HK1104296B

HK1104296B - 2-(pyridin-2-ylamino)-pyrido(2,3d)pyrimidin-7-ones

Info

Publication number: HK1104296B
Application number: HK07109578.4A
Authority: HK
Inventors: M．R．巴维恩; R．J．布思; J．奎因三世; J．T．雷平; D.J.希恩; P.L.图古德; S．N．温德威尔; 周海荣
Original assignee: 沃尼尔．朗伯有限责任公司
Priority date: 2002-01-22
Filing date: 2003-01-10
Publication date: 2011-11-18

Description

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

Technical Field

The present invention relates to substituted 2-aminopyridines which are potent inhibitors of cyclin dependent kinase 4. The compounds of the invention are useful in the treatment of inflammatory and cell proliferative disorders, such as cancer and restenosis.

Background

Cyclin-dependent kinases and related serine/threonine protein kinases are important cellular enzymes that play important roles in regulating cell differentiation and proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits, called 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 possibly other heterodimers (including Cdk3 and Cdk7) are important regulators of cell cycle progression. Additional functions of cyclin/Cdk heterodimers include transcription, DNA repair, differentiation, and regulation of apoptosis (Morgan d.o., annu.rev.cell.dev.biol.1997; 13261-.

It has been shown that increased activity or transient abnormalities in activation of cyclin-dependent kinases lead to the formation of human tumors (Sherr C.J., Science 1996; 274: 1672-. Indeed, the formation of human tumors is commonly associated with alterations in Cdk proteins themselves or their modulators (Cordon-Cardo C., am.J.Pathol.1995; 147: 545. multidot. 560; Karp J.E.and Broder S., nat. Med.1995; 1: 309. multidot. 320; Hall M.et al., adv.cancer Res.1996; 68: 67-108). Protein inhibitors of naturally occurring cdks such as p16 and p27 result in growth inhibition of lung cancer cell lines in vitro (Kamb a., curr. top. microbiol. immunol. 1998; 227: 139-148).

Small molecule Cdk inhibitors may also be useful in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation. Vascular smooth muscle proliferation and intimal hyperplasia secondary to balloon angioplasty are inhibited by overexpression of the cyclin-dependent kinase inhibitor p21 protein (Chang M.W.et al, J.Clin.Invest., 1995; 96: 2260; Yang Z-Y.et al, Proc.Natl.Acad.Sci. (USA) 1996; 93: 9905). Furthermore, CVT-313(Ki 95nM), a purine cdk2 inhibitor, resulted in greater than 80% inhibition of neointimal formation in rats (Brooks E.E.et al, J.biol.chem.1997: 29207-.

Cdk inhibitors can be used to treat diseases caused by a variety of infectious agents, including fungi, protozoan parasites (e.g., plasmodium falciparum), and DNA and RNA viruses. For example, cyclin-dependent kinases are essential for viral replication secondary to Herpes Simplex Virus (HSV) infection (Schang L.M.et al, J.Virol.1998; 72: 5626), and Cdk homologs are known to play a key role in yeast.

Selective Cdk inhibitors can be used to ameliorate the consequences of various autoimmune disorders. Chronic inflammatory disease rheumatoid arthritis is characterized by synovial tissue hyperplasia; inhibition of synovial tissue proliferation should minimize inflammation and prevent joint destruction. Expression of the Cdk inhibitor p16 protein in synovial fibroblasts caused growth inhibition (Taniguchi K.et al, nat. Med.1999; 5: 760-767). Similarly, joint swelling was substantially inhibited by treatment with p 16-expressing adenovirus in a rat model of arthritis. Cdk inhibitors may be effective against other cell proliferative disorders including psoriasis (characterized by keratinocyte hyperproliferation), glomerulonephritis and lupus.

Certain Cdk inhibitors may be useful as chemoprotectants through their ability to inhibit cell cycle progression in normal untransformed cells (Chen et al J. Natl. cancer Institute, 2000; 92: 1999-2008). Pretreatment of cancer patients with Cdk inhibitors prior to the use of cytotoxic agents can reduce the side effects commonly associated with chemotherapy. Tissues in normal proliferation are protected from cytotoxic effects by the action of selective Cdk inhibitors.

Review articles on small molecule inhibitors of cyclin-dependent kinases have noted the difficulty of identifying compounds that inhibit specific Cdk proteins without inhibiting other enzymes. Thus, despite the potential for the treatment of a variety of diseases, no Cdk inhibitors are currently approved for commercial purposes (Fischer, p.m., curr. opin. drug Discovery 2001, 4, 623-634; Fry, D.W. & Garrett, m.d. curr. opin. oncogenic,

Endocrine & Metabolic Invest.2000，2，40-59；Webster，K.R.&Kimball，D.Emerging Drugs 2000，5，45-59；Sielecki，T.M.et al.J.Med.Chem.2000，43，1-18)。

summary of The Invention

The present invention provides compounds of formula I:

wherein:

the dotted line represents an optional bond;

X¹、X²and X³Each independently selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₈Alkoxy radical, C₁-C₈Alkoxyalkyl, CN, NO₂、OR⁵、NR⁵R⁶、CO₂R⁵、COR⁵、S(O)_nR⁵、CONR⁵R⁶、NR⁵COR⁶、NR⁵SO₂R⁶、SO₂NR⁵R⁶And P (O) (OR)⁵)(OR⁶) (ii) a With the proviso that X¹、X²And X³At least one must be hydrogen;

n＝0-2；

R¹each independently of the others is hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Hydroxyalkyl or C₃-C₇A cycloalkyl group;

R²and R⁴Independently selected from hydrogen, halogen, C₁-C₈Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkoxyalkyl group, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, nitrile, nitro, OR⁵、SR⁵、NR⁵R⁶、N(O)R⁵R⁶、P(O)(OR⁵)(OR⁶)、(CR⁵R⁶)_mNR⁷R⁸、COR⁵、(CR⁴R⁵)_mC(O)R⁷、CO₂R⁵、CONR⁵R⁶、C(O)NR⁵SO₂R⁶、NR⁵SO₂R⁶、C(O)NR⁵OR⁶、S(O)_nR⁵、SO₂NR⁵R⁶、P(O)(OR⁵)(OR⁶)、(CR⁵R⁶)_mP(O)(OR⁷)(OR⁸)、(CR⁵R⁶)_mAryl radicals, (CR)⁵R⁶)_m-heteroaryl, -T (CH)₂)_mQR⁵、-C(O)T(CH₂)_mQR⁵、NR⁵C(O)T(CH₂)_mQR⁵and-CR⁵＝CR⁶C(O)R⁷(ii) a Or

R¹And R²May constitute a carbocyclic group containing 3 to 7 ring members, preferably 5 to 6 ring members, up to four of which may optionally be replaced by heteroatoms independently selected from oxygen, sulphur and nitrogen, and wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from halogen, hydroxy, hydroxyalkyl, nitrile, lower C₁-C₈Alkyl, lower C₁-C₈Alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino and mono-or dialkylamino, (CH)₂)_mC(O)_NR⁵R⁶And O (CH)₂)_mC(O)OR⁵Provided that there is at least one carbon atom in the carbon ring and if there are two or more epoxy atoms, then the epoxy atoms are not adjacent to each other;

t is O, S, NR⁷、N(O)R⁷、NR⁷R⁸W or CR⁷R⁸；

Q is O, S, NR⁷、N(O)R⁷、NR⁷R⁸W、CO₂、O(CH₂)_mHeteroaryl, O (CH)₂)_mS(O)_nR⁸、(CH₂) -heteroaryl, or a carbocyclic group containing 3 to 7 ring members, of which up to four are optionally heteroatoms independently selected from oxygen, sulfur and nitrogen, with the proviso that there is at least one carbon atom in the carbon ring and if there are two or more epoxy atoms, the epoxy atoms are not adjacent to each other, wherein the carbocyclic group is unsubstituted or substituted by one, two or three groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino and mono-or dialkylamino;

w is an anion selected from the group consisting of chloride, bromide, trifluoroacetate and triethylammonium;

m＝0-6；

R⁴and X¹、X²And X³One of which may form an aromatic ring containing up to three heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with up to 4 groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono-or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, nitrile, NR⁷SO₂R⁸、C(O)NR⁷R⁸、NR⁷C(O)R⁸、C(O)OR⁷、C(O)NR⁷SO₂R⁸、(CH₂)_mS(O)_nR⁷、(CH₂)_mHeteroaryl, O (CH)₂)_m-heteroaryl, (CH)₂)_mC(O)NR⁷R⁸、O(CH₂)_mC(O)OR⁷、(CH₂)_mSO₂NR⁷R⁸And C (O) R⁷；

R³Is hydrogen, aryl, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₃-C₇Cycloalkyl or C₃-C₇A heterocyclic group;

R⁵and R⁶Independently of each other is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or

R⁵And R⁶When attached to the same nitrogen atom, may form a heterocyclic ring, containing 3 to 8 rings, together with the nitrogen to which they are attachedMembers, up to four of which may optionally be independently selected from oxygen, sulfur, S (O)₂And nitrogen, provided that there is at least one carbon atom in the heterocyclic ring and if there are two or more epoxy atoms, the epoxy atoms 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, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono-or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl, NR, N-hydroxy-acetylamino, N-hydroxy-N-alkyl-N-hydroxy-N-alkyl-⁷SO₂R⁸、C(O)NR⁷R⁸、NR⁷C(O)R⁸、C(O)OR⁷、C(O)NR⁷SO₂R⁸、(CH₂)_mS(O)_nR⁷、(CH₂)_mHeteroaryl, O (CH)₂)_m-heteroaryl, (CH)₂)_mC(O)NR⁷R⁸、O(CH₂)_mC(O)OR⁷And (CH)₂)SO₂NR⁷R⁸；

R⁷And R⁸Independently of each other is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or

R⁷And R⁸When attached to the same nitrogen atom, may form a heterocyclic ring with the nitrogen to which they are attached, containing 3-8 ring members, up to four of which are optionally independently selected from oxygen, sulfur, S (O)₂And a nitrogen, provided that there is at least one carbon atom in the heterocyclic ring and if there are two or more epoxy atoms, the epoxy atoms 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, nitro, or a combination thereof,Hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono-or dialkylamino, N-hydroxyacetamido, aryl, heteroaryl, carboxyalkyl;

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

The present invention identifies 2- (2' -pyridyl) pyrido [2,3-d ] pyrimidinone compounds useful for the treatment of uncontrolled cell proliferative disorders, including but not limited to proliferative disorders such as cancer, restenosis and rheumatoid arthritis. In addition, these compounds are useful for the treatment of inflammation and inflammatory diseases. In addition, these compounds have utility as anti-infective agents. Moreover, these compounds have utility as chemoprotectants through their ability to inhibit cell cycle progression in normal, untransformed cells. Many of the compounds of the present invention show unexpected improvements in the selectivity of the serine/threonine kinases cyclin-dependent kinase 4 and cyclin-dependent kinase 6. The compounds are readily synthesized and can be administered to a patient by a variety of methods.

The compounds of formula I may contain chiral centers and may therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of compounds of formula I, including racemic mixtures and individual enantiomers and diastereomers of such compounds, as well as mixtures thereof, and all pharmaceutical compositions and methods of treatment, as defined above, containing or employing them, respectively.

Since the compounds of formula I of the present invention may have at least two asymmetric centers, they can exist in various stereoisomeric forms or configurations. Here, the compounds can be present in individual (+) and (-) optically active forms and mixtures thereof. The present invention includes within its scope all such forms. The individual isomers can be obtained by known methods, for example, optical resolution, optical selective reaction or chromatographic separation in the preparation of the final product or an intermediate thereof.

The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but 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 the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, 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 invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e.²H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formula I of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent in the course of performing the procedures disclosed in the schemes and/or in the examples and preparations below.

The compounds of formula I can further be formulated into pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, of the compounds of formula I, solvents, and N-oxides.

The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the present invention.

"alkyl" means in the present invention a straight or branched chain hydrocarbon group having 1 to 10 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like.

"alkenyl" means straight and branched chain hydrocarbon groups having 2 to 8 carbon atoms and at least one double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. The term "alkenyl" includes cycloalkenyl and heteroalkenyl groups in which from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for carbon atoms.

"alkynyl" means straight and branched chain hydrocarbon groups having 2 to 8 carbon atoms and at least one triple bond, including but not limited to ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.

"cycloalkyl" means a monocyclic or polycyclic hydrocarbon group having 3 to 8 carbon atoms, such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decahydronaphthyl, norbornyl (norbonyl), cyclohexyl and cyclopentyl. Such groups may be substituted with groups such as hydroxy, keto, amino, alkyl, and dialkylamino groups. Also included are rings in which 1 to 3 heteroatoms replace carbon. Such groups are referred to as "heterocyclyl" which means cycloalkyl groups which also carry at least one nitrogen atom selected from O, S, N or substituted. Examples of such groups include, but are not limited to, oxiranyl, pyrrolidinyl, piperidinyl, tetrahydropyran, and morpholine.

"alkoxy" means a straight or branched chain alkyl group having 1 to 10 carbon atoms and linked through an oxygen. Such radicalsExamples of groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentyloxy. In addition, alkoxy represents a polyether, for example-O- (CH)₂)₂-O-CH₃And the like.

"acyl" represents an alkyl or aryl group (Ar) having 1 to 10 carbon atoms bonded through a carbonyl group, i.e., R-C (O) -. For example, acyl groups include, but are not limited to, C₁-C₆Alkanoyl including substituted alkanoyl wherein the alkyl moiety may be interrupted by NR⁴R⁵Or carboxy or heterocyclyl. Typical acyl groups include acetyl, benzoyl, and the like.

The above alkyl, alkenyl, alkoxy and alkynyl groups are optionally substituted preferably by 1 to 3 groups selected from NR⁴R⁵Phenyl, substituted phenyl, thio C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, carboxy, C₁-C₆Alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5-or 6-membered carbocyclic or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. "substituted nitrogen" means carrying C₁-C₆Alkyl or (CH)₂)_pThe nitrogen of Ph, wherein p is 1, 2 or 3. Perhalogenates and polyhalogenates are 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, methyl (methanyl) thiomethyl, 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-ethylthioethynyl, 4- (1-piperazinyl) -3- (butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexynyl, and the like.

Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-hexyloxy (carboxhexyloxy), and the like.

Further, 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-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyridinylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-ylbutyl, benzyl, 3-chlorobenzyl, and the like.

The term "anion" denotes negatively charged counterions such as chloride, bromide, trifluoroacetate and triethylammonium.

The term "halogen" denotes in the present invention fluorine, bromine, chlorine and iodine.

"heteroaryl" means one or more 5-, 6-or 7-membered ring aromatic ring systems containing at least one, and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Such heteroaryl groups include, for example, thienyl, furyl, thiazolyl, triazolyl, imidazolyl, (iso)Azolyl group,Oxadiazolyl, tetrazolyl, pyridyl, thiadiazolyl,A diazolyl group,Thiadiazolyl, thiatriazolyl, pyrimidinyl, (iso) quinolinyl, 1, 5-naphthyridinyl, phthalimidyl, benzimidazolyl and benzimidazolylAn azole group. Preferred heteroaryl groupsIs pyridine.

"aryl" means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings, at least one of which is aromatic (e.g., 1, 2,3, 4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which may be mono-, di-, or tri-substituted, for example, with halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy. A preferred aryl group is phenyl.

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharyngeal (oral), lip, tongue, oral cavity, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hair cell carcinoma, and leukemia.

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the act of verb treatment, the latter being as just defined.

The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein refers to those carboxylic acid salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, effective for their intended use, and-where possible-zwitterionic forms of the compounds of the present invention.

The term "salts" denotes the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compound or separately by reacting the purified free base form of the compound with a suitable organic or inorganic acid and isolating the salt formed. As long as the compounds of the formula I according to the invention are basic compounds, they are capable of forming a large number of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often necessary to first isolate a pharmaceutically unacceptable salt of the base compound from the reaction mixture and then simply convert it to the free base compound by treatment with a basic agent, after which the free base is converted to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base may be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free bases.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine; see, e.g., Berge et al, supra.

Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are also equivalent to their respective free acids for the purposes of the present invention.

The salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogensulfates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, isethionate and the like. Salts may also be prepared from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, and the like. Pharmaceutically acceptable salts can 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 not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are Salts of amino acids such as arginine Salts, gluconate Salts, galacturonate Salts, and the like (see, e.g., Berge S.M.et al, "Pharmaceutical Salts," J.pharm.Sci., 1977; 66: 1-19, incorporated herein by reference).

Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include C₁-C₆Alkyl esters, wherein the alkyl group is linear or branched. Can acceptThe ester of (A) further comprises C₅-C₇Cycloalkyl esters and arylalkyl esters, such as but not limited to benzyl esters. C₁-C₄Alkyl esters are preferred. Esters of the compounds of the invention may be prepared according to conventional methods, for example "March's Advanced Organic Chemistry, 5 Edition& J.March，John Wiley & Sons，2001。

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include those derived from ammonia, primary C₁-C₆Alkylamine and secondary C₁-C₆Dialkylamine derived amides in which the alkyl group is linear or branched. In the case of secondary amines, the amines may also be in the form of 5-or 6-membered heterocycles containing one nitrogen atom. From ammonia, C₁-C₃Alkyl primary amines and C₁-C₂Secondary dialkylamine derived amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods, for example "March's Advanced organic chemistry, 5 Edition", M.B.Smith& J.March，John Wiley & Sons，2001。

The term "prodrug" means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example by hydrolysis in blood. For a thorough discussion see T.Higuchi and V.Stella, "Pro-drugs as Novel Delivery Systems," Vol.14 of the A.C.S.Symphosis Series and Bioreproducible Carriers in Drug Delivery, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference.

Preferred compounds of the invention are those having formula II:

wherein R is¹、R²、R³、R⁴、X¹、X²And X³Is as defined in formula I.

In a preferred embodiment of the invention, X¹、X²And X³One is hydrogen, halogen or alkyl.

In a further preferred embodiment of the present invention, X¹、X²And X³One is OR⁵、NR⁵R⁶Or COR⁵。

In the most preferred embodiment of the invention, X¹＝X²＝X³＝H。

In another preferred embodiment of the present invention, R¹Is hydrogen, halogen or alkyl.

In a more preferred embodiment of the invention, R¹Is an alkyl group.

In a preferred embodiment of the invention, R²And R⁴Is hydrogen, halogen, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, nitrile, OR⁵、NR⁵R⁶、COR⁵、(CR⁴R⁵)_mC(O)R⁷、CO₂R⁵、CONR⁵R⁶、(CR⁵R⁶)_mAryl or (CR)⁵R⁶)_m-a heteroaryl group.

In a more preferred embodiment of the invention, R²Is hydrogen, halogen, C₁-C₈Alkyl, OR⁵、NR⁵R⁶、COR⁵、(CR⁵R⁶)_mAryl or (CR)⁵R⁶)_m-a heteroaryl group.

In a further preferred embodiment of the invention, R⁴Is hydrogen, OR⁵Or NR⁵R⁶。

In another preferred embodiment of the present invention, R³Is C₁-C₈An alkyl group.

In another preferred embodiment of the present invention, R⁵And R⁶Is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl.

In a further preferred embodiment of the invention, R⁵And R⁶Together with the nitrogen to which they are attached form a carbocyclic ring containing 3-8 members, up to four of which are heteroatoms.

In a more preferred embodiment of the invention, R⁵And R⁶Together with the nitrogen to which they are attached form a carbocyclic ring containing 5 or 6 members, up to two of which are heteroatoms.

In the most preferred embodiment of the invention, R⁵And R⁶Together with the nitrogen to which they are attached, form a piperazine ring.

A further preferred embodiment of the present invention are compounds according to formula I, wherein R is⁴Is a disubstituted amine.

A particularly preferred embodiment of the present invention are compounds according to formula I, wherein R is¹Is methyl, R³Is cyclopentyl.

Preferred embodiments of the present invention include, but are not limited to, the following listed compounds:

8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

8-cyclopentyl-6-ethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

8-cyclopentyl-7-oxo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester hydrochloride,

6-amino-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

6-bromo-8-cyclopentyl-2- [5- ((R) -1-methyl-1-pyrrolidin-2-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

6-bromo-8-cyclohexyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

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

6-acetyl-2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [ bis- (2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- {5- [ bis- (2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopentyl-6-iodo-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6-iodo-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- {6- (8-cyclopentyl-6- (2-ethoxy) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6- (2-ethoxy) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-isopropyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-isopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclohexyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclohexyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopropyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (pyridin-2, 6-yldiamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

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

8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

(1- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -pyrrolidin-3-yl) -carbamic acid tert-butyl ester,

6-acetyl-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -azepan-1-carboxylic acid tert-butyl ester,

6-bromo-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } - [1, 4] diazepan-1-carboxylic acid tert-butyl ester,

6-acetyl-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-5-methyl-2- (5-piperazin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester,

6-bromo-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2, 3d ] pyrimidin-7-one,

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester,

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- {6- [ 8-cyclopentyl-6- (2-ethoxy-ethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6- (2-ethoxy-ethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- {6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopentyl-6-ethoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6-ethoxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [6- (8-cyclopentyl-6-methoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester,

8-cyclopentyl-6-methoxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethoxymethyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethoxymethyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

[ 8-cyclopentyl-7-oxo-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl ] -carbamic acid benzyl ester,

8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -6- (1-ethoxy-vinyl) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -6-propionyl-8H-pyrido [2,3-d ] pyrimidin-7-one.

Other embodiments of the invention include, but are not limited to, the following listed compounds:

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

6-bromo-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-fluoro-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

8-cyclopentyl-6-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

8-cyclopentyl-6-isobutoxy-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

6-benzyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

8-cyclopentyl-6-hydroxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride,

2- [5- (4-tert-Butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester,

6-acetyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

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

2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

6-bromo-8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

6-acetyl-8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

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

2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

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

2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -6-benzyl-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -6-benzyl-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

6-benzyl-8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

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

2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-hydroxymethyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -8-cyclopentyl-6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (8-cyclopentyl-6-hydroxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

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

6-amino-2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (3-ethylamino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-2- {5- [3- (1-amino-1-methyl-ethyl) -pyrrolidin-1-yl ] -pyridin-2-ylamino } -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

1- [6- (6-amino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidine-2-carboxylic acid,

6-amino-8-cyclopentyl-2- [5- (4-diethylamino-butylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-diethylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [ bis- (2-hydroxy-ethyl) -amino ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [ bis- (2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (2-amino-ethylamino) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-dimethylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -N-methyl-acetamide,

6-bromo-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2-methoxy-ethoxymethyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2-diethylamino-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (6-methyl-5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-diethylamino-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- {5- [ bis- (2-hydroxy-ethyl) -amino ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (2-amino-ethylamino) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-dimethylamino-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -N-methyl-acetamide,

6-bromo-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2-methoxy-ethoxymethyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2-diethylamino-ethoxy) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- (6-methyl-5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-diethylamino-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- {5- [ bis- (2-hydroxy-ethyl) -amino ] -pyridin-2-ylamino } -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- [5- (2-amino-ethylamino) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-dimethylamino-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -N-methyl-acetamide,

6-acetyl-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2-methoxy-ethoxymethyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2-diethylamino-ethoxy) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (6-methyl-5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-diethylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- {5- [ bis- (2-hydroxy-ethyl) -amino ] -pyridin-2-ylamino } -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- {5- [ bis- { 2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- [5- (2-amino-ethylamino) -pyridin-2-ylamino ] -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-dimethylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-acetyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -N-methyl-acetamide,

6-acetyl-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2-methoxy-ethoxymethyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2-diethylamino-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (5-pyrrolidin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- (6-methyl-5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azetidin-1-yl-pyridin-2-ylamino) -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azepan-1-yl-pyridin-2-ylamino) -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

6-bromo-8-cyclopentyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

6-bromo-8-cyclopentyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-2- (5-azetidin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-2- (5-azepan-1-yl-pyridin-2-ylamino) -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-amino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

6-amino-8-cyclopentyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-amino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

6-amino-8-cyclopentyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-amino-8-cyclopentyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- (5-azetidin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- (5-azepan-1-yl-pyridin-2-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

6-acetyl-8-cyclopentyl-5-methyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

6-acetyl-8-cyclopentyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azetidin-1-yl-pyridin-2-ylamino) -6-benzyl-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azepan-1-yl-pyridin-2-ylamino) -6-benzyl-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

6-benzyl-8-cyclopentyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

6-benzyl-8-cyclopentyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-benzyl-8-cyclopentyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-hydroxymethyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-hydroxymethyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azetidin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azepan-1-yl-pyridin-2-ylamino) -8-cyclopentyl-6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (8-cyclopentyl-6-hydroxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

8-cyclopentyl-6-hydroxymethyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -6-hydroxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (8-cyclopentyl-6-hydroxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

8-cyclopentyl-6-hydroxymethyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-hydroxymethyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (2-methoxy-ethoxy) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (2-methoxy-ethylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azetidin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- (5-azepan-1-yl-pyridin-2-ylamino) -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -acetamide,

8-cyclopentyl-6-ethyl-2- (5-phenylamino-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (4-fluoro-benzylamino) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

n- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -methanesulfonamide,

8-cyclopentyl-6-ethyl-2- (5-methanesulfonyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- (5-phenyl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (piperazine-1-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-carbonyl) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (morpholine-4-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- [5- (piperazine-1-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-carbonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-carbonyl) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- [5- (morpholine-4-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- [5- (piperazine-1-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-carbonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- [5- (3-amino-pyrrolidine-1-carbonyl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- [5- (morpholine-4-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (piperazine-1-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-carbonyl) -pyridin-2-ylamino ] -6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-carbonyl) -pyridin-2-ylamino ] -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (morpholine-4-carbonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (morpholine-4-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-sulfonyl) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- [5- (piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-5-methyl-2- [5- (morpholine-4-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-sulfonyl) -pyridin-2-ylamino ] -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine- ] -sulfonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- [5- (morpholine-4-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-amino-pyrrolidine-1-sulfonyl) -pyridin-2-ylamino ] -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-sulfonyl) -pyridin-2-ylamino ] -6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- [5- (piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- [5- (morpholine-4-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- [5- (3-amino-pyrrolidine-1-sulfonyl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-sulfonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one, and

6-acetyl-8-cyclopentyl-5-methyl-2- ([1, 6] -naphthyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (1, 1-dioxo-116-thiomorpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-hydroxymethyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- (3-chloro-5-piperazin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

4- [ 6-acetyl-5-methyl-7-oxo-2- (pyridin-2-ylamino) -7H-pyrido [2,3-d ] pyrimidin-8-yl ] -cyclohexanecarboxylic acid,

4- [ 6-acetyl-2- (5-dimethylamino-pyridin-2-ylamino) -5-methyl-7-oxo-7H-pyrido [2,3-d ] pyrimidin-8-yl ] -cyclohexanecarboxylic acid,

6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -3-piperazin-1-yl-pyridine-2-carboxylic acid,

2- (6-acetyl-5-piperazin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-6-ethyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

3- {2- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yloxy ] -ethoxy } -propionic acid,

[6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yloxy ] -acetic acid,

8-cyclopentyl-2- (5- {2- [2- (5-methyl-pyridin-2-yl) -ethoxy ] -ethoxy } -pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

2- [5- (3-benzenesulfonyl-propoxy) -pyridin-2-ylamino ] -8-cyclopentyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-6-ethyl-2- {5- [2- (2-methoxy-ethoxy) -ethoxy ] -pyridin-2-ylamino } -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- (5- { [3- (3, 5-dimethyl-piperazin-1-yl) -propyl ] -methyl-amino } -pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-2- {5- [ (3-imidazol-1-yl-propyl) -methyl-amino ] -pyridin-2-ylamino } -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-5-methyl-2- (5-methyl-pyridin-2-ylamino) -8-piperidin-4-yl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- [5- (3, 4-dihydroxy-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-methoxymethyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one.

The present invention provides a method of treating a disorder or condition selected from the group consisting of: cell proliferation disorders such as cancer, vascular smooth muscle proliferation associated with atherosclerosis, post-operative vascular stenosis, restenosis and endometriosis; infections, including viral infections, such as DNA viruses like herpes, and RNA viruses like HIV, and fungal infections; autoimmune diseases, such as psoriasis, inflammation, like rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis and glomerulonephritis; organ transplant rejection, including graft versus graft disease in a host, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat such disorder or disease.

The invention further provides compounds of formula I useful for treating abnormal cell proliferation, such as cancer. The invention further provides methods of treating abnormal cell proliferation, such as a cancer selected from the group consisting of: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hair cell carcinoma and leukemia comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a method of treating a subject having a disease caused by vascular smooth muscle cell proliferation. Compounds within the scope of the present invention are effective in inhibiting the proliferation and migration of vascular smooth muscle cells. The method comprises administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to inhibit vascular smooth muscle proliferation and/or migration.

The present invention further provides a method of treating a subject with gout comprising administering to said subject in need of treatment a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to treat the condition.

The invention further provides a method of treating a subject having a renal disease, e.g., polycystic kidney disease, comprising administering to said subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition.

Due to their inhibitory activity against cdks and other kinases, the compounds of the invention are also useful research tools for studying the mechanism of action of these kinases in vitro and in vivo.

The above-described methods of treatment are preferably carried out by administering to a subject in need thereof a therapeutically effective amount of a compound of formula I (described below). The compounds of the present invention are substituted 2-aminopyridines which are potent inhibitors of cyclin dependent kinase 4(cdk 4). These compounds are readily synthesized, can be administered by a variety of routes, including oral and parenteral, with little or no toxicity. The compounds of the present invention are members of the class of compounds of formula I.

The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Many of the compounds of the present invention are selective inhibitors of the cyclin dependent kinase cdk4, that is, they inhibit cdk4 more effectively than they inhibit tyrosine kinases and other serine-threonine kinases, including other cyclin dependent kinases, such as cdk 2. Although they are selective for cdk4 inhibition, the compounds of the invention may also inhibit other kinases, but at concentrations higher than those at which they inhibit cdk 4. However, the compounds of the present invention may also inhibit cdk6 at concentrations similar to those necessary to inhibit cdk4, since cdk6 is structurally similar to cdk4 and performs similar functions.

Preferred embodiments of the invention are compounds of formula I that are at least about 100-fold more potent in inhibiting cdk4 than they are in inhibiting cdk 2.

Preferred embodiments of the invention provide methods of inhibiting cdk4 at doses lower than those necessary to inhibit cdk2, comprising the administration of an amount of a preferred compound of formula I that selectively inhibits cdk4 but not cdk 2.

The compounds of formula I of the present invention have useful pharmaceutical and medicinal properties. Many of the compounds of formula I of the present invention exhibit significant selective cdk4 inhibitory activity and are therefore of significant value in the treatment of a variety of clinical conditions in which cdk4 kinase is abnormally elevated or is activated or present at normal levels and activity, but inhibition of cdk activity is required in the treatment of cell proliferative disorders. Such disorders include, but are not limited to, those listed in the following paragraphs.

The compounds of the invention are useful in the treatment of cancer (e.g., leukemia and cancers of the lung, breast, prostate and skin, such as melanoma) and other proliferative diseases, including but not limited to psoriasis, HSV, HIV, restenosis and atherosclerosis. To treat cancer with a compound of the present invention, a therapeutically effective amount of a pharmaceutically acceptable composition comprising at least one compound of the present invention is administered to a patient in need of such treatment, e.g., a patient suffering from cancer or another proliferative disease.

The compounds of the present invention are selective inhibitors of cdk4, that is, they inhibit cdk4 more potently than they inhibit tyrosine kinases and other serine-threonine kinases, including other cyclin-dependent kinases, such as cdk 2. Although they are selective for cdk4 inhibition, the compounds of the invention may also inhibit other kinases, but at concentrations higher than those at which they inhibit cdk 4. However, the compounds of the invention also inhibit cdk6 at concentrations similar to those necessary to inhibit cdk4, since cdk6 is structurally similar to cdk4 and performs similar functions.

Detailed description of the invention

Preparation of compounds of the invention are shown in schemes 1 to 13.

Synthesis of

The compounds of the present invention can be prepared according to general scheme 1. The synthesis (assembly) of components A and B generally requires their combination in a suitable solvent, such as DMSO, toluene or pyridine, and heating the mixture to 80-140C. Depending on the nature of the substituent R4, a deprotection step may be required subsequently.

Scheme 1

The synthesis of the sulfoxides represented by Structure A has been asPCT applications WO 98/33798 and WO 01/70741. Such intermediates are synthesized via established and published protocols (barvias et al, j.med.chem.2000, 43, 4606-. Wherein X¹＝X²＝X³Pyridine derivatives B which are hydrogen may be prepared from commercially available 5-bromo-2-nitropyridines, the displacement of the bromine by nucleophiles such as alcohols or primary or secondary amines, followed by reduction of the nitro group, being carried out with the aid of a base or palladium. A representative example of such a process is depicted in scheme 2. Examples of bases that may be used in this reaction include K₂CO₃Or Na₂CO₃. The bases may be used in the presence of a phase transfer catalyst, e.g. Bu₄And (5) NI. The palladium-promoted reaction is usually carried out using a catalyst, for example Pd (OAc)₂、Pd₂(dba)₃Or Pd (PPh)₃)₄Etc. in a non-polar organic solvent, such as benzene, toluene, tetrahydrofuran or acetonitrile, at a temperature of 25-110 ℃. These catalysts generally employ suitable ligands, such as BINAP, Xantphos or related phosphine-based Pd ligands. The reduction of the nitro group is typically carried out using Raney nickel, although other reducing agents may be used, including palladium on carbon or Fe/HCl.

Scheme 2

When X is present¹、X²Or X³When at least one is other than hydrogen, the pyridine derivative B is prepared by methods known in the art. Examples of representative processes can be found in comprehensive heterocyclic Chemistry, ed.a.r.katritzky, c.w.rees, 1984, Pergamon, NY; volume 2, Chapter 2.08, Pyridines and the airbenzodivages: synthesis, Gumos Jones. Reference may also be made to Comprehensive Heterocyclic Chemistry II, eds.a.r.katritzky, c.w.rees., e.scriven, 1996, Pergamon, NY; volume25, Chapter5.05, pyrimidines and the same Benzoderivatives: synthesis, Gurnos Jones. Representative examples are described in scheme 3.

Scheme 3

An alternative route to compounds of the invention involves the conversion of a pyridopyrimidine core fragment to a pyridopyrimidine C-2 amine, as shown in scheme 4, and the displacement of a leaving group, such as bromine or iodine, in the pyridine fragment using such an amine as a nucleophile. The reaction is carried out using a palladium catalyst to provide the target compound in a yield corresponding to the pathway shown in scheme 1. Examples of palladium catalysts that may be employed in the reaction include Pd (OAc)₂、Pd₂(dba)₃Or Pd (PPh)₃)₄And PdCl₂(PPh₃)₂. These catalysts generally employ suitable ligands, for example BINAP, Xantphos or related phosphino-based Pd ligands (phosphine-based pdligands). Typical solvents include dimethoxyethane, tetrahydrofuran, acetonitrile and toluene. The reaction is generally carried out at a temperature between 25 ℃ and 160 ℃. In some cases, the presence of electron withdrawing groups ortho to the leaving group on the pyridine ring accelerates the reaction (Jonckers, T.H.M.et al.tetrahedron 2001, 57, 7027-.

Scheme 4

In an alternative route to the compounds of the invention, the pyridine fragment is converted to a guanidine, which is condensed with an appropriate ligand (partner) to form a pyrimidine ring via a condensation reaction (scheme 5).

The condensation reaction generally requires heating the reaction components in concentrations of 0.5M to 2M to a temperature of 100 ℃ to 200 ℃ in a suitable nonpolar organic solvent, such as chlorobenzene, nitrobenzene or Dow's heat carrier.

Scheme 5

(PG) is a protecting group which is a substituent,

such as Cbz or Boc.

Alternatively, the synthesis of the compounds of the present invention may be carried out via substituted pyrimidine intermediates, such as those shown in schemes 6-13. Thus, in scheme 6, 4-amino, 5-halo-pyrimidine sulfides are directly converted to pyridopyrimidinones using the chemistry described by Piers (e.g. Piers, E.McEachern, E.J. and Romer, M.A.J. Org.Chem.1997, 62, 6034-. Alternatively, the side chain pyridyl-amine was mounted by displacement of the sulfoxide at C2 using standard procedures (see above) followed by construction of the pyridopyrimidinone via Stille coupling and ring closure reactions. A similar chemistry is used in scheme 7, starting with 2-chloropyrimidine. Stille reactions in schemes 6 and 7 are typically carried out with palladium catalysis, e.g., using Pd (OAc)₂、Pd₂(dba)₃Or Pd (PPh)₃)₄And PdCl₂(PPh₃)₂. Typical solvents include dimethoxyethane, tetrahydrofuran, acetonitrile and toluene, which may be heated to a temperature of 100 ℃ and 200 ℃ during the reaction. Ring closure can occur spontaneously or by gentle heating in a suitable organic solvent to a temperature below 100 ℃. The side chain C2 in scheme 7 is typically attached using POPd, Pd (OAc)₂Or Pd₂(dba)₃And suitable ligands, such as BINAP, Xantphos or related phosphino Pd ligands.

Scheme 6

Scheme 7

Another way to construct a pyridone ring is to start with a simply substituted aldehyde or ketone at C5 of the 4-aminopyrimidine and perform Wittig, Horner-Wadsworth Emmons, Knoevengel or related chemistry, such as enolate anion chemistry, to install the C4-C5 double bond of the pyridopyrimidone system. These reactions are carried out under conditions well known to those skilled in the art, using suitable bases such as NaH, NaOEt, LDA, BuLi, HMDS, and the like. When the geometry of the double bond is such that the pyrimidine and ester are in cis relationship to the newly formed double bond, ring closure will generally occur spontaneously under the reaction conditions. Otherwise, slight heating to temperatures below 100 ℃ in a suitable organic solvent may be required to promote ring closure. When the geometry of the double bond is such that the pyrimidine and ester are in trans relationship on the double bond, isomerization of the double bond can drive the ring closed, for example heating to a temperature between 100 and 200 ℃ in DBU, or treatment with a source of groups such as iodine and UV light under conditions well known to those skilled in the art. The order of ring formation and side chain installation can be reversed from that shown in schemes 11-13.

Scheme 8

Scheme 9

Scheme 10

G₁And G₂Is an electron-withdrawing functional group, e.g. CN, CO₂Et、CO₂Me。

Scheme 11

Scheme 12

Scheme 13

The compounds of the present invention can be formulated for administration in a variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized by those skilled in the art that the following dosage forms may comprise a compound of formula I or a corresponding pharmaceutically acceptable salt or solvate of a compound of formula I.

The invention also encompasses pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. For the preparation of pharmaceutical compositions containing the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can 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, for example talc or starch, which is in a mixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The formulations of the present invention preferably contain from about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. A preferred oral dosage form is a capsule which comprises a preparation of the active compound together with an encapsulating material which provides a capsule as a carrier, with or without the active ingredient being surrounded by a carrier so as to be associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a fatty acid glyceride mixture or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein with stirring. The molten homogeneous mixture is then poured into a suitably sized mold and cooled to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, the liquid preparation can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water and mixing with viscous materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredients, these preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The sustained release dosage form can be prepared using waxes, polymers, microparticles, and the like. Furthermore, osmotic pumps can be used to deliver the active compound uniformly over a long period of time.

The pharmaceutical preparation of the present invention is preferably in unit dosage form. In such dosage forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, for example, small packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Therapeutically effective dosages of the compounds of formula I will vary from about 0.01mg/kg to about 100mg/kg of body weight per day. A typical adult dose will be about 0.1mg to about 3000mg per day. The amount of active ingredient in a unit dose preparation may vary from about 0.1mg to about 500mg, preferably from about 0.6mg to 100mg, depending upon the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired. Administering to a subject in need of treatment with a compound of formula I a dose of about 0.6 to about 500mg per day, in single or multiple administrations over a 24 hour period. Such treatments may be repeated at successive intervals for as long as necessary.

The present invention provides a pharmaceutical composition for treating a disorder or condition selected from the group consisting of: cell proliferation disorders such as cancer, vascular smooth muscle proliferation associated with atherosclerosis, post-operative vascular stenosis, restenosis and endometriosis; infections, including viral infections, such as DNA viruses like herpes, and RNA viruses like HIV, and fungal infections; autoimmune diseases, such as psoriasis, inflammation, like rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis and glomerulonephritis; organ transplant rejection, including host versus graft disease.

The following examples are intended to illustrate specific inventive embodiments and are not intended to limit the scope of the specification or the claims in any way.

One skilled in the art will recognize that the starting materials may be varied and additional steps may be employed to generate compounds encompassed by the present invention, as demonstrated in the examples below. The following examples are for illustrative purposes only and are not intended to, nor should they be construed as, limiting the invention in any way. Those skilled in the art will recognize that variations and modifications can be made without departing from the spirit or scope of the invention.

Example 1

8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d ] prepared as described in WO 98/33798 (incorporated herein by reference) example 107]Pyrimidin-7-one (200mg, 0.7mmol) and 2-aminopyridine (130mg, 1.4mmol) were combined in a 10ml round bottom flask. The flask was purged with nitrogen (10min) and then heated in a 160 ℃ oil bath (30 min). After cooling, the organic residue was triturated with water to give an orange solid which was further purified by reverse phase HPLC [ Vydac C18TP254(30 mm. times.100 mm); a: ACN (acetonitrile) + 0.1% TFA (trifluoroacetic acid); b: h₂O + 0.1% TFA; 10% -76% of B in 40min]. Isolation gave 15mg of 8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid. And Mp: HPLC [ Vydac C18TP254 (4.6X 150mm) > 250 ℃; a: ACN + 0.1% TFA; b: h₂O + 0.1% TFA; 10% -76% of B in 20min]：＞98％Rt＝13.9min.

Example 2

4- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Combining 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d ] under a dry argon atmosphere]Pyrimidin-7-one (0.78g, 2.19mmol, prepared as described in WO 98/33798 (incorporated herein by reference) example 107) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (0.67g, 2.4mmol), without solvent. The flask was evacuated and heated to 120 ℃ for 1 hour. The mixture was purified by silica gel chromatography eluting with chloroform to give a yellow foam, 0.288 g. Recrystallizing from acetonitrile to obtain 4- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.266g, 21%). Ms (apci); m⁺+1: calculated, 570.17, found, 570.0.

Example 3

6-bromo-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d) prepared in example 2]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.26g, 0.46mmol) was dissolved in 1: 1 chloroform/methanol (15ml), to which diethyl ether (25ml) was added. The solution was purged with anhydrous hydrogen chloride gas and stoppered for 18 hours. The resulting white solid was filtered, washed with diethyl ether and dried at 60 ℃ in vacuo to give 6-bromo-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a pale yellow solid (0.254 g). Ms (apci); m⁺+1: calculated value, 470.12, found, 470.0.C₂₁H₂₄BrN₂O-1.25 H₂Elemental analysis of O.2.2 HCl: calculated values: c, 44.01; h, 5.05; n, 17.11, Cl (ion), 13.61; h₂O, 3.93. found: c, 43.74; h, 5.07; n, 16.78; cl (ion), 13.73; h₂O，3.81.

Example 4

4- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

4- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl (piperazine-1-carboxylate) was prepared by adding 8-cyclopentyl-6-ethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] to toluene (10ml)]Pyrimidin-7-one (0.80g, 2.62mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (1.82g, 6.55mmol) followed by heating to 105 ℃ for 10 hours. The resulting suspension was filtered, and the solid was washed with toluene and dried in vacuo to give 4- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.204 g). Ms (apci); m⁺+ 1; calculated value 520.3, found value 520.1

Example 5

8-cyclopentyl-6-ethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (8-cyclopentyl-6-ethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 4]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.204g, 0.39mmol) was dissolved in 1: 1 chloroform/methanol (16ml) and purged with anhydrous hydrogen chloride gas. After stirring for 3.5 hours, diethyl ether (8ml) was added to give a solid precipitate. The solid was filtered, washed with diethyl ether and dried in vacuo to give 0.180g 8-cyclopentyl-6-ethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a yellow solid. Ms (apci); m⁺+1: calculated, 420.52, found, 420.2.

Elemental analysis: c₃₄H₂₉N₇O·1.2H₂O·2.1HCl：Calc’d：C，53.36；H，6.52；N，18.93，Cl(ionic).14.38；H₂O，4.17.Found：C，53.25；H，6.43；N，18.80；Cl(ionic)，14.36；H₂O，3.87

Note: wherein, ionic is ion, Calc'd is a calculated value, found is an actual value, the same as below.

Example 6

2- [5- (4-tert-Butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester

To toluene (5ml) was added 8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester (0.936g, 2.68mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (3.0g, 10.8mmol) were heated to 100 ℃ for 1 hour. Ether (10ml) was added, resulting in the precipitation of a solid. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 2- [5- (4-tert-butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester as a yellow solid (0.42g, 28%). Ms (apci); m⁺+1: calculated value 564.29, found 564.3

Example 7

8-cyclopentyl-7-oxo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester hydrochloride

Ethyl 2- [5- (4-tert-butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylate (0.40g, 0.709mmol, prepared as described in example 6) was dissolved in a mixture of chloroform (15ml) and ethanol (15ml) and the solution was purged with anhydrous hydrogen chloride gas. After 2 hours, ethyl acetate was added and the solid precipitated, filtered, washed with ether and dried in vacuo to give 0.4g of ethyl 8-cyclopentyl-7-oxo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylate hydrochloride as a yellow solid. Ms (apci); mol: calculated, 464.53, found, 464.4.

Elemental analysis: C₂₄H₂₉N₇O₃·0.75

H₂O·2.0HCl：

Calc’d：C，52.41；H，5.96；N，17.83，Cl(ionic)，12.89；H₂O，2.46.Found：C，52.25；H，5.86；N，17.85；Cl(ionic)，12.10；H₂O，1.52

example 8

(8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-yl) -carbamic acid tert-butyl ester

To dry tert-butanol (30ml) was added 8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid (2.48g, 8.02mmol), triethylamine (0.974g, 9.63mmol), diphenylphosphorylazide (2.65g, 9.63mmol) was added over 5 minutes with stirring. The mixture was heated at 75C for 18 hours. The mixture was filtered and the solid was washed with ethyl acetate. The wash solution is concentrated to obtain an oil enriched in the desired product. The oil was triturated with hexane/ether and the washings were filtered through silica gel and celite. The filtrate was concentrated in vacuo to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-6-yl) -carbamic acid tert-butyl ester as a crystalline solid (1.37g, 45%). Ms (apci): m⁺+1: calculated value, 377.16, found 377.2.

Example 9

(8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-yl) carbamic acid tert-butyl ester

To 50: 50 dichloromethane/methanol (12ml) was added (8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-6-yl) -carbamic acid tert-butyl ester (1.3g, 3.45mmol, prepared as in example 8) followed by addition of 2-benzenesulfonyl-3-phenyl-oxaziridine (1.08g, 4.14 mmol). The mixture was stirred at 25 ℃ for 3.5 h, evaporated to give an oil, treated with silica gel and eluted with chloroform. The fraction containing the product is evaporated off,to give (8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-6-yl) -carbamic acid tert-butyl ester as a solid (1.2g, 89%). Ms (apci); m⁺+1: calculated value, 393.15, found 393.1.

Example 10

4- [6- (6-tert-Butoxycarbonylamino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Reacting (8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-6-yl) -carbamic acid tert-butyl ester (1.2g, 3.06ml, prepared as in example 9) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (2.36g, 8.48mmol) were combined in toluene (4ml) and heated to 105 ℃ for 12 hours. The resulting paste was diluted with toluene, filtered, washed with toluene and partitioned between ether and 1N citric acid. The mixture was filtered and the solid was washed with water and diethyl ether. The solid was then dissolved in chloroform, dried over anhydrous magnesium sulfate, filtered, and the filtrate was diluted with ether to give a solid precipitate. The solid was collected by filtration and dried in vacuo to give 4- [6- (6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.311g, 17%). MS (APCI) M⁺+ 1; calculated, 607.3, found, 607.2.

Example 11

6-amino-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

To 1: 1 chloroform/methanol (20ml) was added 4- [6- (6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 10]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.31g, 0.511mmol), and the mixture was purged with anhydrous hydrogen chloride gas and then stirred at room temperature for 18 hours. The resulting solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 6-amino-8-cyclopentylYl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a yellow solid (0.202g, 100%). Ms (apci); m⁺+1: calculated, 407.48, found, 407.4.

Elemental analysis: c₂₁H₂₆N₈O·1.25H₂O.2HCl：Calc’d：C，50.46；H，6.02；N，22.14，Cl(ionic)，15.98；H₂O，4.58.Found：C，50.25；H，6.13；N，22.32；Cl(ionic)，14.13；H₂O，4.49

Example 12

6-bromo-8-cyclopentyl-2- [5- ((S) -1-methyl-1-pyrrolidin-2-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

To dry toluene (4ml) were added 5- (1-methyl-pyrrolidin-2-yl) -pyridin-2-ylamine (1.19g, 6.7mmol, prepared as described in WO 01/70730) and 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (1.0g, 2.81mmol) and the mixture was heated at 105 ℃ for 1 hour. The mixture was cooled, filtered, washed with toluene and diethyl ether and dried in vacuo to give a solid (0.256 g). The solid was dissolved in chloroform (20ml) and treated with anhydrous hydrogen chloride gas to give a gelatinous precipitate. Methanol (2ml) was added to cause the precipitate to dissolve, and the solution was added to rapidly stirring diethyl ether to give a white precipitate. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 6-bromo-8-cyclopentyl-2- [5- ((R) -1-methyl-1-pyrrolidin-2-yl) -pyridin-2-ylamino]-8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (0.30g, 23%) as a white solid. Ms (apci); m⁺+1: calculated, 469.13, found, 469.1.

Elemental analysis: c₂₂H₂₅BrN₆O·0.75H₂O·1.75HCl：Calc’d：C，48.33；H，5.20；N，15.37，Cl(ionic)，11.34；H₂O，2.47.Found：C，48.23；H，5.29；N，15.21；Cl(ionic)，11.55；H₂O，3.81

Example 13

6-bromo-8-cyclohexyl-2- (pyridin-2-yl-amino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Preparation of 6-bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido [2,3-d ] by means of the method described in WO 98/33798]Pyrimidin-7-one (1.04g, 2.81mmol) was combined with 2-aminopyridine (2.5g, 26.6 mmol). The mixture was heated to 92 ℃ for 4 hours in the absence of added solvent to give a solid precipitate. When the temperature is between 24-60 ℃, the mixture is filtered, the resulting solid is washed with toluene, then chloroform, and dried in vacuo to give 6-bromo-8-cyclohexyl-2- (pyridin-2-yl-amino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid (0.126g, 17%). Ms (apci); m⁺+1: calculated, 401.27, found, 401.1.

Elemental analysis:

C₁₈H₁₈BrN₅O：Calc’d：C，54.01；H，4.53；N，17.50；Br，19.96.Found：C，53.87；H，4.52；N，15.21；Br，20.09.

example 14

6-bromo-8-cyclopentyl-2-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one; 6-methyl-nicotinamide-containing compounds

Reacting 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (1.09g, 3.06mmol) and 6-amino-nicotinamide (2.51g, 18mmol) were combined in toluene (8ml) and heated to 100C for 18 hours. The mixture was then diluted with dimethyl sulfoxide (8ml) and heated to l20 ℃ for 2 hours. The mixture was then poured into water (120ml) with rapid stirring. Diethyl ether was added and the resulting solid was collected by filtration. The solid was washed with 1: 1 warm ethyl acetate/tetrahydrofuran and dried in vacuo to give 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid (0.233g, 18%). Ms (apci); m⁺+1: calculated, 429.06, found, 429.1.

Elemental analysis: c₁₈H₁₇BrN₆O₂：

Example 15

6-bromo-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.2g, 0.54mmol, prepared as in example 5 of WO 01/70741) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (0.6g, 2.16mmol) were combined in toluene (3ml) and heated to 110 ℃ overnight. Succinic anhydride (0.2g) was added to quench the reaction and cool to give a solid. Suspending the solid in CH₂Cl₂In (5), filtration gave a white solid. The filtrate was washed with saturated aqueous sodium hydrogencarbonate and then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel chromatography eluting with 75% ethyl acetate: elution with 25% hexane gave 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.04g, 13%). MS (APCI) M⁺+1: calculated value, 584.19, found value, 584.1.

Mixing 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.04g, 0.07mmol) suspended in CH₂Cl₂To (10ml), MeOH was added in order to form a solution (up to about 6 ml). A2M HCl in ether (10ml) was added with stirring. The reaction mixture was stirred at room temperature for a total of 3 days, then the solvent was removed by evaporation under reduced pressure. The remaining solid was suspended in diethyl ether and filtered to give 6-bromo-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid, dried at 50 ℃ in vacuo. Ms (apci); m⁺+1: calculated, 486.15, found, 486.1.

Elemental analysis: c₂₃H₂₆N₇OBr·2.64H₂O·2.0HCl：Calc’d：C，43.68；H，5.55；N，16.21，Cl(ionic)，11.72.Found：C，44.08；H，5.32；N，15.23，Cl(ionic)，11.65.

Example 16

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

8-cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (10.5g, 37.9mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (11.8g, 45.4mmol) were combined in dichloromethane (120ml) and stirred at room temperature for 18H. The mixture was evaporated to give an oil, which was crystallized from ethyl acetate/ether, filtered and dried in vacuo to give 8-cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a white solid (8.88g, 79.6%).

¹H NMRδ(400MHz，CDCl₃)8.94(s，1H)，7.25(d，1H)，6.06-5.99(m，1H)，2.98(s，3H)，2.28-2.21(m，2H)，2.18-2.12(m，2H)，2.02-1.94(m，2H)，1.74-1.67(m，2H).

Example 17

4- [6- (8-cyclopentyl-6-fluoro-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

To toluene (8ml) was added 8-cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (2.0g, 6.77mmol, prepared as in example 16) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (6.0g, 21mmol) were heated to 98 ℃ for 18 hours. The mixture was filtered, washed with toluene and the solid was suspended in diethyl ether. The mixture was filtered, the solid was dissolved in chloroform, washed with 1N citric acid, brine and dried over anhydrous magnesium sulfate. The crude product was triturated with ether and dried in vacuo to give 4- [6- (8-cyclopentyl-6-fluoro-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.88g, 25%). MS (APCI) M⁺+1: calculated, 510.3, found 510.2.

Example 18

8-cyclopentyl-6-fluoro-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (8-cyclopentyl-6-fluoro-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 17]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.195g, 0.38mmol) was dissolved in 1: 1 chloroform/methanol (8ml), purged with anhydrous hydrogen chloride gas, and stirred at room temperature for 2.5 hours. Ether (15ml) was added to the mixture to give a precipitate, which was filtered, washed with ether and dried in vacuo to give 8-cyclopentyl-6-fluoro-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a yellow solid (0.177g, 88%). Ms (apci); m⁺+1: calculated, 410.46, found, 410.3.

Elemental analysis: c₂₁H₂₄N₇O·1.0H₂O·2.0HCl：Calc’d：C，50.73；H，5.75；N，19.46，Cl(ionic)，13.77；H₂O，1.41.Found：C，50.41；H，5.64；N，19.59；Cl(ionic)，14.16；H₂O，3.60.

Example 19

4- [6- (8-cyclopentyl-6-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Reacting 8-cyclopentyl-6-methyl-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (1.0g, 3.43mmol) was added to a solution of 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (1.91g, 6.86mmol) in toluene (5 ml). The mixture was heated to 100 ℃ for 18 hours and then treated with ether to form a precipitate. The precipitate was collected by filtration and then dried in vacuo to give 4- [6- (8-cyclopentyl-6-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as yellow solid (0.411 g). MS (APCI) M⁺+1: calculated, 506.28, found 506.2.

Example 20

8-cyclopentyl-6-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (8-cyclopentyl-6-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 19]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl (0.411g, 0.813mmol) piperazine-1-carboxylate was dissolved in a 1: 1 mixture of methanol/chloroform, purged with anhydrous hydrogen chloride gas, stirred at room temperature for 2 hours, diethyl ether was added and a solid precipitated. The suspension was filtered and the residue was dried in vacuo to give 8-cyclopentyl-6-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a yellow solid (0.393 g). (APCI); m⁺+1: calculated, 406.50, found, 406.2.

Elemental analysis:

C₂₂H₂₇N₇O·2.85H₂O·2.2HCl：Calc’d：C，49.20；H，6.55；N，18.26，Cl(ionic)，14.52；H₂O，9.56

Found：C，49.43；H，6.32；N，17.87；Cl(ionic)，14.38；H₂O，7.35

example 21

4- [6- (8-cyclopentyl-6-isobutoxy-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Oil (0.182g, 4.4mmol) containing 60% sodium hydride was washed with hexane and added to 2-methyl-1-propanol (10 ml). The mixture effervesces to form a solution. To this solution was added 4- [6- (8-cyclopentyl-6-fluoro-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.225g, 0.44mmol, prepared as described in example 17), the mixture was heated at 95 ℃ for 72 hours. The solvent was evaporated, the residue was dissolved in ether and then filtered. Evaporating the filtrate to obtain 4- [6- (8-cyclopentyl-6-isobutyl) etherOxy-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as crystalline solid (0.092g, 37%). MS (APCI) M⁺+1: calculated, 564.3, found 564.3.

Example 22

8-cyclopentyl-6-isobutoxy-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (8-cyclopentyl-6-isobutoxy-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.067g, 0.119mmol) was dissolved in chloroform (5ml) and cooled to 0 ℃. The solution was purged with anhydrous hydrogen chloride gas and stoppered for 3 hours. Diethyl ether was added to the mixture to give a precipitate, which was filtered and dried in vacuo to give 8-cyclopentyl-6-isobutoxy-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a solid (0.056 g). Ms (apci); m⁺+1: calculated, 464.5, found, 464.3.

Elemental analysis: c₂₅H₃₃N₇O₂·1.0H₂O·2.0HCl：Calc’d：C，54.15；H，6.72；N，17.68，Cl(ionic)，12.78；H₂O，3.25.Found：C，54.18；H，6.98；N，17.51；Cl(ionic)，12.15；H₂O，2.60.

Example 23

4- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Reacting 6-benzyl-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d]A solution of pyrimidin-7-one (0.64g, 1.74mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (0.87g, 2.96mmol) in toluene (10ml) was heated to 95 ℃ for 28 hours. The reaction mixture was allowed to cool and then chromatographed on silica gel using a 20 to 50% ethyl acetate in hexane gradientAnd (4) eluting. The product containing fractions were evaporated and the residue triturated with acetonitrile to give a solid. The solid was collected by filtration and dried in vacuo to give 4- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.201g, 19.8%). MS (APCI) M⁺+1: calcd for 582.31, found 582.3.

Example 24

6-benzyl-8-cyclopentyl-2- (5-piperazin-1-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (6-benzyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester prepared in example 23 (0.21g, 0.36mmol) was dissolved in 1: 1 chloroform: methanol (15ml) was purged with anhydrous hydrogen chloride gas and stoppered for 3 hours. The mixture was poured into ether (50ml) to give a precipitate, which was filtered and dried in vacuo to give 6-benzyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (0.162 g).

Elemental analysis:

C₂₈H₃₁N₇₂·1.5 H₂O·1.5HCl：Calc’d：C，57.26；H，6.09；N，16.69，Cl(ionic)，9.05；H₂O，4.60.Found：C，57.95；H，6.23；N，16.80；Cl(ionic)，9.87；H₂O，4.59.

example 25

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

A solution of 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (3.5g, 12.7mmol) and N-bromosuccinimide (2.6g, 14.6mmol) in carbon tetrachloride (100ml) was irradiated with UV light to reach a temperature of 45 ℃ for 3 hours. The mixture was filtered, washed with dilute sodium sulfite solution, then brine, and dried over anhydrous magnesium sulfate. The crude product was chromatographed on silica gel eluting with 1: 1 ethyl acetate: hexanes to give 6-bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a crystalline solid (1.46g, 32% yield), mp103-105 ℃.

Example 26

Acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl ester

To glacial acetic acid (10ml) was added 6-bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] prepared in example 25]Pyrimidin-7-one (1.33g, 3.75mmol) and silver acetate (1.03g, 6.2mmol) were heated to 110 ℃ for 5 hours. The solvent was then evaporated under reduced pressure and the resulting residue was suspended in ethyl acetate and filtered. The resulting solid was recrystallized from ethyl acetate to give acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-6-ylmethyl ester as a solid (0.89g, 71%). MS (APCI) M⁺+ 1; calculated 334.11, found 334.2.

Example 27

Acetic acid 8-cyclopentyl-2-methanesulfonyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl ester

The acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d prepared in example 26 was reacted with ethanol]Pyrimidin-6-ylmethyl ester (0.85g, 2.55mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.8g, 3.06mmol) were combined in dichloromethane (20ml) and stirred at room temperature for 5 hours. Diethyl ether was added to the mixture to give a solid precipitate, which was filtered and dried in vacuo to give acetic acid 8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-6-ylmethyl ester as a solid (0.81g, 91%). MS (APCI) M⁺+ 1; calculated 350.41, found 350.2.

Example 28

4- [6- (6-acetoxymethyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

To toluene (8ml) was added 8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] acetate prepared in example 27]Pyrimidin-6-ylmethyl ester (0.80g, 2.29mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (1.17g, 4.20mmol) were heated to 96 ℃ for 6 hours. The reaction mixture was allowed to cool, then filtered and the residue washed with toluene. The resulting solid was dried in vacuo and then recrystallized from chloroform/diethyl ether to give 4- [6- (6-acetoxymethyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.213g, 16.5%). MS (APCI) M⁺+ 1; calculated, 564.2, found, 564.3.

Example 29

8-cyclopentyl-6-hydroxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

4- [6- (6-Acetoxymethyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 28]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (0.21g, 0.36mmol) was dissolved in 1: 1 chloroform: methanol (8ml), and the solution was purged with anhydrous hydrogen chloride gas and then stirred at room temperature for 3 hours. The mixture was added to diethyl ether (50ml) to give a solid which was collected by filtration, washed with diethyl ether and then dried in vacuo to give 8-cyclopentyl-6-hydroxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a solid (0.17g, 93%). Ms (apci); m⁺+1: calculated, 422.5, found, 422.2.

Elemental analysis: c₂₂H₂₇N₇O₂·1.0H₂O·2.0HCl：Calc’d：C，51.56；H，6.10；N，19.13，Cl(ionic)，13.84；H₂O，3.51.Found：C，51.13；H，5.95；N，19.05；Cl(ionic)，13.70；H₂O，0.67.

Example 30

2- [5- (4-tert-Butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester

Reacting 6-bromo-8-cyclopentyl-5-methyl-2-methylthio-8H-pyrido [2,3-d]A mixture of pyrimidin-7-one (442mg, 1.25mmol, prepared as in example 9 of WO 01/70741), Pd (OAc)2(312mg, 1.4mmol), bis (diphenylphosphino) propane (400mg, 0.97mmol) and N, N-diisopropylethylamine (1.1g, 8.87mmol) in EtOH (20ml) was stirred at about 600PSI CO and heated to 100 ℃ for 16 hours. The resulting solution was filtered and the filtrate was concentrated under reduced pressure to give an orange oil which was purified by chromatography (20% ethyl acetate/hexane) to give 8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester as oil (138mg, 36% yield). M⁺+1: calculated value 348.4, found value, 348.2.

Reacting 8-cyclopentyl-5-methyl-2-methylthio-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester (138mg, 0.40mmol) dissolved in CH₂Cl₂(6ml) 2-benzenesulfonyl-3-phenyloxaziridine (155mg, 0.6mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, then the solvent was removed under reduced pressure and the remaining residue was purified by preparative TLC (50% ethyl acetate/hexane). The more polar product-containing fraction is substituted with CH₂Cl₂Extracting and evaporating the solvent to obtain 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester as a white solid (110mg, 75.7%). M⁺+1: calculated value 364.4, found value 364.2.

Reacting 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Ethyl pyrimidine-6-carboxylate (110mg, 0.30mmol) was heated with a toluene solution of 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (310mg, 1.1mmol) at 100 ℃ for 10 hours, then cooled to room temperature. Diethyl ether was added to the reaction mixture and the product precipitated out. The precipitate was collected by filtration and dried to obtain 2- [5- (4-Boc-piperazin-1-yl) -pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester (50mg, 29%). M⁺+1: calculated 578.3, found 578.4.

Example 31

8-cyclopentyl-5-methyl-7-oxo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester hydrochloride

Anhydrous HCl gas was bubbled through 2- [5- (4-tert-butyloxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester (50mg, 0.086mmol, prepared as described in example 3) CH₂Cl₂EtOH solution, the reaction was stirred for 24 hours. Adding diethyl ether to the reaction mixture, precipitating a solid, separating, and drying to obtain 8-cyclopentyl-5-methyl-7-oxo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester hydrochloride as a yellow solid (12mg, 29%). mp216-218 deg.C. M⁺+ 1; calculated 478.6, found 478.1.HPLC, retention time: 5.77min.

Example 32

4- [6- (6-acetyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Tributyl (1-ethoxyvinyl) tin (0.39ml, 1.15mmol) was added to 4- [6- (6-bromo-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] prepared in example 2]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (440mg, 0.77mmol) and tetrakis (triphenylphosphine) palladium (0) (88 mg, 0.077mmol) in a mixture of toluene (5 ml). The reaction mixture was heated at 110 ℃ for 1 hour and then cooled to room temperature. The resulting solid was collected by filtration, washed with toluene and then dried to give 4- [6- (6-acetyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl esterAnd (c) a base ester. M⁺+1: calculated 534.6, found 534.2.

Example 33

6-acetyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

Anhydrous HCl gas was bubbled through 4- [6- (6-acetyl-8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] at room temperature]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (398mg, 0.74mmol, prepared as described in example 32) in MeOH/CH₂Cl₂(10ml/10ml) for about 5 min. The reaction mixture was stirred overnight and then the solvent was removed under reduced pressure. The remaining solid was triturated with hot ethyl acetate and dried to give 6-acetyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (329mg, 76%). mp > 300 ℃.

Calculated values of elemental analysis:

C₂₃H₂₇N₇O₂·4.25 HCl：C，46.94；H，5.35；N，16.66.Found：C，46.77；H，5.33；N，16.30.M⁺+1：Calc’d：434.2，Found 434.2.

example 34

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

Reacting 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (10.00g, 0.027mol, prepared as described in WO 01/707041, example 6, incorporated herein by reference) was heated with a suspension of 10.37g (0.0373mol) of 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester in toluene (100ml) under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO)₂10% MeOH/DCM) indicated that both starting materials remained. The suspension was heated under reflux for an additional 18 hours. Cooling the resulting suspension to room temperature, and filtering to obtain 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo7, 8-dihydro-pyrido [2,3-d ] s]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93g, 38%). mp > 250 ℃, ms (apci); m⁺+1: calculated value, 584.2, found value, 584.2

Example 35

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester

Mixing 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]Tert-butyl-piperazine-1-carboxylate (5.93g, 0.010mol, prepared as described in example 34), tetrakis (triphenylphosphine) palladium (0) (1.40g, 0.00121mol) and a suspension of tributyl (1-ethoxyvinyl) tin (5.32ml, 0.0157mol) in toluene (30ml) were heated at reflux for 3.5 h. The mixture was cooled and filtered to give a solid. The solid was chromatographed on silica gel using a gradient of 5-66% ethyl acetate/hexane over 15 minutes to give 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d%]Pyrimidin-2-ylamino]-pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50g, 78%). MS (APCI) M⁺+ 1; calculated 576.2, found 576.3.

Example 36

6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride

Introducing hydrogen chloride gas into ice-bath cooled 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino]-pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (4.50g, 0.00783mol, prepared as described in example 35) in DCM (100 ml). The resulting suspension was stoppered, stirred at room temperature overnight, and then diluted with ether (200 ml). The solid was collected by filtration, washed with diethyl ether and dried to give 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyridineAnd [2,3-d ]]Hydrochloride salt of pyrimidin-7-one as a yellow solid (4.01g, 92%). mp200 ℃ HPLC, C18 reverse phase, 10-95% gradient of 0.1% TFA/CH₃0.1% TFA/H of CN₂O solution, in 22 minutes: 99.0%, 11.04 min.

MS(APCI)；M⁺+1: calculated 448.2, found 448.3;

calculated values of elemental analysis: c₂₄H₂₉N₇O₂·2.4H₂O·1.85HCl：C，51.64；H，6.44；N，17.56，Cl(total)，11.75.Found：C，51.31；H，6.41；N，17.20；Cl(total)，12.11.

Example 37

6-bromo-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (370mg, 1mmol, prepared as described in example 6 of WO 01/707041, incorporated herein by reference) and 2-aminopyridine (140mg, 1.5mmol) in toluene (5ml) was heated at 110 ℃ for 18H and then cooled to room temperature. The resulting solid was collected by filtration, washed with toluene, then acetone and dried in vacuo to give 6-bromo-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as an off-white solid (22mg, 30%). mp267-268 ℃.

Calculated values of elemental analysis: c₁₈H₁₈BrN₅O·0.33H₂O：C，53.22；H，4.63；N，17.24.Found：C，52.88；H，4.38；N，17.04.

Example 38

6-bromo-8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one was reacted with 2-aminopyridine according to the procedure described in example 37 to give 6-bromo-8-cyclopentyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one in 37% yield. mp: 273 and 275 ℃.

Calculated values of elemental analysis: c₁₇H₁₆BrN₅O.0.1H₂O：C，52.62；H，4.21；N，18.05.Found：C，52.23；H，4.10；N，17.91.M⁺+1：Calc’d：386.05，Found 385.9.

Example 39

8-cyclopentyl-2-methylsulfanyl-7-oxo-78-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester

To a solution of ethyl 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylate (92g, 8mmol) in THF (80ml) at-20 deg.C under nitrogen was added pyridine (2.6ml, 32mmol) followed by TiCl₄(1.75ml, 16mmol) of CH₂Cl₂(20ml) solution. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10ml), then diluted with ether, washed three times with saturated aqueous ammonium chloride solution and once with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed and the solvent was evaporated to give a yellow oil which was used without further purification. The oil was dissolved in anhydrous DMF (150ml) and washed with 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (119. mu.l, 0.8 mmol). The resulting solution was heated to 80 ℃ for 1 hour, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, then with saturated aqueous ammonium chloride (3 times), then with brine. The organic layer was dried over anhydrous magnesium sulfate, then filtered and the solvent removed in vacuo to give a brown oil which crystallized to give a yellow solid after standing at room temperature. The solid was collected by filtration, washed with ethyl acetate, and then dried in vacuo. The filtrate was concentrated and chromatographed on silica gel, eluting with 20-50% ethyl acetate in hexane to give additional product as a solid after removal of the solvent. The two solids were combined to give the desired product, 8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d]Ethyl pyrimidine-6-carboxylate (1.2g) in 42% yield over two steps.

¹H NMRδ(400MHz，CDCl₃)8.64(s，1H)，8.23(s，1H)，5.90-5.99(m，1H)，4.37(q，J＝1.8Hz，2H)，2.60(s，3H)，2.27-2.35(m，2H)，2.02-2.10(m，2H)，1.81-1.89(m，2H)，1.63-1.70(m，2H)，1.37(t，J＝7Hz，3H).

Example 40

8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester

Reacting 8-cyclopentyl-2-methylthio-7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidine-6-carboxylic acid ethyl ester (1.2g, 3.6mmol) dissolved in CH₂Cl₂(20ml) was treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (1.13g, 4.32mmol) at room temperature and stirred for 1 day. After concentration under reduced pressure, the crude reaction mixture was chromatographed on silica gel, eluting with ethyl acetate, to give 8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidine-6-carboxylic acid ethyl ester as a white solid (0.85g, 68%). Ms (apci); m₊+1: calcd for 350.1, found 350.0.

EXAMPLE 41

4- (6-Nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

5-bromo-2-nitropyridine (203g, 1.365mol), tetra-n-butylammonium iodide (25.2g, 0.068mol), piperazine (152.8g, 1.774mol) and potassium carbonate (207.44g, 1.50mol) were mixed in DMSO (2.6L). The reaction mixture was allowed to warm to 80 ℃ and exotherm to 100 ℃. The mixture was cooled back to 80 ℃ and maintained at this temperature overnight. After cooling to room temperature, the reaction mixture was poured into water (7L) and the resulting solid was collected by filtration. The solid was triturated twice with dichloromethane (1L each). The aqueous mother liquor was extracted with chloroform (4X 2L), and the organic layers were combined, washed with water (2L) and then brine (2L). The mother liquor was re-extracted with chloroform (3X 2L), followed by washing with brine (1.5L). The organic extracts were combined and concentrated to give an orange solid (490.46g) which was used without further purification. The solid was dissolved in THF (2L), water (500ml) and sodium bicarbonate (119.22g, 1.419mol) were added, followed by the addition of di-tert-butyl dicarbonate (262g, 1.2mol) in portions over 2.5 hours, so that the temperature did not rise above 26 ℃. After 3 hours, the volatiles were removed under reduced pressure and the residue was diluted with water (1L) and extracted with dichloromethane (3 × 1L). The organic layers were combined and washed with water (1L). The water was then back-extracted with more dichloromethane (300 ml). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give a brown solid. The material was warmed to 60 ℃ in 2.OL ethyl acetate. The solid was removed by filtration at 60 ℃ to give the product 4- (6-nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester as an orange solid (190.93g, 62%).

Example 42

4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

A solution of 4- (6-nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (83g, 0.269mol) plus Raney nickel (15g, 50% aqueous slurry) in methanol (1.3L) was placed in a Parr shaker and hydrogenated under 50psi of hydrogen for 5 hours. The reaction mixture was filtered through a pad of celite and concentrated to a brown solid. The material was triturated with ether (120ml) for 4 h. Heptane was added and the mixture was cooled to 0 ℃ for 45 minutes. The solid was collected by filtration and dried to give the product 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester as a tan solid (62.46g, 83%). mp130-132 deg.C, MS (ESI); m⁺+1: calculated value, 279.2, found 279.

Calculated values of elemental analysis: c₁₄H₂₂N₄O₃：C，60.41；H，7.97；N，20.13.Found；C，60.45；H，7.60；N，19.87.

Example 43

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

Reacting 8-cyclohexyl-2-methylthio-8H-pyrido [2,3-d]Pyrimidin-7-one (4g, 14.5mmol) was dissolved in dimethylformamide (100ml), and N-bromosuccinimide (3.9g, 21.8mmol) and benzoyl peroxide (0.53g, 2.2mmol) were added to the solution. Mixing the reaction mixtureAfter stirring at room temperature for 3 days, it was diluted with ethyl acetate, washed with water and twice with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6-bromo-8-cyclohexyl-2-methylsulfanyl-8H-pyrido [2,3-d]Pyrimidin-7-one as a cream-colored solid (8 g). Redissolving this crude intermediate in CH₂Cl₂Treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (3.78g, 14.5 mmol). The resulting solution was stirred at room temperature overnight, then concentrated under reduced pressure, chromatographed on silica gel, eluting with ethyl acetate to give 6-bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido [2,3-d ]]Pyrimidin-7-one as a colorless solid (3.72g, 67%).

¹H NMR：δ(400MHz，CDCl₃)8.90(s，1H)，8.13(s，1H)，5.41(br s，1H)，2.96(s，3H)，2.58-1.70(m，2H)，1.87(br d，J＝13Hz，2H)，1.31-1.47(m，2H)，1.28(t，J＝3Hz，2H).

Example 44

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

8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (5g, 19mmol) was suspended in dimethylformamide (80ml) and treated with N-bromosuccinimide (5.1g, 28.7mmol) and benzoyl peroxide (0.7g, 2.87 mmol). After stirring at room temperature for 5 hours, the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution and brine, and the organic layer was then dried over magnesium sulfate. After filtration and removal of the solvent, the crude product was chromatographed on silica gel using 20% ethyl acetate: elution with 80% hexanes provided 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a fluffy white solid (4.2g, 65%).

¹H NMR：δ(400MHz，CDCl₃)8.56(s，1H)，7.98(s，1H)，5.97-6.05(m，1H)，2.59(s，3H)，2.22-2.29(m，2H)，2.06-2.07(m，2H)，1.86-1.88(m，2H)，1.64-1.68(m，2H).

Example 45

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

Sulfide 8-cyclopentyl-5-methyl-2-methylthio-8H-pyrido [2,3-d]Pyrimidin-7-one (7.03g, 25.51mmol) and iodine (7.12g, 28.06mmol) were combined in dry dichloromethane (120 ml). The mixture was protected from light and stirred at room temperature for 27 minutes. Bis (trifluoroacetoxy) iodobenzene (13.16g, 30.61mmol) was added in one portion and the reaction mixture was heated to 37 ℃ for 2 hours and then cooled to room temperature for 2 hours. 50% (w/v) aqueous sodium thiosulfate (114ml) was added, and the two phases were stirred for 30 minutes and then separated. The aqueous phase was extracted with dichloromethane (50ml) and the organic phases were combined and washed with 50% (w/v) aqueous sodium thiosulphate (50ml) and water (4X 130 ml). The organic phase was dried, filtered and concentrated in vacuo to give the crude product which was purified by chromatography (15% heptane/dichloromethane) to give 8-cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d]Pyrimidin-7-one (5.94g, 58%) as a white solid. Ms (esi); m⁺+1: calculated value, 401, found value 401.

¹H NMRδ(300MHz，CDCl₃)8.91(s，1H)，6.12-6.00(m，1H)，2.70(s，3H)，2.62(s，3H)，2.30-2.24(m，2H)，2.15-2.08(m，2H)，1.93-1.81(m，2H)，1.75-1.57(m，2H)

Example 46

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

Reacting 8-cyclopentyl-6-iodo-5-methyl-2-methylthio-8H-pyrido [2,3-d]Pyrimidin-7-one (1.51g, 3.76mmol) and 2-benzenesulfonyl-3-phenylazepino propane (0.98g, 3.76mmol) were combined in dichloromethane (14ml) and stirred at room temperature until no starting material remained. The solvent was removed in vacuo and the residue was purified by chromatography (gradient: 50% ethyl acetate in heptane to 100% ethyl acetate) to give 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido [2, 3-d%]Pyrimidin-7-one (1.16g, 74%) asA white solid. Ms (esi); m⁺+1: calculated value, 418, found value 418.

¹H NMRδ(300MHz，CDCl₃)9.13(s，1H)，6.14-6.02(m，1H)，2.98(s，3H)，2.80(s，3H)，2.27-2.06(m，4H)，2.00-1.87(m，2H)，1.72-1.63(m，2H).

Example 47

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

Prepared from 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one according to the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one.

MS(APCI)Calc’d forC₁₃H₁₄BrN₃O₂S：357，355.0.Found：358(M+1)，356.¹H NMRδ(400MHz，DMSO-d₆)9.14(s，1H)，8.63(s，1H)，5.91-5.86(m，1H)，2.89(s，3H)，2.15(br s，2H)，2.04(brs，2H)，1.87-1.79(m，2H)，1.61-1.58(m，2H).

Example 48

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

Prepared from 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one according to the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one.

MS(APCI)Calc’d for C₁₄H₁₆BrN₃O₂S：371.01，369.01.Found：372.9(M+1)，371.9.¹H NMRδ(400MHz，CDCl₃)9.01(s，1H)，6.06-5.97(m，1H)，2.93(s，3H)，2.67(s，3H)，2.21-2.11(m，2H)，2.10-2.04(m，2H)，1.94-1.87(m，2H)，1.67-1.62(m，2H).

Example 49

4- [6- (8-cyclopentyl-6-iodo-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

In a sealed test tube, 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d]A solution of pyrimidin-7-one (100mg, 0.240mmol) and 2-amino-4-tert-butoxycarbonyl-piperazinylpyridine (96mg, 0.34mmol) in dry toluene (3ml) was heated to 110 ℃ and 120 ℃ for 42 hours. The mixture was cooled to room temperature and diluted with dichloromethane (20 ml). The mixture was washed with water (10ml) and brine (10ml) then dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to give a solid which was triturated with toluene to give 4- [6- (8-cyclopentyl-6-iodo-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-tert-butyl ester (63mg, 41%) as a yellow-orange solid. Ms (esi); m⁺+1: calculated value, 632, found value 632.

¹HNMRδ(300MHz，CDCl₃)8.88(s，1H)，8.73(bs，1H)，8.19(d，J＝9.1Hz，1H)，8.08(d，J＝2.8Hz，1H)，7.33(dd，J＝3，9.1Hz，1H)，5.99(pent.J＝8.7Hz，1H)，3.64-3.60(m，4H)，3.15-3.11(m，4H)，2.69(s，3H)，2.35-2.28(m，2H)，2.13-2.09(m，2H)，1.89-1.86(m，2H)，1.71-1.63(m，2H)，1.50(s，9H).

Example 50

8-cyclopentyl-6-iodo-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Mixing 4- [6- (8-cyclopentyl-6-iodo-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (60mg, 0.096mmol) and anhydrous dichloromethane (4ml) were treated dropwise over 10 minutes with trifluoroacetic acid (0.4ml, 5mmol) under nitrogen. After stirring for 2.6 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2X 2ml) and concentrated under reduced pressure. The residue was then triturated with anhydrous ether (2X 2ml) to give 63mg of an orange solid. The solid is placed in dichloromethane with saturated aqueous carbonPartition between sodium hydrogen carbonate. Insoluble material was removed by filtration. The aqueous layer was extracted with dichloromethane (2X 10ml), the organic solutions combined, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give a yellow residue which was purified by chromatography (5% methanol in dichloromethane + 1% NH)₄OH) to give 8-cyclopentyl-6-iodo-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid (15mg, 28%). Mp > 240C.MS (ESI); m + 1: calculated value, 532, found value 532.

¹HNMRδ(300MHz，CDCl₃)8.79(s，1H)，8.16 d，J＝9.1Hz，1H)，8.02(d，J＝2.8Hz，1H)，7.84(s，1H)，8.02(d，J＝2.8Hz，1H)，7.84(s，1H)，7.35-7.31(m，1H)，5.99(pent.J＝8.7Hz，1H)，3.20-3.13(m，4H)，3.08-3.05(m，4H)，2.69(s，3H)，2.34-2.25(m，2H)，2.11-2.02(m，2H)，1.89-1.86(m，2H)，1.71-1.63(m，2H).

Example 51

8-cyclopentyl-6-ethyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 8-cyclopentyl-6-ethyl-2-methylsulfonyl-8H-pyrido [2,3-d ]]Pyrimidin-7-one (0.115g, 0.47mmol) and 6 '-amino-3, 4, 5, 6-tetrahydro-2H- [1, 3']Bipyridin-4-ol (0.117g, 0.61mmol) was combined in anhydrous xylene and heated overnight at 140 ℃ under nitrogen. The crude reaction mixture was then cooled and quenched with CH₂Cl₂And (6) diluting. The precipitate was collected by filtration and dried in vacuo to give 8-cyclopentyl-6-ethyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3']Bipyridin-6' -ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one (15mg, 7%). Ms (apci); m⁺+1: calculated value, 435.2, found 435.2.

Example 52

4- {6- [ 8-cyclopentyl-6- (2-ethoxy) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester

Under nitrogen atmosphere, 8-cyclopentyl-6- (2-ethoxy) -2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (1.2ml of 0.46M toluene solution, 0.552mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (0.307g, 1.1mmol) were combined in toluene and heated to 110 ℃. After 4 hours, toluene was replaced with xylene (1ml) and heating was continued under reflux overnight. After cooling to room temperature, the crude reaction mixture was dissolved in CH₂Cl₂Washed with saturated aqueous ammonium chloride and then brine. The organic layer was dried (MgSO₄) Filtered and evaporated to dryness. Chromatographing on silica gel with 5% CH₃CH of OH₂Cl₂Elution followed by a second chromatography step, eluting with ethyl acetate, gave 4- {6- [ 8-cyclopentyl-6- (2-ethoxy) -7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-2-ylamino]-pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (70mg, 22%) as a yellow solid. Ms (apci); m⁺+1: calculated value, 580.32, found 580.2.

¹H NMR：δ(400MHz，DMSO)8.50(s，1H)，8.26(d，J＝9Hz，1H)，7.94(d，J＝3Hz，1H)，7.39(dd，J＝3，9Hz，1H)，6.78(s，1H)，5.89-5.98(m，1H)，4.15(t，J＝5Hz，2H)，3.86(t，J＝5Hz，2H)，3.56-3.62(m，6H)，3.09(br t，J＝5Hz，4H)，2.29-2.33(m，2H)，2.07-2.10(m，2H)，1.84-1.92(m，2H)，1.63-1.69(m，2H)，1.47(s，9H)，1.22(t，J＝7Hz，3H).

Example 53

8-cyclopentyl-6- (2-ethoxy) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- {6- [ 8-cyclopentyl-6- (2-ethoxy) -7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-2-ylamino]-pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (70mg, 0.12mmol) dissolved in CH₂Cl₂(2.5ml), a 2M HCl in ether solution (2.5ml) was added. The mixture was stirred at room temperature for 2 hours, resulting in a yellow precipitate. Removal of the solvent under reduced pressureThe resulting solid was suspended in diethyl ether, collected by filtration and then dried overnight at 50 ℃ under vacuum to give 8-cyclopentyl-6- (2-ethoxy) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (30mg, 52%). Ms (apci); m⁺+1: calculated, 480.3, found 480.4.

Calculated values of elemental analysis: c₂₅H₃₃N₇O₃2HCl3.44H₂O：C，48.87；H，6.87；N，15.96.Found；C，48.48；H，6.66；N，15.66.

Example 54

2- {5- [ bis- (2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.4g, 1.08mmol) and N⁵，N⁵-bis- (2-methoxy-ethyl) -pyridine-2, 5-diamine (0.5g, 2.2mmol) was combined in toluene (3.5ml) and heated to 110 ℃. After 5 hours, the reaction mixture was cooled and the crude product was chromatographed directly on silica gel, eluting with a gradient of 25% to 100% ethyl acetate in hexane to give 2- {5- [ bis- (2-methoxy-ethyl) -amino]-pyridin-2-ylamino } -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.49g, 85%) was an orange gum. mp94-95 ℃, ms (apci); m⁺+1: calculated 530.2, found 530.1.

Calculated values of elemental analysis:

C₂₄H₃₂N₆O₃Br₁ 0.13H₂O：C，54.00；H，5.90；N，15.74.Found；C，53.61；H，5.68；N，15.60.

example 55

6-acetyl-2- {5- [ bis- (2-methoxy-ethyl) -amino ] -pyridin-2-ylamino } -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 2- [5- [ bis- (2-methoxy-ethyl) -amino group]-pyridin-2-ylamino } -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.4g, 0.75mmol), tributyl- (1-ethoxy-vinyl) -stannane (0.42g, 1.175mmol) and tetrakis (triphenylphosphine) palladium (0.1g, 0.09mmol) were combined over N₂Purged toluene (4ml) was heated to 110 ℃. After 2 hours, the reaction mixture was allowed to cool and alumina (0.2g) supporting solid 40% KF was added. The mixture was diluted with toluene (15ml) and vortexed for 2 minutes. After filtration and removal of the solvent, the crude product was chromatographed on silica gel, eluting with 50-65% ethyl acetate in hexane to give an orange gum (0.298 g). Dissolving the gum in CH₂Cl₂With 10% KF H₂Washed with O solution, brine and dried (MgSO)₄). After removal of the drying agent and evaporation of the solvent, the remaining material was dissolved in ethyl acetate (10ml) and treated with 1M HCl (aq). The resulting mixture was stirred vigorously at room temperature for 1 hour. Adding sufficient CH₂Cl₂To dissolve the precipitate formed, the organic solution was washed with a saturated aqueous solution of sodium hydrogencarbonate. CH for aqueous layer₂Cl₂Back extraction twice, combined organic layers and dried (MgSO)₄). The drying agent was removed and the solvent evaporated to give a foamy solid which was dissolved in ethyl acetate (20ml), filtered and then diluted with an equal volume of hexane and stored at 4 ℃. Yellow crystals formed, collected by filtration and dried in vacuo to give 6-acetyl-2- {5- [ bis- (2-methoxy-ethyl) -amino]-pyridin-2-ylamino } -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (120mg, 32%). Mp138-138 ℃ MS (APCI); m⁺+1: calculated value, 494.3, found 495.3.

Calculated values of elemental analysis: c₂₆H₃₄N₆O₄：C，63.14；H，6.93；N，16.99.Found；C，63.04；H，6.77；N，16.86.

Example 56

4- [6- (8-isopropyl-7-oxo-7, 8-dihydro-pyrido [2, 3] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

2-chloro-8-isopropyl-8H-pyrido [2,3-d]A mixture of pyrimidin-7-one (338mg, 1.5mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (460mg, 2.0mmol) in toluene (6ml) was heated at 110 ℃ for about 20 hours and then cooled to room temperature. The solid was collected by filtration, washed with toluene and dried. Dissolving the sample in CH₂Cl₂Purified by two preparative TLC plates (10% MeOH/CH)₂Cl₂Elution). Extraction of R_fBand of 0.23 gave 4- [6- (8-isopropyl-7-oxo-7, 8-dihydro-pyrido [2, 3]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as yellow solid (180mg, 26%).¹HNMRδ(400MHz，DMSO)9.29(s，1H)，8.80(br，1H)，8.17～8.9(m，2H)，7.70(d，J＝2.5Hz，1H)，7.2(d，J＝9.8Hz，1H)，6.88(d，J＝9.6Hz，1H)，5.6～5.5(m，1H)，4.06(m，1H)，3.4～3.9(m，4H)，3.14(d，J＝5.2Hz，2H)，2.98(m，4H)，1.52(s，3H)，1.1.50(s，3H)，1.38(s，9H)

Example 57

8-isopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Introducing HCl gas into 4- [6- (8-isopropyl-7-oxo-7, 8-dihydro-pyrido [2, 3] at room temperature]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (180mg, 0.39mmol) in CH₂Cl₂(5ml) in solution. The resulting pale yellow solid was collected by filtration after 5 hours. The solid is hygroscopic and therefore it is dissolved in MeOH and a few drops of water are added to the solution. The solvent was then removed under reduced pressure to yield a glassy solid. The solid was washed with acetone and further dried to give 8-isopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (101mg, 66%). mp237-240 ℃.

¹H NMRδ(400MHz，DMSO-d₆)9.38(br s，1H)，9.28(s，1H)，8.88(br s，1H)，8.14(d，J＝9.5Hz，1H)，8.07(d，J＝9.0Hz，1H)，7.73(s，1H)，7.23(d，J＝9.5Hz，1H)，6.85(d，J＝9.5Hz，1H)，5.57-5.01(m，1H)，3.23(br s，4H)，3.17(br s，4H)，1.49(s，3H)，1.47(s，3H).

Example 58

4- [6- (8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

A mixture of 8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3- ] pyrimidin-7-one (416mg, 1.5mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (460mg, 2.0mmol) in toluene (6ml) was heated at 110 ℃ for about 20 hours and then cooled to room temperature. The resulting solid was collected by filtration, washed with toluene, and dried to give the desired product, 4- [6- (8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester (143mg), 19.4% yield.

¹H NMRδ(400MHz，DMSO)9.97(s，1H)，8.72(s，1H)，8.03(d，J＝3.0Hz，1H)，7.85(m，1H)，7.74(d，J＝9.2Hz，1H)，7.25(m，1H)，6.31(d，J＝9.3Hz，1H)，5.80(m，1H)，3.4(m，4H)，3.28(m，4H)，2.47(m，2H)，1.9(m，2H)，1.87(br，2H)，1.6～1.8(br，2H)，1.5～1.6(m，2H)，1.39(s，9H).

Example 59

8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- [6- (8-cyclopentyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] is reacted at room temperature]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (143mg, 0.29mmol) in CH₂Cl₂A solution in/MeOH (6ml/1.5ml) was treated with HCl gas for about 3 minutes. The solution was stirred at room temperature for about 6 hours, and then the solid was collected by filtration. The solid is treated with CH₂Cl₂Washed and dried in vacuo to give 8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (98mg, 66%). mp213-215 ℃.

Calculated values of elemental analysis:

C₂₁H₂₅N₇O₂.0HCl2.5H₂O：C，49.51；H，5.90；N，15.74；Cl，13.92.Found：C，49.64；H，6.12；N，19.23，Cl，14.20.

example 60

4- [6- (8-cyclohexyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

A mixture of 8-cyclohexyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (430mg, 1.47mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylate (556mg, 2.43mmol) in toluene (5ml) was heated at 100 ℃ for 18 hours. Cooled to room temperature, the resulting solid was collected, washed with toluene, and then dried to give 4- [6- (8-cyclohexyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester (105mg, 14%).

¹H NMRδ(400MHz，DMSO)10.02(s，1H)，8.70(s，1H)，

8.04(d，J＝3.0Hz，1H)，7.72(d，J＝9.2Hz，1H)，7.44(dd，J＝9.2，3.1Hz，1H)，6.28(m，1H)，3.60(m，4H)，3.08(m，4H)，1.6～1.8(m，10H)，1.39(s，9H).

Example 61

8-cyclohexyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

At room temperature, HCl gas was bubbled through 4- [6- (8-cyclohexyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (105mg, 0.21mmol) in CH₂Cl₂(3ml) solution until a solid formed. The mixture was stirred at room temperature for 6 hours, and the resulting solid was collected by filtration. The solid is hygroscopic. Recrystallization from MeOH and addition of a few drops of water gave 8-cyclohexyl-2- (5-piperazine)-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride (40mg, 35%). mp: 228 ℃ and 230 ℃.

Calculated values of elemental analysis: c₂₂H₂₇N₇O2.0HCl3.5 H₂O：C，48.80；H，6.70；N，18.11；Cl，13.09.Found：C，48.88；H，6.39；N，17.95；Cl，12.88.

Example 62

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

Reacting 8-cyclopropyl-2-methylthio-8H-pyrido [2,3-d]Pyrimidin-7-one (0.5g, 2.1mmol) with 2-benzenesulfonyl-3-phenyl-oxaziridine (0.84g, 3.2mmol) in CH₂Cl₂(5ml) the solution was stirred at room temperature for 20 hours. The resulting white solid was collected by filtration, washed with hexane, and then dried to give 8-cyclopropyl-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.388g, 74%).

¹HNMR：δ(400MHz，DMSO)9.15(s，1H)，8.0(d，J＝9.5Hz，1H)，6.74(d，J＝9.5Hz，1H)，2.92(s，1H)，1.18～1.14(m，2H)，0.83～0.79(m，2H).

Example 63

4- [6- (8-cyclopropyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

A mixture of 8-cyclopropyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (388mg, 1.56mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylate (462mg, 2.0mmol) in toluene (5ml) was heated at 100 ℃ for 18 hours. Cooled to room temperature, the solid was collected by filtration, washed with toluene and dried to give 4- [6- (8-cyclopropyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester (96mg, 13%).

¹H NMRδ(400MHz，DMSO)9.97(s，1H)，8.67(s，1H)，8.39(d，J＝9.3Hz，1H)，8.0(d，J＝2.95Hz，1H)，7.71(d，J＝9.3Hz，1H)，6.28(d，J＝9.3Hz，1H)，3.42(br，4H)，3.05(br，4H0，2.80(m，1H)，1.37(s，9H)，1.20(d，J＝6.1Hz，2H)，0.76(br，2H).

Example 64

8-cyclopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Introducing HCl gas into 4- [6- (8-cyclopropyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (96mg, 0.21mmol) in CH₂Cl₂(5ml) solution for several minutes until a solid formed. The mixture was stirred at room temperature for 18 hours, the resulting solid was collected by filtration and washed with CH₂Cl₂Washed and then dried in vacuo to give the desired product 8-cyclopropyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as its hydrochloride salt (83mg, 85%). mp > 300 ℃.

Calculated values of elemental analysis: c₁₉H₂₁N₇O.2.1 HCl.1.5 H₂O：C，48.87；H，5.63；N，20.99.Found：C，49，23；H，5.53；N，20.68.

Example 65

6-bromo-8-cyclopentyl-2- (pyridine-2, 6-diamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (370mg, 1.0mmol) and 2, 6-diaminopyridine (164mg, 1.5mmol) in toluene (5ml) was heated at 120 ℃ overnight. The solid formed upon cooling was collected by filtration, washed with toluene, then sonicated in hot methanol and dried to give the desired product 6-bromo-8-cyclopentyl-2- (pyridine-2, 6-diamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (105mg, 26%). mp > 300 ℃.

Calculated values of elemental analysis:

C₁₇H₁₇N₆OBr：C，50.89；H，4.27；N，20.94.Found：C，51.00；H，4.20；N，21.04.

example 66

A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (370mg, 1.0mmol) and 2, 6-diaminopyridine (163mg, 1.5mmol) in toluene (5ml) was heated at 120 ℃ overnight. The solid formed upon cooling was collected by filtration, washed with toluene and sonicated in hot MeOH. After filtration, the solid was further dried to give the desired product 2- (6-amino-pyridin-2-ylamino) -6-bromo-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (39mg, 9.3%). mp: more than 274.6-276 ℃.

Elemental analysis:

Calc’d for C₁₈H₁₉BrN₆O.0.2H₂O：C，51.61；H，4.67；N，20.06.Found：C，51.42；H，4.44；N，19.87.

example 67

8-cyclopentyl-6-ethyl-2-methanesulfonyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a cooled (0 ℃ C., ice bath) solution of 8-cyclopentyl-6-ethyl-2-methylsulfanyl-8H-pyrido [2,3-d ] under nitrogen]Solution of pyrimidin-7-one (5.0g, 17.28mmol) in dichloromethane (25ml) was added meta-chloroperbenzoic acid (MCPBA) (7.4g, 30.0 mmol). The cooling bath was removed and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was poured into aq₃(saturated solution, 100ml) and extracted three times with dichloromethane (300ml total). The organic layers were combined and dried over magnesium sulfate. Removing the drying agent and evaporating the solvent to obtain a dark orange oil, which is chromatographed on silica gel eluting with a gradient of ethyl acetate/dichloromethane to obtain 8-cyclopentyl-6-ethyl esteryl-2-methanesulfonyl-8H-pyrido [2,3-d]Pyrimidin-7-one as a white powder. Recrystallization from dichloromethane/hexane gave white needles (3.56g, 11.1 mmol). mp174-176 ℃ (uncorrected);

¹H NMRδ(400MHz，CDCl₃)8.87(s，1H)，7.50(s，1H)，5.98-5.89(m，1H)，3.36(s，3H)，2.68(q，J＝7.3Hz，2H)，2.30-2.22(m，2H)，2.16-2.11(m，1H)，1.97-1.89(m，1H)，1.72-1.68(m，1H)，1.26(t，J＝7.3 Hz，3H)；MS(APCI+)322(M+1，100).

example 68

8-cyclopentyl-6- (2-ethoxy) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a suspension of sodium hydride (45mg, 1.1mmol, 60% oil dispersion) in THF (10ml) under a nitrogen atmosphere was added 2-ethoxyethanol (113mg, 1.25 mmol). The reaction mixture was stirred at RT for 30 min. To the mixture was added 8-cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-d]A pyrimidin-7-one. The reaction mixture was then heated to reflux and stirred overnight. The cooled solution was quenched with water (25ml) and extracted with ethyl acetate (50 ml). The organic layer was then treated with aq₄The solution was washed twice with Cl (20ml each) and then with brine (20 ml). The organic layer was dried over magnesium sulfate. Removing the drying agent and evaporating the solvent to give a yellow oil, which is chromatographed on silica gel eluting with an ethyl acetate/hexane gradient to give 8-cyclopentyl-6- (2-ethoxy) -2-methylsulfanyl-8H-pyrido [2,3-d]Pyrimidin-7-one as a clear oil (289mg, 0.83 mmol).

¹H NMRδ(400MHz，CDCl₃)8.52(s，1H)，6.77(s，1H)，6.04-5.95(m，1H)，4.16(t，J＝4.0Hz，2H)，3.86(t，J＝4.0Hz，2H)，3.58(q，J＝8.0Hz，2H)，2.59(s，3H)，2.34-2.25(m，2H)，2.13-2.03(m，2H)，1.91-1.82(m，2H)，1.71-1.60(m，2H)，1.20(t，J＝8.0Hz，3H)；MS(APCI+)350(M+1).

Example 69

8-cyclopentyl-6- (2-ethoxy) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a solution of 8-cyclopentyl-6- (2-ethoxy) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (289mg, 0.83mmol) in chloroform (5ml) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (281mg, 1.07 mmol). The reaction mixture was stirred under RT nitrogen overnight. The solvent was removed and the crude product was chromatographed on silica gel eluting with a 5% methanol-ethyl acetate/hexane gradient to give 8-cyclopentyl-6- (2-ethoxy) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a clear oil (210mg, 0.56 mmol).

¹H NMRδ(400MHz，CDCl₃)8.84(s，1H)，6.89(s，1H)，6.06-5.98(m，1H)，4.23(t，J＝4.0Hz，2H)，3.89(t，J＝4.0Hz，2H)，3.60(q，J＝6.9Hz，2H)，2.95(s，3H)，2.28-2.19(m，2H)，2.15-2.10(m，2H)，1.97-1.88(m，2H)，1.71-1.64(m，2H)，1.21(t，J＝6.9Hz，3H)；MS(APCI+)350(M+1).

Example 70

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

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.7mmol) and 5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamine (1.48g, 7.7mmol) were combined in toluene (3.0ml) under nitrogen. The reaction mixture was heated to reflux and stirred for 4 hours. The reaction mixture was cooled to RT and filtered. The solid was washed with additional toluene (25ml total) and dried in vacuo to give a yellow powder (338mg, 0.78 mmol). mp278-280 deg.C (decomposition);

MS(APCI+)498.500(100)；¹H NMR，(400MHz，CDCl₃)10.71-10.64(m，2H)，9.01(s，1H)，8.10-8.09(m，1H)，7.89(d，J＝0.10Hz，1H)，7.52-7.30(m，1H)，5.97-5.89(m，1H)，3.87-3.84(m，2H)，3.53-3.50(m，2H)，3.22-3.09(m，4H)，2.83-2.82(m，3H)，2.60(s，3H) 2.21-2.15(M, 2H), 1.94(br, 2H), 1.81-1.78(M, 2H), 1.62-1.60(M, 2H); calculated values of elemental analysis: c₂₃H₂₈BrN₇O₁ 3.00H₂O1.65HCl0.60C₂H₅OH：C，43.70；H，5.74；N，14.74.Found；C，43.76；H，5.79；N，14.39.

Example 71

8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one

A6 England (dram) vial was charged with 6-bromo-8-cyclopentyl-5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one (266mg, 0.53mmol) and tetrakis (triphenylphosphine) palladium (0) (61mg, 0.053mmol) with argon instead of air. Toluene (5ml) was added followed by tributyl- (1-ethoxy-vinyl) -stannane (289mg, 0.80 mmol). The vial was heated to 110 ℃ and stirred for 12 hours. The reaction mixture was diluted with chloroform (25ml) and adsorbed on silica gel. Purification by silica gel chromatography (chloroform/2-propanol + 1% TEA gradient) afforded 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one (237mg, 0.48 mmol). MS (APCI +)490(M +1, 100).

Example 72

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

To a solution of 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one (237mg, 0.48mmol) in chloroform (5ml) was added hydrogen chloride (2M in ether, 2.0ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 hours. The solvent was evaporated and the residue was dissolved in ethanol. Evaporation of ethanol gave 6-acetyl-8-cyclopentyl-5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one (239mg, 0.52 mmol).

MS(APCI+)462(M+1，100)；¹HNMRδ(400MHz，DMSO_d6)]0.83(m, 2H), 9.00(s, 1H), 8.1(m, 1H), 7.88-7.82(m, 2H), 5.89-5.80(m, 1H), 3.88-3.85(m, 2H), 3.54-3.51(m, 2H), 3.23-3.11(m, 4H), 2.83-2.82(m, 3H), 2.43(s, 3H), 2.34(s, 3H), 2.23-2.11(m, 2H), 1.93(br, 2H), 1.81-1.77(m, 2H), 1.60-1.59(m, 2H); calculated values of elemental analysis: c₂₅H₃₁N₇O₂，2.70HCl，1.05 C₂H₅OH：C，53.50；H，6.63；N，16.12.Found：C，53.45；H，6.47；N，15.85.

Example 73

(1- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -pyrrolidin-3-yl) -carbamic acid tert-butyl ester

A6-fold vial was charged with {1- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -pyrrolidin-3-yl } -carbamic acid tert-butyl ester (379mg, 0.65mmol) and tetrakis (triphenylphosphine) palladium (0) (75mg, 0.065mmol) with argon instead of air. Toluene (5ml) was added followed by tributyl- (1-ethoxy-vinyl) -stannane (352mg, 0.97 mmol). The vial was heated to 110 ℃ and stirred for 12 hours. The reaction mixture was diluted with chloroform (25ml) and adsorbed on silica gel. Purification by silica gel chromatography (chloroform/2-propanol + 1% TEA gradient) gave (1- {6- [ 8-cyclopentyl-6- (1-1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -pyrrolidin-3-yl) -carbamic acid tert-butyl ester as a yellow solid (394mg, 0.68 mmol). MS: (APCI +)576(M +1, 100), 548.

Example 74

6-acetyl-2- [5- (3-amino-pyrrolidin-1-yl) -pyridin-2-ylamino ] -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a solution of (1- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -pyrrolidin-3-yl) -carbamic acid tert-butyl ester (394mg, 0.68mmol) in chloroform (5ml) was added hydrogen chloride (2M in ether, 2.0ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 hours. The solvent was evaporated and the residue was dissolved in ethanol. Evaporation of ethanol gave 6-acetyl-8-cyclopentyl-5-methyl-2- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one (239mg, 0.52 mmol).

MS(APCI+)487，391，279(100)；¹HNMRδ(400MHz，DMSO_d6)8.98(s, 1H), 8.34(br, 2H), 7.78-7.73(m, 2H), 7.51(br, 1H), 5.89-5.80(m, 1H), 3.98(br, 2H), 3.62-3.51(m, 4H), 2.40-3.23(m, 2H), 2.44(s, 3H), 3.34(s, 3H), 2.25-2.20(m, 2H), 2.16-2.13(m, 1H), 1.93(br, 2H), 1.80-1.78(m, 2H), 1.61-1.58(m, 2H); calculated value of elemental analysis C₂₄H₂₉N₇O₂，2.10HCl，2.85H₂O，0.45 C₂H₅OH：C，50.16；H，6.68；N，16.45；Cl^-，12.49.Found：C，50.37；H，6.90；N，16.45；Cl^-，12.61.

Example 75

6-bromo-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Under a nitrogen atmosphere, 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (2.50g, 6.76mmol) and 6 '-amino-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridin-4-ol (1.96g, 10.13mmol) were combined in toluene (10.0 ml). The reaction mixture was heated to reflux and stirred for 4 hours. The reaction mixture was cooled to RT and filtered. The solid was washed with additional toluene (75ml total) and dried in vacuo to give a yellow powder (566mg, 1.13 mmol).

MS(APCI+)499，501(M+2，100)；¹HNMRδ(400MHz，DMSO-_d6)10.06(s，1H)，8.96(s，1H)，8.04(s，1H)，7.83(d，J＝9.3Hz，1H)，7.46(d，J＝7.3Hz，1H)，5.93-5.89(m，1H)，4.71(s，1H)，3.65-3.60(m，1H)，3.53-3.51(m，2H)，2.88-2.83(m，2H)，2.57(s，3H)，2.]8(br，2H)，1.90-1.8](m, 5H), 1.59-1.48(m, 3H); calculated values of elemental analysis: c₂₃H₂₇Br₁N₆O₂，0.45 H₂O：C，54.43；H，5.54；N，16.56.Found：C，54.04；H，5.23；N.16.33.

Example 76

8-cyclopentyl-6- (1-ethoxy-vinyl) -2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

A6-fold vial was charged with 6-bromo-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (316mg, 0.63mmol) and tetrakis (triphenylphosphine) palladium (0) (72mg, 0.063mmol), with argon replacing the atmosphere. Toluene (5ml) was added followed by tributyl- (1-ethoxy-vinyl) -stannane (343mg, 0.95 mmol). The vial was heated to 110 ℃ and stirred for 12 hours. The reaction mixture was diluted with chloroform (25ml) and adsorbed on silica gel. Purification by silica gel chromatography (chloroform/2-propanol + 1% TEA gradient) afforded 6-bromo-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (255mg, 0.52 mmol). MS (APCI +)463, 491(M +1, 100).

Example 77

6-acetyl-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a solution of 8-cyclopentyl-6- (1-ethoxy-vinyl) -2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (255mg, 0.52mmol) in chloroform (2ml) was added hydrogen chloride (2M in ether, 5.0ml, 10.0 mmol). The reaction mixture was stirred at RT for 12 hours. The solvent was evaporated and the residue was dissolved in ethanol. Evaporation of ethanol gave 6-acetyl-8-cyclopentyl-2- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (213mg, 0.46 mmol).

MS(APCI+)463(M+1，100)；¹H NMRδ(400MHz，DMSO-_d6)10.90(br, 1H), 9.07(s, 1H), 8.19(s, 1H), 7.91(br, 2H), 5.91-5.89(m, 1H), 3.77(br, 1H), 3.62(br, 2H), 3.07(br, 2H), 2.58(s, 3H), 2.40(s, 3H), 2.30(br, 2H), 1.98-1.86(m, 5H), 1.65 (br.4H); calculated values of elemental analysis: c₂₅H₃₀N₆O₃，1.76 C₃H₈O₁，0.36CHCl₃：C，60.20；H，7.33；N，13.75，Found：C，60.48；H，6.97；N，13.35.

Example 78

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -azepan-1-carboxylic acid tert-butyl ester

A solution of 4- (6-amino-pyridin-3-yl) -azepane-1-carboxylic acid tert-butyl ester (614mg, 2.10mmol) in toluene (10ml) was refluxed for 3 hours in a Dean-Stark apparatus. Removing heat source, adding 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] when reflux subsides]Pyrimidin-7-one (700mg, 1.89 mmol). Adding the mixture to N₂Reflux for 12 hours. Succinic anhydride (500mg) was added and refluxing was continued for 3 hours. The reaction mixture was cooled, dissolved in ethyl acetate (100ml), and the organic layer was washed with water (100ml total). The organic layer was dried over magnesium sulfate and the solvent was evaporated. The crude product was chromatographed on silica gel eluting with a chloroform/2-propanol gradient to give 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ]]Pyrimidin-2-ylamino) -pyridin-3-yl]-azepane-1-carboxylic acid tert-butyl ester as yellow powder (414mg, 0.82 mmol). MS (APCI +)500, 600(M +1, 100).

Example 79

6-bromo-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Hydrogen chloride gas was bubbled through a solution of 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -azepan-1-carboxylic acid tert-butyl ester (80mg, 0.13mmol) in chloroform (5ml) for 30 minutes. The solvent was evaporated and the residue triturated with ethanol (5 ml). 6-bromo-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride was collected as a yellow powder (44mg, 0.089 mmol).

MS(APCI+)499，501(M+2，100)；¹H NMRδ(400MHz，DMSO-_d6)8.84(s, 2H), 8.13(s, 1H), 7.66-7.64(m, 1H), 7.42-7.39(m, 1H), 5.86-5.82(m, 1H), 4.36(s, 1H), 3.81(s, 2H), 3.60(s, 2H), 3.16(s, 2H), 2.09(s, 4H), 1.99(s, 2H), 1.79(br, 2H), 1.60(s, 2H), 1.05(s, 2H); calculated values of elemental analysis: c₂₃H₂₈Br₁N₇O₁，0.15HCl，2.55 C₂H₅OH，0.45CHCl₃：C，50.79；H，6.55；N，14.52.Found：C，50.83；H，5.69；N，14.21.

Example 80

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } - [1, 4] diazepane-1-carboxylic acid tert-butyl ester

A6-fold vial was charged with 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -azepan-1-carboxylic acid tert-butyl ester (123mg, 0.25mmol) and tetrakis (triphenylphosphine) palladium (0) (29mg, 0.025mmol) with argon instead of atmospheric air. Toluene (5ml) was added followed by tributyl- (1-ethoxy-vinyl) -stannane (137mg, 0.37 mmol). The vial was heated to 110 ℃ and stirred for 12 hours. The reaction mixture was diluted with chloroform (25ml) and adsorbed on silica gel. Purification by silica gel chromatography (chloroform/ethyl acetate gradient) gave 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } - [1, 4] diazepan-1-carboxylic acid tert-butyl ester as a yellow solid (116mg, 0.20 mmol). MS: (APCI +)125(100), 490, 590(M +1, 100), 624.

Example 81

6-acetyl-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a solution of 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } - [1, 4] diazepan-1-carboxylic acid tert-butyl ester (116mg, 0.20mmol) in chloroform (5ml) was added hydrogen chloride (2M in ether, 5.0ml, 10.0 mmol). The reaction mixture was stirred at RT for 12 hours. The solvent was evaporated and the residue was dissolved in ethanol. Evaporation of ethanol gave 6-acetyl-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (47mg, 0.10 mmol).

MS(APCI+)432，462(M+1，100)；¹H NMRδ(400MHz，DMSO-_d6)9.19(br, 2H), 8.99(s, 1H), 7.91(s, 1H), 7.78-7.75(m, 2H), 5.88-5.80(m, 1H), 3.80-3.77(m, 3H), 3.25(br, 3H), 3.16(br, 2H), 2.44(s, 3H), 2.34(s, 3H), 2.49-2.18(m, 2H), 2.12-2.10(m, 2H), 1.93(br, 2H), 1.81-1.78(m, 2H), 1.61-1.58(m, 2H): calculated values of elemental analysis: c₂₅H₃₁N₇O₂，2.80HCl，0.45 C₃H₈O₂：C，53.35；H，6.25；N，16.25.Found：C，52.96：H，6.62；N，15.95.

Example 82

6-acetyl-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 6-acetyl-2-amino-8-cyclopentyl-5-methyl-8H-pyrido[2，3-d]Pyrimidin-7-one (195mg, 0.681mmol) and sodium tert-butoxide (92mg, 0.953mmol) were suspended in a solvent₂Purged toluene (5 ml). To this suspension was added 2-bromopyridine (78. mu.l), tris (dibenzylideneacetone) dipalladium (0) (25mg, 0.027mmol) and BINAP (34mg, 0.054 mmol). The reaction vial was purged with argon and the reaction was heated at 70 ℃ overnight. The reaction mixture was diluted with ether and methanol, filtered through a pad of celite, and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with a gradient of 40% to 100% ethyl acetate in hexane to give 6-acetyl-8-cyclopentyl-5-methyl-2- (pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a solid (40mg, 16%).

¹H NMRδ(400MHz，CDCl₃)8.84(s，1H)，8.35-8.32(m，2H)，8.21(bs，1H)，7.75-7.71(m，1H)，7.03-7.01(m，1H)，5.89-5.85(m，1H)，2.54(s，3H)，2.37(s，3H)，2.03-2.08(m，2H)，1.92-1.87(m，2H)，1.73-1.67(m，2H).

Ms (apci) calculated for M + H: 363.2, found: 364.1; purity after HPLC purification was 92%.

Example 83

4- [6- (8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.40g, 1.37mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid butyl ester (0.497g, 1.78mmol) were heated in toluene (4ml) to reflux for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with toluene (3 × 10ml) on a funnel to give 4- [6- (8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester as a dark brown-grey solid (0.100g, 16.2%).

¹H NMRδ(400MHz，DMSO-d₆)9.92(s，1H)，8.78(s，1H)，8.02(d，J＝2.9Hz，1H)，7.87(d，J＝9.3Hz，1H)，7.50(dd，J＝2.9，9.0Hz，1H)，6.18(s，1H)，5.77(m，1H)，3.44(m，4H)，3.07(m，4H)，2.39(s，3H)，2.20(m，2H)，1.85(m，2H)，1.71(m，2H)，1.55(m，2H)，1.39(s，9H).

Example 84

8-cyclopentyl-5-methyl-2- (5-piperazin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Tert-butyl 4- [6- (8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylate (0.093g, 0.184mmol) was dissolved in dichloromethane (3ml), 2N HCl in ether (2ml) was added thereto, and the resulting mixture was stirred for 2 days. Additional 2N HCl was added and stirring was continued for 16 hours. The solvent was removed to give 8-cyclopentyl-5-methyl-2- (5-piperazin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.080g, 90.9%).

¹H NMRδ(400MHz，DMSO-d₆)9.92(s，2H)，8.85(s，1H)，8.02(d，J＝2.9Hz，1H)，7.91(d，J＝9.3Hz，1H)，7.78(d，J＝9.3Hz，1H)，6.33(s，1H)，5.79(m，1H)，3.40(m，4H)，3.22(m，4H)，2.39(s，3H)，2.20(m，2H)，1.91(m，2H)，1.74(m，2H)，1.56(m，2H).

Example 85

2, 2-dimethyl-4- (6-nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

5-bromo-2-nitropyridine (10.67g, 52.6mmol), tetra-n-butylammonium iodide (0.97g, 02.63mmol), 2-dimethyl-piperazine (6.60g, 57.8mmol) and potassium carbonate (8.00g, 57.8mmol) were mixed in DMSO (50 ml). The reaction mixture was warmed to 95 ℃ for 5 hours. The reaction mixture was poured into ice shavings (approximately 200ml) and then extracted with dichloromethane (6X 75 ml). The organic phases were combined over MgSO₄Drying, filtering to remove inorganic salts, and concentrating the remaining solvent to obtain an orange solid. The solid was dissolved in methylene chloride (100ml), to which was added trisEthylamine (10.65g, 14.7ml, 105mmol) and di-tert-butyl dicarbonate (13.8g, 63.12 mmol).

After 16 h, more di-tert-butyl dicarbonate (3.8g, 17.41mmol) was added and the mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (100ml) and washed with water (1X 100 ml). The organic layer was then washed with MgSO₄Drying, filtration and evaporation of the solvent gave 2, 2-dimethyl-4- (6-nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester as an orange solid (14.91g, 84.2%).

¹H NMRδ(400MHz，CDCl₃)8.17(d，J＝9.3Hz，1H)，7.97(d，J＝2.9Hz，1H)，7.01(dd，J＝2.9，9.0Hz，1H)，3.91(m，2H)，3.54(m，4H)，1.48(s，9H)，1.43(s，6H).

Example 86

4- (6-amino-pyridin-3-yl) -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

2, 2-dimethyl-4- (6-nitro-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (14.63g, 43.5mmol) was dissolved in THF (400ml), to which Raney nickel (6.8g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50psi) for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to give 4- (6-amino-pyridin-3-yl) -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a purple solid (11.26g, 84.5%).

¹H NMRδ(400MHz，CDCl₃)7.63(d，J＝2.4Hz，1H)，7.06(dd，J＝2.9，8.8Hz，1H)，6.51(d，J＝8.8Hz，1H)，3.68(m，2H)，3.16(m，2H)，2.98(s，2H)，1.48(s，9H)，1.43(s，6H).

Example 87

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.70mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -2, 2-dimethyl-piperazine-1-carboxylate (1.14g, 3.73mmol) were heated to reflux in toluene (10ml) for 16 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with toluene (3 × 10ml) on a funnel to give 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.525g, 31.8%).

¹H NMRδ(400MHz，DMSO-d₆)9.96(s，1H)，8.91(s，1H)，7.89(d，J＝2.7Hz，1H)，7.74(d，J＝8.8Hz，1H)，7.26(dd，J＝3.2，9.3Hz，1H)，6.18(s，1H)，5.86(m，1H)，3.67(m，2H)，3.37(m，4H)，2.54(s，3H)，2.15(m，2H)，1.84(m，2H)，1.71(m，2H)，1.53(m，2H)，1.39(s，9H)，1.33(s，6H).

Example 88

6-bromo-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051g, 0.083mmol) was dissolved in dichloromethane (3ml), 2N HCl (2ml) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated, left for 10 days, then dissolved in 2N HCl (2ml) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2- [5- (3, 3-5 methyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.035g, 71.4%).

¹H NMRδ(400MHz，DMSO-d₆)9.32(s，2H)，8.98(s，1H)，8.04(d，J＝2.7Hz，1H)，7.83(d，J＝9.3Hz，1H)，7.26(m，1H)，5.89(m，1H)，3.34(m，2H)，3.23(m，4H)，2.58(s，3H)，2.14(m，2H)，1.91(m，2H)，1.77(m，2H)，1.57(m，2H)，1.38(s，6H).

Example 89

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.412g, 0.673mmol), tetrakis (triphenylphosphine) palladium (0.093g, 0.081mmol), and tributyl- (1-ethoxy-vinyl) -stannane (0.379g, 1.05mmol) were dissolved in toluene (3ml) and slowly heated to reflux for 1 hour. The solvent was evaporated and the solid was redissolved in dichloromethane (8ml) and purified by silica gel chromatography to give 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.405g, 99.0%).

¹HNMRδ(400MHz，CDCl₃)8.73(s，1H)，8.15(d，J＝9.0Hz，1H)，8.00(s，1H)，7.85(d，J＝2.9 Hz，1H)，7.18(m，1H)，5.90(m，1H)，4.52(d，J＝2.4Hz，1H)，4.18(d，J＝2.4Hz，1H)，3.93(q，J＝7.1Hz，2H)，3.80(m，2H)，3.38(m，2H)，3.26(s，2H)，2.41(s，3H)，2.35(m，2H)，2.06(m，2H)，1.85(m，2H)，1.64(m，2H)，1.49(s，9H)，1.45(s，6H)，1.36(t，J＝7.1Hz，3H).

Example 90

6-acetyl-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

4- (6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.400g, 0.663mmol) was dissolved in ethyl acetate (10ml) and 6N HCl (10ml), stirred at room temperature for 2 hours Evaporation of the solvent gave a yellow solid, dried in a vacuum oven at 50 ℃ for 5 hours triturated with EtOH (20ml), filtered to give 6-acetyl-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -2-yl 5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.120g, 38.1%).

¹H NMRδ(400MHz，DMSO-d₆)9.15(s，2H)，8.93(s，1H)， 8.04(d，J＝3.2Hz，1H)，7.82(d，J＝9.1Hz，1H)，7.64(m，1H)，5.78(m，1H)，3.31(m，2H)，3.24(m，2H)，3.18(s，2H)，2.38(s，3H)，2.28(s，3H)，2.18(m，2H)，1.85(m，2H)，1.73(m，2H)，1.54(m，2H)，1.35(s，6H).

MS (APCI) M + H; calculated value 476.3, found value 476.1

Calculated values of elemental analysis: c₂₆H₃₃N₇O₂4.38HCl：C，49.16；H，5.93；N，15.43.Found；C，49.55；H，6.80；N，14.76.

Example 91

4- (6-amino-pyridin-3-yl) -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

5-bromo-2-nitropyridine (10.81g, 53.3mmol), tetra-n-butylammonium iodide (0.98g, 2.66mmol), 2, 6-dimethyl-piperazine (6.69g, 58.6mmol) and potassium carbonate (8.10g, 58.6mmol) were mixed in DMSO (50 ml). The mixture was warmed to 80 ℃ for 4 hours at which time the reaction was complete by TLC analysis. The reaction mixture was diluted with dichloromethane and washed with water (3X 75 ml). The organic phases were combined over MgSO₄Drying, filtering to remove inorganic salts, and concentrating the remaining solvent to obtain an orange solid. The solid was dissolved in dichloromethane (150ml), to which were added triethylamine (10.8g, 14.8ml, 108mmol) and di-tert-butyl dicarbonate (13.95g, 63.9 mmol). The reaction mixture was heated to reflux for 3 hours, then cooled to room temperature, diluted with dichloromethane (100ml) and washed with water (1 × 100 ml). The organic layer was then passed through Mg8O₄Drying, filtering, evaporating the solvent to obtain an orange solidAnd (3) a body. The orange solid was dissolved in THF (500ml), and Raney nickel (9.23g) was added thereto. The reaction mixture was shaken under a hydrogen atmosphere (50psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give a crude purple solid. The solid was purified by chromatography eluting with ethyl acetate to give 4- (6-amino-pyridin-3-yl) -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a purple solid (4.36g, 26.7%).

₁H NMRδ(400MHz，CDCl₃)7.72(d，J＝2.4Hz，1H)，7.18(dd，J＝2.9，8.8Hz，1H)，6.51(d，J＝8.8Hz，1H)，4.35(s，2H)，4.21(m，2H)，3.08(dd，J＝4.4，11.7Hz 2H)，1.48(s，9H)，1.35(d，J＝6.8Hz，6H).

Example 92

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.70mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -2, 6-dimethyl-piperazine-1-carboxylate (1.14g, 3.73mmol) were heated to reflux in toluene (10ml) for 16 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with toluene (3 × 10ml) on a funnel to give 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.620g, 37.6%).

¹H NMRδ(400MHz，CDCl₃)8.79(s，1H)，8.23(d，J＝8.8 Hz，1H)，7.99 (d，J＝2.7Hz，1H)，7.36(dd，J＝2.7，8.8Hz，1H)，5.99(m，1H)，4.28(m，2H)，3.30(m，2H)，2.93(dd，J＝4.4，11.7Hz 2H)，2.61(s，3H)，2.30(m，2H)，2.11(m，2H)，1.89(m，2H)，1.68(m，2H)，1.49(s，9H)，1.38(d，J＝6.8Hz，6H).

Example 93

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051g, 0.083mmol) was dissolved in dichloromethane (3ml), 2N HCl (2ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, left for 10 days, then dissolved in 2N HCl (2ml) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.039g, 71.4%).

¹H NMRδ(400MHz，DMSO-d₆)9.51(m，1H)，9.02(m，1H)，8.98(s，1H)，8.07(s，1H)，7.83(8，2H)，5.90(m，1H)，3.85(d，J＝11.2Hz，2H)，3.35(m，2H)，2.76(dd，J＝12.0，12.0Hz 2H)，2.58(s，3H)，2.14(m，2H)，1.92(m，2H)，1.77(m，2H)，1.58(m，2H)，1.28(d，J＝6.4Hz，6H).

Example 94

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.450g, 0.735mmol), tetrakis (triphenylphosphine) palladium (0.102g, 0.088mmol), and tributyl- (1-ethoxy-vinyl) -stannane (0.414g, 1.15mmol) were dissolved in toluene (4ml) and heated slowly to reflux for 2 hours. The solvent was evaporated and the solid was redissolved in dichloromethane (8 ml). The solution was purified by silica gel chromatography to give 4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -2, 6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.275g, 61.9%).

¹H NMRδ(400MHz，CDCl₃)8.73(s，1H)，8.20(d，J＝9.0Hz，1H)，8.06(s，1H)，8.00(d，J＝2.7Hz，1H)，7.32(dd，J＝2.7，9.0Hz，1H)，5.89(m，1H)，4.51(d，J＝2.4Hz，1H)，4.26(m，2H)，4.17(d，J＝2.4Hz，1H)，3.93(q，J＝6.8Hz，2H)，3.28(d，J＝11.7，2H)，2.90(dd，J＝4.2，11.7Hz，1H)，2.41(s，3H)，2.35(m，2H)，2.06(m，2H)，1.85(m，2H)，1.65(m，2H)，1.48(s，9H)，1.45(s，6H)，1.36(m，9H).

Example 95

6-acetyl-8-cyclopentyl-2- (3, 5-dimethyl-piperazin-1-pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

4- {6- [ 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl) -2, 2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.250g, 0.414mmol) was dissolved in dichloromethane (3ml), 2N HCl (3ml) was added thereto, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the solid was dried in a vacuum oven at 50 ℃ for 24H to give 6-acetyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.120g, 38.1%).

¹H NMRδ(400MHz，DMSO-d₆)9.51(m，2H)，9.0(m，1H)，8.97(s，1H)，8.08(d，J＝2.7Hz，1H)，7.84(d，J＝9.3Hz，1H)，7.78(m，1H)，5.80(m，1H)，3.35(d，J＝11.5Hz，2H)，3.35(m，2H)，2.75(dd，J＝12.2，2H)，2.40(s，3H)，2.30(s，3H)，2.19(m，2H),1.88(m，2H)，1.76(m，2H)，1.57(m，2H)，1.29(d，J＝6.6Hz，6H).MS(APCI)；M⁺+1: calc'd, 476.3, Found 476.1. calculated values of elemental analysis: c₂₆H₃₃N₇O₂ 2.70 HCl，0.10 H₂O：C，54.23，H，6.28，N，17.03.Found：C，54.60；H，6.68；N，16.57.

Example 96

4- (6-Nitro-pyridin-3-yl) -morpholine

5-bromo-2-nitropyridine (5.41g, 25.3mmol), tetra-n-butylammonium iodide (0.467g, 1.27mmol), morpholine (2.43g, 27.9mmol) and potassium carbonate (3.85g, 27.9mmol) were mixed in DMSO (50 ml). The mixture was warmed to 80 ℃ for 15 hours. The reaction mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with water and then the solvent was evaporated. The residue was then triturated with a dichloromethane/hexane mixture to give 4- (6-nitro-pyridin-3-yl) -morpholine as brown needles (2.90g, 54.8%).

¹HNMRδ(400MHz，CDCl₃)8.16(m，1H)，7.97(d，J＝2.9Hz，1H)，7.15(dd，J＝3.2，9.3Hz，1H)，3.45(m，4H)，1.72(m，4H).

Example 97

5-morpholin-4-yl-pyridin-2-ylamine

4- (6-Nitro-pyridin-3-yl) -morpholine (2.86g, 13.7mmol) was dissolved in THF (100ml), to which Raney nickel (1.03g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 5-morpholin-4-yl-pyridin-2-ylamine as a violet solid (1.91g, 78.0%).

¹H NMRδ(400MHz，CDCl₃)7.76(d，J＝2.0Hz，1H)，7.16(dd，J＝2.7，8.8Hz，1H)，6.50(d，J＝8.8Hz，1H)，4.24(s，2H)，3.84(m，4H)，3.16(m，4H)，3.01(m，4H).

Example 98

6-bromo-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.70mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.668g, 3.73mmol) were heated to reflux in toluene (10ml) for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with toluene (3X 10ml) on the funnel. The resulting solid was re-refluxed in ethyl acetate (15ml), cooled, filtered to give 6-bromo-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as a dark brown-gray solid (0.350g, 26.7%).

¹H NMRδ(400MHz，CDCl₃)8.78(s，1H)，8.17(d，J＝9.0Hz，1H)，8.02(d，J＝2.7Hz，1H)，7.97(s，1H)，7.32(dd，J＝2.9，9.0Hz，1H)，5.99(m，1H)，3.89(m，4H)，3.16(m，4H)，2.61(s，3H)，2.30(m，2H)，2.10(m，2H)，1.88(m，2H)，1.68(m，2H).

Example 99

8-cyclopentyl-6- (1-1-ethoxy-vinyl) -5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (0.290g, 0.597mmol), tetrakis (triphenylphosphine) palladium (0.083g, 0.072mmol) and tributyl- (1-ethoxy-vinyl) -stannane (0.336g, 0.932mmol) were dissolved in toluene (4ml) and heated slowly to reflux for 3 hours. The reaction mixture was purified by silica gel chromatography to give 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as a yellow solid (0.110g, 38.6%).

¹H NMRδ(400MHz， DMSO-d₆)8.95(s，1H)，8.83(s，1H)，8.02(d，J＝2.9Hz，1H)，7.86(d，J＝9.0Hz，1H)，7.44(dd，J＝3.2，9.3Hz，1H)，5.79(m，1H)，4.42(d，J＝2.0Hz，1H)，4.01(d，J＝2.0Hz，1H)，3.79(q，J＝6.8Hz，2H)，3.72(m，4H)，3.09(m，4H)，2.34(s，3H)，2.17(m，2H)，1.85(m，2H)，1.71(m，2H)，1.55(m，2H)，1.21(m，3H).

Example 100

6-acetyl-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one (0.490g, 1.03mmol) was dissolved in dichloromethane (5 ml). A2N HCl in ether (3ml) was added, and the resulting mixture was stirred at room temperature for 4 hours. Then, another 2N HCl in ether solution (2ml) was added and the mixture was stirred for another 12 hours. The reaction mixture was washed with dichloromethane and aqueous NaHCO₃And (6) diluting. Separating the layers, passing the organic layer over MgSO₄Drying, filtration and evaporation of the solvent gave a yellow solid. Recrystallizing the solid from a mixture of hexane, ethyl acetate and dichloromethane to give 6-acetyl-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid (0.280g, 60.7%). Ms (apci); m⁺+1: calculated value, 449.2, found 449.2.

¹H NMRδ(400MHz，DMSO-d₆)8.79(s，1H)，8.17(d，J＝9.0Hz，1H)，8.02(d，J＝2.7Hz，1H)，7.31(dd，J＝2.9，9.0Hz，1H)，5.86(m，1H)，3.88(m，4H)，3.15(m，4H)，2.54(s，3H)，2.36(s，3H)，2.32(m，2H)，2.05(m，2H)，1.87(m，2H)，1.68(m，2H).

Example 101

6 '-Nitro-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridinyl

5-bromo-2-nitropyridine (5.6g, 27.6mmol), tetra-n-butylammonium iodide (0.510g, 1.38mmol), piperidine (2.58g, 30.3mmol) and potassium carbonate (3.85g, 30.3mmol) were mixed in DMSO (50 ml). The reaction mixture was warmed to 80 ℃ for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered. The volume was reduced to remove ethyl acetate and the remaining solution was diluted with water (50 ml). A precipitate formed immediately and was collected by filtration and washed with water on the funnel to give 6 '-nitro-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridinyl as an orange-brown solid (4.90g, 85.7%).

¹H NMRδ(400MHz，CDCl₃)7.76(s，1H)，7.15(d，J＝7.3Hz，1H)，6.49(d，J＝8.5Hz，1H)，3.84(m，5H)，3.00(m，4H)，2.60(s，1H).

Example 102

3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamine

6 '-Nitro-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridinyl (4.69g, 22.6mmol) was dissolved in THF (100ml), and Raney nickel (1.08g) was added thereto. The reaction was shaken under a hydrogen atmosphere (50psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamine as a purple solid (4.86g, 85.7%).

¹H NMRδ(400MHz，CDCl₃)7.76(d，J＝2.4Hz，1H)，7.19(dd，J＝2.9，8.8Hz，1H)，6.47(dd，J＝0.7，8.8Hz，1H)，4.18(s.2H)，2.97(m，4H)，1.71(m，4H)，1.53(m，2H).

Example 103

6-bromo-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.70mmol) and 3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamine (0.668g, 3.73mmol) were heated to reflux in toluene (10ml) for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate collected by filtration and washed with toluene (3X 10ml) on a funnel to give 6-bromo-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as a brown solid (0.358g, 27.3%).

¹HNMRδ(400MHz，CDCl₃)8.79(s，1H)，8.27(s，1H)，8.17(d，J＝9.0Hz，1H)，8.01(s，1H)，7.38(d，J＝6.8Hz，1H)，5.98(m，1H)，3.1(m，4H)，2.60(s，3H)，2.30(m，2H)，2.11(m，2H)，1.88(m，2H)，1.57-1.75(m，8H).

Example 104

8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-5-methyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (0.310g, 0.641mmol), tetrakis (triphenylphosphine) palladium (0.089g, 0.077mmol) and tributyl- (1-ethoxy-vinyl) -stannane (0.361g, 1.0mmol) were dissolved in toluene (3ml) and slowly heated to reflux for 2 hours. The reaction mixture was allowed to cool and then purified by silica gel chromatography to give 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as a yellow solid (0.180mg, 59.2%).

¹H NMRδvvv(400MHz，CDCl₃)8.73(s，1H)，8.16(d，J＝9.0Hz，1H)，8.05(s，1H)，8.01(d，J＝2.9Hz，1H)，7.36(dd，J＝2.9，9.3Hz，1H)，5.90(m，1H)，4.52(d，J＝2.4Hz，1H)，4.18(d，J＝2.2Hz，1H)，3.93(q，J＝7.1Hz，2H)，3.14(m，4H)，2.41(s，3H)，2.36(m，2H)，2.06(m，2H)，1.84(m，2H)，1.56-1.77(m，8H)，1.21(t，J＝7.1Hz，3H).

Example 105

6-acetyl-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Mixing 8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3']Bipyridin-6' -ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one (0.180g, 0.379mmol) was dissolved in ethyl acetate (10ml), and added6N HCl (10ml) and the mixture was then stirred at room temperature for 2 h. The mixture was washed with dichloromethane and aqueous NaHCO₃And (6) diluting. Separating the layers, passing the organic layer over MgSO₄Drying, filtering and evaporating the solvent to obtain 6-acetyl-8-cyclopentyl-5-methyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3']Bipyridin-6' -ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one as a yellow solid (0.120g, 71.0%).

¹H NMRδ(400MHz，CDCl₃)8.78(s，1H)，8.20(d，J＝8.5Hz，1H)，7.95(s，1H)，7.39(m，1H)，5.85(m，1H)，3.15(m，4H)，2.53(s，3H)，2.36(s，3H)，2.33(m，2H)，2.05(m，2H)，1.87(m，2H)，1.77-1.56(m，8H).MS(APCI)；M⁺+1: calc'd, 447.2, Found 447.2. calculated values of elemental analysis: c₂₅H₃₀N₆O₂0.35H₂O：C，66.31；H，6.83；N，18.56.Found：C，66.68；H，6.76；N，18.07.

Example 106

8-cyclopentyl-6- (2-ethoxy-ethyl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one

To a cooled (-78 deg.C) solution of ethyl 4-ethoxy-butyrate (9.85g, 61.47mmol) in THF (25ml) was added lithium bis (trimethylsilyl) amide (77.0ml, 76.85 mmol, 1MTHF solution). The reaction mixture was stirred for 10 minutes to form an anion. 4-Cyclopentamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethyl acetate (150ml total), and the organic layers were combined and concentrated to give a yellow oil. Purification by silica gel chromatography (chloroform/ethyl acetate gradient) afforded 8-cyclopentyl-6- (2-ethoxy-ethyl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (3.22g, 9.65 mmol).

MS(APCI+)334(M+1，100)；¹H NMRδ(400MHz，DMSO-_d6)8.54(s，1H)，7.47-7.46(m，1H)，5.99-5.90(m，1H)，3.69(t，J＝6.25Hz，2H)，3.49(q，J＝7.03Hz，2H)，2.84(t，J＝6.25Hz，2H)，2.59(s，3H)，2.34-2.29(m，2H)，2.08-2.02(m，2H)，1.88-1.83(m，2H)，1.69-1.65(m，3H)，1.17(t，J＝7.04Hz，3H).

Example 107

4- {6- [ 8-cyclopentyl-6- (2-ethoxy-ethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

8-cyclopentyl-6- (2-ethoxy-ethyl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.86mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylate (1.10g, 3.95mmol) were heated to reflux in toluene (10ml) for 16H. The mixture was cooled to room temperature and purified by silica gel chromatography to give 4- {6- [ 8-cyclopentyl-6- (2-ethoxy-ethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester as an orange solid (0.328g, 20.4%).

¹H NMRδ(400MHz，CDCl₃)8.54(s，1H)，8.26(d，J＝9.0Hz，1H)，7.98(d，J＝2.9Hz，1H)，7.45(s，1H)，7.38(dd，J＝2.9，9.3Hz，1H)，5.90(m，1H)，3.70(t，J＝6.3，1H)，3.61(m，4H)，3.51(q，J＝7.1，1H)，3.11(m，4H)，2.84(t，J＝5.9，1H)，2.33(m，2H)，2.08(m，2H)，1.87(m，2H)，1.69(m，2H)，1.48(s，9H)，1.19(t，J＝7.1，1H).

Example 108

8-cyclopentyl-6- (2-ethoxy-ethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- {6- [ 8-cyclopentyl-6- (2-ethoxy-ethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (0.325g, 0.577mmol) was dissolved in dichloromethane (4 ml). A2N HCl in ether (4ml) was added, and the mixture was stirred at room temperature for 18 hours. Evaporation of the solvent gave 8-cyclopentyl-6- (2-ethoxy-ethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.292g, 97.7%). Ms (apci) calculated for M + H: 449.2. measured value: 449.2.

theoretical value of elemental analysis: c₂₅H₃₃N₇O₂2.6HCl，0.35H₂O：C，52.26；H，6.56；N，16.88.Found：C，52.01；H，6.96；N，16.88.

Example 109

8-cyclopentyl-6- (2-methoxy-ethyl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.33g, 3.75mmol) was dissolved in 2-methoxyethanol (10ml), potassium carbonate (0.778g, 5.63mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the salts were washed with ethyl acetate. The organic phases were combined and evaporated to give 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a waxy solid (1.00g, 76.3%).

¹H NMRδ(400MHz，CDCl₃)8.60(s，1H)，7.71(t，J＝1.6Hz，1H)，5.95(m，1H)，4.52(d，J＝1.6Hz，1H)，3.76(m，2H)，3.63(m，2H)，3.41(s，3H)，2.60(s，3H)，2.32(m，2H)，2.06(m，2H)，1.87(m，2H)，1.68(m，2H).

Example 110

8-cyclopentyl-2-methanesulfinyl-6- (2-methoxy-ethoxymethyl) -8H-pyrido [2,3-d ] pyrimidin-7-one

8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.46g, 4.18mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.31g, 5.01mmol) were dissolved in dichloromethane (10ml) and stirred at ambient temperature for 12H. The reaction mixture was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6- (2-methoxy-ethoxymethyl) -8H-pyrido [2,3-d ] pyrimidin-7-one as a white waxy solid (0.60g, 39.3%).

¹H NMRδ(400MHz，CDCl₃)8.94(s，1H)，7.88(t，J＝1.7Hz，1H)，5.95(m，1H)，4.52(d，J＝1.7Hz，1H)，3.80(m，2H)，3.65(m，2H)，3.43(s，3H)，2.98(s，3H)，2.25(m，2H)，2.13(m，2H)，1.94(m，2H)，1.70(m，2H).

Example 111

4- {6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester

8-cyclopentyl-2-methanesulfinyl-6- (2-methoxy-ethoxymethyl) -8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.86mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylate (1.10g, 3.95mmol) were heated to reflux in toluene (10ml) for 16H. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4- {6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140g, 14.7%).

¹H NMRδ(400MHz，CDCl₃)8.60(s，1H)，8.34(m，1H)，7.95(s，1H)，7.69(t，J＝1.4Hz，1H)，7.42(m，1H)，5.91(m，1H)，4.53(d，J＝1.2Hz，1H)，3.78(m，1H)，3.63(m，6H)，3.43(s，3H)，3.11(m，4H)，2.35(m，2H)，2.08(m，2H)，1.88(m，2H)，1.69(m，2H)，1.48(s，9H).

Example 112

8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- {6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d]Pyrimidin-2-ylamino]-pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (0.140g, 0.242mmol) was dissolved in dichloromethane (2 ml). By addition of 2N HClEther solution (2ml) and the reaction mixture was stirred at room temperature for 18 h. Evaporation of the solvent afforded 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Pyrimidin-7-one hydrochloride as a yellow solid (0.116g, 85.9%). Ms (apci); m⁺+1: calculated, 480.3, found 480.2.

Theoretical value of elemental analysis: c₂₅H₃₃N₇O₂2.16HCl：C，53.78；H，6.35；N，17.56.Found；C，54.03；H，6.64；N，17.17.

Example 113

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

3-ethoxy-propionic acid ethyl ester (12.31g, 84.2mmol) was dissolved in tetrahydrofuran (40ml), to which LiHMDS (89ml, 88.9mmol, 1.0M in THF) was slowly added. Neat 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0g, 42.2mmol) was then added and the reaction mixture stirred at ambient temperature for 17 hours and then heated to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers were separated and the organic layer was MgSO₄Drying and evaporating the solvent to obtain crude oil. Dissolving the crude product in ethyl acetate, diluting with hexane to obtain precipitate, filtering, and collecting to obtain 8-cyclopentyl-6-ethoxymethyl-2-methylthio-8H-pyrido [2,3-d ]]Pyrimidin-7-one as an off-white solid (4.70g, 34.9%).

¹H NMRδ(400MHz，CDCl₃)8.47(s，1H)，7.52(t，J＝1.5Hz，1H)，5.82(m，1H)，4.32(d，J＝1.7Hz，1H)，3.53(q，J＝7.1Hz，2H)，2.47(s，3H)，2.17(m，2H)，1.93(m，2H)，1.73(m，2H)，1.54(m，2H)，1.15(t，J＝7.1Hz，3H).

Example 114

8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one

8-cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4.60g, 14.40mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.89g, 18.72mmol) were dissolved in dichloromethane (30ml) and stirred at ambient temperature for 12 hours. The crude product was then purified by silica gel chromatography to give 8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a white waxy solid (2.67g, 55.3%).

¹H NMRδ(400MHz，CDCl₃)8.94(s，1H)，7.81(t，J＝1.7Hz，1H)，5.98(m，1H)，4.50(d，J＝1.7Hz，1H)，3.68(q，J＝7.1Hz，2H)，2.96(s，3H)，2.22(m，2H)，2.12(m，2H)，1.94(m，2H)，1.69(m，2H)，1.31(t，J＝7.1Hz，3H).

Example 115

4- [6- (8-cyclopentyl-6-ethoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.86mmol) and 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (1.10g, 3.95mmol) were heated to reflux in toluene (10ml) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4- [6- (8-cyclopentyl-6-ethoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140g, 14.7%).

¹H NMRδ(400MHz，CDCl₃)8.59(s，1H)，8.26(d，J＝9.3Hz，1H)，7.97(d，J＝2.7Hz，1H)，7.6(t，J＝1.5Hz，1H)，7.38(dd，J＝2.7，9.0Hz，1H)，5.89(m，1H)，4.55(d，J＝1.2 Hz，1H)，3.66(q，J＝7.1Hz，2H)，3.60(m，4H)，3.11(m，4H)，2.34(m，2H)，2.07(m，2H)，1.88(m，2H)，1.69(m，2H)，1.48(s，9H)，1.30(t，J＝6.8Hz，3H).

Example 116

8-cyclopentyl-6-ethoxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- [6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (0.140g, 0.242mmol) was dissolved in dichloromethane (2 ml). A2N HCl in ether (2ml) was added and the reaction mixture was stirred at room temperature for 18 h. Evaporation of the solvent gave 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one as a yellow solid (0.116g, 85.9%). Ms (apci) calculated for M + 1: 450.3. measured value: 450.1.

¹H NMRδ(400MHz，DMSO-d₆)9.12(s，2H)，8.34(s，1H)，8.01(d，J＝2.7Hz，1H)，7.86(s，1H)，7.83(s，1H)，7.76(d，J＝9.5Hz，1H)，5.84(m，1H)，4.32(d，J＝1.2Hz，1H)，3.57(q，J＝6.8Hz，2H)，3.38(m，4H)，3.23(m，4H)，2.26(m，2H)，1.89(m，2H)，1.75(m，2H)，1.58(m，2H)，1.19(t，J＝6.8Hz，3H).

example 117

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

Methyl 3-methoxy-propionate (9.95g, 84.2mmol) was dissolved in tetrahydrofuran (40ml) and LiHMDS (89ml, 88.9mmol, 1.0M in THF) was slowly added thereto. Neat 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0g, 42.2mmol) was then added and the reaction mixture was heated to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers were separated and the organic layer was MgSO₄Drying and evaporating the solvent to obtain crude oil. Dissolving the crude product in ethyl acetate, diluting with hexane to obtain precipitate, filtering, and collecting to obtain 8-cyclopentyl-6-methoxymethyl-2-methylthio-8H-pyrido [2,3-d ]]Pyrimidin-7-one as an off-white solid (3.11g, 24.1%).

¹H NMRδ(400MHz，CDCl₃)8.46(s，1H)，7.49(t，J＝1.7Hz，1H)，5.81(m，1H)，4.28(d，J＝1.7Hz，1H)，3.37(s，3H)，2.47(s，3H)，2.18(m，2H)，1.93(m，2H)，1.73(m，2H)，1.55(m，2H).

Example 118

8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one

8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4.44g, 14.54mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.94g, 18.90mmol) were dissolved in dichloromethane (100ml) and stirred at ambient temperature for 12 hours. The solvent volume was reduced to about 50ml and then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one as an off-white solid (2.51g, 53.7%).

¹H NMRδ(400MHz，CDCl₃)8.93(s，1H)，7.78(t，J＝1.7Hz，1H)，5.99(m，1H)，4.46(d，J＝1.7Hz，1H)，3.53(s，3H)，2.96(s，3H)，2.23(m，2H)，2.12(m，2H)，1.93(m，2H)，1.69(m，2H).

Example 119

4- [6- (8-cyclopentyl-6-methoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester

8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido [2,3-d ] pyrimidin-7-one (2.5g, 7.78mmol) and tert-butyl 4- (6-amino-pyridin-3-yl) -piperazine-1-carboxylate (2.99g, 10.73mmol) were heated in toluene (25ml) to reflux for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4- [6- (8-cyclopentyl-6-methoxymethyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino) -pyridin-3-yl ] -piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.24g, 30.5%).

¹H NMRδ(400MHz，CDCl₃)8.59(s，1H)，8.26(d，J＝9.3Hz，1H)，7.97(d，J＝2.7Hz，1H)，7.6(t，J＝1.5Hz，1H)，7.38(dd，J＝2.7，9.0Hz，1H)，5.89(m，1H)，4.55(d，J＝1.2Hz，1H)，3.66(q，J＝7.1Hz，2H)，3.60(m，4H)，3.11(m，4H)，2.34(m，2H)，2.07(m，2H)，1.88(m，2H)，1.69(m，2H)，1.48(s，9H)，1.30(t，J＝6.8Hz，3H).

Example 120

8-cyclopentyl-6-methoxymethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

4- (6- [ 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (0.110g, 0.205mmol) was dissolved in dichloromethane (2ml) 2N HCl in ether solution (2ml) was added, the reaction mixture was stirred at room temperature for 18 hours and the solvent was evaporated to give 8-cyclopentyl-6- (2-methoxy-ethoxymethyl) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride as a yellow solid (0.096g, 92.1%). Ms (apci) calculated for M + 1: 450.3. measured value: 450.1.

example 121

2, 6-dimethyl-4- (6-nitro-pyridin-3-yl) -morpholine

5-bromo-2-nitropyridine (4.84g, 23.84mmol), tetra-n-butylammonium iodide (0.440g, 1.19mmol), 2, 6-dimethyl-morpholine (3.02g, 26.22mmol) and potassium carbonate (3.62g, 26.22mmol) were mixed in DMSO (45 ml). The reaction mixture was warmed to 80 ℃ for 6 hours. The reaction mixture was diluted with ethyl acetate and filtered. The volume of the filtrate was reduced to remove ethyl acetate and the remaining solution was diluted with water (50 ml). A precipitate formed immediately, which was collected by filtration and then washed with water on the funnel to give 2, 6-dimethyl-4- (6-nitro-pyridin-3-yl) -morpholine as an orange solid (4.39g, 78.0%).

¹H NMRδ(400MHz，CDCl₃)8.16(d，J＝9.0Hz，1H)，8.11(d，J＝2.9Hz，1H)，7.19(dd，J＝2.9，9.3Hz，1H)，3.77(m，2H)，3.65(dd，J＝2.2，12.9Hz，2H)，2.66(dd，J＝10.7，12.5Hz，2H)，1.29(d，J＝6.4Hz，6H).

Example 122

5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamine

2, 6-dimethyl-4- (6-nitro-pyridin-3-yl) -morpholine (4.00g, 16.86mmol) was dissolved in THF (100ml) and Raney nickel (3.10g) was added thereto. The reaction mixture was shaken under a hydrogen atmosphere (50psi) for 4 hours. The catalyst was filtered and the solvent evaporated to give 5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamine as a violet solid (3.05g, 87.4%).

¹H NMRδ(400MHz，CDCl₃)7.74(d，J＝2.4Hz，1H)，7.16(dd，J＝2.9，8.8Hz，1H)，6.49(dd，J＝0.7，8.8Hz，1H)，3.79(m，2H)，2.34(dd，J＝10.5，10.5，2H)，1.22(d，J＝6.3Hz，6H).

Example 123

6-bromo-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.0g, 2.70mmol) and 5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamine (0.668g, 3.73mmol) were heated to reflux in toluene (10ml) for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate collected by filtration and washed with toluene (3 × 10ml) on the funnel to give 6-bromo-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a brown solid (0.358g, 27.3%). Ms (apci) calculated for M + 1: 513.2. measured value: 513.1.

calculated values of elemental analysis: c₂₄H₂₉BrN₆O₂：C，56.14；H，5.69；N，16.37.Found；C，55.90；H，5.62；N，16.10.

Example 124

8-cyclopentyl-6-ethoxymethyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.60g, 1.79mmol) and 3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamine (0.438g, 2.47mmol) were heated to reflux in toluene (6ml) for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off and washed with toluene (2X 4ml) to give 8-cyclopentyl-6-ethoxymethyl-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (0.122g, 15.2%). Ms (apci) calculated for M + 1: 449.3. measured value: 449.3.

calculated values of elemental analysis: c₂₅H₃₂N₆O₂：C，66.94；H，7.19；N，18.74.Found：C.66.72；H，7.13；N，18.57.

Example 125

8-cyclopentyl-6-ethoxymethyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.60g, 1.79mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.442g, 2.47mmol) were heated to reflux in toluene (6ml) for 16 h. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off and washed with toluene (2X 4ml) to give 8-cyclopentyl-6-ethoxymethyl-2- (5-morpholin-4-yl-pyridin-2-ylamino) -8H-pir-inylPyrido [2,3-d]Pyrimidin-7-one (0.142g, 17.6%). Ms (apci); m⁺+1: calculated value, 451.3, found 451.3.

Calculated values of elemental analysis: c₂₅H₃₂N₆O₂：C，63.98；H，6.71；N，18.65.Found；C，64.03；H，6.66；N，18.49.

Example 126

(8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl) -carbamic acid benzyl ester

3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68g, 26.58mmol) was dissolved in tetrahydrofuran (40ml), to which LiHMDS (28ml, 28mmol, 1.0M THF solution) was slowly added. Neat 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15g, 13.29mmol) was then added and the reaction mixture heated to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers were separated and the organic layer was MgSO₄Drying and evaporating the solvent to obtain crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2, 3-d)]Pyrimidin-6-ylmethyl) -carbamic acid benzyl ester as a light yellow waxy solid (1.67g, 29.6%).

¹H NMRδ(400MHz，CDCl₃)8.57(s，1H)，7.56(s，1H)，7.26-7.36(m，5H)，5.93(m，1H)，5.56(t，J＝6.1Hz，1H)，5.08(s，2H)，4.25(d，J＝6.2Hz，2H)，2.60(s，3H)，2.30(m，2H)，2.05(m，2H)，1.86(m，2H)，1.69(m，2H).

Example 127

(8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl) -carbamic acid benzyl ester

Benzyl (8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl) -carbamate (1.67g, 3.93mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (l.34g, 5.11mmol) were dissolved in diaminomethane (20ml) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give benzyl (8-cyclopentyl-2-methanesulfinyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl) -carbamate as a white solid (0.98g, 56.6%).

¹H NMRδ(400MHz，CDCl₃)8.89(s，1H)，7.68(s，1H)，7.32(m，5H)，5.96(m，1H)，5.52(t，J＝6.4Hz，1H)，5.09(s，2H)，4.32(d，J＝6.3Hz，2H)，2.95(s，3H)，2.22(m，2H)，2.12(m，2H)，1.95(m，2H)，1.69(m，2H).

Example 128

[ 8-cyclopentyl-7-oxo-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl ] -carbamic acid benzyl ester

8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.90g, 2.04mmol) and 3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamine (0.497g, 2.82mmol) were heated to reflux in toluene (10ml) for 16H. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off and washed with toluene (2X 4ml) to give benzyl [ 8-cyclopentyl-7-oxo-2- (3, 4, 5, 6-tetrahydro-2H- [1, 3 '] bipyridinyl-6' -ylamino) -7, 8-dihydro-pyrido [2,3-d ] pyrimidin-6-ylmethyl ] -carbamate (0.320g, 28.3%).

¹H NMRδ(400MHz，CDCl₃)8.55(s，1H)，8.12(d，J＝9.0Hz，1H)，8.03(d，J＝2.9Hz，1H)，7.95(s，1H)，7.54(s，1H)，7.27-7.35(m，5H)，5.88(m，1H)，5.62(t，J＝6.1Hz，1H)，5.09(s，2H)，4.25(d，J＝6.4Hz，2H)，2.34(m，2H)，2.04(m，2H)，1.88(m，2H)，1.71(m，5H)，1.60(m，3H).

Example 129

8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -6- (1-ethoxy-vinyl) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

6-bromo-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.062g, 0.121mmol), tetrakis (triphenylphosphine) palladium (0.017g, 0.015mmol) and tributyl- (1-ethoxy-vinyl) -stannane (0.068mg, 0.188mmol) were dissolved in toluene (2ml) and heated slowly to reflux for 12 hours. Additional tetrakis (triphenylphosphine) palladium (0.010g) was added and the reaction heated to reflux for 16 h. The reaction mixture was cooled and purified by silica gel chromatography to give 8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -6- (1-ethoxy-vinyl) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a yellow solid (0.055g, 90.2%).

¹H NMRδ(400MHz，CDCl₃)8.72(s，1H)，8.17(d，J＝9.0Hz，1H)，7.99(d，J＝2.9Hz，1H)，7.83(s，1H)，7.29(dd，J＝2.9，9.0Hz，1H)，5.89(m，1H)，4.51(d，J＝2.5Hz，1H)，4.17(d，J＝2.4Hz，1H)，3.93(q，J＝7.1Hz，2H)，3.83(m，2H)，3.37(d，J＝10.3Hz，2H)，2.44(dd，J＝10.5，10.5，2H)，2.41(s，3H)，2.34(m，2H)，2.06(m，2H)，1.84(m，2H)，1.65(m，2H)，1.36(t，J＝7.1Hz，3H)，1.26(d，J＝6.4Hz，6H).

Example 130

6-acetyl-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino]-6- (1-ethoxy-vinyl) -5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.055g, 0.109mmol) was dissolved in ethyl acetate (3ml) and 1N aqueous HCl (2ml) and stirred at room temperature for 48 hours. The reaction mixture was washed with dichloromethane and aqueous NaHCO₃And (6) diluting. Separating the layers, passing the organic layer over MgSO₄Drying, filtering and evaporating the solvent to obtain 6-acetyl-8-cyclopentyl-2- [5- (2, 6-dimethyl-morpholin-4-yl) -pyridin-2-ylamino]-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (0.020g, 38.4%). MS (APCI) M +1 calculationThe value: 477.3. measured value: 477.2.

¹HNMRδ(400MHz，CDCl₃)8.79(s，1H)，8.1(d，J＝9.0Hz，1H)，8.00(d，J＝2.7Hz，1H)，7.90(s，1H)，7.30(dd，J＝3.1，9.3Hz，1H)，5.87(m，1H)，3.83(m，2H)，3.37(d，J＝10.0Hz，2H)，2.54(s，3H)，2.46(dd，J＝11.7，11.7，2H)，2.37(s，3H)，2.32(m，2H)，2.05(m，2H)，1.87(m，2H)，1.68(m，2H)，1.27(d，J＝6.4Hz，6H).

example 131

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

Ethyl 2- (diethoxy-phosphoryl) -propionate (15.24g, 64mmol) was dissolved in tetrahydrofuran (100ml) and n-butyllithium (47.7ml, 119mmol, 2.5M in hexane) was slowly added thereto at-70 ℃. 4-Cyclopentamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (15g, 63mmol) was dissolved in tetrahydrofuran (70ml) and added to the reaction mixture, and the reaction was allowed to warm to-40 ℃. After 3 hours, the reaction was allowed to warm to room temperature, poured into cold 1N citric acid and extracted with ether. The organic layer was washed with brine, over MgSO₄Drying, filtering and concentrating to obtain yellow oil, and purifying by silica gel chromatography. Dissolving the obtained oil in 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (75ml) was heated to 150 ℃ for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (350ml), washed with 5% HCl and brine, and then over MgSO₄Dried, then filtered and concentrated in vacuo. The remaining residue was diluted with ether and the precipitated solid was filtered off to give 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido [2,3-d]Pyrimidin-7-one as a white solid (6.33g, 31.3%).

¹H NMRδ(400MHz，CDCl₃)8.52(s，1H)，7.39(d，J＝1.2Hz.1H)，5.96，(m，1H)，2.59(s，3H)，2.30(m，2H)，2.19(d，J＝1.2Hz，3H)，2.07(m，2H)，1.86(m，2H)，1.67(m，2H).

Example 132

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

8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (2.56g, 9.30mmol) was dissolved in dichloromethane (17ml) and methyl (17ml), 2-benzenesulfonyl-3-phenyl-oxaziridine was added thereto, and the reaction mixture was stirred for 16 hours. The solvent was removed and diethyl ether was added. The precipitated solid was collected by filtration to give 8-cyclopentyl-2-methanesulfinyl-6-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one as a white solid (2.30g, 84.8%).

¹H NMRδ(400MHz，CDCl₃)8.85(s，1H)，7.54(s，1H)，5.99，(m，1H)，2.95(s，3H)，2.27(d，J＝1.2Hz，3H)，2.24(m，2H)，2.13(m，2H)，1.94(m，2H)，1.70(m，2H).

Example 133

6-bromo-8-cyclopentyl-2- (4-methoxy-benzylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

A suspension of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.00g, 2.70mmol) and 4-methoxybenzylamine (0.39ml, 4.0mmol) in toluene (15ml) was heated at reflux for 2 hours. The solution was cooled and the resulting solid collected by filtration to give 6-bromo-8-cyclopentyl-2- (4-methoxy-benzylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1.04g, 86.4%).

¹H NMRδ(400MHz，CDCl₃)1.6(m，2H)，1.8(m，2H)，2.0(m，2H)，2.2(m，2H)，2.53(s，3H)，3.79 (s，3H)，4.59(m，2H)，5.96(m，1H)，6.1(m，1H)，6.86(d，J＝8.3Hz，2H)，7.27(d，J＝8.1Hz，2H)，8.5(br s，1H).MS(APCI)(C₂₁H₂₃Br₁N₄O₂)：Calc for M+H，443.1；Found，443.1

Example 134

8-cyclopentyl-6- (1-ethoxy-vinyl-2- (4-methoxy-benzylamino)) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

A suspension of 6-bromo-8-cyclopentyl-2- (4-methoxy-benzylamino) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.44g, 1.0mmol), tributyl (1-ethoxyvinyl) tin (0.53ml, 1.6mmol), and tetrakis (triphenylphosphine) palladium (0) (0.14g, 0.12mmol) in toluene (5ml) was heated at reflux for 2 hours. The suspension was cooled to room temperature and filtered. The filtrate was concentrated and the residue triturated with hexane to give a solid. Chromatography on silica gel (5 to 50% ethyl acetate in hexane over 15 min) gave 8-cyclopentyl-6- (1-ethoxy-vinyl-2- (4-methoxy-benzylamino)) -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (0.35g, 81%).

¹H NMRδ(400MHz，CDCl₃)1.34(t，J＝7.1Hz，3H)，1.6(m，2H)，1.7(m，2H)，2.0(m，2H)，2.3(m，2H)，2.34(s，3H)，3.78(s，3H)，3.90(q，J＝7.0Hz，2H)，4.13(d，J＝2.2Hz，1H)，4.48(d，J＝2.2Hz，1H)，4.59(d，J＝5.4Hz，2H)，5.87(m，1H)，6.0(m，1H)，6.86(d，J＝8.6Hz，2H)，7.27(d，J＝8.6Hz，2H)，8.5(brs，1H).MS(APCI)(C₂₅H₃₀N₄O₃)Calc for M+H，435.2；Found，435.3.

Example 135

6-acetyl-2-amino-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one

Reacting 8-cyclopentyl-6- (1-ethoxy-vinyl-2- (4-methoxy-benzylamino) -5-methyl-8H-pyrido [2,3-d ]]A solution of pyrimidin-7-one (2.90g, 6.67mmol) in trifluoroacetic acid (50ml) was heated at reflux for 8 hours. After cooling, the solution was concentrated in vacuo and diluted with water. The resulting suspension was made alkaline with 1N NaOH and the solid was collected by filtration. Dissolving the solid in CH₂Cl₂Chromatographing on silica gel eluting with ethyl acetate to give 6-acetyl-2-amino-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d]Pyrimidin-7-one (1.51g, 79.1%).

mp182-186℃.¹H NMRδ(400MHz，CDCl₃)1.6(m，2H)，1.8(m，2H)，2.0(m，2H)，2.3(m，2H)，2.32(s，3H)，2.52(s，3H)，5.34(s，2H)，5.84(m，1H)，8.63(s，1H).MS(APCI)(C₁₅H₁₈N₄O₂)Calc for M+H，287.1；Found，287.1.

Example 136

Biological assay

To determine the inhibitory potency and selectivity of the compounds of the invention for Cdk4 and related kinases, the compounds were evaluated in standard assays commonly used to measure inhibition of cyclin-dependent kinases and other protein kinases (see, e.g., d.w.fry et al, j.biol.chem.2001, 276, 16617-. These assays were performed as follows.

Determination of Cdk 2/cyclin A inhibition

About IC₅₀Assay and kinetic evaluation the Cdk2 enzyme assay was performed as follows. 96-well filter plates (Millipore MADVN6550) were used. The final assay volume was 0.1ml, containing buffer A (20mM TRIS (TRIS [ hydroxymethyl ] methyl)]Aminomethane) (pH7.4), 50mM NaCl, 1mM dithiothreitol, 10mM MgCl₂)12 mM ATP (containing 0.25. mu. Ci 2²²P]ATP), 20ngCdk 2/cyclin A, l μ g of retinoblastoma protein, and buffer a dilutions of test compound at appropriate ratios (buffer a alone without test compound added was used as a control with no inhibitory effect. Determination of background in the absence of enzymatic Activity Using buffer A containing excess EDTA³²P level). All components except ATP were added to the wells and the plates were placed on a plate mixer for 2 minutes. Adding [ alpha ], [ alpha³²P]ATP initiates the reaction and the plate is incubated at 25 ℃ for 15 minutes. The reaction was stopped by adding 0.1ml of 20% TCA. The plate was kept at 4 ℃ for at least 1 hour so that the substrate precipitated. The wells were then washed 5 times with 0.2ml 10% TCA and measured using a beta plate counter (Wallac Inc., Gaithersburg, Md.)³²And (4) introducing P. Determination of IC of test Compounds Using the meso-position Effect method₅₀(Chou，T-C and Talalay，P.Applications of the median effect principle for the assessmentof low- dose risk of carcinogens and for the quantitation ofsynergism and antagonism of chemotherapeutic age

Determination of Cdk 4/cyclin D inhibition

About IC₅₀Assay and kinetic evaluation the Cdk4 enzyme assay was performed as follows. 96-well filter plates (Millipore MADVN6550) were used. The total volume was 0.1ml, and buffer A (20mM TRIS (TRIS [ hydroxymethyl ] methyl)]Aminomethane) (pH7.4), 50mM NaCl, 1mM dithiothreitol, 10mM MgCl₂) 25 μ MATP (containing 0.25 μ Ci [ alpha ], [ alpha³²P]ATP), 20ngCdk4, 1 μ g retinoblastoma protein, and appropriate ratio buffer a dilutions of test compound. Buffer a alone, without test compound added, was used as a control with no inhibition. Determination of background in the absence of enzymatic Activity Using buffer A containing excess EDTA³²P level. All components except ATP were added to the wells and the plates were placed on a plate mixer for 2 minutes. Adding [ alpha ], [ alpha³²P]ATP initiates the reaction and the plate is incubated at 25 ℃ for 15 minutes. The reaction was stopped by adding 0.1ml of 20% trichloroacetic acid (TCA). The plate was kept at 4 ℃ for at least 1 hour so that the substrate precipitated. The wells were then washed 5 times with 0.2ml 10% TCA, and measured using a beta plate counter (wallac Inc., Gaithersburg, Md.)³²And (3) binding of P. Determination of IC of test Compounds Using the meso-position Effect method₅₀(Chou，T-C and Talalay，P.Applications of the median effect principle for the assessmentof low-dose risk of carcinogens and for the quantitation ofsynergism and antagonism of chemotherapeutic agents.In：NewAvenues in Developmental Cancer Chemotherapy(Eds.Harrap，K.T.and Connors，T.A.)，pp.37-64.Academic Press，New York，1987)。

Measurement of FGFr inhibitory Effect

For the FGF receptor (FGFr) tyrosine kinase assay, use is made of96-well plates (100. mu.l/incubation/well), conditions were optimized to measure from [ gamma. ]³²P]32P incorporation of ATP into glutamate-tyrosine copolymer substrates. Briefly, 82.5. mu.l of incubation buffer B (25mM Hepes (pH7.0), 150mM NaCl, 0.1% Triton X-100, 0.2mM PMSF, 0.2mM Na3VO was added to each well₄，10mM MnCl₂) And 750. mu.g/ml poly (4: 1) glutamate-tyrosine followed by 2.5. mu.l buffer B dilution of the test compound and 5. mu.l of 7.5. mu.g/. mu.l FGFr solution. After incubation at 25 ℃ for 10min, 10ml of [ gamma ] was added to each well³²P]ATP (0.4. mu. Ci plus 50. mu. MATP) and the samples were incubated at 25 ℃ for another 10 minutes. The reaction was stopped by adding 100. mu.l of 30% trichloroacetic acid (TCA) containing 20mM sodium pyrophosphate and the product was precipitated on a glass fiber pad (Wallac). The filters were washed 3 times with 15% TCA containing 100mM sodium pyrophosphate and the radioactivity retained on the filters was counted in a Wallac 1250Betaplate reader. Nonspecific activity is defined as the radioactivity retained on the filter after incubation of the sample with buffer alone (without enzyme). Specific enzyme activity (enzyme plus buffer) is defined as total activity minus non-specific activity. The concentration of test compound that inhibits 50% of specific activity (IC) is determined based on the inhibition curve₅₀)。

The results of several comparative assays of the compounds of the invention with those disclosed in WO 98/33798 are shown in Table 1. For comparison, data for each example compound C2 phenylamino analog is also provided, where possible. These analogs differ from the example compounds in that the pyridyl ring nitrogen atom is replaced by CH, distinguished from the compounds of the invention by a superscript (e.g., the phenylamino analog of example compound 1 is represented as 1'). These C2-phenylaminopyridopyrimidinones were previously described in patent applications WO 98/33798 and WO 01/70741.

TABLE 1

Examples	Cdk4 IC50(μM)	Cdk2 IC50(μM)	FGFr IC50(μM)
				1’	0.21	0.021	2.98
1	0.145	5.01	＞5
				3’	0.002	0.043	0.08
3	0.016	6.052	1.032
				5’	0.001	0.142	0.086
5	0.019	NA	0.99
				7’	0.004	5.950	0.042
7	0.595	＞5	NA
				11’	0.005	0.095	0.088
11	0.012	NA	2.12
				12	0.175	NA	NA
13	＞5	NA	NA
				14	0.260	NA	NA
15’	0.005	0.439	1.74
				15	0.160	＞5	＞5
18’	0.015	0.139	NA
				18	0.051	＞5	NA
20’	0.002	0.059	0.153
				20	0.027	4.05	1.605

22’	0.009	3.149	NA
				22	1.70	＞5	＞5
24’	0.004	＞5	NA
				24	0.005	＞5	＞5

29’	NA	NA	NA
				29	0.013	＞5	4.38
31’	0.006	5	3.943
				31b	0.049	＞5	＞5
33’	0.006	0.556	0.535
				33	0.123	＞5	＞5
36’	0.006	0.233	1.83
				36	0.011	＞5	＞5
37’	NA	NA	NA
				37	＞5	＞5	＞5
38’	0.088	0.080	NA
				38	0.95	＞5	＞5
50	0.145	＞5	＞5
				51’	0.005	0.179	0.711
51	0.135	＞5	NA
				53’	0.018	＞5	0.94
53	0.036	＞5	＞5
				54	1.1	＞5	＞5
55	0.024	＞5	＞5

57’	0.014	0.084	＞5
				57	＞5	＞5	＞5
59’	0.006	0.024	0.081
				59	0.015	2.5	1.52
61’	0.006	0.119	4.35
				61	0.013	0.835	1.38
64	0.92	＞5	4.47
				65	0.430	3.30	＞5
66	0.763	＞5	0.515
				70	0.135	＞5	＞5
72	0.005	＞5
				74	0.014	＞5	＞5
75	0.074	＞5	＞5

77	0.019	＞5	＞5
				81	0.012	＞5	＞5
82	0.440	＞5	＞5
				84’	0.007	＞5	1.078
84	0.580	＞5	＞5
				88’	0.020	1.33	＞5
88
				90	0.021	＞5	＞5
93’	0.015	1.86	＞5
				93	0.063	＞5	＞5

95’	0.005	0.545	1.815
				95	0.037	＞5	＞5
98	1.95	＞5	＞5
				100	0.004	＞5	＞5
103	＞5	＞5	NA
				105	0.005	＞5	＞5
108’	0.007	0.205	0.136
				108	0.124	＞5	＞5
112	0.031	＞5	＞5
				116	0.018	＞5	＞5
120	0.013	3.800	2.470
				124	0.545	＞5	＞5
125	0.018	＞5	＞5
				130	0.030	＞5	＞5

Formulation examples

As noted above, the compounds of the present invention will generally be formulated in compositions with conventional excipients, diluents and carriers, suitable for administration to mammals. The following examples illustrate exemplary compositions, which are provided as further embodiments of the present invention.

Example 137

Tablet formulation

The compound of the present invention is mixed with lactose and corn starch (for mixing) and blended uniformly to obtain powder. Corn starch (for pasting) was suspended in 6m1 water and heated while stirring to form a paste. The paste was added to the mixed powder, and the mixture was granulated. The wet granules were passed through a No.8 hard sieve and dried at 50 ℃. The mixture was lubricated with 1% magnesium stearate and compressed into tablets. The tablets are administered to a patient at a frequency (rate) of 1 to 4 times per day for the prevention and treatment of cancer.

Example 138

Parenteral solution

To a solution of 700ml propylene glycol and 200m1 water for injection was added 20.0g of compound 36b according to the invention. The mixture was stirred and the pH adjusted to 5.5 with hydrochloric acid. The volume was adjusted to 1000ml with water for injection. The solution was sterilized and filled into 5.0ml ampoules, each containing 2.0ml (40mg of compound), sealed under nitrogen. The solution is administered by injection to a patient suffering from cancer and in need of treatment.

The invention and the manner and process of making and using it, have now been described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains to make and use the same. It will be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made thereto without departing from the spirit or scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

1. A compound selected from the group consisting of:

6-acetyl-8-cyclopentyl-2- (5- [1, 4] diazepan-1-yl-pyridin-2-ylamino } -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 3-dimethyl-piperazin-1-yl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -6-propionyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-bromo-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-sulfonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-2- [5- (3, 5-dimethyl-piperazine-1-sulfonyl) -pyridin-2-ylamino ] -5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-8-cyclopentyl-5-methyl-2- ([1, 6] naphthyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one,

6-acetyl-2- (3-chloro-5-piperazin-1-yl-pyridin-2-ylamino) -8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one, and

6-bromo-8-cyclopentyl-5-methyl-2- [5- (piperazine-1-sulfonyl) -pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one.

2. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 which is 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one.

4. Use of a compound of claim 1 in the manufacture of a medicament for treating a disorder or condition caused by abnormal cell proliferation in a mammal.

5. The use of claim 4, wherein the disorder or condition being treated is selected from the group consisting of vascular smooth muscle proliferation associated with atherosclerosis, post-operative vascular stenosis and restenosis, and endometriosis.

6. Use of a compound of claim 1 in the manufacture of a medicament for treating a disorder or condition caused by an infection in a mammal selected from the group consisting of: the infection is selected from the group consisting of viral infection and fungal infection, and the compound is administered to the mammal in an amount effective to treat such condition or disorder.

7. Use of a compound of claim 1 for the manufacture of a medicament for treating a disorder selected from the group consisting of: psoriasis, inflammation, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, organ transplant rejection, said compound being administered to said mammal in an amount effective to treat such disorders or diseases.

8. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of alzheimer's disease in a mammal to which said compound is administered in an amount effective to treat such disorder or disease.

9. Use of a compound of claim 4, wherein the abnormal cell proliferation is a cancer selected from the group consisting of: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx, lip, tongue, oral cavity, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hair cell carcinoma and leukemia.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutical carrier, diluent or excipient.

A pharmaceutically acceptable salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one.