CHROMENE DERIVATIVES AND THEIR ANALOGS AS WNT PATHWAY ANTAGONISTS

Abstract

Compounds of formula (IIc); wherein X.sup.3 and X.sup.4 independently from each other are N or CR.sup.8 wherein R.sup.8 may be same or different; Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 independently from each other are N or CR.sup.9 wherein R.sup.9 may be same or different and wherein up to 3 of the group Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

##STR00001##

Claims

1-16. (canceled)

17. Compound of formula (IIc) ##STR00063## wherein X.sup.3 and X.sup.4 independently from each other are N or CR.sup.8 wherein R.sup.8 may be same or different; Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 independently from each other are N or CR.sup.9 wherein R.sup.9 may be same or different and wherein up to 3 of the group Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 may be N; R.sup.1; R.sup.2; R.sup.3; R.sup.4 and R.sup.5 are selected from H, OH; halogen; CN; C.sub.1-C.sub.6 alkyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; C.sub.4-C.sub.15 heteroarylalkyl; C(O)R.sup.1a; C(O)OR.sup.1a; C(O)N(R.sup.1aR.sup.1b); N(R.sup.1a)S(O).sub.2OR.sup.1b; N(R.sup.1aR.sup.1b); N(R.sup.1a)S(O).sub.2N(R.sup.1bR.sup.1c); N(R.sup.1a)C(O)R.sup.1b; N(R.sup.1a)S(O).sub.2R.sup.1b; N(R.sup.1a)S(O)R.sup.1b; N(R.sup.1a)C(O)N(R.sup.1bR.sup.1c); N(R.sup.1a)C(O)OR.sup.1b; SR.sup.1a; S(O).sub.2OR.sup.1a; S(O).sub.2N(R.sup.1aR.sup.1b); S(O)N(R.sup.1aR.sup.1b); S(O).sub.2R.sup.1a; S(O)R.sup.1a; OR.sup.1a; OC(O)R.sup.1a; and OC(O)N(R.sup.1aR.sup.1b); and wherein alkyl; alkenyl, alkinyl, aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted by one or more groups R.sup.10 which are same or different; optionally two adjacent substituents R.sup.1; R.sup.2; R.sup.3; R.sup.4 and R.sup.5 form together a 5- to 7-membered heterocyclic ring optionally substituted by one or more groups R.sup.10 which may be same or different; and wherein at least 3 of the group of R.sup.1; R.sup.2; R.sup.3; R.sup.4; and R.sup.5 are not H; R.sup.1a; R.sup.1b; and R.sup.1c are independently from each other selected from H; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; and C.sub.4-C.sub.15 heteroarylalkyl; wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted with one or more R.sup.10 which are same or different; R.sup.10 is selected from halogen; CN; OH, C.sub.1-C.sub.6 alkyl; OR.sup.10a; C(O)R.sup.10a; C(O)OR.sup.10a; C(O)N(R.sup.10aR.sup.10b); N(R.sup.10aR.sup.10b); OC(O)R.sup.10a; N(R.sup.10a)C(O)R.sup.10b; S(O).sub.2N(R.sup.10aR.sup.10b); S(O)N(R.sup.10aR.sup.10b); S(O).sub.2R.sup.10a; S(O)R.sup.10a; S(O).sub.2OR.sup.10a; N(R.sup.10a)S(O).sub.2N(R.sup.10bR.sup.10c); SR.sup.10a; N(R.sup.10a)S(O).sub.2R.sup.10b; N(R.sup.10a)S(O)R.sup.10b; N(R.sup.10a)C(O)N(R.sup.10bR.sup.10c); and OC(O)N(R.sup.10aR.sup.10b); wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.10a; R.sup.10b and R.sup.10C are independently from each other selected from H; and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.6 is selected from CN; C(O)R.sup.6a; C(O)OR.sup.6a; C(O)N(R.sup.6aR.sup.6b); C(NR.sup.6a)N(R.sup.6bR.sup.6c); CR.sup.6aNOR.sup.6b; SR.sup.6a; S(O)R.sup.6a; S(O).sub.2R.sup.6a; S(O).sub.2OR.sup.6a; S(O).sub.2N(R.sup.6aR.sup.6b); and S(O)N(R.sup.6aR.sup.6b); R.sup.6a; R.sup.6b; and R.sup.6c are independently from each other selected from H; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; and C.sub.4-C.sub.15 heteroarylalkyl which are optionally substituted with one or more R.sup.11, which are the same or different; R.sup.11 is selected from halogen; CN; OH; C.sub.1-C.sub.6 alkyl; OR.sup.11a; C(O)R.sup.11a; C(O)OR.sup.11a; C(O)N(R.sup.11aR.sup.11b); N(R.sup.11aR.sup.11b); OC(O)R.sup.11a; N(R.sup.11a)C(O)R.sup.11b; SR.sup.11a; S(O)R.sup.11a; S(O).sub.2R.sup.11a; S(O).sub.2OR.sup.11a; S(O).sub.2N(R.sup.11aR.sup.11b); S(O)N(R.sup.11aR.sup.11b); N(R.sup.11a)S(O).sub.2N(R.sup.11bR.sup.11c); N(R.sup.11a)S(O).sub.2R.sup.11b; N(R.sup.11a)S(O)R.sup.11b; N(R.sup.11a)C(O)N(R.sup.11bR.sup.11c); and OC(O)N(R.sup.11aR.sup.11b); wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more R.sup.18 which are same or different; R.sup.18 is selected from halogen, CN, OH; OR.sup.11a; C(O)R.sup.11a; C(O)OR.sup.11a; C(O)N(R.sup.11aR.sup.11b); N(R.sup.11aR.sup.11b); OC(O)R.sup.11a; N(R.sup.11a)C(O)R.sup.11b; SR.sup.11a; S(O)R.sup.11a; S(O).sub.2R.sup.11a; S(O).sub.2OR.sup.11a; S(O).sub.2N(R.sup.11aR.sup.11b); S(O)N(R.sup.11aR.sup.11b); N(R.sup.11a)S(O).sub.2N(R.sup.11bR.sup.11c); N(R.sup.11a)S(O).sub.2R.sup.11b; N(R.sup.11a)S(O)R.sup.11b; N(R.sup.11a)C(O)N(R.sup.11bR.sup.11c); and OC(O)N(R.sup.11aR.sup.11b); R.sup.11a; R.sup.11b; and R.sup.11c are independently from each other selected from H; and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are the same or different; R.sup.7 is selected from H; OH; OR.sup.7a; OC(O)R.sup.7a; OC(O)N(R.sup.7aR.sup.7b); N(R.sup.7aR.sup.7b); N(R.sup.7a)C(O)R.sup.7b; N(R.sup.7a)C(O)N(R.sup.7bR.sup.7c); N(R.sup.7a)C(O)OR.sup.7b; N(R.sup.7a)S(O).sub.2OR.sup.7b; N(R.sup.7a)S(O)R.sup.7b; N(R.sup.7a)S(O).sub.2R.sup.7b; N(R.sup.7a)S(O).sub.2N(R.sup.7bR.sup.7c); R.sup.7a; R.sup.7b; and R.sup.7c are independently from each other selected from H; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; and C.sub.4-C.sub.15 heteroarylalkyl wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; heteroarylalkyl are optionally substituted with one or more R.sup.12, which are same or different; R.sup.12 is selected from halogen; CN; OH; C.sub.1-C.sub.6 alkyl; OR.sup.12a; C(O)R.sup.12a; C(O)OR.sup.12a; C(O)N(R.sup.12aR.sup.12b); N(R.sup.12aR.sup.12b); OC(O)R.sup.12a; N(R.sup.12a)C(O)R.sup.12b; S(O).sub.2N(R.sup.12aR.sup.12b); S(O)N(R.sup.12aR.sup.12b); S(O).sub.2R.sup.12a; S(O)R.sup.12a; S(O).sub.2OR.sup.12a; N(R.sup.12a)S(O).sub.2N(R.sup.12bR.sup.12c); SR.sup.12a; N(R.sup.12a)S(O).sub.2R.sup.12b; N(R.sup.12a)S(O)R.sup.12b; N(R.sup.12a)C(O)N(R.sup.12bR.sup.12c); N(R.sup.12a)C(O)OR.sup.12b; OC(O)N(R.sup.12aR.sup.12b); and S(O).sub.2N(R.sup.11a)C(O)N(R.sup.11bR.sup.11c); wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.12a; R.sup.12b and R.sup.12c are independently from each other selected from H; and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.8 is selected from H; OH; CN, halogen, C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; C.sub.4-C.sub.15 heteroarylalkyl; C(O)R.sup.8a; C(O)OR.sup.8a; C(O)N(R.sup.8aR.sup.8b); C(NR.sup.8a)N(R.sup.8bR.sup.8c); C(R.sup.8a)N(R.sup.8b); OR.sup.8a; OC(O)R.sup.8a; OC(O)N(R.sup.8aR.sup.8b); SR.sup.8a; S(O)R.sup.8a; S(O).sub.2R.sup.8a; S(O).sub.2OR.sup.8a; S(O).sub.2N(R.sup.8aR.sup.8b); S(O)N(R.sup.8aR.sup.8b); S(O).sub.2N(R.sup.8a)C(O)N(R.sup.8bR.sup.8c); N(R.sup.8a)S(O).sub.2N(R.sup.8bR.sup.8c); N(R.sup.8a)S(O).sub.2R.sup.8b; N(R.sup.8a)S(O)R.sup.8b; N(R.sup.8a)S(O).sub.2OR.sup.8b; N(R.sup.8aR.sup.8b); N(R.sup.8a)C(O)R.sup.8b; N(R.sup.8a)C(O)N(R.sup.8bR.sup.8c); and N(R.sup.8a)C(S)N(R.sup.8bR.sup.8c); wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted by one or more R.sup.16, which are same or different; R.sup.8a and R.sup.8b; and R.sup.8c are independently from each other selected from H; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; and C.sub.4-C.sub.15 heteroarylalkyl which are optionally substituted with one or more R.sup.16, which are same or different; R.sup.16 is selected from halogen; CN; OH; C.sub.1-C.sub.6 alkyl; OR.sup.16a; C(O)R.sup.16a; C(O)OR.sup.16a; C(O)N(R.sup.16aR.sup.16b); N(R.sup.16aR.sup.16b); OC(O)R.sup.16a; N(R.sup.16a)C(O)R.sup.16b; S(O).sub.2N(R.sup.16aR.sup.16b); S(O)N(R.sup.16aR.sup.16b); S(O).sub.2R.sup.16a; S(O)R.sup.16a; S(O).sub.2OR.sup.16a; N(R.sup.16a)S(O).sub.2N(R.sup.16bR.sup.16c); SR.sup.16a; N(R.sup.16a)S(O).sub.2R.sup.16b; N(R.sup.16a)S(O)R.sup.16b; N(R.sup.16a)C(O)N(R.sup.16bR.sup.16c); and OC(O)N(R.sup.16aR.sup.16b); wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.16a and R.sup.16b and R.sup.16c are independently from each other selected from H; and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen which are the same or different; R.sup.9 is selected from H; OH; halogen; CN; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl; C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; C.sub.4-C.sub.15 heteroarylalkyl; OR.sup.9a; C(O)R.sup.9a; C(O)OR.sup.9a; C(O)N(R.sup.9aR.sup.9b); S(O).sub.2N(R.sup.9aR.sup.9b); S(O)N(R.sup.9aR.sup.9b); S(O).sub.2R.sup.9a; S(O)R.sup.9a; S(O).sub.2OR.sup.9a; S(O).sub.2N(R.sup.9a)C(O)N(R.sup.9bR.sup.9c); N(R.sup.9a)S(O).sub.2N(R.sup.9bR.sup.9c); SR.sup.9a; OC(O)R.sup.9a; N(R.sup.9a)C(O)R.sup.9b; N(R.sup.9a)S(O).sub.2R.sup.9b; N(R.sup.9a)S(O)R.sup.9b; N(R.sup.9a)C(O)N(R.sup.9bR.sup.9c); N(R.sup.9a)C(S)N(R.sup.9bR.sup.9c); OC(O)N(R.sup.9aR.sup.9b); C(NR.sup.9a)N(R.sup.9bR.sup.9c); N(R.sup.9a)S(O).sub.2OR.sup.9b; N(R.sup.9aR.sup.9b); and C(R.sup.9a)NR.sup.9b; wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are optionally substituted by one or more R.sup.13, which are same or different; R.sup.9a; R.sup.9b; and R.sup.9c are independently from each other selected from H; C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7 heterocyclyl; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkinyl C.sub.3-C.sub.7 aryl; C.sub.3-C.sub.7 heteroaryl; C.sub.4-C.sub.15 aralkyl; and C.sub.4-C.sub.15 heteroarylalkyl which are optionally substituted with one or more R.sup.13, which are same or different; R.sup.13 is selected from halogen; CN; OH; C.sub.1-C.sub.6 alkyl; OR.sup.13a; C(O)R.sup.13a; C(O)OR.sup.13a; C(O)N(R.sup.13aR.sup.13b); N(R.sup.13aR.sup.13b); OC(O)R.sup.13a; N(R.sup.13a)C(O)R.sup.13b; S(O).sub.2N(R.sup.13aR.sup.13b); S(O)N(R.sup.13aR.sup.13b); S(O).sub.2R.sup.13a; S(O).sub.2OR.sup.13a; S(O)R.sup.13a; N(R.sup.13a)S(O).sub.2N(R.sup.13bR.sup.13c); SR.sup.13a; N(R.sup.13a)S(O).sub.2R.sup.13b; N(R.sup.13a)S(O)R.sup.13b; N(R.sup.13a)C(O)N(R.sup.13bR.sup.13c); and OC(O)N(R.sup.13aR.sup.13b); wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; R.sup.13a; R.sup.13b and R.sup.13c are independently from each other selected from H; and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halogen which are same or different; and pharmaceutically acceptable salts thereof.

18. A compound according to claim 17, wherein at least one substituent R.sup.9 is not H, and pharmaceutically acceptable salts thereof.

19. A compound according to claim 17, wherein at least one member of the group X.sup.3, X.sup.4, Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is N; and pharmaceutically acceptable salts thereof.

20. A compound according to claim 17, wherein R.sup.1; R.sup.4; and R.sup.5 are independently from each other selected from H; NH.sub.2; NHCH.sub.3; CH.sub.2OH; CH.sub.2OCH.sub.3; CH.sub.2NH.sub.2; CH.sub.2NHCH.sub.3; OH; OCH.sub.3; Br; F; and C.sub.1; and R.sup.2 and R.sup.3 are independently from each other selected from H; NH.sub.2; NHCH.sub.3; CH.sub.2OH; CH.sub.2OCH.sub.3; CH.sub.2NH.sub.2; CH.sub.2NHCH.sub.3; OH; OCH.sub.3; Br; F; and Cl; or R.sup.2 and R.sup.3 are forming together OCH.sub.2O; and pharmaceutically acceptable salts thereof.

21. A compound according to claim 17, wherein R.sup.8 is selected from H; OH; OR.sup.8a; NH.sub.2; NHR.sup.8a; N(R.sup.8aR.sup.8b); CH.sub.2OH; CH.sub.2OR.sup.16a; CH.sub.2NH.sub.2; CH.sub.2NHR.sup.16a; CH.sub.2N(R.sup.16aR.sup.16b); C(O)NH.sub.2; C(O)NHR.sup.8a; C(O)N(R.sup.8aR.sup.8b); C(O)OH; and C(O)OR.sup.8a; R.sup.8a and R.sup.8b are independently from each other selected from C.sub.1-C.sub.6 alkyl which is optionally substituted with one or more halogen which are the same or different; OH, OR.sup.16a, NH.sub.2; NHR.sup.16a, NR.sup.16aR.sup.16b; R.sup.16a and R.sup.16b are independently from each other selected from C.sub.1-C.sub.6 alkyl; wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen which are the same or different; and R.sup.9 is selected H; OH; OR.sup.9a; NH.sub.2; NHR.sup.9a; N(R.sup.9aR.sup.9b); CH.sub.2OH; CH.sub.2OR.sup.13a; CH.sub.2NH.sub.2; CH.sub.2NHR.sup.13a; CH.sub.2N(R.sup.13aR.sup.13b); C(O)NH.sub.2; C(O)NHR.sup.9a; C(O)N(R.sup.9aR.sup.9b); C(O)OH; and C(O)OR.sup.9a; R.sup.9a and R.sup.9b are independently from each other selected from C.sub.1-C.sub.6 alkyl which is optionally substituted with one or more halogen which are the same or different; OH, OR.sup.13a, NH.sub.2; NHR.sup.13a, NR.sup.13aR.sup.13b; R.sup.13a and R.sup.13b are independently from each other selected from C.sub.1-C.sub.6 alkyl; wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen which are the same or different; and pharmaceutically acceptable salts thereof.

22. Method of using a compound according to claim 17 for modulating the Wnt signalling pathway.

23. Method for the treatment of a disorder or disease associated with an aberrant activation of Wnt signalling in a mammal by using a compound according to claim 17.

24. The method according to claim 23, wherein the Wnt associated disorder or disease is a cell proliferative disorder, rheumatoid arthritis, increased bone density, aging or age-related disorders and/or diseases or Dupuytren disease (superficial fibromatosis).

25. The method according to claim 24, wherein the cell proliferation disorder is cancer or a proliferative skin disorder.

26. The method according to claim 25, wherein the cancer is member of the group multiple myeloma, colon cancer, breast cancer, gastritic cancer, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, uterine cancer, kidney cancer, leukaemia, gliomas, basal cell carcinoma, rhabdomyosarcoma, mesothelioma, osteosarcoma, medulloblastomas and other primary CNS malignant neuroectodermal tumors.

27. A pharmaceutical composition containing a compound of claim 17.

28. Method of using the compound according to claim 17 in a kit.

29. Method for the preparation of a medicament comprising the steps of: a) preparing at least one compound according to claim 17; and b) formulating a medicament containing at least said compound.

30. Method of treating a mammal for the modulation of the Wnt signalling pathway, which method comprises administering to said mammal a therapeutically effective amount of a compound according to claim 17.

Description

EXAMPLES

Example 1

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (1)

[0234] ##STR00009##

[0235] 1-Naphthol (170 mg, 1.2 mmol), 3-bromo-4,5-dimethoxybenzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 l) and then stirred at 80 C. under LC-MS (Liquid chromatography-mass spectrometry) control till the reaction was complete. The reaction mixture was cooled down to room temperature and diluted with water to about 15 ml drop wise addition. The mixture was stirred at room temperature for about 1 h. Thus formed precipitates were collected by filtration, washed well with 60% aqueous ethanol and dried under high vacuum to get 394 mg (0.90 mmol, 90%) of the pure solids of the title compound.

Example 2

2-Amino-4-(4-benzyloxy-3-bromo-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (2)

[0236] ##STR00010##

[0237] 1-Naphthol (2.16 g, 15 mmol), 4-benzyloxy-3-bromo-5-methoxy-benzaldehyde (4 g, 12.5 mmol) and malononitrile (825 mg, 12.5 mmol) were taken in 30 ml ethanol at room temperature, charged with piperidine (200 l) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was then cooled down to room temperature, diluted with 60 ml water and stirred for about 2 h at room temperature. Thus formed precipitates were collected by filtration, washed with 1:1 mixture of ethanol/water and dried under high vacuum yielding pure solids of the title compound (6.0 g, 11.7 mmol, 93.5%).

Example 3

2-Amino-4-(4-allyloxy-3-bromo-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (3)

[0238] ##STR00011##

[0239] 1-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 l) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was then cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed well with 1:1 mixture of ethanol/water and dried under high vacuum yielding 370 mg (0.8 mmol, 80%) of the title compound.

Example 4

4-(4-Allyloxy-3-bromo-5-methoxy-phenyl)-2-amino-4H-benzo[h]chromene-3-carboxylic acid ethyl ester (4)

[0240] ##STR00012##

[0241] 1-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (270 mg, 0.58 mmol, 58%).

Example 5

2-Amino-4-(3-bromo-4-hydroxy-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (5)

[0242] ##STR00013##

[0243] 2-Amino-4-(4-benzyloxy-3-bromo-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (2) (2 g, 3.89 mmol) was taken in 20 ml acetic acid and charged with 10M hydrochloric acid (10 ml) under vigorous stirring at room temperature, and stirred further at room temperature until the reaction was complete. The reaction mixture was then diluted with 50 ml water, stirred for 3 h at room temperature, thus formed solids were separated by filtration, washed with water and then dried under high vacuum (1.61 g, 3.8 mmol, 97.8%).

Example 6

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carboxylic acid ethyl ester(6)

[0244] ##STR00014##

[0245] 1-Naphthol (170 mg, 1.2 mmol), 3-bromo-4,5-dimethoxybenzaldehyde (245 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 l) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml and stirred for 1 h at room temperature. The solids were collected by filtration, washed well with 60% aq. ethanol and dried under high vacuum (420 mg, 0.86 mmol, 86%).

Example 7

2-Amino-4-(3,4,5-trifluoro-phenyl)-4H-benzo[h]chromene-3-carbonitrile (7)

[0246] ##STR00015##

[0247] 1-Naphthol (170 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 l) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml and stirred for about 1 h room temperature. The solids were collected by filtration, washed with 60% aq. ethanol and dried under high vacuum to yield the title compound (284 mg, 0.81 mmol, 81%).

Example 8

2-Amino-7-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (8)

[0248] ##STR00016##

[0249] 1,5-Dihydroxy-naphthalene (704 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (triethylenediamine) (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.18 g, 2.6 mmol, 59%).

Example 9

2-Amino-6-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (9)

[0250] ##STR00017##

[0251] 1,4-Dihydroxy-naphthalene (704 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benz-aldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then refluxed with stirring under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.68 g, 3.7 mmol, 84%).

Example 10

2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10)

[0252] ##STR00018##

[0253] 5-Amino-naphthol (700 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.58 g, 3.5 mmol, 79.5%).

Example 11

2,4,7-Triamino-5-(3,4,5-trifluoro-phenyl)-5H-pyrano[2,3-d]pyrimidine-6-carbonitrile (11)

[0254] ##STR00019##

[0255] 2,4-Diamino-6-hydroxypyrimidine (555 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum to get the title compound (1.47 g, 3.51 mmol, 79.7% of the theoretical yield).

Example 12

7-Amino-4-hydroxy-2-methyl-5-(3,4,5-trifluoro-phenyl)-5H-pyrano[2,3-d]pyrimidine-6-carbon (12)

[0256] ##STR00020##

[0257] 4,6-Dihydroxy-2-methylpyrimidine (555 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.38 g, 3.29 mmol, 74.8% of the theoretical yield).

Example 13

7-Amino-4-hydroxy-5-(3,4,5-trifluoro-phenyl)-5H-pyrano[2,3-d]pyrimidine-6-carbonitrile (13)

[0258] ##STR00021##

[0259] 4,6-Dihydroxypyrimidine (493 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.43 g, 3.53 mmol, 80%).

Example 14

7-Amino-5-(3-bromo-4,5-dimethoxy-phenyl)-2,4-dimethyl-5H-pyrano[2,3-d]pyrimidine-6-carbonitrile (14)

[0260] ##STR00022##

[0261] 4-Hydroxy-2,6-dimethylpyrimidine (546 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 2 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.52 g, 3.64 mmol, 82.8%).

Example 15

7-Amino-5-(3-bromo-4,5-dimethoxy-phenyl)-4-hydroxy-5H-pyrano[2,3-d]pyrimidine-6-carbonitrile (15)

[0262] ##STR00023##

[0263] 2,4-Dihydroxypyridine (488 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 2 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol, 30% mol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.47 g, 3.64 mmol, 82.7%).

Example 16

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-6-methyl-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (16)

[0264] ##STR00024##

[0265] 8-Hydroxyquinaldine (382 mg, 2.4 mmol), 5-bromo-3,4-dimethoxybenzaldehyde (490 mg, 2 mmol) and malononitrile (132 mg, 2 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (22 l, 0.3 mmol) and then stirred at 80 C. under LC-MS control for 3 days. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and then extracted with ethyl acetate (250 ml). The organic solution was washed with 5% sodium bicarbonate solution (250 ml) and then dried over magnesium sulfate, solvent was evaporated under vacuum at 40 C. and the residue was dried under high vacuum giving 217 mg of the title compound (0.48 mmol, 20%).

Example 17

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-5-hydroxy-4H-pyrano[3,2-c]quinoline-3-carbonitrile (17)

[0266] ##STR00025##

[0267] 2,4-Quinolinediol (193 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (11 l, 0.1 mmol) and then stirred at 80 C. under LC-MS control for 21 h whereby the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and stirred for over night at room temperature. The solids were collected by filtration, washed well with 50% aqueous ethanol and dried under high vacuum yielding 395 mg (0.87 mmol, 87%) of the pure title compound.

Example 18

6-Amino-8-(3-bromo-4,5-dimethoxy-phenyl)-8H-5-oxa-1-aza-phenanthrene-7-carbonitrile (18)

[0268] ##STR00026##

[0269] 5-Hydroxyquinoline (174 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (11 l, 0.1 mmol) and then stirred at 80 C. under LC-MS control for 21 h. The reaction mixture was cooled down to the room temperature, diluted with water to about 100 ml and stirred for over night. The solids were collected by filtration, washed with well 1:1 mixture of ethanol/water and dried under high vacuum yielding 134 mg (0.36 mmol, 36%) of the title compound.

Example 19

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-6-hydroxy-H-4-oxa-5-aza-phenanthrene-2-carbonitrile (19)

[0270] ##STR00027##

[0271] 2,8-Quinolinediol (193 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (33 l, 0.3 mmol) and then stirred at 90 C. under LC-MS control for 3 days. The reaction mixture was then cooled down to room temperature, diluted with water to about 100 ml and extracted with ethyl acetate (250 ml). The organic solution was washed with 5% aqueous sodium bicarbonate solution (250 ml) and then dried over magnesium sulfate, solvent was evaporated under vacuum at 40 C and dried (18 mg, 0.04 mmol, 4%).

Example 20

3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20)

[0272] ##STR00028##

[0273] 2-Amino-8-hydroxyquinoline (192 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were suspended in 25 ml ethanol at room temperature, charged with DABCO (33 l, 0.3 mmol) and then stirred at 90 C. under LC-MS control for 6 days. The desired product was formed as a main component with some side products and a small amount of starting material was left. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and stirred for over night at room temperature. Thus resulting precipitates were collected by filtration, washed well with 1:1 mixture of ethanol/water and finally with small portion of 10% ethyl acetate in cyclohexane and then dried under high vacuum to get pure solids (202 mg, 0.45 mmol, 45%) of the title compound.

Example 21

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21)

[0274] ##STR00029##

[0275] 2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (1) (4.38 g, 10 mmol), hydroxylamine hydrochloride (2.80 g, 40 mmol) and potassium carbonate (2.80 g, 1 mmol) were suspended in 80 ml ethanol at room temperature then stirred under LC-MS control 48 h. The reaction was clean with a minor side product (<3%). The reaction mixture was diluted with ethyl acetate to about 150 ml and stirred for 2 h at room temperature. Thus resulting insoluble salt was separated by filtration, washed well with ethyl acetate and the combined organic solution was evaporated to dryness at 40 C. under vacuum and the residue was dried under high vacuum to get solids (4.70 g, 10 mmol, 100% theoretical yield) of the title compound.

Example 22

3-[2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromen-3-yl]-4H-[1,2,4]oxadiazol-5-one (22)

[0276] ##STR00030##

[0277] 2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21), (118 mg, 0.25 mmol) and diimidazole carbonyl (40.5 mg, 0.25 mmol) are suspended in 10 ml tetrahydrofuran at room temperature and then is stirred under LC-MS control under heating. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.

Example 23

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-chloroacetylhydroxy-4H-benzo[h]chromene-3-carboxamidine (23)

[0278] ##STR00031##

[0279] 2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21) (118 mg, 0.25 mmol) and triethylamine (35 ml, 0.25 mmol) are taken in 10 ml tetrahydrofuran at 5 C. and is charged with chloroacetyl chloride (23 mg, 0.25 mmol) by drop wise addition under strong stirring. The reaction mixture is then stirred allowing to come to room temperature under LC-MS control and is stirred further at room temperature till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.

Example 24

4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (24)

[0280] ##STR00032##

[0281] 2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-chloroacetylhydroxy-4H-benzo[h]chromene-3-carboxamidine (23) (137 mg, 0.25 mmol) is taken in 10 ml xylene and refluxed under LC-MS control and is stirred further at room temperature till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.

Example 25

4-(4-Allyloxy-3-bromo-5-methoxy-phenyl)-2-amino-4H-benzo[g]chromene-3-carboxylic acid ethyl ester (25)

[0282] ##STR00033##

[0283] 2-Naphthol (170 g, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 g, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (386 mg, 0.76 mmol, 76%).

Example 26

4-(4-Allyloxy-3-bromo-5-methoxy-phenyl)-2-amino-4H-benzo[g]chromene-3-Carbonitrile (26)

[0284] ##STR00034##

[0285] 2-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (235 mg, 0.51 mmol, 51%).

Example 27

2-Amino-4-(3,4,5-trifluoro-phenyl)-4H-benzo[g]chromene-3-carboxylic acid ethyl ester (27)

[0286] ##STR00035##

[0287] 2-Naphthol (170 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq. ethanol and dried (346 mg, 0.86 mmol, 86%).

Examples 28 and 29

2-Amino-4-(3,4,5-trifluoro-phenyl)-4H-benzo[g]chromene-3-carbonitrile (29) and 2-Amino-4-(3,5-difluoro-4-piperidin-1-yl-phenyl)-4H-benzo[g]chromene-3-carbonitrile (30)

[0288] ##STR00036##

[0289] 2-Naphthol (170 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. Two products were formed. The reaction mixture was cooled down to room temperature, diluted with water to about 50 ml, extracted with ethyl acetate (225 ml), organic solution was dried over magnesium sulfate, solvent was evaporated, residue was washed well with 1:1 mixture of ethanol/water and then dried. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to 2-amino-4-(3,4,5-trifluoro-phenyl)-4H-benzo[g]chromene-3-carbonitrile (28) (137 mg, 38.9%) and 2-amino-4-(3,5-difluoro-4-piperidin-1-yl-phenyl)-4H-benzo[g]chromene-3-carbonitrile (29) (120 mg, 28.8%).

Example 30

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carbonitrile (30)

[0290] ##STR00037##

[0291] 2-(3-Bromo-4,5-dimethoxy-benzylidene)-malononitrile (345 mg, 1.17 mmol) and 2-naphthole (203 mg, 1.4 mmol) were taken in 7 ml ethanol, charged with piperidine (50 L) at room temperature and then stirred at 80 C. for 5 h. The reaction mixture was cooled down to room temperature, diluted with water to 20 ml, solids were separated by filtration, washed with methanol and dried under high vacuum yield pure solids of the title compound (358 mg, 82%).

Example 31

2-Dimethylamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carbonitrile (31)

[0292] ##STR00038##

[0293] 2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carbonitrile (30) (24 mg) was taken in 1 ml dry DMF (dimethylformamide) and then charged with methyl iodide (30 l) and potassium carbonate (30 mg) at room temperature. The reaction was completed after 20 h stirring at room temperature. The title compound was purified on HPLC (21 mm250 mm, RP18, 5 mm) with a Methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to yield pale yellowish solids (18 mg).

Example 32

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carboxylic acid ethyl ester (32)

[0294] ##STR00039##

[0295] 2-Naphthol (170 mg, 1.2 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (245 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 5 ml ethanol at room temperature, charged with piperidine (50 l) and then stirred at 80 C. for 18 h. Reaction was complete and clean. The reaction mixture was then cooled down to room temperature, diluted with water to 20 ml, solids were separated by filtration, washed with methanol and dried under high vacuum (360 mg, 74%).

Example 33

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (33)

[0296] ##STR00040##

[0297] 8-Hydroxychinoline (14.5 g, 100 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (20.4 g, 83.33 mmol) and malononitrile (5.5 g, 83.33 mmol) were taken in 250 ml ethanol at room temperature, charged with DABCO (917 l, 8.33 mmol) and then stirred at 80 C. under LC-MS control for 18 days. The reaction mixture was cooled down to room temperature, diluted with water to about 500 ml and extracted with ethyl acetate (2100 ml). The ethyl acetate solution was washed with 5% sodium bicarbonate solution (2100 ml), dried over magnesium sulfate, solvent was then evaporated under vacuum at 40 C. and the solids were dried under high vacuum to yield 22.5 g (61.6%) of the title compound.

Example 34

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-chloro-1H-4-oxa-10-aza-phenanthrene-2-carbonitrile (34)

[0298] ##STR00041##

[0299] 1-Chloro-4-hydroxyisoquinone (790 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 24 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the precipitates were collected by filtration, washed well with 50% aqueous ethanol and dried under vacuum to yield the title compound (1.7 g, 3.6 mmol, 82%).

Example 35

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-chloro-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (35)

[0300] ##STR00042##

[0301] 5-Chloro-8-hydroxyquinoline (790.2 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 18 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the solid were collected by filtration. It was washed with 50% aqueous ethanol. The solids were taken in 15 ml 2-propanol and stirred at 60 C. for 10 minutes, cooled down by dipping the flask in an ice bath, the solids were filtered and dried under vacuum to get the pure title compound (1.25 g, 2.64 mmol, 60%).

Example 36

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-1-oxa-10-aza-phenanthrene-3-carbonitrile (36)

[0302] ##STR00043##

[0303] 3-Hydroxyisoquinoline (638 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 l, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 24 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the precipitates were collected by filtration, washed well with 50% aqueous ethanol and dried under vacuum to yield the title compound (1.35 g, 3.08 mmol, 70%).

Example 37

3,5-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-benzo[f]chromene-2-carbonitrile (37)

[0304] ##STR00044##

[0305] 3-Aminonaphthol (700.5 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 L, 1.46 mmol) and then stirred at 80 C. under LC-MS control for 24 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the precipitates were collected by filtration, washed well with 50% aqueous ethanol and dried under vacuum to yield the title compound (1.55 g, 3.43 mmol, 78%).

Example 38

6-Amino-8-(3-bromo-4,5-dimethoxy-phenyl)-8H-[1,3]dioxolo[4,5-g]chromene-7-carbonitrile (38)

[0306] ##STR00045##

[0307] 3-Bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol), malononitrile (66 mg, 1 mmol) and sesamol (166 mg, 1.2 mmol) were taken in 10 ml ethanol, charged with piperidine (50 l, 0.5 mmol) and stirred at room temperature for 3 h. The reaction mixture was then stirred at 80 C. for 64 h. Reaction was complete with the desired product. The reaction mixture was first cooled down to room temperature, diluted with water to about 30 ml, precipitates were collected by filtration, washed with 1:1 mixture of water and methanol (30 ml) and dried to pure solids (348 mg, 81%) under high vacuum.

Example 39

6-Amino-8-(3,4,5-trifluoro-phenyl)-8H-[1,3]dioxolo[4,5-g]chromene-7-carbonitrile (39)

[0308] ##STR00046##

[0309] 3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq. ethanol and dried (303 mg, 0.88 mmol, 88%).

Example 40

6-Amino-8-(3,4,5-trifluoro-phenyl)-8H-[1,3]dioxolo[4,5-g]chromene-7-carboxylic acid ethyl ester (40)

[0310] ##STR00047##

[0311] 3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq. ethanol and dried (280 mg, 0.71 mmol, 71%).

Example 41

8-(4-Allyloxy-3-bromo-5-methoxy-phenyl)-6-amino-8H-[1,3]dioxolo[4,5-g]chromene-7-carbonitrile (41)

[0312] ##STR00048##

[0313] 3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (200 mg, 0.44 mmol, 44%).

Example 42

8-(4-Allyloxy-3-bromo-5-methoxy-phenyl)-6-amino-8H-[1,3]dioxolo[4,5-g]chromene-7-carboxylic acid ethyl ester (42)

[0314] ##STR00049##

[0315] 3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 g, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 L) and then stirred at 80 C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (239 mg, 0.47 mmol, 47%).

Example 43

1-[3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-2-cyano-1H-4-oxa-5-aza-phenanthren-6-yl]-3-ethyl-urea (43)

[0316] ##STR00050##

[0317] 3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) and ethylisocyanate (8.4 mg, 0.12 mmol) were taken in 2 ml dry acetonitril and stirred at 60 C. monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (38 mg, 73%).

Example 44

1-[3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-2-cyano-1H-4-oxa-5-aza-phenanthren-6-yl]-3-methyl-thiourea (44)

[0318] ##STR00051##

[0319] 3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) and ethylthioisocyanate (10.4 mg, 0.12 mmol) were taken in 2 ml dry acetonitril and stirred at 60 C. monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (32 mg, 59%).

Example 45

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-6-methylamino-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (45)

[0320] ##STR00052##

[0321] 3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) and potassium carbonate (7.5 mg, 0.05 mmol) were taken in 5 ml dry acetonitril, charged with iodomethane (15.4 mg, 0.11 mmol) and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (41 mg, 87.8%).

Example 46

N-[3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-2-cyano-1H-4-oxa-5-aza-phenanthren-6-yl]-acetamide (46)

[0322] ##STR00053##

[0323] 3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) was taken in 2 ml pyridine at 0 C., charged with acetic anhydride (11 mg, 0.11 mmol) by drop wise addition and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (35 mg, 71.4%).

Example 47

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-7-methoxy-4H-benzo[h]chromene-3-carbonitrile (47)

[0324] ##STR00054##

[0325] 2-Amino-7-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (8) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (43 mg, 92%).

Example 48

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-6-methoxy-4H-benzo[h]chromene-3-carbonitrile (48)

[0326] ##STR00055##

[0327] 2-Amino-6-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (9) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (40 mg, 85.6%).

Example 49

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-7-methylamino-4H-benzo[h]chromene-3-carbonitrile (49)

[0328] ##STR00056##

[0329] 2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (42 mg, 89.9%).

Example 50

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-7-dimethylamino-4H-benzo[h]chromene-3-carbonitrile (50)

[0330] ##STR00057##

[0331] 2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) and potassium carbonate (21 mg, 0.15 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (31.2 mg, 0.22 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (41 mg, 85.4%).

Example 51

2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-7-acetylamino-4H-benzo[h]chromene-3-carbonitrile (51)

[0332] ##STR00058##

[0333] 2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) was taken in pyridine (2 ml) at 0 C., charged with acetic anhydride (11 mg, 0.11 mmol) and stirred further at 0 C. under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (46 mg, 93%).

Example 52

4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-methylamino methyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (52)

[0334] ##STR00059##

[0335] 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (24) (528 mg, 1 mmol) and triethylamine (140 l, 1 mmol) and 2M methanolic solution of methylamine (600 l, 1.2 mmol) is taken in acetonitril (10 ml) and stirred at room temperature under LC-MS control till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.

Example 53

3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-methylamino-1H-4-oxa-10-aza-phenanthrene-2-carbonitrile (53)

[0336] ##STR00060##

[0337] 3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-chloro-1H-4-oxa-10-aza-phenanthrene-2-carbonitrile (34) (47 mg, 0.1 mmol) and triethylamine (14 l, 0.1 mmol) and methylamine (2M in McOH, 75 l, 0.15 mmol) were taken in dry NMP (2 ml) and stirred at 80 C. till the reaction was complete. The reaction mixture was diluted with water to about 7 ml, stirred at room temperature for 2 h, precipitates were collected by filtration, washed with water. The residue was then purified on HPLC (high pressure liquid chromatography) (21 mm250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to pure title compound (36 mg, 77%).

Example 54

Examination of Wnt Signaling Pathway Inhibiting Activity of Selected Compounds

[0338] To screen for small-molecule modulators of the Wnt signaling pathway, a reporter gene based assay describing the modulation of the TCF4 transcription factor was used. More specifically 4000 Hek293T cells were seeded into 384 high density plates. 24 h after seeding a Wnt-sensitive reporter (6TCF-luciferasc (Firefly) (pTOP-FLASH; Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF, Cell, 1997, 88(6), pages 789-99)) and constitutively expressed control reporter (Renilla luciferase pCMV-RL) were transfected into Hek293T. Wnt signaling was stimulated by cotransfecting mouse Wnt1, mouse Frizzled 8 and human LRP6 according to Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction, Nature, 2005, 438(7069), pages 867-872. 24 h after pathway stimulation compounds were added at a concentration of 10 microM and allowed to incubate for 24 h. For the evaluation of the IC.sub.50 the respective compound was applied in increasing concentrations yielding final concentrations per well of 5 nM-100 microM.

[0339] The IC.sub.50-values of the Wnt pathway inhibitory activity of compounds (1), (4), (6), (7), (16) to (20), (28) to (31) and (38) to (42) are shown in table 1.

TABLE-US-00001 TABLE 1 IC.sub.50-values of the Wnt pathway inhibitory activity for of compounds (1), (4), (6), (7), (16) to (20), (28) to (31) and (38) to (42) Wnt1/Frzd8 Compound IC.sub.50 [nM] (1) 46 (4) 86 (6) 855 (7) 316 (16) 1126 (17) 20 (18) 33 (19) 3 (20) 6 (28) 2396 (29) 6482 (30) 697 (31) 1965 (38) 3118 (39) 1365 (40) 3424 (41) 45 (42) 55

Example 55

Examination of Toxicity in Hek293T and HepG2

[0340] For examination of cytotoxicity in these cancer cell lines the commercial available CellTiterGlo Reagent (Promega, USA) was used according to the manufacture.

[0341] Compounds were applied to Hek293T (denoted (a)) or HepG2 (denoted (b)), cultured in Dulbecco's Modified Eagles Medium, supplemented with 10% fetal calf serum and 1% penicillin/streptomycin. Cells were grown in T75 flasks at 37 C., 5% CO2 and trypsinized when 60-80% confluent by adding 2 ml of 0.25% Trypsin-EDTA solution. Cells were then re-suspended into culture medium yielding approx. 4000 cells (a) or 4500 cells (b), suspended in 30 microl medium. 48 h after cell seeding, compounds were added to yield the desired final concentrations. 24 h after compound addition cytotoxicity was evaluated. For this purpose the media was removed and CellTiterGlo was added according to the manufactures manual. In this assay the luciferase emission readout is directly correlated with the cellular amount of ATP, low luciferase emission thus is reflecting cytotoxicity of a compound. For the evaluation of the IC.sub.50 the compound was applied in increasing concentrations yielding final concentrations per well of 5 nM-100 microM.

[0342] IC.sub.50-values of the cytotoxic activity of compounds (1), (4), (6), (7), (16) to (20), (29) to (32) and (39) to (43) against Hek293T and HepG2 are shown in table 2.

TABLE-US-00002 TABLE 2 IC.sub.50-values against Hek293T and HepG2 of compounds (1), (4), (6), (7), (16) to (20), (28) to (31) and (38) to (42) Hek293T HepG2 Compound IC.sub.50 [nM] IC.sub.50 [nM] (1) >90000 >90000 (4) >90000 >90000 (6) >90000 >90000 (7) >90000 >90000 (16) >90000 >90000 (17) >90000 >90000 (18) >90000 >90000 (19) >90000 >90000 (20) >90000 37048 (28) >90000 31676 (29) >90000 42539 (30) >90000 >90000 (31) >90000 >90000 (38) >90000 >90000 (39) >90000 >90000 (40) >90000 >90000 (41) >90000 >90000 (42) >90000 >90000

Example 56

Examination of Cell Line Specific Cytotoxicity

[0343] For examination of cell line-specific cytotoxicity, compounds were applied to human colorectal cancer cells (HCT116, denoted (1); SW480, denoted (2); Dld-1, denoted (3)) and human fibroblasts (HS-68, denoted (4)), cultured in Mc Coy's ((1)) and Dulbecco's Modified Eagles Medium ((2)-(4)), supplemented with 10% ((1)-(3)) and 20% ((4)) fetal calf serum and 1% penicillin/streptomycin. Cells were grown in T75 flasks at 37 C., 5% CO2 and trypsinized when 60-80% confluent by adding 2 ml of 0.25% Trypsin-EDTA (ethylenediaminetetraacetic acid) solution. Cells were then re-suspended into culture medium yielding approx. 750 cells, suspended in 45 microl medium, were plated into each well of a black 384-well plate for fluorescence imaging experiments. 24-36 hr later 5 microl compound solution (100 microM compound dissolved in ultra pure water containing 1% DMSO (dimethylsulfoxide)), were added to achieve a final concentration of 10 microM and were incubated for at least 72 hr. Compound incubation was terminated by (a) fixation and (b) permcabilisation of cells, followed by (c) fluorescence labeling of cell nuclei for cytometric quantification or by immunocytochemistry for microscopic evaluation of cell morphology. The three steps were performed by replacing the solution of the previous step in each well of a 384-well plate by (a) 30 microl PBS (phosphate buffered saline) containing 5% PFA (paraformaldehyde), (b) 30 microl PBS containing 0.2% TritonX-100 and (c) 10 microl PBS containing Hoechst-33342 for cytometry or Hoechst-33342, FITC-(fluorescein isothiocyanate-)labeled alpha-tubulin antibodies and TRITC-(tetramethylrhodamine isothiocyanate-)labeled phalloidin for microscopy. Solutions were incubated for 15 (a,b) and 30 min (c) in the dark at room temperature. Cells were washed twice between each step with 30 microl PBS. The assay system was miniaturized and adapted to automated workflow using liquid-handling robotics.

[0344] Cell line-specific cytotoxicity was quantified by counting the number of Hoechst labeled nuclei per well of a 384-well plate using a plate cytometer. Data obtained with the cytometer was analysed using standard data analysis software.

[0345] Identified hits were further evaluated by visual inspection of fluorescence micrographs obtained from imaging using a conventional fluorescence microscope.

[0346] The results for normal cells (HS68) are shown in table 3.

TABLE-US-00003 TABLE 3 Influence of of compounds ((1), (4), (6), (7), (16) to (20), (28) to (31) and (38) to (42) on normal cells (HS68) HS68 Compound IC.sub.50 [nM] (1) 87 (4) 215 (6) >90000 (7) >90000 (16) 4945 (17) >90000 (18) 2771 (19) nd (20) nd (28) >90000 (29) >90000 (30) 5150 (31) >90000 (38) 4164 (39) >90000 (40) >90000 (41) 641 (42) 469 nd: not determinable

[0347] The examination of the antiproliferative activity against human colon carcinoma cells Dld1, HCT116 and SW480 was carried out in analogy to the procedure carried out for HS68. The respective compound applied in increasing concentrations yielding final concentrations per well of 5 nM-90 microM. Compounds of the present invention have potent antiproliferative activity against human colon carcinoma cells as shown for Dld1, HCT116 and SW480 in Table 4.

TABLE-US-00004 TABLE 4 Influence of compounds (1), (4), (6), (7), (16) to (20), (28) to (31) and (38) to (42) on Dld1, HCT116 and SW480 colon carcinoma cells Dld1 HCT116 SW480 Compound IC.sub.50 [nM] IC.sub.50 [nM] IC.sub.50 [nM] (1) 38 49 56(a) (4) 171 146 332 (6) 3819 8604 5956(a) (7) 474(a) 922 2861 (16) 2901 3340 3158 (17) 643 305(a) 577(a) (18) 185 331 19671 (19) 21 17 nd (20) 14 15 nd (28) 21954 30314 53605 (29) >90000 >90000 38541 (30) 8975 2903 7598 (31) 4557 10004 11999 (38) 719 1054 3087 (39) 1085 666 2692 (40) 15658 >90000 6385 (41) 470 551 618 (42) 293 250 343 nd: not determinable

Examples 57 to 70

[0348] ##STR00061##

TABLE-US-00005 TABLE 5 compounds (57) to (70): Compound R.sup.2 R.sup.9 (57) Br CH.sub.2OH (58) Br CH.sub.2NH.sub.2 (59) Cl OH (60) Cl NH.sub.2 (61) Cl CH.sub.2OH (62) Cl CH.sub.2NH.sub.2 (63) F OH (64) F NH.sub.2 (65) F CH.sub.2OH (66) F CH.sub.2NH.sub.2 (67) OCH.sub.3 OH (68) OCH3 NH.sub.2 (69) OCH3 CH.sub.2OH (70) OCH3 CH.sub.2NH.sub.2

[0349] Compounds (57), (58), (60) to (62), (64) to (66) and (68) to (70) were prepared in analogy to the procedure of examples 19 and 20 using the respective 2,8-quinoline derivatives and the respective 3-R.sup.2-4,5-dimethoxy-benzaldehydes.

[0350] Compounds (59), (63) and (67) were prepared by suspending (3-R.sup.2-4,5-dimethoxy-phenyl)-(2,8-dihydroxy-quinolin-7-yl)-methanone (1 mmol) in 25 ml methanol at room temperature under argon and then charging with malononitrile (4 mmol) and piperidine (1 mmol). The mixture was stirred at room temperature for 16 h. Acetic acid (1 ml), water (10 ml) and then sodium cyanoborohydride (4 mmol) were added and stirred further at room temperature until the reaction was complete. Diluted with water to 100 ml, stirred for 1 h, solids were collected by filtration, washed well with water, 50% aq. ethanol and then with 25% ethylacetate in cyclohexane.

[0351] The Wnt pathway inhibitory activity of compounds (57) to (70) was investigated according to the procedure described in example 54. The IC.sub.50-values of the Wnt pathway inhibitory activity of compounds (57) to (70) were below 100 nM.

[0352] The cytotoxic activity of compounds (57) to (70) was investigated according to the procedure described in example 55. The IC.sub.50-values against Hek293T of compounds (57) to (70) lied above 50 microM.

[0353] The influence of compounds (57) to (70) on colon cancer cell lines Dld1 and HCT116 was determined according to the procedure described in example 56. IC.sub.50-values for the cytotoxicity against these cell lines were below 100 nM for compounds (57) to (70) showing a strong effect on cancer cells being associated with an aberrant Wnt signalling pathway activity.

Example 71

Enantionmeric Separation of 3,6-diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) and Determination of the Activity of the Enantionmers

[0354] Chiral HPLC (High Pressure Liquid Chromatography) and SFC (Supercritical Fluid Chromatography) were used for the analytical and preparative chiral separation of compound (20) respectively.

##STR00062##

1.1. Preparative Separation Method

[0355] The racemic mixture (300 mg) of 3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (compound (20)) was separated into its enantiomers with the following methods:

[0356] Instrument: Thar 80 preparative Supercritical Fluid Chromatography (SFC)

[0357] Column: Chiralcel AS 250 mm25 mm, 5 m

[0358] Mobile phase: 70% Carbondioxide and 30% ethanol with 0.05% 2-aminopropane

[0359] Flow rate: 60 g/min

[0360] Temperature: 40 C.

[0361] Sample preparation: The racemate was dissolved in a 1:1 mixture of ethanol and acetonitrile with a final concentration of 10 mg/ml.

[0362] Injection volume: 2 ml per injection.

1.2. Work up

[0363] After separation, the fractions were dried off via rotary evaporator at bath temperature 30 C. to get the two enantiomers. After separation, 89.2 mg of ()-Isomer with e.e. value 100% and 105.6 mg of (+)-Isomer with e.e. value 100% were obtained respectively.

2. Analytical Method

[0364] Instrument: Shimadzu LC-20AB analytical HPLC

[0365] Column: Chiralcel AS-H, 250 mm4.6 mm, 5 m

[0366] Mobile phase: 80% n-hexane and 20% ethanol with 0.05% 2-propylamine

[0367] Flow rate: 1.0 ml/min

[0368] Detection: 220 nm

[0369] Properties of the pure enantiomers are displayed in Table 6. The e.e values were determined by chiral HPLC.

TABLE-US-00006 TABLE 6 Properties of the enantiomeres (20)-1 and (20)-2 of compound (20) Retention Analytical e.e. NO. Time [].sub.D at 24 C. Salt Purity methods value Net_weight (20)-1 3.28 min 238.53 +/ 0.12 FREE 99.5% NMR, LCMS, 100.0% 89.2 mg HPLC (20)-2 5.42 min +235.14 +/ 0.24 FREE 99.6% NMR, LCMS, 100.0% 105.6 mg HPLC

[0370] The Wnt pathway inhibitory activity was determined as described in example 54. The influence of the racemate and the two separated enantiomeres on colon cancer cell lines Dld1 and HCT116 was determined according to the procedure described in example 56. The results are shown in Table 7.

TABLE-US-00007 TABLE 7 Comparison of the biological activities of the racemate with the pure enantiomers of compound (20) IC.sub.50 IC.sub.50 ()- IC.sub.50 (+)- Activity Racemate (20) Isomer (20)-1 Isomer (20)-2 against Wnt-Pathway 5 nM <5 nM 330 nM against colon cancer 5 nM <5 nM 354 nM cell lines HCT 116 against colon cancer 10 nM <5 nM 356 nM cell lines DLD1