OA12227A

OA12227A - 5-AlkylpyridoÄ2,3-DÜpyrimidines tyrosine kinase inhibitors.

Info

Publication number: OA12227A
Application number: OA1200200281A
Authority: OA
Inventors: Richard John Booth; Ellen Myra Dobrusin; Peter Laurence Toogood; Scott Norman Vanderwel
Original assignee: Warner Lambert Co
Priority date: 2000-03-06
Filing date: 2001-01-29
Publication date: 2004-03-18
Also published as: YU66502A; TNSN01036A1; AR034119A1; SK12472002A3; AU2001233028A1; HUP0300136A2; SV2001000338A; NO20024235D0; IL151480A0; CN1422268A; PL358271A1; BR0109056A; EE200200506A; MA26881A1; HRP20020798A2; EP1268476A1; NZ520962A; CA2401368A1; GT200100037A; ZA200207110B

Abstract

Disclosed are compounds of the formula (I) wherein: R<2> is hydrogen, alkyl, or cycloalkyl; R<3> is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR<4>, -CO2R<4>, -CONR<4>R<5>, -CONR<4>OR<5>, -SO2NR<4>R<5>, -SO2NR<4>R<5>, -SO2R<4>, -SO3R<4>, formula (II), or -NR<4>R<5>; Y is N or CR<7>; R<9> is lower alkyl, haloalkyl, or aryl; X and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitrile, nitro, -NR<4>R<5>, -N(O)R<4>R<5>, -NR<4>R<5>R<6>W, -SR<4>, -C(O)R<4>, -CO2R<4>, -CONR<4>R<5>, -SO2NR<4>R<5>, -SO2R<4>, -SO3R<4>, P(O)(OR<4>)(OR<5>), -T(CH2)mQR<4>, -C(O)T(CH2)mQR<4>, or -NR<4>C(O)T(CH2)mQR<5>; m is 1 to 6. These compounds are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, and restenosis. These compounds are potent inhibitors of cyclin-dependent kinases (cdks) and growth factor-mediated kinases.

Description

-1- 012227

5-ALKYLPYRIDO[2,3-d]PYRIMIDINES TYROSINE KINASE INHIBITORS

FÎELD OF THE INVENTION

This invention relates to 5-alkylpyridopyrimidmes as inhibitors of cyclin-dependent kinases, particuîarly cycïin-dependent kinase 4. The compounds of theinvention are usefol for the treatment of inflammation, cell proliférative diseasessuch as cancer and restenosis, and neurodegenerative diseases such asAlzheimer’s disease.

SUMMARY OF THE KELATED ART

Cyclin-dependent kinases and related serine/threonine protein kinases arecellular enzymes that perforai essentiel fonctions in regulating cell division andprolifération The cyclin-dependent kinase caîalytic units, of whicli nine hâve beenidentified, are activated by regulatory units known as cyclines. The cyclin-dependent kinases include (Cdk) Cdkl, Cdk2, Cdk4, Cdk5, Cdk6, and Wee-1 kinase. Increased activity or temporally abnormal activation of these kinasesresults in development of human tumors and other proliférative disorders such asrestenosis. Compounds that inhibit Cdks, either by blocking the interactionbetween a cyclin and ils kinase partner, or by binding to and inactivating thekinase, cause inhibition of cell prolifération and thus are usefol for treating tumorsand other abnonnally proliferating cells.

Severaî compounds that inhibit Cdks hâve demonstrated both preclinicaland clinical anti-tumor activity. For example, flavopiridoî is a fiavonoid that is apotenî inhibitor of Cdk2 and Cdk4, and has been shown to inhibit several types ofbreast and lung cancer cells (Kaur et al., J. Natl. Cancer Inst., 1992;84:1736-1740;Kaur et al., Int. J. Oncol., 1996;9:1143-1168). In addition, Olomoucine[2-(hydroxyethylamine)-6-benzylamine-9-methylpurine} is a potent inhibitor ofCdk2 and Cdk5 (Vesely étal., Eta-. J. Biochem., 1994;224:771-786), and has beensbown to inhibit prolifération of approximateîy 60 different human turaor cell 012227 -2-

Unes used by the National Cancer Institute (NCI) to screen for new cancerthérapies (Abrahamétal., Biol. Cell, 1995;83:105-120).

In addition to treating cancer, Cdk inhibitors hâve been shown to trcaxcardiovascular disorders such as restenosis and alherosclerosis. Other diseases in 5 which Cdk inhibitors are useful include those caused by a variety of infectiousagents, inclnding DNA and RNA viruses, and inflammatory disorders such asrheumatoid arthritis.

An object of this invention is to provide a group of small molecular weightorganic compounds thaï are potent Cdk inhibitors, and as such are useful for 10 preventing and treating diseases caused by abnormally proliferating cells.

SUMMARY OF THE INVENTION

This invention provides 5-alkyl pyridopyrimidines that arc useful fortreating inflammation, cell proliférative diseases such as cancer and restenosis,and neurodegenerative diseases such as Alzheimer’s disease. The compounds of 15 the invention displav unexpected improvements in phannacokinetic propertiesover prior art compounds, including unanticipated metabolic stability and lowclearance rates. In addition, the compounds of the invention are unexpectedlysélective inhibitors of Cdk4. The compounds of the invention are readilysynthesized, and can be administered to patients by a variety of methods. 20 The compounds of the invention are those having the structure of

Formula I: and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,wherein: 25 r2 is (a) hydrogen; 012227 -3- (b) lower alkyl optionalîy substituted with one, îwo, or ihree groupsindependently seiected from halogen, hydroxy, lower alkoxy,amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, îhioalkyl» nitriîe, aryl, heteroaryl, or a carbocyclic group containingfrom 3 to 7 members, up to two of which members are optioaallyheteroatoms independently seîecîed from oxygen, sulfur, andnitrogen; or (c) a carbocyclic group containing from 3 to 7 members, up to two ofwhich members are optionalîy heteroatoms independently seiectedfrom oxygen, sulfur, and nitrogen, wherein the carbocyclic group isunsubstituted or substituted with one, two, or three groupsindependently seiected from halogen, hydroxy, lower alkyl, loweralkoxy, amino, mono- or dialkylamino, aryl, and heteroaryl; is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, loweralkynyl, lower alkenyl, nitrite, nitro, -COR4, -CO2R4, -CONR4RACONOR5, -SÛ2NR4R5, -SO2R4, -SO3R4, P(O)(OR4){OR5), or

I R4 -NR4R5; Y is N or CR7; R9 is lower alkyl, haloalkyl, or aryl; X and Z are independently hydrogen, halogen, lower alkyl. lower alkoxy,trifluoromethyl, hydroxy, nitrite, nitro, -NR4R^. -N(O)R4R5,-NR4R5R6W, -SR4, -C(O)R4, -CO2R4, -CONR4R5, -SO2NR4R5,-SO2R4, -SO3R4, P(O)(OR4)(OR5), -T(CH2)mQR4, -C(O)T(CH2)mQR4 or-NR4C(O)T(CH2)mQR5; m is 1-6; n is 0-6; T is O, S, NR4, N(O)R4, NR4R5W, or CR4R5; Q is O, S, NR4. N(O)R4, NR4R^W, CO2, or a carbocyclic group containing from3 to 7 members, up to four of which members are optionalîy heteroatoms 01 2227 independently selected from oxygen, sulfur, and nitrogen, wherein thecarbocyclic group is unsubstituted ôr substituted with one, two, or threegroups independently selected from halogen, hydroxy, hydroxyalkyl,loweralkvl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl,alkylcarbonylamino, aminoalkyl, trifiuoromethyl, N-hydroxyacetamide,trifluorome&ylalkyl, amino, or mono or dialkylamino; R.6 is lower alkyl, haloalkyl, or aryl; R7 is NR4R5, N(O)R4R5, NR4r5r9x, OH» OR4, SR4, halo, COR4, (CH2)nR4, CO2R4, CONR4R5, C(O)NR4SO2r5» S(O)R4, SO2R4, so2nr4r5, SO3R4, (CH2)nP(O)(OR4)2, NR4SO2R5, aldéhyde, nitrile, nitro, alkyl,alkoxyalkyl, TCCH^QR4, CCOWCHj^QR4 NR^OJTCCH^QRS,orTCCH^CO^4; W is an anion; R4 and R$ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl,(CH2)nAr, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl, or R4 and R^ together with the nitrogen towhich they are attached fonn a carbocyclic ring containing 3 toS members, up to four of which members are optionally carbonyl groups ·or heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2,and nitrogen, wherein the carbocyclic group is unsubstituted or substitutedwith one, two, three, or four groups independently selected from halogen,hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl,trifiuoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl,amino, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl,carboxyalkyl, NR1 OSOoR11, C(O)NR! °Rj 1, NR* °C(O)Rl 1, C(O)ORl°,C(O)NR10SO2Rll, (CH2)nS(O)nRl°, (CH2)n-heteroaryl, O(CH2)n-heteroaryl, (CH^C^NRl ÛRl 1,0(CH2)nC(O)0Rl°; 012227 10 -5- and additionally can be lower alkyl unsubstituted or substituted with one, two,orthree groxçs independently selected from halogen, 5-oxo-4,5-dihydro-1J5T-1,2,4-triazol-3-yl-sulfanyl, 5-oxo-4,5-dihydro-l/M,2,4-triazoI-3-yl-sulfînyl, 5-oxo-4,5-dihydro-l/M,2,4-triazol-3-yl-sulfonyl, or acarbocyclic group containing from 3 to 7 members, up to four of whichmembers are optionally heteroatoms independenîly selected from oxygen,sulfur, and nitrogen, wherein die carbocyclic group is unsubstituted orsubstituted witb one, two, or three groups independenîly selected fromhalogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyî, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,triîluoromethyb N-hydroxyacetamide, trifluoromethylaîkyl, arnino, ormono· or dialkylamino; and when Y is CR?, ît is part of the part structure R7 " \ wherein R? and Z are as defined above, or can be taken together with the carbons to which they are attached to form 15

20 wherein: G and J are independently CH2, NH, or O; B isNH, S, CH2, or O; D is C or N, provided that Ri θ is nothing when D is N; and RIG and R^ 1 are independenîly hydrogen, halogen, lower alkyl, lower alkoxy, oralkylcarbonyl.

Preferred compounds hâve Formula I wherein Y is CR?. Of this group,preferred compounds are those wherein R? is NR^R^, and R^ and arc taken 01 2227 together with the N to which they are attached to form a ring such as piperazine,piperidine, pyrrolidine. morpholine, each of which ean be optionally subsîituted.

The présent invention also provides phannaceutical compositions thatcomprise a compound of Formula I together with a pharmaceutically acceptablediluent, carrier, or excipient

The présent invention also provides methods for inhibiting cyclin-dependent kinase and growth factor-mediated kinase enzymes.

The présent invention also provides a method of treating subjects sufferingfrom diseases caused by cellular prolifération. The method entails inhibitingprolifération of tumorigenic cells of épithélial origin and vascular smooth muscleprolifération, and/or cellular migration by administering atherapeutically effectiveamount of a compound of Formula î to a suhject in need of treatment

The invention also provides compounds useful in the diagnosis andtreatment of cancer, psoriasis, vascular smooth muscle cell proliférationassociated with atherosclerosis and postsurgical vascular stenosis and restenosis inmammals.

The présent invention also provides a method of treating subjects sufferingfrom diseases caused by DNA tumor viruses such as herpes viruses.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention are thosedescribed by the general Formula I set forth above, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof.

In addition to the compounds of Formula I, the invention encompasses, ina preferred embodiment, compounds of Formula II:

wherein X, Y, Z, and are as defïned above for Formula I. 012227 -7-

Preferred oompounds of Formula Π are those in which X and Z are mdependenily hydrogen, Cl» or F; Y is CR?; and R^ b hydrogen, Cl» F» Br» or CN.In addition, the présent invention also encompasses preferred oompounds ofthe Formula ΙΠ:

Especially preferred oompounds of Formula ΙΠ are those in which X and Zare independently hydrogen, Cl, or F; Y is CR?; and is hydrogen, Cl, F, Br, orCN. 10

In addition» the présent invention also encompasses, as a further preferredembodiment, oompounds ofthe Formula IV:

Preferred oompounds of Formula IV are those in which X and Z areindependently hydrogen, Cl, or F; Y is CR?; and R^ is hydrogen, Cl, F. Br, or CN.

The most preferred invention oompounds hâve lhe Formula V 012227 -8-

wherein: r2 îs alkyl or cycloalkyl; R? is hydrogen or halo; R9 is alkyl; X and Z independently axe hydrogen or halo; R? isNR4R5; and R4 and axe taken together with the nitrogen to which they are artached to forma 5- or 6-membered carbocyclic ring, optionally containing an oxygen,nitrogen, or suliûr heteroatnm, and optionally substituted with alkyl orsubstituted alkyl groups.

Especialîy preferred compounds of Formula V are those wherein R? is 0'φ·0-ό and such groups are optionally substituted by alkyl, acyl, amide, or the like.

Unless otherwise expressly stated, the following définitions are adhered tothroughoutthis disclosure.

By “alkyl,” “lower alkyl,” and “C]-Cj θ alkyl” in the présent invention ismeant a straight or branched hydrocarbon radical having from 1 to 10 carbonatoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pcntyl, n-hcxyl, and the like. -9- 012227

By the terra “halogen” in the présent invention is meanî fluorine, bromine.chlorine, and iodine. “Alkenyl” means straight and branched hydrocarbon radicals having from2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-l-yl, 2«ethenylbutyls 3-hexen-l-yl» and the like. “Alkynyî” means straight and branched hydrocarbon radicals having from2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-l-yl,propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like. “Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl group such ascvclopropyl. cycloheptyl, cyclooctyl, cycîodecyl, cyclobutyl, adamantyl,norpinanyl, decalinyl, norbomyl, cyclohexyî, and cyclopentyl. Such groups can besubstituted with groups such as hydroxy. keto, amino, alkyl, and dialkylamino,and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons.

Such groups are termed “heterocyclvl,” which means a cycloalkyl group alsobearing at least one heteroatom selected from O, S, or N, examples being oxiranyl,pyrrolidinyi, piperidyl, tetrahydropyran, and morpholine.

By “alkoxy,” “lower alkoxy,” and “CpC] o alkoxy” is meant straight orbranched chain alkoxy groups having 1-10 carbon atoms, such as, for example,methoxy; ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxv. 3-hexoxy, and3-methylpentoxy. In addition, alkoxy refers to polyethers such as -O-(CH2)2-Û-CH3. and the like. “Alkanoyl” groups are alkyl groups linked through a carbonyl, i.e.,

Cj-C5-C(O)-. Such groups include fonnyl, acetyl, propionyl, butyryl, andisobutyryl. “Acyl” means an alkyl or aryl (Ar) group bonded through a carbonylgroup, i.e., R-C(O)-. For example, acyl includes a Cj-Cg alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR^R^or acarboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, anddie like.

“Amide” is an amino carbonyl group such as -CONR^pS 012227 -10-

The alkyl, alkenyl, alkoxy, and alkynyl groups described above areoptionally substituted, preferably by 1 to 3 groups selected firom NR4R5, phenyl,substituted phenyl, thio Cj-Cô alkyl, Cj-Cg alkoxy, hydroxy, carboxy,

Cj-Cô alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered 5 carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. “Substituted nitrogen” meansnitrogea bearing CpCg alkyl or (CHo^Ph where n is 1,2, or 3. Perhalo andpolyhalo substitution is also included.

Examples of substituted alkyl groups include 2-aminoethyl, 10 2-hydroxyethyl, pentachloroethy 1, trifluoromethyl, 2-diethy laminoethyl. 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl,methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxvbutyl, 4- chlorobutyl, 3-cyclopropyIpropyI, pentafluoroethyl, 3-morpholinopropyl,piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl. 15 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2- ethylsulfanylethvnyl, 4-(l-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl. 3- diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and thelike.

Typical substituted alkoxy groups include aminomethoxy, 20 trifluoromethoxy, 2-diethylaminoeihoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.

Further, examples of substituted alkyl, alkenyl, and alkynyl groups includediwethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl, 5- ethylmethylamino-3-pentyn-l-yl,4-morpholinobutyl, 25 4-tetrahydropyrinidylbutyl, 3-imidazolidin-l -ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenyïmethyl, and the like.

The term “anion” means a negatively charged counterion such as chloride,bromide, trifluoroacetate, and triethylammonium.

By “heteroaryl” is meant one or more aromatic ring Systems of 5-, 6-, or 30 7-membered rings containing at least one and up to four heteroatoms selectedfrom nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example,thienyl, furanyl, thiazolyl, triazolyl. imidazoîyl, (is)oxazolyl, oxadiazolyl, -11- 012227 tetrazolyl, pyridyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl, pyrimidinyl. (iso)quinolinyl, napthyridinyl, phthalimidyl, benzimidazoîyl, and benzoxazoîyL A preferred heteroaryl is pyridine.

By “aryl” is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings inwhich at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyî, antiiryl,or phenanthryl), which can be mono-, di-, or trisubstituted with, e.g., halogen,lower alkyl, lower alkoxy, lower alkylthio. trifluoromethyl, lower acyloxy, aryl,heteroaryl, and hydroxy. A preferred aryl is phenyl.

The terra “cancer” includes, but is not limited to, the following cancers:breast, ovary, cervix, prostate, testis, esophagus, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epideimoid carcinoma, large cellcarcinoma, adenocarcinoma, bons, colon, adenocarcinoma, adenoma, pancréas,adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma,papillaiy carcinoma, seminoma, melanoma, sarcoma, bîadder carcinoma, îivercarcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoiddisorders, Hodgkin’s, hairy cells, buccal cavity and pharynx (oral), lip, tongue,mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous System, and leukemia.

The terni “pharmaceutically acceptable salts, esters, amides, and prodrugs”as used herein refers to those carboxylate salts, amino acid addition salts, esters,amides, and prodrugs of the compounds of the présent invention which are, withinthe scope of sound medical judgment, suitable for use in contact with the tissuesof patients without undue toxicity, irritation, allergie response, and the like,commensurate with a reasonable benefit/risk ratio, and effective for their intendeduse, as well as the zwitterionic foims, where possible, of the compounds of theinvention. The terni “salts” refers to the relatively nontoxic, inorganic and organicacid addition salts of compounds of the présent invention. These salts can beprepared in situ during the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with a suitableorganic or inorganic acid and isoîating the sait îhus fonned. Représentative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, pahnitate, stéarate, laurate, borate, benzoate, lactate, -12- 012227 phosphate, tosylate, citrate, maleale, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.

These may include cations based on the alkali and alkaline earth meîals, such assodium, lithium, potassium, calcium, magnésium and the like, as well as non-îoxicammonium, quatemary ammonium, and amine cations including, but not limitedto ammonium, tétraméthylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, forexample, Berge S.M. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19which is incorporated berein by reference.)

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include Cj-C^ alkyl esters wherein the alkyl group isa straight or branched chain. Acceptable esters also include C5-C7 cycloalkylesters as well as arylalkyl esters such as, but not limited to benzyl. C] -C4 alkyl esters are preferred. Esters of the compounds of the présent invention may beprepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC}-Cg alkyl amines and secondary Cj-Cg dialkyl amines wherein the alkyleroups are straight or branched chain. In the case of secondary amines the aminemay also be in the form of a 5- or 6-membered heterocycle containing onenitrogen atom. Amides derived from ammonia, Cj-Cj alkyl primary amines andC1-C2 dialkyl secondary amines axe preferred. Amides of the compounds of theinvention may be prepared according to conventional methods.

The term “prodrug” refers to compounds that are rapidly transformedin vivo to yield the parent compound of the above formulac, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Sériés,and in Bioreversible Carriers in Drue Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which are herebyincorporated by reference.

Représentative compounds of the invention are shown below in Table 1. -13- TABLE1 01 2227

16

17 -14- TABLE1 (cont) 012227

34 35 -15- 012227 TABLE 1 (cont)

37

38

40 -16- TABLE1 (cont) 012227

54 -17- TABLE î (cont) 012227

012227

Π8

129 -19- TABLE1 (cont) 012227

157 -20- TABLE 1 (cont) »r 012227

202 012227 TABLE 1 (cont)

012227

•HCl 228 -23- TABLE ] (cont) 012227

CH, îlX

^OH

•HQ

OH 235 -24- TABLE 1 (cont) 012227

196 -25- TABLE1 (cont) 012227

QCH-,

F

Br'

NIL •26- 01 222 7 TABLE 1 (cont)

nh2 -27- TABLE î (cont) 012227

The compounds of the présent invention are useful for treating cancer (forexample, leukemia and cancer of the lung, breast, prostate, and skin such as 5 melanoma) and other proliférative diseases incîuding but not limited îo psoriasis, HSV, HIV, restenosis, and atherosclerosis. To utilize a compound of the présentinvention to treat cancer, a patient having cancer is administered a therapeuticallyeffective amount of apharmaceutically acceptable composition comprising aninvention compound. 10 A further embodiment of this invention is a method of treating subjects suffering from diseases caused by vascular smooth muscle cell prolifération.Compounds within the scope of the présent invention effectively inhibit vascularsmooth muscle cell prolifération and migration. The method entails inhibitingvascular smooth muscle prolifération, and/or migration by administering an 15 effective amount of a compound of Formula î to a subject in need of treatment.

The compounds of the présent invention can be formulated and administered in a wide variety of oral and parentéral dosage forms. incîudingtransdermal and rectal administration. It will be recognized to thosc skiîled in theart that the following dosage forms may comprise as the active component, either 20 a compound of Formula I or a corresponding pharmaceutically acceptable sait, ester, amide, prodrug, or solvaté of a compound of Formula I. A further embodiment of this invention is apharmaceutical compositioncomprising a compound of Formula I togelher with a pharmaceutically acceptablecarrier, diluent, or excipient therefor. For preparing pharmaceutical compositions 25 with the compounds of the présent invention, pharmaceutically acceptable carriers 012227 -2S- can be either a solid or liquid. Solid form préparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensable granules. A solid carriercan be one or more substances whichmay also act as diluents, fiavoring agents,binders, preservatives, tableî disintegrating agents, or an encapsulating material.

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

The compositions of this invention preferably contain from about 5% toabout 70% or more of the active compound. Suitable carriers include magnésiumcarbonate, magnésium stéarate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax,cocoa butter, and the like. A preferred form for oral use are capsules, whichinclude the formulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with or witliout othercarriers, is surrounded by a carrier, which is thus in association with it Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oral administration.

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

Liquid fonn préparations include solutions, suspensions, and émulsionssuch as water or water/propylene glycol solutions. For parentéral injection, liquidpréparations can be fonnulated in solution in aqueous polyethylcne glycolsolution, isotonie saline, 5% aqueous glucose, and the like. Aqueous solutionssuitable for oral use can be prepared by dissolving the active component in waterand adding suitable colorants, flavors, stabilizing and thickening agents as desired.Aqueous suspensions suitable for oral use can be made by dispersing the finelydivided active component in water and mixing with a viscous material, such asnaturel or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other wdl-known suspending agents. -29- 012227

Also incîuded are solid form préparations that are inteaded to beconverted, shortly before use, to îiquid form préparations for oral administration.Such Iiquid forms înclude solutions, suspensions, and émulsions. Thesepréparations may contain, in addition to the active component, colorants, flavors,stabilizers, buffere, artificial and natural sweeteners, dispersants, tixickeners,solubilizing agents, and the like. Waxes, polymers, microparticles, and the îikecan be utilized to préparé sustained-release dosage forms. Also, osmotic pumpscan be employed to deliver the active compound uniformlv over a prolongée!period.

The pharmaceutical préparations of the invention are prefcrably in unitdosage form. In such form, the préparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unit dosage formcan be a packaged préparation, the package containing discrète quantities ofpréparation, such as packeted tablets, capsules, and powders in vials or ampules.Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

The therapeutically effective dose of a compound of Formula I willgenerally be from about 1 mg/kg to about 100 mg/kg of body weight per day.Typical adult doses wül be about 50 mg to about S00 mg per day. The quantity ofactive component in a unit dose préparation may be varied or adjusted from about0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to theparticular application and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents. A subject in needof treatmenl with a compound of Formula I is administered a dosage of about1 mg to about 500 mg per day, either singly or in multiple doses over a 24-hourperiod.

The compounds of the présent invention are capable of binding to andinhibiting the activity of proteins having the abiîity to phosphorylate otherproteins, such as cdks, PDGFr, FGFr, c-Src. and EGFr-FL. Cdks form complexeswith cyclins, and these complexes phosphorylate key proteins allowing celîs toproceed through the cell cycle (Meijer L., Pragress in Cell Cycle Research, 1995;1:351-363). The compounds of tins invention inhibit tbis phosphorylation 012227 and therefore can be used as anti-proliferative agents for the treatment of cancerand/or restenosis and other proliférative diseases.

Because of their inhibitory activity against cdks and other kinases, thecompounds of the présent invention are also useful research tools for studying the5 mechanism of action of those kinases, both in vitro and in vivo.

The examples presented below are intended to illustraie particularembodiments of the invention, and are not intended to limit the scppe of thespécification or the daims in any way.

An illustration of the préparation of compounds of the présent invention isshown in Schemes 1 and 2. 10 -31-

Scheme 1 012227

(EîO)2P(O)CH2CO.Et

NaH

-32-

Scheme 2 012227

MeMgBr

THF

-33- 012227

Those having skill in the art will recognize that the starting materials maybe varied and addidonaî steps employed to produce compounds encompassed bythe présent invention, as demonstrated by the following examples.

As shown in Schemes 1 and 2, a 4-substituted amino-2-methansulfanyl-pyrimidine-5-carboxaldehyde is reacted with an organometaliic compound, suchas, for example, a Grignard reagent, to afford the corresponding secondaryalcohoL The alcohol is subsequentîy oxidized to the ketone. The ketone is thenreacted with a triaîkyl phosphonoacetate in the presence of base to produce thecorresponding 8-substituted-5-alkyl-2-methylsulfanyl-SH-pyrido[2,3-d]pyrimidin- 7-one. The pyrido-pyrimidine then can be halogenated at the 6-position with acommon halogenating agent, such as, for example. N-bromosucccinimide (NBS).

The 2-methylsulfanyl dérivative is oxidized to the corresponding mcthylsulfoxide,which is subsequentîy treated with a desired aniline to afford the 2-phenylaminoinvention compound.

When carrying out varions réactions to préparé invention compounds. itmay be désirable to derivatize reactive groups such as amines, alcohols, and acids,with protecting groups that are readiiy removed when desired. Such protectinggroups simpîy avoid unwanted side reactions. Use of protecting groups is commonin the art of organic chemistry, as described by Greeve and Wuts in ProtectiveGroups in Organic Synthesis, John Wiley and Sons, New York (2η^ ed, 1991).

Typical hydroxy protecting groups incîude either forming groups such as benzyl,and acyî groups such as tert-butoxycarbonyl(Boc), formyl, and acetyl. Aminoprotecting groups include benzyl, acyl such as acetyl, and trialkylsilyl groups.

Carboxylic acid groups typically are protected by conversion to an ester that canbe easily hydrolyzed, for example, trichloroelhyl, tert-butyl. benzyl, and the like.

Some of the invention compounds have one or more chiral centers, andthus can exist as individual optical isomers and mixtures thereof. Compound 246(Table 1), for example, can exist as an RS racemate, or as the individual R or Sisomer. Ail individual isomers and mixtures thereof are included in this invention.Individual isomers are readiiy prepared by a chiral synthesis, or by conventionalresolution techniques well-known to those skilled in the art 012227

The invention is illustrated furthei by the following detailed exampleswhich are not to be construed as limiting the invention in scope or spirit to thespécifie procedures described in them. The starting matériels and variousintennediates utilized in the synthesis of invention compounds may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using weîl-known synthelic methods. The disclosures inthis application of ail articles and référencés, including patents, are incorporatedherein by référencé. EXAMPLE 1 S-Cyclopentyl-ô-fluoro-S-methyl^-methylsulfanyl-SH-pyrido^-dJpyrimidin- 7-one CH.

NaH (771 mg, 19.3 mmol) is suspended in dry THF (20 mL), and themixture is cooled to 0°C in an ice bath. Triethyî 2-fluoro-2-phosphonoacetate(3.9 mL, 19.3 mmol) is added dropwisc with stirring, and the solution is stirred atroom température for 30 minutes. A solution of l-(4-cyclopentylamino- 2-methylsulfanyl-pyrimidin-5-yi)-ethanone in dry THF (40 mL) is added via acannula, and the reaction mixture is stirred at 24°C for 12 hours. The reaction isquenched by the addition of H2O (0.5 mL), and the THF is evapoiated in vacuo.The residue is parîitioned berween ethyl acetate and saturated aqueous sodiumchloride. The aqueous laver is extracted twice with fresh ethyl acetate, and thecombined organic îayers are dried over MgSO4· After removal of the drying agentand évaporation of the solvent, the crude product is purified by chromatographyon silica gel (eluting with 20%-30% ethyl acetate in hexanes) to givc the titledcompound as a coloriess solid (0.61 g, 23%). 012227 EXAMPLE 2 8-Cyclopentyl~6-fluoro-2-meihanesulfinyl-5-methyl-&H-pyrido[2,3‘-dJpyrirttidin- 7-one

5 8-Cyclopentyl-6-fluoro-5-methyl-2-inethylsuIfanyî-8H- pyrido[2,3-d]pyriinidin-7-one (0.61 g, 2.08 mmol) from Example 1 and 3-phenyI-1 -p-nitrophenylsulfonyîoxaziridine (0.65 g, 2.5 mmol) are dissolved in CH2CI2(20 mL) and stirred for 12 hours ai 24°C. Following évaporation of the solvent,the crude product is purified by silica gel chromatography (eluting wiih 10 80%-l 00% ethyl acétate in hexanes) to provide the sulfoxide product as a white solid (0.55 g, 86%). 15 EXAMPLE 3 4-[4-(8-Cyclopentyi-G~fluoro-5~rmthy1-7-oxo-7,8-dihydro- pyrido[2^]pyriimdm-2-y1amino)-phenyl]-piperazine-l -cctrboxylic acid tert-bittyi ester

-36- 012227 8-Cyclopentyl-6-fluoro-2-methanesuIfinyl-5-methyl-8H-pyrido[2.3-d]pyrimidin-7-one (0.3 g, 0.97 mmol) &om Example 2 and 4-(Ar-Boc-piperazin-l-yl)anilme (0.548 g, 1.94 mmol) are suspended in 1,4-dioxane (5 mL)and heated to 80°C for 12 hours. Anhydrous DMSO (2.5 mL) is added, and thctempérature is raised to 100°C. Heating is continued for 24 hours, after which thereaction mixture is cooled to 24°C and partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The organic layer is separated and washedwith H2O, and then with saturated aqueous sodium chloride. After drying overanhydrous MgSÛ4, the solvent is evaporated, and the residue is purified by silica gel chromatography to provide the titled compound as a yeliow solid (0.23 g,45%). EXAMPLE 4 8-CycÎopeutyi~ô~/7uoro-S~methyl-2-(4-piperazin~l~yl~pfieuylanûno)-8H- pyrido[2,3-âJpyrimi{lin-7-one

4-[4-(8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydro-pyrido[2s3-d]pyrimidin-2-ylamino)-phenyl]-piperazme-l -carboxylic acid tert-butyl ester (0.23 g, 0.44 mmol) fiom Exemple 3 is dissolved in a 1:1 mixture oftrifluoroacetic acid (TFA)/CH2Cl2 (20 mL) and stirred at room température for1 hour. Evaporation of the solvents, followed by the addition of anhydrous diethylether, gave an orange solid (compound 34) thaï is collected by. filtration (0.21 g,74%). Mp 254-255°C. Ί * ' -37- 012227

EXAMPLE 5 è-Bromo^S-^yclopenîyl-S-’metiiyl-l-meihylsulfanylSH-pyridop^-dJpyrimidin- 7-one

Br H. 8“CyclopgatyI-5-meihyI-2-meihy!suIfanyî-SH"pyrido[233-d]p3'rimidin- 7-one (I g, 3.64 mmol) is dissolved in diy DMF (15 mL) andN-bromosuccinimide (0.97 g» 5.45 mmol) is added followed by benzoylperoxide 10 (0.13 g, 0.5 mmol). The resulting solution is stiired for 12 hours at 24°C. The mixture is then partitioned between ethyî acetate and H2O. The organic laver isvvashed with H2O, and then with saturated aqueous sodium chloride solution anddried over MgSO4. Removal of the drying agent and évaporation of the solvent gave the desired title product (0.S6 g, 66%) which is used without further 15 purification. 012227 EXAMPLE 6 6-Bromo-8-cydopentyl-5-rnetliyl-2-(4-piperazin-l-yl-phenylamino)-8H·- pyrido[2,3-d]pyrimidin-7-one

5 6-BromoS-cyclopentyî-5-methyl-2-meÎhylsulfanyl-8H- pyrido[2.3-d)pyrimidin-7-one is oxidized as described in Example 2. Thesulfoxide is reacted with 4-(N-Boc-piperazin-l-vl)aniIine as described inExample 3. The N-Boc protecting group is removed by hydrolysis as describedabove for 8-cyclopentyl-6-fîuoro-5-methyl-2-methylsulfanyl-8H- 10 pyrido[2,3-d]pyrimidin-7-one to provide 6-Bromo-S-cyclopentyl-5-methyl-2-(4-piperazm-1 »yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one(compotand 35). Mp >200°C (dec). C23H27N6'OBr 1.9 TFA: Calcd C, 45.90; H, 4.15; N, 11.97. Found: C, 45.53; H,4.09; N, 11.76. 15 EXAMPLE 7 l-(4-Cydopenfylanùno-2-methyîsulfanyl-pyrimîdin-5-yl)~ethan-l-ol

OH

s 1 012227 -39- 4-Cyclopentylamino-2-methanesulfanyl-pyrimidine»5-carboxaldehydc(1.1 g, 4.64 mmol) is dissolved in tetrahydrofuran (30 mL) under nitrogen andthen cooled with an ice baîh. To this clear solution is sîowly added meîhylmagnésium bromide (4.4 mL, 13.2 mmol, 3 M in ether). The reaction is stured for1 hour with the ice bath stiU in place. The reaction is quenched with a smallamount of saturated aqueous ammonium chloride and then partirioned betweenwater and ethyî acetate. The layers are separated, and the aqueous layer isextracted with ethyl acetate. The combined organic layers are washed with brineand then dried over magnésium sulfate. After filtration, the solvent is removedin vacuo to yield the titled compound as an oil (1.09 g, 90%). NMR(400 MHz, CDCI3): δ 1.42-1.59 (m, 5H), 1.60-1.76 (m, 4H), 2.04-2.06 (m, 2H), 2.49 (s, 3H), 4.38-4.43 (m, 1H), 4.69-4.74 (m, 1H), 6.28-6.30 (d, 1H), 7.57 (s, 1H).

EXAMPLES l~(4^Cyclopentylamino-2-methylsulfanyl-pyrimîdin-S-yl)-eihanone

l-(4-Cyclopentylamino-2-meÎhylsuifanyî-pyrimidin-5-yl)-ethan-l-ol(1.09 g, 4.3 mmol) from Example 7 is dissolved in 100 mL of dichloromethane.The solution is purged by bubbling nitrogen gas through it for 2 minutes. To thereaction solution are added, in order: powdered moleculax sieves (4 angstrom),jV-methyl morpholine oxide (1.07 g. 8.6 g), and tetrapropylammoniumpenuthenate (0.227 g, 0.645 mmol). The reaction mixture is stirred at 24°C for2 hours, and small amounts of additional catalyst are periodically added. Thereaction mixture is then run through a silica column (1:1, ethyl acetate:hexanes) toyield the titled compound as a light yellow solid (0.74 g, 70%). NMR 01 2227 (400 MHz, CDCI3): δ 1.51-1.78 (m, 6H), 2.02-2.08 (m, 2H), 2.49 (s, 3H), 2.53 (s, 3H), 4.47-4.53 (m, 1H), 8.53 (s, IH), 9.21 (s, 1H); MS (M+l) 252.2. EXAMPLE 9 8-Cyclopentyl-5-met1iyl-2-inethylsiiîfanyl-8H-pyrido[2,3-d]pyrimidin-7-oiie

A cooled (5°C) flask containing tetrahydrofuran (50 mL) is charged withsodium hydride (1.05 g, 26.3 mmol, 60% dispersion in minerai oil) undernitrogen, and Î.O g of triethyl phosphonoacetate is added. The cooling bath isremoved, and the mixture is stirred at 24°C until it becomes a homogeneous 10 solution. The solution is diluted by the dropwise addition of a solution ofl-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone (3.0 g, 11.9 mmol) in tetrahydrofuran (25 mL). The reaction mixture is heated to refluxfor 2 hours. The reaction mixture is cooled to 24°C, and diluted 50 mL of waterand 50 mL of ethyl acetate. Following séparation of the layers, the organic layer is 15 dried over magnésium sulfate and concentrated in vacuo to near dryness. Hexaneis added, and the solid is stirred vigorously for 5 minutes before being filtered toyield the titied compound as a light pale orange solid (3.01 g, 92%). ]-Η N MR(400 MHz, CDCI3): δ 1.63-2.36 (m, SH), 2.38 (s, 3H), 2.59 (s, 3H), 5.84-5.93 (m,1H), 6.39 (s, 1H), 8.66 (s, 1H). -41- EXAMPLE10 012227 8-Cyclopentyl-2-methanesulflnyî-5~metliyl^8H-pyrido[2,3-d]pyrimidin-7-one

8-Cyclcçentyi-5-methyl-2-methylsulfanyl-8H-pj'rido[2,3-d]pyrimidin-5 7-one (1.0 g, 3.63 mmol) from Example 9 is dissolved in dichîoromeihane (15 mL), and (±)-/rn«s-2-(phenyisulfonyl)-3-phenyloxaziridine is added. Thereaction mixture is stined at 24°C for 12 hours, and then the solution is passedthrougb a siîica column (2% MeOH in CHjCîj) ίο yield the titled sulfoxide as awhite solid (0.67 g, 64%). NMR (400 MHz. DMSO-tf6): δ 1.53-2.19 (m, 8H), 10 2.45 (s, 3H), 2.87 (s, 3H), 5.75-5.84 (m, IH), 6.64 (s, 1H), 9.19 (s, 1H). EXAMPLE 11 4-l4-(8~Cyclopeniyl-5-meihyl-7-oxo-7,S-dihydro~pyrîdol2^-ilJpyrimidÎn- 2-ylanww)-phenyl]-piperazine-l-carboxytic acid tert-butyl ester

1 5 8-Cyc]opentyl-2-methanesulfinyî-5-methyî-8H-pyrido[2,3-d)pyrimidin- 7-one (0.7 g. 2.4 mmoî) from Example 10 and 4-(4'-jV-Boc-piperazinyî)-anilineare dissolved in dimethylsulfoxide (8 mL) and heated to 90°C ovemight Thereaction mixture is cooled îo room température and partitioned between water andethyl acetate. The organic layer is washed with sodium hydrogen carbonate, brine, 20 and then dried over magnésium sulfate. Removal of the drying agent and PCT/USt 01 2227 concentration in vacuo gives the titied product as a yellow solid that is recrystallized firom waîer and acetonitrile (0.55 g, 45%). NMR (400 MHz, CDCI3): δ 1.45 (s, 9H), 1.56-1.87 (m, 6H), 2.23-2.28 (ra, 2H), 2.31 (s, 3H), 3.07 (m, 4H)S 3.55 (m, 4H), 5.77-5.81 (ms 1H), 6.19 (s, 1H), 6.90 (d, 2H), 7.42-7.44 (d, 2H), 7.47 (s, 1H). 8.55 (s, 1H): MS (M+l) 505.1. The Bocprotectinggroup is removed by stining in a kl mixture of trifluoroaceticacid/dichloromethane to give (Compound 1). Mp >215°C (dec). ÈXAMPLE 12 S-Cyclopentyl-5-ethyl-2-(4-piperazin-l-yl-phenyla»iino)~8H-pyrido[2^- a)pyrimidin-7-one (Compound 193)

1 -(4-Cy clopentylamino-2-methyîsulfanyl-pyrimidin-5 -vl)-propan-1 -ol.4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (4.07 g, 17.1 mmol) was dissolved in THF (60 mL) under nitrogen then cooled with an icebath. To this clear solution ElMgBr (13.4 mL, 40.3 mmol, Aldrich 3M in ether)was slowly added. The reaction was stirred for 15 minutes with the ice bath still inplace. The reaction was quenched with a small amount of sat aq. NH4CI thenpartitioned between water and EtOAc. The layers were separated, the organiclayer dried over MgSCty, and after filtration, the solvent was removed in vacuo toyield l-(4-cyclopentylamino-2-raethylsulfanyl-pyrimidin-5-yl)-propan-l-ol as anoil (4.55 g, 99%) which was used without further purification. -43- pct/u 012227 l-(4-Cyclopentyîamino-2-methyïsuîfanyl-pyrimidin-5-yl)-propan-l-one. ] -(4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-propan-l -ol (4.55 g,17.1 mmol) was dissolved in toluene (80 mL) to which manganèse (TV) oxide(3.72 g, 42.8 mmol, Aldrich <5 micron, activated, -85%) was subsequentîy added.The reaction was brought to reflux for 16 hours. The réaction was cooled to roomtempérature and filtered though a celite pad. The filtrate then was concentrated invacuo to yield the product as a light yellow oil (3.79 g, 84%). 8-CyclopenÎyl-5-sthyî-2-methylsulfanyl~8H-pyrido[2.3~d]pyrimidin-7-one.Under nitrogen, a cooled flask with THF (50 mL) was charged with NaH (1.23 g,30.7 mmol. 60% dispersion in minerai oil) to which was added triethylphosphonoacetate (6.09 mL, 30.7 mmol). The cooling bath was removed, and thereaction mixture was stirred ai ambient température until everything dissolved. Asolution of the l-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-propan-1-one (3.0 g, 11.9 mmol) in THF (70 mL) was slowlv added to the preformedanion. Then the réaction mixture was brought to reflux for 60 hours. The reactionwas cooled to room température and diluted with water and EtOAc. The layerswere separaled, and the aqueous layer was extracled with EtOAc. The combinedorganic extracts were washed with brine. dried over MgSO4, filtered, andconcentrated in vacuo to give a waxy solid. The solid residue was triturated withhexanes to give a white solid after filtration (2.67 g, 66%). 8-Cyclopentyl-5~ethyî-2-methanesiiifinyl-8H-pyrido[2,3-d]pyrimidin- 7-one. 8-Cyc]opentyl-5-ethyl-2-methylsulfanyl-SH-pyrido[2,3-d]pyrimidin-7-one(2.57 g, 8.88 mmol) was dissolved in CH2CI2 (50 mL), and 2-benzenc-sulfonyl- · 3-phenyl-oxaziridine was added. The reaction mixture was stirred for 16 hours axroom température. Then the solution was evaporated in vacuo to give an orangeoil. EtOAc was added and a white precipitate formed. This precipitate was filteredand washed with hexanes to yield a white solid (2.12 g, 78%). 4-[4-(8-Cyclopsnîy!-5~et)iy]-7-oxo-7,8-dihydro-pyrido[2! 3-dJpyrimidin-2~ylamino)-phenylJ-piperazine-l-carboxylic acid tert~butyl ester. The sulfoxide. 8-cyclopentyl-5-ethyl-2-methanesulfmyl-SH-pyrido[2,3-cQpyrimidm-7-one (0.2 g,

Vf, 012227 PCT/ÜS·' 0.654 mmol) and 4-(4'-M-Boc-piperazinyl)-aniline were dissolved in DMSO(5 mL) and heaied to 70°C for 16 hours. The reaction mixture was cooled to roorotempérature and partitionedbetween water and EtOAc. The organic layer waswashed with brine then dried over MgSO4. After filtration and concentrate 5 in vacuo, orange solid was obtained which was purified by column chromatography to yield the product as a yellow solid (0.160 g, 47%). 8-CyclopenÎyl-5-eî'hyl-2-f4-piperazin~l-yl-phenylamino)-8H-pyrido[2,3-d]pyrîmidin- 7-one (235) •4-[4-(8-Cyclopentyl-5-ethvl-7-oxo- 7,8-dihydro-pyrido[2,3-d]pyrimidm-2-yIanùno)-phenyI]-piperazine-1 -carboxylic 10 acid tert-butyl ester was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. This mixture was stirred at room température for15 hours, The solvent was evaporated, then the solid was suspended in diethylether and filtered to give a fluffy gray solid (128 mg, 75%). MMR (400 MHz,DMSO-Jg): δ 1.17 (m, 3H), 1.52-1.83 (m, 6H), 2.20 (m, 2H), 2.75 (m, 2H), 15 3.22 (m, 4H), 5.78 (m, 1H), 6.10 (s, 1H), 6.95 (d, 2H), 7.53 (d, 2H), 8.73 (s, 2H), 8.79 (s, 1H), 9.76 (s, 1H); CHN for C23H30N60 + 1-21 TFA. EXAMPLE 13 2-l4-(4-Acetyl-piperaziti-l-yl)-phe.nylamitio]-S-cyc!opcntyi-5-mefhylSB-pyrùlol2)3-dJpyrimidin-7-one (Compound 198)

l-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethane (0.075 g, 0.343 mmol) and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido[2,3-i/]pyrimidin-7-one 20 -45. 01 222 7 (0.100 g, 0.343 mmol) were dissolved in DMSO (5 mL) and heated to 70°C for16 hours. At this point, 20 mg more of the aniline was added, and heating wasconlinued for an additional 4 hours. The reaction was sooîed to room températureand partitioned between water and EtOAc. The organic layer was washed with 5 brine then dried over MgSC>4. Filtration and concentration in vacuo gave an orange solid which was purifîed by coîumn chromatography to yield a yellowsolid (0.049 g, 32%). Mp 261-263’C. EXAMPLE 14 2-[4-((3R^4S)-AminomethylArifluoromethyI-pyrrolidin-l-yl)-phenylamino]- 10 8-cyclopenryi-S-methyl~8H-pyrîâo[2,3~d]pyritmdin-7-oiie (Compound 216)

[(3 R, 4S)-l-(4-Amino-phenyl)-trifluoromethyl-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester. ((3&,4^-4-Trifluoromethyî-pyirolidin-3-yimethyl)-carbamic acid ferf-butyl ester (1.0 g, 3.72 mmol),p-fluoro-nitrobenzene (0.36 mL, 15 3.38 mmol) and diisopropyl ethyl amine (0.65 mL, 3.72 mmol) were dissolved in acetonitrile (10 mL) and refiuxed for 24 hours. The solvent was removed, and themixture was triturated with hexanes and fîltered to yield a crade yellow solid(1.4 g). This product was dissolved in THF and treated with Raney Nickel under ahydrogen atmosphère until no further change in pressure was observable. 20 Folîowing removal of the catalysl by filtration, the product aniline was obtainedby évaporation of the solvent and used without further purification. {(3R, 4S)-[4-(8-Cyclopentyl-5-methyl- 7-oxo-7,8-dihydro-pyrido[2,3-a]pyrmidin-2-ylamino)-phenyl]-trifluoromethyl-pyrrolidin- 3-yimethyî}-carbamic acid tert-buryl ester (222). [(3R,4S>l-(4-Amino-phenyl> 01 2227 trifluoromethyl-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester and 8-cyclopenÎyl-5-methyl-2-methanesulfinyl-8J7-pyrido[2,3-d]pyrimidm-7-one werecoupled and deprotected as previously described for Example 11. CHN for C25H29N6O1F3 + 1.6 TFA. mp >130°C (dec). EXAMPLE 15 8~Cyclopentyl-5~niethyl-2~{4-[2-(4H-[l,2f4]trîazol-3-ylsnlfaiiyl)-ethyl]- phenylamino}-8H-pyrido[2,3-d]pyriinidin-7-oiie (Compound 222)

4-[2(4H-[l,2,4]triazoî-3-ylsulfimyl)-ethyl]-phenylamine. To a suspension] 0 of hexane rinsed 60% sodium hydride (0.83 g), in dimethylformamide (5 mL) at 0°C, was added a solution of 3-mercapto-l,2,4-triazole (2.0 g) indimethylformamide (10 mL) in portions. Aftsr 45 minutes 4-nitrophenethylbromide (4.1g) was added, and the reaction mixture was stirred at roomtempérature for 18 bouts. 1 M Hydrochloric acid (70 mL) was added and the 15 aqueous phase was extracted with diethyl ether (3 x 100 mL), and the combinedorganic extracts were concentrated to dryness. The resulting solid was collected,washed with diethyl ether (2x10 mL) and dried to yield the nitrobenzeneintermediate (3.17 g). MS: MH-. 251 ; MH- 248.9. A solution of this intermediate(1.0 g) was reduced using Raney Nickel (0.5 g) and hydrogen in THF (100 mL). 20 The sample was concentrated to dryness to yield the title compound (0.88 g), MS:MH+, 221; MH-, 219. 8-Cyclopentyl-5-methyî-2-{4-[2~(4H-[l,2,4]triazoî-3-ylsuT.fanyl)~ethyi]-phenyîamino}-8H-pyrido[2,3-d]pyrimidïn-7-one. A solution of 8-cyclopentyl- 5-methyl-2-methanesulfinyl-SH-pyrido[2,3-iQpyrimidin-7-one (0.02 g), 4-(2(47/- ΛΌ P·' ' ,1. 01 222 7 [1,2,4]mazol-3-ylsulfanyl)-ethyl]-phenylamine (0.0166 g) and trifluoroacetic acid(0.06 mL) in aceionitrile (2 mL) was heated at 80°C for 18 bonis. The reactionmixture was cooled and the solvent removed in vacuo. 1 M Sodium hydroxxde(4 mL) was added and the aqueous phase was extracted with diethyî ether(3x4 mL); sodium chloride (20 mg) was added after the fîrst extraction. Theaqueous layer was acidifîed to pH = 1 and extracted with a mixture of ethylacetate/dichloromethane (9:1) (3x4 mL). The combined ethyl acetate/dichloromethane extracts were concentrated to drvness and purified bycolunm chromatography using a gradient of ethyl acetate 60% to 100% inhexanes. Concentration of the appropriate fractions yielded Compound 222(0.014 g). ÎHNMR (dôJDMSO): Ô 1.58 (2H, m), 1.7 (2H, m), 1.88 (2H, m), 23 (2H, m), 2.38 (3H, s), 2.9 (2H, m), 3.4 (2H, m), 5.7 (1H, s), 5.8 (1H, m), 7.18 (2H, d, J = 9), 7.6 (2H, d, J = 9), 8.78 (1H, s). EXAMPLE 16 $-Cyclopentyl-5~meîhyl3~l4-(lH~[13>4]triazol-3-yisiüfanyl)-phenylamno]-8II-pyrido[2,3-d]pyrimidin-7-one (Compound 223)

4-(lH-[],2,4]triazol-3-yh!ulfanyl)-phenylam.ine. To a suspension ofhexanes rinsed 60% sodium hydride (1.16 g) in dimethylformamide (10 mL) at0°C was added a solution of 3-mercapto-I,2,4-triazole (4.0 g) in dimethylformamide (20 mL) dropwise. After 20 minutes, î-fiuoro-4-nitrobenzene(5 g) in dimethylformamide (20 mL) was added, and the réaction mixture wasstirred at room température for 2 hours, then at 60°C for 1S hours. 1 MHydrochloric acid (100 mL) was added, and the solid was collected and dried. Asecond crop of solid (2.1 g) was recovered by crystallization from themother -4S- 012227 WQ· PCT/ liquors. To the combined solids was added dichloromethane (300 naL) and 1 Msodium hydroxide (200 mL), The dichloromethane was further extracted with 1 Msodium hydroxide (100 mL), The combined aqueous phases were extracted withdichloromethane (2 x 300 mL) then acidified to pH = 1. The solid formed wascolleeted and dried to yield the nitrobenzene dérivative (1.96 g). This product wasreduced using Raney Nickel and hydrogcn in tetrahydrofuran (100 mL).

Following removal of the caîalyst, the sample was concentrated to dryness to yieldthe desired product (1.7 g), MS: MH-, 192.9; MH-, 190.0. 8-Cyclopemyl-5-rnethyl-2-[4-(lH-[1,2,4Jtriazol-3-ylsulfanyl)-10 phenylamino]~8H-pyrido[2,3-dJpyrimidin-7-one. This compound was prepared from 4-(lH"[l;i2s4]triazol"3-ylsulfaQyl)-phen3rlamme and 8-cyclopentyl-5-methyl·2-methanesulfinyl-8JT-pyrido[2,3-(/lpyrimidin-7-one by the procedure ofExample 15 to give Compound 223. *HNMR (Dg-DMSO): δ 1.58 (2H, m), 1,75 (2H, m), 1,90 (2H, m), 2.2 (2H, m), 2.38 (3H, s), 5.82 (1H, m), 6.20 (1H, s),15 7.4 (2H, d, J = 9), 7.73 (2H, ds J = 9), 8.85 (IH^bs), 8.82 (1H, s). EXAMPLE 17 S-Cyclopentyl-5-meihyl-7-oxo-2-(4-piperazi»-l~yl-phenyla}nino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester (Compound 224)

20 4-[4-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-ùQpyrimidin-2-ylamino)-phenyl]-piperazine-1 -carboxylic acidZerZ-butyl ester (300 mg, 0.515 mmol), Pd(OAc)2 (23 mg, 0.05 mmol),l,2-bis(diphenylphosphino)-propane 64 mg, 0.155 mmol). and triethylamine(0.18 mL, 1.29 mmol) were combined in methanol and pressurized to 500 PSI in ï\”* »vc 01 2227 CO gas. The réaction mixture was heaîed to 100eC and stiired for 14 hours, thenaîlowed to cool to 24°C. Evaporation of the solvent, followed by chromatographyon S1O2 (45%-50% EtOAc in Hexanes) gave a yellow oil. This oil was dissolvedin CH2CI2 (10 mL) and treated with 2 M HCl in diethyl ether (10 mL) at roorotempérature. A white predpitate formed. After stiiring for 3 hours at roomtempérature, the solvent was evaporated. The residue was re-suspended inanhydrous diethyl ether and filtered to give the titled compound as a yellow solid(34 mg), mp 195-205°C. hîNMR (d6-DMSO): δ 1.52 (br s, 2H), 1.71 (br s, 2H), 1.82 (br s, 2H), 2.14 (br s, 2H), 2.30 (s, 3H), 3.18 (s, 4H), 3.27 (s, 4H), 3.76(s, 3H), 5,8 (s, 1H), 6.96 (d, J - 8 Hz, 2H), 7.53 (d, J - 8 Hz, 2H), 8.85 (s, 1H), 9.04 (s. 1H), 9.97 (s, 1H). EXAMPLE 18

The following compounds are prepared essentially according to theprocedures described in Examples 1 to 17 and as illustrated in Schemes 1 and 2: (a) 8-Cyclopentyî-5-meîhyl-2-(4-piperazin-l-yl-phenylainino)-8H-pyrido[2,3-d]pyrimidin-7-one trifluoroacetic acid sait (Compound 3), mp>215°C(dec); (b) 8-(l-Methylethyl)-5-methyl-2-(4-piperazin-l-yl-phenyiamino)-8H-pyrido[23“d]pyrimidin-7"one (Compound 2), mp >235°C (dec); (c) 8-Cyciopentyî-5-methyl-2-(4-fîuoro-3-methylphenylamino)-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 3); (d) 8-(l -Methylethyl)-5-methyl-2-(4-fluoro-3-methylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 4); (e) 8-Cyclohexyi-5-methyl-2-(4-fluoro-3-methylphcnyiamino)-8H-pyrido[2,3-d3pyrimidin-7“one (Compound 5); (f) 8-CyclohexyI-5-methyl-2-[4-(4-propanoylpiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 6); (g) 8-Cyclopentyl-5-methyl-2-[4-(4-propanoylpiperazin-l-yl)phenylamino]-8H-pyiido[2»3-d]pyrimiâin-7-one trifluoroacetic acid sait(Compound 7), mp 235-237°C; -50- 012227

»C 10 15 20 25 (h) 8-(l-Methyleihyl)-5-methyI-2-[4-(4-propanoylpipcrazin-l-yl)phenylamino]-8H-pyrido[253-d]pyrimidin-7-one (Compound 8); (i) S-Cyciohexyl-5-me±yi-2-(4-piperazù-l-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 9); (j) 8-Cyclopentyl-5-methyI-2-(4-:pyridylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 10); (k) 8-( 1 -Methyleihyl)-5-meihyl-2-(4-pyridylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 11); (l) 8-Cyclopentyl-5-meÎhyl-2-[4-(3-aminopynolidinyl)phenylamino]-8H-pyrido[2,3-d]pyiimidin-7-one trifluoroacetic acid sait (Compound 12), mp >195°C (dec); (m) 8-(l -Methylethyl)-5-methyl-2-[4-(3-aminopyiTolidinyl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 13), mp >227-229°C; (n) N-(l-{4-[(8-cyclopentyl-5-methyl-7-oxo(8-hydropyiidino[2,3-d]-pyTimidin-2-yl))ammo]phenyî}pyrroIidin-3-yl)-3,3-dimethylbutanamide(Compound 14); (o) N-(l-{4-[(5-methyi-8-(l-methylethyl)-7-oxo(8-hydropyridino[2,3-d]-pyrimidm-2-yl))amino]phenyl}pyirolidin-3-yl)-3,3-dimethylbutanamide(Compound 15); (p) 8-CycIopentyî-5-methyI-2-(3-chloro-4-piperazin-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 16), mp 234-237°C; (q) 8-Cyclohexyl-5-methyî-2-(3-chloro-4-piperazin-l -yl-pheuvlamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 17); (r) 8-(l -Methylethyl)-5-methyl-2-(3“Chloro-4-piperazin-1 -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 18); (s) 8-Cyclopentyl-6-fIuoro-5-methyl-2-(3-chloro-4-piperazin-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 19); (t) 8-Cyclohexyl-6-fluoro-5-methyl-2-(3-chloro-4-piperazin-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 21); (u) 8-(l-Methylethyl)-6-fluoro-5-methyl-2-(3-chloro-4-pîperazin-l -yl-phenylamino)-8H-pyrido[2.3-d]pyrimidin-7-one (Compound 20); 30 Λθ 01, 012227 (ν) 8-Cyclopentyl-5»methyl”2“(3-chîoro-4-morpholin-4-yl-phcnylamino)-8H-pyrido[2,3-d]pyriœidûi“7-one (Compound 22); (w) 8“(l-MeÎhylethyl)-5-meihyl”2-C3»chloT!>-4-morphoiin-4-y!-phen.yîaœino)-8H-pyrido[253“djpyrimidiu-7-Qne (Compound 23); (x) 8-Cycîohexyî-5-methyl-2-(3-chloro-4-morpholin-4-yl-phenylaniino)-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 24); (y) 2-({3-shioro-4-(4-(3-morphoEn-4»yîpropyl)plperidyl]phenyI} amino)- 8-cyclopentyJ-5-meihyl-8-hydropyridino[2,3-d3pyriimdîn-7-one (Compound 25); (z) 2-({3-cW.oro-4-[4~(3-rnoxpholin-4-ylpropyl)pipcridyl]phenyl}amino)-8-(l-methylethyl)-5-methyl-8-hydropyridmo[2,3-d]pyrimidin-7-one(Compound 26); (aa) 2-({3<hloro«4“[4-(3-morpholin-4-ylpropyl)pÎperidyl]phenyl}amino)-8-cycîohexyl-5-meihyl-8-hydropyridino[2s3-d3pyrimidin-7-one (Compound 27); (bb) 2-({3»chloro-4-[4-(3-piperazinylpropyl)piperidyl]phenyl)amino)-8-cycIopentyî-6-fluoro-5-methyl-8-hydropyridinoE2,3"d3pyriniidin-7One(Compound 28); (cc) 2-({3-chloro-4-[4-(3-pîperaziny]propy])piperidyl]phenyl}amino)-8-(l-metiiylethyl>6-fluoro-5-methyl-8-hydropyridino[2,3-d]pyrimidin-7-one(Compound 29); (dd) 2-( {3-chloro-4-[4-(3-piperazinylpropyl)piperidy!3phenyl ) amino)-S-cyclohexyl-6-fluoro-5-methyl-8-hydropyridiiio[2,3-d]pyriinidm»7-onc(Compound 30), mp >80°C (dec); (ee) 2-({3-chloro-4-[4-(3-piperazinyIpropyl)piperidyl]phenyi}amino)-8-cyclopeniyl-5-methyI-8-hydropyridma[2,3-d3pyrimid!n-7-one (Compound 31); (ff) 2-( {3-chloro-4-[4-(3-piperazinylpropyl)piperidyl3phenyl} amino)-8-(l-methylethyl)-5-methyl-8-hydropyTidinof2,3-d]pyTiTnjdin-7-one(Compound 32); (gg) 2-({3-chloro-4-[4-(3-piperazinylpropyl)piperidy3]phenyI}anuno)-S-cycloh.exyl-5-methyl-8-hydropyridino[2,3-dJpyrimjdin-7-one (Compound 33); (gg2) 8-Cyclopentyl-2»[4-(pipera2in” 1 -yl)-phenylamino]-6-fiuorO“5-methyI-8H-pyrido[2,3~d3pyrimidin-7~one trifluoroacetate (Compound 34),mp 254-255’C;

V0(T .Η. 01 222 7 (gg3) 8-Cyclopentyî-2-[4-(piperazm-l -yl)-phenylamino]-6-bromo-5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one trifluoroacetaie (Compound 35),mp >200°C; (hh) 8-Cyclopentyl-2-[4-(3,5-dimethyl-pipera2in-l-yl)-phenylamino]- 6-fluoro-5-methyl-8 H-pyrido [2.3-d]pyriinidin-7-one hydrochloride(Compound 36), mp >220eC; (ii) 8>Cyclopentyl-2-(3-fluoro-4-piperazin-l-yl-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 37); (jj) 6-Bromo-8-cyclopentyl-2-{4-(3,5-dimethyl-pipera2m-l-yl)-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride(Compound 38), mp >230“C; (kk) 8-Cyclopentyl-6-fluoro-2-(3-fluoro-4-piperazin-l-yl-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrinudm-7-one (Compound 39); (11) 6-Bromo-8-cyclopentyl-2-(3-fluoro-4-piperazin"l -yî-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 40); (mm) 8-Cyclopenîyl-2-[4-(3,5-dimethyl-piperazin-l -yl)-phenvlamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (Compound 41); (nn) 2-(3-Chloro-4-piperazin-l-yl-phenylanimo)-8-cyclopentyl-5-mcthyl-SH-pyrido[2,3-d]pyrimidin-7-onc (Compound 42): (oo) 2-(3»Chloro-4-piperazm-l-yl-phcnylammo)-8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 43); (pp) 6-Bromo-2-(3-chloro-4-pipera2in-l-yl-phenylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 44); (qq) 8-Cyclopentyl-5-meihyl-2-(4-morpholin-4-yl-phenvlamino)«8H-pyrido[2,3-d]pyrimidin-7-one trifluoroacetate (Compound 45), mp 227-229°C; (rr) 8-Cyclopentyî-6-fluoro-5-methyl-2-(4-morpholm-4-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 46); (ss) 6-Bromo-8-cyclopentyl-5-methyl-2-(4-morphorm-4-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 47); (tt) 8-Cyclopentyî-2-(3-fluoro-4-moipholin-4-yl-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 48); PCT/ 2,,. 012227 (uu) 8-Cyclopenty]-6-fluoro-2-(3-fluoro-4-moipholin-4-yl-pbenyIanimo)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 49); (w) 6~Bromo-8-üyciüpentyI-2“(3-fluoro-4-morpholm=4-yl-phenylamino)-5-meihyl-8H"pyrido[2,3-d}pyrimidm-7“One (Compound 50); (ww) 2-(3-Chloro-4-moipholin-4-yl-pheaylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2.3-d]pyriniidin-7-onc (Compound 51); (xx) 2-(3-CMoro-4-moxpholin-4-yî-phenylamino)-8-cyclopeniyl-6-fluoro-5-methyi-8H-pyrido[2,3-d]pyriinidin-7-one (Compound 52); (yy) 6-Bromo-2-(3-chloro-4-morpholin-4-yl-phenylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 53); (zz) S-CyclopentyI-5-meihyl-2“ {4-[4-(2,2»2-Îrifluoro-ethyl)-piperazin-î-yl]-pheny]amino}-SH-pyrido[253-d]pyrimidm-7-one (Compound 54),mp 198-199eC; (aaa) 8-Cyclopentyl-6-fluoro-5-meihyl-2-{4~[4-(2,2,2-trifluoro-elhyJ)-piperazin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 55); (bbb) 6-Bromo-S-cyclopenîyl-5-methyl-2'{4-[4-(2J2,2-trifluoro-ethyl)-piperazin-1 -yl]-pheny lamino} -8H-pyrido[2,3-d]py rixnidin-7-one (Compound 56); (ccc) 8-Cyclopentyl-5-methyl-2-{4-[4-(3-piperazin-l-yl-propyl)-piperidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyriaiidin-7-one trifluoroacetate(Compound 57), mp>80eC (dec); (ddd) S-CyclopenÎyl“6-fluoro-5“meÎhyl-2- {4-[4-(3-piperazin-1 -yl-propvl)-piperidin-l-yl]-phenylamino}-8H-pyrido[23-d]pyrimidin-7-one (Compound 58).mp >230°C; (eee) 6-Bromo-8-cyclopentyl-5-methyl-2-{4-[4-(3-piperazin-l-yl-propyl)-piperidin-î -yl)-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 59); (fS) 8-Cyclopentyl-5-methyl-2-{4-[4-(3-morpholin-4-yl-propy])-piperidin-1 -yl]-phenylanûno}-8H-pyrido[23-d]pyrimidin-7-one (Compound 60); (ggg) 8-Cycîopentyl-6-fluoro-5-methyl-2- {4-[4-(3-morpholin-4-yl-propyl)-piperidin-1 -yl J-phenyJamino} -8H-pyrido [2,3 -d]pyriinidin-7-one(Compound 61);

.«U 01 222 7 (hhh) 6-Bromo-8-cyclopentyl-5-meihy]-2-{4-[4-(3-morpholin-4-yl-propyl)-piperidin-l-yl]-phenylamino}-8H-pyrido[2.3-d]pyrimidin-7-one(Compound 62); (iii) 6-Bromo-8-cyclopentyl-5-methyl-2-{4-[4-(3-inorpholin-4-yl-propyl)-5 piperidin-l-yl]-phenylamino}-8H-pyrido[2,3“d]pyrimidm-7-one (Compound 63): (jjj) 2-(4-{4-[3-(3-Ammo-pynolidin-l-yl)~propyl]-pjperidin-l-yl}-phenylamino)-8-cyclopentyl-5-methyl-8H-pyrido[23-d]pyrimidin-7-one(Compound 64); (kkk) 2-(4- {4-[3-(3-Amino-pyrrolidin-1 -yl)-propyl j-piperidin-1 -yl} -10 phenylamino)-8-cyclopeniyl-6-fluoro-5-methyl-8H-pyrido[2>3-d]pyrimidin-7-one (Compound 65); (111) 2-(4-{4-[3-(3-Axnino-pyrrolidin-l-yl)-propyl]-piperidin-l-yl}-phenylanuno)-6-bromO"8-cyclopentyl-5-methyî-8H-p}rrido[2,3-d]p)Tiinidin.-7-one(Compound 66); 15 (mnun) 8-Cyclopentyl-2-{3-fluoro-4-[4-(3-piperazin-l-yl-propyl)- piperidin-l-yl]-phenyîan±io}-5-methyl-8H-pyrido[2,3-d]pyrixnidin-7-one(Compound 67); (nnn) S-Cyclopentyl-6-fluoro-2-{3-fluoro-4-[4-(3-piperazin-1 -yl-propyl)-piperidin-l-yl]-phenylamino}-5-methyl-8H-pyrido[2J3-d]pyrimidm-7-one 20 (Compound 68); (ooo) 6-Bromo-8-cyclopenÎyl-2-{3-fluoro-4-[4-(3-piperazin-l-yl-propyl)-piperidin-l-yl]“phenyîamino}-5-methyl-8H*pyrido[2,3-d]pyriniidin-7-one(Compound 69); (ppp) 8-Cyclopentyl-2- {3-fluoro-4-[4-(3-morpholin-4-yl-propyl)-25 piperidin-1 -yl]-phenylamino) -5-methy l-8H-pyrido[2,3-d]pyriniidin-7-one (Compound 70); (qqq) 8-Cyclopentyl-6-fluoro-2- {3-fluoro-4-[4-(3-moipholin-4-yl-propyl)-piperidin-l-yl]-phenylamino}-5-meÎhyl-8H-pyrido[2.3-d3pyrimidin-7-one(Compound 71); 30 (rrr) 6-Bromo-8-cyclopentyl-2-(3-fluoro-4-[4-(3-morphûlin-4-yl-propyl)- piperidin-l-ylJ-phenylan3ino}-5-methyl-8H-pyrido[2,3-d]pyriinidin-7-one(Compound 72); WO0 012227 (sss) 2-(4-(3-Ammo-pyirolidin-l-yî)-phenylamino]-8-cyclopentyî- 5- methyl"8H-pyrido[2,3“^]pyrinüdm-7-one (Compound 73), mp >215°C (dec); (ttt) 2-[4-(3-AmïnO“pyïrolidin-l-yl)-phenylamino)-8-cyclopentyl- 6- fluoro-5-methyî-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 74); (uuu) 2-[4-(3’Amino-pyrrolidin-l"yI)-phenyJaniiiioJ-6-bronio-8-cyclopentyl-5-methyl“8H-pyrido[2,3-d]pyrimidin-7-one (Compound 75); (vw) 2-[4"(3-Amino-pyrrolidiQ-î"yl)-3-fluoro-phenylamino]-8-cycîopentyl-5-mcihyl-8H-p5rrido[2,3-d]pyrimidin-7-one (Compound 76); (www) 2-[4-(3-Aminc-pyrrolidin-l -yl)-3-fluoro-phenylammo]-8-cyclopenty]-6-iluoro-5-methyl-8H-p)TÎdo[2.3-d3pyriniidm-7-one(Componnd 77); (xxx) 2-[4-(3-Ammo-pyrrolidin- 1 -yl)-3-fluoro-phenyîamino)-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d3pyrimidm-7-one (Compound 78); (yyy) 8-Cyclopentyl-5-methyl-2-{4-[3-(2,2,2-trifluoro-elhylamino)-pyrrolidin-1 -ylj-phenylamino) -8H-pyrido[2,3-dJpyrimidin-7-one trifluoroacetate(Compound 79), mp>160°C (dec); (zzz) 8-Cyclopcntyl-6-fluoro-5-methyl-2-{4-[3-(2,2,2-triiluoro-ethylaxnino)-pyirolidin-l-yl3-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 80); (aaaa) 6-Bromo-8-cyclopentyl-5-methyl-2-{4-[3-(2,2,2-trifluoro-ethylamino)-pyrroîidm-l"yl3-phenylainiïio}-8H-pyrido[2,3“d]pyrimidin-7-one(Compound 81); (bbbb) 2-[4-(3-Aniino-pyïTolidm-l -yl)-3-chloro-phenylamino]-8-cy clopenty I-5-methy 1-8 H -pyrido (2,3 -d]pyriraidin-7-one trifluoroacetate(Compound 82), mp >215°C (dec); (cccc) 2-[4-(3-Amino-pyrrolidin-1 -yl)-3-chloro-phenylaminoJ-8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido[2,3-ùjpyrimidin-7-one(Compound 83), mp 221 °C; (dddd) 2-[4-(3-Amino-pyrrolidin-î -yl)-3-chloro-phenylainino]-6-bromo-8-cyclopentyl-5-methyl-SH-pyrido[2,3-d]pyrimidin-7-one (Compound 84); wo tiir, 012227 (eeee) 2-[4-(3-Aminomethyl-4-trifluoromethyl-pyrrolidin-l -vl)-phenylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d3pyrimidm-7-one(Compound 85); (ffiï) 2-[4-(3-Aminomethyl-4-triïluoromethyl-pyrroIidin-1 -vl)-phenylamino]-8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido[23-d]pyrimidin-7-one(Compound 86); (gggg) 2-[4-(3-Aminomethyî-4-trifluoromeihyl-pyrroIidin-l-yl)-phenylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 87); (hhhb) 2-[4-(3-Trifloroethylammomethyl-pyrrolidin-l -yl)-phcnylamino]-8-cyclopentyl»5-methyl-8H-pyrido[2.3-d]pyrimidin-7-oiie (Compound 88); (iiii) 2-[4-(3-TrrQoroethylaminomethyl-pyrrolidin-1 -yl)»phenylamino]-8-cyclopenÎyl-6-fluoro-5-meth.yl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 89); (jjjj) î-^S-Trifloroeftylaminomethyl-pyrrolidin-1 -yl)-phenylaminoj- 6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 90); (kkkk) S-Cyclopentyl-2-[4-(3,3-dimethyl-piperazin-l-yl)-phenylainino]· 5- methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (Compound 91),mp>150°C (dec); (1111) 8”Cyclopeniyl-2-[4-(3.3-dimethyl-pipera2m-l-yl)-phenylanüno3- 6- fiuoro-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-Gne (Compound 92): (mmmm) 6-Bromo-8-cyclopentyl-2-[4-(3,3-dimethyl-piperazin-1 -yl)-phenylamino]-5-methyl-8H-pyrido[2,3-d]pyriniidin-7-one hydrochloride(Compound 93), mp >200°C (dec); (nnm) 8-Cyclopaityl-5-methyl’2-[4-(3,3,4-trimethyl-pipera2in-l-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7"One (Compound 94); (oooo) 8-Cyclopentyl-6-fluoro-5-methyl-2-[4-(3,3.4-Îriniethyl-piperazui-l-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 95); (pppp) 6-Bromo-8-cyclopentyl-5-methyl-2-[4-(3,3,4-triniethyî-piperazin-l-yl)-phenylaminoJ-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 96); 012227 . (qqqq) 2-i4-(4-Acetyî-piperazin-l-yl>phenylamino]-8-cycîopentyl- 5- methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compuund 97); (mr) 2-[4-(4-AcetyÎ-piperazia-l-yl)-phenylamino3-8-cycîopexïîyl- 6- fluoro-5-meihyî-8H-pyrido(2,3-d]pyrimidin-7-one (Compound 98). mp267-269°C; (ssss) 2-[4-(4-Acetyl-piperazin-l -yl)-phenylamino3-6-bromo-8-cycîopenÎyî»5~nieihyl-8H--pyrido[2,3-d3pyrimidm»7»orie (Compound 99); (tttt) 8-Cyclopentyl-2-{4-[4-(2-hydroxy-ethyl)”3,5-dimethyî-piperazin-l-yI]-phenylamino}-5-metbyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 100), mp 156-159°C; (uuuu) 8-Cyclopentyl-6-fluoro-2-{4-[4-(2-hydroxy-ethvl>3,5-dimethyl-piperazin-1 -yrj-phenylammo}-5-methyl-8H-pyrido[2,3-d]pyrinùdin-7-one(Compound 101); (ww) 6-Bromo-8-cyclopentyl-2-{4-(4-(2-hydroxy-ethyl)-3,5-dimethyî-piperaziû,"l-yl]“phenyîamino}-5-ïïieÎhyI-8H-pyi'ido[2;,3-d]pyrimidm-7-onc(Compound 102); (wwww) 8-Cyclopentyi-5-methyî-2-(4-perhydro-1,4-diazepin-1 -yl-phenylamino)-8H-pyrido[2,3-djpyrimidin-7-one hydrochloride (Compound 103),mp 172°C (dec); (xxxx) 8-Cyclopentyl-6-fluoro-5-methyl-2-(4-perhydro-1,4-diazepin-1 -yl-phenylammo)-8H-pyrido[2,3-d3pyrimidin-7-one hydrochloride (Compound 104),mp 192°C (dec); (yyyy) 6-Bromo-8-cyclopentyl-5-methyI-2-(4-perhydro-l ,4-diazepin-] -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 105); (zzzz) 8-Cyclopentyl-5-methyl-2-[4-(4-melhyl-piperazin-l -yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 106),mp211-213°C; (aaaaa) 8-Cycîopentyl-6-fluoro-5-meihyl-2-[4-(4-meihyî-piperazin-l-yl)-phenylamino]-8H-pvrido[2,3-d]pyrimidin-7-one (Compound 107); (bbbbb) 6-Bromo-8-cy clopentyl-5-methyl-2-[4-(4-methyl-piperazin-1 -yl)-phenylamino3-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 108); PCT'’ 012227 (ccccc) 8-Cyclopentyl-5-methyl-2-[4-(4-methyl-perhydro-l ,4-diazepin-l-yl)-phenylanùno]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 109),mp >185ÙC (dec); (ddddd) 8-Cyclopentyl-6-fluoro-5-raethyl-2-l4-(4-methyl-perhydro- 1,4-diazepin-l -yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 110); (eeeee) 6-Bromo-8-cyclopentyl-5-methyl-2-[4-(4-methyl-perhydro- 1,4-diazepin-l -yl)-phenylaminoJ-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 111); (ffiff) {4-[4-(8-Cyc]opentyl-5-methyI-7»oxo-7s8-dihydro-pyrido[2,3-d]pyrimidm-2-ylanùno)-phenyl]-piperazin-l-yl}-aceticacid(Compound 112); (ggggg) {4-[4-(8-Cyclopentyl-6-fîuoro-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyï]-piperazin-î -yl}-acetic acid(Compound 113); (hhhhh) {4-[4-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-l -yl}-acetic acid(Compound 114); (iiiii) 8-Cyclopentyl-5-methyl-2-(4-{4-[3-(lH-tctrazol-5-yl)-propyl]-piperidin-l-yl)-phenyîamino)-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 115); (jinj) 8-Cyclopentyl-6-fl,uûro~5-meîhyl-2-(4"{4-[3-(lH-teîrazol-5-yl)-propylj-piperidin-l-yi}-phenylaminc)”8H-pyrido[2,3"d]pyrimidin-7-one(Compound 116); (kkkkk) 6-Bromo-8-cyclopexïtyl-5-methyl-2"(4-{4-[3-(lH-Îetrazol-5-yl)-propyl]-piperidin-l-yl}-phenyîainino)-8H-pyrido[2>3-d]pyrimidin-7-one(Compound 117); (11111) 8-CyclopeniyI-5-methyl-2-(4-{4-[3-(5-oxo-4,5-dihydro-lH- l,2,4-triazol-3-ylsulfanyl)-propyl]-piperidin-l-yl}-phenylaniino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 118); 012227 (mmrannn) 8-Cyclopentyl-6-fluoro-5-me±yî“2-(4-{4-[3-(5-oxo-4,5-dihydro-lH»1^4-triazol-3“ylsulfaQiyî>propyl]-piperidin-l“yî}-phenylainino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 119); (nnnnn) 6-Bromo-8-cyclopenîyl-5-methyl-2“(4-{4-[3“(5-oxQ-4,5-dihydro-lH-l,2,4"triazol-3-ylsulfaayl)-propyl3-piperidin-l-y]}-phenyIauiino)-8H-pyrido[2,3-d]pyrimidm-7one (Compound 120); (ooooo) 8-Cyclopentyî-5-methyl-2-(4"{4-[3-(5-oxo-4s5-dihydro-lH-ls2,4-tnazole-3-sulfinyl)-propyl]-piperidin-î-yl}-phenyîamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound-121); (PPPPP) 8-Cyclopentyl-6-fluoro-5-mexhyl-2-(4-{4-[3-(5-oxo-4,5-dihydro-1 H-1.2,4-triazoîe“3-sulfinyl)-propyl3“pîperidin-1 -yi}-phenylammo)-8H-pyrido[2,3-d]pyrimidin“7-one (Compound 122): (<Μ<3<ΐ<ϊ) 6-Bromo-8-cyclopentyl-5-meihy]-2-(4-{4-(3-(5-oxo-4!5-dihydro-1H-1,2,4-triazole»3-sulfinyl)-propyl3-piperidin-1 -yl}-phenylamino)-8H-pyrido[23"d3pyrimidin“7«one (Compound 123); (πώτ) 8-Cyclopentyl-5-methyl-2-(4-{4-(3-(5-oxo-4,5-dihydro-lH-1s2,4-Îriazole-3-sulfonyî)-propyl]-piperidin-l -yl}-phenyiamino)-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 124); (sssss) 8-Cyclopentyl-6-fluoro-5-methyl-2-(4-{4-[3-(5-oxo-4.5-dihydro-1H-1,2,4-triazole-3-sulfonyl)-propyl]-piperidin-l -yl)-phenylamino)-8H-pyrido[2.3-d]pyrùnidin-7-ûne (Compound 125); (ttttt) 6-Bromo-8-cyclopentyl-5-methyl-2-(4- {4-(3-(5 -oxo-4,S-dihydro-1 H-1.2,4-triazole-3-sulfonyl)-propyl]-piperidin-l-yl)-phenylamino)-8H-pyrido(2,3-d]pyriinîdm-7-one (Compound 126); (uuuuu) N-(2-{l=[4-(8-CyclQpentyl»5-methyî-7-oxo-7,8-dihydro-pyrido[23-d]pyrimidm-2-ylammo)-phenyI]-piperidm-4-yl}-ethyl)-N-bydroxy-acetamide (Compound 127); (wvw) N-(2-{ l-[4-(8-Cyclopenîyl-6-iluoro-5-methyl-7-oxo-7,8-dihydrc>-pyrido(2,3-d3pyrimidin-2-yîamino)-phenyl]-piperidin-4-yI}-etliyl)-N-hydroxy-acetamide (Compound 128); (wwwww) N-(2-{ï-{4-(6-Bromo-8-cyclopentyJ-5-meÎhyl-7-oxo- 7,8-dihydro-pyrido[2,3-dJpyrimidin-2-ylamino)-phenyl3-piperidin-4-yi}-eihyI)-N-hydroxy-acetamide (Compound 129);

PCT 01 222 7 (xxxxx) N-(3-{l-[4-(8-Cyclopentyl-5-mcthyl-7-oxo-7,8-dihydro-pyrido[23-d]pyrimidin-2-yiammo)-phenyl]-piperidin-4-yl}-propyl)-N-hydroxy-acetamide (Compound 130): (yyyyy) N-(3-{144-(8-Cyclopentyl-6-fiuoro-5-methyl-7-oxo-7s8-dihydro-pyrido[2,3-d]pyrùnidin-2-ylamino)-phenyl]-piperidin-4-yl}-propyl)-N-hydroxy-acetamide (Compound 131); (zzzzz) N-(3-{l-[4-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperidin-4-yl)-propyl)-N-hydroxy-acetamide (Compound 132); (aaaaaa) 2-(Benzofuran-5-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 133); (bbbbbb) 8-Cyclopentyî-2-(lH"indol-5-yîamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-onc (Compound 134); (cccccc) 2-(Benzo[b)thiophen-5-ylamino)-8-cyclopenTy]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 135); (dddddd) 8-Cycîopenxyl-2-(2,3-dimethyl-1 H-indol-5-ylamino)-5-methy 1-8H-pyrido[2,3-d]pyriniidin-7-one (Compound 136); (eeeeee) 2-(9H-Carbazol-3-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 137); (ffffff) 8-Cyclopenty]-2-(lH-indazol-5-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 138); (gggggg) 2-(2-Acetyî-benzofuran-5-ylamino)-8-cyclopcntyl-5-methyl-8K-pyrido[2,3-d]pyrimidm-7-one (Compound 139); (hhhhhh) 8-Cyclopenty’l-5-methyl»2-(4-morpholin-4-yl-phenylamino)-8II-pyrido[2,3-d]pyrimidin-7-one (Compound 140), mp 227-229°C; (iiîiii) 8-Cyclopenlyl-2-[4-(3,5-dimethyi-piperazin-l-yI)-phenylainino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 141); (jjjjjj) 2-(3-Chloro-4-piperazin-l -yl-phenyIamino)-8-cyclopenty]-5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one trifluoroacetate (Compound 142), mp234-237°C; (kkkkkk) 8-Cyclopentyl-5-methyl-2-(4-piperidm-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 143); pct/· -61- 012227 (111111) 8-Cyclopentyl-5-methyl-2-[4-(4-methyl=piperazin-l-yl)-pheuylaffiino]-8H-pyrido[2,3-d]pyriniidiD-7-one (Compound 144); (mnmmmm) N-{l-[4»(8“Cyelopentyl-5-methyl-7-oxo-7f8~dihydro-pyrido[2,3-d3pyrimidin-2-ylaaaino)-phenyl3-piperidiïi-4-yl}-acetamide(Compound 145); (nnimsm) 8-Cycîopentyl-5-methyî-2-(4-piperazin-l-yl-phenylamino)-8H-pyrido[2,3-dJpyrimidm-7-one îrifluoroaceiate (Compound 146), mp 237-240°C; (oooooo) 8-Cyclopentyl-6-fluoro-5-methyî-2-(4-piperazin-l -yî-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 147),mp 254-255’C; (PPPPPP) 6-Iodo-8-cyclopentyl-5-metbyl-2-(4-piperazin-l-yl-phenylammo)-8H“pyrido[23-dÎpyrimidin-7-one (Compound 148); (¾¾¾¾) 2-[3-Chloro-4-(3-ammo-pyrrolidin-1 -yl)»phenyIamino]-8-cyclopentyl-5-meÎkyi-8H-pyrido[2.3-d3pyrimidin-7-one trifiuoroacetate(Compound 149), mp >215°C (dec); (rrrrrr) 8-Cyclopentyl-5-methyl-2-[4-(4-(2.2,2-trifluoroethyl)-piperazin-1 -yl)-phenylamino]-8H-pyrido[2,3-d]pyrirmdin-7-one (Compound 150).mp 198-199°C; (ssssss) 8-Cyclopentyl-2-(4-fluoro-phenylarnino)-5-rnethyl-8H-pyrido[2.3-d]pyrimidin-7-one (Compound 151), mp 217-220°C; (tttttt) 8-Cyclopenîyl-5-meûiyî-2-phenylammo-8H-pyrido[2,3- / d]pyrimidin-7-one (Compound 152), mp 18O-Î83°C; (uuuuuu) 8-Cyclopentyl-2-(3,4-dicMorophenylamino)-5-methyl-8H-pyiido[2,3-d]pyrinïîdin-7-one (Compound 153), mp 225-230°C; (vwvw) 8-lsopropyl-5-methyl-2-(4-piperazin-1 -yl»pheny!amin.o)-8H-pyrido[2,3-d]pyrimidin-7-one trifiuoroacetate (Compound 154), mp >235°C(dec); (wwwwww) 8-Isopropyl-5-methyl-2-[4-(4-propionyl-piperazin-l -yl)-phenylamino]-8H-pyrido[2,3-d)pyrimidin-7-one (Compound 155); (xxxxxx) 8-Cyclohexyl-5-methyl-2-(4-piperazin-l-yI-phenylamino)-8H-pyrido[2s3“d]pyrimidin-7-one (Compound 156); PCT/1 ,, 01 222 7 (yyyyyy) 2-{4-[4-(3-MorphoIin-4-yl-propyI)-piperidin-I-yl]-phenylamino}-8-cyclohexyl-6-fluoro-5-niethy]-8H-pyrido[2.3-d]pyriniidin-7-one(Compound 157), mp 206-209°C; (zzzzzz) 8-Cyclopentyl-5-methyl-2-[4-(2H-1,2,4-triazol-S-ylsulfanylmethyl)-phenylamino]-8H-pyrido[2,3-d]pyrimidm-7-one(Compound 158); (aaaaaaa) 8-Cyclopcntyl-5-methyI-2-[4-(2H-î ,2,4-triazole-3-sulfinylmethyl)-phcnylammo]-8H-pyrido[2,3-d]pyTiinidin-7-onc(Compound 159); (bbbbbbb) 8-Cyclopentyl-5-methyl-2-[4-(2H-l ,2,4-triazole-3-sulfonylmethyl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 160); (ccccccc) 8-Cyclopentyl-5-methyl-2-[4-(5-oxo-4,5-dîhydro-l ,2,4-oxadiazol-3-ylmethyl)-phenylanimo]-8H-pyrido[2,3-d]pyrimidm-7-one(Compound 161); (ddddddd) 8-Cyclopentyl-5-methyl-2-{4-[2-(2H-1.2,4-triazol-3·ylsulfanyl)-eihyl]-phenylamino } -8H-pyrido[2,3-d]pyrimidin-7-one(Compound 162); (eeeeeee) 8-Cyclopentyl-5-methyl-2- {4-[2-(2H-1,2,4-triazole-3-sulfinyl)-ethyl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 163); (fgfEfê) 8-Cyclopentyl-5-methyî-2-{4-[2-(2H-1,2.4-triazole-3-suifanyl)-ethyl]-phenylamino}-8H-pyrido(2,3-d3pyrimidin«7“Oiie (Compound 164); (ggggggg) 8-Cyclopenxyî-5-methyl-2- {4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3~yl)-ethyî]-phenylamino}-8H-pyrido[2,3-djpyriinidin-7-one(Compound 165); (hhhhhhh) 8-Cyclopentyl-5-metbyl-2-[4-(3H-l ,2,3-triazul-4-ylsulfanylmethyl)-phenylamino]-8H-pyrido[2,3-d3pyrimidin-7-one(Compound 166); (iiiiiii) 8-Cyclopentyl-5-methyl-2-{4-[2-(3H-l,2.3-triazol-4-ylsulfanyl)-ethyl]-phenylammo}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 167); WO Ο PC’ 012227 finiîffl 8-Cyclopentyî-5-methyl-2-{4-[4-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3“yl)-piperidin-î-yl]-phenylamino}-8H-pyrido[2,3“d]pyriimdm-7-one(Compound 168); (kkkkkkk) 8-Cydopea.Îyl"5-meihyl-2-{4-[4-(2H-1.2,4»irîazoî-3·-5 ylsulfanyl>piperidia-l-yl3-phenylammo}-8H-pyrido[2s3-d]pyrimidin-7-one (Compound 169); (1111111) 8<yclopentyl-5-methyl-2"{4-[4-(2H4A4-triazole-3-suIfinyî)-piperidm-î-yl]-phenyîamino}-8H-pyrido[2,3-d]pyTiinïdin-7-one(Compound 170); 10 (mmmmnimm) 8-Cyclopentyî-5-meihyl-2-{4-[4-(2H-l,2,4-tria2ole-3- sulfonyl)-piperidin-l-ylî-phenylaxnino}-8H-pyrido[2,3-d3pyrimjdin-7-one(Compound 171), mp 235-237°C; (nnnnnnn) 8-Cyclopentyl-5-methyl-2-{4-[4-(2H-tetrazol-5-yl)-piperidin-l-yl3-phenyîamino}-8H-pyrido[23“d]pyrinùdin-7-one (Compound 172); 15 (ooooooo) 1 -[4-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3- d]pyrimidm-2-ylammo>phenyi]-piperidine-4-carboxylic acid (lH-tetrazol-S-yi)-amide (Compound 173); (ppppppp) 8-Cyclopentyl-5-methyl-2-{4-[4-(3H-l,2,3-triazoM-ylsulfanyi)-piperidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one 20 (Compound 173); ΟϊΨΜΦίΦ 3-ί4-(8^οΙορβ^1-5^β&γ1-7-οχο-7,8-ά^ύτο-ργι^ο[2.3-d3pyrimidin-2-yîamino)-phenyl]-N-(lH-Îeîrazoî-5-yl)-propionamide(Compound 174); (rrmrr) 2-[4-(8-CycIopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-25 d]pyrimidin-2-yîammo)-pbenoxy]-N-( 1 H-tetrazoî-5-yl)-acetamide (Compound 175); (sssssss) 8-Cyclopentyî-5-metbyl-2-[4-(5-oxo-4,5-dihydro-î ,2,4-oxadiazol-3-yImethoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 176), mp >195°C (dec); 50 (ttttttt) 8-Cyclopentyl-5-methyl-2-(4-{4-[2-(2H-l,2,4-triazole-3-suîfinyJ)- ethyl3-piperidin-l-yl}-phenylamino)-8H-pyndo[293-d3pyrimidin-7-one(Compound 177); ”Γ01 2227 -64- (uuuuuuu) 8-Cyclopentyl-5-methyl-2-(4-{4-[2-(2H-l,2,4-triazole-3-suîfonyl)-ethyl]-piperidin-l-yl}-pheaylamino>SH-pyrido[2»3-d]pynmidin-7-one(Compound 178); (vwww) 8-Cyclopcntyl-5-methyl-2-(4-{4-[2-(3H-l,2,3-triazol-4-5 ylsulfanyl)-ethyI]-piperidin-l-yl}-phenylamino)-8H-pyrido[2,3-d]pyriinîdin-7-one (Compound 179); (wwwwwww) 8-Cyclopentyl-5-methyl-2-(4-{4-[2-(2H-l,2,4-ttiazol-3-ylsuüanyl)-ethyl]-piperidin-l-yl}-phenylamiiio)-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 180), mp 234-237°C; 10 (xxxxxxx) 8-Cyclopentyl-5-methyl-2-(4- {4-[2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-ethyl]-piperidin-l-yl}-phenylamino)-8H-pyrido[2,3-d]pyrimidin- 7-one (Compound 181); (yyyyyyy) 8-Cyclopentyl-5-meîhy]-2-{4-[4-(2-oxo-2,3-dihvdro-l ,2,3,5-oxathiadiazol-4-yl)-piperidin-l-yl]-pfaenylammo}-8H-pyrido[2,3-d]pyrimidin-7- 15 one (Compound 182); (zzzzzzz) 8-Cyclopentyl-2-{4-[4-(2,2-dioxo-2,3-dihydro-l .2,3,5-oxathiadiazol-4-yl)-piperidin-l-yl]-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 183); (aaaaaaaa) 8-Cyclopentyl-5-methyl-2-{4-[4-(l-oxo-2,5-dihydro-lH-20 1,2.3,5-îhiaÎriazol-4-yI)-piperidin- l-yl]-pbenylamino}-8H-pyrido[2,3- d]pyrimidin-7-one (Compound 184); (bbbbbbbb) 8-Cyclopentyl-2-{4-[4-(l,l-dioxo-2,5-dihydro-lH-l,2,3,5-•thiatriazol-4-yl)-pÎperidin-1 -ylj-phenylamino} -5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 185); 25 (cccccccc) N-{ l-[4-(8-Cyclopentyl-5-methyl-7-oxo-7,S-dihydro- pyrido[2,3-d]pyrimidin-2-ylamino)-phenyI3-piperidine-4-carbonyl}-methanesulfonamide (Compound 186); (dddddddd) 8-Cyclopeniyl-5-methyl-2-{4-[3-(2H-l,2,4-triazol-3-ylsulfanyl)-pyirolidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one 30 (Compound 187); 01 222 7 (eeeeeeee) 8»Cyciopentyi-5-methyl-2»{4-[3-(2H-1 2.4-triazûle~3-sulfînyl)-pyïïûliàm-l-yl]-phenyiamiïio}-8H-pyrido[253-d]pyrimidiii-7-one(Compound 188); (flïïïïïï) 8-Cyclopemyl-5-methyl-2-{4-[3-(2H-l,2,4-îriazoIe-3-sulfonyl)-pyrrolidin“l»yI3"phsnylamino}”8H-pyrido{2s3-<ijpyiimidin-7"One(Compound 189); (gggggggg) S"Cyclopentyl-5-methyl-2-{4-[3-(3H-î ,2,3-triazol-4-ylsullànyî)-pyiTolidin-î“yl3-phenylaxnino}-8H-pyriilo[2.3-d]pyrimidin.-7-onc(Compound 190); (hhhhhhhh) 8-Cyclopentyl-5-methyl-2-{4-[3-(5-oxo-4,5-djliydro-l,234-oxadia2ol-3"yl)»pyirolidin-3-yl3»phenylamino}“8H=pyrido[2,3’d3pyrirmdin-7"One(Compound 191); (iiiiiüi) 8-Cyclopentyî-5-methyl>2-{4-[4-(3-hydroxypropyi)piperidin-l-yl]-phenylammo}-8H-pyrido[2.3-d]pyrimidm-7-one trifluoroacetate(Compound 192), mp 1S 0-184CC; (iüiiijj.) 8-CyclopentyÎ-5-propyl-2-(4-piperazin-l-yj-phenylarainc)-8H-pyrido[2.3-d]pyrimidin-7-one trifluoroacetate (Compound 193); (kkkkkkkk) 8-Cyclop6ntyl-5-ethyl-2-(4-piperazin-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 194); (11111111) 8-(l-Methylethyl)“5-ethyl-2-(4-piperazùi’l-yî-phenylamino)-8H-pyrido[253-d]pyrimidm-7»one (Compound 195), mp >235°C (dec); (mnHnmmmmm) 8-( 1 -Methylethyl)-5-ethyl-2-(4-piperazin-1 -yl-phenylamino)-8H-pyrido[2,3“d]pyrimidm-7-one trifluoroacetate(Compound 196), mp >235°C (dec); (nimumum) 8-CycIopentyl-5-methyl-2-[4-(3^droxypyrrQÎidin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 197),mp 225-226eC; (oooooooo) 8~Cyclopentyl-5-ethyl-2-[4-(4-acetylpiperazin-l-yî)phenylamino]-8H-pyrido[2,3“d]pyrimidin-7-one (Compound 198); (PPPPPPPP) S“Cyclopentyî-5-methyl-6-fluoro-2-[4-(4-acetylpiperiâin-l-yl)phenylamino]-8H-pyrido[2,3"d3pyrimidm-7-one (Compound 199),mp267-269°C; -66- 012227 (qqqqqqqq) S-Cyclopropyl-5-methyl-2-[4-(4-acetamidopiperidin-1 -yl)phenylaminoJ-8H-pyrido[23-d]pyrimidin-7-cnc (Compound 200), mp 221°C(dec); (qqqqqqqr) 8-Cycîopropyl-5-meftyl-6-fluoro-2-[4-(4-acetamidopiperidin- l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 201).mp >250*C; (rrrrrrrr) 8-Cyclopentyl-5-methyî-2- [4-(homopiperazin-1 -yl)phenylamino]-8H-pyrido[2,3-d]pyrimidîn-7-one hydrochloride(Compound 202), mp 172®C (dec); (ssssssss) 8-Cyclopentyl-5-methyl-6-fluoro-2-[4-(hornopiperazin-l -yl)phenylamiao]-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride(Compound 203), mp 192°C (foam); (tttttttt) 8-Cyclopentyl-5-meîhyl-6-fluoro-2-[4-(3,3-dimetbyî-4-acetylpiperazin-i-yî)phenylamino]-8H-pyxido[233-d]pyrimidin-7-one(Compound 204), mp 200-204°C; (uuuuuuuu) 8-Cyclopentyl-5-methyl-2-[4-(3,3-dimethyl-4-acetvlpiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 205), mp 192-196° C; (wwww) 8-Cyclopentyl-5-methyl-6-fluoro-2-[4-(4-methyîpiperazin-l -yl)phenylamino3-8H-pyrido(2,3-d3pyT«nidin-7-onetrifluoroacetate(Compound 206); (wwwwwwww) 8-Cyclopentyl-5-methyï-2-[4-(N-methylacetamido)phenylaminoj-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 207), mp 185-187eC; (xxxxxxxx) 8-Cyclopentyl-5-methyl-2-{4-[2-(2-hydroxyethoxy)ethylamino]phenyiamino}-8H-pyrido[2,3-d]pyrimidm-7-one(Compound 208), mp 122-126°C; (yyyyyyyy) 8-Cyclopentyl-5-methyl-2-[4-(3-oxopiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 209), mp >235°C(dec);

Pf 012227 (zzzzzzzz) 8-Cyclopentyl-5-methyl-2-[4-(2-methoxyetho3sy)phenylammo]-8H“pyrido[2,3-d3pyrimidin-7-one(Compound 210), mp 156-iS7°C; (aaaaaaaaa) 8-Cyclopentyî-5-meîhyl-2-(9H carbazol-3-yl amino)-8H-pyrido[2,3-djpyrimidin-7-one (Compound 211); (bbbbbbbbb) 8-Cyclopentyl-5-methyl-2-(lH-indazol-5-yl)amîno-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 212); (ccccccccc) 8-Cyclopentyî-5-methyl-2”(2-aceîylbenzofüran-5-yl)amino-SH-pyridc[23-d]pyrimidin-7-one (Compound 213); (ddddddddd) 8~Cyclopentyl-5-methyî-2-[(4-piperidin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 214); (eeeseeeee) 8-Cyclopentyl-5-methyl-2-(23-dimethylindol-5-yl)amino-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 215); (ffiffiffî) 8-CyclopentyI-5-isopropyl-2-[4-(3,5-methy]-4R-aminomeîhylpyrrolidin-l-yl)phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 216); (ëëëëëëëëë) 8-Cyclopenty]-5-methyl-2~{4-[4-(2-liydroxyethyl)pjperazin-l-yl)]phenylamino}“8H-pyrido[2!3-d3pyrimidin-7-one (Compound 217),mpl71-I73°C; (hhhhhhhhh.) 8-Cyclopentyl-5-meîhyl-2-{4-[4--(3-morpholinopropyl)piperidin-l-yl]phenylamino}-8H-pyrido[23-d]pyrîinidin-7-onetriiuoroacetic acid sait (Compound 218), mp 178-181°C; (iiüiixii) 8-Cyclopentyl-5-methyl-2-(benzofuran-5-yl)anüno-8H-pyrido[2,3-d]pyrixnidin-7-one (Compound 219); (iÿnjnj) 8-CyclopentyI-5-methyî-2-(indoî-5-yl)amino-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 220); and (kkkkkkkkk) S-CyclopentyI-5-methyi-2-(thionaphthen-5-yl)amino-8H-pyrido[2,3-d]pyriniidin-7-one (Compound 221);. 8-Cycîopentyl-6-iodo-5-methyl-2-(4-piperazin“l-yl-phenylamino)-8//-pyrido[2,3-ù0pyriinidin-7-one (Compound 225), mp 185-198’C (dec);

PC 01 2227 8-Cyclopentyl-2-{4-(l-(3,5-dimethyl-piperazin-l-yl)-methanoyl]-phenylamino}-5-methyl-8J7-pyrido[2,3-z/]pyrimidin-7-one (Compound 226),mp 181 (foam); 8-Cyclopentyl-2-[4-(3,5-dimethyl-piperazin-l -yl)-phenylamino]-5- ’trifluoromethyl-82f-pyrido[2,3-<fJpyrimidin-7-one (Compound 227),mp 200(foam); 6-Bromo-8-cyclopenÎyl-2-[4-(3,3-dimethyl-piperazin-l-yî)-phenylamino]-5-methyl-87i-pyrido[2,3-d]pyrimidin-7-one (Compound 228), mp >200 (dec); 8-Cyclopenty]-2-[4-(3,5-dimeihyl-piperazin-l-y])-pheny]arnino]-ô-iodo-5-mediyl-8JÏ-pyrido[2,3-4IpyrimidÎn-7-one (Compound 229), mp 225-226°C (dec); 6-Chloro-8-cyclopentyl-2‘[4-(3,5-dimethyl-piperazm-l-yl)-phenylamino]-5-methyl-8//-pyrido[2,3-d]pyrimidin-7-one (Compound 230), mp >250°C; 8-Cyclopentyl-5-methyl-2-[4-(îH-[l^,4]tria2ol-3-ylsulfanyl)-phenylamino]-8H-pyrido[2^-d]pyrimidin-7-one (Compound 231); 4-[4~(S-Cyclopexityl-5-methyî»7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin- 2-ylamino)-phenyl]-piperazine-l-carbaldehyde (Compound 232), mp-244-247°C; 8-Cyclopentyl-2-(4-piperazin-l-yl-phenylamino)-5-trifluoromethyl-877-pyrido[2,3-d]pyrimidin-7-one (Compound 233), mp >275°C (dec); 8-( 1 -Ethyl-propyl)-5-methyl-2-(4-piperazin-1 -yl-phenylamino)-8/f-pyrido[2,3-d}pyrimidin-7-one (Compound 234), mp >180°C (dec); [4-(8-Cyclopentyl-5"methyl-7“Oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin"2-ylamino)-benzyl]-phosphonic acid (Compound 235), mp >250°C; 6-Chloro-8-cyclopentyl-5-methyl-2-(4-piperazin-1 -yl-phenylammo)-8H-pvrido[233-J]pyrimidin-7-one (Compound 236), mp 188°C (dec); 2- [4-(3,5-Dimethyl-piperazm-1 -yl)-phenylamino]-8-(l -ethyl-propyl)-5-methyl-8tf-pyrido[2,3-d]pyrimidin-7-one (Compound 237), mp >185°C (dec); 8-Cyclopentyl-2-[4-(2-hydroxy-ethylamino)-phenylammo]-5-metliyl-S7/-pyrido[2,3-d]pyrimîdm-7-one (Compound 238), mp 197-200°C; 3- [4-(S-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yiammo)-phenyi]-2^A“diethyI-propionamide (Compound 239), mp 13S-140°C; 8-CyclopeQtyl-6-fluoro-2-[4-(2-hydrûxy-ethyl)-phenylamino]-5-methyl-Sff-pyrido[2,3-</lpyrimidin-7-one (Compound 240), mp 241-244°C; η ι>

?C 012227 8“Cyclopentyî-2-[4-(2-hydToxy-ethyî)-phenylamino]-5-methyl-87Z-pyrido[2,3=<dpyrimidin-7-one (Compound 241), mp 191-194°C; 4-(8“Cyclopentyl-5-meîhyi-7“OXO-7»8-dihydro-pyrido[2,3-//Jpyrimidin-2-ylamino)-benzoic acid (Compound 242); 8-Cyclopentyl-2-[4-(3,3-àmethyl-piperaan-l-yî)-phenylamino3-5-metlîyl-87f-pyrido[2,3-<ïjpyrisiidin-7-one (Compound 243), mp >150°C (dec); [4-(8~CydopenÎyl--5”methyl-7-oxo-7)S-dihyàro-pyrido[2,3”d]p>’nnTjàm-2-y3amino)-benzyl]-phosphomc acid diethyl ester (Compound 244),mp >250°C (foam); 8-Cyclopentyl-6-fluoro-2-[4-(2-methoxy-ethylamino)»phenylaminoj-5-methyî-8#-pyrido[2,3-d3pyrimidin-7-one (Compound 245), mp 147-149'5C; (S)-2-Amino-3-(4-(8-cyclopentyl-6-fluoro-5-methyl-7-oxo-7s8-dihydro-pyrido[2,3“fljpyrimidùi~2-y!arnmo)--phenyî]~propionic acid (Compound 246),mp 238°C (dec); 8-Cyclopentyl-2-[4-(2-methoxy-ethoxy)-phenylamino}-5-methyl-8.ii-pyrido[2,3-d3pyrimidin-7-one (Compound 247), mp 156-157°C; 8-Cyclopentyl-2-(4-isopropylamino-phenylamino)-5-methyl-8B'-pyrido[2,3-d]pyrimidin-7-one (Compound 248), mp 216-220eC; 8-Cyclopentyl-2-(4-hydroxy-3,5-dimethyl-phenylamino)-5-methyl-8Z/-pyrido[2,3-d]pyrimidin-7-one (Compound 249), mp 252-254°C; 8-Cyciopentyî-6"fluoro*2“(4-hydroxy-3,5-dimethyi-pheGylamino)-5-methyl-8K-pyrido[2,3-d]pyrimidin-7-one (Compound 250), mp 241-248°C; 8-Cyclopentyl-6-fluoro-2-(4-hydroxy-3,5-dimethvl-phenylamino)-5-methyl-87/-pyrido[2,3“d]pyrimidin-7-onc (Compound 251), mp 240°C (dec). EXAMPLE 19

Biologictti Assays

Several of the invention compounds hâve been evaluated in standardassays routinely used to measure inhibition of cyclin-dependent kinase enzymesand other serine/threonine protein kinases. The assays were camed ont as foîlows:

Cdkl and Cdk2 enzyme assays for IC50 déterminations and kineticévaluation are performed as folîows. 96-well fîlter plates (Milîipore VO1" CT' 012227 MADVN6550) are used. The total volume is 0.1 mL 20 mM TRIS (pH 7.4), 50 mMNaCl, 1 mM dithiothreitol, 10 mM MgCl2,12 mM ATP containing 0.25 pCi [32P]ATP, 20 ng enzyme (Cdk2/cyclin E, Cdk2/cyclin A, or

Cdkl/cyclin B), 1 ug retinoblastoma protein, and appropriate dilutions of tlie particular invention compound. Ail components except the ATP are added to thewells, and the plate is placed on a plate mixer for 2 minutes. The reaction isinitiated by addition of [22P]ATP, and the plate is incubated at 25°C for15 minutes. The reaction is terminaîed by addition of 0.1 mL 20% TC A. The plateis 'kept at 4°C for at least 1 hour to allow the substrate to precipitate. The wells are then washed five times with 0.2 mL 10% TCA, and 32P incorporation is detennined with a beta plate counter (Wallac Inc., Gaithersburg, MD).

The Cdk4 enzyme assay for IC50 détermination and kinetic évaluation isperformed as follows. 96-well filter plates (Millipore MADVN6550) are used.

The total volume is 0.1 mL containing a final concentration of 20 mM TRIS(tris[hydroxymethyl]aminomethane) (pH 7.4), 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl2,25 μΜ ATP containing 0.25 pCi [32p]ATP. 20 ng Cdk4,1 pgretinoblastoma protein, and appropriate dilutions of a compound of the présentinvention. Ail components except the ATP are added to the wells, and the plate isplaced on a plate mixer for 2 minutes. The reaction is started by adding [22P]ATP,and the plate is incubated at 25°C for 15 minutes. The reaction is tenninated byaddition of 0.1 mL 20% trichloroacetic acid (TCA). The plate is kept at 4°C for atleast 1 hour to allow the substrate to precipitate. The wells aie then washed fivetimes with 0.2 mL 10% TCA, and 32p incorporation is detennined with a bctaplate counter (Wallac Inc., Gaithersburg, MD).

For PDGF receptor (PDGFr) and FGF receptor (FGFr) tyrosine kinaseassays, full-length cDNAs for the mouse PDGF-β and human FGFl(flg) receptortyrosine kinases are obtained from J. Escobedo and prepared as describedpreviously (Escobedo et al., J. Biol Chem., 1988;262:1482-1487). PCRprimersare designed to amplify a fragment of DNA that codes for the intracellulartyrosine kinase domain. The fragment is inserted into abacuîovirus vector,cotransfected with AcMNPV DNA, and the recombinant virus is isolated. SF9 4Ό ΟΐΛυ PCT/USe*' 012227 insect cells are infecîed with the viras to overexpress the protein, and the ce]] lysate is used for the assay. PDGFr and FGFr enzyme assays are performed in 96-well plates(100 pL/incubation/well), and conditions are optimized to measure theincorporation of 32p fi-om [γ32ρ]ΑΤΡ into a glutamate-tyrosine co-polymersubstrate. Briefly, to each well is added 82.5 pL incubation buffer containing25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1% Triton X-100,0.2 mM PMSF, 0.2 mM NagVOzt, 10 mM MnCl2, and 750 pg/mL Poly (4:1) glutamate-tyrosinefoüowed by 2.5 pL inhibitor and 5 pL enzyme lysate (7.5 pg/pL FGFr or6.0 pg/pL PDGFr) to initiate the réaction. Following a 10-minute incubation at25°C, 10 mL [γ32ρ]ΑΤΡ (0.4 pCi plus 50 pM ATP) is added to each well, andsamples are incubated for an additional 10 minutes at 25°C. The réaction isterminated by the addition of 100 pL 30% trichloroacetic acid (TCA) containing20 mM sodium pyrophosphate and précipitation of material onto glass fiber mats(Wallac). Filters are washed three times with 15% TCA containing 100 mMsodium pyrophosphate, and the radioactivity retained on the filters is counted in aWallac 1250 Betaplate reader. Nonspecific activity is defîned as radioactivityretained on the filters following incubation of samples with buffer atone (noenzyme). Spécifie enzymatic activity (enzyme plus buffer) is defîned as totalactivity minus nonspecific activity. The concentration of a compound thatinhibited spécifie activity by 50% (IC50) is determined based on the inhibition curve.

The c-Src protein kinase assay is carried out as follows. c-Src kinase ispurified front baculovirus infected insect cell lysâtes using an antipeptidemonoclonal antibody directed against the N-terminal amino acids famino acids2-17) of c-Src. The antibody, covalently linked to 0.65 pm latex beads, is added toa suspension of insect cell lysis buffer comprised of 150 mM NaCl, 50 mM Tris(pH 7.5), 1 mM DTT. 1% NP-40,2 mM EGTA, 1 mM sodium vanadate. 1 mMPMSF, 1 pg/mL each of leupeptin, pepstatin, and aprotinin. insect cell lysatecontaining c-Src protein is incubated with these beads for 3 to 4 hours at 4°C withrotation. At the end of the lysate incubation, the beads are rinsed three times in wo PCT/l'6 -72- 012227 lysis buffer, resuspended in ly sis buffer containing 10% glycerol, and frozen.These latex beads are thawed, rinsed three times in assay buffer (40 xnM Tris(pH 7.5), 5 mM pg Cb) and suspended in the same buffer. In a Millipore 96-welîplate with a 0.65 pm polyvinylidine membrane bottom are added the reaction 5 components: 10 pL c-Src beads, 10 pL 2.5 mg/mL poly GluTyr substrate, 5 pMAIT* containing 0.2 pCi p^P]ATP, 5 pL DMSO containing inhibfrnre or as asolvent control, and buffer to make the final volume 125 pL. The reaction isstarted at room température by addition of ATP and quenched 10 minutes later bythe addition of 125 pL 30% TCA, 0.1 M sodium pyrophosphate for 5 minutes on 10 ice. The plate is then filtered and the welîs washed with two 250-mL aliquots of15% TCA, 0.1 M pyrophosphate. The filters are then punched, counted in a liquidscintillation counter, and the data examined for inhibitory activity in comparisonto a known inhibitor such as erbstatin. The method has been described byThompson et al., J. Med Chem., 1994;37:598-609. 15 The results of the foregoing assays for several représentative invention compounds are presented in Table 1. The metabolic stability of représentativeCompounds was evaluated in human liver microsomes (HLM) and is given inTable 1 as the time in minutes (T Half) required for one-half of the parentcompound to disappear after being added to a HLM homogluate. PCT/l -73- 012227

Table 1(Page 1 of 3)

Compound MP CŸCKÎB CŸCK2Â CŸCK2E CYCK4 " FGF CSRC THALF

No. degrees C IC50 IC50 IC50 IC50 IC50 IC50 HLM en <1<» 2 m r^ < ·<^^22 <<<<<< o222222,0 o 00 eo 00 v© ’S·

CM 2222a a A A 2 c- scs m < vs2 Λ T Ό VSe © —, <? VS —< 2S2S22? 2

vs MT 00 *MM «MM scs ο- oo © <c> ses TT SO SO 04 -BK» W-i 4Λ © î*» Ό f—4 SJ· CS © © CM © © O-R 0 © © 0 © © © CM V*> ICS 2 © 2 © 0 2 O O 0 © © 0 © O* © ©' c4 c\i Λ U O

CM

‘OVSVSVSVSVSVIVSVSVSVS λΛαΑΛΑΛΛΛΛΑ

vs vs v,A A A vs

OS ©

scs © scs «esA en A A

VS vs

A

CO > rn

« — vs vs vs vsΑΛΑ Zs A vs

Zs os <*s 00 —< TC CS Os

Vs

ίΑ a A O c<u uT3 Ό

CM

V VZs A

V. vsZs A C**· t*·*

A A A

VS so t> C-ζ Γ-ΙΛ V> Vs <\| 'C. «

Zs A A O scsΛ Λ cm sirs cmSCS Vs V» SCS c*

CM CM CM

A A c~ os

CM CM

i? 8 O flJ O Q Ch m O (U IC CS © m © © Ji © Ί3 *© vn «MM» "O *n 0 CS CM oo m © 00 73. f»s s-** «rt 04 04 0 CM ^1 04 CM r—1 Z" V> O © «— Ό 4 04 00 A © Ô î © OC Λ «MM «MM< 00 A Cs r—1 00 04 © OO A 04 A Λ 04 A 04 A 04 —0 CM ** 04 CM CMC-'CMsOSTSt'-OOmCS<— Tf scs SCS C- t"

CM OCO O

V <3

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PCT -74- 012227 Ά 3 X S3t— *" o,ai unoo ÙU ~

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CM nr unOn ·>8· oo en en un un cm O cm un — un CM Ό un ae «enΛ Λ un un unΛ Λ Λ

Χ“·\ U O no en On “t? Q M" no c~. no jis en w U Ό CM v© no 3 O 8 CM On O on 80 CM W r>· 90 O S* *n <7 un 2 cm c* 3-un- Sn* S CM 1 O 1 CM B un 1 CM wS—* o i 1 00 OO Os 00 o o CM en CM Ό no CM “ f**· © On oo CM en t** *>M n Λ CM CM CM CM CM A sA Ο

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Q V. < s Wûf -75- 012227 U-

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SC ra·» ni o

JS ca 3 o g- S _o £o 2

CS o c «3 «

Q

II s ρ<· 012227

Vaâous properties of preferrcd 5-methylpyridopyrimidin-7-ones such as8-cyclopentyl-5-methyl-2-[(4-piperaânylphenyl)-amino}-S4iydropyridino[2,3-d]pyrimidin-7-one (Compound 1), including IC5Q, stabiliry, and clearance rate,are displayed in Table 2.

Table 2

Compound 5-Me IC50 (μΜ) Τ’Λ in Clearance

Cdkl/ Cdk2/ Cdk2Z Cdk4 FGFr c-Src PDGFr HLM (mL/min/kg)cyclinB cycliaA cyclinE(min) 1 Yes >5 >5 >5 0.007 1.077 83 57 Yes >5 >5 >5 0.151 6.0S 73 Yes >1.7 >1.7 >5 0.061 >5 80 79 Yes >5 >5 >5 0.975 NA 34 8 152 Yes >1.7 4.91 >5 2.15 NA >50 4 10

From the results displayed in Table 2, it is clear that Compound 1 andother invention compounds specifically inhibit Cdk4, and bas relatively littleeffect on Cdkl and Cdk2. Furthennore, Compound 1 is relatively more stable, andcleared at a slower rate, compared to prior art compounds. These results indicatethat the methyî group in the 5-position confers unique properties onto thepyridopyrimidine and is a preferred embodiment

Formulation Examples

As noted above, the invention compounds will typically be furmulatedwith common excipients, diluents, and carriers to provide compositions that arewell-suited for convenient administration to mammals. The following examplesillustrate typical compositions that are provided in a further embodiment of thisinvention. 15 iVOOl/ -77- EXAMPLE20 012227

Tablet Formulation

Ingrédient Amount Compound 12 50 mg Lactose 80 mg Comstarch (for mix) 10 mg Comstarch (for paste) 8mg Magnésium Stéarate (1%) 2 mg 150 mg

Compound 12 is mixed with the lactose and comstarch (for mix) andblended to uniformity îo apowder. The comstarch (for paste) is suspended in6 mL of water and heated with stirring to forai a paste. The paste is added to themixed powder, and the mixture is granulated. The wet granules are passed îhrougha No. 8 hard screen and dried at 50°C. The mixture is lubricated with 1%magnésium stéarate and compressed into a tablet. The tablets are administered to apatient at the rate of 1 to 4 each day for prévention and treatment ofatherosclerosis. EXAMPLE 21

Parentéral Solution

In a solution of 700 mL of propylene glycol and 200 mL of water forinjection is added 20.0 g of Compound 38. The mixture is stin-ed and the pH isadjusted to 5.5 with hydrochloric acid. The volume is adjusted îo 1000 mL withwater for injection. The solution is sterilized, fiîled into 5.0 mL ampoules, eachcontaining 2.0 mL (40 mg of Compound 3 8)s and seaîed under nitrogeû. Thesolution is administered by injection to a patient suffering fi-om cancer and in needof treatment.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise, and exact tenus as to enable any personskilled in the art îo which it pertams, to make and use the same. It is to beunderstood that the foregoing describes preferred embodiments of the présent V ** " 01 222 7 invention and that modifications may be xnade therein without departing from thespirit or scope of the présent invention as set forth in the daims. To particularlypoint out and disiinctly ciaim the subject matter regarded as invention, thefollowing daims conclude this spécification.

Claims

-79- CLAÏMS ΡΓ“ 012227 What is cîaimed is:

1. A compound of the formula

and pharmaceuticalîv acceptable salts, esters, amides, and prodrugsthereof, wherein: is (a) hydrogen; (b) lower aîkyl optionally substituted with one, two, or threegroups independentiy selected from halogen, hydroxy,lower alkoxy, amino, mono- or dialkylanaino, carboxy,alkoxycarbonyl, thioalkyl, nitrile, aryl, heteroaryl, or acarbocyclic group containing from 3 to 7 members, up xotwo of which members are optionally heteroatomsindependentiy selected from oxygen, sulfur, and nitrogen;or · (c) a carbocyclic group containing from 3 to 7 members, up totwo of which members are optionally heteroatomsindependentiy selected from oxygen, sulfur, and nitrogen,wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independentiyselected from consisting of halogen. hydroxv, lower alkyl,lower alkoxy, amino, mono- or diaUcylamino, aryl, andheteroaryl; 012227 R? is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, loweralkynyl, lower alkenyl, nitrile, nitro, -COR4, -CO2R4. -CONR4R5,CONR4OR5, -SO2NR4R5, -SO2R4, -SO3R4, I R4 P(O)(OR4)(OR5), or-NR4R5; Y is N or CR7; R^ is lower alkyl, haloalkyl, or aiyl; X and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, hydroxy, nitrile, nitro, -NR4R5, -N(O)R4R5,-NR4R5R6W, -SR4, -C(O)R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P(0)(OR4)(OR5), -T(CH2)mQR4, -C(O)T(CH2)mQR4, or-NR4C(O)T(CH2)mQR5; m is 1 to 6; T is O, S, NR4, N(O)R4, NR4R5W, or CR4R5; Q is O, S, NR4, N(O)R4, NR4R^ W, CO2, or a carbocyclic group containing from 3 to 7 members, up to four of which members areoptionally heteroatoms independently selected from oxygen, sulfur,and nitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independently selectedfrom halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyl, aîkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino,or mono or dialkylamino; R6 is lower alkyl, haloalkyl, or aryl; R7 is NR4R5, N(O)R4R5, NR4r5r9w, OH, OR4, SR4, halo, COR4, (CH2)nR4, (CH2)nR4, CO2R4, CONR4R5, C(O)NR4SO2r5, S(O)R4, SO2R4. SO2NR4R5. SO3R4, (CH2)nP(O)(OR4)2, NR4SO2R5, aldéhyde, nitrile, nitro, alkyl, alkoxyaîkyl, •81- 012227 TfCH^QR4, C(O)T(CH2)mQR4,NR4C(O)T(CH2)inQR5, orT(CH2)mCO2R4; n is 0 îo 6; W is an anion; R4 and r5 æ-e independently hydrogen, lower alkyl, îower alkenyl, loweralkynyl, (CH^Ar, arylaîkyî, aryl, heteroaryl, heteroarylaîkyl, cycloalkyl, heterocycloalkyl, or heteroaryl, or R4 and R$ togetherwith the nitrogen to which ihey are aitached form a carbocyclicring containing 3 to 8 raembers, up to four of which members areoptionally carbonyi groups or heteroatoms independently selectedfrom oxygen, sulfur. S(O), S(O)2, and nitrogen, wherein thecarbocyclic group is unsubstituted or substituted with one. two,three. or four groups independently selected front halogen,hydroxy, hydroxyalkyl, lower alkyl, krwer alkoxy, alkoxycarbonyl,alkyîcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, îrifluoromeihyl, trifluoromethylalkyl,trifluoromcthylalkylaminoalkyl, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR10SO2Rn, C(O)NR^R11,NR1®C(O)R^1, C(O)OR10,C(0)NRlOS02Ru, (CH2)nS(0)nRlO, (CH2)n-heteroaryl,O(CH2)n-beteroaiyl, (CH2)nC(O)NR10Rn, O(CH2)nC(O)ORl°; and R4 additionalîy can be lower alkyl unsubstituted or substituted withone, two, or three groups independently selected from halogen, 5 -oxo-4,5-dihy dro-1 H-1,2,4-triazol-3 -y l-su Ifany 1,5-oxo-4,5-dihydro-l#-l,2,4-triazol-3-yl-sulfinyl, 5-oxo-4,5-dihydro-l£f- l,2,4-triazol-3-yl-sulfonyl, or a carbocyclic group containing from3 to 7 members, up to four of which members arc optionallyheteroatoms independently selected from oxygen, sulfur, andnitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independently selected PCT/l 012227 from halogen, hydroxy, hydroxyalkyl, Iower alkyl, lower alkoxy,alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkvl,trifluoromethyl, N-hydroxyacetamide, trifluorometbylalkyl, amino.or mono- or dialkylamino; and r!0 andRjl are independently hydrogen, halogen, lower alkyl, loweralkoxy, or alkylcarbonyl. A compound of the Formula Π

and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R^ îs hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, loweralkynyl, lower alkenyl, nitrile, nitro, -COR4, -CO2R4, CONR4R-,CONR4OR5, -SO2XR4R5: -SO?R4. -SO3R4, -P(O)(OR4)(OR5), I R4 or-NR4R5; Y is N or CR7; X and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, hydroxy, nitrile, nitro, -NR4R^, -N(O)R4r5,-NR4R5R6W, -SR4, -C(O)R4, -CO2R4, -CONR4R5,-SO2NR4r5, -SO2R4, -SO3R4, P(O)(OR4)(OR5), -T(CH2)mQR4. -C(O)T(CH2)mQR4, or -NR4C(O!T(CH2)mQR5;m is 1 to 6; T is O, S, NR4, N(O)R4. NR4R5w, or CR4R5; FL. 012227 Q is O, S, NR4, N(O)R4, NR4r5w, CO2, or a carbocyclic group containing from 3 ίο 7 members, up îo four of which members areoptionally heteroatoms independently selected from oxygen, sulfur,and nitrogen, wherein the carbocyclic group is unsubstituted or 5 substituted with one, two, or three groups independently selected from haîogen, hydroxy, hydroxyalkyl, Iower aikyi, Iower aîkoxy,alkoxycarbonyi, alkylcarbonyl, alkylcarbonyîamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, trifluoromethylaîkyl, amino.or mono or diaîkylamino; 10 R^ is Iower alkyl, haloalkyl, or aryl; R7 is NR4R5, N(O)R4R5, NR4r5R9Xî qh, OR4, SR4, halo, COR4, (CH2)nR4, CO2R4, CONR4R5, C(O)NR4SO2R5, S(O)R4, SO2R4, SO2NR4R5, SO3R4, (CH2)nP(O)(OR4)2, NR4SO2R5,aidehyde, nitrite, nitro, alkyl, aîkoxyalkyl, T(CH2)mQR9, 15 C(O)T(CH2)mQR9, NR9C(O)T(CH2)mQR10, or T(CH2)mCO2R4; n is 0 to 6; W is an anion; R4 and R^ are independently hydrogen, iower aikyi, IoweT alkenyl, iower 20 alkynyl, (CH2)nAr, arylalkyl, aryl, heteroaryl, heteroaryialkyl, cycloalkyl, hcterocycloalkyl, or heteroaryl. or R4 and R$ togetherwith the nitrogen to which they are attached form a carbocyclicring containing 3 to S members, up to four of which members areoptionally carbonyl groups or heteroatoms independently selected 25 from oxygen, sulfur, S(O), S(O)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two,three, or four groups independently selected from halogcn,hydroxy, hydroxyalkyl, Iower alkyl, Iower aîkoxy, alkoxycarbonyi,alkylcarbonyl, alkylcarbonyîamino, aminoalkyl, 3 0 aminoalkylcarbonyl, trifluoromethyl, trifluoromethylaîkyl, -84- 012227 trifluoromethylalkylaminoalkyl, amino, mono- or dialkylamino,N-hydroxyacetamido, aiyl, heteroaryl. carboxyaîkyl, NR^Sü2K1 1, C(O)NRlÛRj 1, NRÎ θ<2(Ο)ϊΟ1, C(O)ORl 0,C(0)NRlOS02R11, (CH2)nS(0)nRlOf (CH2)n-heteroaryl,O(CH2)n-heteroaryl, (CH^C^NRlOR», O(CH2)nC(O)OR^; R^ is lower alkyl, haloalkyl, ox axyl; and additionally can be lower alkyl unsubstituted or substituted withone, two, or three grôups independently selected from halogen,5-oxo-4,5-dihydro-l/f-l ,2,4-triazx»l-3-yl-sulfanyL 5-oxo-4,5-dihydro-l/f-l,2,4-triazoi-3-yl-sulfînyl, 5-oxo-4,5-dihydro-lff- l,2,4-triazol-3-yl-sulfonyl, or a carbocyclic group containing from3 to 7 members, up to four of which members are optionallyheteroaioms independently selected from oxygen. suîfur andnitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independently selectedfrom halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl. N-hydroxyacetamide. trifluoromethylalkyl, amino,or mono- or dialkylamino; and when Y is CR?, it is part of the part structure wherein R? and Z are as defined àbove, or can be taken together with the carbons to which they are attached to fonn

wherein: f* 012227 G and J are independently ¢3¾. NH, or O; B is NH, S, CH2, or* O; D is C or N, provided that Ri θ is nothing when D is N; and Ri® and R* 1 are independently hydrogen, halogen, lower alkyl, loweralkoxy, or alkylcarbonyl. A compound of the Formula ΙΠ

10 and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein; R3 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, loweralkynyi, lower alkenyl, nitrile, nitro, -COR4, -CO2R4. -CONR4R5,CONR4OR5, -SO2NR4Rs, -SO2R4, -SO3R4, P(O)(OR4)(ÛR5), 15 R4 or-NR4R5: Y is N or CR7; X and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, hydroxy, nitrile, nitro, -NR4R^, -N(O)R4R$,
20 -NR4r5r6w, -SR4, -C(O)R4, -CO2R4, -CONR4RS, -SO2NR4R5, -SO2R4, -SO3R4, P(O)(OR4)(OR5), -T(CH2)mQR4 -C(O)T(CH2)mQR4, or -NR4C(O)T(CH2)mQR5;m is 1 to 6; T is O, S, NR4, N(O)R4, NR4R5W, or CR4R5; VO ον PO 012227 Q is O, S, NR4, N(O)R4, NR4R^W, CO2, or a carbocyclic group contaîning from 3 to 7 members, up to four of which members arcoptionally heteroatoms independenrlv selected from oxygen, sulfur,and nitrogen, wherein tbe carbocyclic group is unsubstitutcd or 5 substituted with one, two, or three groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, ami no,or mono or dialkylarnino; 10 R6 is lower alkyl, haloalkyl, or aiyl; R7 is NR4R5, N(O)R4R5, NR4r5r9x OH, OR4, SR4, halo, COR4, (CH2)nR4, CO2R4, CONR4R5, C(O)NR4SO2R5, S(O)R4, SO2R4, SO2NR4R5, SO3R4, (CH2)nP(O)(OR4)2, NR4SO2R5,aldéhyde, nitrile, nitro, alkyl, alkoxyalkyl, T(CH2)mQR9, 15 C(O)T(CH2)mQR9.NR9C(O)T(CH2)nlQRl0,or T(CH2)mCO2R4; n is 0 to 6; W is an anion; R4 and R^ are independently hydrogen, lower alkyl, lower alkenyl, lower 20 alkynyl, (CH2)nAr, arylalkyl, aryî, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloaîkyl, or heteroaryl, or R4 and R^ togetherwith the nitrogen to which they are attached form a carbocyclicring contaîning 3 to 8 members, up to four of which members areoptionally carbonyl groups or heteroatoms independently selected 25 from oxygen, sulfur, S(O), S(O)2, and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two,three, or four groups independently selected from halogen,hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, 30 trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, -87- 012227 v„n <n mono- or dialkylamino, N-hydroxyacetamido, and. heteroaiyl,carboxyaJkyl, NR] °SO2R] 1, C(O)NRÎ OrH , NRÎ <>C(O)Rl1,C(O)ORÏ0, C(O)NRl0sO2Rn, (CH2)nS(O)nR*0, (CH2)n-heteroaryl, O(CH2)n-heteroaryl, (CH^jjC^NR1^5,OCCH^C^ORlO; and addidonally can be lower alkyl unsubstituted or substituted withone, two, or three groups independently selected from halogen,5-oxo-4,5-diliydro-\H- 1,2,4-triazoI-3-yl-suIfanyl, 5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl-sulfinyl, 5-oxo-4,5-dihydro-lH-l,254-triazol-3-yl-sulfonyl or a carbocyclic group containing from3 to 7 members, up to four of which members are optionallyheteroatoms independently selected from oxygen, sulfur andnitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independently selectedfrom halogen, hydroxy, hydroxyalkyl, lower alkyl, lower aîkoxy,aîkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide. trifluoromethylalkvl, amino,or mono- or dialkylamino; and when Y is CR?, it is part of the part structure

wherein R? and Z are as defined above, or can be

taken together with the carbons to which they are attached to form wherein: G and J are independently CH2, NH, or O; 11 PCT/· -88- B is NH, S, CH2, or O; 012227 D is C or N, provided that RIO is nothing when D is N; andr9 îs lower alkyl, haloalkyl, or aiyl; r!0 and r11 are independently hydrogen, halogen, lower alkyl. loweralkoxy, or alkylcarbonyl. A compound of the Formula IV

and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. wherein: is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromelhyl. loweralkynyl, lower alkenyl, nitrile, nitro, -COR4, -CO2R4, CONR4R^.-CONR4OR5, -SO2NR4R5, -SO2R4, -SO3R4, P(ü)(OR4)(OR5), R4 or-NR4R5; Y is N or CR?; X and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, hydroxy, nitrile, nitro, -NR4R^, -N(O)R4r5,-NR4R5R6W, -SR4, -C(O)R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P(O)(OR4)(OR5), -T(CH2)mQR4, -C(O)T(CH2)mQR4, or -NR4C(O)T(CH2)mQR5; m is 1 to 6; T is O, S, NR4, N(O)R4, NR4R5w, or CR4R5; Q is O, S, NR4, N(O)R4, NR4R°W, CO2, or a carbocyclic group containing from 3 to 7 members, up to four of which members are PCI 012227 optionally heteroatoms independenüy seîected from oxygen, sulfur,and nitrogen, wherein the earbocyclic group is unsubstituted orsubstituted with one, two, or three groups independenüy seîectedfrom halogen, hydroxy, hydroxyalkyî, lower alkyî, lower alkoxy,aîkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromeüiyl, N-hydroxyacetamide, trifluoromethylalkyl, amino,oi mono or diaîkyîamino; R6 is lower alkyl, haloalkyl, or aryl; R7 is NR4R5, N(O)R4R5, NR4r5r9x, OH, OR4, SR4, halo, COR4, (CH2)nR4, CO2R4, CONR4R5, C(O)NR4SO2R5, S(O)R4, SO2R4, SO2NR4R5, SO3R4, (CH2)nP(O)(OR4)2,NR4SO2R5saldéhyde, nitrile, nitro, alkyl, alkoxyalkyl, T(CH2)mQR^, C(O)T(CH2)mQR9, NRSCiOyiXCH^QRlO, orTiCH^COoR4; π is 0 to 6; W is an anion; R4 and R$ are independenüy hydrogen, lower alkyl, lower alkenyl, loweralkynyî, (CH2)nAr, arvlaîkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl, or R4 and R$ togetherwith the nitrogen to which they are attached form a earbocyclicring containing 3 to 8 members, up to four of which members areoptionally carbonyl groups or heteroatoms independenüy seîectedfrom oxygen, sulfur, S(O), S(O)2, and nitrogen, wherein theearbocyclic group is unsubstituted or substituted with one. two,three, or four groups independenüy seîected from halogen,hydroxy, hydroxyalkyî, lower alkyl, lower alkoxy, aîkoxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyî, trifluoromethylalkyl,triflnoromethylalkylaminoalkyl. amino, mono- or diaîkyîamino,N-hydxoxyacetamido, aiyî, heteroaayl, carboxyalkyl, -90- 012227 10 15 20 ’vo NRl0SO2R1 ξ C(O)NR10r1 1, NRlÛQOlR11, PCT C(0)NRlOS02Rll, (CH2)nS(0)nRlOf (CH2)n-heîeroaiyl, O(CH2)a-heteroaiyl, (CH2)nC(O)NRl0Rl ζ O(CH2)nC(0)OR10; and R4 additionally can bc lower alkyl unsubstituted or substituted withone, two, or three groups independentiy selected from haîogen,5-oxo-4,5-dihydro-127-l,2,4-triazol-3-yl-sulfanyl, 5-oxo-4,5-dihydro-177-1,2,4-triazol-3-yl-sulfinyl, 5-oxo-4,5-dihydro-1H- l,2,4-triazol-3-yl-sulfonyl, or a carbocyclic group containing from3 to 7 members, up to four of which members are optionallyheteroatoms independentiy selected from oxygen. sulfur andnitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independentiy selectedfrom halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyl, alkyîcarbonyl, alkylcarbonyîainino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, trifîuoromethylalkyL amino,or mono- or dialkylamino: and when Y is CR?, it is part of the part structure wherein R? and Z are as defined above, or can be taken together with the carbons to which they are attached to form

R11 or

11 wherein: G and J are independentiy CHo, NH, or O; B is NH, S, CH2, or O; D is C or N. provided that R^ is nothing when D is N; -SI- 01 222 7 R.9 js lower alkyl, haîoaîkyl, or aryl; and Ri® and RJ1 axe independently hydrogen, halogen, lower alkyl, loweralkoxy, or alkylcarbonyt

5. A compound of Formula V

and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: is (a) hydrogen; (b) lower alky 1 optionalîy substituted with one., two, or threegroups independently selected from halogen, hydroxy,lower alkoxy, amino, mono- or dialkyîamino, carboxy,alkoxycarbonyl, thioalkyl, nitrile, aryl, heteroaryl, or acarbocyclic group containing from 3 to 7 members, up totwo of which members are optionalîy heteroatomsindependently selected from oxygen, sulfur, and niîrogen;or (c) a carbocyclic group containing from 3 to 7 members, up totwo of which members are optionalîy heteroatomsindependently selected from oxygen, sulfur, and niîrogen,wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independentlyselected from consisting of halogen, hydroxy, lower alkyl, ΡΓΤΓ ' 012227 lower alkoxy, amino, mono- or dialkylamino, aryl. andheteroaiyl; R3 is hydrogen, lower alkyi, lower alkoxy, halogen, trifluoromethyl, loweralkynyl, lower alkenyl, nitrile, nitro, -COR4, -CO2R4, -CONR4R^, 5 CONR4OR5, -SO2NR4r5, -SOoR4, -SO3R4, I R4 P(O)(OR4)(OR5), or -NR4R5;r9 is lower alkyi, haloalkyl, or aryl; 10 X and Z are independently hydrogen, halogen, lower alkyi, lower alkoxy, trifluoromethyl, hydroxy, nitrile, nitro, -NR4R5, -N(O)R4R^. -NR4R5r6w, -SR4, -C(O)R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P(O)(OR4)(OR5), -T(CH2)mQR4, -C(O)T(CH2)œQR4, or -NR4C(O)T(CH2)mQR5; 15 misltoô; T is O, S, NR4, N(O)R4, NR4R5W, or CR4R3: Q is O, S, NR4, N(O)R4, NR4R5 W, CO2, or a carbocyclic group containing from 3 to 7 members, up to four of which members areoptionally heteroatoms independently selected from oxygen, sulfur, 20 and nirrcgen, wherein the carbocyclic group is unsubstituted or substituted with one, two, or three groups independently selectedfrom halogen, hydroxy, hydroxyalkyl, lower alkyi, lower alkoxy,alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, trifluoromethyîalkyl, amino, 25 or mono or dialkylamino; R^ is lower alkyi, haloalkyl, or aryl; R7 is NR4R5, N(O)R4r5, NR4r5r9w, OH, OR4, SR4, halo, COR4, (CH2)nR4, (CH2)nR4, CO2R4. CONR4R3, C(O)NR4SO2R5, S(O)R4, SO2R4, SO2NR4R5, SO3R4, (CH2)nP(O)(OR4)2, 30 NR4SO2R5, aldéhyde, nitrile, nitro, alkyi. alkoxyalkyl, • - « t 012227 T(CH2)mQR4, C(O)T(CH2)mQR4, NR4C(O)T(CH2)mQR5, orT(CH2)mCO2R4; n is 0 ίο 6; W is an anion; R4 and R$ are independently hydrogen» lower alkyl, lower alkenyl, loweralkynyl, (CH2)nAr, arylalkyl, aryl. heteroaiyl, heteroaryîaîkyl, cycloalkyl, heterocycloalkyl, or heteroaryl, or R^ and R^ togetherwith the nitrogen to which îhey are attached form a carbocyclicring containing 3 to 8 members, up to four of which members areoptionally carbonyl groupe or heteroatoms independently selectedfrom oxygen, sulfur, S(O), S(O)2, and nitrogen, whcrcin thecarbocyclic group is unsubstituted or subsîituted with one, two, • three, or four groups independently selected from halogen,hydroxy, hydroxyalkyl, lower alkyî, lower alkoxy, alkoxycarbonyl,alkylcarbonyl, alkylcafbonyîamino, aminoaîkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl,trifluoromethylalkylaminoalkyl, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR10sO2rH, C(O)NRl0Rll,NRl0c(O)Rn, C(O)ORÎ0,C(O)NR10SO2Rn, (CH2)nS(O)nRl°, (CH^-heteroaryLO(CH2)n-heteroaryl, (CH2)nC(O)NRÏ0Rll, O(CH2)nC(O)OR10; and R^ additionally can bc lower alkyl unsubstituted or substituted withone, two, or three groups independently selected from halogen. 5-oxo-4,5-dihydro-l/f-l,2,4-tria2ol-3-yl-sulfanyl, 5-oxo-4,5=dihydro-lZf-l,2,4-triazoI-3-yl-suIfinyl, 5-oxo-4,5-dihydro-l.ff· l,2,4-triazol-3-yl-sulfonyl, or a carbocyclic group containing from3 to 7 members, up to four of which members are optionallyheteroatoms independently selected from oxygen, sulfur, andnitrogen, wherein the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups independently selected -94- 012227 6. 6. from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy,alkoxycarbonyl, alkyîcarbonyl, alkylcarbonylamino, aminoalkyl,trifluoromethyl, N-hydroxyacetamide, irifluoromethylalkyl, amino,or mono- or dialkylamino; and RIO and r1 1 are îndependently hydrogen, halogen, lower alkyl, loweralkoxy, or alkyîcarbonyl. A compound according to Çlaim 5 wherein R? is selected from

10 10 15 15 20 20 and wherein such groupe are optionally substituted by alkyl, aryl, oramide. A compound selected from the group consisting of: (a) 8-CyclopentyJ-5-methyl-2-(4-piperazin-l-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 1); (b) 8-(l-Methylethyl)-5-methyl-2-(4-piperazin-l-yl-phenyîamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 2); (c) 8-Cycîopentyl-5-methyl-2-(4-fiuoro-3-methyîphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 3); (d) 8-(l-Methylethyl)-5-methyl-2-(4-fluoro-3-methylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 4); (e) 8-Cyclohexyl-5-methyl-2-(4-fluoro-3-methylphenylamino)-8H-pyrido[23-d]pyrimidin-7-one (Compound 5); (f) 8-Cyclohexyl-5-methyl-2-[4-(4-propanoylpiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 6); (g) 8-Cyclopentyl-5-metbyl-2-[4-(4-propanoylpiperazin- 1 -yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound T); (h) 8-(l -Methy lethyl)-5-methyl-2- [4-(4-propanoylpiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d)pyrimidin-7-one (Compound 8); -95- 012227 (i) 8-Cyclohexyl-5-methyl-2-(4-pipsrazin-l -yl-phenylaxnino)-8H-pyrido[2,3-d]pyrimîdin-7-one (Compound 9); (j) 8-Cyclopeniyî-5-methyl-2»(4-pyridylphenylamino)-SH-pyrido[2,3"d3pyrâmdm-7»one (Compound 10); Oc) 8-(l -Methylethyl)-5-methyl-2-(4-pyridylphenyIamino)-8H-pyrido[2,3-d]pycimidin-7-one (Compound 11); (l) 8-CyclopenÎyî-5-methyl-2-[4-(3-aininopynOlidinyI)-phenyJamino]-8H-pyrido[2,3-d]pyrinudÎn-7-on.e (Compound 12); (m) 8-(î-Meihylethyî)-5-methyl-2-[4-(3-aminopyrroiidinyl)-phenylamino3-8H-pyrido[2»3-d]pyrimidm-7-onc (Compound 13); (n) N-(l-{4-[(8-cyclopentyl-5-methyl-7-oxo(8-hydropyridino-[2,3-d3pyrimidin-2-yî))animo]phenyl)pyrroiidin-3-yi)-3,3"dimethylbutanamide (Compound 14); (o) N-(l-{4-[(5-methyl-8-(l-methylethyl)-7-oxo(8-hydropyridino[2,3-d]pyrimidin-2-yl))aniino3phenyl}pynoiidin-3-yl)-3s3“dùneîhylbutanamide (Compound 15); (p) 8-Cyclopentyl-5-methyl-2-(3-chloro-4-piper3zin-l -yl-phenylaxnino)-8H-pjTido[2,3-d]pyrimidin-7-one (Compound 16); (q) 8-Cyclohexyl-5-methyl-2-(3-chloro-4-piperazin-l -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 17); (r) 8-(l -Methylethyl)-5-methyl-2-(3-chloro-4-piperazin-1 -yî-phenylanüno)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 18); (s) 8-Cyclopenty]-6-fluoro-5-me£hyl-2-(3-chloro-4-piperazin-l-yl-phcnylamino)-8H-pyrido(2.3-d]pyrimidin-7-one (Compound 19); (t) 8-Cyclohexyl-6-fluoro-5-methyl-2-(3-chloro-4-piperazin-l -yl-phenylanûno)-8H-pyrido[23-d3pyrimidin-7-one (Compound 21); (u) 8-(l -Methylethyl)-6-fluoro-5-methyl-2-(3-chloro-4-pipera2in-l-yl-phenylaxnino)-8H-pyrido[2,3”d3pyrimidin-7-one (Compound 20); (v) 8-Cyclopentyl-5-methy 1-2-(3 -chloro-4-morpholm-4-yl-phenylanüno)-8H-pyrido[2,3-d]pyriinidin-7-Qne (Compound 22); (w) 8-(l -Methylethyî)-5-methyl-2-(3-chloro-4-moTpholin-4-yl-pheny]amino)-8H-pyrido[2.3-d]pyrimidin-7-one (Compound 23); -96- PC> 012227 (x) 8-Cyc]ohexyl-5-methyl-2-(3-chIoro-4-morpholm-4-yl-phenyiamino)-8H-pyrido[2,3-ü]pyrimidin-7-one (Compound 24); (y) 2-({3-chloro-4-[4-(3-morpholin-4-ylpropyl)piperidyl]-phenyl}axnino)-8-cyclopenîyI-5-methyl-8-hydropyridino[2,3-d]pyrimidin- 7-one (Compound 25); (z) 2-({3-chloro-4-[4-(3-morpholin-4-ylpropyl)piperidylj-phenyl)amino)-8-(l-methylethyl)-5-methyl-8-hydropyridmo[2,3-d]-pyiimidin-7-one (Compound 26); (aa) 2-( {3-chloro-4-[4-(3-morpholin-4-ylpropyl)piperidvl]-phenyl}anûno)-8-cyciohexyl-5-methyl-8-hydropyridino[2,3-d]pyrimidin- 7-one (Compound 27); (bb) 2-({3-chloro»4-[4-(3-piperazinylpropyl)piperidyl]phenyî}-amino)-8-cyclopentyl-6-fluoro-5-methyl-8-hydropyridino[253-d]pyrimidm-7-one (Compound 28); (cc) 2-({3-chloro-4-[4-(3-piperazinylpropyl)piperidyl]-phenyl}amirio)-8-(l-methylediyl)-6-fluoro-5-meîhyl-8-hydropyridino-[2,3-d]pyrimidin-7-one (Compound 29); (dd) 2-({3-chloro-4-[4-(3-piperazinylpropyl)pipendyl]-phenyl} amino)-8-cyclohexyl-6-fluoro-5-methyl-8-hydropyridjno[2,3-d]pyrimidin-7-one (Compound 30); (ee) 2-( {3’Chloro-4”[4-(3-piperaziaylpropyl)piperidyî]-phenyl)amino)-8"Cyclopentyl”5-meihyl-8-hydropyridino[2,3-d]pyrimidîn- 7-one (Compound 31); (S) 2-({3-chloro-4-[4-(3»piperazinylpropyl)pjperidyî3-phenyl) amino)-8-(l -methyîethyl)-5-methy 1-8-hydropyridino-[2,3-d]pyrimidin-7-one (Compound 32); (gg) 2-({3-chloro-4-[4-(3-piperazinyipropyl)piperidyl]-phenyl ) amino)-8-cyclohexyl-5-methyl-8-hydropyridmo[2,3-d]pyriniidÎn- 7-one (Compound 33); (gg2) 8-Cyclopentyl-2-[4-(piperazin-1 -yl)-phenylamino)-6-fluoro- 5-mcthyl-8H-pyrido[2.3-d]pyrimidin-7-oncÎrifluoroaceiate(Compound 34); PC 012227 (gg3) 8-CyclopeaÎyl’2"[4-(pipcrazin-1 -yl)-phenylamino]-6-bromo- 5-methyl»SH’pyrido[2,3-d3pyrâQidin»7»onetrifluoroacetaie(Compound 35); (hh) 8^ο1ορβηΐχΐ-2-[4·^3,5ΗΐΜβ±γ1-ρΐρβΐΒζύι-ΐ -yl)-phenylamiîio]-6-fîuoro-5-methyl-8H-pyrido[2,3-d]pyriinidin-7-onehydrochloride (Compound 36); (ii) 8-CyclopenÎyî-2-(3-fluoro-4-pipera2dn-l-yl-phenylamino)- 5-methyl-8H-pyrido[2,3"d]pyrânidin-7-one (Compound 37); (jj) 6-Bromo-8”Cvclopentyl-2-i4-(3,5-dimethyl-piperazin-1 -yî)-phenylaaimo3-5-methyl-8H-pyrido[2,3-d]pyrimidin-7“Qne hydrochloride(Compound 38); (kk) 8-Cyclopentyl-6-fluoro-2-(3-fluoro-4-pîperazm-1 -yl-phenylamino)-5-methyl”8H-pyrÎdo[2,3-d}pyrimidin-7-one(Compound 39); (11) 6-Bromo-8-cyclopentyi-2-(3-fluoro-4-piperazin-l-yl-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyriraidin-7-one(Compound 40); (ram) 8-Cyclopentyl-2-[4-(3,5-dimethyl-piperazin-1 -yl)-phenylamino3-5-methyl“8H-pyrido[2,3-d]pyrimidin-7-one(Compound 41); (nn) 2-(3 "Chloro-4-piperazin-1 -y 1-phenylamino)- S-cyclopentyl- 5- methyl-8H-pyrido[23-d]pyrimidin-7-one (Compound 42); (oo) 2-(3-Chloro-4-piperazin-l-yl-phenylamino)-8-cyclopentyl- 6- fluoro-5-meïhy]-8H-pyrido[2,3-d3pyriinidin-7-oae (Compound 43); (pp) 6-Bromo-2-(3-chloro-4-piperazin-l-yl-phenylamino)-S-cyc]openîyl-5-methyl-8H-pyrido[2,3"d]pyrimidin-7-one(Compound 44); (qq) 8-Cyclopenîyl-5-methyl-2-(4-morpholin-4-y!-phenyiamino)-8H-pyrido[2,3-d}pyrimidin-7-one trifluoroacetale (Compound 45); (n·) 8-CydopentyI-6-fluoro-5-methyl-2-(4-moiphoIin-4-yl-phenyîamiao)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 46); (ss) 6-Bromo-8-cyclopentyl-5~meth.yl-2-(4-morpholra-4-yl-phenyîaœino)-8H-pyrido[223-d]pyrimidm-7“One (Compound 47); -98- 1’ 012227 (tt) 8-Cyclopentyl-2-(3-fluoro-4-morpholin-4-yl-phenylamino)- 5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 48); (vu) S-Cÿciopentyl-6-fluoro-2-(3-fluoro-4-morpholm-4-yl-phenylamino)-5-merhyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 49); (w) 6-Bromo-8-cyclopentyl-2-(3-fluoro-4-morpholin-4-yl-phenylamino)-5-mcthyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 50); (ww) 2-(3-Chloro-4-morpholin-4-yl-phenylaniino)-8-cyclopentyl- 5- methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 51); (xx) 2-(3-Chloro-4-moïpholin-4-yl-phenylamino)-8-cyclopentyl- 6- fluoTO-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 52); (yy) 6-Bromo-2-(3-chloro-4-morpholin-4-yl-phenylamino)- 8-cyclopentyI-5-methyî-8H-pyrido[2,3-d]pyrimidîn-7-one(Compound 53); (zz) 8-Cyclopentyl-5-methyl-2- {4-(4-(2,2,2-îrifluoro-ethyl)-piperazîn-l-yl]-pheny]amino}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 54); (aaa) S-Cyclopenxyl-6-fiuoro-5-methy 1-2- {4-(4-(2,2.2-trifluoro-eÎhyl)-piperaziiï-l-yl]-phenylamiQo}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 55); (bbh) 6-Bromo-8-cyclopentyl-5-methyl-2- {4-(4-(2,2,2-trifîuoro-ethyl)-piperazin-î-yl]-phenylaînino)-8H-pyïido(23-d]pyrimîàin-7-one(Compound 56); (ccc) 8-Cyclopentyl-5-meîhvl-2- {4-[4-(3-piperazin-1 -yl-propy 1)-piperidin-l-yl]-phenylamino}-8H-pyndo[2,3-d]pyrimidin-7-onetrifluoroacetaie (Compound 57); (ddd) 8-Cyclopentyl-6-fluoro-5-methyl-2-{4-(4-(3-piperazin-l-yl-propyl)-piperidin-l-yl]-phenylammo}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 58); (eee) 6-Bxomo-8-cyclopentyl-5-methyl-2-{4-[4-(3-piperazin-l -yl-propyl)-piperidin-l-yl]-phenylammo}-8H-pyrido[2,3-d]pyrimidm-7-one(Compound 59); -99- 012227 (fïï) 8-Cycîopenîyl-5-methyl-2-{4-[4-(3-morpholin-4-yl-propyl)-piperiàm-l-yI3-phenylamino}-8H-pyrido[2,3"d]pyriuiiclin-7-one(Corapoüüid 60); (ggg) 8-Cyclopentyî-6-fiuoro-5-meüîyl-2- {4-[4-(3-mûrpholin-5 4-yl-propyl)-pîpKridm-l-yl3»phenylamino}-8H-pyrido[2,3-d3pyrimidin- 7-one (Compound 61); (hhh) 6-BromO“8-cyclopentyl-5-œetiîyl“2°{4-[4-(3-morpholin-4-vl-propyl)-piperidin~3-yl)-phenylamino}-8H-pyrido[2,3-d3pyrraidin- 7-one (Compound 62); 10 (iii) 6-Bromo-8-cyclopenty]-5-niethy]-2-{4-[4-(3-moiphc>lin-4-yl- propyI)-piperidm-l-yI3-phenylamino}-8H-pyrido[2,3~d]pyrimidin-7-one(Compound 63); (ÿj) 2-(4-{4-{3-(3-Anuno-pyrroiidin-l-yî)-propyî3-piperidin-l-Yl}-phenylamino)-8-cyelopeiïtyl-5-methyî-8H-pyrido(2»3-d3pyriniidin-7“one 15 (Compound 64); (kkk) 2-(4-{4-[3-(3-Ammo-pyrroîidin-l -yl)-propyl]-piperidin- l-yl}-phenylamino)-8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido(2,3-d]pyrimidin-7-one (Compound 65); (111) 2-(4-{4-[3-(3-Amino-pyrrolidin-l-yl)-propyl3-piperidin-l-yl}- 20 phenylamino)-6-bromo-8-cycîopenty]-5-methyl-8H- pyridoi2,3-d]pyrimidin-7-one (Compound 66); (mmm) 8-Cyclopentyl-2-{3-fluoro-4-[4-(3-piperazîn-l-yî-propyl)-piperidin-l-yl3-phenylamino}-5-methyl-8H-pyrido[2.3*d3pyrinùdin-7-one(Compound 67); 25 (nnn) 8-Cyclopcntyî-6-fluoro-2-{3-fluoro-4-[4-(3-pipera2in-l-yl- propyî)«piperidin-l-yl]-phenylamino}-5-mcihyl-8H-p}Tido[2,3-d3pyrimidin-7-one (Compound 68): (ooo) 6-Bromo-8-cyclopentyl-2-{3-fluoro-4-[4-(3-piperazin-l-yl-propyl)-piperidîn-l -yl]-phenylanüno}-5-methyl-8H- 30 pyrido[2,3-d]pyrimîdin-7-one (Compound 69); (ppp) 8-Cyclopentyl-2-{3-fîuoro-4-[4-(3-moîphoîin-4-yî-propyl)- piperidm-l-yl]-phenylamino)-5-methyl-8H-pyrido[2,3-d3pyiimidin-7-one(Compound 70); -100- 012227 (qqq) 8-Cyclopentyl-6-fluoro-2-{3-fluoro-4-[4-(3-morpholin-4-yl-propyl)-piperidin-l-yl]-phenylaxnino}-5-methyl-8H-pyrido[2,3-d]-pyrimidin-7-one (Compound 71); (πτ) 6-Bromo-8-cyclopcntyl-2-{3-fluoro-4-[4-(3-morpholin-4-yl-propyl)-piperidin-l-yl]-phenylamino}-5-methyl-8H-pyrido[2,3-d]-pyrimidin-7-one (Compound 72); (sss) 2-[4-(3-Amino-pyrrolidin-l -yl)-phenylamino]-S-cyclopentyl- 5- methyl-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 73); (ttt) 2-[4-(3-Amino-pyrrolidin-l -yl)-phcnylamino]-8-cyclopentyl- 6- fluoro-5-methyl-8H-pyrido[2s3-d]pyrimidin-7-one (Compound 74); (uuu) 2-[4-(3-Amino-pyrroîidin-1 -yl)-phenylamino]-6-biomo- 8-cyclopentyl-5-methyî-8H-pyrido[2,3’d]pyrimidin-7-one(Compound 75); (vw) 2-[4-(3-Ammo-pynolidm-l-yI)-3-fluoro-phenyJamino]- 8-cyclopentyl~5-methyl-8H-pyrido[2,3-d]pyrimidin-7-ane(Compound 76); (www) 2-[4-(3-Amino-pyrroIidin-l-yl)-3-fluoro-phenylamino]- 8-cyclopentyl-6-fluoro-5-methyl-8H-pyridof2.3-d]pyrimidin-7-one(Compound 77); (xxx) 2-[4-(3-Ammo-pyrroIidin-l -yl)-3-fiuoro-phenylamino]- 6- bromo-8-cyclopentyî-5-methyl-8H-pyrido[2,3-d]pyrimidhî-7-onc (Compound 78); (yyy) 8-Cyclopeûtyl-5-methyl-2- {4-r3-(2,2.2-trifluoro-ethylammo)-pyrrolidin-l-yl]-pbenylaïnino)-8H-pyrido(2,3-d]pyrimidin- 7- one trifluoroacetate (Compound 79); (zzz) 8-Cyclopenty3-6-fluoro-5-methyl-2- {4-[3-(2,2.2-trifluoro-ethylamino)-pyrrolidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyriinidin- 7-one (Compound 80); (aaaa) 6-Bromo-8-cyclopentyl-5-methyl-2-{4-[3-(2,2,2-trifluoro-etliylamino)-pyrrolidin-l-yl]-pheny]aminû}-8H-pyrido|2,3-d]pyriniidin- 7-one (Compound 81); -101- 012227 (bbbb) 2-[4-(3-Ammo-pyïTolîdin-l -yl)-3-chloro-phenylamino]- 8-cyclopeûtyl-5-inethyl-8H-pyrido[2,3-d]pyximidin“7-onetrifluoroacetate (Compound 82); (cccc) 2-[4-(3-Aaûno-pyïrolidin-l-yl)-3-cbloro-phenylaniino3- 8-cydopentyl-6-fluoro-5-methyl-8H-pyrido[2,3-d]pyrimidm-7-one(Compound 83); (dddd) 2-(4-(3-Ammo-pyrrolidin-l -yI)-3-chIoro-phenylamino]- 6-bromo=S-cyclopentyl-5-methyI-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 84); (eeee) 2-[4-(3-Aminomethyl-4-irifîuoromethyl-pyrrolidin-1 -y l)-phenylamino3-8-cyclopeûtyl-5-methyl-8H-pyrido(2,3-d]pyrimidin-7-one(Compound 85); (fffiE) 2"[4-(3-Aminomethyî-4-trifluoromethyl-pyrroiidin-1 -yî)-phenylammo]-'8-cyclopeQtyî-6-fluoro-5-meùiyl-8H-pyrido[2,3-d]-pyrimidin-7-one (Compound 86); (gggg) 2-[4-(3-Ammomethyl-4-trifluoromethyî-pyiroiïdin-l -yl)-phcnylamino)-6-bromo-8-cyclopentyl-5-methyî-8H-pyrido[2,3-d)-pyrimidin-7-one (Compound 87); (hhhh) 2-[4-(3-Trifloroethylaminomefhyl-pyrrolidin-1 -yl)-phenyJamino]-8-cycîopentyI-5-methyî-8H-pyrido[2,3-d3pyrimidin-7-one(Compound 88); (ïüi) 2-[4-(3-Trifloroethy]aminomethyl-pyrrolidin-l -yl)-phenylamino]-8-cyclopentyî-6-fluoro-5-methyl-8H-pyrido[2,3-d]-pyrimidin-7-one (Compound 89); (iiij) 2-[4-(3-Trifloroethylaminomethyl-pyrrolidin-l-yl)-phenylaxnino]-6-bromo-8-cyclopentyl-5-mc±yl-8H-pyrido[2.3-d]-pyrimidin-7-one (Compound 90); (kkkk) 8-Cycîopentyî-2-(4-(3}3-dimethyl-piperazin-l -yl)-phenylamino]-5-meîhyl-8H-pyridoi2,3-d3pyrimidin-7-one hydruchloride(Compound 91); (1111) 8-Cyclopentyl-2-(4-(3,3"dünethyî-piperadn-l -yl)-phenylamino3”6-fluoTo-5-methyl-8H-pyrîdo(2,3"d]pyîimîdui-7-one(Compound 92); X* 012227 -102- (mmmm) 6-Bromo-8-cyclopentyl-2-[4-(3,3-dimethyl-piperazin-1 -yl)-phenylanuno]-5-methyl-8H-pyrido [2,3-d]pyrimidin-7-onchydrochloric (Compound 93); (nnnn) 8-Cyclopentyl-5-methyl-2-[4-(3,3,4-trimethyl-piperazin-l-y])-phenylamino]-8H-pyrido[2,3-d]p>'rimidin-7-one (Compound 94); (oooo) 8-Cyclopentyl-6-fluoro-5-methyl-2-[4-(3,3i4-trimeïhyl-piperazin-l-yl)-phenylammo]-8H-pyrido[23-d]pyriinidin-7-one(Compound 95); (pppp) 6-Bromo-8-cyclopentyl-5-methyl-2-[4-(353f4-trimetliyl-piperazm-î-yl)-phenylamino]-8H-pyrido[2>3-d]pyrinùdin-7-one(Compound 96); (QQQ9) 2-[4-(4-Acetyl-piperaan-l-yî)-phenylamino}- 8-cyclopentyl-5-methyl-8H-pyrido[2s3-d]pyrixmdin-7-one(Compound 97); (rrrr) 2-(4-(4-Acetyl-piperazin-1-yî)-phenylamino)-8-cyclopentyl- 6-fluoro-5-methyî-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 98); (ssss) 2-(4-(4-Acetyl-piperazin-1 -yl)-phenylaminoJ-6-bromo- 8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 99); (tttt) 8-Cyclopentyl-2-{4-[4-(2-hydroxy-ethyl)-3,5-dimethyl-piperazin-l-yl]-phenyiamino}-5-methyl-8H-pyrido[2,3-d]pyrimidia-7-one(Compound 100); (uuuu) 8-Cyclopentyl-6-fluoro-2-{4-[4-(2-hydroxy-ethyl)- 3.5- dimethyl-piperazin-î-yl]-phenylamino}-5-mcthyl-8H- pyrido[2,3-d]pyrimidin-7-one (Compound 101); (ww) 6-Bromo-8-cyclopentyl-2- {4-[4-(2-hydroxy-ethy 1)- 3.5- dimethyl-piperazin-l-yl]-phenylamino}-5-methyl-SH-pyrido[2,3-d]-pyrimidin-7-one (Compound 102); (wwww) 8-Cyclopentyl-5-methyl-2-(4-perhydro-l ,4-diazepin-1 -yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride(Compound 103); -103- 012227 (χχχχ) 8-Cyclopentyî-6-fluoro-5-methyî-2-(4-perhydro-l54-dia'2epirs-l-yl-p2henyÎamina)~8H“pyrido[2s3-d]pyrimidin-7-oaehydrochloride (Compound 104); (yyyy) 6-Bromo-8“Cycîopentyl-5-meihyl-2«(4-perhydro- 1.4- diazepm“l»yl-phenylamino)-8H“pyrido[2.3-d]pyrimidùi-7-one(Compound 305); (zzzz) 8-Cyclopentyl-5»methyl-2“[4-(4-methyl-piperazin-1 -yl)-phenylamino]-8H-pyrido[2»3-d3pyrimidm-7-one (Compound 106); (aaaaa) 8-Cycîopentyl-6-fîuoro-5-methyl-2-[4-(4-methyl-piperazin-1 -yî)-phenylamino]"8H»pyrido[2,3-d]pyriinidin-7-one(Compound 107); (bbbbb) 6-Bromo-8-cycIopentyl-5-n)eihyî“2-[4-(4-methyl·piperazin“l“yî)-phenylamino]-8H-pyrido[23-d]pyrimidui-7-one(Compound 108); (ccccc) 8-CycIopentyl-5-methyl-2-[4-(4-methyl-perhydro- 1.4- diazepin-l -yl)-pbenylaxnîno]-8H-pyrido [2,3-d]pyrunidin-7-one(Compound 109); (ddddd) 8-Cyclopentyl-6-fîuorO"5-methyl-2-[4-(4-meîhyl-perhydro-l,4”dia2epin-l-yl)-phenylamino]-8H-pyrido[23-d3pyrimidin- 7-one (Compound 110); (eeeee) 6-Bromo-8-cyclopentyl-5-methyl-2-[4-(4-methyl-perhvdro-1,4-diazepin-î -yl)-phenylamino]-8H-pyrido[2.3-d]pyrimidin- 7-one (Compound 111); (fÏÏËf) {4-[4-(8-€γε1ορ6ηΐγΙ-5-ιηβύιν1'·7-οχο-7,8-ά^ύΓθ-pyrido[23“d]pyriniidüi-2-ylainino)-phenyI]-piperazin-l -yl}-acetic acid(Compound 112); (ggggg) {4-[4-(8-CyclopentyI-6-fîuoro-5-methyl-7-oxo- 7.8- dihydro-p5’rido[233-d]pyrimidin-2-yIamino)-phexïyl)-pipcrazin-l -yl} -acetic acid (Compound 113); (hhhhh) ^[A-iô-BromQ-S-cyclopenÎyl’S-methyW’Oxo- 7.8- dihydro-pyrido[2,3-d]pyrimidm-2-ylamino)-phenyl3-piperazm-l-yî}-acetic acid (Compound 114); -104- PC 012227 (Uni) 8-Cyclopcntyl-5-methy l-2-(4-{4-[3-( 1 H-tetrazol-5-yl)-propyl]-piperidin-l-yl}-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-onc(Compound 115); (Üiîi) S-Cyclopentyl-6-fluoro-S-methyl-2-(4-{4-[3-(lH-ïetrazol-5-yl)-propyl]-piperidin-l -yl} -phcnylamino)-8H-pyrido[2,3-d]pyriniidin- 7-one (Compound 116); (kkkkk) 6-Bromo-8-cyclop«ntyl-5-methyl-2-(4-{4-[3-(lH-tetrazol-5-yl)-propyl]-piperidin-l-yl}-phenylanùno)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 117); (11111) 8-Cyclopentyl-5-methyl-2-(4-{4-[3-(5-oxo-4,5-dihydro- 1H- 1.2.4- triazol-3-ylsulfanyl)-propyl]-piperidin-l-yl}-phenylamino)-8H- pyrido[2,3-d]pyrimidin-7-one (Compound 118); (mnunmm) 8-Cyclopentyl-6-fluoro-5-methyl»2-(4»{4-[3-(5-oxo- 4.5- dihydro-1 H-1,2,4-tnazol-3 -ylsulfany l)-propyl]-piperidin-1-y1}- phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 119); (nnnnn) 6-Bromo-8-cyclopenîyl-5-methyl-2-(4-{4-[3-(5-oxo- 4.5- dihydro-lH-l .2,4-iriazol-3-ylsxdfanyl)-propyl]-piperidm-1 -yl} - phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 120); (ooooo) 8-Cyclopentyl-5-methyl-2-(4-{4-[3-(5-oxo-4.5-dihydro-1 H-1,2,4-triazoIe-3-sulfinyl)-propyl]-piperidin-1 -yl} -phenylamino)-8H-pvrido[23-d]pyrimidin-7-one (Compound 121); (ppppp) 8-Cyclopentyl-6-fluoro-5-methyl-2-(4-{4-[3-(5-oxo- 4.5- dihydro-lH-l,2j4-triazole-3-sulfinyî)-propyl]-piperidin-l -yl }- phenylamino)”8H»pyrido[2,3-d]pyrimidin-7-one (Compound 122); (qqqqq) 6-Bromo-8-cyciopentyl-5-methyl-2-(4-{4-[3-(5-oxo- 4.5- dihydro-lH-l^,4-triazole-3-suîfinyl)-propyl]-piperidin-î-yl}- phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 123); (rrrrr) 8-Cyclopentyl-5-methyl-2-(4-{4-[3-(5-oxo-4;5-dihydro-1H- 1.2.4- triazole-3-sulfonyl)-propyl]-piperidin-l -yl}-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 124); (sssss) 8-Cyclopentyl-6-fluoro-5-methyl-2-(4-{4-[3-(5-oxo- 4.5- dihydro-lH-1,2s4-triazole-3-sulfonyl)-propyl]-piperidin-1 -y 1} -phenylamino)-8H-pyrido(2,3-d]pyrimidin-7-one (Compound 125); -105- 012227 (ttttt) 6-Bromo-8-cyclopentyî-5-methyl-2-(4-{4-[3-(5-oxo- 4,5-dSiydro-lH-ls2,4-tria2ole-3-sulfoayl)-propyl]-piperiâb-l-yl}-phenylainwo)-8H“pyrido[23-d3pyrimidm-7-one (Compound 126); (uuuuu) N-(2-{ l-[4-(8-Cyciopentyl-5-methyî-7-oxo-7,8-dihydro-pyrido[2i3"d]pyrimidin-2-ylaxnino)-phcnyl]-piperidm“4-yI}-ethyi)-N-hydroxy-acetamide (Compound 127); (wvw) N-(2-{ 1 -[4-(8-Cycîopentyl-6-fluoro-5-methyl-7-0xo- 7.8- dihydro-pyrido[23-d3pyrimidin-2-yîanûno)-phenyl3-pÎperidin-4-yl}-ethylj-N-hydroxy-acetamide (Compound 128); (wwwww) N-(2-{ l-[4-(6-Bromo-S-cyclopentyl-5-racThyl-7-oxo- 7.8- dihydro-pyrido[2}3‘d]pyrîmidin-2-ylamino)-phenyl3-piperidin-4-yl}-ethyl^N-hydroxy-acetamide (Compound 129); (xxxxx) N-(3-{l»(4“(8-Cyclopentyî-5-meîhyl-7-oxo-7}8-dihydro-pyrido[2s3“d3pyrimidin-2-ylamino)-phenyl]-piperidin-4-yl}-propyl)-N-hydroxy-acetamide (Compound 130); (yyyyy) N-(3- {1 -[4-(8-Cyclopentyl-6-fluoro-5-methyl-7-oxo- 7.8- dihydro-pyrido[233-d]pyrimidin-2-ylammo)-phenyl]-piperidin-4-yl}-propyl)-N-hydroxy-acetamide (Compound 131); (zzzzz) N-(3-{ 1 -[4-(6-Bromo-8-cyclopentyl-5-ine±yl-7-oxo- 7.8- diliydro-pyrido[2,3-d]pyrimidin-2-yla£nino)-phenyi]-piperidsn-4-yl)-propyl)-N-bydroxy-acetainide (Compound 132); (aaaaaa) 2-(Benzofuran-5-ylamino)-8-cycîopentyl-5-metbyl-8H-pyrido[253-d]pyrimidin-7-one (Compound 133); (bbbbbb) 8-Cyclopentyl-2-(lH-indol-5-ylamino)-5-methyl-8H-pyrido[2,3“d]pyrimidin-7-one (Compound 134); (cccccc) 2-(Benzo[b]thiophcn-5-ylamino)-8-cyclopentyî-5-£nethyl-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 135); (dddddd) 8-Cyclopenty 1-2-(2.3 -dimethy 1-1 H-mdol-5-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-onc (Compound 136); (eeeeee) 2-(9H-Carbazol-3-ylammo)-8-cyclopentyl-5-meihyl-8H-pyrido[2,3“d3pyrimidin-7-one (Compound 137); (fKES) 8-CyclopentyI-2-(lH-indazol-5-yiamino)-5-methyl-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 138); PC 012227 (gggggg) 2-(2-Acetyl-benzofuran-5-ylamino)-8-cyclopentyl-5-me±yl-SH^yrido[23<J]pyriinidm-7-one (Compound 139); (hbhhhh) 8-Cyclopentyl-5-methyl-2-(4-morpholin-4-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 140); (iiiiii) 8-Cyclopentyl-2-[4-(3,5-dimethyl-piperazin-1 -yl)-phenylamino]-5-methyî-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 141); fiffiji) 2-(3-Chloro-4-piperazin-l -yl-phenylanuno)-8-cyclopentyl-5-methyI-8H-pyrido[2,3-d]pyrimidin-7-one trifluoroacetate(Compound 142); (kkkklck) 8-Cyclopentyl-5-methyl-2-(4-piperidin-1 -yl-phenylamino)-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 143); (111111) 8-Cyclopentyl-5-msthyl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 144); (mmmmmxn) N-{ l-[4-(8-Cyclopentyl-5-methyl-7-oxo- 7,8-dihydro-pyrido[2,3-djpyriaùdin-2-ylarn.mo)-phenyl]-piperidin-4-yl}-acetamide (Compound 145); (nnnnnn) 8-CycIopentyl-5-methyl-2-(4-piperazin-1 -yl-phenylammo)-8H-pyrido [2,3-d]pyrimidin-7-one trifluoroacetate(Compound 146); (oooooo) 8-Cyclopentyî-6-fluoro-5-methyl-2-(4~piperazin-l -yl-phenylamino)-8H-pyrido[2,3'd]pyriinidin~7”One (Compound 147): (pppppp) 6-Bromo-8-cyclopenîyl-5-methyl-2-(4-piperazin-1 -yl-phenylamino)-SH-pyrido[2,3-d]pyrimidin-7-one (Compound 148); (qqqqqq) 2-[3-Chloro-4-(3-amino-pyrrolidin-l-yl)-phenylamino]- 8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyriinidin-7-one trifluoroacetate(Compound 149); (irrrrr) 8-Cyclopentyl-5-methyl-2-[4-(4-(2,232-trifluoroethyl)-piperazin-l-yl)-phenylamino]-8H-pyrido[2.3-d]pyriinidin-7-one(Compound 150); (ssssss) 8-Cyclopentyl-2-(4-fluoro-phenylàmino)-5-Tnethyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 151): «V'OO1 PCT/> 012227 (tttttt) 8-Cyclopentyl-5-methyl-2-phenylamino-8H-pyrida[2,3-d}pyrimidin.-7-one (Compound 152); (uuuuuu) 8-Cycîopentyl-2-(3,4»dîchlorophenylamîno)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 153); (www) 8-Isopropyl-5-meîhyl-2-(4-piperazm-l-yl-phenylamino)-8H-pyrido[2,3-d3pyrimidin-7-one îrifluoroacetate (Compound 154); (wwwwww) 8-Îsopropyî-5-methyl-2-[4-(4-propionyl-piperazm-l-yl)-phenylâniin.o]-8H-pyrido[23-d]pyrimidin-7-one (Compound 155); (xxxxxx) S-Cyclohexyî-5-methyl-2-(4-piperazin-1 -y 1-phenylammo)-SH-pyrido[2,3-d]pyrimidxn-7-cne (Compound 156); (yyyyyy) 2-{4-{4-(3-Morpholiîi-4-yl-propyl)-piperidin-l-yl]-phenylanuno}-8-cyclohexyl-6-fluoro-5-methyl-8H-pyrido[2s3-djpyrimidin-7-one (Compound 157); (zzzzzz) 8-CyclopentyI-5-methyl-2-[4-(2H-l ,2.4-triazol-3-ylsulfanyimeÎhyl)-phenylamino3-8H-pyridoi2,3-djpyrimidin-7-one(Compound 158); (aaaaaaa) 8-Cyclopentyl-5-methyl-2»[4-(2H-l ,2.4-triazole-3-sulfînylmethyl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 159); (bbbbbbb) 8-Cyclopentyl-5-methyl-2-[4-(2H-l,2,4-tnazole-3-sulfonylmeihyî)-phaiylammo]-8H-pyrido[2,3-d]pyrimidin-7”One(Compound 160); (ccccccc) S-Cyclopentyl-S-methyl-Z-^-fS-oxo^^-dihydro-1,2,4-oxadiazol-3-ylmethyl)-phenylammo]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 161); (ddddddd) S-Cyclopentyî-5-methyl-2-{4-[2-(2H-l ,2,4-triazol-3-ylsuIfanyl)-ethyl]-phenylainino}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 162); (eeeeeee) 8-CycIopentyl-5-methyl-2-{4-[2-(2H-l ,2,4-triazoie-3-sulfinyl)-ethyl]-pbenylanuno}-8H-pyrido[2s3-d3pyrimidin-7-one(Compound 163); PC 012227 -108- (ffiffif) 8-Cyclopentyl-5-methyl-2-{4-[2-(2H-1,2,4-triazole-3-sulfonyl)-ethyl]-phenylamino}-8H-pyrido[2,3-d]p\TÎmidin-7-one(Compound 164); (ggggggg) 8-Cyclopentyl-5-methyl-2- {4-[2-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)-ethyl]-phenylamino}-8H-pyrido[2,3-d]pyrimidjn-7-one (Compound 165); (hhhhhhh) 8-Cyclopentyl-5-methyl-2-[4-(3H“l,2,3-Îriazol-4-ylsuIfanylmethyl)-phenylammo]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 166); (iiiiiü) 8-Cyclopcntyl-5-mcthyî-2-{4-[2-(3H-1,2,3-triazol-4-ylsulfanyï)-ethyl]-phenylanùno}-8H-pyrido[2,3-d3pyrimidin-7-one(Compound 167); (jÜÜjj) 8-Cyclopentyl-5-methy]-2-{4-[4-(5-oxa-4,5-dihydro-l ,2,4-oxadiazol-3-yl)-piperidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 168); (kkkkkkk) 8-CycÎopentyl-5-methyl-2-{4-[4-(2H-l,2,4-jriazol-3-ylsulfanyl)-pipeiidra-l-yl]-phenylanùno}-8H-pyriào[2,3-d]pyrmudin-7-one (Compound 169); (U1U11) 8-Cyclopentyl-5-meth.yi-2-{4-[4-(2H-l ,2,4-lriazole-3-sulfmyl)-piperidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 170); (mnrammïïm) 8-Cyclopentyl-5-methyl-2-{4-[4-(2H-î,2,4-triazole-3-sulfonyl)-piperidin-l-yl]-phenylamino}-SH-pyrido[2,3-d]pyrimidin-7-one (Compound 171), mp 235-237°C; (nnnmmn) 8-Cyclopentyl-5-methyl-2-{4-[4-(2H-tetrazol-5-y])-piperidin-l-yl]-phenylanùno)-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 172); (ooooooo) 1 -[4-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl3-piperidine-4-carboxylic acid(lH-tetrazol-5-yl)-amide (Compound 173); -109- PC· 012227 (ppppppp) 8»CyclopeatyI-5”methyI~2'-{4-[4-(3H-l ,2.3-îriazo{-4-ylsulfanyI)-pîperidiri-l-yl]»phenylamiîio}~8H-pyrido[2,3-d]pyrimidin-7-one (Compound 173); (qqqqqqq) 3-[4-(S-Cyclopentyl-5-meihyî-7-exo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyî]-N-(lH-teira2ol-5-yl)-propionamids (Compound 174); (nmn) 2"[4-(8-CyclopenÎyl«5-meihyl-7-oxo-7,,8-dihydro-pyrido[2,3-d]pyrimidin»2-ylaniino)*phenoxy]“N-(lH-teira2o]-5-yî)-acetamide (Compound 175); (sssssss) S”Cyclopentyl"5-mcthyI»2-[4-(5-oxo-4,5-dÎhydro-1 ,2,4-oxadiazol-3-ylnieihoxy)-phenylamino]-8H-pyTido[2,3-d]pyrinddin-7-one(Compound 176); (ttttttt) 8“CycJopenîyl-5-methyl-2-(4» {4-[2-(2H-1,2,4-tnazole-3-sulfinyl)-ethyl]-piperidm-l-yl}-phenylaoamo)-8H-pyrido[2,3-d]pyrijnidin-7-one (Compound 177); (uuuuuuu) 8-Cyclopentyl-5-methy 1-2-(4- {4-(2-(211-1,2,4-triazole- 3- sulfonyl)-eihyî]-pipeiidin-l-yl}-phenylamino)-8H-pyrido[2,3- djpyrimidin-ï-one (Compound 178); (wwwv) 8-CyclopenÎyî-5-methyl“2-(4-{4-[2-(3H-l,2,3-tria2ol- 4- ylsulfanyî)-ethyl]-piperidin-î-yl}-pheny]amino)-8H»pyrido[2,3- d3pyrimidin-7-one (Compound 179); (wwwwwww) 8-Cyciopen.tyl-5-methyl-2-(4-{4-[2-(2H- î ,2,4-ÎTÎazol-3-ylsulfaayl)-cîhyl]-piperidiii-l-yl)-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 180); (xxxxxxx) 8-Cyc]opentyî-5-merhyl-2-(4- {4-[2-(5-oxo-4,5-dihy dro-1,2,4-oxadiazol-3-yî)-ethy l]-piperidin-l -y 1} -phenyiamino)-8H-pyrido[2,3-d]pyriniidin-7-one (Compound 181); (yyyyyyy) 8-Cycîopentyl-5-methyî-2- (4-[4-(2-oxo-2.3-dihydro- 1,2,3,5-oxaihiadiazol-4-yl)-piperidin-l-yîJ-phenylainmo}-8H-pyrido[2,3 -d]pyrimidm-7-one (Compound 182); (Z222Z2Z) 8-Cyclopentyl-2-{4-[4-(2,2-dioxO"2,3“dihydro-l,2,3,5-oxathîadia2oî-4-yî)-pÎperîdm-l-yl]-phênylamino}-5-meîhyî-8H-pyrido[2,3-d]pyrimidin-7-oae (Compound 183); -110- 012227 (aaaaaaaa) 8-Cyclopentyl-5-methyl-2-{4-[4-(l-oxo-2,5-dihydro-lH-l,2,3,5-thiatriazol-4-yI)-piperidin-l-yl3-phcnyîamino}-8H-pyrido[2.3-d]pyrimidin-7-oîie (Compound 184); (bbbbbbbb) 8-Cyclopentyl-2-{4-[4-(l ,1 -dioxo-2,5-dihydro-l H- l,293,5-thiatriazol-4-yl)-piperidin-l-yI]-phenylamino}-5-niethyl-8H-pyrido[2,3-dJpyrimidin-7-one (Compound 185); (cccccccc) N-{ 1 -[4-(8-Cyclopentyî-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperidine-4-carbonyl}-methanesulfonaxnide (Compound 186); (dddddddd) 8-Cyclopentyl-5-methyl-2-{4-[3-(2H-1,2,4-triazol-3-ylsulfanyl)-pyrrolidiQ-l-yl]-phenylamino}-8H-pyridoE2,3-d]pyrimidin-7-one (Compound 187); (eeeeeeee) 8-Cyclopentyl-5-methyl-2-{4-[3-(2H-l«2,4-triazole-3-sulfmyl)-pyrroHdin-l-yî]-phenylambio}-8H-pyrido[2,3-d]pyrimidin-7-oiie(Compound 188); (fffîgff) 8-Cyclopentyl-5-methyl-2-{4-[3-(2H-l,2,4-triazole-3-sulfonyl)-pyrcolidin-l-yl]-phenylamino}-8H-pyrido[2,3-d)pyrimidin-7-one(Compound 189); (gggggggg) S-Cyclopentyl-5-methyl-2-{4-[3-(3H-1,2.3-triazol-4-ylsulfanyl)-pyrrolidin-l-yl]-phenylamino}-8H-pyrido[2,3-d]pyriinidin-7-one (Compound 190); (hhhhhhhh) 8-Cyclopentyî-5-methyl-2-{4-[3-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)-pyirolidm-1 -yî]-phenylamino) -8H-pyrido[2,3-d]pyrimidin-7-one (Compound 191); (iiüiiii) 8-Cyclopentyl-5-metfay1-2-(4-[4-(3-hydroxypropyl)piperidin-î-yl]-phenylamino}-8H-pyrido[2,3-d3pyrimidin-7-one trifluoroacetate (Compound 192); (niiiiii) 8-Cyclopentyî-5-methyI-2-(4-piperazin-l-yl-phenylamino)-8H-pyridof2,3-d]pyrimidin-7-one trifluoroacetate(Compound 193); (kkkkkkkk) 8-Cyclopentyl-5-ethyl-2-(4-piperazin-l -yl-phenylamino)-8H-pyrido[2}3-d3pyrimidin-7-one (Compound 194); PC 012227 (11111111) 8-(l-MeÎhyleÎhyI)"5“ethyl-2»(4-piperazm- 1-yl-phenylammo)-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 195); (mmmmmmmm) 8-(Meihyîeîhyl)-5-eÜiyï-2~(4“pipera2in-l-yI-phenylanûno)-8H“pyrido[2,3"d3pyriaîidin-7-oneîrifluoroacetate (Compound 196); (nnnnnnnn) 8’Cyclopentyl-5-meihyl-2”[4-(3-hydroxypyïTolidin-1 -yi)phenyl2mîno3“8H-pyridoi23-d]pyrimidin-7-one (Compound 197); (oooooooo) 8-Cyclopentyl-5-methyl-2-[4-(4-acety]piperazin-] -yl)phenylamino]-8H-pyrido(23’d3pyrimidin-7-onc (Compound 198); (pppppppp) S-Cyc]openîyl-5-methyi-6-fluoro-2”[4-(4-acetylpiperidin-l-yl)phenylamino3»8H>pyrido[2î3"d]pyrimidin-7-one(Compound 199); (ALQQQQQQQ) 8-Cyclopropyl-5-methyl-2-[4-(4-acetamidopiperidin-l>yl)phenylammo]“8H-pyridoP3-d3pyrimidm-7-one (Compound 200); (inxtnr) 8"Cyclopentyl-5-methyl-2»[4”(homopiperazin-l-yl)phenylamino]-8H-pyrido[2,3-d3pyrimidin-7“One hydrochloride(Compound 202); (ssssssss) 8-Cyclopentyl»5-methyl-6-fluoro-2-[4-(homopiperazin- l-yI)phenylamino]-8H-pyrido[2,3-d]pyrixnidin-7-one hydrochloride(Compound 203); (tttttttt) 8-Cyclopentyl-5-methyî-6-fluoTO-2-[4-(3,3-dimethyl-4-acetyîpÎperazin-l-yl)phenylamino3-8H-pyrido[293-d]pyriinidin-7-one(Compound 204); (uuuuuuuu) 8-Cyclopentyl-5-methyl-2"(4-(3,3-diinethyl'4-acctylpiperazm4-yl)phenylaïïùnoj-8H-pyrido[2.3-d]pyrimidin-7-one (Compound 205); (wwww) 8-Cyclopentyî-5-raeîhyl-6-fiuoro-2-[4-(4-methylpiperazm-l-yl)phenylamino]«8H-pyrido[23-d3pyrimidin-7-one(Compound 206); (wwwwwwww) 8-Cyclopentyî-5-methyl-2-[4-(N-methylacetamido)pbenylaniino}-8H-pyrido[2,3-d3pyrimtdin-7-one (Compound 207); -112-. 012227 pc- (xxxxxxxx) 8-CycIopemyl-5-methyl-2-{4-[2-(2-hydroxyethoxy)ethylammo]phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 208); (yyyyyyyy) 8-CyclopemyI-5-methyl-2-[4-(3-oxopipcrazin-1 -yl)phenyiammo]-8H-pyrido[2,3-d]pyrimidin-7-orie (Compound 209); (zzzzzzzz) 8-Cyclopentyl-5-methyl-2-[4-(2-methoxyethoxy)phenylanaino]-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 210); (aaaaaaaaa) 8-Cyclopentyl-5-methyl-2-(carbozol-3-yl)amino-8H-pyrido[2,3-d]pyrimidin-7-onc (Compound 211); (bbbbbbbbb) 8-Cyelopentyl-5-methyl-2-(isoindazol-5-yl)amino-SH-pyrido[2s3-d]pyriniidÎn-7-one (Compound 212); (ccccccccc) 8-Cyclopentyl-5-methyl-2-(2-acetylbenzofuran-5-yl)amino-8H-pyrido[2,3-d]pyrimidm-7-one (Compound 213); (ddddddddd) 8-CyciopemyI-5-methyl-2-[(4-piperidin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 214); (eeeeeeeee) 8-Cyclopentyl-5-methyl-2-(2,3-dimethylindol-5-yl)amino-SH-pyrido[2,3-d]pyrimidin-7-one (Compound 215); (fËEffifS) 8-Cyclopentyl-5-meÎhyl-2-[4-(3,5-methyl-4R-aminomethylpynolidin-î-yl)phenylamino]-SH-pyrido[2s3-d]pyrimiâin-7-one (Compound 216); (ggggggggg) 8-Cyclopentyl-5-meîhyi-2-{4-[4-(2-hydroxyethyl)piperazin-l-yl)]phenylamino}-8H-pyrido[2,3-d]pyriinidin-7-one (Compound 217); (hhhhhhhhh) 8-Cyclopentyl-5-methyl-2-{4-[4-(3-morpholinopropyl)piperidin-l-yl]phenylamino}-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 218); (iiiiiiiii) 8-Cyclopentyl-5-methyl-2-(benzofuran-5-yl)amino-8H-pyrido[2,3-d]pyrimidin-7-oue (Compound 219); (îiüüiü) 8-Cyclopentyl-5-methyl-2-(indol-5-yl)amino-SH-pyrido[2,3-d]pvrimidin-7-one (Compound 220); and (kkkkkkkkk) S-Cyclopentyl-5-methyl-2-(thionaphthen-5-yl)amino-8H-pyrido[2!3-d)pyrimidin-7-one (Compound 221). PC 10 15 20 25 012227

8. A compotsnd selected ûom the group consisting of: 8“Cyclopentyl-6-iodo--5-îaethyî«2-(4-piperazm-1 -yl-phenylamino)-8fi-pyrido[2,3"d3pyrinüdiü“7“Oîie (Compound 225);

8-Cyclopentyl-2-{4-[l "(3,5-dimethyl-piperazin- î -yl)-methanoyl]-phenylanùn.o}-5-methyl-8H-pyrido[2,3-d3pyrimidin-7-one(Compound 226);

8-Cyclopentyl-2-[4-(3,5-diroethyl-piperazm-l -yl)-phenylamino]-5-trifluorometbyl-8H-pyrido[2,3-d3pyrimidîn”7-one (Compound 227);

6-Bromo-8»cyclopentyl“2-[4-(3,3-dimeîhyl-piperazm-1 »yl)-phenylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-onc(Compound 228);

8-Cyclopentyî-2-[4-(3,5-dimethyî-piperazin-1 -yl)~pheny2amino3-6-iodo-5-meihyl-8x¥-pyrido[23"^pyrimidin-7-Qne (Compound 229);

6-Chîoro-8-cyclopentyl“2-[4-(3,5“dimethyî-pipera2in-1 -yl)-phenylamino3“5-methyl-8if-pyrido[2,3-d3pyrimidin-7“One(Compound 230);

8-Cyclopentyl-5-methyl-2-[4-(lH-[l^,4]triazol-3-ylsulfanyl)-phenylamino3-87?-pyrido[2»3"i^pyrinudin“7-one (Compound 231); 4- [4-(8»Cyclopentyl~5-methyl-7-oxo-7,8-dihydro-pyrido[23-ôi]pyrimidm~2-ylainino)-phenyl]-piperazme-l -carbaldehyde(Compound 232);

8-Cyclopenty î-2-(4-piperazin-1 -y I-pheny îam ino)-5 -trifluoromethyî“8ff’pyrido[2,3-^pyrimidÎn-7-oïie (Compound 233); 5- ( 1 -Elhyl-propy l)-5-methyî-2-(4-piperazin-ï -yî-phenylamino)-8H-pyrido[2,3-i(lpyTimidin-7-one (Compound 234); [4-(8-Cyclopentyl-5-methyî-7-oxo-7,S-dihydro-pyrido[2,3-6Qpyrimiàin-2-ylamino)-benzyl]-phosphonic acid (Compound 235);

6- Chloro-8-cyclopentyI-5-methyl-2-(4-piperazin-l-yl-phenylamino)-8if-pyrido(2,3“c0pynmidin-7-one (Compound 236); 2-[4-(3,5-Dimethyl-pîperazm-l -yl)-phenylamino]-8-(l -eîhyl-propyl)"5-methyl“Sff-pyrido[2,3"<3]pyriinidin“7-one (Compound 237);

8-Cyc]opentyî-2-[4»(2-hydroxy-ethyiamino)-phenyIamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 238); 30 -114- 012227 3- [4-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-p>Tido[2.3-d]pyrîmidin-2-ylamino)-phenyl]-NsN-diethyI-propionamide(Compound 239);

8-Cyclopentyl-6-fluoro-2-[4-(2-hydroxy-ethyl)-phenylamino]-5-me±yl-8H-pyrido[2.3-d]pyriniidin-7-one (Compound 240);

8-Cyclopentyl-2-[4-(2-hydroxy-ethyl)-phenylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 241); 4- (8-Cyclopentyl-5-methyl-7-oxû-7,S-dihydro-pyrido[2,3-d]pyrimidm-2-ylamino)-benzoic acid (Compound 242);

8-Cyclopentyl-2-[4-(33*dimeÎhyl-piperazin-l-yl)-phenylaniino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 243); [4-(8-Cyclopeiïtyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylaniino)-benzyl]-phosphonic acid diethyl ester(Compound 244);

8-Cycîopentyl-6-fluoro-2-[4-(2-methoxy-ethylamino)-phenylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one(Compound 245); (S)-2-Amino-3-[4-(8-cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylanuno)-pheny1]-propionic acid(Compound 246);

8-Cyclopentyl-2-[4-(2-methoxy~ethoxy)-phenylamino]-5-methyl-8H-pyrido[2s3-d]pyrimidin-7-one (Compound 247);

8-Cyclopentyî-2-(4-isopropylamino-plicnylamino)-5-methyl-8H-pyrido[2s3-d]pyrimidin-7-one (Compound 248);

8-Cyclopentyl-2-(4-hydroxy-3,5-dimethyl-phenylamino)-5-methyl-8H-pyxido[2,3-d]pyrimidin-7-one (Compound 249);

8-Cyclopentyl-6-fluoro-2-(4-hydroxy-3s5-dimethyl-pîienylamino)- 5-methyl-8H-pyrido[2,3-d3pyrimidin-7-one (Compound 250);

8-Cyclopentyî-6-fluoro-2-(4-hydroxy-3,5-dimethyl-phenyIamiuo)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 251).

-115- 012227

9. A phannaceutical composition comprising a componnd selected fromClaim 1 in combination with a phaimaceutically acceptable carrier, 'diluent, or excipient. 10 Use of a compound according to Claim 1 in the manufacture of a5 médicament for controlling proliférative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliférationassociated with a disorder selected from the group consisting of atherosclerosis, postsurgical vascular stenosis, and restenosis in mammals. jq 11. Use of a compound selected from Claim 1 in the manufacture of a substancefor inhibiting a cyclin-dependent kinase.

12. Use according to claim 11 wherein said cyclin-dependent kinase is cdk4.

13. Use of a compound selected from Claim 1 in the manufacture of a substance for inhibiting growth factor-mediated tyrosine kinase. 15

14. Use according to Claim 13 wherein said growth factor-mediated tyrosinekinase is platelet derived growth factor (PGDF).

15. Use according to claim 13 wherein said growth factor-mediated tyrosinekinase is fibroblast growth factor (FGF).

16. Use of a compound selected from Claim 1 in the manufacture of amédicament for treating a subject suffering from diseases caused byvascular smooth muscle cell prolifération.

17. Use of a compound selected from Claim 1 in the manufacture of amédicament for treating a subject suffering from cancer. 25 PCT'»' 01 2227 18. 6-Bromo-8-cyclopentyl-2-[4-(3,5-dimethyIpipecrazin-l-yl)-phenylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. 19. 8-Cyclopentyl-6-fluoro-5-niethyl-2-[4-(pipera2iQ-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one. 20. 8-Cydopentyl-5-methyl-2-(carbazol-3-yl)-8H-pyrido[2,3-d]pyriniidin-7-one.
21. A compound selected from

8-CyclopenÎyl-5-methyl-2-(carbozoI-3-yl)ammo-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 211);

8-Cyclopentyl-5-methyl-2-(isoindazol-5-yl)amino-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 212);

8-Cycîopentyl-5-methyl-2-(2-acetylbenzofuran-5-yl)amino-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 213);

8-Cyclopentyl-5-methyl-2-[(4-piperidin-l-yl)phenylaminoJ-8H-pyrido[2,3-d]pyrimidîn-7-one (Compound 214);

8-Cyclopentyl-5-methyl-2-(2,3-dimethyIindoI-5-yl)amino-8H-pyrido[2.3-d]pyrimidui-7-one (Compound 215);

8-Cyclopentyl-5-methyl-2-[4»i3,5-methyl-4R-aminomethylpyrroîidin-l-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 216);

8-Cyclopentyl-5-methyl-2- {4-[4-(2-hydroxyethyî)pipera2in-1 -yl)]phenylamino}-SH-pyrido[2,3“d]pyrimidin-7-one (Compound 217);

8-Cyclopentyl-5-metliyl-2-{4-[4-(3-moTpholinopropyl)piperidin-l-yl]phcnylamino}-8H-pyrido[2s3"d]pyrimidin-7-one (Compound 217);

8-Cyclopentyl-5-methyl-2-(benzofuran-5-yl)arnino-8H-pyrido[2s3-d3pyrimidin-7-one (Compound 219);

8-Cyclopentyî-5-meÎhyl-2-(indol-5-yl)amino-8H-pyrido[23-d]pyrimidin-7-one (Compound 220); and

8-Cyclopcntyl-5-methyl-2-(thion2çhthen-5-yl)ainino-8H-pyrido[2,3-d]pyrimidin-7-one (Compound 221). 012227 -117 -
22. Use of a compound of Claim 1 in the manufacture of a médicament fordiagnosing and or treating cancer, psoriasis, vascular smooth muscle cellprolifération associated with atherosclerosis and postsurgical vascular stenosisand restenosis in a mammal.
23. Use of a compound of Claim 1 in the manufacture of a médicament for treating amammal suffering ffom a disease caused by a DNA tumor virus.