SK10632002A3 - Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors - Google Patents

Abstract

Disclosed are compounds of the formula (I) wherein: R<2>, R<7>, R<13>, R<14> and R15 are independently hydrogen, or (un)substituted lower alkyl, (un)substitued lower alkenyl, (un)substituted lower alkynyl, or (un)substituted -(CH2)nR<12>; R<5> is halogen, cyano, nitro, -R<9>, -NR<9>R<10>, or -OR<9>; R<6> is halogen, cyano, nitro, -R<9>, -NR<9>R<10>, -OR<9>, -Co2R<9>, -COR<9>, -CONR<9>R<10>, -NR<9>COR<10>, (un)substituted lower alkenyl, or (un)substituted lower alkynyl; R<8> is -CO2R<13>, -COR<13>, -CONR<13>R<14>, -CSNR<13>R<14>, -C(NR<13>)NR<14>R<15>, -SO3R<13>, -S02R<13>, -SO2NR<13>R<14>, -PO3R<13>R<14>, -POR<13>R<14>, -PO(NR<13>R<14>)2; R<9> and R<10> are independently hydrogen or (un)substituted lower alkyl; R<11> is a heteroaryl or a heterocyclic group; R<12> is a cycloalkyl, a heterocyclic, an aryl, or a heteroaryl group; and n is 0,1,2, or 3. These compounds and their pharmaceutical compositions are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cdks and growth factor-mediated kinases.

Description

Field of the invention

The present invention relates to pyrido [2,3-d] pyrimidine-2,7-diamines that inhibit cyclin-dependent serine / threonine kinase enzymes and growth factor mediated by tyrosine kinase enzymes, and as such are useful in the treatment of cellular diseases and disorders proliferation.

BACKGROUND OF THE INVENTION

Cell cycle kinases are naturally occurring enzymes involved in cell cycle regulation (Meijer L., "Chemical Inhibitors of Cyclin-Dependent Kinases," Progress in Cell Cycle Research, 1995; 1: 351-363). Typical enzymes involved in cell cycle regulation include serine / threonine kinases, such as cdk1, cdk2, cdk4, cdk5, cdk6 and tyrosine kinase dependent kinases. Increased activity or temporary abnormal activation or regulation of these kinases results in the development of tumors and other cell proliferative disorders. Compounds that inhibit cdks, whether by blocking the interaction between cyclin and the corresponding kinase, or by binding and deactivating the kinase, inhibit cell proliferation and are thus useful in the treatment of tumors or other abnormal cell proliferation.

Various cdks inhibiting compounds having preclinical antitumor effects have been demonstrated. For example, flavopyridol is a flavonoid that has been shown to be a potent inhibitor of some types of breast and lung cancer. (Kaur et al., J. Natl. Cancer Inst., 1992: 84: 1736-1740; Int. J. Oncol., 1996; 9: 1143-1168). Compounds inhibiting cdk2 and cdk4 have also been reported. Olomouc [2- (hydroxyethylamino) -6-benzylamine-9-methylpurine] is a potent cdk2 acdk5 β-inhibitor (Veselý et al., Eur. J. Biochem., 1994; 224: 771-786) and has been shown to be an inhibitor of approximately 60 different tumor cell types according to the National Cancer Institute (NCI) monitoring new cancer therapies Abraham et al., Biology of the Cell. 1995 83: 105-120). Recently, a new class of purvalane inhibitors of cdk - an even more potent olomycin derivative has emerged (Gray N.S. et al. Science, 1998: 281: 533-538).

Tyrosine kinases are the basis for the propagation and amplification of the growth factor signal leading to cell cycle development, cell proliferation, differentiation and migration. Tyrosine kinases include cell surface growth factor tyrosine kinases such as FGFr and PDGFr as well as non-receptor tyrosine kinases including c-Src and lck. Inhibition of these enzymes has been demonstrated to have antitumor anti-angiogenic effects. (Harmby et al., Pharmacol. Ther. 1999; 82 (2-3): 169-193).

Several pyrido [2,3-d] pyrimidines are known to inhibit growth factor-mediated cdks and kinases (WO 98/33798). US Patent Nos. 5,733,913 and 5,733,914 disclose 6-aryl-pyrido [2,3-d] pyrimidines.

Despite the progress made in this field, the search for low molecular weight compounds that are applicable orally and suitable for the treatment of a wide variety of human tumors and other cell proliferative disorders, including restenosis, angiogenesis, diabetic retinopathy, psoriasis, postoperative adhesions, continues. , macular degeneration and atherosclerosis. The present invention provides such compounds, their pharmaceutical preparations and their use in the treatment of disorders caused by cellular proliferation.

SUMMARY OF THE INVENTION

The present invention provides novel pyrido [2,3-d] pyrimidine-2,7-diamine compounds that act as inhibitors of cell cycle regulating kinases, such as cyclin-dependent kinases and growth factor-mediated tyrosine kinases. Thus, these compounds are useful in the treatment of cell proliferative disorders such as atherosclerosis and restenosis; cancer; angiogenesis; viral infections involving DNA viruses such as e.g. herpes and RNA viruses such as e.g. HIV; fungal infections; type 1 diabetes, diabetic neuropathy and retinopathy; sclerosis; glomerulonephritis, non-neurovegetative diseases including Alzheimer's disease; autoimmune diseases such as e.g. psoriasis, rheumatoid arthritis and lupus; rejection of transplanted organs; gout; polycystic kidney disease and inflammation such as inflammatory bowel disease.

The present invention provides a pyrido [2,3-d] pyrimidine having the general structure of Formula I

where:

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 may be optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , (CH ₂ ) _n CO ₂ R ⁹ ,

- (CH ₂ ) _n SO ₂ R ⁿ , - (CH 2) n R ⁿ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -SO ³ R ⁹ , -SO ² NR ⁹ R ¹⁰ -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ , or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ , -COR ¹⁰ , (CH 2) ⁿ SO 2 R ⁿ , - (CH 2) _n R ⁿ or

- (CH ₂ ) _n R optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH 2) n CO ² R ⁹ , - (CH 2) _n SO ₂ R ^u, - (CH 2) n R ^n, -COR ^9, -CONR ⁹ R ^10, -SO 3 R ^9, -SO 2 nR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, POR ¹⁰ R ^9, -PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -nr ⁹ co2r ¹⁰ , -nr ⁹ conr ⁹ r ¹⁰ , -NR ⁹ SO ² R ¹⁰ or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , - NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ , -COR ¹⁰ , - (CH 2) n SO ² R ^H , - (CH 2) _n R ^H :

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

R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ₂ R ⁹ , -COR ⁹ ,

-conr ⁹ r ¹⁰ , -nr ⁹ cor '°, -so3r ⁹ , -so2nr ⁹ r ¹⁰ , -so ₂ r ⁹ , -SR ⁹ , -PO3R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2 or lower alkenyl or lower alkynyl optionally substituted with -R ⁹ ;

R ⁸ is H, -CO ² R ¹³ , COR ¹³ , -CONR ¹³ R ¹⁴ , -CSNR ¹³ R ¹⁴ , -C (NR ¹³ ) NR ¹⁴ R ¹⁵ , -SO ³ R ¹³ , -SO ² R ¹³ , -SO ² NR ¹³ R ¹⁴ , - PO3R ¹³ R ^14, POR ¹³ R ^14, -PO (NR ¹⁴ R ⁱ³⁾ 2;

R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached connected, R ⁹ and R ¹⁰ form a cycle of 3 to 7 members, of which up to four may be selected

ABOUT

II ζ / ^ \, O, S and NR ²⁰ wherein R ²⁰ is hydrogen, lower alkyl or -CO-lower alkyl;

R ¹¹ is heteroaryl or heterocyclic;

R is cycloalkyl, heterocycle, aryl or heteroaryl; n is 0, 1, 2 or 3;

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

The invention also provides compositions comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent or pharmacological base.

The present invention also provides methods of inhibiting cyclin-dependent kinases and growth factor-mediating kinase enzymes.

The present invention also provides a method of treating subjects suffering from cell proliferative diseases. The method includes inhibiting the proliferation of tumor-forming 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 the affected subject.

The present invention also provides a method of treating subjects suffering from diseases caused by DNA tumor viruses, such as herpes viruses or salivary gland viruses, by administering a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds claimed by the invention are described by the general formula I above and their pharmaceutically acceptable salts, esters, amides and prodrugs.

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

Where R, R, R and R are as defined for pn of Formula I;

R ¹⁶ , R ¹⁷ and R ¹⁸ are as defined above for the (CH ₂ ) _n R ¹² substituents and are preferably independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano , nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkyl-aminocarbonyl, alkylcarbonyl, -SO ₃ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ , or

R ¹⁶ is a carbocyclic group containing 3 to 7 members, of which up to two are heteroatoms selected from oxygen and nitrogen, wherein the carboxyl group is either unsubstituted or substituted with 1, 2 or 3 groups as defined above, but preferably are independently selected from halogen, hydroxy lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocycloalkyl, heterocyclylsulfonyl or hetrocyclylsulfonylalkyl.

Preferred compounds of formula II are those wherein R ⁵ is hydrogen or lower alkyl; R ⁶ is hydrogen, lower alkyl, cyano or halogen; R ¹⁷ and R ¹⁸ are independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, carboxy, aminocarbonyl, mono- or dialkylaminocarbonyl, -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ COR ¹⁰ ; and R ¹⁶ is an optionally substituted N-piperidine, N-piperazine or N-pyrrolidine wherein the substituents are selected from R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ and -COR ¹⁰ .

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

^K (III) wherein R, R and R are as defined for Formula I; and

R ¹⁹ is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each optionally substituted with up to five groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO ³ R ⁹ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above or are aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl7 alkyl, wherein each aryl, heteroaryl or cycloalkyl 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, -SO ³ R ⁹ , -SO 2 NR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ or (CH 2) _n -carbocyclic groups containing from 3 to 7 members of of which up to two are heteroatoms selected from oxygen and nitrogen, and wherein the carboxyl group is either unsubstituted or substituted with 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 hetrocyclylsulfonylalkyl; and

R ²¹ is hydrogen, lower alkyl or lower alkyl substituted by phenyl or substituted phenyl.

Preferred compounds of formula ΙΠ are those 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; R ¹⁹ is optionally substituted lower alkyl, cycloalkyl or (CH 3 -carbocyclic).

A particularly preferred group of pyrido [2,3-d] pyrimidines has the formula IV:

(IV) wherein R ⁵ , R ⁶ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²¹ are as defined above. Preferred compounds of Formula IV are those wherein R is hydrogen or methyl.

Another particularly preferred group of compounds of the invention has the formula V:

wherein R ⁵ , R ⁶ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²¹ are as defined above. Preferred compounds of formula V are those wherein R ²¹ is hydrogen or methyl.

The most preferred compounds of the invention have the formula VI

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.

As used herein, the terms "alkyl", "lower alkyl" and "(C 1 -C 10) -alkyl" mean straight or branched chain alkyl groups having 1 to 10 carbon atoms, preferably C 1 -C 6 alkyl. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl decyl, octyl and 3-methylpentyl . These groups may be substituted e.g. halogen, C 1 -C 3 alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy and the like. Examples include chloromethyl, 2-aminoethyl and 3-dimethylaminopropyl.

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

"Alkynyl", "lower alkynyl" and "(C 2 -C 10) -alkynyl" mean straight or branched chain alkyl groups having 1 to 10 carbon atoms and a triple bond. Typical alkynyl groups are 2-propynyl and 1,1-dimethyl-3-butynyl. Substituted alkenyl and alkynyl groups are 4,4-dibromo-2-pentenyl and 3-amino-5-hexinyl.

"Alkoxy", "lower alkoxy" and "(C 1 -C 10) -alkoxy" mean straight or branched chain alkoxy groups having 1 to 10 carbon atoms, such as e.g. methoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

The term "alkanoyl" means an alkyl group linked to the carbonyl moiety. Examples are acetyl and pentanoyl. "Aminoalkanoyl" means an alkyl group substituted with an amino group. Examples are aminoacetyl and 3-aminohexanoyl. "Alkylaminoalkanoyl" means an aminoalkanoyl group wherein the amine is substituted with a (C 1 -C 10) alkyl group and includes methylaminoacetyl and 4- (isobutylamino) -octanoyl. "Dialkylaminoalkanoyl" refers to an N, N-di-substituted aminoalkanoyl group such as diisopropylaminoacetyl.

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

The term "aryl" means an unsubstituted aromatic carboxyl group with a single cycle (e.g. phenyl), multiple cycles (e.g. biphenyl) or multiple condensed cycles in which at least one is aromatic (e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl) , anthryl, phenanthryl). The term "substituted aryl" refers to aryl substituted with 1 to 4 substituents selected from alkyl, O-alkyl and S-alkyl, -OH, -SH, -CN, halogen, 1,3-dioxolanyl, -CF 3,

-NO 2, -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , -NHCO-alkyl, - (CH ₂ ) _m CO ₂ H, - (CH ₂ ) _m CO ₂ -alkyl, - (CH ₂ ) _m SO ₃ H, -NH-alkyl, -N (alkyl) ₂ , - (CH ₂ ) _m PO ₃ H ₂ , - (CH ₂ ) _m PO ₃ (alkyl) ₂ , - (CH ₂ ) _m SO ₂ NH ₂ and - (CH ₂ ) _m SO ₂ NH-alkyl, wherein alkyl is as defined above and is 0, 1, 2 or 3. Some examples of substituted aryl groups are methylphenyl, isopropoxyphenyl, chlorophenyl, 2-bromo-3-fluoromethyl-4-nitro 5-aminophenyl, 4-bromobiphenyl, 3-acetamidonaphthyl, 3-dimethylaminoantryl, 3,4-dimethoxyphenanthryl and 2,8-dibromobiphenyl-1-yl.

"Heteroaryl" refers to one or more 5-, 6-or 7-membered aromatic ring systems containing at least 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur. These heteroaryl groups include e.g. thienyl, furanyl, thiazolyl, imidazolyl, (iso) oxazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, (iso) quinoline, naphthyridinyl, phthalimidyl, benzimidazolyl, benzoxazolyl. A "substituted heteroaryl" group may be substituted with 1,2,3 or 4 groups listed above as "substituted aryls" such as 2,3,4,6-tetrahydropyridyl and 2-methoxy-3-trifluoromethylthien-4-yl.

The term "heterocyclic group" refers to a non-aromatic cycle with 5, 6 or 7 members, of which 1 to 4 are nitrogen, oxygen or sulfur. Examples of heterocyclic groups include morpholine, piperidine, piperazine, pyrrolidinyl and tetrahydrothienyl. These groups may be substituted with the same groups described above for substituted heteroaryls.

The term &quot; carbocyclic group &quot; or &quot; cycloalkyl &quot; Examples are cyclopropyl, cyclobutyl and cycloheptyl. These cycles may be substituted with one or more of the groups listed above for aryl, e.g. alkyl, halogen, amine, hydroxy and alkoxy groups. Typical examples are 2-chlorocyclopropyl, 2,3-diethoxycyclopentyl and 2,2,4,4-tetrafluorocyclohexyl. Carbocyclic groups may contain 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen. This system is then referred to as "heterocyclyl" or "heterocyclic". Examples are piperidyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrogenfuranyl and dioxanyl. These heterocyclic groups may be substituted with up to 4 aryl-substituted substituents to form groups such as 3,5-dimethylpiperazin-1-yl, 3,3-diethylpiperazin-1-yl, 3,3,4,411 tetramethylpyrrolidinyl, 3-chloro-2 -dioxanyl and 3,5-dihydroxymorpholino. They may also contain a keto group, such as 3-ketopiperidyl.

The term "cancer" includes, but is not limited to, the following types of tumors: breast, ovary, uterus, prostate, egg, esophagus, glioblastoma, neuroblastoma, stomach, skin, lung, epidermoid carcinoma, adenocarcinoma, bone, intestine, adenoma , pancreas, thyroid, follicular carcinoma, papillocarcinoma, seminocarcinoma, melanoma, sarcoma, liver and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, oral cavity, pharynx, lip, tongue, mouth, thin, the colon, rectum, brain and central nervous system; and leukemia.

Compounds of formulas I-VI may exist as pharmaceutically acceptable salts, esters, amides, and prodrugs. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" refers to those carboxylic salts, amino acid salts, esters, amides, and prodrugs of the compounds of this invention that are suitable for use in contact with the tissues of patients without excessive toxicity, irritability, allergic reactions, etc. in proportion to their reasonable yield / risk ratio and are effective in their intended use as well as their zwitterionic forms. The term "salts" refers to the relatively non-toxic salts of inorganic and organic acids and bases and compounds of the formulas above. These salts may be prepared in situ during the final isolation and purification of the compounds or separately by reaction of the purified compounds in the form of free bases e.g. with a suitable organic or inorganic acid and isolating the salt thus formed. Representative of these salts are hydrobromide, hydrobromide, sulfate, bisulfate, nitrate, acetate, oxalate, valeran, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, p-toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, tartrate, tartrate naphlylate, methanesulfonate, lauryl sulfonate and the like. If the compound of the above formulas has one or more acidic groups, it may form salts by reaction with bases. These salts may contain alkali and alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium and the like. and also based on inorganic bases such as ammonium, tetrahydrogenammonium (quaternary ammonium) and other ammonium ions including tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, tritylamine, ethylamine and the like. Pharmaceutically acceptable salts are well known to those skilled in the art of medicinal chemistry. (See, e.g., Berge S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66; 1-19, which is incorporated herein by reference.)

Examples of pharmaceutically acceptable nontoxic esters of the compounds of this invention include C 1 -C 6 alkyl esters wherein the alkyl group is a straight or branched, substituted or unsubstituted hydrocarbon. Esters also include C5-C7 cycloalkyl esters and aryl alkyl esters such as benzyl and triphenylmethyl, C1-C4 alkyl esters, e.g. methyl, ethyl, 2,2,2-trichloroethyl and tert-butyl. Esters of the compounds of this invention may be prepared by conventional methods, e.g. by reacting the acid with an alcohol.

Examples of pharmaceutically acceptable amides of the compounds of this invention are amides derived from ammonium, primary C 1 -C 6 alkyl amines and secondary C 1 -C 6 dialkylamines, wherein the alkyl group is either straight or branched. In the case of secondary amines, the amines may also be in the form of 5- or 6-membered heterocycles containing 1 nitrogen atom.

Amides derived from ammonia, C 1 -C 3 alkyl primary amines and _Cl-C2 dialkyl secondary amines. The amides of the compounds of this invention can be prepared by conventional methods known to those skilled in the art.

The term "prodrug" refers to compounds that transform rapidly in vivo to produce compounds of the above formulas, for example, by hydrolysis in blood or gastric juice. A detailed discussion of prodrugs is in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Syriosium Šerieš, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both references are incorporated herein by reference. Representative compounds of the invention are listed in Table 1.

Table 1

Ν '

Η

Ν '

Η

Ν '

Η

and ₃ o _χ Αχ /% κ ^ΝΗίΧ '^Η;

^NN HN ^ NH

CH ₃ ? ^X CH ₃

Representative compounds of the invention that are according to Formula I include, but are not limited to, the compounds in Table 1 and their pharmaceutically acceptable acid or base salts, esters or amides, and prodrugs thereof.

The compounds of the invention may exist in both unsolvated and solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are also included within the scope of the invention.

Certain compounds of Formula I have one or more chiral centers and may therefore exist as individual stereoisomers or mixtures thereof. Other compounds may exist in more than one geometric form. The present invention encompasses all optical and geometric isomers and forms and mixtures thereof. Racemic mixtures of the compounds of the invention are readily separated into the individual isomers by routine procedures such as chromatography, fractional crystallization and classical decomposition using optically active acids and salts. The individual isomers may also be prepared by chiral synthesis, including chiral hydrogenation and the like. using commercially available chiral catalysts.

The compounds of the invention are useful in the treatment of cancer (e.g., leukemia and lung, breast, prostate and skin cancers such as melanoma) and other diseases caused by cellular proliferation, including (but not limited to) psoriasis, HSV, HIV, restenosis and atherosclerosis . In order to utilize a compound of the invention for the treatment of cancer, a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the invention is administered to a patient suffering from cancer.

Another aspect of the invention is a method of treating patients suffering from diseases caused by the proliferation of vascular smooth muscle cells. The compounds of the invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. This method inhibits the proliferation and / or migration of vascular smooth muscle cells by administering an effective amount of the compounds of Formulas I to VI to a subject in need of treatment. "Subject" and "patient" are mammals, such as e.g. but it can also be a horse, cattle, sheep, or a cat or a dog.

The compounds of the invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. The following dosage forms may contain as the active ingredient either a compound of formula I or the corresponding pharmaceutically acceptable salt or solvate of a compound of formula I.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formulas I to VI together with a pharmaceutically acceptable carrier, diluent or base. The pharmaceutically acceptable carrier for the preparation of pharmaceutical compositions with the compounds of this invention may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, suppositories, and disposable granules. The solid carrier may be one or more substances which may also serve as a diluent, colorant, binder, preservative, tablet disintegrant or encapsulating material.

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

The compositions of the invention preferably contain from about 5% to about 70% or more of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talk, sugar, pectin, dextrin, starch, gelatin, goat, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. A preferred form for oral use is a capsule which is formed from the active ingredient and the carrier, which is an encapsulating material that surrounds the active ingredient with or without other carriers and is therefore associated therewith. Similar to lozenges. Tablets, powders, cachets, capsules, pills, and lozenges can be used as solid dosage forms for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient, e.g. stirring. The molten homogeneous mixture is poured into a mold of suitable size, allowed to cool and then solidified.

Liquid formulations are solutions, suspensions, and emulsions such as water or water / propylene glycol solutions. For parenteral injection, preparations dissolved in aqueous polyethylene glycol solution, isotonic saline solution, 5% aqueous glucose solution and the like can be used. Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing agents and thickeners as appropriate. Aqueous suspensions suitable for oral use can be made by dispersing finely divided active ingredients in water and mixing them with a viscous material, e.g. with a natural or synthetic resin, methylcellulose, sodium carboxymethylcellulose or other known suspending agents.

Also included are solid forms that are converted to liquid forms for oral administration immediately prior to use. These liquid forms are solutions, suspensions and emulsions. These preparations may contain colorants, flavors, stabilizers, buffers, natural or artificial sweeteners, dispersing agents, thickeners, solvents and the like as active ingredients. Waxes, polymers, microparticles and the like can be used to prepare a more durable preparation. Osmotic pumps can also be used for uniform application over extended periods of time.

The pharmaceutical preparations of the invention are preferably in unit dosage form. The preparation is subdivided into unit doses containing appropriate doses of the active ingredient. This form may be packaged, the package containing an individual amount of the active ingredient, examples being packaged tablets, capsules and powders in ampoules or vials. The unit doses may be in capsules, tablets, powders, in cachets, or lozenges alone, or may be presented in appropriate amounts in packaged form.

A therapeutically effective dose of a compound of Formula I will generally be from about 1 to about 100 mg / kg of body weight per day. Typical adult doses will be from about 50 to about 800 mg per day. The amount of active ingredient in a unit dose of preparation may be varied or adjusted from about 0.1 to about 500 mg, preferably from about 0.5 to 100 mg, depending on the specificity of application and the efficacy of the active ingredient. The composition may, if desired, also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I is administered a dose of from about 1 to about 500 mg per day, either in single or multiple doses over 24 hour periods.

The compounds of the invention are capable of binding and thereby inhibiting the effects of proteins having the ability to phosphorylate other proteins, such as cdks, PDGFr, FGFr, c-Src and EGFr. Cdks form complexes with cyclins, and these complexes phosphorylate key proteins enabling cells to continue the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995; 1; 351-363). The compounds of the invention inhibit this phosphorylation and can therefore be used as antifungal agents in the treatment of cancer and / or restenosis and other diseases caused by cellular proliferation.

Because of their inhibitory effects against cdks and other kinases, the compounds of this invention are useful tools for researching the mechanism of action of these kinases, both in vitro and in vivo.

The preparation and use of the compounds of this invention is described in the following detailed examples. The examples are presented to illustrate particular areas of the invention and are not to be construed as limiting the scope or claims of the invention in any way. The compounds of the invention are prepared by methods well known to those skilled in the art of organic chemistry. These procedures use commercially available starting materials and reagents.

During the synthesis of the compounds of the invention, it may be desirable to protect the reactive functional groups of the molecules involved in the reactions to avoid unwanted side reactions.

Functional groups such as hydroxy, amino and carboxy groups are usually protected by suitable groups, which can be easily removed when necessary. The use of conventional protecting groups is described in detail by Green and Wuts in Protective Groups in Organic Synthesis, John Wiley &amp; Sons, New York (2 ^nd Edition, 1991). Typical hydroxy protecting groups are ether-forming groups such as e.g. benzyl and aryl groups such as e.g. tert-butoxycarbonyl (Boe), formyl and acetyl. The amino protecting groups are benzyl, aryl groups such as e.g. acetyl and trialkylsilyl. Carboxyl groups are usually protected by conversion to an ester that is readily hydrolyzable, for example, trichloroethyl, tert-butyl, benzyl, and the like.

As noted above, some of the compounds of the invention have one or more chiral centers, so that they exist as individual optical and geometric isomers and mixtures thereof. For example, compound 106 has two asymmetric centers and has a cis configuration. The present invention encompasses all of these geometric isomers, enantiomers and RS racemates, as well as the individual R and S isomers of the chiral compounds. All individual isomers and mixtures thereof are included in the present invention. The individual isomers are readily prepared by chiral synthesis or by conventional resolution techniques well known to those skilled in the art.

Illustrations of the preparation of compounds of the invention are shown in Schemes 1-4. The synthesis of compound 1 (Example 15) is shown in Scheme 1, but it should be emphasized that the general schemes are applicable to all compounds of the invention. Each step shown in the schemes is further illustrated by the detailed examples that follow.

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 treatment with LiAlH 4 to give a 5-hydroxymethyl analog which is further oxidized to the 5-formyl derivative. 5-formyl is converted to an unsaturated (acrylate) group which is cyclized to pyrido [2,3-d] pyrimidine. Pyridopyrimidine is converted to a key intermediate, 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine, which is immediately oxidized to give the 2-methylsulfinyl analog. 2-methylsulphinyl group is replaced with an amine R ² NH 2 to form a compound of formula I. The amino group at the 7-pyridopyrimidine cycle is immediately converted to a urea by reaction with an isocyanate, e.g. R ¹⁹ N = C = O.

Scheme 1

Boe

Boe

The reactants in Scheme 1 have the following meanings:

(a) NH ₃ ; (b) LAH; (c) MnO ₂ ; (d) PH ₃ PCHCO ₂ Et; (e) DBU; (f) POCl ₃ ; (g) NH ₃ ; (h) (±) -trans-2- (phenylsulfonyl) -3-phenyloxaziridine; (i) 4- (4-Boc-piperidine) aniline; (j) NaH, t-butyl isocyanate; (k) HCl.

Scheme 2 illustrates an alternative synthesis of pyridopyrimidine having a urea group at the 7-position. While this urea was prepared in Scheme 1 by reacting an isocyanate with 7-amino-pyridopyrimidine, Scheme 2 uses carbonyldiimidazole to provide the intermediate imidazolide. The imidazolide is reacted directly with an amine _NH2 R ⁱ⁹ to form the corresponding urea. Scheme 2 illustrates this process by showing the synthesis of compound 51, which is described in more detail in Example 32.

Scheme 2

Reactants: (a) NaH, carbonyldiimidazole; (b) cyclopentylamine; (c) HCl

Compounds of formula I can also be prepared according to Scheme 3, which depicts the synthesis of compound 4 (Example 45). 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxyaldehyde is reacted with methylmagnesium bromide to give the corresponding 5- (2-hydroxyethyl) -pyrimidine. The alcohol is oxidized to methyl ketone. This is reacted with diethyl cyanophosphonate and cyclized to 5-methyl-7-amino-pyridopyrimidine. A further reaction, as in Scheme 1 or 2, yields a compound of the invention, in this case compound 4.

Scheme 3

Reactants: (a) MeMgBr; (b) MnO ₂ ; (c) (EtO) ₂ P (O) CH ₂ CN

Compounds of formula I may also be prepared according to Scheme 4, which illustrates the synthesis of compound 12 (Example 40). In this scheme, the 2-methylthionic pyrimidine group is first oxidized to the corresponding methylsulfinyl analog. Methylsulphinyl be replaced by reaction with an amine R ² NH _second The 5-carboxyaldehyde is then reacted as in Scheme 1 and cyclized to give the corresponding 7-amino pyridopyrimidine substituted with 2 (R ² NH). The 7-amino group is arylized or derivatized as in Schemes 1-3.

Scheme 4

3 ° C

Reactants: (a) (±) -trans-2- (phenylsulfonyl) -3-phenyloxaziridine; (b) 4- (4-Boc-piperidine) aniline; (c) (EtO) ₂ P (O) CH ₂ CN

Any compound of the invention of formula I-VI can be prepared according to Schemes 1-4, which illustrates the synthesis of compounds 1, 51, 4 and 12. Those skilled in the art of organic chemistry know that the starting materials can be varied to prepare compounds according to Other procedures may be utilized in the present invention, as will be demonstrated in the following examples.

Articles and references, including patents, are incorporated herein by reference.

The patent is further illustrated by the following detailed examples, which are not intended to limit the scope or spirit of the invention. Starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1

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

To a solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran at room temperature was added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide solution. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide solution was added and stirring was continued for an additional 1 hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. Wash the organic layer with brine, dry over magnesium sulfate, filter, and concentrate in vacuo. Ethyl acetate and hexane were added and the resulting solid was collected by filtration to give 10.84 g (79%) of the ethyl ester.

4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid.

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

A solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (13.36 g, 63 mmol) in 250 mL of tetrahydrofuran was added dropwise at room temperature to a suspension of lithium aluminum hydride (3.82 g, 100 mmol) in 250 ml of tetrahydrofuran. After 30 minutes, the reaction is cooled to 0 ° C and isopropyl alcohol is added until the bubbles disappear. The reaction was quenched with 15 mL of water, 15 mL of 15% NaOH, and again 50 mL of water, and the mixture was stirred for 1 hour. The white precipitate was collected by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and 3: 1 hexane: ethyl acetate was added followed by hexane. The solid was dissolved in ethyl acetate and the solution was dried over magnesium sulfate. Filtration followed by concentration in vacuo afforded 8.14 g (76%) of (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol.

Analysis calculated for C6H9N3OS:

C. 42.09; H. 5.30; N. 24.54.

Result: C. 42.31; H. 5.24; N. 24.27.

EXAMPLE 3

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

To a solution of (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol (8.14 g, 48 mmol) in 1 L of chloroform was added manganese oxide (33.13 g, 381 mmol). The suspension was stirred at room temperature overnight, then filtered through celite 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-carboxyaldehyde, m.p. Mp 185-187 ° C, m.p. in literature 183-184 ° C, JOC, 1958; 23; 1738th

Analysis calculated for C6H7N3OS:

C. 42.59; H. 4.17; N. 24.83.

Result: 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-5-carboxyaldehyde (4.08 g, 24.14 mmol) in 100 mL of tetrahydrofuran at room temperature was added (carbetoxymethylene) triphenylphosphorane (10.80 g, 31 mmol). The reaction mixture was heated at reflux overnight, 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-methanesulfanyl). (pyrimidin-5-yl) acrylate: bt 108 ° C.

Analysis calculated for C10H13N3O2S:

C. 50.19; H. 5.48; N. 17.56.

Result: C. 50.22; H. 5.45; N. 17.24.

EXAMPLE 5

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

To a solution of ethyl 3- (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -acrylate (368 mg, 1.53 mmol) in 3 mL of Ν, Ν-diisopropylethylamine at room temperature is added 380 µL of 1,8-diazabicyclo [ 5.4.0] undecane-7-ene. The reaction mixture was heated at reflux for 3 hours, then cooled to room temperature and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The product-containing fraction was partially concentrated in vacuo and the solid collected by filtration to give 134 mg (45%) of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one, m.p. Mp 269-271 ° C.

Analysis calculated for C8H7N3OS:

C. 49.73; H. 3.65; N. 21.75.

Result: C. 49.67; H, 3.46; N. 21.49.

EXAMPLE 6

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

A suspension of 1.0 g (5.2 mmol) of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 5) in 10 ml of phosphorus oxychloride was heated; under reflux for 1 hour. The resulting solution was cooled and concentrated, the solid was triturated with cold water and filtered to give 1.05 g of crude product. Recrystallization from acetonitrile gave 0.76 g (69%) of the desired product, m.p. Mp 201-203 ° C.

MS (APCI) M + 1: Calcd. 212.0; Result 212.0.

Analysis calculated for CsHHCliSiNs:

C. 45.39; H, 2.86; N. 19.85.

Result: C. 45.53; H. 2.90; N. 19.74.

EXAMPLE 7

2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine

A suspension of 2.95 g (13.9 mmol) of 7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine (Example 6) in 200 ml of ammonia-saturated isopropanol is sealed and heated at 40 ° C for 65 hours. The suspension was saturated with ammonia and heated at 40 ° C for an additional 18 hours. The solid residue was collected by filtration and crushed with water to give 1.98 g (74.2%) of product, m.p. &Gt; 250 ° C.

MS (APCI) M + 1: Calcd. 193.1: Result 193.0.

Calcd. For C 8 H 8 Si:

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

Result: C. 50.14; H. 4.22; N. 29.04.

EXAMPLE 8

2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine

A suspension of 10.63 g (55.3 mmol) of 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 7) in 300 mL of dichloromethane and 300 mL of methanol was treated with 18.06 g (69 mL) of the title compound. (1 mmol) of (±) -trans-2- (phenylsulfonyl) -3-phenyloxaziridine with stirring overnight. Filter the suspension to remove a small amount of solid, concentrate to about 25 mL, and dilute with ethyl acetate. The solid was collected by filtration to give 9.27 g (80.5%) of product, m.p. Mp 180 ° C.

MS (APCI) M + 1: Calcd. 209.0: Result 209.1.

EXAMPLE 9

N 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 Heat at 100 ° C overnight. The resulting solution was cooled and poured into water. Ethyl acetate was added to the suspension and the solid was collected by filtration. Further purify by flash chromatography eluting with a gradient of 0% to 20% methanol / dichloromethane over 30 minutes to give 0.14 g (29%) of product, m.p. 255 DEG-260 DEG.

MS (APCI) M + 1: Calcd. 238.1: Result 238.1.

Analysis calculated for C13H11N5.0.18 H2O:

C. 64.92; H, 4.76; N. 29.12.

Result: 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 solution of 0.1022 g (0.431 mmol) of N ^2- phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine (Example 9) in 2 ml of dimethylformamide cooled in an ice bath was added 0.019 g (0.47 mmol). mmol) of 60% sodium hydride. To the resulting ice-cooled solution was added

0.054 ml (0.47 mmol) of tert-butyl isocyanate. The cold solution was stirred for 15 minutes and then for an additional 1 hour at room temperature. The solution was poured into ice water, the solid collected by filtration and washed with hexane to give 0.0849 g (57.8%) of the product (compound 45), m.p.

227 ° C.

MS (APCI) M + 1: Calcd. 337.2: Result 337.1.

Calcd. 0.27 H ₂ O:

C. 63.35; H, 6.07; N. 24.63.

Result: 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 ethyldiisopropylamine in 75 ml of dichloromethane was added 8.69 g (40 mmol) of di-tert-butyl -dicarbonate and stirred at room temperature overnight. The resulting solution was washed with saturated aqueous sodium carbonate 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 over 10 minutes to give 8.62 g%) of product, m.p. Mp 136-140 ° C.

MS (APCI) M + 1: Calcd. 308.2: Result 308.2.

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

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 is added hydrogen to an initial pressure of 54, 5 psi. The reaction mixture was shaken for 14 hours and then filtered. The filtrate was concentrated to give 1.29 g (97%) of product as a solid.

MS (APCI) M + 1: Calcd. 278.2: Result 278.1.

Analysis calculated for C ₁₈ H 23 N ₃ O ₂ :

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

Result: C. 65.22; H. 8.58; N. 14.58.

EXAMPLE 13 4- [4- (7-Amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Replacement of aniline with 4- (4-amino-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (Example 12) in Example 9 afforded 0.0744 g (36.0%) of the product, m.p. Mp 219-220 ° C.

MS (APCI) M + 1: Calcd. 422.2: Result 422.2.

Analysis calculated for C22H27N7O2.0,5 _H2O:

C. 61.38; H. 6.56; N. 22.77.

Result: C. 61.34; H. 6.30; N. 22.47.

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

Replacing N-phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine with 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -tert-butyl ester] -phenyl] -piperazine-1-carboxylic acid (Example 13) in Example 10 gave 0.3354 g (67.9%) of the product (Compound 79); 225 [deg.] C.

MS (APCI) M + 1: Calcd. 521.3: Result 521.2.

Analysis calculated for C27H36N8O3:

C. 62.69; H, 6.97; N. 21.52.

Result: C. 62.33; H. 6.81; N. 21.43.

EXAMPLE 15 1- tert -Butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

To a suspension of 0.100 g (0.192 mmol) of 4- {4- [7- (3-tert-butylureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine acid tert-butyl ester of 1-carboxylic acid (Example 14) in 2 mL of methanol was added 2 mL of 4M hydrogen chloride / dioxane to give a solution. The suspension was stirred at room temperature overnight, then diluted with diethyl ether. Filtration gave 0.0941 g (93.4%) of the product (compound 1), m.p. 215 [deg.] C.

MS (APCI) M + 1: Calcd. 421.2: Result 421.1.

Calcd. For C ₂ H 28 N ₈ O ₁ .2.10 HCL.1.51 H ₂ O:

C. 50.40; H, 6.37; N. 21.37; Cl (total). 14.20.

Result: C. 50.40; H. 6.18; N. 21.03; Cl (total). 14.33.

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

Replacement of tert-butyl isocyanate with cyclohexyl isocyanate in Example 14 gave 0.1463 g (70.4%) of the product (Compound 80), m.p. 241 ° C.

MS (APCI) M + 1: Calcd. 547.3: Result 547.4.

Analysis calculated for C 29 H ₃ 8NsO ₃ .0,28 H2O:

C. 63.13; H, 7.04; N. 20.31.

Result: C. 63.14; H. 6.81; N. 20.25.

EXAMPLE 17 1-Cyclohexyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid ester (Example 16) in Example 14 was obtained 0.0871 g (81.4%) of the product (Compound 9), mp 200 ° C.

MS (APCI) M + 1: Calcd. 447.3: Result 447.3.

Analysis calculated for C 24 H ₃ oN80i.2,55HCL.2,82 H2O:

C. 48.83; H. 6.52; N. 18.98; Cl (total). 15.31.

Result: C. 48.83; H. 6.18; N. 18.89; Cl (total). 15.37.

EXAMPLE 18

^2- (4-Fluoro-3-methyl-phenyl) -pyrido [2,3-d] pyrimidine-2,7-diamine

Replacement of the aniline with 4-fluoro-3-methylaniline in Example 9 afforded 0.2025 g (39.2%) of the product as a solid.

MS (APCI) M + 1: Calcd. 270.1: Result 270.0.

EXAMPLE 19 1- tert -Butyl-3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Substituting N ^2- phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine N ² - (4-fluoro-3-methyl-phenylpyrido [2,3-d] pyrimidine-2,7-diamine) (Example 18 ) in Example 10, 0.0656 g (47.9%) of the product (Compound 46) was obtained, mp 230 ° C.

MS (APCI) M + 1: Calcd. 369.2: Result 369.1.

Analysis calculated for C19H21F1N6O1:

C. 61.94; H. 5.75; N. 22.81.

Result: C. 61.82; H. 5.73; N. 22.75.

EXAMPLE 20 1- (4-Chloro-phenyl) -3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of tert-butyl isocyanate with 4-chlorophenyl isocyanate in Example 19 afforded 0.050 g (37%) of the product (compound 47), m.p. &Gt; 250 ° C.

MS (APCI) M + 1: Calcd. 369.2: Result 369.1.

Calcd. For C21H16F1Cl1N6O1:

C. 59.07; H. 3.89; N. 19.68.

Result: C. 59.09; H, 3.97; N. 19.65.

EXAMPLE 21 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-tert-butyl-urea

To a suspension of 0.145 g (0.277 mmol) of 1- tert -butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Example 15) in Ethyl diisopropylamine (0.19 mL, 1.11 mmol) was added to dichloromethane (5 mL). The suspension was cooled in an ice bath and acetyl chloride (0.024 mL, 0.33 mmol) was added. The suspension was stirred overnight at room temperature and then filtered. The solid was washed with dichloromethane. The filtrate and washings were combined, washed with water, dried (magnesium sulfate) and concentrated. Purify by flash chromatography eluting with methanol / dichloromethane with a gradient of 0% to 5% over 30 minutes to give 0.0674 g (51.8%) of the product (compound 5), m.p. Mp 206-208 ° C.

MS (APCI) M + 1: Calcd. 463.3: Result 463.3.

Analysis calculated for C24H3oNg02.0,40 _H2O:

C. 61.36; H, 6.61; N. 23.85.

Result: C. 61.38; H, 6.37; N, 23.98.

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

Replacing tert-butyl isocyanate with isopropyl isocyanate in Example 14 afforded 0.909 g (69.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 507.3: Result 507.4.

EXAMPLE 23 1-Isopropyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of 4- {4- [7- (3-tert-butyl-ureido) -pyrido [2,3d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Isopropyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid ester in Example 15 yields 0.0287. g (27.9%) of the product (compound 48), bt Mp 192 ° C.

MS (APCI) M + 1: Calcd. 407.2: Result 407.1.

Analysis calculated for C 21 H 26 N 6 O 1 · 2.05 TFA 0.84 H 2 O:

C. 46.00; H. 4.57; N., 17.10.

Result: C. 46.00; H. 4.65; N. 17.09.

EXAMPLE 24 cis-3,5-dimethyl-1- (4-nitro-phenyl) -piperazine

A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitrobenzene 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 product as a solid.

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

Replacement of 1- (4-nitrophenyl) -piperazine with cis-3,5-dimethyl-1- (4-nitro-phenyl) -piperazine (Example 24) in Example 11 afforded 14.87 g (92.8%) of the product as solid.

EXAMPLE 26 4- (4-Amino-phenyl) - cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

Replacement of 4- (4-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester with cis-2-6-dimethyl-4- (4-nitrophenyl) -piperazine-1-carboxylic acid tert-butyl ester in Example 12 affords 5.03 g (64.7%) of the product as a solid.

EXAMPLE 27 4- [4- (7-Amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

Replacing aniline with 4- (4-amino-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 26) in Example 9 afforded 0.6463 g (59.8%) of product, m.p. 245 ° C.

MS (APCI) M + 1: Calcd. 450.3: Result 450.3.

EXAMPLE 28 4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} - cis-2,6-dimethyl- piperazin-carboxylic acid

To replace N ^2- phenylpyrido [2,3-d] pyrimidine-2,7-diamine with 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -tert-butyl ester] - phenyl] -cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 27) in Example 10 gave 0.1828 g (74.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 549.3: Result 549.4.

EXAMPLE 29 1- tert -Butyl-3- {2- [4- (cis-3,5-dunethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of 4- {4- [7- (3-tert-butyl-ureido) -pyrido [2,3d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid ester in Example 15, 0.0910 g (92.9%) of the product (Compound 49) was obtained; 245 ° C.

MS (APCI) M + 1: Calcd. 449.3: Result 449.2.

EXAMPLE 30 4- {4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} - cis-2,6-dimethyl-piperazine-1- carboxylic acid

Replacement of tert-butyl isocyanate with cyclohexyl cyanate in Example 28 afforded 0.1156 (60.8%) of the product as a solid.

MS (APCI) M + 1: Calcd. 575.3: Result 575.3.

EXAMPLE 31 1-Cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea

4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid ester (example 30) in Example 15, 0.1022 g of product (compound 50) was obtained; 228 ° C.

MS (APCI) M + 1: Calcd. 475.2: Result 475.2.

EXAMPLE 32 4- {4- [7- (3-Cyclopentyl-ureido) -pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} - cis-2,6-dimethyl-piperazine acid tert-butyl ester -l-carboxylic acid

To a solution of 4- [4- (7-amino-pyrido [2,3d] pyrimidin-2-yl-amino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester (0.150 g, 0.36 mmol) (Example 13) 0.022 g (0.54 mmol) of 60% sodium hydride are added in 2 ml of dimethylformamide cooled in an ice bath. The cooled solution was stirred for 15 minutes and then treated with 0.088 g (0.54 mmol) of carbonyldiimidazole. The cooled solution was stirred for an additional 30 minutes and then cyclopentylamine (0.071 mL, 0.72 mmol) was added. The resulting solution was stirred at room temperature for 1 hour and then cold water was added. The solid was collected by filtration as the first batch of product. The filtrate was extracted with dichloromethane and the extract was dried over magnesium sulfate and concentrated to give a second crop of product. The two batches were combined and purified by flash chromatography eluting with methanol / dichloromethane eluting with a gradient of 0% to 5% over 30 minutes to give 0.1159 g (60.4%) of the product as a solid.

MS (APCI) M + 1: Calcd. 533.3: Result 533.4.

EXAMPLE 33 1-Cyclopentyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of 4- {4- [7- (3-cyclopentyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} - cis-2,6-dimethyl-piperazine- 1-carboxylic acid 4- {4- [7- (3-cyclopentyl-ureido) -pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} cis-2,6-dimethyl-tert-butyl ester -piperazine-1-carboxylic acid in Example 15, 0.0937 g (80.8%) of the product (Compound 51) was obtained; Mp 210-213 ° C.

MS (APCI) M + 1: Calcd. 433.2: Result 433.2.

Calcd for C ₂₃ H 28 N ₈ O ₁₂ 2.49 HCl 1.65 H ₂ O 10.1 dioxane:

C. 50.02; H, 6.21; N. 19.24; Cl (total). 15.71.

Result: C. 49.89; H. 5.81; N. 19.84; Cl (total). 14.74.

EXAMPLE 34 1- (4-Amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanol

To a suspension of 5.0 g (29 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxyaldehyde (Example 3) in 150 mL of ice-cold tetrahydrofuran was added 23.2 mL of a 3.0 M solution over 20 min. methylmagnesium bromide in diethyl ether (69.4 mmol). After one hour at 0 ° C, another portion of methylmagnesium bromide solution is added and the suspension is allowed to stir at room temperature overnight. The reaction was quenched with 100 mL of saturated ammonium chloride solution and partitioned between water and ethyl acetate. The organic layer was dried (magnesium sulfate) and concentrated to give 5.24 g (96%) of product, m.p. Mp 140-142 ° C.

MS (APCI) M + 1: Calcd. 186.1: Result 185.9.

EXAMPLE 35 1- (4-Amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone

Replacing (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -methanol with 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanol (Example 34) in Example 3 and conducting the reaction in toluene at 80 ° C. ° C, 3.74 g (72%) of the product was obtained as a solid.

MS (APCI) M + 1: Calcd. 184.0: Result 183.9.

EXAMPLE 36 1- (4-Amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone

Replacement of 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35) in Example 8 gave 9.57 g. (88%) of the product as a solid.

MS (APCI) M + 1: Calcd. 200: Result 200.

EXAMPLE 37 4- [4- (5-Acetyl-4-amino-pyrimidin-2-yl-amino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester

Replacement of 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 1- (4-amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone (Example 36) in Example 13 yields 4.04 g. (65%) of the product as a solid.

MS (APCI) M + 1: Calcd. 413: Result 413.

EXAMPLE 38 4- [4- (7-Amino-5-methyl-pyrido [2,3-d] pyrimidin-2-yl-amino) -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 dropwise 2.58 g (14.56 mmol) of diethyl (cyanomethyl) phosphonate. The reaction mixture was stirred at 0 ° C for 5 minutes and then at room temperature for 20 minutes. The mixture was then cooled to 0 ° C and treated with 2 g (4.85 mmol) of 4- [4- (5-acetyl-4-amino-pyrimidin-2-ylamino) -phenyl] -piperazine- tert -butyl ester. 1-carboxylic acid (Example 37). The mixture was stirred at room temperature overnight and then treated with water and a saturated aqueous ammonium chloride solution. The resulting solid was filtered and washed with ether to give 1.069 g (80%) of product.

MS (APCI) M + 1: Calcd. 436: Result 436.

EXAMPLE 39 4- {4- [7- (3-Cyclohexyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester

4- {4- [7-Amino-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester 4- {4- [7] amino-5-methylpyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid (Example 38) in Example 16 gave 0.199 g (42%) of the product as a solid.

MS (APCI) M + 1: Calcd. 561: Result 561.

EXAMPLE 40

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

4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Cyclohexyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -cis-2,6-dimethyl-piperazine-1 ester carboxylic acid (Example 39) in Example 15 gave the product (Compound 12) as a solid, mp 238 [deg.] C.

MS (APCI) M + 1: Calcd. 461: Result 461.

EXAMPLE 41

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

Replacement of 4- [4- (7-amino-5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester 1- (4-amino) 2-methylsulfanyl-pyrimidin-5-yl) ethanone (Example 35) in Example 38 gave 0.97 g (85%) of the product as a solid.

MS (APCI) M + 1: Calcd. 207: Result 207.

EXAMPLE 42

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

Replacing 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 5-methyl-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine (Example 41) in Example 8 0.85 g (83%) of the product was obtained as a solid.

MS (APCI) M + 1: Calcd. 223: Result 223.

EXAMPLE 43 4- [4- (7-Amino-5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

Replacing 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 2-methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-yl-amine (Example 42) in Example 13 0.33 g (20%) of product is obtained as a solid.

MS (APCI) M + 1: Calcd. 436: Result 436.

EXAMPLE 44 4- {4- [7- (3-tert-Butyl-ureido) -5-methyl-pyrido [2,3d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-tert-butyl ester carboxylate

Replacing N ^2- phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine with 4 {4- [7-amino-5-methyl-pyrido [2,3-d] pyrimidin-2-tert-butyl ester 1-yl-amino-1-phenyl} -piperazine-1-carboxylic acid (Example 43) in Example 10 gave 0.17 g (45%) of the product as a solid.

MS (APCI) M + 1: Calcd. 535: Result 535.

EXAMPLE 45 1- tert -Butyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of 4- {4- [7- (3-tert-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester 4- {4- [7- (3-tert-Butyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -bisyl-cis-2,6-butyl ester -dimethylpiperazine-1-carboxylic acid (Example 44) in Example 15 gave 0.070 g (72%) of the product (Compound 4) as a solid, m.p. 230-232 ° C.

MS (APCI) M + 1: Calcd. 435: Result 435.

EXAMPLE 46

6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-pyrimidine-7-one

A solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl) -fluoroacetic acid ethyl ester in 20 mL of tetrahydrofuran was cooled to -78 ° C and 12.9 mL (20.65 mmol) of 1.6 M was added dropwise. of n-butyllithium in hexanes. After stirring at -78 ° C for 30 minutes, 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) is added, the mixture is allowed to warm to room temperature and stirred over night. The reaction is quenched with saturated ammonium chloride solution and then with water. The solid was filtered and washed with diethyl ether to give 2.01 g (92%) of product.

MS (APCI) M + 1: Calcd. 212: Result 212.

EXAMPLE 47

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

Replacement of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one 6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 46) in Example 6 gives 1.86 g (85%) of product as a solid.

MS (APCI) M + 1: Calcd. 230.232: Result 230.232.

EXAMPLE 48

6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of 7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine with 7-chloro-6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine (Example 47) in Example 7 gave 0.29 g. (90%) of the product as a solid.

MS (APCI) M + 1: Calcd. 211: Result 211.

EXAMPLE 49

6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine (Example 48) in Example 8 gives 0.26 g (95%) of the product as a solid.

MS (APCI) M + 1: Calcd. 227: Result 227.

EXAMPLE 50 4- [4- (7-Amino-6-fluoro-pyrido [2,3-d] pyrimidin-2-yl-amino) -phenyl] - cis-2,6-dimethyl-piperazine- l-carboxylic acid

Replacing 6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine with 6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine (Example 49) in Example 27 yields 0.040 g (63%) of the product as a solid.

MS (APCI) M + 1: Calcd. 468: Result 468.

EXAMPLE 51 4- {4- [7- (3-Cyclohexyl-ureido) -6-fluoro-pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl] -cis-2,6-dimethyl-piperazine acid tert-butyl ester 1-carboxylic acid 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester with 4- {4- [7-amino-6-fluoropyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 50) in Example 16 0.10 g (74%) of the product was obtained as a solid.

MS (APCI) M + 1: Calcd. 593: Result 593.

EXAMPLE 52 1- (Y-Cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl] urea

4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Cyclohexyl-ureido) -6-fluoro-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} - cis-2,6-dimethyl-piperazine-1 ester of carboxylic acid (Example 51) in Example 15, 0.060 g of product (75%) (Compound 52) was obtained; Mp 227-229 ° C.

MS (APCI) M + 1: Calcd. 493: Result 493.

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

Substituting 4- [4- (7-amino-5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester with 4- {4- [7-amino-548-methyl-pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} - cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 43) in Example 32, 0.18 g (55%) of the product was obtained as a solid.

MS (APCI) M + 1: Calcd. 547: Result 547.

EXAMPLE 54 1-Cyclopentyl-3- [5-methyl-2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of 4- {4- [7- (3-tert-butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester tert-butyl 4- {4- [7- (3-Cyclopentyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid ester (Example 53) in the example 15, 0.060 g of product (75%) (compound 53) was obtained; 227až229 C.

MS (APCI) M + 1: Calcd. 447: Result 447.

EXAMPLE 55 4- (4- {7- [3- (3-Hydroxy-propyl) -ureido] -pyrido [2,3d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-tert-butyl ester carboxylate

Replacement of cyclopentylamine with 3-amino-1-propanol and sodium hydride with sodium tertiary butoxide in Example 32 afforded 0.1295 g (52.2%) of the product as a solid.

MS (APCI) M + 1: Calcd. 523.3: Result 523.2.

EXAMPLE 56 1- (3-Hydroxy-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7yl] -urea

Replacement of the starting material in Example 15 with the product of Example 55 afforded 0.1077 g of product (75%) (compound 81) as a solid, m.p. 183 ° C.

MS (APCI) M + 1: Calcd. 423.2: Result 423.1.

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

Replacement of 3-amino-1-propanol with N-methylcyclohexylamine in Example 55 gave 0.1932 g (72.7%) of the product as a solid.

MS (APCI) M + 1: Calcd. 561.3: Result 561.2.

EXAMPLE 58 1-Cyclohexyl-1-methyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of the starting material in Example 15 with the product of Example 57 gave 0.1645 g of product (75%) (compound 65) as a solid, m.p. 177 ° C.

MS (APCI) M + 1: Calcd. 461.3: Result 461.2.

EXAMPLE 59 4- (4- {7-f-3 - ((S) -1-hydroxymethyl-3-methyl-butyl) -ureido) -pyrido [2,3-d] pyrimidin-2-yl-amino acid tert-butyl ester } -phenyl) -l-carboxylic acid

Replacement of 3-amino-1-propanol with (S) - (+) - leucinol in Example 55 afforded 0.1048 g (39.1%) of the product as a solid.

MS (APCI) M + 1: Calcd. 565.3: Result 565.3.

EXAMPLE 60 1 - ((S) -1-Hydroxymethyl-3-methyl-butyl) -3- [2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-yl ] urea

Replacement of the starting material in Example 15 with the product of Example 59 afforded 0.0802 g of product (compound 83) as a solid, m.p. 185 ° C.

MS (APCI) M + 1: Calcd. 465.3: Result 465.2.

EXAMPLE 61 4- [4- (7 - {[1- (4-Methyl-piperazin-1-yl) -methanoyl] -amino} -pyrido [2,3-d] pyrimidin-2-yl- amino) phenyl] -l-carboxylic acid

Replacing 3-amino-1-propanol with N-methylpiperazine in Example 55 gives the product as a solid.

MS (APCI) M + 1: Calcd. 548.3: Result 548.3.

EXAMPLE 62 4-Methyl-piperazine-1-carboxylic acid [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide

Replacement of the starting material in Example 15 with the product of Example 61 gave 0.1194 g of product (compound 84) as a solid, m.p. 200 ° C.

MS (APCI) M + 1: Calcd. 448.3: Result 448.2.

EXAMPLE 63 4- (4- {7-f (1-Morpholin-4-yl-methanoyl) -amino) -pyrido [2,3d] pyrimidin-2-yl-amino} -phenyl) -piperazine- l-carboxylic acid

Replacing 3-amino-1-propanol with morpholine in Example 55 gives the product as a solid.

MS (APCI) M + 1: Calcd. 535.3: Result 535.2.

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

Replacement of the starting material in Example 15 with the product of Example 63 afforded 0.1132 g of product (compound 85) as a solid, m.p. 190 ° C.

MS (APCI) M + 1: Calcd. 435.2: Result 435.2.

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

Replacing 3-amino-1-propanol with dipropylamine in Example 55 gives the product as a solid.

MS (APCI) M + 1: Calcd. 549.3: Result 549.3.

EXAMPLE 66

3- [2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-YLJ-I-I-dipropylmočovina

Replacement of the starting material in Example 15 with the product of Example 65 afforded 0.1278 g of product (Compound 86) as a solid, m.p. 190 ° C.

MS (APCI) M + 1: Calcd. 449.3: Result 449.2.

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

Replacing 3-amino-1-propanol with Boc-piperazine in Example 55 gives the product as a solid.

MS (APCI) M + 1: Calcd. 634.3: Result 643.3.

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

Replacement of the starting material in Example 15 with the product of Example 67 gave 0.0342 g of product (compound 87) as a solid, m.p. Mp 220 ° C.

MS (APCI) M + 1: Calcd. 434.2: Result 434.2.

EXAMPLE 69 4- (4- {7- [3 - ((R) -1-hydroxymethyl-2-methyl-propyl) -ureido] -pyrido [2,3-d] pyrimidin-2-yl- amino} -phenyl) -piperazine-1-carboxylic acid Substituting 3-amino-1-propanol with (R) -valinol in Example 55 affords the product as a solid.

MS (APCI) M + 1: Calcd. 551.3: Result 551.3.

EXAMPLE 70 1 - ((R) -1-Hydroxymethyl-2-methyl-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] urea

Replacement of the starting material in Example 15 with Example 69 gave 0.0639 g of product (compound 88) as a solid, m.p. 200 ° C.

MS (APCI) M + 1: Calcd. 451.3: Result 451.2.

EXAMPLE 71 4- (4- {7- [3,3-Bis- (2-hydroxy-ethyl) -ureido] -pyrido [2,3d] pyrimidin-2-yl-amino} -phenyl) - tert-butyl ester piperazin-carboxylic acid

Replacing 3-amino-1-propanol with diethanolamine in Example 55 gives the product as a solid.

MS (APCI) M + 1: Calcd. 553.3: Result 553.2.

EXAMPLE 72 1,1-Bis- (2-hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of the starting material in Example 15 with Example 71 gave 0.0916 g of product (compound 89) as a solid, m.p. 185 ° C.

MS (APCI) M + 1: Calcd. 453.2: Result 453.2.

EXAMPLE 73

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

To 5.00 g (25.9 mmol) of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 5) in 130 mL of DMF was added 5.00 g (28.1 mmol). N-brómsukcúiimidu. The resulting suspension was stirred at room temperature overnight and concentrated. The solid was triturated with hot water and washed with isopropanol to give 5.59 g (79.4%) of product as a solid, m.p. Mp 266-270 ° C.

EXAMPLE 74

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

Replacement of the starting material in Example 7 with the product of Example 73 afforded 1.81 g (82.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 289.9: Result 289.9.

EXAMPLE 75

6-bromo-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of the starting material in Example 7 with the product of Example 74 gave 2.73 g (97.2%) of the product as a solid.

MS (APCI) M + 1: Calcd. 271.0: Result 270.8.

EXAMPLE 76

6-Bronw-2-methylsulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of the starting material in Example 8 with the product of Example 75 gave 1.81 g (81.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 287.0: Result 286.8.

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

Replacement of the starting material in Example 13 with the product of Example 76 gave 1.40 g (44.4%) of the product as a solid.

MS (APCI) M + 1: Calcd 500.1: Result 500.0.

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

Replacement of the starting material in Example 16 with the product of Example 77 afforded 0.1160 g (46.4%) of the product as a solid.

MS (APCI) M + 1: Calcd. 625.2: Result 625.1.

EXAMPLE 79 1- [6-Bromo-2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-cyclohexyl-urea

Replacement of the starting material in Example 15 with the product of Example 78 gave 0.0886 g (77.0%) of the product (Compound 55) as a solid, m.p. 195 ° C.

MS (APCI) M + 1: Calcd. 525.2: Result 525.1.

Calcd for C18H18N3O3: 1.64 H2O: 1.83 HCL:

C. 46.37; H. 5.53; N. 18.02; Cl. 10.44.

Result: C. 46.53; H. 5.34; N. 17.73; Cl. 10.15.

EXAMPLE 80 4- {4- [6-Bromo-7- (3-tert-butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-tert-butyl ester carboxylate

Replacement of the starting material in Example 10 with the product of Example 77 afforded 0.2571 g (42.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 599.2: Result 599.2.

EXAMPLE 81 1- [6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-tert-butyl-urea

Replacement of the starting material in Example 15 with the product of Example 80 gave 0.0481 g of product (compound 91) as a solid, m.p. 195 ° C.

MS (APCI) M + 1: Calcd. 499.2: Result 499.0,

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

Replacement of the starting material of Example 32 with the product of Example 77 and methylamine gave 0.170 g (29.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 557.2: Result 557.1.

EXAMPLE 83 1- [6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrunidin-7-yl] -3-methyl-urea

Replacement of the starting material in Example 15 with the product of Example 82 afforded 0.0963 g (69.0%) of the product (Compound 93) as a solid.

MS (APCI) M + 1: Calcd. 457.1: Result 457.1.

Analysis calculated for Ci9H ₂ 3 iBriNgOf HCL 3 _H2O:

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

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

EXAMPLE 84 4- [4-7-Amino-6-Bromo-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethyl-piperazine-1-tert-butyl ester carboxylate

Replacement of the starting material of Example 27 with Example 76 afforded 2.10 g (63.1%) of the product as a solid.

MS (APCI) M + 1: Calcd. 528.2: Result 528.2.

EXAMPLE 85 4- {4- [6-Bromo-7- (3-tert-butyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl] -cis-2-tert-butyl ester, 6-Dimethyl-piperazine-1-carboxylic acid Replacing the starting material in Example 10 with Example 84 afforded 0.1725 g (72.6%) of the product as a solid.

MS (APCI) M + 1: Calcd. 627.2: Result 627.2.

EXAMPLE 86 1- {6-Bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3d] pyrimidin-7-yl} -3-methyl- urea

Replacement of the starting material in Example 15 with the product of Example 85 afforded 0.1593 g (96.0%) of the product (Compound 94) as a solid, m.p. 202 DEG.

MS (APCI) M + 1: Calcd. 527.2: Result 527.2.

Calcd for C ₂₄ H 31 BrN ₆ O 1 '2.55 HCL' 1.70 H ₂ O:

C. 44.28; H. 5.72; N. 17.21; Cl. 13.89.

Result: C. 44.28; H. 5.72; N. 17.09; CL 12.49.

EXAMPLE 87 4- {4- [6-Bromo-7- (3-cyclohexyl-ureido) -pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -cis-2,6-tert-butyl ester -Dimethyl-piperazine-1-carboxylic acid Substitution of the starting material in Example 16 with Example 84 afforded 0.1750 g (70.7%) of the product as a solid.

MS (APCI) M + 1: Calcd. 653.3: Result 653.3.

EXAMPLE 88 1- {6-Bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3d] pyrimidin-7-yl} -cyclohexyl-urea

Replacement of the starting material in Example 15 with the product of Example 87 gave 0.1614 g (95.4%) of the product (Compound 95) as a solid, m.p. Mp 198 ° C.

MS (APCI) M + 1: Calcd. 553.2: Result 553.2.

Analysis calculated for C 26 H ₃₃ BriN80iBri HCL'2,02 · 2.76 H2O:

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

Result: C. 45.23; H. 5.82; N. 16.08; Cl. 13.53.

EXAMPLE 89

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

Replacement of the aniline with 4-fluoroaniline in Example 9 gave 1.1529 g (45.2%) of the product as a solid, m.p. Mp 245-248 ° C

MS (APCI) M + 1: Calcd. 256.1: Result 255.9.

EXAMPLE 90 1- [2- (4-Fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (3-morpholin-4-yl-propyl) -urea

Replacement of the starting material of Example 32 with the product of Example 89 and 3-morpholin-4-yl with propylamine gave 0.1465 g (58.6%) of the product (Compound 96) as a solid, m.p. 253 DEG -256 DEG.

MS (APCI) M + 1: Calcd. 426.2: Result 426.1.

Analysis calculated for C21H24F1N7O2:

C. 59.28; H. 5.69; N. 23.04.

Result: C. 59.18; H, 5.66; N. 23.04.

EXAMPLE 91 1- [2- (4-Fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea

Replacement of the starting material of Example 32 with the product of Example 89 and 2-hydroxyethylamine gave 0.0811 g (40.3%) of the product (Compound 97) as a solid, m.p. 238 DEG-240 DEG.

MS (APCI) M + 1: Calcd. 343.1: Result 343.1.

Analysis calculated for C ₁₆ H ₁₅ F 3 N ₆ O2:

C. 56.14; H. 4.42; N. 24.55.

Result: C. 55.82; H. 4.52; N. 24.15.

EXAMPLE 92 1- (2-Amino-ethyl) -3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Replacement of the starting material of Example 32 with the product of Example 89 and ethylenediamine gave 0.1000 g (49.3%) of the product (Compound 98) as a solid, m.p. Mp 217-220 ° C.

MS (APCI) M + 1: Calcd. 342.1: Result 342.0.

Calcd. For C16H16FN7Oi'0.2 H2O:

C. 55.71; H, 4.79; N. 28.42.

Result: C. 55.72; H. 4.57; N. 28.07.

EXAMPLE 93 l- (2-dimethylamino-ethyl) -3- [2- (4-fluoro-phenylamino] pyrido _[2> 3-d] pyrimidin-7-yl] -urea

Replacement of the starting material of Example 32 with the product of Example 89 and 2-dimethylaminoethylamine gave 0.0778 g (35.8%) of the product (Compound 99) as a solid, m.p. 251-255 ° C.

MS (APCI) M + 1: Calcd. 370.2: Result 370.0.

Analysis calculated for C18H20F1N7O1:

C. 58.53; H. 5.46; N. 26.54.

Result: C. 58.39; H. 5.51; N. 26.26.

EXAMPLE 94

3,3-dimethyl-l- (4-nitro-phenyl) -piperazine

Replacement of the starting material in Example 24 with 2-2-dimethylpiperazine afforded 29.43 g (88.4%) of the product as a solid.

MS (APCI) M + 1: Calcd. 236: Result 236.

EXAMPLE 95 2-2-Dimethyl-4- (4-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester

Replacement of the starting material in Example 11 with the product of Example 94 gave 11.38 g (93%) of the product as a solid.

MS (APCI) M + 1: Calcd. 336: Result 336.

EXAMPLE 96 4- (4-Amino-phenyl) -2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

Replacement of the starting material in Example 12 with Example 95 gave 12.27 g (78%) of the product as a solid.

MS (APCI) M + 1: Calcd. 306: Result 306

EXAMPLE 97 4- [4- (7-Amino-6-fluoro-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -2,2-dimethyl-piperazine-1-tert-butyl ester carboxylate

Replacement of the starting material in Example 50 with the product of Example 96 gave 0.4346 g (59.0%) of the product as a solid.

MS (APCI) M + 1: Calcd. 468.2: Result 468.3.

EXAMPLE 98 4- {4- [7- (3-Cyclohexyl-ureido) -6-fluoro-pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -2,2-dimethyl-tert-butyl ester -piperazin-carboxylic acid

Replacement of the starting material in Example 16 with Example 97 afforded 0.170 g (31.2%) of the product as a solid.

MS (APCI) M + 1: Calcd. 593.2: Result 593.4.

EXAMPLE 99 1-Cyclohexyl-3- {2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -urea

I

Replacement of the starting material in Example 15 with the product of Example 98 afforded 0.040 g of product (compound 100) as a solid.

MS (APCI) M + 1: Calcd. 493.3: Result 493.2.

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

Replacement of the starting material in Example 50 with the product of Example 12 afforded 0.2017 g (29.7%) of the product as a solid.

MS (APCI) M + 1: Calcd. 440.2: Result440.2.

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

Replacement of the starting material in Example 16 with Example 100 afforded 0.2036 g (78.6%) of the product as a solid.

MS (APCI) M + 1: Calcd. 565.3: Result 565.3.

EXAMPLE 102 1-Cyclohexyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7yl] -urea

Replacement of the starting material in Example 15 with Example 101 gave 0.1084 g (96%) of the product (Compound 11) as a solid.

MS (APCI) M + 1: Calcd. 465.2: Result 465.2.

Analysis calculated for C ^ HH ^FNNNOO 2.75 HCL 3.5H ₂ O:

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

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

EXAMPLE 103 4- {4- [7- (3-tert-Butyl-ureido) -6-fluoro-pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -cis-2-tert-butyl ester 6-Dimethyl-piperazine-1-carboxylic acid Substitution of the starting material in Example 10 with the product of Example 50 afforded 0.070 g (17.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 567.3: Result 567.3.

EXAMPLE 104 1-Cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} - urea

Replacement of the starting material in Example 15 with the product of Example 103 afforded 0.0585 g of product (compound 102) as a solid.

MS (APCI) M + 1: Calcd. 467.3: Result 467.2.

EXAMPLE 105 1- [4- (4-Nitro-phenyl) -piperazinyl] -ethanone

To a solution of 1- (4-nitro-phenyl) -piperazine (5.0 g, 24.1 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (5.04 mL, 28.9 mmol). 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 sodium bicarbonate solution and brine, dried over sodium carbonate and concentrated to give 5.91 g (98.5%) of product as a solid.

MS (APCI) M + 1: Calcd. 250.1: Result 250.0.

EXAMPLE 106 1- [4- (4-Amino-phenyl) -piperazin-1-yl] -ethanone

Replacement of the starting material of Example 12 with the product of Example 105 gave 4.35 g (84.1%) of the product as a solid.

MS (APCI) M + 1: Calcd. 220.1: Result 220.1.

EXAMPLE 107 1- {4- [4- (7-Amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazin-1-yl} -ethanone

Replacement of the starting material in Example 9 with the product of Example 106 afforded 0.1829 g (50.1%) of the product as a solid.

MS (APCI) M + 1: Calcd. 364.2: Result 364.2.

Analysis calculated for C 19 H 21 N 7 O 1 · 1.0 H 2 O:

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

Result: C. 59.51; H. 6.03; N. 25.28.

EXAMPLE 108 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3- (3-morpholin-4-yl-propyl) ) urea

Replacement of the starting material of Example 32 with the product of Example 107 and 3-morpholih-4-yl-propylamine gave 0.0338 g (22.6%) of the product (Compound 103) as a solid, m.p. Mp 222-225 ° C.

MS (APCI) M + 1: Calcd. 534.3: Result 534.2.

Calcd. For C27H35N9O3 · 0.5 H2O:

C. 59.76; H. 6.69; N. 23.25

Result: C. 59.74; H. 6.53; N. 23.35.

EXAMPLE 109

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

Replacing N-bromosuccinimide with N-chlorosuccinimide in Example 74 gave 0.3700 g (31.4%) of the product as a solid, m.p. Mp 264-266 ° C.

MS (APCI) M + 1: Calcd. 228.0: Result 227.9.

EXAMPLE 110

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

Replacement of the starting material in Example 6 with the product of Example 109 afforded 0.6534 g (86.5%) of the product as a solid.

MS (APCI) M + 1: Calcd. 246.0: Result245.8.

EXAMPLE 111

6-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of the starting material of Example 7 with the product of Example 110 afforded 0.38 g (63%) of the product as a solid.

MS (APCI) M + 1: Calcd. 227.0: Result 226.9.

EXAMPLE 112

6-chloro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl-amine

Replacement of the starting material in Example 8 with the product of Example 111 gave 0.2328 g (57.1%) of the product as a solid, m.p. Mp 260-262 ° C.

MS (APCI) M + 1: Calcd. 243.0: Result 242.9.

EXAMPLE 113 tert-Butyl 4- [4- (7-amino-6-chloro-pyrido _[f 2 3-d] pyrimidin-2-yl-amino) phenyl] -cis-2,6-dimethyl-piperazine l-carboxylic acid

Replacement of the starting material of Example 27 with Example 112 afforded 0.22 g (49.0%) of the product as a solid.

MS (APCI) M + 1: Calcd. 484.2: Result 484.3.

EXAMPLE 114 4- {4- [7- (3-tert-Butyl-ureido) -6-chloro-pyrido [2,3d] pyrimidin-2-ylamino] -phenyl} -cis-2-tert-butyl ester 6-Dimethyl-piperazine-1-carboxylic acid Replacing the starting material in Example 10 with the product of Example 113 afforded 0.0995 g (39.2%) of the product as a solid.

MS (APCI) M + 1: Calcd. 567.3: Result 567.3.

EXAMPLE 115 1- tert -Butyl-3- {6-chloro-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} urea

Replacement of the starting material in Example 15 with the product of Example 114 afforded 0.0995 g of product (compound 104) as a solid, b. t. 205 ° C.

MS (APCI) M + 1: Calcd. 483.2: Result 483.2.

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

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

MS (APCI) M + 1: Calcd. 207.1: Result 206.9.

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

Replacement of the starting material in Example 8 with the product of Example 116 gave 1.46 g (30.0%) of the product as a solid, m.p. 185 ° C.

MS (APCI) M + 1: Calcd. 223.1: Result 223.0.

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

Replacement of the starting material in Example 13 with the product of Example 117 gave 0.4934 g (62.9%) of the product as a solid.

MS (APCI) M + 1: Calcd. 436.2: Result 436.2.

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

Replacement of the starting material in Example 16 with Example 118 afforded 0.8535 g (78.8%) of the product as a solid.

MS (APCI) M + 1: Calcd. 561.3: Result 561.3.

EXAMPLE 120

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

Replacement of the starting material in Example 15 with Example 119 gave 0.2548 g (36.0%) of the product (Compound 70) as a solid, m.p. Mp 169-175 ° C.

MS (APCI) M + 1: Calcd. 461.3: Result 461.2.

Analysis calculated for C25H32N8O1 0.25 _H2O:

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

Result: C. 64.57; H. 7.01; N. 23.98.

EXAMPLE 121

3-Cyclohexyl-l- {2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -l-methyl-urea

Using the general procedure of Example 120, 0.1366 g (95.6%) of product (compound 106) was obtained as a solid, m.p. 170 [deg.] C.

MS (APCI) M + 1: Calcd. 489.3: Result 489.3.

Calcd for C27H36N8O1 '3.32 H2O 2.69 HCl:

C. 50.16; H, 7.07; N. 17.33; Cl. 14.75.

Result: C. 50.36; H. 6.98; N. 16.97; Cl. 15.07.

EXAMPLE 122

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

Using the general procedure for Example 120, 0.118 g (94.0%) of the product (Compound 107) was obtained as a solid.

MS (APCI) M + 1: Calcd. 475.3: Result 475.3.

Calcd for C26H34N8O1.0 3.0 HC10.3 diethyl ether:

C. 53.89; H, 6.65; N. 18.48.

Result: C. 53.75; H, 6.96; N. 18.57.

EXAMPLE 123

3-tert-butyl-l- {2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -l-ethyl- urea

Following the general procedure in Example 15, 0.022 g (56%) of the product (Compound 108) was obtained as a solid.

MS (APCI) M + 1: Calcd. 477.3: Result 477.3.

EXAMPLE 124 1-Methyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea

Using the general procedure of Example 40, the product (Compound 64) was obtained as a solid, m.p. Mp 204-206 ° C.

MS (APCI) M + 1: Calcd. 393: Result 393.

EXAMPLE 125

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

Using the general procedure of Example 40, the product (compound 28) was obtained as a solid, m.p. Mp 220-222 ° C.

MS (APCI) M + 1: Calcd. 407: Result 407.

EXAMPLE 126 1- [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-propylurea

Using the general procedure of Example 40, the product (Compound 111) was obtained as a solid, m.p. Mp 223-225 ° C.

MS (APCI) M + 1: Calcd. 421: Result 421.

EXAMPLE 127

N, N-dimethyl-N '- [5-methyl-2 - [[4- (l-piperazinyl) phenyl] amino] pyrido [2,3-d] pyrimidin-7-yl sulfamide

Using the general procedure of Example 40 using dimethyl sulfanyl chloride instead of cyclohexyl isocyanate, the product (compound 71) was obtained as a solid, m.p. Mp 228-230 ° C.

MS (APCI) M + 1: Calcd. 443: Result 443.

EXAMPLE 128 7-Amino-2-methylsulfanyl-pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester

To a solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxyaldehyde (Example 3) in 10 mL of tetrahydrofuran was added 0.126 mL (1.18 mmol) of ethyl cyanoacetate. The solution is cooled to

-10 ° C and 2.36 ml (2.36 mmol) of titanium tetrachloride are added. Next, 0.52 mL (4.72 mmol) of N-methylmorpholine was slowly added. The reaction mixture was warmed to room temperature over 2 hours and partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and the solid was triturated with ether to give 0.30 g (96%) of product as a solid.

MS (APCI) M + 1: Calcd. 265.1: Result 264.9.

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

To a suspension of the product of Example 128 in 50 mL of chloroform was slowly added sulfuryl chloride followed by 2 drops of ethanol. The reaction mixture was stirred at room temperature for 16 hours, poured into ether and the solid filtered to give 0.50 g (98%) of product.

MS (APCI) M + 1: Calcd. 253.1: Result 253.1.

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

A solution of the product of Example 12 and the product of Example 129 in dioxane was refluxed for 1.5 hours. The reaction mixture was poured into hexane / ethyl acetate (1: 1) and the solid was filtered off. Flash chromatography eluting with dichloromethane gave 0.08 g (16%) of the product as a solid.

MS (APCI) M + 1: Calcd. 494.2: Result 494.1.

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

Replacement of the starting material in Example 10 with the product of Example 131 afforded 0.05 g (48%) of the product as a solid.

EXAMPLE 132 7- (3-tert-Butyl-ureido) -2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester

Replacement of the starting material in Example 15 with the product of Example 131 gave 0.036 g of the product (Compound 113) as a solid, m.p. &Gt; 300 ° C.

EXAMPLE 133 1- [6-Fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-isopropyl-urea

Using the general procedure of Example 52, but using 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35), 4- (4-aminophenyl) -piperazine acid tert -butyl ester -1-carboxylic acid (Example 12) and isopropyl isocyanate gave the product (Compound 114) as a solid, m.p. 208 ° C.

MS (APCI) M + 1: Calcd. 439.2: Result 439.3.

EXAMPLE 134 1-Cyclohexyl-3- {2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea

Using the general procedure of Example 17, but using 4- (4-amino-phenyl) -2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 96), 0.095 g (100%) was obtained. product (compound 115) as a solid.

MS (APCI) M + 1: Calcd. 475.6: Result 475.3.

Analysis calculated for C26H34N8O1 'HCl'1,0 3 _H2O:

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

Result: C. 52.00; H. 6.41; N. 18.53; Cl. 16.51; H ₂ O. 3.06.

EXAMPLE 135

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

To a suspension of 2.18 g (54 mmol) of 60% sodium hydride dispersed in oil in 300 mL of tetrahydrofuran cooled to 10 ° C was added 10.2 g (53.4 mmol) of (1-cyano-1-methyl) ethyl ester. -phosphonic (Synthesis, 1975: 516). 4.30 g (25.4 mmol) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (Example 3) was added to the cooled suspension and the reaction mixture was stirred at room temperature for 22 hours. The resulting solution was concentrated and filtered to give a solid which was washed with tetrahydrofuran in 1 N citric acid and precipitated by adjusting the pH to 8 with 50% sodium hydroxide. The solid was filtered to give 1.1 g (21%) of product, m.p. Mp 268-270 ° C.

MS (APCI) M + 1: Calcd. 207.3: Result 207.0.

EXAMPLE 136 1-Cyclohexyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} - urea

Using the general procedure of Example 31, but starting from the product of Example 135, 0.14 g (42%) of the product (compound 116) was obtained as a solid.

MS (APCI) M + 1: Calcd. 589.6: Result 589.3.

Analysis calculated for C27H36N8O1 '2.5 HCl 1.5 Η ₂ Ο:

C. 53.80; H, 6.73; N. 18.01; Cl. 14.11; H ₂ O. 4.06.

Result: C. 53.44; H. 6.89; N. 18.46; Cl. 14.60; H ₂ O. 4.48.

EXAMPLE 137 1- tert -Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3d] pyrimidin-7-yl } urea

Using the general procedure of Example 29, but starting from the product of Example 135, 0.26 g (89%) of the product (Compound 117) was obtained as a solid.

MS (APCI) M + 1: Calcd. 463.6: Result 463.3.

Calcd for C 26 H 36 N ₈ O ₂ 2.4 HCl 1.75 H ₂ O:

C. 51.62; H. 6.91; N. 19.26; Cl. 14.63; H ₂ O. 5.42.

Result: C. 51.23; H. 6.55; N. 18.92; Cl. 14.73; H ₂ O. 5.10.

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

Using the general procedure of Example 15, but starting from the product of Example 135, 1.02 g (100%) of the product (Compound 118) was obtained as a solid.

MS (APCI) M + 1: Calcd. 435.3: Result 435.3.

Analysis calculated for C 23 H 30 N 6 O 15 · HCl 1.75 H2O:

C. 42.60; H. 5.98; N. 17.28; Cl. 27.34; H ₂ O. 4.86.

Result: C. 42.03; H, 6.04; N. 16.81; Cl. 22.95; H ₂ O. 4.72.

EXAMPLE 139 1- {2- [4- (cis-3,5-Dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidine

7-yl} -3-isopropyl-urea

Using the general procedure of Example 33, but starting from the product of Example 135 together with 4- (4-amino-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and isopropylamine as reaction products. and 0.130 [mu] l (100%) of the product (compound 119) was obtained as a solid.

MS (APCI) M + 1: Calcd. 449.3: Result 449.3.

Calcd for C24H32N8O13 HCl 1.75 H2O:

C. 48.90; H. 6.58; N. 19.01; Cl. 16.04; H ₂ O. 5.35.

Result: C. 49.03; H, 6.63; N. 18.70; Cl. 16.03; H ₂ O. 5.19.

EXAMPLE 140 1-Cyclopropyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} - urea

Using the general procedure of Example 33, but starting from the product of Example 135 together with 4- (4-amino-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and cyclopropylamine as reaction reagents. The solids were collected to give 0.099 g (100%) of the product (Compound 120) as a solid.

MS (APCI) M + 1: Calcd. 447.3: Result 447.3.

Analysis calculated for C 24 H 30 N 8 O 1:

C. 49.83; H. 6.19; N. 19.37; Cl. 18.39; H ₂ O. 3.89.

Result: C. 49.76; H, 6.23; N. 18.92; Cl. 15.66; H ₂ O. 3.06.

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

Using the general procedure of Example 137, but starting from (1-cyano-propyl) -phosphonic acid diethyl ester, 0.34 g (95%) of the product (Compound 121) was obtained as a solid.

MS (APCI) M + 1: Calcd. 447.3: Result 447.3.

Analysis calculated for C 26 H 26 N 8 O 1 · 2.5 HCl 1 H 2 O:

C. 53.26; H. 7.05; N. 19.11; Cl. 15.18; H ₂ O. 3.07.

Result: C. 53.63; H, 7.31; N. 18.46; Cl. 15.32; H ₂ O. 3.48.

EXAMPLE 142

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

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

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

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

(e) 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3d] 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-cyclohexylurea (Compound 10);

(g) 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 [2,3d] pyrimidin-7-yl} -3-cyclohexyl-urea (compound) 14);

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

(j) 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidine

7-yl} -3-cyclohexylurea (Compound 16);

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

(1) 1- [2- (3-chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea ( compound 18);

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

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

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

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

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

(r) 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidine

7-yl} -3- (2-hydroxy-ethyl) -urea (Compound 24);

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

(t) 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-ethyl-urea (Compound 26);

(u) 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-d] pyrimidin-7-yl} -3-ethyl-urea (Compound 29);

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

(x) 1- [2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3d] pyrimidin-7-yl} -3-ethyl-urea (compound) 31);

(y) 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidine

7-yl} -3-ethyl-urea (Compound 32);

(z) 1- tert -butyl-3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 33);

(aa) 1-cyclohexyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] urea (Compound 34);

(bb) 1-Ethyl-3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 35);

(cc) 1- (hydroxy-ethyl) -3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 36);

(dd) 1- tert -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);

(gg) 1- [6-Fluoro-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea (Compound 40) );

(hh) 1- tert -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 [2,3-d] pyrimidin-7-yl] -urea (Compound 43);

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

(11) 1-Cyclohexyl-3- [6-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea (Compound 54);

(mm) 1-Cyclo-hexyl-3- [6-cyano-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 56);

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

(oo) 1-Cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound) 58);

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

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

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

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

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

(uu) 1- (4-Amino-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea (Compound 67);

(w) 1- (2-dimethylamino-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Compound 68);

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

(xx) 1-Cyclo-hexyl-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 [2,3-d] pyrimidin-7-yl] -acetamide (Compound 73);

(zz) 4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -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-d] 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-cyclohexylurea (Compound 77);

(ddd) 1- (2- {4- [4- (2-Amino-3-methyl-butanoyl) -piperazin-1-yl] -phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) - 3-cyclohexylurea (compound 78);

EXAMPLE 143

Biological tests

As mentioned above, the compounds of the invention are potent inhibitors of CD KS and as such are also effective in the treatment and prevention of atherosclerosis and other cell proliferative disorders such as cancer mediated by these cdk enzymes. The compounds show excellent inhibitory activity against a variety of cdk enzymes, including cdkcdk1 / cyclinB, cdk2 / cyclinA, cdk2 / cyclinE and cdk4 / cyclinD when tested by standard assays used by those skilled in the art of measuring the effectiveness of cdk inhibitors. Typical assays are performed using the following methods.

Cyclin-dependent kinase 4 (cdk4) assay

Enzyme assays for IC50 determination and kinetics evaluation were performed on 96-well plates (Millipore MADVN6550). The total volume is 0.1 ml containing a final concentration of 20 mM TRIS (tris [hydroxymethyl] amino methane) at pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl 2, 25 μΜ ATP containing 0.25 pCi [ ³² P] ATP, 20 ng cdk4, 1pg retinoblastoma and appropriate concentrations of a compound of the invention. All components except ATP are added to the probes and the plate is placed on the mixer for two minutes. The reaction is started by the addition of [ ³² P] ATP and the plate is incubated for 15 minutes at 25 ° C. The reaction is terminated by the addition of 0.1 ml of 20% trichloroacetic acid (TCA). The plate is kept for at least 1 hour at 4 ° C to allow the substrate to precipitate. The probes are then washed 5 times with 0.2 ml of 10% TCA and the ³² P content is determined by a beta plate counter (Wallac Inc., Gaitersburg, MD).

Cyclin-dependent kinases 1 and 2 (cdk1 / cyclinB, cdk2 / cyclinA, cdk2 / cyclinE)

Enzyme assays for determining the IC50 and evaluating the kinetics are performed on 96-well plates (Millipore MADVN6550) at a total volume of 0.1 ml containing a final concentration of 20 mM TRIS (tris [hydroxymethyl] aminomethane) at pH 7.4, 50 mM NaCl, 1mM ditiotreitol, 10 mM MgCl 2, 12 mM ATP containing 0.25 µCi [ ³² P] ATP, 20 ng enzyme (either cdk1 / B, cdk2 / A or cdk2E), 1 µg retinoblastoma, and appropriate concentrations of the compound of the invention. All components except ATP are added to the probes and the plate is placed on the mixer for two minutes. The reaction is started by the addition of [P] ATP and the plate is incubated for 15 minutes at 25 ° C. The reaction was terminated by the addition of 0.1 mL of 20% (TCA). The plate is left for at least 1 hour at 4 ° C to precipitate the substrate. The probes are then washed 5 times with 0.2 ml of 10% TCA and the P content is determined by a beta plate counter (Wallac Inc., Gaitersburg, MD).

Proline-dependent kinase-dependent S / p25 kinase assay

Enzyme source: recombinant complex - sf9 insect cells infected with baculo virus and cdk5-p25

Purpose: To evaluate the ability of the test agent to inhibit the cdk5 / p25 phosphorylation of histone H1.

Method: His-labeled baculovirus-insect cell complex labeled with Glu p25 (or GST-p25) labeled with a 50 ng / 20 μΐ enzyme buffer (EDB - 50 mM Tris-HCl [pH 8.0], 10 mM NaCl, 10 mM MgCl ₂ and 1 mM DTT). A 20 µL sample of the test reagent (dissolved in EDB) is then combined with 20 µL of the cdk5 / p25 enzyme preparation and allowed to stand at room temperature for 5 minutes. Was added 25 microliters of a solution containing 115 μΙ / ml histone Hl, 30 μΜ ATP (without vanadate), and 30 μϋΐ / ιηΐ γ ^'33 Ρ ATP (Amersham), (all dissolved in EDB), and the mixture was stirred for 45 minutes at 30 C. A 50 μΐ sample of the resulting preparation is added to 100 ml of 150 mM glacial phosphoric acid and left for 30 minutes to facilitate precipitation. The precipitate is filtered through a 96 probe phosphocellulose filter plate and washed successively 3 times with 75 mM phosphoric acid. Add 20 μΐ of scintillation mixture to each probe and count the beta emission with the Trilux Counter (protocol ³³ P). Test samples are compared to the beta emission of the control sample (no test agent: 0% inhibition) and the basal sample (no enzyme, no test agent: 100% inhibition) to determine the percent inhibition of histone H1 phosphorylation. The results of these tests for representative compounds of the present invention are presented in Table 2. The compounds of the invention exhibit IC50 values ranging from 0.027 μΜ to> 5 μΜ against cdkl / B, from 0.010 μΜ to> 5 μΜ against cdk2 / A, from 0.020 μΜ to > 5 μΜ against cdk2 / E and from 0.004 μΜ to> 5 μΜ against cdk4 / D. The most potent compound of all is Compound 9, which has an IC 50 of 0.027 μΜ against cdkl / BM, 0.010 μΜ against cdk2 / A, 0.020 μΜ against cdk2E, and 0.005 μΜ against cdk4D.

TABLE 2. Inhibition of Cdks; IC ₅ o (μΜ) compound Cdkl / 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 0,130 0,130 0,037 9 0,027 0,010 0,020 0,005 11 0,159 0,092 0,125 0,011 12 > 5 > 5 > 5 2,100 28 > 5 > 5 > 5 > 5 45 , 0552 0,054 0,110 0,045 46 0,075 0,300 > 5 47 > 5 > 5 > 5 > 5 48 0,257 0,113 0,098 0,018 49 0,911 0,528 0,475 0,050 50 0,069 0,022 0,035 0,007 1 0,053 0,024 0,030 0,004 52 0,472 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 0,697 0,530 0,017 71 5 5 5 5 79 5 1,066 5 5 80 , 0461 0,092 0,230 0,460 81 2,610 1,560 3,250 0,500 83 0,399 0,305 0,315 0,055 84 > 5 > 5 > 5 > 5 85 > 5 > 5 > 5 > 5 86 > 5 > 5 > 5 > 5 87 > 5 > 5 > 5 > 5

88 , 0418 0,043 0,055 0,025 89 > 5 > 5 > 5 > 5 91 > 5 > 5 > 5 0,070 93 > 5 > 5 > 5 > 5 94 > 5 0,101 95 > 5 0,310 96 6,365 1,108 > 5 > 5 97 0,862 0,278 > 5 > 5 98 0,442 0,157 0,140 1,050 99 1,810 1,012 0,410 > 5 100 0,265 0,153 0,415 0,035 102 3,130 3,590 4,500 0,165 103 > 5 > 5 > 5 > 5 104 > 5 > 5 > 5 0,185 106 0,350 0,440 107 1,728 1,950 1,650 0,019 108 2,425 2,035 3,050 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 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 growth hormone tyrosine kinase enzymes, FGFr and PDGFr, and a tyrosine kinase non-receptor receptor, c-Src. Certain compounds of the invention have been evaluated by standard assays that measure their ability to inhibit tyrosine kinase enzymes. These tests are carried out as follows.

PDGF and FGF receptor tyrosine kinase assays

The entire DNA strands for murine PDGF-β and human FGF-1 receptor tyrosine kinases were obtained from L. Escobeda and prepared as described in J. Biol. Chem., 1991: 262: 1482-1487. The DNA fragments are introduced into a baculovirus carrier, transfected with AcMNPV DNA, and the recombinant virus isolated. SF9 insect cells are infected with the virus and the cell lysate (cell breakdown product) is used for the assay. The assays are performed on 96-well plates (100 μΐ / incubation / probe) and the conditions are optimized to measure the incorporation of ³² P of γ ³² Ρ-ΑΤΡ into the glutamate-tyrosine copolymer substrate. Briefly, 82.5 μΐ of incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na is added to each probe. ₃ VO ₄ , 10 mM MnCl ₂ and 750 pg / ml Poly (4: 1) glutamate-tyrosine, followed by 2.5 μΐ inhibitor and 5 μΐ enzyme lysate (7.5 pg / μΐ FGFTK or 6.0 pg / μΐ PDGF -TK) to initiate the reaction. After a 10 minute incubation at 25 ° C, 10 ml of γ ³² Ρ-ΑΤΡ (0.4 pCi plus 50 μΜ ATP) is added to each probe and the samples are incubated for an additional 10 minutes at 25 ° C. The reaction is terminated by adding 100 μΐ of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate and precipitating the substance onto glass fiber mats (Wallac). The filters are washed 3 times with 15% TCA containing 100 mM sodium pyrophosphate and the residual radioactivity on the filters is measured with a Wallac 1250 Betaplate reader. Non-specific efficacy is defined as the radioactivity remaining on the filters after incubation of the samples with buffer alone (without enzyme). Specific enzyme activity (enzyme plus buffer) is defined as total activity minus non-specific activity. The percentage inhibition is determined at 50 μΜ and for the more active compounds it is determined on the basis of the inhibition curve of the concentration at which the specific activity is inhibited by 50% (IC 50).

C-Src kinase assay

C-Src kinases are purified from insect cell lysates by infected baculovirus using an antipeptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src. The antibody covalently coupled to 0.65 µm latex droplets was added to a suspension of insect cell lysate, a buffer composed of 150 mM NaCl, 50 mM Tris pH 7.5, 1 mM DTT, 1% NP-40, 2 mM EGTA, 1 mM sodium vanadate, 1 mM PMFSF, 1 µg / ml leupeptin, pepstatin and aprotinin. The insect cell lysate containing the c-Src protein is allowed to incubate with the latex droplets for 3-4 hours at 4 ° C on a rotating plate. At the end of the incubation, the droplets are washed 3 times with the original buffer, resuspended in a buffer containing 10% glycerol and frozen. Then they are thawed, washed three times in assay buffer (40 mM Tris, pH 7.5, 5 mM MgCl 2 and suspended in the same buffer. On a 96-well plate. Millipore with a bottom of 0.65 µm polyvinilidine membranes are added these reaction components: 10 μΐ c-Src droplets, 10 μΐ 2.5 mg / ml poly GluTyr substrate, 5 μΜ ATP containing 0.2 pCi labeled P-ATP, 5 μΐ DMSO containing inhibitors or control solvent and buffer to a final volume of 125 μΐ The reaction is started at room temperature by the addition of ATP and terminated 10 minutes later by the addition of 125 μΐ 30% TCA and 0.1 M sodium pyrophosphate, then the filters are measured on a liquid scintillator and the data are examined for inhibition efficiency compared to known inhibitors, This procedure is also described in J. Med. Chem., 1994; 37: 598-609.

The tyrosine kinase inhibition activity for representative compounds of the invention is evaluated in Table 3.

TABLE 3. Tyrosine kinase inhibition:% inhibition at 50 μΜ (IC50 [μΜ] in parenthesis if determined)

compound PDGFr FGFR 1 0,130 0,006 9 89,8 11 (0.131) (0.284) 45 21.9 67.4 46 17.5 19.5 47 10.5 55 (0.033) (0.151) 70 (0.536) (1.15) 80 18.6 117 (0.081) (0.061)

As mentioned above, the invention also provides pharmaceutical compositions comprising the compounds of the invention in admixture with a carrier, diluent or base. The following examples illustrate typical compositions provided by the present invention.

EXAMPLE 144

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

Quantity (mg / capsule) Active compound 250 Starch powder 200 Magnesium stearate 10 Pretty 460

These ingredients are mixed and filled into hard gelatin capsules of 460 mg each. A typical active ingredient is 1-isobutyl-3- [2 - {(2-chloro-4-piperazin-1-yl) -phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea.

The mixture is administered 2 to 4 times daily for the treatment of postoperative restenosis.

EXAMPLE 144a

Mixture for oral suspension

additive number l-Isopropyl-3- [5-methyl-6-bromo- (3-ethyl-pyridin-4-yl 500 mg amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea Sorbitol solution (70% NF) 40 ml Sodium benzoate 150 mg saccharin 10 mg Cherry flavor 50 mg Distilled water 100 ml

The sorbitol solution is added to 40 ml of distilled water, in which pyridopyrimidine is suspended. The saccharin, sodium benzoate and flavor are then added and dissolved. Make up the volume to 100 ml with distilled water. Each milliliter of syrup contains 5 mg of active ingredient.

EXAMPLE 144b

Tablets containing 60 mg of the active ingredient

Active ingredient 60 mg starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (10% solution in water) 4 mg in Starch (sodium carboxymethyl) 4.5 mg Magnesium stearate 0.5 mg Talk 1.0 mg Pretty 150 mg

The active ingredient, starch and cellulose are sieved through a US sieve with mesh No. 45 and mixed properly. The polyvinylpyrrolidone solution is mixed with the powder thus formed and then sieved (U.S. No. 14). The granules are dried at 50-60 ° C and sieved through a US sieve, mesh no. 18. Starch with sodium carboxymethyl, magnesium stearate and talk are sieved through a US sieve, mesh no. 60 and then added to the granules which, after mixing, are compressed on a tablet machine to form 150 mg tablets.

A typical active ingredient used in this preparation is the compound of Example 40 (compound 12). This mixture is well suited for the treatment of diabetic retinopathy.

EXAMPLE 144c

A parenteral composition suitable for injection is prepared by dissolving 100 mg of compound 77 in 250 ml of 0.9% sodium chloride solution and adjusting the pH of the solution to about 7.0. This preparation is useful in the treatment of breast cancer.

EXAMPLE 144d

Preparation of suppositories

A mixture of 500 mg of 1n-butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea and 1500 mg of theobromo oil is mixed homogeneously at 60 ° C. C. The mixture was cooled to 24 ° C in conical forms. Each suppository will weigh about 2 g and can be applied 1-2 times a day to treat viral infections, such as e.g. herpes and HIV.

EXAMPLE 144e

Local preparation

additive Quantity (mg) 1-Cyclohexyls 1-3 - {[2- (4-morpholin-1-yl-phenylamino)] -5,6- 20 difluoro-pyrido [2,3-d] pyrimidin-7-yl] -urea propylene 100 White petrolatum 500 cetearyl 50 glyceryl stearate 100 PEG 100 stearate 100 Ceteth-20 50 Sodium trihydrogenphosphate 80 Pretty 1000

The compound of the invention is mixed homogeneously with the other ingredients to form a thick suspension. The suspension is uniformly applied to the adhesive backing polymer film and cut into 2-inch squares. The patch is applied to the skin of a patient suffering from psoriasis.

EXAMPLE 144f

Slow acting preparation

500 milligrams of 7-acetamido-6-bromo-2 - [- (2-diethylaminoethoxy) phenylamino] pyrido [2,3-d] pyrimidine hydrochloride is placed in an osmotic pump tablet and administered orally to the subject to treat or prevent restenosis.

The present invention and methods and methods for utilizing them have now been described so completely, clearly, concisely and in exact terms that any person skilled in the art will be able to use them. It should further be appreciated that the foregoing examples describe preferred embodiments of the invention, and that any modifications may be made that do not depart from the spirit or scope of the invention as disclosed in the claims. The following claims conclude this disclosure and accurately and thoroughly explain and claim the subject matter of the present invention.

ir wytooz

Claims (20)

PATENT CLAIMS A compound of formula I and its pharmaceutically acceptable salts, esters, amides and medicaments, characterized in that: 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 may be optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , (CH ₂ ) n CO ² , - (CH _{2) n} SO ₂ R ^u, - (CIMR ^11, -COR ^9, -CONR ⁹ R ^10, -SO 3 R ^9, -SO 2 NR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ^10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ , -COR ¹⁰ , - (CH 2) n SO ² R ^H , - (CH 2) _n R 11 ^, or - (CH ₂ ) _n R ¹² optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH 2) n CO ² R ⁹ , - (CH 2) n SO 2 ₂ R ^11, - (CHzjnR ^11, -COR ^9, -CONR ⁹ R ^10, -SO 3 R ^9, -SO 2 NR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, POR ¹⁰ R ^9, - PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ^10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ^10, -OR ^9, -NR ⁹ COR ¹⁰ COR ^10, - (CH2) nSO2R ^H, - (CH 2) _n R ^u; R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -CONR ⁹ R ^10, NR ⁹ COR ^10, -SO ₂ NR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, -POR'R ^10, -PO (NR ⁹ R ¹⁰⁾ ₂ or lower alkenyl or lower alkynyl optionally substituted with -R ⁹ ; R ⁸ is H, -CO ₂ R ¹³ , -COR ¹³ , -CONR ¹³ R ¹⁴ , -CSNR ¹³ R ¹⁴ , -C (NR ¹³ ) NR ¹⁴ R ¹⁵ , -SO ₃ R ¹³ , -SO ₂ R ¹³ , -SO ² NR ¹³ R ¹⁴ , -PO ³ R ¹³ R ¹⁴ , -POR ¹³ R ¹⁴ , -PO (NR ¹³ R ¹⁴ ) 2; R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached are connected, R ⁹ and R ¹⁰ ABOUT II C forms a cycle with 3-7 members, of which up to four may be selected from / \, O, S and NR ²⁰ wherein R ²⁰ is hydrogen, lower alkyl or -CO lower alkyl; R ¹¹ is heteroaryl or heterocyclic; R ¹² is cycloalkyl, heterocycle, aryl or heteroaryl; n is 0,1,2 or 3. A compound of formula Π (II) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, characterized in that: R ⁷ , R ¹³ , R ¹⁴ and R ¹⁵ are independently hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which may be optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , - NR ⁹ R ¹⁰ , -OR ⁹ , (CH 2) n CO ₂ R ⁹ , - (CH 2) _n SO ₂ R ¹¹ , - (CH 2) n R ⁿ , -COR ⁹ , -CONR ⁹ R ¹⁰ , SO ³ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , PO (NR ⁹ R ¹⁰ ) ₂ , -nr ⁹ cor ¹⁰ , -nr ⁹ co2r ¹⁰ , -nr ⁹ conr ⁹ r ^10, NR ⁹ SO 2 R ^10, or heterocyclo optionally substituted with up to three groups independently selected from R ^9, -NR ⁹ R ^10, -OR ^9, - (CH 2) ¹¹ nSO2R, - (CH 2) _n R, or ^the - (CH ₂ ) _n R ¹² optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH 2) n CO ² R ⁹ , - (CH 2) _n SO ₂ R ^u, - (CH 2) n R ^in, -COR ^9, -CONR ⁹ R ^10, -SO 3 R ^9, -SO 2 nR ⁹ R ^10, -SO 2 R ^9, -SR ^9, -PO3R ⁹ R ^10, POR ¹⁰ R ⁹ , -PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ or a heterocycle optionally substituted with up to 3 groups independently selected from -R ^9, -NR ⁹ R ^10, -OR ^9, - (CH 2) ^u nSO2R, - (CH 2) _n R ^H; R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ or lower alkenyl or lower alkynyl optionally substituted with -R ⁹ ; R ⁸ is H, -CO ₂ R ¹³ , -COR ¹³ , -CONR ¹³ R ¹⁴ , -CSNR ¹³ R ¹⁴ , -C (NR ¹³ ) NR ¹⁴ R ¹⁵ , -SO ³ R ¹³ , -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ , -PO ³ R ¹³ R ¹⁴ , -POR ¹³ R ¹⁴ , -PO (NR ¹³ R ¹⁴ ) 2; R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen or amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached connected, R ⁹ and R ¹⁰ form a cycle of 3 to 7 members, of which up to four may ABOUT II be selected from O, S and NR ²⁰ , wherein R ²⁰ is hydrogen, lower alkyl or -CO lower alkyl; R ¹¹ is heteroaryl or heterocyclic; R ¹² is cycloalkyl, heterocycle, aryl or heteroaryl; n is 0, 1, 2 or 3; R ¹⁶ , R ¹⁷ and R ¹⁸ are independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylanminocarbonyl, alkylcarbonyl, -SO ₃ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -NR'COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ or R ¹⁶ is a carbocyclic group containing 3 to 7 members, of which up to two are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is either unsubstituted or substituted with 1, 2 or 3 groups independently selected from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl or hetrocyclylsulfonylalkyl. Third A compound of formula III * (III) and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, characterized in that: R ² is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each of which may be optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH 2) a CO ₂ R ⁹ , - (CH ₂₎ ⁿ SO ₂ R ⁿ , - (CH 2) n R ⁿ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -SO ³ R ⁹ , -SO ² NR ⁹ R ¹⁰ , -so ² R ⁹ , -SR ⁹ , -po ³ r ⁹ , -por ⁹ r ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr'cor ¹⁰ , -nr ⁹ co2r ¹⁰ , -nr ⁹ conr ⁹ r ¹⁰ , -NR ⁹ SO ² R ¹⁰ or heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH ₂ ) _n SO ₂ R ⁿ , - (CH ₂ ) _n R ⁿ or - (CH ₂ ) n R optionally substituted with up to 5 groups independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH 2) n CO 2 R ⁹ - (CH 2 SO 2 R ¹¹ ) - (CH 2 R ¹ *, -COR ⁹ , -CONR ⁹ R ¹⁰ , -SO ³ R ⁹ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO ( NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -nr ⁹ co2r ¹⁰ , -nr ⁹ conr ⁹ r ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ - (CH ₂ ) _n SO ₂ R ⁿ , - (CH ₂ ) _n R ⁿ ; R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SO ₃ R ⁹ , -SR ⁹ , -PO ₃ R ⁹ R ¹⁰ , -POR'R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) ₂ or lower alkenyl or lower alkynyl optionally substituted with -R ⁹ ; R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen or amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached connected, R ⁹ and R ¹⁰ form a cycle of 3 to 7 members, of which up to four may be selected ABOUT II of O, S and NR ²⁰ wherein R ²⁰ is hydrogen, lower alkyl or -CO lower alkyl; R ¹¹ is heteroaryl or heterocyclic; R ¹² is cycloalkyl, heterocycle, aryl or heteroaryl; 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 with up to five groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl , mono or dialkylaminocarbonyl, lower alkylcarbonyl, -SO ₃ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) ₂ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ , or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl 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, -SO ₃ R ⁹ , -SO ² R ⁹ R ¹⁰ , SO 2 NR ⁹ R ¹⁰ -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2 , NR'COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ or a (CH ₂ ) _n -carbocyclic group containing 3 to 7 members of which up to two are heteroatoms selected from oxygen and nitrogen, and wherein the carbocyclic group is either unsubstituted or substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heteroaryl alkyls, heterocyclylsulfonyl or hetrocyclylsulfonylalkyl; and R is hydrogen, lower alkyl or lower alkyl substituted by phenyl or substituted phenyl. A compound of formula IV and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, characterized in that: R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ² R ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -SO ² R ⁹ R ¹⁰ , -SO 2 R ^9, -SO 3 R ^9, -SR ^9, -PO3R ⁹ R ^10, POR ¹⁰ R ^9, -PO (NR ⁹ R ¹⁰⁾ 2, or lower alkenyl or lower alkynyl optionally substituted with R ^9; R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen or amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached connected, R ⁹ and R ¹⁰ form a cycle of 3 to 7 members, of which up to four may be selected O of O, S and NR ²⁰ , wherein R ²⁰ is hydrogen, lower alkyl or -CO lower alkyl; R ¹¹ is heteroaryl or heterocyclic; R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH ₂ ) _n CO ₂ R ⁹ , - (CH 2) _n SO ₂ R ⁿ , - (CH 2) n R ⁿ , -COR ⁹ , -CONR ⁹ R ¹⁰ , - SO3R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ^10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ , -COR ¹⁰ , - (CH 2) aSO 2 R ¹¹ , - (CH 2) ⁿ R ^h ; R ¹⁹ is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each optionally substituted with up to five groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO ₃ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr'cor ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl 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, lower alkylcarbonyl, -SO ₃ R ⁹ , -SO ² R ⁹ R ¹⁰ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr ⁹ cor ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ or (CH ₂ ) _n -carbocyclic a group of 3 to 7 members of which up to two are heteroatoms selected from oxygen and nitrogen, and wherein the carbocyclic group is either unsubstituted or substituted with 1, 2 or 3 groups independently selected from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl or hetrocyclylsulfonylalkyl; and R ²¹ is hydrogen, lower alkyl or lower alkyl substituted with phenyl or substituted phenyl. 5. A compound of formula V and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, characterized in that: R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ² R ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR'COR ¹⁰ , -SO ² NR ⁹ R ¹⁰ , -SO 2 R ^9, -SO 3 R ^9, -SR ^9, -PO3R ⁹ R ^10, POR ¹⁰ R ^9, -PO (NR ⁹ R ¹⁰⁾ 2, or lower alkenyl or lower alkynyl optionally substituted with R ^9; R ⁹ and R ¹⁰ are independently hydrogen or lower alkyl optionally substituted by up to 3 groups selected from halogen or amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached connected, R ⁹ and R ¹⁰ form a cycle of 3 to 7 members, of which up to four may be selected ABOUT II of O, S and NR ²⁰ wherein R ²⁰ is hydrogen, lower alkyl or -CO lower alkyl; R ¹¹ is heteroaryl or heterocyclic; R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from hydrogen, halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH ₂ ) _n CO ₂ R ⁹ , - (CH 2) _n SO ₂ R ¹¹ , - (CH 2) n R ⁿ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -SO ³ R ⁹ , - SO ₂ NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -por ⁹ r ¹⁰ , -PO (NR ⁹ R ¹⁰ ) ₂ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO 2 R ¹⁰ , - NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ² R ¹⁰ , or a heterocycle optionally substituted with up to 3 groups independently selected from R ^9, -NR ⁹ R ^10, -OR ^9, -NR ⁹ COR ^10, -COR ^10, - (CH 2) ^u nSO2R, - (CH 2) _n R ^u; R ¹⁹ is hydrogen or lower alkyl, lower alkenyl or lower alkynyl, each optionally substituted with up to five groups independently selected from halo, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl, -SO ₃ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰⁾ _2, -NR'COR ^10, -NR ⁹ CO 2 R ^10, -NR ⁹ CONR ⁹ R ^10, NR ⁹ SO 2 R ¹⁰ or aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or cycloalkyl alkyl of 1- alkyl, wherein each aryl, heteroaryl or cycloalkyl 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, -SO ₃ R ⁹ , -SO ² R ⁹ R ¹⁰ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SR ⁹ , -PO ³ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2, -nr'cor ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ or (CH ₂ ) _{Q - a} carbocyclic group containing 3 to 7 members of which up to two are heteroatoms selected from oxygen and nitrogen, and wherein the carbocyclic the group is either unsubstituted or substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl or hetrocyclylsulfonylalkyl; and R ²¹ is hydrogen, lower alkyl or lower alkyl substituted by phenyl or substituted phenyl. A compound of formula VI and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, characterized in that: R ⁵ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ or -OR ⁹ ; R ⁶ is halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -SO ² NR ⁹ R ¹⁰ , -SO ² R ⁹ , -SO ₃ R ⁹ , -SR ⁹ , -PO ₃ R ⁹ R ¹⁰ , -POR ⁹ R ¹⁰ , -PO (NR ⁹ R ¹⁰ ) 2 or lower alkenyl or lower alkynyl optionally substituted with -R ⁹ ; R ¹⁷ and R ¹⁸ are independently selected from halogen, cyano or nitro, -R ⁹ , -NR ⁹ R ¹⁰ , -OR ⁹ , - (CH ₂ ) _n CO ₂ R ⁹ , - (CH 2) _n SO ₂ R ¹¹ , - ( CH 2) n R ^n, -COR ^9, -CONR ⁹ R ^10, -SO 2 nR ⁹ R ^10, -SO 2 R ^9, -SO 3 R ^9, -SR ^9, -PO ₃ R ⁹ R ^10, POR ¹⁰ R ^9, PO ( NR ⁹ R ¹⁰ ) 2, -NR ⁹ COR ¹⁰ , -NR ⁹ CO ² R ¹⁰ , -NR ⁹ CONR ⁹ R ¹⁰ , -NR ⁹ SO ₂ R ^10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R ⁹ , -NR ^{9 9} R ¹⁰ , -OR ⁹ , -NR ⁹ COR ¹⁰ , -COR ¹⁰ , - (CH 2 nSCHR ¹¹ , - (CH ₂ ) _n R ^H ; R ²² and R ²³ are independently hydrogen or alkyl. 7. A compound selected from: 1-tert-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-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; l-tert-butyl-3- [6-fluoro-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-tert-butyl-3- [5-methyl-2- (4-piperazin-l-yl-phenylamino) -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-tert-butyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3d] pyrimidin-7-yl} -3-tert-butyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3d] pyrimidin-7-yl} -3-tert-butyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-tert-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 [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; l-Cyclohexyl-3- [6-fluoro-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; l- {2- [4- (4-acetyl-piperazin-l-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [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; l- [2- (3-chloro-4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; l- [6-fluoro-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; l- (2-hydroxy-ethyl) -3- [5-methyl-2- (4-piperazin-l-yl-phenylamino] pyrido [2,3-d] pyrimidin-7-yl] -urea; l- {2- [4- (4-acetyl-piperazin-l-yl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) - urea; l- {2- [4- (4-acetyl-piperazin-l-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxyethyl) - urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) ) urea; l-ethyl-3- [2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l- [2- (3-chloro-4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-ethyl-urea; 1-Ethyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7yl] -urea; l-Ethyl-3- [5-methyl-2- (4-piperazin-l-yl-phenylamino) -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-ethyl-urea; l- {2- [4- (4-acetyl-piperazin-l-yl) -3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3d] pyrimidin-7-yl} -3-ethyl-urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1- tert -butyl-3- (2-phenylamino-pyrido [2,3-d] pyrimidin-7-yl) amino; l-tert-butyl-3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (4-chloro-phenyl) -3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-isopropyl-3- [2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-tert-butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-l-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-d] 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-l-yl) phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} -urea; l-cyclopentyl-3- [5-methyl-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-Cyclohexyl-3- [6-bromo-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-Cyclohexyl-3- [6-cyano-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-chloro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; l-Cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-Cyclohexyl-3- [6-bromo-5-methyl-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; l-Cyclohexyl-3- [6-chloro-5-methyl-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-Isopropyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1-Ethyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] 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-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1- (4-Hydroxy-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1- (4-Amino-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1- (2-Dimethylamino-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; l- (3-morpholin-4-yl-propyl) -3- [2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 3-Cyclohexyl-1-methyl-1- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -quinoline; N, N-dimethyl-N '- [5-methyl-2 - [[4- (1-piperazinyl) phenyl] amino] -pyrido [2,3d] pyrimidin-7-yl] sulfamide; l-cyclohexyl-3- [5-methyl-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] thiourea; N- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -acetamide; 4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -benzenesulfonamide; l-cyclohexyl-3- {2- [4- (l-piperazin-l-yl-methanoyl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -urea; l-cyclohexyl-3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] 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-cyclohexyl urea; 1- (2- {4- [4- (2-Amino-3-methyl-butanoyl) -piperazin-1-yl] -phenylamino} -pyrido [2,3-d] pyrimidin-7-yl) -3-cyclohexyl -urea; 8. A compound selected from: l-tert-butyl-3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-cyclohexyl-3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-ethyl-3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l- (hydroxy-ethyl) -3- [2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-tert-butyl-3- [6-fluoro-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; Cyclohexyl-3- [6-fluoro-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-ethyl-3- [6-fluoro-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l- [6-fluoro-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxyethyl) -urea; l-tert-butyl-3- [5-methyl-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; i i l-cyclohexyl-3- [5-methyl-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; l-Ethyl-3- [5-methyl-2- (pyridin-4-yl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (2-hydroxy-ethyl) -3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-1-yl] -urea; 100 9. A compound selected from: 4- {4- [7- (3-tert-Butyl-ureido) -pyrido [2,3-d] pyrimidine-tert-butyl ester 2-yl-amino] -phenyl} -piperazine-1-carboxylic acid; 4- {4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3d] pyrimidin-2-yl-amino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester; l- (3-hydroxy-propyl) -3- [2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - ((S) -1-hydroxymethyl-3-methyl-butyl) -3- [2- (4-piperazin-1-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-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide; 3- [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -1,1-dipropyl-urea; Piperazine-1-carboxylic acid [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide; 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-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 1- [6-bromo-2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-tert-butyl-urea; l- [6-Bromo-2- (4-piperazin-l-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-methyl-urea; l- {6-bromo-2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-tert-butyl urea; l- {6-bromo-2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea ; l- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (3-morpholin-4-yl-propyl) -urea; 101 1- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; l- (2-amino-ethyl) -3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] 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-tert-Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoropyrido [2,3-d] pyrimidin-7-yl} - urea; 1- {2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3 (3-morpholin-4-yl-propyl) urea; 1-tert-Butyl-3- {6-chloro-2- [4- (cis-3,5-dimethyl-piperazin-1-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-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; 3-tert-Butyl-1- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3d] pyrimidin-7-yl} -1- ethyl urea; 1- [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-propyl-urea; 7- (3-tert-Butyl-ureido) -2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] 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-Cyclo-hexyl-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; l-tert-butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] -6-pyrido [2,3-d] pyrimidin-7-yl} - urea; 102 1-tert-Butyl-3- [6-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3d] pyrimidin-7-yl] -urea; l- {2- [4- (cis-3,5-dimethyl-piperazin-l-yl) phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-isopropyl-urea; 1-Cyclopropyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -urea ; 1-tert-Butyl-3- {2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-ethyl-pyrido [2,3-d] pyrimidin-7-yl} - urea; A pharmaceutical composition comprising a compound according to claim 1, which is admixed with a pharmaceutically acceptable carrier, diluent or excipient. 11. A method of controlling cell proliferative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle cell proliferation associated with a group of disorders such as atherosclerosis, postoperative vascular stenosis and restenosis in mammals, comprising administering a therapeutically effective amount of a compound of of claim 1. 12th 13th 14th divided A method of inhibiting a cdk enzyme, comprising the cdk enzyme with a compound of claim 1. Method according to claim 12, characterized by Method according to claim 12, characterized by The method of claim 12, comprising contacting said cdk being cdkl. wherein said cdk is cdk2. wherein said cdk is cdk4. 16. A method of inhibiting a tyrosine kinase-mediated growth factor, comprising contacting a growth factor-mediated growth factor-tyrosine kinase with a compound of claim 1. 103 17. The method of claim 16, wherein said tyrosine kinase-mediated growth factor is a blood platelet growth factor (PDGF). 18. The method of claim 16, wherein said tyrosine kinase-mediated growth factor is fibroblast secondary growth factor (FGF). 19. A method of treating a subject suffering from diseases caused by vascular smooth muscle cell proliferation, comprising administering to said subject a therapeutically effective amount of a compound of claim 1. 20. A method of treating a subject suffering from cancer comprising administering to said subject a therapeutically effective amount of a compound of claim 1. 21. A method of treating a subject suffering from a cancer included in the group: breast cancer, large cell cancer, pancreatic cancer, colon cancer, melanoma, lung cancer, and leukemia, comprising administering to said subject a therapeutically effective amount of a compound of claim 1.