BG106850A - PYRIDO[2,3-d]PYRIMIDINE-2,7-DIAMINE KINASE INHIBITORS - Google Patents

Abstract

The compounds are potent inhibitors of cdk-kinases and growth factor-mediated kinases. They have the general formula wherein R 2, R 7, R 13, R 14 and R 15 are independently hydrogen or (unsubstituted) lower alkyl, (unsubstituted) lower alkenyl, (unsubstituted) lower alkynyl or (unsubstituted) ; R5 is halogen, cyano, nitro, -R9, -NR9R10 or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, (un) substituted lower alkenyl or (un) substituted lower alkynyl; R8 is -CO2R13, -COR13, -CONR13R14, -CSNR13R14, -C (NR13) NR14R15, -SO3R13, -SO2R13, -SO2NR13R14, -PO3R13R14, -POR13R14, -PO (NR13R14) 2; R9 and R10 are independently hydrogen or (un) substituted lower alkyl; R11 is a heteroaryl or heterocyclic group; R12 is a cycloalkyl, heterocyclic, aryl or heteroaryl group and n has the value of 0, 1, 2 or 3. The compounds and their pharmaceutical compositions are used in the treatment of cell proliferative disorders, for example cancer and restenosis.

Description

The invention relates to pyrido [2,3-d] pyrimidine-2,7 diamines, which inhibit cyclin-dependent serine / threonine kinases and growth factor-mediated tyrosine kinase enzymes, and as such are useful for the treatment of cell proliferative diseases and disorders.

BACKGROUND OF THE INVENTION

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

Cycle Research, 1995; 1: 351-363). Typical enzymes include serine / threonine kinases such as cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6, as well as those involved in the regulation of cell cycle tyrosine kinases. Increased activity, or the temporary activation or regulatory anomalies of these kinases, have been shown to lead to the appearance of tumors in humans as well as other proliferative disorders. Compounds that inhibit cdk, either by blocking the interaction between the cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and thus are useful in the treatment of tumors and other abnormal proliferative cells .

Some cdk inhibiting compounds exhibit preclinical antitumor activity. The flavonoid flavopiridol, for example, has been found to be a potent inhibitor of certain types of breast and lung cancer cells. (Kaur et al., J. Natl. Cancer Inst. 1992; 84: 1736-1740; I nt. J. Oncol., 1996; 9: 1143-1168). © The compound has been found to inhibit cdk2 and cdk4.

Olomoucin [2- (hydroxyethylamino) -6-benzylamine-9-methylpyrin] is a potent inhibitor of cdk2 and cdk5 (Vesely et al., Eur. J. Biochem., 1994; 224: 771-786), and has been found to be that it inhibits the proliferation of about 60 different human tumor cell lines used by the National Cancer Institute (NCI) to investigate new cancer treatments (Abraham et al., Biology of the Cell, 1995; 83: 105-120). Later, more potent olomoucin derivative cdk inhibitors of the purvanolol class emerged (Gray N.S. et al. Science, 1998; 281: 533-538).

u Tyrosine kinases play an essential role in the propagation of signal transduction of growth factor leading to cell cycle development, cell proliferation differentiation and migration. Tyrosine kinases comprise cell surface receptor growth factor tyrosine kinases such as FGFr and PDGFr, as well as non-receptor tyrosine kinases including c-Src and lek. Inhibition of these enzymes has been shown to have antitumor and anti-angiogenesis effects (Hamby et al., Pharmacol. Ther., 1999; 82 (2-3): 169-193).

Some pyrido [2,3-0] pyrimidines are known to inhibit cdk and kinase enzymes mediated by growth factor (WO 98/33798). US Patent Nos. 5,733,913 and 5,733,914 describe 6-aryl-pyrido [2,3b] pyrimidines.

Regardless of the progress made, the search for low molecular weight compounds that are orally biologically effective and useful for the treatment of a wide variety of human tumors and other proliferative disorders including restenosis, angiogenesis, diabetic retinopathy, psoriagiasis, and psoriasis atherosclerosis. The present invention provides such compounds, their pharmaceutical compositions, and their use for the treatment of proliferative disorders.

SUMMARY OF THE INVENTION

The present invention provides novel pyrido [2,3b] pyrimidine-2,7-diamino compounds that act as inhibitors of cell-cycle kinases such as cyclin-dependent kinases as well as growth factor-mediated tyrosine kinases. Thus, these compounds are useful for treating cell proliferative disorders such as atherosclerosis and restenosis; cancer; angiogenesis; viral infections including DNA viruses such as herpes, as well as RNA viruses such as HIV; fungal infections; type 1 diabetes, diabetic nephropathy and retinopathy; multiple sclerosis; glomerulonephritis; neurodegenerative diseases, including Alzheimer's disease; autoimmune diseases such as psoriasis, rheumatoid arthritis and lupus; organ transplant rejection and transplant recipient disease; gout; renal polycystitis; and inflammation, including inflammatory bowel disease.

Accordingly, the present invention provides pyrido [2,3-c] pyrimidine, the generic structure of which is shown by Formula I:

HN '

wherein:

R ₂ , R 7, R 13, R 14 and R 15 are independently hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is

optionally substituted by up to 5 groups, independently selected from halogen, cyano, nitro, -Rg, -NR9R10, -ORg, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n SO ₂ Rii, - (CH ₂ ) _n Rn, -COR ₉ , -CONRgR-ιο, -SO3R9, -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -PO3R9R10, -PORgRw, -PO (NRgRio) 2> -NRgCOR-io, -NRgC0 ₂ Rio, -NRgCONRgRw, -NRgS0 ₂ Rio, or heterocycle optionally substituted with up to 3 groups independently selected from -Rg, -NR9R10, -ORg, -NRgCOR-10, -COR10, - (CH ₂ ) _n SO ₂ Rn , - (CH ₂ ) _n R _n , or - (CH ₂ ) _n R ₁₂ , optionally substituted by up to 5 groups, independently selected from halogen, cyano, nitro, -Rg, -NR 9 R 10, -ORg, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n SO ₂ Ri ₁ , - (CH ₂ ) _n Rn, -CORg, -CONRgR-ιο, -SO3R9, -S0 ₂ NRgRio, -SO ₂ R9, -SRg, - PO3R9R10,

-PORgRio, -PO (NR ₉ Rio) ₂ , -NR9COR10, -NRgC0 ₂ Rio, -NRgCONRgRio, -NR9SO2R1O1 or heterocycle optionally substituted by up to 3 groups independently selected from -Rg, -NR ₉ R ₁₀ , -ORg, -NRgCORw, -COR10, - (CH ₂ ) nSO ₂ Rn, - (CH ₂ ) _n Rn;

R ₅ is halogen, cyano, nitro, -R ₈ , -NR ₉ R ₁₀ or -OR _g ;

R ₆ is halogen, cyano, nitro, -Rg, -NRgR ™, -ORg, -CO ₂ Rg, -CORg, -CONR9R10, -NR9COR10, -S0 ₂ NRgR10, -SO ₂ Rg, -SO3R9, -SRg, - PO3R9R10, -POR9R10, -PO (NR ₉ R ₁₀₎ 2, or © lower alkenyl or lower alkynyl optionally substituted with -Rg;

Rg is H, -CO ₂ Ri3, -COR13, -CONR13R-14, -CSNR13R14, -C (NRi3) NRi4Ri5 , -SO3R13, -SO ₂ Ri3, -SO ₂ NRi3Ri4, -PO3R13R14, -POR13R14, -po ( nr ₁₃ Ri ₄ ) ₂ ;

Rg and R10 are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl or taken together with the nitrogen atom to which they are attached, Rg and © R ₁₀ form a 3-7 membered ring, up to four of which?

C 1 -C 4 may be selected from 'O, S and NR ₂ o, wherein R ₂₀ is hydrogen, lower alkyl, or -CO lower alkyl;

R 1 is a heteroaryl or heterocyclic group;

Ri ₂ e cycloalkyl, heterocyclic, aryl or heteroaryl group; η is 0, 1,2 or 3;

and pharmaceutically acceptable salts, esters, amides and prodrugs thereof.

The present invention also provides a composition that includes a compound of Formula I together with a pharmaceutically acceptable carrier, diluent or excipient.

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

The present invention also provides a method of treating subjects suffering from diseases caused by cell proliferation. The method comprises inhibiting the proliferation of tumor cells of epithelial origin and the proliferation of vascular smooth muscle, and / or cell migration, by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment.

The present invention also provides a method of treating subjects suffering from diseases caused by DNA-tumor viruses such as herpes viruses, comprising administering a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are those described with the general Formula I compounds shown above, as well as their pharmaceutically acceptable salts, esters, amides and prodrugs.

In addition to the compounds of Formula I, the invention provides preferred compounds of Formula II:

wherein R 5, R ₆ , R 7 and R 5 are as defined above for Formula I; R-16, R17 and R ₁₈ are as defined above for the substituents (CH ₂ ) _n R 12 and are preferably independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, apkylcarbonyl, -SO3R9, -SO2NR9R10, -SO2R9, -SRg, -PO3R9R10, -POR9R10, -PO (NR ₉ Rio) 2, -NR9COR10, -NRgCR10, -NRgCC -io, -NR9SO2R10; OR

R16 is a carbocyclic group containing from 3 to 7 members, up to two of which are heteroatoms selected from oxygen and nitrogen, in which the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups, as defined above, but for preferably, selected from the group consisting of halogen, hydroxyl,

u.cMk

Compounds of Formula I wherein R 5 is hydrogen or lower alkyl are preferred; R ₆ is hydrogen, lower alkyl, cyano or halogen; R ₁₇ and Rie are each independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, aminocarbonyl, mono- or dialkylaminocarbonyl, -SO2NR9R10 or -NR9COR10; and Ri ₆ is an optionally substituted N-piperidine, N-piperazine or N-pyrrolidine, for instance where the substituents on the ring are selected from -Rg, -NRgR- | 0, -ORg, -NRgCORio and COR10.

In addition, the present invention also provides preferred compounds of Formula III:

R.

HN ^ N ^ N ^ N ^ ²¹

I wherein R 2, R 5 and R 6 are as defined above for Formula I; and

Rig is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups, independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl , aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO3R9, -SO2NR9R10, -SO2R9, SRg, -PO3R9R10, -POR9R10,

-PO (NRgRio) 2. -NRgCORio. -NRgC02Rio. "NR9CONRgRio, -NR9SO2R10, wherein Rg and R ₁₀ are as defined above, or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein any aryl, heteroaryl or cycloalkyl groups is optionally substituted with up to 5 groups independently selected from

halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO3R9, -SO2NR9R10, -SO2R9, -SRR, -SRR,

-PO3R9R10, -POR ₉ R ₁₀ , -PO (NR ₉ Rio) 2, -NR9COR10.

-NR ₉ C0 ₂ Rio, -NR9CONR9R10, -NR ₉ SO ₂ Ri0i or (CH ₂ ) _n -carbocyclic group containing from 3 to 7 members, up to two of which are heteroatoms selected from oxygen and nitrogen, in which the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups, independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkylarylarylarylarylarylarylalkyl , heterocyclylalkyl, heterocyclylsulfonyl or heterocyclylsulfonylalkyl; and

R21 is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl.

Compounds of Formula III are preferred, wherein R ₅ is hydrogen or lower alkyl, R 6 is hydrogen or halogen, R 2 is optionally substituted phenyl; R 21 is hydrogen or methyl; and R 19 is an optionally substituted lower alkyl, cycloalkyl, or (CH ₂ ) _n -carbocyclic group.

A particularly preferred group of pyrido [2,3-d] pyrimidines have

Formula IV:

wherein R ₅ , R ₆ , R ₁₆ , R ₁₇ , R _{81 81} R ₁₉ and R ₂ i are as defined above. Preferred compounds of Formula IV are those wherein R ₂ i is hydrogen or methyl.

Another particularly preferred group of compounds of the invention are Formula V:

wherein R _5, R _6, R _{16, R-i7, R 18i R} ig and R ₂ i are as defined above. Preferred compounds of Formula V are those wherein R ₂ i is hydrogen or methyl.

The most preferred compounds of the invention have Formula VI:

Il I ' ^χ ^ ^Χχ Ι \ ι ^ Ν ^{; ίί} ^' ^χ Ν — H or alkyl

Ri ₇

R ₂₂

HN

I

0 = 0

I

NH

I alkyl or cycloalkyl

VI

A or alkanoyl wherein R 5, R 6, R 17 and R ₁₈ are as defined above, and R ₂₂ and R 23 are independently hydrogen or alkyl.

In the present invention, the terms "alkyl", "lower alkyl" and "(C1-C10) -alkyl" mean straight or branched chain alkyl groups having from 1 to 10 carbon atoms, preferably C1-C6 alkyl. Typical alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, decyl, octyl and 3methylpentyl. These groups may be substituted, for example, by halogen, C1-C3 alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy and the like. Examples include chloromethyl, 2aminoethyl and 3-dimethylaminopropyl.

By "alkenyl", "lower alkenyl" and "(C ₂ -C ₁₀ ) -alkenyl" is meant a straight or branched chain of alkyl groups having from 1 to 10 carbon atoms and 1 or 2 non-adjacent double bonds. Examples of alkenyls include, but are not limited to, 3-butenyl and 1-methyl-3-pentenyl.

By "alkynyl", "lower alkynyl" and "(C2-C10) alkynyl" is meant a straight or branched chain of alkyl groups having from 1 to 10 carbon atoms and a triple bond. Typical alkenyl groups include 2-propynyl and 1,1-dimethyl-3-butynyl. Substituted alkenyl and alkynyl groups include 4,4-dibromo-2-pentenyl and 3amino-5-hexenyl.

In the present invention, the terms "alkoxy", "lower alkoxy" and "(C 1 -C 10) -alkoxy" mean a straight or branched chain of alkoxy groups having from 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, mpem-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

The term "alkanoyl" means an alkyl group bonded via a carbonyl group. Examples include acetyl and pentanoyl. "Aminoalkanoyl" means that the alkyl group is substituted by an amino group. Examples include aminoacetyl and 3-aminohexanoyl. "Alkylaminoalkanoyl" means an aminoalkanoyl group in which the C 1 -C 10 -alkyl group is substituted in the amino group and includes methylaminoacetyl and 4- (isobutylamino) octanoyl. "Dialkylaminoalkanoyl" means a Ν, диза-disubstituted aminoalkanoyl group such as diisopropylaminoacetyl.

By halogen in the present invention are meant fluorine, bromine, chlorine and iodine.

The term "aryl" means an unsubstituted aromatic carbocyclic group with one ring (e.g., phenyl), with more than one ring (e.g., biphenyl), or with more than one fused ring, at least one of which is aromatic (e.g., 1,2, 3,4 tetrahydronaphthyl, naphthyl, anthryl or phenanthryl). The term "substituted aryl" means an aryl group substituted with 1 to 4

substituents selected from alkyl, O-alkyl and S-alkyl, -OH, -SH, -CN, halogen, 1,3-dioxolanyl, -CF ₃ , -NO2, -NH ₂ , -NHCH ₃ , -N (CH ₃ ) 2, -NHCO-alkyl, - (CH ₂ ) mCO ₂ H, - (CH ₂ ) mCO ₂ -alkyl, - (CH ₂ ) mSO ₃ H, -NHalkyl, -H- (alkyl) ₂ , - ( CH ₂ ) mPO ₃ H ₂ , - (CH ₂ ) tPO ₃ (alkyl) ₂₁ - (CH ₂ ) mSO ₂ NH 2, and - (CH 2 -CH 3 -IN-alkyl, where alkyl is defined above, and m is 0, 1, 2 or 3. Some examples of substituted aryl groups are methylphenyl, isopropoxyphenyl, chlorophenyl, 2-bromo-3-fluoromethyl4-nitro-5-aminophenyl, 4-bromobiphenyl, 3-acetamidonaphthyl, 3-dimethylaminoanthryl, 3,4-dimethylethenyl, 3,4-dimethylethenyl, 3,4-dimethylethenyl, 3,4-dimethylethanol 2,8-dibromobiphenylene-1-yl.

By "heteroaryl" is meant one or more aromatic ring systems of 5-, 6- or 7-membered containing at least one to 4 heteroatoms selected from nitrogen, oxygen or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, pyridyl, imidazolyl, pyrazinyl, (iso) quinolinyl, (is) oxazolyl, pyrimidinyl, naphthyridinyl, tetrazolyl, pyrazolyl, phthalimidyl, benzimidazolyl. The "substituted heteroaryl" group may be substituted by 1, 2, 3 or 4 of the groups mentioned above as "substituted aryl" such as 2,3,4,6tetrachloropyridyl and 2-methoxy-3-fluoromethylthien-4-yl.

The term "heterocyclic group" means a non-aromatic ring having a 5-, 6- or 7-atom ring, 1 to 4 of which are selected from nitrogen, oxygen or sulfur. Examples of heterocyclic groups include morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and tetrahydrothienyl groups. These groups may be substituted by groups of the type described above for substituted heteroaryl.

A "carbocyclic group" or "cycloalkyl" is a non-aromatic cyclic ring or fused rings containing from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl and cycloheptyl groups. These rings may be substituted by one or more of the substituents mentioned above in connection with aryl, for example alkyl, halogen, amino, hydroxy and alkoxy. Typical substituted carbocyclic groups include 2chlorocyclopropyl, 2,3-diethoxycyclopentyl and 2,2,4,4tetrafluorocyclohexyl. The carbocyclic group may contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, and such ring systems are referred to as "heterocyclyl" or "heterocyclic". Examples include piperidyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl and dioxanyl. These heterocyclyl groups may be substituted by up to 4 of the substituents mentioned above in connection with aryl to give groups such as 3,5-dimethylpiperazin-1-yl, 3,3 diethylpiperazin-1-yl, 3,3, 4,4-tetramethylpyrrolidinyl, 3-chloro-2-dioxanyl and 3,5-dihydroxymorpholino. They may also have a ketone group, for example 3-ketopiperidyl.

The term "cancer" includes, but is not limited to, the following tumor types: mammary gland tumor, ovary, neck, prostate, testis, esophagus, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung , epidermoid carcinoma, squamous cell carcinoma, adenocarcinoma, bone, colon, adenoma, pancreatic, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, bladder carcinoma, carcinoma carcinoma, myeloid dist oystva, lymphoid disorders, Alzheimer's

Hodgkin, ciliated epithelial cell carcinoma, oral and pharyngeal (oral) cancer, oral, tongue, mouth, pharynx, small intestine, colon, rectum, colon, brain and central nervous system system; and leukemia.

The compounds of Formulas I to IV may exist as pharmaceutically acceptable salts, esters, amides and prodrugs. The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein refers to those carboxylate salts, amino acid salts, esters, amides and prodrugs of the compounds of the present invention that are appropriate, in accordance with reasonable medical judgment , for use in contact with the tissues of patients without excessive toxicity, irritation, allergic reaction and the like, with a reasonable benefit-risk balance, and effective when used as intended, and the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to relatively non-toxic salts of inorganic acids, of organic acids, and of bases with compounds of the above formulas. These salts can be obtained in situ during the final isolation and purification of the compounds, or by a separate interaction between the purified compound, for example in the form of free base, and a suitable organic or inorganic acid, and isolation of the salt thus obtained. Typical salts include hydrobromide, hydrochloride, sulphate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosinate, tosinate, tosinate, tosinate, tosinate , the mesylate, glucoheptonate, lactobionate and lauryl sulfonate salts and the like. When a compound of any of the above formulas has one or more acid groups, it may form a salt upon reaction with a base. These salts may include cations of alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and related, as well as inorganic bases such as ammonium, quaternary ammonium, and other aminocations, including tetramethylammonium, tetraethylammonium, tetraethylammonium, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Pharmaceutical acceptable receptors are well known to those skilled in the field of medical chemistry. (See, e.g., Berge S.M. et al., “Pharmaceutical Salts,” J. Pharm. Sei., 1977; 66: 1-19, incorporated herein by reference.)

Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include C1-C6 alkyl esters in which the alkyl group is a straight or branched chain substituted or unsubstituted hydrocarbon. The esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as benzyl and triphenylmethyl. C 1 -C 4 alkyl esters such as methyl, ethyl, 2,2,2-trichloroethyl and pem-butyl are preferred. Esters of the compounds of the present invention can be prepared by conventional methods, such as by reaction between acid and alcohol.

Examples of pharmaceutically acceptable amides of the compounds of this invention include amides, ammonia derivatives, primary C 1 -C 6 alkylamines, and secondary C 1 -C 6 dialkylamines in which the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing 1 nitrogen atom. Ammonia derivatives, primary C 1 -C 3 alkylamines, and secondary C 1 -C 2 dialkylamines are preferred. Amides of the compounds of the invention can be prepared by conventional methods well known to those skilled in the art of medical chemistry.

The term "prodrug" refers to compounds which in vivo are rapidly converted to a parent compound of the above formula, for example by hydrolysis in blood or gastric juices. A complete review of prodrugs is provided by Higuchi T. and Stella V., "Pro-drugs as Novel Delivery Systems", Vol.14 of the A.C.S. Symposium Series, as in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both publications cited herein for reference.

Table 1 below shows typical compounds of the invention.

I ng »iiiiftiHWWMn« mimammnm)

MM

Table 1 (continued)

Table 1 (continued)

'Ν' N

Table 1 (continued)

Table 1 (continued)

8W £ IH-WH

with ·

II

n

CN OSN ₃ P ^x | Coosn ₃ ld .ϋΑ at ³ HN ^Z tG Chg C | N | dream ₃ 1 SO ₂ CH ₃

πίΜ0

Typical compounds of the present invention within the scope of Formula I include, but are not limited to, the compounds of Table 1 and their pharmaceutically acceptable salts with acids and bases, esters and amides analogs, and prodrugs thereof.

The compounds of the present invention may exist in both solvate and solvate forms, including hydrated forms. Solvate forms, including hydrate forms, are generally equivalent to unsolvated forms, and should be included within the scope of the present invention.

Some of the compounds of Formula I have one or more chiral centers and may thus exist as individual stereoisomers and stereoisomeric mixtures. Other compounds may exist in more than one geometric form. This invention includes all optical and geometric isomers and forms as well as mixtures thereof. The racemic mixtures of the compounds of the invention are readily separated into individual isomers by routine methods such as chromatography, fractional crystallization and classical separation using optically active acids and salts. Individual isomers can also be prepared by chiral synthesis pathways, including chiral hydrogenation and other similar methods using commercially available chiral catalysts.

The compounds of the present invention are useful for the treatment of cancer (eg, leukemia, lung cancer, breast cancer, prostate cancer, skin cancer, eg melanoma) and other proliferative diseases including, but not limited to, psoriasis, HSV, HIV, restenosis and atherosclerosis. To use a compound of the present invention in the treatment of cancer, a cancer patient is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the invention.

A further embodiment of this invention is a method of treating patients suffering from diseases caused by cellular proliferation of the vascular smooth muscle. Compounds of the scope of the present invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method has the effect of inhibiting the proliferation and / or migration of the vascular smooth muscle as a subject in need of treatment is administered an effective amount of a compound of Formula I to VI. In the sense used herein, "subject" and "patient" mean a mammal, such as a human, but also include horses, cattle, sheep, as well as domestic dogs and cats.

The compounds of the present invention can be combined and administered in a wide variety of oral and parenteral dosage forms, including those administered transdermally and rectally. It will be apparent to those skilled in the art that the following dosage forms may contain, as an active ingredient or compound of Formula I, or a pharmaceutically acceptable salt, solvate or solvate of a compound of Formula I, as appropriate.

A further embodiment of this invention is a pharmaceutical composition comprising a compound of Formula I to VI, together with a pharmaceutically acceptable carrier, diluent or excipient. In order to prepare a pharmaceutical composition comprising compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, capsules, suppositories and granules. The solid carrier may consist of one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants or encapsulating material.

In powders, the carrier is a finely ground solid such as talc or starch mixed with a finely divided active ingredient. In tablets, the active ingredient is mixed in a suitable carrier ratio with the required binding properties and compressed to the desired shape and size.

The formulations of this invention preferably contain about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, carboxy methyl cellulose sodium salt, low-melting wax, cocoa butter and the like. A preferred form for oral administration are capsules, which include the formulation of the active compound with the encapsulating material as a capsule carrier, in which the capsule of the active ingredient, with or without other carriers, is surrounded by a carrier which is thus bound thereto. Similarly, soluble-coated capsules and tablets are included. Tablets, powders, capsules, pills, capsules and film-coated tablets may be used as oral dosage forms suitable for oral administration.

For the preparation of suppositories, low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, then the active ingredient is dispersed homogeneously in the melt by stirring. Melted

The SHE homogeneous mixture is then poured into molds of suitable size and allowed to cool and solidify.

Liquid dosage forms include solutions, suspensions and emulsions, such as aqueous solutions or aqueous propylene glycol solutions. Liquid dosage forms for parenteral injection may be formulated in solutions such as aqueous polyethylene glycol, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions for oral administration may be prepared by dissolving the active ingredient in water and adding the desired amount of coloring, flavoring, stabilizing and thickening agents. Aqueous suspensions suitable for oral administration may be formulated as a finely dispersed active ingredient dispersed in water and mixed with a viscous material such as natural or synthetic resins, methylcellulose, carboxymethylcellulose sodium salt or other well-known dispersing agents.

Solid dosage forms intended to be converted to liquid oral dosage forms are also included. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these preparations may contain coloring agents, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solvents and the like. Waxes, polymers, microgranules and the like can be used to prepare sustained release dosage forms. Osmotic pumps may also be used for uniform dosing of the active substance over an extended period.

The pharmaceutical compositions of the invention are preferably in unit dosage forms. In such form, the preparation is divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged preparation, the pack containing separate amounts of the preparation, for example packaged tablets, capsules, as well as powders in vials and ampoules. The unit dosage form may also be a capsule, tablet, capsule or film tablet by itself, or a suitable number of any of the following.

In general, the therapeutic dose of a compound of Formula I will be from about 1 to about 100 mg / kg body weight per day. Typical adult doses will be about 50 to about 800 mg per day. The amount of active ingredient per unit dose of the formulation may be varied or adjusted from about 0.1 to about 500 mg, preferably about 0.5 to 100 mg, depending on the particular administration and potency of the active ingredient. If desired, the composition may also contain other compatible therapeutic agents. In need of treatment with a compound of Formula I, subjects are administered amounts of from about 1 to about 500 mg per day, or in a single dose or in several doses over a 24-hour period.

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

Due to their inhibitory action against cdk and other kinases, the compounds of the present invention are also useful tools in studying the mechanism of action of these kinases, both in vitro and in vivo.

The preparation and use of the compounds of the present invention are further described in the following detailed example. The examples are intended to clarify the specific features of the invention, but not to limit the scope of the specification and the claims in any way. The compounds of the invention are prepared by synthetic methods that are well known to those skilled in the art of organic chemistry and the starting materials and reagents used are commercially available.

In order to avoid undesirable side effects, reactive functional groups of the reaction molecule composition may be blocked during the synthesis of a compound of the invention. Functional groups such as hydroxy, amino and acidic groups are typically blocked with suitable groups that can be easily removed if desired. The use of conventional blocking groups is described in detail by Green and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, New York (2 ^nd Edition, 1991). Typical hydroxyblocking groups include ether-forming groups such as benzyl, as well as aryl groups such as? -Butoxycarbonyl (BOC), formyl and acetyl groups. Aminoblocking groups include benzyl, aryl as acetyl, and trialkylsilyl groups. The carboxyl groups are usually blocked by being converted to an ester that can be easily hydrolyzed, for example trichloroethyl ester, tert-butyl ester, benzyl ester and the like.

As mentioned above, some of the compounds of the invention have one or more chiral centers and can therefore exist as individual optical isomers and geometric isomers, and as mixtures thereof. Compound 106, for example, has two centers of asymmetry and has a cis configuration. This invention encompasses all such geometric isomers, enantiomers and RS racemates, as well as the individual R or S isomers of chiral compounds. All individual isomers and mixtures thereof are included in this invention. Individual isomers are readily prepared by chiral synthesis or by commonly known separation techniques well known to those skilled in the art.

Schemes 1-4 illustrate the preparation of compounds of the present invention. The synthesis of Compound 1 (Example 15) is outlined in Scheme 1; however, it should be appreciated that the general scheme is applicable to all compounds of the invention. Each step shown in the Schemes is further explained in the following detailed examples.

In Scheme 1, 2-methylthio-4-halo-5-alkoxycarbonylpyrimidine is reacted with ammonium hydroxide to give the corresponding 4-amino derivative. The ester is reduced by reaction with L1AIH4 to give the 5hydroxymethyl analogue, which in turn is oxidized to the 5formyl derivative. The 5-formyl group is converted into an unsaturated (acrylate) group which, by cyclization, forms the pyrido [2,3-b] pyrimidine. Pyridopyrimidine is converted into a key intermediate, namely 2-methylsulfanylpyrido [2,3-d] pyrimidin-7-ylamine, which is easily oxidized to 2methylsulfinyl analogue. The 2-methylsulfinyl group is easily displaced by reaction with the amine R2NH2 to give the compound of the invention of Formula I. The 7-amino group of the pyridopyrimidine ring is easily converted to urea by reaction with isocyanate such as RigN = C = O.

Scheme 1

The lettering reagents of Scheme 1 have the following meaning:

(a) NH ₃ ; (b) LiAIH ₄ ; (c) MnO ₂ ; (d) Ph ₃ PCHCO ₂ C ₂ H ₅ ; (f) DBU (diazabicycloundecane); (f) POCI3; (g) NH ₃ ; (h) (±) ~ trans-2 (phenylsulfonyl) -3-phenyloxazyridine; (i) 4- (4-butoxycarbonyl (BOC) -piperidine) aniline; (j) NaH, mpem-butyl isocyanate; (k) HCI

Scheme 2 illustrates an alternative synthesis of pyridopyrimidine having seventh place urea functionality. While such ureas were prepared according to Scheme 1 by reaction between isocyanate and 7-aminopyridopyrimidine, Scheme 2 used carbonyl diimidazole to give intermediate imidazolid. Imidazolid is readily reacted with amine R19NH2 to give the corresponding urea. Scheme 2 illustrates this process by presenting the synthesis of Compound 51, and is more fully described in Example 32.

Scheme 2

ji I

Conditions: (a) NaH, carbonyldiimidazole; (b) cyclopentylamine; (c) HCI

Compounds of Formula I can also be prepared according to Scheme 3, which describes the synthesis of compound 4 (Example 45). The 4-amino-2-methanesulfanylpyrimidine-5-carbox 35 aldehyde is reacted with methylmagnesium bromide to give the corresponding 5- (2-hydroxyethyl) -pyrimidine. The alcohol is oxidized to a methyl ketone analogue. The methyl ketone is reacted with diethyl cyanomethylphosphonate and cyclized to 5-methyl-7 aminopyridopyrimidine. An additional reaction such as that described in Scheme 1 or 2 results in compounds of the invention being compound 4.

Scheme 3

Conditions: (a) CH3MdBr; (B) MnOH; (c) (C2H5O) 2P (O) CH2CN

Compounds of Formula I can also be prepared according to Scheme 4, which shows the synthesis of compound 12 (Example 40). In this scheme, the 2-methylthio group of pyrimidine is first mMM ttMMM oxidized to give the corresponding methylsulfinyl analogue. The methylsulfinyl group is displaced by reaction with amine R2NH2. The 5-carboxaldehyde is then blocked as in Scheme 1 and cyclized to the corresponding 2- (R ₂ NH) -3aMecTeH 7 aminopyridopyrimidine. The 7-amino group is arylated or otherwise blocked, as shown in Schemes 1-3.

Scheme 4

BOC

N

BOC

Conditions: (a) (±) -Trans-2- (phenylsulfonyl) -3-phenyloxazyridine;

(b) 4- (4-BOC-piperidine) aniline; (c) (C2H5O) 2P (O) CH2CN

Any of the compounds of the invention of Formulas I-VI can be prepared according to Schemes 1-4, in which the synthesis of the compounds 1, 51, 4 and 12, respectively, is clarified. The compounds covered by the present invention may have different starting materials, and additional steps may be used as shown in the following typical examples.

All articles and publications in this Annex, including patents, are hereby incorporated by reference.

The invention is further explained by the following detailed examples, which should not be construed as limiting the invention to the scope and spirit of the specific procedures described therein. The starting materials and the various intermediates may be commercially available, commercially available organic compounds, or synthetic methods.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

EXAMPLE 1 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester

To a solution of 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 ml of THF at room temperature was added 25 ml.

triethylamine and then 35 ml of aqueous ammonium hydroxide solution. After stirring at room temperature for 1% hours, an additional 30 ml of aqueous ammonium hydroxide solution was added and stirred for another hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate and hexane were added and the resulting solid was removed by filtration to give 10.84 g (79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.

EXAMPLE 2 (4-Amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol

To a solution of 4-amino-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester (13.36 g, 63 mmol) in 250 ml of THF at room temperature was added a suspension of lithium aluminum hydride (3.82 g, 100 mmol) in 250 ml of tetrahydrofuran. After 30 minutes, the reaction mixture was cooled to 0 ° C and isopropyl alcohol was added thereto to reduce gas evolution. The reaction was quenched by the addition of 15 ml of water, 15 ml of 15% NaOH and 50 ml of water, and the reaction mixture was stirred for 1 hour. The white precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and a 3: 1 hexane: ethyl acetate mixture was added thereto. The solid was separated, washed with 3: 1 hexane: ethyl acetate and then with hexane. The precipitate was dissolved in ethyl acetate and the solution was dried over magnesium sulfate. Filtration and concentration in vacuo afforded 8.14 g (76%) of (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol.

Calculated for C6H9N3OS:

C, 42.09; H, 5.30; N, 24.54. Found: C, 42.31; H, 5.24; N, 24.27.

EXAMPLE 3

4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde

Magnesium oxide (33.13 g, 381 mmol) was added to (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol (8.14 g, 48 mmol) in 1 l of chloroform. The suspension was stirred overnight at room temperature, then filtered through a celite filter and washed with 300 ml of chloroform. The filtrate was concentrated in vacuo to give 8.14 g (quantitative yield) of 4-amino-

2-methanesulfanyl-pyrimidine-5-carboxaldehyde, m.p. Mp 185-187 ° C. According to literature data 183-184 ° C, JOC, 1958; 23: 1738.

Calculated for C6H7N3OS:

C, 42.59; H, 4.17; N, 24.83. Found: C, 42.84; H, 4.21; N, 24.73.

EXAMPLE 4 Ethyl 3- (4-amino-2-methanesulfanyl-pyrimidin-5-yl) acrylate

To a solution of 4-amino-2-methanesulfanyl-pyrimidine-5carboxaldehyde (4.08 g, 24.14 mmol) in 100 ml of THF at room temperature was added (carbethoxymethylene) triphenylphosphorane (10.80 g, 31 mmol). The reaction mixture was refluxed for 3 hours and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography eluting with 1: 1 ethyl acetate: hexane to give 4.30 g (75%) of ethyl 3- (4-amino-2-methanesulfanylpyrimidine-5- s) acrylate; mp: softened at 108 ° C.

Calculated for C ₁ oH ₁₃ N30 ₂ S:

C, 50.19; H, 5.48; N, 17.56. Found: C, 50.22; H, 5.45; N, 17.24.

EXAMPLE 5

2-Methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

To a solution of ethyl 3- (4-amino-2-methanesulfanyl-pyrimidin5-yl) acrylate (368 mg, 1.53 mmol) in 3 ml of N, N-diisopropylethylamine at room temperature was added 380 μl of 1,8-diazabicyclo [ 5.4.0] undec-7-ene. The reaction mixture was refluxed for 3 hours, then cooled to room temperature and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The product fractions were partially concentrated in vacuo and the precipitate filtered to give 134 mg (45%) of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one, m.p. 269-271 ° C. Calculated for C ₈ H7N ₃ OS:

C, 49.73; H, 3.65; N, 21.75. Found: C, 49.67; H, 3.46; N, 21.49.

EXAMPLE 6

7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine

A suspension of 1.0 g (5.2 mmol) of 2-methanesulfanyl-8H-pyrido [2,3f-pyrimidin-7-one (Example 5) in 10 ml of phosphorus oxychloride was refluxed for 1 hour. The resulting solution was cooled and concentrated to give a solid residue,

I which was triturated with cold water and filtered to give 1.05 g of the crude product. Recrystallization from acetonitrile yielded 0.76 g (69%) of the product, m.p. 201-203 ° C. MS (HYAN) M + 1: Calculated 212.0; 212.0 measured.

Calculated for C ₈ H ₆ CliSiN ₃ :

C, 45.39; H, 2.86; N, 19.85. Found: C, 45.53; H, 2.90; N, 19.74.

EXAMPLE 7 © 2-Methylsulfanyl-pyrido [2,3-cC-pyrimidin-7-ylamine

A suspension of 1.0 g (5.2 mmol) of 7-chloro-2-methylsulfanylpyrido [2,3-d] pyrimidine (Example 6) in 200 ml of ammonia-saturated isopropanol was heated at 40 ° C in an airtight container. for 65 hours. The suspension was re-saturated with ammonia and heated for a further 18 hours at 40 ° C. The precipitate was filtered off and triturated with water to give 1.98 g (74.2%) of the product.

mp> 250 ° C.

MS (HYAN) M + 1: Calculated 193.1; Measured 193.0.

Calcd for C8H ₈ N ₄ Si:

C, 49.98; H, 4.19; N, 29.14.

Found: C, 50.14; H, 4.22; N, 29.04.

EXAMPLE 8

2-Methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine

A suspension of 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7ylamine (Example 7) in 300 ml of dichloromethane and 300 ml of methanol was treated with 18.06 g (69.1 mmol) (±) -L? rans-2- (phenylsulfonyl) -3phenyloxazyridine and the mixture was stirred overnight. The suspension was filtered to remove a small amount of precipitate, concentrated to about 25 ml and diluted with ethyl acetate. Filter the precipitate to give 9.27 g (80.5%) of product. M.P. 180 ° C (dec).

MS (HYAN) M + 1: Calculated 209.0; Measured 209.1.

EXAMPLE 9

H ² -phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine

A suspension of 0.44 g (2.1 mmol) of 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 8) and 0.39 ml (4.2 mmol) of aniline in 2 ml of dimethylsulfoxide were heated at 100 ° C overnight. The resulting solution was cooled and poured into water. Ethyl acetate was added to the slurry and the precipitate filtered. The solid was purified by flash chromatography eluting with a gradient of 0% to 20% methanol / dichloromethane for 30 minutes to give 0.14 g (29%) of the product. M.P. Mp 255-260 ° C.

MS (HYAN) M + 1: Calculated 238.1; Measured 238.1.

Calcd for Ci3HnN5O, 18 H ₂ O;

C, 64.92; H, 4.76; N, 29.12. Found: C, 65.26; H, 4.75; N, 28.76.

EXAMPLE 10

1-tert-butyl-3- (2-phenylamino-pyrido [2,3-d] pyrimidin-7-yl) urea

To a ice-cooled solution of 0.1022 g (0.431 mmol) of H ² -phenyl-pyrido [2,3-b] -pyrimidine-2,7-diamine (Example 9) in 2 ml of dimethylformamide was added 0.019 g (0 , 47 mmol) 60% sodium hydride. The resulting solution, cooled in an ice bath, was treated with 0.054 ml (0.47 mmol) of mpem-butyl isocyanate. The solution was stirred cold for 15 minutes, then at room temperature for 1 hour. The solution was poured into an ice bath, the precipitate formed was filtered off and washed with hexane to give 0.0849 g (57.8%) of product (compound 45). M.P. 227 ° C (dec.).

MS (HYAN) M + 1: Calculated 337.2; Measured 337.1.

Calcd for Ci8H ₂ oN60rO, 27 H ₂ O;

C, 63.35; H, 6.07; N, 24.63. Found: C, 63.73; H, 5.82; N, 24.20.

EXAMPLE 11 4- (4-Nitrophenyl) -piperazine-1-carboxylic acid tert-butyl ester

To a suspension of 7.5 g (36 mmol) of 1- (4-nitrophenyl) -piperazine and 6.94 ml (40 mmol) of ethyl-diisopropylamine in 75 ml of dichloromethane were added 8.69 g (40 mmol) of di-tert- butyldicarbonate and the mixture was stirred overnight at room temperature. The resulting solution was washed with saturated aqueous sodium bicarbonate solution, then with water, dried (magnesium sulfate) and concentrated. The resulting material was purified by flash chromatography eluting with a gradient of 10% to 30% ethyl acetate / hexane for 10 minutes to give 8.62 g (77.5%) of product. M.P. 136-140 ° C.

MS (HYAN) M + 1: Calculated 308.2; Measured 308.2.

EXAMPLE 12 4- (4-Aminophenyl) -piperazine-1-carboxylic acid tert-butyl ester

Hydrogen was added to a suspension of 1.46 g (4.8 mmol) of 4 (4-nitrophenyl) -piperazine-1-carboxylic acid tert-butyl ester (Example 11) and 1 g of Raney nickel in 50 ml of tetrahydrofuran. 3.8 bar. Shake the reaction mixture for 14 hours and then filter. The filtrate was concentrated to give 1.29 g (97%) of the product as a solid.

MS (HYAN) M + 1: Calculated 278.2; Measured 422.2. Calculated for C15H23N3O2;

C, 64.96; H, 8.36; N, 15.15.

Found: C, 65.22; H, 8.58; N, 14.58.

EXAMPLE 13 4- [4- (7-Aminopyrido [2,3-b] pyrimidine- tert-butyl ester)

2-ylamino) phenyl] -piperazine-1-carboxylic acid

Substitution of aniline in Example 9 with 4- (4-aminophenyl) -piperazine-1-carboxylic acid tert-butyl ester (Example 12) afforded 0.0744 g (36%) of the product. M.P. 219-220 ° C.

М MS (HYAN) M + 1: Calculated 422.2; Measured 422.2.

Calculated for ¢ 22 ^ 7 ^ 02-0.5 H ₂ O;

C, 61.38; H, 6.56; N, 22.77. Found: C, 61.34; H, 6.30; N, 22.47.

EXAMPLE 14 4- {4- [7- (3-tert-Butylureido) ~ pyrido [2,3-b] pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If Example 10 replaced N, ^2- phenyl-pyrido [2,3-b] -pyrimidine, 2,7-diamine with 4- [4- (7-aminopyrido [2,3c]] pyrimidine-2- ylamino) phenyl] -piperazine-1-carboxylic acid (Example 13) to give 0.3354 g (67.9%) of product (compound 79). M.P. 225 ° C (dec.).

MS (HYAN) M + 1: Calculated 521.3; Measured 521.2.

Calculated for C27H36N8O3;

C, 62.29; H, 6.97; N, 21.52. Found: C, 62.33; H, 6.81; N, 21.43.

EXAMPLE 15

1-tert-butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea

To a suspension of 0.100 g (0.192 mmol) of 4- {4- [7- (3- (1-methyl-7-butylureido) -pyrido [2,3-d] pyrimidin-2-ylamino] phenyl} -piperazine-p-butyl ester- 1-Carboxylic acid (Example 14) in 2 ml of methanol was added 2 ml of 4M hydrochloride / dioxane to give a solution. The suspension was stirred overnight at room temperature and then diluted with diethyl ether. Filter the precipitate to give 0.0941 g (93.4%) of product (compound 1). M.P. 215 ° C (dec.).

MS (HYAN) M + 1: Calculated 421.2; Measured 421.1. Calculated for C22H2sNaOr2.10 NSI, 51 H ₂ O;

C, 50.40; H, 6.37; N, 21.37; CI (total) 14.20. Found: C, 50.40; H, 6.18; N, 21.03; CI (total) 14.33.

EXAMPLE 16 4- {4- [7- (3-Cyclohexylureido) pyrido [2,3-d] pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If, in Example 14, mpem-butylisocyanate is replaced by cyclohexylisocyanate, 0.1463 g (70.4%) of the product (compound 80) is obtained. M.P. 241 ° C (decomposition).

MS (HYAN) M + 1: Calculated 547.3; Measured 547.4.

Calculated for CdHlOrO3-O2 in H ₂ O;

• C, 63.13; H, 7.04; N, 20.31.

Found: C, 63.14; H, 6.81; N, 20.25.

I j EXAMPLE 17

1-Cyclohexyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3b] -pyrimidin-7-yl] -urea

If, in Example 15, 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Cyclohexylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester (Example 16) was obtained 0.0871 g (81.4%) of product (compound 9). M.P. 200 ° C (decomposition).

Calculated for C2H3N3 (OO2.55 HCI-2.82 H ₂ O;

C, 48.83; H, 6.52; N, 18.98; CI (total) 15.31. Found: C, 48.83; H, 6.18; N, 18.89; CI (total) 15.37.

EXAMPLE 18 N- ^2- (4-fluoro-3-methylphenyl) -pyrido [2,3-d] pyrimidine-2,7 diamine

If Example 9 replaced aniline with 4-fluoro-3-methylaniline, 0.2025 g (39.2%) of the product was obtained as a solid.

MS (HYAN) M + 1: Calculated 270.1; Measured 270.0.

EXAMPLE 19

1-tert-6-yl-3- [2- (4-fluoro-3-methylphenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea

If, in Example 10, M ² -phenyl-pyrido [2,3-d] pyrimidine-2,7 diamine is replaced by N ² - (4-fluoro-3-methylphenyl) -pyrido [2,3b] pyrimidine-2, 7-diamine (Example 18) afforded 0.0656 g (47.9%) of product (compound 46). M.P. 230 ° C (dec.).

MS (HYAN) M + 1: Calculated 369.2; Measured 369.1.

Calculated for C-19H21F1 Ν ₆ Οι;

C, 61.94; Η, 5.75; N, 22.81;

Found: C, 61.82; H, 5.73; Ν, 22.75;

EXAMPLE 20

1- (4-chlorophenyl) -3- [2- (4-fluoro-3-methylphenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea

If Example 19 replaced / lre / l-butyl isocyanate with 4-chlorophenylisocyanate, 0.050 g (37%) of the product was obtained (Compound 47). M.P. > 250 ° C.

MS (HYAN) M + 1: Calculated 423.1; Measured 423.1.

Calculated for C21H16F1CI1 Ν ₆ Οι Ό, 23 H ₂ O;

C, 59.07; H, 3.89; Ν, 19.68;

Found: C, 59.09; H, 3.97; Ν, 19.65;

EXAMPLE 21

1- {2- [4- (4-acetylpiperazin-1-yl) -phenylamino] -pyrido [2,3-b] pyrimidin-7-yl} -3-tert-butylurea

To a suspension of 0.145 g (0.277 mmol) of 1-N-tert-butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-b] -pyrimidin-7-yl] -urea (Example 15 ) in 5 ml of dichloromethane are added 0.19 ml (1.11 mmol) of ethyldiisopropylamine. Cool the suspension in an ice bath and add 0.024 ml (0.33 mmol) of acetyl chloride to it. The suspension was stirred overnight at room temperature, then filtered. The precipitate was washed with dichloromethane. The filtrates were combined, washed with water, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane for 30 minutes to give 0.0674 g (51.8%) of product (compound 5). M.P. 206208 ° C (dec.).

MS (HYAN) M + 1: Calculated 463.3; Measured 463.3.

Calculated for C24H30N8O2-0.40 H ₂ O;

C, 61.36; H, 6.61; N, 23.85; Found: C, 61.38; H, 6.37; N, 23.98;

EXAMPLE 22 4- {4- [7- (3-Isopropylureido) pyrido [2,3-b] -pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If, in Example 14, mpem-butylisocyanate is replaced by isopropylisocyanate, 0.909 g (69.9%) of a solid is obtained. MS (HYAN) M + 1: Calculated 507.3; Measured 507.4.

EXAMPLE 23

1-Isopropyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -urea

If, in Example 15, 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Isopropylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester gave 0.0287 g (27, 9%) of the product (compound 48). M.P. 190 ° C (dec.).

MS (HYAN) M + 1: Calculated 407.2; Measured 407.1.

Calculated for C21H26N8O1 -2.05 TFA-0.84 H2O;

C, 46.00; H, 4.57; N, 17.10; Found: C, 46.00; H, 4.65; N, 17.09;

EXAMPLE 24 Cis-3,5-dimethyl-1- (4-nitrophenyl) -piperazine

A suspension of 6.47 g (47.8 mmol) of 4-fluoronitrobenzene and 10.91 g (95.5 mmol) of cis-2,6-dimethylpiperazine was heated at 45 ° C for 1 hour. The reaction mixture was cooled and shaken with dichloromethane and water. The organic layer was dried (magnesium sulfate) and concentrated to give 11.62 g (> 100%) of a solid.

EXAMPLE 25 Cis-2,6-Dimethyl-4- (4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

If, in Example 11, 1- (4-nitrophenyl) -piperazine is replaced by cis 3,5-dimethyl-1- (4-nitrophenyl) -piperazine (Example 24), 14.87 g (92.8%) of a solid are obtained.

EXAMPLE 26 4- (4-Aminophenyl) -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If in Example 12 4- (4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester is replaced by N-cis-2,6-dimethyl-4- (4-nitrophenyl) -piperazine-1-carboxylic tert-butyl ester acid (Example 25) gave 5.03 g (64.7%) of solid.

EXAMPLE 27 4- [4- (7-Aminopyrido [2,3-b] -pyrimidin-2ylamino) -phenyl] -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If Example 9 replaced aniline with 4- (4-aminophenyl) -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Example 26), 0.6463 g (59.8%) of product was obtained. M.P. 245 ° C (decomp.).

I MS (HYAN) M + 1: Calculated 450.3; Measured 450.3.

ί ί

sj EXAMPLE 28 4- {4- [7- (3-tert-butypureido) pyrido [2,3-b] -pyrimidin-2-ylamino] -phenyl} -cis-2,6 tert-butyl ester; dimethylpiperazine-1-carboxylic acid If, in Example 10, M ² -phenyl-pyrido [2,3-d] pyrimidine-2,7j diamine is replaced by 4- [4- (7-aminopyrido [2, tert-butyl ester]]. 3-Cl] Pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethylpiperazine-151 carboxylic acid (Example 27) afforded 0.1828 g (74.9%) of solid.

MS (HYAN) M + 1: Calculated 549.3; Measured 549.4.

EXAMPLE 29

1-tert-butyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea

If in Example 15 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-tert-butylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] phenyl} -cis-2,6-dimethylpiperazine-1-carboxylic tert-butyl ester acid (Example 28) gave 0.0910 g (92.9%) of the product (compound 49). M.P. 245 ° C (dec.).

MS (HYAN) M + 1: Calculated 449.3; Measured 449.2.

EXAMPLE 30 4- {4- [7- (3-Cyclohexylureido) -pyrido [2,3b] -pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If, in Example 28, mpem-butylisocyanate is replaced by cyclohexylisocyanate, 0.1156 g (60.6%) of a solid is obtained. MS (HYAN) M + 1: Calculated 575.3; Measured 575.3.

EXAMPLE 31

1-cyclohexyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-b] pyrimidin-7-yl} -urea

If in Example 15 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Cyclohexylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] phenyl} -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Example 30) gave 0.1022 g of the product (compound 50). M.P. 228 ° C (dec.).

MS (HYAN) M + 1: Calculated 475.2; Measured 475.2.

tert-butyl ester on

EXAMPLE 32 a 4- {4- [7- (3-cyclopentylureido) -

pyrido [2,3-d] -nupro n-2-ylamino] -phenyl} -piperazine-1-carboxylic acid

A solution of 0.150 g (0.36 mmol) of 4- [4- (7-aminopyrido [2,3-d] pyrimidin-2ylamino) phenyl] -piperazine-1-carboxylic acid solution was cooled in an ice bath. (Example 13) in 2 ml of dimethylformamide were added 0.022 g (0.54 mmol) of 60% sodium hydride. The cooled solution was stirred for 15 minutes, then 0.088 g (0.54 mmol) of carbonyldiimidazole were added. The cooled solution was stirred for a further 30 minutes and 0.071 mL (0.72 mmol) of cyclopentylamine was added thereto. The resulting solution was stirred at room temperature for 1 hour and then poured into cold water. Filtered sludge is the first part of the crop. The filtrate was extracted with dichloromethane, the extract was dried (magnesium sulphate) and concentrated after the second portion of the yield. The two portions were collected and purified by flash chromatography eluting with a gradient of 0% to 5% with methanol / dichloromethane over 30 minutes to give 0.1159 g (60.4%) of the product as a solid substance.

MS (HYAN) M + 1: Calculated 533.3; Measured 533.4.

EXAMPLE 33

1-Cyclopentyl-3- [2- (4-piperazin-1-yl) -phenylamino) pyrido [2,3-d] -pyrimidin-7-yl] -urea

If, in Example 15, 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Cyclopentylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] phenyl} -piperazine-1-carboxylic acid tert-butyl ester (Example 32) gave 0 , 0937 g (80.8%) of the product (compound 51). M.P. 210213 ° C (dec.).

MS (HYAN) M + 1: Calculated 433.2; Measured 433.2.

Calculated for C23H28N8O1 -2.49 HCl-1.65 Η2θ · 0.1 dioxane;

C, 50.02; H, 6.21; Ν, 19.94; CI (total), 15.71 Found: C, 49.89; H, 5.81; Ν, 19.74; CI (total), 14.74

EXAMPLE 34

1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanol

To a ice-cooled suspension of 5.0 g (29 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150 ml of THF over 20 minutes was added 23.2 ml of a 3.0 M solution. of methylmagnesium bromide in diethyl ether (69.4 mmol). After 1 hour at 0 ° C, an additional 23.2 ml of 3.0 M methyl magnesium bromide solution was added, the suspension was allowed to reach room temperature and stirred overnight. The reaction was quenched by the addition of 100 ml of saturated aqueous ammonium chloride solution and the mixture partitioned between water and ethyl acetate. The organic layer was dried (magnesium sulfate) and concentrated to give 5.24 g (96%) of the product. M.P. 140-142 ° C.

MS (HYAN) M + 1: Calculated 186.1; Measured 185.9.

EXAMPLE 35

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

If in Example 3 (4-amino-2-methylsulfanyl-pyrimidin-5-yl) methanol is replaced by 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) ethanol (Example 34), and the reaction is carried out at 80 ° C in toluene medium, 3.74 g (72%) of solid were obtained.

MS (HYAN) M + 1: Calculated 184.0; Measured 183.9.

EXAMPLE 36

1- (4-Amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone

If in Example 8 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7ylamine is replaced by 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) ethanone (Example 35), 9 is obtained. 57 g (88%) solid.

MS (HYAN) M + 1: Calculated 200.0; Measured 200.0.

EXAMPLE 37 4- [4- (5-Acetyl-4-aminopyrimidin-2ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Replacing 2-methanesulfinyl-pyrido [2,3-0] pyrimidin-7-ylamine with 1- (4-amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone (Example 36) gives Example 4.04 d (65%) solid. MS (HYAN) M + 1: Calculated 413.0; Measured 413.0.

EXAMPLE 38 4- [4- (7-Amino-5-methylpyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

To a suspension of 0.58 g (14.6 mmol) of 60% sodium hydride in 10 ml of tetrahydrofuran at 0 ° C was added 2.58 g (14.56 mmol) of diethyl (cyanomethyl) phosphonate. The reaction mixture was stirred for 5 minutes at 0 ° C, then at room temperature for 20 minutes. The mixture was cooled to 0 ° C and 2 g (4.85 mmol) of 4- [4 (5-acetyl-4-aminopyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid (2 g (4.85 mmol) was added thereto ( Example 37). The mixture was stirred overnight at room temperature and then treated with water and saturated aqueous ammonium chloride solution. The precipitate was filtered off and washed with ether to give 1.069 g (80%) MS (HYAN) M + 1: Calculated 436.0; Measured 436.0.

EXAMPLE 39 4- {4- [7- (3-Cyclohexylureido) -5-methyl-pyrido [2,3-d] -nup-yl-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If in Example 16 4- (4- (7-aminopyrido [2,3-d] pyrimidin-2-ylamino) phenyl] -piperazine-1-carboxylic acid methyl-butyl ester is replaced by 4- (4- ( 7amino-5-methylpyrido [2,3-d-pyrimidin-2-ylamino) -phenyl] piperazine-1-carboxylic acid (Example 38) gave 0.199 g (42%) of a solid.

MS (HYAN) M + 1: Calculated 561.0; Measured 561.0.

EXAMPLE 40

1-Cyclohexyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) pyrido [2,3-d] pyrimidin-7-yl] urea

If in Example 15 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by tert-butyl ester on

4- {4- [7- (3-cyclohexylureido) -5-methylpyrido [2,3-d] pyrimidin-2ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 39) the product (compound 12) was obtained in solid state.

F mp 238 ° C (dec.).

MS (HYAN) M + 1: Calculated 461; Measured 461.

EXAMPLE 41

5-methyl-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine

If, in Example 38, 4- [4- (5-acetyl-4-aminopyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester is replaced by 1- (4-amino-2-methylsulfanyl-pyrimidine- 5yl) -ethanone (Example 35) yielded 0.97 g (85%) of the solid product.

М MS (HYAN) M + 1: Calculated 207; Measured 207.

EXAMPLE 42

5-Methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-ylamine

If in Example 8 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine is replaced by 5-methyl-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 41) 0.85 g (83%) of the solid product.

MS (HYAN) M + 1: Calculated 223; Measured 223.

EXAMPLE 43 4- [4- (7-Amino-5-methylpyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

If in Example 13 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine is replaced by 2-methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 42) 0.33 g (20%) of the solid product are obtained.

MS (HYAN) M + 1: Calculated 436; Measured 436.

EXAMPLE 44 4- {4- [7- (3-tert-Butylureido) -5-methylpyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If, in Example 10, the ^2- phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine is replaced by 4- [4- (7-amino-5-methyl-pyrido [2,3-d]] - tert-butyl ester. Pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid (Example 43) afforded 0.17 g (45%) of the solid product.

MS (HYAN) M + 1: Calculated 535; Measured 535.

EXAMPLE 45

1-tert-butyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] -pyrimidin-7-yl] -urea

If, in Example 15, 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid methyl-butyl ester is replaced by 4- {4- [7- (3-tert-Butylureido) -5-methyl-pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester (Example 44) gave 0.070 g (72%) of the product (compound 4) in the solid state. M.P. 230-232 ° C (dec.).

MS (HYAN) M + 1: Calculated 435; Measured 435.

EXAMPLE 46

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

To a cooled to -78 ° C solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl) -fluoroacetic acid ethyl ester in 20 ml of tetrahydrofuran was added dropwise 12.9 ml (20.65 mmol) of a 1.6 M solution. of n-butyllithium in hexane. After stirring for 30 minutes at -78 ° C, 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) were added to the solution, the solution was allowed to reach room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous ammonium chloride solution and then with water. The precipitate was filtered off and washed with diethyl ether to give 2.01 g (92%) of the product.

MS (HYAN) M + 1: Calculated 212; 212 measured.

EXAMPLE 47

7-chloro-6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine

If in Example 6 2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one is replaced by 6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 46) yield 1.86 g (85%) of the solid product.

MS (HYAN) M + 1: Calculated 230, 232; Measured 230, 232.

EXAMPLE 48

6-fluoro-2-methylsulfanyl-pyrido [2,3-b] pyrimidin-7-ylamine

If in Example 7 7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine is replaced by 7-chloro-6-fluoro-2-methylsulfanylpyrido [2,3-d] pyrimidine (Example 47) 0.29 g (90%) of the solid product.

MS (HYAN) M + 1: Calculated 211; Measured 211.

EXAMPLE 49 6-Fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine

If in Example 8 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine is replaced by 6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 48) 0.26 g (95%) of the solid product.

MS (HYAN) M + 1: Calculated 227; Measured 227.

EXAMPLE 50 4- [4 '(7-Amino-6-fluoro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethylpiperazine-1 H carboxylic acid tert-butyl ester

If Example 27 replaces 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine with 6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 49) received 0.040 g (63%) of the solid product.

MS (HYAN) M + 1: Calculated 468; Measured 468.

EXAMPLE 51 4- {4- [7- (3-Cyclohexylureido) -6-fluoropyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethylpiperazin-1 tert-butyl ester -carboxylic acid

If in Example 16 4- [4- (7-aminopyrido [2,3C] -pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- [ 4- (7-amino-6-fluoro-pyrido [2,3C] -pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethylpiperazine-1-carboxylic acid (Example 50) gave 0.10 g ( 74%) of the solid product.

MS (HYAN) M + 1: Calculated 593; Measured 593.

EXAMPLE 52

1-cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-fluoro-pyrido [2,3-d] -pyrimidin-7-yl} -urea

If in Example 15 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Cyclohexylureido) -6-fluoro-pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-piperazine tert-butyl ester- 1-Carboxylic acid (Example 51) afforded 0.060 g (75%) of the product (compound 52) in the solid state. M.P. Mp 227-229 ° C.

MS (HYAN) M + 1: Calculated 493; Measured 493.

EXAMPLE 53 4- {4- [7- (3-Cyclopentylureido) -5-methylpyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If in Example 32 4- [4- (7-Aminopyrido [2,3-d] -pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- [4 - (7amino-5-methylpyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] piperazine-1-carboxylic acid (Example 43) gave 0.18 g (55%) of the solid product .

MS (HYAN) M + 1: Calculated 547; 547 measured.

EXAMPLE 54

1-Cyclopentyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] urea

If in Example 15 4- {4- [7- (3-Pembutylureido) -pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} piperazine-1-carboxylic acid tert-butyl ester is replaced by 4- {4- [7- (3-Cyclopentylureido) -5-methyl-pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester (Example 53) received 0.08 g (70%) of the product (compound 53) in the solid state. M.P. 234 ° C (dec.).

MS (HYAN) M + 1: Calculated 447; Measured 447.

EXAMPLE 55 4- (4- {7- [3- (3-Hydroxypropyl) -ureido] pyrido [2,3-b] -pyrimidin-2-ylamino} -phenyl) -piperazine-1-carboxylic acid tert-butyl ester

If Example 32 replaced cyclopentylamine with 3-amino-1-propanol, and sodium hydride with sodium pem-butoxide, 0.1295 g (52.2%) of the solid product was obtained.

MS (HYAN) M + 1: Calculated 532.3; Measured 523.2.

EXAMPLE 56

1- (3-hydroxypropyl) -3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] -nup imidin-7-yl] -urea

If the product of Example 55 is replaced in Example 15, 0.1077 g of the product (compound 81) is obtained in the solid state. M.P. 183 ° C (dec.).

MS (HYAN) M + 1: Calculated 423.2; Measured 423.1.

EXAMPLE 57 4- {4- [7- (3-Cyclohexyl-3-methylureido) pyrido [2,3-b] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If, in Example 55, 3-amino-1-propanol is replaced by Nmethylcyclohexylamine, 0.1932 g (72.7%) of the solid product are obtained.

MS (HYAN) M + 1: Calculated 561.3; Measured 561.2.

EXAMPLE 58

1-Cyclohexyl-1-methyl) -3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea

If the product of Example 57 is replaced in Example 15, 0.1645 g of the product (compound 65) is obtained in the solid state. M.P. 177 ° C (dec.).

MS (HYAN) M + 1: Calculated 461.3; Measured 461.2.

EXAMPLE 59 4- (4- {7- [3 - (((S) -1-hydroxymethyl-3methylbutyl) -ureido] -pyrido [2,3-b] -pyrimidin-2-ylamino} phenyl) tert-butyl ester) - piperazine-1-carboxylic acid

If, in Example 55, 3-amino-1-propanol is replaced by (S) - (+) leucinol, 0.1048 g (39.1%) of the solid product is obtained.

MS (HYAN) M + 1: Calculated 565.3; Measured 565.3.

EXAMPLE 60

1- ((S) -1-hydroxymethyl-3-methylbutyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-b] pyrimidin-7-yl] - urea

If the product of Example 59 is replaced in Example 15, 0.0802 g of the product (compound 83) is obtained in the solid state. M.P. 185 ° C (dec.).

MS (HYAN) M + 1: Calculated 465.3; Measured 465.2.

EXAMPLE 61 4- [4- (7 - {[1- (methylpiperazin-1-yl) methanoyl] -amino} -pyrido [2,3-b] -pyrimidin-2-ylamino) phenyl] -piperazine tert-butyl ester- 1-carboxylic acid

If, in Example 55, 3-amino-1-propanol is replaced by Nmethylpiperazine, the product is solid.

MS (HYAN) M + 1: Calculated 548.3; Measured 548.3.

EXAMPLE 4-Methylpiperazine carboxylic acid [2- (4-piperazin-7-yl-phenylamino) -pyrido [2,3-d] -nup imidin-7-yl] -amide

If Example 15 replaces the product of Example 61, 0.1194 g of the product (compound 84) is obtained in the solid state. M.P. 200 ° C (decomposition).

MS (HYAN) M + 1: Calculated 448.3; Measured 448.2.

EXAMPLE 63 4- (4- {7 - [(1-morpholin-4-yl-methanoyl) amino] -pyrido [2,3-b] -pyrimidin-2-ylamino} -phenyl) -piperazine tert-butyl ester-

1-carboxylic acid

If Example 55 replaced 3-amino-1-propanol with morpholine, the product was obtained in the solid state.

MS (HYAN) M + 1: Calculated 535.3; Measured 535.2.

EXAMPLE 64 Morpholine-4-carboxylic acid [2- (4-piperazin-1-yl-phenylamino) -pyrido [2 _g 3-6] -pyrimidin-7-yl] -amide

If Example 15 replaces the product of Example 63, 0.1132 g of the product (compound 85) is obtained in the solid state. M.P. 190 ° C (dec.).

MS (HYAN) M + 1: Calculated 435.2; Measured 435.2.

EXAMPLE 65 4- {4- [7- (3,3-Dipropylureido) -pyrido [2,3c] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If, in Example 55, 3-amino-1-propanol is replaced by dipropylamine, the product is solid. MS (HYAN) M + 1: Calculated 549.3; Measured 549.3.

EXAMPLE 66

3- [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -1,1-dipropylurea

If Example 15 replaces the product of Example 65, 0.1288 g of the product (compound 86) is obtained in the solid state. M.P. 190 ° C (dec.).

MS (HYAN) M + 1: Calculated 449.3; Measured 449.3.

EXAMPLE 67 4- [4- (7 - {[1- (4-Box-piperazin-1-yl) methanoyl] -amino} -pyrido [2,3-b] -pyrimidin-2-ylamino) phenyl tert-butyl ester ] -piperazine-1-carboxylic acid

If, in Example 55, 3-amino-1-propanol is replaced with boxpiperazine, the product is solid.

MS (HYAN) M + 1: Calculated 634.3; Measured 634.3.

EXAMPLE 68 Piperazine-1-carboxylic acid [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] -pyrimidin-7-yl] -amide

If the product of Example 67 is replaced by Example 15, 0.0342 g of the product (compound 87) is obtained in the solid state. M.P. 220 ° C (dec.).

MS (HYAN) M + 1: Calculated 434.2; Measured 434.2.

EXAMPLE 69 4- (4- {7- [3 ((R) -1-hydroxymethyl-2methylpropyl) -ureido] -pyrido [2,3-b] -pyrimidin-2-ylamino} phenyl) -piperazine tert-butyl ester -1-carboxylic acid

If, in Example 55, 3-amino-1-propanol is replaced by (P) -valinol the product is obtained in the solid state.

MS (HYAN) M + 1: Calculated 551.3; Measured 551.3.

EXAMPLE 70

1 - ((R) -1-hydroxymethyl-2-methylpropyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -urea

If the product of Example 69 is replaced by Example 15, 0.0639 g of the product (compound 88) is obtained in the solid state. M.P. 200 ° C (decomposition).

MS (HYAN) M + 1: Calculated 451.3; Measured 451.2.

EXAMPLE 71 4- (4- {7- [3,3-Bis- (2-hydroxyethyl) -ureido] pyrido [2,3-b] -pyrimidin-2-ylamino} -phenyl) -piperazine tert-butyl ester- 1carboxylic acid

If, in Example 55, 3-amino-1-propanol is replaced by diethanolamine, the product is obtained in the solid state. MS (HYAN) M + 1: Calculated 553.3; Measured 553.2.

EXAMPLE 72

1,1-bis- (1-hydroxyethyl) -3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea

If the product of Example 69 is replaced in Example 15, 0.0916 g of the product (compound 89) is obtained in the solid state. M.P. 185 ° C (dec.).

MS (HYAN) M + 1: Calculated 453.2; Measured 453.2.

EXAMPLE 73

6-bromo-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

5.00 g (28.1 mmol) of N was added to 5.00 g (25.9 mmol) of 2-methanesulfanyl-8H-pyrido [2,3c] pyrimidin-7-one (Example 5) in 130 ml of dimethylformamide. -bromosuccinimide. The resulting suspension was stirred overnight at room temperature and then concentrated. The precipitate was triturated with hot water, then washed with isopropanol to give 5.59 g (79.4%) of the solid product. M.P. 266-270 ° C.

EXAMPLE 74

6-bromo-7-chloro-2-methylsulfanylpyrido [2,3-d] pyrimidine

Substituting the product of Example 73 in Example 6 yields 2.73 g (97.2%) of the solid product.

MS (HYAN) M + 1: Calculated 289.9; Measured 289.8.

EXAMPLE 75

6-bromo-2-methylsulfanylpyrido [2,3-b] pyrimidin-7-ylamine

Substituting the product of Example 74 in Example 7 yields 2.09 g (82.9%) of the solid product.

MS (HYAN) M + 1: Calculated 270.1; Measured 270.8.

EXAMPLE 76

6-bromo-2-methanesulfinylpyrido [2,3-d] pyrimidin-7-ylamine

Replacing the product of Example 75 with Example 8 yields 1.81 g (81.9%) of the solid product. M.P. 245 ° C (dec.).

MS (HYAN) M + 1: Calculated 287.0; Measured 286.8.

EXAMPLE 77 4- [4- (7-Amino-6-bromopyrido [2,3-b] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 76 in Example 13 yields 1.40 g (44.4%) of the solid product. MS (HYAN) M + 1: Calculated 500.1; Measured 500.0.

EXAMPLE 78 4- {4 [6-Bromo-7- (3-cyclohexylureido) pyrido [2,3-b] -pyrimidin-2-ylamino] -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 77 in Example 16 yielded 0.1160 g (46.4%) of the solid product. MS (HYAN) M + 1: Calculated 625.2; Measured 625.1.

EXAMPLE 79

1- [6-bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-cyclohexylurea

Substituting the product of Example 78 in Example 15 yields 0.0886 g (77.0%) of the product (compound 55) in the solid state. M.P. 195 ° C (dec.).

MS (HYAN) M + 1: Calculated 525.2; Measured 525.1.

Calcd for C24H ₂ gBriN ₈ 0i Ί, 64 H ₂ O-1,83 HCI;

C, 46.37; H, 5.53; N, 18.02; CI, 10.44.

Found: C, 46.53; H, 5.34; N, 17.73; CI, 10.15.

EXAMPLE 80 4- {4- [6-Bromo-7- (3-tert-butylureido) pyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 77 into Example 10 yielded 0.2571 g (42.9%) of the solid product.

MS (HYAN) M + 1: Calculated 599.2; Measured 599.2.

EXAMPLE 81

1- [6-bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -3-tert-butylurea

If the product of Example 80 is replaced in Example 15, 0.0481 g of the product (compound 91) is obtained in the solid state. MS (HYAN) M + 1: Calculated 499.2; Measured 499.0.

EXAMPLE 82 4- {4- [6-Bromo-7- (3-methylureido) pyrido [2,3-d] -pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 77 and methylamine in Example 32 yielded 0.170 g (29.9%) of the solid product. MS (HYAN) M + 1: Calculated 557.2; Measured 557.1.

EXAMPLE 83

1- [6-bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-methylurea

Substituting the product of Example 82 in Example 15 yields 0.0963 g (69%) of the product (compound 93) in the solid state.

MS (HYAN) M + 1: Calculated 457.1; Measured 457.1.

Calculated for C19H21 Br-ιNsOi · 3 HCl-3 H2O;

C, 36.76; H, 4.87; N, 18.05; Cl, 17.13; H ₂ O, 8.71.

Found: C, 36.49; H, 4.35; N, 17.52; Cl, 15.79; H ₂ O, 8.12.

EXAMPLE 84 4- [4- (7-Amino-6-bromopyrido [2,3-c-pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 76 in Example 27 yields 2.10 g (63.1%) of the solid product. MS (HYAN) M + 1: Calculated 528.2; Measured 528.2.

EXAMPLE 85 4- {4- [6-Bromo-7- (3-tert-butylureido) pyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethylpiperazine tert-butyl ester - 1-carboxylic acid

Substituting the product of Example 84 in Example 10 yields 0.1725 g (72.6%) of the solid product. MS (HYAN) M + 1: Calculated 627.2; Measured 627.2.

EXAMPLE 86

1- {6-bromo-2- [4- (cis-3,5-dimethylpiperazin-1-yl) -phenylamino] pyrido [2,3-d] -pyrimidin-7-yl} -3-tert-butylurea

Substituting the product of Example 85 in Example 15 gave 0.1593 g (96.0%) of the product (compound 94) in the solid state. M.P. 202 ° C (dec.).

MS (HYAN) M + 1: Calculated 527.2; Measured 527.2.

Calcd for C24H3iBr- | N ₈ 0i -2,55 NSI, 70 H ₂ O;

C, 44.28; H, 5.72; N, 17.21; CI, 13.89.

Found: C, 44.28; H, 5.72; N, 17.09; CI, 12.49.

EXAMPLE 87 4- {4- [6-Bromo-7- (3-cyclohexylureido) ~ pyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethylpiperazin-1 tert-butyl ester -carboxylic acid

Substituting the product of Example 84 in Example 16 yields 0.1750 g (70.7%) of the solid product. MS (HYAN) M + 1: Calculated 653.3; Measured 653.3.

EXAMPLE 88

1- {6-bromo-2- [4- (cis-3,5-dimethylpiperazin-1-yl) -phenylamino] pyrido [2,3-b] pyrimidin-7-yl} -3-cyclohexylurea

If the product of Example 87 is replaced by Example 15, 0.1614 g (95.4%) of the product (compound 95) is obtained in the solid state. M.P. 198 ° C (dec.).

MS (HYAN) M + 1: Calculated 553.2; Measured 553.2.

Calcd for S2vNzzM ₈ O1Vgg2,76 NS1-2,02 H ₂ O;

C, 45.22; H, 5.81; N, 16.23; CI, 14.17.

Found: C, 45.23; H, 5.82; N, 16.08; CI, 13.53.

EXAMPLE 89

N ² - (4-fluorophenyl) -pyrido [2,3-b] -pyrimidine-2,7-diamine

Substituting 4-fluoroaniline in Example 9 gave 1.1529 g (45.2%) of the solid product. M.P. 245-248 ° C.

MS (HYAN) M + 1: Calculated 256.1; Measured 255.9.

EXAMPLE 90

1- [2- (4 ~ Fluorophenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (3morpholin-4-ylpropyl) -urea

If the product of Example 89 and 3-morpholin-4-ylpropylamine are substituted in Example 32, 0.1465 g (58.6%) of the product (compound 96) is obtained in the solid state. M.P. 253-256 ° C. MS (HYAN) M + 1: Calculated 426.2; Measured 426.1.

Calculated for C21H24F1N7O2;

C, 59.28; H, 5.69; N, 23.04. Found: C, 59.18; H, 5.66; N, 23.04.

EXAMPLE 91

N 1- [2- (4-fluorophenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxyethyl) urea

If the product of Example 89 and 2-hydroxyethylamine are replaced in Example 32, 0.0811 g (40.3%) of the product (compound 97) is obtained in the solid state. M.P. 238-240 ° C.

MS (HYAN) M + 1: Calculated 343.1; Measured 343.1. Calculated for Ci ₆ Hi ₅ FiN ₆ O 2;

C, 56.14; H, 4.42; N, 24.55. Found: C, 55.82; H, 4.52; Ν, 24.15.

f EXAMPLE 92

1- (2-aminoethyl) -3- [2- (4-fluorophenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

If the product of Example 89 and ethylenediamine are replaced in Example 32, 0.1000 g (49.3%) of the product (compound 98) is obtained in the solid state. M.P. 217-220 ° C.

MS (HYAN) M + 1: Calculated 342.1; Measured 342.0. Calculated for C ^ H ^ F ^ yOi Ό, 2 H ₂ O;

C, 55.71; H, 4.79; Ν, 28.42.

Found: C, 55.72; H, 4.57; Ν, 28.07.

EXAMPLE 93

1- (2-dimethylaminoaminoethyl) -3- [2- (4-fluorophenylamino) pyrido [2,3-d] pyrimidin-7-yl] urea

If the product of Example 89 and 2-dimethylaminoethylamine are replaced in Example 32, 0.0778 g (35.8%) of the product (compound 99) are obtained in the solid state. M.P. Mp 251-255 ° C.

MS (HYAN) M + 1: Calculated 370.2; Measured 370.0. Calculated for C18H20F1N7O1;

C, 58.53; H, 5.46; N, 26.54. F Found: C, 58.39; H, 5.51; N, 26.26.

EXAMPLE 94

3,3-dimethyl-1- (4-nitrophenyl) -piperazine

Substituting 2,2-dimethylpiperazine in Example 24 yielded 29.43 g (88.4%) of the product as a solid.

MS (HYAN) M + 1: Calculated 236; Measured 236.

EXAMPLE 95 2,2-Dimethyl-4- (4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 94 in Example 12 gave 11.38 g (93%) of the product as a solid.

MS (HYAN) M + 1: Calculated 336; Measured 336.

EXAMPLE 96 4- (4-Aminophenyl) -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If the product of Example 95 is replaced by Example 12, 12.27 g (78%) of the product are obtained as a solid.

MS (HYAN) M + 1: Calculated 306; Measured 306.

EXAMPLE 97 4- [4- (7-Amino-6-fluoropyrido [2,3b] pyrimidin-2-ylamino) -phenyl] -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If the product of Example 96 is replaced by Example 50, 0.4346 g (59.0%) of the product are obtained as a solid. MS (HYAN) M + 1: Calculated 468.2; Measured 468.3.

EXAMPLE 98 4- {4- [7- (3-Cyclohexylureido) -6-fluoropyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester

If the product of Example 97 is replaced by Example 16, 0.170 g (31.2%) of the product is obtained in solid form.

MS (HYAN) M + 1: Calculated 593.2; Measured 583.4.

EXAMPLE 99

1-cyclohexyl-3- {2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-ylurea

If the product of Example 98 is replaced in Example 15, 0.040 g of the product (compound 100) is obtained in the solid state.

MS (HYAN) M + 1: Calculated 493.3; Measured 493.2.

EXAMPLE 100 4- [4- (7-Amino-6-fluoropyrido [2,3c] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

If the product of Example 12 is replaced by Example 50, 0.2017 g (29.7%) of the product are obtained in solid form. MS (HYAN) M + 1: Calculated 440.2; 440.2 measured.

EXAMPLE 101 | 4- {4- [7- (3-Cyclohexylureido) -6-fluoro tert-butyl ester | Pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid

I ί If the product of Example 100 is replaced in Example 16, 0.2036 g (78.6%) of the product is obtained in solid form.

j MS (HYAN) M + 1: Calculated 565.3; Measured 565.3.

!

EXAMPLE 102

1-Cyclohexyl-3- [6-fluoro-2- (4-piperazin-1-ylphenylamino) pyrido [2,3-b] pyrimidin-7-yl] urea u If the product of Example 101 is replaced in Example 15, 0.1084 g (96.0%) of the product (compound 11) in the solid state.

MS (HYAN) M + 1: Calculated 465.2; Measured 465.2. Calculated for C24H29F- N ₈ Or2.75 HCl-3.5 H 2 O;

C, 45.91; H, 5.10; N, 17.85; CI, 15.53; H ₂ O, 10.04.

Found: C, 46.20; H, 5.86; N, 17.45; Cl, 15.22; H, ₂ O, 8.97.

EXAMPLE 103 4- {4- [7- (3-tert-Butylureido) -6-fluoropyrido [2,3-b] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethylpiperazine-1- carboxylic acid

If the product of Example 50 is replaced by Example 10, 0.070 g (17.9%) of the product are obtained in solid form. MS (HYAN) M + 1: Calculated 567.3; Measured 567.3.

EXAMPLE 104

1-tert-butyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -urea

If the product of Example 103 is replaced by Example 15, 0.0585 g of the product (compound 102) is obtained in the solid state.

MS (HYAN) M + 1: Calculated 467.3; Measured 467.3.

EXAMPLE 105

1- [4- (4-Nitrophenyl) -piperazinyl] -ethanone

To a solution of 5.0 g (24.1 mmol) of 1- (4-nitrophenyl) -piperazine in 100 m dichloromethane was added 5.04 ml (28.9 mmol) of diisopropylethylamine. The solution was cooled in an ice bath, 1.89 ml (26.5 mmol) of acetyl chloride was added and stirred at room temperature overnight. The reaction mixture was washed sequentially with water, 0.5 M HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 5.91 g (98.5%) of product as a solid.

MS (HYAN) M + 1: Calculated 250.1; Measured 250.0.

EXAMPLE 106

1- [4- (4-Aminophenyl) -piperazin-1-yl] -ethanone

If the product of Example 105 is replaced by Example 12, 4.35 g (84.1%) of the solid product is obtained.

MS (HYAN) M + 1: Calculated 220.1; Measured 220.1.

EXAMPLE 107

1- {4- [4- (7-Aminopyrido [2,3-b] pyrimidin-2-ylamino) phenyl] piperazin-1-yl} -ethanone

Substituting the product of Example 106 in Example 9 yields 0.1829 g (50.1%) of the solid product.

MS (HYAN) M + 1: Calculated 364.2; Measured 364.2.

Calcd for CigH2iN ₇ Or1,0 H ₂ O;

C, 59.46; H, 6.11; N, 25.55.

Found: C, 59.51; H, 6.03; N, 25.28.

EXAMPLE 108

1- {2- [4- (4-acetylpiperazin-1-yl) -phenylamino] ~ pyrido [2,3-d] pyrimidin-7-yl} -3- (3-morpholin-4-ylpropyl) -urea

If the product of Example 107 and 3-morpholin-4-ylpropylamine are substituted in Example 32, 0.0338 g (22.6%) of the product (compound 103) is obtained in the solid state. M.P. 222-225 ° C (dec.). MS (HYAN) M + 1: Calculated 534.3; Measured 534.2.

Calculated for C22R10N3O, 5 H ₂ O;

C, 59.76; H, 6.69; Ν, 23.25.

Found: C, 59.74; H, 6.53; Ν, 23.35.

EXAMPLE 109

6-chloro-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one

Replacing Example 74 with N-chlorosuccinimide, 0.3700 g (31.4%) of the solid product are obtained. M.P. Mp 264-266 ° C (dec.).

MS (HYAN) M + 1: Calculated 228.0; Measured 227.9.

EXAMPLE 110

6,7-dichloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine

If the product of Example 109 is replaced by Example 6, 0.6534 g (86.5%) of the solid product is obtained.

MS (HYAN) M + 1: Calculated 246.0; Measured 245.8.

EXAMPLE 111

6-chloro-2-methylsulfanyl-pyrido [2,3-c] pyrimidin-7-ylamine

If the product of Example 110 is replaced by Example 7, 0.38 g (63%) of the solid product is obtained. MS (HYAN) M + 1: Calculated 227.0; Measured 226.9.

EXAMPLE 112

6-chloro-2-methanesulfinyl-pyrido [2,3-c] pyrimidin-7-ylamine

If the product of Example 111 is replaced by Example 8, 0.2328 g (57.1%) of the solid product is obtained. M.P. 260262 ° C.

MS (HYAN) M + 1: Calculated 243.0; Measured 242.9.

EXAMPLE 113 4- [4- (7-Amino-6-chloropyrido [2,3-c] pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Replacing the product of Example 112 with Example 27 gave 0.22 g (49%) of the solid product. MS (HYAN) M + 1: Calculated 484.2; Measured 484.2.

EXAMPLE 114

4- {4- [7- (3-tert-Butylureido) -6-chloropyrido [2,3-b] -pyrimidin-2-ylamino] -phenyl} -cis-2 ₎ 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 113 in Example 10 yielded 0.0995 g (39.2%) of the solid product.

EXAMPLE 115

1-tert-butyl-3- {6-chloro-2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-d] -nup imidin-7 - il} ur ur

If the product of Example 114 is replaced by Example 15, 0.0995 g of product (compound 104) is obtained in the solid state. M.P. 205 ° C (dec.).

MS (HYAN) M + 1: Calculated 483.2; Measured 483.2.

EXAMPLE 116 methyl- (2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl) -amine

Substituting methylamine in Example 7 gave 1.46 g (30.0%) of the solid product.

MS (HYAN) M + 1: Calculated 207.1; Measured 206.9.

EXAMPLE 117 (2-Methanesulfinyl-pyrido [2,3-b] pyrimidin-7-yl) -methylamine

If the product of Example 116 is replaced in Example 8, 1.31 g (83.4%) of the solid product is obtained. M.P. 185 ° C. MS (HYAN) M + 1: Calculated 223.1; Measured 223.0.

EXAMPLE 118 4- [4- (7-Methylamino-pyrido [2,3-b] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Substituting the product of Example 117 in Example 13 yields 0.4934 g (62.9%) of the solid product.

MS (HYAN) M + 1: Calculated 436.2; Measured 436.2.

EXAMPLE 119 4- {4- [7- (3-Cyclohexyl-1-methylureido) pyrido [2,3-d] pyrimidin-2-yl] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

If the product of Example 118 is replaced by Example 16, acetonitrile is used for the solvent and no base is added, 0.8535 g (78.8%) of the product are obtained as a solid.

MS (HYAN) M + 1: Calculated 561.3; Measured 561.3.

EXAMPLE 120

3-cyclohexyl-1-methyl-1- [2- (4-piperazin-1-ylphenylamino) pyrido [2,3-d] piperidin-7-yl] urea

If the product of Example 119 is replaced by Example 15, 0.2548 g (36.0%) of the product (compound 70) is obtained in the solid state. M.P. 169-175 ° C.

MS (HYAN) M + 1: Calculated 461.3; Measured 461.2.

Calculated for C ₂₅ H ₃ N ₆ O ₈ 0i –0.25 H ₂ O;

C, 64.56; H, 7.04; N, 24.09.

Found: C, 64.57; H, 7.01; N, 23.98.

EXAMPLE 121

3-Cyclohexyl-1- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-b] pyrimidin-7-yl} -1-methylurea

Following the general synthesis procedure of Example 120, 0.1366 g (95.6%) of the product (compound 106) was obtained in the solid state. M.P. 170 ° C (dec.).

MS (HYAN) M + 1: Calculated 489.3; Measured 489.3. Calculated for C ₂₇ H ₃₆ N ₈ O 1 -3.32 H ₂ O -2.69 HCl;

C, 50.16; H, 7.07; N, 17.33; CI, 14.75. Found: C, 50.36; H, 6.98; N, 16.97; CI, 15.07.

EXAMPLE 122

3-Cyclohexyl-1-ethyl-1- [2- (4-piperazin-1-ylphenylamino) pyrido [2,3-d] sulf imidin-7-yl] urea

In the general synthesis procedure of Example 120, 0.118 g (94%) of the product (compound 107) was obtained in the solid state. MS (HYAN) M + 1: Calculated 475.3; Measured 475.3.

Calculated for C ₂ 6H ₃₄ N ₈ 0i -3,0 HCI Ό, 3 of diethyl ether;

C, 53.89; H, 6.65; Ν, 18.48.

Found: C, 53.75; H, 6.96; Ν, 18.57.

EXAMPLE 123

3-tert-butyl-1- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -1-ethylurea

In the general synthesis procedure of Example 15, 0.022 g (56%) of the product (compound 108) was obtained in the solid state. MS (HYAN) M + 1: Calculated 477.3; Measured 477.3.

EXAMPLE 124

1-Methyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) pyrido [2,3-d] imidin-7-yl] urea

In the general synthesis procedure of Example 40, the product (compound 64) was obtained in solid state. M.P. Mp 204-206 ° C (dec.).

MS (HYAN) M + 1: Calculated 393; Measured 393.

EXAMPLE 125

1-ethyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3b] pyrimidin-7-yl] -urea

According to the general synthesis procedure of Example 40, the product (compound 28) was obtained in the solid state. M.P. 220-222 ° C (dec.).

MS (HYAN) M + 1: Calculated 407; Measured 407.

EXAMPLE 126

1- [5-Methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3d] sulfonyl-7-yl] -3-nitrophenyl

In the general synthesis procedure of Example 40, the product (compound 111) was obtained in the solid state. M.P. Mp 223-225 ° C. MS (HYAN) M + 1: Calculated 421; Measured 421.

EXAMPLE 127

N, N-duMemun-N '- [5-Memun-2 - [[4- (1-nunepa3UHiLn) (peHun] aMuHo] pyrido [2,3-b] pyrimidin-7-yl-sulfamide

The product (compound 71) was obtained in the solid state by the general synthesis procedure of Example 40 using dimethylsulfamyl chloride instead of cyclohexylisocyanate. M.P. 228-230 ° C (dec.).

MS (HYAN) M + 1: Calculated 443; Measured 443.

EXAMPLE 128 7-Amino-2-methylsulfanyl-pyrido [2,3dnuproxybenzoic acid ethyl ester

To a solution of 4-amino-2-methanesulfanyl-pyrimidine-5carboxaldehyde (Example 3) in 10 ml of tetrahydrofuran was added

O, 126 ml (1.18 mmol) of ethyl cyanoacetate. The solution was cooled to - 10 ° C and 2.36 ml (2.36 mmol) of titanium tetrachloride were added thereto. 0.52 ml (4.72 mmol) of N-methylmorpholine were slowly added to the solution. The reaction mixture was warmed to room temperature for 2 hours and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was concentrated to give a solid which was triturated with ether to give 0.30 g (96%) of the solid.

MS (HYAN) M + 1: Calculated 265.1; Measured 264.9.

EXAMPLE 129 7-Amino-2-chloro-pyrido [2,3-b] pyrimidine-6-carboxylic acid ethyl ester

Sulfuryl chloride and then 2 drops of ethanol were slowly added to a suspension of the product of Example 128 in 50 ml of chloroform. The reaction mixture was stirred at room temperature for 16 hours, poured into ether and the precipitate filtered to give 0.50 g (98%) of product. MS (HYAN) M + 1: Calculated 253.1; Measured 253.1.

EXAMPLE 130 7-Amino-2- [4- (4-tert-butoxycarbonyl® piperazin-1-yl) -phenylamino] -pyrido [2,3-b] pyrimidine-6-carboxylic acid ethyl ester

A solution of the products of Example 12 and Example 129 in dioxane was refluxed for 1 Vi hours.

I The reaction mixture was poured into a mixture of hexane and ethyl acetate (1: 1) and the precipitate filtered. Purification by flash chromatography eluting with dichloromethane afforded 0.08 g (16%) of the solid product.

MS (HYAN) M + 1: Calculated 494.2; Measured 494.1.

I) f EXAMPLE 131 | 2- [4- (4-tert-Butoxycarbonyl-piperazin-1 H -yl) -phenylamino] - 7- (3-tert-butyl ureido) -pyrido [2,3I d] methyl-6-carboxylic acid ethyl ester

I If the product of Example 130 is replaced by Example 10, ί

received 0.05 g (48%) of the solid product.

J

EXAMPLE 132 7- (3-tert-Butylureido) -2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-b] pyrimidine-6-carboxylic acid ethyl ester

If the product of Example 131 is replaced by Example 15, 0.036 g of the product (compound 113) is obtained in the solid state. M.P. > 300 ° C.

EXAMPLE 133

1- [6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -isopropylurea

According to the general synthesis procedure of Example 52, but using 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35), 4- (4-aminophenyl) -piperazine tert-butyl ester -1 Carboxylic acid (Example 12) and isopropylisocyanate as reagents The product (compound 114) was obtained in the solid state. M.P. 208 ° C (dec.).

MS (HYAN) M + 1: Calculated 439.2; Measured 439.3.

EXAMPLE 134

1-Cyclohexyl-3- {2- [4- (3,3-dimethylpiperazin-1-yl) phenylamino] -pyrido [2,3-b] pyrimidin-7-yl} -urea

The general synthesis procedure of Example 17, but using 4- (4-aminophenyl) -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Example 96) yielded 0.95 g (100%) of product (compound 115) in solid state.

MS (HYAN) M + 1: Calculated 475.6; Measured 475.3.

Calculated for C26H34N8O1 -3 HCl Ί H ₂ O;

C, 51.96; H, 6.37; N, 18.64; CI, 17.69; H ₂ O, 2.99.

Found: C, 52.00; H, 6.41; N, 18.53; CI, 16.51; H ₂ O, 3.06.

wo

EXAMPLE 135

6-methyl-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine

To a cooled to 10 ° C suspension of 2.18 g (54 mmol) of sodium hydride dispersed in oil in 300 ml of tetrahydrofuran was added 10.2 g (53.4 mmol) of (1-cyano-1-methylmethyl) -phosphonic diethyl ester acid (Synthesis 1975: 516). 4.30 g (25.4 mmol) of 4-amino-2-methanesulfanylpyrimidine-5-carboxaldehyde (Example 3) were added to the cooled suspension and the reaction mixture was stirred at room temperature for 22 hours. The resulting solution was concentrated and filtered, the solid was washed with tetrahydrofuran, dissolved in 1N citric acid and again precipitated by bringing the pH to 8 with sodium hydroxide. The precipitate was filtered to give 1.1 g (21%) of the product. M.P. 268-270 ° C.

MS (HYAN) M + 1: Calculated 207.3; Measured 207.0.

EXAMPLE 136

1-cyclohexyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3- (1] pyrimidin-7-yl} -urea

Following the general synthesis procedure of Example 31, but using the product of Example 135 as starting material, 0.14 g (42%) of the product (compound 116) was obtained in the solid state. MS (HYAN) M + 1: Calculated 589.6; Measured 589.3.

Calculated for C27H36N8O1 -2.5 HCl Ί, 5 H ₂ O;

C, 53.80; H, 6.73; Ν, 18.01; Cl, 14.11; H, ₂ O, 4.06. Found: C, 53.44; H, 6.89; Ν, 18.46; CI, 14.60; H ₂ O, 4.48.

EXAMPLE 137

1-tert-butyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3-b] pyrimidin-7-yl} -urea

Following the general synthesis procedure of Example 29, but using the product of Example 135 as starting material, 0.26 g (89%) of the product (compound 117) in the solid state are obtained. MS (HYAN) M + 1: Calculated 463.6; Measured 463.3.

Calculated for C ₂ 5H ₃ 6N ₈ O 1 -2.4 HCl · 1.75 H ₂ O;

C, 51.62; H, 6.91; Ν, 19.26; CI, 14.63; H, ₂ O, 5.42. F Found: C, 51.23; H, 6.55; Ν, 18.92; CI, 14.73; H, ₂ O, 5.10.

EXAMPLE 138 1-tert-Butyl-3- [6-methyl-2- (4-piperazin-1-yl) -phenylaminopyrido [2,3-d] imidin-7-yl] -urea

Following the general synthesis procedure of Example 15, but using the product of Example 135 as starting material, 1.02 g (100%) of the product (compound 118) in the solid state are obtained. MS (HYAN) M + 1: Calculated 435.3; Measured 435.3.

Calculated for C ₂₃ H ₃₀ N ₈ Oi –5 NSI, 75 H ₂ O;

φ C, 42.60; H, 5.98; N, 17.28; CI, 27.34; H, ₂ O, 4.86.

Found: C, 42.03; H, 6.04; N, 16.81; CI, 22.95; H, ₂ O, 4.72.

EXAMPLE 139

1- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) -phenylamino] -6-methylpyrido [2,3-b] pyrimidin-7-yl} -3-isopropylurea

The general synthesis procedure of Example 33, but using the product of Example 135 as starting material, together with 4- (4-aminophenyl) -cis-2,6-dimethylpiperazine-1 carboxylic acid tert-butyl ester and isopropylamine as reagents, were obtained 0.130 g (100%) of the product (compound 119) in the solid state. MS (HYAN) M + 1: Calculated 449.3; Measured 449.3.

Calculated for C24H32N8O1 -3 HCl-1.75 H2O;

C, 48.90; H, 6.58; N, 19.01; CI, 16.04; H, ₂ O, 5.35. Found: C, 49.03; H, 6.63; N, 18.70; CI, 16.03; H, ₂ O, 5.19.

EXAMPLE 140

1-cyclopropyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3-b] pyrimidin-7-yl} -urea

The general synthesis procedure of Example 33, but using the product of Example 135 as starting material, together with 4- (4-aminophenyl) -cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester and cyclopropylamine as reagents, gave 0.099 g (100%) of the product (compound 120) in the solid state.

MS (HYAN) M + 1: Calculated 447.3; Measured 447.3.

Calculated for C24H30N8O1;

C, 49.83; H, 6.19; N, 19.37; CI, 18.39; H, ₂ O, 3.89. Found: C, 49.76; H, 6.23; N, 18.92; CI, 15.66; H ₂ O, 3.06.

EXAMPLE 141 1-tert-butyl-3- {2- [4- (cis-3,5-dimethylpiperazin-1-yl) phenylamino] -6-ethyl-pyrido [2,3-d] pyrimidin-7-yl} -urea

Following the general synthesis procedure of Example 137, but using (1-cyanopropyl) -phosphonic acid diethyl ester as a starting material, 0.34 g (95%) of the product (compound 121) was obtained in the solid state.

MS (HYAN) M + 1: Calculated 477.3; Measured 477.3.

Calculated for C26H26N8O1 -2.5 NSI Η ₂ Ο;

C, 53.26; H, 7.05; Ν, 19.11; CI, 15.18; H ₂ O, 3.07.

Found: C, 53.63; H, 7.31; Ν, 18.46; CI, 15.32; H, ₂ O, 3.48.

EXAMPLE 142

The following compounds were essentially prepared according to the procedures described in Examples 1-141 and illustrated in Schemes 1-4:

(a) 1-tert-77-butyl-3- [2- (3-chloro-4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 2);

(b) 1-tert-butyl-3- [6-fluoro-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 3);

(c) 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-tert-butyl -urea (compound 6);

(d) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -3-tert-butyl urea ( compound 7);

(e) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-tert-butyl urea ( compound 8);

(f) 1- [2- (3-chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-cyclohexyl-urea (compound 10);

(e) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea (compound 13);

(h) 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea (compound 14);

(i) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea (compound 15 );

(j) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea (compound 16 );

(k) 1- (2-hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 17);

(I) 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3b] pyrimidin-7-yl] -3- (2-hydroxyethyl) -urea (compound 18) ;

(m) 1- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3b] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea (compound 19);

(n) 1- (2-hydroxy-ethyl) -3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea ( compound 20);

(o) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3b] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea (compound 21);

(p) 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-b] pyrimidin-7-yl} -3- (2-hydroxy -ethyl) -urea (compound 22);

(q) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy) -ethyl) -urea (compound 23);

(d) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy- ethyl) -urea (compound 24);

(s) 1-ethyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -urea (compound 25);

(t) 1- [2- (3-chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3b] pyrimidin-7-yl] -3-ethyl-urea (compound 26);

(i) 1-ethyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 27);

(v) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-b] pyrimidin-7-yl} -3-ethyl-urea (compound 29);

(w) 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-pyrimidin-7-yl} -3-ethyl-urea (Compound 30 );

(x) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-0] pyrimidin-7-yl} -3-ethyl-urea (Compound 31);

(y) 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea ( compound 32);

(S) 1-tert-Butyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3b] pyrimidin-7-yl] -urea (compound 33);

(aa) 1-Cyclohexyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea (compound 34);

(B) 1-ethyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-0] pyrimidin-7-yl] -urea (compound 35);

(cc) 1- (hydroxy-ethyl) -3- [2- (pyridin-4-ylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea (compound 36);

(dd) 1-tert-77-butyl-3- [6-fluoro-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 37);

(ee) 1-cyclohexyl-3- [6-fluoro-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 38);

(ff) 1-ethyl-3- [6-fluoro-2- (pyridin-4-ylamino) pyrido [2,3- d] pyrimidin-7-yl] urea (compound 39);

(99) 1- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3d] naphthyl-1H-7-Hn] -3- (2-trifluoromethyl-ethyl) -pyrene (Compound 40);

(hh) 1-tert-7-butyl-3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] urea (compound 41);

(ii) 1-cyclohexyl-3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 42);

(jj) 1-ethyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3d] npyrimidin-7-yl] -piperidine (compound 43);

(kk) 1- (2-hydroxy-ethyl) -3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3- d] pyrimidin-7-yl] -urea (compound 44);

(II) 1-cyclohexyl-3- [6-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 54);

(mm) 1-cyclohexyl-3- [6-cyano-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-0] pyrimidin-7-yl] -urea (Compound 56);

(nn) 1-cyclohexyl-3- [6-chloro-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 57);

(ooo) 1-cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 58 );

(pp) 1-Cyclohexyl-3- [6-bromo-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 59 );

(qq) 1-Cyclohexyl-3- [6-chloro-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 60) ;

(2R) 1-Isopropyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 61);

(ss) 1- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea (compound 63);

(tt) 1- (4-Hydroxy-cyclohexyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 66) ;

(uu) 1- (4-amino-cyclohexyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 67);

(vv) 1- (2-dimethylamino-ethyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 68);

(ww) 1- (3-morpholino-4-yl-propyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 69);

(xx) 1-cyclohexyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -thiourea (compound 72);

(yy) N- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -acetamide (compound 73);

(zz) 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3-0] pyrimidin-2ylamino] -benzenesulfonamide (compound 74);

(aaa) 1-cyclohexyl-3- {2- [4- (1-piperazin-1-yl-methanoyl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea (compound 75);

(bbb) 1-cyclohexyl-3- [2- (4-fluoro-phenylamino) -pyrido [2,3-pyrimidin-7-yl] -urea (compound 76);

(ccc) 1- (2- {4- [4- (2-amino-4-methyl-pentanoyl) -piperazin-1-yl] phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) -3 -cyclohexyl urea (compound 77);

and (ddd) 1- (2- {4- [4- (2-amino-3-methyl-butanoyl) -piperazin-1-yl] phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) - 3-cyclohexyl urea (compound 78).

EXAMPLE 143

Biological analysis

As noted above, the compounds of this invention are potent inhibitors of cdk, and are accordingly useful in the treatment and prevention of atherosclerosis and other cellular proliferative disorders such as cancer that are mediated by such cdk enzymes. The compounds exhibit superior inhibitory activity against a large number of cdk enzymes, including cdkcdkl / cyclinB, cdk2 / cyclinA, cdk2 / cyclinE and cdk2 / cyclinD, which are evaluated by standard assays commonly used by those skilled in the art for measuring cdk inhibitory activity. The following are typical analyzes.

Analysis of cyclin-dependent kinase 4 (cdk4)

Enzyme assays for determination and kinetic evaluation of IC50 were performed in 96-well filter plates (Millipore MADVN6550). The total volume is 0.1 ml containing a final concentration of 20 mM TRIS (Tris [hydroxymethyl] aminomethane) at pH 7.4, 50 mM NaCI, 1 mM dithiothreitol, 10 mM MgCI ₂ , 25 μΜ ATP containing 0.25 pCi [ ³² P] ATP, 20 ng cdk4, 1 pg retinoblastoma, and suitable dilute solutions of a compound of the present invention. All components except ATP were added to the wells and the plate was placed in a mixer for 2 minutes. With the addition of [ ³² P] ATP, the reaction begins and the plate is incubated at 25 ° C for 15 minutes. The reaction was quenched by the addition of 0.1 ml of 20% trichloroacetic acid (THO). The plate was allowed to stand for at least one hour at 4 ° C to allow the substrate to precipitate. The wells were then washed five times with 0.2 ml of 10% trichloroacetic acid and the inclusions of ³² P were determined with a beta counter (Wallac Inc., Gaithersburg, MD).

Cyclinase-1 kinase assays 1 and 2 (cdk1 / cyclinB, cdk2 / cyclinA, cdk2 / cyclinE)

Enzyme assays for determination and kinetic evaluation of IC50 were performed in a 96-well filter plate (Millipore MADVN6550) in a total volume of 0.1 ml containing 20 mM TRIS (Tris [hydroxymethyl] aminomethane) at pH 7.4, 50 mM NaCI , 1 mM dithiothreitol, 10 mM MgCI ₂ , 12 mM ATP containing 0.25 pCi [ ³² P] ATP, 20 ng enzyme, (cdk1 / B, cdk2 / A or cdk2 / E), 1 pg retinoblastoma, and suitably diluted solutions of a single compound of the present invention. All components except ATP were added to the wells and the plate was placed in a mixer for 2 minutes. With the addition of [ ³² P] ATP, the reaction begins and the plate is incubated at 25 ° C for 15 minutes. The reaction was quenched by the addition of 0.1 ml of 20% trichloroacetic acid (THO). The plate was allowed to stand for at least one hour at 4 ° C to allow the substrate to precipitate. The wells were then washed five times with 0.2 ml of 10% trichloroacetic acid and the inclusions of ³² P were determined with a beta counter (Wallac Inc., Gaithersburg, MD).

Cyclin-dependent kinase analysis 5 / p25 proline-directed protein kinase

Enzyme source: recombinant cdk5-p25 complex expressed by baculovirus-infected recombinant insect cell sf9.

Objective: To evaluate the ability of testagents to inhibit cdk5 / p25 phosphorylation of Histon H1.

Method: His-tagged cdkS / Glu-tagged p25 (or GST-p25) baculovirus-insect cell enzyme complex was diluted to a concentration of 50 ng / 20 μΙ enzyme dilution buffer (EDB - 50 mM TRIS-HCI [pH 8.0], 10 mM NaCl, 10 mM MgCh and 1 mM dithiothreitol (DTT)). Then, a 20 μΙ sample of testagent (dissolved in EDB) was combined with 20 μΙ of the final cdk5 / p25 enzyme preparation and allowed to stand at room temperature for 5 minutes. To this test agent / enzyme preparation was added 25 μΙ of substrate solution containing 115 μΙ / ml Histone H1, 30 μΜ ATP (vanadate free) and 30 pCi / ml γ- ³³ Ρ ATP (Amersham) in the EDB, and the mixture was shaken. vigorously at 30 ° C for 45 minutes. A 50 μΙ sample of the final preparation was added to 100 ml of 150mM phosphoric acid on ice for 30 minutes to facilitate precipitation. The precipitate was then filtered through a 96-well phosphocellulose filter plate and then washed three times with 75 mM phosphoric acid. Thereafter, each well receives a 20 μΙ scintillation cocktail and plaque beta emissions are counted using a Trilux Counter ( ³³ P filter protocol). Samples were compared with the beta-emissions of the control sample (no test agent containing, 0% inhibition) and baseline level (no enzyme, no test agent, 100% inhibition) to determine the percent inhibition of histone H1 phosphorylation.

The results of the previous analyzes for the characteristic compounds of the invention are presented in Table 2 below. The compounds of the invention exhibit IC50 values in the range of 0.027 μΜ to> 5 μΜ against cdk1 / B, from 0.010 μΜ to> 5 μΜ against cdk2 / A, from 0.020 to> 5 μΜ against cdk2 / E, and from 0.004 to> 5 μΜ vs. cdk4 / D. The most potent compound in general is compound 9, which shows IC50 values of 0.027 μΜ, 0.010 μΜ, 0.020 μΜ, 0.005 μΜ against cdk1 / B, cdk2 / A, cdk2 / E and cdk4 / D, respectively.

Table 2. CDk inhibition: IC50 (μΜ)

Compound cdk1 / B cdk2 / A cdk2 / E cdk4 / D 1 0.219 0.060 0,130 0.006 4 > 5 > 5 > 5 1.5 5 0,463 th most common 0,130 0,130 0.037 9 0.027 0.010 0.020 0,005 11 0.159 0,092 0,125 th most common 0.011 12 > 5 > 5 > 5 2,100 28 > 5 > 5 > 5 > 5 45 0,552 th most common 0,054 0,110 0.045 46 0.075 0.300 > 5

Table 2. cdk inhibition: IC50 (μΜ) (continued)

Compound cdk1 / B cdk2 / A cdk2 / E cdk4 / D 47 > 5 > 5 > 5 > 5 48 0.257 0,113 0.098 0.018 49 0.911 0,528 th most common 0.475 0.050 50 0.069 0.022 0.035 0.007 51 0.053 0.024 0.030 0.004 52 0,472 th most common 0.213 0.126 0.027 53 > 5 > 5 > 5 > 5 55 > 5 > 5 > 5 0.300 64 > 5 > 5 > 5 > 5 65 > 5 > 5 > 5 > 5 70 1,448 th most common 0.697 0.530 0.017 71 > 5 > 5 > 5 > 5 79 > 5 1,066 th most common > 5 > 5 80 0,461 th most common 0,092 0.230 0.460 81 2,610 th most common 1,560 th most common 3,250 th most common 0.500 83 0.399 0.305 .315 0,055 84 > 5 > 5 > 5 > 5 85 > 5 > 5 > 5 > 5 86 > 5 > 5 > 5 > 5 87 > 5 > 5 > 5 > 5 88 0,418 th most common 0.043 0,055 0.025 89 > 5 > 5 > 5 > 5 91 > 5 > 5 > 5 0.070 93 > 5 > 5 > 5 > 5

Table 2. cdk inhibition: IC50 (μΜ) (continued)

Compound cdk1 / B cdk2 / A Cdk2 / E cdk4 / D 94 > 5 0,101 95 > 5 0.310 96 6,365 th most common 1,108 th most common 1,550 th most common > 5 97 0.862 0.278 0.345 > 5 98 0,442 th most common 0,157 0,140 1,050 th most common 99 1,810 th most common 1,012 th most common 0,410 th most common > 5 100 0.265 0.153 0,415 th most common 0.035 102 3,130 th most common 3,590 th most common 4,500 0,165 th most common 103 > 5 > 5 > 5 > 5 104 > 5 > 5 > 5 0,185 106 0.350 0.440 107 1,728 th most common 1,950 th most common 1,650 th most common 0.019 108 2,425 th most common 2,035 th most common 3,050 th most common 0.067 111 > 5 > 5 > 5 > 5 113 > 5 > 5 > 5 3,000 114 > 5 > 5 > 5 > 5 115 0.094 0.022 0,051 0.007 116 > 5 > 5 3,750 th most common 0.313 117 > 5 > 5 4,000 0,076 118 > 5 > 5 3,800 0,079 119 > 5 > 5 > 5 1,600 120 > 5 > 5 > 5 1,900 121 > 5 > 5 > 5 0,092

The compounds of this invention are also inhibitors of the receptor tyrosine kinase enzymes of growth factor, FGFr and PDGFr, and of the non-receptor tyrosine kinase enzyme, c-Src. The ability of some of the compounds of the invention to inhibit tyrosine kinase enzymes was evaluated by standard analytical methods. These analyzes were performed as follows:

PDGF and FGF receptor tyrosine kinase assays

Full-length cDNAs for mouse PDGF-β and human FGF-1 (fig) receptor tyrosine kinases were obtained from J. Escobedo and prepared as described in J. Biol. Chem., 1991; 262: 1482-1487. PCR primers are provided to extend the DNA fragment encoding the intracellular tyrosine kinase domain. The fragment was inserted into a baculovirus vector, cotransfected with AcMNPV DNA, and the recombinant virus isolated. Insect SF9 cells are infected with the protein overexpression virus and the cell lysate is used for analysis. Analyzes were performed in 96-well plates (100 μΙ / incubation / well) while optimizing the conditions for measuring the incorporation of ³³ P from γ- ³³ Ρ ATP into the glutamatyrosine copolymer substrate. Briefly, 82.5 μΙ incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCI, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na ₃ VO ₄ was placed in each well. , 10 mM MgCI ₂ and 750 pg / ml Poly (4: 1) glutamate tyrosine, followed by the addition of 2.5 μΙ inhibitor and 5μΙ enzyme lysate (7.5 pg / μΙ FGF-TK or 6.0 pg / pl PDGF-TK) to initiate the reaction. After a 10-minute incubation at 25 ° C, 10 ml of γ- ³³ Ρ ATP (0.4 pCi plus 50 μФ ATP) were added to each well and the samples incubated for another 10

100 minutes at 25 ° C. The reaction was terminated by the addition of 100 μΙ 30% trichloroacetic acid containing 20 mM sodium pyrophosphate and the material precipitated on a glass fiber filter (Wallac). The filters were washed three times with 15% trichloroacetic acid containing 20 mM sodium pyrophosphate, and the residual radioactivity of the filters was recorded with a Wallac Betaplate reader. Nonspecific activity is defined as the residual radioactivity of the filters after incubation of samples containing buffer only (no enzyme). Specific enzyme activity (enzyme and buffer) is defined as the difference between total activity and nonspecific activity. Inhibition (in percent) at 50 µпреде was determined, and for the more potent compounds, the concentration of the compound at which the specific activity was inhibited by 50% (IC ₅₀ ) was determined using the inhibition curve.

Analysis of C-Src kinase

The C-Src kinase from baculovirus infected insect cell lysates was purified using an antipeptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src. The antibody covalently bound to 0.65 µm latex beads was added to a suspension of insect cell lysis buffer containing 150 mM NaCl, 50 mM Tris pH 7.5, 1 mM DTT (dithiothreitol), 1% NP-40, 2 mM EGTA , 1 mM sodium vanadate, 1 mM PMSF and 1 pg / ml leupeptin, pepstatin and aprotinin each. The c-Src protein-containing insect cell lysate was incubated with these beads for 3 to 4 hours at 4 ° C with rotation. At the end of the lysate incubation, the beads are washed

101 times in lysis buffer, resuspended in 10% glycerol containing lysis buffer and frozen. The latex beads were thawed, washed three times in analytical buffer (40mM Tris, pH 7.5, 5mM MgCl ₂ ), and suspended in the same buffer. In the Millipore 96-well plate with a bottom of 0.65 pm polyvinylidene membrane, the reaction components were added: 10 μΙ c-Src beads, 10 μΙ 2.5 mg / ml poly GluTyr substrate, 5 μΜ ATP containing 0.2 μθί labeled ³² Ρ- ΑΤΦ, 5 μΙ DMSO containing solvent or as control sample and buffer to a final volume of 125 μΙ. The reaction was started at room temperature with the addition of ATP and quenched after 10 minutes by the addition of 125 μΙ 30% trichloroacetic acid, 0.1 M sodium pyrophosphate on ice for 5 minutes. The plates were then filtered and the wells were washed with two 250 ml aliquots of 15% trichloroacetic acid, 0.1 M pyrophosphate. The filters are then punctured, read on a liquid scintillation counter, and the inhibitory activity data are examined by comparison with a known inhibitor such as erbstatin. The method is also described in J. Med. Chem., 1994; 37: 598-609.

The tyrosine kinase inhibitory activity of typical compounds of the invention defined in the foregoing assays is given in Table 3.

MS

102

TABLE 3. Inhibition of tyrosine kinases; % inhibition at 50 μΜ (1C ₅₀ values are given in brackets, if determined)

compound PDGFr FGFr 1 94.4 (0.593) 93,7 9 89,8 11 (0,1321) (0,284) 45 21.9 67,4 46 17.5 19,2 47 10.5 55 (0,033) (0,151) 70 (0,536) (US) 80 18.6 117 (0.081) (0,061)

As noted above, the invention also provides pharmaceutical compositions comprising a compound of the invention in admixture with a carrier, diluent or excipient. The following examples illustrate typical compositions of this invention.

EXAMPLE 144

A pharmaceutical composition in the form of solid gelatin capsules for oral administration is prepared using the following ingredients:

amount (mg / capsule) active compound 250 starch powder 200 magnesium stearate 10 total 460

103

The above ingredients were mixed and 460 mg of the mixture was filled with hard gelatin capsules. A typical active ingredient is 1-isobutyl-3 [2 - {(2-chloro-4-piperazin-1-yl) -phenylamino} -pyrido [2,3-0] pyrimidin-7-yl] -urea. The composition is given 2 to 4 times daily for the treatment of post-surgical restenosis.

EXAMPLE 144a

Suspension composition for oral administration

ingredients quantity 1-Isopropyl-3- [5-methyl-6-bromo-2 (3-ethylpyridin-4- 500 mg ylamino) -pyrido [2,3-b] pyrimidin-7-yl] -urea sorbitol solution (70% NF) 40 ml sodium benzoate 150 mg saccharin 10 mg cherry aroma 50 mg distilled water q.s ad 100 ml

Sorbitol is added to 40 ml of distilled water and the pyridopyrimidine is dispersed in the solution. Saccharin, sodium benzoate and aroma are added and dissolved. The volume of the solution was adjusted to 100 ml with distilled water. Each ml of syrup contains 5 mg of active ingredient.

104

EXAMPLE 144b

Tablets containing 60 mg of active ingredient each

Active ingredient 60 mg starch 45 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone (10% aqueous solution) 4 mg sodium carboxymethyl starch 4,5 mg magnesium stearate 0.5 mg talc 1.0 mg total 150 mg

The active ingredient, starch and cellulose are passed through a No. 45 US mesh sieve and mixed thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder and passed through a No. 16 US mesh sieve. The granules were dried at 50-60 ° C and passed through a No. 18 US mesh sieve. Sodium carboxymethyl starch, magnesium stearate and talc pre-screened with No. 60 US mesh sieve are added to the granules, all mixed and pressed into a tablet tablet of 150 mg each.

A typical active ingredient used in the above formulation is the compound of Example 40 (compound 12). This composition is suitable for the treatment of diabetic retinopathy.

EXAMPLE 144c

A suitable injectable parenteral formulation is prepared by dissolving 100 mg of compound 77 in 250 ml in 0.9%.

105 aqueous sodium chloride solution and the pH of the solution was adjusted to about 7. This composition is suitable for the treatment of breast cancer.

EXAMPLE 144d

Preparation of suppositories

A mixture of 500 mg of 1-n-butyl-3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea and 1500 mg of theobromo oil were homogenized at 60 ° C. The mixture was cooled to 24 ° C in suitable forms. Each suppository weighs about 2 g and can be given 1 to 2 times daily to treat viral infections such as herpes and HIV.

EXAMPLE 144f

Preparation for external use

ingredient quantity (mg) 1-cyclohexyl-3 - {[2- (4-morpholin-1-yl-phenyl- 20 amino)] - 5,6-difluoro-pyrido [2, 3H] pyrimidine-7- il} urea propylene glycol 100 white petrolatum 500 cetearyl alcohol 50 glyceryl stearate 100 polyethylene glycol SOostearate 100 Ceteth-20 50 monobasic sodium phosphate 80 total 1000

The compound of the invention was homogenized with the other ingredients to form a thick slurry. The suspension is applied

106 evenly on a polymer film with an adhesive coating on the reverse side and cut into 5 cm squares. The patch is applied to the skin of a patient suffering from psoriasis.

EXAMPLE 144f

Delayed release preparations

500 mg of 7-acetamino-6-bromo-2- [4- (2-diethylaminoethoxy) phenylamino] pyrido [2,3-d] pyrimidine hydrochloride were placed on an osmotic pump tablet and given orally to treat and prevent restenosis.

The invention, as well as the manner and process of its implementation and application, are now described in such a complete, clear, concise and precise language that they allow anyone skilled in the same field to do and apply the same. It should be clear that the foregoing describes preferred embodiments of the present invention, and that changes can be made therein, without departing from the spirit and scope of the present invention, as set forth in the claims. In order to emphasize specifically and to make unambiguous claims on the nature of the object of the invention, the following claims complete this specification.

Claims (21)

Patent Claims 1. Compound of Formula I: and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R ₂ , R 7, R 13, R 14 and R 15 are independently hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups independently selected from halogen, cyano, nitro, -Rg, - NRgRw, -ORg, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n SO ₂ Rii, - (CH ₂ ) _n Rn, -CORg, -CONR9R10, -SOaRg, -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -P03RgRio> -PORgR-ιο, -PO (NRgRio) ₂ , -NRgCORio, -NR ₉ C0 ₂ Rio, -NRgCONRgRio, -NRgS0 ₂ R-io, or a heterocycle optionally substituted with up to 3 groups independently selected from -Rg, -NRgRw, -ORg, -NRgCOR10, -COR10, - (CH ₂ ) _n SO ₂ Ri 1, - (CH ₂ ) _n R _n , or - (CH ₂ ) _n R 12, optionally substituted with up to 5 groups, independently selected from halogen, cyano, nitro, -R ₈ , -NR ₈ R ₁₀ , -OR 8, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n SO ₂ Rn, - (CH ₂ ) _n Rn, -CORg, -CONRgRio, -SO ₃ Rg, -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -POaRgRw, 108 -POR9R10, -PO (NR ₉ Rio) 2, -NR9COR10, -NRgC0 ₂ Rio. -NRgCONRgRio, -NRgS0 ₂ Rio, or a heterocycle optionally substituted with up to 3 groups independently selected from -Rg, -NRgRio, -ORg, -NRgCOR-10, -COR10, - (CH ₂ ) _n SO ₂ R _n , - (CH ₂ ) _n R _n ; R ₅ is halogen, cyano, nitro, -R ₈ , -NR ₈ R ₁₀ or -OR _g ; Re is halogen, cyano, nitro, -Rg, -NR9R10, -ORg, -CO ₂ R ₉ , -CORg, -CONRgRw, -NRgCOR-ιο, -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -PO3R9R10, -PORgR-ιο, -PO (NRgR ₁₀ ) ₂ , or lower alkenyl or lower alkynyl optionally substituted with -Rg; Rs is H, -CO ₂ Ri3, -COR13, -CONR13R14, -CSNR13R14, -C (NRi3) NRi4Ris, -SO3R13, -SO ₂ Ri3, -SO ₂ NRi3Ri4, -PO3R13R14, -POR13R14, -PO ( NR ₁₃ R ₁₄ ) ₂ ; Rg and R-ιο are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl or taken together with the nitrogen atom to which they are attached, Rg and R ₁₀ form a 3-7 membered ring, up to four of which j ί i Oh II may be selected from ', O, S and NR ₂ q, where R ₂₀ is hydrogen, lower alkyl, or -CO lower alkyl; R 1 is a heteroaryl or heterocyclic group; R ₁₂ is a cycloalkyl, heterocyclic, aryl or heteroaryl group; and η is 0, 1, 2 or 3; 109 2. A compound of Formula II and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R7, R13, R14 and Ri ₅ are each independently hydrogen or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted by up to 5 groups independently selected from halogen, cyano, nitro, -Rg, -NRgR- io, -ORg, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n SO ₂ Rn, - (CH ₂ ) _n Rn, -COR ₉ , -CONRgR-ιο, -SO ₃ Rg, -SO2NR9R10 , -SO ₂ Rg, -SRg, -P0 ₃ RgRio, -POR9R10, -PO (NR ₉ Rio) ₂ , -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NRgS0 ₂ R-, or a heterocycle optionally substituted by up to 3 groups independently selected from -Rg, -NRgR-io, -ORg, - (CH ₂ ) _n SO ₂ Rii, - (CH ₂ ) _n R-ii, or - (CH ₂ ) _n Ri ₂ , optionally substituted by up to 5 groups, independently selected from halogen, cyano, nitro, -Rg, -NR9R10, -ORg, - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) nSO ₂ Rn, - (CH ₂ ) _n Rn, -CORg, -CONRgR-ιο, -SO ₃ Rg, -SO ₂ NRgR- | 0, -SO ₂ Rg, -SRg, -P0 ₃ RgRio, 110 -PORgRw, -PO (NR ₉ Rio) 2, -NRgCOR-ιο, -NR ₉ C02Rio> -NR9CONR9R10, -NR9SO2R1O1 or heterocycle optionally substituted by up to 3 groups independently selected from -R _g , -NR ₉ R ₁₀ , -ORg, - (CH 2) nSO ₂ Ri 1, - (CH ₂ ) n R ₁ ; R ₅ is halogen, cyano, nitro, -R ₉ , -NR ₉ R ₁₀ or -OR ₉ ; Re is halogen, cyano, nitro, -Rg, -NR9R10, -OR ₉ , -CO ₂ R ₉ , -CORg, -CONR9R10, -NR9COR10, or lower alkenyl or lower alkynyl optionally substituted with -R _g ; Re is H, -CO2R13, -COR13, -CONR13R14, -CSNR13R14 , -C (NRi3) NRi ₄ Ri5, -SO3R13, -SO2R-I3, -SO ₂ NRi3Ri4, -PO3R- | 3Ri _4, -PORi3Ri ₄ -PO (NRi ₃ Ri ₄ ) ₂ ; Rg and R-ιο are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl or taken together with the nitrogen atom to which they are attached, Rg and R10 form a 3-7 membered ring, up to four of which are O II Q may be selected from ^{x x} , O, S and NR ₂ o, wherein R ₂ o is hydrogen, lower alkyl, or -CO lower alkyl; R 1 is a heteroaryl or heterocyclic group; R12 is a cycloalkyl, heterocyclic, aryl or heteroaryl group; η is 0, 1,2 or 3; and Rie, R17 and Ria are independently hydrogen, halogen, amino, monoyl or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO2R9; 111 -SO2R9, -SRg, -PO3R9R10, -POR9R10. -PO (NR ₉ Rio) 2, -NR9COR10, -NR9CO2R10, -NRgCONRgRio, “NR9SO2R10; or R ₁₆ is a carbocyclic group containing from 3 to 7 members, up to two of which are heteroatoms selected from oxygen and nitrogen, in which the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, N, heteroarylsulfonylalkylthiolcylthiolcylcylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylthiocylalkylalkylthiocylalkylalkylalkyl; 3. A compound of Formula III and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R2 is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups, independently selected from halogen, cyano, nitro, -Rg, -NR9R10, -OR9, - (CH ₂ ) nCO ₂ R9, - (CH2) nSO ₂ Rn, - (CHDnRn, -CORg, -CONR9R10, -SO3R9, -SO2NR9R10, -SO2R9, -SRg, -PO3R9R10, 112 -PORgRio, -PO (NR ₉ Rio) 2, -NRgCOR-ιο, -NR9CO2R10, -NRgCONRgR-io, -NRgS0 ₂ Rio, or a heterocycle optionally substituted by up to 3 groups independently selected from -Rg, -NRgR-10, -ORg, - (CH ₂ ) nSO ₂ Rii, - (CH ₂ ) _n Rii, or - (CH ₂ ) _n Ri 2. optionally substituted by up to 5 groups independently selected from halogen, cyano, nitro, -Rg, -NRgRio, -ORg, - (CH2) nCO2R9, - (CH ₂₎ nSO ₂ Rn, - (CH ₂₎ nRn, -CORg , -CONR ₉ R ₁₀ , -SO3R9, -SO2NR9R10, -SO2Rg, -SRg, -P0 ₃ RgRio, -PORgRio, -PO (NRgRio) 2, -NR9COR10. -NR ₉ C0 ₂ Rio, -NRgCONRgRio, -NR9SO2R10. or a heterocycle optionally substituted by up to 3 groups independently selected from -Rg, -NR9R10, -ORg, - (CH ₂ ) nSO ₂ R ₁₁ , - (CH 2) n Rii; R 5 is halogen, cyano, nitro, -R ₈ , -NR ₈ R ₁₀ or -OR ₉ ; R6 is halogen, cyano, nitro, -Rg, -NR9R10, -ORg, -CO2R9, -CORg, -CONRgRio, -NRgCORio, -SO2NR9R10, -SO2R9, -SO ₃ Rg, -SR ₉ , -P0 ₃ R ₉ Rio , -PORgR10, -PO (NRgR10) 2 or lower alkenyl or lower alkynyl optionally substituted by -Rg; Rg and R10 are independently hydrogen or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl or taken together with the nitrogen atom to which they are attached, Rg and R10 form a 3-7 membered ring, up to four of which are mm 113 II may be selected from, O, S and NR ₂ o where R ₂ is hydrogen, lower alkyl, or -CO lower alkyl; R-1 is a heteroaryl or heterocyclic group; Ri ₂ is a cycloalkyl, heterocyclic, aryl or heteroaryl group; n is 0, 1, 2 or 3; and R 19 is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups, independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl , aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO3R9, -SO ₂ NR ₉ Ri _0, -SO ₂ Rg, -SRg, -PO3R9R10, -POR9R10, -PO (NR ₉ Rio) _2, -NR9COR10. -NRgC0 ₂ Rio, -NR9CONR9R10. -NRgSO ₂ Rio; or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl group is optionally substituted by up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, hydroxy, hydroxy, hydroxy , nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SOgRg, -S0 ₂ R ₉ Rio, -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -PO3R9R10, -POR9R101-PO (NR 9R101-PO (NR ₉ Rio) ) ₂ , -NR ₉ CORio, -NRgC0 ₂ Rio, -NRgCONRgRio, -NR ₉ S0 ₂ Rio, or - (CH ₂ ) _n -carbocyclic group containing from 3 to 7 members, 114 to two of which are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups, independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino , mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl or heterocyclylsulfonylalkyl; and R ₂ i is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. 4. A compound of Formula IV and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R 5 is halogen, cyano, nitro, -R 8, -NR 8 R 10 or -OR 8; Re is halogen, cyano, nitro, -Rg, -NRgR-ιο, -ORg, -CO ₂ Rg, -CORg, -CONRgR-ιο, -NRgCOR-ιο, -SO ₂ NRgR- | 0i -SO ₂ Rg, - SO ₃ Rg, -SRg, -P0 ₃ RgRio, -PORgRio, -PO (NRgRio) 2. OR Lower alkenyl or lower alkynyl optionally substituted by c-Rg; R _g and R ₁₀ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or taken together with the nitrogen atom to which they are attached, Rg and Rio form a 3-7 membered ring, up to four of which may be selected from O II _s. ' ^x , O, S and NR ₂ o, wherein R ₂ o is hydrogen, lower alkyl, or -CO lower alkyl; R 1 is a heteroaryl or heterocyclic group; R16, R17 and Ris are independently selected from halogen, cyano, nitro, -Rg, -NRgRio, -ORg, - (CH2) n CO2R9, - (CH ₂₎ nSO ₂ Rn, - (CH ₂₎ nRn, -CORg, -CONRgR-ιο, -SO3R9, -SO2NRgRio, -SO2R9, -SRg, -PO3R9R10, -PORgR-ιο, -PO (NRgRio) 2> -NRgCOR-io, -NR9CO2R10, -NRgCONRgRw, -RR9, optionally substituted with up to 3 groups independently selected from -Rg, -NRgRio, -ORg, -NRgCORio, -COR10, - (CH ₂₎ nSO ₂ Rii, - (CH ₂₎ nRn; R 19 is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl , aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO3R9, -SO2NR9R10, -SO2R9, -SRg, 116 -PO3R9R10, -PORgRio, -PO (NR ₉ Rio) 2, -NRgCORw, -NR ₉ C0 ₂ Rio, -NRgCONRgRio, -NRgS0 ₂ Rioi or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl, where alkyl; , a heteroaryl or cycloalkyl group is optionally substituted by up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkyl ₃ Rg, -SO ₂ R ₉ Ri _0i -S0 ₂ NRgRio, -SO ₂ Rg, -SRg, -PO3R9R10, -PORgRio, -PO (NRgRio) 2, -NRgCORio, -NRgC0 ₂ Rio, -NRgCONRgRio, -NRgS0 ₂ Rio, or - (CH ₂ ) _n -carbocyclic group containing from 3 to 7 members, up to two of which are heteroatoms selected from oxygen and nitrogen, where the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups, independently selected from the group, consisting of halogen, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylsulfonyl, heteroarylsulfonylcylcylcylcylcylthiol and R ₂ i is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. 117 5. A compound of Formula V u and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R5 is halogen, cyano, nitro, -R8, -NRgR-10 or -ORg; R6 is halogen, cyano, nitro, -Rg, -NRgRio, -ORg, -CO2R9, -CORg, -CONRgR-ιο, -NRgCOR-ιο, -SO2NRgRio, -SO2R9, -SO3R9, -SRg, -PO3R9R10, -P3R9R10 , -PO (NR 8 R 10) 2 or lower alkenyl or lower alkynyl optionally substituted by cR _g ; Rie, R17 and Rie are independently selected from hydrogen, halogen, cyano, nitro, -Rg, -NRgR-ιο, -ORg, - (CH ₂ ) nCO2R9, - (CH ₂ ) nSO ₂ Rii, - (CH ₂ ) nRn , -CORg, -CONRgRw, -SO3R9, -SO2NR ₉ R ₁₀ , -SO2R9, -SRg, -PO3R9R10, -POR9R10, -PO (NR ₉ R ₁₀ ) 2, -NRgCOR-ιο, -NRgCO2R10> -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -Rg, -NRgR-ιο, -ORg, -NR9COR10 , -COR10, - (CH ₂₎ nSO ₂ Rn, - (CH ₂₎ nRn; Rg and R10 are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or taken together with nitrogen the atom to which they are attached, 118 Rg and Rio form a 3-7 membered ring, up to four of which may be selected from O II ' ^x , O, S and NR ₂ o, wherein R ₂ o is hydrogen, lower alkyl, or -CO lower alkyl; R 1 is a heteroaryl or heterocyclic group; Rig is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted by up to 5 groups, independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl , aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO ₃ Rg, -SO ₂ NRgR ₁₀ , -SO ₂ Rg, -SRg, -PO ₃ RgRi ₀₁ -PORgRio, -PO (NR ₉ R ₁₀ ) 2, -NRgCOR -io, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10; or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl group is optionally substituted by up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, hydroxy, hydroxy, hydroxy , nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO ₃ Rg, -SO2R9R10. -SO2NR9R10, -SO2R9, -SR9, -P0 ₃ RgRio, -PORgRio, -PO (NRgRio) 2, -NR9COR10, -NR9CO2R10, NRgCONRgR-io, -NR9SO2R10, or - (CH2) n -carbocyclic group containing from 3 to 7 members, 119 to two of which are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups, independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino , mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl or heterocyclylsulfonylalkyl; and R ₂ i is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. A compound of Formula VI and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, in which: R ₅ is halogen, cyano, nitro, -R ₉ , -NRgRw or -ORg; 120 Re is halogen, cyano, nitro, -Rg, -NR9R10, -OR ₉ , -CO2R9, -CORg, -CONR9R10, -NR9COR10, -SO2NR9R10, -SO ₂ R ₉₎ -SO ₃ R ₉ , -SR _g , -POsRgR-io, -POR9R10, -PO (NR ₉ Rio) 2, or lower alkenyl or lower alkynyl optionally substituted by cR _g ; R-17 and Ria are independently selected from halogen, cyano, nitro, -Rg, -NRgR _10, -ORg, - (CH ₂₎ nCO ₂ R9, - (CH2) nSO2Rn, - (CH ₂₎ nRn, -CORg, -CONR9R10, -SO3R9, -SO2NR9RW, -SO2R9, -SRg, -PO3R9R10, -POR9R10, -PO (NRgRio) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle, optionally substituted by up to 3 groups independently selected from -Rg, -NRgR ₁₀ , -ORg, -NR9COR10, -COR10, - (CH ₂ ) nSO ₂ Rn, - (CH ₂ ) n R 11; R 22 and R ₂ 3 are independently hydrogen or alkyl. 7. Compound selected from: 1- [77re] N-Butyl-3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-tert-butyl-3- [2- (3-chloro-4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-tert-77-butyl-3- [6-fluoro-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -urea; 1-tert-77-butyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2, 3-d] pyrimidin-7-yl} -3-methyl-butyl -in ray; 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-l-ret-butyl-urea ; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-0] pyrimidin-7-yl} -3-tert-butyl urea; 121 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-Pyrrol-7-butyl-urea; 1-cyclohexyl-3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -3-cyclohexyl-urea; 1-cyclohexyl-3- [6-fluoro-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-0] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- (2-hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1- (2-hydroxy-ethyl) -3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-0] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 122 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl ) -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1-ethyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,30] pyrimidin-7-yl] -urea; 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,30] pyrimidin-7-yl] -3-ethyl-urea; 1-ethyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-ethyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -3-chloro-phenylamino] pyrido [2,3-pyrimidin-7-yl} -3-ethyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -5-methylpyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1-tert-77-butyl-3- (2-phenylamino-pyrido [2,3-d] pyrimidin-7-yl) -urea; 1-tert-butyl-3- [2- (4-fluoro-3-methyl-phenylamino) pyrido [2,3-0] pyrimidin-7-yl] -urea; 1- (4-chloro-phenyl) -3- [2- (4-fluoro-3-methyl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 123 1-Isopropyl-3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-tert-Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea ; 1-cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-0] pyrimidin-7-yl} -urea; 1-cyclopentyl-3- [2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} - urea; 1-Cyclopentyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-0] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-b] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-bromo-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-cyano-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-0] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-chloro-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-bromo-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-chloro-5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-isopropyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 124 1-ethyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea; 1- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea; 1-methyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-1-methyl-3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-0] pyrimidin-7-yl] -urea; 1- (4-hydroxy-cyclohexyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (4-amino-cyclohexyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-pyrimidin-7-yl] -urea; 1- (2-dimethylamino-ethyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (3-morpholino-4-yl-propyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 3-cyclohexyl-1-methyl-1- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-pyrimidin-7-yl] -urea; N, N-dimethyl-N '- [5-methyl-2 - [[4- (1-piperazinyl) phenyl] amino] -pyrido [2,3-b] pyrimidin-7-yl] sulfamide; 1-cyclohexyl-3- [5-methyl-2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -thiourea; N- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -acetamide; 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2ylamino] -benzenesulfonamide; 1-cyclohexyl-3- {2- [4- (1-piperazin-1-yl-methanoyl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 125 1-cyclohexyl-3- [2- (4-fluoro-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea; 1- (2- {4- [4- (2-amino-4-methyl-pentanoyl) -piperazin-1-yl] phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) -3-cyclohexylurea ; and 1- (2- {4- [4- (2-amino-4-methyl-butanoyl) -piperazin-1-yl] phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) -3-cyclohexylurea . 8. Compound selected from: 1-N-tert-butyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3C] pyrimidin-7-yl] -urea; 1-ethyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (hydroxy-ethyl) -3- [2- (pyridin-4-ylamino) -pyrido [2,3C] pyrimidin-7-yl] -urea; 1-tert-butyl-3- [6-fluoro-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- [6-fluoro-2- (pyridin-4-ylamino) pyrido [2,3-b] pyrimidin-7-yl] -urea; 1-ethyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-pyrimidin-7-yl] -urea; 1- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3C] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1-tert-butyl-3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3-0] pyrimidin-7-yl] -urea; 126 1-cyclohexyl-3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-ethyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3b] pyrimidin-7-yl] -urea; and 1- (2-hydroxy-ethyl) -3- [5-methyl-2- (pyridin-4-ylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea. 9. Compound selected from: 4- {4- [7- (3-tert-Butyl-ureido) pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid methyl-butyl ester; 4- {4- [7-Cyclohexyl-ureido) pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid methyl-butyl ester; 1- (3-hydroxy-propyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- ((S) -1-hydroxymethyl-3-methyl-butyl) -3- [2- (4-piperazin-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 4-methyl-piperazine-1-carboxylic acid [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide; morpholine-4-carboxylic acid [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide; 3- [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -1,1-dipropylurea; piperazine-1-carboxylic acid [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide; 127 1- ((R) -1-hydroxymethyl-2-methyl-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] urea; 1,1-bis- (2-hydroxy-ethyl) -3- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- [6-bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidine and n-7-yl] -3- (trans) p-butyl-y rhea; 1- [6-bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3C] pyrimidin-7-yl] -3-methyl-urea; 1- {6-bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-N- butylurea; 1- {6-bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexylurea; 1- [2- (4-Fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (3-morpholin-4-yl-propyl) -urea; 1- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1- (2-amino-ethyl) -3- [2- (4-fluoro-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -urea; 1- (2-dimethylamino-ethyl) -3- [2- (4-fluoro-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-cyclohexyl-3- {2- [4- (3,3-dimethyl-piperazin-1-yl) phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-Pyrrole-7-butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl } -urea; 128 1- {2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3- (3-morpholin-4-yl-propyl ) urea; 1-Pyrrole-7-butyl-3- {6-chloro-2- [4- (cis-3,5-dimethyl-piperazin-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} - urea; 3-Cyclohexyl-1- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -1-methyl-urea ; 3-cyclohexyl-1-ethyl-1- [2- (4-piperazin-1-ylphenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; N-pyrrol-1-butyl-1- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} - 1-ethyl-urea; 1- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3c] pyrimidin-7-yl] -3-propyl-urea; 7- (3-N-methyl-7-butyl-ureido) -2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-0] pyrimidine-6-carboxylic acid ethyl ester; 1- [6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl] -3-isopropyl urea; 1-cyclohexyl-3- {2- [4- (3,3-dimethyl-piperazin-1-yl) phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-Cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} - urea; 1-N-tert-Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7- yl} urea; 1-Rel-N-butyl-3- [6-methyl-2- (4-piperazin-1-ylphenylamino] -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-isopropyl-urea ; 129 1-cyclopropyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} - urea; and 1- (tert-Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) phenylamino] -6-ethyl-pyrido [2,3-b] pyrimidine- 7-yl} urea. A pharmaceutical composition comprising a compound of claim 1 admixed with a pharmaceutically acceptable carrier, diluent or excipient. 11. A method for controlling proliferative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliferation associated with a disorder selected from the group consisting of atherosclerosis, post-surgical vascular stenosis, and restenosis of the lesion, characterized by bose that said mammal is administered a therapeutically effective amount of a compound of claim 1. A method for inhibiting a cdk enzyme, wherein the cdk enzyme comes into contact with a compound selected from claim 1. The method of claim 12, wherein said cdk enzyme is cdk1. The method of claim 12, wherein said cdk enzyme is cdk2. 130 The method of claim 12, wherein said cdk enzyme is cdk4. 16. A method of inhibiting growth factor-mediated tyrosine kinase, wherein said growth factor-mediated tyrosine kinase comes into contact with a compound selected from claim 1. • The method of claim 16, wherein said tyrosine kinase mediating growth factor is of platelet origin (PDGF). 18. The method of claim 16, wherein said tyrosine kinase mediating growth factor is of fibroblastic origin (FGF). 19. A method of treating a subject suffering from diseases caused by cellular proliferation of the vascular smooth muscle, wherein said subject is administered a therapeutically effective amount of a compound selected from Claim 1. 20. A method for treating a cancer patient, wherein said subject is administered a therapeutically effective amount of a compound selected from claim 1. 131 21. A method for treating a subject suffering from breast cancer, squamous cell carcinoma, pancreatic cancer, colon, melanoma, lung cancer and leukemia, wherein said subject is administered a therapeutically effective amount of a compound selected of Claim 1.