Fused pyradazine derivatives which are usefule as CDK inhibitors are described herein. The described invention alos includes methods of making such fused pyradazine derivatives as wells as methods of using the same in the treatment of hyperproliferative diseases.

The invention provides the compounds of formula (I) ##STR1## wherein: R.sup.0 and R.sup.1 are independently selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkoxy substituted by one or more fluorine atoms; R.sup.2 is halogen, CN, CONR.sup.4 R.sup.5, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, or NHSO.sub.2 R.sup.4 ; R.sup.3 is C.sub.1-6 alkyl or NH.sub.2 ; and R.sup.4 and R.sup.5 are independently selected from H, C.sub.1-6 alkyl, phenyl, phenyl substituted by one or more atoms or groups (selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkoxy substituted by one or more fluorine atoms), or together with the nitrogen atom to which they are attached form a saturated 4 to 8 membered ring; and pharmaceutically acceptable derivatives thereof. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which: R.sup.0 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, or O(CH.sub.2).sub.n NR.sup.4 R.sup.5 ; R.sup.1 and R.sup.2 are independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkyl, substituted by one or more fluorine atoms, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, SC.sub.1-6 alkyl, C(O)H, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, O(CH.sub.2).sub.n CO.sub.2 C.sub.1-6 alkyl, O(CH.sub.2).sub.n SC.sub.1-6 alkyl, (CH.sub.2).sub.n NR.sup.4 R.sup.5, (CH.sub.2).sub.n SC.sub.1-6 alkyl or C(O)NR.sup.4 R.sup.5 ; with the proviso that when R.sup.0 is at the 4-position and is halogen, at least one of R.sup.1 and R.sup.2 is C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, O(CH.sub.2).sub.n CO.sub.2 C.sub.1-6 alkyl, O(CH.sub.2).sub.n SC.sub.1-6 alkyl, (CH.sub.2).sub.n NR.sup.4 R.sup.5 or (CH.sub.2).sub.n SC.sub.1-6 alkyl, C(O)NR.sup.4 R.sup.5 ; R.sup.3 is C.sub.1-6 alkyl or NH.sup.2 ; R.sup.4 and R.sup.5 are independently selected from H, or C.sub.1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and n is 1-4. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases. ##STR1##

The invention provides a process for preparing a compound of formula (I) ##STR1## and pharmaceutically acceptable derivatives thereof wherein: R.sup.0 and R.sup.1 are independently selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkoxy substituted by one or more fluorine atoms; R.sup.2 is H, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted by one or more fluorine atoms, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, SC.sub.1-6 alkyl, C(O)H, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, halogen, CN, CONR.sup.4 R.sup.5, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, or NHSO.sub.2 R.sup.4 ; R.sup.3 is H or phenyl substituted by SO.sub.2 C.sub.1-6 alkyl or SO.sub.2 NH.sub.2 ; R.sup.4 and R.sup.5 are independently selected from H, C.sub.1-6 alkyl, phenyl, phenyl substituted by one or more atoms or groups R.sup.6, or together with the nitrogen atom to which they are attached form a saturated 4 to 8 membered ring R.sup.6 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkoxy substituted by one or more fluorine atoms; which comprises rearrangement of an azirine of formula (II) ##STR2## wherein R.sup.0 to R.sup.3 are as defined for formula (I), or a protected derivative thereof, in the presence of a catalyst and a solvent.

The invention provides a pharmaceutical composition comprising a compound of formula (I) ##STR1## or a pharmaceutically acceptable salt, solvate, ester or salt or solvate of such ester, of a compound of formula (I) in which: R.sup.0 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, or O(CH.sub.2).sub.n NR.sup.4 R.sup.5 ; R.sup.1 and R.sup.2 are independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted by one or more fluorine atoms, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, SC.sub.1-6 alkyl, C(O)H, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, O(CH.sub.2).sub.n CO.sub.2 C.sub.1-6 alkyl, O(CH.sub.2).sub.n SC.sub.1-6 alkyl, (CH.sub.2).sub.n NR.sup.4 R.sup.5, (CH.sub.2).sub.n SC.sub.1-6 alkyl or C(O)NR.sup.4 R.sup.5 ; with the proviso that when R.sup.0 is at the 4-position and is halogen, at least one of R.sup.1 and R.sup.2 is C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkoxy substituted by one or more fluorine atoms, O(CH.sub.2).sub.n CO.sub.2 C.sub.1-6 alkyl, O(CH.sub.2).sub.n SC.sub.1-6 alkyl, (CH.sub.2).sub.n NR.sup.4 R.sup.5 or (CH.sub.2).sub.n SC.sub.1-6 alkyl, C(O)NR.sup.4 R.sup.5 ; R.sup.3 is C.sub.1-6 alkyl or NH.sub.2 ; R.sup.4 and R.sup.5 are independently selected from H and C.sub.1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and n is 1-4; and a sodium channel inhibitor.