AMIDOPYRIMIDONE DERIVATIVES
20230227449 · 2023-07-20
Assignee
Inventors
- Andrew Simon Bell (Dundee, GB)
- Jérémy Besnard (Dundee, GB)
- Anthony Richard Bradley (Dundee, GB)
- Luke Green (Basel, CH)
- Wolfgang Haap (Loerrach, DE)
- Buelent Kocer (Maulburg, DE)
- Andreas Kuglstatter (Loerrach, DE)
- Xavier Lucas (Basel, CH)
- Patrizio Mattei (Riehen, CH)
- Dmitry Mazunin (Grenzach-Wyhlen, DE)
- Hasane Ratni (Habsheim, FR)
- Claus Riemer (Freiburg, DE)
- Willem Paul Van Hoorn (Dundee, GB)
Cpc classification
C07D239/95
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D405/04
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
Abstract
The present invention provides compounds of formula I or II:
##STR00001##
wherein X.sup.1, X.sup.3, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula I, pharmaceutical compositions comprising them and their use as medicaments.
Claims
1. A compound formula I or II: ##STR00268## wherein X.sup.1 is either N or CH; X.sup.3 is either N or CR.sup.3 the dotted line represents a single bond when R.sup.5 is oxo or a double bond when R.sup.5 is —NH.sub.2, R.sup.1 is (C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1a, (C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1b, halo(C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1a, halo(C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1b, (C.sub.3-C.sub.8)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1c, heteroaryl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1d, heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1e or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1f; R.sup.1a and R.sup.1b are each independently selected from (C.sub.3-C.sub.6)cycloalkyl, hydroxyl, heteroaryl, heterocycloalkyl and phenyl, wherein heteroaryl, heterocycloalkyl or phenyl are optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.1g; R.sup.1c, R.sup.1d, R.sup.1e and R.sup.1f are each independently selected from halogen, oxo, cyano, hydroxyl, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, heteroaryl, heterocycloalkyl and phenyl; R.sup.1g are each independently selected from halogen, cyano, hydroxyl, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl; R.sup.2 is hydrogen, halogen, amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2a, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2b, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2c, heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2dNR.sup.2fR.sup.2g or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2e; R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d and R.sup.2e are each independently selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkoxy; R.sup.2f and R.sup.2g are each independently selected from hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.3 is hydrogen, halogen, cyano, amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.3a, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.3b, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.3c, heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.3d or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.3e; R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d and R.sup.3e are each independently selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, hydroxy, halogen, amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.4a, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.4b, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.4c, heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.4d, —CO.sub.2R.sup.4a or —CONR.sup.4bR.sup.4c; R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d, R.sup.4e are each independently selected from hydrogen and (C.sub.1-C.sub.6)alkyl; and R.sup.5 is —NH.sub.2 or oxo; or pharmaceutically acceptable salts thereof.
2. (canceled)
3. The compound of claim 1, wherein the compound is of formula I′: ##STR00269##
4. The compound of claim 1, wherein the compound is of formula I″: ##STR00270##
5. The compound of claim 1, wherein X.sup.3 is CR.sup.3.
6. The compound of claim 1, wherein X.sup.1 is N.
7. The compound of claim 1, wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl optionally substituted with one R.sup.1a, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one R″ °, heteroaryl optionally substituted with one or two R.sup.1d, heterocycloalkyl optionally substituted with one R.sup.1e or phenyl optionally substituted with one or two R.sup.1f.
8. The compound of claim 1, wherein R.sup.1 is (C.sub.1-C.sub.3)alkyl optionally substituted with one R.sup.1a, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one R.sup.1c, pyrazolyl optionally substituted with one R.sup.1d, indazolyl optionally substituted with one R.sup.1d, indolyl optionally substituted with one R.sup.1d, benzo[d]oxazolyl optionally substituted with one R.sup.1d, benzo[d]thiazolyl optionally substituted with one R.sup.1d, benzo[d]imidazolyl optionally substituted with one R.sup.1d, dioxepanyl optionally substituted with one R.sup.1d, oxazolyl optionally substituted with one R.sup.1d, thiazolyl optionally substituted with one R.sup.1d, pyridinyl optionally substituted with one or two R.sup.1d, pyrimidinyl optionally substituted with one R.sup.1d, dihydropyrrolo[1,2-c]imidazolyl optionally substituted with one R.sup.1e, oxepanyl optionally substituted with one R.sup.1e, dihydro-indolyl optionally substituted with one R.sup.1e, 1,4-dioxepanyl optionally substituted with one R.sup.1e, tetrahydrofuranyl optionally substituted with one R.sup.1e, tetrahydropyranyl optionally substituted with one R.sup.1e, piperidinyl optionally substituted with one R.sup.1e, oxaspiro[2.5]octanyl optionally substituted with one R.sup.1e, dihydrobenzofuranyl optionally substituted with one R.sup.1e or phenyl optionally substituted with one or two R.sup.1f.
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. The compound of claim 1, wherein R.sup.1 is tetrahydropyranyl optionally substituted with one (C.sub.1-C.sub.3)alkyl in alpha.
15. The compound of claim 1, wherein R.sup.1 is heteroaryl substituted with one or two R.sup.1d wherein at least of one R.sup.1d is substituted in ortho, heterocycloalkyl substituted with one R.sup.1e substituted in alpha or phenyl substituted with one or two R.sup.1f wherein at least of one R.sup.1f is substituted in ortho.
16. The compound of claim 1, wherein R.sup.1 is pyridinyl substituted with one or two R.sup.1d wherein at least of one R.sup.1d is substituted in ortho, tetrahydrofuranyl substituted with one R.sup.1e substituted in alpha, tetrahydropyranyl substituted with one R.sup.1e substituted in alpha, oxaspiro[2.5]octanyl or 2,3-dihydrobenzofuranyl substituted with one R.sup.1e.
17. (canceled)
18. (canceled)
19. The compound of claim 1, wherein R.sup.1a and R.sup.1b are each independently selected from heteroaryl, heterocycloalkyl and phenyl.
20. The compound of claim 1, wherein R.sup.1a is selected from tetrahydrofuranyl, pyridinyl, oxetanyl or oxazolyl.
21. The compound of claim 1, wherein R.sup.1c, R.sup.1d, R.sup.1e and R.sup.1f are each independently selected from halogen, oxo, cyano, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkoxy.
22. (canceled)
23. (canceled)
24. (canceled)
25. The compound of claim 1, wherein R.sup.1 is 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, oxepan-3-yl, 1,4-dioxepan-6-yl, dihydro-1H-indol-4-yl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, indazol-4-yl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, 2-methoxy-phenyl, 3-methyl-phenyl, 2-methyl-phenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 2-chlorophenyl, 3-chlorophenyl, 4-fluoro-2-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,3-dimethylphenyl, phenyl, 2,3-difluorophenyl, 2-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2-trifluoromethyl-phenyl, 3-(fluoromethyl)-2-methylphenyl, 3-ethylphenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, benzo[d]oxazol-4-yl, benzo[d]imidazolyl, benzo[d]thiazol-7-yl, 2-oxopiperidin-4-yl, 2-methylpyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, 2-methylpyridin-3-yl, picolinonitrile, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoro-2-methoxypyridin-3-yl, indolyl, 2-chloropyridin-3-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-5-yl, trifluoromethoxypyridin-2-yl, dihydrobenzofuranyl, tetrahydrofuranyl, 4-methyltetrahydrofuran-3-yl, methyl-tetrahydro-2H-pyran-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl or 4-methylthiazol-5-yl,
26. (canceled)
27. (canceled)
28. (canceled)
29. The compound of claim 1, wherein R.sup.2 is hydrogen, halogen, amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2a, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2b, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2e heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2d or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R.sup.2e; and R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d and R.sup.2e are each independently selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkoxy.
30. (canceled)
31. (canceled)
32. (canceled)
33. (canceled)
34. The compound of claim 1, wherein R.sup.2 is trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyclopropyl.
35. The compound of claim 1, wherein R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d and R.sup.2e are each independently selected from halogen and (C.sub.1-C.sub.6)alkyl.
36. (canceled)
37. (canceled)
38. The compound of claim 1, wherein R.sup.2f and R.sup.2g are each independently selected from hydrogen or (C.sub.1-C.sub.3)alkyl, particularly wherein one of R.sup.2f and R.sup.2g is hydrogen while the other is (C.sub.1-C.sub.3)alkyl.
39. (canceled)
40. The compound of claim 1, wherein R.sup.3 is hydrogen, chloro, fluoro or cyano.
41. (canceled)
42. The compound of claim 1, wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d and R.sup.3e are each independently selected from halogen and (C.sub.1-C.sub.3)alkyl.
43. The compound of claim 1, wherein R.sup.4 is hydrogen, cyano, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or —CONR.sup.4bR.sup.4c.
44. (canceled)
45. (canceled)
46. The compound of claim 1, wherein R.sup.4b or R.sup.4c are hydrogen.
47. The compound of claim 1, wherein R.sup.5 is —NH.sub.2.
48. The compound of claim 1, selected from the group consisting of: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(tert-butyl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(3,3-difluoroazetidin-1-yl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-((cis)-2-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[4,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2-one; 4-amino-7-cyclopropyl-1-(2-methylphenyl)quinazolin-2-one; 7-cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione; 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2 (1H)-one; 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione; 4-amino-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-6-fluoro-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)picolinonitrile; 4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[1-(oxolan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(3-fluoro-2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 4-amino-1-(2-methylpyridin-3-yl)-7-propan-2-ylpyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-6-chloro-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-ethoxybenzonitrile; 4-amino-7-cyclopropyl-1-(1-(tetrahydrofuran-2-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-methylpyridin-3-yl)-7-(oxetan-3-yl)quinazolin-2 (1H)-one; 7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione; 4-amino-7-((1RS,2RS)-2-methylcyclopropyl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopentyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-((1SR,2RS)-2-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-2-cyclopentyl-7-(o-tolyl)pyrazolo[3,4-d]pyrimidin-6-one; formic acid; 4-amino-7-cyclopentyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-[(3R)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[(3S)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(4-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-2-oxo-1-(0-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide; 4-amino-1-(2-methoxy-3-pyridyl)-7-tetrahydropyran-2-yl-pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid; 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2-one; 4-amino-7-cyclopropyl-1-[rac-(2R,3 S)-2-methyloxolan-3-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclobutyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; formic acid; 4-amino-7-cyclopropyloxy-1-(2-methylpyridin-3-yl)quinazolin-2-one; 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid; 4-amino-7-cyclopropyl-1-(3-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one; 4-amino-7-(difluoromethyl)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one; 4-amino-7-[(1R,2S)-2-fluorocyclopropyl]-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile; 3-(4-amino-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile; 4-amino-7-cyclopropyl-2-oxo-1-(0-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile; 4-amino-7-methoxy-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one; 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2 (1H)-one; 4-amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one, 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-7-cyclopropyl-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2 (1H)-one; (R)-4-amino-1-(tetrahydro-2H-pyran-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-ethyl-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one; 4-amino-7-[(1S,2R)-2-fluorocyclopropyl]-1-[(3R)-tetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(4-methyloxazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile; 4-amino-7-cyclopropyl-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(2-fluoropropan-2-yl)-1-(2-methylpyridin-3-yl)quinazolin-2-one; 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(4-fluoro-2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(1-ethyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one; 4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[(1R)-1-[(3S)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[(1R)-1-[(3R)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one; 3-(4-amino-6-chloro-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile; 4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-6-chloro-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-7-cyclopropyl-1-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(3-ethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one, 4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(6-methoxypyridin-2-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,3-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(1-(oxazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-2-oxo-7-(trifluoromethyl)quinazolin-1 (2H)-yl)-2-methylbenzonitrile; 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 4-amino-7-cyclopropyl-1-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-[1-(oxetan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(1-pyridin-2-ylethyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2-methyl-3-pyridyl)-7-(2,2,2-trifluoroethyl)quinazolin-2-one hydrochloride; 4-amino-7-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-2-cyclopentyl-7-(2-methyl-3-pyridyl)pyrazolo[3,4-d]pyrimidin-6-one; 4-amino-5-chloro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one; 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one; 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one; 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile; 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one; 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)benzonitrile; 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2 (1H)-one; 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one; 4-amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 4-amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile; 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(1H-benzo[d]imidazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2 (1H)-one; 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2 (1H)-one; 4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-fluorobenzonitrile; (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-[rac-(2S,3S)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; (−)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; (−)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid; 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one; formic acid; 4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one; 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one; and 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one; or pharmaceutically acceptable salts thereof.
49. The compound of claim 1, selected from the group consisting of: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one; 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2 (1H)-one; 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one; 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile; 4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one; 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one; 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one; (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; and 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; or pharmaceutically acceptable salts thereof.
50. A compound of claim 1 for use as a therapeutically active substance.
51. Pharmaceutical compositions comprising compounds of formula I or II of claim 1 or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
52. Compounds of formula I or II of claim 1 or their pharmaceutically acceptable salts above for use as therapeutically active substances.
53. Compounds of formula I or II of claim 1 or their pharmaceutically acceptable salts for the use in the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.
54. (canceled)
55. A method for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma, which method comprises administering compounds of formula I of claim 1 or their pharmaceutically acceptable salts as defined above to a subject.
56. (canceled)
57. The use of compounds of formula of claim 1 or their pharmaceutically acceptable salts for the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.
58. (canceled)
59. The use of compounds of formula I of claim 1 or their pharmaceutically acceptable salts for the preparation of medicaments for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.
60. (canceled)
61. (canceled)
Description
EXAMPLES
[0641]
TABLE-US-00003 Molecular weight From Ex. found Inter- No. Structure Product Name (M + H).sup.+ mediate Prep. 1
Example 91: 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one
[0642] ##STR00200##
Step 1: 4-amino-7-((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0643] To a solution of 4-methoxybenzyl alcohol (59 μl, 474 μmol) in NMP (1 ml) at 0° C. sodium hydride (33 mg, 60% dispersion in mineral oil, 837 μmol) was added and the reaction mixture was stirred for 15 min. 4-amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one (80 mg, 279 μmol) (example 62) was added and the mixture was heated to 150° C. until LCMS showed full conversion. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 4-amino-7-((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one (100 mg, 83%). ([M+H].sup.+ 389.2)
Step 2: 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0644] To a solution of 4-amino-7-((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one (670 mg, 1.55 mmol) in DCM (10 ml) and TFA (957 μl, 12.4 mmol) was added. The resulting solution was stirred for 2.5 h at room temperature before it was quenched with water. The aqueous layer was washed with DCM and evaporated to dryness. The crude product was purified by reversed phase preparative HPLC and yielded 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one as a white solid (400 mg, 96%). ([M+H].sup.+ 269.2)
Step 3: 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one
[0645] To a solution of 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one (14 mg, 51.1 μmol) in NMP (2 ml) sodium chlorodifluoroacetate (156 mg, 102 μmol) and K.sub.2CO.sub.3 (21 mg, 153 μmol) were added. The mixture was heated to 80° C. for 25 min before it was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one (8 mg, 49%). ([M+H].sup.+ 319.1)
Example 92: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
[0646] ##STR00201##
Step 1: 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
[0647] To a solution of 2-chloro-4-(trifluoromethyl)pyridine (200 mg, 1.1 mmol) and 2-(2-methoxyphenyl)acetonitrile (162 mg, 1.1 mmol) in DMF (4 mL) was added NaH (60% dispersion in mineral oil, 88 mg, 2.2 mmol) and reaction was stirred at rt for 1 h before it was quenched with sat. NH.sub.4Cl solution. Reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to give crude yellow oil. Compound was purified by flash column chromatography to afford 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile as light brown oil (221 mg, 69%). ([M+H].sup.+ 293.2)
Step 2: 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
[0648] To a solution of 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (50 mg, 0.17 mmol) in AcOH (0.7 mL) was added 95% H.sub.2SO.sub.4 (0.3 mL) and mixture was stirred for 2 days at 40° C. The reaction mixture was cooled to rt and poured onto ice followed by extraction with EtOAc. The organic layers were washed with sat. NaHCO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by flash column chromatography afforded 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (41 mg, 77%) as white solid. ([M+H].sup.+ 311.2)
Step 3: sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate
[0649] To a mixture of 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol) in EtOH (0.5 mL) was added sodium ethoxide (0.96 mL, 21% in EtOH, 2.58 mmol) followed by dropwise addition of thiophosgene (50 μL, 0.65 mmol) keeping the temperature below 40° C. The mixture was stirred in a sealed tube at 85° C. for 2 h before it was cooled to rt and quenched with ˜3 mL water. The resulting precipitate was filtered, washed with water and dried in vacuo to give sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate (85 mg, 64%) as yellow solid. ([M+H].sup.+ 353.2)
Step 4: 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
[0650] To a solution of sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate (80 mg, 0.21 mmol) in EtOH (2 mL) was added iodomethane (15 μL, 0.24 mmol). The reaction was stirred at rt for 7 h. An additional portion of iodomethane (˜10 μL) was added and stirring at rt was continued for 16 h. The reaction mixture was evaporated and the residue was diluted with EtOAc/water. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by flash column chromatography gave 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (58 mg, 72%) as yellow foam. ([M+H].sup.+ 367.2)
Step 5: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
[0651] To a mixture of 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (51 mg, 0.14 mmol) and ammonium hydroxide solution (1.5 mL, 9.24 mmol) was added THF (0.5 mL). The reaction was stirred at rt for 3 days before it was concentrated. Purification by flash column chromatography afforded 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (23 mg, 49%) as yellow solid ([M+H].sup.+ 336.3)
Example 93: 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0652] ##STR00202##
[0653] 4-amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (20 mg, 62 μmol) (example 41) and Pd/C (7.0 mg, 62 μmol) were stirred at rt under hydrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated in vacuo. Purification by flash column chromatography afforded 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (8 mg, 37%) as a white solid. ([M+H].sup.+ 322.3)
Example 94: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide
[0654] ##STR00203##
Step 1: ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate
[0655] To a suspension of KOtBu (734 mg, 6.54 mmol) in THF (5 ml) at 0° C. were added dropwise over 10 min a mixture of diethyl oxalate (806 μl, 5.94 mmol) and 1-cyclopropylethan-1-one (589 μl, 5.94 mmol). The reaction mixture was stirred at 0° C. for 40 min, quenched with aq. dilute HCl and diluted with water. It was extracted with DCM, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was added to a solution of 2-cyanoacetamide (500 mg, 5.94 mmol) and sodium methoxide (321 mg, 5.94 mmol) in MeOH (5 ml) and heated to 65° C. After 90 min the reaction mixture was cooled to rt and acidified with 6M HCl, extracted with EtOAc, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by flash column chromatography afforded ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate (540 mg, 27%) as a light brown solid. ([M+H].sup.+ 233.2)
Step 2: ethyl 2-chloro-3-cyano-6-cyclopropylisonicotinate
[0656] Ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate (60 mg, 258 μmol) was dissolved in POCl.sub.3 (300 μl, 3.22 mmol) and the reaction mixture was heated to 100° C. for 2.5 h. The POCl.sub.3 was removed in vacuo and the crude product was purified using flash column chromatography to afford ethyl 2-chloro-3-cyano-6-cyclopropylisonicotinate (22 mg, 32%) as a white solid. ([M+H].sup.+ 251.2)
Step 3: ethyl 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate
[0657] Pd(OAc).sub.2 (2 mg, 8.0 μmol) was added to a degassed solution of ethyl 2-chloro-3-cyano-6-cyclopropylisonicotinate (20 mg, 79.8 μmol), o-toluidine (13 μl, 120 μmol), xphos (6 mg, 12 μmol) and Cs.sub.2CO.sub.3 (78 mg, 239 μmol) and the resulting reaction mixture was heated to 100° C. After 2 h it was cooled to rt, filtered through Decalite® and concentrated in vacuo. The crude product was purified using flash column chromatography to afford ethyl 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate (8 mg, 31%) as a yellow solid. ([M+H].sup.+ 322.3)
Step 4: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide
[0658] To a solution of ethyl 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate (8 mg, 25 μmol) in DCM (0.5 ml) trichloroacetyl isocyanate (6 μl, 50 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. After ammonia (7 M in MeOH, 1 ml, 7 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. The crude product was purified by reversed phase preparative HPLC yielding 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide (5 mg, 57%) as a white solid. ([M+H].sup.+ 336.1)
Example 95: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile
[0659] ##STR00204##
[0660] To a solution of 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide (23 mg, 68 μmol) (example 94) and TEA (33 μl, 239 μmol) in DCM (0.5 ml) at 0° C. trifluoroacetic anhydride (15 μl, 102 μmol) was added and the reaction mixture was stirred at rt. Three additional portions of TEA (33 μl, 239 μmol) and trifluoroacetic anhydride (15 μl, 102 μmol) was added every 30 min to afford complete conversion to product. The orange solution was adsorbed on silica and purified by flash column chromatography to afford 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile (7 mg, 31%) as a white solid. ([M+H].sup.+ 318.3)
Example 96: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2 (1H)-one
[0661] ##STR00205##
Step 1: 2-cyclopropyl-4-hydroxypyrimidine-5-carbonitrile
[0662] To a solution of cyclopropanecarboximidamide hydrochloride (200 mg, 1.58 mmol) and ethyl (E)-2-cyano-3-ethoxyacrylate (272 mg, 1.58 mmol) in EtOH (3.5 ml) at 0° C. was added KOtBu (442 mg, 3.94 mmol) and the suspension was stirred at 0° C. for 10 minutes and at reflux for 2 h. The mixture was poured on water and was acidified to pH 3 using aq. 25% HCl followed by extraction with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude 2-cyclopropyl-4-hydroxypyrimidine-5-carbonitrile (196.5 mg, 77%) as a light yellow solid. ([M+H].sup.+ 162.1)
Step 2: 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile
[0663] 2-cyclopropyl-4-hydroxypyrimidine-5-carbonitrile (196 mg, 1.22 mmol) was combined with phosphorus oxychloride (1.42 ml, 15.2 mmol) to give an orange suspension. The reaction mixture was stirred at 110° C. for 1 h. The mixture was cooled to rt and was added dropwise to a well stirred mix of ice/water/EtOAc and washed with sat. aq. NaHCO.sub.3. The aq. layer was extracted with EtOAc and combined organic layers were washed once with sat. aq. NaHCO.sub.3. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield crude 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile (122 mg, 56%). ([M+H].sup.+ 180.1)
Step 3: 2-cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile
[0664] To a degassed solution of 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile (122 mg, 679 μmol), o-toluidine (108 μl, 1.02 mmol) and Cs.sub.2CO.sub.3 (664 mg, 2.04 mmol) in dioxane (2.5 ml) were added xphos (49 mg, 102 μmol) and Pd(OAc).sub.2 (15 mg, 68 μmol) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc and washed 3× with water. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by flash column chromatography afforded 2-cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile (50 mg, 29%) as a off-white solid. ([M+H].sup.+ 251.3)
Step 4: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2 (1H)-one
[0665] To a solution of 2-cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile (50 mg, 200 μmol) in DCE (1 ml) trichloroacetyl isocyanate (52 μl, 439 μmol) was added and the reaction mixture was stirred at at 80° C. overnight. After concentration, ammonia (7 M in MeOH, 6.67 ml, 46.7 mmol) was added and reaction was stirred for 1 h and the reaction concentrated to dryness Purification by flash column chromatography followed by suspension in EtOAc and filtration to yielded 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2 (1H)-one (19 mg, 31%) as a white solid. ([M+H].sup.+ 294.3)
Example 97: 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0666] ##STR00206##
Step 1: 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile
[0667] To a solution of 2-chloro-6-cyclopropylnicotinonitrile (200 mg, 1.12 mmol) in DMSO (4 ml) were added DIPEA (978 μl, 5.6 mmol) and 4-aminopiperidin-2-one TFA salt (509 mg, 2.24 mmol). The reaction mixture was heated to 120° C. for 48 h after which time it was diluted with water and extracted twice with EtOAc. The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile (192 mg, 55%) as a off-white solid. ([M+H].sup.+ 257.2)
Step 2: 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile
[0668] To a solution of 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile (50 mg, 195 μmol) in THF (1 ml) at 0° C. were added 4-methoxybenzyl bromide (34 μl, 234 μmol) and KOtBu (43.8 mg, 390 μmol). The reaction mixture was stirred at rt. 4-methoxybenzyl bromide (34 μl, 234 μmol) was added once again after 2 h and the reaction mixture was stirred for additional 7 h. The reaction mixture was quenched with water and extracted twice with DCM. The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile (33 mg, 36%) as a yellow oil. ([M+H].sup.+ 377.4)
Step 3: 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0669] To a solution of 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile (47 mg, 125 μmol) in DCM (1.5 ml) trichloroacetyl isocyanate (33 μl, 275 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. After ammonia (7 M in MeOH, 4 ml, 28 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. The crude product was purified by flash column chromatography to yield 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (27 mg, 48%) as a white solid. ([M+H].sup.+ 420.4)
Step 4: 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0670] 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (27 mg, 64 μmol) was dissolved in TFA (2 ml, 26 mmol). The reaction mixture was stirred at 75° C. for 67 h before it was concentrated in vacuo and purified by reverse-phase HPLC to yield 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (9 mg, 46%) as a white solid. ([M+H].sup.+ 300.2)
Example 98: 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione
[0671] ##STR00207##
[0672] 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one (55 mg, 188 μmol) (Example 86) was suspended in KOH (2M aqueous, 941 μl, 1.88 mmol) and heated to 110° C. After 4 h the reaction mixture was cooled to room temperature, diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash column chromatography to yield 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (25 mg, 43%) as a white solid. ([M+H].sup.+ 294.3)
Example 99: 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione
[0673] ##STR00208##
Step 1: methyl 2-chloro-6-cyclopropylpyridine-3-carboxylate
[0674] To a degassed solution of methyl 6-bromo-2-chloronicotinate (700 mg, 2.65 mmol) in dioxane (12 ml) were added K.sub.2CO.sub.3 (734 mg, 5.31 mmol), cyclopropylboronic acid (1.14 g, 13.3 mmol) and Pd(dppf).sub.2Cl.sub.2.Math.CH.sub.2Cl.sub.2 (217 mg, 265 μmol). The reaction mixture was heated in the microwave at 80° C. for 1 h before it was poured into water and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography to afford the title compound (498 mg, 87%) as a yellow crystalline solid. ([M+H].sup.+ 212.1)
Step 2: 2-chloro-6-cyclopropylpyridine-3-carboxylic acid
[0675] To a solution of methyl 2-chloro-6-cyclopropylnicotinate (489 mg, 2.31 mmol) in THF (5 ml) and MeOH (5 ml) was added LiOH (1M in water, 4.62 ml, 4.62 mmol). The reaction mixture was stirred at rt over night before volatiles were removed in vacuo. The residue was diluted with water, acidified with 1 M HCl and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (470 mg, 100%) as a white solid. ([M+H].sup.+ 198.1)
Step 3: 2-chloro-6-cyclopropylpyridine-3-carboxamide
[0676] To a solution of 2-chloro-6-cyclopropylnicotinic acid (220 mg, 1.11 mmol) in DMF (2 ml) was added CDI (271 mg, 1.67 mmol). The reaction was heated to 50° C. for 2.5 h before ammonia (25% solution in water, 1.21 g, 1.33 ml, 17.8 mmol) was added at rt and the reaction was allowed to stir for 3 days. The reaction was diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromatography to afford the desired compound (165 mg, 74%) as a white solid. ([M+H].sup.+ 197.2)
Step 4: 6-cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide
[0677] A solution of 2-chloro-6-cyclopropylnicotinamide (79 mg, 402 μmol) and o-toluidine (42.9 μl, 402 μmol) in AcOH (0.5 ml) was heated to 120° C. overnight. The reaction was cooled to rt and basified with 2N NaOH and extracted 3 times with EtOAc. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromatography to afford 6-cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide (50 mg, 46%) as a light yellow solid. ([M+H].sup.+ 268.2)
Step 5: 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione
[0678] A light yellow solution of 6-cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide (47 mg, 176 μmol), CDI (43 mg, 264 μmol) and DBU (53 μl, 352 μmol) in THF (1 ml) was heated to 70° C. for 1 h before it was cooled to rt, diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromatography to afford 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione (33 mg, 63%) as a white solid. ([M+H].sup.+ 294.2)
Example 100: 7-cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione
[0679] ##STR00209##
[0680] 4-amino-7-cyclopropyl-1-(o-tolyl)quinazolin-2 (1H)-one (60 mg, 206 μmol) (example 8) was suspended in KOH (2M in water, 1.03 ml, 2.06 mmol) and heated to 110° C. for 4 h before it was cooled to rt, diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound (56 mg, 90%) as a white solid. ([M+H].sup.+ 293.2)
Example 101: 7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione
[0681] ##STR00210##
[0682] To a mixture of Example 7 (20 mg, 680 μmol) in TI-IF (1 mL) was added tert-butyl nitrite (17 μL, 136 μmol). Reaction was stirred at 60° C. for 2 h before more tert-butyl nitrite (17 μL, 136 μmol) was added and mixture was stirred at 60° C. for additional 5 h. Reaction was cooled to rt and extracted with EtOAc. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo. Compound was purified by flash chromatography to give 7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione (14 mg, 70%) as white solid. ([M+H].sup.+ 295.1)
Example 102: 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one
[0683] ##STR00211##
[0684] 4-amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one (61 mg. 180 μmol) (example 59) and sodium methoxide (15 mg, 270 μmol) were stirred in MeOH (3 ml) for 48 h at rt The solvent was evaporated and the crude product was purified by flash column chromatography to afford 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one (42 mg, 63%) as a white solid. ([M+H].sup.+ 351.2)
Example 103 and Example 104: (+)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0685] ##STR00212##
Step 1: 6-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)nicotinonitrile
[0686] The title compound ([M+H].sup.+ 268.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-fluoro-2-methylaniline (CAS [443-86-7]) using Pd(OAc).sub.2 as a catalyst and xantphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0687] To a solution of 6-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)nicotinonitrile (57 mg, 213 μmol) in DCE (3 ml) trichloroacetyl isocyanate (56 μl, 469 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. After, ammonia (7 M in MeOH, 3.81 ml, 26.6 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. The crude product was purified by flash column chromatography to yield 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one (61 mg, 91%) as a white solid. ([M+H].sup.+ 311.2)
Step 3: (+)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0688] 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one was separated by chiral reversed phase prep-HPLC to afford (+)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one as a white solid and (−)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one as a white solid. ([M+H].sup.+ 420.4) and ([M+H].sup.+ 311.2)
Example 105: 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl).SUB.2 .methoxybenzonitrile
[0689] ##STR00213##
Step 1: 2-amino-6-isopropylnicotinonitrile
[0690] The title compound ([M+H]+ 162.2) was prepared from 2-chloro-6-isopropylnicotinonitrile (CAS [108244-44-6]) using General procedure D.
Step 2: 2-amino-5-chloro-6-isopropylnicotinonitrile
[0691] To a solution of 2-amino-6-isopropylnicotmonitrile (130 mg, 806 μmol) in CHCl3 (5 ml) was added NCS (118 mg, 887 μmol) and reaction was stirred in the dark at 60° C. for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed 2× with water and the combined organic layers were dried and evaporated to dryness to yield crude product (180 mg, 114%) as an orange solid. ([M+H]+ 196.1)
Step 3: 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile
[0692] 2-amino-5-chloro-6-isopropylnicotinonitrile (90 mg, 460 μmol), 3-bromo-2-methoxybenzonitrile (127 mg, 598 μmol), xantphos (26.6 mg, 46 μmol) and Cs.sub.2CO.sub.3 (450 mg, 1.38 mmol) were mixed in dioxane (3 ml) and degassed under argon. Pd(OAc).sub.2 (5.16 mg, 23 μmol) was added and the mixture was stirred over night at 90° C. On the next day again xantphos (27 mg, 46 μmol) and Pd(OAc).sub.2 (5.2 mg, 23 μmol) were added and the reaction was stirred for additional 3 h at 90° C. The crude product was purified by flash column chromatography to yield 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile (75 mg, 50%) as a yellow solid. ([M+H].sup.+ 327.2)
Step 4: 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile
[0693] 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile (70 mg, 214 μmol) was dissolved in DCM (1 ml) and trichloroacetyl isocyanate (121 mg, 76.1 μl, 643 μmol) was added. The mixture was stirred over night at rt before an additional trichloroacetyl isocyanate (121 mg, 76.1 μl, 643 μmol) was added and stirred at rt. After 3 h ammonia (7 M in MeOH, 5 ml, 35 mmol) was added and stirred over night at rt. The reaction mixture was evaporated and the residue was purified by by flash column chromatography to yield 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile (76 mg, 96%) as a white solid. ([M+H]+ 370.2)
Example 106: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one
[0694] ##STR00214##
Step 1: 4-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)benzonitrile
[0695] The title compound ([M+H].sup.+ 267.2) was prepared from 2-chloro-4-cyclopropylbenzonitrile (Angew. Chem. 2018, 12573) by reaction with 3-fluoro-2-methylaniline (CAS [443-86-7]) using Pd(OAc).sub.2 as a catalyst and X-phos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one
[0696] To a solution of 4-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)benzonitrile (76 mg, 284 μmol) in DCM (3 ml) trichloroacetyl isocyanate (75 μl, 625 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. After, ammonia (7 M in MeOH, 6.1 ml, 42.6 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. The crude product was purified by flash column chromatography to yield 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one (70 mg, 80%) as a white solid. ([M+H].sup.+ 308.2)
Example 107: 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3˜d]pyrimidin-2-one
[0697] ##STR00215##
Step 1: 6-cyclopropyl-2-(1,4-dioxepan-6-ylamino)pyridine-3-carbonitrile
[0698] The title compound ([M+H].sup.+ 260.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 1,4-dioxepan-6-amine (EP1958666 A1) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one
[0699] To a solution of 6-cyclopropyl-2-(1,4-dioxepan-6-ylamino)pyridine-3-carbonitrile (15 mg, 60 μmol) in DCM (1 ml) trichloroacetyl isocyanate (35 μl, 290 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. After, ammonia (7 M in MeOH, 1.0 ml, 0.06 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. The crude product was purified by flash column chromatography to 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one (9 mg, 78%) as a white solid. ([M+H].sup.+ 303.1)
Example 108: 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0700] ##STR00216##
Step 1: 6-cyclopropyl-2-((6-(difluoromethoxy)pyridin-2-yl)amino)nicotinonitrile
[0701] The title compound ([M+H].sup.+ 303.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 6-(difluoromethoxy)pyridin-2-amine (CAS [1131007-43-6]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0702] To a solution of 6-cyclopropyl-2-((6-(difluoromethoxy)pyridin-2-yl)amino)nicotinonitrile (87 mg, 210 μmol) in DCE (2 ml) trichloroacetyl isocyanate (62 μl, 525 μmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. The reaction was concentrated to dryness and redissolved in ammonia (7 M in MeOH, 12 ml, 84 mmol) was added and reaction was stirred until LCMS indicated full conversion to product. Evaporation of the methanol and trituration with ethyl aceate afforded 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (35 mg, 48%) as a white solid. ([M+H].sup.+ 346.2)
Example 109: 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one
[0703] ##STR00217##
Step 1: 2-[(2-chloro-3-pyridyl)amino]-4-(trifluoromethoxy)benzonitrile
[0704] The title compound ([M+H].sup.+ 313.8) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS [1214334-83-4]) by reaction with 3-amino-2-chloro-pyridine (CAS [6298-19-7]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one
[0705] To a solution of 2-[(2-chloro-3-pyridyl)amino]-4-(trifluoromethoxy)benzonitrile (100 mg, 320 μmol) in DCM (5 ml) trichloroacetyl isocyanate (187 μl, 1.5 mmol) was added and the reaction mixture was stirred at rt until disappearance of starting material. Ammonia (7 M in MeOH, 5 ml, 35 mmol) was added and reaction was stirred until LCMS indicated full conversion to product.
[0706] The crude product was purified by flash column chromatography to 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one (33 mg, 26%) as a white solid. ([M+H].sup.+ 357.1)
Example 110: 4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one
[0707] ##STR00218##
Step 1: 6-cyclopropyl-2-[2-(trifluoromethoxy)anilino]pyridine-3-carbonitrile
[0708] The title compound ([M+H].sup.+ 320.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-(trifluoromethoxy)aniline (CAS [175205-77-3]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one
[0709] The title compound ([M+H].sup.+ 363.0) was prepared from 6-cyclopropyl-2-[2-(trifluoromethoxy)anilino]pyridine-3-carbonitrile using General procedure C.
Example 111: 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one
[0710] ##STR00219##
Step 1: (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol
[0711] To a solution of 2,4-dibromopyridine (500 mg, 2.11 mmol) in toluene (25 mL) was added dropwise n-BuLi/(1.6M in hexanes, 1.01 mL, 2.53 mmol) at −78° C. and the reaction mixture was stirred for 1 h before addition of 2-chlorobenzaldehyde (326 mg, 2.32 mmol) and the mixture stirred for another 1 h before the reaction mixture was poured into sat. NH.sub.4Cl, extracted with ethyl acetate, the combined extracts were washed with brine and concentrated. Purification by flash column chromatography gave product (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol (500 mg, 71%) as a yellow oil. ([M+H].sup.+ 298.0)
Step 2: (4-bromo-2-pyridyl)-(2-chlorophenyl)methanone
[0712] To a solution of (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol (500 mg, 1.67 mmol) in chloroform (20 mL) was added MnO.sub.2 (1455 mg, 16.75 mmol) at 25° C., the reaction mixture was stirred at 50° C. for 2 h. The mixture was filtered through Celite® and concentrated. Purification by flash column chromatography gave product (4-bromo-2-pyridyl)-(2-chlorophenyl)methanone (450 mg, 91%) as a yellow oil. ([M+H].sup.+ 295.9)
Step 3: (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone
[0713] A mixture of (4-bromo-2-pyridyl)-(2-chlorophenyl)methanone (400 mg, 1.35 mmol), potassium cyclopropyltrifluoroborate (399 mg, 2.7 mmol), K.sub.2CO.sub.3 (558 mg, 4.05 mmol), Pd(dppf)Cl.sub.2 (40.0 mg, 0.130 mmol) in 1,4-dioxane (4 mL) and water (1 mL) stirred at 80° C. for 12 h under inert atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to give product (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone (300 mg, 69%) as a yellow oil. ([M+H].sup.+ 258.1)
Step 4: 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile
[0714] To an ice-cold solution of (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone (500 mg, 191 mmol) and Tosmic (568 mg, 2.9 mmol) in DME (10 mL) was added potassium tert-butylate (1 M in tBuOH, 4.85 ml, 4.85 mmol) and reaction was then heated to 50° C. for 12 h before it was quenched by addition of water. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The product was purified by flash column chromatography to afford 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile as a light yellow oil (500 mg, 67%). ([M+H].sup.+ 269.1)
Step 5: 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide
[0715] To a solution of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile (450 mg, 1.67 mmol) in AcOH (15 mL) was added 95% H.sub.2SO.sub.4 (5 mL) and the mixture was stirred for 2 days at 40° C. The reaction mixture was cooled to rt and poured onto ice followed by extraction with EtOAc. The organic layers were washed with sat. NaHCO.sub.3 solution and brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash column chromatography afforded 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (400 mg, 83%) as yellow solid. ([M+H].sup.+ 287.1)
Step 6: 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one
[0716] To a mixture of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (400 mg, 1.39 mmol) in EtOH (2.5 mL) was added sodium ethoxide (4.2 mL, 21% in EtOH, 11.6 mmol) followed by dropwise addition of thiophosgene (215 μL, 2.79 mmol) keeping the temperature below 40° C. The mixture was stirred in a sealed tube at 85° C. for 2 h before it was cooled to rt and quenched with ˜3 mL water. The mixture was extracted with ethyl acetate, the combined washings washed with brine and concentrated. Purification by flash column chromatography to gave 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one (250 mg, 44%) as yellow solid. ([M+H].sup.+ 329.0)
Step 7: 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one
[0717] To a solution of 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one (200 mg, 0.61 mmol) in DMF (2 mL) was added potassium carbonate (168 mg, 1.22 mmol) iodomethane (45 μL, 0.73 mmol). The reaction was stirred at rt for 7 h. The reaction mixture was evaporated and the residue was diluted with EtOAc/water. The organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash column chromatography gave 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (100 mg, 43%) as yellow oil. ([M+H].sup.+ 343.0)
Step 8: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
[0718] To a mixture of 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one (90 mg, 0.260 mmol) and ammonium hydroxide solution (1.5 mL, 9.24 mmol) was added THF (0.5 mL). The reaction was heated to 50° C. for 48 h after which time it was concentrated. Purification by flash column chromatography afforded 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one (8 mg, 9%) as yellow solid ([M+H].sup.+ 312.2)
Example 112: 4-amino-7-cyclopropyl-1-(6,7-dihydro-51-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one
[0719] ##STR00220##
Step 1: 6-cyclopropyl-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ylamino)pyridine-3-carbonitrile
[0720] The title compound ([M+H].sup.+ 266.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-amine hydrochloride (CAS [272438-86-5]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one
[0721] The title compound ([M+H].sup.+ 309.2) was prepared from 6-cyclopropyl-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ylamino)pyridine-3-carbonitrile using General procedure C.
Example 113: 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one
[0722] ##STR00221##
Step 1: 2-amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile
[0723] To a solution of 2-amino-6-cyclopropyl-pyridine-3-carbonitrile (1000 mg, 6.28 mmol) in chloroform (20 mL) was added N-bromosuccinamide (1173 mg, 6.6 mmol). The mixture was stirred at 20° C. for 16 h in the dark after which time it was concentrated. Purification by flash column chromatography afforded 2-amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (1.4 g, 93% yield) as yellow solid. ([M+H].sup.+ 238.0)
Step 2: 2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile
[0724] A mixture of 2-amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (200 mg, 0.84 mmol) in THF (10 mL) was cooled to 0° C. NaH (141.13 mg, 3.53 mmol, 4.2 eq) was added and the mixture stirred for 0.5 h after which time was added 4-methoxybenzylchloride (0.46 mL, 3.36 mmol) and the mixture then stirred at rt for 12 h. The reaction was quenched by addition of sat.NH.sub.4Cl and extracted with ethyl acetate and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (300 mg, 75%) as light yellow gum ([M+H].sup.+ 480.2)
Step 3: 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile
[0725] A mixture of 2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (300 mg, 0.63 mmol), potassium hydroxide (105 mg, 1.88 mmol, 3), t-BuBretPhos Pd G3 (107 mg, 0.13 mmol), and t-BubretPhos (61 mg, 0.13 mmol) in 1,4-dioxane (3 mL) and water (0.30 mL) was stirred at 80° C. for 2 h. The reaction was then diluted with water, extracted with ethyl acetate and the combined organic washed with brine and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile (260 mg, 70% yield) as orange oil. ([M+H].sup.+ 416.3)
Step 4: 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile
[0726] A mixture of 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile (270 mg, 0.45 mmol), sodium chlorodifluoroaceate (138 mg, 0.91 mmol) and cesium carbonate (444 mg, 1.36 mmol) in DMF (2 mL) was stirred 80° C. for 2 h. The reaction was then diluted with water, extracted with ethyl acetate and the combined organic washed with brine and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (180 mg, 85%) as yellow oil. ([M+H].sup.+ 466.3)
Step 5: 2-amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile
[0727] To 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (160 mg, 0.34 mmol) was added TFA (3.0 mL, 0.34 mmol) at rt and the reaction stirred for 1 h before it was quenched by addition of saturated sodium hydrogen carbonate solution. It was then extracted with ethyl aceate, concentrated and the residue purified by flash column chromatography to afford 2-amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (70 mg, 90%) as colorless oil. ([M+H].sup.+ 226.2)
Step 6: 6-cyclopropyl-5-(difluoromethoxy)-2-(2-methylanilino)pyridine-3-carbonitrile
[0728] The title compound ([M+H].sup.+ 316.2) was prepared from 2-amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile by reaction with 2-bromotoluene using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 7: 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one
[0729] The title compound ([M+H].sup.+ 359.2) was prepared from 6-cyclopropyl-5-(difluoromethoxy)-2-(2-methylanilino)pyridine-3-carbonitrile using General procedure C.
Example 114 &115: (+)-4-amino-1-(2˜chlorophenyl)˜7-cyclopropylpyrido[2,3-d]pyrimidin-2(H)-one & (−)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0730] ##STR00222##
Step 1: 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinonitrile
[0731] The title compound ([M+H].sup.+ 270.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloroaniline (CAS [95-51-2]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one & (−)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0732] The title compounds ([M+H].sup.+ 313.1) were prepared from 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 116 & 117: (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0733] ##STR00223##
Step 1: 2-((2-chloro-3-fluorophenyl)amino)-6-cyclopropylnicotinonitrile
[0734] The title compound ([M+H].sup.+ 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-3-fluoroaniline (CAS [21397-08-0]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0735] The title compounds ([M+H].sup.+ 331.1 & 331.1) were prepared from 2-((2-chloro-3-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 118 & 119: 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (example 118) and 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one (example 119)
[0736] ##STR00224##
Step 1: 2-methyldihydro-2H-pyran-3 (4H)-one
[0737] To a solution of 2-methyl-2H-pyran-3 (6H)-one (WO2010/96338 A1) (6.45 g, 57.5 mmol) in MeOH (250 ml) was added 10% palladium on activated charcoal (317 mg, 298 μmol) and the reaction stirred under an atmosphere of hydrogen (balloon) for 1 h. The reaction was filtered over Celite® and concentrated. Vacuum distillation over a short Vigreux column (Bp: 42-43 @10 mbar) afforded the title compound (4.75 g, 65%) as a colourless liquid. ([M+H].sup.+ 115.1)
Step 2: (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-ol
[0738] To a cooled (−78° C.) solution of 2-methyldihydro-2H-pyran-3 (4H)-one (1.00 g, 8.76 mmol) in dry THF (25 ml) was added L-selectride® 1 M in THF (20 ml, 20 mmol) dropwise over 30 minutes and the mixture stirred for a further 3 h which time the reaction was allowed to come to −10° C. before ethanol (2.4 ml, 41.1 mmol) was added dropwise followed by dropwise addition of water (6 ml, 333 mmol) and finally NaOH 1 M in Water (6 ml, 6 mmol). The temperature was then raised to 0° C. for addition of 36% H.sub.2O.sub.2 (6 ml, 70.5 mmol) dropwise keeping the temperature below 10° C. after which time the mixture was stirred for a further 1 h at rt. The reaction was filtered over Celite®, washing with ethylacetate. The filtrate was washed with sat. NaHCO.sub.3 and 10% sodium thiosulfate-solution. All aqueous layers were re-extracted with DCM:MeOH (9:1) and the organic phases combined, dried (Na.sub.2SO.sub.4) and concentrated. The residue was by flash column chromatography to afford the title compound (0.74 g, 72%) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.23 (m, 3H) 1.35-1.45 (m, 1H) 1.61-1.73 (m, 1H) 1.81-2.01 (m, 3H) 3.43-3.59 (m, 3H) 3.91-4.00 (m, 1H)
Step 3: (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate
[0739] To a solution of (2RS, 2RS)-2-methyltetrahydro-2H-pyran-3-ol (730 mg, 6.28 mmol) in dry DCM (25 ml) was added DABCO (1.41 g, 12.6 mmol). The solution was cooled in an ice bath and toluenesulfonyl chloride (1.8 g, 9.43 mmol) was added and the ice bath removed and the mixture stirred for 20 minutes at rt. The reaction was concentrated and the residue purified by flash column chromatography to afford the title compound (1.37 g, 80%) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.45 Hz, 3H) 1.31-1.41 (m, 1H) 1.62-1.74 (m, 1H) 1.83-1.99 (m, 1H) 2.05-2.16 (m, 1H) 2.45 (s, 3H) 3.40-3.54 (m, 2H) 3.91-3.99 (m, 1H) 4.50 (brs, 1H) 7.30-7.36 (m, 2H) 7.79-7.84 (m, 2H)
Step 4: (2RS,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate
[0740] To a solution of (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate (1.37 g, 5.07 mmol) in dry DMF (8 ml) was added sodium azide (1.65 g, 25.3 mmol) and the suspension heated to 65° C. for 94 h. The reaction was diluted with water and extracted with diethyl ether, the combined organic extracts washed with water and dried (Na.sub.2SO.sub.4), filtered and 30 mL of methanol added to the filtrate, which was then cautiously concentrated (p>250 mbar, water bath 25° C.) to remove the diethyl ether. Acetic acid (1.45 mL, 25.3 mmol) was then added to the methanolic solution followed by 10% palladium on charcoal (132 mg, 124 μmol) and the reaction placed under an atmosphere of hydrogen (balloon) and the mixture stirred for 3 h. The reaction was then filtered over Celite® and concentrated. The residue was suspended in diethyl ether, sonicated and filtered to afford the title compound (176 mg, 16%) as off-white solid. ([M+H].sup.+ 116.1)
Step 5: 6-cyclopropyl-2-(((2RS,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile
[0741] The title compound ([M+H].sup.+ 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (2SR,3RS)-2-methyltetrahydro-2H-pyran-3-amine acetate using DIPEA as base in NMP at 150° C. (General procedure B2).
Step 6: 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one and 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0742] The title compounds ([M+H].sup.+ 301.2 & 301.2) were prepared from 6-cyclopropyl-2-(((2RS,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 120: 4-amino-1-(benzo[d]thiazol-7-yl-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0743] ##STR00225##
Step 1: 2-(benzo[d]thiazol-7-ylamino)-6-cyclopropylnicotinonitrile
[0744] The title compound ([M+H].sup.+ 293.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-amine hydrochloride (CAS [272438-86-5]) using Pd.sub.2(dba).sub.3 as a catalyst and tBuXphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(benzo[d]thiazol-7-yl) 7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0745] The title compound ([M+H].sup.+ 336.1) was prepared from 2-(benzo[d]thiazol-7-ylamino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 121: 4-amino-7-cyclopropyl-1-[(2SR,3SR)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one
[0746] ##STR00226##
Step 1: (2SR,3SR)—N-benzyl-2-methyltetrahydro-2H-pyran-3-amine
[0747] To a solution of 2-methyldihydro-2H-pyran-3 (4H)-one (Example 118, step 1) (500 mg, 4.38 mmol) and sodium triacetoxyborohydride (1.39 g, 6.57 mmol) in dry DCM (14 ml) was added phenylmethanamine (526 μl, 4.82 mmol) and acetic acid (301 μl, 5.26 mmol) at 0° C., the reaction was brought to rt and stirred for 1 h after which time it was diluted with DCM washed with TN NaOH solution, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by flash column chromatography to afford the title compound (736 mg, 65%) as a colourless oil. ([M+H].sup.+ 116.1)
Step 1: (2SR,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate
[0748] To a solution of (2SR,3SR)—N-benzyl-2-methyltetrahydro-2H-pyran-3-amine (730 mg, 3.56 mmol) in THF dry (14 ml) and acetic acid (407 μl, 7.11 mmol) was added 10% palladium on activate charcoal (378 mg, 356 μmol) and the reaction set under an atmosphere of hydrogen (balloon) and stirred for 24 h. The reaction was filtered over Celite® washing with MeOH and concentrated to afford the title compound (628 mg, 75%) as an off-white solid. ([M+H].sup.+ 116.1)
Step 1: 6-cyclopropyl-2-(((2SR,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile
[0749] The title compound ([M+H].sup.+ 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (2SR,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate using Pd.sub.2(dba).sub.3 as a catalyst and tBuXphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0750] The title compound ([M+H].sup.+ 301.2) was prepared from 6-cyclopropyl-2-(((2SR,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile using General procedure C.
Example 122: 4˜amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2 (1H)-one
[0751] ##STR00227##
Step 1: 4-(difluoromethoxy)-2-((3-fluoro-2-methylphenyl)amino)benzonitrile
[0752] The title compound ([M+H].sup.+ 293.1) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS [1214334-83-4]) by reaction with 3-fluoro-2-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2 (1H)-one
[0753] The title compound ([M+H].sup.+ 336.2) was prepared from 4-(difluoromethoxy)-2-((3-fluoro-2-methylphenyl)amino)benzonitrile using General procedure C.
Example 123: 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0754] ##STR00228##
Step 1: 2-((3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile
[0755] The title compound ([M+H].sup.+ 380.6) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-((tert-butyldimethylsilyl)oxy)-2-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0756] The title compound ([M+H].sup.+ 423.8) was prepared from 2-((3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Step 3: 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0757] To a suspension of 4-amino-1-(3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one (47 mg, 111 μmol) in HCl 4 M in dioxane (1 ml) was added MeOH (0.5 ml) was added and the reaction was stirred at rt for 4 h. 1 ml water was then added and mixture was stirred for 30 min after which time the title product (22 mg, 64%) was isolated by filtration as a white solid. ([M+H].sup.+ 309.2)
Example 124 & 125: (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one and (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0758] ##STR00229##
Step 3: (E/Z)-oxepan-3-one oxime
[0759] To a solution of 6,7-dihydrooxepin-3 (2H)-one (1.35 g, 12 mmol, CAS: 497063-30-6) in MeOH (50 ml) was added 10% palladium on activated charcoal (100 mg, 94 μmol) and the reaction ste under an atmosphere of hydrogen (balloon) and the mixture stirred for 30 minutes. The reaction was then filtered over Celite®, washing with methanol and the filtrate partially concentrated (p>100 mbar@20° C.). Hydroxylamine hydrochloride (1.67 g, 24.1 mmol) and potassium acetate (4.73 g, 48.2 mmol) were then added and the reaction heated to 70° C. for 1 hour after which time the reaction was concentrated to dryness and then partioned between water and ethyl actetate. The layers were separated and the aqueous fraction re-extracted with ethylacetate. The combined organic layers were washed with brine and concentrated. The residue was by flash column chromatography to afford the title compounds (1.21 g, 74%) as a colourless oil. ([M+H].sup.+ 130.0)
Step 4: oxepan-3-amine hydrochloride
[0760] To a solution of oxepan-3-one oxime (1.21 g, 9.37 mmol) in 7M ammonia in methanol (150 ml) was added Raney®-Nickel (6.2 g, 9.37 mmol) and the mixture stirred under an atmosphere of hydrogen (balloon) for 90 minutes. The reaction was then filtered over Celite® and concentrated. Purification by flash column chromatography followed by precipitation from diethyl ether (made acidic by addition of 4N HCl in dioxane) afforded the title compound (1.05 g, 76%) as a white solid. ([M+H].sup.+ 116.1)
Step 5: 6-cyclopropyl-2-(oxepan-3-ylamino)nicotinonitrile
[0761] The title compound ([M+H].sup.+ 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with oxepan-3-amine hydrochloride using DIPEA as base in NMP at 150° C. (General procedure B2).
Step 6: (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one and (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0762] The title compounds ([M+H].sup.+ 301.2 & 301.2) were prepared from 6-cyclopropyl-2-(oxepan-3-ylamino)nicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 126: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (21H)-yl)-2-fluorobenzonitrile
[0763] ##STR00230##
Step 1: 2-((3-cyano-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile
[0764] The title compound ([M+H].sup.+ 279.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-amino-2-fluorobenzonitrile using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-fluorobenzonitrile
[0765] The title compound ([M+H].sup.+ 322.1) was prepared from 2-((3-cyano-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 127: 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0766] ##STR00231##
Step 1: 6-cyclopropyl-2-((2-fluoro-3-methylphenyl)amino)nicotinonitrile
[0767] The title compound ([M+H].sup.+ 268.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-fluoro-3-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0768] The title compound ([M+H].sup.+ 311.1) was prepared from 6-cyclopropyl-2-((2-fluoro-3-methylphenyl)amino)nicotinonitrile using General procedure C.
Example 128: 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0769] ##STR00232##
Step 1: 6-cyclopropyl-2-((2,3-dichlorophenyl)amino)nicotinonitrile
[0770] The title compound ([M+H].sup.+ 304.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,3-dichloroaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0771] The title compound ([M+H].sup.+ 347.1) was prepared from 6-cyclopropyl-2-((2,3-dichlorophenyl)amino)nicotinonitrile using General procedure C.
Example 129: 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0772] ##STR00233##
Step 1: 2-((3-chloro-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile
[0773] The title compound ([M+H].sup.+ 284.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-chloro-2-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0774] The title compound ([M+H].sup.+ 327.1) was prepared from 2-((3-chloro-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 130: 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0775] ##STR00234##
Step 1: 2-((2-chloro-3-methylphenyl)amino)-6-cyclopropylnicotinonitrile
[0776] The title compound ([M+H].sup.+ 284.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-3-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0777] The title compound ([M+H].sup.+ 327.1) was prepared from 2-((2-chloro-3-methylphenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 131: 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)˜2-methylphenyl)pyrido[2,3˜d]pyrimidin-2 (1H)-one
[0778] ##STR00235##
Step 1: 6-cyclopropyl-2-((3-(fluoromethyl)-2-methylphenyl)amino)nicotinonitrile
[0779] The title compound ([M+H].sup.+ 282.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-(fluoromethyl)-2-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0780] The title compound ([M+H].sup.+ 325.1) was prepared from 6-cyclopropyl-2-((3-(fluoromethyl)-2-methylphenyl)amino)nicotinonitrile using General procedure C.
Example 132: 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0781] ##STR00236##
Step 1: 6-cyclopropyl-2-((2-(trifluoromethyl)phenyl)amino)nicotinonitrile
[0782] The title compound ([M+H].sup.+ 304.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-(trifluormethyl)aniline (CAS [88-17-5]) using Pd.sub.2(dba).sub.3 as a catalyst and Xphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0783] The title compound ([M+H].sup.+ 347.1) was prepared from 6-cyclopropyl-2-((2-(trifluoromethyl)phenyl)amino)nicotinonitrile using General procedure C.
Example 133: 4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2 (1H)-one
[0784] ##STR00237##
Step 1: bromo-4-(difluoromethoxy)benzonitrile
[0785] To a solution of 2-bromo-4-hydroxy-benzonitrile (30.2 g, 122 mmol) and cesium carbonate (119.3 g, 366 mmol) in DMF (302 mL) was added sodium 2-chloro-2,2-difluoroacetate (55.8 g, 366 mmol) and the reaction mixture was heated to 80° C. for 2 h after which time the reaction was filtered, diluted with ethyl acetate and washed with water, brine and concentrated. Purification by flash column chromatography afforded the title compound (6.0 g, 18%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.72-7.65 (m, 1H), 7.51-7.45 (m, 1H), 7.24-7.14 (m, 1H), 6.81-6.39 (m, 1H).
Step 2: 4-(difluoromethoxy)-2-((2-fluoro-3-methylphenyl)amino)benzonitrile
[0786] The title compound ([M+H].sup.+ 293.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile by reaction with 2-fluoro-3-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 3: 4-amino-7-(difluoromethoxy)-2-(2-fluoro-3-methylphenyl)quinazolin-2 (1H)-one
[0787] The title compound ([M+H].sup.+ 336.1) was prepared from 4-(difluoromethoxy)-2-((2-fluoro-3-methylphenyl)amino)benzonitrile using General procedure C.
Example 134: 4-amino-7-(difluoromethoxy)-1-(m-tocly)quinazolin-2 (1H)-one
[0788] ##STR00238##
Step 1: 4-(difluoromethoxy)-2-(m-tolylamino)benzonitrile
[0789] The title compound ([M+H].sup.+ 275.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (Example 133, step 1) by reaction with m-toluidine using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2 (1H)-one
[0790] The title compound ([M+H].sup.+ 318.1) was prepared from 4-(difluoromethoxy)-2-(m-tolylamino)benzonitrile using General procedure C.
Example 135 & 136: (+)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0791] ##STR00239##
Step 1: 2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile
[0792] The title compound ([M+H].sup.+ 271.1) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with 2-chloro-3-iodopyridine using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: (+)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one and (−)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0793] The title compounds ([M+H].sup.+ 314.2 & 314.2) were prepared from 6-2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 137: 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2 (1H)-one
[0794] ##STR00240##
Step 1: 2-((2-chloropyridin-3-yl)amino)-4-(difluoromethoxy)benzonitrile
[0795] The title compound ([M+H].sup.+ 296.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with 2-chloropyridin-3-amine using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloropyridin-3-yl)-7-difluoromethoxy)quinazolin-2 (1H)-one
[0796] The title compound ([M+H].sup.+ 339.1) was prepared from 2-((2-chloropyridin-3-yl)amino)-4-(difluoromethoxy)benzonitrile using General procedure C.
Example 138: 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0797] ##STR00241##
Step 1: 6-cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile
[0798] The title compound ([M+H].sup.+ 264.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,3-dimethylaniline using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0799] The title compound ([M+H].sup.+ 307.2) was prepared from 6-cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile using General procedure C.
Example 139: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0800] ##STR00242##
Step 1: tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate
[0801] The title compound ([M+H].sup.+ 264.3) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with tert-butyl 4-bromo-1H-indazole-1-carboxylate using Pd.sub.2(dba).sub.3 as a catalyst and Xphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0802] The title compound ([M+H].sup.+ 319.1) was prepared from tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate using General procedure C.
Example 140: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0803] ##STR00243##
Step 1: tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-benzo[d]imidazole-1-carboxylate
[0804] The title compound ([M+H].sup.+ 376.2) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with tert-butyl 4-bromo-1H-benzo[d]imidazole-1-carboxylate (WO2018/132372 A1) using Pd.sub.2(dba).sub.3 as a catalyst and Xphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0805] The title compound ([M+H].sup.+ 317.2) was prepared from tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate using General procedure C.
Example 141: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one
[0806] ##STR00244##
Step 1: methyl 1-(allyloxy)cyclopropane-1-carboxylate
[0807] To an ice cold solution of methyl 1-hydroxycyclopropane-1-carboxylate (10 g, 86.1 mmol) in dry THF (220 ml) was added sodium hydride, 60% dispersion in mineral oil (4.13 g, 103 mmol) and the mixture stirred for 15 minutes before the addition of allyl bromide (9.69 ml, 112 mmol) dissolved in dry THF (50 ml) over 30 min. The mixture was allowed to come to rt and stirred for 16 h after which time the reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted with TBME and the combined organics were dried (Na.sub.2SO.sub.4) and concentrated. Distillation (Bp 79-82° C.@12 mmbar) afforded the title compound (6.25 g, 44.1% yield) as a light yellow oil. ([M+H].sup.+ 157.1)
Step 2: 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide
[0808] To a ice-cold suspension of N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.8 mmol) in dry DCM (12 ml) was added trimethylaluminum 2 M in toluene (6.4 ml, 12.8 mmol) and the mixture stirred for 1 h before a solution of methyl 1-(allyloxy)cyclopropane-1-carboxylate (1 g, 6.4 mmol) in dry DCM (6 ml) was added over 10 min. The ice bath was removed and the reaction stirred for 16 h at rt. The reaction was then cooled to 0° C., quenched by cautious addition of water, followed by 4N aq. HCl and extracted with DCM. The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The reside was by flash column chromatography to afford the title compound (768 mg, 65%) as a colourless oil. ([M+H].sup.+ 186.1)
Step 3: 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one
[0809] To a −78° C. solution of 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide (463 mg, 2.5 mmol) in dry THF (8 ml) was added vinylmagnesium bromide 1 M in THF (2.75 ml, 2.75 mmol) over 10 minutes and the mixture stirred for 1 h. A second portion of vinylmagnesium bromide 1 M in THF (2.75 ml, 2.75 mmol) was added and the reaction warmed to 0° C. over 30 minutes. The reaction was recooled to −78° C. before addition of 4N aq HCl (10 ml) and the temperature raised to rt. The mixture was diluted with water, extracted with TBME, the combined organics were dried (Na.sub.2SO.sub.4) and concentrated to afford the title compound (357 mg, 89%) as a yellow oil.
[0810] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.28 (m, 2H) 1.34-1.41 (m, 2H) 4.04 (dt, J=5.44, 1.51 Hz, 2H) 5.15-5.36 (m, 2H) 5.74 (dd, J=10.38, 1.91 Hz, 1H) 5.92 (ddt, J=17.33, 10.58, 5.39, 5.39 Hz, 1H) 6.40 (dd, J=17.33, 2.01 Hz, 1H) 7.02 (dd, J=17.23, 10.38 Hz, 1H)
Step 4: 4-oxaspiro[2.5]oct-6-en-8-one
[0811] To a solution of 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one (2.7 g, 17.7 mmol) in DCM (324 ml) was added Zhan Catalyst-1B (130 mg, 177 μmol) and the mixture stirred at rt for 3 h. The reaction was concentrated and the residue purified by flash column chromatography to afford the title compound (1.9 g, 83%) as a colourless oil. ([M+H].sup.+ 125.0)
Step 5: 4-oxaspiro[2.5]octan-8-one
[0812] To a solution of 4-oxaspiro[2.5]oct-6-en-8-one (302 mg, 2.43 mmol) in THF (7 ml) was added 10% palladium on activated charcoal (12 mg, 11.3 μmol) and the mixture set under an atmosphere of hydrogen (balloon), stirred for 40 minutes. It was then filtered over Celite® and concentrated to afford the title compound (296 mg, 96%) as a colourless oil. ([M+H].sup.+ 127.1)
Step 6: (S,Z)-2-methyl-N-(4-oxaspiro[2.5]octan-8-ylidene)propane-2-sulfinamide
[0813] To a solution of TiOEt.sub.4 (496 μl, 2.35 mmol) in THF (2 ml) was added 4-oxaspiro[2.5]octan-8-one (148 mg, 1.17 mmol) in THF (2 ml) followed by addition of (S)-(−)-2-methyl-2-propanesulfinamide (174 mg, 1.41 mmol) and the mixture heated for 68 h at 45° C. The reaction was diluted with ethyl acetate, brine was added resulting in a thick suspension which was then filtered over Celite®. The mixture was extracted with ethyl acetate the combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The reside was by flash column chromatography to afford the title compound (120 mg, 44%) as a yellow oil. ([M+H].sup.+ 230.2)
Step 7: (S)-2-methyl-N—((R)-4-oxaspiro[2.5]octan-8-yl)propane-2-sulfinamide
[0814] To a solution of (S,Z)-2-methyl-N-(4-oxaspiro[2.5]octan-8-ylidene)propane-2-sulfinamide (120 mg, 523 μmol) in THF (2.0 ml) was added water (41 μl) and cooled to −50° C. before sodium borohydride (59.4 mg, 1.57 mmol) was added. It was allowed to come to 15° C. over 3 h. The reaction was quenched by addition of methanol (0.5 ml), water (2 ml) and 10% sodium carbonate solution (2 ml) and stirred for 30 min. The reaction was extracted with ethyl acetate, the combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The reside was by flash column chromatography to afford the title compound (65 mg, 54%) as a white solid. ([M+H].sup.+ 232.1)
Step 8: (R)-4-oxaspiro[2.5]octan-8-amine hydrochloride
[0815] To a solution of (S)-2-methyl-N—((R)-4-oxaspiro[2.5]octan-8-yl)propane-2-sulfinamide (60 mg, 0.3 mmol) in dioxane (2 ml) was added 4M HCl in Dioxane (195 μl, 778 μmol) and the mixture stirred for 16 h at rt. The reaction was evaporated to dryness, suspended in diethyl ether and filtered to afford the titled compound (38 mg, 89%) as a white solid. ([M+H].sup.+ 111.1)
Step 9: 6-cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile
[0816] The title compound ([M+H].sup.+ 270.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (R)-4-oxaspiro[2.5]octan-8-amine hydrochloride using Pd.sub.2(dba).sub.3 as a catalyst and tBuXphos as a ligand (General procedure B1).
Step 10: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one
[0817] The title compound ([M+H].sup.+ 313.1) was prepared from (R)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 142: 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one
[0818] ##STR00245##
Step 1: (S)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile
[0819] The title compound ([M+H].sup.+ 270.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (S)-4-oxaspiro[2.5]octan-8-amine hydrochloride (prepared in analogy to example 141 but using (R)-(−)-2-methyl-2-propanesulfinamide in step 6) using Pd.sub.2(dba).sub.3 as a catalyst and tBuXphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one
[0820] The title compound ([M+H].sup.+ 313.1) was prepared from (S)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 143: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-chlorobenzonitrile
[0821] ##STR00246##
Step 1: 3-amino-2-chlorobenzonitrile
[0822] To 2-chloro-3-nitrobenzonitrile (0.5 g, 2.74 mmol), iron powder (3.09 g, 54.8 mmol) and ammonium chloride (3.66 g, 68.5 mmol) were added EtOH (29 ml) and water (12 ml). The reaction was stirred at 70° C. for 3 h. The reaction was filtered over Decalite® washing with DCM, MeOH and EtOAc and the filtrate evaporated to dryness. Suspension in DCM and concentration of the filtrate afforded the titled compound (426 mg, 102%) as an off-white solid. ([M+H].sup.+ 153.0)
Step 2: 2-((2-chloro-3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile
[0823] The title compound ([M+H].sup.+ 295.1) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with 3-amino-2-chlorobenzonitrile using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 3: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-chlorobenzonitrile
[0824] The title compound ([M+H].sup.+ 338.2) was prepared from 2-((2-chloro-3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 144: 4-amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2 (1H)-one
[0825] ##STR00247##
Step 1: 4-(difluoromethoxy)-2-(o-tolylamino)benzonitrile
[0826] The title compound ([M+H].sup.+ 275.2) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with o-toluidine using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2 (1H)-one
[0827] The title compound ([M+H].sup.+ 318.2) was prepared from 4-(difluoromethoxy)-2-(o-tolylamino)benzonitrile using General procedure C.
Example 145 & 146: (+)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile and (−)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile
[0828] ##STR00248##
Step 1: 2-((3-cyano-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile
[0829] The title compound ([M+H].sup.+ 275.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-amino-2-methylbenzonitrile (CAS [69022-35-1] using Pd(OAc).sub.2 as a catalyst and Xphos as a ligand (General procedure B1).
Step 2: (+)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile and (−)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile
[0830] The title compounds ([M+H].sup.+ 318.2 & 318.2) were prepared from 2-((3-cyano-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C followed by separation using chiral HPLC.
Example 147: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0831] ##STR00249##
Step 1: 6-cyclopropyl-2-((3,4-difluorophenyl)amino)nicotinonitrile
[0832] The title compound ([M+H].sup.+ 272.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3,4-difluoroaniline using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0833] The title compound ([M+H].sup.+ 315.1) was prepared from 6-cyclopropyl-2-((3,4-difluorophenyl)amino)nicotinonitrile using General procedure C.
Example 148: 4-amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0834] ##STR00250##
Step 1: 2-(benzo[d]oxazol-4-ylamino)-6-cyclopropylnicotinonitrile
[0835] The title compound ([M+H].sup.+ 277.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with benzo[d]oxazol-4-amine using Pd.sub.2(dba).sub.3 as a catalyst and tBuXphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0836] The title compound ([M+H].sup.+ 320.1) was prepared from 2-(benzo[d]oxazol-4-ylamino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 149: 1-amino-4-(2-chlorophenyl)-6-(trifluoroethyl)pyrido[1,2-c]pyrimidin-3-one
[0837] ##STR00251##
Step 1: 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile
[0838] To a solution of 2-chloro-4-(trifluoromethyl)pyridine (3.35 g, 18.4 mmol) and 2-chlorobenzyl cyanide (2.00 g, 13.1 mmol) in DMF (50 mL) was added NaH (1.47 g, 36.9 mmol) and the reaction mixture was stirred for 20 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, the combined extracts were washed with brine and concentrated. Purification by preparative TLC afforded the title compound (3.00 g, 69% yield) as a yellow oil. ([M+H].sup.+ 297.1)
Step 2: 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide
[0839] To a solution of 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (2.0 g, 6.74 mmol) in AcOH (15 mL) was added 95% H.sub.2SO.sub.4 (5 mL) and mixture was stirred for 2 days at 40° C. The reaction mixture was cooled to rt and poured onto ice followed by extraction with EtOAc. The organic layers were washed with sat. NaHCO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and concentrated. Trituration from hexane afforded the title compound (1500 mg, 69%) as yellow solid. ([M+H].sup.+ 315.1)
Step 3: 4-(2-chlorophenyl)-1-thioxo-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one
[0840] To a mixture of 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (500 mg, 1.59 mmol) in EtOH (2.5 mL) was added sodium ethoxide (4.6 mL, 21% in EtOH, 12.7 mmol) followed by dropwise addition of thiophosgene (245 μL, 3.18 mmol) keeping the temperature below 40° C. The mixture was stirred in a sealed tube at 85° C. for 2 h before it was cooled to rt and quenched with ˜3 mL water. The mixture was extracted with ethyl acetate, the combined washings washed with brine and concentrated. Purification by flash column chromatography to gave the title compound (400 mg, 64%) as yellow solid. ([M+H].sup.+ 357.0)
Step 4: 4-(2-chlorophenyl)-1-methylsulfanyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one
[0841] To a solution of 4-(2-chlorophenyl)-1-thioxo-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (250 mg, 0.70 mmol) in DMF (5 mL) was added potassium carbonate (193 mg, 1.40 mmol) iodomethane (51 μL, 0.84 mmol). The reaction was stirred at rt for 7 h. The reaction mixture was evaporated and the residue was diluted with EtOAc/water. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by flash column chromatography gave the titled compound (150 mg, 55%) as yellow solid. ([M+H].sup.+ 371.0)
Step 5: 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one
[0842] To a mixture of 4-(2-chlorophenyl)-1-methylsulfanyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (100 mg, 0.270 mmol) and ammonium hydroxide solution (1.5 mL, 0.270 mmol) was added THF (1 mL). The reaction was stirred at rt for 48 h after which time it was concentrated. Purification by reversed phase preparative HPLC afforded the titled product (65 mg, 68%) as yellow solid ([M+H].sup.+ 340.0)
Example 150: 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2 (1H)-one
[0843] ##STR00252##
Step 1: 2-((4-oxaspiro[2.5]octan-8-yl)amino)-4-(difluoromethoxy)benzonitrile
[0844] The title compound ([M+H].sup.+ 295.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with 4-oxaspiro[2.5]octan-8-amine hydrochloride using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2 (1H)-one
[0845] The title compound ([M+H].sup.+ 338.2) was prepared from 2-((4-oxaspiro[2.5]octan-8-yl)amino)-4-(difluoromethoxy)benzonitrile using General procedure C.
Example 151: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)benzonitrile
[0846] ##STR00253##
Step 1: 2-((3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile
[0847] The title compound ([M+H].sup.+ 261.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-aminobenzonitrile using Pd.sub.2(dba).sub.3 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)benzonitrile
[0848] The title compound ([M+H].sup.+ 304.1) was prepared from 2-((3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 152: 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0849] ##STR00254##
Step 1: 2-((3-chlorophenyl)amino)-6-cyclopropylnicotinonitrile
[0850] The title compound ([M+H].sup.+ 270.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-chloroaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0851] The title compound ([M+H].sup.+ 313.1) was prepared from 2-((3-chlorophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 153: 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one
[0852] ##STR00255##
Step 1: 2-bromo-4-(ethylamino)benzonitrile
[0853] To a solution of 2-bromo-4-fluorobenzonitrile (700 mg, 3.5 mmol) in DMF (7 mL) were added ethylamine hydrochloride (571 mg, 7 mmol) and K.sub.2CO.sub.3 (967 mg, 7 mmol) and the reaction mixture heated to 90° C. for 6 h. The reaction was diluted with ethyl acetate and washed with water, brine and concentrated. Purification by flash column chromatography afforded the titled compound (850 mg, 75%) as yellow solid. ([M+H].sup.+ 225.1)
Step 2: tert-butyl N-(3-bromo-4-cyano-phenyl)-N-ethyl-carbamate
[0854] To a solution 2-bromo-4-(ethylamino)benzonitrile (750 mg, 2.70 mmol) of di-t-butyldicarbonate (1163 mg, 5.33 mmol) in DCM (15 mL) was added triethylamine (1.11 mL, 8 mmol) and DMAP (65.13 mg, 0.530 mmol). The reaction mixture was stirred at rt for 12 h after which time it was concentrated and the residue purified by flash column chromatography to yield the titled compound (700 mg, 810%) as a yellow oil. ([M+H-tBu].sup.+269.1)
Step 3: tert-butyl N-[4-cyano-3-(2-methylanilino)phenyl]-N-ethyl-carbamate
[0855] The title compound ([M+H-tBu].sup.+296.1) was prepared from tert-butyl N-(3-bromo-4-cyano-phenyl)-N-ethyl-carbamate by reaction with o-toluidine using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 4: tert-butyl N-[4-amino-1-(o-tolyl)-2-oxo-quinazolin-7-yl]-N-ethyl-carbamate
[0856] The title compound ([M+H].sup.+ 395.3) was prepared from tert-butyl N-[4-cyano-3-(2-methylanilino)phenyl]-N-ethyl-carbamate using General procedure C.
Step 5: 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one
[0857] To a solution of tert-butyl N-[4-amino-1-(o-tolyl)-2-oxo-quinazolin-7-yl]-N-ethyl-carbamate (350 mg, 0.89 mmol) in DCM (5 mL) was added TFA (3.0 mL, 0.89 mmol) and the mixture stirred at rt for 2 h. The reaction was quenched by addition of saturated sodium hydrogen carbonate solution, extracted with DCM and the combined organic concentrated. Purification by reversed phase preparative HPLC afforded the title compound (51 mg, 19%) as white solid. ([M+H].sup.+ 295.2)
Example 154: 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0858] ##STR00256##
Step 1: 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile
[0859] The title compound ([M+H].sup.+ 272.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,5-difluoroaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0860] The title compound ([M+H].sup.+ 315.2) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using General procedure C.
Example 155: 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0861] ##STR00257##
Step 1: 2-((2-chloro-4-fluorophenyl)amino)-6-cyclopropylnicotinonitrile
[0862] The title compound ([M+H].sup.+ 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-4-fluoroaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one
[0863] The title compound ([M+H].sup.+ 331.0) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using General procedure C.
Example 156: 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0864] ##STR00258##
Step 1: 2-((2-chloro-5-fluorophenyl)amino)-6-cyclopropylnicotinonitrile
[0865] The title compound ([M+H].sup.+ 288.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-5-fluoroaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0866] The title compound ([M+H].sup.+ 331.0) was prepared from 2-((2-chloro-5-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using General procedure C.
Example 157: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one
[0867] ##STR00259##
Step 1: tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)indoline-1-carboxylate
[0868] The title compound ([M+H].sup.+ 377.2) was prepared from tert-butyl 4-aminoindoline-1-carboxylate (US2010/36123 A1) by reaction with 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one
[0869] tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)indoline-1-carboxylate was first converted to tert-butyl 4-(4-amino-7-cyclopropyl-2-oxo-pyrido[2,3-d]pyrimidin-1-yl)indoline-1-carboxylate using General procedure C and the crude material deprotected using TFA in DCM in analogy to Example 153 to afford the title compound. ([M+H].sup.+ 320.1)
Example 158: 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile
[0870] ##STR00260##
Step 1: 3-((2-cyano-5-(trifluoromethoxy)phenyl)amino)-2-methylbenzonitrile
[0871] The title compound ([M+H].sup.+ 316.1) was prepared from 2-amino-4-(trifluoromethoxy)benzonitrile (CAS [1260847-67-3]) by reaction with 3-chloro-2-methylbenzonitrile (CAS [54454-12-5]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile
[0872] The title compound ([M+H].sup.+ 361.1) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using General procedure C.
Example 159: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one
[0873] ##STR00261##
Step 1: 2-((3-fluoro-2-methylphenyl)amino)-4-(trifluoromethoxy)benzonitrile
[0874] The title compound ([M+H].sup.+ 311.1) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS [1214334-83-4]) by reaction with 3-fluoro-2-methylaniline (CAS [54454-12-5]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one
[0875] The title compound ([M+H].sup.+ 354.1) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using General procedure C.
Example 160: 4-amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one
[0876] ##STR00262##
Step 1: 2-((2,3-dihydrobenzofuran-4-yl)amino)-4-(trifluoromethoxy)benzonitrile
[0877] The title compound ([M+H].sup.+ 321.0) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS [1214334-83-4]) by reaction with 2,3-dihydrobenzofuran-4-amine (CAS [61090-37-7]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one
[0878] The title compound ([M+H].sup.+ 364.2) was prepared from 2-((2,3-dihydrobenzofuran-4-yl)amino)-4-(trifluoromethoxy)benzonitrile using General procedure C.
Example 161: 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0879] ##STR00263##
Step 1: 2-((3-chloro-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile
[0880] The title compound ([M+H].sup.+ 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-5-fluoroaniline (CAS [2106-04-9]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one
[0881] The title compound ([M+H].sup.+ 331.0) was prepared from 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one using General procedure C.
Example 162: 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0882] ##STR00264##
Step 1: 2-((2,3-dihydrobenzofuran-4-yl)amino)-6-(trifluoromethyl)nicotinonitrile
[0883] The title compound ([M+H].sup.+ 306.1) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS [1249836-67-6]) by reaction with 2,3-dihydrobenzofuran-4-amine using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0884] The title compound ([M+H].sup.+ 349.1) was prepared from 2-((2,3-dihydrobenzofuran-4-yl)amino)-6-(trifluoromethyl)nicotinonitrile using General procedure C.
Example 163: 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one
[0885] ##STR00265##
Step 1: 6-cyclopropyl-2-((6-(trifluoromethoxy)pyridin-2-yl)amino)nicotinonitrile
[0886] The title compound ([M+H].sup.+ 321.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 6-(trifluoromethoxy)pyridin-2-amine (CAS [1131007-45-8]) using Pd(OAc)2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one
[0887] The title compound ([M+H].sup.+ 364.1) was prepared from 6-cyclopropyl-2-((6-(trifluoromethoxy)pyridin-2-yl)amino)nicotinonitrile using General procedure C.
Example 164: 4-amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one
[0888] ##STR00266##
Step 1: tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indole-1-carboxylate
[0889] The title compound ([M+H].sup.+ 375.2) was prepared from tert-butyl 4-amino-1H-indole-1-carboxylate (US2009/227575 A1) by reaction with 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one
[0890] tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indole-1-carboxylate was first converted to tert-butyl 4-(4-amino-7-cyclopropyl-2-oxo-pyrido[2,3-d]pyrimidin-1-yl)indoline-1-carboxylate using General procedure C and the crude material deprotected using TFA in DCM in analogy to Example 153 to afford the title compound. ([M+H].sup.+ 318.1)
Example 165: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0891] ##STR00267##
Step 1: 2-((3-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinonitrile
[0892] The title compound ([M+H].sup.+ 296.1) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS [1249836-67-6]) by reaction with 3-fluoro-2-methylaniline using Pd(OAc).sub.2 as a catalyst and xanthphos as a ligand (General procedure B1).
Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one
[0893] The title compound ([M+H].sup.+ 339.1) was prepared from 2-((3-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinonitrile using General procedure C.