AZOLE-FUSED PYRIDAZIN-3(2H)-ONE DERIVATIVES

Abstract

Disclosed are compounds of Formula (1) and pharmaceutically acceptable salts thereof, wherein α, β, n, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10, R.sup.11, X.sup.1, X.sup.2, X.sup.3 and X.sup.7 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula (1), to pharmaceutical compositions comprising them, and to their use for treating diseases, disorders, and conditions associated with GPR139.

##STR00001##

Claims

1. A compound of Formula 1, ##STR00349## a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: α is a single bond, β is a double bond, X.sup.1 is NR.sup.1N, and either (i) X.sup.2 is N and X.sup.3 is CR.sup.3C or (ii) X.sup.2 is CR.sup.2 and X.sup.3 is selected from N and CR.sup.3C; or α is a double bond, β is a single bond, X.sup.3 is NR.sup.3N and either (i) X.sup.1 is N and X.sup.2 is CR.sup.2 or (ii) X.sup.1 is CR.sup.1C and X.sup.2 is selected from N and CR.sup.2; n is selected from 0 and 1; R.sup.1C, R.sup.2, R.sup.3C and R.sup.4 are each independently selected from (a) hydrogen; and (b) C.sub.1-6 alkyl and C.sub.3-8 cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; R.sup.1N and R.sup.3N are each independently selected from C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and C.sub.6-10 aryl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; R.sup.5 is selected from hydrogen and C.sub.1-6 alkyl, and R.sup.6 is selected from C.sub.1-6 alkyl and C.sub.3-8 cycloalkyl; or R.sup.5 and R.sup.6, together with the nitrogen and carbon atoms to which they are each respectively attached, form a C.sub.3-6 heterocyclic ring, the heterocyclic ring being monocyclic and having one ring atom which is a heteroatom; X.sup.7 is selected from N and CR.sup.7; R.sup.7 is selected from (a) hydrogen, halo, cyano, hydroxy and amino; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; R.sup.8 and R.sup.9 are each independently selected from (a) hydrogen, halo, cyano, hydroxy and amino; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or R.sup.8 and R.sup.9, together with the carbon atoms to which they are attached, form a C.sub.4-5 heterocyclic ring, the heterocyclic ring having one or two ring atoms that are heteroatoms, each of heteroatoms being independently selected from N, O and S; R.sup.10 and R.sup.11 are each independently selected from (a) hydrogen, halo, cyano, hydroxy and amino; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

2. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein α is a single bond, β is a double bond, X.sup.1 is NR.sup.1N, and either (i) X.sup.2 is N and X.sup.3 is CR.sup.3C or (ii) X.sup.2 is CR.sup.2 and X.sup.3 is selected from N and CR.sup.3C.

3. The compound, tautomer or pharmaceutically acceptable salt of claim 2, wherein R.sup.1N is selected from C.sub.1-4 alkyl, cyclopropyl and phenyl.

4. The compound, tautomer or pharmaceutically acceptable salt of claim 2, wherein X.sup.2 is N and X.sup.3 is CR.sup.3C.

5. The compound, tautomer or pharmaceutically acceptable salt of claim 2, wherein R.sup.3C is selected from hydrogen, C.sub.1-4 alkyl and cyclopropyl.

6. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein α is a double bond, β is a single bond, X.sup.3 is NR.sup.3N and either (i) X.sup.1 is N and X.sup.2 is CR.sup.2 or (ii) X.sup.1 is CR.sup.1C and X.sup.2 is selected from N and CR.sup.2.

7. The compound, tautomer or pharmaceutically acceptable salt of claim 6, wherein R.sup.3N is selected from C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl.

8. The compound, tautomer or pharmaceutically acceptable salt of claim 6, wherein X.sup.1 is CR.sup.1C and X.sup.2 is selected from N and CR.sup.2.

9. The compound, tautomer or pharmaceutically acceptable salt of claim 6, wherein X.sup.1 is CR.sup.1C and X.sup.2 is N.

10. The compound, tautomer or pharmaceutically acceptable salt of claim 9, wherein R.sup.1C is selected from hydrogen, C.sub.1-4 alkyl and cyclopropyl.

11. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.2 is hydrogen.

12. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.4 is selected from hydrogen, C.sub.1-4 alkyl and cyclopropyl.

13. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.5 is hydrogen.

14. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.6 is methyl.

15. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein n is 0.

16. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein X.sup.7 is CR.sup.7.

17. The compound, tautomer or pharmaceutically acceptable salt of claim 16, wherein R.sup.7 is selected from (a) hydrogen and halo; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

18. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.8 is selected from (a) hydrogen and halo; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

19. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.9 is selected from (a) hydrogen and halo; and (b) C.sub.1-6 alkyl and C.sub.1-6 alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

20. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.10 is selected from hydrogen, halo and C.sub.1-4 alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

21. The compound, tautomer or pharmaceutically acceptable salt of claim 1, wherein R.sup.11 is selected from hydrogen, halo and C.sub.1-4 alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

22. The compound of claim 1, which is selected from the following compounds: (S)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)—N-(1-(3-fluoro-4-methoxyphenyl)ethyl)-2-(3-isopropyl-1,7-dimethyl-4-oxo-1H-pyrazolo[3,4-d]pyridazin-5(4H)-yl)acetamide; (S)-2-(1-(tert-butyl)-4-isopropyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-4-isopropyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-m ethoxyphenyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide; (S)—N-(1-(p-tolyl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1-isopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-isopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(4-chloro-2-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluorophenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,5-dim ethylphenyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,3-difluorophenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-m ethoxy-3-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-m ethoxyphenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-3,7-dim ethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; (S)-2-(1-isopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; (S)-2-(1,3-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; N-(1-(chroman-6-yl)ethyl)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide; (S)—N-(1-(4-chloro-2-methylphenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-mesitylethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(2,4-dimethylphenyl)ethyl)acetamide; (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide; (S)—N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide; (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-mesitylethyl)acetamide; (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; 5-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one; 6-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one; (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; (S)—N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1-isopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; N-(1-(chroman-6-yl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; 2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide; 2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-m ethoxyphenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)—N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)—N-(1-(p-tolyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)—N-(1-(4-(trifluoromethyl)phenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-m ethoxyphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)—N-(1-(2,6-difluorophenyl)ethyl)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-m ethoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,4-difluorophenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-m ethoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide; (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-fluoro-3-m ethoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,4,6-trifluorophenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-fluoro-3-methylphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3,5-difluorophenyl)ethyl)acetamide; (S)—N-(1-(2-chloro-6-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide; (S)-2-(3-methyl-4-oxo-3,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-methyl-4-oxo-3,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-phenylethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluorophenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(2-chloro-6-fluorophenyl)ethyl)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide; (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-phenylethyl)acetamide; (S)—N-(1-(3-fluorophenyl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide; (S)-2-(1-cyclobutyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(1-(tert-butyl)-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (R)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)—N-(1-(4-chlorophenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide; (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide; (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide; (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(methyl-d3)phenyl)ethyl)acetamide; (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(methyl-d3)phenyl)ethyl)acetamide; (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(methyl-d3)phenyl)ethyl)acetamide; (S)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide; (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)—N-(1-(3-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; (S)—N-(cyclopropyl(phenyl)methyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide; (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(4-(methyl-d.sub.3)phenyl)ethyl)acetamide; a tautomer of any one of the aforementioned compounds, and a pharmaceutically acceptable salt of any one of the aforementioned compounds or tautomer thereof.

23. A pharmaceutical composition comprising: a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1; and a pharmaceutically acceptable excipient.

24. A compound, tautomer or pharmaceutically acceptable salt as defined in claim 1 for use as a medicament.

25. A compound, tautomer or pharmaceutically acceptable salt as defined in claim 1 for use in treating a disease, disorder or condition selected from schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance use disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, epilepsy, pain, fibromyalgia, Alzheimer's disease and Parkinson's disease.

26. A method for activating GPR139 in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1.

27. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with GPR139.

28. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is selected from schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance use disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, epilepsy, pain, fibromyalgia, Alzheimer's disease and Parkinson's disease.

29. A combination comprising a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, and at least one additional pharmacologically active agent.

Description

EXAMPLES

[0377] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present disclosure.

[0378] .sup.1H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (6) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl.sub.3 (deuterochloroform), DMSO-d.sub.6 (deuterodimethylsulfoxide), CD.sub.3OD (deuteromethanol), CD.sub.3CN (deuteroacetonitrile), and TEIF-d.sub.8 (deuterotetrahydrofuran). The mass spectra (m/z for [M+H].sup.+) were recorded using either electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0379] Where indicated, intermediate preparations and example compounds are purified by HPLC. Tables 1 to 4 list equipment, materials, and conditions for some of the Fine, separations.

TABLE-US-00001 TABLE 1 HPLC Method A Pump Shimadzu LC-8A or LC-20AP UV/Vis Shimadzu SPD-20A Software LCSolution Column Phenomenex Gemini ® C18, 5 μm, ID 30 mm × 150 mm Mobile ACN (0.035% TFA) in water (0.05% TFA) Phases Gradient 10% to 100% ACN (unless indicated otherwise)

TABLE-US-00002 TABLE 2 HPLC Method B Pump Shimadzu LC-8A or LC-20AP UV/Vis Shimadzu SPD-20A Software LCSolution Column Phenomenex Gemini ® C18, 5 μm, ID 30 mm × 150 mm Mobile Water/ACN (10 mM NH.sub.4HCO.sub.3 in 20/80 water/ACN, Phases pH 9.5-10) in water (10 mM NH.sub.4HCO.sub.3, pH 9.5-10) Gradient 10% to 100% ACN (unless indicated otherwise)

TABLE-US-00003 TABLE 3 HPLC Method C Pump Gilson 322 UV/Vis Gilson 156 UV Software Trilution 2.1 Column Phenomenex Gemini ® 5 μm, ID 25 mm × 150 mm Mobile water (0.05% ammonia hydroxide v/v)/ACN Phases Gradient 30% to 60% ACN, 10 minutes (unless indicated otherwise)

TABLE-US-00004 TABLE 4 HPLC Method D Pump Gilson 322 UV/Vis Gilson 156 UV Software Trilution 2.1 Column Phenomenex Gemini ® 10 μm, ID 25 mm × 150 mm Mobile Water (0.05% HCl)/ACN Phases Gradient 10% to 40% ACN, 10 minutes (unless indicated otherwise)

[0380] Besides HPLC, some of the preparations and examples may employ flash chromatography or preparative thin layer chromatography (TLC). Preparative TLC is typically carried out on silica gel 60 F.sub.254 plates. The preparations and examples may employ SFC to separate enantiomers.

[0381] After isolation by chromatography, the solvent may be removed and the product dried in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, evacuated flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H.sub.2) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

Preparation 1: 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0382] ##STR00005##

Step 1: 4-chloro-5-(1-methylhydrazinyl)pyridazin-3(2H)-one

[0383] ##STR00006##

[0384] To a solution of 4,5-di chloropyridazin-3(2H)-one (500 mg, 3.03 mmol) in MeOH (12.1 mL) was added methylhydrazine (479 μL, 9.09 mmol) dropwise. The reaction mixture was stirred at RT for 16 hours and then filtered. The filter cake was washed with EtOH to provide the title compound as a pale yellow solid (443 mg, 84%).

Step 2: 4-chloro-5-(1-methyl-2-methylenehydrazineyl)pyridazin-3(2H)-one

[0385] ##STR00007##

[0386] To a solution of 4-chloro-5-(1-methylhydrazinyl)pyridazin-3(2H)-one (220 mg, 1.260 mmol) in EtOH (6301 μL) was added formaldehyde (118 μL, 1.512 mmol) dropwise. The reaction mixture was heated at reflux for 2 hours and then filtered. The filter cake was washed with cold. EtOH to give the title compound as a pale yellow solid (245 mg, 104%).

Step 3: 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0387] A solution of 4-chloro-5-(1-methyl-2-methylenehydrazineyl)pyridazin-3(2H)-one (245 mg, 1.313 mmol) in acetone (26.3 mL) was irradiated with a 120V lamp for 15 hours. The reaction mixture was concentrated, dissolved in DCM and purified using an ISCO® automated purification system, eluting with a gradient of 0-100% EtOAc in heptanes. The product-containing fractions were collected and combined, concentrated in a rotary evaporator at 35° C., and dried in vacuo to provide the title compound as a white solid (43 mg, 22%).

Preparation 2: 1,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0388] ##STR00008##

Step 1: ethyl (E)-3-(ethoxymethylene)-2,4-dioxopentanoate

[0389] ##STR00009##

[0390] To a solution of ethyl 2,4-dioxopentanoate (0.888 mL, 6.32 mmol) and acetic anhydride (1.195 mL, 12.65 mmol) was added triethoxymethane (1.052 mL, 6.32 mmol). The reaction mixture was heated at 120° C. for 1 hour and then at 140° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound as a dark brown oil, which was used directly in the next step.

Step 2: ethyl 4-acetyl-1-methyl-1H-pyrazole-5-carboxylate

[0391] ##STR00010##

[0392] To a solution of ethyl (E)-3-(ethoxymethylene)-2,4-dioxopentanoate (1.354 g, 6.32 mmol) in ether (126 mL) at 0° C. was added methylhydrazine (0.333 mL, 6.32 mmol) dropwise. The reaction mixture was dried over MgSO.sub.4, filtered and concentrated to give the title compound as an orange-brown oil, which was used in the step without further purification.

Step 3: 1,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0393] To a solution of ethyl 4-acetyl-1-methyl-1H-pyrazole-5-carboxylate (1240 mg, 6.32 mmol) in ethanol (13 mL) was added hydrazine hydrate (884 μL, 6.32 mmol) dropwise. The reaction mixture was heated at reflux for 2 hours and then concentrated. The resulting crude material was dissolved in DCM and purified using an ISCO® automated purification system (NH column) eluting with a gradient of 0-100% EtOAc in heptanes. The product-containing fractions were collected and combined, concentrated in a rotary evaporator at 35° C. and dried in vacuo to give the title compound as a tan solid (25 mg, 2.4%).

Preparation 3: 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0394] ##STR00011##

Step 1: ethyl 4,4-diethoxy-3-oxobutanoate

[0395] ##STR00012##

[0396] To a mixture of NaH (7.87 g, 196.64 mmol, 60% in mineral oil) in THF (250 mL) was added dropwise a mixture of ethyl 2,2-diethoxyacetate (24.75 g, 140.46 mmol, 25 mL) and EtOAc (13.74 g, 155.91 mmol, 15.26 mL) at 50° C. under N.sub.2. The reaction mixture was stirred at 70° C. for 4 hours and then at 25° C. for 12 hours, quenched with aq HOAc (15%, 150 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with aq NaHCO.sub.3 (100 mL×2) and brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow oil (36 g, crude) which was used into the next step without further purification.

Step 2: ethyl (Z)-2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate

[0397] ##STR00013##

[0398] A mixture of ethyl 4,4-diethoxy-3-oxo-butanoate (36 g, 164.95 mmol) and DMF-DMA (23.59 g, 197.94 mmol, 26.21 mL) in toluene (200 mL) was stirred at 100° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 0:1) to give the title compound as a yellow oil (31 g, 69%).

Step 3: ethyl 1-benzyl-5-(diethoxymethyl)-1H-pyrazole-4-carboxylate

[0399] ##STR00014##

[0400] To a solution of benzylhydrazine (23.55 g, 120.74 mmol, 2 HCl) in EtOH (50 mL) was added Et.sub.3N (33.32 g, 329.28 mmol, 45.64 mL) at 25° C. The mixture was stirred for 0.2 hours and then added to a solution of ethyl (Z)-2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate (30.00 g, 109.76 mmol) in EtOH (150 mL) at 0° C. The reaction mixture was stirred at 25° C. for 0.8 hours and then diluted with water (500 mL) and extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine (800 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (30:1 to 10:1) to give the title compound as a yellow oil (28 g, 77%).

Step 4: 1-benzyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0401] ##STR00015##

[0402] To a solution of ethyl 1-benzyl-5-(diethoxymethyl)-1H-pyrazole-4-carboxylate (28 g, 84.24 mmol) in HOAc (200 mL) were added N.sub.2H.sub.4.H.sub.2O (14.88 g, 252.72 mmol, 14.45 mL, 85%) and HCl aq (12 M, 702.00 μL). The mixture was stirred at 90° C. for 12 hours and then poured into ice water (400 mL) and filtered. The filter cake was washed with water (200 mL) and dried in vacuo to give title compound as a white solid (16.5 g, 87%).

Step 5: 1-benzyl-4-chloro-1H-pyrazolo[3,4-d]pyridazine

[0403] ##STR00016##

[0404] A solution of 1-benzyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (13.00 g, 57.46 mmol) in POCl.sub.3 (204.50 g, 1.33 mol, 123.94 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was diluted with EtOAc (500 mL), washed with NaHCO.sub.3(400 mL) and brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow gum (15 g, crude) which was used without further purification.

Step 6: 1-benzyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0405] ##STR00017##

[0406] A mixture of 1-benzyl-4-chloro-1H-pyrazolo[3,4-d]pyridazine (14.00 g, 57.22 mmol) and NaOMe (9.27 g, 171.66 mmol) in MeOH (200.00 mL) was stirred at 70° C. for 0.5 hours and then diluted with water (400 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10/1 to 0:1) to give the title compound as a yellow solid (8 g, 58%).

Step 7: 4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0407] ##STR00018##

[0408] A solution of 1-benzyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (7.00 g, 29.14 mmol) in H.sub.2SO.sub.4 (40.00 mL) was stirred at 50° C. for 12 hours and then slowly added to act NaHCO.sub.3(400 mL) and extracted with DCM/MeOH (10:1, 500 mL×8). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a yellow solid (3.10 g, 71%).

Step 8: 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0409] ##STR00019##

[0410] To a mixture of 4-methoxy-1H-pyrazolo[3,4-d]pyridazine (1.00 g, 6.66 mmol) and NaOAc (3.82 g, 46.62 mmol) in EtOH (20 mL) and water (20 mL) was added Br.sub.2 (4.26 g, 26.64 mmol, 1.37 mL). The mixture was stirred at 25° C. for 2 hours and then diluted with EtOAc (80 mL), washed with saturated aq Na.sub.2S.sub.2O.sub.3 (30 mL) and brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (5:1, 30 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a yellow solid (1 g, 66%).

Step 9: 3-bromo-1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0411] ##STR00020##

[0412] A mixture of 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (1 g, 4.37 mmol), 2-iodopropane (1.49 g, 8.74 mmol, 873.95 μL) and K.sub.2CO.sub.3 (1.81 g, 13.11 mmol) in DMF (30 mL) was stirred at 25° C. for 12 hours and then diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (100:1 to 40:1) to give the title compound which was used without further purification.

Step 10: 3-cyclopropyl-1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0413] ##STR00021##

[0414] A mixture of regioisomers, 3-bromo-1-isopropyl-4-methoxy-iii-pyrazolo[3,4-d]pyridazine and 3-bromo-2-isopropyl-4-methoxy-2H-pyrazolo[3,4-d]pyridazine (total 550 mg, 2.03 mmol), cyclopropylboronic acid (348.75 mg, 4.06 mmol), Na.sub.2CO.sub.3 (430.32 mg, 4.06 mmol) and Pd(dppf)Cl.sub.2 (148.54 mg, 203.00 μmol) in dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (Sift) eluting with DCM/MeOH (100:1 to 40:1). The resulting product was further purified by preparative TLC (Sift) eluting with petroleum ether/EtOAc (1:3) to give the title compound as a yellow solid (180 mg).

Step 11: 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0415] A solution of 3-cyclopropyl-1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (160.00 mg, 688.82 μmol) in dioxane (5 mL) and HCl aq (2 M, 5.00 MI) was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by HPLC (Method C) to give the title compound as a white solid (102.40 mg, 67% yield, 99% purity).

Preparation 4: 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0416] ##STR00022##

Step 1: 1-isopropyl-4-methoxy-3-methyl-1H-pyrazolo[3,4-d]pyridazine

[0417] ##STR00023##

[0418] A mixture of regioisomers, 3-bromo-1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine and 3-bromo-2-isopropyl-4-methoxy-2H-pyrazolo[3,4-d]pyridazine (total 400 mg, 1.48 mmol), methylboronic acid (180.00 mg, 3.01 mmol), Na.sub.2CO.sub.3 (319.03 mg, 3.01 mmol) and Pd(dppf)Cl.sub.2 (110.12 mg, 150.50 mop in dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (Sift) eluting with DCM/MeOH (100:1 to 40:1). The resulting product was further purified by preparative TLC (SiO.sub.2) eluting with petroleum ether/EtOAc (1:3) to give the title compound as a yellow solid (120 mg).

Step 2: 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0419] A solution of 1-isopropyl-4-methoxy-3-methyl-1H-pyrazolo[3,4-d]pyridazine (120 mg, 581.85 μmol) in dioxane (5 mL) and HCl aq (2 M, 5.00 mL) was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (10:1, 10 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a light-yellow solid (84.10 mg, 75%).

Preparation 5: 1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0420] ##STR00024##

Step 1: ethyl 5-(diethoxymethyl)-1H-pyrazole-4-carboxylate

[0421] ##STR00025##

[0422] To a solution of ethyl (Z)-2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate (5.00 g, 18.29 mmol) in EtOH (100.00 mL) was added N.sub.2H.sub.4.H.sub.2O (1.29 g, 21.95 mmol, 1.25 mL, 85% purity) at 0° C. The mixture was stirred at 25° C. for 1 hour and then diluted with water (200 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 2:1) to give the title compound as a yellow oil (3 g, 68%).

Step 2: ethyl 1-cyclopropyl-5-(diethoxymethyl)-1H-pyrazole-4-carboxylate

[0423] ##STR00026##

[0424] A mixture of ethyl 5-(diethoxymethyl)-1H-pyrazole-4-carboxylate (1.00 g, 4.13 cyclopropylboronic acid (709.13 mg, 8.26 mmol), Cu(OAc).sub.2 (1.13 g, 6.20 mmol), Na.sub.2CO.sub.3 (874.97 mg, 8.26 mmol) and 2-(2-pyridyl)pyridine (966.98 mg, 6.20 mmol) in DCE (20 mL) was stirred at 70° C. for 12 hours under 02 (15 psi). The mixture was diluted with DCM (20 ML), washed with water (20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (30:1 to 10:1) to give the title compound as a colorless oil (600 mg, 51%).

Step 3: 1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0425] To a solution of ethyl 1-cyclopropyl-5-(diethoxymethyl)-1H-pyrazole-4-carboxylate (500.00 mg, 1.77 mmol) in HOAc (10 mL) were added N.sub.2H.sub.4.H.sub.2O (312.90 mg, 5.31 mmol, 303.79 μL, 85% purity) and HCl (12 M, 6.32 μL). The mixture was stirred at 90° C. for 12 hours and then poured into ice water (30 mL) and extracted with DCM/MeOH (10:1, 15 mL×3). The combined organic layers were washed with aq NaHCO.sub.3 (20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was triturated with MTBE (15 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a white solid (130 mg, 42% yield, 100% purity).

Preparation 6: 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0426] ##STR00027##

Step 1: 1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0427] ##STR00028##

[0428] A mixture of 4-methoxy-1H-pyrazolo[3,4-d]pyridazine (400 mg, 2.66 mmol), 2-iodopropane (904.35 mg, 5.32 mmol, 531.97 μL) and K.sub.2CO.sub.3 (1.10 g, 7.98 mmol) in DMF (50 mL) was stirred at 25° C. for 12 hours and then diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (Sift) eluting with DCM/MeOH (100:1 to 40:1). The product was further purified by preparative TLC (SiO.sub.2) eluting with petroleum ether/EtOAc (1:3) to give the title compound as yellow solid (80 mg, 16%).

Step 2: 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0429] A solution of 1-isopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (160 mg, 832.38 μmol) in dioxane (5 mL) and HCl (2 M, 357.34 μL) was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was triturated with MTBE/MeOH (50:1, 30 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a light-yellow solid (100 mg, 67% yield, 99% purity).

Preparation 7: 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0430] ##STR00029##

Step 1: 3-bromo-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine

[0431] ##STR00030##

[0432] A mixture of 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (3.00 g, 13.10 mmol), iodomethane (2.23 g, 15.72 mmol, 978.07 and K.sub.2CO.sub.3 (5.43 g, 39.30 mmol) in DMF (50 mL) was stirred at 25° C. for 2 hours and then diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (5:1 to 0:1) to give the title compound as a yellow solid (1.10 g, crude).

Step 2: 3-cyclopropyl-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine

[0433] ##STR00031##

[0434] A mixture of 3-bromo-4-methoxy-1-methyl-1H-pyrazolo[3,4]pyridazine (600 mg 2.47 mmol), cyclopropylboronic acid (636.14 mg, 7.41 mmol), Na.sub.2CO.sub.3 (784.92 mg, 7.41 mmol) and Pd(dppf)Cl.sub.2 (361.25 mg, 493.71 mop in dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2 and then diluted with water (20 mL) and extracted with DCM (20 ML×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (1:0 to 40:1). The resulting product was further purified by preparative TLC (Sift) eluting with petroleum ether/EtOAc (3:1) to give the title compound as a yellow solid.

Step 3: 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0435] A solution of 3-cyclopropyl-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine (370 mg, 1.81 mmol) in dioxane (5 mL) and HCl aq M, 5 mL) was stirred at 90° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was triturated with petroleum ether/EtOAc (10:1, 10 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a yellow solid (191.1 mg, 56% yield, 100% purity).

Preparation 8: 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0436] ##STR00032##

Step 1: 4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-d]pyridazine

[0437] ##STR00033##

[0438] A mixture of 3-bromo-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine (900 mg, 3.70 mmol), methylboronic acid (443.3 mg, 7.40 mmol), Na.sub.2CO.sub.3 (1.18 g, 11.1 mmol) and Pd(dppf)Cl.sub.2 (541.87 mg, 740.00 μmol) in dioxane (15 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2 and then diluted with water (20 mL) and extracted with DCM (20 mL×2), The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (10:1 to 0:1) to give the title compound as a yellow solid (200 mg, 30%).

Step 2: 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0439] A solution of 4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-d]pyridazine (200 mg, 1.12 mmol) in dioxane (2 mL) and HCl aq (4 M, 2 mL) was stirred at 90° C. for 2 hours and then concentrated in vacuo to give the title compound as a yellow solid (156 mg, 82% yield, 97% purity).

Preparation 9: 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0440] ##STR00034##

Step 1: 4-methoxy-1-methyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyridazine

[0441] ##STR00035##

[0442] A mixture of 3-bromo-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine (900 mg, 3.70 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.24 g, 7.40 mmol), Na.sub.2CO.sub.3 (1.18 g, 11.10 mmol) and Pd(dppf)Cl.sub.2 (270.94 mg, 370 μmol) in dioxane (20 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2 and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (Sift) eluting with DCM/MeOH (100:1 to 50:1) to give the title compound as a yellow solid (400 mg, 49% yield, 92% purity).

Step 2: 3-isopropyl-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine

[0443] ##STR00036##

[0444] A mixture of 4-methoxy-1-methyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyridazine (350 mg, 1.71 mmol) and Pd/C (wet basis) (100.00 mg, 10% purity) in THF (10 mL) was purged with H.sub.2 several times. The reaction mixture was stirred at 10° C. for 12 hours under H.sub.2 (15 psi) and then filtered. The filtrate was concentrated in mew) and purified by HPLC (Method D) to give the title compound as a white solid (120 mg, 34%).

Step 3: 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0445] A solution of 3-isopropyl-4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyridazine (120 mg, 581.85 μmol) in dioxane (2 mL) and HCl act (4 M, 2 mL) was stirred at 90° C. for 1 hour and then concentrated in vacuo, triturated with petroleum ether/EtOAc (10:1, 10 mL) for 30 minutes, and filtered. The filter cake was dried in vacuo to give the title compound as a yellow solid (89.3 mg, 80% yield, 100% purity).

Preparation 10: 1-cyclopropyl-3-methyl-1,5-dihydro-4/1-pyrazolo[3,4-d]pyridazin-4-one

[0446] ##STR00037##

Step 1: 3-bromo-1-cyclopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine

[0447] ##STR00038##

[0448] A mixture of 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (1.00 g, 4.37 mmol), cyclopropylboronic acid (750.12 mg, 8.74 mmol), Cu(OAc).sub.2 (1.19 g, 6.56 mmol), Na.sub.2CO.sub.3 (925.56 mg, 8.74 mmol) and 2-(2-pyridyl)pyridine (1.02 g, 6.56 mmol) in DCE (20 mL) was stirred at 70° C. for 12 hours under O.sub.2 (15 psi) and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 0:1) to give the title compound as a yellow solid (500 mg) which was used without further purification.

Step 2: 1-cyclopropyl-4-methoxy-3-methyl-1H-pyrazolo[3,4-d]pyridazine

[0449] ##STR00039##

[0450] A mixture of 3-bromo-1-cyclopropyl-4-methoxy-1H-pyrazolo[3,4-d]pyridazine (450 mg, 1.67 mmol), methylboronic acid (200.2 mg, 3.34 mmol), Na.sub.2CO.sub.3 (354.48 mg, 3.34 mmol) and Pd(dppf)Cl.sub.2 (122.36 mg, 167.22 mop in dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2 and then diluted with water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 0:1) to give the title compound as a white solid (130 mg, 38%).

Step 3: 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0451] A solution of 1-cyclopropyl-4-methoxy-3-methyl-1H-pyrazolo[3,4-d]pyridazine (120 mg, 587.57 μmol) in dioxane (5 mL) and HCl (4 M, 5 mL) was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (10:1, 10 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a light-yellow solid (85.1 mg, 75% yield, 98% purity).

Preparation 11: 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0452] ##STR00040##

Step 1: ethyl 5-iodo-1H-pyrazole-4-carboxylate

[0453] ##STR00041##

[0454] Ethyl 5-amino-1H-pyrazole-4-carboxylate (34 g, 219.14 mmol) was added portion-wise to a solution of H.sub.2SO.sub.4 (21.93 g, 219.14 mmol, 72.00 mL, 98% purity) in water (60 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. A solution of NaNO.sub.2 (22.68 g, 328.71 mmol, 17.86 mL) in water (100 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for an additional hour. Next, a solution of KI (72.76 g, 438.28 mmol) in water (100 mL) was added dropwise at 0° C. The mixture was stirred at 25° C. for 14.5 hours and then diluted with EtOAc (500 mL). The organic phase was washed with saturated aq Na.sub.2SO.sub.3 (200 mL×3) and brine (100 mL×3), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (50:1 to 4:1) to give the title compound as a white solid (38.10 g, 65%).

Step 2: ethyl 1-cyclopropyl-5-iodo-1H-pyrazole-4-carboxylate

[0455] ##STR00042##

[0456] A mixture of ethyl 5-iodo-1H-pyrazole-4-carboxylate (1.00 g, 3.76 mmol), cyclopropylboronic acid (645.77 mg, 7.52 mmol), Cu(OAc).sub.2 (1.02 g, 5.64 mmol) and pyridine (594.83 mg, 7.52 mmol, 606.97 μL) in DCE (20 mL) was stirred at 50° C. for 12 hours under air and then diluted with DCM (20 mL), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (50:1 to 10:1) to give the title compound as a colorless oil (150 mg, 13%).

Step 3: ethyl 5-acetyl-1-cyclopropyl-1H-pyrazole-4-carboxylate

[0457] ##STR00043##

[0458] A mixture of ethyl 1-cyclopropyl-5-iodo-1H-pyrazole-4-carboxylate (500 mg, 1.63 mmol), tributyl(1-ethoxyvinyl)stannane (883.01 mg, 2.45 mmol, 825.24 μL) and Pd(PPh.sub.3).sub.2Cl.sub.2 (114.41 mg, 163.00 mop in toluene (12 mL) was degassed and purged with N.sub.2 (3×). The reaction mixture was stirred at 110° C. for 2 hours under N.sub.2 atmosphere and then concentrated under reduced pressure. The resulting residue was dissolved in a solution of THF (5 mL) and HCl (2 M, 5 mL). The mixture was stirred at 25° C. for 14 hours and then diluted with saturated aq KF (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (50:1 to 5:1) to give the title compound as a yellow oil (550 mg, crude).

Step 4: 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0459] To a solution of ethyl 5-acetyl-1-cyclopropyl-1H-pyrazole-4-carboxylate (550 mg, 2.47 mmol) in EtOH (10 mL) was added N.sub.2H.sub.4.H.sub.2O (436.41 mg, 7.41 mmol, 423.70 The mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (50:1 to 30:1) to give the title compound as a white solid (87 mg, 18% yield, 97% purity).

Preparation 12: 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0460] ##STR00044##

Step 1: ethyl 5-iodo-1-methyl-1H-pyrazole-4-carboxylate

[0461] ##STR00045##

[0462] To a suspension of ethyl 5-iodo-III-pyrazole-4-carboxylate (1.00 g, 3.76 mmol) and K.sub.2CO.sub.3 (1.04 g, 7.52 mmol) in DMF (15 mL) was added Mel (1.60 g, 11.28 mmol, 701.75 μL). The reaction mixture was stirred at 28° C. for 3 hours and then diluted with EtOAc (50 mL), washed with brine (3×30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (50:1 to 10:1) to give the title compound as a white solid (42.0 mg, 40%).

Step 2: ethyl 5-acetyl-1-methyl-1H-pyrazole-4-carboxylate

[0463] ##STR00046##

[0464] A mixture of ethyl 5-iodo-1-methyl-1H-pyrazole-4-carboxylate (400 mg, 1.43 mmol), tributyl(1-ethoxyvinyl)stannane (774.67 mg, 2.14 mmol, 723.99 μL) and Pd(PPh.sub.3).sub.2Cl.sub.2 (100.37 mg, 143.00 μmol) in toluene (15 mL) was stirred at 100° C. for 2 hours under N.sub.2 and then evaporated in vacuo, diluted with THF (5 mL) and HCl (2 M, 5 mL) and stirred at 28° C. for 12 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with saturated aq KF solution (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (50:1 to 10:1) to give the title compound as yellow oil (270 mg, 96%).

Step 3: 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0465] A mixture of ethyl 5-acetyl-1-methyl-1H-pyrazole-4-carboxylate (250 mg, 1.27 mmol) and NH.sub.2NH.sub.2.H.sub.2O (150.09 mg, 2.55 mmol, 145.72 μL, 85% purity) in HOAc (5 mL) was stirred at 110° C. for 12 hours and then concentrated in vacuo, poured into water (10 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was triturated with MTBE (10 mL) for 15 minutes and filtered to isolate a solid product, which was dried in vacuo to give the title compound as white solid (78 mg, 37% yield, 98% purity).

Preparation 13: 1-isopropyl-7-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0466] ##STR00047##

Step 1: ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate

[0467] ##STR00048##

[0468] To a solution of ethyl 5-iodo-1H-pyrazole-4-carboxylate (3.10 g, 11.65 mmol) and K.sub.2CO.sub.3 (4.83 g, 34.96 mmol) in DMF (40 mL) was added 2-iodopropane (7.92 g, 46.61 mmol, 4.66 mL). The reaction mixture was stirred at 25° C. for 1 hour and then diluted with brine (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (20:1 to 15:1) to give the title compound as a yellow oil (1.25 g, 35%).

Step 2: ethyl 5-acetyl-1-isopropyl-1H-pyrazole-4-carboxylate

[0469] ##STR00049##

[0470] A mixture of ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate (1.20 g, 3.89 mmol), tributyl(1-ethoxyvinyl)stannane (2.11 g, 5.84 mmol, 1.97 mL) and Pd(PPh.sub.3).sub.2Cl.sub.2 (273.04 mg, 389.00 μmol) in toluene (20 mL) was stirred at 100° C. for 2 hours under N.sub.2 and then concentrated in vacuo. THF (10 mL) and HCl (2 M, 10 mL) were added. The mixture was stirred at 28° C. for 12 hours and then diluted with EtOAc (100 mL) and washed with saturated KF solution (50 mL) and brine (50 mL×2). The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and purified by column chromatography (silica gel) eluting with petroleum ether/EtOAc (20:1 to 10:1) to give the title compound as light-yellow oil (700 mg, 80%).

Step 3: 1-isopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0471] A mixture of ethyl 5-acetyl-1-isopropyl-1H-pyrazole-4-carboxylate (200.00 mg, 891.82 μmol) and N.sub.2H.sub.4.H.sub.2O (52.52 mg, 891.82 μmol, 50.99 μL) in EtOH (5 mL) was stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The resulting residue was triturated with MTBE (10 mL) for 15 minutes and filtered to isolate a solid product, which was dried in vacuo to give the title compound as a white solid (116 mg, 68% yield, 95% purity).

[0472] Preparation 14: 1,3,7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

##STR00050##

Step 1: ethyl 5-acetyl-pyrazole-4-carboxylate

[0473] ##STR00051##

[0474] To a solution of ethyl 5-iodo-1H-pyrazole-4-carboxylate (23.00 g, 86.45 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (6.07 g, 8.65 mmol) in toluene (200 mL) was added tributyl(1-ethoxyvinyl)stannane (46.83 g, 129.67 mmol, 43.77 mL), The mixture was degassed and purged with N.sub.2 (3×), stirred at 100° C. for 14 hours under N.sub.2 atmosphere, and then concentrated under reduced pressure. The resulting residue was dissolved in THF (100 mL) and HCl (2 M, 100 mL) and stirred at 25° C. for 2 hours. The mixture was diluted with saturated KF solution (200 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (20:1 to 5:1) to give the title compound as a light-yellow solid.

Step 2: ethyl 5-acetyl-3-bromo-1H-pyrazole-4-carboxylate

[0475] ##STR00052##

[0476] To a solution of ethyl 5-acetyl-1H-pyrazole-4-carboxylate (25.00 g, 137.23 mmol) in EtOH (150 mL) was added NaOAc (90.05 g, 1.10 mol) followed by Br.sub.2 (109.65 g, 686.15 mmol, 35.37 mL) dropwise. The reaction mixture was stirred at 20° C. for 16 hours and then filtered. The filter cake was washed with EtOAc (300 mL) and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (100:1 to 10:1) to give the title compound as a yellow solid.

Step 3: ethyl 5-acetyl-3-bromo-1-methyl-1H-pyrazole-4-carboxylate

[0477] ##STR00053##

[0478] To a solution of ethyl 5-acetyl-3-bromo-1H-pyrazole-4-carboxylate (15.00 g, 57.46 mmol) and K.sub.2CO.sub.3 (23.82 g, 172.38 mmol) in DMF (50 mL) was added MeI (32.62 g, 229.84 mmol, 14.31 mL). The reaction mixture was stirred at 20° C. for 2 hours and then filtered. The filtrate was diluted with brine (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (50:1 to 10:1) to give the title compound as a light-yellow solid (6 g, 38%).

Step 4: ethyl 5-acetyl-1,3-dimethyl-1H-pyrazole-4-carboxylate

[0479] ##STR00054##

[0480] To a solution of ethyl 5-acetyl-3-bromo-1-methyl-1H-pyrazole-4-carboxylate (500 mg, 1.82 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (297.26 mg, 364.00 μmol) and Cs.sub.2CO.sub.3 (1.78 g, 5.46 mmol) in water (1 mL) and toluene (10 mL) was added methylboronic acid (217.89 mg, 3.64 mmol). The mixture was degassed and purged with N.sub.2 (3×) and then stirred at 100° C. for 16 hours under N.sub.2 atmosphere, and filtered, washing the filter cake with EtOAc (10 mL). The filtrate was diluted with brine (20 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, eluting with EtOAc/petroleum ether (0:100 to 15:85). The product was purified further by HPLC (Method C) to give the title compound as a white solid (78 mg, 20%).

Step 5: 1,3,7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0481] To a solution of ethyl 5-acetyl-1,3-dimethyl-1H-pyrazole-4-carboxylate (78 mg, 371.02 μmol) in EtOH (1.0 mL) was added N.sub.2H.sub.4.H.sub.2O (55.72 mg, 1.11 mmol, 54.10 μL). The reaction mixture was stirred at 80° C. for 16 hours and then evaporated under reduced pressure. The resulting residue was purified by HPLC (Method C) to give the title compound as a white solid (58 mg, 88%).

Preparation 15: 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0482] ##STR00055##

Step 1: ethyl 5-acetyl-3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylate

[0483] ##STR00056##

[0484] To a solution of ethyl 5-acetyl-3-bromo-1-methyl-1H-pyrazole-4-carboxylate (500 mg, 1.82 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (297.26 mg, 364.00 μmol) and Cs.sub.2CO.sub.3 (1.78 g, 5.46 mmol) in dioxane (20 mL) and water (1 mL) was added cyclopropylboronic acid (312.68 mg, 3.64 mmol), The mixture was degassed and purged with N.sub.2 (3×) and then stirred at 100° C. for 16 hours under N.sub.2 atmosphere. The mixture was diluted with brine (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO.sub.2) eluting with petroleum ether/EtOAc (5:1) to give the title compound as a yellow oil (200 mg, 47%).

Step 2: 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0485] To a solution of ethyl 5-acetyl-3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylate (270 mg, 1.14 mmol) in EMI (10 mL) was added N.sub.2H.sub.4.H.sub.2O (20191 mg, 3.43 mmol, 196.02 μL). The reaction mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure and purified by HPLC (Method C) to give the title compound as a white solid (80 mg, 34%).

Preparation 16: 3-isopropyl-1,7-di methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0486] ##STR00057##

Step 1: ethyl 5-iodo-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

[0487] ##STR00058##

[0488] A mixture of ethyl 5-iodo-1H-pyrazole-4-carboxylate (72 g, 270.64 mmol), 4-methoxybenzyl chloride (50.86 g, 324.77 mmol, 44.23 mL) and K.sub.2CO.sub.3 (74.81 g, 541.28 mmol) in IMF (700 mL) was stirred at 10° C. for 12 hours and then diluted with water (1.4 L) and extracted with EtOAc (700 mL×2). The combined organic layers were washed with brine (1.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (20:1 to 5:1) to give the title compound as a yellow oil (105 g, crude).

Step 2: ethyl 5-acetyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

[0489] ##STR00059##

[0490] A mixture of ethyl 5-iodo-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (50 g, 129.47 mmol), tributyl(1-ethoxyvinyl)stannane (66.5 g, 184.13 mmol, 62.15 mL) and Pd(PPh.sub.3).sub.2Cl.sub.2 (18.18 g, 25.89 mmol) in toluene (600 mL) was stirred at 100° C. for 12 hours under N.sub.2. The mixture was concentrated in vacuo. The resulting residue was diluted with THF (300 mL) and HCl (2 M, 400 mL), stirred at 10° C. for 2 hours and then diluted with aqueous KF (500 mL) and extracted with EtOAc (800 mL×2). The organic layers were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 4:1) to give the title compound as a yellow oil.

Step 3: 1-(4-oxybenzyl)-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0491] ##STR00060##

[0492] A mixture of ethyl 5-acetyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (50.00 g, 165.38 mmol) and N.sub.2H.sub.4.H.sub.2O (29.22 g, 496.15 mmol, 28.37 mL, 85% purity) in EtOH L) was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo and the resulting residue triturated with petroleum ether/EtOAc (2:1, 300 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as an off-white solid (50 g, crude).

Step 4: 4-chloro-1-(4-methoxybenzyl)-7-methyl-′ 1-pyrazolo[3,4-d]pyridazine

[0493] ##STR00061##

[0494] A mixture of 1-(4-methoxybenzyl)-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (50 g, 184.99 mmol) in POCl.sub.3 (521.9 g, 3.40 mol, 316.30 mL) was stirred at 100° C. for 2 hours and then concentrated in vacuo. The resulting residue was diluted with DCM/MeOH (10:1, 800 mL), washed with water (300 mL) and aq NaHCO.sub.3 (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a yellow oil (60 g, crude).

Step 5: 4-methoxy-1-(4-methoxybenzyl)-7-methyl-1H-pyrazolo[3,4-d]pyridazine

[0495] ##STR00062##

[0496] A mixture of 4-chloro-1-(4-methoxybenzyl)-7-methyl-1H-pyrazolo[3,4-d]pyridazine (60 g, 207.81 mmol) and NaOMe (33.68 g, 623.42 mmol) in MeOH (500 mL) was stirred at 70° C. for 2 hours and then concentrated in vacuo. The resulting residue was diluted with water (400 mL) and extracted with DCM/MeOH (10:1, 500 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (5:1 to 0:1) to give the title compound as a yellow solid (30 g, crude).

Step 6: 4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine

[0497] ##STR00063##

[0498] A solution of 4-methoxy-1-(4-methoxybenzyl)-7-methyl-1H-pyrazolo[3,4-d]pyridazine (28 g, 98.48 mmol) in H.sub.2SO.sub.4 (150 mL) was stirred at 50° C. for 5 hours. The mixture was added to a suspension of NaHCO.sub.3 (500 g) in DCM/MeOH (10:1, 1.2 L) and filtered. The filter cake was washed with DCM/MeOH (10:1, 1.2 L×5) and the combined organic layers were concentrated in vacuo to give the title compound as a yellow solid (20 g, crude).

Step 7: 3-bromo-4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine

[0499] ##STR00064##

[0500] To a mixture of 4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine (10 g, 60.91 mmol) and NaOAc (34.98 g, 426.40 mmol) in EtOH (100 mL) and water (100 mL) was added Br.sub.2 (38.94 g, 243.66 mmol, 12.56 mL). The reaction mixture was stirred at 25° C.′ for 12 hours and then quenched with aq Na.sub.2S.sub.03 (200 mL) and extracted with DCM/MeOH (10:1, 300 mL×8). The combined organic layers were concentrated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (1:1, 100 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a white solid (4.2 g, 28%).

Step 8: 3-bromo-4-methoxy-1,7-dimethyl-1H-pyrazolo[3,4-d]pyridazine

[0501] ##STR00065##

[0502] A mixture of 3-bromo-4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine (5 g, 20.57 mmol), iodomethane (9.7 g, 68.34 mmol, 4.25 mL) and K.sub.2CO.sub.3 (8.53 g, 61.71 mmol) in DMF (100 mL) was stirred at 10° C. for 1 hour and then diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (5:1 to 0:1) to give the title compound as a yellow solid (2.8 g, crude).

Step 9: 4-methoxy-1,7-dimethyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyridazine

[0503] ##STR00066##

[0504] A mixture of 3-bromo-4-methoxy-1,7-dimethyl-1H-pyrazolo[3,4-d]pyridazine (2.8 g, 10.89 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.66 g, 21.78 mmol), Na.sub.2CO.sub.3 (3.46 g, 32.67 mmol) and Pd(dppf)Cl.sub.2 (796.92 mg, 1.09 mmol) in dioxane (20 mL) and water (2 mL) was stirred at 90° C. for 12 hours under N.sub.2 and then filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (100:1 to 50:1) to give the title compound as a yellow solid (2.6 g, crude).

Step 10: 3-isopropyl-4-methoxy-1,7-dimethyl-U-J-pyrazolo[3,4-d]pyridazine

[0505] ##STR00067##

[0506] A mixture of 4-methoxy-1,7-dimethyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyridazine (1.2 g, 5.50 mmol) and Pd/C (100 mg, 10% purity, wet basis) in THF (20 mL) was purged with 112 several times. The reaction mixture was stirred at 10° C. for 12 hours under H.sub.2 (15 psi) and then filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (2:1 to 0:1). The product was further purified by HPLC (Method D) to give the title compound as a white solid (0.45 g, 37%).

Step 11: 3-isopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0507] A solution of 3-isopropyl-4-methoxy-1,7-dimethyl-1H-pyrazolo[3,4-d]pyridazine (0.45 g, 2.04 mmol) in dioxane (10 mL) and aq HCl (4 M, 10 mL) was stirred at 90° C. for 12 hours. The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (114.3 mg, 97%).

Preparation 17: 1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one

[0508] ##STR00068##

Step 1: diethyl 1-methyl-1H-imidazole-4,5-dicarboxylate

[0509] ##STR00069##

[0510] To a solution of diethyl 1H-imidazole-4,5-dicarboxylate (20 g, 94.25 mmol) in DMF (200 mL) were added K.sub.2CO.sub.3 (39.08 g, 282.75 mmol, 3 eq) and Mel (53.51 g, 377.00 mmol, 23.47 mL, 4 eq). The reaction mixture was stirred at 1.0° C. for 8 hours and then filtered. The filter cake was washed with EtOAc (80 mL) and the filtrate was evaporated in vacuo. The resulting residue that was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (1:0 to 1:1) to give the title compound as a yellow oil (14 g, 63% yield, 95% purity).

Step 2: 1-methyl-1H-imidazole-4,5-dicarbohydrazide

[0511] ##STR00070##

[0512] To a stirred solution of diethyl 1-methyl-1H-imidazole-4,5-dicarboxylate (14 g, 61.88 mmol) in EtOH (100 mL) was added N.sub.2H.sub.4.H.sub.2O (12.64 g, 247.54 mmol, 12.28 mL). The reaction mixture was stirred at 80° C. for 16 hours and then evaporated in vacuo to give the title compound as a white solid (11.3 g, crude).

Step 3: 1-methyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione

[0513] ##STR00071##

[0514] To aq HCl (4 M, 100 mL) was added 1-methyl-1H-imidazole-4,5-dicarbohydrazide (11.3 g, 57.02 mmol). The reaction mixture was stirred at 100° C. for 16 hours and then evaporated in vacuo to give the title compound as a white solid (18.3 g, crude).

Step 4: 4,7-dichloro-1-methyl-1H-imidazo[4,5-d]pyridazine

[0515] ##STR00072##

[0516] To POCl.sub.3 (460.35 g, 3.00 mol, 279.00 mL) was added 1-methyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione (9.3 g, 55.98 mmol) and DMF (981.67 mg, 13.43 mmol, 1.03 mL). The reaction mixture was stirred at 100° C. for 18 hours and then evaporated in vacuo. The resulting residue was diluted with saturated aq NaHCO.sub.3 (100 mL) and extracted with DCM (50 mL×5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCO® 40 g SepaFlash®, column) eluting with MeOH/DCM (0:100 to 6:94) to give the title compound as a white solid (3.5 g, 29% yield, 95% purity).

Step 5: 7-chloro-4-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine

[0517] ##STR00073##

and

4-chloro-7-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine

[0518] ##STR00074##

[0519] To a stirred solution of 4,7-di chloro-1-methyl-1H-imidazo[4,5-d]pyridazine (3.5 g, 17.24 mmol) in MeOH (50 mL) was added NaOMe (1.12 g, 20.69 mmol). The reaction mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (15:1) to give a mixture of the title compounds as a white solid (total 3.3 g).

Step 6: 7-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine

[0520] ##STR00075##

and

4-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine

[0521] ##STR00076##

[0522] To a mixture of 7-chloro-4-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine and 4-chloro-7-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine (2.3 g total) in MeOH (100 mL) was added Pd/C (400 mg, 10% purity, wet basis). The mixture was purged with H.sub.2 several times and then stirred at 10° C. for 16 hours under H.sub.2 (15 psi) and filtered. The filter cake was washed with MeOH (40 mL) and the filtrate was evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (ISCO® 40 g SepaFlash® column) eluting with MeOH/DCM (0:100 to 6:94). The products were further purified by HPLC (Method C) to give 7-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine as a white solid (550 mg) and 4-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine as a yellow solid (1 g).

Step 7: 1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one

[0523] A solution of 4-methoxy-1-methyl-1H-imidazo[4,5-d]pyridazine (170 mg, 1.04 mmol) in dioxane (10 mL) and HCl (4 M, 10 mL) was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (1:1, 15 mL) for 30 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a white solid (146.6 mg, 91%).

Preparation 18: 3-methyl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one

[0524] ##STR00077##

[0525] To 7-methoxy-1H-imidazo[4,5-d]pyridazine (550 mg, 3.35 mmol) dissolved in dioxane (10 mL) was added HO (4 M, 11.48 mL). The mixture was stirred at 100° C. for 16 hours and then evaporated in vacuo. The resulting residue was triturated with petroleum ether/EtOAc (5:1, 10 mL) for 10 minutes and filtered. The filter cake was dried in vacuo to give the title compound as a white solid (485 mg, 94%).

Preparation 19: 1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one

[0526] ##STR00078##

Step 1: 4-chloro-1,7-dimethyl-1H-imidazo[4,5-d]pyridazine

[0527] ##STR00079##

[0528] To a solution of 4,7-dichloro-1-methyl-1H-imidazo[4,5-d]pyridazine (500 mg, 2.46 mmol), CH.sub.3B(OH).sub.2 (147.42 mg, 2.46 mmol) and Cs.sub.2CO.sub.3 (2.41 g, 7.39 mmol) in dioxane (20 mL) and water (1 mL) was added Pd(dppt)Cl.sub.2.CH.sub.2Cl.sub.2 (402.23 mg, 492.54 μmol). The mixture was degassed and purged with N.sub.2 (3×) and then stirred at 100° C. for 16 hours under N.sub.2 atmosphere and filtered. The filter cake was washed with EtOAc (20 mL), and the filtrate was evaporated in vacuo and purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with DCM/MeOH (0:100 to 10:90) to give the title compound as a brown solid (250 mg).

Step 2: 4-methoxy-7-dimethyl-1H-imidazo[4,5-d]pyridazine

[0529] ##STR00080##

[0530] To a solution of 4-chloro-1,7-dimethyl-1H-imidazo[4,5-d]pyridazine (530 mg, 2.90 mmol) in MeOH (15 mL) was added NaOMe (470.39 mg, 8.71 mmol). The mixture was stirred at 60° C. for 16 hours and then evaporated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with DCM/MeOH (0:100 to 15:1) to give the title compound as a grey solid (520 mg, 96% yield, 95% purity).

Step 3: 1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one

[0531] A solution of 4-methoxy-1,7-dimethyl-1H-imidazo[4,5-d]pyridazine (520 mg, 2.92 mmol) in dioxane (10 mL) and HCl (4 M, 10 mL) was stirred at 100° C. for 16 hours and then filtered. The filter cake was collected and dried in vacuo to give the title compound as a white solid (397.7 mg, 83%).

Preparation 20: 1,3,4-trimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0532] ##STR00081##

Step 1: ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate

[0533] ##STR00082##

[0534] To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (20 g, 129.73 mmol) in DMF (250 mL) was added NIS (35.02 g, 155.68 mmol) in portions. The mixture was stirred at 18° C. for 16 hours and then diluted with water (250 mL) and extracted with EtOAc, (300 mL×4). The combined organic layers were washed with brine (300 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (20:1 to 4:1) to give the title compound as light-yellow solid.

Step 2: ethyl 4-iodo-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate

[0535] ##STR00083##

[0536] To a mixture of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (42 g, 149.97 mmol) and K.sub.2CO.sub.3 (62.18 g, 449.90 mmol) in DMF (400 mL) was added 4-methoxybenzyl chloride (35.23 g, 224.95 mmol, 30.63 mL). The mixture was stirred at 18° C. for 16 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography (NCO®, 220 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 20:80) to give the title compound as yellow solid.

Step 3: ethyl 4-acetyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate

[0537] ##STR00084##

[0538] To a solution of ethyl 4-iodo-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (30 g, 74.96 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (5.26 g, 7.50 mmol) in toluene (300 mL) was added tributyl(1-ethoxyvinyl)stannane (40.61 g, 112.44 mmol, 37.95 mL). The mixture was degassed and purged with N.sub.2 (3×) and then stirred at 100° C. under N.sub.2 for 14 hours and evaporated under reduced pressure. The resulting residue was dissolved in THF (90 mL). Next, HCl (2 M, 90 mL) was added. The mixture was stirred at 25° C. for 2 hours and then quenched with saturated aq KF (200 mL) and filtered. The filtrate was extracted with DCM (200 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 3:1) to give the title compound as black brown oil (23 g, 97%).

Step 4: ethyl 4-acetyl-3-methyl-1H-pyrazole-5-carboxylate

[0539] ##STR00085##

[0540] A mixture of ethyl 4-acetyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (23 g, 72.70 mmol) and H.sub.2SO.sub.4 (128.80 g, 1.29 mol, 70 mL, 98% purity) was stirred at 50° C. for 5 hours and then slowly added to a suspension of NaHCO.sub.3(240 g) in DCM/MeOH (10:1, 1500 mL). The mixture was stirred for 15 minutes and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (10:1 to 1:1) to give the title compound as yellow solid (4.3 g, 30%).

Step 5: ethyl 4-acetyl-1,3-dimethyl-1H-pyrazole-5-carboxylate

[0541] ##STR00086##

[0542] To a mixture of ethyl 4-acetyl-3-methyl-1H-pyrazole-5-carboxylate (1.8 g, 9.17 mmol) and K.sub.2CO.sub.3 (2.54 g, 18.35 mmol) in DMF (18 mL) was added Mel: (3.91 g, 27.52 mmol, 1.71 mL), The mixture was stirred at 18° C. for 16 hours and then diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 4:96)) to give the title compound as yellow oil (930 mg, 48%).

Step 6: 1,3,4-trimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0543] To a solution ethyl 4-acetyl-1,3-dimethyl-1H-pyrazole-5-carboxylate (700 mg, 3.33 mmol) in EtOH (10 mL) was added N.sub.2H.sub.4.H.sub.2O (510.26 mg, 9.99 mmol, 495.40 μL, 98% purity), The mixture was stirred at 80° C. for 14 hours and then concentrated under reduced pressure to give the title compound as white solid (507.1 mg, 85%).

Preparation 21: 1-isopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0544] ##STR00087##

Step 1: ethyl 4-acetyl-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate

[0545] ##STR00088##

[0546] To a solution of ethyl 4-acetyl-3-meth 4-1H-pyrazole-5-carboxylate (300 mg 1.53 mmol) in DMF (3 mL) was added K.sub.2CO.sub.3 (422.64 mg, 3.06 mmol, 2 eq) and 2-iodopropane (519.85 mg, 3.06 mmol, 305.79 μL). The mixture was stirred at 18° C. for 16 hours and then filtered. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to afford a crude product, which was purified by preparative TLC (SiO.sub.2) eluting with petroleum ether/EtOAc (3:1). The title compound was obtained as a colorless oil (200 mg, 55%).

Step 2: 1-isopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0547] To a solution of ethyl 4-acetyl-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (200 mg, 839.34 μmol) in EtOH (5 mL) was added N.sub.2H.sub.4.H.sub.2O (128.63 mg, 2.52 mmol, 124.88 μL, 98% purity). The mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure to give the title compound as white solid (140 mg, 81%).

Preparation 22: 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0548] ##STR00089##

Step 1: 2-(4-methoxybenzyl)-3,4-dimethyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0549] ##STR00090##

[0550] To a solution of ethyl 4-acetyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (3 g, 9.48 mmol) in EtOH (40 mL) was added N.sub.2H.sub.4.H.sub.2O (1.45 g, 28.45 mmol, 1.41 mL, 98% purity). The reaction mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The crude product was triturated with petroleum ether/EtOAc (3:1, 80 mL) for 15 minutes. The solids were collected by filtration and dried in vacuo to give the title compound as gray solid (3.1 g, crude).

Step 2: 7-chloro-2-(4-methoxybenzyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine

[0551] ##STR00091##

[0552] Intermediate 2-(4-met oxybenzyl)-3,4-dimethyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (25 g, 87.93 mmol) was added to POCl.sub.3 (206.25 g, 1.35 mol, 125 mL). The mixture was stirred at 100° C. for 3 hours and then evaporated under reduced pressure, diluted with DCM/MeOH (10:1, 330 mL) and neutralized to pH 7˜8 by addition of saturated aq NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound as a yellow oil (29 g, crude).

Step 3: 7-methoxy-2-(4-methoxybenzyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine

[0553] ##STR00092##

[0554] To a solution of 7-chloro-2-(4-methoxybenzyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine (29 g, 95.79 mmol) in MeOH (300 mL) was added NaOMe (20.70 g, 383.14 mmol). The mixture was stirred at 70° C. for 16 hours and then filtered. The filter cake was washed with DCM/MeOH (10:1, 55 mL) and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (ISCO® 60 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 100:0) to give the title compound as a yellow solid (18 g, 63%).

Step 4: 7-methoxy-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine

[0555] ##STR00093##

[0556] A mixture of 7-methoxy-2-(4-methoxybenzyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine (15 g, 50.28 mmol) and H.sub.2SO.sub.4 (82.80 g, 827.32 mmol, 45 mL, 98% purity) was stirred at 50° C. for 5 hours and then slowly added to a suspension of NaHCO.sub.3 (150 g) in DCM/MeOH (10:1, 1000 mL). The mixture was stirred for 15 minutes and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (12.9 g, crude).

Step 5: 1-cyclopropyl-7-methoxy-3,4-dimethyl-1H-pyrazolo[3,4-d]pyridazine

[0557] ##STR00094##

[0558] To a solution of 7-methoxy-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazine g, 14.03 mmol) in DCE (30 mL) was added Cu(OAc).sub.2 (3.82 g, 21.04 mmol), 2-(2-pyridyl)pyridine (3.29 g, 21.04 mmol), Na.sub.2CO.sub.3 (2.97 g, 28.06 mmol) and cyclopropylboronic acid (2.41 g, 28.06 mmol). The reaction mixture was stirred at 70° C. for 16 hours and then filtered. The filter cake was washed with DCM (300 mL) and the filtrate was washed with water (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (ISCO® 8 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 50:50) to give the title compound as a yellow solid (470 mg, 14%).

Step 6: 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0559] To a solution of 1-cyclopropyl-7-methoxy-3,4-dimethyl-H-pyrazolo[3,4-d]pyridazine (420 mg, 1.92 mmol) in DCM (6 mL) was added BBr.sub.3 (2.41 g, 9.62 mmol, 927.11 μL) at 0° C. The reaction mixture was stirred at 25° C. for 16 hours and then quenched with water (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by silica gel flash chromatography (NCO® 4 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 40:60). The resulting crude product was washed with DCM (5 mL×2) and filtered. The solids were dried in vacuo to give the title compound as white solid.

Preparation 23: 1,3-dimethyl-1,6-dihydro-7/1-pyrazolo[3,4-d]pyridazin-7-one

[0560] ##STR00095##

Step 1: ethyl 3-methyl-4-vinyl-1H-pyrazole-5-carboxylate

[0561] ##STR00096##

[0562] A mixture of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (20 g, 71.41 mmol), Pd(dppf)Cl.sub.2 (5.23 g, 7.14 mmol), Na.sub.2CO.sub.3 (22.71 g, 214.24 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (22.00 g, 142.83 mmol, 24.23 mL) in dioxane (200 mL) and water (20 mL) was stirred at 100° C. for 14 hours under N.sub.2. The reaction mixture was then diluted with water (500 mL) and extracted with DCM (500 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (100:1 to 10:1) to give the title compound as a yellow oil.

Step 2: ethyl 1,3-dimethyl-4-vinyl-1H-pyrazole-5-carboxylate

[0563] ##STR00097##

[0564] To a solution of ethyl 3-methyl-4-vinyl-1H-pyrazole-5-carboxylate (4 g, 22.20 mmol) in DMF (40 mL) were added Mel (9.45 g, 66.59 mmol, 4.15 mL) and K.sub.2CO.sub.3 (6.14 g, 44.39 mmol). The mixture was stirred at 18° C. for 2 hours and then diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 1.5:98.5) to give the title compound as a white solid (2 g, 46%).

Step 3: ethyl 4-formyl-1,3-dimethyl-1H-pyrazole-5-carboxylate

[0565] ##STR00098##

[0566] To a solution of ethyl 1,3-dimethyl-4-vinyl-1H-pyrazole-5-carboxylate (2 g, 10.30 mmol) in dioxane (20 mL) and water (5 mL) were added NaIO.sub.4 (6.61 g, 30.89 mmol, 1.71 mL) and OsO.sub.4 (0.1 M solution in water, 10.30 mL) at 0° C. The reaction mixture was stirred at 18° C. for 14 hours and then quenched with saturated aq Na.sub.2S.sub.2O.sub.3.5H.sub.2O (100 mL) and extracted with DCM (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (100:1 to 10:1) to give the title compound as a white solid (600 mg, 30%).

Step 4: 1,3-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0567] To a solution of ethyl 4-formyl-1,3-dimethyl-1H-pyrazole-5-carboxylate(600 mg, 3.06 mmol) in EtOH (8 mL) was added N.sub.2H.sub.4.H.sub.2O (468.64 mg, 9.17 mmol, 454.99 μL, 98% purity). The reaction mixture was stirred at 80° C. for 14 hours and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (NCO® 4 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 20:80) to give the title compound as a white solid (315.6 mg, 62%).

Preparation 24: 1-isopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0568] ##STR00099##

Step 1: ethyl 1-isopropyl-3-methyl-4-vinyl-1H-pyrazole-5-carboxylate

[0569] ##STR00100##

[0570] To a solution of ethyl 3-methyl-4-vinyl-1H-pyrazole-5-carboxylate (1 g, 5.38 mmol) in DMF (10 mL) were added K.sub.2CO.sub.3 (1.49 g, 10.77 mmol) and 2-iodopropane (1.83 g, 10.77 mmol, 1.08 mL). The reaction mixture was stirred at 18° C. for 14 hours and then diluted with water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 8 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 20:80) to give the title compound as a colorless oil (580 mg, 48%).

Step 2: ethyl 4-formyl-1-isopropyl-3-methyl-7H-pyrazole-5-carboxylate

[0571] ##STR00101##

[0572] To a solution of ethyl 1-isopropyl-3-methyl-4-vinyl-1H-pyrazole-5-carboxylate (1.8 g, 8.10 mmol) in dioxane (20 mL) and water (5 mL) were added NaIO.sub.4 (5.20 g, 24.29 mmol, 1.35 mL) and 0504 (0.1 M solution in water, 12.15 mL) at 0° C. The reaction mixture was stirred at 18° C. for 16 hours and then quenched with saturated aq Na.sub.2S.sub.2O.sub.3.5H.sub.2O (80 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 4:96) to give the title compound as a white solid (800 mg, 44%).

Step 3: 1-isopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0573] To a solution of ethyl 4-formyl-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (700 mg, 3.12 mmol) in EtOH (10 mL) was added N.sub.2H.sub.4.H.sub.2O (478.35 mg, 9.36 mmol, 464.42 μL, 98% purity). The reaction mixture was stirred at 80° C. for 14 hours and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (NCO® 4 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 12:88) to give the title compound as a white solid (228.3 mg, 37%).

Preparation 25: 1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0574] ##STR00102##

Step 1: ethyl 1-cyclopropyl-3-methyl-4-vinyl-1H-pyrazole-5-carboxylate

[0575] ##STR00103##

[0576] A mixture of ethyl 3-methyl-4-vinyl-1H-pyrazole-5-carboxylate (4 g, 22.20 mmol), cyclopropylboronic acid (3.81 g, 44.39 mmol), Na.sub.2CO.sub.3 (4.71 g, 44.39 mmol), Cu(OAc).sub.2 (6.05 g, 33.30 mmol) and 2-(2-pyridyl)pyridine (5.20 g, 33.30 mmol) in DCE (40 mL) was stirred at 70° C. for 14 hours. The reaction mixture was then diluted with water (300 mL) and acidified with HCl (1 M) until pH<7. The mixture was extracted with DCM (200 mL×3) and the combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (500:1 to 200:1) to give the title compound as a light-yellow oil (3 g, 61%).

Step 2: ethyl 1-cyclopropyl-4-formyl-3-methyl-1H-pyrazole-5-carboxylate

[0577] ##STR00104##

[0578] To a solution of ethyl 1-cyclopropyl-3-methyl-4-vinyl-1H-pyrazole-5-carboxylate (2.8 g, 12.71 mmol) in dioxane (32 mL) and water (8 mL) were added OsO.sub.4 (0.1 M solution in water, 12.71 mL) and NaIO.sub.4 (8.16 g, 38.14 mmol, 2.11 mL) at 0° C. The reaction mixture was stirred at 18° C. for 16 hours and then quenched with saturated aq Na.sub.2S.sub.2O.sub.3.5H.sub.2O (150 mL) and extracted with DCM (200 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sift) eluting with petroleum ether/EtOAc (100:1 to 80:1) to give the title compound as a white solid (900 mg, 32%).

Step 3: 1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0579] To a solution of ethyl 1-cyclopropyl-4-formyl-3-methyl-1H-pyrazole-5-carboxylate (900 mg, 4.05 mmol) in EtOH (10 mL) was added N.sub.2H.sub.4.H.sub.2O (620.60 mg, 12.15 mmol, 602.52 μL, 98% purity). The reaction mixture was stirred at 80° C. for 14 hours and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with EtOAc/petroleum ether (0:100 to 18:82) to give the title compound as a white solid (500.2 mg, 64%).

Preparation 26: 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0580] ##STR00105##

Step 1: methyl 3-bromo-1-methyl-1H-pyrrole-2-carboxylate

[0581] ##STR00106##

[0582] To a mixture of methyl 3-bromo-1H-pyrrole-2-carboxylate (3.5 g, 17.16 mmol) in DMF (40 mL) was added NaH (60% in mineral oil, 1.37 g, 34.31 mmol) at 0° C. After stirring at 0° C. for 30 minutes, Mel (5.2 g, 36.64 mmol, 2.28 mL) was added at 0° C. The mixture was stirred at 15° C. for 1 hour and then diluted with EtOAc (50 mL), poured into saturated aq NH.sub.4Cl (100 mL) and extracted with EtOAc (50 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (3.75 g, crude).

Step 2: methyl 1-methyl-3-vinyl-1H-pyrrole-2-carboxylate

[0583] ##STR00107##

[0584] A mixture of methyl 3-bromo-1-methyl-1H-pyrrole-2-carboxylate (4.3 g, 19.72 mmol), tributyl(vinyl)stannane (27.8 g, 87.67 mmol, 25.50 mL) and Pd(PPh.sub.3).sub.4 (2.28 g, 1.97 mmol) in DMF (60 mL) was degassed and purged with N.sub.2 (3×) and stirred at 100° C. for 12 hours under N.sub.2 atmosphere. Saturated ail KF (150 mL) was added. The mixture was stirred for 30 minutes and then extracted with EtOAc (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 40 g SepaFlash column) eluting with petroleum ether/EtOAc (0:100 to 3:97) to give the title compound as yellow oil.

Step 3: methyl 3-formyl-1-methyl-1H-pyrrole-2-carboxylate

[0585] ##STR00108##

[0586] To a mixture of methyl 1-methyl-3-vinyl-1H-pyrrole-2-carboxylate (1.8 g, 10.79 mmol) and N-methylmorpholine-N-oxide (2.27 g, 19.42 mmol, 2.05 mL) in ACN (30 mL) and water (15 mL) was added dipotassium; dioxido(dioxo)osmium; dihydrate (198.74 mg, 539.38 μmol), After stirring for 3 hours at 15° C., NaIO.sub.4 (4.95 g, 23.14 mmol, 1.28 mL) was added. The mixture was stirred for 0.25 hours and then quenched with Na.sub.2S.sub.2O.sub.3 (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ISCO® 40 g SepaFlash® column) eluting with petroleum ether/EtOAc (0:100 to 10:90) to give the title compound as a yellow oil (0.8 g, 44%).

Step 4: 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0587] To a mixture of methyl 3-formyl-1-methyl-1H-pyrrole-2-carboxylate (800 mg, 4.71 mmol) in EtOH (20 mL) was added. N.sub.2H.sub.4.H.sub.2O (722.40 mg, 14.14 mmol, 701.36 μL, 98% purity), The reaction mixture was stirred at 80° C. for 12 hours and then cooled to 5° C. and filtered. The filter cake was washed with EtOH (10 mL). The residue was collected to give the title compound as a white solid (460 mg, 64%).

Preparation 27: 1-cyclobutyl-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0588] ##STR00109##

Step 1: 2-((benzyloxy)methyl)-5-chloropyridazin-3(2H)-one

[0589] ##STR00110##

[0590] To a mixture of 5-chloropyridazin-3(2/1)-one (2 g, 15.32 mmol) and Cs.sub.2CO.sub.3 (6.49 g, 19.92 mmol) in DMF (30 mL) at 0° C. was added ((chloromethoxy)methyl)benzene (2.56 mL, 18.39 mmol) dropwise. The reaction mixture was stirred at 20° C. for 5 hours and then diluted with isopropyl acetate (400 mL) and washed with saturated aq NH.sub.4Cl solution (400 mL) and brine (300 mL). The organic layer was dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 0 to 50% EtOAc in heptanes, to give the title compound as a yellow oil (2.08 g, 54%).

Step 2: 2-((benzyloxy)methyl)-4-bromo-5-chloropyridazin-3(2H)-one

[0591] ##STR00111##

[0592] To a 1.0 M solution of (2,2,6,6-tetramethylpiperidin-1-yl)zinc(II) lithium chloride in THF (2.87 mL, 2.87 mmol) was added 2-((benzyloxy)methyl)-5-chloropyridazin-3(2H)-one (600 mg, 2.393 mmol) in THF (10 mL) dropwise over a 1-minute period. The solution was stirred at 20° C. for 1 minute. Bromine (0.247 mL, 4.79 mmol) was added in one portion and the solution was stirred at 2.0° C. for 3 hours. Sodium thiosulfate (378 mg, 2.393 mmol) and MeOH (1 mL) were added. The mixture was stirred at 20° C. for 18 hours and then concentrated on Celite® and purified by flash chromatography, eluting with 0 to 50% EtOAc in heptanes, to give the title compound as a white solid (620 mg, 79%).

Step 3: 2-((benzyloxy)methyl)-5-chloro-4-(prop-1-en-2-yl)pyridazin-3(2H)-one

[0593] ##STR00112##

[0594] A mixture of 2-((benzyloxy)methyl)-4-bromo-5-chloropyridazin-3(2H)-one (300 mg, 0.910 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.428 mL, 2.276 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2, (37.2 nig, 0.046 mmol) in dioxane (3 mL) and saturated aq NaHCO.sub.3(3 mL, 3.30 mmol) was heated at 50° C. in an oil bath for 3 hours. LCMS indicated the reaction was incomplete, so more Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (37.2 mg, 0.046 mmol) was added, and the reaction mixture was heated at 50° C. for 8 hours. The reaction was still incomplete, so additional Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (37.2 mg, 0.046 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.215 mL, 1.14 mmol) and saturated aq NaHCO.sub.3(124 mg, 1.821 mmol) were added. The reaction mixture was heated at 50° C. for 7 hours and then diluted with isopropyl acetate (60 mL), washed with saturated aq NH.sub.4Cl (60 mL), vacuum filtered, washed with brine, dried over MgSO.sub.4, and concentrated in vacuo. The product was purified by flash chromatography, eluting with 0 to 20% EtOAc in heptanes, to give the title compound as a white solid (169 mg, 64%).

Step 4: 4-acetyl-2-((benzyloxy)methyl)-5-chloropyridazin-3(2H)-one

[0595] ##STR00113##

[0596] A solution of 2-((benzyloxy)methyl)-5-chloro-4-(prop-1-en-2-yl)pyridazin-3(2H)-one (0.275 g, 09946 mmol), ruthenium(111) chloride trihydrate (0,012 g, 0,047 mmol) and sodium periodate (0.415 g, 1.939 mmol) in THF (2 mL), acetone (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. LCMS indicated the reaction was incomplete, so more sodium periodiate (220 mg, 1.01 mmol) was added, and the reaction mixture was stirred at 20° C. for 2 hours. The reaction was still incomplete, so additional sodium periodate (400 mg, 1.89 mmol) was added. The reaction mixture was stirred at 20° C. for 18 hours and then diluted with isopropyl acetate (50 mL), washed with a solution of sodium thiosulfate (8.2 g, 20.75 mmol) in water (50 mL) followed by brine (40 mL), dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 0 to 50% EtOAc in heptanes, to give the title compound as a clear, colorless oil (200 mg, 72%).

Step 5: 5-((benzyloxy)methyl)-1-cyclobutyl-3-methyl-5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0597] ##STR00114##

[0598] To a solution of 4-acetyl-2-((benzyloxy)methyl)-5-chloropyridazin-3(211)-one (60 mg, 0.205 mmol) and cyclobutylhydrazine hydrochloride (50.3 mg, 0,410 mmol) in DMF (1.5 mL) at −10° C. (salt/ice bath) was added DIPEA (0.179 mL, 1.025 mmol). The mixture was stirred at −10° C. for 10 minutes. The temperature of the mixture was raised to 0° C.′ over a 20-minute period and the mixture was stirred at 0° C. for 2 hours. The mixture was allowed to warm to 20° C. and was then diluted with isopropenyl acetate (40 mL), washed with NH.sub.4Cl solution (40 mL) and with brine, dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 0 to 60% EtOAc in heptanes, to give the title compound as a white solid (57 mg, 86%).

Step 6: 1-cyclobutyl-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0599] To a solution of 5-((benzyloxy)methyl)-1-cyclobutyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (54 mg, 0.166 mmol) in MeOH (2 mL) under nitrogen was added Pd/C (Degussa®, 10%) (30 mg, 0.028 mmol). The slurry was stirred under an atmosphere of hydrogen for 18 hours. Acetic acid (0.048 mL, 0.832 mmol) was added and the mixture stirred at 20° C. for 3 hours. The mixture was filtered through a pad of Celite®, rinsed with methanol and concentrated in vacuo to give the title compound as a white solid.

Preparation 28: 1-(bicyclo[1.1.1]pentan-1-yl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0600] ##STR00115##

Step 1: 5-((benzyloxy)methyl)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0601] ##STR00116##

[0602] To a solution of 4-acetyl-2-((benzyloxy)methyl)-5-chloropyridazin-3(2H)-one (60 mg, 0.205 mmol) and bicyclo[1.1.1]pentan-1-ylhydrazine dihydrochloride (70.1 nig, 0.410 mmol) in DMF (1.5 mL) at −10° C. (salt/ice bath) was added DIPEA (0.215 mL, 1.230 mmol). The mixture was stirred at −10° C. for 30 minutes, during which the temperature increased to 0° C., and then at 0° C. for another 30 minutes. The mixture was allowed to warm to 20° C. and was then diluted with isopropenyl acetate (40 mL), washed with NH.sub.4Cl solution (40 mL) and with brine, dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 0 to 40% EtOAc in heptanes, to give the title compound as a white solid (33 mg, 48%).

Step 2: 1-(bicyclo[1.1.1]pentan-1-yl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0603] To a solution of 5-((benzyloxy)methyl)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (31 mg, 0.092 mmol) in MeOH (2 mL) (heated to completely dissolve solid) was added. Pd/C (Degussa®, 10%) (28 mg, 0.026 mmol) under nitrogen. The slurry was stirred under an atmosphere of hydrogen for 3 hours and then filtered through a pad of Celite®, rinsed with methanol and concentrated in metro to give the title compound as a white solid (21 mg, 93%).

Preparation 29: 1-(tert-butyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0604] ##STR00117##

Step 1: ethyl 1-(tert-butyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate

[0605] ##STR00118##

[0606] To a solution of ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (75 mg, 0.441 mmol) and tert-butylhydrazine hydrochloride (65.9 mg, 0.529 mmol) in ethanol (0.5 mL) was added DIPEA (0.185 mL, 1.058 mmol). The solution was stirred at 20° C. for 3 hours and then concentrated on Celite® and purified by flash chromatography, eluting with 0 to 50% EtOAc in heptanes, to give the title compound as a colorless oil (68 mg, 64%).

Step 2: ethyl 1-(tert-butyl)-5-formyl-3-methyl-1H-pyrazole-4-carboxylate

[0607] ##STR00119##

[0608] A mixture of ethyl 1-(tert-butyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate (52 mg, 0.22 mmol) and Dess-Martin periodinane (138 mg, 0.32 mmol) in acetonitrile (2 mL) was stirred at 20° C. for 16 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography, eluting with 0 to 25% EtOAc in heptanes, to give the tide compound as a white solid (44 mg, 84%).

Step 3: 1-(tert-butyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0609] To a solution of ethyl 1-(tert-butyl)-5-formyl-3-methyl-1H-pyrazole-4-carboxylate (42 mg, 0.176 mmol) in ethanol (1.5 mL) was added anhydrous hydrazine (200 μL, 6.4 mmol) and acetic acid (500 μL, 8.73 mmol), The solution was heated at 70° C. for 16 hours and then concentrated on Celite® and purified by flash chromatography, eluting with 0 to 100% EtOAc in heptanes, to give the title compound as a white solid (31 mg, 85%).

Preparation 30: 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0610] ##STR00120##

Step 1: ethyl 3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate

[0611] ##STR00121##

[0612] A solution of ethyl 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylate (460 mg, 2.368 mmol) and 1-iodopyrrolidine-2,5-dione (799 mg, 3.55 mmol) in DMF (4 mL) was heated to 90° C. for 3 hours. Additional 1-iodopyrrolidine-2,5-dione (1.066 g, 4.736 mmol) was added and the reaction mixture was heated at 65° C. overnight. The reaction mixture was purified by column chromatography to give the title compound (325 mg, 43%).

Step 2: ethyl 3-cyclopropyl-1-methyl-4-vinyl-1H-pyrazole-5-carboxylate

[0613] ##STR00122##

[0614] A solution of ethyl 3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (325 mg, 1.015 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (313 mg, 2.030 mmol) and triphenylphosphine palladium chloride (71.3 mg, 0.102 mmol) in dioxane (4 mL) and aq Na.sub.2CO.sub.3 (1.8 M, 2 mL) was heated to 90° C. overnight. The reaction mixture was purified by column chromatography to give the title compound (87 mg, 39%).

[0615] Step 3: ethyl 3-cyclopropyl-4-formyl-1-methyl-1H-pyrazole-5-carboxylate

##STR00123##

[0616] To a solution of ethyl 3-cyclopropyl-1-methyl-4-vinyl-1H-pyrazole-5-carboxylate (87 mg, 0,395 mmol) in dioxane (4 mL) at 0° C., was added osmium tetroxide (2.5 wt % solution in t-butanol) (0.149 mL, 0.012 mmol). Next, a solution of sodium periodate (169 mg, 0.790 mmol) in water (2 mL) was slowly added. The mixture was stirred at RT for 30 minutes and then diluted with aq Na.sub.2S.sub.2O.sub.3 (1 M, 10 mL) and EtOAc (50 mL). The aqueous layer was washed with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give the title compound (88 mg, 100%).

Step 4: 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0617] To a solution of ethyl 3-cyclopropyl-4-formyl-1-methyl-W-pyrazole-5-carboxylate (88 mg, 0,396 mmol) in EtOH (3 mL) was added hydrazine hydrate (99 mg, 0.096 mL, 1980 mmol). The mixture was stirred at 60° C. overnight and then concentrated under reduced pressure. The concentrate was diluted with sat NaHCO.sub.3 (20 mL) and extracted with DCM (10 mL×3) to give the title compound as an off-white solid (74 mg, 98%).

Preparation 31: 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one

[0618] ##STR00124##

Step 1: ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate

[0619] ##STR00125##

[0620] To a solution of ethyl 2-formyl-1H-pyrrole-3-carboxylate (501 mg, 3.00 mmol) in DMF (7493 μL) was added sodium hydride (180 mg, 4.50 mmol). The mixture was stirred for 1 hour. Next, (2-(chloromethoxy)ethyl)trimethylsilane (532 μL, 3.00 mmol) was added. The reaction mixture was stirred for an additional hour and then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound as an oil (766 mg, 86%).

Step 2: ethyl 4-bromo-2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1-pyrrole-3-carboxylate

[0621] ##STR00126##

[0622] To a solution of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (766 mg, 2.58 mmol) in acetonitrile (6.439 mL) was added N-bromosuccinimide (458 mg, 2.58 mmol). The mixture was stirred for 1 hour and then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The product was purified by flash chromatography, eluting with 0 to 30% EtOAc in heptanes, to give the title compound as an oil (542 mg, 56%).

Step 3: ethyl 2-formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate

[0623] ##STR00127##

[0624] A solution of ethyl 4-bromo-2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (542 mg, 1.440 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (401 μL, 2.88 mmol), SPhos G1, methyl t-butyl ether adduct (110 mg, 0.144 mmol), and potassium phosphate (917 mg, 4.32 mmol) in THF (6.858 mL) and water (343 μL) was heated to 110° C. in a microwave reactor for 30 minutes. The reaction mixture was then concentrated on Celite® and purified by flash chromatography, eluting with 0 to 40% EtOAc in heptanes, to give the title compound as an oil (379 mg, 84%).

Step 4: ethyl 2-formyl-4-methyl-1H-pyrrole-3-carboxylate

[0625] ##STR00128##

[0626] To a solution of ethyl 2-formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (369 mg, 1.185 mmol) in DCM (11.8 mL) was added boron trifluoride diethyl etherate (439 μL, 3.55 mmol). The reaction mixture was stirred at room temperature for 1 hour and then quenched with water and saturated NaHCO.sub.3 and stirred for 2 hours. Ethyl acetate was added. The organic layer was separated, washed with brine, and concentrated to yield a light-red solid. The solid was dissolved in ethanol (9.272 mL) and water (1.854 mL). Potassium carbonate (1.538 g, 11.13 mmol) was added. The mixture was stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure. The product was taken up in EtOAc, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give the title compound as an off-white solid (194 mg, 96%).

Step 5: ethyl 1-cyclopropyl-2-formyl-4-methyl-1H-pyrrole-3-carboxylate

[0627] ##STR00129##

[0628] A solution of ethyl 2-formyl-4-methyl-1H-pyrrole-3-carboxylate (184 mg, 1.016 mmol), cyclopropylboronic acid (262 mg, 3.05 mmol), Na.sub.2CO.sub.3 (323 mg, 3.05 mmol), copper (II) acetate (277 mg, 1,523 mmol), and 2,2′-bipyridine (238 mg, 1.523 mmol) in DCE (5.078 mL) was stirred at 70° C. for 4 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography, eluting with 0 to 80% EtOAc in heptanes, to give the title compound (137 mg, 61%).

Step 6: 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one

[0629] A solution of ethyl 1-cyclopropyl-2-formyl-4-methyl-1H-pyrrole-3-carboxylate (127 mg, 0.574 mmol) and hydrazine hydrate (255 μL, 2.87 mmol) in acetic acid (1.435 mL) was heated at 80° C. for 30 minutes and then concentrated under vacuum. The resulting residue was partitioned between DCM and aqueous NaHCO.sub.3. The organic layer was dried and concentrated to give the title compound (64 mg, 59%).

Preparation 32: 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0630] ##STR00130##

Step 1: ethyl 4-bromo-3-formyl-III-pyrrole-2-carboxylate

[0631] ##STR00131##

[0632] To an ice-cooled solution of ethyl 3-formyl-1H-pyrrole-2-carboxylate (702 mg, 4.20 mmol) in acetic acid (11.2 mL) and dioxane (5.599 mL), was added N-bromosuccinimide (860 mg, 4.83 mmol). The reaction mixture was stirred at 0° C. for 6 hours and then partitioned between brine and EtOAc. The organic layer was separated, washed with saturated aq Na.sub.2CO.sub.3, dried over Na.sub.2SO.sub.4 and purified by flash chromatography, eluting with 0 to 5% DCM in EtOAc, to give the title compound as a solid (348 mg, 34%).

Step 2: ethyl 4-bromo-3-formyl-1-methyl-1H-pyrrole-2-carboxylate

[0633] ##STR00132##

[0634] A solution of ethyl 4-bromo-3-formyl-1H-pyrrole-2-carboxylate (305 mg, 1.240 mmol) in DMF (4.958 mL) was cooled to 0° C. Sodium hydride (99 mg, 2.479 mmol) was added and the mixture was stirred for 30 minutes. Methyl iodide (116 μL, 1,859 mmol) was added, and the mixture was stirred for 1 hour at RT and then diluted with water. A precipitate was isolated by filtration to give the title compound as a solid (160 mg, 50%).

Step 3: ethyl 4-cyclopropyl-3-formyl-1-methyl-1H-pyrrole-2-carboxylate

[0635] ##STR00133##

[0636] A solution of ethyl 4-bromo-3-formyl-1-methyl-1H-pyrrole-2-carboxylate (160 mg, 0.615 mmol), cyclopropylboronic acid (106 mg, 1230 mmol), SPhos G1, methyl t-butyl ether adduct (23.40 mg, 0.031 mmol), and potassium phosphate (392 mg, 1.846 mmol) in toluene (1.465 mL) and water (73.2 μL) was heated to 130° C. for 1 hour and then purified by HPLC (Method B) to give the title compound as an oil (39 mg, 29%).

Step 4: 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0637] A solution of ethyl 4-cyclopropyl-3-formyl-1-methyl-1H-pyrrole-2-carboxylate (39 mg, 0.176 mmol) and hydrazine hydrate (47.0 μL, 0.529 mmol) in acetic acid (881 μL) was heated at 80° C. for 30 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between EtOAc and aqueous NaHCO.sub.3. The organic layer was dried and concentrated to provide the title compound as a solid (30 mg, 90%).

Preparation 33: 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0638] ##STR00134##

Step 1: ethyl 5-formyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0639] ##STR00135##

[0640] A solution of 2.5 M n-butyl lithium in hexanes (1.58 mL, 3.96 mmol) was added dropwise via a syringe to a stirred solution of diisopropylamine (565 μL, 3.96 mmol) in anhydrous THE (2.57 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 minutes and then at 0° C. for 30 minutes. The resulting LDA solution was cooled to −78° C. and a solution of ethyl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.80 mmol) in THF (2.57 mL) was added dropwise. The mixture was stirred at −78° C. for 5 minutes and then DMF (1.12 mL, 14.4 mmol) was added dropwise and the mixture was stirred at −78° C.′ for 1 hour. The cooling bath was removed, and the reaction mixture was slowly warmed to room temperature. After 1 hour at 20° C., the reaction mixture was poured into a rapidly stirred solution of saturated aq NH.sub.4Cl. The product was extracted with EtOAc (×3) and the combined organic phases were washed with saturated aq NH.sub.4Cl, and then dried over anhydrous Na.sub.2SO.sub.4. The supernatant was decanted from the drying agent, and the solvents were removed in mow. The crude isolate was purified by flash column chromatography using an ISCO® automated purification system, eluting with a gradient of 0-20% EtOAc in heptanes. The product-containing fractions were collected and combined, concentrated on a rotary evaporator at 35° C., and dried in vacuo to give the title compound as a light-yellow oil (300 mg, 67%).

Step 2: 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0641] To a flask charged with ethyl 5-formyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (300 mg, 1.20 mmol) in EtOH/HOAc (10:1 v/v, 4.00 mL) was added hydrazine hydrate (174 μL, 3.60 mmol) dropwise at room temperature with stirring. The flask was sealed, and the reaction mixture was heated at 80° C. for 20.5 hours before cooling to room temperature. A resulting white precipitate was collected by vacuum filtration over a fritted funnel to give the title compound as a white, crystalline solid (196 mg, 75N.

Preparation 34: 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

Step 1: 3-bromo-1-isopropyl-4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine and 3-bromo-2-isopropyl-4-methoxy-7-methyl-2H-pyrazolo[3,4-d]pyridazine

[0642] ##STR00136##

[0643] To a solution of 3-bromo-4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine (1.00 g, 4.11 mmol) in DMF (10 mL) were added 2-iodopropane (2.79 g, 16.44 mmol, 1.64 mL) and K.sub.2CO.sub.3 (1.70 g, 12.33 mmol). The mixture was stirred at 15° C. for 3 hours and then filtered and washed with EtOAc (20 mL). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (5:1 to 1:1) to give a mixture of the title compounds as a white solid (220 mg).

Step 2: 1-isopropyl-4-methoxy-3,7-dimethyl-1H-pyrazolo[3,4-d]pyridazine

[0644] ##STR00137##

[0645] To a solution of 3-bromo-1-isopropyl-4-methoxy-7-methyl-1H-pyrazolo[3,4-d]pyridazine and 3-bromo-2-isopropyl-4-methoxy-7-methyl-2H-pyrazolo[3,4-d]pyridazine (1 g) in toluene (6 mL) and water (1 mL) were added methylboronic acid (314.9 mg, 5.26 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (286.4 mg, 350.71 mot) and Cs.sub.2CO.sub.3 (3.43 g, 10.53 mmol). The mixture was degassed and purged with N.sub.2 (3×) and then stirred at 100° C. for 16 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (ISCO® 12 g SepaFlash® column) eluting with a gradient of 0-45% EtOAc in petroleum ether. The crude product was triturated with ACN/DMSO (20:1, 10 mL) in a dry ice/acetone bath and then filtered at sub-ambient temperature. The filter cake was dried under reduced pressure to give the title compound as a white solid (250 mg).

Step 3: 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0646] To a solution of 1-isopropyl-4-methoxy-3,7-dimethyl-1H-pyrazolo[3,4-d]pyridazine (250 mg, 1.13 mmol) in dioxane (10 mL) was added HCl (4 M, 10.00 mL). The mixture was stirred at 90° C. for 16 hours and then concentrated under reduced pressure to give the title compound as a grey solid (172 mg, 72N.

Preparation 35: (S)-2-promo-N-(1-(p-tolyl)ethyl)acetamide

[0647] ##STR00138##

[0648] To a solution of (S)-1-(p-tolyl)ethanamine (16.32 mL, 111 mmol) and EON (15.46 mL, 111 mmol) in DCM (185 mL) at −10° C. was added 2-bromoacetyl bromide (9.66 mL, 111 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 hour and then diluted with water, extracted with DCM, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The crude product was dispersed in hexanes (200 mL), and the resulting slurry stirred for 30 minutes and filtered to give the title compound as a white solid (26.97 g, 95%).

Preparation 36: (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0649] ##STR00139##

[0650] The title compound was prepared like PREPARATION 35, using (S)-1-(4-(trifluoromethyl)phenyl)ethanamine (21.00 g, 111 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as a white solid (30.4 g, 88%).

Preparation 37: (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0651] ##STR00140##

[0652] The title compound was prepared like PREPARATION 35, using (S)-1-(4-methoxyphenyl)ethanamine (48.8 mL, 331 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as an off-white solid (84.7 g, 94%).

Preparation 38: (S)-2-promo-N-(1-(4-chloro-2-methyl phenyl)ethyl)acetamide

[0653] ##STR00141##

[0654] The title compound was prepared like PREPARATION 35, using (S)-1-(4-chloro-2-methylphenyl)ethan-1-amine (700 mg, 4.13 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as white solid (670 mg, 56%).

Preparation 39: (S)-2-bromo-N-(1-(4-chlorophenyl)ethyl)acetamide

[0655] ##STR00142##

[0656] The title compound was prepared like PREPARATION 35, using (S)-1-(4-chlorophenyl)ethan-1-amine (5.68 mL, 40.5 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as an off-white solid (10.1 g, 90%).

Preparation 40: (S)-2-bromo-N-(1-(4-fluoro-3-methylphenyl)ethyl)acetamide

[0657] ##STR00143##

[0658] The title compound was prepared like PREPARATION 35, using (S)-1-(4-fluoro-3-methylphenyl)ethanamine (700 mg, 4.57 mmol) in place of (5)-1-(p-tolyl)ethanamine. The title compound was obtained as a white solid (1.1 g, 88%).

Preparation 41: (S)-2-bromo-N-(1-(3-fluorophenyl)ethyl)acetamide

[0659] ##STR00144##

[0660] The title compound was prepared like PREPARATION 35, using (S)-1-(3-fluorophenyl)ethanamine (700 mg, 5.03 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as a pink solid (1.1 g, 86%).

Preparation 42: (S)-2-bromo-N-(1-phenylethyl)acetamide

[0661] ##STR00145##

[0662] The title compound was prepared like PREPARATION 35, using (S)-1-phenylethan-1-amine (5.32 mL, 41.3 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as a tan solid (8.8 g, 88%).

Preparation 43: (S)-2-bromo-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide

[0663] ##STR00146##

[0664] The title compound was prepared like PREPARATION 35, using (S)-1-(2-fluoro-4-methoxyphenyl)ethanamine (6.338 g, 37.5 mmol) in place of (5)-1-(p-tolyl)ethanamine. The title compound was obtained as a tan solid (7.5 g, 69%).

Preparation 44: 2-bromo-N-(1-(chroman-6-yl)ethyl)acetamide

[0665] ##STR00147##

[0666] The title compound was prepared like PREPARATION 35, using 1-(chroman-6-yl)ethan-1-amine (700 mg, 3.95 mmol) in place of (5)-1-(p-tolyl)ethanamine. The title compound was obtained as a brown oil (829 mg, 70%).

Preparation 45: 2-bromo-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide

[0667] ##STR00148##

[0668] The title compound was prepared like PREPARATION 35, using 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine (600 mg, 3.35 mmol) in place of (S)-1-(p-tolyl)ethanamine. The title compound was obtained as a white solid (590 mg, 59%).

Preparation 46: (S)-2-promo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0669] ##STR00149##

[0670] To a solution of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl (10 g, 52.7 mmol) and Et.sub.3N (14.70 mL, 105 mmol) in DCM (88 mL) at 0° C. was added 2-bromoacetyl bromide (4.58 mL, 52.7 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then diluted with water, extracted with DCM, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The crude product was slurried in hexanes (200 mL), stirred for 3 hours and then filtered to give the title compound as a white solid (12.37 g, 86%).

Preparation 47: (S)-2-bromo-N-(1-(3-fluoro-4-methyl phenyl)ethyl)acetamide

[0671] ##STR00150##

[0672] The title compound was prepared like PREPARATION 46, using (S)-1-(3-fluoro-4-methylphenyl)ethan-1-amine, HCl (4 g, 21.09 mmol) in place of (5)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (5.14 g, 89%).

Preparation 48: (S)-2-bromo-N-(1-(4-methoxy-3-methylphenyl)ethyl)acetamide

[0673] ##STR00151##

[0674] The title compound was prepared like PREPARATION 46, using (S)-1-(4-methoxy-3-methylphenyl)ethanamine, HCl (700 mg, 3.47 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a brown solid (260 mg, 26%).

Preparation 49: (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0675] ##STR00152##

[0676] The title compound was prepared like PREPARATION 46, using (5)-1-(4-(trifluoromethoxy)phenyl)ethan-1-amine, HCl (5 g, 20.69 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (4.87 g, 72%).

Preparation 50: (S)-2-bromo-N-(1-(4-chloro-2-fluorophenyl)ethyl)acetamide

[0677] ##STR00153##

[0678] The title compound was prepared like PREPARATION 46, using (S)-1-(4-chloro-2-fluorophenyl)ethanamine, HCl (700 mg, 3.33 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (660 mg, 67%).

Preparation 51: (S)-2-bromo-N-(1-(2,4-difluorophenyl)ethyl)acetamide

[0679] ##STR00154##

[0680] The title compound was prepared like PREPARATION 46, using (S)-1-(2,4-difluorophenyl)ethanamine, HCl (700 mg, 3.62 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (439 mg 44%).

Preparation 52: (S)-2-promo-N-(1-(2-chloro-4-fluorophenyl)ethyl)acetamide

[0681] ##STR00155##

[0682] The title compound was prepared like PREPARATION 46, using (S)-1-(2-chloro-4-fluorophenyl)ethanamine, HCl (723 mg, 3.44 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (424 mg, 42%).

Preparation 53: (S)-2-bromo-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)acetamide

[0683] ##STR00156##

[0684] The title compound was prepared like PREPARATION 46, using (5)-1-(4-fluoro-3-methoxyphenyl)ethanamine, HCl (1 g, 4.86 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (639 mg, 45%).

Preparation 54: (S)-2-bromo-N-(1-(2,4,6-trifluorophenyl)ethyl)acetamide

[0685] ##STR00157##

[0686] The title compound was prepared like PREPARATION 46, using (S)-1-(2,4,6-trifluorophenyl)ethanamine, HCl (700 mg, 3.31 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as an orange oil (596 mg, 61%).

Preparation 55: (S)-2-bromo-N-(1-(3,5-difluorophenyl)ethyl)acetamide

[0687] ##STR00158##

[0688] The title compound was prepared like PREPARATION 46, using (S)-1-(3,5-difluorophenyl)ethanamine, HCl (700 mg, 3.62 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (594 mg 59%).

Preparation 56: (S)-2-promo-N-(1-(2-chloro-6-fluorophenyl)ethyl)acetamide

[0689] ##STR00159##

[0690] The title compound was prepared like PREPARATION 46, using (S)-1-(2-chloro-6-fluorophenyl)ethanamine, HCl (700 mg, 3.33 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a colorless oil (800 mg, 82%).

Preparation 57: (S)-2-bromo-N-(1-(2,5-dimethylphenyl)ethyl)acetamide

[0691] ##STR00160##

[0692] The title compound was prepared like PREPARATION 46, using (S)-1-(2,5-dimethylphenyl)ethanamine, HCl (700 mg, 3.77 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a brown solid (620 mg, 61%).

Preparation 58: (S)-2-bromo-N-(1-(2,3-difluorophenyl)ethyl)acetamide

[0693] ##STR00161##

[0694] The title compound was prepared like PREPARATION 46, using (S)-1-(2,3-difluorophenyl)ethanamine, HCl (700 mg, 3.62 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (595 mg, 59%).

Preparation 59: (S)-2-bromo-N-(1-(2,4-dimethylphenyl)ethyl)acetamide

[0695] ##STR00162##

[0696] The title compound was prepared like PREPARATION 46, using (S)-1-(2,4-dimethylphenyl)ethan-1-amine hydrochloride (1 g, 5.39 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a white solid (500 mg 34%).

Preparation 60: S)-2-bromo-N-(1-(5-(trifluoromethyl)pyri din-2-yl)ethyl)acetamide

[0697] ##STR00163##

[0698] The title compound was prepared like PREPARATION 46, using (S)-1-(5-(trifluoromethyl)pyridin-2-yl)ethanamine, HCl (500 mg, 2.206 mmol) in place of (S)-1-(2-fluoro-4-methylphenyl)ethan-1-amine, HCl. The title compound was obtained as a green oil (412 mg, 60%).

Preparation 61: (S)-2-bromo-N-(1-mesitylethyl)acetamide

[0699] ##STR00164##

[0700] To a solution of (S)-1-mesitylethan-1-amine, HCl (0.300 g, 1.502 mmol) and Et.sub.3N (0.419 mL, 3.00 mmol) in anhydrous DCM (5 mL) at 0° C. was added 2-bromoacetyl bromide (0.130 mL, 1,502 mmol) dropwise. The reaction mixture was stirred at 0° C. for 3 hours and then quenched with saturated aq NH.sub.4Cl and allowed to warm to 20° C. The mixture was diluted with EtOAc (45 mL), washed with saturated aq NH.sub.4Cl (50 mL) and brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The resulting crude material was purified by chromatography (40 g silica gel column) eluting with 0 to 50% EtOAc in heptane, to give the title compound as a white solid (268 mg, 63%).

Preparation 62: 2-bromo-1-(2-(4-chlorophenyl)pyrrolidin-1-yl)ethan-1-one

[0701] ##STR00165##

[0702] To a solution of 2-(4-chlorophenyl)pyrrolidine (1.7 g, 9.36 mmol) and Et.sub.3N (1.304 mL, 9.36 mmol) in DCM (15.60 mL) at 0° C. was added 2-bromoacetyl bromide (0.813 mL, 9.36 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then diluted with water, extracted with DCM, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The resulting crude material was dissolved in DCM and purified by ISCO® automated purification system, eluting with 0 to 20% MeOH in DCM. The product-containing fractions were combined, and the solvent was removed via rotary evaporation at 35° C. The product was dried in vacuo to give the title compound as a colorless oil (2.62 g, 93%).

Preparation 63: (S)-2-bromo-N-(1-(2,6-difluorophenyl)ethyl)acetamide

[0703] ##STR00166##

Step 1: (S)—N—((S)-1-(2,6-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0704] ##STR00167##

[0705] To a solution of (S)-2-methylpropane-2-sulfinamide (6.64 g, 54.8 mmol), tetraethoxytitanium (25.00 g, 110 mmol) and THF (110 mL) at RT was added 1-(2,6-difluorophenyl)ethanone (10.27 g, 65.8 mmol). The solution was stirred at 75° C. overnight and allowed to cool to RT. The solution was cooled to −45° C. in a dry ice/ACN/acetone bath, added dropwise to a suspension of sodium tetrahydroborate (8.29 g, 219 mmol) and THF (60 mL) at −45° C., and warmed to RT over several hours. After stirring at RT for 48 hours, the solution was cooled to 0° C. in an ice bath and MeOH (20 mL) was added dropwise until gas evolution ceased. The solution was allowed to warm to RT and saturated aq NaCl (about 100 mL) was added. The mixture was filtered and washed with EtOAc. The filtrate was diluted with brine and extracted with EtOAc (100 mL×3). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting crude material was dissolved in DCM and purified by ISCO® automated purification system, eluting with 0 to 70% EtOAc in heptane. The product-containing fractions were combined, and solvent was removed via rotary evaporation at 35° C. The product was dried in vacuo to give the title compound as a clear oil as a clear oil (7.45 g, 52%).

Step 2: (S)-1-(2,6-difluorophenyl)ethan-1-amine

[0706] ##STR00168##

[0707] To a solution of (S)—N—((S)-1-(2,6-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (365 mg, 1.397 mmol) in methanol (2.793 mL) was added 4 M HCl in dioxane (1.397 mL, 5.59 mmol), The reaction mixture was stirred at RT for 16 hours and then concentrated in vacuo to give an HCL salt of the title compound as a white solid (271 mg, 1.3996 mmol). The solid was dissolved in THF (6 mL) and Et.sub.3N (0.2 mL, 1.4 mmol) was added. A resulting white precipitate was filtered off and the filtrate was concentrated to give the free base of the title compound as an off-white solid (108 mg, 49%).

Step 3: (S)-2-bromo-N-(1-(2,6-difluorophenyl)ethyl)acetamide

[0708] To a solution of (S)-1-(2,6-difluorophenyl)ethan-1-amine (4.005 g, 25.5 mmol) and Et.sub.3N (3.55 mL, 25.5 mmol) in DCM (42.5 mL) at −10° C. was added 2-bromoacetyl bromide (2.220 mL, 25.5 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 hour and then diluted with water, extracted with DCM, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude material was dissolved in DCM and purified by ISCO® automated purification system, eluting with 0 to 100% EtOAc in heptane. The product-containing fractions were combined, and solvent was removed via rotary evaporation at 35° C. The product was dried in vacuo to give the title compound as an orange solid (3.204 g, 45.2%).

Preparation 64: (R)-2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0709] ##STR00169##

[0710] To a 100 mL round-bottom flask charged with (R)-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (2.0 g, 10.57 mmol), Et.sub.3N (1.474 mL, 10.57 mmol) and ACN (20 mL) was added 2-chloroacetyl chloride (0,841 mL, 10.57 mmol) at a temperature less than 0° C. The reaction mixture was stirred at 0 to 5° C. for 1 hour and then diluted with water (40 mL) and extracted with DCM (2×). The combined organic layers were washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The resulting solid was slurried in heptane (20 mL) at room temperature and filtered. The filter cake was washed with heptane (5 mL×2) and dried under reduced pressure at room temperature to give the title compound as an off-white solid (2.51 g, 89%).

Preparation 65: (S)-2-bromo-N-(cyclopropyl(phenyl)methyl)acetamide

[0711] ##STR00170##

[0712] To a solution of (S)-cyclopropyl(phenyl)methanamine hydrochloride (0.9743 g, 5.30 mmol) and Et.sub.3N (1.479 mL, 10.61 mmol) in DCM (20.4 mL) at 0° C. was added 2-bromoacetyl bromide (0.462 mL, 5.30 mmol) dropwise via a syringe. The reaction mixture was stirred at 0° C. for 1 hour and then quenched with water (20 mL). The biphasic system was transferred to a separatory funnel and the two layers were separated. The aqueous phase was extracted with DCM (20 mL and then 10 mL). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a pale-orange solid (1.3686 g, 96%).

Preparation 66: (S)-2-bromo-N-(1-(4-(methyl-d.SUB.3.)phenyl)ethyl)acetamide

[0713] ##STR00171##

Step 1: (methyl-d.SUB.3.)magnesium iodide

[0714] ##STR00172##

[0715] To a suspension of M, (3.27 g, 134.52 mmol) and 12 (131.32 mg, 517.39 μmol, 104.22 μL) in Et.sub.2O (25 mL) was added dropwise a solution of iodomethane-d.sub.3 (15 g, 103.48 mmol, 6.44 mL) in Et.sub.2O (75 mL) at 15° C. under N.sub.2. The mixture was stirred at 15° C. for 2 hours to give the title compound as a 0.97 M solution in Et.sub.2O (100 mL).

Step 2: (S)-1-(4-(methyl-d.SUB.3.)phenyl)ethan-1-amine

[0716] ##STR00173##

[0717] To a solution of (S)-1-(4-bromophenyl)ethan-1-amine(4.5 g, 22.49 mmol, 3.24 mL) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (3.67 g, 4.50 mmol) in THF (100 mL) was added dropwise (methyl-d.sub.3)magnesium iodide (0.97 M, 100 mL, 4.31 eq) under N.sub.2. The reaction mixture was stirred at 70° C. for 15 hours and then quenched with HCl (0.5 M, 300 mL) and extracted with EtOAc (300 mL×2). The organic layers were discarded. The aqueous layer was adjusted to PH 9 with Na.sub.2CO.sub.3 and extracted with DCM/MeOH (300 mL×3, 10:1). The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a yellow oil (2.5 g, 80%).

Step 3: (S)-2-promo-N-(1-(4-(methyl-d.SUB.3.)phenyl)ethyl)acetamide

[0718] To a solution of (S)-1-(4-(methyl-d.sub.3)phenyl)ethan-1-amine (2.5 g, 18.09 mmol) and Et.sub.3N (5.49 g, 54.26 mmol, 7.55 mL) in DCM (50 mL) was added dropwise 2-bromoacetyl bromide (4.38 g, 21.70 mmol, 1.89 mL, 1.2 eq) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours and then washed with HCl (1.5 M, 50 mL) and concentrated under vacuum. The residue was purified by silica gel flash chromatography (ISCO® 40 g SepaFlash® column) eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound as a white solid (2.11 g, 57%).

Preparation 67: (S)-2-bromo-N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)acetamide

[0719] ##STR00174##

[0720] To a solution of (S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine hydrochloride (400 mg, 1.694 mmol) and Et.sub.3N (472 μl, 3.39 mmol) in DCM (2,823 mL) at 0° C. was added 2-bromoacetyl bromide (147 μL, 1.694 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then diluted with water, extracted with DCM, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The crude product was slurried in heptanes (20 mL), stirred for 60 hours and then filtered to give the title compound as an off-white solid (349 mg, 64%).

Example 1: (S)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolylethyl)acetamide

[0721] ##STR00175##

[0722] To a solution of (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (30 mg, 0.117 mmol) in DMF (586 μL) was added 4-methyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (29.1 mg, 0.129 mmol) and K.sub.2CO.sub.3 (32.4 mg, 0.234 mmol). The reaction mixture was heated at 50° C. for 3 hours and then poured into DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by preparative HPLC (Method A). The product-containing fractions were combined, condensed in a rotary evaporator at 45° C., and dried in vacuo to give the title compound as a white solid (12.5 mg 27%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.2.6 (s, 3H), 2.52 (s, 3H), 4.73 (s, 2H), 4.87 (quin, J=7.1 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.46-7.58 (m, 3H), 7.64-7.69 (m, 2H), 8.45 (d, J=7.8 Hz, 1H), 8.48-8.51 (m, 1H); ESI-MS m/z [M+H].sup.+ 402.2.

Example 2: (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0723] ##STR00176##

[0724] The title compound was prepared like EXAMPLE 1, using 4-methyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (28 mg, 62%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.29-1.36 (m, 3H), 2.94 (s, 3H), 3.69-3.75 (m, 3H), 4.72 (s, 2H), 4.86 (quin, J=7.2 Hz, 1H), 6.81-6.88 (m, 2H), 7.19-7.26 (m, 2H), 7.45-7.57 (m, 3H), 7.62-7.71 (m, 2H), 8.43 (d, J=7.8 Hz, 1H), 8.46-8.50 (m, 1H); ESI-MS m/z [M+H].sup.+ 418.2.

Example 3: (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0725] ##STR00177##

[0726] The title compound was prepared like EXAMPLE 1, using 4-isopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (37 mg, 55%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.30-1.37 (m, 10H), 2.24-2.29 (m, 3H), 3.24-3.30 (m, 1H), 4.71-4.76 (m, 2H), 4.89 (quin, J=7.2 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.46-7.57 (m, 3H), 7.63-7.68 (m, 2H), 8.42 (d, J=8.3 Hz, 1H), 8.60 (s, 1H); ESI-MS m/z [M+H].sup.+ 430.3.

Example 4: (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0727] ##STR00178##

[0728] The title compound was prepared like EXAMPLE 1, using 4-isopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (51 mg, 81%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.32 (dd, J=6.8, 4.9 Hz, 6H), 1.38 (d, J=6.8 Hz, 3H), 3.24-3.30 (m, 1H), 4.76 (s, 2H), 4.98 (quin, J=7.2 Hz, 1H), 7.47-7.57 (m, 5H), 7.63-7.67 (m, 4H), 8.59-8.65 (m, 2H); ESI-MS m/z [M+H].sup.+ 484.2.

Example 5: (S)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0729] ##STR00179##

[0730] To a vial containing 4-methyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (30 mg, 0.133 mmol) in DMF (553 μL) was added (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (40.1 mg, 0.111 mmol) and K.sub.2CO.sub.3 (18.33 mg, 0:133 mmol). The mixture was stirred for 1 hour at 60° C. After cooling, 1 M HCl was added (200 mL). A resulting precipitate was filtered and dried in vacuo to give the title compound as a white solid (28.4 mg, 55%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.49 (d, J=7.32 Hz, 3H), 2.58 (s, 3H), 4.88 (s, 2H), 5.07 (q, J=7.00 Hz, 1H), 7.22 (d, J=8.79 Hz, 2H), 7.42-7.57 (m, 6H), 7.66-7.72 (m, 2H), 8.31 (s, 1H); ESI-MS m/z [M+H].sup.+ 472.3.

Example 6: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-methyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0731] ##STR00180##

[0732] The title compound was prepared like EXAMPLE 5, using 4-methyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (36 mg, 79%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.46 (d, J=7.08 Hz, 3H), 2.32 (s, 3H), 2.58 (s, 3H), 4.86-4.88 (m, 2H), 5.23 (d, J=7.08 Hz, 1H), 6.88 (d, J=12.20 Hz, 1H), 6.95 (d, J=8.05 Hz, 1H), 7.26 (t, J=7.93 Hz, 1H), 7.48-7.55 (m, 3H), 7.66-7.70 (m, 2H), 8.30 (s, 1H); ESI-MS m/z [M+H].sup.+ 420.3.

Example 7: (S)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0733] ##STR00181##

[0734] To a vial were added 4-isopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.025 g, 0.096 mmol), (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (0.03 g, 0.092 mmol) and K.sub.2CO.sub.3 (0.036 g, 0.263 mmol) in DMF (0.438 mL). The reaction mixture was stirred for 4 hours at RT and then 1 N HCl (1 mL) and methanol (1 mL) were added. The crude material was purified by HPLC (Method B) to give the title compound as a white solid (9.0 mg, 21%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.40 (dd, J=7.08, 4.15 Hz, 6H), 1.47 (d, J=7.32 Hz, 3H), 3.27 (spt, J=6.92 Hz, 1H), 4.82-4.96 (m, 2H), 5.14 (quin, J=7.08 Hz, 1H), 6.33 (d, J=7.81 Hz, 1H), 7.14 (d, J=7.81 Hz, 2H), 7.29-7.33 (m, 2H), 7.46-7.58 (m, 3H), 7.63-7.70 (m, 2H), 8.15 (s, 1H); ESI-MS m/z [M+H].sup.+ 500.3.

Example 8: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-isopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0735] ##STR00182##

[0736] The title compound was prepared like EXAMPLE 7, using 4-isopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (9 mg, 20%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.41 (dd, J=6.83, 2.93 Hz, 6H), 1.46 (d, J=6.83 Hz, 3H), 2.31 (s, 3H), 3.27 (spt, J=6.92 Hz, 1H), 4.73-4.98 (m, 2H), 5.23 (quin, J=7.32 Hz, 1H), 6.51 (d, J=8.30 Hz, 1H), 6.77-6.92 (m, 2H), 7.12 (t, J=7.81 Hz, 1H), 7.43-7.56 (m, 3H), 7.66-7.71 (m, 2H), 8.15 (s, 1H); ESI-MS m/z [M+H].sup.+ 448.4.

Example 9: (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0737] ##STR00183##

[0738] The title compound was prepared like EXAMPLE 7, using 1-(tert-butyl)-4-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (2.0 mg, 45%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.46 (d, J=6.83 Hz, 3H), 1.81 (s, 9H), 2.50 (s, 3H), 3.77 (s, 3H), 4.80-4.92 (m, 2H), 5.09 (quin, J=7.20 Hz, 1H), 6.40 (d, J=7.81 Hz, 1H), 6.74-6.86 (m, 2H), 7.15-7.24 (m, 2H), 7.78 (s, 1H); ESI-MS m/z [M+H].sup.+ 398.3.

Example 10: (S)—N-(1-(3-fluoro-4-methoxyphenyl)ethyl)-2-(3-isopropyl-1,7-dimethyl-4-oxo-1H-pyrazolo[3,4-d]pyridazin-5(4H)-yl)acetamide

[0739] ##STR00184##

[0740] The title compound was prepared like EXAMPLE 7, using 3-isopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluoro-4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (11 mg, 30%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.38 (d, J=6.83 Hz, 6H) 1.43 (d, 0.1-6.83 Hz, 3H) 2.65 (s, 3H) 3.57 (quin, J=6.96 Hz, 1H) 3.85 (s, 3H) 4.17 (s, 3H) 4.73-4.89 (m, 2H) 4.99-5.09 (m, 1H) 6.68 (d, J=7.81 Hz, 1H) 6.86 (t, J=8.79 Hz, 1H) 6.94-7.03 (m, 2H); m/z [M+H].sup.+ 416.3.

Example 11: (S)-2-(1-(tert-butyl)-4-isopropyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0741] ##STR00185##

[0742] To a solution of (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (40 mg, 0,156 mol) in DMF (781 μL) were added 1-(tert-butyl)-4-isopropyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (36.6 mg, 0.156 mmol) and K.sub.2CO.sub.3 (43.2 mg, 0.312 mmol). The reaction mixture was stirred at RT for 18 hours and then diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by preparative HPLC (Method A), The product-containing fractions were combined, concentrated in a rotary, evaporator at 45° C., and dried in vacuo to give the title compound as a white solid (18.4 mg, 76%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.28 (dd, J=6.8, 3.4 Hz, 6H), 1.36 (d, J=7.3 Hz, 3H), 1.75 (s, 9H), 2.27 (s, 3H), 3.16-3.25 (m, 1H), 4.71-4.80 (m, 2H), 4.90 (quin, J=7.3 Hz, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 8.23 (s, 1H), 8.49 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H].sup.+ 410.3.

Example 12: (S)-2-(1-(tert-butyl)-4-isopropyl-7-oxo-1,7-dihydro-6/1-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0743] ##STR00186##

[0744] The title compound was prepared like EXAMPLE 11, using 1-(tert-butyl)-4-isopropyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (48 mg, 81%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.27 (dd, J=6.8, 5.4 Hz, 6H), 1.40 (d, J=7.3 Hz, 3H), 1.74 (s, 9 FT), 3.16-3.25 (m, 1H), 4.78 (s, 2H), 499 (quin, J=7.3 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H), 8.23 (s, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS [M+H].sup.+ 464.3.

Example 13: (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0745] ##STR00187##

[0746] The title compound was prepared like EXAMPLE 11, using 1-(tert-butyl)-4-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (23 mg, 63%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, J=6.8 Hz, 3H), 1.74 (s, 9H), 2.27 (s, 3H), 2.42-2.45 (m, 3H), 4.75 (s, 2H), 4.89 (quin, J=7.2 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 8.10-8.14 (m, 1H), 8.49 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H].sup.+ 382.3.

Example 14: (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0747] ##STR00188##

[0748] The title compound was prepared like EXAMPLE 11, using 1-(tert-butyl)-4-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (19 mg, 45%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 1.74 (s, 9H), 2.44 (s, 3H), 4.73-4.83 (m, 2H), 4.99 (quin, J=7.2 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 8.12 (s, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H].sup.+ 436.2.

Example 15: (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0749] ##STR00189##

[0750] The title compound was prepared like EXAMPLE 11, using 1-(tert-butyl)-4-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (22 mg, 50%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.38 (d, J=6.8 Hz, 3H), 1.74 (s, 9H), 2.44 (s, 3H), 4.71-4.82 (m, 2H), 4.95 (quin, J=7.1 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H), 7.44-7.50 (m, 2H), 8.12 (s, 1H), 8.62 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H].sup.+ 452.2.

Example 16: (S)-2-(1-(tert-butyl)-4-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0751] ##STR00190##

[0752] The title compound was prepared like EXAMPLE 11, using 1-(tert-butyl)-4-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (21 mg, 54%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, J=6.8 Hz, 3H), 1.74 (s, 9H), 2.28 (s, 3H), 2.44 (s, 3H), 4.76 (s, 2H), 5.09 (quirt, 17.2 Hz, 1H), 6.9:3-7.00 (m, 2H), 7.32 (t, J=8.1 Hz, 1H), 8.11-8.14 (m, 1H), 8.60 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H].sup.+ 400.3.

Example 17: (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-1-(4-methoxyphenyl)ethyl)acetamide

[0753] ##STR00191##

[0754] The title compound was prepared like EXAMPLE 11, using 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (16 mg, 56%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.34 (d, J=7.3 Hz, 3H), 1.45 (d, J=6.8 Hz, 6H), 2.48 (s, 3H), 3.72 (s, 3H), 4.65-4.76 (m, 2H), 4.86 (quin, J=7.2 Hz, 1H), 4.91-4.99 (m, 1H), 6.85-6.90 (m, 2H), 7.20-7.27 (m, 2H), 8.46 (d, J=7.8 Hz, 1H), 8.55 (s, 1H); ESI-MS m/z [M+H].sup.+ 384.2.

Example 18: (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0755] ##STR00192##

[0756] The title compound was prepared like EXAMPLE 11, using 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (16 mg, 54%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.95-1.01 (m, 4H), 1.34 (d, J=6.8 Hz, 3H), 1.42 (d, J=6.3 Hz, 6H), 2.39-2.45 (m, 1H), 3.72 (s, 3H), 4.65-4.77 (m, 2H), 4.83-4.96 (m, 2H), 6.85-6.89 (m, 2H), 7.21-7.26 (m, 2H), 8.46 (d, J=7.8 Hz, 1H), 8.53 (s, 1H); ESI-MS m/z [M+H].sup.+ 410.2.

Example 19: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide

[0757] ##STR00193##

[0758] The title compound was prepared like EXAMPLE 11, using 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (14 mg, 44%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.47 (s, 3H), 3.74 (s, 3H), 3.99 (s, 3H), 4.67-4.76 (m, 2H), 5.06 (quin, J=7.2 Hz, 1H), 6.74-6.80 (m, 2H), 7.27-7.35 (m, 1H), 8.47 (s, 1H), 8.55 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 374.2.

Example 20: (S)—N-(1-(p-tolyl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0759] ##STR00194##

[0760] The title compound was prepared like EXAMPLE 11, using 1,3,4-trimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (9 mg, 45%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.25 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 4.15 (s, 3H), 4.67 (s, 2H), 4.86 (quin, J=7.2 Hz, 1H), 7.09-7.14 (m, 2H), 7.17-7.21 (m, 2H), 8.48 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H].sup.+ 354.1.

Example 21: (S)-2-(1-isopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0761] ##STR00195##

[0762] The title compound was prepared like EXAMPLE 11, using 1-isopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide to give the title compound as a white solid (16 mg, 73%). .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (d, J=7.3 Hz, 3H), 1.41 (d, J=6.8 Hz, 6H), 2.25 (s, 3H), 2.43-2.45 (m, 3H), 2.52 (s, 3H), 4.68 (s, 2H), 4.86 (quin, J=7 Hz, 1H), 5.50-5.58 (m, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 8.48 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H].sup.+ 382.1.

Example 22: (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0763] ##STR00196##

[0764] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (17 mg, 74%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.00-1.06 (m, 2H), 1.12-1.18 (m, 2H), 1.33 (d, J=7.3 Hz, 3H), 2.25 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 4.56 (tt, J=7.6, 3.9 Hz, 1H), 4.69 (s, 2H), 4.87 (quin, J=7.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.19 (d, J=8.3 Hz, 2H), 8.48 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H].sup.+ 380.1.

Example 23: (S)-2-(1-isopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-p-tolyl)ethyl)acetamide

[0765] ##STR00197##

[0766] The title compound was prepared like EXAMPLE 11, using 1-isopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (15 mg, 69%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=6.83 Hz, 3H), 1.43 (d, J=6.83 Hz, 6H), 2.25 (s, 3H), 2.44-2.45 (m, 3H), 4.74 (d, J=0.98 Hz, 2H), 4.87 (t, J=7.20 Hz, 1H), 5.49 (quin, J=6.83 Hz, 1H), 7.08-7.13 (m, 2H), 7.16-7.21 (m, 2H), 8.33 (s, 1H), 8.51 (d, J=7.81 Hz, 1H); ESI-MS m/z [M+H].sup.+ 368.1.

Example 24: (S)—N-(1-(4-chloro-2-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0767] ##STR00198##

[0768] The title compound was prepared like EXAMPLE 1, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-chloro-2-fluorophenyl)ethyl)acetamide, and was obtained as a white solid (17 mg, 83%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.06-1.13 (m, 4H), 1.34 (d, J=7.08 Hz, 3H), 2.44 (s, 3H), 3.83-3.88 (m, 1H), 4.69-4.78 (m, 2H), 5.03-5.10 (m, 1H), 7.28 (dd, J=8.42, 2.07 Hz, 1H), 7.37 (dd, J=10.25, 1.95 Hz, 1H), 7.40-7.45 (m, 1H), 8.48 (s, 1H), 8.69 (d, J=7.57 Hz, 1H); ESI-MS m/z [M+H].sup.+ 404.0.

Example 25: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluorophenyl)ethyl)acetamide

[0769] ##STR00199##

[0770] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluorophenyl)ethyl)acetamide, and was obtained as a white solid (18 mg, 85%). NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.07-1.13 (m, 4H), 1.35 (d, J=7.08 Hz, 3H), 2.45 (s, 3H), 3.83-3.89 (m, 1H), 4.74 (s, 2H), 4.92 (t, J=7.32 Hz, 1H), 7.01-7.06 (m, 1H), 7.12-7.17 (m, 2H), 7.35 (td, J=8.05, 6.35 Hz, 1H), 8.49 (s, 1H), 8.58 (d, J=7.81 Hz, 1H); ESI-MS m/z [M+H].sup.+ 370.0.

Example 26: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,5-dimethylphenyl)ethyl)acetamide

[0771] ##STR00200##

[0772] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2,5-dimethylphenyl)ethyl)acetamide, and was obtained as a white solid (14 mg, 66%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.04-1.12 (m, 4H), 1.32 (d, J=6.83 Hz, 3H), 2.16 (s, 3H), 2.19 (s, 3H), 2.45 (s, 3H), 3.85 (tt, J=7.20, 3.66 Hz, 1H), 4.71 (s, 2H), 4.82 (t, J=7.32 Hz, 1H), 6.98-7.02 (m, 1H), 7.04-7.09 (m, 2H), 8.44-8.50 (m, 2H); ESI-MS m/z [M+H].sup.+ 380.1.

Example 27: (S)-2-(1,3-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0773] ##STR00201##

[0774] The title compound was prepared like EXAMPLE 11, using 1,3-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (12 mg, 60%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.25 (s, 3H), 2.42-2.45 (m, 3H), 4.17 (s, 3H), 4.73 (d, J=2.2 Hz, 2H), 4.86 (t. J=7.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 8.32 (s, 1H), 8.50 (d, 8.1 Hz, 1H); ESI-MS m/z [M+H].sup.+ 340.0.

Example 28: (S)-2-(1-cyclopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0775] ##STR00202##

[0776] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (13 mg, 61%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.02-1.08 (m, 2H), 1.14-1.19 (m, 2H), 1.33 (d, J=7.08 Hz, 3H), 2.25 (s, 3H), 2.41 (s, 3H), 4.52 (tt, J=7.47, 3.87 Hz, 1H), 4.75 (d, J=1.71 Hz, 2H), 4.87 (t, J=7.20 Hz, 1H), 7.11 (d, J=8.30 Hz, 2H), 7.19 (d, J=8.05 Hz, 2H), 8.31 (s, 1H), 8.51 (d, J=7.81 Hz, 1H); ESI-MS m/z [M+H].sup.+ 366.1.

Example 29: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0777] ##STR00203##

[0778] The title compound was prepared like EXAMPLE 11, using 1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (5 mg, 26%). .sup.1H NNW. (500 MHz, DMSO-d.sub.6) δ ppm 1.33 (d, J=7.08 Hz, 3H), 2.25 (s, 3H), 2.58 (s, 3H), 3.99 (s, 3H), 4.66-4.75 (m, 2H), 4.86 (t, J=7.44 Hz, 1H), 7.11 (d, J=8.30 Hz, 2H), 7.18-7.21 (m, 2H), 8.20 (s, 1H), 8.46 (d, J=8.05 Hz, 1H); ESI-MS m/z [M+H].sup.+ 340.1.

Example 30: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,3-difluorophenyl)ethyl)acetamide

[0779] ##STR00204##

[0780] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2,3-difluorophenyl)ethyl)acetamide, and was obtained as a white solid (16 mg, 74%). .sup.1H NMR (500 MHz, DMSO-6/6) δ ppm 1.06-1.13 (m, 4H), 1.37 (d, J=7.08 Hz, 3H), 2.44 (s, 3H), 3.85 (tt, J=7.23, 3.75 Hz, 1H), 4.69-4.79 (m, 2H), 5.12 (t, J=7.08 Hz, 1H), 7.16-7.24 (m, 2H), 7.26-7.34 (m, 1H), 8.48 (s, 1H), 8.72 (d, 1-7.57 Hz, 1H); ESI-MS m/z [M+H].sup.+ 388.0.

Example 31: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxy-3-methylphenyl)ethyl)acetamide

[0781] ##STR00205##

[0782] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxy-3-methylphenyl)ethyl)acetamide, and was obtained as a white solid (12 mg, 57%). ESI-MS m/z [M+H].sup.+ 396.0.

Example 32: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0783] ##STR00206##

[0784] The title compound was prepared like EXAMPLE 11, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a white solid (12 mg, 28%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.07-1.13 (m, 4H), 1.41 (d, J=7.08 Hz, 3H), 2.45 (s, 3H), 3.82-3.88 (m, 1H), 4.73-4.82 (m, 2H), 5.00 (t, J=7.44 Hz, 1H), 7.61 (d, J=8.30 Hz, 1H), 8.19 (dd, J=8.30, 2.44 Hz, 1H), 8.49 (d, J=0.73 Hz, 1H), 8.76 (d, J=7.32 Hz, 1H), 8.88-8.91 (m, 1H); ESI-MS m/z [M+H].sup.+ 421.0.

Example 33: (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0785] ##STR00207##

[0786] To a solution of (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (23.88 mg, 0.093 mmol) in DMF (466 μL) were added 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (14 mg, 0.093 mmol) and K.sub.2CO.sub.3 (25.8 mg, 0.186 mmol). The reaction mixture was stirred at WI for 18 hours and then diluted in MT, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by HPLC (Method B). The product-containing fractions were combined, concentrated in a rotary evaporator at 45° C., and dried in vacuo to give the title compound as a white solid (9.2 mg 30%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.11 (s, 3H), 4.71-4.81 (m, 2H), 4.88 (quin, J=7.2 Hz, 1H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 8.22 (s, 1H), 8.50 ((i, J=8.3 Hz, 1H), 8.59 (s, 1H); ESI-MS m/z [M+H].sup.+ 326.3.

Example 34: (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0787] ##STR00208##

[0788] The title compound was prepared like EXAMPLE 33, using 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide; and was obtained as a white solid (13 mg, 37%). .sup.1H NMR (500 MHz, DMSO-16) δ ppm 1.39 (d, J=6.8 Hz, 3H), 4.11 (s, 3H), 4.75-4.85 (m, 2H), 4.98 (quin, J=7.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.69 (d, J=7.8 Hz, 2H), 8.22 (d, J=1.0 Hz, 1H), 8.59 (s, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H].sup.+ 380.1.

Example 35: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0789] ##STR00209##

[0790] The title compound was prepared like EXAMPLE 33, using 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (12 mg, 37%). NMR (500 MHz; DMSO-d.sub.6) δ ppm 1.34 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 4.10 (s, 3H), 4.73-4.83 (m, 2H), 5.09 (quin, J=7.2 Hz, 1H), 6.94-7.03 (m, 2H), 7.29 (t, J=8.1 Hz, 1H), 8.22 (d, J=1.0 Hz, 1H), 8.57-8.63 (m, 2H); ESI-MS m/z [M+H].sup.+ 344.2.

Example 36: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0791] ##STR00210##

[0792] The title compound was prepared like EXAMPLE 33, using 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (11 mg, 47%). .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 2.48 (s, 3H), 4.00 (s, 3H), 4.67-4.77 (m, 2H), 4.88 (quin, J=7.2 Hz, 1H), 7.10-7.16 (m, 2H), 7.21 (d, J=7.8 Hz, 2H), 8.46-8.51 (m, 2H); ESI-MS m/z [M+H].sup.+ 340.2.

Example 37: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0793] ##STR00211##

[0794] The title compound was prepared like EXAMPLE 33, using 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (9 mg, 36%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.39 (d, J=7.3 Hz, 3H), 2.48 (s, 3H), 4.00 (s, 3H), 4.70-4.82 (m, 2H), 4.98 (quip, J=7.2 Hz, 1H), 7.52-7.59 (m, 2H), 7.70 (d, J=8.3 Hz, 2H), 8.47-8.51 (m, 1H), 8.68 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H].sup.+ 394.2.

Example 38: (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0795] ##STR00212##

[0796] The title compound was prepared like EXAMPLE 33, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (8 mg, 37%). ESI-MS m/z [M+H].sup.+ 366.2.

Example 39: (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-totyl)ethyl)acetamide

[0797] ##STR00213##

[0798] The title compound was prepared like EXAMPLE 33, using 1,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (7 mg, 44%) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, J=7.3 Hz, 3H), 2.26-2.29 (m, 3H), 2.42-2.44 (m, 3H), 4.26 (s, 3H), 4.63-4.77 (m, 2H), 4.88 (quin, J=7.2 Hz, 1H), 7.13 (d, J=7.8 Hz, 2H), 7.18-7.25 (m, 2H), 8.16 (s, 1H), 8.49 (d, J=7.8 Hz, 1H); m/z [M+H].sup.+ 340.1.

Example 40: (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0799] ##STR00214##

[0800] The title compound was prepared like EXAMPLE 33, using 1,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (8 mg, 39%). .sup.1H NAIR (500 MHz, DMSO-d.sub.6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 2.43 (s, 3H), 4.26 (s, 3H), 4.75 (s, 2H), 4.99 (quin, J=7.1 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 8.16 (s, 1H), 8.65-8.70 (m, 1H); ESI-MS m/z [M+H].sup.+ 394.1.

Example 41: (S)-2-(1,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0801] ##STR00215##

[0802] The title compound was prepared like EXAMPLE 33, using 1,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (6 mg, 37%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 2.41-2.43 (m, 3H), 4.26 (s, 3H), 4.72 (s, 2H), 5.09 (quin, J=7.2 HZ, 1H), 6.94-7.02 (m, 2H), 7.29 (t, J=8.1 Hz, 1H), 8.14-8.17 (m, 1H), 8.57-8.62 (m, 1H); ESI-MS m/z [M+H].sup.+ 358.1.

Example 42: (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0803] ##STR00216##

[0804] To a solution of (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide (32.6 mg, 0.119 mmol) in MT (0.6 mL) were added 4-cyclopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (30 mg, 0.119 mmol) and K.sub.2CO.sub.3 (32.9 mg, 0,238 mmol). The reaction mixture was stirred at 28-45° C. for 18 hours and then diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by HPLC (Method A). The product-containing fraction was concentrated under reduced pressure to give the title compound as a white solid (24.7 mg, 47%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.02-1.09 (m, 2H), 1.09-1.17 (m, 2H), 1.45 (d, J=6.83 Hz, 3H), 2.13-2.21-(m, 1H), 2.31 (s, 3H), 4.70-4.90 (m, 2H), 5.16-5.25 (m, 1H), 6.42-6.49 (m, 1H), 6.78-6.85 (m, 1H), 6.85-6.89 (m, 1H), 7.08-7.14 (m, 1H), 7.44-7.54 (m, 3H), 7.67-7.71 (m, 2H), 8.19 (s, 1H); ESI-MS m/z [M+H].sup.+ 446.2.

Example 43: (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0805] ##STR00217##

[0806] The title compound was prepared like EXAMPLE 42, using 4-cyclopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (24.8 mg, 49%). ESI-MS m/z [M+H].sup.+ 428.3.

Example 44: (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0807] ##STR00218##

[0808] The title compound was prepared like EXAMPLE 42, using 4-cyclopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (16.8 mg, 29%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.05-1.16 (m, 4H), 1.47 (d, J=7.32 Hz, 3H), 2.13-2.21 (m, 1H), 4.77-4.91 (m, 2H), 5.11-5.19 (m, 1H), 6.29-6.38 (m, 1H), 7.36-7.40 (m, 2H), 7.46-7.57 (m, 5H), 7.66-7.70 (m, 2H), 8.20 (s, 1H); ESI-MS m/z [M+H].sup.+ 482.3.

Example 45: (S)-2-(4-cyclopropyl-7-oxo-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0809] ##STR00219##

[0810] The title compound was prepared like EXAMPLE 42, using 4-cyclopropyl-1-phenyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (21.7 mg, 37%). ESI-MS m/z [M+H].sup.+ 498.2.

Example 46: (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0811] ##STR00220##

[0812] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (17.3 mg, 60%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.48 (d, J=6.83 Hz, 3H), 1.59 (d, J=6.83 Hz, 6H), 2.32 (s, 3H), 2.66 (s, 3H), 4.63-4.72 (m, 1H), 4.81-4.89 (m, 2H), 5.11 (quin, J=7.20 Hz, 1H), 6.35 (br s, 1H), 7.08-7.15 (m, 2H), 7.15-7.21 (m, 2H), 8.11 (s, 1H); ESI-MS m/z [M+H].sup.+ 368.2.

Example 47: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0813] ##STR00221##

[0814] The title compound was prepared like EXAMPLE 42, using 1,3-dimethyl-5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (18.2 mg, 38%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.49 (d, J=6.83 Hz, 3H), 2.56 (s, 3H), 4.02 (s, 3H), 4.86-4.89 (m, 2H), 5.02-5.10 (m, 1H), 7.23 (d, J=8.30 Hz, 2H), 7.41-7.48 (m, 2H), 8.33-8.37 (m, 1H), 8.68 (d, J=7.32 Hz, 1H); ESI-MS m/z [M+H].sup.+ 410.1.

Example 48: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0815] ##STR00222##

[0816] The title compound was prepared like EXAMPLE 42, using 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (12.2 mg, 43%). ESI-MS m/z [M+H].sup.+ 356.2.

Example 49: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0817] ##STR00223##

[0818] The title compound was prepared like EXAMPLE 42, using 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a solid (19.5 mg, 50%). ESI-MS m/z [M+H].sup.+ 386.2.

Example 50: (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0819] ##STR00224##

[0820] The title compound was prepared like EXAMPLE 42, using 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a solid (25.5 mg, 59%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.31-1.40 (m, 6H), 1.47-1.52 (m, 3H), 3.43-3.56 (m, 1H), 4.03 (s, 3H), 4.88 (d, J=2.44 Hz, 2H), 5.01-5.11 (m, 1H), 7.18-7.26 (m, 2H), 7.41-7.48 (m, 2H), 8.35 (s, 1H), 8.67 (d, J=7.32 Hz, 1H); ESI-MS m/z [M+H].sup.+ 438.2.

Example 51: (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0821] ##STR00225##

[0822] The title compound was prepared like EXAMPLE 42, using 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a solid (17.9 mg, 48%). ESI-MS m/z [M+H].sup.+ 368.2.

Example 52: (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo-[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0823] ##STR00226##

[0824] The title compound was prepared like EXAMPLE 42, using 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a solid (24.1 mg, 58%). ESI-MS m/z [M+H].sup.+422.2.

Example 53: (S)-2-(3-isopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0825] ##STR00227##

[0826] The title compound was prepared like EXAMPLE 42, using 3-isopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as solid (14.2 mg, 37%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.33-1.39 (m, 6H), 1.45-1.50 (m, 3H), 3.45-3.56 (m, 1H), 3.77 (s, 3H), 4.04 (s, 3H), 4.83-4.89 (m, 2H), 4.97-5.06 (m, 1H), 6.82-6.91 (m, 2H), 7.22-7.31 (m, 2H), 8.35 (s, 1H), 8.51 (d, J=7.81 Hz, 1H); ESI-MS m/z [M+H].sup.+ 384.2.

Example 54: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0827] ##STR00228##

[0828] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a solid (26.6 mg, 71%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.46 (d, J=6.83 Hz, 3H), 1.55 (d, J=6.35 Hz, 6H), 2.31 (s, 3H), 2.57 (s, 3H), 2.65 (d, J=1.46 Hz, 3H), 4.76-4.89 (m, 2H), 5.04-5.13 (m, 1H), 5.19-5.26 (m, 1H), 6.87 (d, J=11.72 Hz, 1H), 6.93-7.00 (m, 1H), 7.23-7.30 (m, 1H); ESI-MS m/z [M+H].sup.+ 400.2.

Example 55: (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0829] ##STR00229##

[0830] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a solid (0.8 mg, 2%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.46 (d, J=6.83 Hz, 3H), 1.55 (d, J=6.35 Hz, 6H), 2.30 (s, 3H), 2.57 (s, 3H), 2.65 (s, 3H), 4.81 (d, J=9.76 Hz, 2H), 4.98-5.04 (m, 1H), 5.06-5.13 (m, 1H), 7.13 (d, J=7.81 Hz, 2H), 7.22 (d, J=8.30 Hz, 2H), 8.52 (d, J=6.83 Hz, 1H); ESI-MS m/z [M+H].sup.+ 382.2.

Example 56: (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0831] ##STR00230##

[0832] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a solid (20.2 mg, 50%). ESI-MS m/z [M+H].sup.+ 436.2.

Example 57: (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0833] ##STR00231##

[0834] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a solid (2.1 mg, 6%). ESI-MS m/z [M+H].sup.+ 398.2.

Example 58: (S)-2-(1-cyclopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0835] ##STR00232##

[0836] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (9.5 mg, 35%). ESI-MS m/z [M+H].sup.+ 421.1.

Example 59: (S)-2-(1-isopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0837] ##STR00233##

[0838] The title compound was prepared like EXAMPLE 42, using 1-isopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (2.5 mg, 9%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.48-1.55 (m, 9H), 2.55 (s, 3H), 2.60 (s, 3H), 4.82-4.94 (m, 2H), 5.21-5.31 (m, 1H), 5.61-5.72 (m, 1H), 7.34-7.41 (m, 1H), 7.42-7.48 (m, 1H), 7.92-7.97 (m, 1H), 8.73-8.78 (m, 1H); ESI-MS [M+H].sup.+ 437.1.

Example 60: (S)-2-(1,3-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0839] ##STR00234##

[0840] The title compound was prepared like EXAMPLE 42, using 1,3-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (4.0 mg, 16%). ESI-MS m/z [M+H].sup.+ 395.1.

Example 61: N-(1-(chroman-6-yl)ethyl)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0841] ##STR00235##

[0842] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and 2-bromo-N-(1-(chroman-6-yl)ethyl)acetamide, and was obtained as a solid (0.8 mg, 3%). ESI-MS m/z [M+H].sup.+ 422.2.

Example 62: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide

[0843] ##STR00236##

[0844] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a solid (18.8 mg, 62%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.02-1.17 (m, 4H), 1.45 (d, J=7.03 Hz, 3H), 2.23 (d, J=1.76 Hz, 3H), 2.46 (d, J=0.88 Hz, 3H), 3.39 (tt, J=7.12, 3.67 Hz, 1H), 4.85 (d, J=14.68 Hz, 1H), 4.95 (d, J=14.81 Hz, 1H), 5.09 (t, J=7.28 Hz, 1H), 6.64-6.75 (m, 1H), 6.88 (d, J=0.88 Hz, 1H), 6.91 (dd, J=10.85, 1.57 Hz, 1H), 6.97 (dd, J=7.84, 1.69 Hz, 1H), 7.10 (t, J=7.91 Hz, 1H), 8.22 (s, 1H); ESI-MS m/z [M+H].sup.+ 383.2.

Example 63: (S)—N-(1-(4-chloro-2-methylphenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide

[0845] ##STR00237##

[0846] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-chloro-2-methylphenyl)ethyl)acetamide, and was obtained as a solid (22.7 mg, 72%). ESI-MS m/z [M+H].sup.+ 399.1.

Example 64: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-mesitylethyl)acetamide

[0847] ##STR00238##

[0848] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-mesitylethyl)acetamide, and was obtained as a solid (20.2 mg, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.98-1.07 (m, 2H), 1.07-1.16 (m, 2H), 1.46 (d, J=7.28 Hz, 3H), 2.21 (s, 3H), 2.36 (s, 6H), 2.44 (s, 3H), 3.38 (tt, J=7.11, 3.62 Hz, 1H), 4.80-4.94 (m, 2H), 5.51 (t, J=7.28 Hz, 1H), 6.77 (s, 2H), 6.85 (s, 1H), 6.96 (br, d, J=6.65 Hz, 1H), 8.18 (s, 1H); ESI-MS m/z [M+H].sup.+ 393.2.

Example 65: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(2,4-dimethylphenyl)ethyl)acetamide

[0849] ##STR00239##

[0850] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2,4-dimethylphenyl)ethyl)acetamide, and was obtained as a solid (19.9 mg, 66%). ESI-MS m/z [M+H].sup.+ 379.2.

Example 66: (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide

[0851] ##STR00240##

[0852] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-chloro-4-fluorophenyl)ethyl)acetamide, and was obtained as a solid (17.7 mg, 55%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.02-1.10 (m, 2H), 1.10-1.18 (m, 2H), 1.45 (d, J=6.90 Hz, 3H), 2.46 (d, J=1.00 Hz, 3H), 3.40 (tt, J=7.12, 3.67 Hz, 1H), 4.84-4.96 (m, 2H), 5.34 (t, J=7.15 Hz, 1H), 6.89 (d, J=1.00 Hz, 1H), 6.92 (dd, J=8.28, 2.64 Hz, 1H), 6.98 (br d, J=6.78 Hz, 1H), 7.06 (dd, J=8.47, 2.57 Hz, 1H), 7.27-7.32 (m, 1H), 8.22 (s, 1H); ESI-MS [M+H].sup.+ 403.1.

Example 67: (S)—N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)acetamide

[0853] ##STR00241##

[0854] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-chloro-Z-methoxyphenyl)propan-2-yl)acetamide, and was obtained as a solid (20.7 mg, 61%). ESI-MS m/z [M+H].sup.+ 429.1.

Example 68: (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide

[0855] ##STR00242##

[0856] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a solid (10.4 mg, 36%). ESI-MS m/z [M+H].sup.+ 398.2.

Example 69: (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0857] ##STR00243##

[0858] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a solid (10.1 mg, 35%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.05-1.19 (m, 2H), 1.30-1.41 (m, 2H), 1.48 (d, J=6.90 Hz, 3H), 2.33 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 4.57 (tt, J=7.59, 3.89 Hz, 1H), 4.85 (y, J=15.18 Hz, 2H), 5.21-5.30 (m, 1H), 6.61 (br d, J=8.28 Hz, 1H), 6.84 (d, J=11.92 Hz, 1H), 6.89 (d, J=7.65 Hz, 1H), 7.15 (t, J=7.84 Hz, 1H); ESI-MS m/z [M+H].sup.+ 398.2.

Example 70: (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-mesitylethyl)acetamide

[0859] ##STR00244##

[0860] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-mesitylethyl)acetamide, and was obtained as a solid (12.3 mg, 41%). ESI-MS m/z [M+H].sup.+ 408.2.

Example (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0861] ##STR00245##

[0862] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-chloro-4-fluorophenyl)ethyl)acetamide, and was obtained as a solid (14.3 mg, 47%). NMR (400 MHz, CDCl.sub.3) δ ppm 1.08-1.17 (m, 2H), 1.28-1.41 (m, 2H), 1.49 (d, J=7.03 Hz, 3H), 2.55 (s, 3H), 2.56 (s, 3H), 4.58 (tt, J=7.58, 3.84 Hz, 1H), 4.86 (q, J=15.06 Hz, 2H), 5.36 (quin, J=7.06 Hz, 1H), 6.62 (br d, J=6.90 Hz, 1H), 6.95 (td, J=8.28, 2.64 Hz, 1H), 7.09 (dd, J=8.41, 2.64 Hz, 1H), 7.31 (dd, J=8.72, 6.09 Hz, 1H); ESI-MS m/z [M+H].sup.+ 418.1.

Example 72: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0863] ##STR00246##

[0864] A 4 mL vial equipped with a stir bar was charged with K.sub.2CO.sub.3 (33 mg, 0.24 mmol) and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (45 mg, 0.15 mmol). A solution of 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (20 mg, 0.12 mmol) in DMF (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 40° C. for 18 h and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (7.4 mg, 15%). .sup.1H NMR (500 MHz, CD.sub.3CN) δ ppm 1.52 (d, J=6.83 Hz, 3H), 2.72 (s, 3H), 4.28 (s, 3H), 4.89 (d, J=3.42 Hz, 2H), 5.07-5.14 (m, 1H), 7.53-7.59 (m, 2H), 7.64 (d, J=8.30 Hz, 2H), 8.14 (s, 1H); ESI-MS m/z [M+H].sup.+ 394.1.

Example 73: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0865] ##STR00247##

[0866] The title compound (13.4 mg, 27%) was prepared like EXAMPLE 72, using 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.50 (d, J=6.83 Hz, 3H), 2.72 (s, 3H), 4.28 (s, 3H), 4.87 (d, J=3.91 Hz, 2H), 5.04-5.11 (m, 1H), 7.24 (dd, J=8.79, 0.98 Hz, 2H), 7.44-7.49 (m, 2H), 8.14 (s, 1H); ESI-MS m/z [M+H].sup.+ 410.1.

Example 74: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0867] ##STR00248##

[0868] The title compound (6.9 mg, 17%) was prepared like EXAMPLE 72, using 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, ESI-MS m/z [M+H].sup.+ 340.1.

Example 75: (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0869] ##STR00249##

[0870] The title compound (7.7 mg, 18%) was prepared like EXAMPLE 72, using 1-isopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, ESI-MS m/z [M+H].sup.+ 422.1.

Example 76: (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0871] ##STR00250##

[0872] The title compound (4.2 mg, 9.2%) was prepared like EXAMPLE 72, using 1-isopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 438.2.

Example 77: (S)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0873] ##STR00251##

[0874] The title compound (9.6 mg, 25%) was prepared like EXAMPLE 72, using 1-isopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.47 (d, J=6.83 Hz, 3H), 1.60 (d, J=6.83 Hz, 6H), 2.31 (s, 3H), 2.72 (s, 3H), 4.86-4.88 (m, 2H), 4.99-5.05 (m, 1H), 5.15-5.24 (m, 1H), 7.14 (d, J=8.30 Hz, 2H), 7.22-7.25 (m, 2H), 8.18-8.22 (m, 1H); ESI-MS [M+H].sup.+ 368.2.

Example 78: (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0875] ##STR00252##

[0876] The title compound (4.9 mg, 11%) was prepared like EXAMPLE 72, using 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.24 (d, J=4.80 Hz, 2H), 1.38 (s, 2H), 1.51 (d, J=7.07 Hz, 3H), 2.82 (s, 3H), 3.96-4.04 (m, 1H), 4.88 (d, J=2.53 Hz, 2H), 5.06-5.15 (m, 1H), 7.52-7.57 (m, 2H), 7.62 (s, 2H), 8.08 (s, 1H); ESI-MS m/z [M+H].sup.+ 420.4.

Example 79: (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5/1-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0877] ##STR00253##

[0878] The title compound (2.9 mg, 6.3%) was prepared like EXAMPLE 72, using 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 436.4.

Example 80: (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0879] ##STR00254##

[0880] The title compound (2.5 mg, 6.5%) was prepared like EXAMPLE 72, using 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.20-1.27 (m, 2H), 1.36-1.40 (m, 2H), 1.46 (d, J=7.07 Hz, 3H), 2.30 (s, 3H), 2.82 (s, 3H), 3.97-4.04 (m, 1H), 4.98-5.05 (m, 1H), 7.13 (d, J=7.83 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 8.08 (s, 1H); ESI-MS m/z [M+H].sup.+ 366.4.

Example 81: (S)-2-(1-cyclopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0881] ##STR00255##

[0882] The title compound (3.9 mg, 9.4%) was prepared like EXAMPLE 72, using 1-cyclopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 384.4.

Example 82: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0883] ##STR00256##

[0884] A 4 ml, vial equipped with a stir bar was charged with K.sub.2CO.sub.3 (34 mg, 0.24 mmol) and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide (40 mg, 0.15 mmol). A solution of 1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (20 mg, 0.12 mmol) in NMP (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 50° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound as a white solid (322 mg, 7.4%). .sup.1H NMR (500 MHz, CD.sub.3CN) δ ppm 1.43-1.45 (m, 3H), 2.17 (s, 2H), 2.34 (s, 3H), 2.68 (s, 3H), 4.23 (s, 3H), 4.75 (s, 2H), 5.16-5.23 (m, 1H), 6.91 (d, J=11.72 Hz, 1H), 6.99 (d, J=7.81 Hz, 2H), 7.25 (t, J=8.05 Hz, 1H), 8.07 (s, 1H); ESI-MS m/z [M+H].sup.+ 358.1.

Example 83: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-7-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0885] ##STR00257##

[0886] The title compound (10.5 mg, 26%) was prepared like EXAMPLE 82, using 1-isopropyl-7-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.46 (d. J=6.83 Hz, 3H), 1.63 (d, J=6.83 Hz, 6H), 2.31 (s, 3H), 2.69 (s, 3H), 4.84 (d, J=2.93 Hz, 2H), 5.00-5.09 (m, 1H), 5.18-5.27 (m, 1H), 6.73-6.79 (m, 1H), 6.80-6.84 (m, 1H), 6.86-6.90 (m, 1H), 7.14 (s, 1H), 8.26 (s, 1H); ESI-MS m/z [M+H].sup.+ 386.1.

Example 84: 5-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

[0887] ##STR00258##

[0888] The title compound (9.4 mg, 28%) was prepared like EXAMPLE 82, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and 2-bromo-1-(2-(4-chlorophenyl)pyrrolidin-1-yl)ethan-1-one. ESI-MS m/z [M+H].sup.+ 412.1.

Example 85: 6-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

[0889] ##STR00259##

[0890] The title compound (10 mg, 30%) was prepared like EXAMPLE 82, using 1-cyclopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and 2-bromo-1-(2-(4-chlorophenyl)pyrrolidin-1-yl)ethan-1-one. ESI-MS m/z [M+H].sup.+ 412.1.

Example 86: (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0891] ##STR00260##

[0892] A 4 mL vial equipped with a stir bar was charged with Cs.sub.2CO.sub.3 (73 mg, 0.22 mmol) and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (42 mg, 0.14 mmol). A solution of 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (20 mg, 0.11 mmol) in DMF (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 60° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (31 mg, 68%). NMR (500 MHz, CD.sub.3OD) δ ppm 1.52 (d, J=6.83 Hz, 3H), 1.58 (d, J=6.83 Hz, 6H), 4.94 (d, J=4.88 Hz, 2H), 5.01 (s, 1H), 5.07-5.15 (m, 1H), 7.53-7.58 (m, 2H), 7.63 (d, J=8.30 Hz, 2H), 8.21 (s, 1H), 8.53 (s, 1H); ESI-MS m/z [M+H].sup.+ 408.1.

Example 87: (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0893] ##STR00261##

[0894] The title compound (23 mg, 48%) was prepared like EXAMPLE 86, using 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESL-MS m/z [M+H].sup.+ 424.1.

Example 88: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0895] ##STR00262##

[0896] The title compound (30 mg, 73%) was prepared like EXAMPLE 86, using 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 1.44-1.48 (m, 3H), 1.58 (d, J=6.35 Hz, 6H), 2.32 (s, 3H), 4.88-4.97 (m, 2H), 4.97-5.04 (m, 1H), 5.20-5.27 (m, 1H), 6.85-6.90 (m, 1H), 6.97 (d, J=7.81 Hz, 1H), 7.27 (t, J=8.05 Hz, 1H), 8.20 (s, 1H), 8.52 (s, 1H); ESI-MS m/z [M+H].sup.+ 372.2.

Example 89: (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0897] ##STR00263##

[0898] A solution of 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (0.500 g, 2.81 mmol) and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (0.719 g, 2.81 mmol) in DMA (15 mL) was cooled in an ice bath. To the cooled solution was added Cs.sub.2CO.sub.3 (1.371 g, 4.21 mmol) in one portion and the ice bath was allowed to warm to RT. The mixture was stirred overnight and then ice water (60 mL) was slowly added, dropwise. The mixture was stirred vigorously in an ice bath for 1 hour, filtered, washed with water; and recrystallized from EtOAc to give the title compound as a colorless solid (0.493 g, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.65 (d, J=0.75 Hz, 1H), 8.50 (d, J=7.91 Hz; 1H), 8.25 (s, 1H), 7.17-7.25 (m, 2H), 7.09-7.16 (m, 2H), 5.05 (spt, J=6.67 Hz, 1H), 4.88 (quin, J=7.22 Hz, 1H), 4.70-4.82 (m, 2H), 2.27 (s, 3H), 1.49 (d, J=6.65 Hz, 6H), 1.35 (d, J=6.90 Hz, 3H); ESI-MS m/z [M+H].sup.+ 354.4.

Example 90: (S)-2-(1-cyclopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0899] ##STR00264##

[0900] To a solution of (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide (15 mg, 0.054 mmol) in DMF (0.6 mL) was added 1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (8 mg, 0.045 mmol) and K.sub.2CO.sub.3 (16 mg, 0.114 mmol). The reaction mixture was stirred at 28-45° C. for 18 hours and then diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by HPLC (Method B). The product-containing fraction was concentrated under reduced pressure to give the title compound as a white solid (9.6 mg, 57%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.21-1.27 (m, 2H), 1.28-1.33 (m, 2H), 1.47 (d, J=6.83 Hz, 3H), 2.31 (s, 3H), 3.65-3.72 (m, 1H), 4.89 (s, 2H), 5.18-5.27 (m, 1H), 6.49-6.57 (m, 1H), 6.80-6.86 (m, 1H), 6.86-6.90 (m, 1H), 7.10-7.16 (m, 1H), 8.17 (d, J=0.98 Hz, 1H) (d, J=0.98 Hz, 1H); ESI-MS m/z [M+H].sup.+ 370.1.

Example 91: (S)-2-(1-cyclopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0901] ##STR00265##

[0902] The title compound was prepared like EXAMPLE 90, using 1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (33.4 mg, 84%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.21-1.27 (m, 2H), 1.27-1.32 (m, 2H), 1.48 (d, J=7.32 Hz, 3H), 2.32 (s, 3H), 3.65-3.72 (m, 1H), 4.88 (s, 2H), 5.07-5.14 (m, 1H), 6.26-6.33 (m, 1H), 7.10-7.15 (m, 2H), 7.17-7.21 (m, 2H), 8.15-8.17 (m, 1H), 8.31-8.34 (m, 1H); ESI-MS m/z [M+H].sup.+ 352.2.

Example 92: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0903] ##STR00266##

[0904] The title compound was prepared like EXAMPLE 90, using 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (18.5 mg, 62%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.47 (d, J=6.83 Hz, 3H), 1.60 (d, J=6.83 Hz, 6H), 2.31 (s, 3H), 2.66 (s, 3H), 4.64-4.75 (m, 1H), 4.85 (d, J=1.46 Hz, 2H), 5.19-5.28 (m, 1H), 6.48-6.58 (m, 1H), 6.79-6.85 (m, 1H), 6.85-6.91 (m, 1H), 7.10-7.15 (m, 1H), 8.11 (s, 1H); ESI-MS m/z [M+H].sup.+ 386.2.

Example 93: (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0905] ##STR00267##

[0906] The title compound was prepared like EXAMPLE 90, using 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (23.3 mg, 68%). ESI-MS m/z [M+H].sup.+ 438.1.

Example 94: (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0907] ##STR00268##

[0908] The title compound was prepared like EXAMPLE 90, using 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (21.3 mg, 65%). ESI-MS m/z [M+H].sup.+ 422.1.

Example 95: (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0909] ##STR00269##

[0910] The title compound was prepared like EXAMPLE 90, using 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (12.2 mg, 43%). ESI-MS m/z [M+H].sup.+ 412.2.

Example 96: (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0911] ##STR00270##

[0912] The title compound was prepared like EXAMPLE 90, using 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (15.6 mg, 49%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.02-1.08 (m, 2H), 1.09-1.16 (m, 2H), 1.48 (d, J=6.83 Hz, 3H), 1.55 (d, J=6.83 Hz, 6H), 2.51-2.60 (m, 1H), 4.67 (t, J=6.83 Hz, 1H), 4.81-4.92 (m, 2H), 5.13 (quip, J=7.08 Hz, 1H), 6.49-6.57 (m, 1H), 7.15 (d, J=8.30 Hz, 2H), 7.32 (d, J=8.79 Hz, 2H), 8.10 (s, 1H); ESI-MS m/z [M+H].sup.+ 464.2.

Example 97: (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0913] ##STR00271##

[0914] The title compound was prepared like EXAMPLE 90, using 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (3.6 mg, 13%). ESI-MS m/z [M+H].sup.+ 394.2.

Example 98: (S)-2-(3-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0915] ##STR00272##

[0916] The title compound was prepared like EXAMPLE 90, using 3-cyclopropyl-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (9.2 mg, 30%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.02-1.09 (m, 2H), 1.10-1.16 (m, 2H), 1.50 (d, J=7.32 Hz, 3H), 1.56 (d, J=6.83 Hz, 6H), 2.56 (tt, J=8.36, 5.31 Hz, 1H), 4.67 (spt, J=6.67 Hz, 1H), 4.82-4.93 (m, 2H), 5.16 (quin, J=7.08 Hz, 1H), 6.58-6.66 (m, 1H), 7.41 (d, J=7.81 Hz, 2H), 7.56 (d, J=7.81 Hz, 2H), 8.10 (s, 1H); [M+H].sup.+ 448.2.

Example 99: (S)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0917] ##STR00273##

[0918] The title compound was prepared like EXAMPLE 90, using 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (5.5 mg, 17%). ESI-MS m/z [M+H].sup.+ 358.2.

Example 100: (S)-2-(1-isopropyl-3,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0919] ##STR00274##

[0920] The title compound was prepared like EXAMPLE 90, using 1-isopropyl-3,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a solid (4.7 mg, 14%). ESI-MS m/z [M+H].sup.+ 452.2.

Example 101: (S)-2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0921] ##STR00275##

[0922] The title compound was prepared like EXAMPLE 90, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (0.9 mg, 3%). ESI-MS m/z [M+H].sup.+ 435.2.

Example 102: (S)—N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[0923] ##STR00276##

[0924] The title compound was prepared like EXAMPLE 90, using 1,3,4-trimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (0.7 mg, 3%). ESI-MS m/z [M+H].sup.+ 409.1.

Example 103: (S)-2-(1-isopropyl-3-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0925] ##STR00277##

[0926] The title compound was prepared like EXAMPLE 90, using 1-isopropyl-3-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide, and was obtained as a solid (2.7 mg, 10%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.48-1.53 (m, 3H), 1.53-1.58 (m, 6H), 2.53 (s, 3H), 4.90-4.99 (m, 2H), 5.21-5.31 (m, 1H), 5.58-5.70 (m, 1H), 7.13-7.22 (m, 1H), 7.37-7.42 (m, 1H), 7.88-7.93 (m, 1H), 8.13 (s, 1H), 8.71-8.76 (m, 1H); ESI-MS m/z [M+H].sup.+ 423.1.

Example 104: N-(1-(chroman-6-yl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0927] ##STR00278##

[0928] The title compound was prepared like EXAMPLE 90, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and 2-bromo-N-(1-(chroman-6-yl)ethyl)acetamide, and was obtained as a solid (6.3 nig, 23%). NMR (500 MHz, CDCl.sub.3) δ ppm 1.18-1.24 (m, 4H), 1.46 (d, J=6.83 Hz, 3H), 1.94-2.03 (m, 2H), 2.63 (d, J=0.98 Hz, 3H), 2.74 (t, J=6.47 Hz, 2H), 3.53-3.61 (m, 1H), 4.13-4.19 (m, 2H), 4.80-4.89 (m, 2H), 4.99-5.09 (m, 1H), 6.25 (br d, J=7.32 Hz, 1H), 6.69-6.74 (m, 1H), 6.97 (s, 1H), 7.00 (dd, J=8.30, 1.71 Hz, 1H), 8.24 (d, J=0.98 Hz, 1H); ESI-MS m/z [M+H].sup.+ 408.2.

Example 105: 2-(1-cyclopropyl-3,4-dimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide

[0929] ##STR00279##

[0930] The title compound was prepared like EXAMPLE 90, using 1-cyclopropyl-3,4-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and 2-bromo-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide, and was obtained as a solid (5.2 mg, 18%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.06-1.14 (m, 2H), 1.27-1.36 (m, 2H), 1.45 (d, J=6.83 Hz, 3H), 2.52 (s, 3H), 2.56 (s, 3H), 4.24 (s, 4H), 4.51-4.59 (m, 1H), 4.81-4.90 (m, 2H), 5.01-5.09 (m, 1H), 6.26 (br s, 1H), 6.73-6.84 (m, 3H); ESI-MS m/z [M+H].sup.+ 424.2.

Example 106: 2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide

[0931] ##STR00280##

[0932] The title compound was prepared like EXAMPLE 90, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and 2-bromo-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)acetamide, and was obtained as a solid (15.7 mg, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.08-1.19 (m, 4H), 1.33 (d, J=7.07 Hz, 3H), 2.48 (s, 3H), 3.89 (dt, J=7.26, 3.32 Hz, 1H), 4.20-4.26 (m, 4H), 4.67-4.76 (m, 2H), 4.78-4.86 (m, 1H), 6.75-6.84 (m, 3H), 8.48 (d, J=7.83 Hz, 1H), 8.52 (s, 1H); ESI-MS m/z [M+H].sup.+ 410.2.

Example 107: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0933] ##STR00281##

[0934] A slurry of (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (4.03 g, 13.00 mmol), 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2.52 g, 13.26 mmol) and K.sub.2CO.sub.3 (2.69 g, 19.49 mmol) in DMF (40 mL) was stirred at 20° C. for 22 hours. The mixture was taken up in EtOAc (400 mL) and washed with water (400 mL) brine (300 mL). The organic layer was dried over MgSO.sub.4 and concentrated in vacuo to provide a white solid, which was recrystallized from EtOAc to give the title compound as a white solid (4.08 g, 75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.06-1.17 (m, 4H), 1.40 (d, J=7.03 Hz, 3H), 2.46 (s, 3H), 3.81-3.91 (m, 1H), 4.69-4.84 (m, 2H), 4.99 (quin, J=7.09 Hz, 1H), 7.55 (d, J=8.41 Hz, 2H), 7.69 (d, J=8.16 Hz, 2H), 8.49 (s, 1H), 8.64 (d, J=7.53 Hz, 1H); ESI-MS m/z [M+H].sup.+ 420.3.

Example 108: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0935] ##STR00282##

[0936] A 4 mL vial equipped with a stir bar and charged with Cs.sub.2CO.sub.3 (51 mg, 0.16 mmol) and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide (26 mg, 0.095 mmol). A solution of 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (15 mg, 0.079 mmol) in DUE (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 40° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (7.1 mg, 23%). ESI-MS m/z [M+H].sup.+ 384.4.

Example 109: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0937] ##STR00283##

[0938] The title compound (27 mg, 78%) was prepared like EXAMPLE 108, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 436.1.

Example 110: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0939] ##STR00284##

[0940] The title compound (18 mg, 60%) was prepared like EXAMPLE 108, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3CN) δ ppm 1.13 (br s, 4H), 1.36-1.42 (m, 3H), 2.50 (s, 3H), 3.61-3.68 (m, 1H), 3.75 (s, 3H), 4.76 (d, J=6.35 Hz, 2H), 4.89-4.97 (m, 1H), 6.87 (d, J=8.79 Hz, 2H), 7.23 (d, J=8.30 Hz, 2H), 8.33 (s, 1H); ESI-MS m/z [M+H].sup.+ 382.2.

Example 111: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0941] ##STR00285##

[0942] The title compound (14 mg, 45%) was prepared like EXAMPLE 108, using 1,3,7-trimethyl-1,5-dihydro-4/1-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 372.2.

Example 112: (S)—N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0943] ##STR00286##

[0944] The title compound (10 mg, 29%) was prepared like EXAMPLE 108, using 1,3,7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 424.1.

Example 113: (S)—N-(1-(p-tolyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0945] ##STR00287##

[0946] The title compound (5.3 mg 18%) was prepared like EXAMPLE 108, using 1,3,7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 354.1.

Example 114: (S)—N-(1-(4-(trifluoromethyl)phenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0947] ##STR00288##

[0948] The title compound (2.8 mg, 8.2%) was prepared like EXAMPLE 108, using 1,3,7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 408.1.

Example 115: (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0949] ##STR00289##

[0950] The title compound (27 mg, 83%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide. ESI-MS m/z [M+].sup.+ 420.1.

Example 116: (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0951] ##STR00290##

[0952] The title compound (22 mg, 72%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 382.2.

Example 117: (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0953] ##STR00291##

[0954] The title compound (19 mg, 64%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 398.1

Example 118: (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0955] ##STR00292##

[0956] The title compound (16 mg, 49%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS [M+H].sup.+ 450.1.

Example 119: (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0957] ##STR00293##

[0958] The title compound (19 mg, 69%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CD.sub.3CN) δ ppm 0.97-1.05 (m, 4H), 1.34-1.38 (m, 1H), 1.41 (d, J=6.83 Hz, 3H), 2.33 (s, 3H), 2.56 (s, 1H), 2.60 (s, 3H), 4.07 (s, 3H), 4.70 (s, 2H), 4.94-5.01 (m, 1H), 6.94-6.99 (m, 1H), 7.14-7.17 (m, 2H), 7.22 (s, 2H); ESI-MS m/z [M+H].sup.+ 380.2.

Example 120: (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0959] ##STR00294##

[0960] The title compound (19 mg, 59%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 434.1.

Example 121: (S)-2-(3-cyclopropyl-1,7-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[0961] ##STR00295##

[0962] The title compound (20 mg, 70%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1,7-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 396.2.

Example 122: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0963] ##STR00296##

[0964] The title compound (7.9 mg, 27%) was prepared like EXAMPLE 108, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, EST-MS m/z [M+H].sup.+ 366.4.

Example 123: (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(1,3,7-trimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0965] ##STR00297##

[0966] The title compound (5.2 mg, 17%) was prepared like EXAMPLE 108, using 7-trimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide. EST-MS m/z [M+H].sup.+ 370.3.

Example 124: (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[0967] ##STR00298##

[0968] The title compound (5.0 mg, 17%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 384.4.

Example 125: (S)-2-(3-cyclopropyl-1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0969] ##STR00299##

[0970] The title compound (12 mg, 35%) was prepared like EXAMPLE 108, using 3-cyclopropyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 436.3.

Example 126: (S)—N-(1-(2,6-difluorophenyl)ethyl)-2-(1,3-dimethyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0971] ##STR00300##

[0972] To a vial containing 1,3-dimethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (32.8 mg, 0.200 mmol) in DMF (1 mL) was added (S)-2-bromo-N-(1-(2,6-difluorophenyl)ethyl)acetamide (55.6 mg, 0.2 mmol) and K.sub.2CO.sub.3 (33.2 mg, 0.240 mmol). The mixture was stirred for 3 hours at 60° C. and then diluted in DMF (1 mL), filtered through Millipore® Millex-LCR resin and purified by HPLC (Method B). The product-containing fractions were combined, concentrated in vacuo and lyophilized to give the title compound as an off-white solid (15 mg, 21%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.47 (d, J=7.32 Hz, 3H), 2.46 (s, 3H), 3.99 (s, 3H), 4.63-4.68 (m, 1H), 4.73-4.78 (m, 1H), 5.22 (quin, J=7.08 Hz, 1H), 7.02-7.09 (m, 2H), 7.30-7.38 (m, 1H), 8.46 (s, 1H), 8.67 (d, J=6.83 Hz, 1H); ESI-MS m/z [M+H].sup.+ 362.2.

Example 127: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide

[0973] ##STR00301##

[0974] A 4 mL vial equipped with a stir bar was charged with K.sub.2CO.sub.3 (29 mg, 0.21 mmol) and (S)-2-bromo-N-(1-(2-fluoro-4-methoxyphenyl)ethyl)acetamide (37 mg, 0.13 mmol). A solution of 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (20 mg, 0.11 mmol) in DMF (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 60° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method A) to give the title compound (4.2 mg, 10%). ESI-MS [M+H].sup.+ 400.1.

Example 128: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,4-difluorophenyl)ethyl)acetamide

[0975] ##STR00302##

[0976] The title compound (10 mg, 25%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2,4-difluorophenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.19-1.26 (m, 4H), 1.47 (d, J=6.83 Hz, 3H), 2.62 (s, 3H), 3.56-3.62 (m, 1H), 4.87 (s, 2H), 5.19-5.27 (m, 1H), 6.63-6.70 (m, 1H), 6.73-6.83 (m, 2H), 7.20-7.28 (m, 1H), 8.25 (s, 1H); ESI-MS m/z [M+H].sup.+ 388.2.

Example 129: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-methoxyphenyl)ethyl)acetamide

[0977] ##STR00303##

[0978] The title compound (4.0 mg 10%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluoro-4-methoxyphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 400.2.

Example 130: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide

[0979] ##STR00304##

[0980] The title compound (15 mg, 38%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide. .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.17-1.26 (m, 4H), 1.44 (d, J=7.32 Hz, 3H), 2.22 (s, 3H), 2.62 (s, 3H), 3.56-3.61 (m, 1H), 4.86 (d, I-5.86 Hz, 2H), 5.04-5.11 (m, 1H), 6.49 (d, J=7.32 Hz, 1H), 6.90 (d, J=10.74 Hz, 1H), 6.96 (d, J=1.95 Hz, 1H), 7.09 (s, 1H), 8.24 (s, 1H); ESI-MS m/z [M+H].sup.+ 384.1.

Example 131: (S)—N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0981] ##STR00305##

[0982] The title compound (19 mg, 44%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-chloro-4-fluorophenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 404.1.

Example 132: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)acetamide

[0983] ##STR00306##

[0984] The title compound (11 mg, 27%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 400.1.

Example 133: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(2,4,6-trifluorophenyl)ethyl)acetamide

[0985] ##STR00307##

[0986] The title compound (9.0 mg, 21%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2,4,6-trifluorophenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 406.1.

Example 134: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-fluoro-3-methylphenyl)ethyl)acetamide

[0987] ##STR00308##

[0988] The title compound (14 mg, 35%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-fluoro-3-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 384.2.

Example 135: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(3,5-difluorophenyl)ethyl)acetamide

[0989] ##STR00309##

[0990] The title compound (22 mg, 54%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3,5-difluorophenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 388.1.

Example 136: (S)—N-(1-(2-chloro-6-fluorophenyl)ethyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[0991] ##STR00310##

[0992] The title compound (15 mg, 35%) was prepared like EXAMPLE 127, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-chloro-6-fluorophenyl)ethyl)acetamide, ESI-MS m/z [M+H].sup.+ 404.1.

Example 137: (S)-2-(1,7-dimethyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide

[0993] ##STR00311##

[0994] A solution of (S)-2-bromo-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)acetamide (20 mg, 0.064 mmol) and sodium hydride (7.67 mg, 0.192 mmol) in DMF (total volume: 0.5 mL) was stirred at 0° C. for 1 hour. Next, 1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (10.55 mg, 0.064 mmol) was added. The mixture was stirred at RT for 30 minutes and then diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and purified by HPLC (Method A). The product-containing fraction was concentrated under reduced pressure to give the title compound as a solid (16.2 mg 64%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 1.52-1.63 (m, 3H), 2.68 (s, 3H), 4.09 (s, 3H), 4.97 (s, 2H), 5.22-5.35 (m, 1H), 7.78 (d, J=8.30 Hz, 1H), 8.21 (dd, J=8.30, 1.95 Hz, 1H), 8.25-8.32 (m, 2H), 8.92 (s, 1H); ESI-MS m/z [M+H].sup.+ 395.1.

Example 138: (S)-2-(3-methyl-4-oxo-3,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0995] ##STR00312##

[0996] To a vial containing 3-methyl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (30.0 mg, 0.200 mmol) in DMF (1 mL) were added (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (51.2 mg, 0.2 mmol) and K.sub.2CO.sub.3 (33.2 mg, 0.240 mmol). The mixture was stirred at RT overnight and then at 60° C. for 3 hours. The solution was subsequently diluted in DMF (1 mL), filtered through Millipore® Millex-LCR resin and purified by HPLC (Method B). The product-containing fractions were combined, concentrated iii vacuo and lyophilized to give the title compound as an off-white solid (30.4 mg, 46.7%). .sup.1H NMR. (500 MHz, DMSO-d.sub.6) δ ppm 1.33-1.37 (m, 3H), 2.26-2.28 (m, 3H), 4.02-4.04 (m, 3H), 4.74-4.81 (m, 2H), 4.83-4.93 (m, 1H), 7.11-7.16 (m, 2H), 7.19-7.24 (m, 2H), 8.34 (s, 1H), 8.37 (s, 1H), 8.51-8.57 (m, 1H); ESI-MS m/z [M+H].sup.+ 326.3.

Example 139: (S)-2-(3-methyl-4-oxo-3,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[0997] ##STR00313##

[0998] To a vial containing 3-methyl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (30.0 mg, 0.200 mmol) in DMF (1 mL) were added (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (62.0 mg, 0.2 mmol) and K.sub.2CO.sub.3 (33.2 mg, 0.240 mmol). The mixture was stirred at RT overnight and then at 60° C. for 3 hours. The solution was subsequently diluted in DMF (1 mL), filtered through Millipore® Millex-LCR resin and purified by HPLC (Method B). The product-containing fractions were combined, concentrated iii vacuo and lyophilized to give the title compound as an off-white solid (38 mg, 50%). .sup.1H NMR. (500 MHz, DMSO-d.sub.6) δ ppm 1.38-1.42 (m, 3H), 4.02-4.04 (m, 3H), 4.78-4.85 (m, 2H), 4.93-5.03 (m, 1H), 7.53-7.58 (m, 2H), 7.68-7.73 (m, 2H), 8.34-8.35 (m, 1H), 8.38-8.39 (m, 1H), 8.69-8.76 (m, 1H); ESI-MS m/z [M+H].sup.+ 380.2.

Example 140: (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[0999] ##STR00314##

[1000] To a vial containing 1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (30.0 mg, 0.200 mmol) in MT (1 mL) were added (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (51.2 mg, 0.2 mmol) and K.sub.2CO.sub.3 (33.2 mg, 0.240 mmol). The mixture was stirred at 60° C. for 3 hours and then diluted in DMF (1 mL), filtered through Millipore® Millex-LCR resin and purified by HPLC (Method B). The product-containing fractions were combined, concentrated in vacuo and lyophilized to give the title compound as an off-white solid (6.4 mg, 9.8%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.34-1.36 (m, 3H), 2.27-2.28 (m, 3H), 3.90-3.90 (m, 3H), 4.78-4.80 (m, 2H), 4.86-4.90 (m, 1H), 7.12-7.14 (m, 2H), 7.21 (d, J=8.05 Hz, 2H), 8.25-8.28 (m, 1H), 8.48-8.49 (m, 1H), 8.50-8.53 (m, 1H); ESI-MS m/z [M+H].sup.+ 326.2.

Example 141: (S)-2-(1-methyl-4-oxo-1,4-dihydro-5H-imidazo[4,5-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1001] ##STR00315##

[1002] To a vial containing 1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (30.0 mg, 0.200 mmol) in DMF (1 mL) were added (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (62.0 mg, 0.2 mmol) and K.sub.2CO.sub.3 (33.2 mg, 0.240 mmol). The mixture was stirred at 60° C. for 3 hours and then diluted in DMF (1 mL), filtered through Millipore® Millex-LCR resin and purified by HPLC (Method B), The product-containing fractions were combined, concentrated in vacuo and lyophilized to give the title compound as an off-white solid (8.7 mg, 11%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.40 (d, J=7.08 Hz, 3H), 3.90-3.90 (m, 3H), 4.82-4.84 (m, 2H), 4.96-5.01 (m, 1H), 7.55-7.57 (m, 2H), 7.68-7.70 (m, 2H), 8.26-8.28 (m, 1H), 8.48-8.50 (m, 1H), 8.69-8.72 (m, 1H); ESI-MS m/z [M+H].sup.+ 380.2.

Example 142: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1003] ##STR00316##

[1004] To a solution of 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (35 mg, 0.184 mmol) in anhydrous DMF (1 mL) were added (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (57.1 mg, 0.184 mmol) and K.sub.2CO.sub.3 (76 mg, 0.552 mmol). The reaction mixture was stirred at 45° C. for 18 hours and then purified by HPLC (Method B) to give the title compound as an off-white solid (6 mg, 8%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.96-1.12 (m, 4H), 1.50 (d, J=7.03 Hz, 3H), 2.05-2.13 (m, 1H), 4.28 (s, 3H), 4.88 (s, 2H), 5.13-5.24 (m, 1H), 6.26-6.42 (m, 1H), 7.41 (d, J=8.28 Hz, 2H), 7.57 (d, J=8.28 Hz, 2H), 8.16 (s, 1H); ESI-MS [M+H].sup.+ 420.1.

Example 143: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[1005] ##STR00317##

[1006] The title compound was prepared like EXAMPLE 42, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, and was obtained as a white solid (30 mg, 37%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.99 (br d, J=3.01 Hz, 4H), 1.46 (d, J=6.78 Hz, 3H), 2.01-2.12 (m, 1H), 4.24 (s, 3H), 4.83 (s, 2H), 5.07-5.16 (m, 1H), 6.71-6.78 (m, 1H), 7.09-7.17 (m, 2H), 7.31 (d, J=8.28 Hz, 2H), 8.13 (s, 1H); ESI-MS m/z [M+H].sup.+ 436.1.

Example 144: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1007] ##STR00318##

[1008] A mixture of 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (21 mg, 0.111 (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (68.8 mg, 0.222 mmol) and K.sub.2CO.sub.3 (46.0 mg, 0.333 mmol) in DMF (555 μL) was stirred for 5 hours at RT. The reaction mixture was then diluted with methanol and purified by HPLC (Method B) to give the title compound as a white solid (27 mg, 58%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.00-1.06 (m, 2H), 1.11-1.17 (m, 2H), 1.44-1.51 (m, 3H), 2.45 (d, J=1.00 Hz, 3H), 3.31-3.43 (m, 1H), 4.77-4.99 (m, 2H), 5.08-5.25 (m, 1H), 6.75-6.86 (m, 1H), 6.88 (d, J=1.00 Hz, 1H), 7.40 (s, 2H), 7.53 (d, J=8.16 Hz, 2H), 8.21 (s, 1H); ESI-MS m/z [M+H].sup.+ 419.3.

Example 145: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

[1009] ##STR00319##

[1010] The title compound was prepared like EXAMPLE 144, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide, and was obtained as a white solid (12.4 mg, 51%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.90-1.09 (m, 4H), 1.35 (d, J=6.90 Hz, 3H), 2.29 (d, J=0.88 Hz, 3H), 3.09-3.15 (m, 1H), 3.44-3.60 (m, 1H), 3.73 (s, 3H), 4.61-4.73 (m, 2H), 4.79-4.93 (m, 1H), 6.80-6.93 (m, 2H), 7.04-7.15 (m, 1H), 7.20-7.30 (m, 2H), 8.18-8.32. (m, 1H); ESI-MS m/z [M+H].sup.+ 381.0.

Example 146: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-phenylethyl)acetamide

[1011] ##STR00320##

[1012] The title compound was prepared like EXAMPLE 144, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-phenylethyl)acetamide, and was obtained as a white solid (11.3 mg, 34%). .sup.1H NMR. (400 MHz, DMSO-d.sub.6) δ ppm 0.96-1.01 (m, 2H), 1.02-1.09 (m, 2H), 1.35-1.42 (m, 3H), 2.29-2.31 (m, 3H), 3.52-3.62 (m, 1H), 4.68-4.79 (m, 2H), 4.90-5.00 (m, 1H), 7.13-7.17 (m, 1H), 7.22-7.28 (m, 1H), 7.35 (s, 4H), 8.28 (s, 1H), 8.44-8.51 (m, 1H); ESI-MS m/z [M+H].sup.+ 351.2.

Example 147: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrrolo[2,3-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[1013] ##STR00321##

[1014] The title compound was prepared like EXAMPLE 144, using 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (17.3 mg, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.93-1.10 (m, 4H), 1.35 (d, J=6.90 Hz, 3H), 2.23-2.35 (m, 6H), 3.48-3.61 (m, 1H), 4.64-4.75 (m, 2H), 4.83-4.96 (m, 1H), 7.13 (s, 3H), 7.20 (s, 2H), 8.26 (s, 1H), 8.35-8.43 (m, 1H); ESI-MS m/z [M+H].sup.+ 365.2.

Example 148: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluorophenyl)ethyl)acetamide

[1015] ##STR00322##

[1016] To a solution of 3-cyclopropyl-1-meth-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (20 mg, 0.105 mmol) in anhydrous DMF (1 mL) were added (S)-2-bromo-N-(1-(3-fluorophenyl)ethyl)acetamide (30.1 mg, 0.116 mmol) and K.sub.2CO.sub.3 (43.6 mg, 0.315 mmol). The reaction mixture was stirred at RT for 18 hours and then purified by HPLC (Method B) to give the title compound as a white solid (11 mg, 28%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 0.73-0.82 (m, 2H), 0.83-0.93 (m, 2H), 1.25-1.32 (m, 3H), 1.85-1.97 (m, 1H), 4.04 (s, 3H), 4.67 (d, J=1.76 Hz, 2H), 4.81-4.92 (m, 1H), 6.67-6.76 (m, 1H), 6.82-6.86 (m, 1H), 6.88-6.94 (m, 1H), 7.04-7.14 (m, 1H), 7.97 (s, 1H); ESI-MS m/z [M+H].sup.+ 370.3.

Example 149: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[1017] ##STR00323##

[1018] The title compound was prepared like EXAMPLE 148, using 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, and was obtained as a white solid (14 mg, 36%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 0.94-0.99 (m, 2H), 1.03-1.09 (m, 2H), 1.45 (d, J=7.03 Hz, 3H), 2.12 (tt, J=8.34, 5.08 Hz, 1H), 2.29 (s, 3H), 4.21 (s, 3H), 4.78-4.91 (m, 2H), 5.01 (q, J=7.03 Hz, 1H), 7.07-7.12 (m, 2H), 7.16-7.23 (m, 2H), 8.18 (s, 1H); ESI-MS m/z [M+H].sup.+ 366.3.

Example 150: (S)—N-(1-(2-chloro-6-fluorophenyl)ethyl)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[1019] ##STR00324##

[1020] The title compound was prepared like EXAMPLE 148, using 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-chloro-6-fluorophenyl)ethyl)acetamide, and was obtained as a white solid (21 mg, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.82-0.88 (m, 2H), 0.95-1.00 (m, 2H), 1.40 (d, J=7.03 Hz, 3H), 2.13-2.21 (m, 1H), 4.07 (s, 3H), 4.59-4.66 (m, 1H), 4.71-4.77 (m, 1H), 5.31 (t, J=6.78 Hz, 1H), 7.06-7.15 (m, 1H), 7.17-7.29 (m, 2H), 8.26 (s, 1H), 8.65 (d, J=7.03 Hz, 1H); ESI-MS m/z [M+H].sup.+ 404.3.

Example 151: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide

[1021] ##STR00325##

[1022] The title compound was prepared like EXAMPLE 148, using 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (10 mg, 15%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.97-1.13 (m, 4H), 1.47 (d, J=6.78 Hz, 3H), 2.06-2.13 (m, 1H), 2.24 (d, J=1.76 Hz, 3H), 4.29 (s, 3H), 4.80-4.93 (m, 2H), 5.11 (dt, J=14.49, 7.18 Hz, 1H), 6.12-6.21 (m, 1H), 6.90-7.00 (m, 2H), 7.12 (t, J=7.78 Hz, 1H), 8.16 (s, 1H), ESI-MS m/z [M+H].sup.+ 384.2.

Example 152: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide

[1023] ##STR00326##

[1024] The title compound was prepared like EXAMPLE 148, using 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (21 mg, 32%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.99-1.12 (m, 4H), 1.46-1.51 (m, 3H), 2.13 (br s, 1H), 2.32 (s, 3H), 4.28 (s, 3H), 4.81-4.89 (m, 2H), 5.21-5.28 (m, 1H), 6.40 (td, J=5.40, 2.01 Hz, 1H), 6.81-6.91 (m, 2H), 7.13 (t, J=7.91 Hz, 1H), 8.15 (s, 1H); ESI-MS m/z [M+H].sup.+ 384.2.

Example 153: (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-phenylethyl)acetamide

[1025] ##STR00327##

[1026] The title compound was prepared like EXAMPLE 148, using 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-brume-N-(1-phenylethyl)acetamide, and was obtained as a white solid (36 mg, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.46 (d, J=6.78 Hz, 3H), 4.15 (s, 3H), 4.89 (d, J=2.01 Hz, 2H), 5.15 (quin, J=7.15 Hz, 1H), 6.40 (d, J=3.01 Hz, 1H), 6.55 (br d, J=7.28 Hz, 1H), 7.06 (d, J=2.76 Hz, 1H), 7.17-7.23 (m, 1H), 7.26-7.34 (m, 4H), 8.10 (s, 1H); ESI-MS m/z [M+H].sup.+ 311.2.

Example 154: (S)—N-(1-(3-fluorophenyl)ethyl)-2-(1,3,4-trimethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)acetamide

[1027] ##STR00328##

[1028] The title compound was prepared like EXAMPLE 148, using 1,3,4-trimethyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one and (S)-2-bromo-N-(1-(3-fluorophenyl)ethyl)acetamide, and was obtained as a white solid (5 mg, 4%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.45 (d, J=7.03 Hz, 3H), 2.53 (d, J=11.29 Hz, 6H), 4.28 (s, 3H), 4.72-4.89 (m, 2H), 5.06-5.17 (m, 1H), 6.30 (br d, J=7.78 Hz, 1H), 6.85-6.98 (m, 2H), 7.04 (dd, J=7.78, 0.75 Hz, 1H), 7.24 (s, 1H); ESI-MS m/z [M+H].sup.+ 358.3.

Example 155: (S)-2-(1-cyclobutyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1029] ##STR00329##

[1030] A slurry of 1-cyclobutyl-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (23.12 mg, 0.099 mmol) and K.sub.2CO.sub.3 (26.7 mg, 0.193 mmol) in DMF (0.8 mL) was stirred at 20° C. for 2 hours. Next, (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (30 mg, 0.097 mmol) was added and the mixture stirred at 20° C. for 18 hours. The mixture was then diluted with methanol (0.1 mL), filtered through a syringe filter, rinsed with DMF (0.2 mL) and methanol (0.2 mL) and purified by preparative HPLC (Method B) to give the title compound as a white solid (14 mg, 33%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.39 (d, J=7.03 Hz, 3H), 1.74-1.94 (m, 2H), 2.38-2.47 (m, 2H), 2.52 (s, 3H), 2.54-2.65 (m, 2H), 4.68-4.83 (m, 2H), 4.98 (quin, J=7.18 Hz, 1H), 5.23 (quin, J=8.22 Hz, 1H), 7.55 (d, J=8.16 Hz, 2H), 7.69 (d, J=8.16 Hz, 2H), 8.50 (s, 1H), 8.63 (d, J=7.53 Hz, 1H); ESI-MS m/z [M+H].sup.+ 434.4.

Example 156: (S)-2-(1-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1031] ##STR00330##

[1032] The title compound was prepared like EXAMPLE 155, using 1-(bicyclo[1.1.1]pentan-1-yl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (27 mg, 72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (d, J=7.15 Hz, 3H), 2.42 (s, 6H), 2.49 (br s, 3H), 2.71 (s, 1H), 4.70-4.84 (m, 2H), 4.99 (quin, J=7.09 Hz, 1H), 7.55 (d, J=8.41 Hz, 2H), 7.69 (d, J=8.16 Hz, 2H), 8.49 (s, 1H), 8.65 (d, J=7.65 Hz, 1H); ESL-MS m/z [M+H].sup.+ 446.3.

Example 157: (S)-2-(1-(tert-butyl)-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1033] ##STR00331##

[1034] The title compound was prepared like EXAMPLE 155, using 1-(tert-butyl)-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (21 mg, 60%). .sup.1H NMR (400 MHz, DMSO) δ ppm 1.40 (d, J=7.15 Hz, 3H), 1.67 (s, 9H), 2.49 (s, 3H), 4.68-4.84 (m, 2H), 4.98 (quin, J=7.03 Hz, 1H), 7.55 (d, J=8.16 Hz, 2H), 7.69 (d, J=8.16 Hz, 2H), 8.64 (s, 1H), 8.68 (d, J=7.65 Hz, 1H); ESI-MS m/z [M+H].sup.+ 436.3.

Example 158: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[1035] ##STR00332##

[1036] A mixture of 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (15 mg, 0.079 mmol), (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (40.6 mg, 0.159 mmol) and K.sub.2CO.sub.3 (21.91 mg, 0.159 mmol) in DMF (396 μL) was stirred for 5 hours at RT. The reaction mixture was then diluted with methanol and purified by HPLC (Method B) to give the title compound as a solid (8.6 mg, 30%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 0.54-0.69 (m, 2H), 0.86-1.01 (m, 2H), 1.46 (d, J=6.90 Hz, 3H), 1.82-1.97 (m, 1H), 2.30 (s, 3H), 4.00-4.09 (m, 3H), 4.81-4.89 (m, 3H), 4.96-5.07 (m, 1H), 6.98-7.03 (m, 1H), 7.09-7.16 (m, 2H), 7.19-7.27 (m, 2H), 8.23 (s, 1H); ESI-MS m/z [M+H].sup.+ 365.3.

Example 159: (S)-2-(3-cyclopropyl-1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1037] ##STR00333##

[1038] The title compound was prepared like 158, using 3-cyclopropyl-1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as an oil (18.7 mg, 56%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.51-0.66 (m, 2H), 0.80-0.97 (m, 2H), 1.40 (d, J=7.03 Hz, 3H), 1.87-2.01 (m, 1H), 3.99 (s, 3H), 4.63-4.83 (m, 2H), 4.93-5.09 (m, 1H), 7.15 (s, 1H), 7.57 (s, 2H), 7.68 (s, 2H), 8.20 (s, 1H), 8.57-8.65 (m, 1H); ESI-MS m/z [M+H].sup.+ 419.3.

Example 160: (R)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1039] ##STR00334##

[1040] To a 100 mL round-bottom flask charged with 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1.8 g, 9.46 mmol), (R)-2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (2.51 g, 9.46 mmol) and DMA (20 mL) was added K.sub.2CO.sub.3 (1.962 g, 14.20 mmol). The reaction mixture was stirred at RT for 18 hours and then water (80 mL) was added. A precipitate was isolated by filtration, washed with water (20 mL×2) and dried under reduced pressure overnight at 50° C. to give the title compound as an off-white solid (3.74 g, 94%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12 (br d, J=4.95 Hz, 4H), 1.39 (d, J=6.97 Hz, 3H), 2.46 (s, 3H), 3.80-3.94 (m, 1H), 4.06-4.13 (m, 1H), 4.77 (d, J=3.12 Hz, 2H), 4.91-5.11 (m, 1H), 7.55 (d, J=7.98 Hz, 2H), 7.69 (d, J=7.98 Hz, 2H), 8.50 (s, 1H), 8.62-8.80 (m, 1H); ESI-MS m/z [M+H].sup.+ 420.2.

Example 161: (S)—N-(1-(4-chlorophenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide

[1041] ##STR00335##

[1042] A 4 mL vial equipped with a stir bar was charged with K.sub.2CO.sub.3 (48 mg, 0.35 mmol) and (S)-2-bromo-N-(1-(4-chlorophenyl)ethyl)acetamide (39 mg, 0.14 mmol), A solution of 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (25 mg, 0.17 mmol) in DMF (0.5 mL) was added and the vial was capped. The reaction mixture was stirred at 45° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method A) to give the title compound (28 mg, 59%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 1.45-1.50 (m, 3H), 4.11-4.16 (m, 3H), 4.83-4.92 (m, 2H), 4.99-5.08 (m, 1H), 6.46-6.51 (m, 1H), 7.29-7.36 (m, 5H), 8.13-8.19 (m, 1H), 8.47-8.58 (m, 1H); ESI-MS m/z [M+H].sup.+ 345.1.

Example 162: (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(p-tolyl)ethyl)acetamide

[1043] ##STR00336##

[1044] The title compound (16 mg, 35%), was prepared like EXAMPLE 161, using methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide, ESI-MS m/z [M+H].sup.+ 325.1.

Example 163: (S)—N-(1-(4-methoxyphenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide

[1045] ##STR00337##

[1046] The title compound (17 mg, 36%) was prepared like EXAMPLE 161, using 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-methoxyphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 341.1.

Example 164: (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1047] ##STR00338##

[1048] The title compound (25 mg, 48%) was prepared like EXAMPLE 161, using 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide. .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 1.48-1.54 (m, 3H), 4.11-4.16 (m, 3H), 4.85-4.95 (m, 2H), 5.06-5.16 (m, 1H), 6.47-6.52 (m, 1H), 7.28-7.33 (m, 1H), 7.51-7.56 (m, 2H), 7.59-7.64 (m, 2H), 8.13-8.19 (m, 1H), 8.15-8.17 (m, 1H), 8.55-8.69 (m, 1H); ESI-MS [M+H].sup.+ 379.1.

Example 165: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-6-yl)acetamide

[1049] ##STR00339##

[1050] The title compound (35 mg, 73%) was prepared like EXAMPLE 161, using 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide. ESI-MS m/z [M+H].sup.+ 343.1.

Example 166: (S)-2-(1-isopropyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(methyl-d.SUB.3.)phenyl)ethyl)acetamide

[1051] ##STR00340##

[1052] A solution of (S)-2-bromo-N-(1-(4-(methyl-d.sub.3)phenyl)ethyl)acetamide (20 mg, 0.077 mmol) in DMA (0.5 mL) was added to K.sub.2CO.sub.3 (21 mg, 0.15 mmol) and 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (15 mg, 0.085 mmol) in a 4 mL vial equipped with a stir bar. The vial was capped. The reaction mixture was stirred at 26° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (21.8 mg, 79%). ESI-MS m/z [M+H].sup.+ 357.1.

Example 167: (S)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(methyl-d.SUB.3.)phenyl)ethyl)acetamide

[1053] ##STR00341##

[1054] A solution of (S)-2-bromo-N-(1-(4-(methyl-d3)phenyl)ethyl)acetamide (20 mg, 0.077 mmol) in DMA (0.5 mL) was added to K.sub.2CO.sub.3 (21 mg, 0.15 mmol) and 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (16 mg, 0.085 mmol) in a 4 mL vial equipped with a stir bar. The vial was capped. The reaction mixture was stirred at 26° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (19.8 mg, 69%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.05-1.20 (m, 4H), 1.35 (d, J=690 Hz, 3H), 2.47 (s, 3H), 3.84-3.91 (m, 1H), 4.69-4.79 (m, 2H), 4.88 (quin, J=7.34 Hz, 1H), 7.11-7.16 (m, 2H), 7.17-7.25 (m, 2H), 8.52 (d, J=8.24 Hz, 2H), 8.51 (s, 1H); ESI-MS ink [M+H].sup.+ 369.1.

Example 168: (S)-2-(1-isopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(Methyl-d3)phenyl)ethyl)acetamide

[1055] ##STR00342##

[1056] A solution of (S)-2-bromo-N-(1-(4-(methyl-d.sub.3)phenyl)ethyl)acetamide (8 mg, 0.031 mmol) in DMA (0.5 mL) was added to K.sub.2CO.sub.3 (8.5 mg, 0.062 mmol) and 1-isopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (6.5 mg, 0.034 mmol) in a 4 mL vial equipped with a stir bar. The mixture was capped. The reaction mixture was stirred at 26° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (4.7 mg, 41%). EST-MS m/z [M+H].sup.+ 371.2.

Example 169: (S)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(p-tolyl)ethyl)acetamide

[1057] ##STR00343##

[1058] To a 4 mL vial equipped with a stir bar was added 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (22.4 mg, 0.103 mmol), (S)-2-bromo-N-(1-(p-tolyl)ethyl)acetamide (25.0 mg, 0.0980 mmol), K.sub.2CO.sub.3 (16.0 mg, 0.117 mmol) and DMF (326 μL). The vial was capped, and the resulting slurry was stirred at 20° C. for 23 hours. The reaction mixture was diluted with MeOH/DMF, filtered through a 0.45 μm Millipore® Millex-FH Phobic PTFE syringe filter and purified by preparative HPLC (Method B) to give the title compound as a white solid (22.3 mg, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.36 (d, J=7.03 Hz, 3H), 2.27 (s, 3H), 4.18 (s, 3H), 4.73-4.83 (m, 2H), 4.89 (quin, J=7.15 Hz, 1H), 7.10-7.15 (m, 2H), 7.19-7.23 (m, 2H), 8.52 (d, J=7.91 Hz, 1H), 8.68 (s, 1H); ESI-MS m/z [M+H].sup.+ 394.2.

Example 170: (S)—N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[1059] ##STR00344##

[1060] The title compound was prepared like EXAMPLE 169, using 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(2-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (28.2 mg, 72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.35 (d, =7.03 Hz, 3H), 2.28 (s, 3H), 4.18 (s, 3H), 4.74-4.86 (m, 2H), 5.10 (quin, J=7.15 Hz, 1H), 6.93-7.03 (m, 2H), 7.25-7.33 (m, 1H), 8.62 (d, J=7.65 Hz, 1H), 8.68 (s, 1H); ESI-MS m/z [M+H].sup.+ 412.1.

Example 171: (S)—N-(1-(3-fluoro-4-methylphenyl)ethyl)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[1061] ##STR00345##

[1062] The title compound was prepared like EXAMPLE 169, using 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(3-fluoro-4-methylphenyl)ethyl)acetamide, and was obtained as a white solid (20.7 mg, 54%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.36 (d, =7.03 Hz, 3H), 2.20 (d, J=1.51 Hz, 3H), 4.18 (s, 3H), 4.76-4.84 (m, 2H), 4.90 (quin, J=7.18 Hz, 1H), 7.02-7.11 (m, 2H), 7.22 (t, J=7.91 Hz, 1H), 8.57 (d, J=7.78 Hz, 1H), 8.69 (s, 1H); EST-MS m/z [M+H].sup.+ 412.1.

Example 172: (S)-2-(1-methyl-4-oxo-3-(trifluoromethyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

[1063] ##STR00346##

[1064] The title compound was prepared like EXAMPLE 169, using 1-methyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one and (S)-2-bromo-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide, and was obtained as a white solid (25.8 mg, 61%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (d, J=7.15 Hz, 3H), 4.18 (s, 3H), 4.77-4.87 (m, 2H), 4.99 (quin, J=7.09 Hz, 1H), 7.55 (d, J=8.41 Hz, 2H), 7.68 (d, J=8.16 Hz, 2H), 8.69 (s, 1H), 8.71 (d, J=7.53 Hz, 1H); ESI-MS m/z [M+H]+ 448.1.

Example 173: (S)—N-(cyclopropyl(phenyl)methyl)-2-(1-cyclopropyl-3-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyridazin-5-yl)acetamide

[1065] ##STR00347##

[1066] A solution of 1-cyclopropyl-3-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (17 mg, 0.090 mmol) in NMP (0.6 mL) was added to K.sub.2CO.sub.3 (21 mg, 0.15 mmol) and (S)-2-promo-N-(cyclopropyl(phenyl)methyl)acetamide (20 mg, 0.075 mmol) in a 4 mL vial equipped with a stir bar. The vial was capped. The reaction mixture was stirred at 40° C. for 18 hours and then filtered through a 0.45 μm frit and purified by HPLC (Method B) to give the title compound (16.5 mg, 59%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 0.37-0.49 (m, 2H), 0.59-0.67 (m, 2H), 1.17-1.28 (m, 5H), 2.54-2.59 (m, 3H), 3.71-3.80 (m, 1H), 4.32-4.38 (m, 1H), 4.91-4.98 (m, 2H), 7.2.2-7.29 (m, 1H), 7.31-7.36H), 7.38-7.44 (in, 2H), 8.44-8.48 (m, 1H); ESI-MS m/z [M+H].sup.+ 378.1.

Example 174: (S)-2-(1-methyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-d]pyridazin-1-yl)-N-(1-(4-(methyl-d.SUB.3.)phenyl)ethyl)acetamide

[1067] ##STR00348##

[1068] A mixture of (S)-3-bromo-N-(1-(4-(methyl-d.sub.3)phenyl)ethyl)acetamide (20 mg, 0.08 mmol), 1-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (9 mg, 0.06 mmol), potassium carbonate (21 mg, 0.15 mmol) and NMP (1 mL) was stirred at 40° C. for 18 hours and was then purified by HPLC (Method B) to give the title compound (7 mg, 28%). ESI-MS m/z [M+H].sup.+ 328.1.

[1069] Table 5, below, lists biological assay data (GPR139 activation and GPR139 binding affinity) for some of the compounds described in the examples, where larger pEC.sub.50 and pKi values represent higher activation (potency) and binding affinity, respectively. The example compounds shown in Table 5 were tested in accordance with the assays described in the section entitled Biological Activity, above.

TABLE-US-00005 TABLE 5 GPR139 Potency (pEC.sub.50) and Binding Affinity (pKi) Ex. No. pEC.sub.50 pKi 1 7.29 7.26 2 7.25 6.06 3 ≤5.00 7.14 4 ≤5.00 7.04 5 6.65 7.03 6 ≤5.00 7.63 7 ≤5.00 6.79 8 ≤5.00 7.56 9 7.02 — 10 7.10 6.92 11 5.56 6.97 12 5.67 7.47 13 6.99 7.68 14 6.21 7.43 15 6.21 7.24 16 6.70 7.96 17 7.24 5.53 18 6.77 6.45 19 7.17 5.97 20 7.38 6.75 21 6.94 7.55 22 6.98 8.04 23 6.78 6.99 24 7.33 7.01 25 7.63 6.21 26 6.03 4.41 27 6.62 6.66 28 7.28 7.49 29 6.29 4.52 30 7.14 6.59 31 7.24 4.93 32 6.21 4.52 33 7.18 5.28 34 7.15 5.22 35 7.10 5.99 36 7.41 6.60 37 7.58 6.45 38 7.26 7.14 39 7.44 6.64 40 7.48 6.60 41 7.46 7.13 42 ≤5.00 7.71 43 6.15 7.05 44 5.44 6.98 45 ≤5.00 6.65 46 7.11 — 47 7.43 6.79 48 7.48 5.72 49 7.31 7.64 50 6.78 6.90 51 7.49 6.87 52 7.17 6.69 53 7.26 5.99 54 6.97 7.06 55 7.08 6.42 56 6.67 6.32 57 6.88 5.51 58 7.13 5.87 59 6.46 6.13 60 6.67 4.52 61 6.85 7.38 62 7.60 8.67 63 7.07 8.70 64 6.92 8.68 65 7.17 8.43 66 7.10 9.10 67 7.07 8.41 68 7.16 9.46 69 7.16 9.35 70 6.75 9.12 71 7.03 9.40 72 7.26 5.72 73 7.20 5.46 74 7.03 5.61 75 6.21 5.63 76 5.99 — 77 7.04 — 78 7.10 — 79 6.59 — 80 6.60 5.78 81 6.84 6.48 82 7.38 6.26 83 7.03 — 84 6.39 7 02 85 6.13 7.26 86 7.08 — 87 6.90 — 88 7.11 6.17 89 7.35 5.66 90 7.23 — 91 7.23 — 92 7.24 7.00 93 6.63 6.41 94 6.97 6.51 95 6.93 — 96 6.30 — 97 7.31 — 98 6.56 — 99 6.91 7.02 100 6.44 — 101 6.40 6.55 102 6.68 4.82 103 6.66 5.00 104 7.21 6.10 105 6.97 7.01 106 7.24 5.70 107 7.37 6.61 108 7.46 7.12 109 6.55 — 110 7.16 5.78 111 6.83 7.37 112 6.21 6.58 113 6.82 6.75 114 6.88 6.69 115 6.65 7.23 116 7.13 6.47 117 7.30 8.68 118 7.16 7.63 119 7.47 8.10 120 6.74 7.76 121 6.89 7.13 122 7.08 6.61 123 5.67 5.84 124 7.22 8.15 125 6.91 7.32 126 6.49 6.02 127 7.59 6.03 128 7.17 6.59 129 7.27 6.14 130 7.75 7.42 131 7.38 7.37 132 6.15 5.65 133 6.53 6.50 134 7.62 6.23 135 7.85 6.88 136 7.04 7.09 137 5.58 4.52 138 6.44 4.52 139 6.59 5.42 140 6.28 4.52 141 6.34 5.23 142 7.02 6.64 143 6.93 6.75 144 7.08 7.70 145 7.53 7.05 146 7.29 7.46 147 7.48 8.12 148 7.70 6.23 149 7.58 6.66 150 7.32 7.11 151 7.69 7.22 152 7.54 6.96 153 7.05 5.76 154 7.67 6.31 155 7.06 6.75 156 6.97 6.48 157 6.90 6.63 158 7.24 7.32 159 7.00 7.10 160 6.53 4.52 161 8.07 6.98 162 7.88 6.71 163 7.81 5.75 164 7 97 6.70 165 7.90 7.15 166 7.27 5.63 167 7.20 6.50 168 7.36 6.42 169 7.29 7.12 170 7.14 7.68 171 7.38 7.62 172 7.03 6.75 173 — 4.52 174 7.75 6.63

[1070] As used in this specification and the appended claims, singular articles such as “a,” “an,” and “the,” may refer to a single object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing “a compound” may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the disclosure should be determined with reference to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references cited in the disclosure, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes.