylene are unsubstituted or substituted independently with alkyl, alkoxy, cycloalkyl, halogen, hydroxy, hydroxyalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, —SO 3 H, hydroxyamino, alkoxyamino, S(O) 2 NR c R c , —NR c S(O) 2 R c or —S(O) p R d ;
B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl;
wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO 3 H, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O) 2 NR b R b , —NR b S(O) 2 R b or —S(O) p R d ;
wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O) p R d ;
R a is independently selected from the group consisting of hydrogen and alkyl;
R b is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
R c is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl;
R d is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and p is 0, 1 or 2.
11. A compound of formula (I) as claimed in claim 1 or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, which is
2-Morpholin-4-yl-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
8-(1-Benzyl-1H-pyrazol-4-yl)-2-(4-methyl-piperazin-1-yl)-1-propyl-1,7-dihydro-purin-6-one,
8-(1-Benzyl-1H-pyrazol-4-yl)-2-piperidin-1-yl-1-propyl-1,7-dihydro-purin-6-one,
(S)-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic acid,
1-Propyl-2-pyrrolidin-1-yl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-Morpholin-4-yl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one,
(S)-1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic acid amide,
1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-3-carboxylic acid,
1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1,1-purin-2-yl}-piperidine-4-carboxylic acid,
(2R,4R)-4-Hydroxy-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic acid,
2-(4-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-(3-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-(3-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-((S)-2-Methoxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,
2-((R)-3-Hydroxy-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one, or
8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one.
12. A pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), as claimed in claim 1 , or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers or excipients.
13. A pharmaceutical composition comprising, a compound of formula (I), as claimed in claim 1 , or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, in combination with one or more therapeutically active agents.