ZA200006536B

ZA200006536B - Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation.

Info

Publication number: ZA200006536B
Application number: ZA200006536A
Authority: ZA
Inventors: Ellen Myra Dobrusin; James Bernard Kramer; Howard Daniel Hollis Showalter; Susanne A Trumpp-Kallmeyer; James Marino Hamby; Mel Conrad Schroeder; Peter Toogood
Original assignee: Warner Lambert Co
Priority date: 1998-05-26
Filing date: 2000-11-10
Publication date: 2002-02-11

Description

om t -1- - BICYCLIC PYRIMIDINES AND BICYCLIC 3,4-DIHYDROPYRIMIDINES AS

INHIBITORS OF CELLULAR PROLIFERATION

FIELD OF THE INVENTION

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

SUMMARY OF THE RELATED ART

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

Progress in Cell Cycle Research, 1995;1:351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1 (also known as cdc2), cdk2, cdk4, cdks, cdké, and wee-1 kinase. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of human tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.

Several compounds that inhibit cdks have demonstrated both preclinical and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent 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 inhibitor of cdk2 and cdk5 (Vesely, et al., Eur. J. Biochem., 1994;224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al., Biology of the Cell, 1995;83:105-120).

In addition, tyrosine kinases are a class of enzymes that catalyze the ) transfer of the terminal phosphate of adenosine triphosphate (ATP) to tryrosine residues on protein substrates. Tyrosine kinases are an integral part of growth . factor receptors and are essential for the propagation of growth factor signal transduction leading to cellular proliferation, differentiation, and migration.

Growth factor receptors are also known as receptor tyrosine kinases (RTKs). The aberrant regulation of growth factors or their cognate receptors play a critical role in the progression of proliferative diseases. For example, the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF) have been implicated as important mediators of tumor promoted angiogenesis. Solid tumors are dependent upon the formation of new blood vessels from preexisting vessels (angiogenesis) to nourish their growth and to provide a conduit for metastases.

Accordingly, inhibitors of the FGF and VEGF RTKs, as well as other tyrosine kinases, are useful agents for the prevention and treatment of proliferative diseases dependent on these enzymes.

Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis, angiogenesis. diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration, and atherosclerosis.

SUMMARY OF THE INVENTION

This invention provides bicyclic heterocycles that are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, restenosis, angiogenesis, diabetic retinopathy, psoriasis, and endometriosis. We have discovered a group of bicyclic pyrimidine analogs that are potent inhibitors of cyclin-dependent kinases (cdks) and tyrosine kinases. The compounds are readily synthesized and can be administered by a variety of routes, including orally and parenterally, and have little or no toxicity.

The compounds of the invention are members of the class of compounds of Formula [:

¢ + \ B

Bh : wy . ! -3- 3 . RS RY 3

R

N ~~ « : N = *~N 1 Js A 1

R'—W Z G X bo and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond;

Z is N or CH;

Gis N or CH;

Wis NH, S, SO, or SOy;

X is either O, S, or NR10;

R1, R2, and R10 are independently selected from the group consisting of H, (CHy)pAr, COR4, (CHp)pheteroaryl, (CHp)pheterocyelyl, C1-Cj alkyl,

C3-Cqq cycloalkyl, C2-C1g alkenyl, and C2-Cqg alkynyl, wherein n is 0, 1, 2, or 3, and the (CHy)pAr, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4RS, N(O)R4R5, NR4RIROY, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, CORA,

CO,R%, CONRARS, SO)NRARS, SO3R4, PO3R#, aldehyde, nitrile, nitro,

OR? heteroaryloxy, T(CH2)mQR#, T(CH2)mC-(CH2)mQRA,

H

C(O)T(CHp)mQR4, NHC(0)T(CH2);nQRA, T(CH2)mC(O)NRINRS, or

T(CHp);CO7R4 wherein each m is independently 1-6, T is O, S, NR4,

N(O)R4, NR4R6Y, or CR4R3, and Q is O, S, NR, N(O)R, or NRIROY; when the dotted line is present, R3 is absent;

C ) jd ' otherwise R3 has the meanings of R2, wherein R2 is as defined above, as well as N

OH, NR4R5, COOR#, OR4, CONRA4RS, SOoNRAR5, SO3R4, PO3R4,

ORS

T(CH)mQR#, T(CH2),C-(CH2)mQR4,

H wherein T and Q are as defined above;

R4 and RS are each independently selected from the group consisting of hydrogen, C1-Cg alkyl, substituted alkyl, Co-Cg alkenyl, C-Cg alkynyl,

N(C1-Cgalkyl)} or 2, (CH2)pAr, C3-Cjg cycloalkyl, heterocyclyl, and heteroaryl, or R# and RO together with the nitrogen to which they are attached optionally form a ring having 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 groups selected from OH,

OR4, NRARS, (CH)OR4, (CH) NRAR?, T-(CH))mMQRY,

CO-T-(CHy)y QR, NH(CO)T(CHp);QR4, T-(CH2)mCO2R#, or

T(CH7) CONRARS.

RO is alkyl;

R8 and RY independently are H, C-C3 alkyl, NR4R3, N(O)R4R5, NR4RROY, hydroxy, alkoxy, thiol, thioalkyl, halo, COR#, COR, CONRA4R3,

SO,HNR4R3, SO3R4, PO3R4, CHO, CN, or NO; 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.

In a preferred embodiment, the invention provides compounds of

Formula II, III, and IV

' ht » : ir wy 1 -5- - 8 RY 3

R

AN ~~ } NTN ~\N 1 =

R'-W N 1 X

R2 8 RY 3

R

Ny ~~

N™ XY" SN

MC P 1

R'—-W N X

R2 3

R

Ny ~~

N ~~ ~N

Iv

R'—-W \ X

R2 wherein R1, RZ, R3, Ww, RS, and RY are as defined above.

Additionally preferred compounds have 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 a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.

Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdk2, cdc2, and cdk4. Some of the compounds of the present invention also inhibit growth factor mediated tyrosine kinases including those of platelet-derived growth factor (PDGF), fibroblast growth factor (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 instant invention are useful in controlling proliferative disorders such as cancer, psoriasis,

vascular smooth muscle cell proliferation associated with atherosclerosis, diabetic ) retinopathy and angiogenesis, and postsurgical vascular stenosis and restenosis in mammals.

A further embodiment of this invention is a method of treating subjects suffering from diseases caused by cellular proliferation. The method entails inhibiting proliferation of tumorigenic cells of epithelial origin and vascular smooth muscle proliferation, and/or cellular migration by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment.

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 have discovered a new class of compounds that are potent inhibitors of cyclin-dependent kinases (cdks) and tyrosine kinases that are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation.

Compounds within the scope of the present invention are inhibitors of the cyclin- dependent kinases such as cdc2, cdk2, and cdk4, and tyrosine kinases such as

PDGF. FGF, and c-Src. As inhibitors of these kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis, angiogenesis, diabetic retinopathy, and restenosis in mammals.

The compounds of the invention are members of the class of compounds of Formula I: 8 RY

R3 3s N Ay ~~ :

RI-w Lz oN X

R and the pharmaceutically acceptable salts thereof,

! | iy ; wherein: the dotted line (---) represents an optional double bond; : . ZisNorCH;

Gis N or CH;

Wis NH, S, SO, or SO9;

X is either O, S, or NR10;

Rl, R2, and R10 are independently selected from the group consisting of H, (CHo)pAT, COR#4, (CHp)pheteroaryl, (CHp)pheterocyclyl, C1-Cqg alkyl,

C3-Cqg cycloalkyl, C»-Cj alkenyl, and C»-C1 alkynyl, wherein nis 0, 1,2, or 3, and the (CHp)pAr, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4RS, N(O)R4R5, NRARSROY, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalky], halo, CORA,

COoR4, CONR4RS, SONR4R3, SO3R4, PO3R4, aldehyde, nitrile, nitro,

OR5 heteroaryloxy, T(CH2)mQR%, T(CH2)mC-(CH2)mQR?,

H

C(0)T(CH2)mQR4, NHC(O)T(CHy)mQR#, T(CH2);, C(O)NRNR?, or

T(CHy),COoR# wherein each m is independently 1-6, Tis O, S, NR4,

N(O)R4, NR4R6Y, or CR4R5, and Q is O, S, NR, N(O)R5, or NRSROY; when the dotted line is present, R3 is absent; otherwise (when --- is absent) R3 has the meanings of R2, wherein R2 is as defined above, as well as OH, NR4R5, COOR#, OR%, CONRAR3,

SO-NR4RS, SO3R4, PO3R4,

OR>

T(CHp)mQR?, T(CHY)mC-(CH2)mQR,

H wherein T and Q are as defined above;

R#4 and RS are each independently selected from the group consisting of . hydrogen, C1-Cg alkyl, substituted alkyl, Cy-Cg alkenyl, Co-Cg alkynyl,

N(C1-Cgalkyl)] or 2, (CHp)pAr, C3-Cy cycloalkyl, heterocyclyl, and - heteroaryl, or R4 and R3 together with the nitrogen to which they are attached optionally form a ring having 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 R3 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, NR4RS, (CH) OR4, (CH) NRARS, T-(CH)mQRy,

CO-T-(CHp)pQR4, NH(COYT(CH) QR, T-(CH2)mCO2R%, or

T(CH)mCONRAR3;

RS is alkyl;

R8 and RY independently are H, C1-C3 alkyl, NR4RS5, N(O)R4R5, NR4RSROY, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, COpR%, CONRA4R5,

SO,NR4R3, SO3R4, PO3R4, CHO, CN, or NO; 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.

An especially preferred group of compounds have 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 I have the above formula wherein X is O or NHR 10, and R3 is H or substituted aryl.

Also preferred are compounds of Formula I wherein R8 and RY both are hydrogen.

Another preferred group of compounds of Formula have the above formula wherein X is O, and R2 is Et, Pr, i-Pr, i-Bu, i-pentyl, or cycloalkyl. In an especially preferred group of compounds, X 1s O and R2 is cyclopentyl or ethyl.

1 -0- - In yet another preferred group of compounds of Formula I, X is O, W is

NH, and R! is alkyl, substituted alkyl, phenyl, or substituted phenyl, pyridyl or substituted pyridyl. Preferred R1 substituted phenyl groups include 4-piperidinyl (with or without substitution), 4-(2-diethylaminoethoxy), 4-pyrrole, 4-pyrazol, and 4-(4-methyl piperazin-1-yl). In an especially preferred group of compounds, X is 0, and R! is phenyl substituted with hydroxy, alkoxy, NRAR3, or T(CH2)mQR4, where R4 and RS, T, m, and Q all are as defined above. In an even more preferred group of compounds, X is O, and R! is phenyl substituted with NR4RS5 or

T(CH)mQR4, where R4 and RS, T, m, and Q all are as defined above.

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

Further preferred compounds are the pyrimido[4,5-d]pyrimidines of

Formula I wherein Z is N.

Especially preferred compounds provided by the invention have

Formulas II, 111, and IV 8 RY 3

R

Ny ~~

N™ XY" “WN

Pg A 11 1 ~

R'—-W N 1 X

RZ

8 RY 3

R

Ny ~~

N™ XY” S\N

PE P 1) : R'-W N X

R2

8 RY .

R

Ny ~~

DE

Iv

R'—W N X la wherein R1, R2, R3, W, R8, RY, and X are as defined above.

Additionally preferred compounds have the above formulas wherein W is

NH. Also preferred are those compounds wherein R1 is alkyl, substituted phenyl or pyridyl.

Further preferred compounds of the present invention have the Formula V:

N Dl oN N N 0 v

H R? 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, or cycloalkyl such as norbornyl, cyclopentyl, cyclohexyl, or adamantyl. A most preferred Ar group is phenyl, preferably substituted with 1, 2, or 3 groups selected from phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxycarbonylmethyl, carboxy, carboxymethyl, ethoxycarbonyl, 2-carboxyethyl, 2-ethoxycarbonylethyl, NR4R3, and

O(CH»)p-gNR4R5, wherein R4 and R5 are as defined above. Another preferred

Ar group is pyridyl and thiazolyl, for example, 3-pyridyl, 2-thiazolyl, each optionally substituted by alkyl, halo, phenyl, hydroxyphenyl, or alkoxyphenyl.

Other preferred compounds have Formula VI

LAr

NTN N aryl PE ~ PS Vi alkyl —N N N X heteroaryl H

R2 where alkyl, Ar, aryl, heteroaryl, RZ, and X are as defined above. Particularly preferred compounds of Formula VI are those where X is O or NHCOR?, for ) example, NHCO alkyl and NHCONH alkyl. Preferred aryl groups are phenyl and substituted phenyl. Preferred heteroaryl groups are pyridyl and substituted pyridyl.

Compounds of Formula I wherein W is S, SO, or SO7 are especially useful as intermediates leading to compounds where W is NH, but such compounds also display inhibitory activity against cyclin-dependent kinases and tyrosine kinases.

Unless otherwise expressly stated, the following definitions are adhered to throughout 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, n-butyl, sec-butyl, isobutyl, rert-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-1-yl, 3,6-octadien-1-yl, and the like. “Alkynyl” means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one or two triple bonds and includes ethynyl, 3-butyn- 1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, 3,6-octadien-1-yl, and the like. “Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed “heterocyclyl”, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR), examples being oxiranyl, pyrrolidinyi, piperidyl, tetrahydropyran, and morpholine. “Alkoxy” refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, fert-butoxy, and

. . ‘ the like. In addition, alkoxy refers to polyethers such as -O-(CH3);-0-OH3, and | . the like. “Alkanoyl” groups are alkyl linked through a carbonyl, i.e., C1-Cg-C(O)-. .

Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl. “Acyl” means an alkyl or aryl (Ar) group bonded through a carbonyl group, ie, R-C(O)-. For example, acyl includes a C1-Cq alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.

The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NRA4RS,

N(O)RARS5, NR4RSROY, phenyl, substituted phenyl, thio C;-Cyq alkyl, C1-Cjg alkoxy, hydroxy, carboxy, C1-Cq alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. “Substituted nitrogen” means nitrogen bearing C1-C1 alkyl or (CHp),Ph where nis 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, 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, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.

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

- Further examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, - © 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl- butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.

The terms “Ar” and “aryl” refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.

Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. 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 the like. An especially preferred heteroaryl group is pyridyl.

Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, hydroxy, -COOR7, amino of the formula -NR4R>, CONRAR5, and

T(CHp);QR# or T(CH2); COoR# wherein m is 1t0 6, Tis O, S, NR4, N(O)R4,

NR4R6Y, or CR4R3, Q is O, S, NR, N(O)RS, or NRSROY wherein R4 and

RS are as described above, and R7 is H, alkyl or substituted alkyl, for example, methyl, 2-aminoethyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.

The invention compound will be named herein according to the following position assignments 5 4 6 N De N 3

Lz Jr when G=N, 8 1

4 5 . 3 NX N 6 and § _ p . when G = CH. 2 7 G i 1 8

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

RS RY RS R’ 3 R3

R XN. _ .

A PS 1 A 7 PY

RI—w 7 G 0 R'—W Zz G OH

H

Similarly, 2-imino compounds can tantomerize to 2-amino compounds as follows:

RS RO RS RB’ 3 3

L R A. ~R

NX RINT HN ~N rl—w™ 7 6 wrl10 RI—WT ZT 7G NHR?

H

2-Thiones can tantomerize to thiols as follows:

RS R’ RS R° 3 3

R R

— PE . 1 = 1 “

R'—W Z ¢ S R'—W Z G SH

H

All of the tantomeric forms of compounds of Formulas I-1V are contemplated and included within the scope of this invention.

The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms,

including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

The compounds of Formula I are capable of further forming both pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides. This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.

All of these forms are within the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of

Formula I include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus 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, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge, et al., “Pharmaceutical Salts,” J of Pharmaceutical Science, 1977,66:1-19.

The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.

The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines.

Examples of metals used as cations are sodium, potassium, magnesium, calcium,

and the like. Examples of suitable amines are N,N’-dibenzylethylenediamine, | } chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, et al., supra. }

The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.

The compounds of the present invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases including but not limited to psoriasis,

HSV, HIV, restenosis, and atherosclerosis. To utilize a compound of the present

Invention to treat cancer, a patient having cancer is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising an invention compound.

A further embodiment of this invention is a method of treating subjects suffering from diseases caused by vascular smooth muscle cell proliferation.

Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration. The method entails inhibiting vascular smooth muscle proliferation, and/or migration by administering an effective amount of a compound of Formula I to a subject in need of treatment.

The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, a compound of Formula I or a corresponding pharmaceutically acceptable salt or solvate thereof.

A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. For preparing pharmaceutical compositions i with the compounds of the present invention, pharmacuetically acceptable carriers can be either a solid or liquid. Solid form preparations include powders, tablets,

X - pills, capsules, cachets, suppositories, and dispensible granules. A solid carrier can be 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 which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The formulations of this invention preferably contain from about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, 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, which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

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

Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations that are intended to be | . converted, shortly before use, to liquid form preparations for oral administration.

Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles, and the like can be utilized to prepare sustained-release dosage forms. Also, osmotic pumps can be employed to deliver the active compound uniformally over a prolonged period.

The pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules.

Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The therapeutically effective dose of a compound of Formula I and/or

Formula II will generally be from about 1 mg to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 mg to about 800 mg per day. The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I and/or II is administered a dosage of about 1 to about 500 mg per day, either singly or in multiple doses over a 24-hour period.

The compounds of the present invention are capable of binding to and inhibiting the activity of proteins having the ability to phosphorylate other proteins, such as cdks, PDGFr, FGFr, c-Src, and EGFr-FL. Cdks form complexes with cyclins, and these complexes phosphorylate key proteins allowing cells to proceed through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995;1:351-363). The compounds of this invention inhibit this phosphorylation

: and therefore can be used as anti-proliferative agents for the treatment of cancer and/or restenosis and other proliferative diseases. : Because of their inhibitory activity against cdks and other kinases, the compounds of the present invention are also useful research tools for studying the mechanism of action of those kinases, both in vitro and in VIVO.

While the forms of the invention herein constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive rather than limiting, and those skilled in the art will realize that various changes may be made without departing from the spirit or scope of the invention.

The following compounds illustrate specific embodiments provided by the present invention, and the compounds listed below are among the preferred embodiments. 1-Methyl-7-[4-(pyrazol-1-yl)phenylamino]-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino}-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino}-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1 -yllphenylamino}-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; -Isopropyl-7-[4-(pyrazol-1-yl)phenylamino}-3,4-dihydro-pyrimido 4,5- dlpyrimidin-2(1H)-one; 1 -Isopropyl-7-[4-(4-methylpiperazin- 1-yl)phenylamino}-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1 -Isopropyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino}-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-1sopropyl-7- {4-[4-(dimethylamino)piperidin-1 -yl]phenylamino}-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Bicyclo[2.2.1]hept-2-y1-7 -[4-(pyrazol-1-yl)phenylamino]-3 ,4-dihydro- pyrimido[4.5-d]pyrimidin-2( 1 H)-one (ex0);

1-Bicyclo[2.2.1 Thept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino}-3,4- dihydro-pyrimido{4,5-djpyrimidin-2(1 H)-one (exo); : 1-Bicyclo[2.2. 1Jhept-2-yl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]- } 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (exo); 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(dimethylamino)piperidin-1- yl]phenylamino}-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-1-cyclopentyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-{4-[4-(2-Amino -4-methyl-pentanoyl)-piperazin-1-yl}-phenylamino}-1- cyclopentyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one; 1-Methyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin-1-yl]Jphenylamino }- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-{4-(3 -morpholin-4-ylpropyl)piperidin-1- yl]phenylamino} -3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Cyclopentyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin-1- yl]phenylamino}-3 .4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-{4-(4-(3 -morpholin-4-ylpropyl)piperidin-1- yljphenylamino}-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one (exo); 1 -Cyclopentyl-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimidof4,5- d}pyrimidin-2(1H)-one; 1 -Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; i -Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(3-Amino-pyrrolidin-1 -yl)-phenylamino]}-1 -cyclopentyl-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino}-1 -cyclopentyl-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Cyclopentyl-7-(4-piperazin-1 -yl-phenylamino)-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1£)-one; 1-Cyclopentyl-7-[4-(5 -methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-3,4-dihydro-pyrimido [4,5-dpyrimidin-2(1H)-one;

: * 7-[4-(4-Aminoacetyl-piperazin- 1-yl)-phenylamino]-3-(3 ,5-dimethoxy- phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; : 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3 -(2-chloro-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1 -yl)-phenylamino]-3-(2,6-dichloro-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3 -(2-methyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin- 1-yl)-phenylamino}]-3 -(2,6-dimethyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5 -d|pyrimidin-2(1H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3 ,5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-chloro-3,5 -dimethoxy- phenyl)-1-ethyl-3,4-dihydro-pyrimido [4,5-d}pyrimidin-2(1H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3 -(2,6-dichloro-3,5- dimethoxy-phenyl)-l-ethyl-3,4-dihydro-pyrimido[4,5-d] pyrimidin-2(1H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3 -(2-methyl-3,5-dimethoxy- : phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino}-3 -(2,6-dimethyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5-d] pyrimidin-2(1H)-one; 7-(4-Diethylamino-butylamino)-3-(3,5-dimethoxy-phenyl)-1 -ethyl-3.,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-(4-Diethylamino-butylamino)-3-(2-chloro-3 ,5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dichloro-3 ,5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)-one; 7-(4-Diethylamino-butylamino)-3-(2-methyl-3,5 -dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 f)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dimethyl-3, 5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-1-ethyl-3 ,4-dihydro- pyrimido[4.5-d]pyrimidin-2(1H)-one;

7-(Pyridin-4-ylamino)-3-(2-chloro-3,5-dimethoxy-phenyl)-1-ethyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-ethyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dimethyl-3,5-dimethoxy-phenyl)-1-ethyl- 3,4-dihydro-pyrimido{4,5-d]pyrimidin-2(1 H)-one; 7-(Pyridin-4-ylamino)-3-(2-methyl-3,5-dimethoxy-phenyl)-1-ethyl-3,4- dihydro-pyrimido[4,5-d)pyrimidin-2(1H)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino-butylamino)-3,4- dihydro-pyrimido[4,5-d)pyrimidin-2(1 H)-one; 3-(2-Chloro-3 ,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)- phenylamino}-3,4-dihydro-pyrimido [4,5-d)pyrimidin-2(1 H)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(3.5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3 ,4-dihydro- pyrimido[4.5-d]pyrimidin-2(1H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5 -dimethoxy-phenyl)- - 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2,6-Dichloro-3 ,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2.6-Dichloro-3 _5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)- phenylamino]-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one; 7-[3-(Carboxy)-phenylamino}-3 -(2,6-dichloro-phenyl)-1-methyl-3,4- dihydro-pyrimido[4,5-d)pyrimidin-2(1 H)-one; 7-[3-(N -Dimethylaminopropyl-carboxamide)-phenylamino] -3-(2,6- dichloro-phenyl)- 1-methyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one; 7-[3-(N -Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6- dichloro-3-hydroxy-phenyl)- 1-methyl-3,4-dihydro-pyrimido[4.5 -d]pyrimidin- 2(1H)-one; 7-[3-(Carboxy)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)- 1- methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one;

: " 3-(2,6-Dichloro-phenyl)-7-[4-(2-ethylamino-ethoxy)-phenylamino]-1- methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; : 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(2-ethylamino-ethoxy)- phenylamino]-1-methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-phenyl)-1 -methyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-3 -hydroxy-phenyl)-1- methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(2,6-Dichloro-phenyl)-7-(3-hydroxymethyl-phenylamino)- 1-methyl-3.4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(2,6-Dichloro-phenyl)-7-(4-morpholin-4-yl-phenylamino)-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-1 -methyl-7-(4-morpholin-4-yl- phenylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-(3 -hydroxymethyl-phenylamino)-1- methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(3-Carboxypropyl)-phenylamino]-3-(2,6-dichloro-phenyl)- 1-methyl- : 3,4-dihydro-pyrimido(4,5-djpyrimidin-2(1 H)-one; 7-[4-(3-Carboxypropyl)-phenylamino]-3-(2,6-dichloro-3-hydroxy-phenyl)- 1-methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2,6-Dichloro-phenyl)-7-[4-(formyl-phenylamino]- 1-methyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(formyl-phenylamino}- 1 -methyl- 3,4-dihydro-pyrimido[4,5-d}pyrimidin-2(1 H)-one; 1-Methy!-7-[4-(pyrazol-1-yl)phenylamino]pyrimido [4,5-d]pyrimidin- 2(1H)-one; 1-Methyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido(4,5- d)pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino}pyrimido[4,5- d)pyrimidin-2(1 H)-one; 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}- pyrimido[4,5-d]pyrimidin-2(1H)-one;

~ 1-Isopropyl-7-[4-(pyrazol-1 -yl)phenylamino]pyrimido{4,5-d]pyrimidin- . 2(1H)-one; 1-1sopropyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrimido[4,5- . dlpyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-hydroxypiperidin-1 -yh)phenylamino]pyrimido[4,5- dlpyrimidin-2(1H)-one; 1-Isopropyl-7-{ 4-[4-(dimethylamino)piperidin-1 -yl]phenylamino}- pyrimido[4.5-d]pyrimidin-2(1 H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-{4-(pyrazol-1 -yl)phenylamino]pyrimido[4,5- d)pyrimidin-2(1H)-one (exo); 1-Bicyclo[2.2.1 Thept-2-yl-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1£)-one (exo); 1-Bicyclo[2.2.1 Jhept-2-yl-7-[4-(4-hydroxypiperidin-1- yDphenylamino}pyrimido {4,5-d]pyrimidin-2(1H)-one (x0); 1-Bicyclo[2.2.1 Jhept-2-yl-7-{4-[4-(dimethylamino)piperidin- 1- yl]phenylamino} pyrimido [4,5-d]pyrimidin-2(1H)-one (ex0); 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}-phenylamino}-1- cyclopentyl-pyrimido[4,5 -d}pyrimidin-2(1 H)-one; 1-Methyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin- 1- yl)phenylamino } pyrimido[4,5-djpyrimidin-2( 1 H)-one; 1-Isopropyl-7- {4-[4-(3-morpholin-4-ylpropyl)piperidin-1 - yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin-1- yl]phenylamino }pyrimido[4,5 -d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-{4-{4-(3 -morpholin-4-ylpropyl)piperidin- 1- yllphenylamino } pyrimido [4,5-d]pyrimidin-2(1H)-one (exo); 1 _Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-pyrimido [4,5- d)pyrimidin-2(1H)-one; 1-Cyclopentyl-7 ~(4-fluoro-3-methyl-phenylamino)-pyrimido [4,5- dlpyrimidin-2(1 H)-one;

: 7-[4-(3-Amino-pyrrolidin- 1-yl)-phenylamino]-1-cyclopentyl- pyrimido[4,5-d]pyrimidin-2(1 H)-one; : 1-Cyclopentyl-7-(4-piperazin-1-yl-phenylamino)-pyrimido[4,5- d)pyrimidin-2(1H)-one; 1-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-pyrimido{4,5-d]pyrimidin-2(1 H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-1-cycloheptyl-pyrimido[4,5- d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-djpyrimidin-2(1 H)-one; 1-[7-(4-Fluoro-phenylamino)-pyrimido[4,5-d]pyrimidin-2-yl}-3-methyl- urea; 1-Isopropyl-3-(7-phenylamino-pyrimido[4,5-d]pyrimidin-2-yl)-urea; 1-{7-[4-(3-Aminomethyl-pyrrolidin- 1-yl)-phenylamino]-pyrimido{4,5- dlpyrimidin-2-yl}-3-isopropyl-urea; 1-Isopropyl-3-[7-(4-piperazin-1-yl-phenylamino)-pyrimido(4,5- d]pyrimidin-2-yl]-urea; 1-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino}-pyrimido[4,5- d]pyrimidin-2-yl}-3-isopropyl-urea;

N-{7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino}-pyrimido[4,5- d]pyrimidin-2-yl}-3-methyl-butyramide;

N-[7-(4-Piperazin-1-yl-phenylamino)-pyrimido[4,5-d]pyrimidin-2-yl]- isobutyramide;

N-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrimido(4,5- d]pyrimidin-2-yl}-3-methyl-butyramide; 3-Methyl-N-[7-(pyridin-4-ylamino)-pyrimido[4,5-d|pyrimidin-2-yl]- butyramide; 1-Isopropyl-3-[7-(pyridin-4-ylamino)-pyrimido[4,5-d]pyrimidin-2-yl]- urea;

N-{7-[4-(3-Aminomethyl-pyrrolidin-1-yl)-phenylamino]-pyrimido[4,5- d]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-d]pyrimidin-2-yl } -butyramide;

1-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-3,4-dihydro- } pyrimido[4,5-d]pyrimidin-2-yl}-3-isopropyl-urea; 1-[7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- ] : phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-3-ethyl-urea; : 5 1-{3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino-ethoxy)- phenylamino]-3,4-dihydro-pyrimidof4,5-djpyrimidin-2-yl }-3-ethyl-urea; 1-tert-Butyl-3-[ 7-[4-(2-diethylamino-ethoxy)-phenylamino}-3-(3,5- dimethoxy-phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl}-urea; 1-tert-Butyl-3-{3-(2-chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino- ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl } -urea; 1-tert-Butyl-3-[3-(3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3 4- dihydro-pyrimido[4,5-d]pyrimidin-2-yl}-urea; 1-[3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido{4,5-d]pyrimidin-2-yl1]-3-ethyl-urea; 1-tert-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-urea; 1-[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido(4,5-d]pyrimidin-2-yl]-3-ethyl-urea; 1-[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino-butylamino)- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-3-ethyl-urea; 1-tert-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino- butylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-urea; 1-(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Thiophen-2-yl)-7-[4-(4-methylpiperazin- 1 -yl)phenylamino]-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1-yl)phenylamino}-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1-yl)phenylamino}]-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(Hexa-2,4-diene- 1-yl)-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one;

: * 1-(Prop-2-yne-1-yl)-7-[4-(4-methylpiperazin-1-yl)phenylamino}-3,4- dihydro-pyrido{4,3-d]pyrimidin-2(1 H)-one; : 1-[3-(Dimethylamino)prop-1-yl]-7-[4-(4-methylpiperazin-1- yDphenylamino]-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(3-Hydroxyprop-1-yl)-7-[4-(4-methylpiperazin-1-yl)phenylamino}-3,4- dihydro-pyrido{4,3-d]pyrimidin-2(1H)-one; 1-(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin- 1-yl)phenylamino]-3,4- dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(3,5-Dimethylhept-1-y1)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]- 3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 3-(3.5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl-3,4-dihydro- pyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2-Chloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl-3.,4- dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 3-(2,6-Dichloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl- 3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 3-(2-Methyl-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl-3,4- : dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 3-(2,6-Dimethyl-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl- 3,4-dihydro-pyrido{4,3-d]pyrimidin-2(1 H)-one; 7-[4-(4-Aminoacetyl-piperazin- 1-yl)-phenylamino]-3-(3 ,5-dimethoxy- phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2-chloro-3,5- dimethoxy-phenyl)- 1-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-y1)-phenylamino]-3-(2,6-dichloro-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2-methyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino}-3 -(2,6-dimethyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido{4,3-d]pyrimidin-2(1H)-one;

1-(Thiophen-2-y1)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]pyrido[4,3- . dlpyrimidin-2(1H)-one; : 1-(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino)pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1- ylphenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Hexa-2,4-diene- 1-y1)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido{4,3-d]pyrimidin-2(1H)-one; 1-(Prop-2-yne-1-y})-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1/)-one; : 1-[3-(Dimethylamino)prop-1 -yl1}-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(3-Hydroxyprop-1-yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1- yDphenylamino]pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(3,5-Dimethylhept-1-yl)-7- [4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-Cyclopentyl-7-(4-piperazin-1 -ylphenylamino)pyrido[4,3-d]pyrimidin- 2(1H)-one; 7-[4-(3-Aminopyrrolidin-1 -yl)phenylamino]-1 -cyclopentylpyrido[4,3- dlpyrimidin-2(1H)-one; 2-[4-(3-Amino-pyrrolidin-1 -y1)-phenylamino)-8-isopropyl- 8 H-pyrido[4,3- d}pyrimidin-7-one; 8-Cyclopentyl-2-[4-(hexahydro-pyrrolo[3 A-clpyrrol-2-yl)-phenylamino]- 8 H-pyrido[4.3-d]pyrimidin-7-one; 2-[4-(4-Acetyl-piperazin-1 -yl)-phenylamino]-8-cyclopentyl-8 H- pyrido[4,3-d]pyrimidin-7-one;

N-{2-[4-(4-Aminoacetyl-piperazin-1-yl)-phenyl amino]-8-cyclopentyl- pyrido[4,3-d]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 —d]pyrimidin-7-yl)-2,2-dimethyl-propionamide;

: 1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1 H-pyrimido[4,5- dlpyrimidine-2,4-dione; : 7-[4-(2-Diethylaminoethoxy)phenylamino]- 1 -isopropyl-1 H-pyrimido[4,5- d]pyrimidine-2,4-dione; 7-(4-Diethylamino-butylamino)-3-(3,5-dimethoxy-phenyl)-1 -ethyl-1H- pyrimido[4,5-d]pyrimidine-2,4-dione; 7-[4-(2-Diethylamino-ethoxy)-phenylamino}-3-(3,5-dimethoxy-phenyl)-1 - ethyl-1H-pyrimido[4,5-d]pyrimidine-2,4-dione; and 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-l-ethyl- 1 H-pyrimido[4,5- d]pyrimidine-2,4-dione.

Compounds of Formula I wherein Z is N or CH may be prepared according to the syntheses outlined in Schemes 1-3. Although these schemes often indicate exact structures, those with ordinary skill in the art will appreciate that the methods apply widely to analogous compounds of Formula I, given appropriate consideration to protection and deprotection of reactive functional groups by methods standard to the art of organic chemistry. For example, hydroxy groups, in order to prevent unwanted side reactions, generally need to be converted to ethers or esters during chemical reactions at other sites in the molecule. The hydroxy protecting group is readily removed to provide the free hydroxy group. Amino groups and carboxylic acid groups are similarly derivatized to protect them against unwanted side reactions. Typical protecting groups and methods for attaching and cleaving them are described fully by Greene and Wuts in Protective

Groups in Organic Synthesis, John Wiley and Sons, New York, 2nd Ed., 1991), and McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.

Scheme 1 describes a typical method for the preparation of the bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines of the invention. The synthesis begins with 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile or 4-chloro-6- (methylthio)-3-pyridinecarbonitrile, which are readily prepared from common reactants. Displacement of the 4-chloro group with an amine in a solvent such as tetrahydrofuran (THF) in the presence or absence of a tertiary amine such as triethylamine provides the corresponding 4-amino-2-(methylthio)-5-

pyrimidinecarbonitrile or 4-amino-6-(methylthio)-3-pyridinecarbonitrile. The amine used can be anhydrous or in an aqueous solution, as with methyl or ethyl © amine, or cyclopentylamine. The use of aqueous ammonium hydroxide provides the corresponding primary amine at position 4. Reduction of the cyano group with common reducing agents such as LAH, provides the corresponding aminomethyl analog. Cyclization is accomplished by reaction with an agent such as 1,1’- carbonyldiimidazole (CDI). Oxidation of the methylthio group with an oxidant such as an oxaziridine in a solvent such as chloroform at room temperature provides the methyl sulfoxide derivative. Displacement of the sulfoxide with an amine (HoNR1D) results in formation of the corresponding 7-amino-3,4-dihydro- bicyclic pyrimidine. The temperature required for the displacement depends upon the amine used. Aromatic, secondary, and tertiary amines usually require higher temperatures than primary aliphatic or benzyl amines. When aromatic amines such as aniline are used, the reaction is usually run with the amine as the solvent at high temperatures (e.g., 80-150°C).

The bicyclic 3,4-dihydropyrimidines are readily oxidized by reaction with oxidants such as potassium fert-butoxide and oxygen to provide the corresponding bicyclic pyrimidines of the invention.

oo ~31- a =X

Zz jal oN

Z— = ®) 4 Ny SRY

Z ~ wn N @L = == oe a © 5 z= _ 0 = — ant fx, a & <| ZY = — =o 2 AA $52 2 —_ Q Z— g == =< 3 m = © N Q - I, © = agg = &| I a 74 Ny no O oO = Q 2 z= IS ° Zz ~ i = S-7 Z ~

Zz

Rs Z—

Q

~ 74 A\

N

YL = / “No

Z| <0 ~ { z=( _

T = & 4 Z— =

J No 5 2 — = Tw = » — mw , Zz. < = s a 1 = 4) 0 = o =| ET =

Scheme 1a describes a typical method for preparing bicyclic pyrimidines } of Formula I wherein R? is H and X is NHR 10. A suitably substituted 2-methylthio-5-aminomethyl-4-amino-pyrimidine is first reacted with cyanogen } bromide to effect cyclization to a dihydropyrimido pyrimidine. The methylthio group is oxidized to the sulfoxide by reaction with an oxidant such as an oxaziridine or a perbenzoic acid. The methylsulfoxide moiety is readily displaced by reaction with an amine (RINH>) to provide a 7-amino-3, 4-dihydro bicyclic pyrimidine having an amino group at the 2-position. These dihydro pyrimidines are easily converted to the corresponding aromatic pyrimidines by oxidation with common oxidants such as postossium fert-butoxide and oxygen. The 2-amino dihydropyrimidines and 2-amino pyrimidines are valuable biological agents, and also serve as intermediates, wherein the 2-amino group is derivatized by standard methods, for example alkylation or acylation, to provide compounds of Formula I where X is NHR10, e.g.

SOY.

RI-N AA A GANT

H H

. Scheme la . = Zz 3-phenyl-2-(phenyl

POS: BrCN a sulfonyl) oxaziridine x. ~ Zz >

Mes” NT NH, MeS~~ N NH,

NX NE H,NR! Qs tert-BuOK, O,

PS = PE PS Z A

MeS N NH HN N N NH \ 2 2 0 Rl

NTN N BE i 4

OJ we Ae A J Ro

HN” NT ONT NH, H H rR*c(o)cl b1 rR!

JOE 0 ~ ZZ

HN” ON AAA

H rR!

Schemes 1b and 1c describe general processes for preparing bicyclic B pyrimidines of Formula I wherein G is C. In Scheme 1b, a 2-methylthio-4-halo-5- cyano pyrimidine is reacted with an alkyl malonate in the presence of a base such as sodium hydride to provide a pyrimidyl malonate derivative. RZ groups such as 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 as sodium carbonate or triethylamine. The 5-cyano group of the pyrimidyl malonate intermediate readily reacts with a reducing agent to effect reduction to an amino methyl group, the amino of which then displaces one of the alkoxy groups of the malonate portion to effect ring closure to provide the corresponding dihydro pyridopyrimidine. Decarboxylation of the remaining malonate carboxy group is readily accomplished by reaction with a base such as an alkali hydroxide, thus affording a 2-methylthio-5,6-dihydropyridopyrimidine. The methylthio group 1s oxidized to a sulfoxide, which is then readily displaced by reaction with an amine (RINH») to give a 2-amino-5,6-dihydropyridopyrimidine. Further oxidation by reaction with an alkali metal alkoxide and oxygen provides a fully aromatic 7-hydroxy-pyridopryimidine of the formula

NT | SN

H

R2

Scheme 1b . CN ) CN CN NX

NT ethyl malonate NTS R2(hal)

PI —_—— MN P COOEt ———™ yz COOEt

MeS NZ cl NaH MeS N base MeS N z

Cc

COOEt R> COOE! reducing NT H 3-phenyi-2-(phenyl agent bh ~ H aq. KOH Me PP sulfonyl) oxaziridine > M = > MeS N ¢] >

MeS N 0 4 H 3 COOEt R

R

NTN ONE N" Sy” NH a

Ppp TRS UR enBuok.0, ML

MeS{ N [6] > i) N —_— i) N OH

Claims

CLAIMS What is claimed is: }

" 1. A compound of Formula I h RS Rr’ 3 R J ~~ NZ | “N R'—W Zz i X RZ and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; Z is Nor CH; Gis Nor CH; Wis NH, S, SO, or SO3; X is either O, S, or NR10;

RI. RZ, and R10 are independently selected from the group consisting of Co H, (CHp)pAT, CORA, (CHp)pheteroaryl, (CHp)pheterocyclyl, C1-Cy0 alkyl, C3-Cy cycloalkyl, Cy-C1g alkenyl, and C>-Cyg alkynyl, whereinn is 0, 1, 2, or 3, and the (CHp)pATr, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4RY, N(O)R4RS3, NRARSROY, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4, COR, CONRARS, SO;NRARS, SO3R%, PO3R4, aldehyde, nitrile, nitro,

ORS heteroaryloxy, T(CH2),QR4, T(CH2);C-(CHo)mQR4, h

C(O)T(CH2)mQR*, NHC(O)T(CHp)mQR4, T(CH);C(O)NR4NR?, or T(CHp),COoR4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R?, and Q is O, S, NR, N(O)R5, or NRSROY;

when the dotted line is present, R3 is absent;

otherwise R3 has the meanings of RZ, wherein R2 is as defined above, as well as OH, NR4RS, COOR4, OR4, CONR4R?, SO,NR4R5, SO3R4, PO3R4, OR>

T(CH2)mQR4, T(CH3)y C-(CH2)QR4, H wherein T and Q are as defined above;

R4 and R? are each independently selected from the group consisting of hydrogen, C-Cg alkyl, substituted alkyl, C»-Cg alkenyl, C»-Cg alkynyl, N(C1-Cgalkyl)1 or 2, (CH2)pAr, C3-Cq cycloalkyl, heterocyclyl, and heteroaryl, or R4 and RO together with the nitrogen to which they are attached optionally form a ring having

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 R# and R3 together with the nitro gen to which they are attached form a ring, the said ring is optionally substituted by 1 to 3 groups selected from OH, OR4, NR4R3, (CHy)yOR4, (CH) NR4R5,

T-(CH2)mQRyY, CO-T-(CH)QR%, NH(CO)T(CH3),,QR4, T-(CH2)y, CORA, or T(CH3); CONR4RS, RO is alkyl; : R8 and RY independently are H, C}-C3 alkyl, NR4R3, N(O)R4R5, NR4RS5R6Y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR#, CO,R4, CONR4R5, SO,NR4R5, SO3R4, PO3R4, CHO, CN, or NO»; 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.
2. A compound of Claim 1 wherein Z and G both are N, W is NH, and RS, and R? both are hydrogen.
3. A compound of Claim 2 having the formula N~ ~N R*—N N N 0) H R2
4. A compound of Claim 3 wherein R1 is phenyl or substituted phenyl, pyridyl or substituted pyridyl.
5. A compound of Claim 4 wherein RZ is an alkyl, substituted alkyl, or cycloalkyl unsubstituted or substituted.
6. A compound selected from: 1-Methyl-7-[4-(pyrazol-1-yl)phenylamino]pyrimido[4,5- d]pyrimidin-2(1 H)-one;

: oo -109- 1-Methyl-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1 H)-one; } : 1-Methyl-7-[4-(4-hydroxypiperidin-1- yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1-ylJphenylamino}- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Isopropyl-7-[4-(pyrazol-1-yl)phenylamino]pyrimido[4,5- dlpyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-methylpiperazin-1- yDphenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-hydroxypiperidin-1- yl)phenylamino]pyrimido[4,5-d}pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-[4-(dimethylamino)piperidin-1-yl}phenylamino}- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-1-yl)phenylamino]- pyrimido{4,5-d]pyrimidin-2(1 H)-one (exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1- : yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one (exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-hydroxypiperidin-1- yl)phenylaminoJpyrimido[4,5-d]pyrimidin-2(1H)-one (exo); 1-Bicyclo[2.2.1]hept-2-yl-7- {4-[4-(dimethylamino)piperidin-1- yl]phenylamino} pyrimido{4,5-d]pyrimidin-2(1 H)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-1-cyclopentyl- pyrimido[4,5-djpyrimidin-2(1H)-one; 7-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1-yl]- phenylamino}-1-cyclopentyl-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Methyl-7-{4-[4-(3-morpholin-4-ylpropy})piperidin-1- yl]phenylamino} pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Isopropyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1- yl]phenylamino} pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Cyclopentyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1- yllphenylamino} pyrimido[4,5-d]pyrimidin-2(1)-one;

-110- I 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-morpholin-4- . ylpropyl)piperidin-1-yl}phenylamino} pyrimido[4,5-d]pyrimidin-2(1 H)- one (exo); 1-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-pyrimido[4,5- dlpyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-pyrimido[4,5- d]pyrimidin-2(1H)-one; 7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino]-1-cyclopentyl- pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1 -Cyclopentyl-7-(4-piperazin-1 -yl-phenylamino)-pyrimido[4,5- d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo|3,4-c]pyrrol-2- yl)-phenylamino}-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-1-cycloheptyl- pyrimido{4,5-d]pyrimidin-2(1 H)-one; and 1-Cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-d]pyrimidin- 2(1H)-one.
7. A compound of Claim 2 having the formula N 98 N ~~ rR’ RI—N AN N A, H 5

R
8. A compound of Claim 7 wherein R1 is alkyl, pyridyl, or phenyl, each optionally substituted with hydroxy, alkoxy, NRAR3, or T(CH2)m,QRA.
9. A compound selected from: . 1-Methyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1 H)-one;

: 1-Methyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino}-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; } 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1 -yl]Jphenylamino}- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Isopropyl-7-[4-(pyrazol-1 -yl)phenylamino}-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-hydroxypiperidin-1 -yl)phenylamino}]-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 1-Isopropyl-7-{ 4-[4-(dimethylamino)piperidin-1 -yl]phenylamino}-

3.4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-1 -yl)phenylamino}-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one (ex0); 1-Bicyclo[2.2.1 Jhept-2-yl-7-[4-(4-methylpiperazin-1- yhphenylamino}-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one (exo); 1-Bicyclo[2.2.1}hept-2-yl-7- [4-(4-hydroxypiperidin-1- : yl)phenylamino]-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one (exo); 1-Bicyclo[2.2.11hept-2-yl-7-{4- [4-(dimethylamino)piperidin-1- yl]phenylamino}-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one (exo); 7-[4-(4-Aminoacetyl-piperazin-1 -y1)-phenylamino]-1-cyclopentyl- 3 4-dihydro-pyrimido[4,5-d}pyrimidin-2(1 H)-one; 7- {4-[4-(2-Amino-4-methyl-pentanoy!)-piperazin- 1-yl}- phenylamino}-1-cyclopentyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin- 2(1H)-one; 1-Methyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin-1- yl]phenylamino}-3 .4-dihydro-pyrimido[4,5-d}pyrimidin-2(1 /)-one; 1-Isopropyl-7 -{4-[4-(3-morpholin-4-ylpropyl)piperidin- 1- yl]phenylamino}-3 ,4-dihydro-pyrimido[4,5 -d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-{4-[4-(3 -morpholin-4-ylpropyl)piperidin-1- yllphenylamino}-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one;

-112- SE 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- d]pyrimidin-2(1H)-one (exo); 1-Cyclopentyl-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido(4,5- d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino]-1-cyclopentyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino}-1-cyclopentyl-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-piperazin-1-yl-phenylamino)-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-{4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl)-phenylamino]-3,4-dihydro-pyrimido[4,5-djpyrimidin-2(1 H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino}-3-(3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(1 H)- one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2-chloro- 3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin- 2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino}-3-(2,6- dichloro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido[4,5- d]pyrimidin-2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino}-3-(2-methyl- 3,5-dimethoxy-phenyl)-1 —ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin- 2(1H)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2,6- dimethyl-3,5-dimethoxy-phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5- dlpyrimidin-2(1 H)-one;

) | -113- : 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5 -dimethoxy- phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; . 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-chloro-3 9- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)- one; 7-[4-(2-Diethylamino-ethoxy)-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-(2-Diethylamino-ethoxy)-phenylamino]-3-(2-methyl-3 ,5- dimethoxy-phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)- one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3 -(2,6-dimethyl-3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrimido{4, 5-d}pyrimidin-2(1H)- one; 7-(4-Diethylamino-butylamino)-3-(3,5 -dimethoxy-phenyl)-1-ethyl- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-(4-Diethylamino-butylamino)-3-(2-chloro-3,5-dimethoxy- phenyl)-1-ethyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1H)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dichloro-3 ,5-dimethoxy- phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1)-one; 7-(4-Diethylamino-butylamino)-3-(2-methyl-3,5-dimethoxy- phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1 H)-one; 7-(4-Diethylamino-butylamino)-3-(2,6-dimethyl-3 ,5-dimethoxy- phenyl)-1-ethyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1/)-one; 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-1-ethyl-3,4- dihydro-pyrimido{4,5-d]pyrimidin-2(1)-one; 7-(Pyridin-4-ylamino)-3-(2-chloro-3 ,5-dimethoxy-phenyl)-1-ethyl- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3 ,5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H}-one; 7-(Pyridin-4-ylamino)-3-(2,6-dimethyl-3 ,5-dimethoxy-phenyl)-1- ethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one;

114- I 7-(Pyridin-4-ylamino)-3-(2-methyl-3,5-dimethoxy-phenyl)-1-ethyl-

3.4-dihydro-pyrimido[4,5-d]pyrimidin-2(1/)-one; 7-(Pyridin-4-ylamino)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- - cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino- butylamino)-3,4-dihydro-pyrimido{4,5-d]pyrimidin-2(1 H)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[{4-(2-diethylamino-ethoxy)- phenylamino]-3,4-dihydro-pyrimido[4,5-djpyrimidin-2(1 H)-one; 3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido[4,5-d]Jpyrimidin-2(1H)-one; 7-[4-(2-Diethylamino-ethoxy)-phenylamino}-3-(3,5-dimethoxy- phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido{4,5-d]pyrimidin-2(1 H)-one; and 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino- ethoxy)-phenylamino]-3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(1 H)-one.
10. A compound of Claim 2 having the formula HAN a
11. A compound selected from: 1-[7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- phenyl)-3,4-dihydro-pyrimido[4,5-d}pyrimidin-2-yl]-3-ethyl-urea; 1-{3-(2-Chloro-3,5-dimethoxy-phenyl)-7-[4-(2-diethylamino- ethoxy)-phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-y1}-3- ethyl-urea; 1-tert-Butyl-3-[7-[4-(2-diethylamino-ethoxy)-phenylamino]-3-(3,5- dimethoxy-phenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl}-urea;

: 1-tert-Butyl-3-{3-(2-chloro-3,5-dimethoxy-phenyl)-7-[4-(2- diethylamino-ethoxy)-phenylamino]-3,4-dihydro-pyrimido{4,5- : d)pyrimidin-2-yl}-urea; 1-tert-Butyl-3-[3-(3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)- 3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]j-urea; 1-[3-(3 _5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4-dihydro- pyrimido{4,5-d]pyrimidin-2-yl}-3-ethyl-urea; 1-tert-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4- ylamino)-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2-yl]-urea; 1 -[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(pyridin-4-ylamino)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2-y!]-3-ethyl-urea; 1-[3-(2-Chloro-3,5-dimethoxy-phenyl)-7-(4-diethylamino- butylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl]-3-ethyl-urea; 3-Methyl-N-{7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-3,4-dihydro-pyrimido[4,5 -d]pyrimidin-2-yl}-butyramide; 1-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-3 ,4-dihydro- pyrimido[4,5-d]pyrimidin-2-yl}-3-isopropyl-urea; and 1-tert-Butyl-3-[3-(2-chloro-3,5-dimethoxy-phenyl)-7-(4- diethylamino-butylamino)-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2-yl]- urea.
12. A compound of Claim 2 having the formula SOW RI_N"N Pl R*
13. A compound selected from: 1-[7-(4-Fluoro-phenylamino)-pyrimido [4,5-d]pyrimidin-2-y1]-3- methyl-urea; 1-Isopropyl-3-(7-phenylamino-pyrimido[4,5-d] pyrimidin-2-yl)- urea;

1-{7-[4-(3-Aminomethyl-pyrrolidin-1-yl)-phenylamino]- pyrimido{4,5-d]pyrimidin-2-yl}-3-isopropyl-urea; 1-Isopropyl-3-[7-(4-piperazin-1-yl-phenylamino)-pyrimido[4,5- d]pyrimidin-2-yl}-urea; 1-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrimido[4,5- d]pyrimidin-2-yl}-3-isopropyl-urea; N-{7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino]-pyrimido([4,5- d)pyrimidin-2-y1}-3-methyl-butyramide; N-[7-(4-Piperazin-1-yl-phenylamino)-pyrimido[4,5-d]pyrimidin-2- yl]-isobutyramide; N-{7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino}-pyrimido[4,5- d]pyrimidin-2-yl}-3-methyl-butyramide; 3-Methyl-N-[7-(pyridin-4-ylamino)-pyrimido[4,5-d]pyrimidin-2- yl]-butyramide; 1-Isopropyl-3-[7-(pyridin-4-ylamino)-pyrimido{4,5-d}pyrimidin-2- yl}-urea; and N-{7-[4-(3-Aminomethyl-pyrrolidin-1-yl)-phenylamino]- pyrimido{4,5-d]pyrimidin-2-yl}-3-methyl-butyramide.
14. A compound of Claim 1 wherein W is §, SO, or SO».
16. A compound selected from: 1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1 A- pyrimido[4,5-d]pyrimidine-2,4-dione;

: 7-[4-(2-Diethylaminoethoxy)phenylamino]-1 -isopropyl-1H- pyrimido[4,5-d]pyrimidine-2,4-dione; : 7-(4-Diethylamino-butylamino)-3-(3 ,5-dimethoxy-phenyl)-1-ethyl- 1H-pyrimido[4,5-d]pyrimidine-2,4-dione; 7-[4-(2-Diethylamino-ethoxy)-phenylamino]-3-(3,5-dimethoxy- phenyl)-1-ethyl-1 H-pyrimido[4,5-d] pyrimidine-2,4-dione; and 7-(Pyridin-4-ylamino)-3-(3,5-dimethoxy-phenyl)-l-ethyl-14- pyrimido[4,5-d]pyrimidine-2,4-dione.
17. A compound of Claim 1 wherein Z is N, Gis CH, Wis NH, and R38 and R? both are hydrogen.
18. A compound of Claim 17 having the formula Na a R Nee : RZ
19. A compound selected from: 2-[4-(3-Amino-pyrrolidin-1 -y1)-phenylamino]-8-isopropyl-8 H- pyrido[4,3-d]pyrimidin-7-one; 8-Cyclopentyl-2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- phenylamino]-8 H-pyrido[4,3-d]pyrimidin-7-one; 2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino] -8-cyclopentyl-8H- pyrido[4,3-djpyrimidin-7-one; N-{2-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-8- cyclopentyl-pyrido[4,3-d]pyrimidin-7-y1}-2,2-dimethyl-propionamide; and N-(2-{4- [4-(2-Amino-4-methyl-pentanoyl)-piperazin-1 -yl]- phenylamino}-8-cyclopentyl-pyrido[4,3-d]pyrimidin-7-y1)-2,2-dimethyl- propionamide.

-118- oo :
20. A compound of Claim 1 wherein Z is CH, G is N, W is NH, and R8 and . RY both are hydrogen.
21. A compound of Claim 20 having the formula N7 SN LJ ba
22. A compound selected from: 1-(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d}pyrimidin-2(1 H)-one; 1-(Thiophen-~2-yl1)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d}pyrimidin-2(1 H)-one; 1-(Thiophen-2-ylmethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido{4,3-d]pyrimidin-2(1H)-one; 1-(Hexa-2,4-diene-1-yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Prop-2-yne-1-yl)-7-[4-(4-methylpiperazin-1- yDphenylamino]pyrido[4,3-djpyrimidin-2(1 H)-one; 1-[3-(Dimethylamino)prop-1-yl}-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(3-Hydroxyprop-1-yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(3,5-Dimethylhept-1-yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]pyrido[4,3-d]pyrimidin-2(1 H)-one;

‘ 1-Cyclopentyl-7-(4-piperazin-1 -ylphenylamino)pyrido(4,3- d]pyrimidin-2(1H)-one; and 7-[4-(3-Aminopyrrolidin-1-yl)phenylamino]-1- cyclopentylpyrido[4,3-d]pyrimidin-2(1 H)-one.
23. A compound of Claim 20 having the formula RN SN Lo
24. A compound selected from: 1-(2-Benzyloxyethyl)-7-[4-(4-methylpiperazin-1 -y)phenylamino}- 3,4-dihydro-pyrido[4,3-d]pyrimidin-2(1H)-one; 1-(Thiophen-2-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino]-3,4- dihydro-pyrido[4,3-d)pyrimidin-2(1 H)-one; 1-(Thiophen-2-ylmethyl)-7 -[4-(4-methylpiperazin-1- yl)phenylamino]-3,4-dihydro-pyrido{4.3 -d]pyrimidin-2(1 H)-one; 1 -(Tetrahydrofuran-2-yl)-7-[4-(4-methylpiperazin- 1- yl)phenylamino]-3 ,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-(Hexa-2,4-diene-1-y1)-7-[4-(4-methylpiperazin-1- yl)phenylamino]-3,4-dihydro-pyrido[4.3 -d]pyrimidin-2(1 H)-one, 1-(Prop-2-yne-1-yl)-7-[4-(4-methylpiperazin-1 -yl)phenylamino}-

3.4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one; 1-[3-(Dimethylamino)prop-1-yl] -7-[4-(4-methylpiperazin-1- yl)phenylamino]-3,4-dihydro-pyrido[4,3 -d]pyrimidin-2(1 H)-one; 1-(3-Hydroxyprop-1-yl)-7- [4-(4-methylpiperazin-1- yl)phenylamino]-3,4-dihydro-pyrido[4,3 ~-d]pyrimidin-2(1 H)-one; 1-(Pyridin-4-ylmethyl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]-3,4-dihydro-pyrido[4,3-d]pyrimidin-2( 1H)-one; 1-(3,5-Dimethylhept-1 -yl)-7-[4-(4-methylpiperazin-1- yl)phenylamino]-3 ,4-dihydro-pyrido[4,3-d]pyrimidin-2(1 H)-one;

PCT/US99/10187 3-(3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1-ethyl-3,4- ] dihydro-pyrido({4,3-d]pyrimidin-2(1 A)-one; 3-(2-Chloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1- ethyl-3,4-dihydro-pyrido(4,3-d]pyrimidin-2(1 H)-one; 3+(2,6-Dichloro-3,5-Dimethoxy-phenyl)-7-(pyridin-4-ylamino)-1- ethyl-3,4-dihydro-pyrido(4,3-d]pyrimidin-2( 1 A)-one; 3-(2-Methyl-3,5-Dimethoxy-pheny!)-7-(pyridin-4-ylamino)-1- = ethyl-3,4-dihydro-pyrido(4,3-d]pyrimidin-2(1 A)-one: 3-(2,6-Dimethyl-3,5-Dimethoxy-pheny!)-7-(pyridin-4-ylamino)-1 - ethyl-3,4-dihydro-pyrido(4.3-d]pyrimidin-2(1 &)-one; 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(3,5- dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4.3-d]pyrimidin-2(1 A)- one; 7-(4-(4-Aminoacetyl-piperazin- 1 -yl)-phenylamino]-3-(2-chloro-

3.5-dimethoxy-phenyl}-1-ethyl-3 ,d-dihydro-pyrido[4,3-d]pyrimidin- 2(1H)-one; 7-{4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2,6- dichloro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3- d]pyrimidin-2(1 H)-one; 7-{4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-3-(2-methyi-

3.5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-pyrido[4,3-d}pyrimidin- 2(1H)-one; and : 7-[4-(4-Aminoacetyl-piperazin-1-y1)-phenylamino]-3-(2,6- dimethyl-3,5-dimethoxy-phenyl)- 1 -ethyl-3,4-dihydro-pyrido[4,3- dpyrimidin-2(1 H)-one.
25. Use of a compound of Formula I 8 RS 3 See RI-w Az EN X . R* AMENDED SHEET oo R © pCTiuseonolsT 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; Wis NH, S, SO, or S05; . X is either O.

S, or NR1O; R1, R2, and R10 are independently selected from the group consisting of H, (CHa)gAr.

COR%, (CHy)gheteroaryl, (CHa)qheterocyclyl, ) C1-Cyp alkyl, C3-C1o cycloalkyl, C>-Cyg alkenyl, and C7-Cyy alkynyl, whereinn is 0, 1, 2, or 3, and the (CHy)pAr, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 3 groups selected from NR4R3. N(O)R*R3, NR4R3ROY, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo.

COR4, COoR#, CONR4RY, SOoNR4R3, SO5R%, PO3R4, aldehyde, nitrile, nitro, OR3 _ heteroaryloxy, T(CH2)mQR#, T(CH2);mC-(CH2)MQRA, H : C(O)T(CH7)mQR4, NHC(O)T(CH2)mQR4, T(CH2)mC(O)NRANR3, or T(CH7)py CO7R4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R#4, NR4R6Y, or CR4R3, and Qis O, S, NR, N(O)R3, or NRSROY; when the dotted line is present, R3 is absent; otherwise R3 has the meanings of R2, wherein R2 is as defined above, as well as OH, NR4R3, COOR#, OR4, CONR4R3, SOoNR4RS, SO3R4, PO3RY, AMENDED SHEET

PCT/US99/10187

OR3 T(CH2)mQR#*, T(CH2)pmC-(CH2)m QRS, H wherein T and Q are as defined above; R4 and R35 are each independently selected from the group consisting of hydrogen, C-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C,-Cg alkynyl, N(C1-Cgalkyl)] or 2. (CH2)qAT, C3-Cjo cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R? together with the nitrogen to which they are attached opuonally form a ring having “3 to 7 carbon atoms and said ring optionally contains I, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur; when R% and R3 together with the nitrogen to which they are antached ~ form a ring, the said ring is optionally substituted by 110 3 groups selected from OH, OR#, NR4R3, (CH); OR4, (CH) NR4RS, T-(CH)mQR4, CO-T-(CH2)mQR#, NH(CO)T(CH)QR?, T-(CH2);nCO2R4, or T(CH); CONRARS.

RS is alkyl; . R8 and RY independently are H, C}-C3 alkyl, NR4RS, N(O)R4RS, NR4R3ROY, hydroxy, alkoxy, thiol, thicalkyl, halo, COR4, CO2R#, CONR4R3, SO;NR4R3, SO3R4, PO3R4, CHO, CN, or NO»; when the dotted line is absent, R? is additionally carbonyl. thiocarbonyl, imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion, in the manufacture of a medicament for controlling proliferative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliferation associated with a disorder selected . AMENDED SHEET

) PCT/US99/16187 - 122a - from the group consisting of atherosclerosis, postsurgical vascular stenosis, and restenosis in mammals, diabetic retinopathy and angiogenesis. )
26. A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of Forumula I R3 N ~~ N N ~-N I 1 ML - A } R*=-W yA G, X - R= 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; Wis NH, S, SO, or SOy; X is either O, S, or NRO, BN

. PCT/USIONOIST oo

R! R2, and R!0 are independently selected from the group consisting of - H, (CHp)pAr, COR#, (CHp)pheteroaryl, (CHa)pheterocyclyl, C1-Cyg alkyl, C3-C cycloalkyl, C»-C1g alkenyl, and C»-Cq alkynyl, wherein n is 0, 1, 2, or 3, and the (CH)pAT, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4R3, N(O)R4RS5, NR4RSR6Y, alkyl, phenyl, substituted phenyl, } (CH»)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, ] COR4, CO;R#, CONR4R3, SO;NR4R3, SO3R4, PO3R4, aldehyde, nitrile, nitro, ors heteroaryloxy, T(CH2)mQR#, T(CH2)mC-(CH2)mQR4, : : C(O)T(CHp)mQR?, NHC(O)T(CHmQR#, T(CH2)y C(O)NRANRS, or T(CH2)mCO2R* wherein each m is independently 1-6, T is O, S, NR4, N(O)R#, NR4RY, or CR4RJ, and Q is O, S, NR3, N(O)RS, or NRROY; when the dotted line is present, R3 is absent; otherwise R3 has the meanings of R2, wherein R2 is as defined above, as well as OH, NR4R3, COOR4, OR4, CONR4R3, SOZNRAR3, SO3R%4, PO3R4, AMENDED SHEET

. PCT/US99/10187 OR? T(CH2)mQR?, T(CH2)mC-(CH2)mQR4, wherein T and Q are as defined above; R#4 and RY are each independently selected from the group consisting of : hydrogen, C1-Cg alkyl, substituted alkyl, C3-Cg alkenyl, C>-Cg alkynyl, N(C;-Cgalkyl)] or 2: (CHa)pAr, C3-Cq cycloalkyl, heterocyclyl, and heteroaryl, or R4 and RS together with the } nitrogen to which they are attached optionally form a ring having - 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 RS 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, NR4R3, (CH) OR4, (CHo)mNR4R7, T-(CH))mQR4, CO-T-(CH2);QR4, NH(CO)T(CH)mQR4, T-(CH2);mCO4R4, or T(CH2) CONRARS. RS is alkyl; oo R8 and RY independently are H, C1-C3 alkyl, NR4R5, N(O)R4R3, NR4RSROY, hydroxy, alkoxy, thiol, thioalkyt, halo, COR%, COoR4, CONR4R3, SOoNR4R3, SO3R4, PO3R4, CHO, CN, or NO2; when the dotted line is absent, R® is additionally carbonyl, thiocarbonyl, imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion.
27. A method of Claim 26 wherein said cyclin-dependent kinase is cdc2.
28. A method of Claim 26 wherein said cyclin-dependent kinase is cdk2. AMENDED SHEET

. PCT/US99/10187
29. A method of Claim 26 wherein said cyclin-dependent kinase is cdk4 or : cdk®. ]
30. A method of inhibiting a growth factor-mediated tyrosine kinase comprising contacting said growth factor-mediated kinase with a compound of Formula I 8 rR? ' R3- - IN ~~ N IAN ~~N I R'=W Z G, X .. } : R* and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; - " ZisNorCH; R Gis Nor CH; Wis NH, §, SO, or SO9; ] X is either O, S, or NR!1O: R1,R2, and R10 are independently selected from the group consisting of H, (CHp)pAr, COR4, (CH2)pheteroaryl, (CH»)pheterocyclyl,” C1-Cyo alkyl, C3-Cy cycloalkyl, C2-C1g alkenyl, and C7-Cy alkynyl, wherein nis 0, 1, 2, or 3, and the (CH2)pAr, (CHp)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4R3, N(O)R4R3, NR4RR6Y, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR%4, CO9R4, CONR4R3, SOoNR4R3, SO3R#4, PO3R4, aldehyde, nitrile, nitro, AMENDED SHEET

. PCT/US99/10187 OR? heteroaryloxy, T(CH)mQR#, T(CH2)mC-(CH2)mQR4, H C(O)T(CH2);mQR?, NHC(O)T(CH2)mQR4, T(CH2)mC(O)NRANR?, or T(CH2);mCO2R# wherein each m is independently 1-6, T is O, S, NR%, N(O)R#, NR4ROY, or CR4R?, and Q is O, S, NR, N(O)R3, or NRIROY; when the dotted line is present, R3 is absent; otherwise R3 has the meanings of R2, wherein R2 is as defined above. as well as OH, NR4R5, COOR#4, OR4, CONR4R3, SO2NR4R?, SO3R4, PO3R4, OR> T(CH2)mQR?, T(CH2)mCCH2)mQR?, : BE H wherein T and Q are as defined above; R4 and RS are each independently selected from the group consisting of hydrogen, C1-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C2-C¢ alkynyl, N(C1-CgalkyD)j or 2, (CH2)nAr, C3-Cyg cycloalkyl, ‘heterocyclyl, and heteroaryl, or R% and R3 together with the nitrogen to which they are attached optionally form a ring having 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 R#4 and RS 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, OR%, NR4R3, (CH2)pOR?, (CH2)mNRAR3, AMENDED SHEET

” PCT/US99/10187 T<(CH2)mQR4, CO-T-(CH2)mQR*, NH(CO)T(CH)QR%, T-(CH2)mCO2R4, or T(CH)CONRARS. Ris alkyl; R8 and RY independently are H, C1-C3 alkyl, NR4R3, N(O)R4RS3, NRA4R3ROY, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO,R#4, CONRARS, SOoNRAR?, SO3R4, PO3R4, CHO, CN, or NO»; . | when the dotted line is absent, R? is additionally carbonyl, thiocarbonyl, } imine and substituted imine, oxime and oxime ether, and Y is a halo counter-ion. -
31. A method of Claim 30 wherein said growth factor-mediated tyrosine kinase is platelet derived growth factor (PDGF). ]
32. A method of Claim 30 wherein said growth factor-mediated tyrosine kinase is fibroblast growth factor (FGF).
33. A method of Claim 30 wherein said growth factor-mediated tyrosine ) kinase is vascular endothelial growth factor (VEGF). :
34. A method of inhibiting a non-receptor tyrosine kinase comprising contacting said non-receptor tyrosine kinase with 2 compound of ; Formula 8 rR? 3

R . D yd N AS ~N 1 R'=-W Zz G, X R and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; AMENDED SHEET

. PCT/US99/10187

Z is N or CH; GisNor CH; W is NH, S, SO, or SO7; X is either O, S, or NR 10; R1,R2 and R10 are independently selected from the group consisting of H, (CHa)qAr, CORY, (CHy)pheteroaryl, (CHp)gheterocyclyl, C1-Cjq alkyl, C3-Cj cycloalkyl, C2-Cq alkenyl, and C2-Cy alkynyl, wherein nis 0, 1, 2, or 3, and the (CH)pAr, (CH»p)pheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 3 groups selected from NR4R3, N(O)R4R3, NR4R3R6Y, alkyl, phenyl, substituted phenyl, (CHp)pheteroaryl, hydroxy, -alkoxy, phenoxy, thiol, thioalkyl, halo, ‘COR4, CO7R%, CONR4RS, SOoNR4R3, SO3R4, PO3R?, - aldehyde, nitrile, nitro, ORS5 heteroaryloxy, T(CH2)mQR?, I — C(O)T(CH2)mQR%, NHC(O)T(CH2)mQR4, T(CH2)C(O)NRANRS, or T(CH)y CO2R# wherein each mis independently 1-6, T is O, S, NR4, N(O)R4, NR4RSY, or CR4RS, and Qis O, S, NR, N(O)R3, or NRSROY; when the dotted line is present, R3 is absent; otherwise R3 has the meanings of R2, wherein R2 is as defined above, as well as OH, NR4R5, COOR#, OR4, CONR4R3, SOoNR4RS, SO3R4, PO3RY, AMENDED SHEET

“ PCT/US99/10187 ORS T(CH2)mQR*, T(CH2)mC-(CH2)mMmQR?, H wherein T and Q are as defined above; R# and R3 are each independently selected from the group consisting of : hydrogen, C-Cg alkyl, substituted alkyl, C2-Cg alkenyl, C2-Cg alkynyl, N(C1-Cgalkyl)| or 2, (CH2)pAr, C3-C1q cycloalkyl, heterocyclyl, and heteroaryl, or R#4 and RS together with the nitrogen to which they are attached optionally form a ring having : 3 to 7 carbon atoms and said ring optionally contains 1, 2, or i 3 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 form a ring, the said ring is optionally substituted by I to 3 groups selected from OH, OR4, NR4R3, (CH»)mOR#4, (CH) NR4RJ, } T-(CH2)mQRY, CO-T«(CH2)QR4, NH(CO)T(CH2),QRY, T«(CH2)rCO2R4, or T(CH)yy CONRARS. RS is alkyl; R8 and R? independently are H, C1-C3 alkyl, NR¥RJ, N(O)R4R3, : NR4RSROY, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO-R4, CONR4R3, SO)NR4R3, SO3R4, PO3R4, CHO, CN, or NOy; when the dotted line is absent, R? is additionally carbonyl, thiocarbonyl, imine and substituted imine, oxime and oxime ether, and . Y is a halo counter-ion.
35. A method of Claim 34 wherein said non-receptor tyrosine kinase is selected from a transforming gene of the Rous sarcoma retrovirus (Src) family. AMENDED SHEET

- PUL/USYY/ 1018 /
36. A method of inhibiting a serine kinase in a mammal comprising administering a serine kinase inhibiting amount of a compound of Claim 1.
37. Use of a compound as claimed in Claim 1 in the manufacture of a medicament for treating a subject suffering from diseases caused by vascular smooth muscle cell proliferation.
38. Use of a compound as claimed in Claim 1 in the manufacture of a medicament for treating a subject suffering from cancer.
39. A method of inhibiting angiogenesis in a mammal comprising administering an anti-angiogenic effective amount of a compound of Claim 1. -
40. Use of a compound as claimed in Claim 1 in the manufacture of a medicament for treating a disease state caused by angiogenesis, wherein the disease state is selected from human cancer, macular degeneration, diabetic retinopathy, surgical adhesions, and psoriasis.
41. A method of inhibiting 2 wee-1 kinase enzyme in a mammal comprising oo administering a wee-1 kinase inhibiting amount of a compound of Claim 1.
42. A compound selected from: oC 7-[53-(Carboxy)-phenylamino]-3-(2,6-dichloro-phenyl)-1-methyl- 3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(1 H)-one; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6- dichloro-phenyl)-1-methyl-3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(1 A)- ore; 7-[3-(N-Dimethylaminopropyl-carboxamide)-phenylamino]-3-(2,6- dichloro-3-hydroxy-phenyl)-1-methyl-3.4-dihydro-pyrimido[4,5- dlpyrimidin-2(1 H)-one; 7-[3-(Carboxy)-phenylamino}-3-(2,6-dichloro-3-hydroxy-phenyl)- 1-methyl-3,4-dihydro-pyrimido{4,5-d]pyrimidin-2(1 H)-one; AMENDED SHEET

: PCT/US99/10187 3-(2,6-Dichloro-phenyl)-7-[4-(2-ethylamino-ethoxy)- phenylamino}-1-methyl-3 ,4-dihydro-pyrimido[4,5-d]pyrimidin-2( 1 H)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(2-ethylamino-ethoxy)- phenylamino}-1-methyl-3 »4-dihydro-pyrimido(4,5-d]pyrimidin-2( 1 H)-one; 7-[4-(Carboxamide)-phenylamino] -3-(2,6-dichloro-phenyl)-1- methyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one; : 7-[4-(Carboxamide)-phenylamino]-3-(2,6-dichloro-3-hydroxy- phenyl)-1-methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one: 3-(2,6-Dichioro-phenyl)-7-(3-hydroxymethyl-phenylamino)- I- - methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 A)-one; - 3-(2,6-Dichloro-phenyl)-7-(4-morpholin-4-yl-phenylamino)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 3-(2,6-Dichloro-3-hydroxy-phenyl)-1 -methyl-7-(4-morpholin-4-yl- BN phenylamino)-3,4-dihydro-pyrimido(4,5-d]pyrimidin-2(1 A)-one: _ : 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-(3-hydroxymethyl- phenylamino)-1-methyl-3,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 H)-one; - 7-[4~(3-Carboxypropyl)-phenylamino]-3~(2,6-dichloro-phenyl)-1 - methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 H)-one; 7-[4-(3-Carboxypropy!)-phenylamino]-3-(2,6-dichloro-3-hydroxy- - phenyl)-1-methyl-3 ,4-dihydro-pyrimido [4,5-d]pyrimidin-2(1 A)-one; 3-(2,6-Dichloro-phenyl)-7-[4-(formyl-phenylamino}- 1-methyl-3,4- _ dihydro-pyrimido[4,5-d}pyrimidin-2(1H)-ore; and 3-(2,6-Dichloro-3-hydroxy-phenyl)-7-[4-(formyl-phenylamino}- 1- ] methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1 A)-one.
43. A pharmaceutical formulation comprising a compound of Claim 1 in combination with a pharmaceutically acceptable carrier, diluent, or excipient. AMENDED SHEET

- PCT/US99/10187
44. Use of a compound of Formula I as defined in Claim 26, in the manufacture of a medicament for inhibiting a cyclin-dependent kinase.
45. Use according to Claim 44 wherein said cyclin-dependent kinase is cdc2.
46. Use according to Claim 44 wherein said cyclin-dependent kinase is cdk2. :
47. Use according to Claim 44 wherein said cyclin-dependent kinase is cdk4 or cdk6. -
48. Use of a compound of Formula I as defined in Claim 30, in the manufacture of a medicament for inhibiting a growth factor-mediated tyrosine kinase.
49. Use according to Claim 48 wherein said growth factor-mediated tyrosine kinase is platelet derived growth factor (PDGF).
50. Use according to Claim 48 wherein said growth factor-mediated tyrosine Kinase is fibroblast growth factor (FGF).
51. Use according to Claim 48 wherein said growth factor-mediated tyrosine kinase is vascular endothelial growth factor (VEGF).
52. Use of a compound of Formula I as defined in Claim 34, in the Co manufacture of a medicament for inhibiting a non-receptor tyrosine kinase. : AMENDED SHERT

; PCT/US99/10187
53. Use according to Claim 52 wherein said non-receptor tyrosine kinase is selected from a transforming gene of the Rous sarcoma retrovirus (Src) family.
54. Use of a compound as claimed in Claim 1 in the manufacture of a medicament for inhibiting a serine kinase in a mammal.
55. Use of a compound as claimed in Claim 1 in the manufacture of a medicament for inhibiting angiogenesis in a mammal.
56. Use of a compound as claimed in Claim 1 in the manufacture of a ’ medicament for inhibiting a wee-1 kinase enzyme in a mammal. )
57. A substance or composition for use in a method for controlling : proliferative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliferation associated with a disorder selected from the group consisting of atherosclerosis, postsurgical vascular stenosis, and restenosis in mammals, diabetic retinopathy and angiogenesis, said substance or composition comprising a compound of Formula I as defined in Claim 235, and said method comprising administering to said mammal a therapeutically effective amount of said substance or composition.
58. A substance or composition for use in a method of inhibiting a cyclin- dependent kinase, said substance or composition comprising a compound of Formula I as defined in Claim 26, and said method comprising contacting the cyclin-dependent kinase with said substance or composition.
59. A substance or composition for use in a method according to Claim 58 wherein said cyclin-dependent Kinase is cdc2. AMENDED SHEET

‘ PCT/US99/10187
60. A substance or composition for use in a method according to Claim 58 wherein said cyclin-dependent kinase is cdk2.
61. A substance or composition for use in a method according to Claim 58 wherein said cyclin-dependent kinase is cdk4 or cdk6.
62. A substance or composition for use in a method of inhibiting a growth factor-mediated tyrosine kinase, said substance or composition comprising a compound of Formula I as defined in Claim 30, and said method comprising contacting said growth factor-mediated kinase with said substance or composition. oC
63. A substance or composition for use in a method according to Claim 62 wherein said growth factor-mediated tyrosine kinase is platelet derived growth factor (PDGF).
64. A substance or composition for use in a method according to Claim 62 wherein said growth factor-mediated tyrosine kinase is fibroblast growth factor (FGF).
65. A substance or composition for use in a method according to Claim 62 wherein said growth factor-mediated tyrosine kinase is vascular endothelial growth factor (VEGF). :
66. A substance or composition for use in a method of inhibiting a non- receptor tyrosine kinase, said substance or composition comprising a compound of Formula I as defined in Claim 34, and said method comprising contacting said non-receptor tyrosine kinase with said substance or composition. AMENDED SHEET

. PCT/US99/10187
67. A substance or composition for use in a method according to Claim 66 wherein said non-receptor tyrosine kinase is selected from a ] transforming gene of the Rous sarcoma retrovirus (Src) family.
68. A substance or composition for use in a method of inhibiting a serine kinase in a mammal, said substance or composition comprising a compound as claimed in Claim 1, and said method comprising ] administering a serine kinase inhibiting amount of said substance or composition.
69. A substance or composition for use in a method of treating a subject ~ suffering from diseases caused by vascular smooth muscle cell : proliferation, said substance or composition comprising a compound as _ claimed in Claim 1, and said method comprising administering to said subject, a therapeutically effective amount of said substance or composition.
70. A substance or composition for use in a method of treating a subject suffering from cancer, said substance or composition comprising a compound as defined in Claim 1, and said method comprising administering to said subject, a therapeutically effective amount of said substance or composition.
71. A substance or composition for use in a method of inhibiting angiogenesis in a mammal, said substance or composition comprising a compound as claimed in Claim 1, and said method comprising administering an anti-angiogenic effective amount of said substance or composition.
72. A substance or composition for use in a method according to Claim 71 for treating a disease state caused by angiogenesis, wherein the disease AMENDED SHEET

PCT/US99/10187 state is selected from human cancer, macular degeneration, diabetic retinopathy, surgical adhesions, and psoriasis.
73. A substance or composition for use in a method of inhibiting a wee-1 kinase enzyme in a mammal, said substance or composition comprising a compound as claimed in Claim 1, and said method comprising administering a wee-1 kinase inhibiting amount of said substance or composition.
74. A compound according to any one of Claims, 1, 6, 9, 11, 13, 16, 19, 22, 24 or 42, substantially as herein described and illustrated. ]
75. Use according to any one of Claims 25, 37, 38, 44, 48, 52, 54, 55 or 56, substantially as herein described and illustrated.
76. A method according to any one of Claims 26, 30, 34, 36, 39 or 41, substantially as herein described and illustrated.
77. A pharmaceutical formulation according to Claim 43, substantially as herein described and illustrated.
78. A substance or composition for use in a method of treatment according to any one of claims 57 to 73 substantially as herein described and illustrated.
79. A new compound; new use of a compound of Formula I as defined in any one of Claims 1, 25, 26, 30 or 34; a new method of inhibiting a kinase, or inhibiting angiogenesis; a new non-therapeutic method of treatment; a new pharmaceutical formulation; or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET