Amino-substituted dihydropyrimido[4,5-D]pyrimidinone derivatives Number:7,091,345 from the United States Patent and Trademark Office (PTO) owispatent Compounds of formula I ##STR00001## are described. These compounds are protein kinase inhibitors, in particular they inhibit the src family tyrosine kinases. Thus, these compounds are useful for the treatment of diseases mediated by src tyrosine kinases, including cell proliferative disorders such as cancer. Also described are methods of making and using compounds of formula I as well as pharmaceutical compositions containing these compounds.<H dihydropyrimido, pyrimidinone, Amino, substitut, 7091345.html, Patent, pto, 7091345

Title: Amino-substituted dihydropyrimido[4,5-D]pyrimidinone derivatives

Abstract: Compounds of formula I ##STR00001## are described. These compounds are protein kinase inhibitors, in particular they inhibit the src family tyrosine kinases. Thus, these compounds are useful for the treatment of diseases mediated by src tyrosine kinases, including cell proliferative disorders such as cancer. Also described are methods of making and using compounds of formula I as well as pharmaceutical compositions containing these compounds.

Patent Number: 7,091,345 Issued on 08/15/2006 to Cai, et al.

Inventors: Cai; Jianping (West Caldwell, NJ), Dimoudis; Nikolaos (Wielenbach, DE), Honold; Konrad (Penzberg, DE), Luk; Kin-Chun (North Caldwell, NJ), Scheiblich; Stefan (Penzberg, DE), Sudergat; Hilke (Munich, DE), Tiefenthaler; Georg (Sindelsdorf, DE), Tonn; Oliver (Penzberg, DE)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)

Appl. No.: 10/697,543

Filed: October 30, 2003

Foreign Application Priority Data


Nov 04, 2002 [EP]			02024573

Current U.S. Class: 544/256 ; 544/118; 544/230; 546/19

Current International Class: C07D 471/04 (20060101); A61K 31/519 (20060101); C07D 491/113 (20060101)

Field of Search: 544/230,256,118 514/262.1,234.2 546/19

References Cited [Referenced By]

U.S. Patent Documents


4473560	September 1984	Biere
4503049	March 1985	Biere
4784993	November 1988	Bosies
5866556	February 1999	Heikkila-Hoikka

Foreign Patent Documents


0 084 822	Aug., 1983	EP
0 085 321	Aug., 1983	EP
0 170 228	Feb., 1986	EP
0 186 405	Jul., 1986	EP
0 304 962	Mar., 1989	EP
WO 94/09017	Apr., 1994	WO
WO 99/61444	Dec., 1999	WO
WO 00/24744	May., 2000	WO
WO 01/29041	Apr., 2001	WO
WO 01/29042	Apr., 2001	WO
WO 01/44258	Jun., 2001	WO

Other References

Kinko, K. et al., Can. J. Chem. vol. 51 (1973) p. 333-337. cited by other .
Merrifield, B. et al., Fed. Proc. Fed. Amer. Soc. Exp. Biol. vol. 21 (1962) p. 412. cited by other .
Okuda, T. et al., J. Org. Chem. vol. 24 (1959) p. 14-16. cited by other .
Ansel, H. et al., Pharm. Dosage Forms & Drug Delivery Systems (6.sup.th Ed.) 1995 p. 196. cited by other.

Primary Examiner: McKenzie; Thomas C.
Attorney, Agent or Firm: Johnston; George W. Rooha-Tramaloni; Patricia S.

Claims

The invention claimed is:

1. A compound of formula I ##STR00015## wherein R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; A is selected from the group ##STR00016## R.sup.5 is hydrogen, halogen, hydroxy, cyano, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl) or --SO.sub.2N(alkyl).sub.2; R.sup.6, R.sup.6' are each independently selected from hydrogen, alkyl or oxo; R.sup.7 is hydrogen, acyl, alkoxycarbonyl, alkoxyalkyl, alkyl or alkyl substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo, alkoxy, alkoxyalkyl, alkyl or alkyl substituted with hydrogen, hydroxy, cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9', provided that when either R.sup.8 or R.sup.8' represent an oxo group, this oxo group is not adjacent to an S(O).sub.m group; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; X is oxygen or S(O).sub.m; the dashed line is an optional second chemical bond; n is 0, 1 or 2; m is 0, 1 or 2; and p is 0, 1 or 2; or a pharmaceutically acceptable salt or N-oxides thereof.

2. A compound according to claim 1, wherein R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; A is selected from ##STR00017## R.sup.5 is hydrogen, halogen, hydroxy, cyano, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl) or --SO.sub.2N(alkyl).sub.2; R.sup.6, R.sup.6' are each independently selected from hydrogen, alkyl or oxo; R.sup.7 is hydrogen, acyl, alkoxycarbonyl, alkoxyalkyl, alkyl or alkyl substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo, alkoxy, alkoxyalkyl, alkyl or alkyl substituted with hydrogen, cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9', provided that when either R.sup.8 or R.sup.8' represent an oxo group, this oxo group is not adjacent to an S(O).sub.m group; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; X is oxygen or S(O).sub.m; the dashed line is an optional second chemical bond; n is 0, 1 or 2; m is 0, 1 or 2; and p is 0, 1 or 2; or a pharmaceutically acceptable salt or N-oxides thereof.

3. The compound of claim 2 wherein R.sup.2 is bromine and n=0.

4. The compound of claim 2 wherein n is 1 and R.sup.2 and R.sup.3 are each independently selected from fluorine, chlorine, bromine or iodine.

5. The compound of claim 4 wherein R.sup.2 is bromine and R.sup.3 is fluorine.

6. The compound of claim 5 wherein the R.sup.3 is at the 6-position of the phenyl ring.

7. The compound of claim 4 wherein R.sup.2 and R.sup.3 are both chlorine.

8. The compound of claim 2, wherein A is selected from A-1, A-2, A-3, A-4, A-5 or A-6; R.sup.1 is alkyl or aryl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.2 is halogen or cyano; R.sup.3 each R.sup.3 is independently selected from halogen; n is 0 or 1; m is 0, 1 or 2; R.sup.5 is hydrogen; and R.sup.4 hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 selected from 7-(Benzo[1,3]dioxol-5-ylamino)-3-(2,4-dichloro-phenyl)-1-(4-methoxy-pheny- l)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one; and 2-[7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6-ylamin- o)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-benzonitri- le.

10. The compound of claim 2 wherein A is A-1; R.sup.5 is hydrogen; p is 0; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 which is selected from 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-acetyl-spiro[1,3-benzodioxolo-2,4'-p- iperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-ethoxycarbonyl-spiro[1,3-benzodioxol- o-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-acetyl-spiro[1,3-benzodioxol- o-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-ethoxycarbonyl-spiro[1,3-ben- zodioxolo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(- 1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-ethyl-spiro[1,3-benzodioxolo- -2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-(2-methoxyethyl)-spiro[1,3-benzodiox- olo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-on- e, and 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-(2-methoxyethyl)-spiro- [1,3-benzodioxolo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyri- midin-2(1H)-one.

12. The compound according to claim 10 which is selected from 3-(2-bromo-phenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4'-piperidine]- -5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-methyl-spiro[1,3-benzodioxolo-2,4'-p- iperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluoro-phenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4'-pi- peridine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluoro-phenyl)-3,4-dihydro-7-(1'-methyl-spiro[1,3-benzodioxo- lo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one- , 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-cyanomethyl-spiro[1,3-benzodioxolo-- 2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, and 3-(2-bromo-5-methoxyphenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4- '-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one.

13. The compound according to claim 2 wherein A is a group A-2; R.sup.5 is hydrogen; X is oxygen; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl that optionally may be substituted with cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9'; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, which is selected from 3-(2-bromo-phenyl)-7-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-1-methyl-3,- 4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(2-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[- 1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[- 1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]dioxin-- 6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(2-dimethylaminomethyl-2,3-dihydro-benzo[1,- 4]dioxin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one- , 3-(2-bromo-phenyl)-7-(3-dimethylaminomethyl-2,3-dihydro-benzo[1,4]dioxin- -6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(3-dimethylaminomethyl-2,3-dihydro-benzo[1,- 4]dioxin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one- , 3-(2-bromo-phenyl)-7-(2-cyclopropylaminomethyl-2,3-dihydro-benzo[1,4]dio- xin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(2-morpholin-4-ylmethyl-2,3-dihydro-benzo[1- ,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-morpholin-4-ylmethyl-2,3-dihydro-benzo[1- ,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-morpholin-4-ylmethyl-2,3-dihydr- o-benzo[1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-on- e, and 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-pyrrolidin-1-ylmethyl-2,3- -dihydro-benzo[1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimid- in-2-one.

15. The compound according to claim 1 wherein A is a group A-2; R.sup.5 is hydrogen; X is oxygen; R.sup.8 is hydrogen R.sup.8' is alkyl substituted with hydroxy; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15, which is selected from 3-(2-bromo-phenyl)-7-(2-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylam- ino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(3-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylam- ino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(3-hydroxymethyl-2,3-dihydro-benzo[1,4]diox- in-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, and 3-(2-bromo-6-fluoro-phenyl)-7-(2-hydroxymethyl-2,3-dihydro-benzo[1,4]diox- in-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.

17. The compound of claim 2 wherein A is A-2; R.sup.5 is hydrogen; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' are hydrogen; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17, which is selected from 3-(2-bromo-phenyl)-7-(2,3-dihydro-benzo[1,4]oxathiin-7-ylamino)-1-methyl-- 3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-7-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-be- nzo[1,4]oxathiin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimid- in-2-one, and 3-(2-bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.

19. The compound of claim 2 wherein A is A-3; R.sup.5 is hydrogen; R.sup.7 is hydrogen or alkyl; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo or alkoxy, provided that when one of R.sup.8, R.sup.8' is oxo the dashed line is absent, and provided further that when R.sup.8 and R.sup.8' are selected from hydrogen or alkoxy the dashed line may represent an additional bond to form a double bond; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19 which is selected from 3-(2-bromo-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-7-y- lamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]th- iazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1,3-dioxo-1,2 3,4-tetrahydro-1I.lamda..sup.4-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1- H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3,4-dihydro-2H-benzo[1,4]thiazin-- 7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-y- lamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-ben- zo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, and 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,- 4]thiazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.

21. The compound according to claim 19 which is selected from 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]th- iazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(3-methoxy-4-methyl-1-oxo-1,4-dihydro-1.lamda..sup.4- -benzo[1,4]thiazin-7-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrim- idin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-ben- zo[1,4]thiazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-1,1-dioxo-1,2,3,4-tetrah- ydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4- ,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1,1-dioxo-1,2,3,4-tetrahydro-1.la- mda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyri- midin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1- .lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]p- yrimidin-2-one, and 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tet- rahydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimid- o[4,5-d]pyrimidin-2-one.

22. The compound of claim 2, wherein A is A-4; R.sup.5 is hydrogen; R.sup.6, R.sup.6' are each independently selected from hydrogen or oxo; R.sup.7 is hydrogen or alkyl that optionally may be substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; m is 0, 1 or 2; R.sup.4 is hydrogen; or a pharmaceutically acceptable salts thereof.

23. The compound according to claim 22 which is selected from 5-[6-(2-bromo-phenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]py- rimidin-2-ylamino]-2-methyl-isoindole-1,3-dione, 3-(2-bromo-phenyl)-1-methyl-7-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino- )-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one; hydrochloride salt, 5-[6-(2-bromo-phenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]py- rimidin-2-ylamino]-isoindole-1,3-dione, 5-[6-(2-bromo-6-fluoro-phenyl)-8-methyl-7-oxo-5,6,7, 8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-2-methyl-isoindole-1,3-d- ione, and 3-(2-bromo-6-fluoro-phenyl)-7-[2-(2-hydroxy-1,1-dimethyl-ethyl)-- 2,3-dihydro-1H-isoindol-5-ylamino]-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]- pyrimidin-2-one; hydrochloride.

24. The compound of claim 2, wherein A is A-5; R.sup.5 is hydrogen; X is oxygen; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 24 which is 7-(benzo[1,3]dioxol-5-ylamino)-3-(2-bromo-phenyl)-1-methyl-3,4-dihydro-1H- -pyrimido[4,5-d]pyrimidin-2-one.

26. A compound of claim 2, wherein A is A-5'; R.sup.5 is hydrogen; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26 which is selected from 3-(2-bromo-6-fluoro-phenyl)-7-(3,3-dioxo-2,3-dihydro-3.lamda..sup.6-benzo- [1,3]oxathiol-5-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-- 2-one, and 3-(2-bromo-phenyl)-7-(3,3-dioxo-2,3-dihydro-3.lamda..sup.6-benz- o[1,3]oxathiol-5-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin- -2-one.

28. The compound of claim 2, wherein A is A-6, R.sup.5 is hydrogen; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 28 which is selected from 3-(2-Bromo-5-methoxy-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-b- enzo[1,4]oxathiin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimi- din-2-one, 7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6- -ylamino)-3-(2-fluoro-6-methoxy-phenyl)-1-methyl-3,4-dihydro-1H-pyrimido[4- ,5-d]pyrimidin-2-one, 3-(2-Bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-- one; enantiomer 1, 3-(2-Bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-- one; enantiomer 2, 3-(2-Bromo-phenyl)-1,4-dimethyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahyd- ro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5- -d]pyrimidin-2-one; enantiomer 2, 3-(2-Bromo-phenyl)-1,4-dimethyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahyd- ro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5- -d]pyrimidin-2-one; enantiomer 1, and 2-[7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6-ylamin- o)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-3-fluoro-b- enzonitrile.

30. A compound of the formula A-1-I, ##STR00018## wherein R.sup.5 is hydrogen, halogen, hydroxy, cyano, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl) or --SO.sub.2N(alkyl).sub.2; R.sup.6 each R.sup.6 is independently selected from hydrogen, alkyl or oxo; R.sup.7 is hydrogen, acyl, alkoxycarbonyl, alkoxyalkyl, alkyl or alkyl substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; m is 0, 1 or 2; p is 0, 1 or 2; and X is NO.sub.2 or an optionally protected NH.sub.2 group.

31. A pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable adjuvant.

32. A process for the preparation of a compound of formula I comprising reacting a compound of formula ##STR00019## wherein R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; and L signifies a group selected from benzylsulphonyl, phenylsulphonyl, alkanesulphonyl, p-tolylsulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, chloro, bromo, iodo, and fluoro; with an amine of the formula ##STR00020## wherein A is selected from ##STR00021## and R.sup.5, R.sup.6, R.sup.6', R.sup.7, R.sup.8, R.sup.8' and p have the meanings given in claim 2.

33. The process of claim 32 wherein the group L is selected from methanesulfonyloxy and iodo.

34. A process for the preparation of a compound of formula I, comprising (a) reacting a compound of formula II ##STR00022## with ammonia or protected ammonia; (b) cleaving any optional protecting group from the resulting compound of step (a) to give a compound of formula (IV); ##STR00023## and (c) reacting the compound of formula (IV) with a bicyclic compound of formula ##STR00024## wherein, in the above formulas R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), or --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; n is 0, 1 or 2; m is 0, 1 or 2; L and L' independently represent a group selected from benzylsulphonyl, phenylsulphonyl, alkanesulphonyl, p-tolylsulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, chloro, bromo, iodo, and fluoro; and A has the meaning given in claim 2.

35. The process of claim 34 wherein the group L' is selected from iodo and methanesulfonyloxy.

36. The process of claim 34 wherein the reaction of Compound (IV) with Compound (V) may be catalyzed by a transition metal catalyst.

37. The process of claim 34 further comprising converting a basic compound of formula I synthesis into a pharmaceutically acceptable salt using an acid, or converting an acidic compound of formula I into a pharmaceutically acceptable salt using a base.

38. The process of claim 34 further comprising converting the resulting compound of formula I into a an N-oxide by oxidation with an oxidizing agent.

39. The process of claim 38 wherein the oxidizing agent is selected from 3-chloro-perbenzoic acid, trifluoroperacetic acid, or dimethyldioxiran.

Description

FIELD OF THE INVENTION

The present invention relates to novel bicyclic-substituted dihydropyrimido[4,5-d]pyrimidinones. These compounds and their pharmaceutically acceptable salts are useful in the treatment or control of cell proliferative disorders, including cancer. The present invention also relates to a process for the manufacture of the compounds of the invention, pharmaceutical compositions containing these compounds, as well as methods of using these compounds to treat cell proliferative disorders.

BACKGROUND OF THE INVENTION

Protein kinases are known to mediate cell proliferation. Inhibition of such kinases is useful in the treatment of cell proliferative diseases.

Some substituted bicyclic nitrogen heterocycles are known in the art for their protein kinase, specifically tyrosine kinase, inhibitory activity. WO 01/29042 and WO 01/29041 relates to alkylamino-substituted dihydropyrimido[4,5-d]pyrimidinone derivatives with p38 inhibitory activity. WO 99/61444 relates to dihydropyrimido[4,5-d]pyrimidinones, substituted with aryl and hetarylamines, sulfides, sulfoxides and sulfones as inhibitors for cyclin-dependent kinases (cdks) and tyrosine kinases. Aryl and heteroarylamine substituted dihydropyrimido[4,5-d]pyrimidinones are also discussed in WO 00/24744 as inhibitors of T-cell tyrosine kinase p56.sup.lck.

There continues to be a need for easily synthesized, small-molecule compounds effective in inhibiting the catalytic activity of protein kinases.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula

##STR00002## wherein A, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined herein.

The compounds according to this invention show activity as protein kinase inhibitors, in particular src family tyrosine kinase inhibitors, and are therefore useful for the treatment of diseases mediated by said tyrosine kinases. The family of tyrosine kinases plays an important role in the regulation of cell signaling and cell proliferation by phosphorylating tyrosine residues of peptides and proteins. Inappropriate activation of tyrosine kinases is known to be involved in a variety of disease states including inflammatory, immunological, CNS disorders, or oncological disorders, or bone diseases. Compounds of the present invention may be used as active agents in the prevention and therapy of, for example, transplant rejection, inflammatory bowel syndrome, rheumatoid arthritis, psoriasis, restenosis, allergic asthma, Alzheimers disease, Parkinson, stroke, osteoporosis, cancer, and benign hyperplasias.

The compounds of the present invention have surprisingly been found to show improved pharmacokinetic parameters in vivo, together with at least the same inhibitory activity against src-tyrosine kinases and therefore provide an enhanced bioavailability, compared to the compounds known in the art.

The present invention thus relates to compounds of formula I and their pharmaceutically acceptable salts and their enantiomeric forms, methods of preparation of these compounds, pharmaceutical compositions containing the compounds, as well as a method of using these compounds for the control, prevention or treatment of cell proliferative disorders, including the treatment or control of cancer, specifically solid tumors such as breast, colon or lung cancer.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" alone means a straight-chain or branched-chain alkyl group containing from 1 to 6, preferably from 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, n-hexyl as well as their isomers.

As used herein, the term "alkoxy" refers to a straight or branched chain hydrocarbonoxy group wherein the "alkyl" portion is an alkyl group as defined above. Examples include methoxy, ethoxy, propyloxy, i-propyloxy, n-butyloxy, 2-butyloxy, tert-butyloxy as well as n-pentyloxy and n-hexyloxy together with their isomers.

The term "alkoxyalkyl" means an alkyl group as defined above substituted by an alkoxy group as defined above, such groups are for example methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, tert-butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers.

The term "cycloalkyl" means a saturated, monocyclic ring containing 3 to 8, preferably from 3 to 6, carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

In the term "alkoxycarbonyl" alkoxy has the meaning given above. Examples of such groups are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, 2-butoxycarbonyl, tert-butoxycarbonyl as well as n-pentyloxycarbonyl and n-hexyloxycarbonyl together with their isomers.

The terms "acyl" and "acylamino" refer to groups R'--C(O)-- and R'--C(O)--NH-- in which R' is an alkyl group as defined above.

The term "aryl" as used herein denotes a phenyl and naphthyl, e.g. 1-naphthyl, 2-naphthyl.

The term "arylalkyl" as used herein denotes an aryl group as defined above attached to a straight chain alkylene group having 1 to 3 carbon atoms. Example of such groups are benzyl, 1-phenethyl, 2-phenethyl as well as phenpropyl and phenbutyl together with their isomers.

The term "heteroaryl" means a six or five membered aromatic ring which contains up to 3 heteroatoms selected independently from N, O or S. Examples for such heteroaryl groups are pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, furanyl, triazolyl.

The term "heteroarylalkyl" as used herein denotes a heteroaryl group as defined above attached to a straight chain alkylene group having 1 to 3 carbon atoms.

All the aforementioned groups may optionally be substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl (m=0, 1 or 2), --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2.

The term "effective amount" or "therapeutically effective amount" means an amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, that significantly inhibits cells proliferation, such as proliferation of tumor cells.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, adjuvant etc., means pharmacologically acceptable and substantially non-toxic to the patient to which the particular compound is administered.

In one embodiment, the invention relates to compounds of formula I

##STR00003## wherein R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; A is selected from the group

##STR00004## R.sup.5 is hydrogen, halogen, hydroxy, cyano, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl) or --SO.sub.2N(alkyl).sub.2; R.sup.6, R.sup.6' are each independently selected from hydrogen, alkyl or oxo; R.sup.7 is hydrogen, acyl, alkoxycarbonyl, alkoxyalkyl, alkyl or alkyl substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo, alkoxy, alkoxyalkyl, alkyl or alkyl substituted with hydrogen, hydroxy, cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9', provided that when either R.sup.8 or R.sup.8' represent an oxo group, this oxo group is not adjacent to an S(O).sub.m group; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; X is oxygen or S(O).sub.m; the dashed line is an optional second chemical bond; n is 0, 1 or 2; m is 0, 1 or 2; and p is 0, 1 or 2; or a pharmaceutically acceptable salt or N-oxides thereof.

In another embodiment, the invention relates to compounds of formula I

##STR00005## wherein R.sup.1 represents hydrogen or alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.2 represents halogen, cyano or CF.sub.3; R.sup.3 each R.sup.3 is independently selected from halogen, hydroxy, cyano, nitro, amino, acylamino, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, or alkyl, alkoxy or alkoxyalkyl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.4 represents hydrogen, alkyl, alkoxy or cyano; A is selected from the group

##STR00006## R.sup.5 is hydrogen, halogen, hydroxy, cyano, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl) or --SO.sub.2N(alkyl).sub.2; R.sup.6, R.sup.6' are each independently selected from hydrogen, alkyl or oxo; R.sup.7 is hydrogen, acyl, alkoxycarbonyl, alkoxyalkyl, alkyl or alkyl substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo, alkoxy, alkoxyalkyl, alkyl or alkyl substituted with hydrogen, cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9', provided that when either R.sup.8 or R.sup.8' represent an oxo group, this oxo group is not adjacent to an S(O).sub.m group; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; X is oxygen or S(O).sub.m; the dashed line is an optional second chemical bond; n is 0, 1 or 2; m is 0, 1 or 2; and p is 0, 1 or 2; or a pharmaceutically acceptable salt or N-oxide thereof.

Another embodiment of the invention contemplates compounds of formula I wherein R.sup.2 represents bromine and n=0.

Another embodiment of the invention contemplates compounds of formula I wherein R.sup.2 and R.sup.3 are each independently selected from fluorine, chlorine, bromine or iodine and n=1. Preferred are compounds of formula I wherein R.sup.2 represents bromine and R.sup.3 represents fluorine. Most preferably R.sup.3 is located at the 6-position of the phenyl ring. Also preferred are the compounds of formula I wherein R.sup.2 and R.sup.3 both represent chlorine and n=1.

Another embodiment of the invention contemplates compounds, wherein A is a group selected from formula A-1, A-2, A-3, A-4, A-5 or A-6 as defined above; R.sup.1 is optionally substituted alkyl or aryl, each of which may be optionally substituted with halogen, hydroxy, cyano, nitro, amino, acylamino, alkyl, alkoxy, alkoxyalkyl, --CONH.sub.2, --SO.sub.2NH.sub.2, --S(O).sub.m-alkyl, --NH-alkyl, --N(alkyl).sub.2, --CONH(alkyl), --CON(alkyl).sub.2, --SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2; R.sup.2 is halogen or cyano; R.sup.3 each R.sup.3 is independently selected from halogen; n is 0 or 1; R.sup.5 is hydrogen; and R.sup.4 hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

Such compounds are for example: 7-(benzo[1,3]dioxol-5-ylamino)-3-(2,4-dichloro-phenyl)-1-(4-methoxy-pheny- l)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one or 2-[7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6-ylamin- o)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-benzonitri- le.

Another embodiment of the invention contemplates compounds of formula I, wherein A is a group A-1 as defined above.

Especially preferred are compounds of formula I, wherein A is a group A-1; R.sup.5 is hydrogen; R.sup.7 is as defined above; p is 0; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such compounds include: 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-acetyl-spiro[1,3-benzodioxolo-2,4'-p- iperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-ethoxycarbonyl-spiro[1,3-benzodioxol- o-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-acetyl-spiro[1,3-benzodioxol- o-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-ethoxycarbonyl-spiro[1,3-ben- zodioxolo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(- 1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-ethyl-spiro[1,3-benzodioxolo- -2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-(2-methoxyethyl)-spiro[1,3-benzodiox- olo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-on- e, 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-(1'-(2-methoxyethyl)-spiro[1,3- -benzodioxolo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidi- n-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4'-piperidine]- -5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-methyl-spiro[1,3-benzodioxolo-2,4'-p- iperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluoro-phenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4'-pi- peridine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-bromo-6-fluoro-phenyl)-3,4-dihydro-7-(1'-methyl-spiro[1,3-benzodioxo- lo-2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one- , 3-(2-bromo-phenyl)-3,4-dihydro-7-(1'-cyanomethyl-spiro[1,3-benzodioxolo-- 2,4'-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one, and 3-(2-bromo-5-methoxyphenyl)-3,4-dihydro-7-(spiro[1,3-benzodioxolo-2,4- '-piperidine]-5-yl)amino-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one.

A further preferred embodiment of the invention includes compounds of formula I wherein A is a group A-2 as defined above.

Especially preferred are compounds of formula I, wherein A is a group A-2; R.sup.5 is hydrogen; X is oxygen; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl that optionally may be substituted with cyano, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, piperidin-1-yl, --S(O).sub.m-alkyl, or a group NR.sup.9R.sup.9'; R.sup.9 and R.sup.9' are each independently selected from hydrogen, alkyl or cycloalkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Examples of such compounds include: 3-(2-bromo-phenyl)-7-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-1-methyl-3,- 4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(2-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[- 1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[- 1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]dioxin-- 6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(2-dimethylaminomethyl-2,3-dihydro-benzo[1,- 4]dioxin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one- , 3-(2-bromo-phenyl)-7-(3-dimethylaminomethyl-2,3-dihydro-benzo[1,4]dioxin- -6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(3-dimethylaminomethyl-2,3-dihydro-benzo[1,- 4]dioxin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one- , 3-(2-bromo-phenyl)-7-(2-cyclopropylaminomethyl-2,3-dihydro-benzo[1,4]dio- xin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(2-morpholin-4-ylmethyl-2,3-dihydro-benzo[1- ,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-morpholin-4-ylmethyl-2,3-dihydro-benzo[1- ,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-morpholin-4-ylmethyl-2,3-dihydr- o-benzo[1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-on- e, and 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-pyrrolidin-1-ylmethyl-2,3- -dihydro-benzo[1,4]dioxin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimid- in-2-one.

Also especially preferred are compounds of formula I, wherein A is a group A-2; R.sup.5 is hydrogen; X is oxygen; R.sup.8 is hydrogen R.sup.8' is alkyl substituted with hydroxy; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Examples of such compounds include: 3-(2-bromo-phenyl)-7-(2-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylam- ino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(3-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylam- ino)-1methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(3-hydroxymethyl-2,3-dihydro-benzo[1,4]diox- in-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, and 3-(2-bromo-6-fluoro-phenyl)-7-(2-hydroxymethyl-2,3-dihydro-benzo[1,4]diox- in-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.

Also especially preferred are compounds of formula I, wherein A is a group A-2; R.sup.5 is hydrogen; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' represent hydrogen; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such compounds include for example: 3-(2-bromo-phenyl)-7-(2,3-dihydro-benzo[1,4]oxathiin-7-ylamino)-1-methyl-- 3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-7-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-be- nzo[1,4]oxathiin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimid- in-2-one, and 3-(2-bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.

A further preferred embodiment of the invention includes compounds of formula I wherein A is a group A-3 as defined above.

Especially preferred are compounds of formula I, are those wherein A is a group A-3; R.sup.5 is hydrogen; R.sup.7 is hydrogen or alkyl; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' are each independently selected from hydrogen, oxo or alkoxy, provided that when one of R.sup.8, R.sup.8' is oxo the dashed line is absent, and provided further that when R.sup.8 and R.sup.8' are selected from hydrogen or alkoxy the dashed line may represent an additional bond to form a double bond; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such compounds are for example: 3-(2-bromo-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-7-y- lamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]th- iazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1,3-dioxo-1,2,3,4-tetrahydro-1.la- mda..sup.4-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyri- midin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3,4-dihydro-2H-benzo[1,4]thiazin-- 7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-y- lamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-ben- zo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(3-oxo-3,4-dihydro-2H-benzo[1,4]th- iazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]th- iazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-7-(3-methoxy-4-methyl-1-oxo-1,4-dihydro-1.lamda..sup.4- -benzo[1,4]thiazin-7-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrim- idin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-3-oxo-3,4-dihydro-2H-ben- zo[1,4]thiazin-6-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-1,1-dioxo-1,2,3,4-tetrah- ydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4- ,5-d]pyrimidin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1H-dioxo-1,2,3,4-tetrahydro-1.lam- da..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrim- idin-2-one, 3-(2-bromo-phenyl)-1-methyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1- .lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]p- yrimidin-2-one, and 3-(2-bromo-6-fluoro-phenyl)-1-methyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tet- rahydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimid- o[4,5-d]pyrimidin-2-one.

A further preferred embodiment of the invention includes compounds of formula I wherein A is a group A-4 as defined above.

Especially preferred are compounds of formula I, wherein A is a group A-4; R.sup.5 is hydrogen; R.sup.6, R.sup.6 are each independently selected from hydrogen or oxo; R.sup.7 is hydrogen or alkyl that optionally may be substituted with hydroxy, cyano, --S(O).sub.m-alkyl, amino, --NH-alkyl or --N(alkyl).sub.2; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such compounds include for example: 5-[6-(2-bromo-phenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]py- rimidin-2-ylamino]-2-methyl-isoindole-1,3-dione, 3-(2-bromo-phenyl)-1-methyl-7-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino- )-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one; hydrochloride salt, 5-[6-(2-bromo-phenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]py- rimidin-2-ylamino]-isoindole-1,3-dione, 5-[6-(2-bromo-6-fluoro-phenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido- [4,5-d]pyrimidin-2-ylamino]-2-methyl-isoindole-1,3-dione, and 3-(2-bromo-6-fluoro-phenyl)-7-[2-(2-hydroxy-1,1-dimethyl-ethyl)-2,3-dihyd- ro-1H-isoindol-5-ylamino]-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin- -2-one; hydrochloride.

A further preferred embodiment of the invention are the compounds of formula I wherein A is a group A-5 as defined above.

Especially preferred are compounds of formula I, wherein A is a group A-5; R.sup.5 is hydrogen; X is oxygen; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such a compound is for example: 7-(benzo[1,3]dioxol-5-ylamino)-3-(2-bromo-phenyl)-1-methyl-3,4-dihydro-1H- -pyrimido[4,5-d]pyrimidin-2-one.

Also especially preferred are compounds of formula I, wherein A is a group A-5; R.sup.5 is hydrogen; X is S(O).sub.m; m is 0, 1 or 2; R.sup.8, R.sup.8' are each independently selected from hydrogen or alkyl; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Such compounds include for example: 3-(2-bromo-6-fluoro-phenyl)-7-(3,3-dioxo-2,3-dihydro-3.lamda..sup.6-benzo- [1,3]oxathiol-5-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-- 2-one, and 3-(2-bromo-phenyl)-7-(3,3-dioxo-2,3-dihydro-3.lamda..sup.6-benz- o[1,3]oxathiol-5-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin- -2-one.

A further preferred embodiment of the invention are the compounds of formula I wherein A is a group A-6 as defined above.

Especially preferred are compounds of formula I, wherein A is a group A-6; R.sup.5 is hydrogen; R.sup.6, R.sup.6', R.sup.7 have the significance given above; R.sup.1 is alkyl; R.sup.2 is halogen; R.sup.3 is halogen; n is 0 or 1; and R.sup.4 is hydrogen; or a pharmaceutically acceptable salt thereof.

Examples of such compounds include 3-(2-Bromo-5-methoxy-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-b- enzo[1,4]oxathiin-ylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidi- n-2-one, 7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6-y- lamino)-3-(2-fluoro-6-methoxy-phenyl)-1-methyl-3,4-dihydro-1H-pyrimido[4,5- -d]pyrimidin-2-one, 3-(2-Bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-- one; enantiomer 1, 3-(2-Bromo-phenyl)-7-(4,4-dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]o- xathiin-6-ylamino)-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-- one; enantiomer 2, 3-(2-Bromo-phenyl)-1,4-dimethyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahyd- ro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5- -d]pyrimidin-2-one; enantiomer 2, 3-(2-Bromo-phenyl)-1,4-dimethyl-7-(4-methyl-1,1,3-trioxo-1,2,3,4-tetrahyd- ro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylamino)-3,4-dihydro-1H-pyrimido[4,5- -d]pyrimidin-2-one; enantiomer 1, and 2-[7-(4,4-Dioxo-3,4-dihydro-2H-4.lamda..sup.6-benzo[1,4]oxathiin-6-ylamin- o)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-3-fluoro-b- enzonitrile.

A further embodiment of the invention is the process for the manufacture of the present amino-substituted dihydropyrimido[4,5-d]pyrimidinone derivatives of formula I. Said compounds can be prepared a) by reacting a compound of the general formula

##STR00007##

wherein R.sup.1 to R.sup.4 and n are as defined earlier, any hydroxy or amino group present may be in protected form, and L signifies a leaving group such as a sulfonyl derivative as for example benzylsulphonyl, phenylsulphonyl, alkanesulphonyl, a sulfonyloxy derivative as for example p-tolylsulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy, an alkanesulfinyl, or a halogen such as chloro, bromo, iodo, fluoro,

with an amine of the general formula

##STR00008##

wherein A is as defined earlier

and, where required, deprotecting a protected ydroxyl or protected amino group present in the reaction product; or b) by reacting a compound of formula (II) with ammonia, or with an protected amine such as benzylamine and subsequently cleaving off the protecting group, to give the amino derivative of formula

##STR00009##

wherein the symbols are as defined above;

which is then be reacted with a bicyclic compound of formula

##STR00010##

wherein L' represents a leaving group as defined for L, preferably a halogen such as chloro, bromo, iodo, or a sulfonyloxy derivative as for example p-tolylsulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy;

the reaction of (IV) with (V) may be catalysed by a transition metal catalyst known in the art, and c) if desired, converting a basic compound of formula I obtained into a pharmaceutically acceptable salt with an acid, or converting an acidic compound of formula I obtained into a pharmaceutically acceptable salt with a base, and d) if desired, converting a compound of formula I into a N-oxide by reaction oxidation with an oxidizing agent like 3-chloro-perbenzoic acid, trifluoroperacetic acid, or dimethyldioxiran.

The reaction of a compound of formula II with an amine of formula III in accordance with process (a) can be carried out in the presence or absence of a solvent. When a solvent is used, this can conveniently be a halogenated aliphatic hydrocarbon, e.g. dichloromethane or 1,2-dichloroethane, an open-chain ether, e.g. diethyl ether or diisopropyl ether or diethylene glycol dimethyl ether, a cyclic ether, e.g. tetrahydrofuran (THF), an optionally halogenated aromatic hydrocarbon, e.g. benzene, toluene, a xylene or chlorobenzene, or a formamide, e.g. dimethylformamide (DMF), or N-methylpyrrolidone (NMP) or dimethylsulfoxide (DMSO), or sulfolane. Suitably, the reaction is carried out at a temperature in the range of about 0.degree. C. to about 200.degree. C., preferably at about 100.degree. C. to about 200.degree. C. The reaction can be carried out in the presence of an acid, like hydrochloric acid (HCl), toluene sulfonic acid, trifluoro acetic acid, or mchlorobenzoic acid. Furthermore, the bicyclic anilines of formula III may be reacted as preformed salts. Alternatively, the reaction can be carried out in the presence of a base like potassium carbonate, triethyl amine, potassium tert-butoxide, sodium hydride, lithiumdiisopropylamide (LDA), buthyl lithium, or lithium hexamethyl disilazide. When using strong bases, the reaction may also be carried out at lower temperatures in the range from -20.degree. C. to 50.degree. C.

A hydroxy or amino or carboxylic acid group present in a starting material of formula II or III, may optionally be protected according to methods known in the art. A hydroxy group can for example be protected in the form of an ether, e.g. alkyl or silyl ether, or an ester, e.g. alkyl ester. With respect to protected amino, phthalimido is an example of such a group. An example of a protected carboxylic acid is an ester, e.g. alkyl ester.

Deprotection of such protected groups present in a product obtained by reacting a compound of formula II with an amine of formula III can be carried out in a manner known per se. Thus, for example, an ether such as an alkyl ether can be converted into hydroxy by treatment with hydrobromic acid; and an ester such as an alkyl ester can be converted into hydroxy using an alkali metal aluminium hydride such as lithium aluminium hydride. Again, for example, the phthalimido group can be converted into amino by treatment with hydrazine hydrate. A protected carboxylic acid group such as an ester, e.g. alkyl ester, can for example be converted into the free carboxylic acid group by cleaving it with an alkali metal hydroxide.

In the process according to b) a compound of formula II is reacted with ammonia or an protected amine to form the 2-amino-derivative of formula IV. The cleavage of an protecting group such the 4-methoxybenzyl group, can be carried out using methods which are known per se. For example, the cleavage can be carried out using trifluoroacetic acid, conveniently at an elevated temperature, preferably at the reflux temperature of the reaction mixture.

The 2-amino derivative of formula IV can be coupled to the bicyclic residue of formula V analogous to the method of WO2001 44258, e.g. by catalysis with a Pd-phosphine complex like Pd(OAc).sub.2/BINAP, Pd(dba).sub.2/P(tert-Bu).sub.3 or Xantphos, in the presence of a base like Cs.sub.2CO.sub.3, NaOtert-Bu, NaOPh, or K.sub.3PO.sub.4, in an inert solvent like toluene or xylene, or THF, or NMP, in the temperature range between 50 and 180.degree. C.

Compounds of formula I, wherein A is a group A-1, A-2, A-3, A-4, A-5, or A-6 and one of the groups R.sup.7, R.sup.8 or R.sup.8' are an optionally substituted aminoalkyl group, can be prepared from the compounds of formula I bearing the corresponding hydroxy-alkyl sub