[go: up one dir, main page]

MXPA02007221A - PYRIDO[2,3 d]PYRIMIDINE 2,7 DIAMINE KINASE INHIBITORS. - Google Patents

PYRIDO[2,3 d]PYRIMIDINE 2,7 DIAMINE KINASE INHIBITORS.

Info

Publication number
MXPA02007221A
MXPA02007221A MXPA02007221A MXPA02007221A MXPA02007221A MX PA02007221 A MXPA02007221 A MX PA02007221A MX PA02007221 A MXPA02007221 A MX PA02007221A MX PA02007221 A MXPA02007221 A MX PA02007221A MX PA02007221 A MXPA02007221 A MX PA02007221A
Authority
MX
Mexico
Prior art keywords
pyrimidin
pyrido
urea
piperazin
phenylamino
Prior art date
Application number
MXPA02007221A
Other languages
Spanish (es)
Inventor
Ellen Myra Dobrusin
Original Assignee
Warner Lambert Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co filed Critical Warner Lambert Co
Publication of MXPA02007221A publication Critical patent/MXPA02007221A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

Disclosed are compounds of the formula (I) wherein: R2, R7, R13, R14 and R15 are independently hydrogen, or (un)substituted lower alkyl, (un)substitued lower alkenyl, (un)substituted lower alkynyl, or (un)substituted (CH2)nR12; R5 is halogen, cyano, nitro, R9, NR9R10, or OR9; R6 is halogen, cyano, nitro, R9, NR9R10, OR9, Co2R9, COR9, CONR9R10, NR9COR10, (un)substituted lower alkenyl, or (un)substituted lower alkynyl; R8 is CO2R13, COR13, CONR13R14, CSNR13R14, C(NR13)NR14R15, SO3R13, S02R13, SO2NR13R14, PO3R13R14, POR13R14, PO(NR13R14)2; R9 and R10 are independently hydrogen or (un)substituted lower alkyl; R11 is a heteroaryl or a heterocyclic group; R12 is a cycloalkyl, a heterocyclic, an aryl, or a heteroaryl group; and n is 0,1,2, or 3. These compounds and their pharmaceutical compositions are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cdks and growth factor mediated kinases.

Description

INHIBITORS OF PIRID? R2.3-dlPIRIMIDIN-2.7-DIAMINA CINASA FIELD OF THE INVENTION This invention relates to pyrido [2,3-d] pyrimidine-2,7-diamines which inhibit cyclin-dependent serine / threonine-kinase enzymes and growth factor-mediated tyrosine kinase enzymes, and as such are useful to treat diseases and disorders of cell proliferation.
BACKGROUND OF THE INVENTION Summary of the Related Art Cell cycle kinases are enzymes that occur naturally and are involved in the regulation of the cell cycle (Meijer, L., 15"Chemical Inhibitors of Cyclin-Dependent Kinases", Progress in Cell Cycle Research, 1995; 1: 351-363). Typical enzymes include serine / threonine kinases such as the cyclin-dependent kinases (cdks) cdkl, cdk2, cdk4, cdkd, cdk6, as well as tyrosine kinases involved in cell cycle regulation. It has been shown that increased activity or activation 20 or temporarily abnormal regulation of these kinases cause the development of human tumors and other proliferative disorders. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its co-participant kinase, or by binding to the kinase and inactivating it, .M. »> * to? .f *** cause the inhibition of cell proliferation, and are therefore useful for treating tumors or other cells with abnormal proliferation. Some compounds that inhibit cdks have been shown to possess preclinical antitumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur et al., J. Nati, Cancer Insk., 1992; 84: 1736-1740; Int. J. Oncol., 1996; 9: 1143-1168). It has been shown that this compound inhibits cdk2 and cdk4. Olomoucin [2- (hydroxyethylamino) -6-benzylamino-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely et al., Eur. J. Biochem., 1994; 224: 771-786), and has been demonstrated which inhibits the proliferation of approximately 60 cell lines different from human tumors used by the National Cancer Institute (NCI) for the rapid discriminant screening of novel anticancer therapies (Abraham et al., Biology of the Cell, 1995; 83: 105-120). More recently, the class of cdk inhibitors represented by purvalanol has emerged as more potent olomoucine derivatives (Gray N. S. et al., Science, 1998; 281: 533-538). Tyrosine kinases are essential for the propagation of growth factor signal transduction that leads to cell cycle progression, cell proliferation, differentiation, and migration. Tyrosine kinases include cell surface growth factor receptor tyrosine kinases such as FGFr and PDGFr, as well as receptor-unrelated tyrosine kinases, which include c-Src and Ick. It has been shown that the inhibition of these enzymes produces antitumor and anti-angiogenic activity (Hamby et al., Pharmacol. Ther., 1999; 82 (2-3): 169-193). Various pyrido [2,3-d] pyrimidines which inhibit cdks and kinase enzymes mediated by growth factor are known (WO 5 98/33798). U.S. Pat. Nos. 5,733,913 and 5,733,914 describe 6-aryl-pyrido [2,3-d] pyrimidines. Despite the progress made, the search continues for low molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders, including restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions. , macular degeneration, and atherosclerosis. The present invention provides such compounds, their pharmaceutical formulations, and their use in the treatment of proliferative disorders.
BRIEF DESCRIPTION OF THE INVENTION This invention provides new pyrido [2,3-d] pyrimidine-2,7-d-amino compounds that function as inhibitors of cell cycle regulatory kinases such as cyclin-dependent kinases and growth factor-mediated tyrosine kinases. . Thus, these compounds are useful for treating cell proliferative disorders such as atherosclerosis and restenosis; Cancer; angiogenesis; viral infections including DNA viruses such as herpes and RNA viruses such as HIV; t¿É? mMí Ub ^ BS ÍÍÍ Í. ^. r¿.ÁlÍt.J, yty.y.i .. and ..- ÍL. fungal infections; Type I diabetes, neuropathy and diabetic retinopathy; multiple sclerosis; glomerulonephritis; neurodegenerative diseases that include Alzheimer's disease; autoimmune diseases such as psoriasis, rheumatoid arthritis, and lupus; rejection of organ transplants and host disease versus graft; drop; polycystic kidney disease; and inflammation, which includes inflammatory bowel disease. Accordingly, the present invention provides pyrido [2,3-d] pyrimidines having the generic structure of Formula I wherein: R2, R7, R13, R14 and R15 are, independently, hydrogen, or lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro , -R9, -NR R10, -OR9, - (CH2) C02R9, - (CH2) nSO2R11, - (CH2) R11, -COR9, -CONR9R10, -SO3R9, - SO2NR9R10, -SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, -NR9COR10, - COR10, - (CH2) nSO2R11, - (CH2) nR11, or - (CH2) nR12 optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, - (CH2) nCO2R9 , - (CH2) nSO2R11, - (CH2) nR11, -COR9, -CONR9R10, -SO3R9, -SO2NR9R10, -S02R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, -NR9COR10, -COR10, - (CH2) nS02R11, - (CH2) nR11; R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, -S02NR9R10, -S02R9, -SO3R9, -SR9, -PO3R9R10, -POR9R10, -PO ( NR9R10) 2, either lower alkenyl or lower alkynyl optionally substituted with -R9; R8 is H, -C02R13, -COR13, -CONR13R14, -CSNR3R14, -C (NR13) NR14R15, -SO3R13, -SO2R13, -S02NR13R14, -PO3R13R14, POR13R14, -PO (NR13R14) 2; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, or, when taken together with the nitrogen to which they are attached, R9 and R10 form a ring that has 3-7 members, of which up to «A or II four can be selected from / c \, O, S and NR20, where R20 is hydrogen, lower alkyl, or -CO- (lower alkyl); R11 is a heteroaryl group or a heterocyclic group; R 12 is a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is 0, 1, 2, or 3, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, are. The present invention also provides a composition comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient. The present invention also provides methods for inhibiting cyclin dependent kinase enzymes and kinase enzymes mediated by growth factor. The present invention also provides a method for treating subjects suffering from diseases caused by cell proliferation. The method involves inhibiting the proliferation of tumorigenic cells of epithelial origin and proliferation of vascular smooth muscle, and / or cell migration, by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment. The present invention also provides a method for treating subjects suffering from diseases caused by DNA tumor viruses such as herpes virus, which comprises administering a compound of "UlTriilfl t * ^ - * f ^ i? ** t íjffrtÉnJj Formula I.
DETAILED DESCRIPTION OF THE INVENTION The compounds encompassed by the present invention are those described by the general Formula I above, and pharmaceutically acceptable salts, esters, amides and prodrugs thereof. In addition to the compounds of Formula I, the invention provides preferred compounds of Formula II: wherein R5, R6, R7, and R8 are as defined above for Formula I; R16, R17, and R18 are as defined above for substituents (CH2) nR12, and are preferably, independently, hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano, nitro , carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO2R9, - tt &l ??? »» < J jlá? MM * r > a? llltáaH? I ** á *?) v? t * - ^? *? fcJMtl.ll and y e. " y, ax ..- and. -Art «» rtMBm? * -? • * - SO2NR9R10, -SO2R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R10, -NR9CONR9R10, -NR9SO2R10; or R16 is a carbocyclic group containing 3-7 members, of which up to 2 members are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or is substituted with 1, 2, or 3 groups such as have been defined above, but preferably independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclylsulfonyl-alkyl. Preferred compounds of Formula II are those in which R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, cyano or halogen; R17 and R18 are independently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, aminocarbonyl, mono- or dialkylaminocarbonyl, -SO2NR9R10, or -NR9COR10; and R16 is optionally substituted N-piperidine, N-piperazine or N-pyrrolidine, in which, for example, the substituents on the ring are selected from -R9, -NR9R10, -OR9, -NR9COR10, and COR10. In addition, the present invention also provides preferred compounds of Formula III: ? k? ? í? j * * f-f * ¡f. ~ í jy, ^ y * y. ^ s. *. wherein R2, R5, and R6 are as defined above for Formula I; and R19 is hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, (lower alkyl) -carbonyl, -SO3R9, -SO2NR9R10, - SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, - NR9CONR9R10, -NR9S02R1 °, wherein R9 and R10 are as defined above, or alternatively aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, wherein each of the aryl, heteroaryl or cycloalkyl groups is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxy-alkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO3R9, -S O2NR9R10, -SO2R9, - SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a carbocyclic group (CH2) n containing 3-7 members, of which up to 2 members are selected heteroatoms of oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or is substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclylsulfonylalkyl; and R21 is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. Preferred compounds of Formula III are those in which R5 is hydrogen or lower alkyl, R6 is hydrogen or halogen, R2 is optionally substituted phenyl; R21 is hydrogen or methyl; and R19 is optionally substituted, lower alkyl, cycloalkyl or carbocyclic of (CH2) n. An especially preferred group of pyrido [2,3-d] pyrimidines has Formula IV: kiÁjAwty? • £ - £ - & * - * rl i r -Wfcfittf-i - feáfct.t in which R5, R6, R16, R17, R18, R19, and R21 are as defined above. Preferred compounds of Formula IV are those in which R21 is hydrogen or methyl. Another especially preferred group of compounds of the invention has Formula V: wherein R5, R6, R16, R17, R18, R19, and R21 are as defined above. Preferred compounds of Formula V are those in which R21 is hydrogen or methyl. The most preferred compounds of the invention have Formula VI - -? it? i fit) rt-irtr "n-frf -f" íñ rTr I ffr tT **? f i? w - -rj ^ * ^ - *. iMfej.LL A in which R5, R6, R17, and R8 are as defined above, and R22 and R23 are, independently, hydrogen or alkyl. With the expressions "alkyl", "lower alkyl", and "C1-C10 alkyl" it is meant in the present invention linear or branched chain alkyl groups having 1 to 10 carbon atoms, such as, preferably, C6 alkyl . Typical alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, decyl, octyl. , and 3-methylpentyl. These groups may be substituted, for example, with halo, C1-C3 alkyl, amino, alkylamino, dialkylamino, hydroxy, akoxy and the like. Examples include chloromethyl, 2-amino-ethyl, and 3-dimethyl-aminopropyl. With the expressions "alkenyl", "lower alkenyl", and "alkenyl" C2-C? 0"is meant straight or branched chain alkyl groups having 1 to 10 carbon atoms and having 1 or 2 non-adjacent double bonds The examples of alkenyls include, but are not limited to, 3 -butenyl and 1-methyl-3-pentenyl With the expressions "alkynyl", "lower alkynyl", and "C2-C10 alkynyl" is meant straight or branched chain alkyl groups having 1 to 10 carbon atoms and they have a triple bond Typical alkynyl groups include 2-propynyl and 1,1-dimethyl-3-butynyl The substituted alkenyl and alkynyl groups include 4,4-dibromo-2-pentenyl and 3-amino-5-hexynyl. the expressions "alkoxy", "lower alkoxy", or "C1-C10 alkoxy" in i.i my iiiiiaiit iiiÉtti & ^^. and, in the present invention, straight or branched chain alkoxy groups are intended to be used in the present invention. having 1 to 10 carbon atoms such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. The term "alkanoyl" means an alkyl group linked through a carbonyl moiety. Examples include acetyl and pentanoyl. "Aminoalkanoyl" means that the alkyl group is substituted with an amino group. Examples include aminoacetyl and 3-aminohexanoyl. "Alkylaminoalkanoyl" means an aminoalkanoyl group in which the amine is substituted with a C1-C10 alkyl group, and includes methylaminoacetyl and 4- (isobutylamino) -octanoyl. "Dyalkylaminoalkanoyl" means a substituted N, N-d-aminoalkanoyl group, such as diisopropylaminoacetyl. In the present invention, halogen means fluorine, bromine, chlorine and iodine. The term "aryl" means an unsubstituted aromatic carbocyclic group having a single ring (for example phenyl), multiple rings (for example biphenyl), or multiple fused rings of which at least one is aromatic (for example 1, 2, 3,4-tetrahydronaphthyl, naphthyl, anthryl or phenanthryl). The term "substituted aryl" means, unless otherwise indicated, an aryl substituted with 1 to 4 substituents selected from alkyl, O-alkyl and S-alkyl, -OH, -SH, -CN, halo, 1, 3 -dioxolanyl, -CF3, -NO2, -NH2, -NHCH3, - N (CH3) 2, -NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, - NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) m, PO3 (alkyl) 2, - (CH2) mS02NH2, and - (CH2) mSO2NH-alkyl wherein alkyl is as defined above and is 0, 1, 2, or 3. Some examples of substituted aryl groups are methylphenyl, isopropoxyphenyl, chlorophenyl, 2-bromo-3-trifluoromethyl 4-nitro-5-aminophenyl, 4-bromobiphenyl, 3-acetamydonaphthyl, 3-dimethylaminoantrile, 3,4-dimethoxyphenanthryl, and 2,8-dibromobiphenylene-1-yl. By the term "heteroaryl" is meant one or more aromatic ring systems of 5, 6, or 7 members, containing at least 1 and up to 4 heteroatoms selected from nitrogen, oxygen or sulfur. These heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is) oxazolyl, tetrazolyl, pyridyl, pyridonyl, pyrimidinyl, pyrazole, (iso) quinolinyl, naphthyridinyl, phthalimidyl, benzimidazolyl, benzoxazolyl. A "substituted heteroaryl" group may be substituted with 1, 2, 3, or 4 of the above-mentioned groups for "substituted aryl", such as 2,3,4,6-tetrachloropyridyl and 2-ethoxy-3-trifluoromethylthien-4. -Ilo. The term "heterocyclic group" means a non-aromatic ring having 5, 6, or 7 ring atoms, of which 1 to 4 are selected from nitrogen, oxygen, or sulfur. Examples of heterocyclic groups include morpholino, piperidino, piperazino, pyrrolidinyl, and tetrahydrothienyl. These groups can be substituted with the same groups described above for substituted heteroaryl. A "carbocyclic group" or "cycloalkyl" is a non-aromatic cyclic ring or fused rings, having 3 to 7 carbon members in the ring. Examples include cyclopropyl, cyclobutyl, and cycloheptyl. These rings may be substituted with one or more of the aforementioned substituent groups for aryl, for example alkyl, halo, amino, hydroxy, and alkoxy. Typical substituted carbocyclic groups include 2-chlorocyclopropyl, 2,3-diethoxycyclopentyl, and 2,2,4,4-tetrafluorocyclohexyl. The carbocyclic group may contain 1 or 2 heteroatoms selected from oxygen, sulfur, and nitrogen, and such ring systems are referred to as "heterocyclyl" or "heterocyclic". Examples include piperidyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, and dioxanyl. These heterocyclyl groups can be substituted with up to 4 of the mentioned substituent groups for aryl, in order to provide groups such as 3-chloro-2-dioxolanyl, and 3,5-dihydroxymorpholino. They can also carry a keto group, for example 3-ketopiperidyl. The term "cancer" includes the following cancers, but is not limited thereto: breast, ovarian, cervical, prostate, testicular, esophageal, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung , squamous cell carcinoma, megalocytic carcinoma, adenocarcinoma, bone, colon, adenoma, pancreas, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, carcinoma of the liver and bile ducts, carcinoma of kidney, myeloid disorders, lymphoid, Hodgkin's disorders, hairy cell carcinoma, oral cavity and pharynx (oral), labial, lingual, mouth, pharynx, small intestine, • tt ^ BMft ** * f "'" - "ir If'tir'f ** i colon, rectum, large intestine, brain and central nervous system, and leukemia Compounds of Formulas I to VI may exist as pharmaceutically acceptable salts, esters, amides, and prodrugs The term "pharmaceutically acceptable salts, esters, amides, and prodrugs", as used herein refers to those carboxylate salts, salts by the addition of amino acids, esters , amides, and prodrugs of the compounds of the present invention which are, within the scope of well-founded medical judgment, suitable for use in contact with the tissues of patients without showing excessive toxicity, irritation, allergic response, etc., provided with with respect to a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, when possible, of the compounds of the invention.The term "salts" refers to the salts per addition. ion of relatively non-toxic inorganic and organic acids of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound, in its free base form, with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the salts of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate , naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, and the like. When the compound of the above formulas has one or more acidic groups, it can form a salt by reaction with a base. These salts may include cations based on the alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as inorganic bases such as ammonium, quaternary ammonium, and other amine cations, including tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts are well known to those skilled in the art of medical chemistry. (See, for example, Berge, S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference). Examples of non-toxic and pharmaceutically acceptable esters of the compounds of the invention include Cr C &, alkyl esters in which the alkyl group is linear or branched and is substituted or unsubstituted. The esters also include cycloalkyl esters «5-07, as well as arylalkyl esters such as benzyl and triphenylmethyl. Preferred are CrC alkyl esters, such as methyl, ethyl, 2,2,2-trichloroethyl and t-butyl. The esters of the compounds of the present invention can be prepared according to conventional methods, for example by reaction of an acid with an alcohol. Examples of pharmaceutically acceptable amides of the compounds of this invention include amides derived from ammonia, (CrCßJ alkyl primary amines and di- (CrC6 alkyl) secondary amines, in which alkyl groups are linear or branched. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing 1 nitrogen atom. Amides derived from ammonia, (C-t-C3) alkyl primary amines, and secondary di- (alkyl d-C2) amines are preferred. The amides of the compounds of the invention can be prepared according to conventional methods. The term "prodrug" refers to compounds that are rapidly transformed in vivo to provide the precursor compound of the above formulas, for example by hydrolysis in the blood. In the work of Higuchi T. and Stella V., "Pro-drugs as Novel Delivery Systems", volume 14 of the series A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, compiled by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference, an in-depth discussion of the prodrugs is provided. Representative compounds of the invention are shown in Table 1 below.
TABLE 1 Í ^.?. ^. Íi ... íMi.? .. i. l ^ - .. ... ^ ,, ^ ..... ^ .. ^ ... ^^^ VímlÍHl Íñ kÍ? Ml ÍÉáÍ \ M? Íñf?, Á-'í - "" - m? - - ». * - ^ M ^ k. ~ * - ^ - ^ ... ^ J« ^., Ja - ^. ^ ... ^ ^ '' ^ ~ |||, t | i < MÍlAlhUaL Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to, the compounds of Table 1 and their salts by the addition of acids or bases, ester or amide analogues, and prodrugs thereof, pharmaceutically acceptable. The compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms, and should be within the scope of the present invention. Some of the compounds of Formula I have one or more chiral centers, and may therefore exist as individual stereoisomers and mixtures thereof. Other compounds may exist in more than one geometric form. This invention includes all isomers and optical forms | gj ¡^ ^^ and -tj "~ - '"' tj * "'"' "" ". *", .....-., .yjüt bj **. ^^^? ki i? i and geometric, and mixtures thereof. The racemic mixtures of compounds of the invention are easily resolved into individual isomers by routine methods such as chromatography, fractional crystallization, and classical resolution using optically active acids and salts. The individual isomers can also be prepared by chiral synthesis, including chiral hydrogenations and the like, employing commercially available chiral catalysts. The compounds of the present invention are useful for treating cancer (e.g., leukemia, and lung, breast, prostate, and skin cancer, such as melanoma) and other proliferative diseases, including psoriasis, HSV, HIV, restenosis. , and atherosclerosis, but without being limited to them. To use a compound of the invention in the treatment of cancer, a patient suffering from cancer is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the invention. A further embodiment of this invention is a method for treating subjects suffering from diseases caused by the proliferation of vascular smooth muscle cells. The compounds included within the scope of the present invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method involves inhibiting the proliferation and / or migration of vascular smooth muscle cells by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment. The terms "subject" and "patient", as used herein, they mean a mammal such as a human being, but also include horses, cattle, sheep, and companion animals such as dogs and cats. The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. Those skilled in the art will recognize that the following dosage forms may comprise as active component both a compound of Formula I and a corresponding pharmaceutically acceptable salt or solvate of a compound of Formula I. A further embodiment of this invention consists of a composition Pharmaceutical comprising a compound of Formulas I to VI together with a pharmaceutically acceptable carrier, diluent or excipient therefor. To prepare pharmaceutical compositions with the compounds of the present invention, pharmaceutically acceptable carriers can be both solid and liquid. Solid preparation forms include powders, tablets, pills, capsules, seals, suppositories, and dispensable granules. A solid carrier may be constituted by one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the vehicle is a finely divided solid such as talc or starch, which is mixed with the finely divided active component. In the tablets, the active component is mixed in suitable proportions with the vehicle, which has the necessary binding properties, and is compacted to give the desired shape and size. The formulations of this invention preferably contain from about 5% to about 70% or more of active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low temperature melting wax, cocoa butter, and the like. Capsules are a preferred form for oral use, and include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active component, with or without other vehicles, is surrounded by a vehicle, which is find it in association with it. Similarly, envelopes and pills are included. Tablets, powders, capsules, pills, seals and pills can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a wax melting at low temperature is first melted, for example a mixture of fatty acid glycerides or cocoa butter, and is dispersed homogeneously therein, for example by stirring, the active component. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, and in this way solidifies.
Liquid form preparations include solutions, suspensions and emulsions such as solutions in water or in water / propylene glycol. For parenteral injection, the liquid preparations can be formulated in solution in an aqueous solution of polyethylene glycol, in isotonic saline solution, in 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing agents and thickeners, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water, and mixing it with a viscous material, for example natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are preparations in solid form which are intended to be converted, shortly before use, into liquid form preparations for oral administration. These liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. To prepare sustained release dosage forms, waxes, polymers, microparticles, and the like can be used. Osmotic pumps can also be used to supply the active compound evenly I »HiüliliÉH - * - ¿Aa" - - - * "- • aMMitf | aHaa | M | ,. ^ A..At long period of time. The paceutical preparations of the invention are preferably presented in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, in which the package contains discrete quantities of preparation, for example packaged tablets, capsules, and powders within vials or ampoules. The unit dosage form can also be a capsule, tablet, seal or tablet in themselves, or it can be the appropriate number of any of these, in packaged form. The therapeutically effective dose of a compound of Formula I will generally be at about 1 to about 100 mg / kg of body weight per day. Typical doses for adults will be approximately 0 to approximately 800 mg per day. The amount of active component in a unit dose preparation can be varied or adjusted from about 0.1 to about 500 mg, preferably from about 0.5 to 100 mg, according to the particular application and potency of the active component. If desired, the composition may also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I is administered a dosage of about 1 to about 500 mg per day, either once or in multiple doses over a period of 24 hours.
The compounds of the present invention are capable of binding to, and inhibiting the activity of, proteins that have the ability to phosphorylate other proteins, such as cdks, PDGFr, FGFr, c-Src, and EGFr. Cdks form complexes with cyclins, and these complexes phosphorylate key proteins that allow cells to pass through the cell cycle phases (Meijer, L., Progress in Cell Cycle Research, 1995; 1: 351-363). The compounds of this invention inhibit this phosphorylation and, therefore, can be used as antiproliferative agents for the treatment of cancer and / or restenosis, and other proliferative diseases. Due to their inhibitory activity against cdks and other kinases, the compounds of the present invention also constitute useful research tools for studying the mechanism of action of these kinases, both in vitro and in vivo. In the following detailed example, the preparation and use of the compounds of this invention are further described. The examples are intended to illustrate particular embodiments of the invention, and not to limit in any way the scope of the specification or the claims. The compounds of the invention are prepared by synthetic methodologies well known to those skilled in the art of organic chemistry, and utilize commercially available starting materials and reagents. It may be desirable during the synthesis of a compound of the invention to derivatize reactive functional groups of the molecule undergoing reaction, in order to avoid unwanted side reactions. Functional groups such as hydroxy, amino, and acid groups are typically protected with suitable groups which can be easily removed when desired. The use of common protective groups has been described in detail by Green and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, New York (2nd edition, 1991). Typical hydroxyl protecting groups include ether-forming groups, such as benzyl, and aryl groups such as t-butoxycarbonyl (Boc), formyl and acetyl. Amino protecting groups include benzyl, acyl such as acetyl, and trialkylsilyl groups. The carboxylic acid groups are typically protected by conversion into an aster which can be easily hydrolyzed, for example trichloroethyl, t-butyl, benzyl, and the like. As noted above, some of the compounds of the invention have one or more chiral centers, and may therefore exist as optical isomers and individual geometric isomers, and mixtures thereof. For example, Compound 106 has two asymmetric centers, and has the cis configuration. This invention includes all of these geometric isomers, enantiomers and RS racemates, as well as the individual R or S isomers of chiral compounds. All individual isomers and mixtures thereof are included in this invention. The individual isomers are readily prepared by chiral synthesis, or by conventional resolution techniques well known to those skilled in the art.
- * - ** - * - * - *** ~ ^ * * - "An illustration of the preparation of compounds of the present invention is shown in schemes 1-4. The synthesis of Compound 1 (Example 15) is shown in Scheme 1; however, it should be recognized that the general scheme is applicable to all compounds of the invention. Each of the steps shown in the Schemes is additionally illustrated in the detailed examples that follow. In Scheme 1, a 2-methylthio-4-halo-5-alkoxycarbonylpyrimidine is reacted with ammonium hydroxide to provide the corresponding 4-amino derivative. The ester is reduced by reaction with LiAlH, to provide the 5-hydroxymethyl analogue, which in turn is oxidized to a 5-formyl derivative. The 5-formyl group is converted into an unsaturated group (acrylate), which is cyclized to form a pyrido [2], 3-djpyrimidine. The pyridopyrimidine is converted into a key intermediate, namely 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine, which is readily oxidized to provide a 2-methylsulfinyl analogue. The 2-methylsulfonyl group is easily displaced by reaction with an amine R2NH2 to provide the compounds of the invention of Formula I. The 7-amino group of the pyridopyrimidine ring is easily converted to a urea by reaction with an isocyanate such as R ? 9N = C = O ltli? l? tf É if? f ^^ 'Aj ^' '- ^^^ DIAGRAM 1 áúít lí ÉrÉtíiÍríim-É? IMift? GMI irirtf i - * - * - --- *. «** - *« - ^^ "^,«. ^ - ^^ L .. ^ Á ^^^^ MMMH ...
The reactants shown in Scheme 1 have the following meanings: (a) NH 3; (b) LAH; (c) MnO2; (d) Ph3PCHCO2Et; (e) DBU; (f) POCI3; (g) NH3; (h) (±) -trans-2- (phenylsulfonyl) -3-phenyl-oxaziridine, (i) 4- (4- Bocpiperidine) -aniline; (j) NaH, t-butyl isocyanate; (k) HCl. Scheme 2 illustrates an alternative synthesis of pyridopyrimidines having a urea functionality in the 7-position. While such ureas are prepared in Scheme 1 by reaction of an isocyanate with a 7-amino-pyridopyrimidine, Scheme 2 uses carbonyldiimidazole to provide an intermediate imidazolide. The imidazolide reacts readily with an amine R19NH2 to provide the corresponding urea. Scheme 2 illustrates this procedure showing the synthesis of compound 51, which is described in greater detail in Example 32.
SCHEME 2 Conditions: (a) NaH, carbonyldiimidazole; (b) cyclopentylamine, (c) HCl The compounds of Formula 1 can also be prepared according to Scheme 3, in which the synthesis of compound 4 is represented (Example 45). 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde is reacted with methylmagnesium bromide to provide the corresponding 5- (2-hydroxyethyl) -pyrimidine. The alcohol is oxidized ^ .. ^ a ^ ^^ ^^^^^ ^ .Al ^ iAMAi provide the methyl ketone analogue. The methyl ketone is reacted with diethyl cyanomethyl phosphonate and cyclized to give a 5-methyl-7-amino-pyridopyrimidine. The subsequent reaction in the same manner as in Schemes 1 or 2 provides compounds of the invention such as compound 4.
SCHEME 3 Conditions: (a) MeMgBr, (b) MnO2; (c) (EtO) 2P (O) CH 2 CN The compounds of Formula 1 can also be prepared according to Scheme 4, in which the synthesis of compound 12 is illustrated (Example 40). In this scheme, the 2-methylthio group of a pyrimidine is first oxidized to give the corresponding analogue of metisulfinyl. The methylisulfinyl group is displaced by reaction with an amine R2NH2. The 5-carboxaldehyde is then derivatized in the same manner as in Scheme 1, and cyclized to give the corresponding 2- (substitution with R 2 NH) -7-amino-pyridopyrimidine. The 7-amino group is arylated or otherwise derivatized, as illustrated in Schemes 1-3.
SCHEME 4 Conditions: (a) (±) -trans-2- (phenylsulfonyl) -3-phenyloxaziridine; (b) 4- ?? il il? -jáilí? I iliiirili mi ináMiliriiiiiiiiiiiiiíf T "- - - - ^ --- ^ ~.?.« ~ ». (4-Bocpiperidine) -aniline; (c) (EtO) 2P (O) CH2CN Any of the compounds of Formula 1 of the invention can be prepared according to Schemes 1-4, in which the syntheses of compounds 1, 51, 4, and 12, respectively. Those skilled in the art will recognize that the starting materials may vary and that additional steps may be employed to produce compounds comprised by the present invention, as demonstrated in the following specific examples. The descriptions contained within this application for all works and references, including patents, are incorporated herein by reference. The invention is further illustrated by the following detailed examples, which should not be taken as limiting the invention, in scope or spirit, to the specific procedures described therein. The starting materials and various intermediates can be obtained from commercial sources, be prepared from commercially available organic compounds, or be prepared using well-known synthetic methods.
EXAMPLE 1 Ethyl ester of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid To a solution at room temperature of ethyl ester of acid "? # lt ti? nMMttiA fr imt •? t ^ 'fa ^ *' '' ^ '" tf * ta ^^ »M *' '***" *' "ifi ttltri 4-chloro-2-methanesulfanyl- pyrimidine-5-carboxylic acid (15.0 g, 65 mmol) in 200 ml of tetrahydrofuran is added 25 ml of triethylamine followed by 35 ml of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 ml of aqueous ammonium hydroxide is added, and stirring is continued for 1 hour. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate and hexane are added, and the resulting solid is collected by filtration, to provide 10.84 g (79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
EXAMPLE 2 (4-Amino-2-methanesulfanyl-pyrimidin-5-iM-methanol A solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (13.36 g, 63 mmol) in 250 ml of tetrahydrofuran is added dropwise to a suspension at room temperature of lithium aluminum hydride ( 3.82 g, 100 mmol) in 250 ml of tetrahydrofuran. After 30 minutes the reaction is cooled to 0 ° C, and isopropyl alcohol is added until the formation of bubbles decreases. The reaction is quenched with 15 ml of water, 15 ml of 50% NaOH, and 50 ml of water, and the mixture is stirred for 1 hour. The white precipitate is filtered off and washed with hllÍÍ ltTifcA ^ B4¿ * "tiA" t, -a ^ 't' "* - **** -. *. *. •. ^^? .. ^^.? ^ * ^ ...? * * * * * * * • • • • ethyl acetate The filtrate is concentrated in vacuo and hexane: ethyl acetate 3: 1 is added, the solids are collected and washed with hexane: ethyl acetate 3: 1, followed by hexane The solid is dissolved in ethyl acetate, and the solution is dried over magnesium sulfate The filtration, followed by concentration in vacuo, affords 8.14 g (76%) of (4-amino-2-methanesulfanil -pyrimidin-5-yl) -methanol Analysis calculated for C6H9N3OS: C, 42.09; H, 5.30; N, 24.54. Found: C, 42.31; H, 5.24; N, 24.27.
EXAMPLE 3 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde Manganese oxide (33.13 g, 381 mmol) is added to (4-amino-2-methanesulfanyl-pyrimidin-5-yl) -methanol (8.14 g, 48 mmol) in 1 liter of chloroform. The suspension is stirred at room temperature overnight and then filtered through Celite and washed with 300 ml of chloroform. The filtrate is concentrated in vacuo to provide 8.14 g (quantitative yield) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde, melting point (m.p.) 185-187 ° C. P.f. from the bibliography = 183-184 ° C, JOC, 1958; 23: 1738. Analysis calculated for C6H7N3OS: C, 42.59; H, 4.17; N, 24.83. * j ^ &| |, ^^ HW & át ?? tm ^^^^ ¿¿¿L ±.
Found: C, 42.84; H, 4.21; N, 24.73.
EXAMPLE 4 3- (4-Amino-2-methanesulfanyl-pyrimidin-5-yl) ethyl acrylate To a room temperature solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (4.08 g, 24.14 mmol) in 100 ml of tetrahydrofuran is added (carboxymethylene) triphenylphosphorane (10.80 g, 31 mmol). The reaction mixture is refluxed for 3 hours, and then stirred at room temperature overnight. Concentrate the reaction mixture in vacuo, and purify the residue by flash chromatography, eluting with 1: 1 ethyl acetate: hexane, to provide 4.30 g (75%) of 3- (4-amino-2-methanesulfanyl-pyrimidine. -5-yl) ethyl acrylate; p.f. = softens at 108 ° C. Analysis calculated for C 10 H 13 N 3 O 2 S: C, 50.19; H, 5.48; N, 17.56. Found: C, 50.22; H, 5.45; N, 17.24.
EXAMPLE 5 2-Methanesulfanyl-8H-pyrido 2,3-dl-pyrimidin-7-one To a room temperature solution of ethyl 3- (4-amino-2-methanesulfanyl-pyrimidin-5-yl) acrylate (368 mg, 1.53 mmol) in 3 ml of íflÉl itiiiiiliÉiiiíiMiliiii Ti t í¿twr¿ * J ^^ < u * ^^ - ^ - ~ - '•' "•" • • * * "- * • * *** i? N, N-diisopropylethylamine are added 380 μl of 1,8-diazabicyclo [5.4.0] undec The reaction mixture is refluxed for 3 hours and then cooled to room temperature and concentrated, the residue is purified by flash chromatography eluting with ethyl acetate and the fractions are partially concentrated in vacuo. containing the product, and the solids are separated by filtration to provide 134 mg (45%) of 2- methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one, mp 269-271 ° C. for C8H N3OS: C, 49.73; H, 3.65; N, 21.75. Found: C, 49.67; H, 3.46; N, 21.49.
EXAMPLE 6 7-Chloro-2-methylsulfanyl-pyridor2.3-c1pyrimidine A suspension of 1.0 g (5.2 mmol) of 2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 5) in 10 ml of phosphorus oxychloride is heated under reflux for 1 hour. The resulting solution is cooled, and concentrated to provide a solid, which is triturated with cold water and filtered to provide 1.05 g of crude product. Recrystallization from acetonitrile gives 0.76 g (69%) of the product, m.p. 201-203 ° C. MS (APCl) M + 1: calculated 212.0; found 212.0. Analysis calculated for CßHßCliSiNa: C, 45.39; H, 2.86; N, 19.85.
Found: C, 45.53; H, 2.90; N, 19.74.
EXAMPLE 7 2-Methylsulfanyl-pyridof2t3-d1-pyrimidin-7-ylamine A suspension of 2.95 g (13.9 mmol) of 7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine (Example 6) is sealed in 200 ml of isopropanol saturated with ammonia, and heated to 40 ° C. for 65 hours. The suspension is again saturated with ammonia, and heated at 40 ° C for another 18 hours. The solid is collected by filtration, and triturated with water to provide 1.98 g (74.2%) of the product, m.p. > 250 ° C. MS (APCl) M + 1: calculated 193.1; Found 193.0. Analysis calculated for C, 49.98; H, 4.19; N, 29.14. Found: C, 50.14; H, 4.22; N, 29.04.
EXAMPLE 8 2-Methanesulfinyl-pyrido 2,3-dlpyrimidin-7-ylamine A suspension of 10.63 g (55.3 mmol) of 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 7) in 300 ml of dichloromethane and 300 ml of methanol is treated with 18.06 g (69.1 mmol) of (+) - trans-2- (phenylsulfonyl) -3-phenyloxaziridine, and stirred overnight. The suspension is filtered to remove a small amount of solid, concentrated to approximately 25 ml, and diluted with ethyl acetate. The solid is collected by filtration to provide 9.27 g (80.5%) of the product, m.p. 180 ° C (with decomposition). MS (APCl) M + 1: calculated 209.0; found 209.1.
EXAMPLE 9 N2-Phenyl-pyridoF2.3-dlpyrimidine-2.7-diamine A suspension of 0.44 g (2. mmol) of 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 8) and 0.39 ml (4.2 mmol) of aniline is heated at 100 ° C overnight. in 2 ml of dimethisulfoxide. The resulting solution is cooled and poured into water. Ethyl acetate is added to the suspension, and the solid is collected by filtration. This solid is purified by flash chromatography, eluting with gradient from 0% to 20% methanol in dichloromethane over the course of 30 minutes, to provide 0.14 g (29%) of the product, m.p. 255-260 ° C. MS (APCl) M + 1: calculated 238.1; found 238.1. Analysis calculated for Ci3HnN50.18H2O: C, 64.92; H, 4.76; N, 29.12. Found: C, 65.26; H, 4.75; N, 28.76. g ^ l ^^^ ^ ..? . .. ^,. ^. m ffe - * - .v ... * ** »A & J EXAMPLE 10 1-t-Butyl-3- (2-phenylamino-pyridof2.3-d] pyrimidin-7-yl) -urea To a solution of 0.1022 g (0.431 mmol) of N "-phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine (Example 9) in 2 ml of dimethylformamide, cooled in an ice bath, are added 0.019 g (0.47 mmol) of 60% sodium hydride, the resulting solution, cooled in an ice bath, is treated with 0.054 ml (0.47 mmol) of t-butyl isocyanate. minutes, and then at room temperature for 1 hour.The solution is poured into ice water to provide a solid, which is collected by filtration and washed with hexane to provide 0.0849 g (57.8%) of the product (compound 45), mp. 227 ° C (with decomposition) MS (APCl) M + 1: calculated 337.2, Found 337.1 Analysis calculated for Ci8H20N6 ?? "0.27H2O: C, 63.35; H, 6.07; N, 24.63. Found: C, 63.73; H, 5.82; N, 24.20.
EXAMPLE 11 4- (4-Nitro-phenyl) -piperazine-1-carboxylic acid t-butyl ester It is treated with 8.69 g (40 mmol) of di-t-butyl dicarbonate a suspension of 7.5 g (36 mmol) of 1- (4-nitrophenyl) -piperazine and 6.94 ml (40 mmol) of ethyl-diisopropylamine in 75 ml of dichloromethane, and stir lilííiiitriii ílt ¡I f ^^ "'~ * ~ 1? i ** ^ > ^ - ^ ??"' M -? - * ~~ * ~ * ^ '~ * *. ^, ^ -r-rlifcW .ÍM¿, I 11 room temperature overnight. The resulting solution is washed with saturated aqueous sodium bicarbonate and then with water, dried (magnesium sulfate), and concentrated. The resulting material is purified by flash chromatography, eluting with a 10% to 30% gradient of ethyl acetate in hexane over the course of 10 minutes, to provide 8.62 g (77.5%) of the product, m.p. 136-140 ° C. MS (APCl) M + 1: calculated 308.2; found 308.2.
EXAMPLE 12 4- (4-Amino-phenyl) -piperazine-1-carboxylic acid t-butyl ester To a suspension of 1.46 g (4.8 mmol) of 4- (4-nitrophenyl) -piperazine-1-carboxylic acid t-butyl ester (Example 11) and 1 g of Raney nickel in 50 ml of tetrahydrofuran is added hydrogen to a Initial pressure of 3.76 bar. The reaction is shaken for 14 hours and then filtered. The filtrate is concentrated to provide 1.29 g (97%) of the product as a solid. MS (APCl) M + 1: calculated 278.2; Found 278.2. Analysis calculated for C? SH23N3? 2: C, 64.96; H, 8.36; N, 15.15. Found: C, 65.22; H, 8.58; N, 14.58.
SkJLA AA, *. AHtoi, 1 ^. ^ - «H. . ^ * * i ~ * my MJL *. *. *. **. "T ******* ^ **" ** i-tMÉ, afr *, »f,? Tf ífltnifÉiW rilÉÑ ri ft EXAMPLE 13 4- [4- (7-Amino-pyridof2) t-butyl ester .3-d1-pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid By replacing in Example 9 aniline with 4- (4-amino-phenyl) -piperazine-1-carboxylic acid t-butyl ester (Example 12), 0.0744 g (36.0%) of the product, m.p. 219-220 ° C. MS (APCl) M + 1: calculated 422.2; Found 422.2. Analysis calculated for C22H27N7O2 • 0.5H2O: C, 61.38; H, 6.56; N, 22.77. Found: C, 61.34; H, 6.30; N, 22.47.
EXAMPLE 14 4- Tertiary butyl ester. { 4-f7- (3-t-butyl-ureido) -pyridof2.3-d1-pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid Replacing in Example 10 N2-phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine by 4- [4- (7-amino-pyrido [2,3-d] pyrimidine-] t-butyl ester 2-ylamino) -phenyl] -piperazine-1-carboxylic acid (Example 13), 0.3354 g (67.9%) of the product (compound 79), mp. 225 ° C (with decomposition). MS (APCl) M + 1: calculated 521.3; found 521.2. Analysis calculated for C 27 H 36 N 8 3 3: C, 62.29; H. 6.97; N, 21.52.
Found: C, 62.33; H, 6.81; N, 21.43.
EXAMPLE 15 1-t-Butyl-3-r 2 - (4-piperazin-1-yl-phenylamino) -pyrido 2,3-d-1-pyrimidin-7-ill-urea To a suspension of 0.100 g (0.192 mmol) of 4-t-butyl ester. { 4 - [7- (3-t-Butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 14) in 2 ml of methanol is added 2 ml of 4M hydrogen chloride in dioxane, to provide a solution. The suspension is stirred at room temperature overnight, and then diluted with diethyl ether. The material is collected by filtration to provide 0.0941 g (93.4%) of the product (compound 1), m.p. 215 ° C (with decomposition). MS (APCl) M + 1: calculated 421.2; Found 421.1. Analysis calculated for C22H28N80? • 2.10HCI • 1.51 H2O: C, 50.40; H, 6.37; N, 21.37; Cl (total), 14.20. Found: C, 50.40; H, 6.18; N, 21.03; Cl (total), 14.33.
EXAMPLE 16 4- Tertiary butyl ester. { 4-f7- (3-cyclohexyl-ureido) -pyrido [2,3-dlpyrimidin-2-ylamino-1-phenyl) -piperazine-1-carboxylic acid By replacing in Example 14 the t-butyl isocyanate by i? i i ni plÉiÉiiir- ^ sa ^ '- í TTHH I I -G - »" - ** "* - **» ---- - - > * - ** - * • • * < * "'- - -« - »- • *.« - «- cyclohexyl isocyanate, 0.1463 g (70.4%) is obtained from the product (compound 80), mp 241 ° C (with decomposition) MS (APCl) M +1: calculated 547.3, found 547.4 Analysis calculated for C29H38N8? 3 • 0.28H2O: C, 63.3; H, 7.04; N, 20.31 Found: C, 63.14; H, 6.81; N, 20.25.
EXAMPLE 17 1-Cyclohexyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea By replacing in Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by 4-t-butyl ester. { 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 16), 0.0871 g (81.4%) of the product (compound 9), m.p. 200 ° C (with decomposition). MS (APCl) M + 1: calculated 447.3; Found 447.3. Analysis calculated for C24H3oN8O? • 2.55HCI • 2.82H2O: C, 48.83; H, 6.52; N, 18.98; Cl (total), 15.31. Found: C, 48.83; H, 6.18; N, 18.89; Cl (total), 15.37.
EXAMPLE 18 N2- (4-Fluoro-3-methyl-fenih-Piridor2.3-d? Pyrimidin-2,7-diamine Replacing in Example 9 the aniline by 4-fluoro-3-methylaniline, 0.2025 g (39.2%) are obtained. of the product as a solid MS (APCl) M + 1: calculated 270.1, found 270.0.
EXAMPLE 19 1-t-Butyl-3- [2- (4-fluoro-3-methyl-phenylamino) -pyridof2.3-d1-pyrimidin-7-ill-urea Replacing in Example 10 the N-enyl-pyridoxys.S-d-pyrimidine-2,7-diamine by N2- (4-fluoro-B-methyl-phenyl) -pyrido [2,3-d] pyrimidine-2,7- diamine (Example 18), 0.0656 g (47.9%) of the product are obtained (compound 46), mp 230 ° C (with decomposition). MS (APCl) M + 1: calculated 369.2; Found 369.1. Analysis calculated for C19H21F1N6O1: C, 61.94; H, 5.75; N, 22.81. Found: C, 61.82; H, 5.73; N, 22.75.
EXAMPLE 20 1-4-Chloro-phenin-3-f2- (4-fluoro-3-methyl-phenylamino) -pyridof 2.3-dlPyrimidin-7-ill-urea By replacing in Example 19 the t-butyl isocyanate by Í .Latatn-LJl > t? What is it? rtf 4-chlorophenyl isocyanate, 0.050 g (37%) of the product are obtained (compound 47), mp > 250 ° C. MS (APCl) M + 1: calculated 423.1; Found 423.1. Analysis calculated for C2? Hi6N6Or 0.23H2O: C, 59.07; H, 3.89; . N, 19.68. Found: C, 59.09; H, 3.97; N, 19.65.
EXAMPLE 21 1-. { 2- f4- (4-Acetyl-piperazin-1-yl) -phenylamino-Vpyridof2.3-d1-pyrimidin-7-yl) -3-t-butyl-urea To a suspension of 0.145 g (0.277 mmol) of 1-t-butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (Example 15) Into ml of dichloromethane is added 0.19 ml (1.11 mmol) of ethyl-diisopropyl-amine. The solution is cooled in an ice bath and treated with 0.024 ml (0.33 mmol) of acetyl chloride. The suspension is stirred at room temperature overnight and then filtered. The solid is washed with dichloromethane. The filtrate and washings are combined, washed with water, dried (magnesium sulfate), and concentrated. The material is purified by flash chromatography, eluting with a gradient from 0% to 5% methanol in dichloromethane over the course of 30 minutes, to provide 0.0674 g (51.8%) of the product (compound 5), m.p. 206-208 ° C (with decomposition). MS (APCl) M + 1: calculated 463.3; Found 463.3. i_l A X.? »*? T? -t .. ~. * J *? Ém ",", ^ ^^^^^., ... ^, ^. ^^^. n .. ^^^ ^^ JU. i, tr- |, "Í - fn, m-ftfafc, * -! Analysis calculated for C24H30N8O2 • 0.40H2O: C, 61.36; H, 6.61; N, 23.85. Found: C, 61.38; H, 6.37; N, 23.98.
EXAMPLE 22 4- (4- [7- (3-isopropyl-ureido) -pyridof2.3-d1-pyrimidin-2-ylamino-1-phenyl} -piperazine-1-carboxylic acid t-butyl ester By replacing in Example 14 the t-butyl isocyanate with isopropyl isocyanate 0.909 g (69.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 507.3; Found 507.4.
EXAMPLE 23 1-lsopropyl-3-12- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea Replacing in Example 15 the t-butyl ether of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by t-butyl ester of 4-acid. { 4- [7- (3-isopropyl-ureido) -pyrido [2,3- d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 22), 0.0287 g (27.9%) of the product (compound 48), m.p. 190 ° C (with decomposition).
MS (APCl) M + 1: calculated 407.2; found 407.1. Analysis calculated for C2? H26N8O? • 2.05TFA • 0.84H2O: C, 46.00; H, 4.57; N, 17.10. Found: C, 46.00; H, 4.65; N, 17.09.
EXAMPLE 24 Cis-3,5-dimethyl-1- (4-nitro-phenyl) -piperazine A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitro-benzene and 10.91 g (95.5 mmol) of cis-2,6-dimethyl-piperazine is heated at 45 ° C for 1 hour. The reaction mixture is cooled and shaken with dichloromethane and water. The organic layer is dried (magnesium sulfate) and concentrated to provide 11.62 g (> 100%) of the product as a solid.
EXAMPLE 25 cis-2,6-dimethyl-4- (4-nitro-phenyl) -piperazine-1-carboxylic acid t-butyl ester Replacing in Example 11 1 - (4-nitro-phenyl) -piperazine by cis-3,5-dimethyl-1- (4-nitro-phenyl) -piperazine (Example 24), 14.87 g (92.8%) are obtained of the product as a solid.
EXAMPLE 26 4- (4-Amino-phenyl) -cis-2 t-butyl ester. 6-dimethyl-piperazine-1-carboxylic acid Replacing in Example 12 the 4- (4-nitro-phenyl) -piperazine-1-carboxylic acid t-butyl ester by cis-2,6-dimethyl-4- (4-nitro-phenyl) t-butyl ester ) -piperazine-1-carboxylic acid (Example 25), 5.03 g (64.7%) of the product is obtained as a solid.
EXAMPLE 27 4- Ethyl t-butyl ester | - (7-amino-pyridof2.3-dlpyrimidin-2-ylamino) -phen-p-cis-2. 6-dimethyl-piperazine-1-carboxylic acid By replacing in Example 9 the aniline with cis-4- (4-amino-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid t-butyl ester (Example 26), 0.6463 g (59.8 g. %) of the product, pf 245 ° C (with decomposition). MS (APCl) M + 1: calculated 450.3; found 450.3.
EXAMPLE 28 4- (4- [7- (3-t-Butyl-ureido) -pyridof2.3-dlpyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-p-pperazin-4-butyl ester -1-carboxylic Replacing in Example 10 the N-enyl-pyridop.S-djpyrimidin- ¿I.Jí¿ -.? I, rL iillrt jÉtiiii ii ijti tw¿in? t rh ^ r ^ a --- M? lfc ^ Jit * afclMa- ^^ • "• '•• ^ - ^^^' a'-aafc ^^ ria ^ * ^^» ^. »» ^ * 2,7-diamine by 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethyl-tert-butyl ester piperazin-1-carboxylic acid (Example 27), 0.1828 g (74.9%) of the product is obtained as a solid MS (APCl) M + 1: calculated 549.3, found 549.4.
EXAMPLE 29 1- t-Butyl-3-. { 2-f4- (cis-3,5-dimethyl-piperazin-1-in-phenylaminoj -pyridor2.3- dlpyrimidin-7-yl.}. -urea Replacing in Example 15 the t-butyl ester of acid 4-. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3- d] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 28), 0.0910 g (92.9%) of the product (compound 49), m.p. 245 ° C (with decomposition). MS (APCl) M + 1: calculated 449.3; Found 449.2.
EXAMPLE 30 4- Tertiary butyl ester. { 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3-dlpyrimidin-2-ylamino-1-phenyl > -cis-2,6-dimethyl-piperazine-1-carboxylic acid By replacing in Example 28 the t-butyl isocyanate with cyclohexyl isocyanate, 0.1156 g (60.8%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 575.3; Found 575.3.
EXAMPLE 31 1-Cyclohexyl-3-. { 2-f4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyridof2.3-dlpyrimidin-7-yl} -urea Replacing in the. Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by 4-t-butyl ester. { 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3- d] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-piperazin-1-carboxylic acid (Example 30), 0.1022 g of the product (compound 50), m.p. 228 ° C (with decomposition). MS (APCl) M + 1: calculated 475.2; Found 475.2.
EXAMPLE 32 4- Tertiary butyl ester. { 4-f7- (3-cyclopentyl-ureido) -pyridof2.3- d1-pyrimidin-2-ylamino] -phenyl) -piperazine-1-carboxylic acid To a solution of 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester (Example 13) in 2 ml of dimethylformamide, cooled in an ice bath, 0.022 g (0.54 mmol) of 60% sodium hydride are added. The mixture is stirred for 15 minutes cooled solution, and then treated with 0.088 g (0.54 mmol) of carbonyldiimidazole. The cooled solution is stirred for another 30 minutes, and then treated with 0.71 ml (0.72 mmol) of cyclopentylamine. The resulting solution is stirred at room temperature for 1 hour, and then added to cold water. By filtration - the solid is collected to provide a first crop of the material. The aqueous filtrate is then extracted with dichloromethane, and the extracts are dried (magnesium sulfate) and concentrated to provide a second crop of material. The two crops are combined and purified by lightning chromatography, eluting with a gradient from 0% to 5% methanol in dichloromethane, over the course of 30 minutes, to provide 0.1159 g (60.4%) of the product as a solid. MS (APCl) M + 1: calculated 533.3; Found 533.4.
EXAMPLE 33 1-Cyclopentyl-3 - [2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-d] pyrimidin-7-ill-urea Replacing in Example 15 the t-butyl ester of acid 4-. { 4- 20 [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by t-butyl ester of 4-acid. { 4- [7- (3-cyclopentyl-ureido) -pyrido [2,3- d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 32), 0.0937 g (80.8%) of the product (compound 51), m.p. 210-213 ° C (with decomposition). MS (APCl) M + 1: calculated 433.2; Found 433.2. Analysis calculated for C23H28N8O? • 2.49 HCl • 1.65H2O • O.1 dioxane C, 50.02; H, 6.21; N, 19.94; Cl (total), 15.71. Found: C, 49.89; H, 5.81; N, 19.74; Cl (total), 14.74.
EXAMPLE 34 1- (4-Amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanol To a suspension of 5.0 g (29 mmol) of 4-amino-2-methyl-sulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150 ml of tetrahydrofuran, cooled in an ice bath, are added over the course of 20 hours. minutes, 23.2 ml of a 3.0 M solution of methylmagnesium bromide in diethylether (69.4 mmol). After 1 hour at 0 ° C, another 23.2 ml of the 3.0 M solution of methylmagnesium bromide is added, the suspension is allowed to come to room temperature, and stirred overnight. The reaction is quenched with 100 ml of saturated aqueous ammonium chloride, and partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and concentrated to provide 5.24 g (96%) of the product, m.p. 140-142 ° C. MS (APCl) M + 1: calculated 186.1; Found 185.9.
EXAMPLE 35 1- (4-Amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone Replacing in Example 3 (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -methanol with 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanol (Example 34), and carrying After the reaction at 80 ° C in toluene, 3.74 g (72%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 184.0; Found 183.9.
EXAMPLE 36 1- (4-Amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone Replacing in Example 8 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine by 1 - (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35), 9.57 g (88%) of the product are obtained as a solid. MS (APCl) M + 1: calculated 200; Found 200.
EXAMPLE 37 4- [4- (5-Acetyl-4-amino-pyrimidin-2-ylamino) -phenyl-piperazine-1-carboxylic acid t-butyl ester Replacing in Example 13 the 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine by 1 - (4-amino-2-methanesulfinyl-pyrimidin-5-yl) -ethanone (Example 36), 4.04 g (65%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 413; Found 413.
EXAMPLE 38 4- [4- (7-Amino-5-methyl-pyrido-2,3-d1-pyrimidin-2-ylamino) -phenyl-piperazine-1-carboxylic acid t-butyl ester To a suspension of 0.58 g (14.6 mmol) of 60% sodium hydride in 10 ml of tetrahydrofuran, at 0 ° C, 2.58 g (14.56 mmol) of diethyl (cyanomethyl) phosphonate are added dropwise. The reaction mixture is stirred at 0 ° C for 5 minutes, and then at room temperature for 20 minutes. The mixture is then cooled to 0 ° C and treated with 2 g (4.85 mmol) of 4- [4- (5-acetyl-4-amino-pyrimidin-2-ylamino) -phenyl] t-butyl ester] -piperazine-1-carboxylic acid (Example 37). The mixture is stirred at room temperature overnight, and then treated with water and saturated aqueous ammonium chloride. By filtration the resulting solid is collected, and washed with ether to provide 1069 g (80%) of the product. MS (APCl) M + 1: calculated 436; Found 436 ..
EXAMPLE 39 4- Tertiary Butyl Ester. { 4- [7- (3-cyclohexyl-ureido) -5-methyl-pyridof2.3-d1-pyrimidin-2-ylaminol-phenyl} -piperazine-1-carboxylic Replacing in Example 16 the 4- [4- (7-amino-pyrido [2,3-dj pyrimidin-2-ylamino) -phenyl] -piperazin-1-carboxylic acid t-butyl ester per t-butyl ester of 4- [4- (7-amino-5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid (Example 38), 0.199 g (42%) are obtained ) of the product as a solid. MS (APCl) M + 1: calculated 561; Found 561.
EXAMPLE 40 1-Cyclohexyl-3- | "5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-dlpyrimidin-7-ip-urea By replacing in Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by 4-t-butyl ester. { 4- [7- (3-cyclohexyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 39), the product (compound 12) is obtained as a solid, m.p. 238 ° C (with decomposition). MS (APCl) M + 1: calculated 461; Found 461. á ÉMlllJÉilhilfr * - "-" n ^ * - • fcJ ^ - ^ «** ^" «* '- *"' * '* < * '«*« T? T - frtiff ia EXAMPLE 41 5-Methyl-2-methylsulfanyl-pyridof2.3-dlpyrimidin-7-ylamine Replacing in Example 38 the t-butyl ester of 4- [4- (5-acetyl-4-amino-pyrimidin-2-ylamino) -phenyl] -piperazine-1 -carboxylic acid 1- (4-amino-2 -methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35), 0.97 g (85%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 207; Found 207.
EXAMPLE 42 2-Methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-ylamine Replacing in Example 8 2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine by 5-methyl-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 41 ), 0.85 g (83%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 223; Found 223.
EXAMPLE 43 t-butyl ester of 4-r4- (7-amino-5-methyl-piridor2.3-dlpirimidin-2- ylamino) -fen¡p-piperazin-1 -carboxylic acid Replacing in Example 13 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-ylamine 2-metanosulfin¡l-5-methyl-pyrido [2,3-d] pyrimidin-7- llÉ? j < ? L 1 r j lÜIlili iíÉÉHillifi ~ - ---- - ^ "•" "• • * ^^ ^^ ylamine (Example 42), 0.33 g (20%) of product as a solid. MS (APCl) M + 1: calculated 436; Found 436.
EXAMPLE 44 4- Tertiary butyl ester. { 4-r7- (3-b-Butyl-ureidol-5-methyl-pyrid-2,3-d] pyrimidin-2-ylamino-1-phenyl-1-piperazine-1-carboxylic acid Replacing in Example 10 N2-phenyl-pyrido [2,3-d] pyrimidine-2,7-diamine for t-butyl ester of 4- [4- (7-amino-5-methyl-pyrido [2, 3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid (Example 43), 0.17 g (45%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 535; Found 535.
EXAMPLE 45 1-t-Butyl-3-r5-methyl-2- (4-piperazin-1-yl-fenilaminol-piridof2.3-dlPirimidin-7- yl] -urea By replacing in Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by 4-t-butyl ester. { 4- [7- (3-t-butyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 44), 0.070 g (72%) of the product (compound 4) is obtained as a solid, m.p. 230-232 ° C (with decomposition). É ÉliÉÉÉ É Éff MS MS MS MS (((((((((((((((((((APCl) M + 1: calculated 435; Found 435.
EXAMPLE 46 6-Fluoro-2-methylsulfanyl-8H-pyrido2.3-d1pyrimidin-7-one A solution of 1.74 g (10.33 mmol) of ethyl (dietoxy-phosphoryl) -fluoroacetic acid ethyl ester in 20 ml of tetrahydrofuran is cooled to -78 ° C and treated dropwise with 12.9 ml (20.65 mmol) of a 1.6 M solution of n-butyl lithium in hexanes. After stirring for 30 minutes at -78 ° C, the solution is treated with 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3), allowed to warm to room temperature, and stir overnight. The reaction is treated with saturated ammonium chloride, and then with water. The solid is collected by filtration and washed with diethyl ether to provide 2.01 g (92%) of the product. ~ MS (APCl) M + 1: calculated 212; Found 212 EXAMPLE 47 7-Chloro-6-fluoro-2-methylsulfanyl-pyridof2.3-dlpyrimidine Replacing in Example 6 2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one by 6-fluoro-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7- ona (Example 46), 1.86 g (85%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 230.232; Found 230.232.
EXAMPLE 48 6-Fluoro-2-methylsulfanyl-pyridd2.3-d1-pyrimidin-7-ylamine By replacing in Example 7 7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine by 7-chloro-6-fluoro-2-methylsulfanyl-pyrido [2,3-djpyrimidine (Example 47), 0.29 g (90%) of the product as a solid. MS (APCl) M + 1: calculated 211; Found 211.
EXAMPLE 49 6-Fluoro-2-methanesulfinyl-pyridof2.3-d1-pyrimidin-7-ylamine Replacing in Example 8 2-methylsulfanyl-pyrido [2,3- d] pyrimidin-7-ylamine by 6-fluoro-2-methylsulfanyl-pyrido [2,3-d] pyrimidin-7-ylamine (Example 48), 0.26 g (95%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 227; Found 227.
EXAMPLE 50 4-f4- (7-Amino-6-fluoro-pyridof2.3-d) pyrimidin-2-ylamino) -phenyl-1-cis-2,6-dimethyl-piperazine-1-carboxylic acid t-butyl ester Replacing in Example 27 the 2-methanesulfonyl-pyrido [2,3-d] pyrimidin-7-ylamine by 6-fluoro-2-methanesulfoyl-pyrido [2,3-d] pyrimidin-7- ilamine (Example 49), 0.040 g (63%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 468; found 468.
EXAMPLE 51 4- Tertiary butyl ester. { 4-f7- (3-cyclohexyl-ureido) -6-fluoro-pyridof2.3- d] pyrimidin-2-ylamino-1-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid Replacing in Example 16 the 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester per t-butyl ester 4- [4- (7-amino-6-fluoro-pyrido [2,3- d] pyrimidin-2-ylamino) -phenyl] -cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 50 ), 0.10 g (74%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 593; Found 593.
EXAMPLE 52 1-Cyclohexyl -3-. { 2-l - (cis -3,5-dimethyl-piperazin-1-yl) -phenylamino-6-fluoro-pyridof2.3-dlpyrimidin-7-yl} -urea By replacing in Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid t-butyl ester of 4- acid. { 4- [7- (3-cyclohexyl-ureido) -6-fluoro-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid (Example 51), 0.060 g (75%) of the product (compound 52) are obtained as a solid, m.p. 227-229 ° C. MS (APCl) M + 1: calculated 493; Found 493.
EXAMPLE 53 4- Tertiary butyl ester. { 4-f7- (3-cyclopentyl-ureido) -5-methyl-pyrido T2.3- dlpyrimidin-2-ylaminol-phenyl} -piperazine-1-carboxylic acid Replacing in Example 32 the 4- [4- (7-amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester by 4- [4- (7-Amino-5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester (Example 43) are obtained 0.18 g (55%) of the product as a solid. MS (APCl) M + 1: calculated 547; Found 547.
EXAMPLE 54 1-Cyclopentyl-3-f5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyridof2. 3- dlpyrimidin-7-ip-urea By replacing in Example 15 the t-butyl ester of 4-acid. { 4- [7- (3-t-butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid by 4-t-butyl ester. { 4- [7- (3-cyclopentyl-ureido) -5-methyl-pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid (Example 53), 0.08 g (70%) of the product (compound 53) is obtained as a solid, m.p. 234 ° C fl tf tlrf - "** • * '-" • "^. ^" «^ -» * »* * ^ ...-« - ---.- r ** r4f * «r, ~ *? & k ?. (with decomposition). MS (APCl) M + 1: calculated 447; Found 447.
EXAMPLE 55 4- (4-f7-R3- (3-hydroxy-propyl) -ureido-1-pyrido-2,3-d-pyrimidin-2-ylamino} -phenyl) -piperazine-1-carboxylic acid t-butyl ester By replacing in Example 32 cyclopentylamine with 3-amino-1-propanol, and sodium hydride with sodium t-butoxide, 0.1295 g (52.2%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 523.3; found 523.2.
EXAMPLE 56 1- (3-Hydroxypropyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido-2,3-d-pyrimidin-7-yl] -urea By replacing in Example 15 the product of Example 55, 0.1077 g of the product (compound 81) is obtained as a solid, m.p. 183 ° C (with decomposition). MS (APCl) M + 1: calculated 423.2; Found 423.1. Íit? A? I. ? J «? Lc ^ - '* - *** - Hw -J? F 1 GT * i? i p m mi an ii r - - > ** - ^ - * •. *. T ^., ^^^^ »^, - > - ^? ^^ M. < á¡s ^? á .J- i.
EXAMPLE 57 4- Tertiary butyl ester. { 4-R7- (3-cyclohexyl-3-methyl-ureido) -pyridof2.3-d1-pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid By replacing in Example 55 3-amino-1-propanol with N-methylcyclohexylamine, 0.1932 g (72.7%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 561.3; found 561.2.
EXAMPLE 58 1-Cyclohexyl-1-methyl-3-r2- (4-piperazin-1-yl-phenHamino) -pyrido2.3-d] pyrimidin-7-yl] -urea By replacing in Example 15 the product of Example 57, 0.1645 g of the product (compound 65) is obtained as a solid, m.p. 177 ° C (with decomposition). MS (APCl) M + 1: calculated 461.3; Found 461.2.
EXAMPLE 59 4- (4-. {7-f3 - ((S) -1-Hydroxymethyl-3-methyl-butyl) -ureido) -pyrido [2,3-d] pyrimidin-2-ylamino acid t-butyl ester ) -phenyl) -piperazine-1-carboxylic acid By replacing in Example 55 3-amino-1-propanol with (S) - (+) - leucinol, 0.1048 g (39.1%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 565.3; Found 565.3.
EXAMPLE 60 1- (S) -1-Hydroxymethyl-3-methyl-butyl) -3-f2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-d1-pyrimidin-7-yl-1-urea By replacing in Example 15 the product of Example 59, 0.0802 g of the product (compound 83) is obtained as a solid, m.p. 185 ° C (with decomposition). MS (APCl) M + 1: calculated 465.3; Found 465.2.
EXAMPLE 61 4- [4- (7- { [1- (4-Methyl-piperazin-1-yl) -methanoyl-1-amino} -pyrido [2,3-dl-pyrimidin-2-ylamino] -sy-butyl ester ) -phenill-piperazine-1-carboxylic acid By replacing in Example 55 3-amino-1-propanol with N-methylpiperazine, the product is obtained as a solid. MS (APCl) M + 1: calculated 548.3; found 548.3.
EXAMPLE 62 r2- (4-Piperazin-1-yl-phenylamino) -pyridof2.3-dlpyrimidin-7-in-amide of 4-methyl-piperazin-1-carboxylic acid By replacing in Example 15 the product of Example 61, 0.1194 g of the product (compound 84) is obtained as a solid, m.p. 200 ° C (with decomposition). MS (APCl) M + 1: calculated 448.3; Found 448.2.
EXAMPLE 63 4- (4. {7-f (1-morpholin-4-yl-methanoyl) -amino] -pyridof2.3-dTpyrimidin-2-ylamino} -phenyl) -t-butyl ester piperazine-1-carboxylic By replacing in Example 55 3-amino-1-propanol with morpholine, the product is obtained as a solid. MS (APCl) M + 1: calculated 535.3; Found 535.2.
EXAMPLE 64 r2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amido-1-carboxylic acid amide By replacing in Example 15 the product of Example 63, 0.1132 g of the product (compound 85) is obtained as a solid, m.p. 190 ° C (with decomposition). MS (APCl) M + 1: calculated 435.2; found 435.2.
EXAMPLE 65 4- Tertiary butyl ester. { 4-f7- (3,3-dipropyl-ureido) -pyrido2.3- d] pyrimidin-2-ylamino] -phenyl) -piperazine-1-carboxylic acid By replacing in Example 55 3-amino-1-propanol with dipropylamine, the product is obtained as a solid. MS (APCl) M + 1: calculated 549.3; Found 549.3.
EXAMPLE 66 3-r2- (4-Piperazin-1-yl-phenylamino) -pyridof2.3-dlpyrimidin-7- -yl1-1.1-dipropyl-urea By replacing in Example 15 the product of Example 65, 0.1278 g of the product (compound 86) is obtained as a solid, m.p. 190 ° C (with decomposition). MS (APCl) M + 1: calculated 449.3; Found 449.2. tllr lllt il tlÜlJftf '«* ^^ -'- < ^ - 't- > ^ ^ ^^ - '^ > * ^ «« ^ - ^ ^ ^ ^ ^ ^ ^ ^ hnfc. * -afeifoftm - rv if tltti Éttjij EXAMPLE 67 4- (4- (7- { F1- (4-Boc) piperazin-1-yl) -methanoyl] -amino.} - pyridof2.3-d] pyrimidin-2-ylamino) -phenyl-1-piperazine-1-carboxylic acid By replacing in Example 55 3-amino-1-propanol with Boc-piperazine, the product is obtained as a solid. MS (APCl) M + 1: calculated 634.3; Found 634.3.
EXAMPLE 68 f2- (4-Piperazin-1-yl-phenylamino) -pyridof2.3-piperazine-1-carboxylic acid-3-piperazine-7-ill-amide By replacing in Example 15 the product of Example 67, 0.0342 g of the product (compound 87) is obtained as a solid, m.p. 220 ° C (with decomposition). MS (APCl) M + 1: calculated 434.2; Found 434.2.
EXAMPLE 69 4- (4-. {7-f3 - ((R) -1-Hydroxymethyl-2-methyl-propylene-1-pyrido-2,3-dl-pyrimidin-2-ylamino} - t-butyl ester. phenyl) -Piperazine-1-carboxylic acid Replacing in Example 55 3-amino-1-propanol by (R) - Valinol, you get the product as a solid. MS (APCl) M + 1: calculated 551.3; Found 551.3.
EXAMPLE 70 1 - ((R) -1-Hydroxymethyl-2-methyl-propyl) -3-f2 - (4-piperazin-1-yl-phenylamino) -pyridof2.3-d1-pyrimidin-7-yl-urea By replacing in Example 15 the product of Example 69, 0.0639 g of the product (compound 88) is obtained as a solid, m.p. 200 ° C (with decomposition). MS (APCl) M + 1: calculated 451.3; found 451.2.
EXAMPLE 71 4- (4. {7- [3. 3-bis- (2-hydroxy-ethyl) -ureido] -pyridof2.3-dlpyrimidin-2-ylamino) -phenyl ester - t-butyl ester - piperazine-1-carboxylic By replacing in Example 55 3-amino-1-propanol with dietanolamine, the product is obtained as a solid. MS (APCl) M + 1: calculated 553.3; Found 553.2. if Él Él Él Él Él Él Él "" "" "" "" "" "" "" ^ ^ ^ ^ EJ EJ EJ EJ EXAMPLE 72 1.1-Bis-f2-hydroxy-ethyl) -3-f2- (4-piperazin-1-yl-phenylamino) -pyridor2.3- dlpirimidin-7-ill-urea By replacing in Example 15 the product of Example 71, 0.0916 g of the product (compound 89) is obtained as a solid, m.p. 185 ° C (with decomposition). MS (APCl) M + 1: calculated 453.2; Found 453.2.
EXAMPLE 73 6-Bromo-2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one To 5.00 g (25.9 mmol) of 2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (Example 5) in 130 ml of DMF is added 5.00 g (28.1 mmol) of N-bromosuccinimide. The resulting suspension is stirred at room temperature overnight and concentrated. The solid is triturated with hot water, and then washed with isopropanol to provide 5.59 g (79.4%) of the product as a solid, m.p. 266-270 ° C. il íf it lliiffirfiiÉiilliifai tf ^^ - ^ f - - - ^^. «* - J-Í - ^ * Í- > C »A ^, ^«. «^. H *,». ^,. G? HH »IM- '-i liiElrurr Tf -MilMEM EXAMPLE 74 6-Bromo-7-chloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine By replacing in Example 6 the product of Example 73, 2.73 g (97.2%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 289.9; Found 289.8.
EXAMPLE 75 6-Bromo-2-metMsulfanyl-pyridor2.3-dlpyrimidin-7-tlamine By replacing in Example 7 the product of Example 74, 2.09 g (82.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 271.0; found 270.8.
EXAMPLE 76 6-Bromo-2-methanesulfinyl-pyridof2.3-dlpyrimidin-7-ilamine By replacing in Example 8 the product of Example 75, 1.81 g (81.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 287.0; Found 286.8.
EXAMPLE 77 4- Ethyl t-butyl ester | - (7-amino-6-bromo-p2-o-aryl-2,3-d? Pyrimidin-2-ylamino) -phenyl-piperazine-1-carboxylic acid By replacing in Example 13 the product of Example 76, 1.40 g (44.4%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 500.1; found 500.0.
EXAMPLE 78 4- Tertiary butyl ester. { 4-R6-Bromo-7- (3-cyclohexyl-ureido) -pyrido2.3-dlpyrimidin-2-ylaminol-phenyl} -piperazin-1-carboxylic acid By replacing in Example 16 the product of Example 77, 0.1160 g (46.4%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 625.2; Found 625.1.
EXAMPLE 79 1- [6-Bromo-2 - (4-piperazin-1-yl-phenylamino) -pyridof2.3-d1-pyrimidin-7-yl] -3-cyclohexyl-urea By replacing in Example 15 the product of Example 78, 0.0886 g (77.0%) of the product (compound 55) is obtained as a solid, m.p. 195 ° C (with decomposition).
MS (APCl) M + 1: calculated 525.2; Found 525.1. Analysis calculated for C ^ H ^ BnNsOí • 1.64H2O • 1.83HCI: C, 46.37; H, 5.53; N, 18.02; Cl, 10.44. Found: C, 46.53; H, 5.34; N, 17.73; Cl, 10.15.
EXAMPLE 80 4- Tertiary butyl ester. { 4-f 6-bromo-7- (3-t-butyl-ureido) -pyridof2.3-d1-pyrimidin-2-ylaminol-phenyl} -piperazine-1-carboxylic acid By replacing in Example 10 the product of Example 77, 0.2571 g (42.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 599.2; Found 599.2.
EXAMPLE 81 1-f6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-dlpyrimidin-7-yl-3-t-butyl-urea By replacing in Example 15 the product of Example 80, 0.0481 g of the product (compound 91) is obtained as a solid. MS (APCl) M + 1: calculated 499.2; Found 499.0. .a **********. ***** ** **** »EXAMPLE 82 4- Ethyl t-butyl ester. { 4- [6-Bromo-7- (3-methyl-ureido) -pyrido [2,3-dlpyrimidin-2-ylaminol-phenyl]} -piperazine-1-carboxylic acid By replacing in Example 32 the product of Example 77 and methylamine, 0.170 g (29.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 557.2; Found 557.1.
EXAMPLE 83 1-f6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-d] pyrimidin-7-ill-3-methyl-urea By replacing in Example 15 the product of Example 82, 0.0963 g (69%) of the product (compound 93) is obtained as a solid. MS (APCl) M + 1: calculated 457.1; Found 457.1. Analysis calculated for C? GH21Br? N8O? • 3HCl • 3H2O: C, 36.76; H, 4.87; N, 18.05; Cl, 17.13; H2O, 8..71. Found: C, 36.49; H, 4.35; N, 17.52; Cl, 15.79; H2O, 8.12.
EXAMPLE 84 4-R4- (7-Amino-6-bromo-pyrido-2,3-d1-pyrimidin-2-ylamino) -phene-phenyl-2,6-dimethyl-piperazine-1-carboxylic acid t-butyl ester By replacing in Example 27 the product of Example 76, 2.10 g (63.1%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 528.2; found 528.2.
EXAMPLE 85 4-f4-R6-Bromo-7- (3-t-butyl-ureido) -pyrido2.3-d1-pyrimidin-2-ylamino-1-phenyl < 4 > -cis-2,6-dimethyl-piperazine-1-carboxylic acid By replacing in Example 10 the product of Example 84, 0.1725 g (72.6%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 627.2; Found 627.2.
EXAMPLE 86 1-. { 6-Bromo-2-14- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino-1-pyrido [2,3-dlpyrimidin-7-yl} -3-t-butyl-urea By replacing in Example 15 the product of Example 85, 0.1593 g (96.0%) of the product (compound 94) is obtained as a solid, m.p. 202 ° C (with decomposition). ^ ^ i .ua ^ ^ ah ^ ^ Hl ^ "•" ^ "" - - * • - * --HiMÉffiT? IIIHIME MS (APCl) M + 1: calculated 527.2; found 527.2. Analysis calculated for C24H3? Br? N8O? • 2.55HC1 • 1.70H2O: C, 44.28; H, 5.72; N, 17.21; Cl, 13.89. Found: C, 44.28; H, 5.72; N, 17.09; Cl, 12.49.
EXAMPLE 87 4- Tertiary butyl ester. { 4- [6-Bromo-7- (3-cyclohexyl-ureido) -pyridof2.3-d] pyrimidine-2-ylaminoglyceryl} -cis-2,6-dimethyl-piperazine-1-carboxylic acid By replacing in Example 16 the product of Example 84, 0.1750 g (70.7%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 653.3; Found 653.3.
EXAMPLE 88 1-. { 6-Bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylaminol-pyridof 2.3-d] pyrimidin-7-yl} -3-cyclohexyl-urea By replacing in Example 15 the product of Example 87, 0.1614 g (95.4%) of the product (compound 95) is obtained as a solid, m.p. 198 ° C (with decomposition). MS (APCl) M + 1: calculated 553.2; Found 553.2. Analysis calculated for C26H33N8O? Br? • 2.76HCI • 2.02H2O: C, 45.22; H, 5.81; N, 16.23; Cl, 14.17.
Found: C, 45.23; H, 5.82; N, 16.08; Cl, 13.53.
EXAMPLE 89 N2- (4-Fluoro-phenyl) -pyrido2.3-dlpyrimidine-2.7-diamine By replacing in Example 9 4-fluoroaniline, 1.1529 g (45.2%) of the product is obtained as a solid, m.p. 245-248 ° C. MS (APCl) M + 1: calculated 256.1; Found 255.9.
EXAMPLE 90 1-f2- (4-Fluoro-phenylamino) -pyridof2.3-d1-pyrimidin-7-ip-3- (3-morpholin-4-yl-propyl) -urea Replacing in Example 32 the product of Example 89 and 3-morpholin-4-yl-propylamine, 0.1465 g (58.6%) of the product (compound 96) is obtained as a solid, m.p. 253-256 ° C. MS (APCl) M + 1: calculated 426.2; Found 426.1. Analysis calculated for C2-? H24F? N7O2: C, 59.28; H, 5.69; N, 23.04. Found: C, 59.18; H, 5.66; N, 23.04.
What is it? ? t ^ mv -m | f - "- ** •" - * < "- * - * '•' -.> -..- * -« ** ->. ~~? ***? F - »- -? Üké ^ i EXAMPLE 91 1 -f2- (4 -Fluoro-phenylamino) -pyridof2.3-dlpyrimidn-7-ill-3- (2-hydroxy-ethyl-urea) By replacing in Example 32 the product of Example 89 and 2-hydroxyethylamine, 0.0811 g (40.3%) of the product (compound 97) is obtained as a solid, m.p. 238-240 ° C. MS (APCl) M + 1: calculated 343.1; Found 343.1. Analysis calculated for Ci6H 5F? N6O2: C, 56.14; H, 4.42; N, 24.55. Found: C, 55.82; H, 4.52; N, 24.15.
EXAMPLE 92 1- (2-Amino-ethyl) -3 - \ 2 - (4-fluoro-phenylamino) -pyrido-2,3-d-pyrimidin-7-urea-urea By replacing in Example 32 the product of Example 89 and ethylenediamine, 0.1000 g (49.3%) of the product (compound 98) is obtained as a solid, m.p. 217-220 ° C. MS (APCl) M + 1: calculated 342.1; Found 342.0. Analysis calculated for C 16 H 16 F 1 N 7 O 1 • 0.2 H 2 O: C, 55.71; H, 4.79; N, 28.42.
Found: C, 55.72; H, 4.57; N, 28.07.
EXAMPLE 93 1- (2-Dimethalam8-ethyl) -3-f2- (4-fluoro-phenylamino) -pyridof2.3-d1-pyrimidin-7-yl] -urea By replacing in Example 32 the product of Example 89 and 2-dimethylamino-ethylamine, 0.0778 g (35.8%) of the product (compound 99) is obtained as a solid, m.p. 251-255 ° C. MS (APCl) M + 1: calculated 370.2; Found 370.0. Analysis calculated for C18H20 1N7O1. C, 58.53; H, 5.46; N, 26.54. Found: C, 58.39; H, 5.51; N, 26.26.
EXAMPLE 94 3.3-Dimethyl-1- (4-nitro-phenyl) -piperazine By replacing in Example 24 2,2-dimethyl-piperazine, 29.43 g (88.4%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 236; found 236.
EXAMPLE 95 2,2-Dimethyl-1- (4-nitro-phenyl) -piperazine-1-carboxylic acid t-butyl ester By replacing in Example 11 the product of Example 94. 38 g (93%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 336; Found 336 EXAMPLE 96 4- (4-Amino-phenyl) -2,2-dimethyl-piperazine-1-carboxylic acid t-butyl ester By replacing in Example 12 the product of Example 95, 12.27 g (78%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 306; Found 306.
EXAMPLE 97 4-f4- (7-Amino-6-fluoro-pyrido-2,3-d-pyrimidin-2-ylamino) -pheip-2/2-dimethyl-piperazine-1-carboxylic acid t-butyl ester - ß "^^ By replacing in Example 50 the product of Example 96, 0.4346 g (59.0%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 468.2; found 468.3.
EXAMPLE 98 4- Tertiary butyl ester. { 4-f7- (3-cyclohexyl-ureido) -6-fluoro-pyridof2.3- d1-pyrimidin-2-ylaminol-phenyl) -2,2-dimethyl-piperazine-1-carboxylic acid By replacing in Example 16 the product of Example 97. 0.170 g (31.2%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 593.2; Found 593.4.
EXAMPLE 99 1-Cyclohexyl-3-. { 2-f4- (3,3-Dimethyl-piperazin-1-yl) -phenyl-amino] -6-fluoro-pyrido [2,3-d1-pyrimidin-7-yl} -urea By replacing in Example 15 the product of Example 98, 0.040 g of the product (compound 100) is obtained as a solid. MS (APCl) M + 1: calculated 493.3; Found 493.2.
EXAMPLE 100 4-f4- (7-Amino-6-fluoro-pyridof2.3-dlpyrimidin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid t-butyl ester By replacing in Example 50 the product of Example 12, 0.2017 g (29.7%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 440.2; Found 440.2. lililí 1 Éiiiimi iJ-ti '' - '-i rr? ^ - '** - ^ - * < ^ * - * ~ '^ * f * - < nai * n * nt t -füÍSßM ÉÉit EXAMPLE 101 4- Tertiary butyl ester. { 4- [7- (3-Cyclohexyl-ureido) -6-fluoro-pyridof2.3-dlpyrimidin-2-ylaminol-phenyl} -piperazine-1-carboxylic acid By replacing in Example 16 the product of Example 100, 0.2036 g (78.6%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 565.3; Found 565.3.
EXAMPLE 102 1-Cyclohexyl-3-r6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-d] pyrimidin-7-ip-urea By replacing in Example 15 the product of Example 101, 0.1084 g (96.0%) of the product (compound 11) is obtained as a solid. MS (APCl) M + 1: calculated 465.2; Found 465.2. Analysis calculated for C24H29F1NI • 2.75HCI • 3.5H2O: C, 45.91; H, 5.10; N, 17.85; Cl, 15.53; H2O, 10.04. Found: C, 46.20; H, 5.86; N, 17.45 Cl, 15.22; H2O, 8.97.
EXAMPLE 103 4- < t-butyl ester of acid 4-r7-f3-t-butyl-ureido -6-fluoro-pyridof2.3- d1-pyrimidin-2-ylamino-1-phenyl) -cis-2,6-dimethyl-piperazine-1-carboxylic acid By replacing in Example 10 the product of Example 50, 0.070 g (17.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 567.3; found 567.3.
EXAMPLE 104 1-t-Butyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyridof2.3-d1-pyrimidin-7-yl} -urea By replacing in Example 15 the product of Example 103, 0.0585 g of the product (compound 102) is obtained as a solid. MS (APCl) M + 1: calculated 467.3; Found 467.3.
EXAMPLE 105 1- [4- (4-Nitro-phenyl) -piperazinyl] -ethanone To a solution of 5.0 g (24.1 mmol) of 1- (4-nitro-phenyl) -piperazine in 100 mL of dichloromethane was added 5.04 mL (28.9 mmol) of diisopropyl-ethylamine. The solution is cooled in an ice bath, treated with 1.89 ml (26.5 mmol) of acetyl chloride, and stirred at room temperature. during one night. The reaction is washed successively with water, 0.5 M HCl, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and concentrated to provide 5.91 g (98.5%) of the product as a solid. MS (APCl) M + 1: calculated 250.1; Found 250.0.
EXAMPLE 106 1-f4- (4-Amino-phenyl) -piperazinyl] -ethanone By replacing in Example 12 the product of Example 105, 4.35 g (84.1%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 220.1; Found 220.1.
EXAMPLE 107 1-. { 4- [4- (7-Amino-pyrido [2,3-d] pyrimidin-2-ylamino) -phenyl-1-piperazin-1-yl} - Etanone By replacing in Example 9 the product of Example 106, 0.1829 g (50.1%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 364.2; Found 364.2. Analysis calculated for C19H21N7O1 • 1.0H2O: C, 59.46; H, 6.11; N, 25.55. Found: C, 59.51; H, 6.03; N, 25.28.
EXAMPLE 108 1-. { 2-f4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyridof2.3-d1-pyrimidin-7-yl} -3- (3- morpholin-4-yl-propyl) -urea Replacing in Example 32 the product of Example 107 and 3-morpholin-4-yl-propylamine, 0.0338 g (22.6%) of the product (compound 103) is obtained as a solid, m.p. 222-225 ° C (with decomposition). MS (APCl) M + 1: calculated 534.3; found 534.2. Analysis calculated for C27H35N9O3 • 0.5H2O: C, 59.76; H, 6.69; N, 23.25. Found: C, 59.74; H, 6.53; N, 23.35.
EXAMPLE 109 6-Chloro-2-methylsulfanyl-8H-pyridor 2. 3 -dlpyrimidin-7-one Replacing in Example 74 N-chlorosuccinimide, 0.3700 g (31.4%) of the product is obtained as a solid, m.p. 264-266 ° C (with decomposition). MS (APCl) M + 1: calculated 228.0; found 227.9.
EXAMPLE 110 6. 7 -Dichloro-2-methylsulfanyl-pyrido [2,3-d] pyrimidine By replacing in Example 6 the product of Example 109, 0.6534 g (86.5%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 246.0; Found 245.8.
EXAMPLE 111 6-Chloro-2-methylsulfanyl-pyrido [2,3-dlpyrimidin-7-ylamine By replacing in Example 7 the product of Example 110, 0.38 g (63%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 227.0; Found 226.9.
EXAMPLE 112 6-Chloro-2-methanesulfinyl-pyridof 2. 3 -dlpyrimidin-7-i lamina By replacing in Example 8 the product of Example 111. 0.2328 g (57.1%) of the product is obtained as a solid, m.p. 260-262 ° C. MS (APCl) M + 1: calculated 243.0; found 242.9.
EXAMPLE 113 4-r4-f7-amino-6-chloro-pyrimido-2,3-d-pyrimidin-2-ylamino) -phenyl-1-cis-2,6-dimethyl-piperazine-1-carboxylic acid t-butyl ester By replacing in Example 27 the product of Example 112, 0.22 g (49%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 484.2; found 484.2.
EXAMPLE 114 4- (4-f7- (3-t-Butyl-ureido) -6-chloro-pyridof2.3-d] pyrimidin-2-ylamido-phenyl} -cis-2.6- acid t-butyl ester dimethyl-piperazine-1-carboxylic acid By replacing in Example 10 the product of Example 113, 0.0995 g (39.2%) of the product is obtained as a solid.
EXAMPLE 115 1-t-Butyl-3-. { 6-chloro-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylaminol-pyridof2.3-d] pyrimidin-7-yl} -urea By replacing in Example 15 the product of Example 114, 0.0995 g of the product (compound 104) is obtained as a solid, m.p. 205 ° C (with decomposition). MS (APCl) M + 1: calculated 483.2; found 483.2.
IléiiltlftliHÉlillliiíif i *** «- ~ - --- ••• - • • • * - - - - * -.-- && EXAMPLE 116 Methyl- (2-methylsulfanyl-pyridof2.3-d] pyrimidin-7-yl) -amine By replacing in Example 7 methylamine, 1.46 g (30.0%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 207.1; Found 206.9.
EXAMPLE 117 (2-Methanesulfinyl-pyrido [2,3-dlpyrimidin-7-yl) -methyl-amine By replacing in Example 8 the product of Example 116, 1.31 g (83.4%) of the product is obtained as a solid, m.p. 185 ° C. MS (APCl) M + 1: calculated 223.1; Found 223.0.
EXAMPLE 118 4- [4- (7-Methylamino-pyridof2,3-dlpyrimidin-2-ylamino) -phenyl-piperazine-1-carboxylic acid t-butyl ester By replacing in Example 13 the product of Example 117, 0.4934 g (62.9%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 436.2; Found 436.2.
EXAMPLE 119 4-f4-R7- (3-cyclohexyl-1-methyl-ureido) -pyridof2.3-d] pyrimidin-2-n-phenyl ester t-butyl ester} -piperazine-1-carboxylic acid By replacing in Example 16 the product of Example 118. and using acetonitrile as solvent and no base, 0.8535 g (78.8%) of the product is obtained as a solid. MS (APCl) M + 1: calculated 561.3; found 561.3.
EXAMPLE 120 3-Cyclohexyl-1-methyl-1-f2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-d] pyrimidin-7-yl] -urea By replacing in Example 15 the product of Example 119, 0.2548 g (36.0%) of the product (compound 70) is obtained as a solid, m.p. 169-175 ° C. MS (APCl) M + 1: calculated 461.3; Found 461.2. Analysis calculated for C29H32N8O? • 0.25H2O: C, 64.56; H, 7.04; N, 24.09. Found: C, 64.57; H, 7.01; N, 23.98.
EXAMPLE 121 3-Cyclohexyl-1-. { 2-r4- (cis-3,5-dimethyl-piperazin-1-ip-phenylamino-1-pyridof2.3-d] pyrimidin-7-yl}. -1-methyl-urea Using the general procedure by which Example 120 has been synthesized, 0.1366 g (95.6%) of the product (compound 106) is obtained as a solid, m.p. 170 ° C (with decomposition). MS (APCl) M + 1: calculated 489.3; found 489.3. Analysis calculated for • 3.32H2O • 2.69HCI: C, 50.16; H, 7.07; N, 17.33; Cl 14.75. Found: C, 50.36; H, 6.98; N, 16.97; Cl 15.07.
EXAMPLE 122 3-Cyclohexyl-1-ethyl-1- [2- (4-piperazin-1-yl) -phenylamino) -pyridor-2,3-d-pyrimidin-7-yl-urea Using the general procedure by which Example 120 has been synthesized, 0.118 g (94%) of the product (compound 107) is obtained as a solid. MS (APCl) M + 1: calculated 475.3; Found 475.3. Analysis calculated for C26H34N80? • 3.OHCl • O.dietylether: C, 53.89; H, 6.65; N, 18.48. Found: C, 53.75; H, 6.96; N, 18.57.
EXAMPLE 123 3-t-Butyl-1- (2-f4- (cis-3,5-dimethyl-piperazin-1-p-phenyl-amino-pyridof2.3-d1-pyrimidin-7-yl}.
Using the general procedure by which Example 15 has been synthesized, 0.022 g (56%) of the product (compound 108) is obtained as a solid. MS (APCl) M + 1: calculated 477.3; Found 477.3.
EXAMPLE 124 1-Methyl-3-f5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d1-pyrimidin-7-n-urea Using the general procedure by which Example 40 has been synthesized, the product (compound 64) is obtained as a solid, m.p. 204-206 ° C (with decomposition). MS (APCl) M + 1: calculated 393; Found 393.
EXAMPLE 125 1-Ethyl-3-f5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido-2,3-dlpyrimidin-7-urea-urea Using the general procedure by which it has been synthesized in Example 40, the product (compound 28) is obtained as a solid, m.p. 220-222 ° C (with decomposition). MS (APCl) M + 1: calculated 407; Found 407.
EXAMPLE 126 1- [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyridon-2, 3-d, pyrimidin-7-yl] -3-propi I-urea Using the general procedure by which Example 40 has been synthesized, the product (compound 111) is obtained as a solid, m.p. 223-225 ° C. MS (APCl) M + 1: calculated 421; Found 421.
EXAMPLE 127 N.N-Dimethyl-N- [5-methyl-2-rf4- (1-piperazinyl) phenyl-1-amino] -pyridof2.3-dlpyrimidin-7-yl-sulfamide Using the general procedure by which Example 40 has been synthesized, but using dimethyl sulfamyl chloride in place of cyclohexyl isocyanate, the product (compound 71) is obtained as a solid, m.p. 228-230 ° C (with decomposition). MS (APCl) M + 1: calculated 443; Found 443.
EXAMPLE 128 7-Amino-2-methylsulfanyl-pyridof2.3-d] pyrimidine-6-carboxylic acid ethyl ester To a solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 10 ml of tetrahydrofuran is added 0.126 ml (1.18 mmol) of ethyl cyanoacetate. The solution is cooled to -10 ° C, and treated with 2.36 ml (2.36 mmol) of titanium tetrachloride. 0.52 ml (4.72 mmol) of N-methylmorpholine are slowly added to the solution. The reaction is warmed to room temperature over the course of 2 hours, and is partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer is concentrated to provide a solid, which is triturated with ether to provide 0.30 g (96%) of the product as a solid. MS (APCl) M + 1: calculated 265.1; found 264.9.
EXAMPLE 129 7-Amino-2-chloro-pyridof2.3-d] pyrimidine-6-carboxylic acid ethyl ester To a suspension of the product of Example 128 in 50 ml of chloroform is slowly added sulfuryl chloride, followed by 2 drops of ethanol. The reaction is stirred at room temperature for 16 hours, poured into ether, and the solid collected to provide 0.50 g (98%) of the product.
Bi i LaiMiÉii e iüm i? I? R? Irtiit > ^ * '^' - ^^ A ^ j ^, ^,? * I!, A "* ii ** MS (APCl) M + 1: calculated 253 1, found 253 1.
EXAMPLE 130 7-Amino-2- [4- (4-t-butoxycarbonyl-piperazin-1-yl) -phenylamino-1-pyridof2.3-d] pyrimidine-6-carboxylic acid ethyl ester A dioxane solution of the product of Example 12 and the product of Example 129 is heated at reflux for 1.5 hours. The reaction is poured into hexane / ethyl acetate (1: 1), and the solid is collected. Flash chromatography using dichloromethane as eluent provides 0.08 g (16%) of the product as a solid. MS (APCl) M + 1: calculated 494.2; Found 494.1.
EXAMPLE 131 Ethyl ester of 2-f4- (4-t-butoxycarbonyl-piperazin-1-yl) -phenylamino-7- (3-t-butyl-ureido) -pyrido [2,3-d1-pyrimidine-6-carboxylic acid] By replacing in Example 10 the product of Example 130, 0.05 g (48%) of the product is obtained as a solid.
EXAMPLE 132 7- (3-t-Butyl-ureido) -2- (4-piperazin-1-yl) -phenylamino) -pyridof2.3-d1-pyrimidine-6-carboxylic acid ethyl ester By replacing in Example 15 the product of Example 131, 0.036 g of the product (compound 113) is obtained as a solid, m.p. > 300 ° C.
EXAMPLE 133 1-f6-Fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyridof2.3-dlpyrimidin-7-yl-3-isopropyl-urea Using the general procedure by which Example 52 has been synthesized, but using as reactants 1- (4-amino-2-methylsulfanyl-pyrimidin-5-yl) -ethanone (Example 35), t-butyl ester of 4-amino acid - (4-Amino-phenyl) -piperazine-1-carboxylic acid (Example 12), isopropyl socianate, the product (compound 114) is obtained as a solid, mp. 208 ° C (with decomposition). MS (APCl) M + 1: calculated 439.2; Found 439.3.
EXAMPLE 134 1-Cyclohexyl-3-. { 2-r4- (3,3-Dimethyl-p-piperazin-1-yh-phenylamino-1-pyrid-2,3-d1-pyrimidin-7-yl) -urea Using the general procedure by which Example 17 has been synthesized, but using 4- (4-amino-phenyl) -2,2-dimethyl-plperazin-1-carboxylic acid t-butyl ester (Example 96), 0.95 g (100%) of the product (compound 115) as a solid. MS (APCl) M + 1: calculated 475.6; Found 475.3. Analysis calculated for C29H34N80? • 3HCI • 1H20: C, 51.96; H, 6.37; N, 18.64; Cl, 17.69; H20, 2.99. Found: C, 52.00; H, 6.41; N, 18.53; Cl, 16.51; H2O, 3.06.
EXAMPLE 135 6-Methyl-2-methylsulfanyl-pyridof2.3-d] pyrimidin-7-yl-amine To a suspension in 300 ml of tetrahydrofuran of 2.18 g (54 mmol) of sodium hydride dispersed at 60% in oil, cooled to 10 ° C, are added 10.2 g (53.4 mmol) of diethyl ester of acid (1-cyano- 1-methyl-methyl) -phosphonic (Synthesis, 1975: 516). 4.30 g (25.4 mmol) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (Example 3) are added to the cooled suspension, and the reaction is stirred at room temperature for 22 hours. The resulting solution is concentrated and filtered to provide a solid, which it is washed with tetrahydrofuran, dissolved in 1N citric acid, and reprecipitated by adjusting the pH to 8 with 50% sodium hydroxide. The solid is collected by filtration to provide 1.1 g (21%) of the product, m.p. 268-270 ° C. MS (APCl) M + 1: calculated 207.3; found 207.0.
EXAMPLE 136 1-Cyclohexyl-3-. { 2-r4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino-1-6-methyl-pyridof2.3-d1-pyrimidin-7-yl} -urea Using the general procedure by which Example 31 has been synthesized, but using the product of Example 135 as a starting material, 0.14 g (42%) of the product (compound 116) is obtained as a solid. MS (APCl) M + 1: calculated 589.6; found 589.3. Analysis calculated for C27H36N8O? • 2.5HCl 1.5H2O: C, 53.80; H, 6.73; N, 18.01; Cl, 14.11; H20, 4.06. Found: C, 53.44; H, 6.89; N, 18.46; Cl, 14.60; H2O, 4.48.
EXAMPLE 137 1-t-Butyl-3-f 2 -f 4 - (cis-3,5-d.methyl-piperazin-1-yl) -phenylamino-1-6-methyl-pyrido [2,3-d-pyrimidin-7-yl} -urea Using the general procedure by which Example 29 has been synthesized, but using the product of Example 135 as a starting material, 0.26 g (89%) of the product (compound 117) is obtained as a solid. MS (APCl) M + 1: calculated 463.6; Found 463.3. Analysis calculated for C25H36N80? • 2.4HCI • 1.75H20: C, 51.62; H, 6.91; N, 19.26; Cl, 14.63; H20, 5.42. Found: C, 51.23; H, 6.55; N, 18.92; Cl, 14.73; H20, 5.10.
EXAMPLE 138 1-t-Butyl-3- [6-methyl-2- (4-piperazin-1-yl) -phenylamino-pyrido [2,3-dlpyrimidin-7-ill-urea] Using the general procedure by which Example 15 has been synthesized, but using the product of Example 135 as the starting material, 1.02 g (100%) of the product (compound 118) is obtained as a solid. MS (APCl) M + 1: calculated 435.3; found 435.3. Analysis calculated for C23H3oN8O? • 5HCl • 1.75H2O: C, 42.60; H, 5.98; N, 17.28; Cl, 27.34; H2O, 4.86. Found: C, 42.03; H, 6.04; N, 16.81; Cl, 22.95; H2O, 4.72.
EXAMPLE 139 1-. { 2- f4- (cis-3,5-Dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyridof2.3-dlpyrimidin-7-yl) -3-isopropyl-urea Using the general procedure by which Example 33 has been synthesized, but using the product of Example 135 as a starting material, together with 4 - (4-aminophenyl) -cis- 2,6-dimethyl-tert-butyl ester piperazine-1-carboxylic acid and isopropylamine as reactants, 0.130 g (100%) of the product (compound 119) is obtained as a solid. MS (APCl) M + 1: calculated 449.3; Found 449.3. Analysis calculated for C24H32N80? • 3HCI • 1.75H2O: C, 48.90; H, 6.58; N, 19.01; Cl, 16.04; H20, 5.35. Found: C, 49.03; H, 6.63; N, 18.70; Cl, 16.03; H2O, 5.19.
EXAMPLE 140 1-Cyclopropyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino-1-6-methyl-pyridof2.3-dlpyrimidin-7-yl} -urea Using the general procedure by which Example 33 has been synthesized, but employing the product of Example 135 as the starting material, together with 4- (4-aminophenyl) -cis-2,6-dimethyl- t-butyl ester piperazine-1-carboxylic acid and cyclopropylamine as reactants, 0.099 g (100%) of the product (compound 120) is obtained as a solid.
MS (APCl) M + 1: calculated 447.3; Found 447.3. Analysis calculated for C24H30N8O ?: C, 49.83; H, 6.19; N, 19.37; Cl, 18.39; H2O, 3.89. Found: C, 49.76; H, 6.23; N, 18.92; Cl, 15.66; H2O, 3.06.
EXAMPLE 141 1-t-Butyl-3- (2-f4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-ethyl-pyridof2.3-d1-pyrimidin-7-yl} -urea Using the general procedure by which Example 137 has been synthesized, but using diethyl ester of (1-cyano-propyl) -phosphonic acid as a starting material, 0.34 g (95%) of the product (compound 121) is obtained as a solid. MS (APCl) M + 1: calculated 477.3; Found 477.3. Analysis calculated for C26H26N8O? • 2.5HCI - 1 H2O: C, 53.26; H, 7.05; N, 19.11; Cl, 15.18; H20, 3.07. Found: C, 53.63; H, 7.31; N, 18.46; Cl, 15.32; H2O, 3.48.
EXAMPLE 142 The following compounds are prepared essentially in accordance with the procedures described in Examples 1-141, and which are shown in Schemes 1-4: (a) 1-t-Butyl-3- [2- (3-chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 2); (b) 1-t-Butyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 3); (c) 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea (compound 6); (d) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea (compound 7); (e) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea (compound 8); (f) 1 - [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -3-cyclohexyl-urea (compound 10); (g) 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl urea (compound 13); (h) 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl urea (compound 14); (i) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl urea (compound 15); 0) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl urea (compound 16); (k) 1- (2-Hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 17) ); (1) 1- [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido- [2,3- • ifiliilitf? T '?? Jyridin-7-yl] -3- (2-hydroxy-ethyl) -urea (compound 18); (m) 1- [6-Fluoro-2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) ) -urea (compound 19); (n) 1- (2-Hydroxy-ethyl) -3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 20); (o) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] -pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea (compound 21); (p) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenyl-amino] -pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea (compound 22); (q) 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea (compound 23); (r) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea (compound 24); (s) 1-Ethyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -urea (compound 25); (t) 1 - [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -3-ethyl-urea (compound 26) ); (u) 1-Ethyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 27); (v) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea (compound 29); (w) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea (compound 30); illlÉJ ll JlilBÜIllitl iÉ rl) 1f - A ^ "~ • ftfe - ^ - 1" ^ - ^ il? lWip? i? tilnnlnir- • ^ - ^ •. * - * »- 'U' ^ * (x) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea (compound 31); (y) 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea (compound 32); (z) 1-t-Butyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 33); (aa) 1-Cyclohexyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 34); (bb) 1-Ethyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 35); (ce) 1- (H -droxy-ethyl) -3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 36); (dd) 1-t-Butyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 37); (ee) 1-Cyclohexyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-d] -pyrimidin-7-yl] -urea (compound 38); (ff) 1-Ethyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -urea (compound 39); (gg) 1- [6-Fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-d] -pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea (compound 40); (hh) 1-t-Butyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -urea (compound 41); (ii) 1-Cyclohexyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3- - i.sub.10 aje.r d] pyrimidin-7-yl] -urea (compound 42); (jj) 1-Ethyl-3- [5-methyl-2- (pyridin-4-ylammon) -pyrido- [2,3-d] pyrimidin-7-yl] -urea (compound 43 ); (kk) 1- (2-Hydroxy-ethyl) -3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea (compound 44); (11) 1-Cyclohexyl-3- [6-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 54); (mm) 1-Cyclohexyl-3- [6-cyano-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 56); (nn) 1-Cyclohexyl-3- [6-chloro-2- (4-piperazin-1-yl-phenylamino) -pyridono [2,3-d] pyrimidin-7-yl] -urea (compound 57); (oo) 1-Cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 58); (pp) 1-Cyclohexyl-3- [6-bromo-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 59); (qq) 1-Cyclohexyl-3- [6-chloro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 60); (rr) 1-lsopropyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 61); (ss) 1- [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea (compound 63); (tt) 1- (4-Hydroxy-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 66); (uu) 1- (4-Amino-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 67); (w) 1- (2-Dimethylamino-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 68); (ww) 1- (3-Morpholino-4-yl-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 69); (xx) 1-Cyclohexyl-3 - [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -thiourea (compound 72); (yy) N- [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -acetamide (compound 73); (zz) 4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -benzenesulfonamide (compound 74); (aaa) 1-Cyclohexyl-3-. { 2- [4- (1-Piperazin-1-yl-methanoyl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea (compound 75); (bbb) 1-Cyclohexyl-3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea (compound 76); (ccc) 1 - (2- { 4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino.} - pyrido [2,3-d] pyrimidine- 7-yl) -3-cyclohexyl urea (compound 77); and (ddd) 1- (2- { 4- [4- (2-Amino-3-methyl-butanoyl) -piperazin-1-yl] -phenylamino.} - pyrido [2,3-d] ] pyrimidin-7-yl) -3-cyclohexyl-urea (compound 78).
EXAMPLE 143 Biological assay As noted above, the compounds of this invention are potent inhibitors of cdks and, accordingly, are useful for treating and preventing atherosclerosis and other cell proliferative disorders such as cancer, which are mediated by such cdk enzymes. . The compounds exhibit excellent inhibitory activity against several cdk enzymes, including cdkl / cyclinB, cdk2 / cyclin, cdk2 / cyclin, and cdk4 / cyclin, when evaluated in standard assays routinely used by those skilled in the art to measure inhibitory activities of cdk. Typical tests are carried out in the following manner.
Cyclin-dependent kinase 4 assay (cdk4) Enzymatic assays for Cl50 determinations and kinetic evaluation are performed on 96-well filter plates (Millipore MADVN6550). The total volume is 0.1 ml, which contains a final concentration of 20 mM TRIS (tris [hydroxymethyl] aminomethane), at pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl 2, 25 μM ATP containing 0.25 μCi of [32P ] ATP, 20 ng of cdk4, 1 μg of retinoblastoma, and appropriate dilutions of a compound of the present invention. All the components except the ATP are added to the wells, and the plate is placed in a plate mixer t Aá áAr - * - ff | tf iAf -? ft ?? ki * ~. ~. < * a-? 1"• - *" • - - "*" • * - • * - * * * HU ilílMifÜ ¡f ti mi '"" "'" ma "fa" JM > "*" - ** "" * * * -át? Íl? * "for 2 minutes, start the reaction by adding [32 P] ATP, and incubate the plate at 25 ° C for 15 minutes, finish the reaction by adding 0.1 ml of 20% trichloroacetic acid (TCA). plate at 4 ° C for at least 1 hour to allow the substrate to precipitate, then the wells are washed 5 times with 0.2 ml of 10% TCA and the incorporation of "P with a beta plate counter ( Wallac Inc., Gaithersburg, MD).
Cyclin-dependent kinase 1 and 2 assays (cdkl / cyclin B, cdk2 / cyclin, cdk2 / cyclinE) Enzymatic assays for IC50 (Table 2) and kinetic evaluation are performed on 96-well filter plates (Millipore MADVN6550 ), in a total volume of 0.1 ml of TRIS (tris [hydroxymethyl] aminomethane) 20 mM, at pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, MgCl2, 10 mM, 12 μM ATP containing 0.25 μCi of [32 P] ATP, 20 ng of enzyme (cdk1 / B, cdk2 / A, or cdk2E), 1 μg of retinoblastoma, and appropriate dilutions of the particular compound of the invention. All the components except the ATP are added to the wells, and the plate is placed in a plate mixer for 2 minutes. The reaction is started by adding [32 P] ATP, and the plate is incubated at 25 ° C for 15 minutes. The reaction is terminated by adding 0.1 ml of 20% trichloroacetic acid (TCA). The plate is maintained at 4 ° C for at least 1 hour to allow the substrate to precipitate. The wells are then washed 5 times with 0.2 ml of 10% TCA and Y, ,". h ... ^ m, < .... m, t "S-_ ..," ¿^ .. ^., ^ Lj ^ f. ^ -. »-. determines the incorporation of 32P with a beta counter for plates (Wallac Inc., Gaithersburg, MD).
Proline-directed protein kinase assay for cyclin-dependent 5 / p25 kinase Enzyme source: recombinant cdk5-p25 complex expressed in insect sf9 cells infected with recombinant baculovirus.
Purpose: to evaluate the ability of the test agents to inhibit histone Hl phosphorylation by cdk5 / p25.
Method: Enzyme-labeled cdk5 complex in His / p25 labeled in Glu, from insect-baculovirus cells, was diluted at a concentration of 50 ng / 20 μl in enzyme dilution buffer (EDB - 50 mM Tris-HCl [pH 8, 0], 10 mM NaCl, 10 mM MgCl 2, and 1 mM DTT). A 20 μl sample of test agent (diluted in EDB) is then combined with 20 μl of the final cdk5 / p25 enzyme preparation, and allowed to stand for 5 minutes at room temperature. Then twenty-five microliters of substrate solution containing 115 μl / ml of Histone Hl, ATP (free of vanadate) 30 μM, and Y-32P ATP 30 μCi / ml (Amersham) are added to the test agent / enzyme preparation. in EDB, and shaken by shaking at 30 ° C for 45 minutes. A 50 μl sample of the final preparation is added to 100 ml of 150 mM phosphoric acid, on ice, for 30 minutes to facilitate precipitation. The precipitate is then filtered through a 96-well phosphocellulose filter plate and subsequently rinsed 3 times with 75 mM phosphoric acid. Next, each well receives 20 μl of scintillation cocktail, and the plates are counted in terms of beta emissions using a Trilux Counter (32P filter protocol). The beta emissions of the test samples are compared with those of the control (without test agent present, taken as 0% - of inhibition) and with those of the baseline (without enzyme, without test agent; 100% inhibition) to determine the inhibition percentage of Histone H1 phosphorylation. The results of the preceding tests for representative compounds of the invention are presented in Table 2 below. The compounds of the invention show IC 50 values ranging from 0.027 μM to > 5 μM versus cdk1 / B, from 0.010 μM to > 5 μM versus cdk2 / A, from 0.020 μM to > 5 μM versus cdk2 / E, and from 0.004 μM to > 5 μM versus cdk4 / D. The most potent compound globally is compound 9, which has IC50 values of 0.027 μM, 0.010 μM, 0.020 μM, 0.005 μM, versus cdk1 / B, cdk2A, cdk2E, and cdk4D, respectively.
TABLE 2 Cdks inhibition; Ciso iuMi Compound Cdk1 / B Cdk2 / A Cdk2 / E Cdk4D 1 0.219 0.060 0.130 0.006 4 > 5 > 5 > 5 1.5 D * J. * Q 0. 30 0.130 0.037 9 0.027 0.010 0.020 0.005 1 1 0.159 0.092 0.125 0.011 > 5 > 5 45 0.552 0 054 0.1 10 0 045 46 0.075 0.300 > 5 47 > 5 > 5 > 5 > 5 49 0.91 1 0.528 0.475 0.050 50 0.069 0.022 0.035 0.007 52 0.472 0.213 0.126 0.027 53 > 5 > 5 > 5 > 5 55 > 5 > 5 > 5 0.300 64 > 5 > 5 > 5 > 5 > 5 - > t ^ "* 5> 5 70 1,448 0.697 0.530 0.017 71 > 5 > 5 > 5 > 5 - r- 1.066 80 0.461 0.092 0.230 0.460 81 2 610 1 560 3,250 0.500 83 0.399 0.305 0.315 0.055 84 > 5 > 5 > 5 > 5 5 > 5 5 86 > 5 > 5 > 5 > 5 87 > 5 > 5 > 5 > 5 89 > 5 > 5 91 > 5 > 5 > 5 0.070 93 > 5 > 5 > 5 > 5 94 > 5 0.101 96 6.365 1.108 1.550 > 5 97 0.862 0.278 0.345 > 5 99 1. 810 1. 012 0.410 > 5 100 0.265 0.153 0 415 0.035 102 3,130 3,590 4,500 0.165 fc-fcta-i. Á - ¿fc ^ 103 > 5 > 5 > 5 > 5 104 > 5 > 5 > 5 0.185 106 0.350 0.440 107 1.728 1.950 1.650 0.019 108 2.425 2. 035 3.050 0.067 111 > 5 > 5 > 5 > 5 113 > 5 > 5 > 5 3,000 114 > 5 > 5 > 5 > 5 115 0. 094 0. 022 0. 051 0.007 116 > 5 > 5 3. 750 0.313 117 > 5 > 5 4. 000 0.076 118 > 5 > 5 3,800 0.079 119 > 5 > 5 > 5 1,600 120 > 5 > 5 > 5 1,900 121 > 5 > 5 > 5 0.092 The compounds of this invention are also inhibitors of growth factor receptor tyrosine kinase enzymes, FGFr and PDGFr, and of receptor-unrelated tyrosine kinase enzyme, c-Src. Several of the compounds of the invention have been evaluated by means of standard assays that measure their ability to inhibit tyrosine kinase enzymes. These tests are carried out in the following manner: PDGF and FGF receptor tyrosine kinase assays. Full-length cDNAs are obtained from J.Escobe for mouse PDGF-P receptor tyrosine kinases and human FGF-1 (flg), and are prepared as described in J. Biol. Chem., 1991; 262: 1482-1487. PCR primers are designed to amplify a DNA fragment encoding the intracellular tyrosine kinase domain. The fragment is inserted into a baculovirus vector, cotransfected with AcMNPV DNA, and the virus is isolated recombinant. Insect SF9 cells are infected with the virus to over-express the protein, and the cell lysate is used for the assay. Assays are performed in 96-well plates (100 μl / incubation / well), and conditions are optimized to measure the 32P incorporation from y32P "ATP to a glutamate-tyrosine copolymer substrate. well 82.5 μl of incubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na3VO4, 10 mM MnCl2, and 750 μg / ml poly (glutamate tyrosine) (4: 1), followed by 2.5 μl of inhibitor and 5 μl of enzyme lysate (FGF-TK 7.5 μg / μl or PDGF-TK 6.0 μg / μl) to initiate the reaction. 10 minutes at 25 ° C, 10 ml of y32p-ATP (0.4 μCi plus 50 μM ATP) are added to each well, and the samples are incubated for an additional 10 minutes at 25 ° C. The reaction is terminated by the addition of 100 μl of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate, and precipitation of material on fiberglass locks (Wallac). wash 3 times the filters with 15% TCA containing 100 mM sodium pyrophosphate, and the radioactivity retained in the filters is counted by means of a Wallac 1250 Betaplate reader. The non-specific activity is defined as the radioactivity retained in the filters after incubation of samples with only buffer (without enzyme). The specific enzymatic activity (enzyme plus buffer) is defined as total activity minus non-specific activity. The% inhibition is determined at 50 μM, and for the most potent compounds the concentration of the compound that has 50% inhibited the specific activity (C o) is determined. based on the inhibition curve.
C-Src kinase assay c-Src kinase was purified from Used from baculovirus-infected insect cells, using an antipeptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src. The antiquake, covalently bound to 0.65 μm latex beads, is added to a suspension in insect cell lysis buffer composed of 150 mM NaCl, 50 mM Tris pH 7.5, 1 mM DTT, 1% NP-40, 2 mM EGTA , 1 mM sodium vanadate, 1 mM PMSF, 1 μg / ml leupeptin, 1 μg / ml pepstatin, and 1 μg / ml aprotinin. The insect cell lysate containing c-Src protein is incubated with these beads for 3 to 4 hours, at 4 ° C, with rotation. Once the incubation with lysate is complete, the beads are rinsed 3 times in lysis buffer, resuspended in lysis buffer containing 10% glycerol, and frozen. The latex beads are thawed, rinsed 3 times in assay buffer (40 mM Tris, pH 7.5, 5 mM MgCl 2), and suspended in the same buffer. To a 96-well Millipore plate, with a 0.65 μm polyvinylidene membrane bottom, the reaction components are added: 10 μl of c-Src beads, 10 μl of poly (GluTyr) substrate 2.5 mg / ml, 5 μM ATP. containing 0.2 μCi of labeled 32P-ATP, 5 μl of DMSO containing inhibitors or as control solvent, and buffer to make the final volume to be 125 μl. The reaction is started at room temperature by the addition of ATP, and deactivated 10 minutes later by adding 125 μl of 30% TCA and 0.1 M sodium pyrophosphate, for 5 minutes and on ice. The plate is then filtered, the wells are washed with two aliquots of 250 ml of 5% TCA and 0.1 M pyrophosphate. The filters are then drilled, counted in a liquid scintillation counter, and the data examined. to the inhibitory activity compared to a known inhibitor such as erbstatin. The method is also described in J. Med. Chem., 1994; 37: 598-609. In Table 3 the inhibitory activity of tyrosine kinases is shown for representative compounds of the invention evaluated in the preceding tests.
TABLE 3 Inhibition of tyrosine kinases. % inhibition at 50 μM (C n [μM] in parentheses when determined) Compound PDGFr FGFr 1 94.4 (0.593) 93. 7 9 89. 8 11 (0.131) (0.284) 45 21. 9 67.4 46 17.5 19.5 47 10.5 55 (0.033) (0.151) 70 (0.536) (1/15) 80 18 6 117 (0.081) (0.061) »,, ...», ... y¿m * • ... - *. * - - - •• "'Js.ja ^ = Aaaa» > Lfa * aafcj * ~ »L -» «^ 1 As noted above, the invention also provides pharmaceutical compositions comprising a compound of the invention combined with a carrier, diluent, or excipient. The following examples illustrate typical compositions provided by this invention.
EXAMPLE 144 A pharmaceutical composition is prepared in the form of hard gelatin capsules for oral administration, using the following ingredients: Amount (mg / capsule) Active compound 250 Powdered starch 200 Magnesium stearate 10 Total 460 The above ingredients are mixed and mixed. They are packaged in hard gelatine capsules, in quantities of 460 mg. A typical active ingredient is 1- isobutyl-3- [2-. { (2-chloro-4-piperazin-1-yl) -phenylamino} -py [2,3-d] pyrimidin-7-yl] -urea. The composition is administered 2 to 4 times a day for the treatment of post-surgical restenosis.
EXAMPLE 144a Compositions for oral suspension Ingredient Quantity l-lsopropyl-3- [5-methyl-6-bromo-2- 500 mg (3-ethylpyridin-4-ylamino) -pyrido [2,3- -d] pyrimidin-7-yl] -urea Solution of sorbitol (70%, NF) 40 ml Benzoate sodium 150 mg Saccharin 10 mg Cherry flavor 50 mg Distilled water, sufficient quantity 100 ml for The sorbitol solution is added to 40 ml of distilled water, and the pyridopyrimidine is suspended therein. Saccharin, sodium benzoate, and flavoring are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each milliliter of syrup contains 5 mg of ingredient active.
EXAMPLE 144b Tablets each containing 60 mg of ac ingredient Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinyl pyrrolidone (as a 10% solution 4 mg in water) Carboxymethyl sodium starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 m Total 150 m They are passed through a US No. 45 mesh screen, the active ingredient, starch, and cellulose, and mixed thoroughly. HE mix the polyvinylpyrrolidone solution with the resulting powder, and then pass through a No. 14 mesh US sieve. The granules are dried at a temperature of 50 to 60 ° C, and passed through a No. 18 mesh US sieve. Next, the carboxymethyl starch, the magnesium stearate, and the talcum, previously passed through a No. 60 mesh US sieve, are added to the granules, which, after being mixed, are tablets in a tablet machine to provide tablets weighing 150 mg each. A typical active ingredient used in the preceding preparation is the compound of Example 40 (Compound 12). This composition is very suitable for the treatment of diabetic retinopathy.
EXAMPLE 144c A composition for parenteral administration, suitable for administration by injection, is prepared by dissolving 100 mg of compound 77 in 250 ml of 0.9% aqueous sodium chloride solution, and adjusting the pH of the solution to about 7.0. This formulation is very suitable for the treatment of breast cancer.
EXAMPLE 144d Preparation for suppositories Mix at 60 ° C until uniformity is obtained, a mixture of 500 mg of 1-n-butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidine- 7-yl] -urea and 1,500 mg of theobroma oil. The mixture is cooled to 24 ° C in tapered molds. Each suppository will weigh approximately 2 g and can be administered 1 to 2 times each day for the treatment of viral infections such as herpes and HIV.
EXAMPLE 144e Topical Preparer Ingredient Quantity (mg) l-Cyclohexyl-3-. { [2- (4-morpholin-1-yl-20-phenylamino)] - 5,6-difluoro-pyrido [2,3-d] pyrimidin-7'-yl] -urea Propylene glycol 100 White petrolatum 500 Cetearyl alcohol 50 Stearate glyceryl 100 PEG 100 stearate 100 Ceteth-20 50 Monobasic sodium phosphate 80 Total 1,000 The compound of the invention is mixed until uniform with the other ingredients, to achieve a thick suspension. The suspension is uniformly applied to a polymer film with adhesive on the other side, and cut into 5.1 cm squares. The patch is applied to the skin of a patient suffering from psoriasis.
EXAMPLE 144f Slow Release Preparation Five hundred milligrams of 7-acetamido-6-bromo-2- [4- (2-diethylaminoethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine hydrochloride were placed in an osmotic pump tablet, and were administered via orally to a subject for the treatment and prevention of restenosis. The invention has already been described, and the manner and procedure of preparing and using it, in terms so complete, clear, concise and accurate as to enable and be prepared and used by any person skilled in the art to which it refers. It should be understood that the foregoing describes preferred embodiments of the present invention, and that modifications may be made thereto without departing from the spirit or scope of the present invention as set forth in the claims. To point out in particular and clearly claim the subject matter considered as an invention, the following claims conclude this specification. ÉááMBifgi4É¿atáfcft-

Claims (9)

NOVELTY OF THE INVENTION CLAIMS
1. - A compound of Formula I and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R 2, R 7, R 13, R 14, and R 15 are, independently, hydrogen, or else lower alkyl, lower alkenyl, or lower alkynyl, each which is optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, - (CH2) nCO2R9, - (CH2) nS02R11, - (CH2) R11, -COR9, -CONR9R10 , -SO3R9, -S02NR9R10, -S02R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 selected groups independently of -R9, -NR9R10, -OR9, -NR9COR10, -COR10, - (CH) nS02R11, - (CH2) nR11, or - (CH2) nR12 optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro , -R9, -NR9R10, -OR9, - (CH2) nCO2R9, - (CH2) nSO2R11, - (CH2) nR11, -COR9, - CONR9R10, -SO3R9, -SO2NR9R10, -SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 selected groups independently of -R9, -NR9R10, -OR9, -NR9COR10, - COR10, - (CH2) nS02R11, - (CH2) nR11; R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, -SO2NR9R10, -SO2R9, -SO3R9, -SR9, - P03R9R1 °, -POR9R10, -PO (NR R10) 2, or lower alkenyl or lower alkynyl optionally substituted with -R9; R8 is H, -C02R13, -COR13, -CONR13R14, -CSNR13R14, -C (NR13) NR14R15, -SO3R13, -SO2R13, -SO2NR13R14, PO3R13R14, -POR13R14, -PO (NR13R14) 2; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, or, when taken together with the nitrogen to which they are attached, R9 and R10 form a ring having 3-7 members, of which up to four may be selected from O, S and NR20, wherein R20 is hydrogen, lower alkyl, or -CO- (lower alkyl ); R11 is a heteroaryl group or a heterocyclic group; R 12 is a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is 0, 1, 2, or 3.
2. - A compound of Formula II and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R7, R13, R14, and R15 are, independently, hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, - (CH2) nC02R9, - (CH2) nS02R11, - (CH2) R11, -COR9, -CONR9R10, - SO3R9, - SO2NR9R10, -SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from - R9, -NR9R10, -OR9, - (CH2) nS02R11, - (CH2) nR11, or - (CH2) nR12 optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9 , - (CH2) nC02R9, - (CH2) nS02R11, - (CH2) R11, -COR9, -CONR9R10, -SO3R9, -S02NR9R1 °, -S02R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2 , - NR9COR10, -NR9CO2R10, -NR 9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, - (CH2) nSO2R11, - (CH2) nR11; R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, or else lower alkenyl or lower alkynyl optionally substituted with -R9; R8 is -CO2R13, -COR13, -CONR 3R14, -CSNR13R14, -C (NR13) NR14R15, -SO3R13, S02R13, -S02NR13R14, -PO3R13R14, -POR13R14, -PO (NR13R14) 2; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, phenyl or substituted phenyl, or, when they are taken together with the nitrogen to which they are attached, R9 and R10 form a ring having 3-7 members, of which up to four may be selected from, O, S and NR20, wherein R20 is hydrogen, lower alkyl, or -CO- (lower alkyl); R 1 is a heteroaryl group or a heterocyclic group; R 12 is a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is 0, 1, 2, or 3; and R16, R17, and R18 are, independently, hydrogen, halogen, amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, - SO2R9, -SO2NR9R10, -SO2R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9S0 R1 °; or R16 is a carbocyclic group containing 3-7 members, of which up to 2 members are heteroatoms ...,. ^^^, ^ ..,., ^^ ^ ^ b ...., ^ A ^. ^ ^. JB ^ jaaA, ^^ ¡¡¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿jjl selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or is substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl , arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclylsulfonylalkyl.
3. A compound of Formula III and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R 2 is hydrogen, or else lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, - (CH2) CO2R9, - (CH2) nSO2R11, - (CH2) nR11, -COR9, -CONR9R10, -S03R9, -SO2NR9R10, -S02R9, -SR9 , -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R1 °, -NR9CONR9R10, -NR9S02R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, - (CH2) nSO2R11, - (CH2) nR11, or ?to? 1. ^^^^^^^^^^^^^^^^^^^ (CH2) nR12 optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, - (CH2) nCO2R9, - (CH2) nSO2R11, - (CH2) nR11, -COR9, -CONR9R10, -SO3R9, -SO2NR9R10, -SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R1 °, -NR9CONR9R10, -NR9S02R1 °, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, - (CH2) nSO2R11, - (CH2) nR11; R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, -S02NR9R10, -SO2R9, -SO3R9, -SR9, -PO3R9R10, -POR9R10, -PO ( NR9R10) 2, either lower alkenyl or lower alkynyl optionally substituted with -R9; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, phenyl or substituted phenyl, or, when they are taken together with the nitrogen to which they are attached, R9 and R10 form a ring having 3-7 members, of which up to four may be selected from °, O, S and NR20, wherein R20 is hydrogen, lower alkyl, or well -CO- (lower alkyl); R11 is a heteroaryl group or a heterocyclic group; R 12 is a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is 0, 1, 2, or 3, and R19 is hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or k ...?. yt .i. ? .. i? ^ ^, .ry1 .... ¿¿¿.ííí ^, yJ, .. a. to! ii ^^ yy * ..? .í? dt fr.ff.tft .. 1 dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, (lower alkyl) -carbonyl, -SO3R9, -SO2NR9R10, -SO2R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9C02R10, -NR9CONR9R10, -NR9S02R10or alternatively aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, in which each of the aryl, heteroaryl or cycloalkyl groups is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy , lower alkoxy, cyano, nitro, carboxy, carboxy-alkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO3R9, -SO2R9R10, -SO2NR9R10, -S02R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9S02R10, or a carbocyclic (CH2) n group containing 3-7 members, of which up to 2 members are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, hetero Arylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclisisulfonylalkyl; and R21 is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. .am.Jtj. Ai. ^ .Alfc ^ - *. «.m ^ ihA-i t 4.- A compound of Formula IV and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -C02R9, -COR9, -CONR9R10, -NR9COR10, -S02NR9R10, -SO2R9, -SO3R9, -SR9, -PO3R9R10, -POR9R10, -PO ( NR9R10) 2, either lower alkenyl or lower alkynyl optionally substituted with -R9; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, phenyl or substituted phenyl, or, when they are taken together with the nitrogen to which they are attached, R9 and R10 form a ring that has 3-7 members, of which up to four may be selected from? , O, S and NR20, wherein R20 is hydrogen, lower alkyl, or -CO- (lower alkyl); R11 is a heteroaryl group or a heterocyclic group; R16, R17, and R18 are independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, (CH2) nCO2R9, - (CH2) nSO2R11, - f fi? ft. { yjáff¡-.p?. & A *? £ t¡t * .. f .-? I .. ~~ i ** l¿f Jifrj.) (CH2) R11, -COR9, -CONR9R10, -SO3R9, -SO2NR9R10, -SO2R9, - SR-PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10, -OR9, -NR9COR10 , -COR10, - (CH2) nSO2R11, - (CH2) nR11; R19 is hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, (lower alkyl) -carbonyl, -SO3R9, -S? 2NR9R10, -SO2R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10 , -NR9CONR9R10, -NR9SO2R10, or alternatively aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, in which each of the aryl, heteroaryl or cycloalkyl groups is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxy-alkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO3R9, -SO2R9R10, -S02NR9R1 °, -SO2R9, -SR9, -PO3R9R10, -POR9R10 , -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR CONR9R10, -NR9SO2R10, or a carbocyclic (CH2) n group containing 3-7 members, of which up to 2 members are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or is substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonyl-alkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclisulfonyl-alkyl; and R21 is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl. 5. A compound of Formula V and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, cyano, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, -S02NR9R10, -S02R9, -SO3R9, -SR9, -PO3R9R10, -POR9R10, -PO ( NR 9 R 0) 2, or alternatively lower alkenyl or lower alkynyl substituted with -R 9; R16, R17, and R8 are independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, (CH2) nCO2R9, - (CH2) nSO2R11, - (CH2) R11, -COR9, -CONR9R10, - SO3R9, -SO2NR9R10, -S02R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9S02R10, or a heterocycle optionally substituted with up to 3 groups independently selected from - R9, -NR9R10, - OR9, -NR9COR10, -COR10, - (CH) nSO2R11, - (CH2) nR11; R9 and R10 are, independently, hydrogen, or lower alkyl, optionally substituted with up to 3 groups selected from the group consisting of halogen, amino, mono- or dialkylamino, hydroxy, or lower alkoxy, phenyl or substituted phenyl, or, when they are taken together with the nitrogen to which they are attached, R9 and R10 form a ring having 3-7 members, of which up to four may be selected from, O, S and NR20, wherein R20 is hydrogen, lower alkyl, or -CO- (lower alkyl); R11 is a heteroaryl group or a heterocyclic group; R19 is hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, (lower alkyl) -carbonyl, -SO3R9, -SO2NR9R10, -SO2R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10 , -NR9SO2R10, or alternatively aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, in which each of the aryl, heteroaryl or cycloalkyl groups is optionally substituted with up to 5 groups independently selected from halogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxy-alkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, alkylcarbonyl, -SO3R9, -S02R9R10, -SO2NR9R10, -S02R9, -SR9, -P03R9R1 °, -POR9R10, -PO (NR9R10 ) 2, -NR COR10, -NR9CO2R10, -NR9CONR9R10, -NR9SO2R10, or a group tt ?? áil? Í * - "" ** "• '*" "~ - - *" - "-"' - * "- carbocyclic (CH2) n containing 3-7 members, of which up to 2 members are selected heteroatoms of oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or is substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclisisulfonylalkyl, and R21 is hydrogen, lower alkyl, or lower alkyl substituted with phenyl or substituted phenyl 6.- A compound of Formula VI and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R5 is halogen, cyano, nitro, -R9, -NR9R10, or -OR9; R6 is halogen, damage, nitro, -R9, -NR9R10, -OR9, -CO2R9, -COR9, -CONR9R10, -NR9COR10, -SO2NR9R10, -SO2R9, -SO3R9, -SR9, -PO3R9R10, -POR9R10, - PO (NR 9 R 10) 2, or alternatively lower alkenyl or lower alkynyl substituted with -R 9; R17, and R18 are independently selected from halogen, cyano, nitro, -R9, -NR9R10, -OR9, (CH2) nCO2R9, - (CH2) nSO2R11, (CH2) nR11, -COR9, -CONR9R10, -SO3R9, -SO2NR9R10 , -S02R9, -SR9, -PO3R9R10, -POR9R10, -PO (NR9R10) 2, -NR9COR10, -NR9CO2R10, -NR9CONR9R10, -NR9S02R10, or a heterocycle optionally substituted with up to 3 groups independently selected from -R9, -NR9R10 , -OR9, -NR9COR10, -COR10, - (CH2) nSO2R11, - (CH2) nR11; R22 and R23 are, independently, hydrogen or alkyl. 7. A compound selected from: 1-t-Butyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -urea; 1-t-Butyl-3- [2- (3-chloro-4-piperazin-1-l-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-t-Butyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-t-Butyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrid- [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea; 1-Cyclohexyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrid [2,3-d] pyrimidin-7-yl] -3-cyclohexyl-urea; 1-Cyclohexyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [5-methyl-2- (4-piperazin-1-yl-phenyl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} - 3-cyclohexyl-urea; 1- (2-Hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1 - [6-Fluoro-2- (4-piperazin-1-yl) -phenylamino) -pyrido- [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1- (2-Hydroxy-ethyl) -3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyridono [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3- (2-hydroxy-ethyl) -urea; 1-Ethyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - [2- (3-Chloro-4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-etl-urea; 1-Ethyl-3- [6-fluoro-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Ethyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1-. { 2- [4- (4-Acetyl-piperazin-1-yl) -3-chloro-phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -5-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-ethyl-urea; 1 -t- The following is an example of the following compounds: -butyl-3- (2-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-t-Butyl-3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (4-Chloro-phenyl) -3- [2- (4-fluoro-3-methyl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-lsopropyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-t-Butyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-Cyclohexyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-pyrimidin-7-yl} -urea; 1-Cyclopentyl-3 - [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 -Cyclohexyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-Cyclopentyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-bromo-2- (4-piperazin-1-yl-phenyl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-cyano-2- (4-piperazin-1-yl-phenyl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-chloro-2- (4-piperazin-1-yl-phenyl-amino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-fluoro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-bromo-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-chloro-5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-lsopropyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Ethyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Methyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-1-methyl-3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7- hy * - * 1- ^ * il] -urea; 1- (4-Hydroxy-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1- (4-Amino-cyclohexyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido ^ .S-d-pyrimidin-yl-urea; 1- (2-D-methylamino-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrid [2,3-d] pyrimidin-7-yl] -urea; 1- (3-Morpholino-4-yl-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 3-Cyclohexyl-1-methyl-1 - [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; N, N-Dimethyl-N'- [5-methyl-2 - [[4- (1-piperazinyl) -phenyl] -amino] -pyrido [2,3-d] pyrimidin-7-yl) -sulfamide; I-Cyclohexyl-3- [5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -thiourea; N- [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -acetamide; 4- [7- (3-Cyclohexyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -benzenesulfonamide; 1-Cyclohexyl-3-. { 2- [4- (1-piperazin-1-yl-methanoyl) -phenyl-amino] -pyrido [2,3- d] pyrimidin-7-yl} -urea; 1-Cyclohexyl-3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] -pyrimidin-7-yl] -urea; 1- (2- {4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -pyrido [2,3-d] pyrimidin-7-yl ) -3-cyclohexyl-urea; and 1- (2- {4- [4- (2-Amino-3-methyl-butanoyl) -piperazin-1-yl] -phenylamino} -pyrido [2,3-d] pyrimidin-7- il) -3- cyclohexyl-urea. 8. A compound selected from: 1-t-Butyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3-d] -pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [2- (pyridin-4-ylamino) -pyrid [2,3-d] pyrimidin-7-yl] -urea; 1-Ephyl-3- [2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1- (Hydroxy-ethyl) -3- [2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-t-Butyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-Ethyl-3- [6-fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-d] - pyrimidin-7-yl] -urea; 1- [6-Fluoro-2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1-t-Butyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3- d] pyrimidin-7-yl] -urea; 1-Ethyl-3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (2-Hydroxy-ethyl) -3- [5-methyl-2- (pyridin-4-ylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 9.- A compound selected from: 4- Tertiary butyl ester. { 4- [7- (3-t-Butyl-ureido) -pyrido [2,3-d] pyrimidin-2-ylamino] -phenyl} -piperazine-1-carboxylic acid; 4-acid t-butyl ester. { 4- [7- (3-cyclohexyl-ureido) -pyrido [2,3- d] pyrimidin-2-ylamino] -phenyl} -piperazin-1-carboxylic acid; 1- (3-Hydroxy-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1 - ((S) -1-Hydroxymethyl-3-methyl-butyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; [4- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide of morpholin-1-carboxylic acid; 3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -1,1-dipropyl-urea; [2- (4-Piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -amide of piperazin-1-carboxylic acid; 1 - ((R) -1-Hydroxymethyl-2-methyl-propyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] - urea; 1,1-Bis- (2-hydroxy-ethyl) -3- [2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- [6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-t-butyl-urea; 1 - [6-Bromo-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-methyl-urea; 1 -. { 6-Bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-t-butyl-urea; 1-. { 6-Bromo-2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3-cyclohexyl-urea; 1- [2- (4-Fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (3-morpholin-4-yl-propyl) -urea; 1- [2- (4-Fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3- (2-hydroxy-ethyl) -urea; 1- (2-Amino-ethyl) -3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1- (2-Dimethylamino-ethyl) -3- [2- (4-fluoro-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 1-Cyclohexyl-3-. { 2- [4- (3,3-Dimethyl-piperazin-1-yl) -phenyl-amino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-t-Butyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-fluoro-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1 -. { 2- [4- (4-Acetyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -3- (3-morpholin-4-yl-propyl) -urea; 1-t-Butyl-3-. { 6-Chloro-2- [4- (cis-3,5-dimethyl-p¡perazin-1-yl) -phenlamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 3-Cyclohexyl-1 -. { 2- [4- (cis-3,5-di methyl-piperazin-1-yl) -phenlamino] -pyrido [2,3-d] pyrimidin-7-yl} -1-methyl-urea; 3-Cyclohexyl-1-ethyl-1 - [2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -urea; 3-t-Butyl-1 -. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 1 - [5-Methyl-2- (4-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-propyl-urea; 7- (3-t-Butyl-ureido) -2- (4-piperazin-1-yl) -phenylamino) -pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester; 1 - [6-Fluoro-5-methyl-2 - (4-p-piperazin-1-yl-phenylamino) -pyrido [2,3-d] pyrimidin-7-yl] -3-isopropyl-urea; 1-Cyclohexyl-3-. { 2- [4- (3,3-Dimethyl-piperazin-1 -yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-Cyclohexyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-t-Butyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -urea; 1-t-Butyl-3- [6-methyl-2- (4-piperazin-1-yl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-yl] -urea; iil 'il fi? fcit? Éff # ÉBlftit "* -a' * a * fc ^" ^ - »- ^ ia t- irtthti iiiniT? itwiwiiw 1-. { 2- [4- (cis-3,5-Dimethyl-p-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -3-isopropyl-urea; 1-Cyclopropyl-3-. { 2- [4- (cis-3,5-dimethyl-piperazin-1-yl) -phenylamino] -6-methyl-pyrido [2,3-d] pyrimidin-7-yl} -urea; and 1-t-Butyl-3-. { 2- [4- (cis-3,5-dimethyl-p¡perazin-1-yl) -phenylamino] -6-ethyl-pyrido [2,3-d] pyrimidin-7-yl} -urea. 10. The pharmaceutical composition comprising a compound selected according to claim 1 combined with a pharmaceutically acceptable carrier, diluent, or excipient. 11. The use of a compound according to claim 1 for preparing a pharmaceutical composition for controlling proliferative disorders selected from the group consisting of cancer, psoriasis, vascular smooth muscle proliferation associated with a disorder selected from the group consisting of atherosclerosis, vascular stenosis post-surgical, and restenosis in mammals. 12. The use of a compound according to claim 1 for preparing a pharmaceutical composition for inhibiting a cdk enzyme. 13. The use as claimed in claim 12, wherein said cdk is cdkl. 1
4. The use as claimed in claim 12, wherein said cdk is cdk2. 1
5. The use as claimed in claim 12, wherein said cdk is cdk4. 1
6. The use of a compound according to claim 1 for preparing a pharmaceutical composition for inhibiting a tyrosine kinase mediated by growth factor. 1
7. The use as claimed in claim 16, wherein said growth factor-mediated tyrosine kinase is platelet-derived growth factor (PDGF). 1
8. The use as claimed in claim 16, wherein said tyrosine kinase mediated by growth factor is fibroblast growth factor (FGF). 1
9. The use of a compound according to claim 1 for preparing a pharmaceutical composition for treating diseases caused by vascular smooth muscle cell proliferation in a subject. 20. The use of a compound according to claim 1 for preparing a pharmaceutical composition for treating cancer in a subject. 21. The use of a compound according to claim 1 for preparing a pharmaceutical composition for treating cancer related to breast cancer, megalocytic carcinoma, pancreatic cancer, colon cancer, melanoma, lung cancer, and leukemia in a subject. U Üilf irhügf - "" ^ - "- * - * ^ ** ^ - ^,. ^. ^? ^^, iiftüaf« hrt,
MXPA02007221A 2000-01-25 2001-01-23 PYRIDO[2,3 d]PYRIMIDINE 2,7 DIAMINE KINASE INHIBITORS. MXPA02007221A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17826100P 2000-01-25 2000-01-25
PCT/IB2001/000069 WO2001055147A1 (en) 2000-01-25 2001-01-23 PYRIDO[2,3-d]PYRIMIDINE-2,7-DIAMINE KINASE INHIBITORS

Publications (1)

Publication Number Publication Date
MXPA02007221A true MXPA02007221A (en) 2002-11-29

Family

ID=22651853

Family Applications (1)

Application Number Title Priority Date Filing Date
MXPA02007221A MXPA02007221A (en) 2000-01-25 2001-01-23 PYRIDO[2,3 d]PYRIMIDINE 2,7 DIAMINE KINASE INHIBITORS.

Country Status (34)

Country Link
EP (1) EP1254137A1 (en)
JP (1) JP4047010B2 (en)
KR (1) KR20020065939A (en)
CN (1) CN1395578A (en)
AP (1) AP2002002586A0 (en)
AR (1) AR030044A1 (en)
AU (1) AU2542501A (en)
BG (1) BG106850A (en)
BR (1) BR0107751A (en)
CA (1) CA2397961C (en)
CO (1) CO5261549A1 (en)
CR (1) CR6706A (en)
CZ (1) CZ20022475A3 (en)
DZ (1) DZ3266A1 (en)
EA (1) EA200200643A1 (en)
EE (1) EE200200405A (en)
GT (1) GT200100016A (en)
HN (1) HN2001000013A (en)
HU (1) HUP0204141A3 (en)
IL (1) IL150545A0 (en)
IS (1) IS6443A (en)
MA (1) MA26868A1 (en)
MX (1) MXPA02007221A (en)
NO (1) NO20023527L (en)
OA (1) OA12161A (en)
PA (1) PA8510701A1 (en)
PE (1) PE20011066A1 (en)
PL (1) PL356802A1 (en)
SK (1) SK10632002A3 (en)
SV (1) SV2002000294A (en)
TN (1) TNSN01014A1 (en)
WO (1) WO2001055147A1 (en)
YU (1) YU50402A (en)
ZA (1) ZA200205879B (en)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
CN1847229B (en) 2000-10-23 2011-05-04 史密丝克莱恩比彻姆公司 2,4,8- trisubstituted-8H- pyridine[2,3-d] pyridine -7-one compound
PE20030008A1 (en) * 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
EP1499320B1 (en) 2002-04-19 2007-08-22 Smithkline Beecham Corporation Novel compounds
US7504410B2 (en) * 2002-11-28 2009-03-17 Schering Aktiengesellschaft Chk-, Pdk- and Akt-inhibitory pyrimidines, their production and use as pharmaceutical agents
US7157455B2 (en) * 2003-02-10 2007-01-02 Hoffmann-La Roche Inc. 4-Aminopyrimidine-5-one derivatives
TW200502236A (en) * 2003-03-28 2005-01-16 Hoffmann La Roche Novel pyrido[2,3-d]pyrimidin-7-carboxylic acid derivatives, their manufacture and use as pharmaceutical agents
FR2873118B1 (en) 2004-07-15 2007-11-23 Sanofi Synthelabo PYRIDO-PYRIMIDINE DERIVATIVES, THEIR APPLICATION IN THERAPEUTICS
EP1794160A1 (en) * 2004-09-21 2007-06-13 F.Hoffmann-La Roche Ag 6-(2-alkyl-phenyl) - pyrido[2,3-d] pyrimidines useful as proteine kinase inhibitors
EP1868612A4 (en) 2005-03-25 2010-03-24 Glaxo Group Ltd Novel compounds
PE20061193A1 (en) 2005-03-25 2006-12-02 Glaxo Group Ltd DERIVATIVES OF 3,4-DIHYDROPYRIMIDO [4,5-d] PYRIMIDIN-2- [1H] -0NA AS KINASE INHIBITORS p38
UY29440A1 (en) 2005-03-25 2006-10-02 Glaxo Group Ltd NEW COMPOUNDS
CN101495475A (en) 2005-03-25 2009-07-29 葛兰素集团有限公司 Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives
FR2887882B1 (en) 2005-07-01 2007-09-07 Sanofi Aventis Sa PYRIDO [2,3-D] PYRIMIDINE DERIVATIVES, THEIR PREPARATION, THEIR THERAPEUTIC APPLICATION
CN101243081A (en) * 2005-07-21 2008-08-13 霍夫曼-拉罗奇有限公司 Pyrido[2,3-d]pyrimidine-2,4-diamine compounds as PTP1B inhibitors
BRPI0614804A2 (en) * 2005-08-09 2011-04-12 Irm Llc compounds and compositions as protein kinase inhibitors
FR2896246B1 (en) 2006-01-13 2008-08-15 Sanofi Aventis Sa PYRIDO-PYRIMIDONE DERIVATIVES, THEIR PREPARATION, THEIR THERAPEUTIC APPLICATION
EP1914234A1 (en) 2006-10-16 2008-04-23 GPC Biotech Inc. Pyrido[2,3-d]pyrimidines and their use as kinase inhibitors
JO2985B1 (en) 2006-12-20 2016-09-05 Takeda Pharmaceuticals Co MAPK/ERK Kinase Inhibitors
FR2910813B1 (en) * 2006-12-28 2009-02-06 Sanofi Aventis Sa NEW THERAPEUTIC USE FOR THE TREATMENT OF LEUKEMIA
EP2112150B1 (en) 2008-04-22 2013-10-16 Forma Therapeutics, Inc. Improved raf inhibitors
EP2352732B1 (en) * 2008-12-01 2013-02-20 Merck Patent GmbH 2,5-DIAMINO-SUBSTITUTED PYRIDO[4, 3-d]PYRIMIDINES AS AUTOTAXIN INHIBITORS AGAINST CANCER
GB201104267D0 (en) 2011-03-14 2011-04-27 Cancer Rec Tech Ltd Pyrrolopyridineamino derivatives
GB201216018D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Pharmacologically active compounds
GB201216017D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Inhibitor compounds
ES2817448T3 (en) 2013-03-14 2021-04-07 Icahn School Med Mount Sinai Pyrimidine compounds as kinase inhibitors
GB201403536D0 (en) 2014-02-28 2014-04-16 Cancer Rec Tech Ltd Inhibitor compounds
KR101671404B1 (en) * 2014-09-02 2016-11-02 한국원자력의학원 Pyrimidine derivatives having anti-cancer effect, combination therapeutic effect with radiation, and anti-diabetic effect, and PPAR activity, and medical use thereof
CN107286180B (en) * 2016-04-11 2019-07-02 上海勋和医药科技有限公司 Heteropyridopyrimidinone derivatives as CDK inhibitors and their applications
GB201709840D0 (en) 2017-06-20 2017-08-02 Inst Of Cancer Research: Royal Cancer Hospital Methods and medical uses

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK281724B6 (en) * 1994-11-14 2001-07-10 Warner-Lambert Company 6-ARYLPYRIDO [2,3-D] PYRIMIDINS, THEIR USE AND PHARMACEUTICAL COMPOSITIONS ON THEIR BASE
IL115256A0 (en) * 1994-11-14 1995-12-31 Warner Lambert Co 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use
US5620981A (en) * 1995-05-03 1997-04-15 Warner-Lambert Company Pyrido [2,3-D]pyrimidines for inhibiting protein tyrosine kinase mediated cellular proliferation
KR20010043829A (en) * 1998-05-26 2001-05-25 로즈 암스트롱, 크리스틴 에이. 트러트웨인 Bicyclic Pyrimidines and Bicyclic 3,4-Dihydropyrimidines as Inhibitors of Cellular Proliferation

Also Published As

Publication number Publication date
EA200200643A1 (en) 2002-12-26
OA12161A (en) 2006-05-08
PE20011066A1 (en) 2001-10-22
AP2002002586A0 (en) 2002-09-30
ZA200205879B (en) 2003-09-29
WO2001055147A1 (en) 2001-08-02
SV2002000294A (en) 2002-07-16
EP1254137A1 (en) 2002-11-06
YU50402A (en) 2005-11-28
IS6443A (en) 2002-06-25
BG106850A (en) 2003-02-28
GT200100016A (en) 2001-10-19
IL150545A0 (en) 2003-02-12
PL356802A1 (en) 2004-07-12
CN1395578A (en) 2003-02-05
CA2397961C (en) 2008-08-26
NO20023527L (en) 2002-09-10
CA2397961A1 (en) 2001-08-02
CO5261549A1 (en) 2003-03-31
EE200200405A (en) 2003-12-15
MA26868A1 (en) 2004-12-20
AU2542501A (en) 2001-08-07
DZ3266A1 (en) 2001-08-02
AR030044A1 (en) 2003-08-13
JP2003523357A (en) 2003-08-05
CR6706A (en) 2005-04-04
HN2001000013A (en) 2001-06-18
PA8510701A1 (en) 2002-12-11
NO20023527D0 (en) 2002-07-24
HUP0204141A2 (en) 2003-04-28
JP4047010B2 (en) 2008-02-13
HUP0204141A3 (en) 2005-03-29
SK10632002A3 (en) 2003-06-03
KR20020065939A (en) 2002-08-14
CZ20022475A3 (en) 2003-03-12
BR0107751A (en) 2002-11-12
TNSN01014A1 (en) 2005-11-10

Similar Documents

Publication Publication Date Title
MXPA02007221A (en) PYRIDO[2,3 d]PYRIMIDINE 2,7 DIAMINE KINASE INHIBITORS.
US7053070B2 (en) Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors
CA2329703C (en) Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
US7390805B2 (en) 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US20230142839A1 (en) N4-phenyl-quinazoline-4 -amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases
EP0964864B1 (en) Pyrido 2,3-d pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation
AU2007254491A1 (en) Compositions and methods for FGF receptor kinases inhibitors
SK3542002A3 (en) Pteridinones as kinase inhibitors
SK141097A3 (en) Pyrido[2,3-d]pyrimidines for inhibiting protein tyrosine kinase mediated cellular proliferation
US20040044012A1 (en) Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
JP2008504281A (en) Compounds and compositions as protein kinase inhibitors
JP2013530250A (en) Bicyclic pyrimidine compounds
US7323469B2 (en) 7H-pyrrolo[2,3-d]pyrimidine derivatives
OA11554A (en) Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation.
EP1801112A1 (en) Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
MXPA00010738A (en) Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
HK1065483B (en) 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives

Legal Events

Date Code Title Description
FA Abandonment or withdrawal