SUBSTITUTED PYRAZOLOQUINAZOLINONES AND PYRROLOQUINAZOLINONES AS ALLOSTERIC MODULATORS OF GROUP II METABOTROPIC GLUTAMATE RECEPTORS
20170305913 · 2017-10-26
Assignee
Inventors
- Stephan SCHANN (Illkirch Graffenstaden, FR)
- Stanislas Mayer (Eschau, FR)
- Baptiste Manteau (Lingolsheim, FR)
Cpc classification
A61P1/04
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61P25/18
HUMAN NECESSITIES
A61P1/14
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
A61P25/14
HUMAN NECESSITIES
A61P21/00
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
International classification
Abstract
The present invention provides pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) and the compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. These pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.
Claims
1. A pharmaceutical composition, comprising a compound of formula (I): ##STR00138## wherein: A is N or —CH; R.sup.1, R.sup.2 and R.sup.4 are each independently selected from the group consisting of R.sup.7, halogen, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, —NR.sup.7COOR.sup.8, aryl, and heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from the group consisting of R.sup.7, halogen, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, and —NR.sup.7COOR.sup.8; R.sup.3 is selected from the group consisting of hydrogen, halogen, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, —NR.sup.7COOR.sup.8, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, cycloalkyl and heterocycloalkyl, wherein said C.sub.1-C.sub.4 alkyl and said C.sub.2-C.sub.4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C.sub.1-C.sub.4 alkyl; halogen; —CF.sub.3; —CN; —OH; —O(C.sub.1-C.sub.4 alkyl); C.sub.1-C.sub.4 alkyl substituted with one or more —OH groups; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); R.sup.5 is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R.sup.7, halogen, —CN, —NR.sup.7R.sup.8, —CONR.sup.7R.sup.8, —COR.sup.7, —OR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, and —COOR.sup.7; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, cycloalkyl, and heterocycloalkyl, wherein said C.sub.1-C.sub.4 alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, —CF.sub.3, —CN, —OH and —O(C.sub.1-C.sub.4 alkyl), and further wherein, if R.sup.6 is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, cycloalkyl, halogen, —CF.sub.3, —CN, —OH and —O(C.sub.1-C.sub.4 alkyl); and each R.sup.7, R.sup.8 and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C.sub.1-C.sub.4 alkyl and said C.sub.2-C.sub.4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF.sub.3, —CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and further wherein, if R.sup.7, R.sup.8 or R.sup.9 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: C.sub.1-C.sub.4 alkyl; halogen; —CF.sub.3; —CN; —OH; —O(C.sub.1-C.sub.4 alkyl); C.sub.1-C.sub.4 alkyl substituted with one or more —OH groups; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
2. A compound of formula (I): ##STR00139## wherein: A is N or —CH; R.sup.1, R.sup.2 and R.sup.4 are each independently selected from the group consisting of R.sup.7, halogen, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, —NR.sup.7COOR.sup.8, aryl, and heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from the group consisting of R.sup.7, halogen, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, and —NR.sup.7COOR.sup.8; R.sup.3 is selected from the group consisting of hydrogen, —F, —Cl, —I, —CN, —OR.sup.7, —NR.sup.7R.sup.8, —COOR.sup.7, —SO.sub.3H, —B(OH).sub.2, —CONR.sup.7R.sup.8, —COR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, —NR.sup.7C(O)NR.sup.8R.sup.9, —NR.sup.7C(S)NR.sup.8R.sup.9, —NR.sup.7COOR.sup.8, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, cycloalkyl and heterocycloalkyl, wherein said C.sub.1-C.sub.4 alkyl and said C.sub.2-C.sub.4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C.sub.1-C.sub.4 alkyl; halogen; —CF.sub.3; —CN; —OH; —O(C.sub.1-C.sub.4 alkyl); C.sub.1-C.sub.4 alkyl substituted with one or more —OH groups; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); R.sup.5 is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R.sup.7, halogen, —CN, —NR.sup.7R.sup.8, —CONR.sup.7R.sup.8, —COR.sup.7, —OR.sup.7, —SR.sup.7, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2NR.sup.7R.sup.8, —NR.sup.7COR.sup.8, —NR.sup.7SO.sub.2R.sup.8, —OCOR.sup.7, and —COOR.sup.7; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, cycloalkyl, and heterocycloalkyl, wherein said C.sub.1-C.sub.4 alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, —CF.sub.3, —CN, —OH and —O(C.sub.1-C.sub.4 alkyl), and further wherein, if R.sup.6 is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, cycloalkyl, halogen, —CF.sub.3, —CN, —OH and —O(C.sub.1-C.sub.4 alkyl); and each R.sup.7, R.sup.8 and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C.sub.1-C.sub.4 alkyl and said C.sub.2-C.sub.4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF.sub.3, —CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and further wherein, if R.sup.7, R.sup.8 or R.sup.9 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: C.sub.1-C.sub.4 alkyl; halogen; —CF.sub.3; —CN; —OH; —O(C.sub.1-C.sub.4 alkyl); C.sub.1-C.sub.4 alkyl substituted with one or more —OH groups; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein the heterocycloalkyl is a saturated ring group which may be a monocyclic ring or a bridged ring, spiro ring and/or fused ring system, wherein said ring group contains one or more ring heteroatoms, wherein said ring heteroatoms are independently selected from the group consisting of O, S and N, and wherein one or more S ring atoms, if present, and/or one or more N ring atoms, if present, may be oxidized.
3. (canceled)
4. (canceled)
5. The pharmaceutical composition of claim 1, wherein R.sup.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, —CN, C.sub.1-C.sub.4 alkyl, cycloalkyl, heterocycloalkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O-cycloalkyl, —O-heterocycloalkyl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CO—NH-cycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —CO—NH-heterocycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —NH—CO-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-CO-cycloalkyl, —NH—CO-heterocycloalkyl, and —N(C.sub.1-C.sub.4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of: C.sub.1-C.sub.4 alkyl; halogen; —CF.sub.3; —CN; —OH; —O(C.sub.1-C.sub.4 alkyl); C.sub.1-C.sub.4 alkyl substituted with one or more —OH groups; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl).
6. (canceled)
7. The pharmaceutical composition of claim 1, wherein R.sup.1, R.sup.2 and R.sup.4 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, —CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O—(C.sub.1-C.sub.4 alkylene)-OH, —O—(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —O-cycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —O-aryl, —O—(C.sub.1-C.sub.4 alkylene)-aryl, —O-heteroaryl, —O—(C.sub.1-C.sub.4 alkylene)-heteroaryl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —NH-aryl, —N(C.sub.1-C.sub.4 alkyl)-aryl, —NH-heteroaryl, —N(C.sub.1-C.sub.4 alkyl)-heteroaryl, —NH—(C.sub.1-C.sub.4 alkylene)-aryl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-aryl, —NH—(C.sub.1-C.sub.4 alkylene)-heteroaryl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heteroaryl, —CO—(C.sub.1-C.sub.4 alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —CO—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —CO-aryl, —CO-heteroaryl, —CO—(C.sub.1-C.sub.4 alkylene)-aryl, —CO—(C.sub.1-C.sub.4 alkylene)-heteroaryl, —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CO—NH-cycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —CO—NH—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —CO—NH-heterocycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —CO—NH—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —CO—N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —CO—NH-aryl, —CO—N(C.sub.1-C.sub.4 alkyl)-aryl, —CO—NH—(C.sub.1-C.sub.4 alkylene)-aryl, —CO—N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-aryl, —CO—NH-heteroaryl, —CO—N(C.sub.1-C.sub.4 alkyl)-heteroaryl, —CO—NH—(C.sub.1-C.sub.4 alkylene)-heteroaryl, —CO—N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heteroaryl, —NH—CHO, —N(C.sub.1-C.sub.4 alkyl)-CHO, —NH—CO(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO(C.sub.1-C.sub.4 alkyl), —NH—CO-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-CO-cycloalkyl, —NH—CO—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —NH—CO-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-CO-heterocycloalkyl, —NH—CO—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1—C.sub.4 alkylene)-heterocycloalkyl, —NH—CO-aryl, —N(C.sub.1-C.sub.4 alkyl)-CO-aryl, —NH—CO—(C.sub.1-C.sub.4 alkylene)-aryl, —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkylene)-aryl, —NH—CO-heteroaryl, —N(C.sub.1-C.sub.4 alkyl)-CO-heteroaryl, —NH—CO—(C.sub.1-C.sub.4 alkylene)-heteroaryl, and —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkylene)-heteroaryl, wherein said aryl, said heteroaryl, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl).
8. (canceled)
9. The pharmaceutical composition of claim 1, wherein R.sup.5 is heteroaryl having 5 or 6 ring members and comprising one or more ring heteroatoms independently selected from the group consisting of O, S and N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O-cycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —CO—(C.sub.1-C.sub.4 alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, and —CO—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl).
10. The pharmaceutical composition of claim 1, wherein R.sup.5 is pyridinyl which is optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O-cycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-cycloalkyl, —NH—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —N(C.sub.1-C.sub.4 alkyl)-(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, —CO—(C.sub.1-C.sub.4 alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C.sub.1-C.sub.4 alkylene)-cycloalkyl, and —CO—(C.sub.1-C.sub.4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.4 alkyl, halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl).
11. The pharmaceutical composition of claim 1, wherein R.sup.5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin-4-yl, wherein said one or two substituent group(s) is/are selected independently from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O-cycloalkyl, and —O-heterocycloalkyl.
12. (canceled)
13. The pharmaceutical composition of claim 1, wherein R.sup.5 is 2-trifluoromethyl-pyridin-4-yl.
14. (canceled)
15. The pharmaceutical composition of claim 1, wherein R.sup.6 is methyl.
16. The pharmaceutical composition of claim 1, wherein A is N.
17. The pharmaceutical composition of claim 1, wherein said compound is selected from the group consisting of: 2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(4-methyl-5-oxo-4,5-dihydro-pyrazolo[1,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile; 2-(2-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(2-methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(2,2-difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl(D.sub.3)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(2,2-difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(2-methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-4-methyl(D.sub.3)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; N-[4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-7-yl]-acetamide; 7-amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-(2-methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-(4-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxymethyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazoin-5-one; 8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-4-methyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4,8-dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carbonitrile; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid amide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid methylamide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid dimethylamide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid diethylamide; 4-methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2-hydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 6-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 9-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7,8-dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7,8-difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-pyridin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(3-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(3-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 3-[7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-8-ylamino]-propionitrile; 7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-8-(7-hydroxymethyl-1-aza-spiro[3.5]non-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
18. A pharmaceutical composition comprising the compound as defined in claim 2 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
19. (canceled)
20. (canceled)
21. A method of treating and/or preventing a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of the pharmaceutical composition of claim 1 to a subject in need of such treatment or prevention.
22. The method of claim 21, wherein the condition to be treated or prevented is selected from the group consisting of: epilepsy; dementias; parkinsonism and movement disorders; motor neuron disease or amyotrophic lateral sclerosis; neurodegenerative and/or hereditary disorders of the nervous system; disorders of the peripheral nervous system; multiple sclerosis and other demyelinating diseases of the nervous system; infantile cerebral palsy; paralytic syndromes including hem iplegia and hem iparesis; cerebrovascular disorders; migraine; headache; myoneural disorders; disorders of the eye and visual pathways; intracranial trauma/injury and their sequels; trauma/injury to nerves and spinal cord and their sequels; poisoning and toxic effects of nonmedicinal substances; accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; neurological and psychiatric adverse effects of drugs, medicinal and biological substances; disturbance of sphincter control and sexual function; mental disorders; delirium and cognitive disorders; substance related disorders; schizophrenia and psychotic disorders; mood disorders; anxiety disorders; eating disorders; sleep disorders and sleep/wake disorders; medication-induced movement disorders; endocrine and metabolic diseases; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; cancers; and autism spectrum disorders.
23. The method of claim 21, wherein the condition to be treated or prevented is selected from the group consisting of dementias, parkinsonism and movement disorders, acute or chronic pain, anxiety disorders, schizophrenia, mood disorders, endocrine or metabolic diseases, and cancers.
24. The method of claim 23, wherein said dementias are selected from the group consisting of: dementias of the Alzheimer's type (DAT); Alzheimer's disease; Pick's disease; vascular dementias; Lewy-body disease; dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency; AIDS-dementia complex; Creutzfeld-Jacob disease; and atypical subacute spongiform encephalopathy.
25-31. (canceled)
32. A method of treating and/or preventing Alzheimer's disease, the method comprising the administration of the pharmaceutical composition of claim 1 to a subject in need of such treatment or prevention.
33. The method of claim 21, wherein said subject is a human.
34. A method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), comprising the following steps: (a) contacting mGluR2 with the compound of claim 2, wherein said compound is radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating bound, labeled compound; (b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2.
35. The compound of claim 2, wherein said compound is selected from the group consisting of: 2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(4-methyl-5-oxo-4,5-dihydro-pyrazolo[1,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile; 2-(2-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(2-methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(2,2-difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl(D.sub.3)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(2,2-difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-(2-methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-4-methyl(D.sub.3)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; N-[4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-7-yl]-acetamide; 7-amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-(2-methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-(4-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxymethyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazoin-5-one; 8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-4-methyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4,8-dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carbonitrile; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid amide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid methylamide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid dimethylamide; 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic acid diethylamide; 4-methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2-hydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 6-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 9-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7,8-dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7,8-difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(4-hydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-pyridin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(3-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(3-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 4-methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 3-[7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-8-ylamino]-propionitrile; 7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 7-Fluoro-8-(7-hydroxymethyl-1-aza-spiro[3.5]non-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(3-Hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; 8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
Description
EXAMPLES
[0447] In this section, the term “compound” is used to refer to a synthesis intermediate while the term “example” refers to a compound of general formula (I) according to the present invention.
[0448] The compounds/examples described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound/example defined by the chemical formula and the compound/example defined by the chemical name.
Experimental
Experimental Section
[0449] All reagents were commercial grade and used without further purification. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Microwave experiments were performed with a Biotage initiator. The microwave modulates the power in order to reach the selected temperature as fast as possible. The time of each experiment is the time at the selected temperature.
[0450] Column chromatography were performed using a Biotage isolera 4® autopurification system, with the Biotage® SNAP cartridge KP-SIL. Thin layer chromatography was carried out using pre-coated silica gel F-254plate.
[0451] Reaction were monitor and molecules were characterized using a waters equity system couple with SQD2 platform or water HPLC system couple with Waters micromass platform. The HPLC system could be used also in preparative mode.
HPLC System:
[0452] The HPLC system was a Waters platform with a 2767 sample manager, a 2525 pump, a photodiode array detector (190-400 nM). The column used was a XSelect C.sub.18 3.5 μM (4.6×50 mm) in analytical mode and a XSelect C.sub.18 5 μM (30×100 mm) in preparative mode. The mobile phase in both cases consisted in an appropriate gradient of A and B. A was water with 0.05% of TFA and B was MeOH with 0.05% of TFA. Flow rate was 1 mL per min in analytical mode and 25 mL min in preparative mode. All LCMS were performed at room temperature. HPLC is coupled with a Waters micromass platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization.
UPLC System:
[0453] The UPLC system was a Waters Aquity platform with a photodiode array detector (190-400 nM). The column used was a Acuity CSH C.sub.18 1.7 μM (2.1×30 mm) The mobile phase consisted in a gradient of A and B. A was water with 0.025% of TFA and B was Acetonitrile with 0.025% of TFA. Flow rate was 0.8 mL per min. All analysis were performed at 55° C. UPLC is coupled with a Waters SQD2 platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization.
[0454] .sup.1H NMR spectra were recorded on a Bruker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual CDCl.sub.3 (7.24 ppm), DMSO (2.50 ppm) or D.sub.2O (4.78 ppm). Splitting patterns are designated as s (singlet), d (doublet), dd (double-doublet), t (triplet), tt (triplet-trplet), td (triplet-doublet), q (quartet), quint (quintuplet), sex (sextuplet), sept (septuplet), m (multiplet), b (broad), bs (broad singlet).
[0455] Melting Points are measured on a Barnstead Electrothermal 9100 and are not corrected.
[0456] Most compounds and examples, when it is possible, are triturated in Et.sub.2O or pentane before drying.
General Procedure I: Formation of 4H-Pyrazolo[1,5-a]quinazolin-5-one E from Hydrazine D and Activated Acid a Via a Keto-Nitrile B not Isolated (Cf. Scheme 1)
[0457] Method (i): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in DME (c=0.6 mol.Math.L.sup.−1) cooled at −78° C., BuLi (1.6N in hexane-2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at −78° C., then a solution of the acid derivative A (acid chloride or ester −1.0 equiv.) in DME (cf=0.15 mol.Math.L.sup.−1) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour and then was allowed to warm to room temperature and the next step was performed.
[0458] Acetic acid (same volume as DME) was added, DME was removed under reduced pressure and hydrazine D, HCl salt (1.0 equiv.) was introduced. The reaction mixture was heat under reflux for 2 hours. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHCO.sub.3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours. Sometimes, DME was switched by THF.
[0459] Method (ii): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in DME (c=0.8 mol.Math.L.sup.−1) cooled at −78° C., BuLi (1.6N in hexane-2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at −78° C., then a solution of the acid derivative A (acid chloride or ester −1.0 equiv.) in DME (cf=0.15 mol.Math.L.sup.−1) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour and then was allowed to warm to room temperature and the next step was performed.
[0460] Acetic acid (10.0 equiv.) was added and hydrazine D, HCl salt (1.0 equiv.) was introduced. The reaction mixture was warmed for 18 hours at 100° C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHCO.sub.3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours.
[0461] Method (iii): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in THF (c=0.8 mol.Math.L.sup.−1) cooled at −78° C., BuLi (1.6N in hexane-2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at −78° C., then a solution of the acid derivative A (acid chloride or ester −1.0 equiv.) in THF (cf=0.15 mol.Math.L.sup.−1) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then was allowed to warm to room temperature and hydrolysed with saturated aqueous NH.sub.4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO.sub.4 or Na.sub.2SO.sub.4 and concentrated. The ketonitrile B was used in the next step without further purification and was supposed quantitative.
[0462] To a solution of ketonitrile B (1.0 equiv.) in acetic acid (c=0.15 mol.Math.L.sup.−1) hydrazine D, HCl salt was added (1.0 equiv.). The reaction mixture was heated for 2 Hours at 120° C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHCO.sub.3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours.
[0463] Method (iv): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in THF (c=0.6 mol.Math.L.sup.−1) cooled at −78° C., BuLi (1.6N in hexane-2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at −78° C., then a solution of the acid derivative A (acid chloride or ester −1.0 equiv.) in THF (cf=0.15 mol.Math.L.sup.−1) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, and then acetic acid (same volume as THF) was added before the mixture was allowed to warm to room temperature.
[0464] THF was removed under reduced pressure and hydrazine D, HCl salt (1.0 equiv.) was introduced. The reaction mixture was heated for 2 hours at reflux. After cooling, the reaction mixture was hydrolysed with saturated aqueous NaHCO.sub.3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours.
Compound 1: 2-(2-Chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0465] Compound 1 was obtained according to general procedure I(i), starting from 2-Chloro-isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 91% yield.
[0466] .sup.1H-NMR (400 MHz, DMSO): 6.63 (s, 1H, Ar); 7.52-7.56 (m, 1H, Ar); 7.89-7.94 (m, 1H, Ar); 7.98 (dd, J 5.1 Hz, J 1.5 Hz, 1H, Ar); 8.06 (bs 1H, Ar); 8.18 (d, J 8.0 Hz, J 1.3 Hz, 1H, Ar); 8.21 (d, J 7.8 Hz, 1H, Ar); 8.50 (d, J 5.1 Hz, 1H, Ar). Signal for NH is not observed.
[0467] M/Z (M[.sup.35Cl]+H).sup.+=297.1.
General Procedure II: Formation of N-substituted 4H-Pyrazolo[1,5-a]quinazolin-5-one G from 4H-Pyrazolo[1,5-a]quinazolin-5-one E in Presence of Electrophile F (cf. Scheme 2)
[0468] Method (i): Under anhydrous condition, to a solution of quinazolin-5-one E (1.0 equiv.) in DMF (c=0.2 molL.sup.−1) cooled by an ice bath, NaH (60% in mineral oil, 1.7 equiv.) was added in 3 portions. The mixture was stirred for 15 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed with saturated aqueous NH.sub.4Cl solution. The precipitate was collected, washed with water, Et.sub.2O and was dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours.
[0469] Method (ii): Under anhydrous condition, to a solution of quinazolin-5-one E (1.0 equiv.) in DMF (c=0.2 molL.sup.−1) cooled by an ice bath, tBuOK (1.7 equiv.) was added. The mixture was stirred for 5 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed with saturated aqueous NH.sub.4Cl solution. The precipitate was collected, washed with water, dried under reduced pressure and purified if required.
[0470] Method (iii): Under anhydrous condition, to a solution of quinazolin-5-one E (1.0 equiv.) in DMA (c=0.2 molL.sup.−1) cooled by an ice bath, NaH (in mineral oil 60%, 1.7 equiv.) was added in 3 portions. The mixture was stirred for 10 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed. The precipitate was collected, washed with water, a minimum amount of EtOH, Et.sub.2O and was dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours.
Example 1: 2-(2-Chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0471] ##STR00012##
[0472] Example 1 was obtained according to general procedure II(i), starting from compound 1 in presence of iodomethane. The reaction mixture was stirred at room temperature for 120 min. Example 1 was obtained as a beige solid in 70% yield.
[0473] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, N—CH.sub.3); 7.08 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.96 (m, 2H, Ar); 8.02 (bs, 1H, Ar); 8.19-8.27 (m, 2H, Ar); 8.52 (d, J 5.2 Hz, 1H, Ar).
[0474] M/Z (M[.sup.35Cl]+H).sup.+=311.1.
General Procedure III: Negeshi Coupling: Cross-Coupling Reaction of a Halide and an Organozinc Derivative
[0475] Under inert atmosphere, a mixture of halide, (1.0 equiv.), organozinc derivative (1.5-4.0 equiv.), PdCl.sub.2(dppf).sub.2 (0.1 equiv.) and CuI (0.2 equiv.) in Dioxane (C=0.1 molL.sup.−1) was heated for 1 hour at 80° C. After cooling, the reaction mixture was hydrolysed and extracted with EtOAc or DCM. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
[0476] In some cases, the HCl salt was prepared.
General Procedure IV: Formation of HCl Salt
[0477] Method (i): To a solution of the free base in DCM, HCl in Et.sub.2O (2N, 5 equiv.) was added. The resulting precipitate was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.
[0478] Method (ii): To a solution or suspension of the free base in MeOH, HCl in MeOH (1.25N, 5 equiv.) was added. The mixture was vigorously stirred, then concentrated. The residue was taken in Et.sub.2O. The resulting solid was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.
[0479] Method (iii): The free base was suspended in MeOH and HCl in MeOH (1.25N, 5 equiv.) was added. The suspension was vigorously stirred, and then the solid was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.
Example 2: 4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0480] ##STR00013##
[0481] Example 2 was obtained according to general procedure III starting from example 1 in presence of dimethylzinc (in toluene 2M-1.5 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 10%) afforded example 2 as a beige solid in 58% yield.
[0482] .sup.1H-NMR (400 MHz, DMSO): 2.56 (s, 3H, CCH.sub.3); 3.57 (s, 3H, NCH.sub.3); 6.96 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.72-7.73 (m, 1H, Ar); 7.82 (bs, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.19-8.22 (m, 2H, Ar); 8.55-8.56 (m, 1H, Ar).
[0483] M/Z (M+H).sup.+=291.2.
Example 3: 2-(2-Ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0484] ##STR00014##
[0485] Example 3 was obtained according to general procedure III starting from example 1 in presence of diethylzinc (in toluene 1M-1.5 equiv.). Purification by flash-chromatography (EtOAc in cyclohexane, 40 to 70%) and salt formation according to procedure IV(i) afforded example 3 as a beige solid in 52% yield.
[0486] .sup.1H-NMR (400 MHz, DMSO): 1.40 (t, 3H, J 7.6 Hz, CCH.sub.2CH.sub.3); 3.08 (Q, 2H, J 7.6 Hz, CCH.sub.2CH.sub.3); 3.58 (s, 3H, NCH.sub.3); 7.25 (s, 1H, Ar); 7.58-7.63 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar); 8.21-8.30 (m, 3H, Ar); 8.37 (bs, 1H, Ar); 8.83 (d, J 6.1 Hz, 1H, Ar). Signal for HCl is not observed.
[0487] M/Z (M+H).sup.+=305.2.
[0488] MP: >250° C.
Example 4: 2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0489] ##STR00015##
[0490] Example 4 was obtained according to general procedure III starting from example 1 in presence of propylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 10%) and salt formation according to procedure IV(ii) afforded example 4 as a white solid in 37% yield.
[0491] .sup.1H-NMR (400 MHz, DMSO): 0.98 (t, 3H, J 7.5 Hz, CCH.sub.2CH.sub.2CH.sub.3); 1.85 (sex, 2H, J 7.5 Hz, CCH.sub.2CH.sub.2CH.sub.3); 3.03 (q, 2H, J 7.5 Hz, CCH.sub.2CH.sub.2CH.sub.3); 3.58 (s, 3H, NCH.sub.3); 7.24 (s, 1H, Ar); 7.59-7.63 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar); 8.22-8.28 (m, 3H, Ar); 8.36 (bs, 1H, Ar); 8.84 (d, J 6.1 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0492] M/Z (M+H).sup.+=319.2.
[0493] MP: >250° C.
Example 5: 2-(2-Cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0494] ##STR00016##
[0495] Example 5 was obtained according to general procedure III starting from example 1 in presence of cyclopropylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (EtOAct in cyclohexane, 50 to 80%) and salt formation according to procedure IV(i) afforded example 5 as a beige solid in 38% yield.
[0496] .sup.1H-NMR (400 MHz, DMSO): 1.25-1.33 (m, 4H, 2CH.sub.2); 2.42-2.47 (m, 1H, CCH); 3.57 (s, 3H, NCH.sub.3); 7.22 (s, 1H, Ar); 7.57-7.61 (m, 1H, Ar); 7.93-7.99 (m, 2H, Ar); 8.10-8.11 (m, 1H, Ar); 8.20-8.25 (m, 2H, Ar); 8.67 (d, J 5.9 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0497] M/Z (M+H).sup.+=317.3.
[0498] MP: 248-251° C.
Example 6: 2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0499] ##STR00017##
[0500] Example 6 was obtained according to general procedure III starting from example 1 in presence of cyclobutylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 5%) and salt formation according to procedure IV(iii) afforded example 6 as a white solid in 8% yield.
[0501] .sup.1H-NMR (400 MHz, DMSO): 1.90-1.99 (m, 1H, CH); 2.07-2.19 (m, 1H, CH); 2.43-2.48 (m, 4H, 2CH.sub.2); 3.59 (s, 3H, NCH.sub.3); 3.98 (quint, J 8.9 Hz, 1H, CH); 7.30 (s, 1H, Ar); 7.58-7.62 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar);); 8.22-8.28 (m, 3H, Ar); 8.30 (bs, 1H, Ar); 8.79 (d, J 5.9 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0502] M/Z (M+H).sup.+=331.0.
[0503] MP: 236-244° C.
Example 7: 2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0504] ##STR00018##
[0505] Example 7 was obtained according to general procedure III starting from example 1 in presence of cyclopentylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 10%) and salt formation according to procedure IV(iii) afforded example 7 as a white solid in 9% yield.
[0506] .sup.1H-NMR (400 MHz, DMSO): 1.73-1.77 (m, 2H, 2CH); 1.86-192 (m, 4H, 4CH); 2.18-2.24 (m, 2H, 2CH); 3.44-3.53 (m, 1H, CH); 3.58 (s, 3H, NCH.sub.3); 7.30 (s, 1H, Ar); 7.58-7.62 (m, 1H, Ar); 7.94-7.99 (m, 1H, Ar);); 8.23 (dd, J 8.0 Hz, J 1.3 Hz, 1H, A); 8.25-8.27 (m, 2H, Ar); 8.32 (bs, 1H, Ar); 8.80 (d, J 5.9 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0507] M/Z (M+H).sup.+=345.2.
[0508] MP: >250° C.
Example 8: 2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0509] ##STR00019##
[0510] Example 8 was obtained according to general procedure III starting from example 1 in presence of cyclohexylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 10%) and salt formation according to procedure IV(ii) afforded example 8 as a white solid in 25% yield.
[0511] .sup.1H-NMR (400 MHz, DMSO): 1.27-1.48 (m, 3H, 3CH); 1.66-1.79 (m, 3H, 3CH); 1.87-1.90 (m, 2H, 2CH); 1.99-2.02 (m, 2H, 2CH); 3.03-3.10 (m, 1H, CH); 3.59 (s, 3H, NCH.sub.3); 7.30 (s, 1H, Ar); 7.59-7.62 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar);); 8.23 (dd, J 8.0 Hz, J 1.1 Hz, 1H, A); 8.26-8.28 (m, 2H, Ar); 8.31 (bs, 1H, Ar); 8.81 (d, J 5.9 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0512] M/Z (M+H).sup.+=359.3.
[0513] MP: >250° C.
Example 9: 4-Methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0514] ##STR00020##
[0515] Under inert atmosphere, example 1 (1.0 equiv.), potassium vinyltrifluoroborate (2.0 equiv.), PdOAc.sub.2 (0.1 equiv.), Ruphos (0.2 equiv.) and Cs.sub.2CO.sub.3 (3.0 equiv.) in a mixture of dioxanne/water (90/10) (C=0.1 molL.sup.−1) was submitted to microwave irradiation (130° C., 20 min, P<70 W). To the uncompleted reaction, PdCl.sub.2(dppf).sub.2 (0.1 equiv.) and potassium vinyltrifluoroborate (2.0 equiv.), were added and the mixture was submitted to microwave irradiation (130° C., 20 min, P<70 W) for a second time. After cooling, the reaction mixture was hydrolysed and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by flash-chromatography (EtOAc in cyclohexane, 0 to 50%). Example 9 was obtained as a brown solid in 63% yield.
[0516] .sup.1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH.sub.3); 5.56 (dd, J 10.8 Hz, J 1.6 Hz, 1H, CH); 6.36 (dd, J 17.4 Hz, J 1.6 Hz, 1H, CH); 6.92 (dd, J 17.4 Hz, J 10.8 Hz, 1H, CH); 7.02 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.82 (dd, J 5.1 Hz, J 1.6 Hz, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 8.04 (bs, 1H, Ar); 8.21-8.23 (m, 2H, Ar); 8.66 (d, J 5.1 Hz, 1H, Ar).
[0517] M/Z (M+H).sup.+=303.2.
General Procedure V: Suzuki Coupling: Cross-Coupling Reaction of a Halide and Boronic Acid Derivatives
[0518] Under inert atmosphere, a mixture of halide (1.0 equiv.), boronic acid derivative (1.5-equiv.), PdCl.sub.2(dppf).sub.2 (0.1 equiv.) and aqueous Na.sub.2CO.sub.3 (1.2 M-3.0 equiv.) in DMF (C=0.15 molL.sup.−1) was heated for 3 hours at 100° C. After cooling, the reaction mixture was hydrolysed. The precipitate was collected, washed with water, Et.sub.2O, dried under reduced pressure and purified to afford the product.
Example 10: 2-(2-Isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0519] ##STR00021##
[0520] Example 10 was obtained according to general procedure V starting from example 1 in presence of Isopropenylboronic acid pinacol ester. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 10 as a beige solid in 68% yield.
[0521] .sup.1H-NMR (400 MHz, DMSO): 2.23 (s, 3H, CCH.sub.3); 3.58 (s, 3H, NCH.sub.3); 5.40 (m, 1H, CH); 6.04 (m, 1H, CH); 7.08 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.84 (dd, J 5.1 Hz, J 1.4 Hz, 1H, Ar); 7.91-7.95 (m, 1H, Ar); 8.13 (bs, 1H, Ar); 8.20-8.24 (m, 2H, Ar); 8.67 (d, J 5.1 Hz, 1H, Ar).
[0522] M/Z (M+H).sup.+=317.2.
Example 11: 2-(2-Isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0523] ##STR00022##
[0524] To a solution of example 10 (1.0 equiv.) in MeOH (C=0.05 molL.sup.−1), Pd/C (10% w/w) was added. The reaction mixture was purged with hydrogen and stirred for 48 hours at 60° C. under 4 bars hydrogen pressure. Catalyst was filtered off on celite and washed with MeOH. Filtrate was concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%). Salt formation according to procedure IV(iii) afforded example 11 as a white solid in 11% yield.
[0525] .sup.1H-NMR (400 MHz, DMSO): 1.44 (d, 6H, J 7.0 Hz, CH(CH.sub.3).sub.2); 3.44 (sept, 1H, J 7.0 Hz, CH(CH.sub.3).sub.2); 3.58 (s, 3H, NCH.sub.3); 7.31 (s, 1H, Ar); 7.58-7.62 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar); 8.23 (dd, J 8.0 Hz, J 1.4 Hz, 1H, Ar); 8.25-8.30 (m, 2H, Ar); 8.36 (bs, 1H, Ar); 8.82 (d, J 6.1 Hz, 1H, Ar). Signal for HCl salt is not observed.
[0526] M/Z (M+H).sup.+=319.0.
[0527] MP: >250° C.
General Procedure VI: CN Introduction Starting from a Halide or a Pseudo Halide
[0528] Under inert atmosphere, a mixture of halide, (1.0 equiv.), zinc cyanide (1.6-equiv.) and Pd(PPh.sub.3).sub.4 (0.1 equiv.) in DMF (C=0.2 molL.sup.−1) was submitted to microwave irradiation (130° C., 10 min, P<70 W). After cooling, the reaction mixture was hydrolysed with a saturated aqueous K.sub.2CO.sub.3 solution. The precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 12: 4-(4-Methyl-5-oxo-4,5-dihydro-pyrazolo[1,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile
[0529] ##STR00023##
[0530] Example 12 was obtained according to general procedure VI starting from example 1. Purification by flash-chromatography (MeOH in DCM, 0 to 10%) afforded example 12 as a white solid in 94% yield.
[0531] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 7.02 (s, 1H, Ar); 7.55-7.59 (m, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 8.21-8.25 (m, 3H, Ar); 8.48 (bs, 1H, Ar); 8.85 (d, J 5.1 Hz, 1H, Ar).
[0532] M/Z (M+H).sup.+=302.2.
[0533] MP: >250° C.
Compound 2: 2-(2-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0534] Compound 2 was obtained according to general procedure I(ii), starting from 2-fluoro-isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 83% yield.
[0535] .sup.1H-NMR (400 MHz, DMSO): 6.64 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.71 (bs 1H, Ar); 7.91-7.96 (m, 2H, Ar); 8.16-8.21 (m, 2H, Ar); 8.33 (d, J 5.2 Hz, 1H, Ar); 12.42 (bs, 1H, NH).
[0536] M/Z (M+H).sup.+=281.3.
Example 13: 2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0537] ##STR00024##
[0538] Example 13 was obtained according to general procedure II(i), starting from compound 2 in presence of iodomethane. The reaction mixture was stirred at room temperature for 120 min. Example 13 was obtained as a brown solid in 78% yield.
[0539] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.08 (s, 1H, Ar); 7.56-7.60 (m, 1H, Ar); 7.70 (bs 1H, Ar); 7.92-7.97 (m, 2H, Ar); 8.22-8.24 (m, 2H, Ar); 8.37 (d, J 5.2 Hz, 1H, Ar).
[0540] M/Z (M+H).sup.+=295.2.
Example 14: 2-(2-Methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0541] ##STR00025##
[0542] To a solution of example 13 (1.0 equiv.) in MeOH (C=0.10 molL.sup.−1) sodium methoxyde (2.0 equiv.) was introduced. The reaction mixture was submitted twice to microwave irradiation (150° C., 5 min.). Sodium methoxyde (2.0 equiv.) was added and the reaction mixture was submitted to microwave irradiation (150° C., 5 min.). After cooling, the precipitate was collected, washed with water and Et.sub.2O and was dried under reduced pressure to afford example 14 as a white solid in 66% yield.
[0543] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 3.92 (s, 3H, OCH.sub.3); 6.98 (s, 1H, Ar); 7.34 (bs, 1H, Ar); 7.53-7.57 (m, 2H, Ar); 7.91-7.95 (m, 1H, Ar); 8.19-8.22 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1H, Ar).
[0544] M/Z (M+H).sup.+=307.2.
[0545] MP: >250° C.
Example 15: 2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0546] ##STR00026##
[0547] To a suspension of example 13 (1.0 equiv.) in EtOH (C=0.10 molL.sup.−1) sodium ethoxyde (5.0 equiv.) was introduced. The reaction mixture was submitted twice to microwave irradiation (150° C., 15 min.). Sodium ethoxyde (2.0 equiv.) was added four times and after each addition the reaction mixture was submitted to microwave irradiation (150° C., 15 min.). After cooling, the precipitate was collected, washed with saturated aqueous NH.sub.4Cl solution, water and Et.sub.2O and was dried under reduced pressure to afford example 15 as a beige solid in 19% yield.
[0548] .sup.1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.0 Hz, OCH.sub.2CH.sub.3); 3.55 (s, 3H, NCH.sub.3); 4.36 (q, 2H, J 7.0 Hz, OCH.sub.2CH.sub.3); 6.98 (s, 1H, Ar); 7.32 (bs, 1H, Ar); 7.52-7.56 (m, 2H, Ar); 7.90-7.94 (m, 1H, Ar); 8.18-8.21 (m, 2H, Ar); 8.25 (d, J 5.3 Hz, 1H, Ar).
[0549] M/Z (M+H).sup.+=321.0.
[0550] MP: 180-182° C.
General Procedure VII: Alcohol Introduction Via Nucleophilic Substitution
[0551] Method (i): Under inert atmosphere, to a suspension of quinazolinone (1.0 equiv.) in DMA (C=0.1 molL.sup.−1), alcohol (2.5 equiv.) and NaH (2.0 equiv.) were added. The reaction mixture was submitted to microwave irradiation (150° C., 5 min.). After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0552] Method (ii): Under inert atmosphere, to a suspension of quinazolinone (1.0 equiv.) in DMA (C=0.1 molL.sup.−1), alcohol (2.5 equiv.) and NaH (2.0 equiv.) were added. The reaction mixture was heated for 3 hours at 100° C. After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0553] Method (iii): Under inert atmosphere, to a solution of quinazolinone (1.0 equiv.) and alcohol (10.0 equiv.) in THF (C=0.2 molL.sup.−1), tBUOK (1.2 equiv.) was added. The reaction mixture was stirred for 17 hours at room temperature and then was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 16: 2-(2-Isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0554] ##STR00027##
[0555] Example 16 was obtained according to general procedure VII(i) starting from example 13 in presence of isopropanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 16 as a white solid in 13% yield.
[0556] .sup.1H-NMR (400 MHz, DMSO): 1.33 (d, 6H, J 6.2 Hz, OCH(CH.sub.3).sub.2); 3.55 (s, 3H, NCH.sub.3); 5.30 (Sept, 1H, J 6.2 Hz, OCH(CH.sub.3).sub.2); 6.98 (s, 1H, Ar); 7.28 (bs, 1H, Ar); 7.49-7.56 (m, 2H, Ar); 7.90-7.94 (m, 1H, Ar); 8.18-8.21 (m, 2H, Ar); 8.24 (d, J 5.2 Hz, 1H, Ar).
[0557] M/Z (M+H).sup.+=335.2.
[0558] MP: 173-176° C.
Example 17: 2-(2-Cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0559] ##STR00028##
[0560] Example 17 was obtained according to general procedure VII(i) starting from example 13 in presence of cyclobutanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 17 as a white solid in 24% yield.
[0561] .sup.1H-NMR (400 MHz, DMSO): 1.63-1.72 (m, 1H, CH); 1.72-1.85 (m, 1H, CH); 2.04-2.14 (m, 2H, 2CH); 2.40-2.47 (m, 2H, 2CH); 3.56 (s, 3H, NCH.sub.3); 5.20 (quint, J 7.4 Hz, 1H, CH); 7.00 (s, 1H, Ar); 7.31 (bs, 1H, Ar); 7.52-7.57 (m, 2H, Ar); 7.91-7.96 (m, 1H, Ar); 8.19-8.24 (m, 3H, Ar).
[0562] M/Z (M+H).sup.+=347.2.
[0563] MP: 218-222° C.
Example 18: 4-Methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0564] ##STR00029##
[0565] Example 18 was obtained according to general procedure VII(i) starting from example 13 in presence of 3-hydroxyoxetane. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 18 as a white solid in 20% yield.
[0566] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 4.61 (dd, J 7.0 Hz, J 5.7 Hz, 2H, OCH(CHaHb)2O); 4.90-4.94 (m, 2H, OCH(CHaHb)2O); 5.62 (quint, J 5.7 Hz, 1H, OCH(CHaHb)2O); 7.01 (s, 1H, Ar); 7.43 (bs, 1H, Ar); 7.53-7.60 (m, 2H, Ar); 7.91-7.95 (m, 1H, Ar); 8.19-8.22 (m, 3H, Ar).
[0567] M/Z (M+H).sup.+=349.2.
[0568] MP: 219-223° C.
Example 19: 2-(2-Cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0569] ##STR00030##
[0570] Example 19 was obtained according to general procedure VII(ii) starting from example 13 in presence of cyclopropanemethanol. Trituration in Et.sub.2O afforded example 19 as a white solid in 71% yield.
[0571] .sup.1H-NMR (400 MHz, DMSO): 0.33-0.37 (m, 2H, 2CH); 0.55-0.60 (m, 2H, 2CH); 1.23-1.31 (m, 1H, CH); 3.55 (s, 3H, NCH.sub.3); 4.15 (d, J 7.1 Hz, 2H, OCH.sub.2); 6.99 (s, 1H, Ar); 7.36 (bs, 1H, Ar); 7.52-7.56 (m, 2H, Ar); 7.90-7.95 (m, 1H, Ar); 8.18-8.21 (m, 2H, Ar); 8.23 (d, J 5.3 Hz, 1H, Ar).
[0572] M/Z (M+H).sup.+=347.0.
[0573] MP: 185-189° C.
Example 20: 2-[2-(2-Methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0574] ##STR00031##
[0575] Example 20 was obtained according to general procedure VII(i) starting from example 13 in presence of 2-methoxyethanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 20 as a white solid in 40% yield.
[0576] .sup.1H-NMR (400 MHz, DMSO): 3.33 (s, 3H, OCH.sub.3); 3.55 (s, 3H, NCH.sub.3); 3.66-3.71 (m, 2H, OCH.sub.2); 4.42-4.44 (m, 2H, OCH.sub.2); 6.99 (s, 1H, Ar); 7.36 (bs, 1H, Ar); 7.52-7.56 (m, 2H, Ar); 7.90-7.94 (m, 1H, Ar); 8.18-8.21 (m, 2H, Ar); 8.25 (d, J 5.3 Hz, 1H, Ar).
[0577] M/Z (M+H).sup.+=351.2
[0578] MP: 169-173° C.
Example 21: 4-Methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0579] ##STR00032##
[0580] Example 21 was obtained according to general procedure VII(i) starting from example 13 in presence of 2,2,2-trifluoroethanol. Trituration in Et.sub.2O afforded example 21 as a white solid in 75% yield.
[0581] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 5.05 (q, J 9.0 Hz, 2H, OCH.sub.2CF.sub.3); 7.05 (s, 1H, Ar); 7.52-7.57 (m, 2H, Ar); 7.69 (d, J 5.3 Hz, 1H, Ar); 7.91-7.95 (m, 1H, Ar); 8.20-8.22 (m, 2H, Ar); 8.31 (d, J 5.3 Hz, 1H, Ar).
[0582] M/Z (M+H).sup.+=375.2
[0583] MP: 219-223° C.
Example 22: 4-Methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0584] ##STR00033##
[0585] Example 22 was obtained according to general procedure VII(ii) starting from example 13 in presence of 2,2-difluoroethanol. Trituration in Et.sub.2O afforded example 22 as a white solid in 84% yield.
[0586] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 4.63 (td, J 15.1 Hz, J 3.6 Hz, 2H, OCH.sub.2CHF.sub.2); 6.43 (tt, J 54.8 Hz, J 3.6 Hz, 1H, OCH.sub.2CHF.sub.2); 7.02 (s, 1H, Ar); 7.45 (bs, 1H, Ar); 7.52-7.57 (m, 1H, Ar); 7.63 (dd, J 5.3 Hz, J 1.2 Hz, 1H, Ar); 7.90-7.94 (m, 1H, Ar); 8.19-8.21 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1H, Ar).
[0587] M/Z (M+H).sup.+=357.1
[0588] MP: 209-213° C.
Example 23: 2-[2-(2,2-Difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0589] ##STR00034##
[0590] Example 23 was obtained according to general procedure VII(ii) starting from example 13 in presence of 2,2-difluoropropan-2-ol. Trituration in Et.sub.2O afforded example 23 as a white solid in 86% yield.
[0591] .sup.1H-NMR (400 MHz, DMSO): 1.77 (t, J 19.2 Hz, 3H, OCH.sub.2CF.sub.2CH.sub.3); 3.55 (s, 3H, NCH.sub.3); 4.62 (t, J 13.1 Hz, 2H, OCH.sub.2CF.sub.2CH.sub.3); 7.03 (s, 1H, Ar); 7.46 (bs, 1H, Ar); 7.52-7.57 (m, 1H, Ar); 7.63 (dd, J 5.3 Hz, J 1.3 Hz, 1H, Ar); 7.90-7.94 (m, 1H, Ar); 8.19-8.21 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1H, Ar).
[0592] M/Z (M+H).sup.+=371.1
[0593] MP: 189-191° C.
Example 24: 4-Methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0594] ##STR00035##
[0595] Example 24 was obtained according to general procedure VII(ii) starting from example 13 in presence of 2,2,3,3,-pentafluoropropanol. In order to complete the reaction, 2,2,3,3,-pentafluoropropanol (2.5 equiv.) and NaH (2.0 equiv.) were introduced a second time, then the mixture was warmed for 3 hours at 100° C. Trituration in Et.sub.2O afforded example 24 as a white solid in 55% yield.
[0596] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 5.15 (t, J 13.8 Hz, 2H, OCH.sub.2CF.sub.2CF.sub.3); 7.07 (s, 1H, Ar); 7.50 (bs, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.70 (d, J 5.3 Hz, 1H, Ar); 7.90-7.95 (m, 1H, Ar); 8.20-8.22 (m, 2H, Ar); 8.32 (d, J 5.3 Hz, 1H, Ar).
[0597] M/Z (M+H).sup.+=425.1
[0598] MP: 150-155° C.
Example 25: 4-Methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0599] ##STR00036##
[0600] To a suspension of example 13 (1.0 equiv.) in 1,1,1,3,3,3-hexafluoro-2-propanol (C=0.07 molL.sup.−1), potassium tertbutoxyde (10.0 equiv.) was introduced. The reaction mixture was submitted to microwave irradiation (150° C., 60 min.). After cooling, the reaction mixture was hydrolysed with saturated aqueous NH.sub.4Cl solution and then extracted with DCM. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%). Example 25 was obtained as a white solid in 19% yield.
[0601] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.10 (s, 1H, Ar); 7.21 (sept, 1H, J 6.5 Hz, CH(CF.sub.3).sub.2); 7.54-7.58 (m, 1H, Ar); 7.67 (bs, 1H, Ar); 7.67 (dd, J 5.3 Hz, J 1.4 Hz, 1H, Ar); 7.91-7.95 (m, 1H, Ar); 8.20-8.23 (m, 2H, Ar); 8.38 (d, J 5.3 Hz, 1H, Ar).
[0602] M/Z (M+H).sup.+=443.2
[0603] MP: 188-194° C.
Compound 3: 2-(2-Trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0604] Compound 3 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 86% yield.
[0605] .sup.1H-NMR (400 MHz, DMSO): 6.76 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.18 (dd, J 7.9 Hz, J 1.2 Hz, 1H, Ar); 8.23-8.28 (m, 2H, Ar); 8.40 (bs, 1H, Ar); 8.85 (d, J 5.0 Hz, 1H, Ar); 12.39 (bs, 1H, NH).
[0606] M/Z (M+H).sup.+=331.2.
Example 26: 4-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0607] ##STR00037##
[0608] Example 26 was obtained according to general procedure II(i), starting from compound 3 in presence of iodomethane. The reaction mixture was stirred at room temperature for 120 min. Example 26 was obtained as a white solid in 86% yield.
[0609] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.18 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.19-8.24 (m, 3H, Ar); 8.37 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0610] M/Z (M+H).sup.+=345.2.
[0611] MP: 232-244° C.
Example 27: 4-Methyl(D.SUB.3.)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0612] ##STR00038##
[0613] Example 27 was obtained according to general procedure II(ii), starting from compound 3 in presence of deuterated iodomethane (CD.sub.3I). The reaction mixture was stirred at room temperature for 60 min. Trituration in Et.sub.2O afforded example 27 as a gray solid in 63% yield.
[0614] .sup.1H-NMR (400 MHz, DMSO): 7.16 (s, 1H, Ar); 7.53-7.58 (m, 1H, Ar); 7.90-7.96 (m, 1H, Ar); 8.18-8.23 (m, 3H, Ar); 8.36 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0615] M/Z (M+H).sup.+=348.1.
[0616] MP: 232-237° C.
Example 28: 4-Ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0617] ##STR00039##
[0618] Example 28 was obtained according to general procedure II(ii), starting from compound 3 in presence of iodoethane. The reaction mixture was stirred at room temperature for 30 min. Purification by preparative HPLC afforded example 28 as a white solid in 18% yield.
[0619] .sup.1H-NMR (400 MHz, DMSO): 1.34 (t, 3H, J 7.1 Hz, NCH.sub.2CH.sub.3); 4.13 (q, 2H, J 7.1 Hz, NCH.sub.2CH.sub.3); 7.27 (s, 1H, Ar); 7.55-7.59 (m, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 8.20-8.26 (m, 3H, Ar); 8.39 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0620] M/Z (M+H).sup.+=359.0.
[0621] MP: 214-220° C.
Example 29: 4-(2,2-Difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0622] ##STR00040##
[0623] Example 29 was obtained according to general procedure II(ii), starting from compound 3 in presence of 1,1-difluoro-2-iodoethane. The reaction mixture was stirred at room temperature overnight, then at 70° C. for 2 hours. Purification by preparative HPLC afforded example 29 as a white solid in 19% yield.
[0624] .sup.1H-NMR (400 MHz, DMSO): 4.55 (td, J 14.5 Hz, J 3.8 Hz, 2H, NCH.sub.2CHF.sub.2); 6.47 (tt, J 55.1 Hz, J 3.8 Hz, 1H, NCH.sub.2CHF.sub.2); 7.35 (s, 1H, Ar); 7.58-7.62 (m, 1H, Ar); 7.96-8.00 (m, 1H, Ar); 8.22-8.28 (m, 3H, Ar); 8.36 (bs, 1H, Ar); 8.90 (d, J 5.0 Hz, 1H, Ar).
[0625] M/Z (M+H).sup.+=395.4.
[0626] MP: 223-230° C.
Example 30: 4-(2-Methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0627] ##STR00041##
[0628] Example 30 was obtained according to general procedure II(ii), starting from compound 3 in presence of 2-bromoethylmethyl ether. The reaction mixture was stirred for 17 hours at room. Purification by preparative HPLC afforded example 30 as a white solid in 30% yield.
[0629] .sup.1H-NMR (400 MHz, DMSO): 3.28 (s, 3H, OCH.sub.3); 3.74 (t, J 5.9 Hz, 2H, OCH.sub.2CH.sub.2N); 4.29 (t, J 5.9 Hz, 2H, OCH.sub.2CH.sub.2N); 7.25 (s, 1H, Ar); 7.56-7.60 (m, 1H, Ar); 7.93-7.97 (m, 1H, Ar); 8.20-8.26 (m, 3H, Ar); 8.39 (bs, 1H, Ar); 8.88 (d, J 5.0 Hz, 1H, Ar).
[0630] M/Z (M+H).sup.+=389.1.
[0631] MP: 165-174° C.
General Procedure VIII: Formation of Ester a Via Innate Carbon-Hydrogen Functionalization
[0632] Under inert atmosphere, a mixture of ethyl isocotinate (1.0 equiv.) and sulfinate (2.0 equiv.) was suspended in a mixture of DCM:water (8:2-C=0.14 mol.Math.L.sup.−1). TFA (1.0 equiv.), then tertbutylhydroperoxide (3.0 equiv.) were added and the mixture was vigorously stirred. When the starting material is consumed, the mixture was hydrolysed with a saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO.sub.4 or Na.sub.2SO.sub.4 and concentrated. Compounds were used in the next steps without further purification.
Compound 4: 2-Difluoromethyl-isonicotinic Acid Ethyl Ester
[0633] Compound 4 was obtained according to general procedure VIII using bis {[(difluoromethyl)sulfonyl]oxy}zinc (DFMS). The reaction mixture was stirred for 4 hours at room temperature. Compound 4 was isolated as a yellow oil in a quantitative yield. To facilitate the extraction step, EDTA (8% w/w) was added to the NaHCO.sub.3 solution.
[0634] .sup.1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.1 Hz, OCH.sub.2CH.sub.3); 4.39 (q, 2H, J 7.1 Hz, OCH.sub.2CH.sub.3); 7.09 (t, J 54.7 Hz, 1H, CHF.sub.2); 8.02 (d, J 5.0 Hz, 1H, Ar); 8.06 (s, 1H, Ar); 8.92 (d, J 5.0 Hz, 1H, Ar).
[0635] M/Z (M+H).sup.+=202.0.
Compound 5: 2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0636] Compound 5 was obtained according to general procedure I(ii), starting from compound 4 in presence of 2-hydrazino-benzoic acid as a brown solid in 64% yield.
[0637] .sup.1H-NMR (400 MHz, DMSO): 6.68 (s, 1H, Ar); 7.03 (t, J 54.8 Hz, 1H, CHF.sub.2); 7.54-7.58 (m, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 8.12-8.13 (m, 1H, Ar); 8.18 (dd, J 8.0 Hz, J 1.2 Hz, 1H, Ar); 8.20-8.24 (m, 2H, Ar); 8.77 (d, J 5.2 Hz, 1H, Ar); 12.46 (bs, 1H, NH).
[0638] M/Z (M+H).sup.+=313.2.
Example 31: 4-Methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0639] ##STR00042##
[0640] Example 31 was obtained according to general procedure II(ii), starting from compound 5 in presence of iodomethane. The reaction mixture was stirred for 16 hours at room temperature. Purification by flash-chromatography (MeOH in DCM, 0 to 10%) afforded example 31 as a white solid in 26% yield.
[0641] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.04 (t, J 55.0 Hz, 1H, CHF.sub.2); 7.12 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.10-8.12 (m, 1H, Ar); 8.20-8.24 (m, 3H, Ar); 8.80 (d, J 5.0 Hz, 1H, Ar).
[0642] M/Z (M+H).sup.+=327.2.
[0643] MP: 192-196° C.
Compound 6: 2-(1,1-Difluoro-ethyl)-isonicotinic Acid Ethyl Ester
[0644] Compound 6 was obtained according to general procedure VIII using sodium 1,1-difluoromethanesulfinate. The reaction mixture was stirred for 20 hours at room temperature. Compound 6 was isolated as a yellow oil in quantitative yield. To ensure a full conversion, sodium 1,1-difluoromethanesulfinate (2.0 equiv.) and tertbutyl hydroperoxide (3.0 equiv.) were added a second time after 18 hours.
[0645] .sup.1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.1 Hz, OCH.sub.2CH.sub.3); 2.03 (t, J 19.2 Hz, 1H, CF.sub.2CH.sub.3); 4.39 (q, 2H, J 7.1 Hz, OCH.sub.2CH.sub.3); 7.99-8.01 (m, 1H, Ar); 8.03-8.04 (m, 1H, Ar); 8.90 (d, J 5.0 Hz, 1H, Ar).
[0646] M/Z (M+H).sup.+=216.4.
Compound 7: 2-[2-(1,1-Difluoro-ethyl)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0647] Compound 7 was obtained according to general procedure I(ii), starting from compound 6 in presence of 2-hydrazino-benzoic acid as a brown solid in 61% yield.
[0648] .sup.1H-NMR (400 MHz, DMSO): 2.06 (t, J 19.1 Hz, 1H, CF.sub.2CH.sub.3); 6.68 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.08-8.10 (m, 1H, Ar); 8.18 (dd, J 8.0 Hz, J 1.3 Hz, 1H, Ar); 8.23-8.24 (m, 2H, Ar); 8.75 (d, J 5.2 Hz, 1H, Ar); 12.46 (bs, 1H, NH).
[0649] M/Z (M+H).sup.+=327.2.
Example 32: 2-[2-(1,1-Difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0650] ##STR00043##
[0651] Example 32 was obtained according to general procedure II(i), starting from compound 7 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 32 was obtained without further purification as a beige solid in 55% yield.
[0652] .sup.1H-NMR (400 MHz, DMSO): 2.07 (t, J 19.1 Hz, 1H, CF.sub.2CH.sub.3); 3.57 (s, 3H, NCH.sub.3); 7.13 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.95 (m, 1H, Ar); 8.07-8.08 (m, 1H, Ar); 8.20-8.24 (m, 3H, Ar); 8.78 (d, J 5.0 Hz, 1H, Ar).
[0653] M/Z (M+H).sup.+=341.2.
[0654] MP: 196-207° C.
Example 33: 2-[2-(1,1-Difluoro-ethyl)-pyridin-4-yl]-4-methyl(D.SUB.3.)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0655] ##STR00044##
[0656] Example 33 was obtained according to general procedure II(i), starting from compound 7 in presence of iodomethane D.sub.3. The reaction mixture was stirred for 2 hours at room temperature. Example 33 was obtained without further purification as a beige solid in 52% yield.
[0657] .sup.1H-NMR (400 MHz, DMSO): 2.07 (t, J 19.1 Hz, 1H, CF.sub.2CH.sub.3); 7.13 (s, 1H, Ar); 7.54-7.58 (m, 1H, Ar); 7.91-7.95 (m, 1H, Ar); 8.07-8.09 (m, 1H, Ar); 8.20-8.24 (m, 3H, Ar); 8.78 (d, J 5.2 Hz, 1H, Ar).
[0658] M/Z (M+H).sup.+=344.2.
[0659] MP: 198-205° C.
General Procedure IX: Formation of Hydrazine D from the Corresponding Amino Derivative C (Cf. Scheme 1)
[0660] To a suspension of amino acid A (1.0 equiv.) in concentrated aqueous HCl solution (0.15 mol.Math.L.sup.−1) cooled by an ice bath, a cold solution of NaNO.sub.2 (1.2 equiv.) in water (c=2.8 mol.Math.L.sup.−1) was added dropwise. The reaction mixture turned yellow with a suspension. After 1 hour, under vigorous stirring, a cold solution of SnCl.sub.2 (3.1 equiv.) in concentrated aqueous HCl solution (c=2.8 mol.Math.L.sup.−1) was added dropwise. A suspension was obtained. The reaction mixture was filtered off 2 hours later. The solid was washed with a minimum of a cold aqueous HCl solution (1N) before being dried under reduced pressure at 80° C. with P.sub.2O.sub.5 for 18 hours.
Compound 8: 2-hydrazino-5-methyl-benzoic Acid, HCl
[0661] Compound 8 was obtained according to general procedure IX, starting from 2-amino-5-methyl-benzoic acid, as a beige solid in 90% yield.
[0662] .sup.1H-NMR (400 MHz, DMSO): 2.26 (s, 3H, CH.sub.3); 7.06 (d, J 8.5 Hz, 1H, Ar); 7.41 (dd, J 8.5 Hz, 2.2 Hz, 1H, Ar); 7.72 (d, J 2.2 Hz, 1H, Ar); 8.93 (bs, 1H, NH); 10.50 (bs, 3H, NH.sub.3).
[0663] M/Z (M+H).sup.+=167.1.
Compound 9: 7-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0664] Compound 9 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 8 as a brown solid in 30% yield.
[0665] .sup.1H-NMR (400 MHz, DMSO): 2.45 (s, 3H, CH.sub.3); 6.61 (s, 1H, Ar); 7.66-7.68 (m, 1H, Ar); 7.95 (bs, 1H, Ar); 8.08-8.10 (m, 1H, Ar); 8.22 (bs, 1H, Ar); 8.35 (bs, 1H, Ar); 8.82 (bs, 1H, Ar). Signal for NH is not observed.
[0666] M/Z (M+H).sup.+=345.2.
Example 34: 7-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0667] ##STR00045##
[0668] Example 34 was obtained according to general procedure II(i), starting from compound 9 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 34 was obtained without further purification as a beige solid in 55% yield.
[0669] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 7.14 (s, 1H, Ar); 7.73-7.75 (m, 1H, Ar); 7.99 (m, 1H, Ar); 8.10-8.12 (m, 1H, Ar); 8.21-8.22 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.86-8.87 (m, 1H, Ar). Signal for CH.sub.3 is not observed.
[0670] M/Z (M+H).sup.+=359.1.
[0671] MP: 215-218° C.
Compound 10: 5-Chloro-2-hydrazino-benzoic Acid, HCl
[0672] Compound 10 was obtained according to general procedure IX, starting from 2-amino-5-chlorobenzoic acid, as a beige solid in 88% yield.
[0673] .sup.1H-NMR (400 MHz, DMSO): 7.07 (d, J 8.9 Hz, 1H, Ar); 7.57 (dd, J 8.9 Hz, 2.5 Hz, 1H, Ar); 7.75 (d, J 2.5 Hz, 1H, Ar); 9.08 (bs, 1H, NH); 10.73 (bs, 3H, NH.sub.3).
Compound 11: 7-Chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0674] Compound 11 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 10 as a brown solid in 31% yield.
[0675] .sup.1H-NMR (400 MHz, DMSO): 6.65 (s, 1H, Ar); 7.88 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 8.07 (d, J 2.4 Hz, 1H, Ar); 8.20 (d, J 8.8 Hz, 1H, Ar); 8.23-8.24 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.83 (d, J 4.9 Hz, 1H, Ar). Signal for NH is not observed.
[0676] M/Z (M[.sup.35Cl]+H).sup.+=365.0.
Example 35: 7-Chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0677] ##STR00046##
[0678] Example 35 was obtained according to general procedure II(i), starting from compound 11 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 35 was obtained without further purification as a white solid in 68% yield.
[0679] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.96 (dd, J 8.7 Hz, J 2.4 Hz, 1H, Ar); 8.10 (d, J 2.4 Hz, 1H, Ar); 8.22-8.24 (m, 2H, Ar); 8.36 (bs, 1H, Ar); 8.88 (d, J 5.0 Hz, 1H, Ar).
[0680] M/Z (M[.sup.35Cl]+H).sup.+=379.4.
[0681] MP: 231-236° C.
Compound 12: 2-hydrazino-5-methoxy-benzoic Acid, HCl
[0682] Compound 12 was obtained according to general procedure IX, starting from 2-amino-5-methoxybenzoic acid, as a beige solid in quantitative yield.
[0683] .sup.1H-NMR (400 MHz, DMSO): 3.75 (s, 3H, OCH.sub.3); 7.15 (d, J 8.9 Hz, 1H, Ar); 7.25 (dd, J 8.9 Hz, 2.8 Hz, 1H, Ar); 7.42 (d, J 2.8 Hz, 1H, Ar); 8.84 (bs, 1H, NH); 10.17 (bs, 3H, NH.sub.3).
[0684] M/Z (M+H).sup.+=183.1.
Compound 13: 7-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0685] Compound 13 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 12 as a brown solid in 37% yield.
[0686] .sup.1H-NMR (400 MHz, DMSO): 3.86 (s, 3H, OCH.sub.3); 6.44 (s, 1H, Ar); 7.33-7.35 (m, 1H, Ar); 7.57 (bs, 1H, Ar); 8.06-8.08 (m, 1H, Ar); 8.16 (bs, 1H, Ar); 8.30 (bs, 1H, Ar); 8.77 (bs, 1H, Ar). Signal for NH is not observed.
[0687] M/Z (M+H).sup.+=361.0.
Example 36: 7-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0688] ##STR00047##
[0689] Example 36 was obtained according to general procedure II(i), starting from compound 13 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 36 was obtained without further purification as a beige solid in 48% yield.
[0690] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 3.91 (s, 3H, OCH.sub.3); 7.20 (s, 1H, Ar); 7.55 (dd, J 9.0 Hz, J 2.8 Hz, 1H, Ar); 7.63 (d, J 2.8 Hz, 1H, Ar); 8.21 (d, J 9.0 Hz, 1H, Ar); 8.24-8.26 (m, 1H, Ar); 8.38 (bs, 1H, Ar); 8.88 (d, J 5.0 Hz, 1H, Ar).
[0691] M/Z (M+H).sup.+=375.1.
[0692] MP: 201-205° C.
Compound 14: 2-hydrazino-5-trifluoromethyl-benzoic Acid, HCl
[0693] Compound 14 was obtained according to general procedure IX, starting from 2-amino-5-trifluoromethylbenzoic acid, as a beige solid in 64% yield.
[0694] .sup.1H-NMR (400 MHz, DMSO): 7.27 (d, J 8.9 Hz, 1H, Ar); 7.89 (dd, J 8.9 Hz, 2.1 Hz, 1H, Ar); 8.10 (d, J 2.1 Hz, 1H, Ar); 9.38 (bs, 1H, NH); 10.58 (bs, 3H, NH.sub.3).
[0695] M/Z (M+H).sup.+=221.2.
Compound 15: 7-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0696] Compound 15 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 14 as a brown solid in 40% yield.
[0697] .sup.1H-NMR (400 MHz, DMSO): 6.68 (s, 1H, Ar); 8.17 (dd, J 8.6 Hz, J 1.5 Hz, 1H, Ar); 8.26 (d, J 5.0 Hz, 1H, Ar); 8.35-8.37 (m, 2H, Ar); 8.39 (bs, 1H, Ar); 8.84 (d, J 5.0 Hz, 1H, Ar). Signal for NH is not observed.
[0698] M/Z (M+H).sup.+=399.1.
Example 37: 7-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0699] ##STR00048##
[0700] Example 37 was obtained according to general procedure II(i), starting from compound 15 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 37 was obtained without further purification as a brown solid in 33% yield.
[0701] .sup.1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH.sub.3); 7.25 (s, 1H, Ar); 8.24-8.27 (m, 2H, Ar); 8.39-8.41 (m, 3H, Ar); 8.88 (d, J 4.9 Hz, 1H, Ar).
[0702] M/Z (M+H).sup.+=413.2.
[0703] MP: 205-210° C.
Compound 16: 5-fluoro-2-hydrazino-5-trifluoromethyl-benzoic Acid, HCl
[0704] Compound 16 was obtained according to general procedure IX, starting from 2-amino-5-fluoromethylbenzoic acid, as a beige solid in 46% yield.
[0705] M/Z (M+H).sup.+=171.8.
Compound 17: 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0706] Compound 17 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 16 as a brown solid in 54% yield.
[0707] .sup.1H-NMR (400 MHz, DMSO): 6.78 (s, 1H, Ar); 7.80-7.89 (m, 2H, Ar); 8.26-8.31 (m, 2H, Ar); 8.40 (bs, 1H, Ar); 8.85 (d, J 4.9 Hz, 1H, Ar); 12.64 (bs, 1H, NH).
[0708] M/Z (M+H).sup.+=349.0.
Example 38: 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0709] ##STR00049##
[0710] Example 38 was obtained according to general procedure II(iii), starting from compound 17 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 38 was obtained without further purification as a beige solid in 84% yield.
[0711] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.82 (td, J 9.0 Hz, J 2.9 Hz, 1H, Ar); 7.90 (dd, J 8.7 Hz, J 2.9 Hz, 1H, Ar); 8.23-8.24 (m, 1H, Ar); 8.28 (dd, J 9.0 Hz, J 4.6 Hz, 1H, Ar); 8.37 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0712] M/Z (M+H).sup.+=363.0.
[0713] MP: >250° C.
Compound 18: 5-Bromo-2-hydrazino-benzoic Acid, HCl
[0714] Compound 18 was obtained according to general procedure IX, starting from 2-amino-5-bromo-benzoic acid, as a beige solid in a quantitative yield.
[0715] .sup.1H-NMR (400 MHz, DMSO): 7.10 (d, J 8.9 Hz, 1H, Ar); 7.78 (dd, J 8.9 Hz, 2.5 Hz, 1H, Ar); 7.97 (d, J 2.5 Hz, 1H, Ar); 9.08 (bs, 1H, NH); 10.64 (bs, 3H, NH.sub.3).
[0716] M/Z (M[.sup.79Br]-18+H).sup.+=213.
Compound 19: 7-Bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0717] Compound 19 was obtained according to general procedure I(i), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 8 as a brown solid in 24% yield.
[0718] .sup.1H-NMR (400 MHz, DMSO): 6.77 (s, 1H, Ar); 8.08 (dd, J 8.7 Hz, J 2.3 Hz, 1H, Ar); 8.16 (d, J 8.7 Hz, 1H, Ar); 8.21 (d, J 2.3 Hz, 1H, Ar); 8.24-8.26 (m, 1H, Ar); 8.39 (bs, 1H, Ar); 8.85 (d, J 5.1 Hz, 1H, Ar); 12.62 (bs, 1H, NH).
[0719] M/Z (M[.sup.79Br]+H).sup.+=409.2.
Example 39: 7-Bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0720] ##STR00050##
[0721] Example 39 was obtained according to general procedure II(i), starting from compound 19 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 39 was obtained without further purification as a brown solid in 85% yield.
[0722] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, N—CH.sub.3); 7.20 (s, 1H, Ar); 8.09 (dd, J 8.8 Hz, J 2.3 Hz, 1H, Ar); 8.17 (d, J 8.8 Hz, 1H, Ar); 8.23-8.25 (m, 2H, Ar); 8.37 (bs, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[0723] M/Z (M[.sup.79Br]+H).sup.+=423.1.
[0724] MP: 223-235° C.
General Procedure X: Amine Introduction Via Buchwald, Ullmann or Nucleophilic Substitution
[0725] Method (i): Under inert atmosphere, a mixture of halide (1.0 equiv.), amine (2.4 equiv.), tBuOK (1.6 equiv.; 2.4 more equivalent are added when the amine is an HCl salt) and BrettPhos precatalyst (0.1 equiv.) were suspended in DMA (C=0.1 molL.sup.−1). The mixture was warmed overnight at 80° C. After cooling, the reaction mixture was hydrolysed with saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0726] Method (ii): Under inert atmosphere, a mixture of halide (1.0 equiv.), amine (2.4 equiv.), a solution of LiHMDS in THF (1.0 N; 1.2 equiv.) and BrettPhos precatalyst (0.1 equiv.) were suspended in DME (C=0.1 molL.sup.−1) and stirred for 2 hours at room temperature. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
[0727] Method (iii): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1.2 equiv.), a solution of LiHMDS in THF (1.0 N; 2.4 equiv.) and BrettPhos precatalyst (0.1 equiv.) were suspended in DME (C=0.1 molL.sup.−1) and warmed for 2 hours at 60° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0728] Method (iv): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1.5 equiv.), K.sub.3PO.sub.4 (4.0 equiv.), CuI (0.1 equiv.) and DMPAO (0.2 equiv.) in DMSO (C=0.1 molL.sup.−1) was heated for 17 hours at 100° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0729] Method (v): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1.5 equiv.), tBuOK (3.0 equiv.) palladium acetate (0.1 equiv.) and BINAP (0.2 equiv.) were suspended in toluene (C=0.06 molL.sup.−1) and heated for 2 hours at 120° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
[0730] Method (vi): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (5.0 equiv.), K.sub.2CO.sub.3 (5.0 equiv.) in DMA (C=0.1 molL.sup.−1) was heated for 1 hour at 90° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 40: 4-Methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0731] ##STR00051##
[0732] Example 40 was obtained according to general procedure X(i) starting from example 39 in presence of methylamine hydrochloride. Purification by flash-chromatography (MeOH in DCM, 0 to 1%) afforded example 40 as a yellow solid in 34% yield.
[0733] .sup.1H-NMR (400 MHz, DMSO): 2.77 (d, J 5.0 Hz, 3H, NHCH.sub.3); 3.55 (s, 3H, NCH.sub.3); 6.30 (q, J 5.0 Hz, 1H, NHCH.sub.3); 7.09 (s, 1H, Ar); 7.14-7.17 (m, 2H, Ar); 8.00-8.02 (m, 1H, Ar); 8.18-8.20 (m, 1H, Ar); 8.32 (bs, 1H, Ar); 8.84 (d, J 5.1 Hz, 1H, Ar).
[0734] M/Z (M+H).sup.+=373.7.
[0735] MP: >250° C.
Example 41: 4-Methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0736] ##STR00052##
[0737] Example 41 was obtained according to general procedure X(i) starting from example 39 in presence of methylamine(D3) hydrochloride. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 41 as a beige solid in 30% yield.
[0738] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 6.26 (bs, 1H, NH); 7.09 (s, 1H, Ar); 7.14-7.17 (m, 2H, Ar); 7.99-8.02 (m, 1H, Ar); 8.18-8.29 (m, 1H, Ar); 8.32 (bs, 1H, Ar); 8.84 (d, J 5.1 Hz, 1H, Ar).
[0739] M/Z (M+H).sup.+=377.0.
[0740] MP: >250° C.
Example 42: N-[4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-7-yl]-acetamide
[0741] ##STR00053##
[0742] Under inert atmosphere, a mixture of bromide 39, (60.0 mg, 1.0 equiv.), acetamide (8.8 mg, 1.05 equiv.), Cs.sub.2CO.sub.3 (93.4 mg, 2.0 equiv.), Pd.sub.2dba.sub.3 (7.3 mg, 0.1 equiv.) and XantPhos (16.4 mg, 0.2 equiv.) were suspended in DMA (2.8 mL, C=0.05 molL.sup.−1). The mixture was heated for 2 hours at 110° C. After cooling, the reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified by flash-chromatography (MeOH in DCM, 0 to 3%) to afford example 42 as a beige solid in 63% yield.
[0743] .sup.1H-NMR (400 MHz, DMSO): 2.09 (s, 3H, COCH.sub.3); 3.56 (s, 3H, NCH.sub.3); 7.15 (s, 1H, Ar); 8.09 (dd, J 9.0 Hz, J 2.4 Hz, 1H, Ar); 8.16 (d, J 9.0 Hz, 1H, Ar); 8.20-8.22 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.47 (d, J 2.4 Hz, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar); 10.32 (s, 1H, NH).
[0744] M/Z (M+H).sup.+=402.0.
[0745] MP: >250° C.
Example 43: 7-Amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0746] ##STR00054##
[0747] In a seal tube, a suspension of amide 42 (23.2 mg, 1.0 equiv.) in HCl MeOH solution (1.25 N; 1.2 mL, C=0.05 molL.sup.−1) was heated for 18 hours at 80° C. The reaction mixture was concentrated. The resulting residue was suspended in Et.sub.2O. Solid was collected, washed with Et.sub.2O and dried under reduced pressure to afford example 43 as a brown solid in 71% yield.
[0748] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 7.15 (s, 1H, Ar); 7.41 (dd, J 8.8 Hz, J 2.5 Hz, 1H, Ar); 7.64 (d, J 2.5 Hz, 1H, Ar); 8.10 (d, J 8.8 Hz, 1H, Ar); 8.20-8.22 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.86 (d, J 5.2 Hz, 1H, Ar). Signal for NH.sub.2 is not observed.
[0749] M/Z (M+H).sup.+=360.1.
[0750] MP: 245-250° C.
Example 44: 7-Dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0751] ##STR00055##
[0752] Example 44 was obtained according to general procedure X(i) starting from example 39 in presence of dimethylamine (2 N in THF). After hydrolysis, example 44 was extracted with EtOAc. Organic layers were washed with brine, dried over MgSO.sub.4. Purification by flash-chromatography (MeOH in DCM, 0 to 10%) afforded example 44 as a yellow solid in 7% yield.
[0753] .sup.1H-NMR (400 MHz, DMSO): 3.04 (s, 6H, N(CH.sub.3).sub.2); 3.60 (s, 3H, NCH.sub.3); 7.01 (s, 1H, Ar); 7.36-7.39 (m, 2H, Ar); 8.10 (d, J 8.6 Hz, 1H, Ar); 8.17-8.19 (m, 1H, Ar); 8.31 (bs, 1H, Ar); 8.84 (d, J 5.1 Hz, 1H, Ar).
[0754] M/Z (M+H).sup.+=387.5.
[0755] MP: >250° C.
Example 45: 7-Ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0756] ##STR00056##
[0757] Example 45 was obtained according to general procedure X(i) starting from example 39 in presence of ethylamine hydrochloride. Ethylamine HCl (0.2 equiv.), tBuOK (0.2 equiv.) and BrettPhos precatalyst (0.1 iquiv.) were added and the reaction mixture was heated for two more hours at 80° C. Purification by flash-chromatography (EtOAc in CyHex, 0 to 50%) afforded example 45 as a beige solid in 26% yield.
[0758] .sup.1H-NMR (400 MHz, DMSO): 1.21 (t, J 7.1 Hz, 3H, NHCH.sub.2CH.sub.3); 3.09-3.15 (m, 2H, NHCH.sub.2CH.sub.3); 3.55 (s, 3H, NCH.sub.3); 6.21 (t, J 5.2 Hz, 1H, NHCH.sub.2CH.sub.3); 7.09 (s, 1H, Ar); 7.16-7.20 (m, 2H, Ar); 8.00 (d, J 8.7 Hz, 1H, Ar); 8.18-8.19 (m, 1H, Ar); 8.32 (bs, 1H, Ar); 8.84 (d, J 5.0 Hz, 1H, Ar).
[0759] M/Z (M+H).sup.+=388.0.
[0760] MP: 239-242° C.
Example 46: 7-Cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0761] ##STR00057##
[0762] Example 46 was obtained according to general procedure X(i) starting from example 39 in presence of cyclobutylamine. Purification by preparative HPLC afforded example 46 as a beige solid in 16% yield.
[0763] .sup.1H-NMR (400 MHz, DMSO): 1.73-1.92 (m, 4H, CH.sub.2+2CHaHb); 2.35-2.40 (m, 2H, 2CHaHb); 3.55 (s, 3H, NCH.sub.3); 3.92 (sex, J 7.1 Hz, 1H, NHCH(CH.sub.2).sub.2); 6.55 (d, J 7.1 Hz, 1H, NHCH(CH.sub.2).sub.2); 7.10 (s, 1H, Ar); 7.13 (dd, J 8.8 Hz, J 2.5 Hz, 1H, Ar); 7.16 (d, J 2.5 Hz, 1H, Ar); 8.00 (d, J 8.8 Hz, 1H, Ar); 8.18-8.20 (m, 1H, Ar); 8.33 (bs, 1H, Ar); 8.84 (d, J 5.0 Hz, 1H, Ar).
[0764] M/Z (M+H).sup.+=414.2.
[0765] MP: 220-225° C.
Example 47: 4-Methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0766] ##STR00058##
[0767] Example 47 was obtained according to general procedure X(ii) starting from example 39 in presence of morpholine. Purification by flash-chromatography (MeOH in DCM, 0 to 1%) afforded example 47 as a grey solid in 21% yield.
[0768] .sup.1H-NMR (400 MHz, DMSO): 3.22-3.25 (m, 4H, 2 CH.sub.2); 3.57 (s, 3H, NCH.sub.3); 3.75-3.80 (m, 4H, 2 CH.sub.2); 7.14 (s, 1H, Ar); 7.55 (d, J 2.8 Hz, 1H, Ar); 7.62 (dd, J 9.1 Hz, J 2.8 Hz, 1H, Ar); 8.11 (d, J 9.1 Hz, 1H, Ar); 8.21-8.22 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0769] M/Z (M+H).sup.+=430.3.
[0770] MP: 149-163° C.
Example 48: 7-Hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0771] ##STR00059##
[0772] Under inert atmosphere, in a seal tube, to a well degased mixture of bromide 39 (100.0 mg, 1.0 equiv.), Pd.sub.2dba.sub.3 (12.2 mg, 0.1 equiv.) and tBuXPhos (10.2 mg, 0.1 equiv.) in dioxane (0.5 mL, C=0.5 molL.sup.−1), a well degased solution of KOH (79.5 mg, 6.0 equiv.) in water (0.5 mL, C=2.8 molL.sup.−1) was added dropwise and was heated for 16 hours at 100° C. After cooling, the reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%) to afford example 48 as a white solid in 35% yield.
[0773] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.13 (s, 1H, Ar); 7.35 (dd, J 8.8 Hz, J 2.6 Hz, 1H, Ar); 7.52 (d, J 2.6 Hz, 1H, Ar); 8.09 (d, J 8.8 Hz, 1H, Ar); 8.19-8.21 (m, 1H, Ar); 8.34 (bs, 1H, Ar); 8.86 (d, J 4.9 Hz, 1H, Ar); 10.17 (s, 1H, OH).
[0774] M/Z (M+H).sup.+=361.5.
[0775] MP: >250° C.
General Procedure XI: Hydroxy Group Alkylation
[0776] Under inert atmosphere, to a suspension of hydroxyl quinazolinone (1.0 equiv.) in DMF (C=0.1 molL.sup.−1), tBuOK (1.5 equiv.) was added. After 15 minutes, electrophile (1.2 equiv.) was introduced and the reaction mixture was heated for 18 hours at 80° C. After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 49: 7-Ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0777] ##STR00060##
[0778] Example 49 was obtained according to general procedure XI starting from example 48 in presence of iodoethane. Iodoethane (1.2 equiv.) and tBuOK (1.5 equiv.) were added and the reaction mixture was heated for 48 hours at 80° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 49 as a yellow solid in 27% yield.
[0779] .sup.1H-NMR (400 MHz, DMSO): 1.37 (t, J 7.0 Hz, 3H, OCH.sub.2CH.sub.3); 3.55 (s, 3H, NCH.sub.3); 4.13 (q, J 7.0 Hz, 2H, OCH.sub.2CH.sub.3); 7.11 (s, 1H, Ar); 7.47 (dd, J 9.0 Hz, J 2.8 Hz, 1H, Ar); 7.53 (d, J 2.8 Hz, 1H, Ar); 8.11 (d, J 9.0 Hz, 1H, Ar); 8.17-8.19 (m, 1H, Ar); 8.31 (bs, 1H, Ar); 8.85 (d, J 5.1 Hz, 1H, Ar).
[0780] M/Z (M+H).sup.+=389.1.
[0781] MP: 152-158° C.
Example 50: 7-(2-Methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0782] ##STR00061##
[0783] Example 50 was obtained according to general procedure XI starting from example 48 in presence of 2-bromoethylmerthyl ether. 2-bromoethylmerthyl ether (1.2 equiv.) and tBuOK (1.5 equiv.) were added and the reaction mixture was heated for 48 hours at 80° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 50 as a white solid in 34% yield.
[0784] .sup.1H-NMR (400 MHz, DMSO): 3.34 (s, 3H, OCH.sub.3); 3.56 (s, 3H, NCH.sub.3); 3.70-3.72 (m, 2H, OCH.sub.2); 4.22-4.24 (m, 2H, OCH.sub.2); 7.14 (s, 1H, Ar); 7.53 (dd, J 9.0 Hz, J 2.8 Hz, 1H, Ar); 7.59 (d, J 2.8 Hz, 1H, Ar); 8.15 (d, J 9.0 Hz, 1H, Ar); 8.20-8.21 (m, 1H, Ar); 8.34 (bs, 1H, Ar); 8.86 (d, J 5.0 Hz, 1H, Ar).
[0785] M/Z (M+H).sup.+=419.2.
[0786] MP: 182-189° C.
Example 51: 4-Methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0787] ##STR00062##
[0788] Example 51 was obtained according to general procedure VII(i) starting from example 38 in presence of 4-hydroxyethylmorpholine. Salt formation according to procedure IV(iii) afforded example 51 as a beige solid in 34% yield.
[0789] .sup.1H-NMR (400 MHz, DMSO): 3.25-3.29 (m, 4H, 2NCH.sub.2); 3.50-3.54 (m, 2H, NCH.sub.2); 3.62 (s, 3H, NCH.sub.3); 3.88-3.90 (m, 4H, 2 OCH.sub.2); 4.54-4.56 (m, 2H, OCH.sub.2); 7.09 (s, 1H, Ar); 7.62 (dd, J 8.9 Hz, J 2.5 Hz, 1H, Ar); 7.77 (d, J 2.5 Hz, 1H, Ar); 8.21-8.22 (m, 1H, Ar); 8.25 (d, J 8.9 Hz, 1H, Ar); 8.35 (bs, 1H, Ar); 8.87 (d, J 4.9 Hz, 1H, Ar).
[0790] M/Z (M+H).sup.+=474.1.
[0791] MP: >250° C.
Compound 20: 2-Hydrazino-5-trifluoromethoxy-benzoic Acid, HCl
[0792] Compound 20 was obtained according to general procedure IX, starting from 2-Amino-5-trifluoromethoxylbenzoic acid, as a white solid in 59% yield.
[0793] .sup.1H-NMR (400 MHz, DMSO): 7.22 (d, J 9.1 Hz, 1H, Ar); 7.66 (dd, J 9.1 Hz, 2.4 Hz, 1H, Ar); 7.77 (d, J 2.4 Hz, 1H, Ar); 9.12 (bs, 1H, NH); 10.62 (bs, 3H, NH.sub.3).
Compound 21: 7-Trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0794] Compound 21 was obtained according to general procedure I(i), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 20 as a brown solid in 61% yield.
[0795] .sup.1H-NMR (400 MHz, DMSO): 6.82 (s, 1H, Ar); 7.94-7.97 (m, 1H, Ar); 8.02-8.03 (m, 1H, Ar); 8.27-8.30 (m, 1H, Ar); 8.35-8.37 (m, 1H, Ar); 8.42 (bs, 1H, Ar); 8.85-8.87 (m, 1H, Ar); 12.69 (bs, 1H, NH).
[0796] M/Z (M+H).sup.+=415.2.
Example 52: 4-Methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0797] ##STR00063##
[0798] Example 52 was obtained according to general procedure II(iii), starting from compound 21 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 52 was obtained without further purification as a white solid in 55% yield.
[0799] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.22 (s, 1H, Ar); 7.95 (dd, J 9.0 Hz, 1.7 Hz, 1H, Ar); 8.05 (d, 1.7 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.34 (d, 9.0 Hz, 1H, Ar); 8.38 (bs, 1H, Ar); 8.89 (d, 4.9 Hz, 1H, Ar).
[0800] M/Z (M+H).sup.+=429.2.
[0801] MP: 240-245° C.
Compound 22: 2-Hydrazino-5-methanesulfonyl-benzoic Acid, HCl
[0802] Compound 22 was obtained according to general procedure IX, starting from 2-amino-5-methylsulfonylbenzoic acid, as a white solid in 51% yield.
[0803] .sup.1H-NMR (400 MHz, DMSO): 3.19 (s, 3H, SO.sub.2CH.sub.3); 7.26 (d, J 8.9 Hz, 1H, Ar); 8.03 (dd, J 8.9 Hz, 2.3 Hz, 1H, Ar); 8.32 (d, J 2.3 Hz, 1H, Ar); 9.55 (bs, 1H, NH); 10.62 (bs, 3H, NH.sub.3).
Compound 23: 7-Methanesulfonyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0804] Compound 23 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 22 as a brown solid in 40% yield.
[0805] .sup.1H-NMR (400 MHz, DMSO): 3.35 (s, 3H, SO.sub.2CH.sub.3); 6.85 (s, 1H, Ar); 8.31-8.32 (m, 1H, Ar); 8.40-8.46 (m, 3H, Ar); 8.62 (bs, 1H, Ar); 8.88 (d, 4.9 Hz, 1H, Ar); 12.76 (bs, 1H, NH).
[0806] M/Z (M+H).sup.+=409.0.
Example 53: 7-Methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0807] ##STR00064##
[0808] Example 53 was obtained according to general procedure II(iii), starting from compound 23 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 53 was obtained without further purification as a white solid in 54% yield.
[0809] .sup.1H-NMR (400 MHz, DMSO): 3.36 (s, 3H, SO.sub.2CH.sub.3); 3.60 (s, 3H, NCH.sub.3); 7.28 (s, 1H, Ar); 8.27-8.28 (m, 1H, Ar); 8.41-8.46 (m, 3H, Ar); 8.65 (d, J 1.6 Hz, 1H, Ar); 8.92 (d, 5.1 Hz, 1H, Ar).
[0810] M/Z (M+H).sup.+=423.1.
[0811] MP: >250° C.
Compound 24: 2-Hydrazino-4-methoxy-benzoic Acid, HCl
[0812] Compound 24 was obtained according to general procedure IX, starting from 2-amino-4-methoxybenzoic acid, as a white solid in 96% yield.
[0813] .sup.1H-NMR (400 MHz, DMSO): 3.81 (s, 3H, OCH.sub.3); 6.50 (dd, J 8.8 Hz, 2.4 Hz, 1H, Ar); 6.71 (d, J 2.4 Hz, 1H, Ar); 7.82 (d, J 8.8 Hz, 1H, Ar); 9.09 (bs, 1H, NH); 10.03 (bs, 3H, NH.sub.3).
[0814] M/Z (M+H).sup.+=183.1.
Compound 25: 8-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0815] Compound 25 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 24 as a pale brown solid in 76% yield.
[0816] .sup.1H-NMR (400 MHz, DMSO): 4.01 (s, 3H, OCH.sub.3); 6.75 (s, 1H, Ar); 7.12 (dd, J 8.9 Hz, 2.4 Hz, 1H, Ar); 7.65 (d, J 2.4 Hz, 1H, Ar); 8.09 (d, J 8.9 Hz, 1H, Ar); 8.28-8.30 (m, 1H, Ar); 8.43 (bs, 1H, Ar); 8.85 (d, J 5.1 Hz, 1H, Ar); 12.34 (bs, 1H, NH).
[0817] M/Z (M+H).sup.+=361.1.
Example 54: 8-Methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0818] ##STR00065##
[0819] Example 54 was obtained according to general procedure II(iii), starting from compound 25 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 54 was obtained without further purification as a beige solid in 68% yield.
[0820] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 4.00 (s, 3H, OCH.sub.3); 7.12 (dd, J 8.8 Hz, J 2.5 Hz, 1H, Ar); 7.17 (s, 1H, Ar); 7.64 (d, J 2.5 Hz, 1H, Ar); 8.12 (d, J 8.8 Hz, 1H, Ar); 8.26-8.28 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.89 (d, J 5.0 Hz, 1H, Ar).
[0821] M/Z (M+H).sup.+=375.1.
[0822] MP: >250° C.
Compound 26: 4-Fluoro-2-hydrazino-benzoic Acid, HCl
[0823] Compound 26 was obtained according to general procedure IX, starting from 2-amino-4-fluorobenzoic acid, as a white solid in 71% yield.
[0824] .sup.1H-NMR (400 MHz, DMSO): 6.69-6.73 (m, 1H, Ar); 6.93 (dd, J 11.9 Hz, J 2.5 Hz, 1H, Ar);
[0825] 7.93 (dd, J 8.9 Hz, J 6.8 Hz, 1H, Ar); 9.14 (bs, 4H, NHNH.sub.3).
[0826] M/Z (M+H).sup.+=171.2.
Compound 27: 8-Fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0827] Compound 27 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 26 as a pale brown solid in 53% yield.
[0828] .sup.1H-NMR (400 MHz, DMSO): 6.77 (s, 1H, Ar); 7.40 (td, J 8.8 Hz, J 2.5 Hz, 1H, Ar); 7.99 (dd, J 9.5 Hz, J 2.5 Hz, 1H, Ar); 8.23 (dd, J 8.8 Hz, J 5.9 Hz, 1H, Ar); 8.27-8.29 (m, 1H, Ar); 8.43 (bs, 1H, Ar); 8.86 (d, J 5.0 Hz, 1H, Ar); 12.53 (bs, 1H, NH).
[0829] M/Z (M+H).sup.+=349.1.
Example 55: 8-Fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0830] ##STR00066##
[0831] Example 55 was obtained according to general procedure II(iii), starting from compound 27 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 55 was obtained without further purification as a beige solid in 70% yield.
[0832] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.41 (td, J 8.8 Hz, J 2.5 Hz, 1H, Ar); 8.00 (dd, J 9.3 Hz, J 2.5 Hz, 1H, Ar); 8.25-8.28 (m, 2H, Ar); 8.41 (bs, 1H, Ar); 8.90 (d, J 5.0 Hz, 1H, Ar).
[0833] M/Z (M+H).sup.+=363.1.
[0834] MP: >250° C.
Compound 28: 4-Chloro-2-hydrazino-benzoic Acid, HCl
[0835] Compound 28 was obtained according to general procedure IX, starting from 2-amino-4-chlorobenzoic acid, as a white solid in 38% yield.
[0836] .sup.1H-NMR (400 MHz, DMSO): 7.00 (dd, J 8.6 Hz, 2.0 Hz, 1H, Ar); 7.23 (d, J 2.0 Hz, 1H, Ar); 7.88 (d, J 8.6 Hz, 1H, Ar); 9.16 (bs, 1H, NH); 10.74 (bs, 3H, NH.sub.3).
Compound 29: 8-Chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0837] Compound 29 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 28 as a pale brown solid in 57% yield.
[0838] .sup.1H-NMR (400 MHz, DMSO): 6.78 (s, 1H, Ar); 7.60 (dd, J 8.5 Hz, 2.0 Hz, 1H, Ar); 8.16 (d, J 8.5 Hz, 1H, Ar); 8.25 (d, J 2.0 Hz, 1H, Ar); 8.29-8.31 (m, 1H, Ar); 8.44 (bs, 1H, Ar); 8.86 (d, J 5.0 Hz, 1H, Ar); 12.57 (bs, 1H, NH).
[0839] M/Z (M[.sup.35Cl]+H).sup.+=365.0.
Example 56: 8-Chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0840] ##STR00067##
[0841] Example 56 was obtained according to general procedure II(iii), starting from compound 29 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 56 was obtained without further purification as a beige solid in 77% yield.
[0842] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.19 (s, 1H, Ar); 7.59 (dd, J 8.6 Hz, 2.0 Hz, 1H, Ar); 8.18 (d, J 8.6 Hz, 1H, Ar); 8.23 (d, J 2.0 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[0843] M/Z (M[.sup.35Cl]+H).sup.+=379.1.
[0844] MP: 220-225° C.
Compound 30: 2-Hydrazino-4-trifluoromethyl-benzoic Acid, HCl
[0845] Compound 30 was obtained according to general procedure IX, starting from 2-amino-4-trifluoromethylbenzoic acid, as a beige solid in 62% yield.
[0846] .sup.1H-NMR (400 MHz, DMSO): 7.26 (d, J 8.7 Hz, 1H, Ar); 7.92 (dd, J 8.7 Hz, 2.0 Hz, 1H, Ar); 8.11 (d, J 2.0 Hz, 1H, Ar); 9.42 (bs, 1H, NH); 10.74 (bs, 3H, NH.sub.3).
[0847] M/Z (M+H).sup.+=221.2.
Compound 31: 8-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0848] Compound 31 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 30 as a brown solid in 50% yield.
[0849] .sup.1H-NMR (400 MHz, DMSO): 6.68 (s, 1H, Ar); 8.17 (dd, J 8.7 Hz, 1.9 Hz, 1H, Ar); 8.25-8.26 (m, 1H, Ar); 8.34-8.39 (m, 3H, Ar); 8.84 (d, J 5.1 Hz, 1H, Ar). Signal for NH is not observed.
[0850] M/Z (M+H).sup.+=399.1.
Example 57: 4-Methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0851] ##STR00068##
[0852] Example 57 was obtained according to general procedure II(i), starting from compound 31 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 57 was obtained without further purification as a brown solid in 33% yield.
[0853] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 7.23 (s, 1H, Ar); 8.24-8.26 (m, 2H, Ar); 8.37-8.39 (m, 3H, Ar); 8.90 (d, J 4.9 Hz, 1H, Ar).
[0854] M/Z (M+H).sup.+=413.2.
Compound 32: 4-Bromo-2-hydrazino-benzoic Acid, HCl
[0855] Compound 32 was obtained according to general procedure I, starting from 2-amino-4-bromo-benzoic acid, as a white solid in a quantitative yield.
[0856] .sup.1H-NMR (400 MHz, DMSO): 7.14 (dd, J 8.5 Hz, 1.9 Hz, 1H, Ar); 7.37 (d, J 1.9 Hz, 1H, Ar); 7.81 (d, J 8.5 Hz, 1H, Ar); 9.15 (bs, 1H, NH); 10.63 (bs, 3H, NH.sub.3).
[0857] M/Z (M[.sup.79Br]-18+H).sup.+=213.
Compound 33: 8-Bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0858] Compound 33 was obtained according to general procedure I(i), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 32 as a brown solid in 69% yield.
[0859] .sup.1H-NMR (400 MHz, DMSO): 6.60 (s, 1H, Ar); 7.64 (dd, J 8.5 Hz, 1.9 Hz, 1H, Ar); 8.03 (d, J 8.5 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.31 (d, 1.9 Hz, 1H, Ar); 8.38 (bs, 1H, Ar); 8.82 (d, J 5.0 Hz, 1H, Ar). Signal for NH is not observed.
[0860] M/Z (M[.sup.79Br]+H).sup.+=409.0.
Example 58: 8-Bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0861] ##STR00069##
[0862] Example 58 was obtained according to general procedure II(ii), starting from compound 33 in presence of iodomethane. The reaction mixture was stirred for 1 hour at room temperature. Example 58 was obtained without further purification as a beige solid in 84% yield.
[0863] .sup.1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH.sub.3); 7.16 (s, 1H, Ar); 7.71 (dd, J 8.5 Hz, 1.9 Hz, 1H, Ar); 8.07 (d, J 8.5 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.34 (d, 1.9 Hz, 1H, Ar); 8.34 (bs, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar).
[0864] M/Z (M[.sup.79Br]+H).sup.+=423.2.
Example 59: 4-Methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0865] ##STR00070##
[0866] Example 59 was obtained according to general procedure X(v) starting from example 58 in presence of morpholine. Purification by flash-chromatography (MeOH in DCM, 0 to 2%) afforded example 59 as a beige solid in 44% yield.
[0867] .sup.1H-NMR (400 MHz, DMSO at 80° C.): 3.46-3.48 (m, 4H, 2 CH.sub.2); 3.56 (s, 3H, NCH.sub.3); 3.80-3.84 (m, 4H, 2 CH.sub.2); 7.00 (s, 1H, Ar); 7.13 (dd, J 9.0 Hz, 2.3 Hz, 1H, Ar); 7.52 (d, 2.3 Hz, 1H, Ar); 8.03 (d, J 9.0 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0868] M/Z (M+H).sup.+=430.3.
[0869] MP: >250° C.
Example 60: 4-Methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0870] ##STR00071##
[0871] Example 60 was obtained according to general procedure X(iii) starting from example 58 in presence of pyrolidine. The reaction was heated for 1 hour. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 60 as a beige solid in 25% yield.
[0872] .sup.1H-NMR (400 MHz, CDCl.sub.3): 2.08-2.12 (m, 4H, 2 CH.sub.2); 3.48-3.52 (m, 4H, 2 CH.sub.2); 3.60 (s, 3H, NCH.sub.3); 6.28 (s, 1H, Ar); 6.63 (dd, J 9.0 Hz, 2.4 Hz, 1H, Ar); 7.14 (d, 2.4 Hz, 1H, Ar); 7.95-7.97 (m, 1H, Ar); 8.11 (d, J 9.0 Hz, 1H, Ar); 8.22 (bs, 1H, Ar); 8.77 (d, J 5.1 Hz, 1H, Ar).
[0873] M/Z (M+H).sup.+=414.2.
[0874] MP: >250° C.
Example 61: 4-Methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0875] ##STR00072##
[0876] Example 61 was obtained according to general procedure X(iii) starting from example 58 in presence of methyl amine HCl. The reaction was performed with 3.0 equiv of LiHMDS. The reaction mixture was heated for 4 hours, then methylamine HCl (1.2 equiv.), LiHMDS (1N in THF; 3.0 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for one hour at 60° C. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 61 as a beige solid in 44% yield.
[0877] .sup.1H-NMR (400 MHz, DMSO): 2.86 (d, J 4.9 Hz, 3H, NHCH.sub.3); 3.50 (s, 3H, NCH.sub.3); 6.72 (dd, J 8.8 Hz, 2.2 Hz, 1H, Ar); 7.06 (s, 1H, Ar); 7.08-7.12 (m, 2H, Ar+NHCH.sub.3); 7.87 (d, J 8.8 Hz, 1H, Ar); 8.22-8.24 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.87 (d, J 5.2 Hz, 1H, Ar).
[0878] M/Z (M+H).sup.+=374.0.
[0879] MP: >250° C.
Example 62: 8-(4-Methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0880] ##STR00073##
[0881] Example 62 was obtained according to general procedure X(iii) starting from example 58 in presence of 4-methoxypiperidine HCl. The reaction was performed with 3.0 equiv of LiHMDS. The reaction mixture was heated for 2 hours, then 4-methoxypiperidine HCl (1.2 equiv.), LiHMDS (1N in THF; 3.0 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for one hour at 60° C. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 62 as a beige solid in 48% yield.
[0882] .sup.1H-NMR (400 MHz, DMSO): 1.51-1.59 (m, 2H, 2 CH.sub.aH.sub.b); 1.95-1.99 (m, 2H, 2CH.sub.aH.sub.b); 3.23-3.30 (m, 5H, OCH.sub.3+2NCH.sub.aH.sub.b); 3.45-3.51 (m, 4H, NCH.sub.3+OCH); 3.45-3.51 (m, 2H, 2 NCH.sub.aH.sub.b); 7.08 (s, 1H, Ar); 7.11 (dd, J 9.0 Hz, 2.4 Hz, 1H, Ar); 7.45 (d, 2.4 Hz, 1H, Ar); 7.93 (d, J 9.0 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0883] M/Z (M+H).sup.+=458.2.
[0884] MP: >250° C.
Example 63: 8-(4-Hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0885] ##STR00074##
[0886] Example 63 was obtained according to general procedure X(iii) starting from example 58 in presence of 4-hydroxypiperidine. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 63 as a beige solid in 20% yield.
[0887] .sup.1H-NMR (400 MHz, DMSO): 1.43-1.52 (m, 2H, 2 CH.sub.aH.sub.b); 1.85-1.89 (m, 2H, 2 CH.sub.aH.sub.b); 3.16-3.24 (m, 2H, 2NCH.sub.aH.sub.b); 3.51 (s, 3H, NCH.sub.3); 3.73-3.80 (m, 1H, OCH); 3.82-3.87 (m, 2H, 2 NCH.sub.aH.sub.b); 4.77 (d, 4.2 Hz, 1H, OH); 7.09 (s, 1H, Ar); 7.11 (dd, J 9.1 Hz, 2.4 Hz, 1H, Ar); 7.45 (d, 2.4 Hz, 1H, Ar); 7.93 (d, J 9.1 Hz, 1H, Ar); 8.26-8.28 (m, 1H, Ar); 8.38 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0888] M/Z (M+H).sup.+=444.1.
[0889] MP: 112-117° C.
Example 64: 8-Dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0890] ##STR00075##
[0891] Example 64 was obtained according to general procedure X(iii) starting from example 58 in presence of dimethyl amine HCl. The reaction was performed with 3.0 equiv of LiHMDS. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 64 as a beige solid in 43% yield.
[0892] .sup.1H-NMR (400 MHz, CDCl.sub.3): 3.18 (s, 6H, N(CH.sub.3).sub.2); 3.60 (s, 3H, NCH.sub.3); 6.28 (s, 1H, Ar); 6.76 (dd, J 9.0 Hz, 2.5 Hz, 1H, Ar); 7.29 (d, 2.5 Hz, 1H, Ar); 7.96-7.98 (m, 1H, Ar); 8.12 (d, J 9.0 Hz, 1H, Ar); 8.22 (bs, 1H, Ar); 8.77 (d, J 5.1 Hz, 1H, Ar).
[0893] M/Z (M+H).sup.+=388.0.
[0894] MP: >250° C.
Example 65: 4-Methyl-8-(4-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0895] ##STR00076##
[0896] Example 65 was obtained according to general procedure X(iii) starting from example 58 in presence of N-methylpiperazine. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) and salt formation according to procedure IV(ii) afforded example 65 as a brown solid in 35% yield.
[0897] .sup.1H-NMR (400 MHz, DMSO): 2.85 (s, 3H, NCH.sub.3); 3.13-3.24 (m, 2H, 2NCH.sub.aH.sub.b); 3.36-3.42 (m, 2H, 2NCH.sub.aH.sub.b); 3.54-3.58 (m, 5H, NCH.sub.3+2NCH.sub.aH.sub.b); 4.23-4.26 (m, 2H, 2NCH.sub.aH.sub.b); 7.15 (s, 1H, Ar); 7.21 (dd, J 9.0 Hz, 2.4 Hz, 1H, Ar); 7.78 (d, 2.4 Hz, 1H, Ar); 8.03 (d, J 9.0 Hz, 1H, Ar); 8.27-8.29 (m, 1H, Ar); 8.41 (bs, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar); 10.76 (bs, 1H, NH).
[0898] M/Z (M+H).sup.+=443.1.
[0899] MP: >250° C.
Example 66: 4-Methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[0900] ##STR00077##
[0901] Example 66 was obtained according to general procedure X(ii) starting from example 58 in presence of piperazine (5.0 equiv.). The reaction was performed with 3.0 equiv of LiHMDS and THF was used as solvent. After hydrolysis, the resulting solid was collected, washed with water, dried over MgSO.sub.4 and purified by flash-chromatography (MeOH in DCM, 0 to 20%). Salt formation according to procedure IV(iii) afforded example 66 as a beige solid in 21% yield.
[0902] .sup.1H-NMR (400 MHz, DMSO/D20): 3.25-3.29 (m, 4H, 2NCH.sub.2); 3.46 (m, 3H, NCH.sub.3); 3.65-3.69 (m, 4H, 2NCH.sub.2); 6.90 (s, 1H, Ar); 7.12 (dd, J 9.0 Hz, 1.9 Hz, 1H, Ar); 7.47 (d, 1.9 Hz, 1H, Ar); 7.96 (d, J 9.0 Hz, 1H, Ar); 8.14-8.16 (m, 1H, Ar); 8.29 (bs, 1H, Ar); 8.88 (d, J 4.9 Hz, 1H, Ar).
[0903] M/Z (M+H).sup.+=429.1.
[0904] MP: >250° C.
Example 67: 8-(4-Hydroxymethyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazoin-5-one
[0905] ##STR00078##
[0906] Example 67 was obtained according to general procedure X(iii) starting from example 58 in presence of 4-piperidinemethanol. The reaction mixture was heated for 2 hours, then 4-piperidinemethanol (1.2 equiv.), LiHMDS (1N in THF; 2.4 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for 17 hours at 60° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 67 as a beige solid in 28% yield.
[0907] .sup.1H-NMR (400 MHz, DMSO): 1.18-1.28 (m, 2H, 2 CH.sub.aH.sub.b); 1.64-1.72 (m, 1H, CH); 1.78-1.82 (m, 2H, 2 CH.sub.aH.sub.b); 2.93-3.00 (m, 2H, 2NCH.sub.aH.sub.b); 3.27-3.31 (m, 2H, 2NCH.sub.aH.sub.b); 3.50 (s, 3H, NCH.sub.3); 4.05-4.08 (m, 2H, CH.sub.2OH); 4.50-4.52 (m, 1H, CH.sub.2OH); 7.07 (s, 1H, Ar); 7.10 (dd, J 9.1 Hz, 2.4 Hz, 1H, Ar); 7.42 (d, 2.4 Hz, 1H, Ar); 7.92 (d, J 9.1 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0908] M/Z (M+H).sup.+=458.2.
[0909] MP: 205-210° C.
Example 68: 8-(3-Hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0910] ##STR00079##
[0911] Example 68 was obtained according to general procedure X(iv) starting from example 58 in presence of 4-hydroxyazetidine. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 68 as a beige solid in 51% yield.
[0912] .sup.1H-NMR (400 MHz, DMSO): 3.51 (s, 3H, NCH.sub.3); 3.81 (dd, J 8.7 Hz, 4.4 Hz, 2H, 2NCH.sub.aH.sub.b); 4.29-4.33 (m, 2H, 2NCH.sub.aH.sub.b); 4.63-4.70 (m, 1H, CHOH); 5.82 (d, 6.2 Hz, 1H, CHOH); 6.55 (dd, J 8.8 Hz, 2.3 Hz, 1H, Ar); 6.91 (d, 2.3 Hz, 1H, Ar); 7.10 (s, 1H, Ar); 7.95 (d, J 8.8 Hz, 1H, Ar); 8.25-8.26 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar).
[0913] M/Z (M+H).sup.+=416.0.
[0914] MP: >250° C.
Example 69: 8-(3-Hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0915] ##STR00080##
[0916] Example 69 was obtained according to general procedure X(iv) starting from example 58 in presence of 4-azetidin-3-ylmethanol HCl. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 69 as a beige solid in 38% yield.
[0917] .sup.1H-NMR (400 MHz, DMSO): 2.84-2.93 (m, 1H, CH); 3.51 (s, 3H, NCH.sub.3); 3.62 (t, J 5.4 Hz, 2H, 2CHCH.sub.2OH); 3.82 (dd, J 8.1 Hz, J 5.4 Hz, 2H, 2NCH.sub.aH.sub.b); 4.10 (t, J 8.1 Hz, 2H, 2NCH.sub.aH.sub.b); 4.84 (t, 5.4 Hz, 1H, CH.sub.2OH); 6.53 (dd, J 8.7 Hz, 2.2 Hz, 1H, Ar); 6.89 (d, 2.2 Hz, 1H, Ar); 7.08 (s, 1H, Ar); 7.94 (d, J 8.7 Hz, 1H, Ar); 8.24-8.25 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar).
[0918] M/Z (M+H).sup.+=430.1.
[0919] MP: >250° C.
Example 70: 8-(3-Hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0920] ##STR00081##
[0921] Example 70 was obtained according to general procedure X(iii) starting from example 58 in presence of 3-pyrolidinol. The reaction mixture was heated for 2 hours, then 3-pyrolidinol (1.2 equiv.), LiHMDS (1N in THF; 2.4 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for 17 hours at 60° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 70 as a beige solid in 47% yield.
[0922] .sup.1H-NMR (400 MHz, DMSO): 1.95-2.01 (m, 1H, CH.sub.aH.sub.b); 2.06-2.15 (m, 1H, CH.sub.aH.sub.b); 3.28-3.30 (m, 1H, NCH); 3.50-3.54 (m, 5H, 2NCH+NCH.sub.3); 3.58 (dd, J 10.7 Hz, 4.5 Hz, 1H, NCH.sub.aH.sub.b); 4.47 (m, 1H, CHOH); 5.07 (d, 3.7 Hz, 1H, CHOH); 6.72 (dd, J 8.9 Hz, 2.3 Hz, 1H, Ar); 7.04 (d, 2.3 Hz, 1H, Ar); 7.07 (s, 1H, Ar); 7.94 (d, J 8.9 Hz, 1H, Ar); 8.24-8.26 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.86 (d, J 5.0 Hz, 1H, Ar).
[0923] M/Z (M+H).sup.+=430.2.
[0924] MP: >250° C.
Example 71: 8-(4-Hydroxy-4-methyl-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0925] ##STR00082##
[0926] Example 71 was obtained according to general procedure X(iv) starting from example 58 in presence of 4-methylpiperidin-4-ol. The reaction mixture was heated for 17 hours, then 4-methylpiperidin-4-ol (0.8 equiv.), K.sub.3PO.sub.4 (2.0 equiv.), CuI (0.05 equiv.) and DMPAO (0.1 equiv.) were added. The reaction mixture was further heated for 24 hours at 100° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 71 as a beige solid in 22% yield.
[0927] .sup.1H-NMR (400 MHz, DMSO): 1.18 (s, 3H, CCH.sub.3); 1.53-1.64 (m, 4H, 2 CH.sub.2); 3.37-3.43 (m, 2H, 2 NCH.sub.aH.sub.b); 3.51 (s, 3H, NCH.sub.3); 3.68-3.73 (m, 2H, 2NCH.sub.aH.sub.b); 4.44 (s, 1H, OH); 7.09 (s, 1H, Ar); 7.11 (dd, J 9.1 Hz, 2.4 Hz, 1H, Ar); 7.45 (d, 2.4 Hz, 1H, Ar); 7.93 (d, J 9.1 Hz, 1H, Ar); 8.26-8.28 (m, 1H, Ar); 8.38 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[0928] M/Z (M+H).sup.+=458.2.
[0929] MP: >250° C.
Example 72: 4,8-Dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0930] ##STR00083##
[0931] Example 72 was obtained according to general procedure III starting from example 58 in presence of a solution of dimethylzinc in toluene (2M-4.0 equiv.). The reaction was performed without CuI and was heated for 17 hours at 90° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) and trituration of the resulting solid by EtOH and then Et.sub.2O afforded example 72 as an orange solid in 24% yield.
[0932] .sup.1H-NMR (400 MHz, DMSO): 2.54 (s, 3H, CH.sub.3); 3.55 (s, 3H, NCH.sub.3); 7.15 (s, 1H, Ar); 7.36-7.39 (m, 1H, Ar); 8.05 (bs, 1H, Ar); 8.08 (d, J 8.2 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0933] M/Z (M+H).sup.+=359.0.
[0934] MP: >250° C.
Example 73: 8-Cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0935] ##STR00084##
[0936] Example 73 was obtained according to general procedure III starting from example 58 in presence of a solution of cyclopropylzinc bromide in THF (0.5N-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 73 as a beige solid in 26% yield.
[0937] .sup.1H-NMR (400 MHz, DMSO): 0.90-0.93 (m, 2H, 2CH.sub.aH.sub.b); 1.13-1.18 (m, 2H, 2CH.sub.aH.sub.b); 2.20-2.27 (m, 1H, CH); 3.55 (s, 3H, NCH.sub.3); 7.15 (s, 1H, Ar); 7.22 (dd, J 8.3 Hz, J 1.6 Hz, 1H, Ar); 7.93 (d, J 1.6 Hz, 1H, Ar); 8.06 (d, J 8.3 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.38 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0938] M/Z (M+H).sup.+=385.2.
[0939] MP: >250° C.
Example 74: 8-Cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0940] ##STR00085##
[0941] Example 74 was obtained according to general procedure III starting from example 58 in presence of a solution of cyclopentylzinc bromide in THF (0.5N-2.2 equiv.). Purification by flash-chromatography (EtOAc in cyHex, 0 to 50%) afforded example 74 as a beige solid in 22% yield.
[0942] .sup.1H-NMR (400 MHz, DMSO at 80° C.): 1.67-1.77 (m, 4H, 2CH.sub.2); 1.84-1.88 (m, 2H, 2CH.sub.aH.sub.b); 2.13-2.19 (m, 2H, 2CH.sub.aH.sub.b); 3.25-3.30 (m, 1H, CH); 3.59 (s, 3H, NCH.sub.3); 7.06 (s, 1H, Ar); 7.47 (dd, J 8.2 Hz, J 1.4 Hz, 1H, Ar); 8.10 (d, J 1.4 Hz, 1H, Ar); 8.14 (d, J 8.2 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.87 (d, J 5.0 Hz, 1H, Ar).
[0943] M/Z (M+H).sup.+=413.4.
[0944] MP: 246-250° C.
Example 75: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carbonitrile
[0945] ##STR00086##
[0946] Example 75 was obtained according to general procedure VI starting from example 58. The reaction was heated for 17 hours at 100° C. Purification by flash-chromatography (MeOH in DCM, 0 to 2%) afforded example 75 as a beige solid in 22% yield.
[0947] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.93 (dd, J 8.1 Hz, 1.4 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.29 (d, J 8.1 Hz, 1H, Ar); 8.40 (bs, 1H, Ar); 8.65 (d, J 1.4 Hz, 1H, Ar); 8.89 (d, J 5.0 Hz, 1H, Ar).
[0948] M/Z (M+H).sup.+=370.2.
[0949] MP: >250° C.
Example 76: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic Acid
[0950] ##STR00087##
[0951] To a solution of example 75 (287 mg, 1.0 equiv.) in DMSO (4 mL, C=0.2 molL.sup.−1), a solution of aqueous NaOH (1N, 4 mL, 5.1 equiv.) was added and the mixture was heated for 17 hours at 90° C. After cooling, the reaction mixture was hydrolyzed with an aqueous HCl solution (1N). The solid was collected, washed with water and dried under reduced pressure at 50° C. with P.sub.2O.sub.5. Trituration in Et.sub.2O afforded example 76 as a yellow solid in 69% yield.
[0952] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 7.24 (s, 1H, Ar); 8.04 (dd, J 8.1 Hz, 1.4 Hz, 1H, Ar); 8.28-8.31 (m, 2H, Ar); 8.40 (bs, 1H, Ar); 8.69 (d, J 1.4 Hz, 1H, Ar); 8.89 (d, J 5.0 Hz, 1H, Ar). Signal for COOH is not observed.
[0953] M/Z (M+H).sup.+=389.1.
[0954] MP: >250° C.
General Procedure XII: Amide Formation Via Acid Activation
[0955] Method (i): Under inert atmosphere, to a solution of acid (1.0 equiv.) in DMF (C=0.1 molL.sup.−1), BOP (1.1 equiv.), diisopropylamine (1.1 equiv.), and amine (1.1 equiv.) were added. The resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the amide.
Example 77: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic Acid Amide
[0956] ##STR00088##
[0957] Example 77 was obtained according to general procedure XII(i) starting from example 58 with ammoniac as nucleophile (0.5 N in Dioxane). The reaction mixture was stirred for 3 hours at room temperature. Trituration in EtOH, DCM and then Et.sub.2O afforded example 77 as a beige solid in 23% yield.
[0958] .sup.1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH.sub.3); 7.21 (s, 1H, Ar); 7.77 (bs, 1H, CONH.sub.aH.sub.b); 8.00 (dd, J 8.2 Hz, 1.2 Hz, 1H, Ar); 8.25-8.29 (m, 2H, Ar); 8.40-8.42 (m, 2H, 1Ar+CONH.sub.aH.sub.b); 8.68 (d, J 1.2 Hz, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[0959] M/Z (M+H).sup.+=388.0.
[0960] MP: >250° C.
Example 78: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic Acid Methylamide
[0961] ##STR00089##
[0962] Example 78 was obtained according to general procedure XII(i) starting from example 58 with methylamine HCl as nucleophile (2.2 equiv. of iPr.sub.2NEt was added instead of 1.1 equiv.). Trituration in EtOH then Et.sub.2O afforded example 78 as a white solid in 33% yield.
[0963] .sup.1H-NMR (400 MHz, DMSO): 2.86 (d, J 4.6 Hz, 3H, CONHCH.sub.3); 3.57 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.94 (dd, J 8.3 Hz, 1.6 Hz, 1H, Ar); 8.24-8.26 (m, 2H, Ar); 8.39 (bs, 1H, Ar); 8.60 (d, 1.6 Hz, 1H, Ar); 8.88-8.90 (m, 2H, 1Ar+CONHCH.sub.3).
[0964] M/Z (M+H).sup.+=402.5.
[0965] MP: >250° C.
Example 79: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic Acid Dimethylamide
[0966] ##STR00090##
[0967] Example 79 was obtained according to general procedure XII(i) starting from example 58 with dimethylamine HCl as nucleophile (3.0 equiv. of iPr.sub.2NEt was added instead of 1.1 equiv.). The reaction mixture was stirred for 17 hours at room temperature. Trituration in EtOH then Et.sub.2O afforded example 79 as a beige solid in 3% yield.
[0968] .sup.1H-NMR (400 MHz, DMSO): 2.94 (s, 3H, CON(CH.sub.3)(CH.sub.3)); 3.06 (s, 3H, CON(CH.sub.3)(CH.sub.3)); 3.58 (s, 3H, NCH.sub.3); 7.22 (s, 1H, Ar); 7.54-7.55 (m, 1H, Ar); 8.20-8.28 (m, 3H, Ar); 8.41 (bs, 1H, Ar); 8.88-8.89 (m, 1H, 1Ar).
[0969] M/Z (M+H).sup.+=415.9.
Example 80: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazoline-8-carboxylic Acid Diethylamide
[0970] ##STR00091##
[0971] Example 80 was obtained according to general procedure XII(i) starting from example 58 with diethylamine as nucleophile. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 80 as a white solid in 40% yield.
[0972] .sup.1H-NMR (400 MHz, DMSO): 1.06-1.23 (m, 6H, CON(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3)); 3.19-3.25 (m, 2H, CON(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3)); 3.48-3.54 (m, 2H, CON(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3)); 3.58 (s, 3H, NCH.sub.3); 7.22 (s, 1H, Ar); 7.50-7.53 (m, 1H, Ar); 8.14 (bs, 1H, Ar); 8.25 (d, J 8.2 Hz, 1H, Ar); 8.27-8.28 (m, 1H, Ar); 8.41 (bs, 1H, Ar); 8.88 (d, J 4.9 Hz, 1H, 1Ar).
[0973] M/Z (M+H).sup.+=444.3.
[0974] MP: 240-245° C.
Example 81: 4-Methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0975] ##STR00092##
[0976] Example 81 was obtained according to general procedure XII(i) starting from example 58 with morpholine as nucleophile. Trituration in DCM then Et.sub.2O afforded example 81 as a white solid in 34% yield.
[0977] .sup.1H-NMR (400 MHz, DMSO): 3.52-3.58 (m, 4H, 2 CH.sub.2); 3.62 (s, 3H, NCH.sub.3); 3.64-3.69 (m, 4H, 2 CH.sub.2); 7.11 (s, 1H, Ar); 7.55 (d, J 8.0 Hz, 1H, Ar); 8.23-8.29 (m, 3H, Ar); 8.37 (bs, 1H, Ar); 8.88 (d, J 4.7 Hz, 1H, Ar).
[0978] M/Z (M+H).sup.+=458.3.
[0979] MP: >250° C.
Example 82: 4-Methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0980] ##STR00093##
[0981] Example 82 was obtained according to general procedure XII(i) starting from example 58 with pyrolidine as nucleophile. Trituration in EtOH then Et.sub.2O afforded example 82 as a beige solid in 56% yield.
[0982] .sup.1H-NMR (400 MHz, DMSO): 1.82-1.96 (m, 4H, 2 CH.sub.2); 3.40 (t, J 6.4 Hz, 2H, 2NCH.sub.aH.sub.b); 3.54 (t, J 6.8 Hz, 2H, 2NCH.sub.aH.sub.b); 3.58 (s, 3H, NCH.sub.3); 7.21 (s, 1H, Ar); 7.64 (dd, J 8.2 Hz, 1.5 Hz, 1H, Ar); 8.24 (d, 8.2 Hz, 1H, Ar); 8.26-8.27 (m, 2H, Ar); 8.40 (bs, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[0983] M/Z (M+H).sup.+=442.0.
[0984] MP: >250° C.
Example 83: 8-(2-Hydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0985] ##STR00094##
[0986] Example 83 was obtained according to general procedure VII(iii) starting from example 55 in presence of ethylene glycol. The reaction mixture was heated for 3 hours at 60° C., then tBuOK (1.2 equiv.) were added and the mixture was heated for additional 17 hours at 60° C. Trituration in DCM and Et.sub.2O afforded example 83 as a beige solid in 47% yield.
[0987] .sup.1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH.sub.3); 3.79-3.82 (m, 2H, OCH.sub.2CH.sub.2OH); 4.23 (t, J 4.9 Hz, 2H, OCH.sub.2CH.sub.2OH); 4.97 (t, J 5.4 Hz, 1H, OCH.sub.2CH.sub.2OH); 7.11 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 7.13 (s, 1H, Ar); 7.61 (d, J 2.4 Hz, 1H, Ar); 8.09 (d, J 8.8 Hz, 1H, Ar); 8.24-8.26 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.87 (d, J 5.0 Hz, 1H, Ar).
[0988] M/Z (M+H).sup.+=405.1.
[0989] MP: 128-134° C.
Compound 34: 2-Hydrazino-6-trifluoromethyl-benzoic Acid, HCl
[0990] Compound 34 was obtained according to general procedure IX, starting from 2-amino-6-trifluoromethylbenzoic acid, as a white solid in 35% yield.
[0991] .sup.1H-NMR (400 MHz, DMSO): 7.33-7.43 (m, 2H, Ar); 7.60-7.67 (m, 1H, Ar); 8.06 (bs, 1H, NH); 10.32 (bs, 3H, NH.sub.3).
[0992] M/Z (M-18+H).sup.+=203.0.
Compound 35: 6-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0993] Compound 35 was obtained according to general procedure I(iii), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 34 as a brown solid in 25% yield.
[0994] .sup.1H-NMR (400 MHz, DMSO): 6.34 (s, 1H, Ar); 7.78 (d, J 7.4 Hz, 1H, Ar); 7.82-7.86 (m, 1H, Ar); 8.17-8.19 (m, 1H, Ar); 8.32 (bs, 1H, Ar); 8.50 (d, J 8.1 Hz, 1H, Ar); 8.79 (d, J 5.1 Hz, 1H, Ar).
[0995] M/Z (M+H).sup.+=399.1.
Example 84: 4-Methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0996] ##STR00095##
[0997] Example 84 was obtained according to general procedure II(i), starting from compound 35 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 84 was obtained without further purification as a grey solid in 19% yield.
[0998] .sup.1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 7.99-8.01 (m, 1H, Ar); 8.06-8.11 (m, 1H, Ar); 8.27-8.28 (m, 1H, Ar); 8.41 (bs, 1H, Ar); 8.66-8.68 (m, 1H, Ar); 8.91-8.92 (m, 1H, Ar).
[0999] M/Z (M+H).sup.+=413.1.
Compound 36: 6-Fluoro-2-hydrazino-benzoic Acid, HCl
[1000] Compound 36 was obtained according to general procedure IX, starting from 2-amino-6-fluoromethylbenzoic acid, as a beige solid in 48% yield.
[1001] .sup.1H-NMR (400 MHz, DMSO): 6.65 (dd, J 106 Hz, J 8.4 Hz, 1H, Ar); 6.9 (d, J 8.5 Hz, 1H, Ar); 7.51-7.57 (m, 1H, Ar); 8.70 (bs, 1H, NH); 10.28 (bs, 3H, NH.sub.3).
[1002] M/Z (M+H).sup.+=171.8.
Compound 37: 6-Fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1003] Compound 37 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 36 as a pale brown solid in 53% yield.
[1004] .sup.1H-NMR (400 MHz, DMSO): 6.72 (s, 1H, Ar); 7.32 (dd, J 11.2 Hz, J 8.5 Hz, 1H, Ar); 7.88-7.94 (m, 1H, Ar); 8.08 (d, J 8.2 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.85 (d, J 4.8 Hz, 1H, Ar). Signal for NH is not observed.
[1005] M/Z (M+H).sup.+=349.1.
Example 85: 6-Fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1006] ##STR00096##
[1007] Example 85 was obtained according to general procedure II(iii), starting from compound 37 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 85 was obtained without further purification as a brown solid in 69% yield.
[1008] .sup.1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH.sub.3); 7.19 (s, 1H, Ar); 7.36 (dd, J 11.0 Hz, J 8.2 Hz, 1H, Ar); 7.91-7.96 (m, 1H, Ar); 8.11 (d, J 8.3 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.90 (d, J 5.1 Hz, 1H, Ar).
[1009] M/Z (M+H).sup.+=363.1.
[1010] MP: >250° C.
Compound 38: 2-Hydrazino-3-methoxy-benzoic Acid, HCl
[1011] Compound 38 was obtained according to general procedure IX, starting from 2-amino-3-methoxylbenzoic acid, as a white solid in 19% yield.
[1012] .sup.1H-NMR (400 MHz, DMSO): 3.89 (s, 3H, OCH.sub.3); 7.18 (t, J 8.1 Hz, 1H, Ar); 7.34 (dd, J 8.1 Hz, 1.3 Hz, 1H, Ar); 7.55 (dd, J 8.1 Hz, J 1.3 Hz, 1H, Ar); 9.04 (bs, 1H, NH); 9.75 (bs, 3H, NH.sub.3).
Compound 39: 9-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1013] Compound 39 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 38 as a brown solid in 24% yield.
[1014] .sup.1H-NMR (400 MHz, DMSO): 3.92 (s, 3H, OCH.sub.3); 6.32 (s, 1H, Ar); 7.26 (t, J 7.8 Hz, 1H, Ar); 7.33 (dd, J 7.8 Hz, J 1.5 Hz, 1H, Ar); 7.74 (dd, J 7.8 Hz, J 1.5 Hz, 1H, Ar); 8.10-8.11 (m, 1H, Ar); 8.24 (bs, 1H, Ar); 8.71 (d, J 5.2 Hz, 1H, Ar). Signal for NH is not observed.
[1015] M/Z (M+H).sup.+=361.1.
Example 86: 9-Methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1016] ##STR00097##
[1017] Example 86 was obtained according to general procedure II(iii), starting from compound 39 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. The solid was further washed with DCM, DCM/MeOH, EtOH and Et2O to obtained example 86 as a white solid in 14% yield.
[1018] .sup.1H-NMR (400 MHz, DMSO): 3.61 (s, 3H, NCH.sub.3); 4.06 (s, 3H, OCH.sub.3); 7.07 (s, 1H, Ar); 7.52 (t, J 8.0 Hz, 1H, Ar); 7.64 (d, J 8.0 Hz, 1H, Ar); 7.92 (d, J 8.0 Hz, 1H, Ar); 8.22-8.24 (m, 1H, Ar); 8.34 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar).
[1019] M/Z (M+H).sup.+=374.9.
[1020] MP: >250° C.
Compound 40: 2-Hydrazino-4,5-dimethoxy-benzoic Acid, HCl
[1021] Compound 40 was obtained according to general procedure IX, starting from 2-amino-4,5-dimethoxybenzoic acid, as a beige solid in 92% yield.
[1022] .sup.1H-NMR (400 MHz, DMSO): 3.73 (s, 3H, OCH.sub.3); 3.85 (s, 3H, OCH.sub.3); 7.00 (s, 1H, Ar); 7.36 (s, 1H, Ar); 9.00 (bs, 1H, NH); 10.24 (bs, 3H, NH.sub.3).
Compound 41: 7, 8-Dimethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1023] Compound 41 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 40 as a brown solid in 57% yield.
[1024] .sup.1H-NMR (400 MHz, DMSO): 3.90 (s, 3H, OCH.sub.3); 4.04 (s, 3H, OCH.sub.3); 6.74 (s, 1H, Ar); 7.44 (s, 1H, Ar); 7.68 (s, 1H, Ar) 8.27-8.28 (m, 1H, Ar); 8.41 (bs, 1H, Ar); 8.84 (d, J 5.2 Hz, 1H, Ar); 12.39 (bs, 1H, NH).
Example 87: 7,8-Dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1025] ##STR00098##
[1026] Example 87 was obtained according to general procedure II(iii), starting from compound 41 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 87 was obtained without further purification as a beige solid in 63% yield.
[1027] .sup.1H-NMR (400 MHz, DMSO): 3.60 (s, 3H, NCH.sub.3); 3.92 (s, 3H, OCH.sub.3); 4.06 (s, 3H, OCH.sub.3); 7.05 (s, 1H, Ar); 7.62 (s, 1H, Ar); 7.72 (s, 1H, Ar); 8.24-8.25 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.86 (d, J 5.2 Hz, 1H, Ar).
[1028] M/Z (M+H).sup.+=405.0.
[1029] MP: >250° C.
Compound 42: 4,5-Difluoro-2-hydrazino-benzoic Acid, HCl
[1030] Compound 42 was obtained according to general procedure IX, starting from 2-amino-4,5-dimethoxybenzoic acid, as a beige solid in 67% yield.
[1031] .sup.1H-NMR (400 MHz, DMSO): 7.28 (dd, J 13.0 Hz, J 6.7 Hz, 1H, Ar); 7.87 (dd, J 11.2 Hz, J 9.6 Hz, 1H, Ar); 9.12 (bs, 1H, NH); 10.64 (bs, 3H, NH.sub.3).
Compound 43: 7, 8-Difluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1032] Compound 43 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 42 as a brown solid in 48% yield.
[1033] .sup.1H-NMR (400 MHz, DMSO): 6.80 (s, 1H, Ar); 8.15 (dd, J 10.2 Hz, J 8.2 Hz, 1H, Ar); 8.26-8.31 (m, 2H, Ar); 8.44 (bs, 1H, Ar); 8.86 (d, J 5.1 Hz, 1H, Ar); 12.67 (bs, 1H, NH).
[1034] M/Z (M+H).sup.+=366.9.
Example 88: 7, 8-Difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1035] ##STR00099##
[1036] Example 88 was obtained according to general procedure II(iii), starting from compound 43 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 88 was obtained without further purification as a white solid in 13% yield.
[1037] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 7.20 (s, 1H, Ar); 8.15 (dd, J 10.2 Hz, J 8.2 Hz, 1H, Ar); 8.23-8.30 (m, 2H, Ar); 8.39 (bs, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[1038] M/Z (M+H).sup.+=380.9.
[1039] MP: >206-212° C.
Compound 44: 4-Fluoro-2-hydrazino-5-methoxy-benzoic Acid, HCl
[1040] Compound 44 was obtained according to general procedure IX, starting from 2-amino-4-fluoro-5-methoxybenzoic acid, as a white solid in 78% yield.
[1041] .sup.1H-NMR (400 MHz, DMSO): 3.82 (s, 3H, OCH.sub.3); 7.16 (d, J 13.5 Hz, 1H, Ar); 7.58 (d, J 9.5 Hz, 1H, Ar); 9.13 (bs, 1H, NH); 10.55 (bs, 3H, NH.sub.3).
Compound 45: 8-Fluoro-7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1042] Compound 45 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 43 as a brown solid in 49% yield.
[1043] .sup.1H-NMR (400 MHz, DMSO): 3.98 (s, 3H, OCH.sub.3); 6.75 (s, 1H, Ar); 7.76 (d, J 8.7 Hz, 1H, Ar); 8.06 (d, J 11.2 Hz, 1H, Ar); 8.24-8.26 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.84 (d, J 5.1 Hz, 1H, Ar); 12.55 (bs, 1H, NH).
[1044] M/Z (M+H).sup.+=379.0.
Example 89: 8-Fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1045] ##STR00100##
[1046] Example 89 was obtained according to general procedure II(iii), starting from compound 45 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 89 was obtained without further purification as a brown solid in 79% yield.
[1047] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 3.98 (s, 3H, OCH.sub.3); 7.16 (s, 1H, Ar); 7.76 (d, J 8.6 Hz, 1H, Ar); 8.05 (d, J 11.1 Hz, 1H, Ar) 8.21-8.22 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar).
[1048] M/Z (M+H).sup.+=393.0.
[1049] MP: 220-230° C.
Example 90: 8-(4-Hydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1050] ##STR00101##
[1051] Example 90 was obtained according to general procedure X(vi) starting from example 89 in presence of 4-hydroxypiperidine. Trituration in DCM afforded example 90 as a white solid in 80% yield.
[1052] .sup.1H-NMR (400 MHz, DMSO): 1.54-1.62 (m, 2H, 2 CH.sub.aH.sub.b); 1.89-1.93 (m, 2H, 2 CH.sub.aH.sub.b); 2.93-2.99 (m, 2H, 2NCH.sub.aH.sub.b); 3.54-3.56 (s, 5H, 2NCH.sub.aH.sub.b+NCH.sub.3); 3.67-3.73 (m, 1H, OCH); 3.92 (s, 3H, OCH.sub.3); 7.14 (s, 1H, Ar); 7.50 (s, 1H, Ar); 7.57 (s, 1H, Ar) 8.25-8.26 (m, 1H, Ar); 8.36 (bs, 1H, Ar); 8.86 (d, J 5.0 Hz, 1H, Ar). Signal for OH is not observed.
[1053] M/Z (M+H).sup.+=474.1.
[1054] MP: >250° C.
Compound 46: 8-Dimethylamino-7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1055] Compound 46 was obtained according to general procedure X(vi) starting from compound 43 in presence of dimethylamine (2 N in THF). The reaction mixture was heated for 1 hour, then dimethylamine (2 N in THF, 1.6 equiv.) was added again. The reaction mixture was further heated for 17 Hrs at 90° C., then dimethylamine (2 N in THF, 1.6 equiv.) was added a last time. The reaction mixture was further heated for 24 hours at 90° C. Compound 46 was isolate without further purification.
[1056] M/Z (M+H).sup.+=392.0.
Example 91: 8-Dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1057] ##STR00102##
[1058] Example 91 was obtained according to general procedure II(iii), starting from compound 46 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 91 was obtained without further purification as a white solid in 64% yield.
[1059] .sup.1H-NMR (400 MHz, DMSO): 3.14 (s, 6H, N(CH.sub.3).sub.2); 3.57 (s, 3H, NCH.sub.3); 7.04 (s, 1H, Ar); 7.48 (d, J 8.0 Hz, 1H, Ar); 7.73 (d, J 14.3 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.34 (bs, 1H, Ar); 8.87 (d, J 5.2 Hz, 1H, Ar).
[1060] M/Z (M+H).sup.+=406.0.
[1061] MP: >250° C.
Compound 47: 5-Bromo-4-fluoro-2-hydrazino-benzoic Acid, HCl
[1062] Compound 47 was obtained according to general procedure IX, starting from 2-amino-5-bromo-4-fluorobenzoic acid, as a white solid in 85% yield.
[1063] .sup.1H-NMR (400 MHz, DMSO): 7.15 (d, J 11.5 Hz, 1H, Ar); 8.08 (d, J 8.0 Hz, 1H, Ar); 9.20 (bs, 1H, NH); 10.58 (bs, 3H, NH.sub.3).
Compound 48: 7-Bromo-8-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1064] Compound 48 was obtained according to general procedure I(iv), starting from 2-trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 47 as a reddish solid in 52% yield.
[1065] M/Z (M[.sup.79Br]+H).sup.+=427.0.
Example 92: 7-Bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1066] ##STR00103##
[1067] Example 92 was obtained according to general procedure II(iii), starting from compound 48 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature. Example 92 was obtained without further purification as a brown solid in 97% yield.
[1068] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.21 (s, 1H, Ar); 8.16 (d, J 9.0 Hz, 1H, Ar); 8.23-8.25 (m, 1H, Ar); 8.38-8.40 m, 2H, Ar); 8.90 (d, J 5.1 Hz, 1H, Ar).
[1069] M/Z (M[.sup.79Br]+H).sup.+=441.0.
[1070] MP: 230-235° C.
Example 93: 7-Bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1071] ##STR00104##
[1072] Example 93 was obtained according to general procedure VII(iii) starting from example 92 in presence of methanol. Trituration in Et.sub.2O afforded example 93 as a beige solid in 78% yield.
[1073] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 4.13 (s, 3H, OCH.sub.3); 7.20 (s, 1H, Ar); 7.72 (s, 1H, Ar); 8.26 (s, 1H, Ar); 8.27-8.29 (m, 1H, Ar); 8.40 (bs, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[1074] M/Z (M[.sup.79Br]+H).sup.+=453.0.
[1075] MP: >250° C.
Example 94: 8-Methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1076] ##STR00105##
[1077] Example 94 was obtained according to general procedure X(iii) starting from example 93 in presence of methylamine HCl. DMA was used as solvent and the reaction was heated for 1 hour at 60° C. After hydrolysis with a saturated aqueous NH.sub.4Cl solution, example 95 was extracted with EtOAc. The organic layers were combined, washed with brine and dried over MgSO.sub.4. Purification by preparative HPLC afforded example 94 as a yellow solid in 11% yield.
[1078] .sup.1H-NMR (400 MHz, DMSO/D.sub.2O): 2.80 (s, 3H, NHCH.sub.3); 3.55 (s, 3H, NCH.sub.3); 4.06 (s, 3H, OCH.sub.3); 5.66 (s, 3H, NHCH.sub.3); 7.00 (s, 1H, Ar); 7.09 (s, 1H, Ar); 7.54 (s, 1H, Ar); 8.22-8.23 (m, 1H, Ar); 8.35 (bs, 1H, Ar); 8.85 (d, J 5.1 Hz, 1H, Ar).
[1079] M/Z (M+H+CH.sub.3CN).sup.+=445.1.
[1080] MP: >250° C.
Compound 49: 7-Chloro-2-(2-chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1081] Compound 49 was obtained according to general procedure I(i), starting from 2-chloro-isonicotinic methyl ester in presence of hydrazine 10 as a brown solid in 51% yield.
[1082] .sup.1H-NMR (400 MHz, DMSO): 6.68 (s, 1H, Ar); 7.96-7.99 (m, 2H, Ar); 8.07 (bs, 1H, Ar); 8.09 (d, J 2.3 Hz, 1H, Ar); 8.22 (d, J 8.7 Hz, 1H, Ar); 8.50 (d, J 5.2 Hz, 1H, Ar); 12.55 (bs, 1H, NH).
[1083] M/Z (M[.sup.35Cl].sub.2+H).sup.+=331.1.
Example 95: 7-Chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1084] ##STR00106##
[1085] Example 95 was obtained according to general procedure II(iii), starting from compound 49 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. DMF was used instead of DMA. Example 95 was obtained without further purification as a beige solid in 82% yield.
[1086] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.11 (s, 1H, Ar); 7.94-7.98 (m, 2H, Ar); 8.02 (bs, 1H, Ar); 8.11 (d, J 2.3 Hz, 1H, Ar); 8.21 (d, J 8.9 Hz, 1H, Ar); 8.52 (d, J 5.1 Hz, 1H, Ar).
[1087] M/Z (M[.sup.35Cl].sub.2+H).sup.+=345.1.
[1088] MP: >250° C.
Example 96: 7-Chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[1089] ##STR00107##
[1090] Example 96 was obtained according to general procedure III starting from example 95 in presence of a solution of cyclopropylzinc bromide in THF (0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 5%) and salt formation according to procedure IV(i) afforded example 96 as a beige solid in 51% yield.
[1091] .sup.1H-NMR (400 MHz, DMSO): 1.17-1.23 (m, 4H, 2CH2); 2.28-2.35 (m, 1H, CCH); 3.51 (s, 3H, NCH.sub.3); 7.15 (s, 1H, Ar); 7.91 (bs, 1H, Ar); 7.94 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 7.98-7.99 (m, 1H, Ar); 8.08 (d, J 2.4 Hz, 1H, Ar); 8.19 (d, J 8.8 Hz, 1H, Ar); 8.60 (d, J 5.8 Hz, 1H, Ar). Signal for HCl salt is not observed.
[1092] M/Z (M[.sup.35Cl].sub.2+H).sup.+=351.4.
[1093] MP: 245-250° C.
Compound 50: 7-Chloro-2-(2-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1094] Compound 50 was obtained according to general procedure I(ii), starting from 2-fluoro-isonicotinic methyl ester in presence of hydrazine 10 as a brown solid in 54% yield.
[1095] .sup.1H-NMR (400 MHz, DMSO): 6.66 (s, 1H, Ar); 7.71 (bs, 1H, Ar); 7.92-7.93 (m, 1H, Ar); 7.98 (dd, J 8.7 Hz, J 2.5 Hz, 1H, Ar); 8.09 (d, J 2.5 Hz, 1H, Ar); 8.20 (d, J 8.7 Hz, 1H, Ar); 8.33 (d, J 5.2 Hz, 1H, Ar); 12.59 (bs, 1H, NH).
[1096] M/Z (M[.sup.35Cl]+H).sup.+=315.4.
Example 97: 7-Chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1097] ##STR00108##
[1098] Example 97 was obtained according to general procedure II(iii), starting from compound 50 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. DMF was used instead of DMA. Example 97 was obtained without further purification as a white solid in 71% yield.
[1099] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.07 (s, 1H, Ar); 7.66 (bs, 1H, Ar); 7.88-7.90 (m, 1H, Ar); 7.97 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 8.10 (d, J 2.4 Hz, 1H, Ar); 8.19 (d, J 8.8 Hz, 1H, Ar); 8.36 (d, J 5.2 Hz, 1H, Ar).
[1100] M/Z (M[.sup.35Cl]+H).sup.+=329.2.
[1101] MP: >250° C.
Example 98: 7-Chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[1102] ##STR00109##
[1103] Example 98 was obtained according to general procedure VII(i) starting from example 97 in presence of 2,2,2-trifluoroethanol. The reaction was stirred for 5 hours at room temperature. Trituration in Et.sub.2O afforded example 98 as a white solid in 87% yield.
[1104] .sup.1H-NMR (400 MHz, DMSO): 3.54 (s, 3H, NCH.sub.3); 5.05 (q, J 9.1 Hz, 2H, OCH.sub.2CF.sub.3); 7.06 (s, 1H, Ar); 7.50 (bs, 1H, Ar); 7.66-7.67 (m, 1H, Ar); 7.96 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 8.10 (d, J 2.4 Hz, 1H, Ar); 8.19 (d, J 8.8 Hz, 1H, Ar); 8.31 (d, J 5.3 Hz, 1H, Ar).
[1105] M/Z (M[.sup.35Cl]+H).sup.+=409.4
[1106] MP: 180-190° C.
Compound 51: 2-(2-Chloro-pyridin-4-yl)-7-methoxy-4H-pyrazolo[1,5-a]quinazolin-5-one
[1107] Compound 51 was obtained according to general procedure I(i), starting from 2-chloro-isonicotinic methyl ester in presence of hydrazine 12 as a brown solid in 54% yield.
[1108] .sup.1H-NMR (400 MHz, DMSO): 3.90 (s, 3H, OCH.sub.3); 6.65 (s, 1H, Ar); 7.53 (d, J 9.0 Hz, J 2.9 Hz, 1H, Ar); 7.60 (d, J 2.9 Hz, 1H, Ar); 7.96 (d, J 5.2 Hz, J 1.4 Hz, 1H, Ar); 8.04 (bs, 1H, Ar); 8.16 (d, J 9.0 Hz, 1H, Ar); 8.48 (d, J 5.2 Hz, 1H, Ar); 12.45 (bs, 1H, NH).
[1109] M/Z (M[.sup.35Cl]+H).sup.+=327.2.
Example 99: 2-(2-Chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1110] ##STR00110##
[1111] Example 99 was obtained according to general procedure II(iii), starting from compound 51 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. DMF was used instead of DMA. Example 99 was obtained without further purification as a brown solid in 75% yield.
[1112] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 3.90 (s, 3H, OCH.sub.3); 7.05 (s, 1H, Ar); 7.52 (d, J 9.0 Hz, J 2.9 Hz, 1H, Ar); 7.60 (d, J 2.9 Hz, 1H, Ar); 7.93 (d, J 5.2 Hz, J 1.4 Hz, 1H, Ar); 8.00 (bs, 1H, Ar); 8.15 (d, J 9.0 Hz, 1H, Ar); 8.51 (d, J 5.2 Hz, 1H, Ar).
[1113] M/Z (M[.sup.35Cl]+H).sup.+=341.2.
[1114] MP: >250° C.
Example 100: 2-(2-Cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[1115] ##STR00111##
[1116] Example 100 was obtained according to general procedure III starting from example 99 in presence of a solution of cyclopropylzinc bromide in THF (0.5M-3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to 5%) and salt formation according to procedure IV(i) afforded example 100 as an orange solid in 39% yield.
[1117] .sup.1H-NMR (400 MHz, DMSO): 1.26-1.33 (m, 4H, 2CH.sub.2); 2.38-2.45 (m, 1H, CCH); 3.57 (s, 3H, NCH.sub.3); 3.90 (s, 3H, OCH.sub.3); 7.19 (s, 1H, Ar); 7.54 (dd, J 9.0 Hz, J 2.8 Hz, 1H, Ar); 7.60 (d, J 2.8 Hz, 1H, Ar); 7.96 (bs, H, Ar); 8.08-8.09 (m, 1H, Ar); 8.17 (d, J 9.0 Hz, 1H, Ar); 8.66 (d, J 5.9 Hz, 1H, Ar). Signal for HCl salt is not observed.
[1118] M/Z (M+H).sup.+=347.5.
[1119] MP: 230-240° C.
Compound 52: 2-(2-Fluoro-pyridin-4-yl)-7-methoxy-4H-pyrazolo[1,5-a]quinazolin-5-one
[1120] Compound 52 was obtained according to general procedure I(ii), starting from 2-chloro-isonicotinic methyl ester in presence of hydrazine 12 as a greenish solid in 40% yield.
[1121] M/Z (M+H).sup.+=311.4.
Example 101: 2-(2-Fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1122] ##STR00112##
[1123] Example 101 was obtained according to general procedure II(iii), starting from compound 52 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. DMF was used instead of DMA. Example 101 was obtained without further purification as a brown solid in 34% yield.
[1124] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 3.90 (s, 3H, OCH.sub.3); 7.04 (s, 1H, Ar); 7.53-7.55 (m, 1H, Ar); 7.61-7.66 (m, 2H, Ar); 7.89 (bs, 1H, Ar); 814-8.16 (m, 1H, Ar); 8.34-8.35 (m, 1H, Ar).
[1125] M/Z (M+H).sup.+=325.2.
[1126] MP: 235-245° C.
Example 102: 7-Methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[1127] ##STR00113##
[1128] Example 102 was obtained according to general procedure VII(i) starting from example 101 in presence of 2,2,2-trifluoroethanol. The reaction was stirred for 1 hour at 50° C. Trituration in EtOH and cyclohexane afforded example 102 as a beige solid in 60% yield.
[1129] .sup.1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH.sub.3); 3.90 (s, 3H, OCH.sub.3); 5.04-5.06 (m, 2H, OCH.sub.2CF.sub.3); 7.03 (s, 1H, Ar); 7.50-7.54 (m, 2H, Ar); 7.61-7.67 (m, 2H, Ar); 8.14-8.16 (m, 1H, Ar); 8.30 (bs, 1H, Ar).
[1130] M/Z (M+H).sup.+=405.2
[1131] MP: 172-180° C.
Compound 53: 2-(1-Methyl-1H-pyrazol-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1132] Compound 53 was obtained according to general procedure I(i), starting 1-Methyl-1H-pyrazole-4-carboxylic acid methyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 55% yield.
[1133] .sup.1H-NMR (400 MHz, DMSO): 3.89 (s, 3H, NCH.sub.3); 6.10 (s, 1H, Ar); 7.43-7.47 (m, 1H, Ar); 7.84-7.89 (m, 2H, Ar); 8.04-8.06 (m, 1H, Ar); 8.11-8.14 (m, 1H, Ar); 8.19 (bs, 1H, Ar); 12.10 (bs, 1H, NH).
[1134] M/Z (M+H).sup.+=266.2.
Example 103: 4-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1135] ##STR00114##
[1136] Example 103 was obtained according to general procedure II(i), starting from compound 53 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 Hrs. Example 103 was obtained without further purification as a beige solid in 78% yield.
[1137] .sup.1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH.sub.3); 3.91 (s, 3H, NCH.sub.3); 6.48 (s, 1H, Ar); 7.45-7.49 (m, 1H, Ar); 7.86-7.90 (m, 2H, Ar); 8.05-8.08 (m, 1H, Ar); 8.16-8.18 (m, 2H, Ar).
[1138] M/Z (M+H).sup.+=280.2.
[1139] MP: 195-199° C.
Example 104: 4-Methyl-2-pyridin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[1140] ##STR00115##
[1141] To a solution of example 1 (50.0 mg, 1.0 equiv.) in MeOH (1.6 mL, C=0.1 molL.sup.−1), Pd/C (10% w/w, 17 mg) was added. The reaction mixture was sparged with hydrogen and hydrogen pressure was maintained for 18 hours through balloon. The reaction mixture was filtered off through a celite pad. The pad was washed with MeOH and the filtrate was concentrated. Purification by flash-chromatography (MeOH in DCM, 0 to 10%) and salt formation according to procedure IV(iii) afforded example 104 as a beige solid in 19% yield.
[1142] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 7.22 (s, 1H, Ar); 7.59-7.63 (m, 1H, Ar); 7.95-7.99 (m, 1H, Ar); 8.22-8.26 (m, 2H, Ar); 8.38-8.40 (m, 2H, Ar); 9.83 (d, J 6.3 Hz, 2H, Ar). Signal for HCl salt is not observed.
[1143] M/Z (M+H).sup.+=277.2.
[1144] MP: >250° C.
Compound 54: 2-(2-Chloro-6-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1145] Compound 54 was obtained according to general procedure I(i), starting from 2-chloro-6-methylpyridine-4-carboxylic acid methyl ester in presence of 2-hydrazino-benzoic acid as a yellow solid in 87% yield.
[1146] .sup.1H-NMR (400 MHz, DMSO): 2.52 (s, 3H, CH.sub.3); 6.52 (s, 1H, Ar); 7.47-7.51 (m, 1H, Ar); 7.82-7.88 (m, 3H, Ar); 8.13-8.18 (m, 2H, Ar). Signal for NH is not observed.
[1147] M/Z (M[.sup.35Cl]+H).sup.+=311.1.
Example 105: 2-(2-Chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1148] ##STR00116##
[1149] Example 105 was obtained according to general procedure II(i), starting from compound 54 in presence of iodomethane. The reaction mixture was stirred for 2 hours at room temperature. Example 105 was obtained without further purification as a beige solid in 89% yield.
[1150] .sup.1H-NMR (400 MHz, DMSO): 2.53 (s, 3H, CH.sub.3); 3.54 (s, 3H, NCH.sub.3); 7.02 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.80-7.81 (m, 2H, Ar); 7.90-7.94 (m, 1H, Ar); 8.18-8.20 (m, 2H, Ar).
[1151] M/Z (M[.sup.35Cl]+H).sup.+=325.2.
[1152] MP:236-242° C.
Example 106: 2-(2-Cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCl Salt
[1153] ##STR00117##
[1154] Example 106 was obtained according to general procedure III starting from example 105 in presence of a solution of cyclopropylzinc bromide in THF (0.5N-3.0 equiv.). After hydrolysis, the solid was collected, washed with water and MeOH. To the MeOH filtrate, aqueous HCl solution (1N) was added. The resulting precipitate was collected, washed with water, Et.sub.2O and was dried under reduced pressure to afford example 106 as a white solid in 26% yield.
[1155] .sup.1H-NMR (400 MHz, DMSO): 1.26-1.36 (m, 4H, 2CH2); 2.53-2.55 (m, 1H, CCH); 2.74 (s, 3H, CCH.sub.3); 3.56 (s, 3H, NCH.sub.3); 7.21 (s, 1H, Ar); 7.57-7.61 (m, 1H, Ar); 7.72 (bs, 1H, Ar); 7.93-7.98 (m, 1H, Ar); 8.6 (bs, 1H, Ar); 8.19-8.24 (m, 2H, Ar). Signal for HCl salt is not observed.
[1156] M/Z (M+H).sup.+=331.3.
[1157] MP: >250° C.
Compound 55: 2-(3-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1158] Compound 55 was obtained according to general procedure I(i), starting 3-fluoro-isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 33% yield. The reaction mixture was heated for 18 hours instead of 2 hours.
[1159] .sup.1H-NMR (400 MHz, DMSO): 6.40 (d, J 3.5 Hz, 1H, Ar); 7.55-7.59 (m, 1H, Ar); 7.92-7.97 (m, 1H, Ar); 8.09 (dd, J 6.6 Hz, J 5.1 Hz, 1H, Ar); 8.17-8.22 (m, 2H, Ar); 8.53-8.54 (m, 1H, Ar); 8.71 (d, J 2.8 Hz, 1H, Ar); 12.36 (bs, 1H, NH).
[1160] M/Z (M+H).sup.+=281.3.
Example 107: 2-(3-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1161] ##STR00118##
[1162] Example 107 was obtained according to general procedure II(ii), starting from compound 55 in presence of iodomethane. The reaction mixture was stirred for 1 hour at room temperature. Example 107 was obtained without further purification as a grey solid in 69% yield.
[1163] .sup.1H-NMR (400 MHz, DMSO): 3.51 (s, 3H, NCH.sub.3); 6.80 (d, J 3.0 Hz, 1H, Ar); 7.56-7.50 (m, 1H, Ar); 7.93-7.97 (m, 1H, Ar); 8.08-8.11 (m, 1H, Ar); 8.22-8.24 (m, 2H, Ar); 8.55-8.57 (m, 1H, Ar); 8.74 (d, J 2.8 Hz, 1H, Ar).
[1164] M/Z (M+H).sup.+=295.3.
[1165] MP: 244-247° C.
Compound 56: 2-(3-Chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1166] Compound 56 was obtained according to general procedure I(i), starting 2-chloro-isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 71% yield. The reaction mixture was heated for 18 hours instead of 2 hours.
[1167] .sup.1H-NMR (400 MHz, DMSO): 6.58 (s, 1H, Ar); 7.55-7.59 (m, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 8.02 (d, J 5.1 Hz, 1H, Ar); 8.18-8.21 (m, 2H, Ar); 8.63 (d, J 5.1 Hz, 1H, Ar); 8.78 (s, 1H, Ar); 12.41 (bs, 1H, NH).
[1168] M/Z (M[.sup.35Cl]+H).sup.+=297.2.
Example 108: 2-(3-Chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1169] ##STR00119##
[1170] Example 108 was obtained according to general procedure II(ii), starting from compound 56 in presence of iodomethane. The reaction mixture was stirred for 1 hour at room temperature. Example 108 was obtained without further purification as a grey solid in 57% yield.
[1171] .sup.1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH.sub.3); 6.93 (s, 1H, Ar); 7.56-7.60 (m, 1H, Ar); 7.92-7.96 (m, 1H, Ar); 7.99 (d, J 5.1 Hz, 1H, Ar); 8.19-8.24 (m, 2H, Ar); 8.64 (d, J 5.1 Hz, 1H, Ar); 8.79 (s, 1H, Ar).
[1172] M/Z (M[.sup.35Cl]+H).sup.+=311.1.
[1173] MP:230-236° C.
Example 109: 4-Methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1174] ##STR00120##
[1175] Example 109 was obtained according to general procedure III starting from example 108 in presence of a solution of dimetylzinc in Toluene (2N-3.0 equiv.). After hydrolysis, the solid was collected. The solid was dissolved in a DMSO/MeOH mixture. Smopex resin was added and the suspension was stirred for 1 hour at room temperature. The resin was filtered off, washed with DMSO and MeOH. Water was added to the filtrate. The resulting solid was collected, washed with water, EtOH, and Et.sub.2O and was dried under reduce pressure to afford example 109 as a beige solid in 27% yield.
[1176] .sup.1H-NMR (400 MHz, DMSO at 80° C.): 2.64 (s, 3H, CCH.sub.3); 3.60 (s, 3H, NCH.sub.3); 6.70 (s, 1H, Ar); 7.52-7.56 (m, 1H, Ar); 7.71 (d, J 4.3 Hz, 1H, Ar); 7.92-7.94 (m, 1H, Ar); 8.18 (d, J 8.2 Hz, 1H, Ar); 8.23 (d, J 8.0 Hz, J 1.0 Hz, 1H, Ar); 8.52-8.61 (m, 2H, Ar).
[1177] M/Z (M+H).sup.+=291.3.
[1178] MP: 145-150° C.
Example 110: 8-(3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1179] ##STR00121##
[1180] Example 110 was obtained according to general procedure XII(i), starting from example 58 with 3-hydroxyazetidine hydrochloride as nucleophile (diisopropylamine was added in excess in order to release the free base). Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 110 as a white solid in 40% yield.
[1181] .sup.1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH.sub.3); 3.85-3.88 (m, 1H, NCHaCHb); 4.09-4.12 (m, 1H, NCHaCHb); 4.33-4.35 (m, 1H, NCHaCHb); 4.50-4.56 (m, 2H, NCHaCHb+CH(OH)); 5.82 (bs, 1H, OH); 7.21 (s, 1H, Ar); 7.73 (dd, J 8.1 Hz, J 1.5 Hz, 1H, Ar); 8.23 (d, J 8.1 Hz, 1H, Ar); 8.29 (dd, J 5.1 Hz, J 1.0 Hz, 1H, Ar); 8.36 (d, J 1.4 Hz, 1H, Ar); 8.39 (s, 1H, Ar); 8.89 (d, J 5.1 Hz, 1H Ar).
[1182] M/Z (M+H).sup.+=444.1.
[1183] MP: >250° C.
Example 111: 8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1184] ##STR00122##
[1185] Example 111 was obtained according to general procedure VII(iii) starting from example 55 in presence of 1,3-propanediol. The reaction mixture was heated for 17 hours at 60° C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 111 as a white solid in 66% yield.
[1186] .sup.1H-NMR (400 MHz, DMSO): 1.97 (quint, J 6.2 Hz, 2H, HOCH.sub.2CH.sub.2CH.sub.2O); 3.55 (s, 3H, NCH.sub.3); 3.63 (q, J 5.4 Hz, 2H, HOCH.sub.2CH.sub.2CH.sub.2O); 4.30 (t, J 6.3 Hz, 2H, HOCH.sub.2CH.sub.2CH.sub.2O); 4.63 (t, J 5.1 Hz, 1H, HOCH.sub.2); 7.14 (dd, J 8.8 Hz, J 2.4 Hz, 1H, Ar); 7.17 (s, 1H, Ar); 7.64 (d, J 2.3 Hz, 1H, Ar); 8.12 (d, J 8.8 Hz, 1H, Ar); 8.29 (dd, J 5.1 Hz, J 0.9 Hz, 1H, Ar); 8.40 (s, 1H, Ar); 8.90 (d, J 5.1 Hz, 1H, Ar).
[1187] M/Z (M+H).sup.+=419.1.
[1188] MP: 223-226° C.
Compound 57: 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one
[1189] Compound 57 was obtained according to general procedure I(i), starting 2-Cyclopropyl-isonicotinic acid methyl ester in presence compound 26 as a brown solid in 55% yield.
[1190] 1H-NMR (400 MHz, DMSO): 1.25-1.27 (m, 4H, 2CH.sub.2); 2.36-2.42 (m, 1H, CCH); 6.81 (s, 1H, Ar); 7.42 (td, J 8.7 Hz, J 2.4 Hz, 1H, Ar); 7.99 (dd, J 9.4H, J 2.4 Hz, 1H, Ar); 8.02 (bs, 1H, Ar); 8.09-8.11 (m, 1H, Ar); 8.24 (dd, J 8.7 Hz, J 5.8 Hz, 1H, Ar); 8.64 (d, J 5.8 Hz, 1H, Ar); 12.60 (bs, 1H, NH).
[1191] M/Z (M+H).sup.+=321.0.
Example 112: 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1192] ##STR00123##
[1193] Example 112 was obtained according to general procedure II(iii), starting from compound 57 in presence of iodomethane. The reaction mixture was stirred at room temperature for 60 min. Example 112 was obtained as a beige solid in 70% yield.
[1194] .sup.1H-NMR (400 MHz, DMSO): 1.01-1.04 (m, 4H, 2CH.sub.2); 2.18-2.23 (m, 1H, CCH); 3.57 (s, 3H, NCH.sub.3); 7.00 (s, 1H, Ar); 7.40 (td, J 8.7 Hz, J 2.3 Hz, 1H, Ar); 7.70 (d, J 5.1 Hz, 1H, Ar); 7.86 (bs, 1H, Ar); 7.93 (dd, J 9.2H, J 2.3 Hz, 1H, Ar); 8.27 (dd, J 8.7 Hz, J 5.9 Hz, 1H, Ar); 8.52 (d, J 5.1 Hz, 1H, Ar).
[1195] M/Z (M+H).sup.+=335.1.
[1196] MP: 230-235° C.
Example 113: 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1197] ##STR00124##
[1198] Example 113 was obtained according to general procedure X(vi) starting from example 112 in presence of 4-hydroxypiperidine. Example 113 was obtained as a beige solid in 75% yield.
[1199] .sup.1H-NMR (400 MHz, DMSO): 0.99-1.01 (m, 4H, 2CH.sub.2), 1.44-1.52 (m, 2H, 2CHaHb); 1.86-1.89 (m, 2H, 2CHaHb); 2.17-2.23 (m, 1H, CCH); 3.19-3.25 (m, 2H, 2NCHaHb); 3.51 (s, 3H, NCH.sub.3); 3.74-3.79 (m, 1H, CH(OH)); 3.83-3.86 (m, 2H, 2NCHaHb); 4.77 (bs, 1H, OH); 6.88 (s, 1H, Ar); 7.16 (dd, J 9.1 Hz, J 2.2 Hz, 1H, Ar); 7.45 (d, J 2.2 Hz, 1H, Ar); 7.69-7.70 (m, 1H, Ar); 7.85 (bs, 1H, Ar); 7.95 (d, J 9.1 Hz, 1H); 8.49 (d, J 5.1 Hz, 1H, Ar).
[1200] M/Z (M+H).sup.+=416.3.
[1201] MP: 221-233° C.
Compound 58: 2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one
[1202] Compound 58 was obtained according to general procedure I(ii), starting from compound 4 in presence compound 26. After 17 hours at 100° C. with AcOH (10 equiv.) the reaction was not completed. DME was concentrated and AcOH (same volume as DME) was added. The reaction mixture was heated at 120° C. for 3 hours. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHCO.sub.3 solution. The precipitate was collected, washed with water, EtOH and dried under reduced pressure at 60° C. with P.sub.2O.sub.5 for 18 hours. Compound 58 was isolated as a brown solid in 45% yield.
[1203] 1H-NMR (400 MHz, DMSO): 6.68 (s, 1H, Ar); 7.02 (t, J 54.9 Hz, 1H, CHF.sub.2); 7.39 (td, J 8.7 Hz, J 2.5 Hz, 1H, Ar); 7.95 (dd, J 9.4H, J 2.5 Hz, 1H, Ar); 8.13 (d, J 5.1 Hz, 1H, Ar); 8.21-8.25 (m, 2H, Ar); 8.78 (d, J 5.1 Hz, 1H, Ar); 12.49 (bs, 1H, NH).
[1204] M/Z (M+H).sup.+=331.1.
Example 114: 2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1205] ##STR00125##
[1206] Example 114 was obtained according to general procedure II(iii), starting from compound 58 in presence of iodomethane. The reaction mixture was stirred at room temperature for 90 min. Example 114 was obtained as a beige solid in 77% yield.
[1207] .sup.1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH.sub.3); 7.04 (t, J 54.9 Hz, 1H, CHF.sub.2); 7.12 (s, 1H, Ar); 7.40 (td, J 8.7 Hz, J 2.4 Hz, 1H, Ar); 7.96 (dd, J 9.3H, J 2.4 Hz, 1H, Ar); 8.11 (d, J 4.8 Hz, 1H, Ar); 8.23-8.27 (m, 2H, Ar); 8.81 (d, J 4.8 Hz, 1H, Ar).
[1208] M/Z (M+H).sup.+=345.0.
[1209] MP: 220-226° C.
Example 115: 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1210] ##STR00126##
[1211] Example 115 was obtained according to general procedure X(vi) starting from example 114 in presence of 4-hydroxypiperidine. Trituration in EtOH afforded example 115 as a beige solid in 74% yield.
[1212] .sup.1H-NMR (400 MHz, DMSO): 1.45-1.52 (m, 2H, 2CHaHb); 1.87-1.89 (m, 2H, 2CHaHb); 3.19-3.25 (m, 2H, 2NCHaHb), 3.52 (s, 3H, NCH.sub.3); 3.76-3.79 (m, 1H, CH(OH)); 3.83-3.86 (m, 2H, 2NCHaHb); 4.78 (d, J 3.8 Hz, 1H, OH); 6.90-7.17 (m, 3H, CHF.sub.2+2Ar); 7.45 (s, 1H, Ar); 7.96 (d, J 9.0 Hz, 1H, Ar); 8.14 (d, J 4.5 Hz, 1H, Ar); 8.22 (bs, 1H, Ar); 8.79 (d, J 4.5 Hz, 1H, Ar).
[1213] M/Z (M+H).sup.+=426.2.
[1214] MP: >250° C.
Compound 59: 2-Cyclobutyl-isonicotinic Acid Methyl Ester
[1215] Compound 59 was obtained according to general procedure III starting from 2-Chloro-isonicotinic acid methyl ester in presence of cyclobutylzinc bromide (in THF 0.5M-3.0 equiv.). Purification by flash-chromatography (EtOAc in Cyclohexane, 0 to 80%) afforded compound 59 as yellow oil in 46% yield.
[1216] .sup.1H-NMR (400 MHz, DMSO): 1.80-1.90 (m, 1H, CH); 1.96-2.08 (m, 1H, CH); 2.25-2.33 (m, 4H, 2CH.sub.2); 3.76 (quint, J 8.6 Hz, 1H, CCH); 3.90 (s, 3H, OCH.sub.3); 7.63-7.65 (m, 2H, Ar); 8.73 (d, J 4.9 Hz, 1H, Ar).
[1217] M/Z (M+H).sup.+=192.1.
Compound 60: 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one
[1218] Compound 60 was obtained according to general procedure I(i), starting compound 59 in presence compound 26 as a brown solid in 37% yield.
[1219] .sup.1H-NMR (400 MHz, DMSO): 1.88-1.94 (m, 1H, CH); 2.00-2.16 (m, 1H, CH); 2.28-2.45 (m, 4H, 2CH.sub.2); 3.86 (quint, J 8.7 Hz, 1H, CCH); 6.76 (s, 1H, Ar); 7.41 (td, J 8.6 Hz, J 2.3 Hz, 1H, Ar); 7.98 (dd, J 9.4H, J 2.3 Hz, 1H, Ar); 8.05-8.12 (m, 2H, Ar); 8.24 (dd, J 8.6 Hz, J 5.9 Hz, 1H, Ar); 8.70 (d, J 5.5 Hz, 1H, Ar); 12.56 (bs, 1H, NH).
[1220] M/Z (M+H).sup.+=335.2.
Example 116: 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1221] ##STR00127##
[1222] Example 116 was obtained according to general procedure II(iii), starting from compound 60 in presence of iodomethane. The reaction mixture was stirred at room temperature for 120 min. Example 116 was obtained as a brown solid in 44% yield.
[1223] .sup.1H-NMR (400 MHz, DMSO): 1.85-1.96 (m, 1H, CH); 1.98-2.11 (m, 1H, CH); 2.32-2.39 (m, 4H, 2CH.sub.2); 3.56 (s, 3H, NCH.sub.3); 3.74 (quint, J 8.6 Hz, 1H, CCH); 7.02 (s, 1H, Ar); 7.39 (td, J 8.6 Hz, J 2.3 Hz, 1H, Ar); 7.75-7.80 (m, 2H, Ar); 7.93 (d, J 8.6 Hz, 1H, Ar); 8.26 (dd, J 8.6 Hz, J 6.1 Hz, 1H, Ar); 8.63 (d, J 4.7 Hz, 1H, Ar).
[1224] M/Z (M+H).sup.+=349.0.
[1225] MP: 210-220° C.
Compound 61: 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one
[1226] Compound 61 was obtained according to general procedure I(i), starting from 2-chloro-isonicotinic methyl ester in presence of compound 26 as a brown solid in 44% yield.
[1227] .sup.1H-NMR (400 MHz, DMSO): 6.66 (s, 1H, Ar); 7.39 (td, J 8.7 Hz, J 2.6 Hz, 1H, Ar); 7.95 (dd, J 9.5 Hz, J 2.6 Hz, 1H, Ar); 7.99 (dd, J 5.2 Hz, J 1.4 Hz, 1H, Ar); 8.09 (bs, 1H, Ar); 8.22 (dd, J 8.7 Hz, J 5.8 Hz, 1H, Ar); 8.50 (d, J 5.2 Hz, 1H Ar); 12.40 (bs, 1H, NH).
[1228] M/Z (M[.sup.35Cl]+H).sup.+=315.1.
Example 117: 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1229] ##STR00128##
[1230] Example 117 was obtained according to general procedure II(iii), starting from compound 61 in presence of iodomethane. The reaction mixture was stirred at room temperature for 60 min. Example 117 was obtained as a beige solid in 71% yield.
[1231] .sup.1H-NMR (400 MHz, DMSO): 3.54 (s, 3H, NCH.sub.3); 7.09 (s, 1H, Ar); 7.38-7.42 (m, 1H, Ar); 7.94-7.97 (m, 2H, Ar); 8.05 (s, 1H, Ar); 8.24-8.27 (m, 1H, Ar); 8.54 (d, J 5.1 Hz, 1H Ar).
[1232] M/Z (M[.sup.35Cl]+H).sup.+=329.1.
[1233] MP: >250° C.
Example 118: 2-(2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[1234] ##STR00129##
[1235] Example 118 was obtained according to general procedure X(vi) starting from example 117 in presence of 4-hydroxypiperidine. Trituration in EtOH afforded example 118 as a beige solid in 86% yield.
[1236] .sup.1H-NMR (400 MHz, DMSO): 1.48-1.56 (m, 2H, 2CHaHb); 1.91-2.00 (m, 2H, 2CHaHb); 3.23-3.36 (m, 2H, 2NCHaHb); 3.55 (s, 3H, NCH.sub.3); 3.78-3.84 (m, 1H, CH(OH)); 3.88-3.92 (m, 2H, 2NCHaHb); 4.81 (bs, 1H, OH); 7.04 (s, 1H, Ar); 7.17 (dd, J 9.1 Hz, J 2.3 Hz, 1H, Ar); 7.50 (d, J 2.1 Hz, 1H, Ar); 7.97-8.03 (m, 2H, Ar); 8.10 (s, 1H, Ar); 8.56 (d, J 5.1 Hz, 1H, Ar).
[1237] M/Z (M[.sup.35Cl]+H).sup.+=410.1.
[1238] MP: >250° C.
Example 119: 7-Fluoro-8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1239] ##STR00130##
[1240] Example 119 was obtained according to general procedure X(vi) starting from example 88 in presence of 3-hydroxyazetidine. Purification by flash-chromatography (MeOH in DCM, 0 to 7%) afforded example 119 as a white solid in 56% yield.
[1241] .sup.1H-NMR (400 MHz, DMSO): 3.52 (s, 3H, NCH.sub.3); 385-3.98 (m, 2H, 2NCHaCHb); 4.44-4.47 (m, 2H, 2NCHaCHb); 4.63-4.68 (m, 1H, CH(OH)); 5.83 (d, J 6.1 Hz, 1H, OH); 7.01 (d, J 7.8 Hz, 1H, Ar); 7.12 (s, 1H, Ar); 7.63 (d, J 12.6 Hz, 1H, Ar); 8 26 (d, J 4.8 Hz, 1H, Ar); 8.37 (s, 1H Ar); 8.89 (d, J 5.1 Hz, 1H, Ar).
[1242] M/Z (M+H).sup.+=434.2.
[1243] MP: >250° C.
Example 120: 7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1244] ##STR00131##
[1245] Example 120 was obtained according to general procedure VII(iii) starting from example 88 in presence of 3-hydroxyoxetane. The reaction mixture was stirred for 1 hour at room temperature. Purification by flash-chromatography (MeOH in DCM, 0 to 2%) afforded example 120 as a white solid in 35% yield.
[1246] .sup.1H-NMR (400 MHz, DMSO): 3.61 (s, 3H, NCH.sub.3); 4.75-4.78 (m, 2H, 2OCHaCHb); 5.13 (t, J 6.9 Hz, 2H, 2OCHaCHb); 5.77-5.83 (m, 1H, CH(O)); 7.25 (s, 1H, Ar); 7.52 (d, J 7.1 Hz, 1H, Ar); 8.03 (d, J 11.0 Hz, 1H, Ar); 8.37 (d, J 5.1 Hz, 1H, Ar); 8.46 (s, 1H, Ar); 8.92 (d, J 5.1 Hz, 1H, Ar).
[1247] M/Z (M+H).sup.+=435.1.
[1248] MP: >250° C.
Example 121: 3-[7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5-a]quinazolin-8-ylamino]-propionitrile
[1249] ##STR00132##
[1250] Example 121 was obtained according to general procedure X(vi) starting from example 88 in presence of 3-aminopropionitrile. Example 121 was isolated as a beige solid in 64% yield.
[1251] .sup.1H-NMR (400 MHz, DMSO): 3.06 (t, J 6.4 Hz, 2H, NHCH.sub.2CH.sub.2CN); 3.62 (s, 3H, NCH.sub.3); 3.71-3.76 (m, 2H, NHCH.sub.2CH.sub.2CN); 7.20 (s, 1H, Ar); 7.24-7.27 (m, 1H, NH); 7.47 (d, J 7.3 Hz, 1H, Ar); 7.81 (d, J 11.7 Hz, 1H, Ar); 8.35-8.36 (m, 1H, Ar); 8.47 (s, 1H, Ar); 8.80 (d, J 5.1 Hz, 1H, Ar).
[1252] M/Z (M+H).sup.+=431.1.
[1253] MP: >250° C.
Example 122: 7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1254] ##STR00133##
[1255] Example 122 was obtained according to general procedure X(vi) starting from example 88 in presence of DL-prolinol. Example 122 was isolated as a brown solid in 64% yield.
[1256] .sup.1H-NMR (400 MHz, DMSO): 1.91-1.92 (m, 4H, 2 CH.sub.2); 3.39-3.59 (m, 6H, NCH.sub.3+NCH.sub.2+NCH); 3.66 (bs, 1H, HOCHaCHb); 4.22 (bs, 1H, HOCHaCHb); 4.91 (bs, 1H, OH); 7.11 (s, 1H, Ar); 7.28 (d, J 7.7 Hz, 1H, Ar); 7.67 (d, J 14.7 Hz, 1H, Ar); 8.24-8.25 (m, 1H, Ar); 8.35 (s, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[1257] M/Z (M+H).sup.+=462.2.
[1258] MP: >250° C.
Example 123: 7-Fluoro-8-(7-hydroxymethyl-1-aza-spiro[3.5]non-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1259] ##STR00134##
[1260] Example 123 was obtained according to general procedure X(vi) starting from example 88 in presence of (1-Aza-spiro[3.5]non-7-yl)-methanol. Purification by TLC-preparative (MeOH in DCM, 4%) afforded example 123 as a beige solid in 32% yield.
[1261] .sup.1H-NMR (400 MHz, DMSO): 0.98-1.04 (m, 2H, 2CHaHb); 1.34 (bs, 1H, CH); 1.73-1.75 (m, 2H, 2CHaHb); 1.91-2.01 (m, 4H, 2CH.sub.2); 2.16-2.24 (m, 2H, CH.sub.2); 3.10 (t, J 5.6 Hz, 2H, NCH.sub.2); 3.51 (s, 3H, NCH.sub.3); 4.03-4.11 (m, 2H, HOCH.sub.2); 4.43 (t, J 5.3 Hz, 1H, OH); 7.08-7.12 (m, 2H, Ar); 7.69 (d, J 13.3 Hz, 1H, Ar); 8.24 (d, J 5.1 Hz, 1H, Ar); 8.34 (s, 1H, Ar); 8.88 (d, J 5.2 Hz, 1H, Ar).
[1262] M/Z (M+H).sup.+=516.2.
[1263] MP: >250° C.
Example 124: 8-(3-Hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1264] ##STR00135##
[1265] Under inert atmosphere, in a seal tube, a mixture of example 58 (1.0 equiv.), 3-hydroxypiperidine (1.2 equiv.), a solution of LiHMDS in THF (1.0 N; 3.0 equiv.) and RuPhos precatalyst (0.1 equiv.) were suspended in THF (C=0.1 molL.sup.−1) and warmed for 17 hours at 65° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 124 as a beige solid in 19% yield.
[1266] .sup.1H-NMR (400 MHz, DMSO): 1.41-1.58 (m, 2H, CH.sub.2); 1.81-1.94 (m, 2H, CH.sub.2); 2.96-3.15 (m, 2H, NCHaHb+NCHaHc); 3.51 (s, 3H, NCH.sub.3); 3.59-3.66 (m, 1H, NCHaCHb); 3.76-3.79 (m, 1H, NCHaCHc); 3.84-3.88 (m, 1H, CH(OH)); 4.96 (d, J 4.2 Hz, 1H, OH); 7.07-7.10 (m, 2H, Ar); 7.43 (d, J 2.4 Hz, 1H, Ar); 7.95 (d, J 9.0 Hz, 1H, Ar); 8.28 (dd, J 5.1 Hz, J 1.0 Hz, 1H, Ar); 8.38 (s, 1H, Ar); 8.87 (d, J 5.1 Hz, 1H, Ar).
[1267] M/Z (M+H).sup.+=444.1.
[1268] MP: >250° C.
Example 125: 8-(2, 6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1269] ##STR00136##
[1270] Under inert atmosphere, in a seal tube, a mixture of example 58 (1.0 equiv.), 2,6-dimethylmorpholine (1.2 equiv.), a solution of LiHMDS in THF (1.0 N; 3.0 equiv.) and RuPhos precatalyst (0.1 equiv.) were suspended in THF (C=0.1 molL.sup.−1) and warmed for 3 days at 65° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 125 as a beige solid in 19% yield.
[1271] .sup.1H-NMR (400 MHz, DMSO): 1.22 (d, J 6.2 Hz, 6H, 2CH3); 2.53-2.56 (m, 2H, 2NCHaCHb); 3.51 (s, 3H, NCH3); 3.68-3.75 (m, 2H, 2NCHaCHb); 3.92-3.94 (m, 2H, 2OCH); 7.10 (s, 1H, Ar); 7.16 (dd, J 9.1 Hz, J 2.4 Hz, 1H Ar); 7.46 (d, J 2.3 Hz, 1H, Ar); 7.97 (d, J 9.0 Hz, 1H, Ar); 8.27-8.28 (m, 1H, Ar); 8.38 (s, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[1272] M/Z (M+H).sup.+=458.1.
[1273] MP: >250° C.
Example 126: 8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[1274] ##STR00137##
[1275] Under inert atmosphere, in a seal tube, a mixture of example 58 (1.0 equiv.), 1-amino-2-methyl-2-propanol (1.2 equiv.), a solution of LiHMDS in THF (1.0 N; 3.0 equiv.) and BrettPhos precatalyst (0.1 equiv.) were suspended in THF (C=0.1 molL.sup.−1) and warmed for 17 hours at 65° C. The reaction mixture was hydrolysed with a saturated aqueous NH.sub.4Cl solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 126 as a white solid in 6% yield
[1276] .sup.1H-NMR (400 MHz, DMSO): 1.21 (s, 6H, 2CH.sub.3); 3.16 (d, J 5.5 Hz, 2H, NCH.sub.2); 3.51 (s, 3H, NCH.sub.3); 4.58 (s, 1H, OH); 6.87-6.88 (m, 2H, NH+Ar); 7.07 (s, 1H, Ar); 7.29 (s, 1H, Ar); 7.86 (d, J 8.8 Hz, 1H, Ar); 8.24 (d, J 4.7 Hz, 1H, Ar); 8.36 (s, 1H, Ar); 8.88 (d, J 5.1 Hz, 1H, Ar).
[1277] M/Z (M+H).sup.+=432.0.
[1278] MP: >250° C.
Example 127: Human mGluR2 and mGluR3 Evaluation Using Ca.SUP.++ Functional Assay
[1279] Examples of the present invention were tested successively for their agonist and negative allosteric modulator activities on human mGluR2 (hmGluR2) and mGluR3 (hmGluR3) transiently over-expressed in HEK-293 cells. Compounds exert agonist activity if, by themselves in absence of glutamate, they are able to activate hmGluR2 or hmGluR3; and they exert negative allosteric modulator activity if they decrease the action of glutamate (which is employed at its EC.sub.80 concentration).
Cell Culture and Transfection
[1280] HEK-293 cells are maintained in Modified Eagle's Medium supplemented with 10% Foetal Calf Serum, 1% Penicillin/Streptomycin and 1% non-essential amino acids at 37° C./5% CO.sub.2.
[1281] Cells are co-transfected by electroporation with four DNA plasmids encoding hmGluR2 or hmGluR3, a chimeric G protein allowing redirection of the activation signal to intracellular calcium pathway (Brabet I et al., Neuropharmacology 37(8), 1043-51, 1998), and two glutamate transporters minimizing receptor desensitization by endogenous glutamate. After transfection, cells are cultured for 24 h at 37° C./5% CO.sub.2.
Calcium Assay IC.SUB.50 .Determination
[1282] Receptor activity is detected by changes in intracellular calcium measured using the fluorescent Ca.sup.2+ sensitive dye, Fluo4AM (Molecular Probes).
[1283] On the day of the assay, culture medium is aspirated and replaced during 3 hours by medium without serum supplemented with 1% Glutamax, 1% Penicillin/Streptomycin and 1% non-essential amino acids. Then, cells are washed with freshly prepared buffer B (HBSS 1×(PAA), Hepes 20 mM, MgSO.sub.4-7H.sub.2O 1 mM, Na.sub.2CO.sub.3 3.3 mM, CaCl.sub.2-2H.sub.2O 1.3 mM, 0.1% BSA, Probenecid 2.5 mM) and loaded at 37° C. in 5% CO.sub.2 for 1.5 hours with buffer B containing 1 μM Fluo4AM, 0.1 mg/mL Pluronic Acid, 7 μg/mL Glutamate Pyruvate Transaminase and 2 mM sodium pyruvate. Afterwards cells are washed twice with buffer B. Then cells are detached using StemPro Accutase (Fischer Scientific), resuspended in buffer B and seeded in 384 well plate at a density of 30,000 cells per well. Addition of compounds and intracellular Ca.sup.2+ measurements (excitation 485 nm, emission 525 nm) are performed by the fluorescence microplate reader FLIPRTetra (Molecular Devices).
[1284] Agonist and negative allosteric modulator activities of compounds are consecutively evaluated on the same cell plate. Agonist activity is first tested during 10 minutes with the addition of compound alone on the cells. Then, cells are stimulated by an EC.sub.80 glutamate concentration and fluorescence is recorded for additional 3 minutes. EC.sub.80 glutamate concentration is the concentration giving 80% of the maximal glutamate response. Agonist or negative allosteric modulator activity(ies) are evaluated in comparison to basal signals evoked by buffer B or EC.sub.80 glutamate alone, respectively.
[1285] For IC.sub.50 determination, a dose-response test is performed using 20 concentrations (ranging over 6 logs) of each compound. Dose-response curves are fitted using the sigmoidal dose-response (variable slope) analysis in GraphPad Prism program (Graph Pad Inc) and IC.sub.50 of negative allosteric modulator activity is calculated. Dose-response experiments are performed in duplicate, two times independently.
[1286] The compounds of the present invention were found to have no agonist activity on hmGluR2 and hmGluR3. On hmGluR2, the compounds of the present invention have preferably an IC.sub.50 of 5 μM or less, more preferably 1 μM or less and the ratio [IC.sub.50 hmGluR3]/[IC.sub.50 hmGluR2] is higher than 3, more preferably is higher than 5.
[1287] The following list represents selected examples of the compounds of the present invention showing hmGluR2 negative allosteric modulator activity with an IC.sub.50<1 μM and a ratio [IC.sub.50 hmGluR3]/[IC.sub.50 hmGluR2] higher than 3: [1288] Examples: 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 14, 15, 16, 17, 19, 21, 22, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 44, 45, 48, 49, 55, 56, 58, 61, 63, 64, 68, 70, 77, 78, 79, 80, 81, 82, 85, 87, 88, 89, 90, 91, 94, 95, 96, 98, 99, 100, 102, 105, 106, 108, 110, 113, 114, 115, 116, 117, 119, 120, 121, 122, and 125.