OA11554A - Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation. - Google Patents

Description

C11554 -1-

B1CYCL1C PYRIMIDINES AND BICYCLIC 3,4-DIHYDROPYRlMIDINES ASINHIBITORS OF CELLULAR PROLIFERATION

F1ELD OF THE INVENTION

This invention relates to bicyclic heterocycles that inhibit cyclin-dependent 5 kinase and tyrosine kinase enzymes, and as such are useful to treat cell proliférative disorders such as angiogenesis, atherosclerosis, restenosis, andcancer.

SUMMARY OF THE RELATED ART

Cell cycle kinases are naturally occurring enzymes involved in régulation 10 of the cell cycle (Meijer L., “Chemical Inhibitors of Cyclin-Dependent Kinases”,

Progress in Cell Cycle Research, 1995;1:351-363). Typical enzymes include thecyclin-dependent kinases (cdk) cdkl (also known as cdc2), cdk2, cdk4, cdk5,cdk6, and wee-1 kinase. Increased activity or temporally abnormal activation ofthese kinases has been shown to resuit in development of human tumors and other 15 proliférative disorders such as restenosis. Compounds that inhibit cdks, either byblocking the interaction between a cyclin and its kinase partner, or by binding toand inactivating the kinase, cause inhibition of cell prolifération, and are thususeful fortreating tumors or other abnormally proliferating cells.

Severalicompounds that inhibit cdks hâve demonstrated both preclinical 20 and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that hasbeen shown ito be apotent inhibitor of several types of breast and lung cancer cells(Kaur, et al., J. Natl. Cancer Inst., 1992;84:1736-1740; Int. J. Oncol., 1996:9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4.Olomoucine [2-(hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potent 25 inhibitor of cdk2. and;cdk5 (Vesely, et al., Eur. J. Biochem., 1994;224:771-786),and has been shown to inhibit prolifération of approximately 60 different humantumor cell Unes used by the National Cancer Institute (NCI) to screen for newcancer thérapies (Abraham, et al., Biology of the Cell, 1995;83:105-120). -i- 0115 54 ln addition, tyrosine kinases are a class of enzymes that catalyze thetransfer of the terminal phosphate of adenosine triphosphate (ATP) to tryrosineresidues on protein substrates. Tyrosine kinases are an intégral part of growthfactor receptorsiand are essential for the propagation of growth factor signal 5 transduction leading to cellular prolifération, différentiation, and migration.

Growth factor réceptors are also known as receptor tyrosine kinases (RTKs). Theaberrant régulation of growth factors or their cognate receptors play a critical rôlein the progression of proliférative diseases. For example, the fibroblast growthfactor (FGF) and the vascular endothélial growth factor (VEGF) hâve been 10 implicated as important mediators of tumor promoted angiogenesis. Solid tumorsare dépendent upon the formation of new blood vessels from preexisting vessels(angiogenesis) to nourish their growth and to provide a conduit for métastasés.Accordingly; inhibitors of the FGF and VEGF RTKs, as well as other tyrosinekinases, are useful agents for the prévention and treatment of proliférative diseases 15 dépendent: on these enzymes.

Despite the progress that has been made, the search continues for small molecularweight compounds that are orally bioavailable and useful for treating awide variety of human tumors and other proliférative disorders such as restenosis,angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular 20 degeneration, and athéroscléroses.

SUMMARY OF THE INVENTION

This invention provides bicyclic heterocycles that are useful for treatingcell proliférative disorders, such as cancer, atherosclerosis, restenosis,angiogenesis, diabetic retinopathy, psoriasis, and endometriosis. We hâve 25 discovered a group of bicyclic pyrimidine analogs that are potent inhibitors of cyclin-dependent kinases (cdks) and tyrosine kinases. The compounds are readilysynthesized and can be administered by a variety of routes, including orally andparenterally, and hâve little or no toxicity. ' The compounds of the invention are members of the class of compounds 30 of Formulai: -o- π i rs r9 011554

and the pharmaceutically acceptable salts thereof,wherein: the dotted line represents an optional double bond; 5 Z is N or CH; G is N or CH; W is NH, S. SO, or SO2; X is either O, S, or NRJ θ; RJ, R-, and are independently selected from the group consisting of H, 10 (CH2)nAr, COR4, (CH2)nheteroaryl, (CH2)nheterocyclyl, C j -C ] q alkyl, C3-C10 cycloalkyl, C2'C}() alkenyl, and C2-C]Q alkynyl, wherein n is 0,1,2, or 3, and the (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl,and alkynyl groups are optionally substituted by up to 5 groups selectedfrom NR4R5, N(O)R4R5, NR4R5R^Y, alkyl, phenyl, substituted phenyl, 15 (CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4, CCbRA CONR4R5, SO2NR4r5, SO3R4, PO3R4, aldéhyde, nitrile, nitro, OR5

I heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, 20 j

H C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4, T(CH2)mC(O)NR4NR5, orT(CH2)mCO2R4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R4 NR4R6Y, or CR4R5, and Q is O, S, NR5, N(O)R5, or NR5r6Y;25 when the: dotted line is présent, R^ is absent; ./ -4- C11554 otherwise R3 has the meanings of R2, wherein R2 is as defined above, as well asOH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4r5, SO3R4, PO3R4, OR5

I 5 T(CH2)mQR4, T(CH2)mC-(CH2)mQR4,

I

H wherein T and Q are as defined above; R4 and R$ are each independently selected from the group consisting of10 hydrogen, C] -Cg alkyl, substituted alkyl, C2-Cô alkenyl, C2-C(j alkynyl, N(Ci-Cgalkyl)i or 2, (CH2)nAr, C3-Ciq cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R^ together with the nitrogen to which they areattached optionally form a ring having 3 to 7 carbon atoms and said ringoptionaHy contains 1,2, or 3 heteroatoms selected from the group 15 consisting of nitrogen, substituted nitrogen, oxygen, and suliur; when R4 and together with the nitrogen to which they are attached form a ring the said ring is optionally substituted by 1 to 3 groups selected from OH,OR4, NR4R5, (CH2)mOR4, (CH2)mNR4R5, T-(CH2)mQR4,CO-T-(CH2)mQR4, NH(CO)T(CH2)mQR4, T-(CH2)mCO2R4, or 20 T(CH2)mCONR4R5. R6 is alkyl; R8 and R^ independently are H, Cj-C3 alkyl, NR4R^, N(O)R4R5, NR4r5r6y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, or NO2; 25 when the dotted line is absent, R^ is additionally carbonyl, thiocarbonyl, imineand substituted imine, oxime and oxime ether, and Y is a halo counter-ion.

In a preferred embodiment, the invention provides compounds of

Formula Π, III, and IV 01*554 -5- 8

wherein R 5 R^, r3} W, r8? and R^ are as defined above. 5 Additionally preferred compounds hâve the above formulas wherein W is NH. Also preferred are those compounds wherein R1 is substituted alkyl, phenyl,or pyridyl.

This invention also provides pharmaceutical formulations comprising acompound of Formula 1 together with a pharmaceutically acceptable carrier, 10 diluent, or excipient therefor.

Compounds within the scope of the présent invention are inhibitors of the cyclin-dependent kinases such as cdk2, cdc2, and cdk4. Some of the compoundsof the présent invention also inhibit growth factor mediated tyrosine kinasesincluding those of platelet-derived growth factor (PDGF), fïbroblast growth factor 15 (FGF), and epidermal growth factor (EGF), as well as non-receptor tyrosine kinases such as c-Src. As inhibitors of cyclin-dependent, as well as growth factor-mediated and non-receptor tyrosine kinases, the compounds of the instantinvention are useful in controlling proliférative disorders such as cancer, psoriasis,

J C11E54 vascular smooth muscle cell prolifération associated with atherosclerosis, diabéticretinopathy and angiogenesis, and postsurgical vascular stenosis and restenosis inmammals. A further embodiment of this invention is a method of treating subjects5 suffering from diseases caused by cellular prolifération. The method entails inhibiting prolifération of tumorigenic cells of épithélial origin and vascularsmooth muscle prolifération, and/or cellular migration by administering atherapeutically effective amount of a compound of Formula I to a subject in needof treatment. 10 A further embodiment of this invention is a method of treating subjects suffering from diseases caused by DNA tumor viruses such as herpes viruses.

DETAILED DESCRIPTION OF THE INVENTION

We hâve discovered a new class of compounds that are potent inhibitors ofcyclin-dependent kinases (cdks) and tyrosine kinases that are useful agents for 15 treating subjects suffering from diseases caused by abnormal cell prolifération.

Compounds within the scope of the présent invention are inhibitors of the cyclin-dependent kinases such as cdc2, cdk2, and cdk4, and tyrosine kinases such asPDGFr. FGFr, and c-Src. As inhibitors of these kinases, the compounds of the instant invention are useful in controlling proliférative disorders such as cancer, 20 psoriasis, vascular smooth muscle prolifération associated with atherosclerosis,postsurgical vascular stenosis, angiogenesis, diabétic retinopathy, and restenosisin mammals.

The compounds of the invention are members of the class of compoundsof Formula I:

and the pharmaceutically acceptable salts thereof, -7- Û11554 wherein: the dotted line (—) represents an optional double bond; Z is N or CH; G is N or CH; 5 W is NH, S, SO, or SO2; X is either O, S, or NRJO; RJ, R-, and are independently selected from the group consisting of H, (CH2)nAr, COR4, (CH2)nheteroaryl, (CH2)nheterocyclyl, C j -C jq alkyl,C3-C10 cycloalkyl, C2-Cjq alkenyl, and C2-Cio alkynyl, wherein n is 0, 10 1, 2, or 3, and the (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selectedfrom NR4R5, N(O)R4R5, NR4R5r6y, alkyl., phenyl, substituted phenyl,(CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4,CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, aldéhyde, nitrile, nitro, 15 OR5 t heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4,

I

H 20 C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4, T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, and Q is O, S, NR5, N(O)R5, or NR5R6Y;when the dotted line is présent, R5 is absent; otherwise (when — is absent) R5 has the meanings of R^, wherein R^ is as 25 defined above, as well as OH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, OR5

I T(CH2)mQR4, T(CH2)mC-(CH2)mQR4,

30 I

H wherein T and Q are as defined above; -8- Π'Ε.Η R4 and are each independently selected from the group consisting of hydrogen, Cj-Cg alkyl, substituted alkyl, C2-C6 alkenyl, C?-Cg alkynyl,N(C j-Cgalkyl)! or 2» (CH2)nAri C3-Cjo cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R^ together with the nitrogen to which they are5 attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1,2, or 3 heteroatoms selected from the groupconsisting of nitrogen, substituted nitrogen, oxygen, and sulfur; when R4 and R$ together with the nitrogen to which they are attached form a ring,the said ring is optionally substituted by 1 to 3 groups selected from OH, 10 OR4, NR4R5, (CH2)mOR4, (CH2)mNR4R5, T-(CH2)mQR4, CO-T-(CH2)mQR4 NH(CO)T(CH2)mQR4, T-(CH2)mCO2R4, orT(CH2)mCONR4R5; R^ is alkyl; R8 and R^ independently are H, CJ-C3 alkyl, NR4R$, N(O)R4r5, NR4r5r6y} 15 hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, or NO2; when the dotted line is absent, R^ is additionally carbonyl, thiocarbonyl, imineand substituted imine, oxime and oxime ether, andY is a halo counter-ion. 20 An especially preferred group of compounds hâve the above formula wherein X is O.

Another preferred group of compounds are those wherein W is NH. A preferred group of compounds of Formula 1 hâve the above formula wherein X is O orNHR^, and R^ is H or substituted aryl. 25 Also preferred are compounds of Formula 1 wherein R^ and R^ both are hydrogen.

Another preferred group of compounds of Formula 1 hâve the above formula wherein X is O, and R^ is Et, Pr, z'-Pr, z'-Bu, z'-pentyl, or cycloalkyl. In an especially preferred group of compounds, X is O and R^ is cyclopentyl or ethyl. -9- 10 15

Cl 1 S 54 ln yet another preferred group of compounds of Formula 1, X is O, W isNH, and RJ is alkyl, substituted alkyl, phenyl, or substituted phenyl, pyridyl or substituîed pyridyl. Preferred RJ substituted phenyl groups include 4-piperidinyl(with or without substitution), 4-(2-diethylaminoethoxy), 4-pyrrole, 4-pyrazol, and4-(4-methyl piperazin-l-yl). In an especially preferred group of compounds, X isO, and RJ is phenyl substituted with hydroxy, alkoxy, NR^R^, or T(CH2)mQR^, where R^ and R^, T, m, and Q ail are as defined above. In an even more preferredgroup of compounds, X is O, and R^ is phenyl substituted with NR^r5 orT(CH2)mQR4. where R^ and R^, T, m, and Q ail are as defined above.

Another preferred group of compounds of Formula I are those wherein X isNH.

Further preferred compounds are the pyrimido[4,5-JJpyrimidines ofFormula 1 wherein Z is N.

Especially preferred compounds provided by the invention hâveFormulas Π, III, and IV

II

R“

X

III 10 15 -10

wherein RÀ R-, R^, W, R^, r9; and X are as defined above.

Additionally preferred compounds hâve the above formulas wherein W is NH. Also preferred are those compounds wherein R1 is alkyl, substituted phenylor pyridyl.

Further preferred compounds of the présent invention hâve the Formula V:

H R2 where R2 is as defined above, and Ar is phenyl, substituted phenyl, or heteroaryl.Ideally, R- is alkyl such as ethyl, isopropyl, propyl, butyl, or isopentyl, orcycloalkyl such as norbomyl, cyclopentyl, cyclohexyl, or adamantyl. A mostpreferred Ar group is phenyl, preferably substituted with 1, 2, or 3 groups selectedfrom phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxy carbonylmethyl, carboxy, carboxymethyl,ethoxycarbonyl, 2-carboxy ethyl, 2-ethoxycarbonylethyl, NR^RS, and0(CH2)o_6NR4r5, wherein R^ and R$ are as defined above. Another preferredAr group is pyridyl and thiazolyl, for example, 3-pyridyl, 2-thiazolyl, eachoptionally substituted by alkyl, halo, phenyl, hydroxyphenyl, or alkoxyphenyl.

Other preferred compounds hâve Formula VI

-U- c 1 i 5 E 4 where alkyl, Ar, aryl, heteroaryl, R2, and X are as defined above. Particularly preferred compounds of Formula VI are those where X is O or NHCOR^, forexample, NHCO alkyl and NHCONH alkyl. Preferred aryl groups are phenyl andsubstituted phenyl. Preferred heteroaryl groups are pyridyl and substituted pyridyl.

Compounds of Formula 1 wherein W is S, SO, or SO? are especiallyuseful as intermediates leading to compounds where W is NH, but suchcompounds also display inhibitory activity against cyclin-dependent kinases andtyrosine kinases.

Unless otherwise expressly stated, the following définitions are adhered tothroughout this disclosure. “Alkyl” means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise) and includes, for example, methyl,ethyl, n-propyl, isopropyl, «-butyl, jec-butyl, isobutyl, ZerZ-butyl, n-pentyl,isopentyl, n-hexyl, and the like. “Halo” includes fluoro, chloro, bromo, and iodo. “Alkenyl” means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one or two double bonds and includes ethenyl, 3-buten- 1-yl, 2-ethenylbutyl, 3-hexen-l-yl, 3,6-octadien-l-yl, and the like. “Alkynyl” means straight and branched hydrocarbon radicals having from2 to 10 carbon atoms and one or two triple bonds and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, 3,6-octadien-l-yl, and the like. “Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl group such ascyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,norpinanyl, decalinyl, norbomyl, cyclohexyl, and cyclopentyl. Such groups can besubstituted with groups such as hydroxy, keto, and the like. Also inciuded arerings in which 1 to 3 heteroatoms replace carbons. Such groups are termed“heterocyclyl”, which means a cycloalkyl group also bearing at least oneheteroatom selected from O, S, or NR2’ examples being oxiranyl, pyrrolidinyl,piperidyl, tetrahydropyran, and morpholine. “Alkoxy” refers to the alkyl groups mentioned above bound throughoxygen, examples of which include methoxy, ethoxy, isopropoxy, ZerZ-butoxy, and -12- 01 1054 the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-OH3, andthe like. “Alkanoyl” groups are alkyl linked through a carbonyl, i.e., Cj-Cç-CXO)-.Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl. 5 “Acyl” means an alkyl or aryl (Ar) group bonded through a carbonyl group, ie, R-C(O)-. For example, acyl includes a Cj-Cjo alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4r5 or acarboxylic or heterocyçlic group. Typical acyl groups include acetyl, benzoyl, andthe like. 10 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected front NR^R^,N(O)R4r5, NR4r5r6y, phenyl, substituted phenyl, thio Cj-Cjo alkyl, Cj-Cjoalkoxy, hydroxy, carboxy, Cj-C]q alkoxy carbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms 15 selected front nitrogen, substituted nitrogen, oxygen, and sulfur. “Substituted nitrogen” means nitrogen bearing Cj-Cjo alkyl or (CH2)nPh where n is 0, 1,2,or 3. Perhalo and polyhalo substitution is also embraced.

Examples of substituted alkyl groups include 2-aminoethyl,pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, 20 ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2- (4-methylpiperazinyl)ethyl.

Examples of substituted alkynyl groups include 2-methoxyethynyl, 25 2-ethylsulfanyethynyl, 4-(l-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3- diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and thelike.

Typical substituted alkoxy groups include 2-aminoethoxy,trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 30 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. -13- C11554

Further examples of substituted alkyl, alkenyl, and alkynyl groups includedimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl,5-ethylmethylamino-3-pentyn-l -yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyi, 3-imidazolidin-1 -ylpropyl, 4-tetrahydrothiazol-3-yl-5 butyl, phenylmeîhyl, 3-chlorophenylmethyl, and the like.

The lerms “Ar” and “aryl” refer to unsubstituted and substituted aromaticgroups. Heteroaryl groups hâve from 4 to 9 ring atoms, from 1 to 4 of which areindependently selected from the group consisting of O, S, and N. Preferredheteroaryl groups hâve 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. 10 Mono and bicyclic aromatic ring Systems are included in the définition of aryl andheteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2.6- dibromophenyl, 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 2.4.6- tribromophenyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl,1-naphthyl, 4,7-dichloro-2-naphthyl, pyrrole, pyrazole, imidazole, thiazole, and 15 the like. An especially preferred heteroaryl group is pyridyl.

Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groupsindependently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl,hydroxy, -COOR^, amino of the formula -NR4R5, CONR4R5, and T(CH2)niQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, 20 NR4r6y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5r6y wherein R4 and R5 are as described above, and R? is H, alkyl or substituted alkyl, for example,methyl, 2-aminoethyl, trichloroethyl, diphenylmethyl, and the like. The alkyl andalkoxy groups can be substituted as defined above. For example, typical groupsare carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and 25 alkoxyalkyl.

The invention compound will be named herein according to the followingposition assignments

when G = N -14- 011 554 and

It will be appreciated by those skilled in the art that the compoundsdefined by the above formula can exist in tantomeric forms. For example, a 2-ketocompound can tantomerize to a 2-enol when R- is hydrogen as follows:

H

Similarly, 2-imino compounds can tantomerize to 2-amino compounds as follows: N‘ R8 R9

N' -R~

HN R8 R9

-R"

R1 — W 'Z G 1

H A,

^NR

10 R1 —W N'

NHR 10 2-Thiones can tantomerize to thiols as follows: 10 R8 R9

XN A.

R1—W Z G 'S R8 R9 -R-

Ail of the tantomeric forms of compounds of Formulas 1-IV are contemplated and included within the scope of this invention.

The compounds of the présent invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, 011E54 -15- including hydrated forms, are équivalent to unsolvated forms and are intended tobe encompassed within the scope of the présent invention.

The compounds of Formula 1 are capable of further forming bothpharmaceutically acceptable formulations comprising salts, including but not 5 limited to acid addition and/or base salts, solvatés and N-oxides. This inventionalso provides pharmaceutical formulations comprising a compound of Formula 1together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.Ail of these forms are within the présent invention.

Pharmaceutically acceptable acid addition salts of the compounds of 10 Formula 1 include salts derived form inorganic acids such as hydrochloric, nitric,phosphoric. sulfuric, hydrobromic, hydriodic, phosphorus, and the lîke, as well asthe salts derived from organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus 15 include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate,malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, 20 toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acidssuch as arginate, gluconate, galacturonate, and the like; see, for example, Berge,et al., “Pharmaceutical Salts,” J. q/Pharmaceutical Science, 1977;66:1-19.

The acid addition salts of the basic compounds are prepared by contacting 25 the free base form with a sufficient amount of the desired acid to produce the saitin the conventional manner. The free base form may be regenerated by contactingthe sait form with a base and isolating the free base in the conventional manner.The free base forms differ from their respective sait forms somewhat in certainphysical properties such as solubility in polar solvents, but otherwise the salts are 30 équivalent to their respective free base for puiposes of the présent invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth métal hydroxides, or of organic aminéeExamples of metals used as cations are sodium, potassium, magnésium, calcium, -16- 011554 and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyîglucamine,and procaine; see, for example, Berge, et al., supra.

The base addition salts of acidic compounds are prepared by contacting the 5 free acid form with a sufficient amount of the desired base to produce the sait in the conventional manner. The free acid form may be regenerated by contacting thesait form with an acid and isolating the free acid in a conventional manner. Thefree acid forms differ from their respective sait forms somewhat in certainphysical properties sûch as solubility in polar solvents, but otherwise the salts are 10 équivalent to their respective free acid for purposes of the présent invention.

The compounds of the présent invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such asmelanoma) and other proliférative diseases including but not limited to psoriasis,HSV, HIV, restenosis, and athéroscléroses. To utilize a compound of the présent 15 invention to treat cancer, a patient having cancer is administered a therapeuticallyeffective amount of a pharmaceutically acceptable composition comprising aninvention compound. A further embodiment of this invention is a method of treating subjectssuffering from diseases caused by vascular smooth muscle cell prolifération. 20 Compounds within the scope of the présent invention effêctively inhibit vascularsmooth muscle cell prolifération and migration. The method entails inhibitingvascular smooth muscle prolifération, and/or migration by administering aneffective amount of a compound of Formula I to a subject in need of treatment.

The compounds of the présent invention can be formulated and 25 administered in a wide variety of oral and parentéral dosage forms, including transdermal and rectal administration. It will be recogntzed to those skilled in theart that the following dosage forms may comprise as the active component, acompound of Formula I or a corresponding pharmaceutically acceptable sait orsolvaté thereof. 30 A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I together with a pharmaceutically acceptablecarrier, diluent, or excipient therefor. For preparing pharmaceutical compositions -π- 011554 with the compounds of the présent invention, pharmacuetically acceptable carrierscan be either a solid or liquid. Solid form préparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensible granules. A solid carrier canbe one or more substances which may also act as diluents, flavoring agents,binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid such as talc or starch whichis in a mixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The formulations of this invention preferably contain from about 5% toabout 70% or more of the active compound. Suitable carriers include magnésiumcarbonate, magnésium stéarate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth. methylcellulose, sodium carboxymethylcellulose, a low melting wax,cocoa butter, and the like. A preferred form for oral use are capsules, whichinclude the formulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with or without othercarriers, is surrounded by a carrier, which is thus in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fattyacid glycerides or cocoa butter, is first melted and the active component isdispersed homogenously therein, as by stirring. The molten homogenous mixtureis then poured into convenient size molds, allowed to cool, and thereby to solidify.

Liquid form préparations include solutions, suspensions, and émulsionssuch as water or water/propylene glycol solutions. For parentéral injection, liquidpréparations can be formulated in solution in aqueous polyethylene glycolsolution, isotonie saline, 5% aqueous glucose, and the like. Aqueous solutionssuitable for oral use can be prepared by dissolving the active component in waterand adding suitable colorants, flavors, stabilizing and thickening agents as desired.Aqueous suspensions suitable for oral use can be made by dispersing the finelydivided active component in water and mixing with a viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. -18- 011554

Also included are solid form préparations that are intended to beconverted, shortly before use, to liquid form préparations for oral administration.Such liquid forms include solutions, suspensions, and émulsions. Thesepréparations may contain, in addition to the active component, colorants, flavors, 5 stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles, ahd the likecan be utilized to préparé sustained-release dosage forms. Also, osmotic pumpscan be employed to deliver the active compound uniformally over a prolongedperiod. 10 The pharmaceutical préparations of the invention are preferably in unit dosage form. In such form, the préparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unit dosage formcan be a packaged préparation, the package containing discrète quantities ofpréparation, such as packeted tablets, capsules, and powders in vials or ampules. 15 Also, the unit dosage form can be a capsule, tabîet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

The therapeutically effective dose of a compound of Formula 1 and/orFormula 11 will generally be from about 1 mg to about 100 mg/kg of body weightper day. Typical adult doses will be about 50 mg to about 800 mg per day. The 20 quantity of active component in a unit dose préparation may be varied or adjustedfrom about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg accordingto the particular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeutic agents. Asubject in need of treatment with a compound of Formula 1 and/or II is 25 administered a dosage of about 1 to about 500 mg per day, either singly or inmultiple doses over a 24-hour period.

The compounds of the présent invention are capable of binding to andinhibiting the activity of proteins having the ability to phosphorylate otherproteins, such as cdks, PDGFr, FGFr, c-Src, and EGFr-FL. Cdks form complexes 30 with cyclins, and these complexes phosphorylate key proteins allowing cells toproceed through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995; 1:351 -363). The compounds of this invention inhibit this phosphorylation -19- 011554 and therefore can be used as anti-proliferative agents for the treatment of cancerand/or restenosis and other proliférative diseases.

Because of their inhibitory activity against cdks and other kinases, thecompounds of the présent invention are also useful research tools for studying the 5 mechanism of action of those kinases, both in vitro and in vivo.

While the forms of the invention herein constitute presently preferredembodiments, many others are possible. It is not intended herein to mention ail ofthe possible équivalent forms or ramifications of the invention. It is understoodthat the ternis used herein are merely descriptive rather than limiting, and those 10 skilled in the art will realize that various changes may be made without departingfrom the spirit or scope of the invention.

The following compounds illustrate spécifie embodiments provided by theprésent invention, and the compounds listed below are among the preferredembodiments. 15 l-Methyl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihydro- pyrimido[4.5-ùQpyrimidin-2( 1 i/)-one; l-Methyl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-3,4-dihydro-pyrimido [4,5-JJpyrimidin-2( 1//)-one; 1 -Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino]-3,4-dihydro-20 pyrimido[4,5-</|pyrimidin-2(l//)-one; 1 -Methy 1-7- {4- [4-(dimethy lamino)piperidin-1 -y 1 ] pheny lamino} -3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l//)-one; 1 -Isopropyl-7-[4-(pyrazol-1 -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 177)-one; 25 1 -Isopropyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro- pyrimido[4,5-ifjpyrimidin-2( 177)-one; 1 -Isopropyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-ùQpyrimidin-2( 1 //)-one; l-Isopropyl-7-{4-[4-(dimethylamino)piperidin-l-yl]phenylamino}-3,4-30 dihydro-pyrimido[4,5-<7]pyrimidin-2(l/y)-one; 1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(pyrazol-1 -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2(l/i)-one (exo); -20- 011554 1 -Bicyclo[2.2.1 ]hêpt-2-yl-7-[4-(4-methylpiperazin-1 -yl)phenyIamino]-3,4-dihydro-pyrimido[4,5-</]pyrirnidin-2( lH)-one (exo); 1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-hydroxypiperidin-l -yl)phenylamino]- 3.4- dihydro-pyrimido[4.5-d]pyrimidin-2( 1 H)-one (exo); 5 1 -Bicyclo[2.2.1 ]hept-2-yl-7-{4-[4-(dimethyIamino)piperidin-1- yl]phenylamino}-3,4-dihydro-pyrimido[4,5-i(Jpyrimidin-2(l/i)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-1 -cyclopentyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2( 177)-one; 7- (4-[4-(2-Amino-4-methy l-pentanoyl)-piperazin-1 -yl]-phenylamino} -1 -10 cyclopentyl-3,4-dihydro-pyrimido[4,5-c(]pyrimidin-2(l//)-one; 1 -Methyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 -yljphenylamino}- 3.4- dihydro-pyrimido[4,5-i/]pyrimidin-2( 177)-one; 1 -lsopropyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1 -yl]phenylamino}-3,4-dihydro-pyrimido[4,5-iZJpyrimidin-2(l//)-one; 15 1 -Cyclopentyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 - yl]phenylaraino}-3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2(l//)-one; 1 -Bicyclo[2.2.1 ]hept-2-yl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 -yl]phenylamino}-3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2(177)-one (exo); ]-Cyclopentyl-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido[4,5-20 i/]pyrimidin-2( 1 H)-one ; l-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-3,4-dihÿdro-pyrimido[4.5-£/jpyrimidin-2( 177)-one; l-CyclopentyI-7-(4-fluoro-3-methyI-phenylamino)-3,4-dihydro-pyrimido[4.5-c(]pyrimidin-2( 1 H)-one; 25 7-[4-(3-Amino-pyrrolidin-1 -yl)-phenylamino]-1 -cyclopentyl-3,4-dihydro- pyrimido[4.5-J)pyrimidin-2( 17/)-one; 7-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino]-1 -cyclopentyl-3,4-dihydro-pyrimido[4.5-fi()pyrimidin-2(l//)-one; 1 -Cyclopentyl-7-(4-piperazin-1 -y l-phenylamino)-3,4-dihydro-30 pyrimido[4.5-£/]pyrimidin-2(lZ/)-one; l-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c)pyrrol-2-yl)- phenylamino]-3,4-dihydro-pyrimido[4,5-i/lpyrimidin-2(l//)-one; -2>- 011554 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2-chloro-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l/7)-one; 5 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6-dichloro-3,5- dimethoxy-phenyl)- l-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2-methyl-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2(17/)-one; 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6-dimethyl-3,5-10 dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1 i/)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2(lH)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-chloro-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-d3pyrimidin-2(lH)-°ne; 15 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2,6-dichloro-3,5- dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-cQpyTimidin-2(l//)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-methyl-3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-cf]pyrimidin-2(l 77)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2,6-dimethyl-3,5-20 dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2( 1 i/)-one; 7-(4-Diethylamino-butylamino)-3 -(3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l/Y)-one; 7-(4-Diethylamino-butylamino)-3 -(2-chloro-3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l£/)-one; 25 7-(4-Diethylamino-butylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l· ethyl-3,4-dihydro-pyrimido[4,5-<7}pyrimidin-2(lH)-one; 7-(4-Diethylamino-butylamino)-3 -(2-methyl-3,5 -dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2(l/Y)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dimethyl-3,5-dimethoxy-phenyl)-l30 ethyl-3,4-dihydro-pyrimido[4,5-<flpyrimidin-2(l H)-one; 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4.5-i/]pyrimidin-2(l//)-one; 011554 7-(Pyridin-4-ylamino)-3-(2-chloro-3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-i(lpyrimidin-2( 1 /7)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1 #)-one; 5 7-(Pyridin-4-yiamino)-3-(2,6-dimethyl-3,5-dimethoxy-phenyl)-1 -ethyl- 3,4-dihydro-pyrimido[4,5-J]pyrimidin-2( 12/)-one; 7-(Pyridin-4-ylamino)-3-(2-methyl-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-i(|pyrimidin-2( 1 //)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichlorb-3,5-dimethoxy-phenyl)-1 -10 cyclopentyl-3,4-dihydro-pyrimido[4,5-£dpyrimidin-2(177)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino-butylamino)-3,4- dihydro-pyrirnido[4,5-if|pyrimidin-2(l//)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-c/]pyrimidin-2( 1 //)-one; 15 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido[4.5-<7]pyrimidin-2(l//)-one; 3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido[4,5-i/jpyrimidin-2(l//)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy-phenyl)-20 3,4-dihydro-pyrimido[4,5-<7]pyrimidin-2(l//)-one; 3 -(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2( 17/)-one; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)- phenylamino]-3,4-dihydro-pyriniido[4,5-d]pyrimidin-2(l//)-one; 25 7-[3-(Carboxy)-phenylamino]-3-(2,6-dichloro-phenyl)-1 -methyl-3,4- dihydro-pyrimido[4,5-</]pyrimidin-2(17/)-one; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6- dichloro-phenyl)-l-methyl-3,4-dihydro-pyrimido[4,5-ô/]pyrimidin-2(l/7)-one; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6-30 dichloro-3-hydroxy-phenyl)-1 -methyl-3,4-dihydro-pyrimido[4,5-üQpyrimidin- 2(l#)-one; 7-[3-(Carboxy)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)-1 -methyl-3,4-dihydro-pyrimido[4,5-4/]pyrimidin-2(l//)’One’ •23- 01 1 554 3-(2,6-Dichloro-phenyl)-7-[4-(2-ethylamino-ethoxy)-phenylamino]-l- methyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 17/)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(2-ethylamino-ethoxy)- phenylamino]-1 -methyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 1 7/)-one; 5 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-phenyl)-l -methyl-3,4- dihydro-pyrimido[4,5-i/lpyriniidin-2( 177)-one; 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)-l- methyl-3,4-dihydro-pyrimido[4,5-/7]pyrimidin-2( 1 #)-one; 3-(2,6-Dichloro-phenyl)-7-(3-hydroxymethyl-phenylamino)-l-methyl-3,4- 10 dihydro-pyrimido[4,5-i/]pyrimidin-2(l H)-one; 3-(2,6-Dichloro-phenyl)-7-(4-morpholin-4-yl-phenylamino)-3,4-dihydro- pyrimido[ 4,5-</]pyrimidin-2( 177)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-1 -methyl-7-(4-morpholin-4-yl- pheny lamino)-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2( 177)-one; 15 · 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-(3-hydroxymethyl-phenylamino)-l- methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( l/7)-one; 7-[4-(3-Carboxypropyl)-phenylamino]-3-(2,6-dichloro-phenyl)-l-methyl- 3.4- dihydro-pyrimido[4,5-d]pyrimidin-2( 1/7)-one; 7-[4-(3-Carboxypropyl)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)20 1-methyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2(l/Y)-one; 3-(2,6-Dichloro-phenyl)-7-[4-(formyl-phenylamino]- 1-methyl-3,4-dihydro-pyrimido [4,5-</}pyrimidin-2( 1 Z/)-one ; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(formyl-phenylamino]- 1-methyl 3.4- dihydro-pyrimido[4,5-iZ]pyrimidin-2( 177)-one; 25 1 -Methyl-7-[4-(pyrazol-1 -yl)phenylamino]pyrimido[4,5-J]pyrimidin- 2(l//)-one; 1 -Methyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido[4,5-i/]pyrimidin-2(lf/)-one; 1 -Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino]pyriimdo[4,5-30 rfJpyrimidin-2(l//)-one; 1 -Methyl-7-{4-[4-(dimethylamino)piperidin-l -yljphenylamino}-pyrimido[4,5-J|pyrimidih-2( 1 #)-one; -24- 011554 1 -Isopropyl-7-[4-(pyrazol-1 -yl)phenylamino]pyrimido(4,5-cQpyrimidin- 2(l/i)-one; 1 -Isopropyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido[4,5-J)pyrimidin-2( 1 /7)-one; 5 l-Isopropyl-7-[4-(4-hydroxypiperidin-l-yl)phenylamino]pyrimido[4,5- <Zjpyrimidin-2( 1 //)-one; 1 -Isopropyl-7-{4-[4-(dimethylamino)piperidin-1 -yljphenylamino}-pyrimido[4.5-d]pyrimidin-2(l//)-one; l-Bicyclo[2.2.1]hept-2-yl-?r[4-(pyrazol-l-yl)phenylamino]pyrimido[4,510 i7]pyriraidin-2(I7/)-one (exo); 1 -Bicvclo[2.2.1 ]hept-2-yI-7-[4-(4-methylpjperazin-1 -yl)phenyIamino]pyrimido[4,5-ùGpyrimidin-2( 1 H)-one (exo); 1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(li/)-one (exo); 15 1 -Bicyclo[2.2. l]hept-2-yl-7-{4-[4-(dimethylamino)piperidin-1 - yl]phenylamino}pyrimido[4,5-<7]pyrimidin-2(17/)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-1 -cyclopentyl-pyrimido[4.5-d]pyrimidin-2( 1 H)-one; 7- {4- [4-(2-Amino-4-methyl-pentanoyl)-piperazin-1 -yl]-pheny lamino} -120 cÿclopentyl-pyrimido[4,5-</]pyriniidin-2( 17/)-one; 1 -Methyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 -yl]phenylamino}pyrimido[4,5-J]pyrimidin-2( 1 H)-one; 1 -Isopropyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 -yl]phenylamino} pyrimido[4,5-</]pyrimidin-2( 17/)-one; 25 1 -Cyclopentyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1 - yl]phenylamino }pyrimido[4,5-c/]pyrimidin-2( 1 H)-one; l-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(l/7)-one (exo); l-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-pyrimido[4,5-30 cQpyrimidin-2(l/Y)-one; l-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-pyrimido[4,5-6Qpyrimidin-2( 1 H)-one; -25- 011554 7-[4-(3-Amino-pyrroIidin-1 -yl)-phenylamino]-1 -cyclopentyl-pyrimido[4.5-d]pyrimidin-2(17f)-one; 1 -Cyclopentyl-7-(4-piperazin-l -yl-phenylamino)-pyrimido[4,5-i/Jpyrimidin-2( 17/)-one; 5 l-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-pyrimido[4,5-d]pyrimidin-2( 177)-one; 7-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino]-1 -cycloheptyl-pyrimido[4,5-i/Jpyrimidin-2( 1//)-one; 1 -Cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-d)pyrimidin-2( 1 7/)-one;10 1 -[7-(4-Fluoro-phenylamino)-pyrimido[4,5-iZ]pyrimidin-2-yl]-3-methyl- urea; l-Isopropyl-3-(7-phenylamino-pyrimido[4,5-ii]pyrimidin-2-yl)-urea; 1 - {7-[4-(3-Aminomethyl-pyrrolidin-1 -y l)-phenylamino]-pyrimido[4,5- d]pyrimidin-2-yl} -3 -isopropyl-urea; 15 l-Isopropyl-3-[7-(4-piperazin-l-yl-phenylamino)-pyrimido[4,5- d]pyrimidin-2-yl]-urea; l-{7-[4-(4-Acetyl-piperazin-l-yl)-phenylamino]-pyrimido[4,5- cQpyrimidin-2-yl}-3-isopropyl-urea; N-{7-[4-(3-Amino-pyrrolidin-l-yl)-phenylamino]-pyrimido[4,5-20 </]pyrimidin-2-yl}-3-methyI-butyramide; N-[7-(4-Piperazin-1 -yl-phenylamino)-pyrimido[4,5-d]pyrimidin-2-yl]-isobutyramide; N-{7-[4-(4-Acetyl-piperazin-l-yl)-phenylamino]-pyrimido[4,5- i/Jpyrimidin-2-yl}-3-methyï-butyramide; 25 3-Methyl-N-[7-(pyridin-4-ylamino)-pyrimido[4,5-i/Jpyrimidin-2-yl]- butyramide; l-Isopropyl-3-[7-(pyridin-4-ylamino)-pyrimido[4,5-</]pyrimidin-2-yl]- urea; N- {7-[4-(3-Aminomethyl-pyrrolidin-1 -yl)-phenylamino]-pyrimido[4,5-30 i/]pyrimidin-2-yl}-3-methyl-butyramide; 3-Methyl-N-{7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-phenylamino]-3.4-dihydro-pyrimido[4,5-i7]pyrimidin-2-yl} -butyramide; -26- C15554 1 - {7-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino]-3,4-dihydro-pyrimido[4,5-ôQpyrimidin-2-yl} -3-isopropyl-urea; l-[7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- phenyl)-3,4-dihydro-pyrimido[4,5-djpyrimidin-2-yl]-3-ethyl-urea; 5 1 - {3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-dielhylamino-ethoxy)- phenylamino]-3,4-dihydro-pyrimido[4,5-i/]pyriinidin-2-yl}-3-ethyl-urea; l-/er/-Butyl-3-[7-[4-(2-diethylamino-ethoxy)-phenylamino]-3-(3,5- dimethoxy-phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin~2-yl]-urea; l-/er/-Butyl-3-{3-(2-chloro-3j5-diméthoxy-phenyl)-7-[4-(2-diethylamino-10 ethoxy )-pheny lamino] -3,4-dihy dro-pyrimido [4,5 -d} pyrimidin-2-yl} -urea; l-/err-Butyl-3-[3-(3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-</]pyrimidin-2-yl]-urea; l-[3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido[4,5-</]pyrimidin-2-yl]-3-ethyl-urea; 15 1 -tez7-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)· 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-urea; l-[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro pyrimido[4,5-<7jpyrimidin-2-yl]-3-ethyl-urea; 1 -[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethy lamino-butylamino)-20 3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2-yl]-3-ethyl-urea; l-ter/-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino- butylamino)-3,4-dihydro-pyrimido[4,5-if|pyriinidin-2-yl]-urea; I -(2-BenzyIoxyethyl)-7-[4-(4-methy Ipiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido [4,3 -cdpyrimidin-2( 1 /7)-one; 25 1 -(Thiophen-2-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4- dihydro-pyrido[4,3-</]pyrimidin-2( 1 //)-one; 1 -(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1 -yl)phenyïamino]-3,4·dihydro-pyrido [4,3 -zi] pyrimidi n-2 ( 1 //)-one ; 1 -(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-30 dihydro-pyrido[4.3-d]pyrimidin-2(l//)-one·, 1 -(Hexa-2,4-diene-1 -yl)-7-[4-(4-methylpiperazin-l -yl)phenylamino]-3,4-dihydro-pyrido[4,3-ô/]pyrimidin-2( l//)-°ne; -27- Cil 5 5 4 1 -(Prop-2-yne-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4- dihydro-pyrido[4,3-6(|pyrimidin-2(l 7/)-one; 1 -[3-(Dimethylamino)prop-l -yl]-7-[4-(4-methylpiperazin-l - yl)phenylamino]-3,4-dihydro-pyrido[4,3-iZ]pyrimidin-2( 17/)-one; l-(3-Hydroxyprop- l-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4 dihydro-pyrido[4,3-J]pyrimidin-2( 177)-one; 1 -(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4- dihydro-pyrido[4,3-cf]pyrimidin-2( 1 //)-one; l-(3,5-Dimethylhept-l-yl)-7-[4-(4-methylpiperazin-l-yl)phenylamino]- 3.4- dihydro-pyrido[4,3-ô/Jpyrimidin-2( 1 //)-one; 3-(3.5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-l-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2( 1 /7)-one; 3-(2-Chloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-y lamino)-1 -ethyl-3,4-dihydro-pyrido[4,3-^]pyrimidin-2( 177)-one; 3-(2,6-Dichloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1 -ethyl- 3.4- dihydro-pyrido [4,3 -ùT|pyrimidin-2( 1 //)-one; 3-(2-Methyl-3,5-Dxmethoxy-phenyl)-7-(pyridin-4-ylamino)-l-ethyl-3,4-dihydiO-pyrido[4,3-<Y]pyrimidin-2( 17/)-one; 3-(2,6-Dimethyl-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-l-ethyl- 3.4- dihydro-pyrido[4,3-i/]pyrimidin-2( 1 H)-one; 7-(4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-3-(3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrido[4,3-JJpyrimidin-2(l//)-one; . 7-(4-(4-Aminoacetyl-piperazin-l-yI)-phenylamino]-3-(2-chloro-3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrido[4,3-c/]pyrimidin-2( 1 H)-one; 7-[4-(4-Amxnoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrido[4,3-6/]pyrimidin-2(l//)-one; 7-(4-(4-Anxinoacetyl-piperazin-l-yl)-phenylamino]-3-(2-methyl-3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrido[4,3-</Jpyrimidin-2( 17/)-one; 7-(4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6-dimethyl-3,5dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrido[4,3-i/]pyrimidin-2( 177)-one; 1 -(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1 -yl)pheny lamino]pyrido [4,3 -</Jpyrimidm-2( 177)-one; -28-

Ci ί £54 1 -(Thiophen-2-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4,3-d]pyrimidin-2( 1 /7)-one; 1 -(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4,3-iZ]pyrimidin-2( 1//)-one; 5 1 -(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido[4,3-i7]pyrimÎdm-2(l/7)-one; 1 -(Hexa-2,4-diene-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4,3-d]pyrimidin-2(l/7)-one; 1 -(Prop-2-yne-1 -yl)-7-[4-(4-methylpiperazin-1 -10 yl)phenylamino]pyrido[4,3-dipyrimidin-2(177)-one; 1 -[3-(Dimethylamino)prop-1 -yl]-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4,3-^pyrimidin-2( 1/7)-one; 1 -(3-Hydroxyprop-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylarmno]pyrido[4,3-i/]pyrimidin-2( 1 H)-one; 15 1 -(Pyridin-4-ylméthyl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido [4,3-<7]pyriinidm-2( 177)-one; l -(3.5-Dimethylhept-1 -y I)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4.3-d]pyrimidin-2(l //)-one; 1- Cyclopentyl-7-(4-piperazin-l-ylphenylamino)pyrido[4,3-<7]pyrimidin- 20 2(l/7)-one; 7-[4-(3-Aminopyrrolidin-1 -yl)phenylamino]-1 -cyclopentylpyrido[4,3-</]pyrimidin-2( 1 /7)-0 ne; 2- [4-(3-Amino-pyrrolidin-l-yl)-phenylamino]-8-isopropyI-8/7-pyrido[4,3</Jpyrimidin-7-one; 25 8-Cyclopentyl-2-[4-(hexahydro-pynolo[3,4-c]pyrrol-2-yl)-phenylamino]- 8/7-pyrido[4.3-i7jpyrimidin-7-one; 2-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino)-8-cyclopentyl-8/7-pyrido[4,3-i7]pyrimidin-7-one; N-{2-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-8-cyclopentyl- 30 pyrido[4,3-</]pyrimidin-7-yl}-2,2-dimethyl-propionamide; N-(2- {4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1 -yl]-phenylamino} 8-cyclopentyl-pyrido[4.3-ûf]pyrimidin-7-yl)-2,2-dimethyl-propionamide; -29- 011554 1 -Isopropyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-1 //-pyrimido[4,5-d]pyrimidine-2,4-dione; 7-[4-(2-Diethylaminoethoxy)phenylamino]-1 -isopropyl-17/-pyrimido[4,5-ù0pyrimidine-2,4-dione; 5 7-(4-Diethylamino-butylamino)-3-(3,5-dimethoxy-phenyl)-1 -ethyl-1//- pyrimido[4,5-<Z]pyrimidine-2,4-dione; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy-phenyl)-l-ethyl-17/-pyrirnido[4,5-cf]pyrirnidine-2,4-dione; and 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-l-ethyl-l//-pyrimido[4,5- 1 θ </)pyrimidine-2,4-dione.

Compounds of Formula I wherein Z is N or CH may be preparedaccording to the synthèses outlined in Schemes 1-3. Although these schemes oftenindicate exact structures, those with ordinary skill in the art will appreciate that themethods apply widely to analogous compounds of Formula I, given appropriate 15 considération to protection and deprotection of reactive functional groups by methods standard to the art of organic chemistry. For example, hydroxy groups, inorder to prevent unwanted side reactions, generally need to be converted to ethersor esters during Chemical reactions at other sites in the molécule. The hydroxyprotecting group is readily removed to provide the free hydroxy group. Amino 20 groups and carboxylic acid groups are similarly derivatized to protect themagainst unwanted side reactions. Typical protecting groups and methods forattaching and cleaving them are described fully by Greene and Wuts in ProtectiveGroups in Organic Synthesis, John Wiley and Sons, New York, (2nd Ed., 1991),and McOmie, Protective Groups in Organic Chemistry, Plénum Press, New York, 25 1973.

Scheme 1 describes a typical method for the préparation of the bicyclicpyrimidines and bicyclic 3,4-dihydropyrimidines of the invention. The synthesisbegins with 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile or 4-chloro-6-(methylthio)-3-pyridinecarbonitrile, which are readily prepared from common 30 reactants. Displacement of the 4-chloro group with an amine in a solvent such astetrahydrofuran (THF) in the presence or absence of a tertiary amine such astriethylamine provides the corresponding 4-amino-2-(methylthio)-5- -30- pyrimidinecarbonîtrile or 4-amino-6-(methylthio)-3-pyridinecarbonitrile. Theamine used can be anhydrous or in an aqueous solution, as with methyl or ethylamine, or cyclopentylamine. The use of aqueous ammonium hydroxide providesthe corresponding primary amine at position 4. Réduction of the cyano group with 5 common reducing agents such as LAH, provides the corresponding aminomethylanalog. Cyclization is accomplished by reaction with an agent such as 1,1'-carbonyldiimidazole (CD1). Oxidation of the methylthio group with an oxidantsuch as an oxaziridine in a solvent such as chloroform at room températureprovides the methyl sulfoxide dérivative. Displacement of the sulfoxide with an 10 amine (FbNRl) results in formation of the corresponding 7-amino-3,4-dihydro-bicyclic pyrimidine. The température required for the displacement dépends uponthe amine used. Aromatic, secondary, and tertiary amines usually require highertempératures than primary aliphatic or benzyl amines. When aromatic aminessuch as aniline are used, the reaction is usually run with the amine as the solvent 15 at high températures (e.g., 80-150°C).

The bicyclic 3,4-dihydropyrimidines are readily oxidized by reaction with oxidants such as potassium ZerZ-butoxide and oxygen to provide the correspondingbicyclic pyrimidines of the invention. 011554 SCHEME 1 ΓΊ

I

Z

-32- 011554

Scheme la describes a typical method for preparing bicyclic pyrimidinesof Formula I wherein R2 is H and X is NHR^. A suitably substituted2-methylthio-5-aminomethyl-4-amino-pyrimidine is first reacted with cyanogenbromide to effect cyclization to a dihydropyrimido pyrimidine. The methylthio 5 group is oxidized to the sulfoxide by reaction with an oxidant such as an oxaziridine or a perbenzoic acid. The methylsulfoxide moiety is readily displacedby reaction with an amine (R^NH2) to provide a 7-amino-3,4-dihydro bicyclicpyrimidine having an amino group at the 2-position. These dihydro pyrimidinesare easily converted to the correspônding aromatic pyrimidines by oxidation with 10 common oxidants such as postossium zerz-butoxide and oxygen. The 2-amino dihydropyrimidines and 2-amino pyrimidines are valuable biological agents, andalso serve as intermediates, wherein the 2-amino group is derivatized by standardmethods, for example alkylation or acylation, to provide compounds of Formula Iwhere X is NHR^, e.g.,

15 -33-

Scheme la 011554

3-phenyl-2-(phenylsulfonyl) oxaziridine

O

NH-i iVSioo or R4C(O)C1

R 1

H 4 -34- 011554

Schemes lb and le describe general processes forpreparing bicyclicpyrimidines of Formula I wherein G is C. In Scheme lb, a 2-methylthio-4-halo-5-cyano pyrimidine is reacted with an alkyl malonate in the presence of a base suchas sodium hydride to provide a pyrimidyl malonate dérivative. R.2 groups such as 5 alkyl and cycloalkyl can be inserted by reacting the pyrimidyl malonate intermediate with an alkyl or cycloalkyl halide in the presence of a base such assodium carbonate or triethylamine. The 5-cyano group of the pyrimidyl malonateintermediate readily reacts with a reducing agent to effect réduction to an aminomethyl group, the amino of which then displaces one of the alkoxy groups of the 10 malonate portion to effect ring closure to provide the corresponding dihydro pyridopyrimidine. Décarboxylation of the remaining malonate carboxy group isreadily accomplished by reaction with a base such as an alkali hydroxide, thusaffording a 2-methylthio-5,6-dihydropyridopyrimidine. The methylthio group isoxidized to a sulfoxide, which is then readily displaced by reaction with an amine 15 (R^Ntb) to give a 2-amino-5,6-dihydropyridopyrimidine. Further oxidation by reaction with an alkali métal alkoxide and oxygen provides a fully aromatic7-hydroxy-pyridopryimidine of the formula

N'

OH -35-

Scheme 1b 011554

-36- 011554

Scheme le shows a typical conversion of the 7-hydroxy pyridopyrimidineprepared as described above to 7-substituted amino compounds of Formula I (X = NHRl θ). The 7-hydroxy compound is first reacted with a phosphorus oxyhalide to provide the corresponding 7-halo pyridopyrimidine. The 7-halo group is 5 readily displaced by reaction with an amine such as ammonia to give a 7-aminocompound, which can be derivatized by standard processes to afford

O

II

pyridopyrimidine of Formula I where X is NHR* θ, for example NHCRA 10 -37-

Scheme le 011554

-38- 011554

Scheme 2 illustrâtes a slightly different process for preparing inventioncompounds. starting with a suitably substituted pyridyl or pyrimidyl aldéhyde ofthe formula

5 where R- is, for example, H or alkyl such as-ethyl. Ail of the reactions in

Scheme 2 are carried out by well-known procedures. The aldéhyde is condensedwith an N-substituted amine (J^NR^) to provide an imine. The imine is reducedto a secondary amine, and the reduced amine is cyclized and subsequentlyconverted to the key sulfoxide intermediate. The sulfoxide group is readily 10 displaced by reaction with virtually any primary amine to give invention compounds of the general formula

-39-

Scheme 2 01 1 554

A preferred group of invention compounds hâve Formula I wherein R? isaryl such as disubstituted, trisubstituted, or tetrasubstituted phenyl. These are 5 readily prepared by any of the foregoing processes, for example, by reacting asuitably substituted aniline with a pyridyl or pyrimidyl aldéhyde as illustrated inScheme 2. Typical anilines that can be employed in the reaction hâve the formula /=Vx (Substituent^^ H2N_Î / where the substituents are selected from phenyl, chloro, bromo, methyl, methoxy,hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxycarbonylmethyl,carboxy, carboxymethyl, ethoxycarbonyl, 2-carboxyethyl, 2-ethoxycarbonylethyl,NR^R^, and O(CH2)0-6 NR^r5, where R^ and R^ are defined above. 10 -40- 011554

As noted above, a preferred group of invention compounds hâve Formula Iwherein X is NR^, as well as those wherein X is O. Typical inventioncompounds are prepared according to Scheme 3, starting with the reduced iminedescribed in Scheme 2 (where R^ = H). The reduced imine is cyclized by reaction 5 with cyanogen bromide. and the 7-methylthio group is oxidized to the

corresponding sulfoxide, ail as described above. The methylsulfoxide group isdisplaced by reaction with a primary amine (H2NRI), foliowed by derivatizationof the 2-amino group by reaction with alkylating agents or acylating agents (e.g.,alkyl isocyanates or acyl halides) to provide invention compounds of Formula I

-41-

Scheme 3 01 1 5 5 4

-42- 011554

Ali of the invention compounds are readily purified by standard methodswhen desired. Typical purification steps employed include chromatography oversolid supports such as silica gel or alumina. Elution generally is carried out usingcommon solvents such as acetone, ethyl acetate, tetrahydrofuran, éthanol, 5 triethylamine, and mixtures of such solvents. Other purification processes cansimilarly be employed, including crystallization from common solvents such asmethanol, éthanol, diethyl ether, ethyl acetate, and the like. Sometimes suchcrystallizations can afford solvatés such as an éthanol solvaté, as well as hydrates,and ail such solvatés and hydrates are included in the scope of this invention. 10 The foregoing general reaction schemes are further described by the following detailed examples which are for illustrative purposes only and are notintended, nor should they be construed, as limiting the invention in any manner.Those skilled in the art will appreciate that variations and modifications can bemade without violating the spirit or scope of the invention. 15 Préparations 1-10 and Examples 1-47 are spécifie embodiments of the general reaction schemes shown in Scheme 1 above. PREPARATION 1 4-Hydroxy-2-(methylthio)-5-pyrimÎdinecarbonitriIe

To a 5°C solution of 119 g (703 mmol) of freshly distilled ethyl 20 (ethoxymethylene)cyanoacetate in 800 mL of methanol is added 108 g (599 mmol) of 2-methyl-2-thiopseudourea. To this mixture is added a solution ofsodium methoxide prepared by dissolving 35.6 g (1.55 mol) of sodium métal in800 mL of methanol. The solution is warmed to room température and stirred for6 hours. After standing ovemight, the solvent is removed under reduced pressure, 25 the residue is dissolved in 1.5 L of water at 50°C with stirring, and the solution isfiltered hot. The filtrate is acidified to pH 2 with concentrated HCl and kept atroom température ovemight. The precipitated product is collected and dried togive 48.3 g (48%) of the title compound, which is used directly in the next step. 011554 -43- PREPARATION 2 4- Chloro-2-(methylthio)-5-pyrimidinecarbonitrile A mixture of 48.3 g (289 mmol) of 4-hydroxy-2-(methylthio)- 5- pyrimidinecarbonitrile and 150 mL of phosphorus oxychloride is heated at 5 reflux for 3 hours. The reaction mixture is cooled tp room température, filtered,and the filtrate is concentrated to dryness. The residue is partitioned betweendichloromethane and ice water. The organic phase is washed with water, driedover magnésium sulfate, and concentrated to a residue that is diluted with 750 mLof hexane. The stirred mixture is heated to reflux and the hot hexane solution is 10 decanted from the insoluble material. Upon cooling to room température, crystalsform and are collected to afford 32 g (60%) of the title compound. PREPARATION 3 4-(Cyclopentylamino)-2-(methylthio)-5-pyrimidinecarbonitrile

To a 0°C solution of 10.0 g (53.9 mmol) of 4-chloro-2-(methylthio)-

1 5-pyrimidinecarbonitrile in 100 mL of dichloromethane is added 9.0 mL (64.6 mmol) of triethylamine followed by dropwise addition of 6.4 mL(64.6 mmol) of cyclopentylamine. The reaction mixture is stored at 0-10°C for16 hours, diluted with 100 mL of hexane, and filtered. The filtrate ischromatographed on silica gel eluting with 1:4:5 ethyl acetate/dichloromethane/ 20 hexane to obtain 4.6 g (36%) of product. The filtered solids, containing bothproduct and triethylamine hydrochloride, are resuspended in 50 mL ofdichloromethane and chromatographed as above to obtain 7.2 g (57%) ofadditional product: mp 119-122°C.

Analysis calculated for Cj 1H14N4S: 25 C, 56.38; H, 6.02; N, 23.91.

Found: C, 56.48; H, 5.99; N, 24.12. PREPARATION 4 4-(Isopropylamino)-2-(methyIthio)-5-pyrimidinecarbonitrile

To a 0°C solution of 20.0 g (107.7 mmol) of 4-chloro-2-(methylthio)-

30 5-pyrimidinecarbonitrile in 200 mL of dichloromethane is added 18.0 mL -44- 011554 (129.3 mmol) of triethylamine followed by dropwise addition of 11.0 mL(129.3 mmol) of isopropylamine. The reaction mixture is stirred at 0°C for3 hours, then for 30 minutes at room température. The resulting precipitate oftriethylamine hydrochloride is filtered. The filtrate is chromatographed on a short 5 column of silica gel eluting with dichloromethane. The pure fractions are pooled,concentrated, suspended in hexane, and filtered to obtain 13.7 g (61%) of product.The impure fractions, containing both product and triethylamine hydrochloride,are diluted with ethyl acetate, washed twice with water, and once with brine. Theorganic phase is dried over magnésium sulfate and concentrated. The residue is 10 crystallized from 1:9 ethyl acetate/hexane to give 3.6 g (16%) of additional product: mp 121.0-122.5°CAnalysis calculated for C9H12N4S: C, 51.90; H, 5.81; N, 26.90.

Found: C, 51.80; H, 5.82; N, 26.73. 15 PREPARATION 5 4-(Bicyclo[2.2.1]hept-2-ylamino)-2-(methylthio)-5-pyrimidinecarbonitrile (exo)

To a 0°C solution of 10.0 g (53.9 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 100 mL of dichloromethane is added 9.0 mL

20 (64.6 mmol) of triethylamine followed by dropwise addition of 7.0,mL (59.3 mmol) of exo-2-aminonorbOmane. The reaction mixture is stirred at 0°C for2 hours. The resulting precipitate of triethylamine hydrochloride is filtered. Thefiltrate is washed three times with saturated aqueous solution of sodiumbicarbonate. The aqueous phase is back extracted twice with dichloromethane. 25 The combined organic phase is concentrated, and the residue is purified by filtering through a short column of silica gel eluted with dichloromethane to give8.9 g (64%) ofthe title compound.

Analysis calculated for C13H16N4S: C, 59.97; H, 6.19; N, 21.52. 30 Found: C, 59.70; H, 6.08; N, 21.41. 011554 -45- PREPARATION 6 4- (MethyIamino)-2-(methyIthio)-5-pyrimidinecarbonitrile

Through a 5°C solution of 14.5 g (78.1 mmol) of 4-chloro-2-(methylthio)- 5- pyrimidinecarbonitrile in 800 mL of diethyl ether is bubbled methylamine gas 5 for a period of 15 minutes. The reaction mixture is allowed to warm to room température, set ovemight, and filtered. The solids are washed with diethyl ether,then efficiently with 50 mL of water, and dried to give 12.0 g (81%) of the titlecompound: mp 189-190°C.

Analysis calculated for CyHg^S: 10 C, 46.65; H, 4.47; N, 31.09.

Found: C, 46.79; H, 4.60; N, 31.26. PREPARATION 7 5-(Aminomethyl)-4-(cyclopentylamino)-2-(metbylthio)pyrimidine

To a stirred 0°C suspension of 1.7 g (44.8 mmol) of LAH in 70 mL of 15 tetrahydrofuran is added dropwise a solution of 5.0 g (21.3 mmol) of 4- (cyclopentylamino)-2-(methylthio)-5-pyrimidinecarbonitrile in 250 mL oftetrahydrofuran. The reaction is allowed to warm slowly to room températureovemight. The mixture is recooled to 0°C, and treated with a saturated solution ofammonium sulfate until there is no more effervescence. After stirring for another 20 15 minutes, the gray solids are filtered and washed four times with hot ethyl acetate. The combined organic washes are concentrated, and the residue ischromatographed on silica gel eluting with 1:1:8 methanol/hexanè/chloroform toobtain 4.0 g (79%) of the title compound: mp 58-60°C.

Analysis calculated for Cj jHig^S: 25 C, 55.43; H, 7.61; N, 23.51.

Found: C, 55.45; H, 7.56; N, 23.49. PREPARATION 8 5- (Aminomethyl)-4-(isopropyIainino)-2-(methylthio)pyriinidine

To a stirred 0°C suspension of 5.9 g (156.3 mmol) of LAH in 200 mL of 30 tetrahydrofuran is added dropwise a solution of 15.5 g (74.4 mmol) of 011554 4- (isopropylamino)-2-(methylthio)-5-pyrimidinecarbonitrile in 500 mL oftetrahydrofuran. The reaction is allowed to warm slowly to roora températureovemight. The mixture is recooled to 0°C , and treated with a saturated solution ofammonium sulfate until there is no more effervescence. After stirring for another 5 15 minutes, the gray solids are filtered and washed six times with hot ethyl acetate. The combined organic washes are concentrated, and the residue ispurified by chromatography in two portions on a 4 x 15 cm Biotage silica gelcolumn that is eluted with 60:38:2 acetonitrile/dichloromethane/triethylaminefollowed by 60:33:5:2 acetonitrile/dichloromethane/methanol/triethylamine to 10 obtain 12.9 g (82%) of the title compound as a yellow oil.

Mass Spectrum (CI) (m+l)/z 213. PREPARATION 9 5- (Aminomethyl)-4-(bicyclo{2.2.1]hept-2-ylamino)-2-(methylthio)pyrimidine(exo) 15 To a stirred 0°C suspension of 2.5 g (65.3 mmol) of LAH in 100 mL of tetrahydrofuran is added dropwise a solution of 8.5 g (32.6 mmol) of 4- (bicyclo[2.2.1 ]hept-2-yl-amino)-2-(methylthio)-5-pyrimidinecarbonitrile in375 mL of tetrahydrofuran. The reaction is allowed to warm slowly to roomtempérature ovemight. The mixture is recooled to 0°C and treated with a saturated 20 solution of ammonium sulfate until there is no more effervescence. After stirringfor another 15 minutes, the gray solids are filtered and washed four times with hotethyl acetate. The combined organic washes are concentrated, and the residue ispurified by chromatography on silica gel that is eluted with methanol/dichloromethane 1:9 followed by 2:8 to obtain 5.8 g (68%) of the title compound. 25 Analysis calculated for C j 3H20N4S : C, 59.06; H, 7.62; N, 21.19.

Found: C, 58.94; H, 7.86; N, 21.04. PREPARATION 10 5- (Aminomethyl)-4-(methyianiino)-2-(niethylthio)pyrimidine 30 To a stirred 0°C suspension of 17.0 g (448 mmol) of lithium aluminum hydride in 500 mL of tetrahydrofuran is added dropwise a solution of 30.0 g 011554 (166 mmol) of 4-(methylamino)-2-(methylthio)-5-pyrimidinecarbonitrile in 1.5 Lof tetrahydrofuran. The reaction is allowed to warm slowly to room températureovemight. The mixture is recooled to 0°C, and treated with a saturated solution ofammonium sulfate until there is no more effervescence (80-100 mL). After 5 stirring for another 15 minutes, the gray solids are filtered and washed 3 timeswith hot tetrahydrofuran and once with hot ethyl acetate. The combined organicwashes are concentrated, and the residue is chromatographed on silica gel elutingwith 0.5:25:75 triethylamine/methanol/chloroform to obtain 21.6 g (70%) of an oilwhich solidified on standing of the title compound. 10 Mass Spectrum (Cl) (m+l)/z 185. EXAMPLE 1 l-Cyclopentyl-7-methanesuIfanyl-3,4-dihydro-pyrimido[4,5-rflpyrimidin- 2(l//)-one

To a 0°C solution of 4.2 g (17.6 mmol) of 5-(aminomethyl)-4- 15 (cyclopentylamino)-2-(methylthio)pyrimidine in 100 mL of tetrahydrofuran isadded 3.4 g (21.1 mmol) of Ι,Γ-carbonyldiimidazole. The solution is stirred at0°C for 30 minutes, then heated at a gentle reflux ovemight. The mixture isconcentrated to a solid residue that is stirred as a suspension in chloroform for4 hours. The powdery solid is collected and dried to give 2.6 g of product 20 contaminated with about 5% imidazole. The filtrate is chromatographed on silicagel eluting with 6:4 ethyl acetate/dichloromethane to give 1.6 g of productcontaminated with about 10% iniidazole. A small portion is crystallized fromchloroform to obtain an analytically pure sample of the title compound:mp 179-182°C. 25 Analysis calculated for C j 2H j (5N4OS : C, 54.52; H, 6.10; N, 21.19.

Found: C, 54.42; H, 6.11 ; N, 21.29. 011554 -48- EXAMPLE2 l-Isopropyl-7-methanesulfanyl-3,4-dihydro-pyrimido[4,5-d]pyriinidin- 2(LH)-one Το a 0°C solution of 12.0 g (56.5 mmol) of 5-(aminomethyl)-4- 5 (isopropylamino)-2-(methylthio)pyrimidine in 300 mL of tetrahydrofuran is added11.0 g (67.8 mmol) of l,l'-carbonyldiimidazole. The solution is stirred at 0°C for30 minutes, then heated at a gentle reflux ovemight. The mixture is concentratedto a solid residue that is dissolved in chloroform, washed twice with IN HCl,water, a saturated solution of sodium bicarbonate, and brine. The organic phase is 10 dried over magnésium sulfate and concentrated. The crude solid residue is crystallized from chloroform/hexane to obtain 9.7 g (72%) of the title compound:mp 175.0-176.5OC.

Analysis calculated for CiqH^Nz^OS: C, 50.40; H, 5.92; N, 23.51. 15 Found: C, 50.35; H, 5.90; N, 23.54. EXAMPLE 3 l-Bicyclo[2.2.1]hept-2-yl-7-methanesulfanyl-3,4-dÎhydro-pyrimido[4,5-</]pyrimidÎn-2(l//)'one (exo)

To a 0°C solution of 4.6 g (17.6 mmol) of 5-(aminomethyl)-4- 20 (bicyclo[2.2.13hept-2-yl-amino)-2-(methylthio)pyrimidine in 100 mL of tetrahydrofuran is added 3.7 g (22.7 mmol) of l.l'-carbonyldiimidazole. Thesolution is stirred at 0°C for 30 minutes, room température for 2 hoürs, thenheated at a gentle reflux for 48 hours. The mixture is diluted with brine andextracted with diethyl ether. The organic phase is concentrated, and the residue is 25 purified by chromatography on silica gel that is eluted with methanol/dichloromethane 5:95 then 10:90 to obtain 2.2 g (85%) of the titlecompound: mp 133-134°C.

Analysis calculated for C14H18N4OS: C, 57.91; H, 6.25; N, 19.29. 30 Found: C, 57.61; H, 6.09; N, 19.12. 011554 -49- EXAMPLE 4 7-Methanesulfanyl-l-methyl-3,4-dihydro-pyrimido(4,5-d]pyrimidin- 2(l//)-one

To a 0°C solution of 21.2 g (152.2 mmol) of 5-(aminomethyl)-4- 5 (methylamino)-2-(methylthio)pyrimidine in 900 mL of tetrahydrofuran and 100 mL of dimethylformamide is added 3.4 g (21.1 mmol) of 1,1'-carbonyldiimidazole. The solution is stirred at 0°C for 1 hour, then heated at agentle reflux for 10 hours. The mixture is cooled, and the solid is collected,washed with diethyl ether, and dried to give 18.6 g (78%) of the title compound: 10 mp263-265°C.

Analysis calculated for CgHjQ^OS: C, 45.70; H, 4.79; N, 26.65; S, 15.25.

Found: C, 46.15; H, 4.59; N, 26.62; S, 15.51. EXAMPLE 5 15 l-CyclopentyI-7-methanesulfînyI-3,4-dihydro-pyrimido{4,5-</]pyrimidin-2(l//)-one

To a room température solution of 3.7 g (14.0 mmol) of 1-cyclopentyl-7-methanesulfanyl-3,4-dihydro-pyrimido[4,5-<i]pyrimidin-2(l//)-one in 40 mL ofchloroform is added 4.4 g (16.8 mmol) of 3-phenyl-2-(phenylsulfonyl)- 20 oxaziridine. The reaction mixture is stirred for 3 hours, filtered, and washed with1:1 chloroform/hexane to give 2.85 g (73%) of the title compound: mp 235-236°C(dec).

Analysis calculated for C12H16N4O2S: C, 51.41; H, 5.75; N, 19.98. 25 Found: C, 50.43; H, 5.55; N, 19.52. EXAMPLE 6 l-Isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimidol4,5-i/]pyrimidin- 2(lH)~one

To a room température solution of 7.0 g (29.4 mmol) of 1-isopropyl- 30 7-methanesulfanyl-3,4-dihydro-pyrimido[4,5-J)pyrimidin-2(l//)-one in 80 mL of -50- 011554 chloroform is added 9.2 g (35.2 mmol) of 3-phenyl-2-(phenylsulfonyl)oxaziridine.The reaction mixture is stirred ovemight, diluted with 40 mL of hexane, filtered,and washed with 1:1 chloroform/hexane to give 6.4 g (85%) of the titlecompound: mp 218-219°C (dec). 5 Analysis calculated for C j θΗ 14N4O2S: C, 47.23; H, 5.55; N, 22.03.

Found: C, 46.88; H, 5.40; N, 21.56. EXAMPLE 7 l-Bicyclo[2.2.1]hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido(4,5- 10 d]pyrimidin-2(lfl)-one (exo)

To a room température solution of 2.0 g (6.9 mmol) of l-bicyclo[2.2.1]hept-2-yl-7-methanesulfanyI-3,4-dihydro-pyrimido[4,5-</lpyrimidin-2(li/)-one in 20 mL of chloroform is added 2.1 g (8.3 mmol) of3-phenyl-2-(phenylsulfonyl)oxaziridine. The reaction mixture is stirred ovemight, 15 200 mg (0.76 mmol) more of 3-phenyl-2-(phenylsulfonyl)oxaziridine is added, and stirred ovemight. The product is isolated by chromatography on a 4 x 15 cmBiotage silica gel column by applying the reaction mixture to the column andeluting in a gradient fashion with methanol/chloroform 2:98 then 4:96 then 8:92 togive 1.1 g (51%) of the title compound: mp 220-222°C (dec). 20 Mass Spectrum (CI) (m+l)/z 307 and 264. EXAMPLE 8 7-Methanesulfinyl-l-methyl-3,4-dihydro-pyrimido[4,5-i/lpyrimidin-2(17ï)-oneTo a room température solution of 9.0 g (42.8 mmol) of 7-methanesulfanyl-l-methyl-3,4-dihydro-pyrimido[4,5-c/)pyrimidin-2(l//)-one 25 in 100 mL of chloroform is added 12.5 g (47.8 mmol) of 3-phenyl-2- (phenylsulfonyl)oxaziridine. The reaction mixture is stirred for 6 hours, 3.1g(11.9 mmol) more of 3-phenyl-2-(phenylsulfonyl)oxaziridine is added, and stirredovemight. The reaction mixture is stored ovemight at 0°C, filtered, and driedunder vacuum at 75°C to a constant weight of 9.7 g (100%) of the title compound: 30 mp 225-228°C (dec). -51-

Mass Spectrum (CI) (m+l)/z 227. 011554 EXAMPLE 9 l-CycIopentyl-7-(4-methoxyphenyIamÎno)-3,4-dihydro-pyrimido(4,5- </]pyrimidin-2(l//)-one A solution of 300 mg (1.07 mmol) of l-cyclopentyl-7-methanesulfinyl- 3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2(17/)-one, 527 mg (4.28 mmol) ofp-anisidine. and 1.5 mL of dimethyl sulfoxide is heated at 130°C for 30 hours,then cooled and diluted with ethyl acetate. The mixture is washed three times withaqueous sodium chloride solution, dried over magnésium sulfate, andconcentrated. The residual solids are washed with 9:1:0.1:0.1 chloroform/ethylacetate/ethanol/triethylamine then with chloroform, and suspended in 150 mL of7:3 chloroform/methanol. The suspension is diluted with 20 mL of hexane, stirredfor 3 hours, and filtered to afford 88 mg (24%) of the title compound as an off-white powder: mp 247-249°C (dec).

Analysis calculated for C18H21N5O2: C, 63.70; H, 6.24; N, 20.63.

Found: C, 63.45; H, 6.04; N, 20.62. EXAMPLE 10 l-Cyclopentyl-7-[4-(piperÎdin-l-yi)phenylamino]-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(ljH)-one A solution of 377 mg (2.14 mmol) of l-(4-aminophenyl)piperidine, 300 mg (1.07 mmol) of l-cyclopentyl-7-methanesulfïnyl-3,4-dihydro-pyrimido[4.5-</}pyrimidin-2(li/)-one, 745 mg (3.21 mmol) of camphorsulfonicacid, and 2 mL ofp-dioxane is heated at 130°C for 1 hour in a sealed tube. Themixture is cooled and diluted with chloroform. The solution is washed twice withsaturated aqueous sodium bicarbonate and once each with aqueous sodiumchloride then brine. The organic phase is dried over magnésium sulfate andconcentrated to leave a dark green residue that is dissolved in chloroform andchromatographed on silica gel eluting with 9:1:0.5 ethyl acetate/ethanol/triethylamine. The product fractions are pooled and concentrated to leave -52- 011554 a residue that is dissolved in chloroform. The solution is diluted with ethyl acétatewhile most of the chloroform is being boiled away. Upon cooling, crystals formand are then collected to leave 101 mg (24%) of the title compound:mp 254-277°C (dec). 5 Analysis calculated for 022^28^6^ C, 67.32; H, 7.19; N, 21.41.

Found: C, 67.10; H, 7.06; N, 21.58. EXAMPLE 11 l-Cyclopentyl-7-[4-(4-methylpiperazÎn-l-yî)phenylamino]-3,4-dihydro- 10 pyrimido[4,5-i/lpyrimidin-2(l//)-one

To a solution of 2.0 g (7.1 mmol) of l-cyclopentyl-7-methanesulfinyl- 3.4- dihydro-pyrimido[4,5-d]pyrimidin-2(177)-one and 2.7 g (14.3 mmol) ofl-(4-aminophenyl)-4-methylpiperazine in 32 mL of acetonitrile is added 2.75 mL(35.7 mmol) of trifluoroacetic acid. The mixture is heated at 85°C ovemight. The 15 cooled reaction mixture is diluted with ethyl acetate and washed two times withsaturated aqueous sodium bicarbonate solution and once with brine. Thecombined aqueous phase is back extracted with dichloromethane. The combinedorganic phase is dried over magnésium sulfate and concentrated. The dark solidresidue is stirred for 2 hours in 30 mL of 1:1 dichloromethane/ethyl acetate, 20 filtered, washed with ethyl acetate, and dried to give 2.3 g (80%) of the titlecompound: mp 236-239°C (dec).

Analysis calculated for C22H29N7O: C, 64.84; H, 7.17; N, 24.06.

Found: C, 64.55; H, 7.00; N, 24.00. 25 General method for the préparation of other l-cyclopentyI-7-(substitutedphenylamino)-3,4-dihydro-pyrimidol4,5-</]pyrimidin-2(l//)-ones

To a solution of 200 mg (0.71 mmol) of l-cyclopentyl-7-methanesulfinyl- 3.4- dihydro-pyrimido[4.5-d]pyrimidin-2(l//)-one and two équivalents of thesubstituted aniline in 3.2 mL of acetonitrile is added trifluoroacetic acid. The 30 mixture is heated at 85°C ovemight, cooled to room température, diluted with 011554 -53- ethyl acetate or dichloromethane, and washed two times with saturated aqueoussodium bicarbonate solution and once with brine. The organic phase is dried overmagnésium sulfate, and concentrated to leave a residue that is further processed asdescribed above to give a compound of Formula I. 5 The following spécifie invention compounds were prepared according to the foregoing general process. EXAMPLE 12 l-CycIopentyl-7-[4-(pyrazoI-l-yl)phenylaminol-3,4-dihydro-pyrimido[4,5- */]pyrimidin-2(l//)-one 10 Prepared from 222 mg ( 1.43 mmol) of 1 -(4-aminophenyl)-4-(pyrazol-

l-yl)piperidine and 165 gL (2.1 mmol) of trifluoroacetic acid. After heating, aheavy precipitate forms. The cooled reaction mixture is diluted with 4 mL of ethylacetate and filtered. The solids are washed with ethyl acetate and dried to give275 mg (79%) of the trifluoroacetate sait of the title compound: mp 256-258°C 15 (dec). «

Analysis calculated for C22H2gNgO2-C2HF3O2: C, 53.99; H, 4.53; N, 20.03.

Found: C, 53.82; H, 4.52; N, 20.05. EXAMPLE 13 20 l-Cyclopentyl-7-{3-methyl-4-|2-(diethylamino)ethoxy]phenylamino}- 3,4-dihydro-pyrimido[4,5-ii]pyrimidin-2(lf/)-one

Prepared from 317 mg (1.43 mmol) of 3-methyl-4-[2-(diethylamino)-ethoxyjaniline and 165 gL (2.1 mmol) of trifluoroacetic acid. The crude residue issuspended in ethyl acetate/dichloromethane and stirred for several hours. The 25 solids are collected, washed with ethyl acetate, and dried to give 210 mg (67%) ofthe title compound: mp 175-177°C.

Analysis calculated for C24H34N5O2'· C, 65.73; H, 7.81; N, 19.16.

Found: C, 65.42; H, 7.73; N, 19.17. .54. C1Î554 EXAMPLE 14 l-Cyclopentyl-7-|4-(pyrrol-l-yl)phenylamino]-3,4-dihydro- pyrimidol4,5-d]pyrimidin-2(17/)-one

Prepared from 226 mg (1.43 mmol) of l-(4-aminophenyl)pyrrole and 5 165 pL (2.1 mmol) of trifluoroacetic acid. The crude residue is suspended in ethyl acetate/dichloromethane/acetonitrile and stirred for several hours. The solids arecollected, washed with ethyl acetate, and dried to give 90 mg (32%) of the titlecompound: mp >200°C (dec).

Analysis calculated for C21H22N(jOO.33 FbO: 10 C. 66.31; H, 6.00; N, 22.09.

Found: C, 66.35; H, 5.92; N, 21.94. EXAMPLE 15 l-Cyclopentyl-7-[4-(4-hydroxypiperidin-l-yl)phenylamino]-3,4-dihydro- pyrimido{4,5-d]pyrimidin-2(lH)-one 15 Prepared from 274 mg (1.43 mmol) of 1 -(4-aminophenyl)- 4-hydroxypiperidine and 330 pL (4.3 mmol) of trifluoroacetic acid. The cruderesidue is suspended in ethyl acetate/dichloromethane/acetonitrile and stirred forseveral hours. The solids are collected, washed with ethyl acetate, and dried togive 140 mg (47%) of the title compound: mp >200°C (dec). 20 Analysis calculated for C22H28N6O2 0.5 H2O: C, 63.29; H, 7.00; N, 20.13.

Found: C, 63.27; H, 6.65; N, 19.99. EXAMPLE 16 l-Cyclopentyl-7-(4-(3-hydroxypiperidin-l-yl)phenylamino]-3,4-dihydro- 25 pyrimido(4,5-<ijpyrimidin-2(l//)-one

Prepared from 274 mg (1.43 mmol) of l-(4-aminophenyl)- 3-hydroxypiperidine and 330 pL (4.3 mmol) of trifluoroacetic acid. The cruderesidue is suspended in ethyl acetate/dichloromethane and stirred for severalhours. The solids are collected, washed with ethyl acetate, and dried to give 30 135 mg (42%) of the title compound: mp >200°C (dec). -55- 011554

Analysis calculated for ¢22^28^602 0.15 CH2CI2-' C, 63.16; H, 6.77; N, 19.95.

Found: C, 63.18; H, 6.66; N, 19.97. EXAMPLE 17 5 l-Cyclopentyl-7-{4-[4-(dimethylamino)piperidin-l-yl]phenylamino}- 3.4- dihydro-pyriiuido[4,5-rf]pyrimidin-2(l/7)-one

Prepared from 313 mg (1.43 mmol) of l-(4-aminophenyl)-4-(dimethylamino)piperidine and 275 pL (3.75 mmol) of trifluoroacetic acid. Thecrude residue is suspended in ethyl acetate/dichloromethane and stirred for several 10 hours. The solids are collected, washed with ethyl acetate, and dried to give 80 mg(24%) of the title compound: mp >200°C (dec).

Analysis calculated for C24H33N7O2O.23 CPbCb: C, 63.95; H, 7.41; N, 21.54.

Found: C, 63.99; H, 7.38; N, 21.28. 15 EXAMPLE 18 l-Cyclopentyl-7-(4-(3,5-dimethylpiperazin-l-yl)phenylamino]-3,4-dihydro- pyrimido[4,5-rfJpyrimidin-2(LH)-one

Prepared from 292 mg (1.43 mmol) of l-(4-aminophenyl)- 3.5- dimethylpiperazine and 165 mL (2.1 mmol) of trifluoroacetic acid. The crude 20 residue is purified by chromatography on a 1.2 x 7 cm Biotage silica gel column that is eluted with 50:40:5:5 acetonitrile/ethyl acetate/methanol/triethylamine.Product fractions are pooled and concentrated to leave a residue that is crystallizedfrom dichloromethane/ethyl acetate to give 16 mg (5%) of the title compound:mp >200°C (dec). 25 Analysis calculated for C23H31N7OO.I5 CH2CI2O.OI C4H8O2'· C, 64.01; H, 7.27; N, 22.53.

Found: C, 63.98; H, 7.06; N, 22.60. 011554 -56- EX AMPLE 19 l-Cyclopentyl-7-(4-(2-hydroxymethylpiperidin-l-yI)phenylamino]- 3,4-dihydro-pyrimidol4,5-d]pyrimidin-2(li/)‘®ne

Prepared from 294 mg (1.43 mmol) of 1 -(4-aminophenyl)- 5 2-hydroxymethylpiperidine and 330 gL (4.3 mmol) of trifluoroacetic acid. Thecrude residue is purified by chromatography on a 1.2 x 7 cm Biotage silica gelcolumn that is eluted with 3:2 ethyl acetate/dichloromethane. Product fractions arepooled and concentrated to give 130 mg (43%) of the title compound:mp 220-221°C. 10 Analysis calculated for C23H3QN5O2'. C, 65.38; H, 7.16; N, 19.89.

Found: C, 65.13; H, 7.15; N, 19.87. EXAMPLE 20 l-Cyclopentyl-7-{4-[4-(3-hydroxypropyl)piperidin-l-yl]phenylamino}- 15 3,4-dihydro-pyrimido[4,5-<f|pyrimidin-2(l//)-one

Prepared from 335 mg (1.43 mmol) of 1 -(4-aminophenyl)- 4-(3-hydroxypropyl)piperidine and 330 gL (4.3 mmol) of trifluoroacetic acid. Thecrude residue is suspended in ethyl acetate/dichloromethane and stirred for severalhours. The solids are collected and crystallized from ethyl acetate/ 20 dichloromethane. The impure product is further purified by dissolution in 9:2:1 ethyl acetate/ethanol/triethylamine then passage through a column of silicagel eluting with the same solvent to give 31 mg (10%) of the title compound:mp>230°C.

Analysis calculated for C25H34N6O2: 25 C, 65.67; H, 7.51; N, 18.31.

Found: C, 65.50; H, 7.40; N, 18.30. -π- 011554 EXAMPLE 21 l-Cyclopentyl-7-[4-(2-(morpholin-l-yl)ethyl)piperidin-l-yl)phenylamino]- 3,4-dihydro-pyrimido[4,5-dlpyrimidin-2(l//)-one

Prepared from 500 mg (1.43 mmol) of l-(4-aminophenyl)-4-(2-(l- 5 morpholino )ethyl))piperidine and 275 pL (4.3 mmol) of trifluoroacetic acid. The crude residue is dissolved in 15 mL of dichloromethane, and the solution isconcentrated to 5 mL, then diluted with 15 mL of ethyl acetate to precipitatesolids. The suspension is stirred for 2 hours, filtered, and washed with ethylacetate. The brown powder is dissolved in dichloromethane and filtered through a 10 short column of silica with 1:9 methanol/chloroform. The filtrate is concentratedto a pink powder that is dissolved in 20 mL of dichloromethane and 3 drops ofmethanol. The solution is diluted with 30 mL of ethyl acetate, then while stirringslowly, concentrated to 30 mL under a stream of nitrogen. The precipitated palepowder is filtered and dried to give 54 mg (11%) of the title compound: mp 15 218-220°C.

Analysis calculated for C22H28N6O2O.I CH2CI2O.I H2O: C, 65.41; H, 7.70; N, 19.00.

Found: C, 65.70; H, 7.74; N, 19.37.

General method for the préparation of l-isopropyI-7-(substituted 20 phenylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(liZ)-onesTo a solution ofl-isopropyl-7-methanesulfinyl-3,4-dihydro- pyrimido[4,5-J]pyrimidin-2(lf/)-one and two équivalents of the substitutedaniline in acetonitrile is added trifluoroacetic acid. The mixture is heated at 85°Covemight, cooled to room température, diluted with ethyl acetate or 25 dichloromethane, and washed two times with saturated aqueous sodiumbicarbonate solution and once with brine. The organic phase is dried overmagnésium sulfate, and concentrated to leave a residue that is further processed asdescribed in the following examples to give a compound of Formula I.

The following spécifie invention compounds were prepared according to 30 the foregoing general process. -58- 011554 EXAMPLE 22 l-Isopropÿl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(l/0-one

Prepared from 400 mg (1.57 mmol) of 1 -isopropyl-7-methanesulfmyl- 5 3,4-dihydro-pyrimido[4,5-£/]pyrimidin-2( 1 /7)-one, 600 mg (3.14 mmol) of l-(4-aminophenyl)-4-methylpiperazine and 605 pL (7.85 mmol) of trifluoroaceticacid in 6.4 mL of acetonitrile. The reaction mixture is heated at 85°C for 48 hours.After the workup, the crude residue is triturated in ethyl acetate/dichloromethaneand filtered. The solids are redissolyed in dichloromethane, and the solvent is 10 evaporated under a flow of nitrogen while ethyl acetate is added to maintain avolume of 5 mL. The suspension is filtered, and the solids are washed with ethylacetate/dichloromethane, and dried to give 470 mg (78%) of the title compound:mp 234-237°C (dec).

Analysis calculated for C20H27N7OO.I5 C4H8O2O.O5 CH2CI2: 15 20 C, 62.17; H, 7.15; N, 24.58.Found: C, 62.01; H, 7.06; N, 24.57. EXAMPLE 23 7-[4-(4-Hydroxypiperidin-l-yl)phenylamino]-l-isopropyl-3,4-dihydro-py rimido [4,5-J] py rimidin-2(177)-one

Prepared from 200 mg (0.79 mmol) of l-isopropyl-7-methanesulfinyl- 3,4-dihydro-pyrimido[4,5-6dpyrimidin-2(l//)-one, 302 mg (1.57 mmol) ofl-(4-aminophenyl)-4-hydroxypiperidine and 182 pL (2.36 mmol) oftrifluoroacetic acid in 3.2 mL of acetonitrile. After the workup, the crude residueis triturated in ethyl acetate/dichloromethane and filtered. The filtrate isconcentrated further to produce a second crop of crystals. The two are combinedand dried to give 45 mg (13%) of the title compound: mp >120°C (dec).Analysis calculated for ¢20^26^602^-3 C4H8O2O.5 fbO: 25 C, 60.93; H, 7.09; N, 20.11.

Found: C, 60.95; H, 6.82; N, 20.35. 011554 -59- EXAMPLE 24 7-{4-(4-(Dimethylamino)piperidin-l-yl]phenylamino}-l-isopropyl- 3.4- dihydro-pyrimido[4,5-rflpyrimidin-2(l//)-one; compound withtrifluoroacetic acid 5 Prepared from 400 mg (1.57 mmol) of 1-isopropyl-7-methanesulfinyl- 3.4- dihydro-pyrimido[4,5-</|pyrimidin-2(l//)-one, 690 mg (3.14 mmol) ofl-(4-aminophenyl)-4-(dimethylamino)piperidine and 605 pL (7.86 mmol) oftrifluoroacetic acid in 5 mL of acetonitrile. Afiter heating the reaction mixtureovemight, a heavy precipitate forms. The cooled reaction mixture is diluted with 10 6 mL of ethyl acetate and flhered. The solids are washed twice with ethyl acetate, once with ethyl acetate/dichloromethane and dried to give 389 mg (38%) of thetrifluoroacetate sait of the title compound: mp 215-217°C (dec).

Analysis calculated for C22H3JN7O-2.0 C2HF3O2O.I C4HgO2‘0.25 H2O: C, 48.72; H, 5.31; N, 15.06. 15 Found: C, 48.67; H, 5.15; N, 15.05. EXAMPLE 25 l-Isopropyl-7-14-(pyrazol-l-yl)phenylamino]-3,4-dihydro-pyrimidol4,5-z/]pyrimidin-2(l/i)-one; compound with trifluoroacetic acid

Prepared front 200 mg (0.79 mmol) of 1 -isopropyl-7-methanesulfinyl- 20 3.4-dihydro-pyrimido[4,5-Jlpyrimidin-2(l/7)-one, 250 mg (1.57 mmol) of 1 -(4-aminophenyl)pyrazole and 182 pL (2.36 mmol) of trifluoroacetic acid in3.2 mL of acetonitrile. After heating the reaction mixture ovemight, a heavyprecipitate forms. The cooled reaction mixture is diluted with ethyl acetate andfiltered. The solids are washed with ethyl acetate and dried to give 315 mg (86%) 25 of the trifluoroacetate sait of the title compound: mp 249-252°C (dec).

Analysis calculated for Cj 8H19N7O C2HF3O2: C, 51.84; H, 4.35; N, 21.16.

Found: C, 51.94; H, 4.37; N, 21.02. 011554 -60- EXAMPLE 26 l-IsopropyI-7-{4-[4-(3-(morpholin-l-yl)propyl)piperidin-l-yl]phenylamino}- 3.4- dihydro-pynmidoI4,5-J]pyrimidin-2(lH)-one

Prepared from 200 mg (0.79 mmol) of 1 -isopropyl-7-methanesulfinyl- 5 3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one, 477 mg (1.57 mmol) of1 -(4-aminophenyl)-4-(3-( 1 -morpholino)propyl))piperidine and 303 pL(3.93 mmol) of trifluoroacetic acid in 3.2 mL of acetonitrile. After the workup, thecrude residue is triturated in ethyl acetate/dichloromethane and filtered. The solidsare washed with ethyl acetate and dried to give 140 mg (33%) of the title 10 compound: mp 203-205°C (dec).

Analysis calculated for C27H39N7O2O.I C4HgO20.25 H2O: C, 64.92; H, 8.01; N, 19.34.

Found: C, 65.14; H, 7.96; N, 19.27. EXAMPLE 27 15 l-Bicyclol2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-l-yl)phenylamino]- 3.4- dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one (exo)

To a suspension of 300 mg (0.98 mmol) of l-bicyclo[2.2.1]hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-Jlpyrimidin-2(l//)-one and 374 mg(1.96 mmol) of l-(4-aminophenyl)-4-methylpiperazine in 4.0 mL of acetonitrile is 20 added 377 gL (4.90 mmol) of trifluoroacetic acid. The mixture is heated at 85°Covemight. The cooled reaction mixture is diluted with ethyl acetate and washedtwo rimes with saturated aqueous sodium bicarbonate solution and once withbrine. The organic phase is dried over magnésium sulfate and concentrated. Thedark solid residue is triturated in 4 mL of 1:1 dichloromethane/ethyl acetate, 25 filtered, washed with ethyl acetate, and dried to give 266 mg (63%) of the titlecompound: mp 251 -254°C (dec).

Analysis calculated for C24H31N7O: C, 66.49; H, 7.21; N, 22.61.

Found: C, 66.14; H, 7.16; N, 22.22. 011554 EXAMPLE 28 l-MethyI-7-[4-(4-methylpiperazin-l-yl)phenyIamino]-3,4-dihydro-pyrimido[4,5-z/]pyrimidin-2(l//)-one; compound with trifluoroacetic acid

To a solution of 300 mg (1.32 mmol) of 7-methanesulfinyl-l-methyl- 5 3,4-dihydro-pyrimido[4,5-£/Jpyrimidin-2(lif)-one and 507 mg (2.65 mmol) of 1 -(4-aminophenyl)-4-methylpiperazine in 5 mL of acetonitrile is added 510 gL(6.6 mmol) of trifluoroacetic acid. After heating the reaction mixture at 85°Covemight, a heavy precipitate forms. The cooled reaction mixture is diluted with 2 mL of ethyl acetate and filtered. The solids are washed three times with ethyl 10 acetate/acetonitrile and dried to give 560 mg (84%) of the trifluoroacetate sait of the title compound: mp 234-235°C (dec).

Analysis calculated for C ] 8H23N7O2.O C2HF3O2: C, 45.44; H, 4.33; N, 16.77.

Found: C. 45.49; H, 4.35; N, 16.77. 15 EXAMPLE 29 7»[4-(4-Hydroxypiperidin-l-yl)phenyîamino]-l-methyl-3,4-dihydro-pyrimido[4,5-rflpyrimidin-2(17/)-one; compound with trifluoroacetic acid

To a solution of 400 mg (1.77 mmol) of 7-methanesulfinyl-l-methyl- 3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one and 680 mg (3.53 mmol) of 20 l-(4-aminophenyl)-4-hydroxypiperidine in 6 mL of acetonitrile is added 408 gL(5.3 mmol) of trifluoroacetic acid. After heating the reaction mixture at 85°Covemight, a heavy precipitate forms. The cooled reaction mixture is diluted with2 mL of ethyl acetate and filtered. The solids are washed with ethyl acetate andrecrystallized from acetonitrile to give 565 mg (51%) of the trifluoroacetate sait of 25 the title compound: mp 228-229°C (dec).

Analysis calculated for CigP^NgC^^.O C2HF3O2 C2H3N: C, 46.23; H, 4.36; N, 15.72.

Found: C, 46.55; H, 4.48; N, 15.52.

P 011554 EXAMPLE 30 7-{4-[4-(Dimethylamino)piperidin-l-ylJphenylamino}-l-methyl-3,4-dihydro-pyrimido[4,5-rf]pyrimidin-2(l/7)-one; compound with trifluoroacetic acid

To a solution of 400 mg (1.77 mmol) of 7-methanesulfinyl-l -methyl- 5 3,4-dihydro-pyrimido[4,5-£/]pyrimidin-2(l//)-one and 775 mg (3.53 mmol) of1 -(4-aminophenyl)-4-(dimethylamino)piperidine in 6 mL of acetonitrile is added680 pL (8.8 mmol) of trifluoroacetic acid. After heating the reaction mixture at85°C ovemight, aheavy precipitate forms. The cooled reaction mixture is dilutedwith 6 mL of ethyl acetate and filtered. The solids are washed with ethyl acetate 10 and recrystallized from acetonitrile then acetonitrile/dichloromethane/ trifluoroacetic acid to give 202 mg (17%) of the trifluoroacetate sait ôf the titlecompound: mp 190-191°C (dec).

Analysis calculated for C20H27N7O2.O C2HF3O2 H2O O.3 C2H3NO.2CH2C12: 15 C, 45.39; H, 4.96; N, 15.59.

Found: C. 45.37; H, 5.12; N, 15.42. EXAMPLE 31 l-Methyl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-rf]pyrimidin-2(177)-one; compound with trifluoroacetic acid 20 To a solution of 200 mg (0.88 mmol) of 7-methanesulfinyl- 1-methyl- 3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one and 281 mg (1.77 mmol) ofl-(4-aminophenyl)pyrazole in 3.2 mL of acetonitrile is added 204 pL (2.65 mmol)of trifluoroacetic acid. After heating the réaction mixture at 85°C ovemight, aheavy precipitate forms. The cooled reaction mixture is diluted with 2 mL of ethyl 25 acetate and filtered. The solids are washed with ethyl acetate to give 356 mg(93%) of the trifluoroacetate sait of the title compound: mp 250-251°C (dec).Analysis calculated for C16H15N7OC2HF3O2: C, 49.66; H, 3.70; N, 22.52.

Found: C. 49.70; H, 3.60; N, 22.18. ' -63- 011554

General Procedure for oxidation of l-alkyl-7-[(substituted)phenylamino]- 3,4-dihydro-pyrimidol4,5-dlpyrimidin-2(lH)-ones t0 l-alkyl-7-[(substituted)phenylaminoJ-pyrimidol4,5-i/]pyrimidin-2(l//)-ones

To a room température solution of the 1 -alkyl-7-[(substituted) 5 phenylamino]-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one in THF or DMSO is added 4 équivalents of potassium /erz-butoxide. An oxygen atmosphèreis introduced, and the solution is stirred ovemight. The mixture is diluted withethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate,water, and brine. The organic phase is dried over magnésium sulfate and 10 concentrated to give a residue that is triturated in an appropriate solvent, then the precipitated product is collected. Further purification can be carried out bystandard procedures to provide a compound of Formula I. EXAMPLE 32 l-Cyclopentyl-7-[4-(4-methyIpiperazin-l-yl)phenylamino|pyrimido- 15 l4,5-d]pyrimidin-2(lZ/)-one

Prepared from 150 mg (0.37 mmol) of l-cyclopentyl-7-[4-(4- methylpiperazin-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-i/}-pyrimidin-2(177)-one and 165 mg (1.47 mmol) of potassium Zer/-butoxide in 6 mL of THF.The dark orange semi-solid is triturated in diethyl ether, and the yellow powder is 20 collected and dried to give 100 mg (67%) of the title compound: mp 220-225°C(dec).

Analysis calculated for C22H27N7O: C, 65.16; H, 6.71; N, 24.18.

Found: C, 65.22; H, 6.55; N, 23.78. 25 EXAMPLE 33 l-Cyclopentyl-7-l4-(4-hydroxypiperidin-l-yl)phenylamîno]pyrimido[4,5- d]pyrimidin-2(LH)-one

Prepared from 60 mg (0.15 mmol) of l-cyclopentyl-7-[4-(4-hydroxypiperidm-l-yl)phenylamino]-3,4-dihydro-pyritnido[4,5-eflpyrimidin- 30 2(177)-one and 66 mg (0.58 mmol) of potassium fêr/-butoxide in 1.5 mL of DMSO. The crude semi-solid residue is triturated in 15 mL of 2:1 diethyl -<*- 011554 ether/hexane, and the orange amorphous solid is collected and dried to leave20 mg (30%) ofthe title compound: mp >185°C (dêc). MS (CI) (m+l)/z407. EXAMPLE 34 5 l-Cyclopentyl-7-{3-methyl-4-[2-(diethylamino)ethoxy]-phenylamino}pyrimido[4,5-</]pyriinidin-2(l//)-one

Prepared from 70 mg (0.16 mmol) of l-cyclopentyl-7-{3-methyl-4-[2-(diethylamino)eihoxyJphenyIamino}-3i4-dihydro-pyrimido[4,5-i/]pyrimidin2(1 H)-one and 72 mg (0.58 mmol) of potassium /er/-butoxide in 3.0 mL of 10 DMSO. The crude semi-solid residue is dissolved in a mixture of ferf-butyl methyl ether and hexane. The solution is allowed to evaporate slowly to less thanI mL, then diluted with 2 mL of 1:3 diethyl ether/hexane. The precipitated solidsare collected and dried to give 17 mg (24%) ofthe title compound: mp >95°C(dec). 15 MS (CI)(m+l)/z437and232. EXAMPLE 35 l-Cyclopentyl-7-[4-(3-hydroxypiperidin-l-yl)phenylamino]pyrimido[4,5-rf]- pyrimidin-2(lif)-one

Prepared from 75 mg (0.18 mmol) of 1 -cyclopentyl-7-[4-(3- 20 hydroxypiperidin-1 -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-</]pyrimidin- 2(lH)-one and 82 mg (0.73 mmol) of potassium Ze/7-butoxide in 4.0 mL of THF.The semi-solid residue is triturated in diethyl ether, and the orange amorphoussolid is collected and dried to give 35 mg (45%) of the title compound: mp>135°C(dec). 25 Analysis calculated for C22H26N6O2 O.I5 C2Hi()OO.75 H2O: C, 62.96; H, 6.78; N, 19.49.

Found: C, 62.98; H, 6.54; N, 19.47. EXAMPLE 36 l-CyclopentyI-7-[4-(pyrazoI-l-yl)phenylamino]pyrimido[4,5-rfJpyrimidin- 30 2(l//)-one 011554 -65-

Prepared from 100 mg (0.20 mmol) of the trifluoroacetate sait ofl-cyclopentyl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2(l//)-one and 115 mg (1.02 mmol) of potassium /er/-butoxide in5.0 mL of THF. The semi-solid residue is triturated in diethyl ether, and the 5 orange amorphous solid is collected and dried to give 31 mg (40%) of the titlecompound: mp >135°C (dec).

Analysis calculated for C20H19N7O O.I C2H10OO.5 H2O: C, 62.85; H, 5.43; N, 25.15.

Found: C, 63.09; H, 5.30; N, 25.04. 10 EXAMPLE 37 l-Cyclopentyl-7-(4-methoxyphenylamino)pyrimido[4,5-</lpyrimidin- 2(lf/)-one

Reaction of l-cyclopentyl-7-(4-methoxyphenylamino)-3,4-dihydro-pyrimido[4.5-6Qpyrimidin-2(l//)-one by the general procedure described above 15 gives the title compound. MS (CI) (m+l)/z 338. EXAMPLE 38 l-Cyclopentyl-7-[4-(piperidin-l-yl)phenylamino]pyriinido[4,5-</]pyrimidin- 2(lf7)-one 20 Reaction of l-cyclopentyl-7-[4-(piperidin-l-yl)phenylamino]-3,4-dihydro- pyrimido[4.5-ùQpyrimidin-2(l//)-one by the general procedure described abovegives the title compound. MS (CI) (m+l)Zz391. EXAMPLE 39 25 l-Cyclopentyl-7-[4-(2-(morpholin-l-yl)ethyl)piperidin-l-y])phenylainino]-pyrimido[4,5-ûQpyrimidin-2(l//)-one

Prepared from 37 mg (0.07 mmol) of l-cyclopentyl-7-[4-(2-(morpholin- l-yl)ethyl)piperidin-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2(lH)-one and 33 mg (0.29 mmol) of potassium /er/-butoxide in 2.0 mL of THF. 30 The semi-solid residue is triturated in diethyl ether, and the orange amorphous -66- 011554 solid is collected and dried to give 11.8 mg (32%) of the title compound: mp>140°C (dec). MS (CI) (m+l)/z 504. EXAMPLE 40 5 l-Isopropyl-7-l4-(4-methylpiperazin-l-yl)phenylamino]pyrimido[4,5-J] pyrimidin-2(l/Z)-one

Prepared from 200 mg (0.52 mmol) of 1 -isopropyl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-ar]pyrimidin-2(l/7)-one and 235 mg (2.10 mmol) of potassium /er/-butoxide in 10 mL of 10 tetrahydrofuran. The semi-solid is triturated in 14 mL of 1:1 diethyl ether/hexane,and the powder is collected and dried to give 135 mg (68%) of the title compound:mp 228-229°C (dec).

Analysis calculated for C20H25N7OO.O3 C5H14 O.5 H2O: C, 61.98; H, 6.81; N, 25.07. 15 Found: C, 61.95; H, 6.73; N, 25.04. EXAMPLE 41 7-{4-[4-(Dimethylamino)piperidin-l-yl]phenyIamino}-l-isopropyI- pyrimido[4,5-z/]pyrimidin-2(l/Z)-one

Prepared from 200 mg (0.31 mmol) of 7-{4-[4-(dimethylamino)piperidin- 20 l-yl]phenylamino}-l-isopropyl-3,4-dihydro-pyrimido[4,5-iZ]pyrimidin-2(l/7)-onetrifluoroacetic acid and 211 mg (1.88 mmol) of potassium ter/-butoxide in 7 mLof tetrahydrofuran. The reaction mixture is stirred for 48 hours, and the workup isdone as described in the general procedure, then the reaction is repeated for 72hours. After the workup, the semi-solid is triturated in diethyl ether, and the 25 powder is collected and dried to give 24 mg ( 18%) of the title compound:mp>100°C (dec).

Analysis calculated for C22H29N7O H2OO. 1 CH2CI2: C, 61.16; H, 7.25; N, 22.59.

Found: C, 61.11; H, 6.98; N, 22.49. -67- Γ i 1 c. c. 4 EXAMPLE 42 b 1 ' l-Isopropyl-7-[4-(pyrazol-l-yl)phenylaminojpyrimido(4,5-£flpyriinidin-2(l/i)- one

Prepared from 150 mg (0.32 mmol) of l-isopropyl-7-[4-(pyrazol-l- 5 yl)phenylamino]-3,4-dihydro-pyrimido[4,5-i/)pyrimidin-2( 1 H)-one, trifluoroaceticacid and 218 mg (1.94 mmol) of potassium /ert-butoxide in 10 mL oftetrahydrofuran. The reaction mixture is stirred for 48 hours, 50 mg (0.44 mmol)of potassium ZerZ-butoxide is added, and the reaction is continued for 72 hours.After the workup, the semi-solid is triturated in diethyl ether, and the powder is 10 collected and dried to give 86 mg (73%) of the title compound: mp 243-247°C(dec).

Analysis calculated for ΟίβΗιγΝγΟΌ^ Η2ΟΌ.Ι5 C^jqO: C, 60.05; H, 5.42; N, 26.36.

Found: C, 60.19; H, 5.36; N, 26.09. 15 EXAMPLE 43 l-Isopropyl-7~{4-[4-(3-(morpholin-4-yl)propyl)piperidin-l-yI]phenylamino}- pyrimido[4,5-</]pyrimidin-2(lZ7)-one

Prepared from 100 mg (0.20 mmol) of l-isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-l-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-t/]pyrimidin- 20 2(17Y)-one and 88.5 mg (0.79 mmol) of potassium /erZ-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred ovemight, 88.5 mg (0.79 mmol) ofpotassium terf-butoxide is added, and the reaction is continued for 48 hours. Afterthe workup, the semi-solid is five times suspended in diethyl ether and rotovappedto dryness to give 87 mg (85%) of the title compound: mp >95°C (dec). 25 Analysis calculated for C18H17N7O O.8H2OO.I C4H1QO: C, 64.09; H, 7.77; N, 19.10.

Found: C, 64.02; H, 7.50; N, 19.08. a -68- EXAMPLE 44 01 1 5 5 4 l-Bicycloi2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-pyrimidol4,5-rf)pyrimidin-2(l.i7)-one, exo

Prepared from 200 mg (0.46 mmol) of l-bicyclo[2.2.1]hept-2-yl-7-[4-(4-5 methylpiperazin-l-yl)phenyIamino]-3,4-dihydro-pyrimido[4,5-</lpyrimidin-2(l//)- one, exo and 207 mg (1.84 mmol) of potassium /er/-butoxide in 10 mL oftetrahydrofuran. The reaction mixture is stirred for 48 hours. After the workup, thesemi-solid is triturated in diethyl ether/hexane, and the powder is collected anddried to give 140 mg (70%) of the title compound: mp >210°C (dec). 10 Analysis calculated for C24H29N7OO.5 H2O: C, 65.43; H, 6.86; N, 22.26.

Found: C, 65.29; H, 6.74; N, 21.90. EXAMPLE 45 l-Methyl-7-l4-(4-methylpiperazin-l-yl)phenylamino]pyrimido[4,5-15 d]pyrimidin-2(lJ9)-one

Prepared from 250 mg (0.50 mmol) of l-methyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2( 1 H)-one,trifluoroacetic acid and 336 mg (2.99 mmol) of potassium /err-butoxide in 12 mLof tetrahydrofuran. The reaction mixture is stirred for 48 hours. After the workup, 20 the semi-solid is triturated in diethyl ether, and the powder is collected and driedto give 110 mg (61%) of the title compound: mp 259-260°C (dec).

Analysis calculated for Ci{5Η21Ν7ΟΌ.4 H2O: C, 60.29; H, 6.13; N, 27.34.

Found: C, 60.54; H, 5.99; N, 27.05. 25 EXAMPLE 46 7-{4-[4-(Dimethylamino)piperidin-l-yl]phenylamino}-l-methyl- pyrimidoJ4,5-d]pyrimidin-2(l//)-one

Prepared from 170 mg (0.26 mmol) of 7-{4-[4-(dimethylamino)piperidin-l-yl]phenylamino}-l-methyl-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(lH)-one,

30 trifluoroacetic acid and 233 mg (2.07 mmol) of potassium /er/-butoxide in 20 mL -69- 011554 of tetrahydrofuran. The reaction mixture is stirred for 6 days, and the workup isdone as described in the general procedure, including a back-extraction of thecombined aqueous phase with chloroform. The combined organic phase was driedover magnésium sulfate, filtered, and concentrated. The semi-solid is triturated in 5 diethyl ether/hexane, and the powder is collected and dried to give 64 mg (60%)of the title compound: mp 198-202°C (dec).

Analysis calculated for C20H25N7O· 1.7 H2O: C, 58.58; H, 6.98; N, 23.91.

Found: C, 58.73; H, 6.71; N, 23.92. 10 EXAMPLE 47 l-MethyI-7-(4-(pyrazol-l-yl)phenylaminolpyrimido[4,5-rf]pyrimidin-2(l//)- one

Prepared front 200 mg (0.46 mmol) of l-methyl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-£/)pyrimidin-2(l//)-one, trifluoroacetic 15 acid and 309 mg (2.76 mmol) of potassium /er/-butoxide in 15 mL of tetrahydrofuran. The reaction mixture is stirred ovemight. After the workup, thesemi-solid is triturated in diethyl ether, and the powder is collected and dried togive 102 mg (65%) of the title compound: mp >290°C (dec).

Analysis calculated for C16H13N7OO.4 fbO-OJ C4H10O: 20 C, 59.11; H, 4.67; N, 28.72.

Found: C, 59.42; H, 4.39; N, 28.46.

Examples 48-65 are spécifie embodiments of the general reaction schemesshown in Scheme 2. EXAMPLE 48 25 5-[(3,5-Dimethoxy-phenyIimino)-methyl]-2-methylsulfanyI-pyrimidin-4-yIamine

To a suspension of 4.36 g (23.7 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (made as described in WO 98/33798) and 3.65 g(23.7 mmol) of 3,5-dimethoxyaniline in 165 mL of water was added 4.5 ml, of 30 glacial acetic acid. The reaction was stirred at 25°C ovemight and filtered. The -70- 011554 filter pad was washed with water, and the filtrate was dried in vacuo to give 7.02 g(96%) of the title compound, which was used as is in the next step. MS (APCI) (m+l)/z 305.1. EXAMPLE 48a 5 {5-[(3,5-Dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}- ethyl-amine

To a stirred suspension of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (5.0 g, 25.09 mmol, made by the method described in J. Med.

Chem., 1998;41( 17):3276-3292) and 3,5-dimethoxy aniline (3.84 g, 25.09 mmol) 10 water (190 mL) was added glacial acetic acid (5 mL). The reaction mixture wasstirred at ambient température for 24 hours and the suspension fïltered. Theinsoluble product was dried on the filter to afford 7.79 g (92%) of the titledcompound: mpl00-105oC.

Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe = 450°C) (m+l)/z 333.1 15 Analysis calculated for C16H20N4O2S1: C, 57.81; H, 6.06; N, 16.85.

Found: C, 57.63; H, 6.06; N, 16.86. EXAMPLE 49 5-[(3,S-Dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin- 20 4-ylamine

Into 18.2 mL (18.2 mmol) of a 1 M solution of lithium aluminum hydride(LAH) in tetrahydrofuran (THF) cooled to 5°C was added a solution of 5.55 g(18.3 mmol) of 5-[(3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 94 mL of dry THF over 20 minutes. The reaction was

25 stirred for 1.5 hours at 5°C, then quenched by slow sequential addition of 0.72 mL of water, 3.0 mL of 25% NaOH, and an additional 1.66 mL of water. The reaction mixture was fïltered through Celite, and the filter pad was washed wéll with THF.

The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed three times with a solution of -71- 011554 saturated sodium chloride, dried over magnésium sulfate, and concentratedin vacuo to give 5.10 g (91%) of the title compound.

Analysis calcuiated for C44H18N4O2S: C, 54.88; H, 5.92; N, 18.29; S, 10.47. 5 Found: C, 54.92; H, 5.93; N, 18.32; S, 10.68. EXAMPLE 49a {5-14-(3,5-Dimethoxy-phenylamino)-methyl]-2-methylsulfanyI-pyrimidin- 4-yI}-ethyl-amine

To a solution of {5-[(3,5-dimethoxy-phenylimino)-methyl]-2-10 methylsulfanyl-pyrimidin-4-yl}-ethyl-amine (5.91 g, 17.78 mmol) in dry THF (100 mL) at 5°C was added dropwise 17.78 mL of a 1 M solution of LAH in THFover a period of 20 minutes. The reaction mixture was stirred at 5°C for 1 hourand then quenched in the following order with the dropwise addition of 0.8 mL ofwater, 3.2 mL of 25% NaOH, and 1.8 mL of water. The reaction mixture was 15 partitioned between one-half saturated brine and EtOAc. The organic layer was separated, washed with water, dried over magnésium sulfate, fïltered, andevaporated. The residue was purified by column chromatography eluting with asolvent gradient of 1% to 3% methanol in dichloromethane to give 5.4 g (91%) ofthe titled compound: Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe = 450°C) 20 (m+l)/z 335.2

Analysis calcuiated for C j 6H22N4O2S1 : C, 57.46; H, 6.63; N, 16.75.

Found: C, 57.75; H, 6.62; N, 16.52. EXAMPLE 50 25 3-(3,5-Dimethoxy-phenyl)-7-methylsulîanyl-3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(l//)-one

Into a solution of 5.0 g (16.3 mmol) of 5-[(3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 55 mL of dimethylformamidecooled to 5°C, was added 1.63 g (40.8 mmol) of sodium hydride as a 60% minerai 30 oil suspension. The ice bath was removed, and the reaction was stirred for 1 hour. -72- 01 1 554

To the reaction was then added 7.94 g (48.9 mmol) of Ι,Γ-carbonyldiimidazole.After stirring the mixture a further 2.5 hours, the mixture was concentratedin vacuo. The residue was partitioned between dichloromethane and a saturatedsolution of ammonium chloride. The dichloromethane layer was washed twice 5 with each of saturated ammonium chloride, water, and a saturated solution of sodium chloride. The dichloromethane solution was dried over magnésium sulfateand concentrated in vacuo. The residue was chromatographed on silica gel, elutingwith chloroform/methanol (10:0.25 v/v), to give 3.24 g (60%) of the titlecompound. 10 MS (APCI) (m+l)/z 333.2 EXAMPLE 50a 3-(3,5-Dimethoxy-phenyl)-l-ethyI-7-methylsulfanyI-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(l/7)-one

To a solution of {5-(4-(3,5-dimethoxy-phenylamino)-methyl]-2- 15 methylsulfanyl-pyrimidin-4-yl}-ethyl-amine (6.42 g, 19.2 mmol) and diisopropylethylamine (4.96 g, 38.39 mmol) in dichloromethane (120 mL) at 5°C was addeddropwise 10 mL of a 20% solution of phosgene in toluene over a period of20 minutes. The reaction mixture was allowed to warm to ambient températureand stirred for 4 hours. The mixture was washed with one-half saturated 20 NaHCC>3 and water, then dried over magnésium sulfate and filtered. The filtratewas evaporated under reduced pressure and the residue purified by columnchromatography, eluting with a solvent gradient of 1% to 3% methanol indichloromethane to afford 5.96 g (86%) of the titled compound: mp 134-136°C.Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe - 450°C) (m+l)/z 361.2 25 Analysis calculated for C17H20N4O3S : C, 56.65; H, 5.59; N, 15.54.

Found: C, 56.49; H, 5.54; N, 15.33. 011554 -73- EXAMPLE51 3-(3,5-Dimethoxy-phenyl)-7-methanesuIFinyl-3,4-dihydro-pyrimido[4,5- d]pyrimidin-2(lZ7)*one

Into a solution of 2.0 g (6.02 mmol) of 3-(3,5-dimethoxy-phenyl)-7-methylsulfanyI-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(lZ/)-one in 450 mLchloroform was added 1.73 g (6.62 mmol) of trans-2-(phenylsulfonyl)-3-phenyloxaziridine. The reaction was stirred at room température ovemight, thenconcentrated in vacuo. The residue was chromatographed down silica gel, elutingfirst with chloroform. then with a solution of chloroform/methanol (10/0.25 v/v),and finally chloroform/methanol (9:1 v/v), giving 1.87 g (85%) of the titlecompound: mp 220-222°C.

Analysis calculated for C15H16N4O4SO.3O FbOO.lO CHCI3: C, 49.59; H, 4.60; N, 15.32; S, 8.77; H2O, 1.48.

Found: C, 49.62; H, 4.34; N, 15.20; S, 8.87; H2O, 1.42. EXAMPLE 51a 3-(3,5-Dimethoxy-phenyl)-l-ethyl-7-methanesulfïnyl-3,4-dihydro-py rimido [4,5-rf] py riraidin-2( li/)-on e

To a solution of3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methylsulfanyI- 3,4-dihydro-pyrimido[4,5-ùQpyrimidin-2(l/7)-one (5.61 g, 15.57 mmol) indichloromethane (100 mL) at ambient température was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (4.88 g, 18.69 mmol, PD 0191006, Org.Synth.,1987;66:203-210) in portions. The reaction mixture was stirred ovemight, thenwashed with brine and water. The organic layer was dried over magnésiumsulfate, filtered, and evaporated under reduced pressure. The residue was purifiedby column chromatography eluting with a solvent mixture of 3% methanol indichloromethane to yield 4.6 g (78%) of the titled compound: mp 167-169°C.Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe = 450°C) (m+1 )/z 377.1Analysis calculated for C17H20N4O3S: C, 54.24; H, 5.36; N, 14.88.

Found: C, 53.95; H, 5.27; N, 14.51. '· l -74- 011554 EXAMPLE 52 7-(4-DiethyIamino-butylamino)-3-(3,5-dimethoxy-phenyl)-3,4-dihydro- pyrimido{4,S-rf]pyrimidin-2(l//)-one A suspension of 0.2261 g (0.65 mmol) of 3-(3,5-dimethoxy-phenyl)- 5 7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l//)-one and 0.103 g(0.71 mmol) of diethylaminobutylamine in 10 mL of dry dioxane was warmed to60°C and stirred ovemight. To the réaction mixture was added 0.306 g(2.13 mmol) of diethylaminobutylamine and 0.1658 g (0.71 mmol) ofcamphorsulfonic acid. The reaction mixture was stirred for another 18 hours at 10 60°C. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate.The ethyl acetate layer was washed with a saturated solution of sodiumbicarbonate, then with water, dried over magnésium sulfate, and concentratedin vacuo. The residue was chromatographed down silica gel, eluting with ethyl 15 acetate/ethanol/triethylamine (9:2:1 v/v/v) to give 0.173 g (62%) of the titlecompound: mp 203-207°C.

Analysis calculated for C22H32N5O3: C, 61.66; H, 7.53; N, 19.61.

Found: C, 61.31 ; H, 7.32; N, 19.23. 20 EXAMPLE 53 7-(4-DiethyIamino-butylamino)-3-(3,5-dimethoxy-phenyI)-l-ethyI- 3.4- dihydro-pyrimido[4,5-d}pyrimîdin-2(l/7)-one A mixture of3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methanesulfmyl- 3.4- dihydro-pyrimido[4,5-i/]pyrimidin-2(17:/)-one (0.5 g, 1.33 mmol), 25 4-diethylaminobutylamine (0.38 g, 2.66 mmol,) and trifluoroacetic acid (0.31 g,2.66 mmol) in acetonitrile (6 mL) was heated in a sealed tube at 90°C for18 hours. The solvent was removed under reduced pressure and the residue takenup in IN HCl. The solution was made basic with 50% NaOH and extracted twicewith dichloromethane. The combined organic layers were dried over magnésium 30 sulfate, filtered, and evaporated. The residue was purified by radial ' -75- 011554 chromatography eluting with a solvent mixture of ethyl acetate/methanol/ethyl(89:10:1 v/v/v) to give 0.34 g (56%) of the titled compound: mp 83-85°C.

Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe = 450°C) (m+l)/z 458.2Analysis calculated for C24H36N6O3: 5 C, 63.13; H, 7.95; N, 8.41.

Found: C, 62.85; H, 7.84; N, 18.06. EXAMPLE 53a 7-|4-(2-DiethyIamino-ethoxy)-phenyIamino]-3-(3,5-dimethoxy-phenyI)- l-ethyI-3,4-dihydro-pyrimido(4,5-<flpyriimdin-2(177)-one 10 A mixture of 3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methanesulfmyl- 3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l//)-one (0.5 g, 1.33 mmol), 4-(2-diethylaminoethoxy)aniline (0.55 g, 2.66 mmol, Helv. Chim. Acta,1960;43:1971-1979) and trifluoroacetic acid (0.46 g, 3.98 mmol) in acetonitrile(6 mL) was heated in a sealed tube at 100°C for 18 hours. The solvent was 15 removed under reduced pressure and the residue dissolved in water. The solutionwas made basic with IN NaOH and extracted twice with EtOAc. The combinedorganic layers were dried over magnésium sulfate, filtered, and evaporated. Theresidue was suspended in ether (20 mL), triethylamine (0.27 g, 2.66 mmol), andBOC2O (0.32 g, 1.46 mmol) added, and the mixture stirred at ambient 20 température for 4 hours. The reaction mixture was diluted with hexane and cooledto 0°C. The insoluble product wàs collected by filtration and washed with hexaneto afford 0.56 g (81%) of the titled compound: mp 139-141°C.

Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe = 450°C) (m+l)/z 521.3Analysis calculated for C28H36N6O4 O.I9 CF3CO2H: 25 C, 62.86; H, 6.73; N, 15.50.

Found: C, 62.85; H, 6.65; N, 15.56. -76- 011554

General Experimental for the Parallel Synthesis of 3-AryI-7-(substitutedalkylamino)-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(177)-ones and 3-Aryl-l-alkyl-7-(substituted alkylamino)-3,4-dihydro-pyrimido[4,5-z/]pyrimidin-2(lZZ)_ones 5 Into an Argonaut Technologies’ Quest 210 10 mL reactor was added 0.100 g (0.287 mmol) of3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl- 3.4- dihydro-pyrimido[4,5-<7]pyrimidin-2(l//)-one in 5 mL of dry dioxane or0.100 g (0.266 mmoi) or 3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methanesuIfinyl- 3.4- dihydro-pyrimido[4,5-i/lpyrimidin-2(l//)-one in 4 mL of dry dioxane and 10 0.0753 g (0.3157 mmol) of camphorsulfonic acid in 2 mL of dry dioxane. To the reaction mixture was added a solution of from 2.7 to 3.3 équivalents of amine(RjNFb) in 1 mL dioxane. The reaction mixture was agitated at 65°C for 18 hours, then cooled to room température. The dioxane was evaporated under astream of nitrogen, and the residue was partitioned between ethyl acetate and a 15 solution of saturated sodium bicarbonate. The ethyl acetate layer was washedtwice with a dilute solution of sodium bicarbonate, then once with water. Theethyl acetate layer was dried with magnésium sulfate and concentrated to drynessusing a stream of nitrogen. The residue was chromatographed down silica gelgiving the title compound. 20 EXAMPLE 54 3-(3,5-Dimethoxy-phenyl)-7-{2-[(pyridin-4-ylmethyl)-amino]-ethylamino}- 3.4- dihydro-pyrimido[4,5-z/]pyrimidin-2(lZ/)-one i

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-if]pyrimidin-2(l//)-one and 0.1423 g 25 (0.941 mmol) of N-(4-picoly)ethylenediamine were reacted. The residue was chromatographed eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0162 g (13%) of the title compound: HPLC = 92% pure. MS (APCI) (m+l)/z 436.2 011554 -77- EXAMPLE 54a 3-(3,5-Dimethoxy-phenyl)-7-[3-(4-methyl-piperazin-l-yl)-propylamino]- 3.4- dihydro-lH-pyrimido[4,5-iGpyrimidin-2(l/0-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7- 5 methanesulfinyl-3,4-dihydro-pyrimido[4,5-£/]pyrimidin-2(l//)-one and 0.1234 g(0.785 mmol) of 3-(4-methyl-piperazin-l-yl)-propylamine were reacted. Theresidue was chromatographed over silica gel, eluting with ethylacetate/ethanol/triethylamine (9:2:1 v/v/v), then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0443 g (35%) of the title 10 compound: HPLC = 92% pure. MS (APCI) (m+l)/z 442.2 EXAMPLE 54b 3-(3,5-Dimethoxy-phenyl)-7-(4-(4-methyl-piperazin-l-yI)-butylaminol- 3.4- dihydro-pyrimido[4,5-iflpyriinidin-2(l./7)-one 15 Using the general procedure above, 3-(3,5-dimethoxy-phenyl)- 7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-iZlpyrimidin-2(l//)-one and 0.1354 g(0.791 mmol) of 4-(4-methyl-piperazin-l-yl)-butylamine were reacted. Theresidue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to 20 give 0.0401 g (31 %) of the title compound: HPLC = 99% pure. MS (APCI) (m+l)/z 456.2 EXAMPLE 54c 3-(3,5-Dimethoxy-phenyl)-7-[5-(4-methyl-piperazin-l-yI)-pentylamino]- 3.4- dihydro-pyrimido[4,5-rf]pyrimidin-2(lH)-one 25 Using the general procedure above, 3-(3,5-dimethoxy-phenyl)- 7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-c/]pyrimidin-2(l//)-one and 0.1475 g(0.805 mmol) of 5-(4-methyl-piperazin-l-yl)-pentylamine were reacted. Theresidue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to 30 give 0.0322 g (24%) of the title compound: HPLC = 97% pure. MS (APCI) (m+l)/z 470.2 011554 -78- EXAMPLE 55 7-(3-Diethylamino-propylamino)-3-(3,5-dimetboxy-phenyl)-3,4-dihydro- pyrimido[4,5-£?lpyrimidin-2(lû)-one

Using the general procedure above, 3-(3,5-dmethoxy-phenyl)-7- 5 methanesulfinyl-3,4-dihydro-pyrimido[4,5-</jpyrimidin-2(l tf)-one and 0.1121 g(0.861 mmol) of diethylaminopropylamine were reacted. The residue waschromatographed eluting with acetonitrile/ethanol/triethylamine (8:1:0.5 v/v/v) togive 0.0476 g (40%) of the title compound: HPLC = 89% pure. MS (APCI) (m+l)/z 415.2 10 EXAMPLE 56 3-(3,5-Dimethoxy-phenyl)-l-ethyl-7-{2-l(pyridin-4-ylmethyI)-aminoJ- ethylamino}-3,4-dihydro-pyrimido[4,5-d]pyriinidin-2(lJ/)-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-</|pyrimidin-2(17/)-one and 0.1317 g 15 (0.871 mmol) ofN-(4-picoly)ethylenediamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine(9:2:1 v/v/v), to give 0.0307 g (25%) of the title compound: HPLC = 87% pure.MS (APCI) (m+l)/z 464.2 EXAMPLE 57 20 3-(3,5-Dimethoxy-phenyl)-l-ethyl-7-|3-(4-methyI-piperazin-l-yl)-propylamino]-3,4-dihydro-pyrimidof4,5-d|pyrimidin-2(l//)-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-l-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-if]pyrimidin-2(l//)-one and 0.1142 g(0.726 mmol) of 3-(4-methyl-piperazin-l-yl)-propylamine were reacted. The 25 residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 vIvIn), to give 0.0712 g (57%) of the title compound: HPLC = 96% pure. MS (APCI) (m+l)/z 470.2 011554 -79- EXAMPLE 58 3-(3,5-Dimethoxy-phenyl)-l-ethyl-7-[4-(4-methyl-piperazin-l-yl)-butylamino]-3,4-dihydro-pyrimido[4,5-rf}pyriiiiidin-2(l/7)-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-l-ethyl-5 7-methanesulfInyl-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l//)-one and 0.1253 g (0.732 mmol) of 4-(4-methyl-piperazin-l-yl)-butylamine were reacted. Theresidue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.0527 g (41%) of the title compound: HPLC = 94% pure. 10 MS (APCI) (m+l)/z 484.3 EXAMPLE 59 3-(3,5-Dimethoxy-phenyl)-l-ethyl-7-[5-(4-methyl-piperazin-l-yl)- pentylamino]-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2(l/f)-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1 -ethyl-7-15 methanesulfinyl-3,4-dihydro-pyrimido[4,5-<f)pyrimidin-2(l//)-one and 0.1365 g (0.745 mmol) of 5-(4-methyl-piperazin-l-yl)-pentylamine were reacted. Theresidue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.041 g (31%) of the title compound: HPLC - 98% pure. 20 MS (APCI) (m+l)/z 498.3 EXAMPLE 60 7-(3-Diethylamino-propylamino)-3-(3,5-dimethoxy-phenyI)-l-ethyI- 3,4-dihydro-pyriniido[4,5-</]pyriniidin-2(l/ï)-one

Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-l-ethyl-7-25 methanesulfmyl-3,4-dihydro-pyrimido[4,5-£/]pyrimidin-2(l//)-one and 0.1038 g (0.797 mmol) of diethylaminopropylamine were reacted. The residue was chromatographed over silica gel, eluting with acetonitrile/ethanol/triethylamine (8:1:0.5 v/v/v), to give 0.0719 g (61 %) of the title compound: HPLC = 81% pure. MS (APCI) (m+l)/z 443.2 011554 -80- PREPARATION 11 2-Chloro-3,5-dimethoxy-benzoic acid e

Into a solution of 12 g (52.0 mmol) of 2-chloro-3,5-dimethoxy-benzoicacid methyl ester (prepared according to the method of T. R. Kasturi and 5 E. M. Abraham, Indian Journal of Chemistry, 1973; 11:1099-1104) in 40 mL ofmethanol was added 60 mL (60 mmol) of IN potassium hydroxide solution. Afterstirring ovemight at room température, the methanol was removed in vacuo, andthe residue was suspended in 800 mL of water. The aqueous layer was extractedthree times with diethyl ether and the acidified with concentrated hydrochloric 10 acid to a pH of 3. The resulting white solid was filtered, washed well with water,and air-dried to give 9.82 g (87%) of the title compound. MS (APCI) (m+l)/z217 PREPARATION 12 (2-Chloro-3^-dimethoxy-phenyl)-carbamic acid, ZerZ-butyl ester 15 Into a solution of 9.57 g (44.18 mmol) of 2-chloro-3,5-dimethoxy-benzoic acid and 4.78 g (47.3 mmol) of triethylamine in 250 mL of toluene was added13.57 g (49.3 mmol) diphenylphosphoryl azide. The reaction was refluxed for4 hours. To the reaction was added 3.63 g (49.0 mmol) of Ze/7-butanol. Thereaction was refluxed ovemight then concentrated in vacuo. The residue was 20 partitioned between a cold IN solution of citric acid and ethyl acetate. The ethylacetate layer was washed twice with each of the following: cold IN citric acidsolution, water, and then saturated sodium bicarbonate solution. The ethyl acetatelayer was dried with magnésium sulfate and concentrated in vacuo. The residuewas dissolved in tetrahydrofuran, added silica gel and concentrated to dryness. 25 The residue was chromatographed on silica gel, eluting with hexane/diethyl ether(9:1 v/v), to give 8.14 g (64%) of the title compound: mp 94.5-95.5°C.

Analysis calculated for 3NO4CI: C, 54.26; H, 6.31; N, 4.87; Cl, 12.32.Found: C, 54.20; H, 6.17; N, 4.90; Cl, 12.08. 011554 -81- PREPARATION 13 2-Chloro-3,5-dimetboxy-phenylamine Το 6.01 g (0.021 mmol) of (2-chloro-3,5-dimethoxy-phenyl)-carbamic acid iert-butyl ester was added 15 mL of trifluoroacetic acid. The reaction was 5 stirred for 3 hours at room température, then concentrated in vacuo. The residuewas made basic with a saturated solution of sodium bicarbonate, then extractedthree times with dichloromethane. The combined dichloromethane layers weredried with magnésium sulfate and concentrated in vacuo to give 3.98 g of the titlecompound, which was used as is in the following example. 10 MS (APCI) (m+l)/z 188 EXAMPLE 61 {5-((2-ChIoro-3,5-dimethoxy-phenylimino)-methyIl-2-methyIsulfanyl- pyrimidin-4-yl}-ethyl-amine

Into a solution of 3.78 g (20.2 mmol) of 2-chloro-3,5-dimethoxy- 15 phenylamine in 110 mL of toluene was added 3.97 g (20.15 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaIdehyde. The reaction vesselwas equipped with a Dean-Stark trap, and the reaction was warmed to reflux.

After 3 hours, two drops of concentrated sulfuric acid were added to the reaction.The reaction was refluxed ovemight then concentrated in vacuo to give 7.36 g 20 (93%) of the title compound, which was used as is in the following example: mp 196.5-198.5°C. MS (APCI) (m+l)/z 367.0 EXAMPLE 62 {5-{(2-Chloro-3,5-dimethoxy-phenylamino)-methyI]-2-methylsulfanyI- 25 pyrimidin-4-yl}-ethyI-amine

Into a suspension of 6.96 g (18.97 mmol) of {5-[(2-chloro-3,5-dimethoxy- phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine in 200 mLof dry THF cooled to 5°C was added 18.97 mL (18.97 mmol) of a 1 M solution ofLAH in THF. After stirring for 1 hour, the cold reaction was quenched by 30 sequential addition of 0.8 mL of water, 3.0 mL of 25 NaOH, and 1.7 mL of water.The reaction was filtered through Celite, the fïlter pad washed well with THF, and 011554 -82- the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane,added silica gel, and concentrated in vacuo. This residue was chromatographed onsilica gel, eluting with hexane/ethyl acetate (2:1 v/v), giving 5.15 g (74%) of thetitle compound: mp 116.5-118.5°C. 5 Analysis calculated for Ci6¾ 1N4O2CIS: C, 52.10; H, 5.74; N, 15.19; Cl, 9.61; S, 8.69.

Found: C, 52.45; H, 5.67; N, 14.99; Cl, 9.38; S, 8.66. EXAMPLE 63 3-(2-Chloro-3,5-dimethoxy-phenyl)-l-ethyl-7-methylsulfanyl-3,4-dihydro- 10 pyrimido[4,5-i/]pyrimidin-2(lif)-one

Into a solution of 1.00 g (2.71 mmol) of {5-[(2-chloro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine in 7 mL ofdry DMF cooled to 5°C was added 0.271 g (6.78 mmol) of sodium hydride as a60% minerai oil suspension. The ice bath was removed, and the reaction was 15 stirred for 1 hour. To the reaction was then added 1.32 g (8.13 mmol) of 1,1 '-carbonyldiimidazole. After stirring a further 2 hours, the reaction wasconcentrated in vacuo. The residue was partitioned between dichloromethane anda saturated solution of ammonium chloride. The aqueous layer was washed twicewith dichloromethane. The dichloromethane layers were combined, dried over 20 magnésium sulfate, and concentrated in vacuo. The residue was dissolved indichloromethane, added silica gel, and concentrated in vacuo. The residue waschromatographed on silica gel, eluting with dichloromethane/ethyl acetate(9:0.5 v/v). to give 0.7507 g (70%) of the title compound: mp 189-191 °C.Analysis calculated for C17H19N4O3CIS: 25 C, 51.71; H, 4.85; N, 14.19.

Found: C. 51.95; H, 4.81; N, 13.88. EXAMPLE 64 3-(2-Chloro-3,5-dimethoxy-phenyl)-l-ethyl-7-methanesulfinyl-3,4-dihydro- py rimido [4,5-î/] py rimidin-2(l/7)-one 011554 -83-

Into a solution of 0.7457 g (1.89 mmol) of 3-(2-chloro-3,5-dimethoxy-phenyl)-l-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido[4,5-<Z]pyrimidin-2(l//)-one in 7 mL chloroform was added 0.5428 g (2.08 mmol) of trans- 2- (phenylsulfonyl)-3-phenyloxaziridine. The reaction was stirred at room5 température ovemight, then concentrated in vacuo. The residue was chromatographed down silica gel, eluting with ethyl acetate/ethanol (9:1 v/v), togive 0.697 g (90%) of the title compound.

Analysis calculated for C17H19N4O4CIS O.O6 CH2CI2: C, 49.26; H, 4.63; N, 13.47. 10 Found: C. 49.58; H, 4.69; N, 13.08. EXAMPLE 65 3- (2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethyIamino-butylamino)-l-ethyl- 3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(lJ/)-one A solution of 0.1074 g (0.2614 mmol) of 3-(2-chloro-3,5-dimethoxy-15 phenyl)-7-(4-diethylamino-butylamino)-l -ethyl-3.4-dihydro-pyrimido[4,5- </]pyrimidin-2(l//)-one, 0.113 g (0.784 mmol) of diethylaminobutylamine, and0.067 g (0.287 mmol) of camphorsulfonic acid in 4 mL of dry dioxane waswarmed at 60°C. After stirring ovemight the reaction was concentrated in vacuo,and the residue was dissolved in dichloromethane. The dichloromethane solution 20 was extracted three times with a saturated solution of sodium bicarbonate, driedover magnésium sulfate, and concentrated in vacuo. The residue waschromatographed down silica gel, eluting with ethyl acetate/ethanol/triethylamine(9:1:0.5 v/v/v), to give 0.106 g (82%) of the title compound. MS (APCI) (m+l)/z 491.1 25 Examples 66-67 are depicted in Scheme 3. EXAMPLE 66 3-(3,5-Dimethoxy-phenyl)-7-methylsulfanyl-3,4-dihydro-pyrimido[4,5- rf]pyrimidin-2-ylamine

Into a solution of 25.0 g (81.6 mmol) of 5-[(3,5-dimethoxy-phenylamino)- 30 methyI]-2-methylsulfanyl-pyrimidin-4-ylamine in 125 mL of dry -84- 01 1 554 dimethylformamide cooled to 5°C, was added a solution of 10.1 g (95.5 mmol) ofcyanogen bromide in 25 mL of dry dimethylformamide portionwise. After theaddition of the cyanogen bromide solution the ice bath was removed, and thereaction was allowed to warm to room température over 30 minutes. The reaction 5 was warmed to 80°C for 4 hours, then added to 500 mL of IN NaOH. Theaqueous suspension was extracted with dichloromethane (7 x 150 mL). Thedichloromethane layers were combined and concentrated in vacuo. The residuewas dissolved in dichloromethane, extracted three times with a saturated solutionof sodium chloride, dried over magnésium sulfate, and concentrated in vacuo. The 10 residue was dissolved in tetrahydrofuran, added silica gel, and concentratedin vacuo. The residue was chromatographed down silica gel, eluting First withethyl acetate. then switching to ethyl acetate/ethanol (9:1 v/v), giving productwhich was slightly impure. This product was rechromatographed down silica gel,eluting with first chloroform, then switching to chloroform/methanol (9:0.5 v/v), 15 to give 7.34 g (24%) of the title compound: mp 198-204°C.

Analysis calculated for C15H17N5O2SO.3O CHCI3: C, 50.04; H, 4.75; N, 19.07; S, 8.73.

Found: C, 50.11; H, 4.59; N, 19.18; S, 8.91. EXAMPLE 67 20 3-(3,5-Dimethoxy-phenyI)-7-methanesuIfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-y lamine

Into a solution of 2.00 g (6.04 mmol) of 3-(3,5-dimethoxy-phenyl)-7-methylsulfanyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2-ylamine in 50 mL ofchloroform was added a solution of 1.73 g (6.64 mmol) of trans-2- 25 (phenylsulfonyl)-3-phenyloxaziridine in 20 mL of chloroform. The reaction wasstirred ovemight at room température, then concentrated in vacuo. The residuewas dissolved in dichloromethane, added silica gel, and concentrated! in vacuo.The residue was chromatographed down silica gel, eluting first with ethyl acetatethen ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 1.4306 g (68%) of 30 the title product. -85- 011554

Analysis calculated for C15HJ7N5O3SO.25 EtOAcO.25 H2O: C, 51.37; H, 5.26; N, 18.73.

Found: C, 51.15; H, 5.23; N, 18.44. PREPARATION 14 5 Ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylateTo a 0°C solution of 10.0 g (43.0 mmol) of ethyl 4-chloro-2- (methylthio)pyrimidine-5-carboxylate and 7.2 mL (51.6 mmol) of triethylamine in100 mL of dichloromethane is added 4.4 mL (51.6 mmol) of isoproylamine. Thereaction solution is stirred at 0°C for 2 hours then allowed to warm to room 10 température. The reaction mixture is diluted with ethyl acetate, washed twice withaqueous HCl. twice with water, once with a saturated solution of sodiumbicarbonate, and brine. The organic phase is dried over magnésium sulfate,filtered, and concentrated to give 11.1g (quant.) of the title compound as an oilwhich solidified on standing: mp 159-160°C. 15 Mass Spectrum (CI) (m+1 )/z 256. PREPARATION 15 4-(Isopropylamino)-2-(methylthio)pyrimidine-5-carboxyIic acid

To a solution of 5.0 g (19.6 mmol) of ethyl 4-(isopropylamino)-2- (methylthio)pyrimidine-5-carboxylate in 20 mL of éthanol is added a solution of 20 0.8 g (20.6 mmol) of sodium hydoxide in 30 mL of water. The reaction suspension is stirred at room température ovemight. The reaction solution isdiluted with 100 mL of water and washed twice with diethyl ether. The aqueousphase is neutralized with 20.6 mL of IN HCl. The precipitate is filtered andwashed twice with water, dried under vacuum at 70°C to give 4.0 g (90%) of the 25 title compound: mp 202-203°C (dec).

Analysis calculated for C9H13N3SO2: C, 47.56; H, 5.77; N, 18.49.

Found: C, 47.38; H, 5.70; N, 18.29. -86- 01 1 5 5 4 PREPARATION 16 N-Allyl-4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxamide Το 3.5 (15.4 mmol) of 4-(isopropylamino)-2-(methylthio)pynrnidine-5- carboxylic acid is added 9.0 mL (123.2 mmol) of thionyl chloride, and the 5 réaction mixture is heated at 50°C for 1 hour, cooled to room température, andconcentrated. The residue is twice suspended in anhydrous toluene andconcentrated to give a colorless solid, 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride.

To a 0°C suspension of 4-(isQpropylamino)-2-(methylthio)pyrimidine-5- 10 carboxylic acid chloride in 10 mL of tetrahydrofuran is added 3.5 ml. (46.2 mmol)of allylamine and 20 mL of tetrahydrofuran. The reaction suspension is allowed towarm briefl y to room température, then stored at 0°C ovemight. The reactionmixture is diluted with ethyl acetate, washed with IN HCl, a saturated solution ofsodium bicarbonate, and brine. The organic phase is dried over magnésium 15 sulfate, filtered, and concentrated to give 2.1 g (51 %) of the title compound:mp 159-161°C.

Analysis calculated for C12H18N4SO: C, 54.11; H, 6.81; N, 21.03.

Found: C, 54.42; H, 6.69; N, 21.13. 20 PREPARATION 17 N-(4-MethoxybenzyI)-4-(isopropylamino)-2-(methylthio)pyrimidine-5- carboxamide

To a 0°C suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine- 5-carboxylic acid chloride (as prepared in the above example, Préparation 16) in 25 30 mL of tetrahydrofuran is added 6.0 mL (46.3 mmol) of 4-methoxybenzylamine and 30 mL of tetrahydrofuran. The reaction suspension is allowed to warm brieflyto room température, then stored at 0°C ovemight. The reaction mixture is dilutedwith dichloromethane, washed with IN HCl and water. The combined aqueousphase is washed with dichloromethane. The combined organic phase is washed 30 with a saturated solution of sodium bicarbonate and brine, dried over magnésium -87- 01 1 554 sulfate, filtered, and concentrated. The residue is crystallized from ethylacetate/hexane to give 3.27 g (61%) of the title compound: mp 176-177°C.Analysis calculated for C47H22N4SO2: C, 58.94; H, 6.40; N, 16.17. 5 Found: C, 58.87; H, 6.34; N, 16.26. EXAMPLE 68 3-Allyl-7-(imidazol-l-yl)-l-isopropyl-l/7-pyrimido(4,5-rf]pyriniidine-2,4-dioneTo a 0°C suspension of 563 mg (14.1 mmol) of sodium hydride (60% disp.) is added 1.5 g (5.63 mmol) ofN-allyl-4-(isopropylamino)-2- 10 (methylthio)pyrimidine-5-carboxamide, and the reaction mixture is stirred for 15 minutes. To the reaction mixture is added in small portions 2.7 g (16.9 mmol)of l,T-carbonyldiimidazole. The reaction mixture is stirred ovemight at roomtempérature, diluted with ethyl acetate, and washed with a saturated solution ofsodium bicarbonate, water, and brine. The combined aqueous phase is washed 15 with ethyl acetate. The combined organic phase is dried over magnésium sulfate,filtered, and concentrated. The residue is chromatographed on silica eluting with4:6 ethyl acetate/hexane. The single component fractions are collected andcrystallized from dichloromethane/hexane to give 457 mg (26%) of the titlecompound: mp 158-160°C. 20 Analysis calculated for CjsHigN^Cb: C, 57.68; H, 5.16; N, 26.91.

Found: C, 57.57; H, 4.90; N, 26.98.

The mixed component fractions are also collected and crystallized as above to give 782 mg (44%) of analytically pure title compound. 25 EXAMPLE 69 7-(Imidazol-l-yl)-l-isopropyl-3-(4-methoxybenzyl)-lJÏ-pyrimjdol4,5- d]pyrimidine-2,4-dione

To a 0°C suspension of 865 mg (21.6 mmol) of sodium hydride (60%disp.) is added 3.0 g (8.66 mmol) of N-(4-methoxybenzyl)-4-(isopropylamino)-2- 30 (methylthio)pyrimidine-5-carboxamide, and the reaction mixture is stirred for -88- 011554 1 hour. Το the reaction mixture is added in small portions 4.2 g (26.0 mmol) of1,l'-carbonyldiimidazole. The reaction mixture is warmed at 50°C for 5 hours,concentrated to dryness, and dissolved in 300 mL of 6N HCl. The solution iswashed with diethyl ether, made basic with 50% aqueous solution of sodium 5 hydroxide while maintaining the solution température below 40°C. The suspension is cooled to 15°C, and the precipitate is filtered, washed with water,and dried under vacuum at 65°C to give 3.1 g (91%) of the title compound:mp 148-150°C (dec).

Analysis calculated for 020^20^6^3'· 10 C, 61.22; H, 5.14; N, 21.42.

Found: C, 60.92; H, 5.25; N, 21.17. EXAMPLE 70 3-Allyl-l-isopropyl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-l//- pyrimido|4,5-i/]pyrimidine-2,4-dione 15 A mixture of 300 mg (0.96 mmol) of 3-allyl-7-(imidazol-1 -yl)-l- isopropyl-177-pyrimido[4,5-<flpyrimidine-2,4-dione and 551 mg (2.88 mmol) ofl-(4-aminophenyl)-4-methylpiperazine is heated at 180°C for 2 hours. Thereaction mixture is cooled, dissolved into chloroform, and chromatographed onsilica eluting with 4:96 methanol/chloroform. The resulting material is crystallized 20 from methanol/water to give 251 mg (60%) of the title compound: mp 176-177°C.Analysis calculated for ¢23^9^02^0: C, 60.91; H, 6.89; N, 21.62.

Found: C, 60.79; H, 6.80; N, 21.54. EX AMPLE 71 25 l-Isopropyl-3-(4-methoxybenzyl)-7-[4-(4-methylpiperazin-l-yl)phenyIamino]-17/-pyrimido[4,5-d]pyrimidine-2,4-dione A mixture of 700 mg (1.78 mmol) of7-(imidazol-l-yl)-l-isopropyl-3-(4-methoxybenzyl)-l//-pyrimido[4,5-</]pyrimidine-2,4-dione and 1.02 g (5.35 mmol)of 1 -(4-aminophenyl)-4-methylpiperazine is heated at 180°C for 2 hours. The 30 reaction mixture is cooled, dissolved into chloroform, and chromatographed on -89- 01 1 55 4 silica eluting with 5:95 methanol/chloroform. The resulting material is crystallizedfrom methanol/water to give 530 mg (58%) of the title compound: mp 215-216°C.Analysis calculated for C28H33N7O3: C, 65.22; H, 6.45; N, 19.02. 5 Found: C, 65.28; H, 6.41; N, 19.00. EXAMPLE 72 3- Allyl-7-{4-(2-Diethylaminoethoxy)phenylamino]-l-isopropyl-lZ7-pyrimido [4,5-rf] py rimidine-2,4-dione A mixture of 200 mg (0,64 mmol) of 3-allyl-7-(imidazol-l-yl)-l- 10 isopropyl-l//-pyrimido[4,5-if]pyrimidine-2,4-dione and 400 mg (1.92 mmol) of 4- (2-diethylaminoethoxy)aniline is heated at 180°C for 3 hours. The reactionmixture is cooled, dissolved into chloroform, and chromatographed on silicaeluting with 4:96 methanol/chloroform. The resulting oily material partiallycrystallizes on standing, and the mixture is triturated with diethyl ether/hexane and 15 filtered to give 106 mg (36%) of the title compound: mp 90-96°C.

Analysis calculated for C24H32N6O3: C, 63.70; H, 7.13; N, 18.57.

Found: C, 63.39; H, 7.15; N, 18.36. EXAMPLE 73 20 7-[4-(2-DiethyIaminoethoxy)phenylamino]-l-isopropyl-3-(4-methoxybenzyI)-l/7-pyrimido[4,5-i/]pyrimidine-2,4-dione A mixture of 700 mg (1.78 mmol) of 7-(imidazol-l-yl)-l-isopropyl-3-(4-methoxybenzyl)-l//-pyrimido[4,5-i/]pyrimidine-2,4-dioneand 1.1 g (5.35 mmol)of 4-(2-diethylaminoethoxy)aniline is heated at 180°C for 4 hours, then cooled. To 25 the reaction mixture is added 357 mg (3.6 mmol) of succinic anhydride, 1 mL ofchloroform, and 3 mL of dimethylformamide. The reaction mixture is heated at50°C for 2 hours, cooled, and diluted with chloroform. The mixture is washedwith a saturated solution of sodium bicarbonate and brine. The organic phase isdried over magnésium sulfate, filtered, and concentrated. The residue is 30 chromatographed on silica eluting with 5:95 methanol/chloroform to give a yellow . t -90- 011554 solid which is crystallized from methanol/water to give 590 mg (61%) of the titlecompound: mp 139-141 °C.

Analysis calculated for C29H36N6O4: C, 65.39; H, 6.81; N, 15.78. 5 Found: C, 65.35; H, 6.83; N, 15.70.

As noted above, the compounds of this invention are potent inhibitors ofcyclin-dependent kinases and tyrosine kinases, and accordingly, are useful intreàting and preventing atherosclerosis, and other cell proliférative disorders likecancer. The compounds hâve low toxicity. The compounds hâve exhibited 10 excellent inhibitory activity against a wide variety of cyclin-dependent kinases, ailin assay Systems routinely utilized to measure such activity. A typical assay, forinstance, measures inhibitory activity against the cyclin D dépendent kinase 4enzyme (cdk4/D). The invention compounds of Formula I exhibited IC5Q valuesranging generally from about 0.04 μΜ to >40 μΜ. The cdk4 assay was carried out 15 as follows.

Cyclin-Dependent Kinase 4 (çdk4) Assay

Enzyme assays for IC50 déterminations (Tables 1 and 2) and kinetic

évaluation were performed in 96 well filter plates (Millipore MADVN6550). Thetotal volume was 0.1 mL containing a final concentration of 20 mM TRIS

20 (tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl2, 25 μΜ ATP containing 0.25 μϋϊ of p2p]ATP, 20 ng of cdk4,1 μg of retinoblastoma, and appropriate dilutions of a compound ofthe présent invention. Ail components except the ATP were added to the wells,and the plate was placed on a plate mixer for 2 minutes. The réaction was started 25 by adding p2p]ATP and the plate was incubated at 25°C for 15 minutes. The reaction was terminated by addition of 0.1 mL of 20% trichloroacetic acid (TCA).The plate was kept at 4°C for at least 1 hour to allow the substrate to precipitate.

The wells were then washed five times with 0.2 mL of 10% TCA and 32pincorporation was determined with a beta plate counter (Wallac Inc., 30 Gaithersburg. MD). -91- 011554

Cyclin-Dependent Kinase Assays (cdk2/cyclinE, cdk2/cyclinA. cdc2/cyclinB)Enzyme assays for IC50 déterminations and kinetic évaluation were

performed in a 96-well filter plate (Millipore MADVN6550) in a total volume of0.1 mL of 20 mM TRIS (tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM 5 NaCl, 1 mM dithiothreitol, 10 mM MgCl2, 12 mM ATP containing 0.25 gCi of [32p]ATP, 20 ng of enzyme (either cdk2/cyclinE, cdk2/A, or cdc2/cyclinB), 1 ggretinoblastoma, and appropriate dilutions of the particular invention compound.Ail components except the ATP were added to the wells, and the plate was placedon a plate mixer for 2 minutes. The reaction was begun by addition of p2p]ATP, 10 and the plate was incubated at 25°C for 15 minutes. The reaction was terminatedby addition of 0.1 mL of 20% TC A. The plate was kept at 4°C for at least 1 hourto allow the substrate to precipitate. The wells were then washed five times with0.2 mL of 10% TCA and 32p incorporation determined with a beta plate counter(Wallac Inc., Gaithersburg, MD). 15 When measured against cdk2/E, the invention compounds exhibited IC50 values ranging generally from about 0.9 μΜ to >40 μΜ. Against cdk2/A, thecompounds exhibited IC5Q values ranging from about 0.5 μΜ to >40 μΜ, andagainst cdc2/B, generally from about 5 μΜ to >40 μΜ. The assays were carriedout as described above, and spécifie data for the invention compounds is given in 20 the following tables. 011554 -92- TABLE 1

Example R1 R2 IC5Q (μΜ) or % Inhibition at 40 μΜ cdk4/D cdk2Æ cdk2/A cdkl/B 9 Ph-4-OMe cyclopentyl 5.75 10 Ph-4-piperidine . cyclopentyl 1.55 11 Ph-4-(4-Me)piperazine cyclopentyl 0.039 2.12 0.76 11.6 • 12 Ph-4-pyrazole cyclopentyl 1.80 4.60 1.33 12.20 13 Ph-3-Me-4-OCH2CH2NEt2 cyclopentyl 0.3 14 Ph-4-pyrrole cyclopentyl 17.8 38% 5.1 >20 15 Ph-4-(4-OH)-piperidine cyclopentyl 0.70 2.2 0.6 16.76 16 Ph-4-(3 -OH)-piperidine cyclopentyl 0.63 1.5 0.64 14.93 17 Ph-4-(4-NMe2)-piperidine cyclopentyl 0.31 3.55 1.31 20.20 18 Ph-4-(3,5 -Me2)-piperazine cyclopentyl 0.35 2.0 19 Ph-4-(2-CH2OH)-piperidine cyclopentyl 0.5 20 Ph-4-[4-(CH2)3OH]- cyclopentyl 0.42 5.35 2.72 >40 piperidine 21 Ph-4-[4-(CH2)2 morpholine]-piperidine cyclopentyl 0.165 3.00 1.37 36.14 22 Ph-4-(4-Me)piperazine isopropyl 0.34 68% 9.31 25% 23 Ph-4-(4-OH)-piperidine isopropyl 16.85 4.39 >40 24 Ph-4-(4-NMe2)-piperidine isopropyl 34.00 12.35 >40 25 Ph-4-pyrazole isopropyl 10.00 2.31 36.50 26 Ph-4-[4-(CH2)3morpholine] -piperidine isopropyl 47% 27.00 6.46 >40 27 Ph-4-(4-Me)piperazine norbomyl 0.77 1.10 0.53 9.77 28 Ph-4-(4-Me)piperazine methyl 15% 22% >40 >40 29 Ph-4-(4-OH)-piperidine methyl >40 28% >40 >40 30 Ph-4-(4-NMe2)-piperidine methyl 18.25 >40 >40 31 Ph-4-pyrazole methyl 18% 21% >40 >40 -93- TABLE la 011554

O

Example R1 R3 IC50 (μΜ) or % Inhibition at 40 μΜ cdk4/D cdk2/E cdk2/A cdkl/B 70 Ph-4-(4-Me)piperazine allyl 3.45 0% >40 >40 72 Ph-4-O(CH2)2 NEt2 allyl 7.35 0% >40 >40 71 Ph-4-(4-M e)piperazine 4-OMe-benzyl 2.1 >40 >40 73 Ph-4-O(CH2)2 NEt2 4-OMe-benzyl 4.5 >40 >40

Table 2 présents data for spécifie pyrimido[4,5-J]pyrimidines (doublebond at the 3.4-position). TABLE 2

R1—NH

Example R1 R2 IC50 (P-M) or % Inhibition at 40 μΜ cdk4/D cdk2/E cdk2/A cdkl/B 32 Ph-4-(4-Me)piperazine cyclopentyl 0.05 1.38 0.83 7.51 0 ·-* Ph-4-(4-OH)-piperidine cyclopentyl 0.038 4.2 0.98 9.76 34 Ph-3-Me-4- OCH2CH2NE(2 cyclopentyl 0.079 3.15 3.22 7.51 35 Ph-4-(3 -OH)piperidine cyclopentyl 0.082 1.05 0.99 8.54 36 Ph-4-pyrazole cyclopentyl 0.435 2.44 1.33 16.13 37 Ph-4-OMe cyclopentyl 0.22 0.9 0.40 4.76 38 Ph-4-piperidine cyclopentyl 0.15 2.78 0.77 35.25 39 Ph-4-[4-(CH2)2 morpholinej-piperidine cyclopentyl 0.3 1.85 î.44 24.61 40 Ph-4-(4-Me)-piperazine isopropyl 16.50 4.51 42% -94- 011554 TABLE 2 (cont’d)

Example r1 r2 IC5Q (μΜ) or % Inhibition at 40 μΜ cdk4/D cdk2/E cdk2/A cdkl/B 41 Ph-4-(4-NMe2)- piperidine isopropyl >40 14.76 >40 42 Ph-4-pyrrazole isopropyl 3.9 >40 5.81 >40 43 Ph-4-[4-(CH2)3 morpholine]-piperidine isopropyl 0.54 38.0 7.49 >40 44 Ph-4-(4-Me)-piperazine norbomyl 0.018 1.2 1.03 7.36 45 Ph-4-(4-Me)-piperazine methyl 16.2 16% >40 >40 46 Ph-4-(4-NMe2)- piperidine methyl >40 >40 >40 47 Ph-4-pyrazole methyl >40 41% >40 >40

Several of the invention compounds hâve also shown good inhibitoryactivity against cdkô/Tb and cdk6/Ü3 enzymes. These assays are carried out in amanner similar to that described above for cdk4, by simply employing theappropriate cdk6 kinase enzyme. 5 The compounds of Formula I also hâve shown good inhibitory activity against certain growth factor receptor tyrosine kinase enzymes, including those offibroblast growth factor (FGF) and platelet derived growth factor (PDGF). Theinvention compounds range in IC5Q inhibition against FGF tyrosine kinasegenerally from about 0.3 μΜ to >50 μΜ. Against PDGF tyrosine kinase, the 10 invention compounds exhibit IC50 from about 0.02 μΜ to >50 μΜ. The assaysused to détermine these activities were carried out as follows: PDGF and FGF Receptor Tyrosine Kinase Assays

Full-length cDNAs for the mouse PDGF-β and human FGF-1 (flg) receptor tyrosine kinases were obtained from J. Escobedo and prepared asdescribed in J. Biol. Chem., 1991;262:1482-1487. PCRprimers were designedto 15 .95. 01 1 554 amplify a fragment of DNA that codes for the intracellular tyrosine kinasedomain. The fragment was inserted into a baculovirus vector, cotransfected withAcMNPV DNA, and the recombinant virus isolated. SF9 insect cells wereinfected with the virus to overexpress the protein, and the cell lysate was used for 5 the assay. Assays were performed in 96-well plates (100 gL/incubation/well), andconditions were optimized to measure the incorporation of 32p ffOm γ^^ρ.ΑΤΡinto a glutamate-tyrosine co-polymer substrate. Briefly, to each well was added82.5 gL of incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl,0.1% Triton X-100,0.2 mM PMSF, 0.2 mM NajVO^ 10 mM MnCl2, and 10 750 gg/mL of Poly (4:1 ) glutamate-tyrosine followed by 2.5 gL of inhibitor and 5 gL of enzyme lysate (7.5 gg/gL FGF-TK or 6.0 gg/gL PDGF-TK) to initiate thereaction. Foïlowing a 10 minute incubation at 25°C, 10 mL of γ32ρ_ΑΤΡ (0.4 gCiplus 50 gM ATP) was added to each well, and samples were incubai ?d for anadditional 10 minutes at 25°C. The reaction was terminated by the addition of 15 100 gL of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate and précipitation of material onto glass fiber mats (Wallac). Filterswere washed three times with 15% TCA containing 100 mM sodiumpyrophosphate, and the radioactivity retained on the filters counted in aWallac 1250 Betapiate reader. Nonspecific activity was defrned as radioactivity 20 retained on the filters foïlowing incubation of samples with buffer alone (no enzyme). Spécifie enzymatic activity (enzyme plus buffer) was defined as totalactivity minus nonspecific activity. The concentration of a compound thatinhibited spécifie activity by 50% (IC50)was determined based on the inhibitioncurve, and typical results are reported in the foïlowing tables. 011554 -96- TABLE 3

Example R1 IC5Q (μΜ) or % Inhibition at 40 μΜ R2 PDGF FGF 9 Ph-4-OMe cyclopentyl 0.36 10 Ph-4-piperidine . cyclopentyl 0.64 11 Ph-4-(4-Me)piperazine cyclopentyl 0.175 0.023 • 13 Ph-3-Me-4-OCH2CH2NEt2 cyclopentyl 0.5-0.05 15 Ph-4-(4-OH)-piperidine cyclopentyl 0.5-0.05 16 Ph-4-(3-OH)-piperidine cyclopentyl 0.83 17 Ph-4-(4-NMe2)-piperidine cyclopentyl 0.32 18 Ph-4-(3,5 -diMe)-piperazine cyclopentyl 0.21 19 Ph-4-(2-CH2OH)-piperidine cyclopentyl 0.5-0.05 21 Ph-4-[4-(CH2)2-morpholine]- cyclopentyl 1.1 piperidine 22 Ph-4-(4-Me)-piperazine isopropyl 25 Ph-4-pyrazole isopropyl 27 Ph-4-(4-Me)-piperazine norbomyl 30 Ph-4-(4-Me)-piperazine methyl 011554 -97- TABLE 3 a R4

Example R1 R2 R3 R4 R5 R6 IC50 (μΜ) PDGF FGF 53 (CH2)4NEt2 Et H OMe OMe H 5 0.06 53a Ph-4-O(CH2)2NEt2 Et H OMe OMe H <0.5 0.02

Example R1 R3 IC50 (μΜ) or % Inhibition at 40 μΜ PDGF FGF 71 Ph-4-(4-Me)piperazine · allyl >50 >50 73 Ph-4-O(CH2)2NEl2 allyl >50 >50 72 Ph-4-(4-Me)piperazine 4-OMe-benzyl >50 >50 74 Ph-4-O(CH2)2NEt2 4-OMe-benzyl >50 >50 011554 TABLE 4 R1—NH ^N'^O >2 R2 Example R1 R2 æ50 (PM) or % Inhibition at 40 μΜ PDGF FGF 32 Ph-4-(4-Me)piperazine cyclopentyl 1.63 0.37 35 Ph-4-(3-OH)-piperidine cyclopentyl 2.8 3.49 36 Ph-4-pyrazole cyclopentyl >50 >50 39 40 Ph-4-[4-(CH2)2 morpholinejpiperidine Ph-4-(4-Me)piperazine cyclopentyl isopropyl 3.76 1.13 41 Ph-4-(4-NMe2) piperidine isopropyl >50 11.73 43 Ph-4-[4-(CH2)2 morpholinejpiperidine isopropyl 4.93 44 46 Ph-4-(4-Me)piperazine Ph-4~(4-NMe2) piperidine norbomyl methyl 0.47 22.6

The Src (the transforming gene of the Rous sarcoma retrovirus) family ofnon-receptor protein kinases, which ail contain a SH2 domain, are involved in anumber of cellular signaling pathways. For example, Src is involved in growthfactor receptor signaling; integrin-mediated signaling; T- and B-cell activation and 5 osteoclast activation. It is known that the Src SH2 domain binds to -everal keyreceptor and non-receptor tyrosine kinases such as tyrosine kinases containingreceptors for PDGF, EGF, HER2/Neu (an oncogene form of EGF), FGF, focaladhesion kinase, pl30 protein, and p68 protein. In addition, pp60c-Src has beenshown to be involved in the régulation of DNA synthesis, mitosis, and other 10 cellular activities.

Thus, it would be useful to hâve compounds that inhibit the binding ofproteins containing an SH2 domain to cognate phosphorylated proteins, as theinhibition of binding of proteins containing an SH2 domain to cognatephosphorylated proteins can be used to treat proliférative diseases such as cancer, 011554 -99- osteoporosis, inflammation, allergy, restenosis, and cardiovascukr disease, whichail rely on signal transduction involving proteins that contain an 3H2 domain thatbinds to phosphorylated proteins during the cellular signaling process.

Several of the invention compounds hâve been evaluated in a standard 5 assay to measure their ability to inhibit cellular Src protein kinase (c-Src). The invention compounds exhibited IC50 values ranging generally from about 0.4 toabout 50 μΜ. The assay was carried out as follows: c-Src kinase was purified from baculovirus infected insect cell lysâtesusing an antipeptide monoclonal antibody directed against the N-terminal amino 10 acids (amino acids 2-17) of c-Src. The antibody, covalently linked to 0.65 gmlatex beads. was added to a suspension of insect cell lysis buffer comprised of150 mM NaCl, 50 mM Tris pH 7.5,1 mM DTT, 1% NP-40,2 mM EGTA, 1 mMsodium vanadate, 1 mM PMSF, 1 gg/mLeach of leupeptin, pepstatin, andaprotinin. Insect cell lysate containing c-Src protein was incubated with these 15 beads for 3 to 4 hours at 4°C with rotation. At the end of the lysate incubation, the beads were rinsed three times in lysis buffer, resuspended in lysis buffercontaining 10% glycerol, and frozen. These latex beads were thawed, rinsed threetimes in assay buffer (40 mM Tris, pH 7.5,5 mM ggCl2) and suspended in thesame buffer. In a Millipore 96-welI plate with a 0.65 gm polyvinylidine 20 membrane bottom were added the reaction components: 10 gL c-Src beads, 10 gLof 2.5 mg/mL poly GluTyr substrate, 5 μΜ ATP containing 0.2 gGi labeled32p-ATP, 5 gL DMSO containing inhibitors or as a solvent control, and buffer tomake the final volume 125 gL. The reaction was started at room température byaddition of the ATP and quenched 10 minutes later by the addition of 125 gL of 25 30% TCA, 0.1 M sodium pyrophosphate for 5 minutes on ice. The plate was then filtered and the wells washed with two 250 mL aliquots of 15% TCA, 0.1 Mpyrophosphate. The filters were then punched, counted in a liquid scintillationcounter, and the data examined for inhibitory activity in comparison to a knowninhibitor such as erbstatin. The method is also described in J. Med. Chem., 30 1994;37:598-609. Tables 5 and 6 list c-Src inhibitory concentrations (IC50) for représentative invention compounds. -100- TABLE 5 G11554

Example R1 R2 c-Src IC50 (μΜ) 10 Ph-4-piperidine cyclopentyl >50 11 Ph-4-4-(Me)-piperazine cyclopentyl 0.71 14 Ph-4-pyrrole cyclopentyl >50 15 Ph-4-(4-OH)-piperidine cyclopentyl 2.4 16 Ph-4-(3-OH)-piperidine cyclopentyl " 4.12 17 Ph-4-(4-NMe2)-piperidine cyclopentyl 0.37 18 Ph-4-(3,5-diMe)-piperazine cyclopentyl 0.40 19 Ph-4-(2-CH2OH)-piperidine cyclopentyl ' 4.42 21 Ph-4-[4-(CH2)2morphoIine]-piperidine cyclopentyl 1.60 22 Ph-4-(4-Me)-piperazine isopropyl 1.51 TABLE 6 R1—N/^NZH \ N i7 R2 Example R1 R2 c-Src IC50 (μΜ) 32 Ph-4-(4-Me)piperazine cyclopentyl 3.95 35 Ph-4-(3-OH)piperidine cyclopentyl 4.65 39 Ph-4-[4-(CH2)2morpholine]piperidine cyclopentyl 3.23 40 Ph-4-(4-Me)piperazine isopropyl 4.30 41 Ph-4-(4-NMe2)piperidine isopropyl 306 44 Ph-4-(4-Me)piperazine norbomyl 2.30

The compounds of Formula I are useful for treating cell proliférativedisorders conceming angiogenesis and hâve been evaluated in a human umbilicalvein endothélial cell in vitro assay. The assay described below is used to -101- 011554 détermine the anti-proliferative effects of the invention compounds on humanumbilical vein endothélial cells, and the results are shown in Table 7.

Human Umbilical Vein Endothélial Cell (HUVEC) Prolifération Assay

Ninety-six well tissue culture plates are seeded with 100 μι of cells in ail 5 wells of rows A->G with row H remaining empty as a blank. HUVEC (Clonetics,San Diego, CA) are grown in endothélial growth medium (EGM media,

Clonetics), containing 2% fêtai bovine sérum. The cell seed density for HUVECcells is 20,000 per mL. C6 cells (ATCC Cat. No. CCL-107) are seeded at 6000 permL in F10 medium (nutrient mixture Hemes) supplemented with 15% horse

10 sérum, 2.5% fêtai bovine sérum, and 6.0 mL 200 mM Glutamine per 600 mL medium. A90 cells (Suny, Buffalo, NY) are also seeded at 6000 per mL, but theyare grown in RPM1 1640 (Roswell Park Memorial Institute) plus 10% fêtai bovinesérum. Unless noted otherwise, tissue culture media and components are fromGIBCO. The cells are allowed to incubate at 37°C, 5% CC>2, and 100% relative 15 humidity for 16-24 hours.

Invention compounds are prepared by dissolving them in DMSO at a

concentration of 5 mM, followed by dilution to 50 μΜ in EGM media. Onehundred microliters of the compounds are applied to duplicate wells in column 1of the previously prepared cell plates. Column 1 row H receives 100 μι of EGM 20 media. The compounds in column 1 are diluted across the plates using serial two-fold dilutions.

The plates are incubated as above for an additional four daysbefore beingstained with Sulphorhodaihine B. Staining is performed as follows: The media isremoved from the plates, and the cells are fixed using 10% trichloroacetic acid for 25 30 minutes at 4°C. Following fixation, the plates are washed five times with distilled water after which 100 μΕ of Sulphorhodamine B is added to each well.Suiphorhodamine B is dissolved in 1% acetic acid to a concentration of .075%.Following staining, excess stain is removed from the wells, and the plates arewashed four times with 1% acetic acid. The plates are allowed to air dry before 30 the bound dye is solubilized in 100 μί of 10 mM unbuffered TRIS base.

Absorbance is measured on a 96 well plate reader at 540 nM using a reference -102- 011 554 fîlter wavelength of 630 nM. The concentration of compound needed to suppress50% of cell prolifération (IC5Q) is determined from the absorbance measurements.

Sulphorhodamine B and TRIS are from Sigma Chemical Company? Acetic acidand trichloroacetic acid are from Mallinckrodt AR. TABLE 7 R4

Example R1 R2 R3 R4 R5 R6 HUVEC æ50 (UM) 52 (CH2)4NEt2 H H OMe OMe H 6.65 53 (CH2)4NEt2 Et H OMe OMe H 0.192 53a Ph-4-O(CH2)2NEt2 Et H OMe OMe H 54 (CH2)2NHCH2-(4-pyridyl) H H OMe OMe H >25 54a (CH2)3-4-Me-piperazine H H OMe OMe H 5.99 54b ( CH2)4-4-Me-piperazine H H OMe OMe H 4.96 54c (CH2)5-4-Me-piperazine . H H OMe OMe H 5.78 55 (CH2)3NEt2 H H OMe OMe H >25 56 (CH2)2-NHCH2-(4- pyridyl) Et H OMe OMe H 1.93 57 (CH2)3-4-Me-piperazine Et H OMe OMe H 0.152 58 ( CH2)4-4-Me-piperazine Et H OMe OMe H 0.134 59 (CH2)5-4-Me-piperazine Et H OMe OMe H 0.112 60 (CH2)3NEt2 Et H OMe OMe H 0.943 65 (CH2)4NEt2 Et Cl OMe OMe H 0.036 -103- 011554

The compounds of Formula I hâve also been evaluated in several standardin vivo cell culture assays and shown to hâve good inhibitory activity againsttyrosine kinase enzymes.

The invention compounds can be formulated in conventional manners to5 provide convenient dosage forms for delivery to mammals by various routes, including oral, parentéral (i.e., subcutaneous, intravenous, and intramuscular),transdermal, e.g., slow release skin patch or cream, as well as by slow releasedelivery devices such as osmotic pumps, supposi tories, and buccal seals. Thefollowing examples further illustrate how the compounds are readily formulated. 10 EXAMPLE75 50 mg Tablet Formulation i

Per Tablet Per 10,000Tablets 0.050 g l-Cyclopentyl-7-{3-methyl-4-[2-(diethylamino)-ethoxy]phenylamino}-3,4-dihydro~17/-pyrimido-[4,5 -ifJpyrimidin-2-one 500 g 0.080 g lactose 800 g 0.010 g com starch (for mix) 100 g 0.008 g com starch (for paste) 80 g 0.148 g 1480 g 0.002 g magnésium stéarate (1%) 20 g 0.150 g 1500 g

The pyrimidopyrimidine, lactose, and corn starch (for mix) are blended touniformity. The com starch (for paste) is suspended in 600 mL of water andheated with stirring to form a paste. This paste is used to granulate the mixed 15 powders. The wet granules are passed through a No. 8 hand screen and dried at80°C. The dry granules are then passed through a No. 16 screen. The mixture islubricated with 1% magnésium stéarate and compressed into tablets in aconventional tableting machine. The tablets, as well as ail invention compounds,are useful for treating cancers such as breast, prostate, lung, ovarian, colon, 20 pancreatic, melanoma, esophageal, brain, Kaposi’s sarcoma, and lymphomas. -104- 011554

Particular concems to be treated include small-cell lung carcinoma, low gradehuman bladder carcinoma, and human colorectal cancer. EXAMPLE 76

Préparation of Oral Suspension

Ingrédient Amount l-Cyclopentyl-7-{4-[4-(dimethylamino)piperidin-l -yljphenylamino}- 500 mg

3,4-dihydro-1 7/-pyrimido[4,5-</]pyrimidin-2-oneSorbitol solution (70% N.F.) 40 mL

Sodium benzoate 150 mg

Saccharin 10 mg

Cherry flavor 50 mg

Distilled water qs 100 mL 5 The sorbitol solution is added to 40 mL of distilled water, and the pyrido pyrimidine is suspended therein. The saccharin, sodium benzoate, and flavoringare added and dissolved. The volume is adjusted to 100 mL with distilled water.Each milliliter of syrup contains 5 mg of invention compound. EXAMPLE 77 10 Préparation of Parentéral Solution

In a solution of 700 mL of propylene glycol and 200 mL of water for injection is suspended 20.0 g of 1 -cyclopentyl-7-[4-(4-methylpiperazin- ;l-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(l//)-one with stirring. Aftersuspension is complété, the pH is adjusted to 5.5 with hydrochloric acid, and the 15 volume is made up to 1000 mL with water for injection. The formulation is sterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (representing40 mg of invention compound) and sealed under nitrogen. EXAMPLE 78

Suppositories 20 A mixture of 400 mg of l-cyclopentyl-7-[4-(piperidin- 1-yljphenylamino jpyrimido[4,5-iZjpyrimidin-2(l/7)-one, and 600 mg of -105- 01 1 554 theobroma oil is stirred at 60°C to uniformity. The mixture is cooled and allowed to harden in a tapered mold to provide a 1 g suppository. EXAMPLE 79

Slow Release Formulation 5 Five hundred milligrams of 1 -cyclopentyl-7-[4-(3-hydroxypiperidin- 1 -yl)phenylamino]-3,4-dihydro-l//-pyrimido[4,5-d]pyrimidin-2-one is convertedto a hydrochloride sait and placed into an Oros osmotic pump for controlledrelease for treatment of athéroscléroses. EXAMPLE 80 10 Skin Patch Formulation

Fifty milligrams of l-cyclopentyl-7-{3-methyl-4-[2-(diethylamino)- ethoxy]phenylamino}-pyrimido[4,5-d]pyrirnidin-2(l//)-one is admixed with50 mg of propylene glycol monolaurate in a polydimethylsiloxane adhesive. Themixture is layered onto an elastic film made with an adhesive formulation of 15 polybutene, polyisobutylene, and propylene glycol monolaurate. The layers areplaced between 2 layers of polyuréthane film. A release liner is attached to theadhesive surface, and is removed prior to application to a skin surface. Thepropylene glycol monolaurate serves as a permeation-enhancing agent.

Claims (28)

1. 011554 -106- CLAIMS What is claimed is:

   1. A compound of F ormula I

   5 and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; Z is N or CH; G is N or CH; 10 W is NH, S, SO, or SO2; X is either O, S, or NR^; R1. R-, and R^θ are independently selected from the group consisting ofH, (CH2)nAr, COR4, (CH2)nheteroaryl, (CH2)nheterocyclyl, C1 -C1 θ alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C j θ 15 alkynyl, wherein n is 0,1,2, or 3, and the (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groupsare optionally substituted by up to 5 groups selected from NR4R^,N(O)R4r5, Nr4r5r6y, alkyl, phenyl, substituted phenyl,(CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, 20 COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, aldéhyde, nitrile, nitro, -107- 011554 OR5 I heteroaryloxy, T(CH2)mQR4, T(CH?)mC-(CH2)mPR4, I 5 H C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4,T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m isindependently 1-6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5,and Q is O, S, NR5, N(O)R5, or NR5r6y; 10 when the dotted line is présent, R^ is absent; otherwise R^ has the meanings of R-, wherein R- is as defined above, as well as OH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4r5,SO3R4, PO3R4, OR5 15 | T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, I H wherein T and Q are as defrned above; 20 R4 and R5 are each independently selected from the group consisting of hydrogen, C]-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C2-Cgalkynyl, N(Ci-C6alkyl)i or 2, (CH2)nAr, C3-C10 cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R5 together with thenitrogen to which they are attached optionally form a ring having25 3 to 7 carbon atoms and said ring optionally contains 1,2, or 3 heteroatoms selected from the group consisting of nitrogen,substituted nitrogen, oxygen, and sulfur; when R4 and R5 together with the nitrogen to which they are attached form a ring, the said ring is optionally substituted by 1 to 3 groupsselected from OH, OR4, NR4R5, (CH2)mOR4, (CH2)mNR4R5, 30 011554 -108- T-(CH2)mQR4, CO-T-(CH2)mQR4, NH(CO)T(CH2)mQR4,T-(CH2)mCO2R4, or T(CH2)mCONR4R5. R^ is alkyl; R8 and R 9 independently are H, C1-C3 alkyl, NR4R5, N(O)R4R5, 5 NR4r5r6ys hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4r5, SO3R4, PO3R4, CHO, CN, orNO2; when the dotted line is absent, R^ is additionally carbonyl, thiocarbonyl,imine and substituted imine, oxime and oxime ether, and 10 Y is a halo counter-ion.
2. 2. A compound of Claim 1 wherein Z and G both are N, W is NH, and R^,and R9 both are hydrogen.
3. 3. A compound of Claim 2 having the formula

   15 4. A compound of Claim 3 wherein Rl is phenyl or substituted phenyl, pyridyl or substituted pyridyl.
4. 5. A compound of Claim 4 wherein R^ is an alkyl, substituted alkyl, orcycloalkyl unsubstituted or substituted.
5. 6. A compound selected from:

   1 -Methyl-7-[4-(pyrazol-1 -yl)phenylamino]pyrimido[4,5- </|pyrimidin-2( 1 H)-one; -109- 011554

   1 -Methyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido[4,5-i/Jpyrimidin-2( 1 //)-one; l-Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino]pyrimido[4,5-ô/Jpyrimidin-2( 1//)-one; 5 l-Methyl-7-{4-[4-(dimethylarnino)piperidin-l-yl]phenylamino}- pyrimido [4,5-i/]pyrimidin-2( 1 //)-one ; l-Isopropyl-7-[4 -(pyrazol-1 -yl)phenylamino]pyrimido[4.5-</)pyriniidin-2(l 7/)-one;

   1 -Isopropyl-7-[4-(4-methylpiperazin-1 -10 yl)phenylamino]pyrimido[4,5-d]pyrimidin-2( 1 //)-one; l-Isopropyl-7-[4-(4-hydroxypiperidin-l-yl)phenylamino]pyrimido[4,5-^lpyrimidin-2( 177)-one;

   1 -IsopropyI-7- {4-[4-(dimethylamino)piperidin-1 -yljphenylamino} -pyrimido[4,5-û]pyrimidin-2(l /7)-one; 15 l-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-l-yl)phenylanïino]- pyrimido[4,5-i/]pyrimidin-2( 1 H)-one (exo);

   1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido[4,5-i/]pyrimidin-2(l//)-one (exo);

   1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-hydroxypiperidin-1 -20 yl)phenylamino]pyrimido[4,5-i/]pyrirriidin-2(l//)-one (exo);

   1 -Bicyclo[2.2.1 ]hept-2-yl-7-{4-[4-(dimethy lamino)pirrridin-1 -yI]phenylamino}pyrimido[4,5-</]pyriniidin-2(lZ/)-one (exo); 7- [4-(4- Aminoacetyl-piperazin-1 -yl)-phenylamino]-1 -cyclopentyl-pyrimido[4,5-</]pyrimidin-2( 17/)-one; 25 7- {4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1 -y 1] - phenylamino}-l-cyclopentyl-pyrimido[4,5-J)pyrimidin-2(l//)-one;

   1 -Methyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l -yl]phenylamino} pyrimido [4,5-d]pyrimidin-2( 1 H)-one; l-Isopropyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l-30 yljphenylamino} pyrimido [4,5-<^pyrimidin-2(l//)-one; l-Cyclopentyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-l -yl]phenylamino}pyrimido[4,5-d]pyriinidin-2( 17/)-one; 011554 -110- l-Bicyclo[2.2.1]hept-2-yl-7*{4-[4-(3-morpholin-4-ylpropyl)piperidin-l-yl]phenylamino}pyrimido[4,5-ô/]pyrimidin-2(l/7)-one (exo); l-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-pyrimido[4,5-5 d] pyrimidin-2( 1 H)-one ; l-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-pyrimido[4,5-iZ]pyrimidin-2( 177)-one; 7-[4-(3-Amino-pyrrolidin-l-yl)-phenylamino]-l-cyclopentyl- pyrimido[4,5-£/]pyrimidin-2(J//)-one; 10 l-Cyclopentyl-7-(4-piperazin-1 -yl-phenylamino)-pyrimido[4,5- i/]pyrimidin-2( 1 /7)-one; l-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl)-phenylamino]-pyrimido[4,5-i/]pyrimidin-2(l/7)-one; 7-[4-(4-Acetyl-piperazin-l -yl)-phenylamino]-l -cycloheptyl-15 pyrinndo[4,5-i/}pyrimidin-2(l//)-°ne; and l-Cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-J]pyrimidin- 2(lff)-one.
6. 7. A compound of Claim 2 having the formula

   20 8. A compound of Claim 7 wherein RJ is alkyl, pyridyl, or phenyl, each optionally substituted with hydroxy, alkoxy, NR^rS, or T(CH2)mQR^.
7. 9. A compound selected from: l-Methyl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihy^ij- pyrimido[4,5-i/|pyrimidin-2(17/)_one; 25 l-Methyl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-3,4-dihydro pyrimido[4,5-<y]pyrimidin-2( 17/)-one; 011554 -111- l-Methyl-7-[4-(4-hydroxypiperidin-l-yl)phenylamino]-3,4-dihy dro-pyrimido [4,5-i/]pyrimidin-2( 1 //)-one; l-Methyl-7-{4-[4-(dimethylamino)piperidin-l-yl]phenylamino}- 3.4- dihy dro-pyrimido [4,5-<7]pyrimidin-2(l.H)-one;

   1 -Isopropyl-7-[4-(pyrazol-1 -yl)phenylamino]-3,4· eihydro- pyrimido[4,5-<7]pyrimidin-2(l//)-one; l-Isopropyl-7-[4-(4-methylpiperazin-l-yl)phenylamino]-3,4- dihvdro-pyrimido[4,5-cf]pyrimidin-2(l//)-one; l-Isopropyl-7-[4-(4-hydroxypiperidin-l-yl)phenylamino]-3,4-10 dihydro-pyrimido[4,5-c/]pyrimidin-2(l/f)-one;

   1-Isopropy 1-7-{4-[4-(dimethylamino)piperidin-l-yl]phenylamino}· 3.4- dihydro-pyrimido[4,5-Jjpyrimidin-2( 1 H)-one; l-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-l-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-c?]pyrimidin-2(177)-one (exo);

   1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-methylpiperazin-l - yl)phenylamino]-3,4-dihydro-pyrimido[4,5-</jpyrirnidin-2( 177)-one (exo);

   1 -Bicyclo[2.2.1 ]hept-2-yl-7-[4-(4-hydroxypiperidin-l -yl)phenylamino]-3,4-dihydro-pyrimido[4,5-</)pyrimidin-2(l/7)-one (exo);

   1 -Bicy cio [2.2.1 ]hept-2-y 1-7 - {4- [4-(dimethylamino)piperidin-1 -20 yljpheny lamino } -3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 177)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-1 -cyclopentyl- 3.4- dihy dro-pyrimido[4,5-</)pyrimidin-2( 177)-one; 7-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1 -yl] -phenylamino)-Î-cyclopentyl-3,4-dihydro-pyrimido[4,5-J}pyrimidin- 25 2(lH)-one;

   1 -Methyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l - yI]phenylamino}-3,4-dihydro-pyrimido[4,5-i(Jpyrimidin-2^ 17/)-one;

   1 -Isopropy 1-7- (4-[4-(3-morpholin-4-y lpropyl)piperidin-1 - yl]phenylamino}-3,4-dihydro-pyrimido[4,5-£7Jpyrimidin-2( 17/)-one; 30 l-Cyclopentyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l- y l]phenylamino } -3,4-dihy dro-pyrimido [4,5 -ûQpyrimidin-2( 1 77)-one ; 011554 -112- l-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-l-yl]phenylamino}-3,4-dihydro-pyrimidoÎ4,5-<^pyrimidin-2(l//)-one (exo); l-Cyclopentyl-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido[4,5-5 </]pyrimidin-2(l//)-one; l-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-3,4-dihydro-pyrimido[4,5-i7]pyrimidin-2( 177)-one; l-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-3,4-dihydro- pyrimido[4,5-i/lpyrimidin-2(l//)-one; 10 7-[4-(3-Amino-pyrrolidin-l -yl)-phenylamino]-1 -cyclopentyl-3,4- dihydro-pyrimido[4,5-<7]pyrimidin-2( 1 /7)-one; 7-[4-(4-Acetyl-piperazin-l-yl)-phenylamino]-l-cyclopentyl-3,4-dihydro-pyrimido[4,5-iZ]pyrimidin-2( 17/)-one;

   1 -Cyclopentyl-7-{4-piperazin-l -yl-phenylamino)-3,4· dihydro-15 pyrirnido[4,5-üQpyrimidin-2( l/7)-one;

   1 -Cyclopentyl-7-[4-(5-methyl-hexahydro-pynOlo[3,4-c]pyrrol-2-yl)-phenylamino]-3,4-dihydro-pyrimido[4,5-</]pyrimidin-2( 1 77)-one; 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(3,5-dimethoxy-phenyl)-l -ethyl-3,4-dihydro-pynmido[4,5-<7]pyrii;iidin-2( 1 77)- 20 one; 7-(4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2-chloro- 3.5- dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-t7]pyrimidin-2(l//)-one; 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6-25 dichloro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5- <7]pyrimidin-2( 1 77)-one; 7-[4-(4-Aminoacetyl-piperazin-l -yl)-phenylamino]-3-(2-methyl- 3.5- dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(177)-one; 30 7-[4-(4-Aminoacetyl-piperazin-l-yl)-phenylamino]-3-(2,6- dimethyl-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimi.îo(4,5-cf]pyrimidin-2( 1 77)-one; 011554 -113- 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-JJpyrimidin-2( 1 /7)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-chloro-3,5-dimethoxy-phenyl)-1 -ethy 1-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 1H)- 5 one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2,6-Æchloro-3,5- dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)- one; 7-[4-(2-Diethylamino-ethoxy)-phenylaminoJ-3-(2-methyl-3,5-10 dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-</jpyrimidin-2( 177)- one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2,6-dimethyl-3,5- { dimethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2( 1H)-one; 15 7-(4-Diethylamino-butylamino)-3-(3,5-dimethoxy-phenyl)-1 -ethyl 3.4- dihydro-pyrimido[4,5- J]pyrimidin-2( 177)-one; 7-(4-Diethylamino-butylamino)-3 -(2-chloro-3,5-dimethoxy-phenyl)-! -ethyl-3,4-dihydro-pyrimido[4,5-J]pyrimidin-2(177)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dichloro-3,5-dimethoxy-20 phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-û0pyrimidin-2(177)-one; 7-(4-Diethylamino-butylamino)-3-(2-methyl-3,5-dimethoxy-phenyl)-l -ethyl-3,4-dihydro-pyrimido[4,5-<7]pyrimidin-2( 177)-one; 7-(4-Dîethylamino-butylamino)-3-(2,6-dimethyl-3,5-/dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5-i/lpyrimidin-2( 17i)-one; 25 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-l -ethyl-3,4- dihydro-pyrimido[4.5-<7]pyrimidin-2(17/)-one; 7-(Pyridin-4-ylamino)-3-(2-chloro-3,5-dimethoxy-phenyÎ)-l-ethyl 3.4- dihydro-pyrimido[4,5-i/]pyrimidin-2( 1 77)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1 -30 ethyl-3,4-dihydro-pyrimido[4,5-i7]pyrimidin-2(177)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dimethyl-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimidoÎ4,5-£(lpyrimidin-2(l 7/)-one; -114- 011554 7-(Pyridin-4-ylamino)-3-(2-methyl-3,5-dimethoxy-phenyl)-1 -ethyl- 3.4-dihydro-pyrimido[4,5-i/]pyrimidin-2(l//)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1 -cyclopentyl-3,4-dihydro-pyrimido[4,5-<Z]pyrimidin-2(l//)-orie; 5 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino- butylamino)-3,4-dihydro-pyrimido[4,5-i/Jpyrimidin-2(l//)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)- phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(17/)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-10 dihydro-pyrimido[4,5-£/]pyrimidin-2(l/7)-one; 3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido[4,5-i()pyrimidin-2(l//)-one; 7-[4-(2-DiethyIamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- phenyl)-3,4-dihydro-pyrimido[4,5-i7Jpyrimidin-2(l//)-one; 15 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-if]pyrimidin-2(l//)-one; and 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino- ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-i/lpyrimidin-2(l/7)-one.
8. 10. A compound of Claim 2 having the formula
9. 11. A compound selected from: l-[7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-3-ethyl-urea; l-{3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino- 25 ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-z/}pyrimidin-2-yl}-3- ethyl-urea; l-/er/-Butyl-3-[7-[4-(2-diethylamino-ethoxy)-pheny'i.mino]-3-(3,5 dimethoxy-phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-urea; -115- 011554 l-/er/-Butyl-3-{3-(2-chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2-y 1} -urea; l-/er/-Butyl-3-[3-(3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-5 3.4-dihydro-pyrimido[4,5-i/]pyrimidin-2-yl]-urea; l-[3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido[4,5-</|pyrimidin-2-yl]-3-ethyl-urea; 5 l-/er/-Butyl-3-[3-(2-chloro-3.5-dimethoxy-phenyl)-7-(pyridin-4- ylamino)-3,4-dihydro-pyrimido[4,5-ifJpyrimidin-2-yl]-urea; 10 1 -[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-</]pyrimidin-2-yl]-3-ethyl-urea; 1 -[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino-butylamino)-3,4-dihydro-pyrimido[4,5-</]pyrirnidin-2-yl]-3-ethyl-urea;

   3-Methyl-N-{7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-15 phenylamino]-3,4-dihydro-pyrimido[4,5-ifJpyrimidin-2-yl }-butyramide; l-{7-[4-(4-Acetyl-piperazin-l-yl)-phenylamino]-3,4-dihydro-pyrimido[4,5-£ÎJpyrimidin-2-yl} -3-isopropy 1-urea; and l-/eri-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)77-(4- diethylamino-butylamino)-3,4-dihydro-pyrimido[4,5-<7]pyrimidin-2-yl]- 20 urea.
10. 12. A compound of Claim 2 having the formula
11. 13. A compound selected from: l-[7-(4-Fluoro-phenylamino)-pyrimido[4,5-«y]pyrimidin-2-yl]-3- 25 melhyl-urea; l-IsopropyI-3-(7-phenylamino-pyrimido[4,5-<7]pyrimidin-2-yl)- urea; -116- 011554 l-{7-[4-(3-Aminomethyl-pyrrolidin-l-yl)-phenylamino]- pyrimido[4,5-<7]pyrimidin-2-yl}-3-isopropyl-urea;

    1 -Isopropyl-3-[7-(4-piperazin-1 -y l-phenylamino)-pyrimido[4,5-J]pyrimidin-2-yl] -urea; 5 1 -{7-[4-(4-Acetyl-piperazin-l -yl)-phenylamino]-pyrimido[4,5- i/Jpyrimidin-2-yl} -3 -isopropyl-urea; N-{7-[4-(3-Amino-pyrrolidin-l-yl)-phenylamino]-pyrimido[4,5-ôTjpyrimidin-2-yl}-3-methyl-butyramide; N-[7-(4-Piperazin- r-yl-phenylamino)-pyrimido[4,5-d]pyrimidin-210 ylj-isobutyramide; N-{7-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino]-pyrimido[4,5-djpyrimidin-2-yl} -3 -methyl-butyramide;

    3-Methyl-N-[7-(pyridin-4-ylamino)-pyrimido[4,5-rf}pyrimidin-2- ylj-butyramide;

    1 -Isopropyl-3-[7-(pyridin-4-ylamino)-pyrimido[4,5-<tf]pyrimidin-2 yl]-urea; and N-{7-[4-(3-Aminomethyl-pyrrolidin-l-yl)-phenylaminoj-pyrimido[4,5-ôf]pyrimidin-2-yl} -3-methyl-butyramide.
12. 14. A compound of Claim 1 wherein W is S, SO, or SO2- 20 15. A compound of Claim 1 hav.ing the formula
13. 16. A compound selected from:

    1 -Isopropyl-7-[4-(4-methylpiperazin-1 -y l)phenylamino]-1H- pyrimido[4,5-</Jpyrimidine-2,4-dione; -117- 011554 17. 10 18. 17. 10 18. 7-[4-(2-Diethylaminoethoxy)phenylamino]-1 -isopropyl-1H-pyrimido[4,5-i/]pyrimidine-2,4-dione; 7-(4-Diethylamino-butylamino)-3-(3,5-dimethoxy-phenyl)-l-ethyl- l//-pyrimido[4,5-i/Jpyrimidine-2,4-dione; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy-phenyl)-1 -ethyl-1 //-pyrimido[4,5-4]pyrimidine-2,4-dione; and 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-l-ethyl-l/7- pyrimido[4,5-d]pyrimidine-2,4-dione. A compound of Claim 1 wherein Z is N, G is CH, W is NH, and andR9 both are hydrogen. A compound of Claim 17 having the formula

    19. 15 19. 15 A compound selected from: 2-[4-(3-Amino-pyrrolidin-1 -yl)-phenylâmino]-8-isopropyl-8//-pyrido[4,3-i/]pyrimidin-7-one;

    8-Cyclopentyl-2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-8//-pyrido[4,3-ôf]pyrimidin-7-one; 2-[4-(4-Acetyl-piperazin-l-yl)-phenylamino]-8-cyclopentyl-8/7- pyrido[4,3-d]pyrimidm-7-one; N- {2-(4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-8-cyclopentyl-pyrido[4,3-</Jpyrimidin-7-yl}-2,2-dimethyl-propionamide; and N-(2-{4-(4-(2-Amino-4-methyl-pentanoyl)-piperazin- l-yl]-phenylamino}-8-cyclopentyl-pyrido[4,3-i/]pyrimidin-7-yl)-2,2-dimethyl-propionamide. 011554 -118-
14. 20. A compound of Claim 1 wherein Z is CH, G is N, W is NH, and R8 and both are hydrogen.
15. 21. A compound of Claim 20 having the formula

    5 22. A compound selected from: 1 -(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido[4,3-iZ]pyrimidin-2( 1 H)-one; 1 -(Thiophen-2-yl)-7-[4-(4-methylpiperazin-l - y l)phenylamino]pyrido[4,3-</}pyrimidin-2( 1 H)-one; 10 l-(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-l- yl)phenylamino]pyrido[4,3-J]pyrimidin-2(l//)-one; 1 -(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido[4,3-Jjpyrimidin-2(l//)-one; 1 -(Hexa-2,4-diene-l -yl)-7-[4-(4-methylpiperazin-1 - 15 yl)phenylaminojpyrido[4,3-J}pyrimidm-2(l/y)-one; 1 -(Prop-2-yne-1 -yl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido[4,3-rZlpyrimidin-2(l 7/)-one; 1 -[3-(Dimethylamino)prop-l -y l]-7-[4-(4-methylpiperazin-l - yl)phenylamino]pyrido[4,3-i/Jpyrimidin-2( 177)-one; 20 l-(3-Hydroxyprop-l-yl)-7-[4-(4-methylpiperazin-l- yl)phenylamino]pyrido[4,3-</]pyrimidin-2( 1 //)-one; 1 -(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1 - yl)phenylamino]pyrido[4,3-cf|pyrimidin-2( 1 H)-one; 1 -(3,5-Dimethylhept-l -yl)-7-[4-(4-methylpiperazin-1 - 25 yl)phenylamino]pyrido[4,3-6Qpyrimidin-2(l//)-one; 011554 -119- 5 23. 5 23. l-Cyclopentyl-7-(4-piperazin-l-ylphenylamino)pyrido[4,3-d]pyrimidin-2(l//)-one; and 7-(4-(3 - Aminopyrr olidin-1 -y l)pheny 1 amino] -1 -cyclopentylpyrido[4,3-</]pyrimidin-2( 1 H)-one. A compound of Claim 20 having the formula

    10 10 15 15 20 20 24. 24. A compound selected from: l-(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-l-yl)phenylamino]- 3.4- dihydro-pyrido[4,3-J)pyrimidin-2( 177)-one; 1 -(Thiophen-2-yl)-7-[4-(4-met’nylpiperazin-1 -yl)phenylamino]-3,4dihydro-pyrido[4,3-ûQpyrimidin-2(l//)-one; l-(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido[4.3-i/]pyrimidin-2(l//)-one; 1 -(T etrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido[4,3-i/]pyrimidin-2( 1 ÂQ-one; 1 -(Hexa-2,4-diene-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido[4,3-i/Jpyrimidin-2(l 77)-one; 1 -(Prop-2-yne-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]- 3.4- dihydro-pyrido [4,3 -</Jpyrimidin-2( 1 //)-one; 1 -[3-(Dimethy lamino)prop-1 -y l]-7-[4-(4-methy lpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido[4,3-</]pyrimidin-2(l/-;)-one; 1 -(3-Hydroxyprop-1 -yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4-dihydro-pyrido[4,3-idpyrimidin-2( 1 /7)-one; 1 -(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1 -yl)phenylanûno]-3,4-dihydro-pyrido[4,3-</]pyrimidin-2(l/y)-one; l-(3,5-Dimethylhept-l-yl)-7-[4-(4-methylpiperazin-l- yl)phenylamino]-3,4-dihydro-pyrido[4,3-^]pyrimidin-2(l/7)-one; ι· -120- 3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-l-èti\yl-3,4- dihydro-pyrido[43-^pyrimidin-2( 1 #)-one; 3-(2-Chloro-3,5-Dimethoxÿ-phenyl)77-(pyridin-4-ylamino)-l- ethyl-3,4-dihydro-pyrido[4,3-ii]pyrimidin-2(lJfY)-one; 5 3-(2,6-Dichloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-l- ethyl-3,4-dihydro-pyrido[4,3-i(lpyrimidin-2(l/y)-one; - 3-(2-Methyl-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylaniino)-l- I ethyÎ-3,4-dihydro-pyrido[43-^pyrimidin-2(l//)-one; 3-(2,6-Dimethyl-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1 - 10 ethyl-3,4-dihydro-pyrido[4,3-i/]pynniidin-2(l/i)-one; 7-[4-(4-Aminoacetyl-piperazin-1 -y l)-phenylamino]-3-(3,5- dirriethoxy-phenyl)-1 -ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(l H)-one; 7-[4-(4-Aminoacetyl-piperazin-l.-yl)-phenylamino]~3-(2-chloro- 15 3.5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrido[4!3-i/lpyrimidin- 2(lH)-one; 7-[4-(4-Aminoacetyl-piperazin-1 -yI)-phenylamino]-3-(2,6-dichioro-3,5-dimethoxy-phenyl)-1 -ethy 1-3,4-dihydro-pyrido[4,3-i/]pyrimidin-2(l 7/)-one; 20 7-[4-(4-Amirioacetyl-piperazin-l-yl)-phenyiainino]-3-(2-methyl- 3,5-dimethoxy-phenyl)-.l-ethyl-3,4-dihydro-pyrido[4,3-£Î]pyrimidin-2(l//)-one; and 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-3-(2,6-dimethyl-3,5-dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrido[4,3- 25 cfjpyrimidin-2(lH)-one.
16. 25. . Use of a compound of Formula I

    and the pharmaceutically acceptable salts thereof, wherein: -121- the dotted line represents an optional double bond; 2 is N or CH; G is N or CH; W is NH, S, SO, or SO2; X is either O, S, or NRlO; l R\, r2, and R^ are independently selected from the group consisting ofH, (CH2)nAr, COR4, (CH2)nheteroaryl, (CH2)nheterocyclyl, 10 Cl-Cio alkyl, C3-C10 cycloalkyl, C2-Cio alkenyl, and C.2-C10 alkynyl, wherein n is 0, 1,2, or 3, and the (CH2)nAr,(CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groupsare optionâlly substituted by up to 5 groups selected from NR4R5,N(O)R4r5, NR4r5r6y, alkyl, phenyl, substituted phenyl,(CH2)nheteroaryl, hÿdroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4,aldéhyde, nitrile, nitro, OR5 20 I heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, I H C(O)T(CH2)mQR4, NHÇ(O)T(CH2)mQR4, T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m is25 independently 1-6, T is O, S, NR4, N(O)R4, NR4R^Y, or CR4R5,andQisO, S,NR5,N(O)R5, orNR5R6Y; when the dotted line is présent, R^ is absent; otherwise R^ has the meanings of wherein R- is as defined above, aswell as OH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4R5,SO3R4, PO3R4, 30 -122- OR^ 1 T(CH2)mQR4, T(ÇH2)mC-(CH2)mQR4, . 1 H wherein T and Q are as defined above; 5 R4 and R^ are each independently selected from the group consisting ofhydrogen, Cj-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C7-C5alkynyl, N(Ci-C^alkyl)} or 2, (CH2)nAr, C3-C10 cycloalkyl,heterocyclyl, and heteroaryl, or R4 and R5 together with the jq nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1,2, or3 heteroatoms selected from the group consisting of nitrogen,substituted nitrogen, oxygen, and sulfur; when R4 and R^ together yvith the nitrogen to which they are attached 15 form a ring, the said ring is optionally substituted by 1 to 3 groups selected from OH, OR4, NR4R5, (CH2)mOR4, (CH2)mNR4R5IT-(CH2)mQR4, CO-T-(CH2)mQR4, NH(CO)T(CH2)mQR4,T-(CH2)mCO2R4 orT(CH2)mCONR4R5. 20 R6 is alkyl; R? and R^ independently are H, C j -C3 alkyl, NR4R$, N(O)R4R5, NR4r5r6y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, or 25 N°* . when the dottéd line is absent, R 9 is additionally carbonyl, thiocarbonyl, imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion for the manufacture of a médicament to control proliférative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle 30 prolifération associated with a disorder selected from the group consisting of athéroscléroses, postsurgicàl vascular stenosis, and restenosis in mammals, diabetic retinopathy and angiogenesis. - )23-
17. 26. Use of a compound of Formula I

    and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; ZisNprCH; Gis N or CH; W is NH, S, SO, or SO2; X is either O, S, or NRJO; RÂ R.2, and R^ are independently selected from the group consisting ofH, (CH2)nAr, COR4, (CH2)nheteroaiyl, (CH2)nheterocyclyI,Cj-Cjo alkyl, C3-Cio cycloalkyl, C2-Ciq aîkenyl, and C2-Cioalkynyl, wherein n is 0, 1,2, or 3, and the (CH2)nAr,(CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groupsare optionally substituted by up to 5 groups selected from NR4R5,N(O)R4R5, NR4R5r6y, alkyl, phenyl, substituted phenyl, . (CH2)nheteroaryl, hydroxy, alkoxy, phenôxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4,aldéhyde, nitrile, nitrO, OR5 1 heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, ! H C(O)T(CH2)mQR4,NHC(O)T(CH2)mQR4, • T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R4, NR4R^Y, or CR4R5, and Q is O, S, NR5, N(O)R5, or NR5R6Y; when the dotted line is présent, R? is absent; otherwise R3 has the meanings of R2, wherein R2 js as defined above, aswéU as OH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4R5, 5 SO3R4, PO3R4, OR5 i T(CH2)mQR4, T(CH2)raC-(CH2)mQR4, I- H 10 wherein T and Q are as defined above; R4 and R3 are each independently selected from the group consisting ofhydrogen, Cj-Cg alkyl, substituted aîkyl, C2-Cg alkenyl, C2-Cèalkynyl, N(Ci-C6alkyl.)i or 2, (CH^pAr, C3-C10 cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R3 together witb thenitrogen to which they are attached optionally form a ring having3 to 7 carbon atoms and said ring optionally contains 1,2, or3 heteroatoms selected from the group consisting of nitrogen,substituted nitrogen, oxygen, and sulfur; when R4 and R3 together with the nitrogen to which they are attached 20 form a ring, the said ring is optionally substituted by 1 to 3 groups selected from OH, OR4, NR4R5, (CH2)mOR4, (CH^NR^5, T-(CH2)mQR4, CO-T-(CH2)mQR4, NH(CO)T(CH2)mQR4, T-iCH2)mC02R4,orT(CH2)mCONR4R5. 25 R&amp; is alkyl; R8 and R^ independently are H, C4-C3 alkyl, NR4R3, N(O)R4R3,NR4R3r6y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4,CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, orNO2; 30 o when the dotted line is absent, Ry is additionally carbonyl, thiocarbonyl, imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion for the manufacture of a médicament to inhibit acyclin-dependent kinase. ' -125- 27. 28. ' 29. 5. 30. Usë as claimed in Claim 26 wherein said cyclin-dependent kinase is cdc2. Use as claimed in Claim 26 wherein said cyclin-dependent kinase is cdk2. Use as claimed in Claim 26 wherein said cyclin-dependent kinase is cdk4 or cdk6. 'Use of a compound of Formula I

    or a pharmaceutically acceptable sait thereofwherein: the dotted line represents an optional double bond; Z is N or CH; > G is N or CH; W is NH, S, SO, or SO2; X is either O, S, or Νρΐθ; Rl , R^, j r1 0 gj-g independently selected from the group consisting of ’θ H, (CH2)nAr, COR4, (CH2)nheteroaryl. (CH2)nheterocyclyl, Ci-Cio alkyl, C3-C10 cycloalkyl, C2-Cio alkenyl, and C2-Cioalkynyl, wherein n is 0,1,2, or 3, and the (CH2)nAr, cycloalkyl, alkenyl, and alkynyl groups 25 are optionally substituted by up to 5 groups selected from NR4r5, N(O)R4r5, NR4r5r6y, alkyl, phenyl, substituted phenyl,(CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo,COR4, CO2R4, CONR4R5, SO2NR4r5, SO3R4, PO3R4,aldéhyde, nitrile, nitro, 3Ô ORS i heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, H 011554 -126- 10 15 20 25 30 C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4,T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m isindependently 1-6, T is O, S, NR4, N(O)R4 NR4R6Y, or CR4R5,and Q is O, S, NR5, N^RS, or NR5R6Y; when the dotted line is présent, R^ is absent; otherwise R^ has the meanings of R-, wherein R- is as defined above, aswell as OH, NR4R5, COOR4, OR4, CONR4R5. SO2NR4R5,SO3R4,PO3R4, OR5 Ί T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, I H wherein T and Q are as defined above; R4 and R^ are èach independently selected from the group consisting ofhydrogen, Cj-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C2-C(jalkynyl, N(C|-C6alkyl)j or 2, (CH^Ar, C3-C|o cycloalkyl, heterocyclyl, and heteroaiyl, or R4 and R^ together with thenitrogen to which they are attached optionally form a ring having3 to 7 carbon atoms and said ring optionally contains 1,2, or3 heteroatoms selected from the group consisting of nitrogen,substituted nitrogen, oxygen, and sulfur; when R4 and R$ together with the nitrogen to which they are attached form a ring, the said ring is optionally substituted by 1 to 3 groupsselected from OH, OR4, NR4R5, (CH2)mOR4, (CH2)mNR4R5, T-(CH2)mQR4, CO-T-(CH2)mQR4, NH<CO)T(CH2)mQR4,T-(CH2)mCO2R4, or T(CH2)mCONR4R5. -127- 011554 R.6 is alkyl; R 8 and R9 independently are H, C4-C3 alkyl, NR4R^, N(O)R4r5, NR4R5r6y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, orNO2; when the dotted line is absent, R9 is additionally carbonyl, thiocarbonyl,imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion for the manufacture of a médicament'to inhibit a growth factor-mediated tyrosine kinase.,, 31; Use as claimed in Claim 30 wherein said growth factor-mediated tyrosine kinaseis platelet derived growth factor (PDGF).
18. 32. Use as claimed in Claim 30 wherein said growth factor-mediated tyrosine kinaseis fibroblast growth factor (FGF).
19. 33. Use as claimed in Claim 30 wherein said growth factor-mediated tyrosine kinaseis vascular endothélial growth factor (VEGF)
20. 34. Use of a compound of Formula I

    or a pharmaceutically acceptable sait thereofwherein: the dotted line represents an optional double bond; 20 -128- 011554 Z is N or CH; G is N or CH; W is NH, S, SO, or SO2; X is either O, S, or NRl θ; 5 Rl, R^, and R^O are independently selected from the group consisting of H, (CH2)nAr, COR4, (CH2)nheteroaryl, (CH2)nheterocyclyl,Ci-Cjo alkyl, C3-C10 cycloalkyl, C2-Cio alkenyl, and C2-C)oalkynyl, wherein n is 0,1, 2, or 3, and the (CH2)nAr,(CH2)nheteroaryi, alkyl, cycloalkyl, alkenyl, and alkynyl groups 10 are optionally substituted by up to 5 groups selected from NR4R5, N(O)R4r5, NR4r5r6y, alkyl, phenyl, substituted phenyl,(CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo,COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4,aldéhyde, nitrile, nitro, 15 OR5 I heteroaryloxy, T(CH2)mQR4, T(CH2)mC-(CH2)mQR4, I H 20 C(O)T(CH2)mQR4,NHC(O)T(CH2)mQR4, T(CH2)mC(O)NR4NRA or T(CH2)mCO2R4 wherein each m isindependently 1 -6, T is O, S, NR4, N(O)R4, NR4R^Y, or CR4R$,and Q is O, S, NR5, N(O)R5, or NR5R6Y; when the dotted line is présent, R^ is absent; 25 otherwise R^ has the meanings ofR2, wherein R2 is as defined above, as well as OH, NR4R5, COOR4, OR4, CONR4R5, SO2NR4R5,SO3R4, PO3R4, -129- 01 1 5 54 or5 I T(CH2)mQR4, T(CH2)mC-(CH2)mQR4 5 H wherein T and Q are as defined above; R4 and R^ are each independently selected from the group consisting ofhydrogen, Cj-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C2-Céalkynyl, NCCpC^alkyl)! or2, (CH2)nAr, C3-C10 cycloalkyl, 10 heterocyclyl, and heteroaryl, or R4 and R$ together with the nitrogen to which they are attached optionally form a ring having3 to 7 carbon atoms and said ring optionally contains 1,2, or3 heteroatoms selected from the group consisting of nitrogen,substituted nitrogen, oxygen, and sulfur; 15 when R4 and R^ together with the nitrogen to which they are attached form a ring, the said ring is optionally substituted by 1 to 3 groupsselected from OH, OR4, NR4r5, (CH2)mOR4, (CH2)mNR4R5,T-(CH2)rnQR4, CO-T-(CH2)mQR4, NH(CO)T(CH2)mQR4,T-(CH2)mCO2R4, or T(CH2)mCONR4R5. 20 R^is alkyl; R8 and independently are H, C1-C3 alkyl, NR4R5, N(O)R4r5, NR4r5r6y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4r5, SO3R4, PO3R4, CHO, CN, orNO2; 25 when the dotted line is absent, R^ is additionally carbonyl, thiocarbonyl, imine and substituted imine, oxime and oxime éther, and Y is a halo counter-ion for the manufacture of a médicament to inhibit anon-receptor tyrosine kinase.
21. 35. Use as claimed in Claim 34 wherein said non-receptor tyrosine kinase is selected30 from a transforming gene of the Rous sarcoma retrovirus (Src) family. -130- 011554
22. 36. Use of a compound of Claim 1 for the manufacture of a médicament for inhibiting a serine kinase in a mammal. 5
23. 37. Use of a compound of Claim 1 for the manufacture of a médicament for thetreatment of a disease caused by vascular smooth muscle cell prolifération.
24. 38. Use of a compound of Claim 1 for the manufacture of a médicament for thetreatment of cancer. 10
25. 39. Use of a compound of Claim 1 for the manufacture of a médicament for inhibitirtga disease State caused by angiogenesis.
26. 40. Use as claimed in claim 39 wherein the disease State caused by angiogenesis isselected from human cancer, macular degeneration, diabetic retinopathy, surgicaladhesions and psoriasis.
27. 41. Use of a compound of Claim 1 for the manufacture of a médicament for inhibitinga wee-1 kinase enzyme in a mammal.
28. 42. A compound selected from: 7-[3-(Carboxy)-phenylamino]-3-(2,6-dichloro-phenyl)-1 -methyl-3s4-dihydro-pyrimido[4,5-i/lpyrimidin-2(l//)-one; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6-dichloro-phenyl)-1 -methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1H)-one; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)-1 -methyl-3,4-dihydro-pyrinndo[4,5- 25 <7]pyrimidin-2(l//)-one; 7-[3-(Carboxy)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)-1-methyl-3,4-dihydro-pyrimido[4,5-</)pyrimidin-2( 1 H)-one; 011554 -131- 3-(2,6-Dichloro-phenyl)-7-[4-(2-ethylamino-ethoxy)-phenylamino]-l-methyl-3,4-dihydro-pyrimido[4,5-t/]pyrimidin-2(l/7)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(2-ethylamino-ethoxy)- phenylamino]-l-methyl-3,4-dihydro-pyrimido[4,5-c(lpyrimidin-2(17/)-one; 5 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-phenyl)-l- methyl-3,4-dihydro-pyrimido[4,5-JJpyrimidin-2( 1//)-θηε; 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyi)-l -methyl-3,4-dihydro-pyrimido[4,5- d]pyrimidin-2( 17/)-one; 3-(2,6-DichIoro-phenyl)-7-(3-hydroxymethyl-phenylamino)-1 - 10 methyl-3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2( 1 H)-one ; 3-(2,6-Dichloro-phenyl)-7-(4-morpholin-4-yl-phenylamino)-3,4- dihvdro-pyrimido[4,5 -d]pyrimidin-2( 177)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-1 -methyl-7-(4-morpholin-4-yl- phenylamino)-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 1 H)-one; 15 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-(3-hydroxymethyl- phenylamino)-l-methyl-3,4-dihydro-pyrimido[4,5-</Jpyrimidin-2(177)-one; 7-(4-(3 -Carboxypropyl)-phenylamino]-3 -(2,6-dichloro-pheny 1)-1 -methyl-3,4-dihydro-pyrimido[4,5-i/]pyrimidin-2( 1 H)-one; 7-[4-(3-Carboxypropyl)-phenylamino]-3-(2,6-dichloro-3-hydroxy- 20 phenyl)-l-meîhyl-3,4-dihydro-pyriniido[4,5-i2]pyrimidin-2(ln)-one; 3-(2,6-Dichloro-phenyl)-7-[4-(fonnyl-phenylâmino}-1 -methyl-3,4- dihydro-pyrimido[4,5-cQpyrimidm-2(l/i)-one; and 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(formyl-phenyîamino]- 1 - methyl-3,4-dihydro-pyrimido[4,5-rf]pyrimidin-2( 177)-one. 25 43. A pharmaceutical formulation comprising a compound of Claim 1 in combination with a pharmaceutically acceptable carrier, diluent, orexcipient.