SK12472002A3 - 5-Alkylpyrido[2,3-d]pyrimidines tyrosine kinase inhibitors - Google Patents

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

Technical field

The present invention relates to 5-alkylpyridopyrimidines as inhibitors of cyclin-dependent kinases, cyclin-dependent kinases 4. The compounds of the present invention are useful for the treatment of inflammation, cellular proliferative diseases such as cancer and restenosis, and neurodegenerative diseases such as Alzheimer's disease.

BACKGROUND OF THE INVENTION

Cyclin-dependent kinases and related serine / threonine protein kinases are cellular enzymes that perform essential functions in regulating cell division and proliferation. Cyclic-dependent kinase catalytic units (nine identified) are activated by regulatory units known as cyclins. Cyclin-dependent kinases (Cdk) include Cdk1, Cdk2, Cdk4, Cdk5, Cdk6, and Wee-1 kinases. Increased activity or temporarily abnormal activation of these kinases leads to the development of human tumors and other proliferative diseases such as restenosis. Compounds that inhibit Cdk, either by blocking the interaction between cyclin and its kinase or by binding and deactivating kinase, inhibit cell proliferation and are therefore useful in the treatment of tumors and other abnormally proliferating cells.

Some compounds that inhibit Cdk have demonstrated both preclinical and clinical antitumor activity. For example, flavopiridol, a flavonoid that is a potent inhibitor of Cdk2 and Cdk4, inhibits some types of breast and lung cancer (Kant et al., J. Natl. Cancer Inst. 1992, 84: 1736-1740; Kaur et al., Int. J. Oncol. 1996; 9: 1143-1168. A potent inhibitor of Cdk2 and Cdk5 is olomouc, i.e. [2- (hydroxyethylamine) -6-benzylamine-9-methylpurine] (Vesely et al., Eur. J. Biochem, 1994; 224: 7711

786) and inhibits the proliferation of about 60 different types of human tumor cells used by the National Institute of Cancer (NCI) to test novel methods of cancer treatment (Abraham et al., Biol. Cell 1995; 83: 105-120).

In addition to the treatment of cancer, Cdk inhibitors are useful for the treatment of cardiovascular diseases such as restenosis and atherosclerosis. Other diseases for which Cdk inhibitors are suitable are diseases caused by various infectious agents, such as DNA and RNA viruses, and inflammatory diseases, such as rheumatoid arthritis.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a group of low molecular weight organic compounds that are potent Cdk inhibitors and are useful for the prevention and treatment of diseases caused by abnormal cell proliferation.

The invention provides 5-alkylpyridopyrimidines which are useful for the treatment of inflammation, cellular proliferative diseases such as cancer and tenosis, and neurodegenerative diseases such as Alzheimer's disease. Compounds of the present invention exhibit unexpected pharmacokinetic properties over known compounds, including unexpected metabolic stability and low breakdown rate. In addition, the compounds of the present invention are unexpectedly selective Cdk4 inhibitors. The compounds of the present invention are easy to prepare and can be administered to patients in a variety of ways.

The compounds of the present invention are compounds of formula I

and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, and in Formula I:

R ² is (a) a hydrogen atom;

(b) a lower alkyl group optionally substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, thioalkyl, nitrile, aryl, the heteroaryl group or the carbocyclic group having from 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or (c) a carbocyclic group of 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, aryl and heteroaryl;

R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ₂ R ⁴ ,

CONR ⁴ R ^5, -CON (R ⁴⁾ OR ^5, -SO 2 NR ⁴ R ^5, -SO 2 R ^4, -SO ₃ R ^4, P (O) (OR ⁴⁾ (OR ⁵⁾ or a group -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 -NR ⁴ R ⁵ , -N (O) R ⁴ R ⁵ , -C (O) R ⁴ , group

-SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , nitro, -NR ⁴ R ⁵ R ^e W, -SR ⁴ , CO ₂ R ⁴ , -CONR ⁴ R ⁵ , - SO ₃ R ⁴ , -T (CH ₂ ) _m QR ⁴ group, -C (O) T (CH ₂ ) _m QR ^{4 group}

P (O) (OR ⁴ ) (OR ⁵ ), or -NR ⁴ C (O) T (CH ₂ ) _m QR ⁵ ;

m is 1 to 6;

n is an integer from 0 to 6;

T is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, or CR ⁴ R ⁵ ;

Q is chlorine, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, CO ₂ or a carbocyclic group of 3 to 7 members, of which up to 4 are optionally heteroatoms independently selected from the group consisting of: oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl,

N-hydroxyacetamide, trifluoromethylalkyl, amino or mono- or dialkylamino;

R ⁶ is lower alkyl, haloalkyl or aryl;

R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ X, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) nR ⁴ , CO ² R ⁴ , CONR ⁴ R ⁵ , C (O) NR ⁴ SO ² R ⁵ , S (O) R ⁴ , SO ² R ⁴ , SO ² NR ⁴ R ⁵ , SO ³ R ⁴ , (CH 2) n P (0) (OR ⁴ ) 2, NR ⁴ SO ² R ⁵ , aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ⁴ , C (O) T (CH 2) _m QR ⁴ , NR ⁴ C (O) T (CH 2) _m QR ⁵ or T (CH ₂ ) _m CO ₂ R ⁴ ;

W is an anion;

R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH 2) n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring of 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (0) 2 and a nitrogen atom wherein the carbocyclic group is unsubstituted or substituted by one, two, three or four groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl , alkylcarbonylamino, aminoalkyl, aminoalkylcarbon yl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR (SO 2) R ¹¹ , C (O) NR ¹⁰ R ¹¹ , NR ¹⁰ C (O) R ¹¹ , C (O) OR ¹⁰ , C (O) NR ¹⁰ SO ² R ¹¹ , (CH 2) _n S (O) _n R ¹⁰ , (CH 2) n -heteroaryl, 0 (CH 2) n -heteroaryl, (CH 2) n C (O) NR ¹⁰ R ^{1: 1} , O (CH 2) _n C (O) OR ¹⁰ ; and

R ⁴ may further be a lower alkyl group unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-disgroup, group, group, members, of hydro-1H-1, 2,4-triazol-3-ylsulfanyl

5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-ylsulfinyl

A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulphonyl or carbocyclic group containing from 3 to 7, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl alkoxy, alkoxycarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethylacetyl, N-hydroxyacetyl, a group, amino or mono- or dialkylamino group; and wherein residues Y and CR ^{7 are} part of a fragment, the alkylcarbonyl lower

R '7, where R and Z are as defined above, or together with the carbon atoms to which they are attached, form fragments

G and J are independently CH ₂ , NH or O;

B is NH, S, CH ₂ or O;

D is C or N with the proviso that the residue R ¹⁰ is absent, D is N; and

R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl.

Preferred compounds are of formula I wherein Y is CR ⁷ . In this group, compounds are suitable wherein R ⁷ is NR ⁴ R ⁵ and R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a ring such as the piperazine, piperidine, pyrrolidine and morpholine ring, each of which may be optionally substituted.

The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable diluent, carrier or excipient.

The present invention also provides a method of inhibiting cyclin-dependent kinases and growth factor-driven kinase enzymes.

The present invention also provides a method of treating patients suffering from a cell proliferative disease. The method includes inhibiting tumor cell proliferation of epithelial origin and vascular smooth muscle proliferation and / or cell migration by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I.

The present invention also provides compounds useful for the diagnosis and treatment of cancer, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis and postoperative vascular stenosis and mammalian restenosis.

The present invention also provides a method of treating patients suffering from diseases caused by DNA tumor viruses such as herpes.

The novel compounds of the present invention are described by the above formula I including their pharmaceutically acceptable salts, esters, amides and prodrugs.

In addition to the compounds of formula I, in a preferred embodiment, the invention provides compounds of formula II

wherein X, Y, Z and R ³ are as defined above for Formula I.

Preferred compounds of formula II are those wherein X and Z are independently hydrogen, chlorine or fluorine; Y is CR ⁷ and R ³ is hydrogen, chlorine, fluorine, bromine or cyano.

The present invention further provides preferred compounds

Highly preferred compounds of formula III are independently hydrogen, chlorine or those wherein X and Z are fluoro; Y is a group

CR ⁷ and R ³ are hydrogen, chlorine, fluorine, bromine or cyano.

Further, in a preferred embodiment, they are the subject of the present invention

(IV).

Preferred compounds of formula IV are those wherein X and Z are independently hydrogen, chlorine or fluorine; Y is CR ⁷ and R ³ is hydrogen, chlorine, chlorine, fluorine or bromine or CN.

Most preferred compounds of the present invention are compounds of formula V

where

R ² is alkyl or cycloalkyl;

R ³ is hydrogen or halogen;

R ⁹ is an alkyl group;

X and Z are independently hydrogen or halogen;

R ⁷ is NR ⁴ R ⁵ ; and

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form

A 5- or 6-membered carbocyclic ring optionally containing a heteroatom such as an oxygen, nitrogen or sulfur atom and optionally substituted with alkyl or substituted alkyl groups.

Particularly preferred compounds of formula V are those wherein R ^{7 is a} group

And these groups are substituted with an alkyl group, an acyl group, and the like.

optionally amide

Unless otherwise stated, the terms used herein have the following meanings.

The alkyl group, a lower alkyl group and a C _x Cio-alkyl, according to the present invention, a straight or branched hydrocarbon radical of 1 to 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t-butyl, n-pentyl, isopropyl, n-hexyl and the like.

The term halogen atom according to the present invention means fluorine, bromine, chlorine and iodine.

Alkenyl is a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and one double bond, for example ethenyl, 3-buten-1-yl,

2-ethenylbutyl, 3-hexen-1-yl and the like.

Alkynyl is a straight or branched hydrocarbon radical having 2 to 6 carbon atoms and one triple bond, for example, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1- and the like.

A cycloalkyl group is a monocyclic or polycyclic hydrocarbon group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl and cyclopentyl. These groups may be substituted by groups such as hydroxy, keto, amino, alkyl and dialkylamino. Also included are rings wherein 1 to 3 carbon atoms are replaced by heteroatoms. These groups are designated as heterocyclyl groups, which is a cycloalkyl group containing at least one heteroatom selected from the group consisting of oxygen, sulfur or nitrogen, for example oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyranyl and morpholine.

Alkoxy, lower alkoxy and C 1 -C ₁₀ -alkoxy is a straight or branched alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, p-butoxy, t-butoxy, p-butoxy, p-butoxy,

2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 1-hexoxy and

3-methylpentoxy. The term alkoxy further refers to polyethers such as -O- (CH ₂ ) ₂ -O-CH ₃ and the like.

Alkanoyl is an alkyl group attached via a carbonyl group, i.e. a C ₁ -C ₅ -C (O) - group. These include formyl, acetyl, propionyl, butyryl and isobutyryl.

An acyl group is an alkyl or aryl (Ar) group attached through a carbonyl group, i.e., an RC (O) - group. Acyl groups include C 1 -C 8 -alkanoyl groups including substituted alkanoyl groups wherein the alkyl moiety may be substituted with NR ⁴ R ⁵ or a carboxyl or heterocyclic group. Typical acyl groups are acetyl, benzoyl and the like.

An amide group is an aminocarbonyl group such as -CONR ⁴ R ⁵ .

The alkyl, alkenyl, alkoxy and alkynyl groups described above are optionally substituted with suitably 1 to 3 groups selected from the group consisting of NR ⁴ R ⁵ , phenyl, substituted phenyl, thio-C 1 -C ₆ -alkyl, C 1 -C 6 _6- alkoxy, hydroxy, carboxy, C 1 -C ₆ -alkoxycarbonyl, halogen, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. Substituted carbon atom is the nitrogen atom bearing the _C-Ce alkyl or _{(CH2) n} Ph where n is 1, 2 or 3 is made to the per-halo, and polyhalo substitution.

Examples of substituted alkyl groups are 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl,

3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-car12 boxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl and 2- (4-methyl) ethyl group.

Examples of substituted alkynyl groups are 2-methoxyethynyl, 2-ethylsulfanylethynyl, 4- (1-piperazinyl) -3-butynyl, 3-phenyl-5-hexynyl,

3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl and the like.

Typical substituted alkoxy groups are aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxyhexyloxy and the like.

Further examples of substituted alkyl, alkenyl and alkynyl groups are dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,

4-morpholinobutyl, 4-tetrahydropyrimidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-ylbutyl, phenylmethyl,

3-chlorophenylmethyl and the like.

The term anion refers to a negatively charged counterion such as chloride, bromide, trifluoroacetate.

A heteroaryl group is one or more aromatic ring systems containing 5-, 6- or 7-membered rings containing at least one to 4 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. These heteroaryl groups include thienyl, furanyl, thiazolyl, triazolyl, imidazolyl, (is) oxazolyl, oxadiazolyl, tetrazolyl, pyridyl,

thiadiazolyl group, oxadiazolyl group, iadiazolyl oxate group, , thiatriazolyl group, pyrimidinyl group, (Iso) quinolinyl, group, naphthyridinyl group, phthalimidyl group, benzimidazolyl group a benzoxazolyl group. advantageous

the heteroaryl group is a pyridine group.

An aryl group is an aromatic carbocyclic group formed by one ring (for example a phenyl group), several rings (for example a biphenyl group) or several fused rings of which at least one is aromatic, (for example

1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl or phenanthryl), which may be mono-, di- or trisubstituted by the group consisting of halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. A preferred aryl group is a phenyl group.

The term cancer refers to, but not limited to, breast, ovarian, throat, prostate, test, esophagus, glioblast, neuroblast, stomach, skin, keratoacanth, lung, epidermis, large cells, bones, colon, rectum, adenocarcinoma, adenoma, pancreas , thyroid, follicle, undifferentiated cancer, papilla, testicles, melanora, sarcoma, bladder, liver and bile ducts, kidney, myeloid, node, Hodkin, hair cells, oral cavity and larynx (mouth), lips, tongue, face, thin colon, colorectal, colon, rectum, brain and central nervous system, and leukemia.

Pharmaceutically acceptable salts, esters, amides, and prodrugs are carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are within the scope of medical technology suitable for contacting patient tissues without undue toxicity, irritability, allergic reactions and Similarly. With a reasonable benefit / risk ratio and effective for the intended use; and also, if possible, zwitterions of the compounds of the present invention. Salts are non-toxic addition salts of inorganic and organic acids and compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by separately reacting the isolated compound as the free base with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of salts are hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate , glucoheptonate, lactobionate and lauryl sulfonate and the like. These salts may also contain alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like. Also, non-toxic ammonium, ammonium quaternary and amine cations such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. See, for example, Berge S. M. et al., Pharmaceutical Salts,

J. Pharm. Sci., 1977; 66: 1-19.

Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention are C 1 -C ₆ -alkyl esters wherein the alkyl group has a straight or branched chain. Acceptable esters also include C ₅ -C 7 -cycloalkyl esters and arylalkyl esters such as (but not limited to) benzyl ester. C 1 -C ₄ -alkyl esters are preferred. Esters of the compounds of the present invention may be prepared by conventional procedures.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention are amides derived from ammonia, primary C _1-6 -alkylamines and secondary C _1-6 -alkylamines, wherein the alkyl groups have straight or branched chains. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, primary C 1 -C ₃ -alkylamines and secondary C 1 -C ₂ -alkylamines are preferred. The amides of the compounds of the present invention are prepared by conventional procedures.

A prodrug is a compound that in vivo rapidly converts to the parent compound of the above formula by hydrolysis in blood. For details, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Syria Syria and Bioreversible Carriers in Drug Design, Edward B. Roche, American Pharmaceutical Association and Pergamon Press 1987.

Examples of compounds of the present invention are shown in Table 1 below.

Table 1

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

102

Table 1 (continued)

Table 1 (continued)

• cf ₃ cooh

ΌΗ

192

Table 1 (continued)

202

Table 1 (continued)

Table 1 (continued)

196

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

NHCf ^ CH

The compounds of the present invention are useful for the treatment of cancer (e.g., leukemia and lung, breast, prostate and skin cancer such as melanoma) and other proliferative diseases such as psoriasis, HSV, HIV, restenosis and atherosclerosis, among others. When using a compound of the present invention to treat cancer, a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the present invention is administered to the cancer patient.

Another embodiment of the present invention is a method of treating patients suffering from vascular smooth muscle cell proliferation. The compounds of the present invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method includes inhibiting vascular smooth muscle cell proliferation and / or migration by administering an effective amount of a compound of Formula I to a patient in need of such treatment.

The compounds of the present invention may be formulated and administered. in the form of various oral and parenteral dosage forms, including those for transdermal and rectal administration. It will be appreciated by those skilled in the art that the following dosage forms may contain, as the active ingredient, either a compound of Formula I or a corresponding pharmaceutically acceptable salt, ester, amide, prodrug or solvate of a compound of Formula I.

Another embodiment of the present invention is a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent or excipient. In preparing a pharmaceutical composition comprising a compound of the present invention, the pharmaceutically acceptable carrier may be either solid or liquid. Solid compositions include powders, tablets, pills, capsules, cachets, suppositories, and loose granules. The solid carrier may comprise one or more substances which may also act as a diluent, flavor, binder, preservative, tablet disintegrant or encapsulating material.

In the powder, the carrier is a finely divided solid, such as talc or starch, which forms a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and then compressed to the desired shape and size.

The compositions of the present invention suitably comprise 5% to 70% or more by weight of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-soluble wax, cocoa butter and the like. A preferred form for oral use are capsules, which may contain a mixture of the active compound with an encapsulating agent as a capsule-forming carrier, in which the active ingredient, with or without another carrier, is surrounded by a carrier which is thus associated therewith. The same applies to wafers and caramels. Solid dosage forms suitable for oral administration include tablets, powders, capsules, pills, cachets, and caramels.

In preparing suppositories, a low-soluble wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and then the active ingredient is dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into a mold of suitable size and then allowed to solidify by cooling.

Liquid formulations include solutions, suspensions, and emulsions such as a solution in water or a water / propylene glycol mixture. For the preparation of parenteral injections, a liquid formulation is prepared as a solution in aqueous polyethylene glycol, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and optionally adding a suitable colorant, flavor, stabilizer and thickening agent. Aqueous suspensions suitable for oral use may be prepared by dispersing the finely divided active ingredient in water and mixing with a viscous material such as a natural or synthetic resin, methylcellulose, sodium carboxymethylcellulose or other known suspending agent.

Another form is solid compositions intended to be converted into oral liquid form just prior to use. Such liquid forms are solutions, suspensions and emulsions. These compositions may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. Waxes, polymers, microparticles and the like can be used in the preparation of sustained release dosage forms. Ozmotic pumps may also be used to continuously administer the active compound over a prolonged period of time.

The pharmaceutical compositions of the present invention are suitably in unit dosage form. In this form, the composition is subdivided into units containing a suitable amount of the active ingredient. The dosage unit may be a packaged composition, a pack containing a certain amount of composition, such as packs of tablets, capsules and powder in vials or ampoules. The dosage unit may also be a capsule, tablet, cachet, or caramel itself, or may be a suitable number in a package.

I

The therapeutically effective dose of the compound of formula I is generally from 1 mg / kg to 100 mg / kg body weight per day. A typical dose for an adult patient is 50 mg to 800 mg per day. The amount of active ingredient in the unit of composition is from 0/1 mg to 500 mg, suitably from 0.5 mg to 100 mg, depending on the particular application and the efficacy of the active ingredient. The composition may, if desired, also contain other compatible therapeutic agents. For a subject in need of treatment with a compound of Formula I, it is administered a dose of 1 mg to 500 mg per day, either once or several times for 24 hours.

The compounds of the present invention are capable of binding and inhibiting proteins capable of phosphorylating other proteins, such as Cdk, PDGFr, FGFr, c-Src and EGFr-FL. Cdk complexes with cyclins, and these complexes phosphorylate key proteins, allowing cells to continue the cell cycle (Meijer L., Progress in Cell Cycle Research 1995; 1: 351-363). The compounds of the present invention inhibit this phosphorylation and can therefore be used as antiproliferative agents in the treatment of cancer and / or restenosis and other proliferative diseases.

Since they inhibit Cdk and other kinases, the compounds of the present invention are also useful in investigating the mechanism of action of these kinases, both in vitro and in vivo.

The following examples are intended to illustrate particular embodiments of the invention but are not intended to limit the scope of the description or claims in any way.

Illustrations of the preparation of compounds of the present invention are Schemes 1 and 2.

Scheme 1

(EtO), P (O) CH, CO ₂ Et, NaH

Y

.oxaziridín

2.Boc-Pip-aniline

IN

I

Boe

r / • y

H TFA

Scheme 2

It will be apparent to those skilled in the art that other starting materials may be used in the preparation of the compounds of the present invention and steps other than the following examples may be performed.

As shown in Schemes 1 and 2, a 4-substituted anilino-2-methanesulfanylpyrimidine-5-carboxaldehyde is reacted with an organometallic compound, such as a Grignard reagent, to yield the corresponding secondary alcohol. The alcohol is then oxidized to a ketone, the ketone reacts with a trialkylphosphonoacetate in the presence of a base to yield the corresponding 8-substituted

5-alkyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one. Pyridopyrimidine can then be halogenated. at position 6 with a conventional halogenating agent such as N-bromosuccinimide (NBS). The methylsulfanyl derivative is then oxidized to the corresponding methylsulfoxide, which is then reacted with the corresponding aniline to give the 2-phenylamino compound of the present invention.

In the preparation of the compounds of the present invention, it may be desirable to derivatize reactive groups such as amino, alcohol and acid with protecting groups that are readily removed if desired. These protecting groups simply prevent unwanted side reactions. The use of protecting groups is common in the field of organic chemistry, see Greeve and Wuts, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, New York, 2nd edition, 1991. A typical hydroxy protecting group is an ether-forming group such as benzyl and acyl. a group such as t-butoxycarbonyl, formyl and acetyl. The amino protecting group is an acyl group such as an acetyl group and a trialkylsilyl group. The carboxylic acids are typically protected by conversion to esters that can be easily hydrolyzed with a group such as trichloroethyl, t-butyl, benzyl and the like.

Certain compounds of the present invention have one or more chiral centers and may exist as individual optical isomers and mixtures thereof. Compound 246 (Table

1) can exist, for example, as the RS racemate or as a single isomer of R or S. All individual isomers and mixtures thereof are part of the present invention. The individual isomers may be readily prepared by chiral synthesis or by conventional separation techniques well known to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The invention is further illustrated by the following detailed examples, which in no way limit the procedures it describes. The starting materials and various intermediates used in the synthesis of the compounds of the present invention can be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods. All articles and references, including patents, mentioned herein are considered to be references.

Example 1

- Cyclopentyl-6-fluoro-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

Sodium hydride (771 mg, 19.3 mmol) was suspended in dry tetrahydrofuran (20 mL) and the mixture was cooled to 0 ° C in an ice bath. Triethyl 2-fluoro-2-phosphonoacetate (3.9 mL, 19.3 mmol) was then added dropwise with stirring, and the solution was stirred at room temperature for 30 minutes. A solution of 1- (4-cyclopentylamino-2-methylsulfanylpyrimidin-5-yl) ethanone in dry tetrahydrofuran (40 mL) was then added via cannula and the reaction mixture was stirred at 24 ° C for 12 hours. The reaction was quenched by the addition of 0.5 mL of water and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted twice with fresh ethyl acetate, and the combined organic layers were dried over magnesium sulfate. After removal of the desiccant and evaporation of the solvent, the crude product is chromatographed on silica gel eluting with 20-30% ethyl acetate in hexane to give the title compound as a colorless solid (61 g, 23%).

Example 2

8-Cyclopentyl-6-fluoro-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one

CH

8-Cyclopentyl-6-fluoro-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (0.61 g, 2.08 mmol) from Example 1 and 3-phenyl- Dissolve 1-p-nitrophenylsulfonyloxaziridine (0.65 g, 2.5 mmol) in dichloromethane (20 mL) and stir at 24 ° C for 12 h. After evaporation of the solvent, the crude product is chromatographed on silica gel eluting with 80-100% ethyl acetate in hexane to give the sulfoxide product as a white solid (0.55 g, 86%).

Example 3 4- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-butyl ester -carboxylic acid

- [4- (8-Cyclopentyl-6-fluoro-5-methanesulfinyl-5-methyl-8H-pyrido [1,3-d] pyrimidin-7-one (0.3 g, 0.97 mmol) from Example 2) and 4- (NBoc-piperazin-1-yl) aniline (0.548 g, 1.94 mmol) was suspended in

1,4-dioxane (5 mL) was heated at 80 ° C for 12 h. Anhydrous dimethylsulfoxide (2.5 mL) was then added and the temperature was raised to 100 ° C. Heating is then continued for 24 hours. The reaction mixture was then cooled to 24 ° C and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and washed with water and then with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound as a yellow solid (0.23 g, 45%).

Example 4

8-Cyclopentyl-6-fluoro-5-methyl-2- (4-piperazin-l-yl-phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one

4- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-butyl ester- of carboxylic acid (0.23 g, 0.44 mmol) from Example 3 was dissolved in 20 mL of a 1: 1 mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 hour. The solvent was evaporated and anhydrous diethyl ether was added to give an orange solid (compound 34) which was collected by filtration (0.21 g, 74%), mp 254-255 ° C.

C ₂₃ H ₂₇ N ₆ OF-1.93TFA: calculated C 50.21; H, 4.54; N, 13.08; Found: C, 49.83; H, 4.45; N, 12.99.

Example 5

6-Bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyridop [2,3-d] pyrimidin-7-one

br

8-Cyclopentyl-6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (1 g, 3.64 mmol) was dissolved in 15 mL of dry dimethylformamide (15 mL) and N-bromosuccinimide (0.97 g, 5.45 mmol) was added followed by benzoyl peroxide (0.13 g, 0.5 mmol). The resulting solution was stirred at 24 ° C for 12 hours and the mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Removal of the drying agent and evaporation gave the title compound (0.86 g, 66%), which was used without further purification.

Example 6

6-Bromo-8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one

H

br

6-Bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one is oxidized as described in Example 2. The sulfoxide is then reacted with 4- (N-Boc- piperazin-1-yl) aniline as described in Example 3. The N-Boc protecting group was removed by hydrolysis as described above for 8-cyclopentyl-6-fluoro-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidine -7one to give 6-bromo-8-cyclopentyl-5-methyl-2- (4-piperazin-lylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 35), melting point> 200 ° C (dec.).

₂ C 3 H ₂ - N ₆ Figure 1.9 TFA: Calculated C 45.90; H, 4.15; N, 11.97. Found: C, 45.53; H, 4.09; N, 11.76.

Example 7

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethane-l-ol

4-Cyclopentylamino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (1.1 g; 4.64 mmol) was dissolved in tetrahydrofuran (30 mL) under nitrogen and then cooled in an ice bath. To this clear solution was slowly added methylmagnesium bromide (4.4 mL, 13.2 mmol, 3M solution in ether). The reaction mixture was stirred in an ice bath for 1 hour and then quenched with a small amount of saturated ammonium chloride solution and partitioned between water and ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated in vacuo to give the title compound as an oil (1.09 g, 90%).

^X H NMR (400 MHz, CDC1 _3): δ 1.42 to 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).

Example 8

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethan-1-ol (1.09 g, 4.3 mmol) from Example 7 was dissolved in 100 mL of dichloromethane. Nitrogen was bubbled through the solution for 2 minutes. Powdered molecular sieves (4Π), N-methylmorpholine oxide (1.07 g, 8.6 g) and tetrapropylammonium ruthenate (0.227 g, 0.645 mmol) were then added sequentially to the reaction mixture. The reaction mixture was stirred at 24 ° C for 2 hours, a small amount of catalyst was added periodically. The reaction mixture is then chromatographed on silica gel (1: 1, ethyl acetate: hexane) to give the title compound as a pale yellow solid (0.74 g, 70%).

³ H NMR (400 MHz, CDCl ₃ ): 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,

1H), 9.21 (s, 1H); MS (M + 1) 252.2.

Example 9

8-Cyklypentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

50 ml of tetrahydrofuran are added to the flask and sodium hydride (1.05 g, 26.3 mmol, 60% dispersion in mineral oil) is added under cooling to 5 ° C followed by 1.0 g of triethylphosphonoacetate. The cooling bath was removed and the mixture was stirred at 24 ° C until a homogeneous solution was obtained. A solution of 1- (4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (3.0 g, 11.9 mmol) in tetrahydrofuran (25 mL) was then added dropwise. The reaction mixture is then heated to boiling for 2 hours, then cooled to 24 ° C and diluted with 50 ml of water and 50 ml of ethyl acetate. After separation of the layers, the organic layer is dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. Hexane was then added and the mixture was stirred vigorously for 5 minutes and then filtered to give the title compound as a light orange solid (3.01 g, 92%).

^X H NMR (400 MHz, CDC1 _3): δ 1.63 to 2.36 (m, 8 H), 2.38 (s, 3H);

2.59 (s, 3H), 5.84-5.93) (m, 1H), 6.39 (s, 1H), 8.66 (s, 1H).

Example 10

8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one

The 8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (1.0 g, 3.63 mmol) from Example 9 was dissolved in dichloromethane (15 mL) and (±) -trans-2- (phenylsulfonyl) 3-phenyloxaziridine was added. The reaction mixture was stirred at 24 ° C for 12 h and then purified by silica gel chromatography eluting with 2% methanol in dichloromethane to afford the title sulfoxide as a white solid (0.67 g, 64%).

^{Χ Η} NMR (400 MHz, _DMSO-d6): 8 1.53 to 2.19 (m, 5 H), 2.45 (s, 3H);

2.87 (s, 3H), 5.75-5.84 (m, 1H), 6.64 (s, 1H), 9.19 (s, 1H).

Example 11 4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,9-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester of

8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (0.7 g, 2.4 mmol) from Example 10 and 4- (4'-N-) Boc-piperazinyl) -aniline was dissolved in dimethylsulfoxide (3 mL) and heated to 90 ° C overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removal of the desiccant and concentration in vacuo gave the title compound as a yellow solid, which was recrystallized from water and acetonitrile to give 0.55 g of product (45%).

1 H NMR (400 MHz, CDC1 ₃ ): δ 1,45 (WITH, 9H), 1.56 to 1.87 (m, 6H) 2.23-2.28 (m, 2H) 2.31 (s, 3H) 3.07 (M, 4H), 3.55 (m, 4H) 5.77 to 5.81 (m, 1 H), 6.19 (S, 1 H), 6.90 (D, 2H), 7.42 -7.44 (d, 2H), 7.47 (s, 1H) , 8.55 (s, 1H) ; MS (M + 1) 505.1. protecting

the Boe group was removed by stirring in a 1: 1 mixture of trifluoroacetic acid and dichloromethane to give compound 1. Melting point> 215 ° C (dec.).

Example 12

8-Cyclopentyl-5-ethyl-2- (4-piperazinyl-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 193)

H

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-ol

4-Cyclopentylamino-2-methylsulfanylpyrimidine-5-carbaldehyde (4.07 g, 17.1 mmol) was dissolved in 60 mL of tetrahydrofuran under nitrogen atmosphere, cooled in an ice bath and EtMgBr (13.4 g) was slowly added to this clear solution. mL, 40.3 mmol, Aldrich, 3M solution in ether). The reaction mixture was stirred in an ice bath for 15 minutes, then quenched with a small amount of saturated aqueous ammonium chloride solution and partitioned between water and EtOAc. The layers were separated, the organic was dried over MgSO ₄ , filtered and concentrated in vacuo. There was thus obtained 1- (4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-ol as an oil (4.55 g, 99%), which was used without further purification.

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-one

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-ol (4.55 g, 17.1 mmol) was dissolved in toluene (80 mL) and then activated manganese dioxide (3.72 g) was added. , 42.8 mmol, Aldrich, <5 µm, 85%). The reaction mixture was heated to reflux for 16 hours, then cooled to room temperature and filtered through diatomaceous earth. The filtrate was then concentrated in vacuo to give the product as a pale yellow oil (3.79 g, 84%).

8-Cyclopentyl-5-ethyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

Under a nitrogen atmosphere, NaH (1.23 g, 30.7 mmol, 60% dispersion in mineral oil) was added to cooled tetrahydrofuran (50 mL) followed by triethylphosphonoacetate (6.09 mL, 30.7 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature until complete dissolution. To the prepared anion was slowly added a solution of 1- (4-cyclopentylamino-2-methylsulfanylpyrimidin-5-yl) -propan-1-ol (3.0 g, 11.9 mmol) in tetrahydrofuran (70 mL). The reaction mixture is then heated to reflux for 60 hours. The mixture was then cooled to room temperature and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated in vacuo to give a waxy solid. The product was triturated with hexane and filtered to give a white solid (2.67 g, 66%). ¹

- Cyclopentyl-5-ethyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one

8-Cyclopentyl-5-ethyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (2.57 g, 8.88 mmol) was dissolved in dichloromethane (50 mL) and 2 benzenesulfonyl-3-oxaziridine. The reaction mixture was stirred at room temperature for 16 hours and the solution was evaporated to give an orange oil. Ethyl acetate was then added and a white precipitate formed. This precipitate was collected by filtration and washed with hexane to give a white solid (2.12 g, 78%).

4- [4- (8-Cyclopentyl-5-ethyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperazine-1-carboxylic acid t-butyl ester

8-Cyclopentyl-5-ethyl-2-methanesulfinyl-8H-pyrido [2,3-d] pyrimidin-7-one (sulfoxide, 0.2 g, 0.654 mmol) and 4- (4'-N-Bocpiperazinyl) - The aniline was dissolved in dimethylsulfoxide (5 mL) and heated at 70 ° C for 16 h. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over MgSO ₄ . Filtration and concentration in vacuo gave an orange solid which was chromatographed on silica gel to give the product as a yellow solid (0.160 g, 47%).

- Cyclopentyl-5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrrolo [

2,3-d] pyrimidin-7-one (235) 4- [4- (8-Cyclopentyl-5-ethyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2) t-butyl ester -Ylamino) -phenyl] -piperazine-1-carboxylic acid was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 15 hours at room temperature, the solvent evaporated and the solid material ¹ is suspended in diethyl ether. Filter the mixture to afford tufts of gray solid (128 mg, 75%).

^X NN4R H (400 MHz, DMSO-d 6): δ 1.17 (m, 3H), 1.52 to 1.83 (m, 6H);

2.20 (m, 2H), 2.75 (m, 2H), 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 C 3 H ₃ oN ₂ 0 ₆ + 1.21 TFA.

Example 13

2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 198)

^ 0

1- [4- (4-Amino-phenyl) -piperazin-1-yl] -ethane (0.075 g, 0.343 mmol) and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido [2,3-d] 1 H pyrimidin-7-one (0.100 g, 0.343 mmol) was dissolved in DMSO (5 mL) and the mixture was heated at 70 ° C for 16 h. An additional 20 mg of aniline is then added and heating is continued for an additional 4 hours. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over MgSO ₄ . Filtration and concentration in vacuo gave an orange solid which was chromatographed on silica gel to give a yellow solid (0.049 g, 32%). Melting point 261-263 ° C.

Example 14

2- [4 - ((3R, 4S) -Aminomethyltrifluoromethylpyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 216) t [(3R, 4S) -1- (4-Amino-phenyl) -trifluoromethyl-pyrrolidin-3-ylmethyl] -carbamic acid tert -butyl ester ((3S, 4S) -4-Trifluoromethyl-pyrrolidin-3-ylmethyl) -carbamic acid t-butyl ester ( 1.0 g, 3.72 nunol), p-fluoronitrobenzene (0.36 mL, 3.38 mmol) and diisopropylethylamine (0.65 mL, 3.72 mmol) were dissolved in acetonitrile (10 mL) and stirred for 24 h. heats to boil. The solvent was removed and the mixture was overlayed in hexane and filtered to give a crude yellow solid (1.4 g). This material was dissolved in tetrahydrofuran and Raney nickel and hydrogen were added until the pressure change was complete. After removal of the catalyst by filtration, the aniline product is obtained by evaporation of the solvent which is used without further purification.

{(3R, 4S) - [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -trifluoromethyl-pyrrolidine- t-butyl ester 3-ylmethyl} -carbamic acid (222) [(3R, 4S) -1- (4-Aminophenyl) -trifluoromethyl-pyrrolidin-3-ylmethyl] -carbamic acid t-butyl ester and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H -pyrido [2,3-d] pyrimidin-7-one is combined and deprotected as described in Example 11 above. CHN for C ₂₅ H ₂₉ N ₆ OF ₃ + 1.6 TFA; melting point > 130 ° C (decomposition).

Example 15

9-Cyclopentyl-5-methyl-2- {4- [2- (4H- [1,2,4] triazol-3-ylsulfanyl) -ethyl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine -7-one (compound 222)

4- [2 (4H- [1,2,4] triazol-3-ylsulfanyl) ethyl] phenylamine

To a suspension of hexane washed 60% sodium hydride (0.83 g) in dimethylformamide (5 mL) at 0 ° C was added portionwise a solution of 1-mercapto-1,2,4-triazole (2.0 g) in dimethylformamide (10 mL). ml). After 45 minutes, 4-nitrophenethyl bromide (4.1 g) was added and the reaction mixture was stirred at room temperature for 18 hours. 1M hydrochloric acid (70 ml) was added and the aqueous phase was extracted with diethyl ether (3 x 100 ml). The combined organic extracts were concentrated to dryness and the resulting solid collected, washed with diethyl ether (2 x 10 mL) and dried to give the nitrobenzene intermediate (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 tetrahydrofuran (100 mL). Concentrate to dryness to give the title compound (0.88%), MS: MH ⁺ 221; MH - 219.

8-Cyclopentyl-5-methyl-2- (4- [2- (4H- [1,2,4] triazol-3-ylsulfanyl) -ethyl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine -7-one t

A solution of 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido [2,3-d] pyrimidin-7-one (0.02 g), 4- [2 (4H- [1,2,4] triazole) 3-Ylsulfanyl) -ethyl) -phenylamine (0.0166 g) and trifluoroacetic acid (0.06 mL) in 2 mL acetonitrile was heated at 80 ° C for 18 h. The mixture was then cooled and the solvent removed in vacuo. Then 1M sodium hydroxide solution (4 ml) was added and the aqueous phase was extracted with diethyl ether (3 x 4 ml); sodium chloride (20 mg) was added after the first extraction. The aqueous layer was acidified to pH 1 and extracted with ethyl acetate / dichloromethane (9: 1) (3 x 4 mL). The combined organic extracts were concentrated to dryness and chromatographed on silica gel eluting with a gradient of ethyl acetate 60% to 100% in hexane. Concentration of the appropriate fractions gave compound 222 (0.014 g).

^X H NMR (d 6 -DMSO): δ 1.58 (2H, m), 1.7 (2H / m), 1.89 (2H, m),

2.2 (2H, m), 1.38 (3H, s), 2.9 (2H, m), 3.4 (2H, m), 5.7 (1H, s), 5.8 (IH) m), 7.18 (2H, d, J = 9), 7.6 (2H, d, J = 9), 8.79 (1H, s).

Example 16

8-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound) 223)

4- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine

A solution of hexane-washed 60% sodium hydride (1.16 g) in dimethylformamide (10 mL) was added dropwise at 0 ° C.

Of 3-mercapto-1,2,4-triazole (4.0 g) in dimethylformamide (20 mL). After 20 minutes, 1-fluoro-4-nitrobenzene (5 g) in dimethylformamide (20 mL) was added and the reaction mixture was stirred at room temperature for 2 hours and then at 60 ° C for 18 hours. Then f

1M hydrochloric acid (100 ml) and solid were collected and dried. A second portion of the solid (2.1 g) was obtained by crystallization of the mother liquors. The combined solids were dissolved in dichloromethane (300 mL) and 1 M sodium hydroxide (200 mL) was added. The organic layer was extracted with 1M sodium hydroxide (100 mL) and the combined aqueous phases were extracted with dichloromethane (2 x 300 mL) and then acidified to pH = 1. The resulting solid was collected and dried to give the nitrobenzene derivative (1.96 g) . This product was reduced with Raney nickel and hydrogen in tetrahydrofuran (10 mL). After removal of the catalyst, the sample was concentrated to dryness to give the desired product (1.7 g), MS: MH ⁺ 192.9; MH + 190.0.

8-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfanyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one

This compound is prepared from 4- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido [2,3-d] pyrimidine- 7-one according to the procedure described in Example 15 to give compound 223.

^X H NMR (D 6 -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, with) , 7.4 (2H, d, J = 9); 7.73 (2H, d, J = 9); 8.85 (1H, bs), 8.82 (1 H,

with) .

Example 17

8-Cyclopentyl-5-methyl-7-oxo-2- (4-piperazin-1-yl-phenylamino) -7,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acid methyl ester (Compound 224)

4 - [(4- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine) t-butyl ester -1-carboxylic acid (300 mg, 0.515 mmol), Pd (OAc) ₂ (23 mg, 0.05 mmol), 1,2-bis ((diphenylphosphino) propane (64 mg, 0.155 mmol) and triethylamine (0 (18 ml, 1.1.9 mmol) was dissolved in methanol and a CO atmosphere (500 PSI) was introduced, the reaction mixture was heated at 100 ° C for 14 h and then cooled to 24 ° C. Purify on silica gel (45% to 50% EtOAc in hexane) to give a yellow oil. This oil was dissolved in dichloromethane (10 mL) and 2M HCl in diethyl ether (10 mL) was added at room temperature to give a white precipitate. After stirring for one hour at room temperature, the solvent was evaporated and the residue was suspended in anhydrous diethyl ether and then collected by filtration to give compound i.

title compound as a yellow solid (34 mg), m.p. 195-205 ° C.

^X H NMR (d 6 -DMSO): δ 1.52 (SD, 2H), 1.71 (bs, 2H), 1.82 (with, 1H), 2 14 (bs, 2H), 2.30 (s, 3H), 3.18 (s, 4H); 3.27 (s, 4H), 3.76 (with 3H), 5.8 (s, 1H), 6.96 (d, J = 8Hz, 2H), 7.53 (D, J = 8 Hz, 2H), 9.85 (s, 1H), 9.04 (s, 1H), 9.97 (S, 1 H).

Example 18

The following compounds were also prepared as described in Examples 1 through 17 and Schemes 1 and 2:

(a) Trifluoroacetic acid salt and 8-cyclopentyl-5-methyl-2- (4-piperazin-1-ylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 1), m.p.> 215 ° C (decomposition);

(b) 8- (1-Methyl-ethyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 2), melting point> 235 ° C (dec.);

(c) 8-Cyclopentyl-5-methyl-2- (4-fluoro-3-methylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 3);

(d) 8- (1-methylethyl) -5-methyl-2- (4-fluoro-3-methylphenylamino) 8H-pyrido [2,3-d] pyridin-7-one (compound 4);

(e) 9-Cyclohexyl-5-methyl-2- (4-fluoro-3-methylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 5);

(f) 8-Cyclohexyl-5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 6);

(g) trifluoroacetic acid salt of 8-cyclopentyl-5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compounds 7), mp 235-237 ° C;

(h) 8- (1-methylethyl) -5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 8);

(i) 8-Cyclohexyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 9);

(j) 8-Cyclopentyl-5-methyl-2- (4-pyridylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 10);

(k) 8- (1-methylethyl) -5-methyl-2- (4-pyridylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 11);

(1) trifluoroacetic acid salt and 8-cyclopentyl-5-methyl-2- [4- (3-aminopyrrolidinyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 12), melting point> 195 ° C (dec.);

(m) 8- (1-methylethyl) -5-methyl-2- [4- (3-aminopyrrolidinyl) phenylamino] -8H-pyrido (2,3-d] pyrimidin-7-one (compound 13), melting point &Gt; 227-229 ° C;

(n) N- (1- {4 - [(8-Cyclopentyl-5-methyl-7-oxo (8-hydropyridino [2,3-d] pyrimidin-2-yl)) amino] phenyl) pyrrolidin-3 -yl) 3,3-dimethylbutanamide (compound 14);

(o) N- (1- {4 - [(5-methyl-8- (1-methylethyl) -7-oxo (8-hydropyridino [2,3-d] pyrimidin-2-yl)) amino] phenyl Pyrrolidin-3-yl) -3,3-dimethylbutanamide (Compound 15);

(p) 8-Cyclopentyl-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 16), temperature mp 234-237 ° C;

(q) 8-Cyclohexyl-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 17);

(r) 8- (1-Methyl-ethyl) -5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 18) ;

1 ', (s) 8-Cyclopentyl-6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 19);

(1) 8-Cyclohexyl-6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 21) );

(u) 8- (1-Methyl-ethyl) -6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 20);

(v) 8-Cyclopentyl-5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 22);

(w) 8- (1-methylethyl) -5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 23) (x) )

8-Cyclohexyl-5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 24);

(y) 2 - ({3-chloro [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl) amino) -8-cyclopentyl-5-methyl-8-cyclropyridino [2,3-d] pyrimidin-7 -one (compound 25); ^1,1 (z) 2 - ({3-Chloro-4- [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl} amino) -8- (1-methylethyl) -5-methyl-8-hydropyridine [2,3-d] pyrimidin-7-one (Compound 26);

(aa) 2 - ({3-Chloro-4- [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl} amino-8-cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidine -7-one (compound 27);

(bb) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8-cyclopentyl-6-fluoro-5-methyl-8-hydropyridino [2,3d] pyrimidine- 7-one (compound 28);

(cc) 2 - ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl) phenyl) amino] -8- (1-methylethyl) -6-fluoro-5-methyl-8-hydropyridine [2] 3d] pyrimidin-7-one (Compound 29);

(dd) 2 - ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclohexyl-6-fluoro-5-methyl-8-hydropyridino [2,3d] pyrimidine- 7-one (compound 30), m.p. > 80 ° C (dec.);

(ee) 2 - ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclopentyl-5-methyl-8-hydropyridino [2,3-d] pyrimidine

7-one (compound 31), (ff) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8- (1-methylethyl) -5-methyl-8- hydropyridino [2,3-d] pyrimidin-7-one (Compound 32);

(gg) 2 - ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidin-7-one (Compound 33) (gg2) 8-Cyclopentyl-2- [4- (piperazin-1-yl) phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 34 melting point 254 DEG -255 DEG C .;

(gg3) 8-Cyclopentyl-2- [4- (piperazin-1-yl) phenylamino] -6-bromo-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 35) , melting point > 200 ° C;

(hh) 9-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) -phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7one hydrochloride (compound 36), melting point > 220 ° C;

(ii) 8-Cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 37);

(jj) 6-Bromo-8-cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) -phenylamino) -5-methyl-8H-pyrido] [2,3-d] pyrimidin-7 hydrochloride -one (compound 38), melting point > 230 ° C;

(kk) 8-Cyclopentyl-6-fluoro-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound) 39);

(11) 6-Bromo-8-cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound) 40);

(mm) 8-Cyclopentyl-2- [4- (3,5-methylpiperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 41);

(nn) 2- (3-Chloropiperazin-1-yl-phenylamino) -4-cyclopentyl-5-methyl

8H-pyrido [2,3-d] pirimidin-7-one (Compound 42);

(oo) 2- (3-Chloro-4-piperazin-1-yl-phenylamino) -8-cyclopent-yl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 43) ;

(pp) 6-Bromo-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pirimidin-7-one (Compound 44) ;

(qq) 8-Cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 45), mp 227-229 ° C;

(rr) 9-Cyclopentyl-6-fluoro-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 46);

(ss) 6-Bromo-8-cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 47);

(tt) 8-Cyclopentyl-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 48);

(uu) 8-Cyclopentyl-6-fluoro-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 49) ;

(w) 6-bromo-8-cyclopentyl-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one; (compound 50) (ww) 2- (3-chloro-4-morpholin-4-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 51);

(xx) 2- (3-Chloro-4-morpholin-4-yl-phenylamino) -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-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) 9-Cyclopentyl-5'-methyl-2- {4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] -phenylamino} -8H-pyrido [2,3d] pyrimidine- 7-one (compound 54), mp 198-199 ° C;

9-cyclopentyl-6-fluoro-5-methyl-2- (4- [4- (2,2,2-trifluoro-ethyl) -piperazin-l-yl) phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 55);

6-Bromo-8-cyclopentyl-5-methyl-2- (4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl) -phenylamino} -8H-pyrido [2,3-d] -pyrimidin-7-one (compound 56);

8-Cyclopentyl-5-methyl-2- {4- [4- (3-piperazin-1-ylpropyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (compound 57), m.p. > 80 ° C (dec.);

8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-piperazin-1-ylpropyl) piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine

7-one (compound 58), melting point> 230 ° C;

6-Bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidin-7 -one (compound 59);

8-Cyclopentyl-5-methyl-2- {4- [4-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 60);

8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 61);

I

6-Bromo-8-cyclopentyl-5-methyl-2- (4- [4- (3-morolin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 62);

6-Bromo-8-cyclopentyl-5-methyl-2- (4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine -7-one (compound 63);

2- (4- {4- [3- (3-amino-pyrrolidin-yl) -propyl] -piperidin-l-yl} phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d Pyrimidin-7one (Compound 64);

2- (4- {4- [3- (3-Minopyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2] 3-d] pyrimidin-7-one (Compound 65);

2- (4- {4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2] 3d] pyrimidin-7-one (Compound 66);

8-Cyclopetyl-2- {3-fluoro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrimidin-7-one (Compound 67);

8-Cyclopentyl-6-fluoro-2- {3-Fluoro-4- [4- (3-piperazin-1ylpropy) piperidin-l-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine 7-one (compound 68);

6-Bromo-8-cyclopentyl-2- (3-fluoro-4-piperazin-1-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7 -one (compound 69);

8-Cyclopentyl-2- {3-Fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine

7- (compound 70);

8-Cyclopentyl-6-fluoro-2- {3-fluoro-4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidin-7-one (compound 71);

6-Bromo-8-cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidin-7-one (compound 72);

2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-one (compound 73), m.p.> 215 ° C;

2- [4- (3-Amino-pyrrolidin-l-yl) phenylamino] -8-cyklpentyl-6-fluoro

5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 74);

2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl

5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 75);

2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound

76);,

2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluorophenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one ( compound

77);

2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluorophenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound

78);

8-Cyclopentyl-5-methyl-2- (4- [3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (compound 79), melting point higher than 160 ° C (dec.);

8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine 7one (compound 80);

6-Bromo-8-cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine 7one (compound 81);

2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 82) , melting point> 215 ° C (dec.);

2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 83), melting point 221 ° C;

2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 84);

2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 85);

»

2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 86) ;

2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 87 );

2- [4- (3-Triflorethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 88);

2- [4- (3-Triflorethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 89);

2- [4- (3-Triflorethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 90;

8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 91), melting point &Gt; 150 ° C (dec.);

8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 92);

6-Bromo-g-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 93), melting point > 200 ° C (decomposed);

8-Cyclopentyl-5-methyl-2- [4- (3,3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 94);

8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (3,3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 95) ;

6-Bromo-8-cyclopentyl-5-methyl-2- [4- (3,3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 96) ;

2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 97;

2- [4- (4-acetylpiperazin-1-yl) phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 98), m.p. 267-269 C;

2- [4- (4-Acetyl-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 99);

8-Cyclopentyl-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperazin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 100), melting point 156-159 ° C;

8-Cyclopentyl-6-fluoro-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperazin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 101);

6-Bromo-8-cyclopentyl-2- {4- [4- (2-hydroxyethyl) -3,5-dimethyl-piperazin-l-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine -7-one (compound 102);

8-Cyclopentyl-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 103), melting point 172 ° C (dec.);

8-Cyclopentyl-6-fluoro-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido (2,3-d] pyrimidin-7-one hydrochloride (compound 104), temperature mp 192 ° C (dec.);

6-Bromo-8-cyclopentyl-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 105);

8-Cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] 8H) pyrido [2,3-d] pyrimidin-7-one (compound 106), m.p. 211-213 ° C;

8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 107)

6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 108)

8-Cyclopentyl-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 109) temperature melting above 185 ° C (dec.);

8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 110),

6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 111), {4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3d] pyrimidin-2-ylamino) -phenyl] -piperazin-1-yl} -acetic acid (Compound 112);

{4- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperazin-1-yl} acetic acid an acid (compound 113);

{4- [4- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperazin-1-yl acetic acid (compound 114);

8-Cyclopentyl-5-methyl-2- (4- {4- [3- (1H-tetrazol-5-yl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidine -7-one (compound 115);

8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (ΙΗ-tetrazol-5-yl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3] -d] pyrimidin-7-one (compound 116);

6-bromo-8-cyclopentyl-5-methyl-2- (4- (4- [3- (1H-tetrazol-5-yl) -propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2, 3-d] pyrimidin-7-one (Compound 117);

8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl) propyl] piperidin-1- yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 118);

8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydrol-1, 2,4-triazol-3-ylsulfanyl) propyl] piperidine- lyl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 119)

6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H 1,2,4-triazol-3-ylsulfanyl) propyl] piperidine -1-yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (compound 120);

8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5 ^- oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 121);

8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfinyl) propyl] piperidine 1-yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 122);

6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro

1,2,4-triazol-3-sulfinyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 123);

8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-sulfonyl) propyl] piperidin-l-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 124);

8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfonyl) propyl] piperidine- 1-yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 125);

6-Bromo-8-cyclopentyl-5-methyl-2- (4- (4- [3- (5-oxo-4,5-dihydro

1,2,4-triazole-3-sulfonyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 126);

N- (2- {1- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] piperidin-4-yl} ethyl -N-hydroxyacetamide (compound 127);

N- (2- {1- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-yl} ethyl) -N-hydroxyacetamide (compound 128);

N- (2- {1- [4- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-yl} ethyl) -N-hydroxyacetamide (compound 129);

N- (3- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] piperidin-4-yl} propyl -N-hydroxyacetamide (Compound 130);

N- (3- {1- [4- (8-cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-yl} propyl) N-hydroxyacetamide (compound 131);

N- (3- {1- [4- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-ylpropyl) N-hydroxyacetamide (Compound 132);

2- (benzofuran-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 133);

8-Cyclopentyl-2- (1H-indol-5-ylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 134);

2- (benzo [b] thiophen-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 135);

8-Cyclopentyl-2- (2,3-dimethyl-1H-indol-5-ylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 136);

2- (9H-carbazol-3-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3]

d] pyrimidin-7-one (Compound 137);

8-Cyclopentyl-2- (1H-indazol-5-ylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 138);

2- (2-acetyl-benzofuran-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 139);

8-Cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 140);

8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 141);

2- (3-Chloro-4-piprazin-1-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (compound ·

142), mp 234-237 ° C;

8-Cyclopentyl-5-methyl-2- (4-piperidin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 143);

8-Cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 144);

N- (1- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-pyrimidin-2-ylamino) phenyl] piperidin-4-yl) acetamide (Compound 145);

8-Cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 146), m.p. 237-240 ° C;

8-Cyclopentyl-6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 147), m.p. 254-255 ° C ;

6-Iodo-8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 148);

2- [3-Chloro-4- (3-amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,367] trifluoroacetate

d] pyrimidin-7-one (compound 149), melting point above

215 ° C (dec.);

8-Cyclopentyl-5-methyl-2- [4- (4-2,2,2-trifluoroethyl) piperazin-1-yl-phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 150), temperature mp 198-199 ° C; ^!

8-Cyclopentyl-2- (4-fluorophenylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 151), m.p. 217-220 ° C;

8-Cyclopentyl-5-methyl-2-phenylamino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 152), m.p. 180-183 ° C;

8-cyclopentyl-2- (3,4-dichlorophenylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (compound 153), m.p.

230 [deg.] C .;

8-Isopropyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 154), m.p. 217-220 ° C;

8-Isopropyl-5-methyl-2- [4- (4-propionyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 155);

8-Cyclohexyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 156);

2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8cyklohexyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7 one (compound 157, melting point 2.6 - 209 ° C;

8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfariylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound)

158);

8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfinylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound)

159);

8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfonylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound)

160);

8-Cyclopentyl-5-methyl-2- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole)

3-ylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 161);

8-Cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazol-3-ylsulfanyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound

162);

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);

8-Cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazole-3-sulfonyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound

164);

8-Cyclopentyl-5-methyl-2- {4- [2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ethyl] phenylamino} -8H-pyrido [2] 3-d] pyrimidin-7-one (Compound 165);

8-Cyclopentyl-5-methyl-2- [4-3H-1,2,3-triazol-4-ylsulfanylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 166);

8-Cyclopentyl-5-methyl-2- {4- [2- (3H-1,2,3-triazol-4-ylsulfanyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound 167);

8-Cyclopentyl-5-methyl-2- {4- [4- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) -piperidin-l-yl] phenylamino} -8H pyrido [2,3-d] pyrimidin-7-one (Compound 168);

8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazol-3-ylsulfanyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 169);

8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazole-3-sulfinyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 170);

8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazole-3-sulfonyl) -piperidin-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidin-7-one (compound 171) mp 235-237 ° C;

8-Cyclopentyl-5-methyl-2- {4- [4- (2H-tetrazol-5-yl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 172 1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperidine-4-carboxylic acid (1H-tetrazol-5-yl) -amide acids (Compound 173);

8-Cyclopentyl-5-methyl-2- {4- [4- (3H-1,2,3-triazol-4-ylsulfanyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 173);

3- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] -N- (1H-tetrazol-5-yl) propionamide (compound 174);

2- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenoxy] -N- (1H-tetrazol-5-yl) acetamide (compound 175);

8-Cyclopentyl-5-methyl-2- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole)

3-ylmethoxy) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 176), m.p. &gt; 195 ° C (dec.);

8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazol-3-sulfinyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [ 2,3-d] pyrimidine

7-one (compound 177);

8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazole-3-sulfonyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] , 3-d] pyrimidine

7-one (compound 178);

8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,3-triazol-4-ylsulfanyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] , 3-d] pyrimidine

7-one (compound 179);

8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazol-3-ylsulfanyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] 3-d] pyrimidin-7-one (compound 180) mp 234-237 ° C;

8-Cyclopentyl-5-methyl-2- (4- {4- [2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3d] pyrimidin-7-one (Compound 181);

8-Cyclopentyl-5-methyl-2- {4- [4- (2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl) -piperidin-1-yl] -phenylamino} -8H- pyrido [2,3d] pyrimidin-7-one (compound 182);

8-Cyclopentyl-2- {4- [4- (2,2-dioxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl) piperidin-l-yl] phenylamino} -5- methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 183);

8-Cyclopentyl-5-methyl-2- {4- [4- (1-oxo-2,5-dihydro-1H-1,2,3,5-oxatiatriazol-4-yl) piperidin-1-yl] phenylamino} - 8H-pyrido [2,3d] pyrimidin-7-one (Compound 184);

8-Cyclopentyl-2- {4- [4- (1,1-dioxo-2,5-dihydro-1H-1,2,3,5-oxatiatriazol-4-yl) piperidin-1-yl] phenylamino} - 5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 185);

N- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] piperidine-4-carbonyl} methanesulfonamide (Compound 186) ;

8-Cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazol-3-ylsulfanyl) -pyrrolidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidin-7-one (Compound 187);

8-Cyclopentyl-5-methyl-2- (4- [3- (2H-1,2,4-triazole-3-sulfinyl) -pyrrolidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidin-7-one (Compound 188);

8-Cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazole-3-sulfonyl) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 189);

8-Cyclopentyl-5-methyl-2- (4- [3- (3H-1,2,3-triazol-4-ylsulfanyl) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 190);

8-Cyclopentyl-5-methyl-2- {4- [3- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) -pyrrolidin-l-yl] phenylamino} -8H pyrido [2,3-d] pyrimidin-7-one (Compound 191);

8-Cyclopentyl-5-methyl-2- {4- [4- (3-hydroxypropyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 192) mp 180-184 ° C;

8-Cyclopentyl-5-propyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 193);

8-Cyclopentyl-5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 194);

8- (1-methylethyl) -5-ethyl-2- (4-piperazin-1-ylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 195), melting point above 235 ° C (dec.) dec);

8- (1-methylethyl) -5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (compound 196) melting point above 235 ° C ( decomposition);

8-Cyclopentyl-5-methyl-2- [4- (3-hydroxypyrrolidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 197), mp 225-226 ° C ;

8-Cyclopentyl-5-ethyl-2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 198);

8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 199), m.p. 267 up to 269 ° C;

8-Cyclopropyl-5-methyl-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 200), m.p. 221 ° C (with decomposition);

8-Cyclopropyl-5-methyl-6-fluoro-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 201), higher melting point as 250 ° C;

8-cyclopentyl-5-methyl-2- [4- (homopiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 202), m.p. 172 ° C (dec.) );

8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (homopiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 203), melting point 192 ° C (foam);

8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (3,3-dimethyl-4-acetyl-piperazin-l-yl) phenylamino] 8H-pyrido [2,3-d] pyrimidin-7-one (compound 204), m.p. 200-204 ° C;

8-Cyclopentyl-5-methyl-2- [4- (3,3-dimethyl-4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 205), temperature mp 192-196 ° C;

8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 206);

8-Cyclopentyl-5-methyl-2- [4- (N-methylacetamido) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 207), m.p. 185-187 ° C;

8-Cyclopentyl-5-methyl-2- {4- [2- (2-hydroxyethoxy) ethyl amino] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 208), m.p. 122 up to 126 ° C;

8-Cyclopentyl-5-methyl-2- [4- (3-oxopiperazin-1-yl) phenylamino] 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 209), melting point above 235 ° C (dec.);

8-Cyclopentyl-5-methyl-2- [4- (2-methoxyethoxy) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 210), m.p. 156-157 ° C (dec.) ;

8-Cyclopentyl-5-methyl-2- (9H-carbazol-3-ylamino) -8H-pyrido [2,3d] pyrimidin-7-one (Compound 211);

8-Cyclopentyl-5-methyl-2- (1H-indazol-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 212);

cyclopentyl-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-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 214);

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

8-Cyclopentyl-5-isopropyl-2- [4- (3,5-dimethyl-4R-aminomethyl-pyrrolidin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 216) ;

8-Cyclopentyl-5-methyl-2- {4- [4- (2-hydroxyethyl) piperazin-1-yl)] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 217), temperature mp 171-173 ° C;

8-Cyclopentyl-5-methyl-2- {4- [4- (3-morpholinopropyl) piperidin-1-yl)] phenylamino} -8H-pyrido [2,3-d] ^: pyrimidin-7-one trifluoroacetate (Compound 217) mp 171-173 ° C;

8-Cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 219);

8-Cyclopentyl-5-methyl-2- (indol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 220);

8-Cyclopentyl-5-methyl-2- (thionaphthen-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 221);

8-Cyclopentyl-6-iodo-5-methyl-2- (4-piperazin-1-yl-phenyl amino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 225) Melting point 185-198 ' C (dec.);

8-Cyclopentyl-2- {4- [1- (3,5-dimethylpiperazin-1-yl) methanoyl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 226 mp 181 ° C (foam);

8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -5-trifluoromethyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 227), m.p. 200 ° C (foam);

6-Bromo-8-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 228) a melting point above 200 ° C (decomposed);

8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -6-iodo-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 229), temperature mp 225-226 ° C (dec.);

6-chloro-8-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 230) , a melting point above 250 ° C;

8-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfanyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound)

231);

4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperazine-1-carbaldehyde (Compound

232), mp 244-247 ° C;

8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5-trifluoromethyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 233), m.p.> 275 ° C (dec.);

8- (1-ethyl-propyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 234), m.p. dec);

[4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzyl] phosphonic acid (Compound 235), melting point above 250 ° C ;

6-Chloro-8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 236), m.p.> 188 ° C (with decomposition);

2- [4- (3,5-Dimethyl-piperazin-1-yl) -phenylamino] -8- (1-ethyl-propyl) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 237), a melting point greater than 185 ° C (decomposed);

8-Cyclopentyl-2- [4- (2-hydroxyethylamino) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 238), m.p.

Mp 197-200 ° C;

3- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] -N, N-diethylpropionamide (Compound 239), m.p. 138 up to 140 ° C;

8-Cyclopentyl-6-fluoro-2- [4- (2-hydroxyethyl) phenylamino] -5-methyl 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 240), m.p. 241-244 ° C;

8-Cyclopentyl-2- [4- (2-hydroxyethyl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 241), mp 191-194 ° C;

4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzoic acid (Compound 242);

8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 243), m.p. &gt; 150 ° C (dec.);

[4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzyl] phosphonic acid diethyl ester (Compound 244), melting point above 250 ° C (foam);

8-Cyclopentyl-6-fluoro-2- [4- (2-methoxyethylamino) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 245), m.p. 147-149 ° C (with decomposition);

(S) -2-Amino-3- [4- (8-cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] propionic acid (Compound 246), mp 238 ° C (dec.);

8-Cyclopentyl-2- [4- (2-methoxyethoxy) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 247), m.p. 156-157 ° C;

8-Cyclopentyl-2- (4-isopropylaminophenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 248), m.p. 216-220 ° C;

8-Cyclopentyl-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 249), mp 252-254 ° C;

8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 250), m.p. 241-248 ' C;

8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 251), m.p. 240 ° C ( decomposition).

Example 19

Biological testing

Certain compounds of the present invention were evaluated by standard assays routinely used to measure inhibition of cyclin-dependent kinase enzymes and other serine / threonine protein kinases. Testing was as follows:

Procedure for Cdk1 and Cdk2 enzyme assays to determine IC ₅₀ and kinetics: 96-well filter plates (Millipore MALVN6550) are used, total volume is 0.1 ml with a final concentration of 20 mM TRIS (pH 7.4), 50 mM NaCl, 1 mM dithiothreitol, 10 mM

MgCl ₂ , 12 mM ATP containing 0.25 μύϊ [ ³² P] ATP, 20 ng enzyme (Cdk2 / cyclin E, Cdk2 / cyclin A or Cdk1 / cyclin B), 1 µg retinoblastoma protein and appropriate dilution of the compound of the present invention. All components except ATP are plated and placed on a plate mixer for 2 minutes. The reaction is initiated by the addition of [ ³² P] ATP and the plate is incubated for 15 minutes at 25 ° C. The reaction is then quenched by addition

0.1 ml of 20% TCA (trichloroacetic acid). The plate is cooled to 4 ° C for at least 1 hour to precipitate the substrate. The wells are then washed five times with 0.2 ml of 10% TCA and the ³² P content is determined using a beta plate counter (Wallac Inc., Gaithersburg, MD).

The Cdk4 enzyme assay for IC ₅₀ and kinetics is performed as follows: 96-well filter plates (Millipore MADVN6550) are used, total volume is 0.1 ml with a final concentration of 20 mM TRIS (tris [hydroxymethyl] aminomethane; pH 7.4 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl ₂ , 25 μΜ ATP containing 0.2 5 μϋϊ [ ³² P] ATP, 20 ng Cdk4, 1 μg retinoblastoma protein and appropriate dilutions of the compound of the present invention. All ingredients except ATP are placed in the wells and the plate is placed on the plate mixer for 2 minutes. The reaction is initiated by the addition of [ ³² P] ATP and the plate is incubated for 15 minutes at 25 ° C. The reaction was then quenched by the addition of 0.1 mL of 20% TCA. The plate is cooled to 4 ° C for at least 1 hour while the substrate is precipitated. The wells are then washed five times with 0.2 ml of 10% TCA and the ³² P content is determined using a beta plate counter (Wallac Inc., Gaithersburg, MD).

The PDGF receptor (PDGFr) and FGF receptor (FGFr) tyrosine kinase assays are performed with the full length cDNA of murine PDGF-β and human FGF1 (flg) receptor tyrosine kinase obtained from J. Escobeda and prepared as described above (Escobedo et al., J Biol. Chem., 1988; 262: 1482-1487). The PCR primers are designed to amplify a DNA fragment that encodes an intracellular tyrosine kinase domain. The fragment is inserted into a bacilovirus vector cotransfected with AcMPNPV DNA and the recombinant virus is then isolated. The virus is then infected with SF9 insect cells under strong protein expression and the cell lysate used for the assay.

The PDGFr and FGFr enzyme assays are performed in 96-well plates (100 µl / incubation / well) and conditions are optimized to measure ³² P input from [γ ³² Ρ] ΑΤΡ to glutamate-tyrosine copolymer substrate. Each well is charged with 82.5 μΐ incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na3VO4, 10 mM MnCl2. and 750 µg / ml Poly (4: 1) glutamate-tyrosine and then 2.5 µΐ inhibitor and 5 µΐ enzyme lysate (7.5 µg / µl FGFr or 6.0 µg / µl PDGFr) to initiate the reaction. This is followed by a 10 minute incubation at 25 ° C and then 10 ml of [γ ³² Ρ] ΑΤΡ (0.4 Ci plus 50 mM ATP) is added to each well and the sample is incubated for an additional 10 minutes at 25 ° C. The reaction is terminated by adding 100 μ 100 of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate and precipitating the material on a glass fiber tuft (Wallac). The filter is washed three times with 15% TCA containing 100 mM sodium pyrophosphate and the radioactivity retained on the filter is determined by a Wallac 1250 beta counter. Non-specific activity is defined as the radioactivity retained on the filter after incubation of enzyme-free samples (buffer only). Specific enzyme activity (enzyme plus buffer) is defined as total activity minus non-specific activity. The concentration of compound that inhibits specific activity by 50% (IC 50) is determined from the inhibition curve.

The following is a procedure for the c-Src protein kinase assay: c-Src kinase is isolated from a lysate of bacilovirus-infected cells using an anti-peptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src. The antibody covalently bound to 0.65 µm latex beads is added to the suspension, insect cell lysate buffer containing 150 mM NaCl, 50 mM Tris (pH 7.5), 1 mM DTT, 1% NP-40, 2 mM EGTA, 1 mM sodium vanadate, 1 mM PMSF, 1 µg / ml leupeptin, 1 µg / ml pepstatin and 1 µg / ml aprotinin. The insect cell lysate containing the c-Src protein is incubated at 40 ° C with the indicated beads for 3 to 4 hours. At the end of the lysate incubation, the beads are washed three times with lysate buffer, resuspended in lysate buffer containing 10% glycerol and frozen. The latex beads are then heated, washed three times with assay buffer (40 mm Tris, pH 7.5, 5 mM MgCl ₂ ) and resuspended in the same buffer. The following reagents are added to the wells of a Millipore 96-well plate with a 0.65μτη bottom layer of polyvinylidine membrane: 10 μΐ c-Src beads, 10 μΐ 2.5mg / ml polyGluTyr substrate, 5 μΜ ATP containing 0.2 μ (2ί [ ³² P] ATP, 5 μΐ DMSO containing inhibitor or solvent only (control) and buffer to reach a final volume of 125 μΐ The reaction is started at room temperature by addition of ATP and stopped after 10 minutes by adding 125 μΐ 30% TCA 0.1M pyrophosphate The plate is then filtered and the well walls are washed with two 250 ml aliquots of TCA and 0.1M pymphosphate, then the filter is pre-plated, measured with a liquid scintillation counter, and the data used to determine inhibitory activity compared to known inhibitors such as This method is described in Thompson et al., J. Med. Chem. 1994; 37: 598-609.

The results of these tests for some of the compounds of the present invention are shown in Table 1. The metabolic stability of some compounds is measured in human liver microsomes (HLM) and is shown in Table 1 as the time in minutes (half-life T) required to degrade half of the parent compound. HLM homogluate.

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Various properties of preferred 5-methylpyridopyrimidin-7-ones such as 8-cyclopentyl-5-methyl-2 - [(4-piperazinylphenyl) amino] -8-hydropyridino [2,3-d] pyrimidin-7-one (compound 1) ), including IC ₅₀ , stability and clearance rate, are shown in Table 2.

I

Table 2

Bile. 5-Me Cdkl / cyclin B Cdk2 / cyclin A IC ₅ o Cdk 2 / cyclin (ΜΜ) T 1/2 h HLM (Min) PDGFr clearance (Ml / min / kg) CDK4 E FGFR C-SRC 1 Yes > 5 > 5 > 5 0,007 1,077 83 25.5 (n = 2) 57 Yes > 5 > 5 > 5 0,151 6.08 73 Yes > 1.7 > 1.7 > 5 0,061 > 5 80 79 Yes > 5 > 5 > 5 0,975 ON THE 34 8 152 Yes > 1.7 4, 91 > 5 2.15 ON THE > 50 4

From the results presented in Table 2, it can be seen that Compound 1 and other compounds of the invention specifically inhibit Cdk4 and have relatively little effect on Cdk1 and Cdk2. Further, compound 1 is relatively more stable and is removed at a lower rate compared to prior art compounds. These results show that the methyl group at the 5-position confers unique properties on pyridopyrimidine and is a preferred embodiment.

Examples of resources

As noted above, the compounds of the present invention will typically be formulated with conventional excipients, diluents and carriers to provide compositions suitable for conventional administration to mammals. The following examples illustrate typical compositions that represent other embodiments of the present invention.

Example 20

Tablet formulation

Zložka_Množstvo

Compound 12 50 mg

Lactose 80 mg

Corn starch (for mixing) 10 mg

Corn starch (for mixing) 8 mg

Magnesium stearate (1%) - 2 mg

Total 150 mg

Compound 12 is mixed with lactose and corn starch (for mixing) and mixed thoroughly to a powder. The corn starch (for paste) is suspended in 6 ml of water and heated with stirring to form a paste. The paste is added to the mixed powder and the mixture is granulated. The wet granules are passed through a No. 8 hard screen and dried at 50 ° C. The mixture is lubricated with 1% magnesium stearate and compressed into a tablet. The tablets are administered to patients in an amount of 1 to 4 every day to prevent and treat atherosclerosis.

Example 21

Parenteral solution

To a solution of 700 ml propylene glycol and 200 ml water for injection was added 20.0 g of compound 38. The mixture was stirred and the pH adjusted to

5.5 using hydrochloric acid. Adjust the volume to 1000 ml with water for injections. The solution is sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (40 mg of compound 38) and capped under nitrogen. The solution is administered by injection to a patient suffering from cancer and, if necessary, treatment.

The present invention, and the method and process for carrying out and using it, are now described fully, clearly, simply and accurately so that one skilled in the art can practice and utilize it. It is to be understood that the preferred embodiments of the present invention have been described above and that modifications may be made so as not to go beyond the scope of the present invention as set forth in the claims. Hereinafter, the subject matter of the invention will be described in detail by the claims which summarize the above description.

Claims (21)

PATENT CLAIMS A compound of formula I and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R ² is (a) a hydrogen atom; (b) a lower alkyl group optionally substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, thioalkyl, nitrile, aryl, the heteroaryl group or the carbocyclic group containing 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or (c) a carbocyclic group of 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, aryl and heteroaryl; R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower I alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ² R ⁴ , -CONR ⁴ R ⁵ , -CON (R ⁴ ) 2 OR ⁵ , -SO ² NR ⁴ R ⁵ , -SO 2 R ⁴ , -SO ₃ R ⁴ , P (O) (OR ⁴ ) (OR ⁵ ) 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 ^s, -N (O) R ⁴ R ^5, -NR ⁴ R ⁵ R ⁶ W, -SR ⁴ , -C (O) R ⁴ , -CO ₂ R ⁴ , -CONR ⁴ R ⁵ , -SO ² NR ⁴ R ⁵ , -SO ² R ⁴ , -SO ₃ R ⁴ group P (O) (OR ⁴ ) (OR ⁵ ), -T (CH ₂ ) _m QR ⁴ , or -NR ⁴ C (O) T (CH ₂ ) _m QR ⁵ ; m is 1 to 6; group -C (O) T (CH ₂ ) _m QR ⁴ n is an integer from 0 to 6; T is oxygen, sulfur, NR ⁴ , group N (O) R ⁴ group NR ⁴ R ⁵ W or CR ⁴ R ⁵ ; Q is O, S, NR ^4, group N (O) R ⁴ group NR ⁴ R ⁵ W, CO ₂ or a 3 to 7 membered carbocyclic group, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkylcarbonyl, aminoalkyl, N-hydroxyacetamide, alkoxycarbonyl, alkylcarbonylamino, trifluoromethyl, trifluoromethylalkyl, amino or mono- or dialkylamino; R ⁶ is lower alkyl, haloalkyl or aryl; R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ W, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) n R ^4, a group CO 2 R ^4, CONR ⁴ R ^5, 'C (O) NR ⁴ SO 2 R ^5, s (O) R ^4, SO 2 R ^4, a group SO 2 NR ⁴ R ^s group, SO 3 R ^4, (CH2) nP (0) (OR ⁴ ) 2, NR ⁴ SO ² R ⁵ , aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ⁴ , C (O) T (CH 2) _m QR ⁴ , NR ⁴ C (O) T (CH 2) _m QR ⁵ or T (CH ₂ ) _m CO ₂ R ⁴ ; n is 0 to 6; W is an anion; R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH 2) n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring containing 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (O) 2 and a nitrogen atom wherein the carbocyclic group is unsubstituted or substituted by one, two, three or four groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl alkylcarbonylamino, aminoalkyl, aminoalkylcarb onyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR ¹⁰ SO ² R ¹¹ , C (O) NR ¹⁰ R ¹¹ , NR ¹⁰ C 11 (O) R ¹¹ , C (O) OR ¹⁰ , C (O) NR ¹⁰ SO ² R ¹¹ , (CH 2) n S (O) n R ¹⁰ , (CH 2) _n -heteroaryl, 0 (CH ₂ ) _n - heteroaryl, (CH ₂ ) _n C (O) NR ¹⁰ R ^1X , O (CH ₂ ) _n C (O) OR ¹⁰ ; and R &lt; ⁴ &gt; may further be an unsubstituted lower alkyl group or a group, group, group or members substituted by one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-dihydro-1H-1,2, 4-triazol-3-ylsulfanyl 5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-ylsulfinyl A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulphonyl or carbocyclic group containing from 3 to 7, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkoxy, alkoxycarbonyl alkyl, lower group, alkylcarbonyl, alkylcarbonylamino, alkylmethylaminoalkyl, trifluoromethyl, trifluoromethyl, a group, amino or mono dialkylamino group; and N-hydroxyacetamido, trialebo R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. A compound of formula II esters, amides and prodrugs, wherein R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ² R ⁴ , -CONR ⁴ R ⁵ , group -CON ^(R4) 2 oR ^5, -SO 2 NR ⁴ group ^R5, -SO 2 R ^4, -SO ₃ R ^4, P (0) (oR ⁴⁾ (oR ^5), or -NR ⁴ R ^5; Y is N or CR ⁷ ; 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 ^S R ⁶ W, -SR ⁴ , -C (O) R ⁴ , -CO ₂ R ⁴ , -CONR ⁴ R ⁵ , -SO ² NR ⁴ R ⁵ , -SO ² R ⁴ , -SO ₃ R ⁴ , P (O) (OR ⁴ ) (OR ⁵ ), -T (CH ² ) _m QR ⁴ , -C (O) T (CH 2) _m QR ^4, or -NR ⁴ C (O) T ( CH ₂ ) _m QR ⁵ ; m is the number 1 to 6; n is an integer from 0 to 6; T is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , 4 t> 5 NR ⁴ R ⁵ W or CR'R *; Q is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, CO _2, or a carbocyclic group of 3 to 7 members, of which up to 4 are optionally heteroatoms independently selected from the group consisting of: oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkylcarbonyl, aminoalkyl, N-hydroxyacetamide, alkoxycarbonyl, alkylcarbonylamino, trifluoromethyl, trifluoromethylalkyl, amino or mono- or dialkylamino; R ⁶ is lower alkyl, haloalkyl or aryl; R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ W, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) nR ⁴ , CO ² R ⁴ , CONR ⁴ R ⁵ , C (O) NR ⁴ SO ² R ⁵ , S (O) R ⁴ , SO2R ⁴ , SO2NR ⁴ R ⁵ , SO ³ R ⁴ , (CH 2) nP (O) (OR ⁴⁾ 2, "NR ⁴ SO 2 R ^a, aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ^4, C (0) T (CH 2) m QR ⁴ , NR ⁴ C (O) T (CH 2) _m QR ⁵ or T (CH ₂ ) _m CO ₂ R ⁴ ; n is 0 to 6; W is an anion; R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH 2) n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring containing from 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (O) 2 and a nitrogen atom wherein the carbocyclic group is unsubstituted or substituted by one, two, three or four groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl an alkylcarbonylamino group, an aminoalkyl group, an aminoalkylcarbon group yl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR ¹⁰ SO ² R ¹¹ , C (0) NR ¹⁰ R ¹¹ , NR ¹⁰ C 11 (O) R ¹¹ , C (O) OR ¹⁰ , C (O) NR ¹⁰ SO ² R ¹¹ , (CH 2) n S (O) n R ¹⁰ , (CH 2) n -heteroaryl, 0 (CH ₂ ) _n - heteroaryl, (CH ₂ ) _n C (O) NR 4 R ¹¹ , O (CH ₂ ) _n C (O) OR ¹⁰ ; R ⁹ is lower alkyl, haloalkyl or aryl; and R ⁴ can further be a lower alkyl group unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl a 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfinyl group, A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl group, or a carbocyclic group containing 3 to 7 members, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen , sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from hydroxy, a lower alkylcarbonyl group comprising a halogen atom, a hydroxyalkyl group, a lower alkyl alkoxy group, an alkoxycarbonyl group, an alkylcarbonylamino group, , trifluoromethyl, N-hydroxyacetamido, trifluoromethylalkyl, amino or mono- or dialkylamino; and and when Y is CR ⁷ , it is part of the structure wherein R ⁷ and Z are defined by the carbon to which they are attached above or together form fragments, 11 U, 10 or, where G and J are independently CH ₂ , NH or O; B is NH, S, CH ₂ or O; D is C or N with the proviso that the residue R ¹⁰ is absent, D is N; and R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. A compound of formula III and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ² R ⁴ , -CONR ⁴ R ⁵ , -CON ^(R4) 2 oR ^5, -SO 2 NR ⁴ group ^R5, -SO 2 R ^4, -SO ₃ R ^4, P (0) (oR ⁴⁾ (oR ^5), or -NR ⁴ R ^5; Y is N or CR ⁷ ; 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 N, -SR ^4, -C (O) R ^4, -CO ₂ R ^4, -CONR ^{4 R5,} -SO 2 NR ⁴ R ^5, -SO 2 R ^4, -SO ₃ R ⁴ , P (O) (OR ⁴ ) (OR ⁵ ), - T (CH ² ) _m QR ⁴ , -C (O) T (CH 2) _m QR ^4, or -NR ⁴ C (O) T ( CH ₂ ) _m QR ⁵ ; m is 1 to 6; n is an integer from 0 to 6; T is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, or CR ⁴ R ⁵ ; Q is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, CO _2, or a carbocyclic group of 3 to 7 members, of which up to 4 are optionally heteroatoms independently selected from the group consisting of: oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl lower alkoxy, alkylcarbonyl, aminoalkyl, An N-hydroxyacetamide group, an alkoxycarbonyl group, an alkylcarbonylamino group, a trifluoromethyl group, a trifluoromethylalkyl group, an amino group or a mono- or dialkylamino group; R ⁶ is lower alkyl, haloalkyl or aryl; R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ W, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) nR ⁴ , CO ² R ⁴ , CONR ⁴ R ⁵ , C (O) NR ⁴ SO ² R ⁵ , S (O) R ⁴ , SO ² R ⁴ , SO ² NR ⁴ R ⁵ , SO ³ R ⁴ , (CH 2) n P (0) (OR ⁴ ) 2, NR ⁴ SO ² R ⁵ , aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ⁴ , C (O) T (CH 2) _m QR ⁴ / NR ⁴ C (O) T (CH 2) _m QR ⁵ or T (CH ₂ ) _m CO ₂ R ⁴ ; n is 0 to 6; W is an anion; R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH ₂ ) _n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring containing 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O) , S (O) 2 and a nitrogen atom wherein the carbocyclic group is unsubstituted or substituted by one, two, three or four groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl , alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkyl carbonyl, trifluoromethyl, trifluoromethylalkyl, trifluórmetylalkylamínoalkýlová, amino, mono- or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR ¹⁰ SO 2 R ^{i: l,} C (O) NR ¹⁰ R ^u, NR ¹⁰ C (O) R ^u, C (O) OR ^10, C (0) NR ¹⁰ SO 2 R ^11, (CH 2) _n S (0) "R ^10, (CH 2)" -heteroaryl, 0 (CH 2 ) - heteroaryl, (CH 2) n C (O) NR ¹¹ R ¹¹ , O (CH 2) n C (O) OR ¹⁰ ; and R ⁴ may further be a lower alkyl group unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- ylsulfanyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfinyl, A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl group or a 3 to 7 membered carbocyclic group, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen , sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, amino , trifluoromethyl, N-hydroxyacetamido, trifluoromethylalkyl, amino or mono- or dialkylamino; and and when Y is CR ⁷ , it is part of the structure where R ⁷ and Z are as defined above, or together with the carbon atoms to which they are attached, form fragments -nll or * 'where G and J are independently CH ₂ , NH or O; B is NH, S, CH ₂ or O; D is C or N with the proviso that the residue R ¹⁰ is absent, D is N; R ⁹ is lower alkyl, haloalkyl, or _t- aryl; R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. 4. A compound of formula IV x and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ² R ⁴ , -CONR ⁴ R ⁵ , -CON ^(R4) 2 oR ^5, -SO 2 NR ⁴ group ^R5, -SO 2 R ^4, -SO 3 R ^4, p (0) (oR ⁴⁾ (oR ^5), or -NR ⁴ R ^s; Y is N or CR ⁷ ; 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 N, -SR ^4, -C (O) R ^4, -CO 2 R ^4, -CONR ⁴ R ⁵ group, -S02NR ^{4 R5,} a group -SO 2 R ^4, -SO 3 R ⁴ group, P (O) (OR ⁴ ) (OR ⁵ ), - T (CH ² ) _m QR ⁴ , -C (O) T (CH 2) _m QR ^4, or -NR ⁴ C (O) T (CH ₂ ) _m QR ⁵ ; m is 1 to 6; T is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, or CR ⁴ R ⁵ ; Q is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R 8 ^with W, CO ₂ or a carbocyclic group containing 3 to 7 members, of which up to 4 are optionally heteroatoms independently 100 selected from the group consisting of oxygen, sulfur and nitrogen wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkylcarbonyl group, amateur group, N-hydroxyacetamide, amino or mono- or R ⁶ is lower alkyl aryl; alkoxycarbonyl, alkylcarbonylamino, trifluoromethyl, trifluoromethylalkyl, dialkylamino; , haloalkyl or R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ W, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) nR ⁴ , CO ² R ⁴ , CONR ⁴ R ^S , C (O) NR ⁴ SO ² R ⁵ , S (O) R ⁴ , SO ² R ⁴ , SO ² NR ⁴ R ⁵ , SO ³ R ⁴ , (CH 2) n P (0) (OR ⁴ ) 2, NR ⁴ SO ² R ⁵ , aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ⁴ , C (O) T (CH 2) _m QR ⁴ , NR ⁴ C (O) T (CH 2) _m QR ^s or T (CH ₂ ) _m CO ₂ R ⁴ ; n is 0 to 6; W is an anion, · R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH ₂ ) _n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring containing 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from 101 is an oxygen, sulfur, S (O), S (O) _2, and nitrogen atom wherein the carbocyclic group is unsubstituted or substituted with one, two, three or four groups independently selected from the group consisting of halogen , hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylamino, dialkylamino, , carboxyalkyl, NR ¹⁰ SO 2 R ¹¹ group, ΟίΟίΝΚ ¹ ^ ^11, NR ¹⁰ C (O) R ^l, C (O) OR ^10, C (0) NR ¹⁰ SO 2 R ^11, (CH 2) n S ( O) nR ¹⁰ , (CH 2) _n -heteroaryl, O (CH ₂ ) _n -heteroaryl,. (CH ₂ ) _n C (O) NR ¹⁰ R ¹¹ , O (CH ₂ ) _n C (O) OR ¹⁰ ; and R ⁴ may further be a lower alkyl group unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-dis, group, group, members, of hydro-1H-1, 2,4-triazol-3-ylsulfanyl 5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-ylsulfinyl A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl or carbocyclic group containing from 3 to 7, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein, the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl alkoxy, alkoxycarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl amide, N-hydroxymethyl, trifluoromethylalkyl, amino or mono- or dialkylamino; and alkylcarbonyl 102 and when Y is CR ⁷ , it is part of the structure by carbon atoms, where R ⁷ and Z are as defined above, or together with the buttons to which they are attached form fragments or R ¹⁰ G J G and J are independently CH ₂ , NH or O; B is NH, S, CH ₂ or O; D is C or N with the proviso that the residue R ¹⁰ is absent, D is N; aryl; R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. 5. Compound of formula V (V) 103 and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein R ² is (a) a hydrogen atom; (b) a lower alkyl group optionally substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, thioalkyl, nitrile, aryl , a heteroaryl group or a carbocyclic group of 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or (c) a carbocyclic group of 3 to 7 members and up to 2 of these members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, aryl and heteroaryl; R ³ is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR ⁴ , -CO ² R ⁴ , -CONR ⁴ R ⁵ , -CON ^(R4) 2 oR ^5, -SO 2 NR ⁴ group ^R5, -SO 2 R ^4, -SO ₃ R ^4, P (0) (oR ⁴⁾ (oR ^5), or -NR ⁴ R ^5; Y is N or CR ⁷ ; 104 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 , -CO ₂ R ⁴ , -CONR ⁴ R ⁵ , -SO ² NR ⁴ R ⁵ , -SO ² R ⁴ , -SO ₃ R ⁴ , P (O) (OR ⁴ ) (OR ⁵ ), -T (CH ² ) _m QR ⁴ , -C (O) T (CH 2) _m QR ^4, or -NR ⁴ C (O) T ( CH ₂ ) _m QR ⁵ ; m is 1 to 6; T is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, or CR ⁴ R ⁵ ; Q is oxygen, sulfur, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁵ W, CO ₂ or a carbocyclic group containing 3 to 7 members, of which up to 4 are optionally heteroatoms independently selected from the group consisting of: oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl lower alkoxy, alkylcarbonyl, aminoalkyl, N-hydroxyacetamide, group, alkoxycarbonyl, alkylcarbonylamino, trifluoromethyl, trifluoromethylalkyl, amino or mono- or dialkylamino; R ⁶ is lower alkyl, haloalkyl or aryl; R ⁷ is NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁹ W, OH, OR ⁴ , SR ⁴ , halogen, COR ⁴ , (CH 2) nR ⁴ , group CO2R ⁴ , group CONR ⁴ R ⁵ , group 105 C (O) NR ⁴ SO 2 R ^5, S (O) R ^4, SO 2 R ^4, a group SO 2 NR ⁴ R ⁵ group, SO 3 R ^4, (CH2) nP (O) (0R ⁴⁾ 2, NR ⁴ SO 2 R ⁵ , aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, T (CH 2) _m QR ^4, C (O) T (CH 2) m QR ^4, NR ⁴ C (0) T (CH 2) _m QR ⁵ or T (CH ₂ ) _m CO ₂ R ⁴ ; n is 0 to 6; W is an anion; R ⁴ and R ⁵ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH 2) n Ar, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a carbocyclic ring containing from 3 to 8 members, of which up to 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (O) 2 and a nitrogen atom wherein the carbocyclic group is unsubstituted or substituted by one, two, three or four groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl alkylcarbonylamino, aminoalkyl, aminoalkylcarb an alkoxycarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluórmetylalkylamínoalkylová, amino, mono- or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR ¹⁰ SO 2 R ^11, C (O) NR ¹⁰ R ^11, NR ¹⁰ C (O) R ¹¹ , C (O) OR ¹⁰ , C (O) NR ¹⁰ SO ² R ¹¹ , (CH 2) n S (O) n R ¹⁰ , (CH ₂ ) _n - heteroaryl, O (CH ₂ ) _n - heteroaryl, (CH ₂ ) _n C (O) NR ¹⁰ R ¹¹ , O (CH ₂ ) _n C (O) OR ¹⁰ ; and 106 R ⁴ may further be a lower alkyl group unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, 5-oxo-4,5-disgroup, group, group, members, of hydro-1H-1, 2,4-triazol-3-ylsulfanyl 5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-ylsulfinyl A 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulphonyl or carbocyclic group containing from 3 to 7, of which up to 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl alkoxy, alkoxycarbonyl, lower alkylcarbonyl, alkylcarbonylamino, aminomethyl, trifluoromethyl, -hydroxyacetamido, trifluoromethylalkyl, amino or mono- or dialkylamino; and R ¹⁰ and R ¹¹ are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. A compound according to claim 5, wherein R ⁶⁷ is selected from the group consisting of and wherein these groups are optionally substituted with an alkyl, aryl or amide group. 107 Ί. A compound selected from the group consisting of 8-Cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 1); (b) 8- (1-methylethyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 2); (c) 8-Cyclopentyl-5-methyl-2- (4-fluoro-3-methylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 3); (d) 8- (1-methylethyl) -5-methyl-2- (4-fluoro-3-methylphenylamino) 8H-pyrido [2,3-d] pyridin-7-one (compound 4); (e) 9-Cyclohexyl-5-methyl-2- (4-fluoro-3-methylphenylamino) -8H-. pyrido [2,3-d] pyrimidin-7-one (compound 5); (f) 8-Cyclohexyl-5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 6); (g) trifluoroacetic acid salt of 8-cyclopentyl-5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 7); (h) 8- (1-methylethyl) -5-methyl-2- [4- (4-propanoylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 8); (i) 8-Cyclohexyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 9); (j) 8-Cyclopentyl-5-methyl-2- (4-pyridylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 10); (k) 8- (1-methylethyl) -5-methyl-2- (4-pyridylphenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 11); (1) 8-cyclopentyl-5-methyl-2- [4- (3-aminopyrrolidinyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 12); 108 (m) 8- (1-methylethyl) -5-methyl-2- [4- (3-aminopyrrolidinyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 13); (n) N- (1- {4 - [(8-Cyclopentyl-5-methyl-7-oxo (8-hydropyridino [2,3-d] pyrimidin-2-yl)) amino] phenyl) pyrrolidin-3 -yl) 3,3-dimethylbutanamide (compound 14); (o) N- (1- {4 - [(5-methyl-8- (1-methylethyl) -7-oxo (8-hydropyridino [2,3-d] pyrimidin-2-yl)) amino] phenyl Pyrrolidin-3-yl) -3,3-dimethylbutanamide (Compound 15); (p) 8-Cyclopentyl-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 16); (q) 8-Cyclohexyl-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 17); (r) 8- (1-Methyl-ethyl) -5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 18); (s) 8-Cyclopentyl-6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 19) ; (t) 8-Cyclohexyl-6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 21) ; (u) 8- (1-Methyl-ethyl) -6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7 -one (compound 20); (v) 8-Cyclopentyl-5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 22); (w) 8- (1-Methyl-ethyl) -5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 23) ; (X) 8-Cyclohexyl-5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 24); 109 (y) 2 - ({3-chloro [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl) amino) -8-cyclopentyl-5-methyl-8-cyclropyridino [2,3-d] pyrimidine- 7-one (compound 25); (z) 2 - ({3-chloro-4- [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl} amino) -8- (1-methylethyl) -5-methyl-8-hydropyridine [2, 3-d] pyrimidin-7-one (compound 26); (aa) 2 - ({3-Chloro-4- [4- (3-morpholin-4-ylpropyl) piperidyl] phenyl} amino-8-cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidine -7-one (compound 27); (bb) 2- ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8-cyclopentyl-6-fluoro-5-methyl-8-hydropyridino [2,3d] pyrimidine- 7-one (compound 28); (cc) 2- ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl) phenyl)} amino) -8- (1-methylethyl) -6-fluoro-5-methyl-8-hydropyridine [2] 3d] pyrimidin-7-one (Compound 29); (dd) 2 - ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclohexyl-6-fluoro-5-methyl-8-hydropyridino [2,3d] pyrimidine- 7-one (compound 30); (ee) 2- ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclopentyl-5-methyl-8-hydropyridino [2,3-d] pyrimidine 7-one (compound 31), (ff) 2- ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8- (1-methylethyl) -5-methyl-8- hydropyridino [2,3-d] pyrimidin-7-one (Compound 32); (gg) 2- ({3-Chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidin-7-one (Compound 33) . 110 (gg2) 8-Cyclopentyl-2- [4- (piperazin-1-yl) phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 34 ); (gg3) 8-Cyclopentyl-2- [4- (piperazin-1-yl) phenylamino] -6-bromo-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 35) ; (hh) 9-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) -phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7one hydrochloride (Compound 36 ); (ii) 8-Cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 37); (jj) 6-Bromo-8-cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) -phenylamino) -5-methyl-8H-pyrido] [2,3-d] pyrimidine hydrochloride -7-one (compound 38); (kk) 8-Cyclopentyl-6-fluoro-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound) 39); (11) 6-Bromo-8-cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound) 40); (mm) 8-Cyclopentyl-2- [4- (3,5-methylpiperazin-1-yl) -phenylamino] 5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 41); (nn) 2- (3-Chloro-piperazin-1-yl-phenylamino) -4-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 42); (oo) 2- (3-Chloro-4-piperazin-1-yl-phenylamino) -8-cyclopent-yl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 43) ; (pp) 6-Bromo-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pirimidin-7-one (Compound 44) ; 111 (qq) 8-Cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 45), m.p. 227-229 ° C ; (rr) 9-Cyclopentyl-6-fluoro-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 46); (ss) 6-Bromo-8-cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 47); (tt) 8-Cyclopentyl-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 48); (uu) 8-Cyclopentyl-6-fluoro-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 49) ; (w) 6-Bromo-8-cyclopentyl-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 50) ; (ww) 2- (3-Chloro-4-morpholin-4-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 51); (xx) 2- (3-Chloro-4-morpholin-4-yl-phenylamino) -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-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) 9-Cyclopentyl-5-methyl-2- {4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound 54); 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- [4- (2,2,2-trifluoro-ethyl) -piperazin-l-yl) phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 55); 112 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl) -phenylamino} -8H-pyrido [2,3-d] - pyrimidin-7-one (Compound 56); 8-Cyclopentyl-5-methyl-2- {4- [4- (3-piperazin-1-ylpropyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 57); 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-piperazin-l-yl-propyl) -piperidin-l-yl] phenylamino) -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 58); 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidin-7 -one (compound 59); 8-Cyclopentyl-5-methyl-2- {4- [4-morpholin-4-ylpropyl) piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 60); 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 61); 6-Bromo-8-cyclopentyl-5-methyl-2- (4- [4- (3-morolin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 62); 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8 H -pyrido [2,3-d] pyrimidine -7-one (compound 63); 2- (4- {4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] Pyrimidin-7one (Compound 64); 2- (4- {4- [3- (3-Minopyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2] 3-d] pyrimidin-7-one (Compound 65); 113 2- (4- {4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2] 3d] pyrimidin-7-one (Compound 66); 8-Cyclopetyl-2- {3-fluoro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrimidin-7-one (Compound 67); 8-Cyclopentyl-6-fluoro-2- {3-Fluoro-4- [4- (3-piperazin-1ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine 7-one (compound 68); 6-bromo-8-cyclopentyl-2- {3-fluoro-4-piperazin-1-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7 -one (compound 69); 8-Cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine om (compound 70); 8-Cyclopentyl-6-fluoro-2- {3-fluoro-4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidin-7-one (compound 71); 6-Bromo-8-cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidin-7-one (compound 72); 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-one (Compound 73); 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclpentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 74); 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 75); 114 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 76); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluorophenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one ( compound 77); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluorophenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 78); 8-Cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3d] pyrimidin-7-one trifluoroacetate (compound 79); 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidine- 7one (compound 80); 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidine- 7one (compound 81); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one trifluoroacetate (Compound 82); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 83); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 84); 115 2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 85); 2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 86) ; 2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 87 ); 2- [4- (3-Triflorethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 88; 2- [4- (3-Trifluoroethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 89); 2- [4- (3-Triflorethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 90); 8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 91); 8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 92); 6-Bromo-g-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 93); 8-Cyclopentyl-5-methyl-2- [4- (3,3,4-trimethyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 94); 116 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (3,3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 95) ; 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (3,3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 96) ; . 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 97; 2- [4- (4-acetylpiperazin-1-yl) phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 98); 2- [4- (4-Acetyl-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 99); 8-Cyclopentyl-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperazin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 100); 8-Cyclopentyl-6-fluoro-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperazin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine -7-one (compound 101); 6-Bromo-8-cyclopentyl-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperazin-1-yl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidine -7-one (compound 102); 8-Cyclopentyl-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 103); 8-Cyclopentyl-6-fluoro-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 104); 6-Bromo-8-cyclopentyl-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 105); 117 8-Cyclopentyl-5-methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -8H) -pyrido [2,3-d] pyrimidin-7-one (compound 106); 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 107); 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 108); 8-Cyclopentyl-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 109); 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 110); 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 111); {4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazin-1-yl} -acetic acid ( Compound 112); {4- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazin-l-yl acetic acid (compound 113); {4- [4- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazin-1-yl acetic acid (compound 114); 8-Cyclopentyl-5-methyl-2- (4- {4- [3- (1H-tetrazol-5-yl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidine -7-one (compound 115); 118 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- (4- [3- (ΙΗ-tetrazol-5-yl) -propyl] -piperidin-1-yl} phenylamino) -8 H -pyrido [2,3- -d] pyrimidin-7-one (compound 116); 6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (1H-tetrazol-5-yl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3] -d] pyrimidin-7-one (Compound 117); 8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-lH-l, 2,4-triazol-3-ylsulfanyl) -propyl] -piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 118); 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl) propyl] piperidine- 1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 119); 6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl) propyl] piperidin-1- yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (compound 120); 8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfanyl) propyl] piperidin-1-yl (phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 121); 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- (4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfinyl) -propyl] -piperidin 1-yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 122); 6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfinyl) propyl] piperidine-1- yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 123); 8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfonyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 124); 119 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-sulfonyl) -propyl] -piperidin 1-yl} phenylamino) 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 125); 6-Bromo-8-cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxo-4,5-dihydro 1,2,4-triazole-3-sulfonyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 126); N- (2- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] piperidin-4-yl} ethyl -N-hydroxyacetamide (compound 127); N- (2- {l- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine 4-yl} ethyl) -N-hydroxyacetamide (compound 128); N- (2- {1- [4- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-yl} ethyl) -N-hydroxyacetamide (compound 129); N- (3- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3d] pyrimidin-2-ylamino) phenyl] piperidin-4-yl} propyl) - N-hydroxy-acetamide. (Compound 130); N- (3- {1- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-ylpropyl) N-hydroxyacetamide (Compound 131); N- (3- {1- [4- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine- 4-ylpropyl) N-hydroxyacetamide (Compound 132); 2- (benzofuran-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 133); 8-Cyclopentyl-2- (1H-indol-5-ylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 134); 120 2- (benzo [b] thiophen-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 135); 8-Cyclopentyl-2- (2,3-dimethyl-1H-indol-5-ylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 136); I 2- (9H-carbazol-3-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 137); 8-Cyclopentyl-2- (1H-indazol-5-ylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 138); 2- (2-acetyl-benzofuran-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 139); 8-Cyclopentyl-5-methyl-2- (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 140); 8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 141); 2- (3-Chloro-4-piprazin-1-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 142); 8-Cyclopentyl-5-methyl-2- (4-piperidin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 143); 8-Cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 144); N- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-pyrimidin-2-ylamino) phenyl] piperidin-4-yl} acetamide (Compound 145); 8-Cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 146); 121 8-Cyclopentyl-6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 147); 6-Iodo-8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 148); 2- [3-chloro-4- (3-aminopyrrolidin-1-yl) phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3d] pyrimidin-7-one trifluoroacetate (compound 149); 8-Cyclopentyl-5-methyl-2- [4- (4-2,2,2-trifluoroethyl) piperazin-1-yl-phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 150); 8-Cyclopentyl-2- (4-fluorophenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 151); 8-Cyclopentyl-5-methyl-2-phenylamino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 152); 8-Cyclopentyl-2- (3,4-dichlorophenylamino) -5-methyl-8H-pyrido [2,3d] pyrimidin-7-one (Compound 153); 8-Isopropyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 154); 8-Isopropyl-5-methyl-2- [4- (4-propionyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 155); 8-Cyclohexyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 156); 2- {4- [4- (3-morpholin-4-yl-propyl) -piperidin-l-yl] phenylamino} -8cyklohexyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7 one (compound 157); 8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfanylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 158); 122 8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfinylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound) 159); 8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfonylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound) 160); 8-Cyclopentyl-5-methyl-2- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7 -one (compound 161); 8-Cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazol-3-ylsulfanyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound 162); 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); 8-Cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazole-3-sulfonyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound 164); 8-Cyclopentyl-5-methyl-2- {4- [2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ethyl] phenylamino} -8H-pyrido [2, d. 3-d] pyrimidin-7-one (Compound 165); 8-Cyclopentyl-5-methyl-2- [4-3H-1,2,3-triazol-4-ylsulfanylmethyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 166); 8-Cyclopentyl-5-methyl-2- {4- [2- (3H-1,2,3-triazol-4-ylsulfanyl) -ethyl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7- one (compound 167); 123 8-Cyclopentyl-5-methyl-2- {4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) piperidin-1-yl] phenylamino} -8H-pyrido [ 2,3d] pyrimidin-7-one (Compound 168); 8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazol-3-ylsulfanyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 169); 8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazole-3-sulfinyl) -piperidin-l-yl] phenylamino) -8 H -pyrido [2,3-d] pyrimidin-7-one (Compound 170); 8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazole-3-sulfonyl) -piperidin-l-yl] phenylamino) -8 H -pyrido [2,3-d] pyrimidin-7-one (Compound 171); 8-Cyclopentyl-5-methyl-2- {4- [4- (2H-tetrazol-5-yl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 172 1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperidine-4-carboxylic acid (1H-tetrazol-5-yl) -amide acids (Compound 173); 8-Cyclopentyl-5-methyl-2- {4- [4- (3H-1,2,3-triazol-4-ylsulfanyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 173); 3- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] -N- (1H-tetrazol-5- yl) propionamide (compound 174); 2- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenoxy] -N- (1H-tetrazol-5-yl) acetamide (compound 175); 8-Cyclopentyl-5-methyl-2- [4- (5-oxo-4,5-dihydro-l, 2,4-oxadiazole 3-ylmethoxy) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 176); 124 8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazole-3-sulfinyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] 3d] pyrimidin-7-one (Compound 177); 8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazole-3-sulfonyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] 3-d] pyrimidin-7-one (Compound 178); 8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,3-triazol-4-ylsulfanyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2] 3-d] pyrimidin-7-one (Compound 179); 8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazol-3-ylsulfanyl) -ethyl] -piperidin-l-yl} phenylamino) -8 H -pyrido [2 3-d] pyrimidin-7-one (Compound 180); 8-Cyclopentyl-5-methyl-2- (4- (4- [2- (5-oxo-4,5-dihydro-l, 2,4oxadiazol-3-yl) -ethyl] -piperidin-l-yl} phenylamino) -8H-pyrido [2,3d] pyrimidin-7-one (Compound 181); 8-Cyclopentyl-5-methyl-2- {4- [4- (2-oxo-2,3-dihydro-2,3,5-oxathiadiazol-4-yl) piperidin-1-yl] phenylamino} - 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 182); 8-Cyclopentyl-2- {4- [4- (2,2-dioxo-2,3-dihydro-2,3,5-oxathiadiazol-4-yl) piperidin-l-yl] phenylamino} -5- methyl-8H-pyrido [2,3d] pyrimidin-7-one (compound 183); 8-Cyclopentyl-5-methyl-2- {4- [4- (l-oxo-2,5-dihydro-l, 2,3,5oxatiatriazol-4-yl) piperidin-l-yl] phenylamino} - 8H-pyrido [2,3d] pyrimidin-7-one (Compound 184); 8-Cyclopentyl-2- {4- [4- (1,1-dioxo-2,5-dihydro-1H-1,2,3,5-oxatiatriazol-4-yl) piperidin-1-yl] phenylamino} - 5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 185); 125 N- {1- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine-4-carbonyl} methanesulfonamide (Compound 186); 8-Cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazol-3-ylsulfanyl) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 187); 8-Cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazole-3-sulfinyl) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] Pyrimidin-7-one (Compound 188); 8-Cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazole-3-sulfonyl) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 189); 8-Cyclopentyl-5-methyl-2- {4- [3- (3H-1,2,3-triazol-4-ylsulfanyl) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 190); 8-Cyclopentyl-5-methyl-2- {4- [3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) pyrrolidin-1-yl] phenylamino} -8H- pyrido [2,3d] pyrimidin-7-one (compound 191); 8-Cyclopentyl-5-methyl-2- {4- [4- (3-hydroxypropyl) piperidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 192) mp 180-184 ° C; 8-Cyclopentyl-5-propyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 193); 8-Cyclopentyl-5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 194); 8- (1-methylethyl) -5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 195); 126 8- (1-methylethyl) -5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 196); 8-Cyclopentyl-5-methyl-2- [4- (3-hydroxypyrrolidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 197) 8-Cyclopentyl-5-ethyl-2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 198); 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 199) 8-Cyclopropyl-5-methyl-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 200); 8-Cyclopropyl-5-methyl-6-fluoro-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 201) 8-Cyclopentyl hydrochloride -5-methyl-2- [4- (homopiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 202); 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (homopiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 203); 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (3,3-dimethyl-4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 204); 8-Cyclopentyl-5-methyl-2- [4- (3,3-dimethyl-4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 205) trifluoroacetate 8 -cyclopentyl-5-methyl-6-fluoro-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 206); 8-Cyclopentyl-5-methyl-2- [4- (N-methylacetamido) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 207); 127 8-Cyclopentyl-5-methyl-2- {4- [2- (2-hydroxyethoxy) ethylamino] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 208); . 8-Cyclopentyl-5-methyl-2- [4- (3-oxopiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 209); I 8-Cyclopentyl-5-methyl-2- [4- (2-methoxyethoxy) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 210); 8-Cyclopentyl-5-methyl-2- (9H-carbazol-3-ylamino) -8H-pyrido [2,3d] pyrimidin-7-one (Compound 211); 8-Cyclopentyl-5-methyl-2- (1H-indazol-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 212); 8-Cyclopentyl-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-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 214); 8-Cyclopentyl-5-methyl-2- (2,3-dimethylindol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 215); 8-Cyclopentyl-5-isopropyl-2- [4- (3,5-dimethyl-4R-aminomethyl-pyrrolidin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 216) ; 8-Cyclopentyl-5-methyl-2- {4- [4- (2-hydroxyethyl) piperazin-1-yl)] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 217)? 8-Cyclopentyl-5-methyl-2- {4- [4- (3-morpholinopropyl) piperidin-1-yl)] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 217); 8-Cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 219); 128 8-Cyclopentyl-5-methyl-2- (indol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 220); 8-Cyclopentyl-5-methyl-2- (thionaphthen-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 221); 8-Cyclopentyl-6-iodo-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 225); 8-Cyclopentyl-2- {4- [1- (3,5-dimethylpiperazin-1-yl) methanoyl] phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 226) ); 8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -5-trifluoromethyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 227); 6-Bromo-8-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 228) 8-Cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -6-iodo-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 229); 6-Chloro-8-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 230) 8-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfanyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 231) ); 4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] piperazine-1-carbaldehyde (Compound 232); 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5-trifluoromethyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 233); 8- (1-ethyl-propyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 234); 129 [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzyl] phosphonic acid (Compound 235); 6-Chloro-8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 236); 2- (4- (3,5-dimethylpiperazin-1-yl) phenylamino] -8- (1-ethylpropyl) 5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 237); 8-Cyclopentyl-2- [4- (2-hydroxyethylamino) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 238); 3- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] -1H-diethylpropionamide (Compound 239); 8-Cyclopentyl-6-fluoro-2- [4- (2-hydroxyethyl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 240); 8-Cyclopentyl-2- [4- (2-hydroxyethyl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 241); 4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzoic acid (Compound 242); 8-Cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 243); [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzyl] phosphonic acid diethyl ester (Compound 244); 8-Cyclopentyl-6-fluoro-2- [4- (2-methoxyethylamino) 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-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] propionic acid (Compound 246); 130 8-Cyclopentyl-2- [4- (2-methoxyethoxy) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 247); 8-Cyclopentyl-2- (4-isopropylamino-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 248); I 8-Cyclopentyl-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 249); 8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 250); 8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 251). A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient. A method for controlling proliferative diseases selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliferation associated with a disease selected from the group consisting of atherosclerosis, post-surgical vascular stenosis, and restenosis comprising comprising a therapeutically effective amount of a compound of the foregoing. mammal. 11. A method of inhibiting a kinase-dependent kinase, comprising contacting a cyclin-dependent kinase with a compound of claim 1, administering claim 1 of a cyclin, in contact First The method of claim 11, wherein the cyclin-dependent kinase is cdk4. 13. A method of inhibiting growth factor-mediated tyrosine kinase comprising: a 131 contacting a growth factor-mediated kinase with a compound of claim 1. The method of claim 13, wherein said growth factor-mediated tyrosine kinase is a platelet-derived growth factor (PDGF). The method of claim 13, wherein said growth factor-mediated tyrosine kinase is fibroblast growth factor (FGF). 16. A method of treating a patient suffering from a disease by vascular smooth cell proliferation comprising comprising a therapeutically effective amount of a compound of the subject. 17. A method of treating a patient suffering from comprising a therapeutically effective amount of a compound of the subject. caused by muscle, administration of claim 1 by cancer, administration of claim 1 18. 6-Bromo-8-cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one. 19. 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (piperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one. 20. 8-Cyclopentyl-5-methyl-2- (carbazol-3-yl) -8H-pyrido [2,3-d] pyrimidin-7-one. 21. A compound selected from the group consisting of 8-Cyclopentyl-5-methyl-2- (carbazol-3-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 211); 132 8-Cyclopentyl-5-methyl-2- (isoindazol-5-yl) amino-8H-pyrido [2,3] d] pyrimidin-7-one (Compound 212); 8-Cyclopentyl-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-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 214); 8-Cyclopentyl-5-methyl-2- (2,3-dimethylindol-5-yl) amino-8H-pyrrolo [2,3-d] pyrimidin-7-one (Compound 215); 8-Cyclopentyl-5-methyl-2- [4- (3,5-dimethyl-4R-aminomethyl-pyrrolidin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 216) ; 8-Cyclopentyl-5-methyl-2- (4- [4- (2-hydroxyethyl) piperazin-1-yl)] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 217); 8-Cyclopentyl-5-methyl-2- (4- [4- (3-morpholinopropyl) piperidin-1-yl)] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 218); 8-Cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 219); 8-Cyclopentyl-5-methyl-2- (indol-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 220); and 8-Cyclopentyl-5-methyl-2- (thionaphthen-5-yl) amino-8H-pyrido [2,3d] pyrimidin-7-one (Compound 221).