MXPA06009359A

MXPA06009359A - 2-(pyridin-3-ylamino)-pyrido[2,3-d]pyrimidin-7-ones

Info

Publication number: MXPA06009359A
Application number: MXPA/A/2006/009359A
Authority: MX
Inventors: Mark Robert Barvian; Scott Norman Vanderwel; Peter Laurence Toogood
Original assignee: Warnerlambert Company Llc
Priority date: 2004-02-18
Filing date: 2006-08-17
Publication date: 2006-12-13

Abstract

1 wherein R', R2, R3, R4, and X1 are as defined in the specification. The 2-(pyridin-3-ylamino)-pyrido[2,3-d]pyrimidin-7-one compounds of formula I, which are inhibitors of cyclin-dependent kinases 2 and 4 (Cdk2 and Cdk4), are useful in treating cell proliferative disorders.

Description

2- (PlRIDIN-3-ILAMINO) -PIRID? R2,3-D1PIRlMlDlN-7-ONAS FIELD OF THE INVENTION This invention relates to 2- (pyridin-3-ylamino) -pyrido [2,3-d] pyrimidin-7-ones which are potent inhibitors of cyclin-dependent kinases. The compounds of the invention are useful for the treatment of inflammation, and cell proliferative diseases, such as cancer and restenosis.

BACKGROUND OF THE INVENTION The cyclin-dependent kinases and serine / threonine protein kinases are important cellular enzymes that perform essential functions in the regulation of cell division and proliferation. The catalytic cyclin-dependent kinase units are activated by regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified (Johnson D. G. and Walker C. L., Annu, Rev. Pharmacol, Toxicol, 1999; 39: 295-312). Cyclin B / cdk1, cyclin A / cdk2, cyclin E / cdk2, cyclin D / cdk4, cyclin D / cdk6, and probably other heterodimers including Cdk3 and Cdk7 are important regulators of cell cycle progression. Additional functions of the cyclin / Cdk heterodimers include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan D. O., Annu, Rev. Cell, Dev. Biol. 1997; 13261-13291). The increased activity or temporarily abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors (Sherr C.J., Science 1996; 274: 1672-1677). In fact, the development of human tumors and other diseases caused by aberrant cell proliferation are commonly associated with alterations in the Cdk proteins themselves or in their regulators (Cordon-Cardo C, Am. J. Pathol, 1995; 147: 545-560 Karp JE and Broder S., Nat. Med. 1995; 1: 309-320, Hall M. et al., Adv. Cancer Res. 1996; 68: 67-108). For example, natural protein inhibitors of Cdk such as p16 and p27 cause inhibition of in vitro growth in lung cancer cell lines (Kamb A., Ctvrr Top, Microbiol.Immunol., 1998; 227: 139-148 ). Small molecule Cdk inhibitors can be used in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders that are due to proliferation of aberrant cells. Proliferation of vascular smooth muscle and intimal hyperplasia following balloon angioplasty are inhibited by overexpression of cyclin-dependent kinase inhibitor p21 protein (Chang MW et al., J. Clin.Invest., 1995; 96: 2260; Yang ZY., Et al., Proc Nati, Acad. Sci. (United States) 1996; 93: 9905. In addition, the inhibitor CVT-313 of cdk2 purine (Ki = 95 nM) results in an inhibition. greater than 80% of neointima formation in rats (Brooks EE et al., J. Biol. Chem. 1997: 29207-2911) .Cdk inhibitors can be used to treat diseases caused by a variety of infectious agents. , including fungi, protozoan parasites such as Plasmodium falciporum, and DNA and RNA viruses For example, cyclin dependent kinases are required for viral replication after infection by herpes simplex virus (HSV) (Schang LM et al., J. Virol. 1998; 72; 5626) and it is known that homologs of Cdk play essential roles in yeast. Selective Cdk inhibitors can be used to improve the effects of various autoimmune disorders. The chronic inflammatory disease, rheumatoid arthritis, is characterized by synovial tissue hyperplasia; The inhibition of synovial tissue proliferation should minimize inflammation and should prevent the destruction of the joints. Expression of the p16 protein inhibitor of Cdk in synovial fibroblasts led to growth inhibition (Taniguchi K. et al., Nat. Med. 1999; 5: 760-767). Similarly, in a rat arthritis model, joint inflammation was substantially inhibited by treatment with an adenovirus expressing p16. Cdk inhibitors may be effective against other cell proliferation disorders including psoriasis (characterized by hyperproliferation of keratinocytes), glomerulonephritis, and lupus.

Some inhibitors of Cdk may be useful as chemoprotective agents by their ability to inhibit the progression of the cell cycle of normal non-transformed cells (Chen et al., J. Nati, Cancer Institute, 2000; 92: 1999-2008). Pretreatment of a cancer patient with a Cdk inhibitor prior to the use of cytotoxic agents can reduce the side effects commonly associated with chemotherapy. The tissues of normal proliferation are protected from the cytotoxic effects by the action of the selective Cdk inhibitor.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds of the formula I: wherein: X1 is hydrogen, halogen, Ci-C6 alkyl, Ci-β haloalkyl, CT-C8 alkoxy, d-C8 alkoxyalkyl, CN, NO2, OR5, NR5R6, C02R5, COR5, S (O) nR5, CONR5R6, NR5COR6, NR5SO2R6, SO2NR5R6, or P (O) (OR5) (OR6); R 1 is hydrogen or C 1 -C 3 alkyl; R2 is hydrogen, halogen, Ci-C6 alkyl > O-C 1 -C 6 alkyl, C (O) R 7, C 2 R 7, C 2 -C 6 alkenyl, d-C 6 alkynyl, phenyl, O-phenyl, NR 7 -phenyl, or heteroaryl; R3 is hydrogen, phenyl, Ci-C8 alkyl, C3-C7 cycloalkyl, or C3-C7 heterocyclyl; R 4 is hydrogen, halogen, C 1 -C 8 alkyl, OR 5, SR 5, or NR 5 R 6; R5 and R6 are in each case independently, hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R5 and R6, when they are attached to the same nitrogen atom, taken together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 members in the ring, up to four of said members can be optionally replaced with heteroatoms independently selected from oxygen, sulfur, S (O), S (O) 2, and nitrogen, however, provided that there is at least one carbon atom in the heterocyclic ring and that if there are two or more oxygen atoms in the ring , the oxygen atoms in the ring are not adjacent to each other, in which the heterocyclic group is unsubstituted or substituted with one, two or three groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl , alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono- or dialkylamino or, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR7SO2R8, C (O) NR7R8, NR7C (O) R8, C (O) nR7, C (O) NR7SO2R8, (CH2) mS (O) nR7, (CH2) m -heteroaryl, O (CH2) m -heteroaryl, (CH2) mC (O) NR7R8, O (CH2) mC (O) OR7, and (CH2) SO2NR7R8; m is 0 to 4; R7 is hydrogen, C-i-C8 alkyl, C2-C8 alkenyl, C2-Ce alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; R8 and R9 are hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. The compounds of formula I may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and all stereoisomers of the compounds of formula I, both in racemic mixtures as individual enantiomers and diastereomers of such compounds, and mixtures thereof, and all pharmaceutical compositions and methods of treatment defined later that contain or employ them, respectively. The compounds of formula I and derivatives thereof are selective inhibitors of serine / threonine kinases, cyclin-kinase, dependent kinases 2 and 4 and cyclin-dependent kinase 6. The term "derivatives" includes salts, preferably pharmaceutically acceptable salts, amines, esters and prodrugs of the compounds of formula I. These compounds and derivatives thereof are easily synthesized and can be administered to patients by a variety of methods. This invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula I or a therapeutically acceptable salt thereof and a carrier, diluent, or pharmaceutically acceptable excipient therefor. The 2- (pyridin-3-ylamino) -pyrido [213-d] pyrimidinones of formula I and their pharmaceutically acceptable salts and the pharmaceutical formulations containing them are useful for treating non-controlled cell proliferative diseases, including but not limitation, proliferative diseases such as cancer, restenosis and rheumatoid arthritis. In addition, these compounds and the salts thereof are useful for treating inflammation and inflammatory diseases, as anti-infective agents, and as chemoprotective agents. The treatment methods identified above are preferably carried out by administering a therapeutically effective amount of a compound of formula I and the pharmaceutically acceptable salts thereof to a subject in need of treatment. Preferred compounds of the present invention are those having the formula IA: wherein R2, R3, R4, and X1 are as defined for formula I. In a preferred embodiment of the present invention, X1 is hydrogen. Preferred embodiments of the present invention include, but are not limited to, the compounds listed below and derivatives, preferably the pharmaceutically acceptable salts thereof: 8-isopropyl-2- (pyridin-3-ylamino) -8H-pyrido [ 2,3-d] pyrimidin-7-one; 8-cyclopentyl-2- (6-methoxy-pyridin-3-ylammon) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-Bromo-8-cyclopentyl-2- (6-p yperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3-d] pyrimidin-7-one; 6-bromo-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-bromo-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -H-pyrido [2,3-d] pyrimidin-7-one; 6-Acetyl-8-cyclopentyl "5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyridop.S-d-pyrimidin-1-one; 6-ethyl-8-isopropyl -2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 6-benzyl-8-isopropyl-2- (6-piperazine) -1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-isopropyl-2- (6-piperazin-1-yl-pyridine -3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 8-isopropyl-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) ethyl ester ) -7,8-dihydro-pyrido [2,3-d] pyrimidine-6-carboxylic acid, 6-ethyl-8- (2-methoxy-ethyl) -2- (6-piperazin-1-yl-pyridin-3) -ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-benzyl-8-isopropyl-2- [6- (2-methoxy-ethoxy) -pyridin-3-ylamino] - 8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-2- (5-chloro-6-piperazin-1-yl-pyridin-3-ylamino) -8-isopropyl-8H-pyrido [ 2,3-d] pyrimidin-7-one; 8-isopropyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-thiazol-2-yl-8H-pyrido [2,3- d] pyrimidin-7-one; 3- [6-fluoro-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7H-pi] [2,3-d] pyrimidin-8-yl] propionic acid; 8-isopropyl-2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino] -6-phenoxy-8H-pyrido [2,3- d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-2- (6- [1,4] diazepan-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 6-ethynyl-8-isopropyl-2- (6-piperazin-1-yl-pyrridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 8-benzyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-vinyl-8 H -pyrido [2,3-d] pyrimidin-7-one; 8- (2-Cyclopropyl-ethyl) -2- (6-morpholin-4-yl-pyridin-3-ylamino) -6-phenylamino-8H-pyrido [2,3- d] pyrimidin-7-one; 8-cyclopentyl-6-proponyl-2- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-ylamino) -8H-pyrido [2,3- d] pyro Midn-7-one; 2- [6- (3,5-dimethyl-piperazin-1-yl) -pyridin-3-ylamino] -6-hydroxymethyl-8-isopropyl-8 H -pyrido [2,3- d] pyrimidin-7-one; 8-cyclopentyl-6-etl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3- d] pyrimidin-7-one; 6-Chloro-8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 6-acetyl-8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 8-isopropyl-5-methyl-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7,8-dihydropyrido [2,3- d] pyrimidine- ethyl ester 6-carboxylic; 6-ethyl-8- (2-methoxy-ethyl) -5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7- ona; 6-Benzyl-8-isopropyl-2- [6- (2-methoxy-ethoxy) -pyridin-3-ylamino] -5-methyl-8H-pyrido [2,3- d] pyrimidin-7 -one; 6-acetyl-2- (5-chloro-6-piperazin-1-yl-pyridin-3-ylamino) -8-isopropyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one; 8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylammon) -6-thiazoI-2-yl-8H-pyrido [2,3-d] pyrimidine -7-ona; 3- [6-fluoro-5-methyl-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7H-pyrido [2,3-d] pyrimidin-8-yl] -propionic; 8-isopropyl-5-methyl-2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino] -6-phenoxy-8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-2- (6- [1,4] diazepan-1-yl-pyridin-3-ylamino) -5-methyl-8H-pyrido [2,3-d] pyrimidin-7 -one; 8- (2-Dimethylamino-ethyl) -6-ethynyl-5-methyl-2- (6-moryolin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7- ona; 8-benzyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-vinyl-8 H -pyrido [2,3- d] pyrimidin-7-one; 8- (2-Cyclopropyl-ethyl) -5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -6-phenylamino-8H-pyrido [2,3-d] pyrimidin-7- ona; d-cyclopentyl-d-methyl-d-propionyl ^ -IS ^ .de-tetrahydro ^ H- [1, 2 '] bipyridinyl-5'-ylamine) -8H-pyrido [2,3- d] pyrimidin-7-one; and 2- [6- (3,5-dimethyl-piperazin-1-yl) -pyridin-3-ylamino] -6-hydroxymethyl-8-isopropyl-5-methyl-8H-pyrido [2,3-d] ] pyrimidin-7-one.

DETAILED DESCRIPTION OF THE INVENTION The invention comprises compounds of formula I: wherein: X 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, Ci-C 8 alkoxy > alkoxyalkyl of dC8, CN, NO2, OR5, NR5R6, C02R5, COR5, S (O) nR5, CONR5R6, NR5COR6, NR5S02R6, SO2NR5R6, or P (0) (OR5) (OR6); R1 is hydrogen or dC3 alkyl; R2 is hydrogen, halogen, Ci-C6 alkyl, O-C6 alkyl, C (0) R7, CO2R7, Ci-C6 alkenyl, Ci-C6 alkynyl, phenyl, O-phenyl, NR7-phenyl, or heteroaryl; R3 is hydrogen, phenyl, CT-C8 alkyl, C3-C7 cycloalkyl > or C3-C7 heterocyclyl; R 4 is hydrogen, halogen, Ci-Cs alkyl, OR 5, SR 5, or NR 5 R 6; R5 and R6 are in each case independently, hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R5 and R6, when they are attached to the same nitrogen atom, taken together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 members in the ring, up to four of said members can be optionally replaced with heteroatoms independently selected from oxygen, sulfur, S (O), S (O) 2, and nitrogen, however, provided that there is at least one carbon atom in the heterocyclic ring and that if there are two or more oxygen atoms in the ring, the oxygen atoms in the ring are not adjacent to each other. yes, wherein the heterocyclic group is unsubstituted or substituted with one, two or three groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl , amino, nitrile, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR7SO2R8, C (O) NR7R8, NR7C (O) R8, C (O) OR7, C (O) NR7SO2R8, (CH2) mS (O) nR7, (CH2) m-heteroaryl, 0 (CH2) m-heteroaryl, (CH2) mC (O) NR7R8, O (CH2) mC (O) OR7, and (CH2) SO2NR7R8; m is 0 to 4; R7 is hydrogen, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; R8 and R9 are hydrogen, CT-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. Since the compounds of formula I of this invention may possess asymmetric centers, they are capable of appearing in various stereoisomeric forms or configurations. Therefore, the compounds can exist in optically active (+) and (-) separated forms, as well as mixtures thereof. The present invention includes all these forms within its scope. The individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediates. The compounds of the present invention can exist in unsolvated forms as well as in the solvated forms, including the hydrated forms. In general, solvated forms, which include hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. The present invention also includes isotopically labeled compounds, which are identical to those indicated in formula I, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 180, 17O, 31P, 32P, 35S, 8F, and 36CI, respectively. The compounds of the present nvención, prodrugs thereof, and esters, amides and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this nvention Certain isotopically-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in tissue distribution assays of drugs and / or substrates. The tritiated isotopes, i.e. 3 H and Carbon 14, i.e., 14 C, are particularly preferred for their easy preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo or reduced dosage requirements half-life and, therefore, they may be preferred in some circumstances. Isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples and Preparations below, by substituting a reactive non-isotopically labeled reagent for a isotopically labeled easily available. The compounds of formula I are capable of further forming pharmaceutically acceptable formulations comprising salts, including, but not limited to, acid and / or base addition salts and solvates of a compound of formula I. By "alkyl", herein invention is meant a straight or branched hydrocarbon radical having between 1 and 10 carbon atoms, preferably between 1 and 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like. "Alkenyl" means radicals straight and branched hydrocarbons having 2 to 8 carbon atoms and at least one double bond and includes, but is not limited to, ethenyl, 3-yl-buten-1-, 2-ethenylbutyl, 3-hexen -1-ilo, and the like. The term "alkenyl" includes cycloalkenyl, and heteroalkenyl wherein 1 to 3 heteroatoms selected from O, S, N, or substituted nitrogen may replace carbon atoms. "Alkynyl" means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one triple bond and includes, but is not limited to, ethinyl, 3-butin-1-yl, propynyl, 2-butin-1. -yl, 3-pentin-1-yl, and the like. "Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group having 3 to 8 carbon atoms, for example cyclopropyl, cicioheptilo, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, ciciohexilo, and cyclopentyl. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are referred to as "heterocyclyl", which means a cycloalkyl group which also carries at least one heteroatom selected from O, S, N or substituted nitrogen. Examples of such groups include, but are not limited to, oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. "Alkoxy" means straight or branched alkyl groups having between 1-10 carbon atoms and linked by oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3 -hexoxi and 3-methylpentoxy. In addition, alkoxy refers to polyethers such as -0- (CH2) 2-0-CH3, and the like. "Acyl" means an alkyl or aryl (Ar) group having between 1-10 carbon atoms attached through a carbonyl group, ie, R-C (O) -. For example, acyl includes, but is not limited to, an alkanoyl of CT-C6, which includes substituted alkanoyl, in which the alkyl part may be substituted with NR8R9 or a carboxyl or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably with 1 to 3 groups selected from NR8R9, phenyl, substituted phenyl, keto, amino, alkyl, thioalkyl of CT-C6, alkoxy of CT-C6, hydroxy , carboxy, C6-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen" means nitrogen carrying CT-C6 alkyl or (CH2) phenyl in which p is 1, 2, or 3. The perhalo and polyhalo substitution is also included. Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2- carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2- (4-methylpiperazinyl) ethyl. Examples of substituted alkynyl groups include, but are not limited to, 2-methoxyethynyl, 2-ethylsulfanythynyl, 4- (1-piperazinyl) -3- (butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3- butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxyhexyloxy, and the like. Additionally, examples of substituted alkyl, alkenyl, and alkynyl groups include, but are not limited to, dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyne-1- ilo, 4-morpholinobutyl, 4-tetrahydropyridinylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. The term "anion" means a negatively charged counterion such as chloride, bromide, and trifluoroacetate. The term "aryl", as used herein, unless otherwise indicated, includes an aromatic ring system of C 6 -do without heteroatoms having a single ring (eg, phenyl), multiple rings (eg example, biphenyl), or multiple fused rings in which at least one is aromatic, (e.g., 1, 2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), wherein each aromatic ring in said system Aryl ring may be optionally substituted with between one and three substituents independently selected from halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, carbocyclic, heteroaryl, and hydroxy. A preferred aryl is phenyl which may be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo, (C-C) alkyl optionally substituted with between one and three halogen atoms and (CT-) alkoxy C4) optionally substituted with between one and three halogen atoms. The term "aryloxy", as used in this specification unless otherwise indicated, means "aryl-O-", wherein "aryl" is as defined above. The term "heteroaryl", as used herein, unless otherwise indicated, includes an aromatic heterocycle containing from five to ten members in the ring, of which between 1 and 4 may be heteroatoms selected, independently, between N, S and O, and said rings may be unsubstituted, monosubstituted or disubstituted with substituents selected, independently, from the group consisting of halo, alkyl of (CT-C4) and alkoxy of (CT-C), said groups being alkyl and alkoxy optionally substituted with between one and three halogen atoms. Such heteroaryl groups include, but are not limited to, thienyl, furanyl, thiazolyl, triazolyl, imidazolyl, isoxazoyl, oxadiazolyl, tetrazolyl, pyridyl, pyrrolyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl, pyrimidinyl, isoquinolinyl, quinolinyl, naphthyridinyl, phthalimidyl, benzimidazolyl, and benzoxazolyl. A preferred heteroaryl is pyridine. The term "heteroaryloxy", as used in this specification, unless otherwise indicated, means "heteroaryl-O-", wherein heteroaryl is as defined above. The term "leaving group", as used in this specification, refers to any group (X) that can leave the carbon to which it is attached carrying with it the two electrons that comprise the bond between the leaving group and that carbon ( the XC link). Typical leaving groups include but are not limited to: halides (e.g., F ", CI", Br ", I"), esters (e.g., acetate), sulfonate esters (e.g., mesylate, tosylate), ethers ( EtO ", PhO"), sulfides (PhS ", MeS"), sulfoxides, and sulfones. The term "one or more substituents", as used in this specification, refers to a number of substituents ranging from one to the maximum number of possible substituents based on the number of available binding sites. The terms "halo" or "halogen" in the present invention means fluorine, bromine, chlorine, and iodine. The term "cancer" includes, but is not limited to, the following cancers: breast, ovarian, cervical, prostate, testicular, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile ducts, cavity mouth and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon - rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermis carcinoma, large cell carcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell leukemia, and other leukemias. The term "treat", as used in this specification, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or preventing one or more symptoms of such a condition or disorder. . The term "treatment", as used in this specification, refers to the act of treating, as "treating" has been defined immediately before. The term "treat" as used in this specification can be applied to any suitable mammal. Such mammals include, but are not limited to, canines, felines, bovines, sheep, horses, humans and the like. The invention further provides compounds of formula I that are useful for treating the proliferation of abnormal cells such as cancer. The invention provides a method of treating disorders of abnormal cell proliferation such as a cancer selected from the group consisting of cancers of the breast, ovary, cervix, prostate, testes, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile ducts, oral cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon - rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermis carcinoma , large cell carcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cells , and leukemia comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutical salt thereof. acceptable entity thereof, to a subject in need of such treatment. A further embodiment of this invention is a method of treating subjects suffering from diseases caused by the proliferation of vascular smooth muscle cells. The compounds within the scope of the present invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method comprises administering to a subject in need of treatment an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, sufficient to inhibit the proliferation and / or migration of vascular smooth muscle cells. The invention further provides a method of treating a subject suffering from gout comprising administering to said subject an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, sufficient to treat the condition. This invention further provides a method of treating a subject suffering from kidney disease, such as polycystic kidney disease, comprising administering to said subject in need of treatment an amount of a compound of formula I, or a pharmaceutically acceptable salt of the same, enough to treat the condition. Due to the selective inhibitory activity against Cdk and other kinases, the compounds of the present invention are also useful for studying the mechanism of action of those kinases, both in vitro and in vivo. Many of the compounds of the present invention are selective inhibitors of cyclin-dependent Cdk2 and Cdk4 kinases, which are said to inhibit Cdk2 and Cdk4 more than they inhibit other tyrosine kinases and other serine-threonine kinases. The compounds of the present invention can also inhibit Cdk6 at concentrations similar to those required for the inhibition of Cdk4. A preferred embodiment of the present invention provides a method of inhibiting Cdk2 and / or Cdk4, which comprises administering a compound of formula I in an amount that selectively inhibits Cdk2 and / or Cdk4. The term "selectively inhibits" means that the preferred compound inhibits Cdk2 and / or Cdk4 at a lower dose than that required to inhibit other kinases. The term "pharmaceutically acceptable salts, esters, amides, or prodrugs" as used herein refers to the salts, esters, amides, and prodrugs of the compounds of the present invention that are within the scope of sound medical judgment. , suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, and the like, in proportion to a reasonable benefit / risk ratio, and effective for their proposed use, as well as the forms of bipolar ions, when possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ during the isolation and final purification of the compounds or by separately reacting the purified compound in its base form or free acids with a suitable organic or inorganic acid or base and isolating the salt thus formed. Insofar as the compounds of formula I of this invention are basic compounds, all are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the basic compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent. and then converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms to some extent in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for purposes of the present invention. Such acid addition salts can be prepared from organic acids. Representative salts include the hydrobromide salts, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate , laurylsulfonate and isethionate, and the like. Such acid addition salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and similar. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, ciorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. The pharmaceutically acceptable base addition salts can be formed from acidic compounds of formula I. Such salts are formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. The base addition salts of the acid compounds of formula I are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms to some extent in certain physical properties such as solubility in polar solvents. The pharmaceutically acceptable base addition salts may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including , but are not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine and the like; see, for example, Berge et al., supra. Also contemplated in this invention are amino acid salts such as arginate, gluconate, galacturonate, and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Science, 1977; 66: 1-19 which is incorporated herein by reference.) Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include CT-C6 alkyl esters in which the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to, benzyl. Preferred esters include CT-C alkyl. The esters of the compounds of the present invention can be prepared according to conventional procedures "March's Advanced Organic Chemistry, 5th edition". MB Smith and J. March, John Wiley and Sons, 2001. Examples of non-toxic, pharmaceutically acceptable amides of the compounds of this invention include the amides derived from ammonia, alkyl CT-C6 primary amines and dialkyl C-C6 secondary amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6- membered heterocycle containing a nitrogen atom. Amides derived from ammonia, C-C3 alkyl primary amines and dialkyl CT-C2 secondary amines are preferred. The amides of the compounds of the invention can be prepared according to conventional methods such as "March's Advanced Organic Chemistry, 5th edition". M. B. Smith and J. March, John Wiley and Sons, 2001.

The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough description is provided in T. Higuchi and V. Stella, "Prodrugs as novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference. An illustration of the preparation of the compounds of the present invention is shown in schemes 1-7 below: Synthesis The compounds of the invention can be prepared according to the general scheme 1. The coupling of the components A and B generally requires their combination with or without a suitable solvent such as dimethylsulfoxide (DMSO), toluene or acetonitrile, and heating of this Mix up to 80 - 150 ° C. Both the sulfoxide and the sulfone provide a suitable leaving group or a mixture of the two can be employed. The selection of sulfoxide or sulfone generally depends on the purity of the coupled product obtained, in particular the degree of contamination with by-products of 2-hydroxypyrimidine.

SCHEME 1 The synthesis of sulfoxides and sulfones represented by structure A have been previously described in PCT applications WO 98/33798 and WO 01/70741 and WO 03/00059. Such intermediates are assembled by established and published protocols (see Barvian et al., J. Med. Chem. 2000, 43, 4606-4616) starting from the commercially available pyrimidine, 4-chloro-2-methylsulfanyl ethyl ester. -pyrimidine-5-carboxylic acid. A variety of R3 groups are tolerated by this chemistry and these can be introduced at an early stage in the synthesis scheme by displacement of chlorine by an appropriate amine (scheme 2a), or later by alkylation of the amide pyridone nitrogen (scheme 2b).

SCHEME 2A SCHEME 2B HN W = Me-S-, or ^ LG is a leaving group, for example, I, Br. Base = tetramethylguanidine or an equivalent organic base, or CsC03. The R2 substituents can be introduced using a substituted Horner-Wadsworth Emmons reagent as shown in Scheme 3.

As an alternative, additional chemistry can be carried out in the R2 group after the closure of the ring, including the displacement of fluorine by alkoxides and alkylamines and anilines.

SCHEME 3 The halogenation in R2 can be easily carried out using for example N-bromosuccinimide. The halogen can then be replaced using any of a number of reactions known to those skilled in the art, including but not limited to, metal-halogen exchange and palladium-catalyzed cross coupling reactions such as Stille coupling, Suzuki coupling, carbonylation and related reactions (scheme 4).

SCHEME 4 K -. Uijlljij.

The pyridine derivatives B in scheme 1, wherein X 1 is hydrogen can be prepared from commercially available 5-bromo-2-nitropyridine by promotion promoted by base or palladium of the bromine by a nucleophile such as an alcohol or a primary or secondary amine, followed by the reduction of the nitro group. A representative example of this method is illustrated in Scheme 5. Examples of bases that can be used for this reaction include K CO3, or Na2CO3. These bases can be used in the presence of a phase transfer catalyst such as Bu4NI. The palladium-promoted reactions are typically carried out with catalysts such as Pd (OAc) 2, Pd2 (dba) 3, or Pd (PPh3) 4 and the like in non-polar organic solvents such as benzene, toluene, tetrahydrofuran or acetonitrile at temperatures between 25 and 25. - 110 ° C. These catalysts are typically employed with a suitable ligand, such as 2,2'- (Bis (diphenylphosphino) -1, V-binaphthyl (BINAP), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos). , or a related phosphine-based Pd ligand The reduction of the nitro group is typically performed using Raney Nickel although other reducing agents can also be used including palladium on carbon, or Fe / HCl.

SCHEME 5 O? - r v-. I B.}. r. StuWI When X1 is not hydrogen, the B derivatives of pyridine are prepared by methods known to those skilled in the art. Examples of representative methods can be found in Comprehensive Heterocyclic Chemistry, Eds. A. R. Katritzky, C. W. Rees, 1984, Pergamon, NY; volume 2, chapter 2.08, Pyridines and their Benzoderivatives; Synthesis, Gurnos Jones. Also with reference to Comprehensive Heterocyclic Chemistry II, Eds. A. R. Katritzky, C. W. Rees., E. Scriven, 1996, Pergamon, NY; volume 25, chapter 5.05, Pyridines and their Benzoderivatives: Synthesis, Gurnos Jones. For example, 2,3-dibromo-5-nitropyridine is commercially available and may be selectively substituted at the 2-position to generate the B fragments of the side chain where X 1 = Br (scheme 6). As described above, a variety of palladium-mediated chemistries are available for the subsequent replacement of bromine by other groups including alkenes, aryls, amines and alcohols and these procedures would be well known to those skilled in organic synthesis.

SCHEME 6 An alternative route to prepare the compounds of the present invention involves the conversion of the pyridopyrimidine core fragment to a pyridopyrimidine C-2 amine as shown in scheme 7 and use of this amine as a nucleophile to displace a leaving group such as bromide or iodide of a fragment of pyridine. This reaction proceeds with palladium catalyst providing the objective compounds in equivalent yields to the pathway shown in Scheme 1. Examples of palladium catalysts that may be employed in this reaction include Pd (OAc) 2, Pd2 (dba) 3, or Pd (PPh3) 4 and PdCI2 (PPh3) 2. These catalysts are typically employed with a suitable ligand such as (2,2 '- (bis (diphenylphosphino) -l, V-binaphthyl (BINAP), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos). or a related phosphine-based Pd ligand Typical solvents include dimethoxyethane, tetrahydrofuran, acetonitrile and toluene The reactions are typically carried out at temperatures between 25 ° C and 160 ° C. In some cases, the reaction is accelerated by the presence of electron-withdrawing substituents in ortho position accepting electrons to the leaving group of the pyridine ring (Jonckers, TH M et al., Tetrahedron 2001, 57, 7027-7034).

SCHEME 7 X, - "N 'N" "O Similar types of organometallic couplings can be performed to install R4 at a late stage in the synthesis as shown in scheme 8.

SCHEME 8 The examples presented below are proposed to illustrate the particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way. Those skilled in the art will recognize that the starting materials may be varied and additional steps may be employed to produce the compounds encompassed by the present invention, as demonstrated by the following examples. The following examples are for illustrative purposes only and are not intended, nor are they considered, as limiting the invention in any way. Those skilled in the art will appreciate that variations and modifications can be made without violating the spirit or scope of the invention.

EXAMPLE 1 8-isopropyl-2- (pyridin-3-ylamino) -8H-pyrido [2,3-d1-pyrimidin-7-one 8-isopropyl-2- (pyridin-3-ylamino) -8H-pyridof2,3-d] pyrimidin-7-one was prepared according to scheme 1. P. of F. = 156 - 158 ° C.

EXAMPLE 2 8-cyclopentyl-2- (6-methoxy-pyridin-3-ylamino) -8H-pyridof2,3-dlpyrimidin-7-one 8-cyclopentyl-2- (6-methoxy-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one was prepared according to scheme 1. P. of F. = 181 182 ° C.

EXAMPLE 3 6-Bromo-8-cyclopentyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyridof2,3-d1-pyrimidin-7-one hydrochloride salt The hydrochloride salt of 6-bromo-8-cyclopentyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2], 3-d] pyrimidin-7-one was prepared from the 4- [5- (6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido-tert -butyl ester [2,3 -d] pyrimidin-2-ylamino) pyridin-2-yl] -piperazine-1-carboxylic acid according to the general procedure described in Example 6. DMSO (DMSO-de, 400 MHz) d 10.09 (s, 1 H), 9.22 (s, 2H), 8.73 (s, 1 H), 8.45 (s, 1 H), 8.44 (s, 1 H), 8.33 (s, 1 H), 7.98 (d, J = 8 Hz , 1 H), 7.13 (d, J = 9 Hz, 1 H), 5.82 (sa, 1 H), 3.75 (s, 4H), 3.18 (s, 4H), 2.29 - 2.12 (m, 2H), 1.87 -78 (m, 4H), 1.59-1.56 (m, 2H). MS (IQPA +) 472.1.

EXAMPLE 4 6-bromo-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyridof2,3-d1-pyrimidin-7-one; 6-Bromo-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one was prepared from 6-Bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d] pyrimidin-7-one and 6-morpholin-4-ylpyridin-3-ylamine by the general procedure of scheme 1. P. de F. = 254 - 256 ° C. 1 H NMR (CDCl 3, 400 MHz) d ppm 1.61 (m, 2H), 1.81 (m, 2H), 1. 96 (m, 2H), 2.24 (m, 2H), 2.57 (s, 3H), 3.48 (m, 4H), 3.83 (m, 4H), 5.90 (m, 1 H), 6.67 (d, J = 9.0 Hz, 1H), 7.05 (s, 1 H), 7.81 (dd, J = 9.0, 2.7 Hz, 1 H), 8.28 (d, J = 2.7 Hz, 1 H), 8.68 (s, 1 H). m / z 487.1, 485.1 (M + 1). CHN C22H25BrN6O2 0.19 H20, calculated for C, 54.06, H, 5.23, N, 17.19; Found C, 53.67, H, 5.11, N, 16.80.

EXAMPLE 5 6-Acetyl-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d1-pyrimidin-7-one; 6-Acetyl-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one was prepared from 6-Bromo-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one using procedures described in WO 03/062236, incorporated in this specification by reference. P. of F. = 224 - 226 ° C.

EXAMPLE 6 6-Bromo-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyridof2,3-d1-pyrimidin-7-one The 4- [5- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino-tert -butyl ester was dissolved. ) pyridin-2-yl] -piperazine-1-carboxylic acid (1.00 g, 1.71 mmol) in EtOAc (20 ml) to which 1.0 N HCl (20 ml) was added and stirred at room temperature overnight. The solvent was then removed in vacuo, suspended in MeCN, then the solid was filtered to give 6-bromo-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H - pyrido [2,3-d] pyrimidin-7-one in the form of a yellow solid (0.965 g, 93%). P. of F. = 290 ° C (foams). 1 H NMR (DMSO-d 6, 400 MHz) d ppm 1.56 (m, 2H), 1.77 (m, 2H), 1. 88 (m, 2H), 2.13 (m, 2H), 2.56 (s, 3H), 3.19 (m, 4H), 3.73 (m, 4H), 5.88 (m, 1 H), 7.09 (d, J = 10.0 Hz, 1 H), 7.97 (d, J = 7.08 Hz, 1 H), 8.44 (d, J = 2.4 Hz, 1 H), 8.93 (s, 1 H), 9.13 (s, 2H), 9.99 (s, 1H). m / z 486.1, 484.1 (M + 1). CHN C22H26BrN7O 3.30 HCl, calc'd for C, 43.70, H, 4.88, N, 16.21; Found C, 43.39, H, 5.10, N, 16.14.

EXAMPLE 7 6-Acetyl-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyridof2,3-d1-pyrimidin-7-one 6-Acetyl-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one was prepared from of 4- [5- (6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) pyridin-2-tert-butyl ester -yl] -piperazine-1-carboxylic acid using the procedures described in WO 03/062236, P. of F. = 125 ° C (foams).

EXAMPLE 8 4- (5-Amino-pyridin-2-yl) -piperazine-1-carboxylic acid tert -butyl ester Combine together in DMSO (100 ml) 2-bromo-5-nitropyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and ester The tert-butyl of piperazine-1-carboxylic acid (11.5 g, 61.7 mmol) was heated gently to 50 ° C for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitation was filtered, washed with water, and then dried in a vacuum oven to yield 4- (5-nitro-pyridin-2-yl) -piperazine-1-carboxylic acid tert -butyl ester (16.1 g, 93%) in the form of a light orange solid. 1 H NMR (CDCl 3, 400 MHz) d ppm 1.47 (s, 9H), 3.55 (m, 4H), 3. 75 (m, 4H), 6.55 (d, J = 9.3 Hz, 1 H), 8.21 (dd, J = 9.5, 2.7 Hz, 1 H), 9.03 (d, J = 2.7 Hz, 1 H). The 4- (5-nitro-pyridin-2-yl) -piperazine-1-carboxylic acid tert -butyl ester (16.0 g) was dissolved, 51.9 mmol) in THF (400 ml), NiRa (4 g) was added and placed in an atmosphere of H2 at 50 psi (344.74 kPa) for 5 hours. The catalyst was removed by filtration through Celite and the solvent was evaporated in vacuo to give the 4- (5-amino-pyridin-2-yl) -piperazine-1-carboxylic acid tert -butyl ester (14.5 g, 100% ). 1 H NMR (CDCl 3, 400 MHz) d ppm 1.46 (s, 9 H), 3.31 (m, 6 H), 3.53 (m, 4 H), 6.56 (d, J = 8.8 Hz, 1 H), 6.98 (dd, J = 8.8, 2.9 Hz, 1 H), 7.78 (dd, J = 2.9, 0.7 Hz, 1 H). m / z 279.1 (M + 1).

EXAMPLE 9 6-morpholin-4-yl-pyridin-3-ylamine 6-morpholin-4-yl-pyridin-3-ylamine was prepared from 2-bromo-5-nitropyridine and morpholine by the general procedure described in Example 8. 1 H NMR (CDCl 3, 400 MHz) d ppm 3.31 (m , 6H), 3.82 (m, 4H), 6. 55 (dd, J = 8.8, 0.7 Hz, 1 H), 6.99 (dd, J = 8.8, 2.9 Hz, 1 H), 7.79 (dd, J = 2.9, 0.5 Hz, 1H). m / z 180.1 (M + 1).

Biological Assays To determine the inhibitory potency and selectivity of compounds of the present invention against Cdk4 and related kinases, the compounds were evaluated in conventional assays routinely used to measure the inhibition of cyclin-dependent kinase enzymes and other protein kinases (see for example DW Fry et al., J. Biol. Chem. 2001, 276, 16617-16623). The tests were carried out as described below.

Assay for the inhibition of Cdk2 / cyclin A The assays of the enzyme Cdk2 for the determination of Cl50 values and kinetic evaluation are carried out as follows. 96-well filter plates are used (Millipore MADVN6550, Bedford, MA). The final assay volume is 0.1 ml containing pH A buffer (20 mM TRIS (tris [hydroxymethyl] aminomethane) (pH 7.4), 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl 2), 12 mM ATP containing [32 P ] ATP 0.25 μCi, 20 ng of Cdk2 / cyclin A, 1 μg of retinoblastoma protein, and the test compound at appropriate dilutions in pH A buffer (pH A buffer alone without added test compound was used as a control for no inhibition The pH A regulator containing excess ethylenediaminetetraacetic acid (EDTA) was used to determine the background level of 32P in the absence of enzymatic activity). All components except ATP are added to the wells, and the plate is placed in a plate mixer for 2 minutes. The reaction is initiated by the addition of [32 P] ATP, and the plate is incubated at 25 ° C for 15 minutes. The reaction is terminated by the addition of 0.1 ml of 20% trichloroacetic acid (TCA). The plate is kept at 4 ° C for at least 1 hour to allow the substrate to precipitate. The wells are then washed five times with 0.2 ml of 10% TCA, and the 32P incorporation is determined with a beta plate counter (Wallac inc, Gaithersburg, MD). The CI5o value of the test compound was determined using the medium effect method (Chou, T-C and Talalay, P. Applications of the median effect principle for the assessment of low-risk risk of carcinogens and for the quantitation of synergism and antagonism of chemotherapeutic agents in New Avenues in Developmental Cancer Chemotherapy (Eds. Harrap, KT and Connors, TA), pp. 37-64. Academic Press New York, 1987).

Assay for the inhibition of Cdk4 / cyclin D The assay of the enzyme Cdk4 for the determinations of the Cl50 value and kinetic evaluation is carried out as follows. 96-well filter plates are used (Millipore MADVN6550, Bedford, MA). The total volume is 0.1 ml containing pH A regulator (20 mM TRIS (tris [hydroxymethyl] aminomethane) (pH 7.4), 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl 2), 25 μM ATP containing [32 P] ATP 0.25 μCi, 20 ng of Cdk4, 1 μg of retinoblastoma protein, and the test compound in appropriate dilutions in pH regulator A. The pH A buffer alone without added test compound was used as a control for no inhibition. The pH A buffer containing excess EDTA was used to determine the background 32P level in the absence of enzymatic activity. All components except ATP are added to the wells, and the plate is placed in a plate mixer for 2 minutes. The reaction is initiated by the addition of [32 P] ATP, and the plate is incubated at 25 ° C for 15 minutes. The reaction is terminated by the addition of 0.1 ml of 20% trichloroacetic acid (TCA). The plate is kept at 4 ° C for at least 1 hour to allow the substrate to precipitate. Then the wells are washed five times with 0.2 ml of 10% TCA, and the incorporation of 32P is determined with a beta plate counter (Wallac inc, Gaithersburg, MD). The Cl50 value of the test compound was determined using the medium effect procedure (Chou, T-C and Talalay, P. Applications of the median effect principle for the assessment of low-risk risk of carcinogens and for the quantitation of synergism and antagonism of chemotherapeutic agents in New Avenues in Developmental Cancer Chemotherapy (Eds. Harrap, KT and Connors, TA), pp. 37-64. Academic Press New York, 1987).

Assay for inhibition of fibroblast growth factor receptor kinase (FGFr) For tyrosine kinase assays of FGF receptor (FGFr) 96-well plates (100 μl / incubation / well) are used, and conditions are optimized to measure the incorporation of 32 P from [α 32 P] ATP into glutamate-tyrosine copolymer substrate. In summary, 82.5 μl of incubation pH regulator B are added to each well (25 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) (pH 7.0), 150 mM NaCl, 0.1 X-100 Triton %, 0.2 mM PMSF (phenylmethylsulfonyl fluoride (protease inhibitor)), 0.2 mM Na3VO4, 10 mM MnCl2) and 750 μg / ml of Poly (4: 1) glutamate-tyrosine followed by 2.5 μl of the test compound in buffer pH B and 5 μl of a 7.5 μg / μl solution of FGFr to start the reaction. After an incubation at 25 ° C for 10 minutes, 10 ml of [? 32P] ATP (0.4 μCi plus 50 μM ATP) is added to each well, and the samples are incubated for an additional 10 minutes at 25 ° C. The reaction is terminated by the addition of 100 μl of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate and the precipitation of the material on glass fiber mats (Wallac). The filters are washed three times with 15% TCA containing 100 mM sodium pyrophosphate, and the radioactivity retained in the filters is counted in a Wallac 1250 Betaplate reader. The non-specific activity is defined as radioactivity retained on the filters after the incubation of the samples with pH regulator alone (without enzyme). The specific enzymatic activity (enzyme plus pH regulator) is defined as the total activity minus the non-specific activity. The concentration of the test compound which inhibits the specific activity by 50% (Cl50) is determined based on the inhibition curve.

Assay for the inhibition of plaque-derived growth factor receptor (PDGFr) The enzymatic assays for the determinations of Cl50 values were carried out in 96-well filter plates (Millipore MADVN6550, Bedford, MA). The total volume was 100 μl / incubation / well) containing (20 mM Hepes (pH 7.4), 50 μM sodium vanadate, 40 mM magnesium dichloride, 10 mM manganese chloride, 10 μM adenosine triphosphate (ATP) containing [? 32P] ATP (0.5 μCi, 20 μg of polyglutamic acid / tyrosine (Sigma Chemical Co., St. Louis, MO), 10 ng of the PDGF receptor intracellular domain and appropriate dilutions of the inhibitors. ATP was added to the well and the plate was incubated with shaking for 10 minutes at 25 [deg.] C. The reaction started by the addition of [? 32P] ATP, and the plate was incubated for 10 minutes at 25 [deg.] C. The reaction was terminated. by adding 100 μl of 20% trichloroacetic acid (TCA).

The plate is kept at 4 ° C for at least 15 minutes to allow the substrate to precipitate. The wells are washed five times with 0.2 ml of 10% TCA and the radioactivity retained in the filters is counted in a Wallac 1250 reader Betaplate The non-specific activity is defined as radioactivity retained on the filters after the incubation of the samples with pH regulator alone (without enzyme). The specific enzymatic activity (enzyme plus pH regulator) is defined as the total activity minus the non-specific activity. The concentration of the test compound which inhibits the specific activity by 50% (CI5o) is determined based on the inhibition curve. The results of the above tests for the compounds of Examples 1 to 7 are presented in Table 1.

TABLE 1 Formulations and administration The compounds of this invention will typically be formulated with common excipients, diluents, and carriers to provide compositions that will be suitable for convenient administration to mammals. The following examples illustrate typical compositions that are provided in a further embodiment of this invention. The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. Those skilled in the art will recognize that the following dosage forms may comprise as the active component, a compound of formula I or a corresponding pharmaceutically acceptable salt or solvate of a compound of formula I. This invention also comprises a pharmaceutical formulation comprising an amount Therapeutically effective of a compound of formula I together with a pharmaceutically acceptable carrier, diluent, or excipient. To prepare the pharmaceutical compositions with the compounds of the present invention, the pharmaceutically acceptable carriers can be either a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. The formulations of this invention preferably contain between about 5% and about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter, and the like. A preferred form for oral use are capsules, which include the formulation of the active compound with encapsulating material as a vehicle providing a capsule in which the active component with or without other vehicles, is surrounded by a vehicle, which is of this type. way in association with him. Similarly, envelopes and dragees are included. Tablets, powders, capsules, pills, sachets, and lozenges can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component dispersed homogeneously therein, as by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, therefore solidify. Liquid form preparations include solutions, suspensions, and emulsions such as aqueous solutions or water / propylene glycol. For parenteral injection the liquid preparations can be formulated in solution in aqueous solution of polyethylene glycol, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water and mixing with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are preparations in solid forms which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, coloring agents, flavorings, stabilizers, pH regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. Waxes, polymers can be used, microparticles, and the like to prepare sustained release dosage forms. Also, osmotic pumps may be employed to distribute the active compound uniformly over a prolonged period of time. The pharmaceutical preparations of the invention are preferably prepared in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders packed in vials or ampoules. Also, the unit dosage form can be the capsule itself, tablet, envelope, or lozenge, or it can be the appropriate number of any of these in packaged form. The compounds of the present invention may be freeze dried, spray dried or evaporated dried to provide a solid bed, powder, or film of crystalline or amorphous material. Radiofrequency or microwave drying can be used for this purpose.

The therapeutically effective dose of a compound of formula I will vary between about 0.01 mg / kg and about 100 mg / kg of body weight per day. Typically adult doses will be between about 0.1 mg and about 3000 mg per day depending, of course, on the mode of administration, the particular application and the potency of the active component. For example, oral administration may require a total daily dose of between 10 mg and 3000 mg, while the intravenous dose may require only between 0.1 mg and 1000 mg / kg of body weight. These dosages are based on an average human subject weighing approximately 65 to 70 kg. The doctor will be able to easily determine the doses for subjects whose weight falls outside this range, such as children and the elderly. The composition, if desired, may also contain other compatible therapeutic agents. The total daily dose can be administered in single or divided doses. Such treatment may be repeated at successive intervals as long as necessary. The compounds of the invention can be administered alone or in combination with other drugs and are generally administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used in this specification to describe any ingredient other than the compound of the invention. The choice of excipient will depend largely on the particular mode of administration.

The compounds of the invention can be administered orally. Oral administration may involve ingestion, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled), chewable gums, multi- and nano-particles, gels, films (including mucoadhesive), ovules , sprayers and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as soft or hard capsule fillers and typically comprise a carrier, for example water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from an envelope. The compounds of the invention can also be used in rapidly dissolving, rapidly dissolving dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

Formulation of tablets of the compound of example 7 Formulation of tablets Ingredient Amount Compound of example 7 50 mg * Lactose 80 mg Corn starch (for mixing) 10 mg Corn starch (for pasta) 8 mg Magnesium stearate (1%) 2 mg 150 mg * Amount adjusted according to the activity of the drug. A compound of the present invention is mixed with lactose and corn starch (for mixing) and mixed until uniformly giving a powder. The corn starch (for pasta) is suspended in 6 ml of water and heated with agitation to form a paste. This paste is added to the mixed powder, and the mixture is granulated. The wet granules are passed through a No. 8 hand sieve and dried at 50 ° C. The mixture is lubricated with 1% magnesium stearate and compressed to form tablets. The tablets are administered to the patient at a rate of 1 to 4 per day for the prevention and treatment of cancer.

Another composition of a typical tablet according to the invention may comprise: * Amount adjusted according to the activity of the drug. A typical tablet can be prepared using conventional procedures known to the formulation chemist, for example, by direct compression, granulation (dry, wet, or in the molten state), coagulation in the molten state, or extrusion. The tablet formulation may comprise one or more layers or may be coated or uncoated. Examples of excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulfate, preservatives, antioxidants, flavors and dyes. Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, dual controlled, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other modified release formulations are described in U.S. Patent No. 6,106,864. The compounds of the invention can also be administered directly into the blood stream, into the muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrathecal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle), needleless injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of between 3 and 9), but, for some applications, may be more adequately formulated in the form of a non-aqueous solution sterile or as a dry form to use together with a suitable vehicle such as sterile, pyrogen-free water. The preparation of the parenteral formulations under sterile conditions, for example, by lyophilization, can be easily achieved using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by suitable processing, for example, the use of high-energy spray-dried dispersions (see WO 01/47495) and / or by using appropriate formulation techniques, such as the use of solubility enhancing agents. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, dual controlled, targeted and programmed release. To a solution of 700 ml of propylene glycol and 200 ml of water for injection are added 20.0 g of the compound of example 7 of the present invention. The mixture is stirred and the pH adjusted to 5.5 with hydrochloric acid. The volume is adjusted to 1000 ml with water for injection. The solution is sterilized, poured into 5.0 ml ampoules, each containing 2.0 ml (40 mg of compound), and sealed under nitrogen. The solution is administered by injection to a patient suffering from cancer and in need of treatment. The compounds of the invention can also be administered topically to the skin or mucosa, either dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated see, for example, J. Pharm. Sci., 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include distribution by ontophoresis, electroporation, phonophoresis, sonophoresis, and needleless or microneedle injection. Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, dual controlled, targeted and programmed release. Thus, the compounds of the invention can be formulated into a more solid form for administration in the form of an implanted reservoir providing long-term release of the active compound. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, or in the form of a mixture, for example, in a dry mixture with lactose, or in the form of a a particle of mixed components, eg, phospholipid mixture) from a dry powder inhaler or in the form of an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or a nebulizer, with or without the use of a suitable propellant, such as dichlorofluoromethane. The pressurized container, pump, sprayer, atomizer, or nebulizer contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or an alternative agent suitable for dispersion, solubilization, or compound extension. active, the propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for distribution by inhalation (typically less than 5 microns). This can be achieved by any suitable fragmentation method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain between 1 μg and 10 mg of the compound of the invention per actuation and the actuation volume may vary between 1 μl and 100 μl. A typical formulation may comprise a compound of this invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Capsules, blister packs and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose (HPMC)) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a behavior modifier such as / -leucine, mannitol, or magnesium stearate. In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that distributes a measured quantity. The units according to the invention are typically arranged to administer a metered dose or "puff" appropriate for the pathological condition, age and size of the individual. The global daily dose can be administered in a single dose or, more usually, as divided doses throughout the day. Formulations for inhaled / intranasal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained, pulsed, dual controlled, directed and programmed. The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, dual controlled, targeted and programmed release. The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a suspension or micronized solution in isotonic, pH adjusted, sterile saline.

Other formulations suitable for ocular and ear administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative. , such as benzalkonium chloride. Such formulations can also be distributed by iontophoresis. Formulations for ocular / ear administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, dual controlled, targeted or programmed release. The compounds of the invention can be combined with soluble macromolecular entities such as cyclodextrin or polymers containing polyethylene glycol to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability. For example, drug-cyclodextrin complexes are found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. The most commonly used for these purposes are the alpha, beta and gamma cyclodextrins, examples of which can be found in international patent applications numbers WO 91/11172; WO 94/02518 and WO 98/55148. The invention provides a pharmaceutical composition for treating a disorder or condition selected from the group consisting of cell proliferative disorders, such as cancer, vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis, restenosis, and endometriosis; infections, including viral infections such as DNA viruses such as herpes and RNA viruses such as HIV, and fungal infections; autoimmune diseases such as psoriasis, inflammation such as rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis, rejection of organ transplantation, including host disease versus graft. The invention and the manner and procedure of preparing and using it are now described in terms so complete, clear, concise and accurate as to enable any person skilled in the art to which it belongs, to prepare and use the same. It is to be understood that the foregoing describes the preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the description and claims. All documents that include patents and published patent applications are incorporated by reference. In order to show in a particular way and claim in a different manner the subject matter considered as an invention, the following claims conclude this specification.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula ? wherein X1 is hydrogen, halogen, CT-C6 alkyl, haloalkyl of CT-C6, alkoxy of CT-C8, alkoxyalkyl of CT-C8, CN, NO2, OR5, NR5R6, C02R5, COR5, S (O) nR5 , CONR5R6, NR5COR6, NR5SO2R6, SO2NR5R6, or P (O) (OR5) (OR6); R1 is hydrogen or CT-C3 alkyl; R2 is hydrogen, halogen, CT-C6 alkyl, O-C6 alkyl, C (O) R7, CO2R7, alkenyl of CT-C6, alkynyl of CT-C6, phenyl, O-phenyl, NR7-phenyl, or heteroaryl; R3 is hydrogen, phenyl, CT-C8 alkyl, C3-C7 cycloalkyl, or C3-C7 heterocyclyl; R 4 is hydrogen, halogen, C 1 -C 8 alkyl, OR 5, SR 5, or NR 5 R 6; R5 and R6 are in each case independently, hydrogen, CT-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R5 and R6, when they are attached to the same nitrogen atom, taken together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 members in the ring, up to four of said members can be optionally replaced with heteroatoms independently selected from oxygen, sulfur, S (O), S (O) 2, and nitrogen, however, provided that there is at least one carbon atom in the heterocyclic ring and that if there are two or more oxygen atoms in the ring , the oxygen atoms in the ring are not adjacent to each other, wherein the heterocyclic group is unsubstituted or substituted with one, two or three groups independently selected from halogen, hydroxy, hydroxyalkyl, Ct-C6 alkyl, d-alkoxy Cß, alkoxycarbonyl, d-C6 alkylcarbonyl, Ct-C6 alkylcarbonylamino, Ct-C6 aminoalkyl, d-C6 aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amin or, nitrile, mono- or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR7S02R8, C (0) NR7R8, NR7C (0) R8, C (0) OR7, C (O) NR7SO2R8, (CH2) mS ( O) nR7, (CH2) m-heteroaryl, O (CH2) m-heteroaryl, (CH2) mC (O) NR7R8, O (CH2) mC (O) OR7, and (CH2) SO2NR7R8; m is 0 to 4; R7 is hydrogen, CT-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; R8 and R9 are hydrogen, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.

2. - The compound according to claim 1, further characterized in that R1 is methyl.

3. The compound according to claim 1, further characterized in that X1 is hydrogen.

4. A compound selected from 8-isopropyl-2- (pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 8-cyclopentyl-2- (6-methoxy-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7- one; 6-bromo-8-cyclopentyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3-d] pyrimidin-7-one; 6-bromo-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-bromo-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-ethyl-8-isopropyl-2- (6-p-piperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3- d] pyrimidin-7-one; 6-benzyl-8-isopropyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3-d] pyrimidin-7-one; or 6-acetyl-8-isopropyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8 H -pyrido [2,3- d] pyrimidin-7-one.

5. A compound selected from ethyl ester of 8-isopropyl-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7,8-dihydro-pyrido [2,3-d] ] pyrimidine-6-carboxylic acid; 6-ethyl-8- (2-methoxy-ethyl) -2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 6-benzyl-8-isopropyl-2- [6- (2-methoxy-ethoxy) -pyridin-3-ylamino] -8H-pyrido [2,3- d] pyrimtdin-7-one; 6-Acetyl-2- (5-chloro-6-piperazin-1-yl-pyridin-3-ylamino) -8-isopropyl-8H-pyrido [2,3- d] pyrimidin-7-one; 8-isopropyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-thiazol-2-yl-8H-pyrido [2,3-d] pyrimidin-7-one; 3- [6-fluoro-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7H-pyrido [2,3-d] pyrimidin-8-yl] propionic; 8-isopropyl-2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino] -6-phenoxy-8H-pyrido [2,3- d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-2- (6- [1,4] diazepan-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- djpyrimidin-7-one; 6-ethynyl-8-isopropyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; or 8-benzyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-vinyl-8 H -pyrido [2,3- d] pyrimidin-7-one.

6. A compound selected from 8- (2-cyclopropyl-ethyl) -2- (6-morpholin-4-yl-pyridin-3-ylamino) -6-phenylamino-8H-pyrido [2,3- d] pyrimidine -7-ona; 8-cyclopentyl-6-propionyl-2- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-ylamino) -8H-pyrido [2,3- d] pyrimidine-7 -oha; 2- [6- (3,5-dimethyl-piperazin-1-yl) -pyridin-3-ylamino] -6-hydroxymethyl-8-isopropyl-8H-pyrido [2,3- d] pyrimidin-7- ona; 8-cyclopentyl-6-ethyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 6-Chloro-8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; 8-isopropyl-5-methyl-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7,8-dihydropyrido [2,3-d] pyrimidine- ethyl ester 6-carboxylic; 6-ethyl-8- (2-methoxy-ethyl) -5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidin-7- ona; 6-benzyl-8-isopropyl-2- [6- (2-methoxy-ethoxy) -pyridin-3-ylammon] -5-methyl-8 H -pyrido [2,3- d] pyrimidin-7-one; or 6-acetyl-2- (5-chloro-6-piperazin-1-yl-pyridin-3-ylamino) -8-isopropyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one .

7. - A compound selected from 8-isopropyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-thiazol-2-yl-8H-pyrido [2,3- d] pyrimidin-7-one; 3- [6-fluoro-5-methy1-7-oxo-2- (6-piperazin-1-yl-pyridin-3-ylamino) -7H-pyrido [2,3-d] pyrimidin-8- acid il] -propionic; 8-isopropyl-5-methyl-2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino] -6-phenoxy-8H-pyrido [2,3-d] pyrimidin-7-one; 6-acetyl-8-cyclopentyl-2- (6- [1,4] diazepan-1-yl-pyridin-3-ylamino) -5-methyl-8H-pyrido [2,3-d-pyrimidin-7-one; 8- (2-Dimethylamino-ethyl) -6-ethynyl-5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -8H-pyrido [2,3-d] pyrimidine- 7-one; 8-benzyl-5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -6-vinyl-8 H -pyrido [2,3- d] pyrimidin-7-one; 8- (2-Cyclopropyl-ethyl) -5-methyl-2- (6-morpholin-4-yl-pyridin-3-ylamino) -6-phenylamino-8H-pyrido [2,3-d] pyrimidin-7- ona; 8-cyclopenti) -5-methyl-6-propionyl-2- (3, 4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl-5'-ylamino) -8H-pyrido [2,3- d] pyrimidin-7-one; or 2- [6- (3,5-dimethyl-piperazin-1-yl) -pyridin-3-ylamino] -6-hydroxymethyl-8-ylpropyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one; or the pharmaceutically acceptable salts thereof.

8. The use of a compound of claim 1, for the manufacture of a medicament for the treatment of a disorder or condition caused by abnormal cell proliferation in a mammal.

9. The use as claimed in claim 8, wherein the disorder or condition being treated is proliferation of vascular smooth muscle associated with atherosclerosis; postsurgical vascular stenosis and restenosis; or endometriosis.

10. The use as claimed in claim 8, wherein the abnormal cell proliferation is a cancer selected from the group consisting of cancer of the breast, ovary, cervix, prostate, testes, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile ducts, oral cavity and pharynx, lip, tongue, mouth, pharynx, small intestine, colon - rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermal carcinoma, large cell carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders , Hodgkin's disease, hairy cells, and leukemia.