CZ20022929A3 - 5-Alkylpyrido[2,3-d]pyrimidine inhibitors of tyrosine kinases - Google Patents

Description

5-Alkylpyrido [2,3-d] pyrimidine tyrosine kinase inhibitors

FIELD OF THE INVENTION The present invention relates to 5-alkylpyridopyrimidines as cyclin dependent kinase inhibitors, cyclin dependent kinases 4. The compounds of the present invention are useful for the treatment of inflammation, cellular proliferative diseases such as. is cancer and restenosis, and non-degenerative diseases such as Alzheimer's disease.

Background Art.

Cyclin dependent kinases and related serine / threonine protein kinases are cellular enzymes that perform essential functions in regulating cell division and proliferation. Cyclin dependent kinase units (nine identified) are activated by regulatory units known as cyclins. Cyclin-dependent kinases (Cdk) include the Cdk1, Cdk2, Cdk4, Cdk5, Cdk6 and Wee-1 kinases. Increased activity or temporarily abnormal activation of these kinases results in the development of human tumors and other proliferative diseases such as restenosis. Compounds that inhibit Gdk either. by blocking the interaction between cyclin and its kinase or binding and inactivating kinase, they inhibit cell proliferation and are therefore useful for treating tumors and other abnormally proliferating cells. Some compounds that inhibit Cdk have demonstrated both preclinical and clinical antitumor activity. For example, fla-vopiridol, 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). Strong

·· · 2 · I ·

hibitor Cdk2 and Cdk5 is olomoucin ie. [2- (hydroxyethylamine) -6-benzylamine-9-methylpurine] (Vesely et al., Eur. J. Biochem, 1994; 224: 771-786) and inhibits proliferation of about. 60 different types of human tumor cells used by the National Cancer Institute (NCI) for testing new cancer treatments (Abraham et al., Biol. Cell 1995; 83: 105-120). .

In addition to cancer treatment, 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 RNAviruses, and inflammatory diseases such as rheumatoid arthritis.

Summary of the Invention " The object of the present invention is a group of low molecular weight organic compounds which are potent inhibitors of Cdk and are useful for the prevention of% of treatment of diseases caused by abnormal cell proliferation. 'Γ ΐ.

The present invention provides 5-alkylpyridopyrimidines which are useful in the treatment of inflammation, cellular proliferative diseases such as cancer and tenosa, and neurodegenerative diseases such as Alzheimer's disease. Compounds of the present invention exhibit unexpected pharmacokinetic properties, including, unexpected metabolic stability and low degradation rates over known compounds. In addition, the compounds of the present invention are unexpectedly selective Cdk4 inhibitors. The compounds of the present invention are readily prepared and can be administered to patients in various ways.

The compounds of the present invention are compounds of the general formula (I).

and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, and in Formula I, that ‘/ in R 2 is (a) a hydrogen atom; (b) a lower alkyl group optionally substituted with 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, heteroaryl, or carbocyclic group containing from 3 to 7 members and up to 2 'may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen; or (c) a carbocyclic group containing 3 to 7 members and up to 2 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 alkynyl, lower alkenyl, nitrile

the group is a group of the group na, 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) ( OR5) or -NR4R5; Y is nitrogen 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, -CO 2 R 4, -CONR 4 R 5, -SO 2 NR 4 R 5, -SO 2 R 4, group. -SO3R4,. P (O) (OR4) (OR5), -T (CH2) mQR4, -C (O) T (CH2) mQR4, or -NR4C (O) T (CH2) mQR5; m is 1 to 6; n is 0 to 6; T is an oxygen atom, -sulfur, NR 4, N (O) k 4, NR 4 R 5 W or CR 4 R 5; ΐ-, Q is chloro, sulfur, NR 4, N (O) R 4, NR 4 R 5 W, CO 2, or carbocyclic group containing 3 to 7 members, of which 4 are optionally heteroatoms independently selected from the group consisting of atom 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

AND

trifluoromethyl. group,. N-hydroxyacetamide group, trifluoromethyl alkyl group, amino group or 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 X, OH, OR 4, SR 4, halogen, COR 4, (CH 2) n R 4, CO 2 R 4, CONR 4 R 5, C (O) NR 4 SO 2 R 5 , S (O) R4, SO2R4, SO2NR4R5,. group. SO3R4, (CH2) nP (O) (OR4) 2, NR4SO2R5, aldehyde, nitrile, ri-group, alkyl, alkoxyalkyl, T (CH2) mQR4, C (O) T (CH2) groups mQR4, NR4C (O) T (CH2) mQR5 or T (CH2) mCO2R4 '; W is neither he; . . ,. R4 and R5 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH2) nAr, aralkyl, aryl, heteroaryl,. heteroarylalkyl, vcycloalkyl, heterocycloalkyl. the group, or R 4 and R 5 together with the nitrogen atom to which they are attached form a carbocycle ring containing 3 to 8 'members, of which: 4 4 are optionally carbonyl or heteroatoms independently selected from the group consisting of oxygen and sulfur , S (O), S (O) 2 and N, 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, aminoalkylcarbonyl, trifluoromethyl, trifluoromethyllalkyl, trifluoromethylalkylaminoalkyl, amino, mono- or dialkylamino, N-hydroxyacetamido, aryl , heteroaryl, carboxyalkyl, group 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 1, (CH 2) n S (O) n R 10, (CH 2) n -heteroaryl, O (CH 2) n -heteroaryl. a group, (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 / unsubstituted or substituted one, two or three groups independently selected from the group consisting of an atom. halogen, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-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 carbocyclic group containing from 3 to 7 members, of which 4 are optionally heteroatoms independently selected from the group consisting of an oxygen, sulfur and nitrogen atom, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from, I. Which is a halogen atom, a hydroxy group, a hydroxyalkyl group, a lower alkyl group, a lower alkoxy group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonylamino group, an aminoalkyl group, a trifluoromethyl group, an N-hydroxyacetamido group, a trifluoromethyl alkyl group, an amino group, or mono- or dialkylamino; and wherein Y and CR7 are part of the fragment

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

G, and J are independently -CH 2, NH, or alkyl; B is NH, sulfur, CH 2 or oxygen; . D is carbon or nitrogen, with the proviso that R10 is absent when D is nitrogen; and R 10 and R 11 are independently hydrogen, halogen, or lower. alkyl, lower alkoxy or alkylcarbonyl. Preferred compounds have formula I wherein Y is CR 7. Suitable compounds in this group are those wherein R7 is NR4R5 and R4 and R5 together with the atom; nitrogen ,. to which they are attached form a ring such as a piperazine, piperidino, pyrrolidine and morpholine ring, each of which may be optionally substituted. The present invention also provides pharmaceutical compositions. 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 enzyme. The present invention also provides a method of treating patients suffering from a cell proliferative disorder. The method includes inhibiting epithelial tumor cell proliferation

the origin and proliferation of vascular smooth muscle and / or cell migration by administering to a patient in need of treatment 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 restenosis in mammals. 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), the present invention provides, in a suitable embodiment, compounds of formula (II)

(II)

Y, Z and R 3 are as defined above for formula I wherein X, Preferred compounds of formula II are those wherein X 1 and Z are independently hydrogen, chloro or fluoro; Y is CR 7, and R 3 is hydrogen, chlorine, fluorine, bromine, or carbon.

Further preferred compounds of formula III are the subject of the present invention

Very preferred compounds of formula III are those wherein X and Z are independently hydrogen, chloro or fluoro; Y is CR 7 and R 3 is hydrogen, chloro, fluoro, bromo, or keto.

Furthermore, in a preferred embodiment, the present invention provides compounds of formula IV

Preferred compounds of formula IV are those wherein X and Z are independent. 1e is hydrogen, chlorine or fluorine; Y is GR 7 and R 3 is hydrogen, chloro, chloro, fluoro, or bromo or CN.

The most preferred compounds of the present invention are compounds of formula V 10

wherein R 2 is an alkyl group or a cycloalkyl group; R3 is hydrogen or halogen; R 9 is alkyl; 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 O · ¢)

O or '-' and these groups are optionally substituted by alkyl, acyl, amide and the like.

Unless otherwise indicated, the terms used herein have the following meanings. "Alkyl group", "lower. an alkyl group " and a "C 1 -C 10 -alkyl group"; is a straight or branched hydrocarbon having from 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl , n-pentyl, isopropyl, n-hexyl and the like.

The term " halogen atom " means according to the present invention fluorine, bromine, chlorine and iodine atoms. "Alkenyl " is a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and one double bond, for example an ethenyl group. 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl and the like. &Quot; Alkynyl " is straight or branched hydrocarbon. the remainder - containing 2 to 6 atoms ....... carbon and one triple bond - *. · " . either, for example, an ethynyl group, a 3-butynyl-yl group, a "propynyl group, a 2-butyn-1-yl group, a 3-pentyn-1-yl group, and the like. i · > Cycloalkyl " is a monocyclic or polycyclic hydrocarbon group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, nor-pinanyl, decalinyl, norbornyl, cyclohexyl and cyclopentyl. These groups may be substituted with groups such as hydroxy, keto, amino, alkyl and dialkylamino. Further, it includes rings wherein 1 to 3 carbon atoms are replaced by heteroatoms. These groups are

12 are referred to as "heterocyclyl groups" which means 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 morpholino group. "Alkoxy "" lower alkoxy " a. " 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, t-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy; na, hexoxy, 2-hexoxy, 1-hexoxy and 3-methylpentoxy. The term alkoxy further denotes polyethers as. is -O- (CH 2) 2 -O-CH 3 and the like "Alkanoyl " is an alkyl group attached via a carbonyl group i.e. a C1-C5-C (O) - group. These groups include formyl, acetyl, propionyl, butyryl, and the like. isobutyryl group. "Acyl " is an alkyl or aryl (Ar) group attached via a carbonyl group, ie. R-C (O) -. Acyl groups include C 1 -C 6 -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. is an aminocarbonyl group such as -CONR 4 R 5.

The alkyl, alkenyl, alkoxy and alkynyl groups described above are optionally substituted with 1 to 3 groups selected from the group consisting of NR 4 R 5, Fe 13, 9 e · 9 · 9 · 9 eS. A phenyl group, a substituted phenyl group, a thio-C 1 -C 6 -alkyl group, a C 1 -C 6 -alkoxy group, a hydroxy group, a carboxy group, a C 1 -C 6 -alkoxycarbonyl group a group, a halogen atom, a nitrile group, a cycloalkyl group 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 atom's atoms. "Substituted nitrogen atom" is a nitrogen atom bearing a C 1 -C 6 -alkyl group or a (CH 2) n Ph group wherein n is 1, 2 or. Perhalogen and polyhalo-gene substitutions are also possible. Examples of substituted alkyl groups are 2-aminoethyl, 2-hydroxyethyl, penta-chloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, tethanylsulfanylmethyl, methoxymethyl, 3 the hydroxypentyl group, the 2-carboxybutyl group, the 4-fluorobutyl group, the 3-cyclopropylpropyl group, the peritafluoroethyl group, the 3-morpholinopropyl group, the piperazinylmethyl group, and the 2- (4-methylpiperazinyl) ethyl group. group. " Examples of substituted alkynyl groups are 2-methoxyethnyl-, 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. 9 # 4 99 • · 999 9 9 • • 9% * • * 9 - m λ - - · * 99 «9«

WJ 14

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. a group, a 3-chlorophenylmethyl group and the like.

The term " anion " denotes a negatively charged counter ion such as chloride, bromide, trifluoroacetate. "Heteroaryl " is one or more aromatic ring systems containing 5-, 6- or 7-membered rings containing at least one to four heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. Such heteroaryl groups include thienyl, / uranyl, thiazolyl, triazolyl, imidazolyl, (is) oxazolyl, oxadiazolyl. the group is a tetrazolyl group, a pyridyl group, a thiadiazolyl group, an oxadiazolyl group, an oxathiadiazolyl group, a thiatriazolyl group, a pyrimidinyl group, a (iso) quinolinyl group, a naphthyridinyl group, a phthalimidyl group, a benzimidazolyl group and a benzoxazolyl group. A preferred heteroaryl group is a pyridine group. "Aryl group " is an aromatic carbocyclic group consisting of one ring (e.g., phenyl), several rings (e.g., a biphenyl group) or several fused rings of which at least one is aromatic, (e.g., 1,2,3,4-tetrahydro-naphthyl, naphthyl, anthryl or phenanthryl, which may be mono-, di- or trisubstituted by a residue from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkyl group,

15 is alkylthio, trifluoromethyl, lower acyl. alkoxy, aryl, heteroaryl, and hydroxy. A preferred aryl group is phenyl.

The term "cancer" refers to, but is not limited to, breast, avian, throat, prostate, test, esophagus, glioblastoma, neuroblastoma, stomach, skin, keratoacanth, lung, epidermis, large cell, bone, colon, rectum, adenocarcinoma , adenoma, pancreas, thyroid, follicle, undifferentiated carcinoma, papillus, - testes, melanoma, sarcoma., urinary, bladder, liver and biliary tract, kidney, myeloid, nodules, Hodkin, hair cells, oral yolk and larynx (mouth) lip, tongue, face, small intestine, colorectal, colon, rectum, brain-central nervous system and leukemia, "Pharmaceutically acceptable salts, esters, amides, and prodrugs"; are salts of carboxylates, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are within the scope of the medical art for contacting patient tissues without undue toxicity, irritation, allergic response, and the like at a reasonable benefit / risk ratio; for the intended use - as well as the possibility of 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 can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the isolated compound in the form of 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, melate, glucoheptonate, lactobionate and lauryl sulfonate etc. 16

These salts may also contain alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, ammonium, and amine cations such as, but not limited to, ammonium, tetramethylammonium , tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. For example, Berge S. M. et al., "Pharmaceutical Salts, " J. Pharm. Sci.T, 1977; 66: 1-I9. 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 C5-C7-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 can be prepared by conventional methods! Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention are amides derived from ammonia, primary C1-6-alkylamines and secondary, C1-6-dialkylamines, where. have straight-chain alkyl groups. or ... branched chains. In the case of secondary amines, the amine may also be in the form of r5- or. Preferred are amides derived from ammonia, primary C 1 -C 3 -alkyl amines and secondary C 1 -C 3-dialkyl amines. Compounds of the present invention are prepared by conventional methods. "Prodrug " is a compound which in vivo, for example, by hydrolysis in blood, rapidly changes to the parent compound of the above formula. See the detailed information. T. Higuchi and V. Stella, " Pro-drugs as Novel Delivery Systems " part. 14, A.C.S. Symposium Series and BioreversibleCarriers in Drug Design, by Edward B. Roche, American Pharmaceutical Association and Pergamon Press 1987. \ t Examples of compounds of the present invention are shown in Table 1 below:; ;.

1S ¢ 9 «· · # φ # 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 © # © • • • 9 9 »___,« «._______» * > _, »>« _____ · Ο _ · * * ·

Table 1-

16 17

P 6 * 6 6 6 6 6 6 6 Pt Pt Pt Pt Pt Pt 6 6 6 6 6 6 6 6 6 6 6 6 - · ** ..... m * .— • · · ·

Table 1 (continued)

6 «9 • to 9 9 9» 9 9 9 9 9 9 90 90 90 90 90 90 90 90 90 90 90 90 • • • • • • • • •

Table 1 (continued)

e * ee * 9 · t · 9 · 9 · 9 · 9 · t · · · · · · · 4 ··········································· ... ·· .. __ ___ * β * _____ ··. 9999

Table 1 (continued)

45

47

23 Table 1 (continued)

129

• · ·· · · · · · ·

Table 1 (continued)

202 Z (o

Table 1 (continued)

2. * Table 1 (continued)

228 2.8

Table 1 (continued)

21 21

- ** r

Table 1 (continued);

Ο · · · · · · · 06 · · · · · · · · · · · · · · · · · · · · · · · · «« β «__0 0 ... .0 0 ...._ ..« 0 0__00 0____0 «_00 0 0 -« '«β **' .....

Table 1 (continued)

CH3 207

31 ·· ·· «• · # ββ«

Table 1 (continued)

· · · · · · · · · · · · · · · · · · · · ·

Table 1 (continued)

NHCH2CH3

The compounds of the present invention are useful for the treatment of cancer (e.g., leukemia and cancer, lung, breast, prostate and skin, such as melanoma) and other proliferative diseases such as, but not limited to, psoriasis, HSV, HIV, tenosoma, and atherosclerosis. Using a compound of the present invention for treating cancer, a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the present invention is administered to cancer patients.

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 the proliferation and / or migration of vascular smooth muscle cells by administering an effective amount of a compound of Formula I to patients in need thereof.

The compounds of the present invention may be formulated and administered in the form of a variety of 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 either the compound of Formula I or the corresponding pharmaceutically acceptable salt thereof as an active ingredient.

The salt, ester, amide, prodrug or solvate of the compound of formula (I) may be used.

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 be 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 contain 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 melting wax, cocoa butter, and the like. active compounds with an encapsulating substance as a capsule-forming carrier in which the active ingredient, with or without an additional carrier, is surrounded by a carrier so attached thereto. Similarly, wafers and caramel. Tablets, powders, capsules, pills, cachets and toffee can be used as solid dosage forms suitable for oral administration. 6 0 · • ♦ 99 «• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. * Λ. .......... 9 9 99 99 ββ · β * • * 9 · · * · * · · 9 Ο 9 6 «-» λ-- · Λ 1 * _- - 3 4 ' In the preparation of suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and then dispersed homogeneously therein, for example, by stirring the active ingredient. The molten homogeneous mixture is then poured into a suitable size mold and then allowed to cool to solidify.

Liquid compositions include solutions, suspensions, and emulsions, such as a solution in water or a water / propylene glycol mixture. In the preparation of parenteral injections, a liquid solution is prepared in the form of 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 coloring, flavoring, stabilizing and thickening agent . Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water and mixing with a viscous substance such as natural or synthetic acacia, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspending agent.

Another form of solid formulations is intended to be converted immediately prior to use to the liquid form for oral administration. These liquid forms are solutions, suspensions, and emulsions. In addition to the active ingredient, these compositions may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizers, and the like. Waxes, polymers, microparticles, and the like may be used in the preparation of sustained release dosage forms. osmotic pumps can also be used for a longer period of time

The pharmaceutical compositions of the present invention are suitably in unit dosage form. In this form, the composition is divided into units containing a suitable amount of the active ingredient. The unit of dosage may be a packaged device,

35 packs containing a certain amount of composition, such as packs of tablets, capsules, and powders in vials or ampoules. The unit dose may also be a capsule, tablet, wafer or toffee itself, or may be a suitable number in the package.

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 a adult patient is 50 mg to 800 mg per day. The amount of active ingredient * in the composition of the composition is from about 0.1 mg to about 0.1 mg. : -: 500 mg, suitably from 0.5 mg to 100 mg, depending on the particular application of the active ingredient. The composition may, if necessary,:. it should also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I is administered a dose. 1. mg to 500 mg per day, either once or several times within 24 hours.

The compounds of the present invention are capable of binding to and inhibiting proteins capable of phosphorylating other proteins. teins such as Cdk, .PDGFr; FGFr, c-Src and EGFr-FL. Cdk forms complexes with cyclins and these complexes phosphorylate key proteins, allowing cells to continue in the cell cycle

. " A " (Meijer L., Progress in Cell Cycle Research 1995; 1: 351-363). The compounds of the present invention inhibit phosphorylation, and therefore can 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 disclosure or claims in any way.

e o e

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

Scheme 1

β · 6 · 9 37

Scheme.2

0¾¾

NBS.DMF Q-H 'oxffitírid ÍEt0) j' " fiv'rxC ° 2Et1N‘H i »3

THF Q-H, F

Q-Dr oxanridin2 ° 2

L - ^ \ t

TFA, CH 2 Cl 2

R?

DMSO O ώ

xTFA a

It will be apparent to those skilled in the art that other starting materials may be used in the production of the compounds of the present invention and that other steps may be performed as outlined in the following examples. 38

As shown in Schemes 1 and 2, the 4-substituted anilino-2-methanesulfanylpyrimidine-5-carboxaldehyde reacts with an organometallic compound, such as the Grignard reagent, to yield the corresponding secondary alcohol. The alcohol is then oxidized to a ketone, the ketone is reacted with a trialkylphosphonoacetate in the presence of a base to give the corresponding 8-substituted 5-alkyl-2-methylsulphanyl-8H-pyrido [2,3-d] pyrimidin-7-one. The pyridopyrimidine can then be halogenated at the 6-position 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 obtain the 2-phenylamino compound of the present invention. In preparing the compounds of the present invention, it may be desirable to derivatize reactive groups, such as an amino group, an alcohol, and an acid, with protecting groups that are easily removed if desired. These protects easily the unwanted side reactions. The use of protecting groups in organic chemistry is common. Greeve and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 2nd Edition, 1991. A typical hydroxy protecting group is an ether-forming group such as a benzyl group and an acyl group such as a t-butoxycarbonyl group; formyl and acetyl. The amino protecting group is an acyl group such as an acetyl group, and a trialkylsilyl group. Carboxylic acids are typically. Some compounds of the present invention possess one or more chiral centers and may exist as individual optical isomers and mixtures thereof. The term " isomers " may be easily hydrolyzed by a group such as trichloroethyl, t-butyl, benzyl or the like. For example, Compound 246 (Table 1) may exist as the RS racemate or as a single R or S isomer. All individual isomers and mixtures thereof are part of the present invention. Single isomers. it is easy to prepare chiral. synthesis or conventional separation techniques well known to those skilled in the art. EXAMPLES OF THE INVENTION. "

The invention is further illustrated by the following detailed examples, which are not intended to be limiting in any way. Starting materials and various intermediates used in the synthesis of 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, which are incorporated herein by reference, are to be understood as references. Example 1

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

Sodium hydride (771 mg, 19.3 mmol) was suspended in dry tetrahydrofuran (20 mL) and 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. Then a solution of 1- (4-cyclopentylamino-2-methylsulfanylpyrimidin-5-yl) -ethanone in dry tetrahydrofuran (40 mL) and reaction mixture was added via cannula.

was stirred at 24 ° C for 12 hours. The reaction mixture 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-methylT8H-pyridone [2,3-d] pyrimidine-7-ol.

8-Cyclopentyl-6-fluoro-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (0.61 g 2.08 mmol) from Examples 1 and 3 -phenyl-1p-nitrophenylsulfonyloxazidine (0.65 g, 2.5 mmol) *. ? was dissolved in dichloromethane (20 mL) and stirred 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-dihydropyridoic acid) t-butyl ester

- [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid - -

4- [4- (8-Cyclopentyl-6-fluoro-5-thiophenyl-5-methyl-8H-pyrido [1,3-d] pyrimidin-7-one (0.3 g, 0.97 mmol) ) of Example 2 and 4- (N-Boc-piperazin-1-yl) aniline (0.548 g, 1.94 mmol) was suspended in 1,4-dioxane (5 mL) and heated to 80 ° C for 12 h. C. then anhydrous dimethylsulfoxide (2.5 ml) was added and the temperature was raised to 100 [deg.] C. The heating was then continued for 24 hours, then the reaction mixture was cooled to 24 [deg.] C. and extracted between ethyl acetate and saturated solution. The organic layer is separated and washed with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent is evaporated off and the residue is purified by chromatography on silica gel to give the title compound as a yellow solid. substances (0.23 g, 45%). '* 42 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • -2- (4-piperazin-1); -yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one

4- [4- (8-Cyclopentyl-1- 6-fluoro-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2'-ylamino) -phenyl tert-butyl ester 1-piperazine-1-carboxylic acid (0.23 g, 0.44 mmol) from Example 3 was dissolved in 20 mL of trifluoroacetic acid / dichloromethane and stirred at room temperature for 1 hour. Then 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. C23H27N6OF'1, 93TFA: calculated C, 50.2; H 4.54; N, 13.08; Cale 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

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 benzyl peroxide (0.13 g, 0.5 mmol). The resulting solution was stirred at 24 ° C for 12 hours and then the mixture was 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 desiccant 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 H (4-piperazin-1-ylphenyl-amino) -8H-pyrido [2,3-d] pyrimidine-7-one;

6-Bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one is oxidized as described in Example 44. The sulfoxide is then reacted with 4- (N-Boc-piperazin-1-yl) -aniline as described in Example 3. The N-Boc protecting group is removed by hydrolysis as described above. 8-cyclopentyl-6-fluoro-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one to give 6-bromo-8-cyclopentyl-5-methyl-2- (4-piperazin-1-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 35), mp > 200 ° C (decomposition). C23H27N6Brr 1.9 TFA: calculated C 45.90; H, 4.15; N, 11.97. Found: C, 45.53; H, 4.09; N, 11.76. r '. Example 7 1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethan-1-ol

H3C

4-Cyclopentylamino-2-methanesulfanylpyrimidine-5-carboxaldehyde (1.1 g; 4/64 mmol mmol was dissolved in tetrahydrofuran (30 mL) under a nitrogen atmosphere then cooled in ice) To this clear solution was slowly added methylmagnesium bromide (4.4 mL, 13.2 mmol, 3M solution in ether) and the reaction mixture was stirred in an ice bath for 1 hour then quenched with a small amount of saturated ammonium chloride solution and extracted between water. The layers were separated and the aqueous was extracted with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. • · · · · · · · · · · · · · · · · · · · · ___________ · · · _ · ♦ ........ The solvent is evaporated off in vacuo to give the title compound as an oil (1.09 g, 90%). MHz, CDCl 3): δ 1.42-1.59 (m, 5H), 1.60-1.76 (m, 4H), 2.04-2.06 (m, 2H), 2.49 (s). , 3H), 4.38-4-43 (m, 1H), 4.69-4.74 (m, 1H), 6.28-6.30. (d, 1H), 7.57 (s, 1H). Example 8 1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -ethane on

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 (4¾), N-methylmorpholine oxide (1.07 g, 8.6 g), and tetra-propylammonium perruthenate (0.227 g, 0645 mmol) were then gradually added to the reaction mixture. The reaction mixture was stirred at 24 ° C for 2 hours, a small amount of catalyst was added periodically. Reaction. the mixture is then chromatographed on silica gel (1: 1, ethyl acetate: hexane) to afford the title compound as a pale yellow solid (0.74 g, 70%). 1 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 ·· · · 9 9 9 * * · • ^ f 6 $ ίβ 6: 6 β • 9 · ·· 9 · · · * ····· 9 9 · · · · eeee 9 9 · · · mm · 9 9 “99 9 - 9 p, p · 9 8-Cyclypentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one ·. ·

Tetrahydrofuran (50 ml) was charged to the flask and sodium hydride (1.05 g, 26.3 mmol, 60% dispersion in mineral oil) and triethylene phosphonoacetate (1.0 g) were added under cooling to 5 ° C. 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 was then heated to reflux for 2 hours, then cooled to 24 ° C and diluted with 50 mL of water and 50 mL of ethyl acetate. After separating the layers, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to near dryness. Hexane was then added and the mixture stirred vigorously for 5 minutes then filtered to give the title compound as a pale orange solid (3.01 g, 92%). @ 1 H NMR (400 MHz, CDCl3): .delta. 1.63-2.36 (m, " 8 ") ", 2, 38 < 38 > S, 3H), 2.59 (s, 3H), 5.84 -5.93) (m, 1H), 6.3? (s / 1H), 8.66 (s, 1H). Example 10. . . ... 8 -Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one

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-phenyloxazitidine is added. The reaction mixture was stirred at 24 ° C for 12 hours and then chromatographed. Purify on silica gel eluting with 2% methanol in dichloromethane to afford the title sulfoxide as a white solid (0.67 g, 64%). 1 H NMR (400 MHz, DMSO-d 6): δ 1.53-2.19 (m, 5H), 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] pyrazole-7,9-dihydropyrido [2,3-d] pyrazole-t-butyl ester) rimidine -2-ylamino) -phenyl] -piperazine-1-carboxylic acid

8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (0.7 g, 2.4 mmol) from Examples 10 and 4 (4 " -N -Boc-piperazinyl) -aniline is dissolved in dimethylsulfonic acid.

The 48 'foxide (3 ml) was 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, CDCl 3): δ 1.45 (s, 9H), 1.56-1.87 (m, 6H) t 2.23-2.28 (m, 2H), 2.31 (s) 3H, 3.07 (m, 4H), 3.55 (m, 4H), 5.77-5.81 (m, 1H), 6.19 (s, 1H), 6.90 (d, 4H), 3.05 (m, 4H), 3.55 (m, 4H); 2H), 7.42-7.44 (d, 2H) -, 7.47 (s, 1H), 8.55 (s, 1H); MS (M + 1) 505.1. The Boc protecting group is removed by stirring in a 1: 1 mixture of trifluoroacetic acid and dichloromethane to yield. Compound 1. Melting point > 215 ° C (decomposition); Example 12 8 - Cyclopentyl-5-ethyl-2- (4-piperazinyl-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 193) 3

1- (4-Cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propyl-1-ol 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (4.07 g, 17.1 mmol) was dissolved in 60 mL under nitrogen atmosphere Tetrahydrofuran, the mixture was cooled in an ice bath and added slowly to the clear solution. EtMgBr (13.4 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 extracted 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-Cyclopentyl-amino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-one- (4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propyl- The ol (4.55 g, 17.1 mmol) was dissolved in toluene (80 mL) and then activated manganese dioxide (3.72 g, 42.8 mmol, Aldrich, < 5 μτη, 85%) was added. The reaction mixture is heated to boiling 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%). r. ... '- 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) and then triethylphosphonoacetate (6.09 mL, 30.7 mmol) were added to the cooled tetrahydrofuran (50 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature until complete dissolution. A solution of 1- (4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl) -propan-1-ol (3.0 g, 11.9 mmol) in tetrahydrofuran (70 mL) was added slowly to the prepared anion.

· · · ____ ________ __ · · _ · · - ~ = 50 - «- * -;

The reaction mixture was 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 covered with hexane and filtered to give a white solid (2.67 g, -66%). 8-Cyclopentyl-5-ethyl-2-methylsulfanyl-8H-pyrido- [2,3-d] pyrimidin-7-one 8-Cyclopentyl-5-ethyl-2-methylsulfanyl-8H-pyrido [2,3-d] pyridine-7-one (2.57 g, 8.88 mmol) was dissolved in dichloromethane (50 mL), and 2-benzenesulfonyl-3-phenyloxaziridine was added. The reaction mixture was stirred at room temperature for 16 hours and the solution was evaporated to give an orange oil. Ethyl acetate was 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-4-tert-butyl) -butyl ester 8-Cyclopentyl-5-ethyl-2-methanesulfinyl-8H 7,7-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid -pyrido [2,3-d] pyrimidin-7-one (sulfoxide, 0.2 g, 0.654 mmol) and 4- (4 ' -N-Bis-piperazinyl) -aniline are dissolved in dimethylsulfoxide (5 mL) and the mixture was heated at 70 ° C for 16 h. The reaction mixture was cooled to room temperature and extracted 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%).

51 8-Cyclopentyl-5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (235) t-Butyl ester 4- [4- (8 -cyclopentyl-5-ethyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-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 was evaporated and the solid was suspended in diethyl ether. The mixture was filtered to give tufts of gray solid (128 mg, 75%). NNN 4 R (400 MHz, DMSO-d 6): δ 1.17 (m, 3H), 1.52-1.83 (m, 6H), 2.20 (m, 2H), 2.75 (m, 2H) 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 8 H 50 N 8 O + 1.21 TFA. Example 13 2, [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-5-ethyl-8H-pyrido [2,3-d] pyrimidin-7-one ( compound 198)

1- [4- (4-Aminophenyl) -piperazin-1-yl] -ethane (0.075 g, 0.343 mmol) and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido [2,3-d] pyrimidine -7-on (0.100 g, 0.343 mmol) was dissolved in DMSO (5 mL) and the mixture was heated at 70 ° C for 16 h. Then add an additional 20 mg of aniline and heat

52 hours continue for another 4 hours. The reaction mixture was cooled to room temperature and extracted 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) r-Aminomethyl-trifluoromethyl-pyrrpridin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidine -7 - on (Compound. 216)

((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 heated to reflux for 24 h. The solvent was removed and the mixture was covered with hexane and filtered to give a crude yellow solid (1.4 g). This material was dissolved in tetrahydrofuran and Ra-Nickel and hydrogen were added until the change in pressure was complete. After removal of the catalyst by filtration, the product (anilines used without further purification) is obtained by evaporation of the solvent. {(3R, 4S) - [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8) t-butyl ester - dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -

You. trifluoromethyl-pyrrolidin-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 above in Example 11 ... 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-ylsulfonyl) -ethyl] -phenylamino) -8H-pyrido [2,3-d] d] pyrimidin-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). 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 was 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). The sample was concentrated to dryness to afford the title compound (0.88%), MS:. MH * 221; MH + 219. 8 -Cyclopentyl-5-methyl-2- (4- [2- (4H- [1,2,4] triazol-3-ylsulfonyl) -ethyl] -phenylamino} -4H-pyrido [2 ', 3-d] pyrimidin-7-one

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 hours. The mixture was then cooled and the solvent removed in vacuo. 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. (Ϊ- - ·. V. Is acidified to pH 1 and extracted with ethyl acetate / dichloro-ethane (9: 1) (3 x 4 ml). The combined organic extracts are concentrated to dryness and chromatographed on silica gel. silica gel eluting with a gradient of ethyl acetate of 60% to 100% in hexane Concentration of the appropriate fractions yielded compound 222 (0.014 g) 1 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 (1H, 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-yl-sulfanyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidine-7 -on (Compound 223)

AND

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

A solution of 3-mercapto-1,2,4-triazole (4.0 g) in dimethylformamide was added dropwise to the suspension of hexane washed 60% sodium hydride (1.16 g) in dimethylformamide (10 ml) at 0 ° C. 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. Ilyl hydrochloric acid (100 mL) was then added and the solid was collected and dried. A second portion of the solid (2.1 g) was obtained by crystallization of the mother liquor. The combined solids were dissolved in dichloromethane (300 mL) and 1M sodium hydroxide (200 mL) was added. The organic layer was extracted with 1M hydroxide " 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 Rane's nickel and hydrogen in tetrahydrofuran (100 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; *

56

This compound was prepared from 4- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine and 8-cyclopentyl-5-methyl-2-methanesulfinyl-8H-pyrido [2,3- d] pyrimidin-7-one as described in Example 15 to afford Compound 223. 1 H NMR (D 6 -DMSO): δ 1.58 (2H, m), 1.75 (2H, m), 1.90 (2H, 2.2 (2H, m); 2.38 (3H, s); 5.82 (1H, m); 6.20 (1H, s); 9), 7.73-- (2H, d, J = 9), 8.85 (1H, ss), 8.82 (1H, s) '. " Example 17

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

4 - [(4- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-N ', 7,8-dihydropyrido [2,3-d] pyrimidine-2-yl) t-butyl ester * ylamino) -phenyl] -piperazine-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) were dissolved in methanol and a CO (500 PSI) atmosphere was added and the reaction mixture was heated to 100 ° C for 14 h and then cooled. at 24 DEG C. After evaporation of the solvent, the residue is chromatographed on silica gel (45% to 50% EtOAc in hexane) to give a yellow gel which is dissolved in dichloromethane (10 ml) and warmed to room temperature.

57 " '" 2M HCl in diethyl ether (10 mL) was added to the reaction mixture. A white precipitate formed, the mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was suspended in anhydrous diethyl ether and then separated by filtration to give the title compound as a yellow solid (34 mg), mp 195-205 ° C. NMR (d6, -DMSQ): δ 1.52 (ss, 2H), 1.71 (s, 2H), 1.82 (s, 1H), 2.14 and v (ss, 2H) 2.30 1 (s, 5H), 3.18 (s, 4H), 3.27 (s, 4H), 3.76 (s, 3H), 5.8 (S, 1H), 6.96 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H), 9.85 (s, 1H), 9.04 (s, 1H), 9.97 ( S / 1H). Example 18

Following the procedures described in Examples 1 to 17 and Schemes 1 and 2, the following compounds were prepared: (a) trifluoroacetic acid salt and 8-cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 1), mp > 215 ° C (decomposition); (b) 8- (1-Methylethyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) - (8H-pyrido [2,3-d] pyrimidin-7-one (Compound 2), Temperature mp > 235 ° C (decomposition); . (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-propanoyl-piperazin-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-propanoyl-1'-piperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine; 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-pyridyl-phenylamino) -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-ol (compound 11); (1) trifluoroacetic acid salt of α8-cyclopentyl-5-methyl-2- [4- (3-aminopyrrolidinyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 12), melting point > 195 ° C (decomposition); (m) 8- (1-methylethyl) -5-methyl-2- [4- (3-aminopyrrolidinyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 13), melting point 227-229 ° C; (η) N- (1- {4 - [(8-cyclopentyl-5-methyl-7-oxo (8-hydropyridino [2,3-d] pyrimidin-2-yl)) amino] phenyl) pyrrolidine- 3-yl) -3,3-dimethylbutanamide (Compound 14); (o) N- (1- {4 - [(5-methyl-8- (1-methylethyl) -7-oxo (8-hydropyridino)

59 [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-Methylethyl) -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-methylethyl) -6-fluoro-5-methyl-2- (3-chloro-4-piperazin-1-ylphenyl) - 8H-pyrido [2 3-d] pyrimidin-7-one (Compound 20); (v) 8-cyclopentyl-5-methyl-2H- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 22); 8- (1-methylethyl) -5-methyl-2- (3-chloro-4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidine-7- on (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] pyrimidine -7-on (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-yl-propyl) -piperidyl] -phenyl} -amino-8-cyclohexyl-5-methyl-8-hydropyridino [2,3 (d) -pyrimidin-7-one (compound 27) (bb) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8-cyclopentyl-6- fluoro-5-methyl-8-pyridino [2,3-d] pyrimidin-7-one (compound 28) (cc) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] (phenyl)} amino) -8- (1-methylethyl) -6-fluoro-5-methyl-8-pyridino [2,3-d] pyrimidin-7-one (Compound 29); (dd) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] -phenyl) amino) -8-cyclohexyl-6-fluoro-5-methyl-8-hydropyridine [2, 3-d] pyrimidin-7-one (compound 30), melting point > 80 ° C (decomposition); - (ee) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclopentyl-5-methyl-8-hydropyridino [2,3-d] pyrimidin-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);

61 (gg) 2 - ({3-Chloro-4- [4- (3-piperazinyl-propyl) -piperidyl] -phenyl} -cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidin-7-one ( Compound 33) 8-Cyclopentyl-2- [4- (piperazin-1-yl) -phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine-7- (gg2) trifluoroacetate 254-255 DEG C. (gg3) 8-cyclopentyl-2- [4- (piperazin-1-yl) -phenylamino] -6-bromo-5-methyl-8H-pyrido [trifluoroacetate] trifluoroacetate; 2,3-d] pyrimidin-7-one (compound 35), melting point > 200 ° C 9-cyclopentyl-2- [4- (3,5-dimethylpiperazin-1-yl) hydrochloride yl) -phenylamino] -6-fluoro-5-methyl-8H-pyridone [2,3-d] pyrimidin-7-one (Compound 36), melting point > 22.0 ° C; (ii) 8- cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidine-7-oh (compound 37); 8-cyclopentyl-2- [4- (3,5-dimethyl-piperazin-1-yl) -phenylamino) -5-methyl-8H-pyrido] [2,3-d] pyrimidin-7-one (Compound 38), the temperature was > 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); v (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-methyl-piperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 41 ); (nn) 2- (3-chloro-piperazin-1-yl-phenylamino) -4-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 42); 62 **

Φβ · (οο) 2- (3-chloro-4-piperazin-1-yl-phenylamino) -8-cyclopent-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine-7 -on (Compound 43); (Pp) 6-bromo-2- (3-chloro-4-piperazin-1-yl-phenylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidine-7- on (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); 8-Cyclopentyl-6-fluoro-2- (3-fluoro-4-morpholin-4-yl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidine-7-oh% (Compound 49 (W) 6-bromo-8-cyclopentyl-2- (3-fluoro-4 * morpholin-4-ylphenyl-amino) -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] pyrimidin-7-one (Compound 54), m.p. 198-199 ° C; 9-cyclopentyl-6-fluoro-5-methyl- 2- (4- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 55); 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl) -phenylamino} -8H-pyrido [2,3- d] pyrimidin-7-one (compound: 56). 8-Cyclopentyl-5-methyl-2- {4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine-trifluoroacetate 7-one (compound 57), melting point > 80 ° C (decomposition); - · ..... v.; - - " 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2- -d] pyrimidin-7-one (compound 58), melting point > 230 ° C; 6-bromo-8-cyclopentyl-5-methyl-2- (4 [4- (3-morpholine) -4-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-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-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 61) 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-morolin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3 -d] pyrimidin-7-one (compound 62); 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-morpholin-4-yl-propyl) -piperidine-1 -yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 63) 2- (4- (4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -propyl) -piperidin-1-yl} phenylamino) - 8-c yclententyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 64); - 2 - (4- {4- [3 - (3-min. pyrrolidin-1-one) -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 [2,3-d] pyrimidin-7-one (Compound 66) .delta .- Cyclopethyl-2- (3'-fluoro-4- [4- (3-piperazin-1-ylpropyl) piperidin-1-yl] -) phenylamino} -5-methyl-18H-pyrimidin-7-one (Compound 67); 8-cyclopentyl-6-fluoro-2- {3-fluoro-4- [4 - (3'-piperazin-1-yl-propyl-piperidin-1-yl) -phenylamino} -5-methyl-1H-pyrido [2,3-d] pyrimidin-7-one (compound, 68); -cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyridone [2,3-a]; d] pyrimidin-7-one (Compound 69); 8-Cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidin-7-one (Compound 70); '65 '65 *% *. 9

. 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-yl-propyl) -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; . · I.:.:. ' ! 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 74) ; . - ~ ... · 'V. · .. ·. . . 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -6,6-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; - '' '76); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [ 2,3-d] pyrimidin-7-one (Compound 77); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenyl-amino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidine-7- on (Compound 78); 8-Cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate (Compound 79), m.p. > 160 ° C (decomp.); 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine- 7-one (Compound 80); 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3-a] t >; d] pyrimidin-7-one (Compound 81); 2- [4- (3-Amino-pyrrolidin-T-yl) - 3-chlorophenyl-amino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidine-7 trifluoroacetate -one (compound 82), melting point > 215 ° C (decomposition); 2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine-7- on (Compound 83), mp 221 ° C; ... 2- [4- (3-Amino-pyrrolidin-1-yl-3-chloro-phenylamino) -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidine-7 -on- (compound 84); . 2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-b] -2-d] pyrimidine-7- on "X compound .85); 2- [4- (3-Aminomethyl-4-trifluoromethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-indole. pyrido [2,3-d] 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-a]. 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); 67 67 · # * ·· + · * Μ · · · · ··· ψ *; ) N- [4- (3-Trifluoroethylaminomethyl-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine- 7-one (Compound 89); 2- [4- (3-Triflorethylaminomethylpyrrolidin-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-dimethylpip, erazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (compound 91), melting point, 150 ° C (dec.); , 8 - Cyclopentyl - 2.-. [4- (3,3-Dimethyl-piperazin-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-pyrrolo [2,3-d] pyrimidine-7 hydrochloride mp (compound 93), melting point > 200 ° C (decomposition); 8-Cyclopentyl-5-methyl-2- [4- (3,3,4-trimethyl-piperazin-1-yl) -phenylamino] -8H-pyridof-2,3-d] -pyrimidin-7-one (Compound 94); · ·. . -------. ·. ? -? 8-Cyclopentyl-6-fluoro-5-methyl-2? [4- (3,3,4-trimethyl-piperazin-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] pyrimidine-7- on - (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-acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 98), m.p. 68 68 · »9 · ·.

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] pyrimidine- 7-. mp (compound 100), mp 156-159 ° C; ; 8-Cyclopentyl-6-fluoro-2- {4- [4- (2-hydroxy-ethyl) -3,5-dimethyl-piperazin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrido [2,3-d] pyrimido [2,3-d] pyrimido [2,3-d] pyrimido [2,3-d] pyrimidin-2-yl] -phenyl; 3-d] pyrimidin-7-one (Compound 101); - * · - - - 6-Bromo-8-cyclopentyl-2- {4- [4- (2-hydroxyethyl) -3,5-dimethylpiperidin-1-yl] phenylamino} -5- methyl-8H-pyrido [2,3-d] pyrimidine. din-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), 172 ° C (dec.).

8-Cyclopentyl-6-fluoro-5-methyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -8H-pyrrolo [2,3-d] pyrimidin-7-one hydrochloride 4 (Compound 104), melting point 192 ° C * (decomposition) -1H-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] pyrimidine; 7-one (Compound 106), mp 211-213 ° C; 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine; 7-one (Compound 107); 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 108);

69 e ·· · · ··· · · * · • · · ··· · 8-Cyclopentyl-5-methyl -2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 109), m.p. ° C (decomp.); - 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine-7- on (Compound 110),. 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methyl-hydro-1,4-diazepin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 111). ,. {4- [4- (8-Cyclopentyl-5-methyl-7 ', 7', 7 ', 8'-dihydropyrido [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-dihydropyrrolo [2,3-d] pyrimidin-2-ylamino) phenyl] piperazine-1 . Yl} acetic acid (compound 113); i {4- [4- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-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] pyrimidin-7-one (Compound 115); '1. 8-cyclopentyl-6-fluoro-5-methyl-2- (4- {4- [3- (1H-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] -piperidine-1 70 w * ··: ::. · Β • ♦ · · · β · * · ·· «# * · ·· · ♦ ·· · * • · * * S c * ···· 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} piperidin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 119); 6-bromo-8-cyclopentyl-5-methyl-2 - (4 - {[4 '- [(5-oxo-4,5-dihydro-1H-1,2-4-triazole) 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-chloro-4- (4-dihydro-1H-1,2,4-triazol-3-ylsulfonyl) propyl] piperidine 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-sulfonyl) 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-sulfonyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [ 2,3-d] pyrimidin-7-one (Compound 123) 8-Cyclopentyl-5-methyl-2- (4- {4- [3- (5-oxp-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); 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 H-1,2,4-triazole-3-sulfonyl) propyl] piperidine-1-O-3-ol;

Gt > 'J > 3 0 0 # > ^ '3 0' 3? (R) - (-) - O '7'-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 126); N- (2- {1- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrrolo [2,3-d] 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] piperidin-4-yl} ethyl) -N-hydroxyacetamide (Compound 128); N- (2- {1- [4- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-12,3-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 [2,3-d] 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-oxo-propyl) [2,3-d] pyrimidine- 2-ylamino) phenyl] piperidin-4-yl} propyl) -2-hydroxyacetamide (Compound 132); 2- (benzofuran-5-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 133); 8-cyclopentyl-2- (1H-indol-5-ylamino) -5-methyl-8H-pyrido [2,3-d] 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-1 H -indol-5-ylamino) -5-methyl-8 H -pyrido [2,3- d] pyrimidin-7-one (Compound 136);

72 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-9H-pyrido [2,3-d] 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-dimethyl-piperazin-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), m.p. 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-pyridb [2,3-d] pyrimidin-7-Oh (Compound 144); - -. 'In ......... _ ^; N- {1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [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), mp 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. 255 ° C; 1- 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 [2,3-d] pyrimidin-7-one trifluoroacetate (compound 149) , melting point above 215 ° C (decomposition); 8-Cyclopentyl-5-methyl-2-propyl-4-yl-2-trifluoromethyl-piperazin-1-yl-phenylamino] -8H-pyrido [2,3-d] pyrimidine-7- mp (compound 150), mp 198-199 ° C; 8-cyclopentyl-2- (4-fluoro-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 151), mp 217-220 ° C; . . . 8-cyclopentyl-5-methyl-2-phenylamino-8H-pyrido [2,3-d] pyrimidin-7-one. (Compound 152), m.p. 180 DEG -183 DEG C .; ^. ·. 8-cyclopentyl-2- (3,4-dichlorophenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one; (compound · 153), m.p. 225-210 ° C; Trifluoroacetate 8-isopropyl-5-methyl-2- (4-piperazin-1-ylphenylamino) -8H-pyrido [2 3-d] pyrimidin-7-one (Compound 154), mp 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-1-yl] -phenylamino} -8-cyclohexyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine- 7-one (compound 157, mp 2.6-209 ° C; 8-cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfanyl-methyl) 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-Tylsulfonyl) methyl) 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-hydroxy-diazol-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-ylsulfonyl-phenyl) -ethyl] -phenylamino} -8H-pyrido [2 3-d] pyrimidin-7-one (Compound 162) 8-Cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazol-3-sulfonyl) ethyl phenylamino} -8Hpyrido [2,3-d] pyrimidin-7-one (Compound 163); .-.and. '.... 1. *. ··. · ... ·. 8-cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazol-3-ylsulfonyl) ethyl] enylamino} -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-ylsulfanyl-methyl] -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 166 );

75 8-Cyclopentyl-5-methyl-2- {4- [2- (3H-1,2,3-triazol-4-ylsulfonyl) -ethyl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine -7-one (Compound 167); • 8-cyclopentyl-5-methyl-2 '- {4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) piperidin-1-yl] phenylamino) -8H-pyrido [2,3-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); S-cyclopentyl-S-methyl-4- {4- [4- (2H-1,2,4,4-triazole-3-yl) sulfinyl} piperidin-1-yl] phenylamino} -8H pyrido [2,3-vd] pyrimidin-7-one * (Compound 170); 8-cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazole-3-sulfonyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2, 3-d] pyrimidin-7-one (compound 171) mp 235-237 ° C; 8-Cyclopentyl-5-methyl-2- {4- [4- (2H-1-tetrazol-5-yl) -piperidin-1-yl] -phenylamino} - [2,3-d] pyrimidin-7-one ( compound 172); ...... -r · - ·· 7 " ' 1- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- (1H-tetrazol-5'-yl) amide (1H) ylamino) phenyl] piperidine-4-carboxylic acid (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); ·· '

76 2- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenoxy] -N- (1H-tetrazol-5-yl) acetamide (compound 175); 8-cyclopentyl-5-methyl-1,2- [4 ', 4' (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ylmethoxy) phenylamino] -8H-pyrido [2 3-d] pyrimidin-7-one (Compound 176), m.p. > 195 ° C (decomp.); 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] pyrimidin-7-one (Compound 177); 8-cyclopentyl-5-methyl-2- (4- {4- [27- (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- (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 [2,3-d] 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 ', 3-d] pyrimidin-7-one (Compound 182); 8-cyclopentyl-2- {4- [4- (2,2-dioxo-2,3-dihydro-1,2,3,5-oxa-thiadiazol-4-yl) piperidin-1-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-oxathiatriazol-4-yl) piperidin-1-yl] phenylamino -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 184); 8-Cyclopentyl-2- {4- [4- (1,7-dioxo-2,5-dihydro-1H-1,2 ', 3,5-oxathiatriazol-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-dione} 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-ylsulfonyl) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3 -d] pyrimidin-7-one (Compound 187). .1 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 188); ? 8-cyclopentyl-5-methyl-2- {4- [3- (2H-1,2,4-triazol-3-, sulfonyl) pyrrolidin-1-yl] -phenyl} -pyrrolidin-2-yl; 3-d] pyrimidin-7-one (Compound 189)? -? - 8-Cyclopentyl-5-methyl: -2- {4- [3- (3H-1,2,3-triazol-4-ylsulfa -nyl) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 190) v · 8- cyclopentyl-5-methyl-2- {4- [ 3- (5-oxo-4,5-dihydro-1,2,4-oxadiazin-3-yl) pyrrolidin-1-yl] phenylamino} -8H-pyrido [2,3-d] pyrimidine-7 -on (Compound 191); 8-Cyclopentyl-5-methyl-2- {4- [4- (3-hydroxy-propyl) -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-1-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 (decomp.); 8- (1-Methylethyl) -5-ethyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one trifluoroacetate; (compound .196) melting point, higher.,. -35 ° C (decomposition); 8-Cyclopentyl-5-methyl-2- [4- (3-hydroxypyrrolidin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 197), m.p. . 226, (R) -8-cyclopentyl-5-ethyl-2- (4- (4-acetylpiperazin-1-yl) phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 198) 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one. (compound 199) Melting point 267-269 ° C. 8-Cyclopropyl-5-methyl-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2 3-d] pyrimidin-7-one (Compound 200), mp 221 ° C (dec.); 8-cyclopropyl-5-methyl-6-fluoro-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 201), m.p. > 250 ° C, 8-Cyclopentyl-5-methyl-2- [4- (homopiperazine- 1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 202), m.p. 172 ° C (dec.);

79 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (homopiperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 203) mp 192 ° C (foam); 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (3,3-dimethyl-4-acetyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one; (Compound 204), mp 200-204 ° C; in 8-cyclopentyl-5-methyl-2- [4- (3 '; 3-dimethyl-4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine- 7-one (compound: 205), mp 192-196 ° C, 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-methylpiperazin-1-yl) phenylamino] trifluoroacetate. 8H-pyrido [2,3-d] pyrimidin-7-one (Compound 206); 8-cyclopentyl-5-methyl-2- (4- (N-methylacetamido) phenylamino] -8H-pyrido [2,3-d] pyrimidine-1-one (compound 207), m.p. 8- cyclopentyl-5-methyl-2- {4- [2- (2-hydroxyethoxy) ethylamino] phenylamino} -8H-pyrido [2,3-d] pyrimidinep7-one (compound -208) , cyclopentyl-5-methyl-2- [4- (4-methyl-2-methylpyrrolidin-2-yl) pyridine-5-methyl-2- (3-Oxopiperazin-1-yl) phenylamino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 209), m.p. > 235 DEG C. (dec.); -cyclopentyl-5-methyl-2- [4- (2-methoxy-ethoxy) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 210), m.p. 8-cyclopentyl-5-methyl-2- (9H-carbazol-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 211); 5-methyl-2- (1H-indazol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 212);

80 8-cyclopentyl-5-methyl-2- (2-acetyl-benzofuran-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 2-14); 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) mp 171-173 ° C; 8-Cyclopentyl-5-methyl-2-t {4- [4- (3-morpholino-propyl) piperidin-1-yl]] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7 trifluoroacetate -one (compound 217), mp 171-173 ° C; 8-cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 219); . 8-cycloperttyl-5-methyl-2- (indol-5-yl) amino-8H-pyrrolo [2,3-d] pyrimidin-7-one (Compound 22.0); 8-cyclopentyl-5-methyl-2- (thionaphth-5-yl) amino-8H-pyrido [2,3-d] 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) m.p. to 198 ° C (dec.); 8-Cyclopentyl-2- {4- [1- (3,5-dimethyl-piperazin-1-yl) -methoxy] -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), m.p. > 200 DEG C. (decomposition); 8-cyclopentyl-2- [4- (3,5-dimethylpiperazin-6-yl)] phenylamino] -6-iodo-5-methyl; -8H-pyrido [2,3-d] pyrimidin-7-one (compound 229), m.p. 225-226 ° C (dec.); 6-chloro-8-cyclopentyl-2 - [4 - (3 3-dimethylpiperazin-1-yl-1 H -nylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 230), m.p. 250 DEG C. 8-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfonyl) 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-one; 3-d] pyrimidin-2-yl-amino) phenyl] piperidine-1-carbaldehyde (Compound 232), m.p. 244-247 ° C. 8-cyclopentyl-2- (4-piperazin-1-ylphenylamino) -5-trifluoromethyl-8H-pyrido [2,3- d] pyrimidin-7-one - (Compound 233), m.p. 275 ° C (decomposition); 8- (1-ethyl-propyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 234), m.p. C (decomposition); ~ ·.

[4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) benzyl] phosphonic acid (Compound 235), m.p. ° 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 (decomposition); 2- [4- (3,5-Dimethyl-piperazin-1-yl) -phenylamino] -1,8-dimethyl-propyl-5-methyl-8H-pyrido [2,3-d] pyrimidine-7 -on (Compound 237), melting point above 185 ° C (decomposition); 8-Cyclopentyl-2H-4- (2-hydroxyethylamino) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 238), mp 197-120 ° C; -.IN. 3- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] -N, N-diethylpropionamide (Compound 239) ), mp 138-140 ° C; 8-cyclopentyl-6-fluoro-2- [4- (2-hydroxyethyl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 240), m.p. 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 ; Í_ · - ..... ....... 1 *. 4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -benzoic acid (Compound 242); 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one .. (Compound 243), Temperature melting above 150 ° C- (decomposition); [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -benzyl] -phosphonic acid diethyl ester (Compound 244), m.p. ° 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. to 149 ° C (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 245) mp 238 ° C (decomp.); 8-cyclopentyl-2- [4- (2-methoxyethoxy) phenylamino]. -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 247), mp 156-157 ° C; 8-cyclopentyl-2- (4-isopropylamino-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 248), mp 216-220 ° C; 8-cyclopentyl-2- (4-hydroxy-3,5-dimethylphenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 249), m.p. 254 ° C; 8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethyl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 250), m.p. 241-248 ° C; ... . n. 8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethyl-phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound; 251), m.p. ° C (decomp.). Example 19. -

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

Cdk1 and Cdk2 Enzyme Assays for IC50 and Ki-Kits: 96-well filter plates (Millipore MADVN6550), total volume of 0.1 mL with a final concentration of 20 mM TRIS (pH 7.4), 50 mM NaCl are used , 1 mM dithiothreitol, 10 mM MgCl 2, 12 mM ATP containing 6.25 µCi [32 P] ATP, 20 ng enzyme (Cdk2 / cyclin E, Cdk2 / cyclin A or Cdk1 / cyclin B), 1 µl retinoblastoma protein and appropriate compounds of the present invention. All components except ATP are plated and the plate is placed on a 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 terminated by the addition of 0.1 mL of 20% TCA (trichloroacetic acid). The plate was 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 32P content determined using a beta plate counter (Wallac Inc., Gaithersburg, MD). - · _, '

The Cdk4 enzyme assay for IC 50 determination 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 µl ATP containing 0.25 µΟΐ [32 P] ATP, 20 ng Cdk 4, 1 µg retinoblastoma protein and appropriate dilutions of the compound of the present invention All ingredients except TPTP are placed in the wells and the plate is 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. then quenched by the addition of 0.1 ml of 20% TCA, the plate is cooled to 4 ° C for at least 1 hour to precipitate the substrate, and the wells are then washed five times with 0.2 ml of 10% TCA and the 32P content is determined using a beta plate counter (Wallac Inc. , Gaithersburg, MD).

The PDGF receptor (PDGFr) and FGF receptor (FGFr) tyrosine kinase assay is performed with the full length cDNA in PDGF-β mice and 99 9 9 9 _ ··· 9 9 9 9 Μ · «» Μ. Human FGF1 (flg) receptor tyrosine kinase obtained from J. Escobeda and prepared as described above (Escobedo et al., J. Biol. Chern., 1988; 262: 1482-1487). ). PCR primers are designed to amplify a DNA fragment that encodes an intracellular tyrosine kinase domain. The fragment is inserted into the bacilovirus vector cotransfected with AcMPNPV DNA and the recombinant virus is then isolated. SF9 insect cells are then infected with the virus, under strong protein expression and cell lysate is used for the assay. .....

The PDGFr and FGFr enzymes are assayed in 96-well plates (100 µl / incubation / well) and conditions are determined. optimize for measuring 32P from [γ32Ρ] ATP to the glucomate-tyrosine copolymer substrate. Incubate 82.5 μΐ of incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na3VC > 4 to each well. 10 mM MnCl2 and 750 μg / ml Poles (4: 1) glutamate-tyrosine followed by 2.5 μΐ inhibitor and 5 μΐ enzyme lysate (7.5 pg / μΐ FGFr or 6.0 .. PDGFr) to initiate the reaction. Then follows 10 minutes in-,? at 25 ° C and then 10 mL of each well is added. <, ... [γ32Ρ] ΑΤΡ (0.4 Ci plus 50 mM ATP) and the sample is incubated additionally; . 10 minutes at 25 ° C. The reaction is terminated by the addition of 100 µl of 30% trichloroacetic acid (TCA) containing 20 mM pyrophos-; sodium precipitate and precipitate the material onto a tuft., glass. fibers (Wallac). The filter was washed three times with 15% TCA containing 100 mM sodium pyrophosphate and the radioactivity retained on the filter was determined with a Beta Wallac 1250 reader. Nonspecific activity is defined as radioactivity retained on the filter after incubation of samples without enzyme (buffer only). Specific enzymatic activity (enzyme plus buffer) is defined as total activity minus non-specific activity. The concentration of compound that inhibits specific activity at 50% (IC 50) is determined from the inhibition curve. * 9 * ♦ 86 ♦ 4 * 9 * ♦ 86 ♦ 4 ·· «9 4:: ·. ≪ ::. * Μ ·· »< The following is a procedure for the c-Src protein kinase assay: c-Src kinase is isolated from bacilovirus-infected cell lysate using an anti-peptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src. Antibody covalently bound to 0.65 μιη latex beads was added to a suspension of lysate buffer of insect cells containing 150 mM NaCl, 50 mM Tris (pH 7.5), 1 µM DTT, 1% NP-40, 2 mM EGTA, 1 mM sodium vanadate, 1 mM PMSF, 1 µg / ml leupeptin, 1 µg / ml pepstate, and µg / ml aprotinin. The insect cell lysate containing the c-Src protein was incubated at 40 ° C with the indicated for 3-4 hours. beads. 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. Into the wells of a 96-well Millipore bottom with 0.65 µm " The polyvinyl lidine membrane layer is subjected to the following reaction composition: 1.0 µl c-Src beads, 10 µl 2.5 mg / ml polyGluTyr substrate, 5 µf, "v". '· &Quot; μΜ ATP containing 0.2 μ01 ·. [32Ρ] _ΑΤΡ, 5 μΐ DMSO containing, inhibitor or solvent only (control) and buffer to achieve a final volume of 125 μϊ. The reaction is started at room temperature by the addition of ATP and stopped after 10 minutes by adding 125 µL of 30% TCA 0.1 M sodium pyrophosphate for 5 minutes on ice. The plate was then filtered and the well walls were washed with two 250 mL aliquots of TCA and 0.1 M pymphate. Filters up. .then. perforated, measured with a liquid scintillation counter, and the data used to determine * inhibitory activity compared to known inhibitors such as erbstatin. 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 (T half) required to break down half of the parent compound after its addition to HLM homogluate. 00 00 a • a cu s a a

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CD H ηη, 26 103 OJ OJ OJ 0 0 0 0 0 0 0 0 0 0 0 0 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 «. * Ο ο ° ο Ο ο ο ο H- Γ- ΓΟ0 OJ0 oo OJ ^ oo O 03 03 5 5 ο ο ο ι ι ι in in in in in in in Λ Λ Λ in in in in ι ι ι ι ι ι ι ι ι ι ι ι Λ Λ Λ Λ ι ι ι ι ι ι ι ι ι νο νο; ιη - ο ιη οι ο * ιη Λ Γ Γ ι ι ι η γ γ '*' - C0 ιη, 94, 305 565 ηη η 85ημείωση 85 σε 33 ιη νο 31 Λ Λ Λ Λ (!) Λ • ο Λ Λ Α Α CN ι ι ιη ... " 'Η «17 - •' · - 03 1—1 ο. νο: ιη ιη Λ Λ Λ Λ Λ ΛΛ ** ΛΛ ** 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.. 03 ιη η ιη ιη ΛΛ ιη r-Λ ιη Λ 1 ο ο νο0 'σι 1 Ν 1 νο νο gt > I I 0 I Γ0 Η 00 Ν I Ν 0 00 00-00 KJ (ι yS 03 νο νο 0 0 ο ι 03, __, Γ- 00 σι < ύ .___, 03 ιΰ Η Μ3 03 03 03 03 03 γ-1 03 03 Η γ 1 1 1 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 1 1 Ο id Μ I Ο &; 235 ιη Η Ο ι — 1 1— (1—1 Ο 03 Ο 03 γΗ Η C0 0 Η 03 γ ιη Ν 00 λ; 03 νο νο γΗ / 0 0 0 03 Γ Γ Γ ω 03 Η 03 03 03 Γ 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 ι 03 0 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 Η Η 03 Η 03 03 OJ 03 03 03 Γ0 Η Η Η 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 β © β # • •

L_L o s a oc hq • rl e eh u Pi u o in a

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LO m lo ID CN CN-CN

· O O O ID ID ID · · · · · · · · · · · lt lt lt lt lt lt lt lt lt < O u gt O O O O O O O O O O Λ Λ O • O O O O O O O O O O O O O H H

CU Φ G ΐτ > c 4J > υ§ «Η C0

iry in icv in in Λ Λ N N 1 N O 0 > 1 N - what N o 0 o σ 0 «_S, UU 'O CN rH rH U (NH TS " - cd' - as lSS rH r - rH r - rH VD rH co σ > σ CO λ: O, 4i Λί what rH rH rH rH CN CN N1 CN Λ

WHAT THE RH ID V £ > OH ro ro ID CN CN Q CN Q U * γΗ Ν0Λ CQ • Η Τι Μ 'γΗ ΰ Φ α honors Ti' 3 g 91 Different 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 cleavage rate, Table 2.

Table 2

Merge. 5-Me XCso (μΜ) T 1/2 in 'HLM (min) Clearance (ml / min / kg) Cdk1 / cyclin B Cdk2 / cyclin A Cdk2 /: cyclin Cdk4 FGFr E-c-SRC PDGFr 1 yes > 5 > 5 >5; Q, 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 >5; 0.975 -NA 34. 8 - '- 152 YES > 1.7 4,91 > 5' 2,15- NA > 50 4 From the results shown in Table 2, it is clear that Compound 1 and other compounds of the invention specifically they inhibit Cdk4 and have a relatively small effect of ν Cdk1 and Cdk2. Further, Compound 1 is relatively more stable and is removed at a lower rate compared to the prior art compounds. These results indicate that the 5-position methyl group imparts unique properties to the pyridopyrimidine and is a preferred embodiment. '. _ ^, '* í 92 • · Resources examples

As mentioned above, the compounds of the present invention will typically be formulated with conventional additives, diluents, and carriers to provide compositions that are suitable for conventional administration to mammals. The following examples illustrate typical compositions that represent a further embodiment of the present invention. Example 20

Tablet formulation

Folder ····. _ Quantity

Compound 12 ·. 50 mg

Lactose 80 mg

Maize starch (for mixing) 10 mg

Corn starch (for pollen) 8 mg ·

Magnesium Stearate (1%) _ 2 mg

Total 150 mg

Compound 12 is mixed with lactose and corn starch (for mixing) and mixed thoroughly into powder, 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 granulates. The wet granules are screened 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 at 1 to 4 every day to prevent and treat atherosclerosis. Example 21

Parenteral solution

To a solution of 700 ml of propylene glycol and 200 ml of water for injection add 20.0 g of compound 38. Stir the mixture and adjust the pH.

93 to 5.5 with hydrochloric acid. Adjust the volume to 1000 ml with water for injection. The solution is sterilized, filled into 5.0 ml ampoules each containing 2.0 ml (40 mg of compound 38) and sealed under nitrogen in the ampoule. The solution is administered by injection to a cancer patient and, if necessary, treatment. The present invention and method and process for its implementation and use are: now fully, clearly, concisely and precisely described so that a person skilled in the art can realize and utilize. It will be understood that the preferred embodiments of the present invention have been described above and that modifications may be made without departing from the scope of the present invention as set forth in the claims. Further, the invention will be described precisely by the claims which summarize the above description.

Claims (21)

94 94 REQUIREMENTS P A T E Ν Τ 1. 1. Compound of Formula I and pharmaceutically, acceptable salts, esters, amides, and prodrugs thereof, where. R2 is (a) a hydrogen atom; (b) a lower alkyl group optionally substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, thioalkyl, a nitrile group, an aryl group, a heteroaryl group, or a carbocyclic group containing 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 containing 3 to 7 members and up to 2 such 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 alkynyl, lower alkenyl, nitrile, nitro, -COR 4, -CO 2 R 4, -CONR 4 R 5, -CON (R 4) 2 OR 5,. group. -SO 2 NR 4 R 5, -SO 2 R 4, - - SO 3 R 4, - P (O) (GR 4) (OR 5) or -NR 4 R 5; Y is nitrogen 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) R4R5, -NR4R5R6W, -SR4, -C (O) R4, -CO2R4, -CONR4R5, -SO2NR4R5, " -SO2R1, -SO3R4, P (O) (OR4) (OR5), -T (CH2) mQR4, -C (O) T (CH2) mQR4 ... or -NR4C (Ό) T (CH 2) mQR 5; m is 1 to 6; n is 0 to 6; T is O, S, 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 carbocyclic groups containing 3 to 7 members, of which 4 are optionally heteroatoms independently selected from oxygen, sulfur and nitrogen, where the carbocyclic group is unsubstituted • β * * 6 ·· ·· »* β * *, · β« __ β9Φ. 96 or substituted with 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 a group, a trifluoromethyl alkyl group, an amino group or a mono- or dialkylamino group; R 6 is lower alkyl, haloalkyl or aralkyl; 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 / 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) nP (O) (OR 4) 2, NR 4 SO 2 R 5, aldehyde, nitrile, nitro, alkyl, alkoxyalkyl, -T (CH 2) m R R 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; in " | W je anion; R4 and R5 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH2) nAr, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R4; R 5 together with the nitrogen atom to which they are attached form a carbocyclic ring containing 3 to 8 members, of which 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), the group S (O) 2 and the 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, alcohol oxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkyl boronyl, trifluoromethyl, trifluoromethyllalkyl, trifluoromethylalkylaminoalkyl, amino, mono- or dialkylamino, N -hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR 10 SO 2 R 11, C (O) NR 10 R 11, 1, 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) C (O) NR 10 R 11, O (CH 2) n C (O) OR 10; and R 4 may further be lower alkyl " a 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, 5- OXO-4,5-dihydro-1H-1,2,4-triazole-3-ylsulfinyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl, or carbocyclic the group having from 3 to 7 members, of which 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 atom halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamido, trifluoromethylalkyl, amino, or o mono- or dialkylamino; 98 98 »4 • 4». 2. A compound of formula II -. and pharmaceutically acceptable salts thereof (esters, amides and pre-drugs) wherein R3 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl; a group, a nitrile group, a nitro group, a -COR 4 group. -CO 2 R 4, -CNON 4 R 5, -CON (R 4) 2 O 5, R 5, R 4, SO 2 NR 4 R 5, -SO 2 R 4, -SO 3 R 4, P (O) (OR 4). - * - -NR 4 R 5; Y is nitrogen 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 W, -SR 4, - C (O) R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P (O) (OR4) (OR5), -T (CH2) mQR4, -C ( O) T (CH 2) m QR 4 or -NR 4 C (O) T (CH 2) m QR 5; m is 1 to 6; * E e # * < N is a number 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 containing 3 to 7 members, of which 4 are optionally heteroatoms independently selected from the group consisting of; an oxygen, sulfur and nitrogen atom, 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, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, amino-alkyl, trifluoromethyl, N-hydroxyacetamide, "trifluoromethyl, amino, or mono- or dialkylamino"; R 6 is lower alkyl, halo, alkyl 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 / CO 2 R 4 '. CONR 4 R 5, C (O) NR 4 SO 2 R 5, S (O) 4 R 4, SO 2 R 4, SO 2 NR 4 R 5, SO 3 R 4, (CH 2) n P (O) (OR 4) 2, NR 4 SO 2 R 5, aldehyde, nitrile, nitro groups - n, 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; · _ E t t t * * ((((((((((((((((oc oc oc oc oc oc oc oc oc oc oc oc oc oc 100 R4 and R5 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH2) nAr, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl , a heterocycloalkyl group, 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 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (O) 2 and nitrogen, 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 a group, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl. a group, a trifluoromethyl group, a trifluoromethylalkyl group, a trifluoromethylalkylaminoalkyl group, an amino group, a mono- or dialkylamino group, an N-hydroxyacetamido group, an aryl group, a heteroaryl group, a carboxyalkyl group, a group NR 10 SO 2 R 11, a group C (O) NR 10 R 11, a group NR 10 C (O) R 11, C (O) OR10, C (O) NR10SO2R11, (CH2) nS (O) nR10, v- (CH2) n-heteroaryl, O (CH2) n-heteroaryl, (GH2) nC (O) NR 10 R 1: 1, O (CH 2) n C (O) OR 10; R 9 is lower alkyl, haloalkyl or aryl; and R4 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-triazol-3-ylsulfanyl group, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfinyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl group, 101 or a carbocyclic group containing from 3 to 7 members, of which 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 it consists of a halogen atom, a hydroxy group, a hydroxyalkyl group, a lower alkyl group, a lower alkoxy group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonylamino group, an aminoalkyl group, a trifluoromethyl group, an N-hydroxyacetamido group, a trifluoromethyl alkyl group, an amino group, or a mono- or dialkylamino group; and '' and when Y is a group CR7, it is part of the structure ΛΑΛΑ / ιΑ Λ, where s; carbon atoms, R7 and Z are as defined above to which they are attached, form or together fragments. G and J are independently CH 2, NH, or oxygen; B is NH, sulfur, CH 2, or oxygen; D is a carbon or nitrogen atom with the proviso that R10 is absent when D is a nitrogen atom; and 102 R 10 and R 11 are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. 3. A compound of formula III (III) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, where. R3 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkynyl, lower alkenyl, nitrile, nitro, -COR4 > -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 nitrogen 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 W, -SR 4, - C (O) R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P (O) (OR4) (OR5), -T (CH2) mQR4, -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 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 oxygen, sulfur / NR 4, N (O) R 4, NR 4 R 5 W, CO 2, or a carbocyclic group containing from 3 to 7 members, of which 4 are optionally heteroatoms independently selected from 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, 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 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 (O) (OR 4) 2, NR 4 SO 2 R 5, aldehyde a group, a nitrile group, a nitro group, an alkyl group, an alkoxyalkyl group. a group T (CH2) mQR4, C (O) T (CH2) mQR4, NR4C (O) T (CH2) mQR5 or T (CH2) mCO2R4; n is 0 to 6; W is an anion; R4 and R5 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH2) nAr, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R4; R 5 together with the nitrogen atom to which they are attached form a carbocyclic ring containing 3 to 8 members, of which 4 are optionally carbonyl-ringed by non-heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), the group S (O) 2 and the 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 a group, an alkylcarbonyl group, an alkylcarbonylamino group, an aminoalkyl group, an aminoalk ylcarbonyl, 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 (O R11, C (OjOR10, C (O) NR10SO2R1-; L, (CH2) nS (O) nR10, (CH2) n-heteroaryl, O (CH2) n-heteroaryl, (CH2) n C (O) NR 10 R 11 ', O (CH 2) n C (O) OR 10; and R4 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-triazol-3-ylsulfanyl group, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfinyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl a group or a carbocyclic group containing from 3 to 7 members, of which 4 are optionally heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the carbo-G is. ¢ .- 105 is a cyclic group unsubstituted or substituted with 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-hydroxyacetamido, trifluoromethylalkyl; a group, amino or mono- or dialkylamino; · · · · · · · · · · · · ·. and when Y is CR 7, it is part of the structure. . Where R7 and Z are as defined above, or together with the carbon atoms to which they are attached form fragments .or, 11 AWWV (Φ) (r) 8- (1-methylethyl) -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-Methylethyl) -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] pyrimidine-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] pyrimidine -7-on (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] -pyrimidin-7-one (compound 27); (bb) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl] amino) -8-cyclopentyl-6-fluoro-5-methyl- 8-Hydro-pyridino [2,3-d] pyrimidin-7-one (Compound 28) (oc) 2 - ({3-Chloro-4- [4- (3-piperazinyl-propyl) -piperidyl) -phenyl] -amino} -8- (1-methylethyl) -6-fluoro-5-methyl-8-pyridino [2,3-d] pyrimidin-7-one (compound 29), - (dd) 2 - ({3-chloro -4- [4- (3-piperazinylpropyl) piperidyl] phenyl) amino) -8-cyclohexyl-6-fluoro-5-methyl-8-hydropyridino [2,3-d] pyrimidin-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- on (compound 31), (ff) 2 - ({3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] phenyl} amino) -8- (1-methylethyl) -5-methyl-8-hydropyridine, [2,3-d] pyrimidin-7-one (Compound 32); (gg) 2 - (, {3-chloro-4- [4- (3-piperazinylpropyl) piperidyl] -N- phenyl} cyclohexyl-5-methyl-8-hydropyridino [2,3-d] pyrimidine- 7-one (compound 33), (gg2) 8-cyclopentyl-2- [4- (piperazin-1-yl) -phenylamino] -6-trifluoroacetate -fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 34); (gg3) 8-cyclopentyl-2- [4- (piperazin-1-yl) -phenylamino] trifluoroacetate 6-Bromo-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 35) 9-Cyclopentyl-2- [4- (3,5-dimethyl-piperazine) hydrochloride 1-yl) -phenylamino] -6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (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-dimethyl-piperazin-1-yl) -phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-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) -phenyl-amino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one ( compound (41) - '(N) -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-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] pyrimidin-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-morphopholin-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); -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] pyrimidine (Xx) 2- (3-chloro-4-morpholin-4-yl-phenylamino) -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine -7-on (compound 52); V = (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] pyrimidin-7-one (Compound 54); 8-Cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl) -phenylamino} -8H-pyrido [2,3-d] ] -pyrimidin-7-one (Compound 55); 120 * 9 · 9 9 # 9 e 9 9 9 e 9 9 · 9 · 9 • 9 9 9 9 9 9 · 99. 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl] -phenylamino} -8H- pyrido [2,3-d] pyrimidin-7-one (Compound 56); 8-Cyclopentyl-5-methyl-2- {4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine trifluoroacetate 7-one (compound 57); 8-cyclopentyl-6-fluoro-5-methyl-2- {4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino) -8H-pyrido [2,3 -d] pyrimidin-7-one (Compound 58); 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3-propen-4-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-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- (37-morpholin-4-yl-propyl) -piperazin-1-yl] -phenylamino} -8H-pyrido [2,3 -d] -pyrimidin-7-one (compound 61) 6-bromo-8-cyclopentyl-5-methyl-2- (4- [4- (3-morpholin-4-yl-propyl) -piperidine-1] -yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (compound 62); 6-bromo-8-cyclopentyl-5-methyl-2- {4- [4- (3- morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-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-7-one (Compound 64 Ϊ2Ϊ G · * # • • • • ++ ++ ++ ++ ++ ++ ++ ++.................... (((( - {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 [2,3-d] pyrimidin-7-one (Compound 66); 8-cyclopethyl-2- {3-fluoro-4 '- [4- (3-piperazin-1-ylpropyl) piperidin-1] -yl] -phenylamino} -5-methyl-8H-pyrimidin-7-one (Compound 67); . 8-cyclopentyl-6-fluoro-2- {3-fluoro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3 -d] pyrimidin-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] pyrimidine-7 -on (Compound 69); 8-Cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3- d] pyrimidine-7-ol (Compound 70); 8-cyclopentyl-6-fluoro-2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 71); 4. A compound of formula (VI) 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 (R 4) | OR 5, -SO 2 NR 4 R 5, -SO 2 R 4, -SO 3 R 4, P (O) (OR 4) (R 5), or -NR 4 R 5; Y is a nitrogen atom or a CR7 group; 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) R4, -CO2R4, -CONR4R5, -SO2NR4R5, -SO2R4, -SO3R4, P (O) (OR4) (OR5), -T (CH2) mQR4, -C ( O) T (CH 2) m QR 4 or -NR 4 C (O 1 T (CH 2) m QR 5; m is 1-6; T is O, S, NR 4, N (O) R 4, NR 4 R 5 W or CR 4 R 5; 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 4 are optionally heteroatoms independently selected from 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 a halogen atom, a hydroxy group, a hydroxyalkyl group, a lower alkyl group, a lower alkoxy group; alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, / trifluoromethyl .... a group, an N-hydroxyacetamide, a group, a trifluoromethyl alkyl 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 10 O 4 R 5, NR 4 R 5 R 9 W, OH, OR 4. the group '' SR4, the halogen atom, the group COR4, the group (CH2) nR4 / group CO2R4, the group CONR4R5, the group C (O) NR4SO2R5; S (O) R 4, SO 2 R 4, SO 2 NR 4 R 5, SO 3 R 4, (CH 2 nP (O) (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; a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a (CH 2) n Ar, an arylalkyl group, an aryl group, a heteroaryl group, a heteroarylalkyl group, a cycloalkyl group, a heterocycloalkyl group, 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 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 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, aminoalkylcarbo -nyl group, trifluoromethyl group, trifluoromethylalkyl group,. trifluoromethyl-alkylaminoalkyl, amino, mono- or dialkylamino; aryl, heteroaryl, carboxyalkyl, NR 10 SO 2 R 11, -C (O) NR 10 R 11, NR 11 C (O) R 11, C (O) OR 10, C (O) NR 10 SO 2 R 11, (CH 2) n S (O) R 10, (CH 2) n -heteroaryl, O (CH 2) n -heteroaryl, -, (CH 2) n C (O) NR 10 R 11, 'O (CH 2 is n C (Ό) OR 10; furthermore, a lower alkyl group may be unsubstituted or substituted with 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-1H-1,2,4-triazol-3-ylsulfinyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulfonyl group, or a carbocyclic group containing from 3 to 7 members, of which 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-hydroxyacetamido, trifluoromethylalkyl, amino or mono - or a dialkylamino group; and and when Y is CR 7, it is part of the structure wherein R 7 and Z are as defined above or together with the carbon atoms to which they are attached form fragments liû; wherein B is NH, S, CH 2 or O; D is a carbon or nitrogen atom with the proviso that R10 is absent when D is a nitrogen atom; R 9 is lower alkyl, haloalkyl or aryl; R 10 and R 11 are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. 5. A compound of formula V and pharmaceutically acceptable salts, esters, amides and pre-drugs thereof; - > wherein R 2 is (a) a hydrogen atom; (b) a lower alkyl group optionally substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl; a thioalkyl group, a nitrile group, an aryl group and a heteroaryl group, or a carbocyclic group .... containing from 3 to 7 members and up to 2 members may optionally be heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or. * = _.... (c) a carbocyclic group containing from 3 to 7 members 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 a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group, a mono- or dialkylamino group, an aryl group and a heteroaryl group; # ·· * f ··· «* > R3 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a lower alkynyl group, a lower alkenyl group, a nitrile group, a nitro group, a group -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 nitrogen 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 4 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 R R 4, -C (O) T (CH 2) m R R 4 or -NR 4 C (O) T (CH 2) m QR 5; is 1 to 6; "is oxygen, sulfur, NR 4, N (O) R 4, NR 4 R 5, or CR 4 R 5; ; " 'S - * .. · .... · ·' _. Q is O, S, NR 4, N (O) R 4, NR 4 R 5 W, CO 2, or a carbocyclic group containing 3 to 7 members, of which 4 are optionally heteroatoms independently selected from the group consisting of O , 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- an alkyl group, a trifluoromethyl group, an N-hydroxyacetamide group, a trifluoromethyl alkyl 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) n R 4, CO 2 R 4, CONR 4 R 5, C (O) NR 4 SO 2 R 5, S (O) R4, SO2R4, SO2NR4R9, SO3R4, (CH2) nP (O) (OR4j2, NR4SO2R5, aldehyde, nitrile, nitro, alkyl, and alkoxyal keel group, T (CH 2) m QR 4, C (O) T (CH 2) m QR 4, NR 4 C (O) T (GH 2) mQR 5 or T (CH 2) mCO 2 R 4, n is 0 to 6; R4 and R5 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (CH2) nAr, arylalkyl, aryl, heteroaryl, heteiroarylalkyl, cycloalkyl, heterocycloalkyl; 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 a 4 are optionally carbonyl groups or heteroatoms independently selected from the group consisting of oxygen, sulfur, S (O), S (O) 2, and nitrogen wherein the carbocyclic group is unsubstituted or substituted by one, two, three, or four independently selected from the group consisting of halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyl, and the like; bonylamino, aminoalkyl group; , aminoalkylcarbonyl, trifluoromethyl, trifluoromethyllalkyl, trifluoromethylalkylaminoalkyl, amino, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, 'NR10SO2R11, C (O) NR10R11; 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 1 ', O (CH 2) n C (O) OR 10; 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-triazol-3-ylsulfanyl 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-ylsulphinyl group, 5-oxo-4,5-dihydro-1 1,2-1,2,4-1riazol-3-ylsulphonyl moiety a group or a carbocyclic group containing from 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 atom-halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamido, trifluoro methylalkyl, amino or mono- or dialkylamino; and R 10 and R 11 are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. 114 6-Bromo-8-cyclopentyl-2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -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); 122 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; - [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (compound 77); No. 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -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-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido (2,3-d] pyrimidine-7 trifluoroacetate -one (Compound 79); A compound according to claim 5, wherein R 7 is selected from the group consisting of ......: . . and wherein these groups are optionally substituted with an alkyl group, an aryl group, or an amide group; R @ 10 and R @ 11 are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. - 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-methyl- | enylamino) -8H-pyrido [2,3-3] 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-propanoyl-piperazin-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); 115 (h) 8- (1-Methylethyl) -5-methyl-2- [4- (4-propanoylpiperazine) 1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 8); (i) 8-cyclohexyl-5-methyl-2- (4-piperazin-1-ylphenylamino) - 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-pyridine) dylphenylamino) -. 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); (m) 8- (1-methylethyl) -5-methyl-2- [4- (3-aminopyrrolidinyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 13); (η) N- (1- {4 - [(8-cyclopentyl-5-methyl-7-oxo (8-hydropyridino- [2,3-d] pyrimidin-2-yl)) amino] phenyl} pyrrolidine 3-ylbutyl amide (compound 14); · · '*; - * (o) N- (i-) - {4 - [(5-methyl-8- (1-methylethyl) -7-oxo (8-hydropyridin-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-piperazinone) 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-phenyl) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 17); 116 116 Λ Φ * Φ “··· φ * 4 8-Cyclopentyl-2- (3,4-dichloro-phenylamino) -5-methyl-8H-pyrido [2,3-d] 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); OR " . 8-isopropyl-5-methyl-2- [4- (4-propionyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (compound 55); -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-1-yl] -phenylamino} -8-cyclohexyl-6-fluoro-5-methyl-8H-pyrido [2,3-d] pyrimidine -7-one (Compound 157); 8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfanyl-methyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 158); ; 8-Cyclopentyl-5-methyl-2- [4- (2H-1,2,4-triazol-3-ylsulfinyl-methyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidine-7- on (Compound 159); in 8-cyclopentyl-5-methyl-2- [4- (2H, 1,2,2,4-triazol-3-ylsulfonyl-4-methyl) phenylamino] -8H-pyrido (2,3-d] pyrimidine-7- on (compound 160); -1,8-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-triazole-3) -ylsulphanyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 162); 131 '8-cyclopentyl-5-methyl-2- {4- [2- (2H-1,2,4-triazole-3-sulfinyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidine- 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-ylsulfanyl]. methyl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one. (Compound 166); 8-cyclopentyl-5-methyl-2- {4- [2- (3H-1,2,3-triazol-4-ylsulfonyl) ethyl] phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 167); 8-cyclopentyl-5-methyl-2- {4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) piperidin-1-yl] phenylamino} -8H- pyrido [2,3-d] pyrimidin-7-one (Compound 168); ·. 8-cyclopentyl-5-methyl-2- {4- [4- (2H-1,2,4-triazol-3-ylsulfonyl) -piperidin-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2 ']; 3-d] pyrimidin-7-one (Compound 169); Δ 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-1-yl] -phenylamino} -8H-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-dihydropyrido [2,3-d] pyrimidin-2-ylamino) phenyl] (1H-tetrazol-5-yl) amide piperidine-4-carboxylic acid (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-4-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-oxadiazol-3-ylmethoxy) phenylamino] -8H-pyrido [2,3-yd] pyrimidin-1-one (compound 176). cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4-triazole-3-sulfinyl) ethyl] piperidin-1-yl} phenylamino) -8H-pyrido [2 3-d] pyrimidin-7-one (Compound 177); 8-Cyclopentyl-5-methyl-2- (4- {4- [2- (2H-1,2,4,4-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} phenyl mino) -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-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 180); 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 3-d] 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 [2,3-d] pyrimidin-7-one (Compound 182); 8-Cyclopentyl-2- {4- [4- (2,2-dioxo-2,3-dihydro-1,2,3,5-oxa-1-yl] -1,4-yloxy) piperidin-1-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-oxathiatriazol-4-yl) piperidin-1-yl phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 184); 8-Cyclopentyl-2- {4- [4- (1,1-dioxo-2,5-dihydro-1'-1,2,3,5-oxathiatriazol-4-yl) piperidin-1-yl] phenyl} amino} - 5-methyl-8H pyrido [2,3-d] pyrimidin-7-one (Compound 185); N- {1- [4- (8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-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) -pyrrolidine- 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 [2,3-d] pyrimidin-7-one (Compound 191); trifluoroacetate 8-cyclopentyl-5-methyl-2- {4- [4- (3-hydroxy-propyl) -piperidine-1-yl] -phenylamino} -8H-pyrido [2,3-d] pyrimidine- 7-one (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); 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-acetyl-piperazin-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] pyrimidine-7-one (compound 200); -5-methyl-6-fluoro-2- [4- (4-acetamidopiperidin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 201); · ·. ·. 8-Cyclopentyl-5-methyl-2- [4- (homopiperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride (Compound 202) ; 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (homopiperazin-1-yl) hydrochloride hydrochloride; phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one. (Compound 203); :. 8-cyclopentyl-5-methyl-6-fluoro-2- [4- (3,3-dimethyl-4-acetylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine-7 on (Compound 204) .; ,. 8-Cyclopentyl-5-methyl-2- [4- (3,3-dimethyl-4-acetyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one - (compound, 205); 8-Cyclopentyl-5-methyl-6-fluoro-2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -8H-pyrido [2 ', trifluoroacetate; 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); 8-Cyclopentyl-5-methyl-2- {4- [2- (2-hydroxy-ethoxy) -ethylamino] -phenylamino} -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 208); E · · ft · ft ft ft ft ft ft ft ft ft ft ft ft ft 9. . m / z 136 8-cyclopentyl-5-methyl-2- [4- (3-oxo-piperazin-1-yl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 209); 8-Cyclopentyl-5-methyl-2- [4- (2-methoxy-ethoxy) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 210); 8-cyclopentyl-5-methyl-2- (9H-carbazol-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 211); 8-cyclopentyl-5-methyl-2- (1H-indazol-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-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-pyridazo [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 211); 8-Cyclopentyl-5-methyl-2- {4- [4- (3-morpholino-propyl) -piperidin-1-yl)] -phenylamino} -8H-pyrido [2,3-d] pyrrolidin-7-trifluoroacetate one (Compound 217); 8-cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 219); 8-cyclopentyl-5-methyl-2- (indol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 220); 131 99 99 9 9 > 9 9 9 999 9 · 9 9 9 9 9 9 »«, _____ · ·, _ ee · - 99 •. > 8,9-cyclopentyl-5-methyl-2- (thionaphthen-5-yl) amino-8H-pyrido [2,3-d] 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-dimethyl-piperazin-1-yl) -methoxy] -phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one ( compound 226), · - · *. 8-Cyclopentyl-2- [4- (3,5-dimethyl-piperazin-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 22 9); 6-chloro-8-cyclopentyl-2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidine-7- on (Compound 230); 18-Cyclopentyl-5-methyl-2- [4- (1H- [1,2,4] triazol-3-ylsulfonyl) -phenylamino] -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 231); ‘4- [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [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); * 44 *. ...... 138 * 44 *. ...... 138 Ή - £ Λ4: »'· > * 8- (1-ethyl-propyl) -5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 234); [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-Dimethyl-piperazin-1-yl) -phenylamino] -8- (1-ethyl-propyl) -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-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -N, N-diethyl-propionamide (compound 239) ; 8-Cyclopentyl-6-fluoro-2- [4- (2-hydroxy-ethyl) -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-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -benzoic acid (Compound 242); 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 243); [4- (8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -benzyl] -phosphonic acid diethyl ester (Compound 244); Ψ * * · * 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 β β β β β β β β fluoro-2- [4- (2-methoxyethylamino) phenyl] η 1 -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 245); (S) -2-Amino-3- [4- (5-cyclopentyl-6-fluoro-5-methyl-4-oxo-8,8-dihydropyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -propionic acid (Compound 246); 8-Cyclopentyl-2- [4- (2-methoxyethoxy] phenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 247); isopropylaminophenylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 248) 8-Cyclopentyl-2- (4-hydroxy-3,5-dimethylphenyl amino) -5 -methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 249) 8-Cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethyl-phenylamino) -5-methyl-8H -pyrido [2,3-d] pyrimidin-7-one (compound 250); 8-cyclopentyl-6-fluoro-2- (4-hydroxy-3,5-dimethyl-phenylamino) -5-methyl-8H-piyrido [2 , 3-d] pyrimidin-7-one (Compound 251). 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) ; • 8-Cyclopentyl-6-fluoro-5-methyl-2- [4- (3 > 3,4-trimethylpiperazin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine-7 -on (Compound 95); "- 6-Bromo-8-cyclopentyl-5-methyl-2- [4,4 '(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] pyrimidine-7- on (compound 98); 2- [4- (4-Acetyl-1-yl) -phenylamino] -6-bromo-8-cyclopentyl-5-methyl-8H-pyridine. ido [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-12,3-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] pyrimidin-7-one (Compound 101); 6-Bromo-8-cyclopentyl-2- {4- [ 4- (2-hydroxyethyl) -3,5-dimethyl-piperazin-1-yl] -phenylamino} -5-methyl-8H-pyrido [2,3-d] pyrimidin-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) ; 8 - Cyclopentyl-5-methyl-2-. [4- (4-methylpiperazin-1-yl) phenyl] amino] -8H) pyrido [2,3,3] pyrimidin-7'-one (Compound 106) ; 8-cyclopentyl-6-fluoro-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyrido D 2; 3-d] pyrimidin-7-one (Compound - 107); . .... . 6-Bromo-8-cyclopentyl-5-methyl-2- [4- (4-methylpiperazin-1-yl) phenylamino] -8H-pyridazo [2,3-d] pyritinidin-7-one (Compound 108) ; . ,. 4 '' - 8-Cyclopentyl-5-methyl-2- [4-f (4-methylperhydro-1,4-diazepin-1-yl) phenylamino] -8H-pyrido [2,3-d] pyrimidine-7 -on (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] pyrimidine-7 -on (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); 126 '{4- [4- (8-Cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1 -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} phenylatino) -8H-pyrido [2,3-d] pyrimidine -7-on (Compound 115); N -cyclopentyl-fluoro-5-methyl-2- (4- {4 '- [3 - (1H-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] piperidine -1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound H8); 'T; " 8-Cyclopentyl-6-fluoro-5-methyl-2- (4- (4- [3- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl-sulfanyl) -propyl] -piperidine -1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (compound H9); 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-triazole) -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) 1 H-1,2,4-triazole-3-sulfinyl) propyl] piperidin-1-yl} phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 123); '' J; r * " '' '' " 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); 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-1H-1,2,4-triazole-3- sulfonyl) propyl-3-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-dihydropyrrolo [2,3-d] pyrimidine-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-dihydropyrrolo [2,3-d] pyrimidin-2-ylamino) phenyl] piperidine-4- yl} propyl) -N-hydroxyacetamide (compound 130); N- (3- {1- [4- (8-cyclopentyl-6-fluoro-5-methyl-7-oxo-7,8-dihydropyridone) [2,3-d] pyrimidin-2-ylamino) phenyl] piperidin-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 piperidin-4-yl] propyl) -N-hydroxyacetamide (Compound 132); 2- (benzofuran-5, -ylamino) -8-cyclopentyl-5-methyl-8H-; pyrido [2,3-d] pyrimidin-7-one (compound 133) 8-Cyclopentyl-2- (1H-indol-5-ylamino) -5-methyl- 8H-pyrido [2,3-d] 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-ylmethyl) -4-methyl-8H-pyrido [2,3-d] 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-27 (4-morpholin-4-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (Compound 140); 8-Cyclopentyl-2- [4- (3,5-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 141); 2- (3-chloro-4-piperazin-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-methyl-piperazin-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); . 8-Cyclopentyl-6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -8H-pyrido [2,3-d] pyrimidin-17-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 [2,3-d] pyrimidin-7-one trifluoroacetate (compound 149); 8-Cyclopentyl-5-methyl-2- [4- (4-2,2,2-trifluoroethyl) piperazin-1-ylphenylamino] -8H-pyrido [2,3-d] pyrimidine- 7-on (compound 150); 8-Cyclopentyl-2- (4-fluoro-phenylamino) -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-6-fluoro-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2 '; 3-d] pyrimidin-7-one (Compound 80); 6-Bromo-8-cyclopentyl-5-methyl-2- {4- [3- (2,2,2-trifluoro-ethylamino) -pyrrolidin-1-yl] -phenylamino} -8H-pyrido [2,3] -d] pyrimidine-: 7-pn (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) ; 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 ); 123 ........ 2- [4- (3-Amino-pyrrolidin-1-yl) -3-chloro-phenylene] -6-bromo-8- cyclopentyl-5-methyl-8H-pyrido [2,3 -d] pyrimidin-7-one (compound 84); 2- [4- (3-Aminomethyl-1,4-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 [2,3-d] pyrimidine-7- on (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-Trifluoroethylaminomethyl-pyrroliidin-1-yl) -phenylamino] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 88; 2- [ 4- (3-Trifluoroethylaminomethylpyrrolidin-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-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one hydrochloride ( compound 91); % • '9 0 6 • · • · 49 9 999 4 Ψ · 4 94 4 4 49 4 4 · · ·· • • • »· 9 4 49 4 4 4 ftt 49 14Ϊ 9. A pharmaceutical composition characterized by. ·· .V. comprising a compound of claim 1 in combination. with a pharmaceutically acceptable carrier, diluent or excipient. A method of 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 mammalian restenosis, comprising administering a therapeutically effective amount of a compound of claim 1 to said mammal. * • * · * Μ · · · · · · · • • • • • • • »» »» »» »» »» »» »» » - * »* · - -; 11. A method for inhibiting a cyclin-dependent kinase, comprising contacting a cyclin-dependent kinase with a compound of claim 1. Wherein G and J are independently CH 2, NH, or oxygen; ‘* B is NH, S, CH 2 or O; D is a carbon or nitrogen atom with the proviso that R10 is absent when D is nitrogen, R9 is lower alkyl, haloalkyl or aryl; 9 99 9 Φ * * * * '4 4 · · · · · · · · · · · · · · · · · · · · 9 9 9 9 9 9 9 9 9 β '" ~ ”** - - -« - = »" " R 10 and R 11 are independently hydrogen, halogen, lower alkyl, lower alkoxy or alkylcarbonyl. ' 12. The method of claim 11, wherein the cyclin dependent kinase is cdk4. 13. A method of inhibiting growth factor-mediated tyrosine kinase comprising contacting a growth factor-mediated kinase with a compound of claims 1. A method according to claim 13, characterized in s e by being named tyrosine. growth factor-mediated kinase is a platelet-derived growth factor (PDGF). 15. The method of claim 13, wherein said growth factor-mediated tyrosine kinase is fibroblast growth factor (FGF). A method of treating a patient suffering from a disease caused by vascular smooth muscle cell proliferation comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 17 *. A method of treating a patient suffering from cancer, comprising; comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 18. 6-Bromo-8-cyclopentyl-2 [4- (3,5-dimethyl-piperazin-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. A compound selected from the group consisting of 8-cyclopentyl-5-methyl-2- (carbazol-3-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 211) ; 8-cyclopentyl-5-methyl-2- (isoindazol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 212); 8-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-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] pyrimidine; -7-one (Compound 218); 8-cyclopentyl-5-methyl-2- (benzofuran-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 219); 8-cyclopentyl-5-methyl-2- (indol-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 220); and 8-cyclopentyl-5-methyl-2- (thionaphthen-5-yl) amino-8H-pyrido [2,3-d] pyrimidin-7-one (Compound 221). ! and