CN1395578A - Byrido [2,3-d] pyrimidine-2, 7-diamine kinase inhibitors - Google Patents

Byrido [2,3-d] pyrimidine-2, 7-diamine kinase inhibitors Download PDF

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CN1395578A
CN1395578A CN01804048A CN01804048A CN1395578A CN 1395578 A CN1395578 A CN 1395578A CN 01804048 A CN01804048 A CN 01804048A CN 01804048 A CN01804048 A CN 01804048A CN 1395578 A CN1395578 A CN 1395578A
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pyrido
pyrimidin
urea
piperazine
phenylamino
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R·J·布斯
E·M·杜布鲁辛
V·P·V·N·珠斯于拉
D·J·麦克纳玛拉
P·L·图古德
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Warner Lambert Co LLC
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    • 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
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    • 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
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    • 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 System
    • 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

Abstract

Disclosed are compounds of the formula (I) wherein: R<2>, R<7>, R<13>, R<14> and R<15> are independently hydrogen, or (un)substituted lower alkyl, (un)substitued lower alkenyl, (un)substituted lower alkynyl, or (un)substituted -(CH<2>)<n>R<12>; R<5> is halogen, cyano, nitro, -R<9>, -NR<9>R<10>, or -OR<9>; R<6> is halogen, cyano, nitro, -R<9>, -NR<9>R<10>, -OR<9>, -Co<2>R<9>, -COR<9>, -CONR<9>R<10>, -NR<9>COR<10>, (un)substituted lower alkenyl, or (un)substituted lower alkynyl; R<8> is -CO<2>R<13>, -COR<13>, -CONR<13>R<14>, -CSNR<13>R<14>, -C(NR<13>)NR<14>R<15>, -SO<3>R<13>, -S0<2>R<13>, -SO<2>NR<13>R<14>, -PO<3>R<13>R<14>, -POR<13>R<14>, -PO(NR<13>R<14>)<2>; R<9> and R<10> are independently hydrogen or (un)substituted lower alkyl; R<11> is a heteroaryl or a heterocyclic group; R<12> is a cycloalkyl, a heterocyclic, an aryl, or a heteroaryl group; and n is 0,1,2, or 3. These compounds and their pharmaceutical compositions are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cdks and growth factor-mediated kinases.

Description

Pyrido [2,3-d] pyrimidine-2, the 7-diamine kinase inhibitors
Invention field
The present invention relates to pyrido [2,3-d] pyrimidine-2, the 7-diamines, they suppress the Tyrosylprotein kinase of cyclin dependant serine/threonine kinase and somatomedin mediation, therefore can be used for treating cell breeding disease and obstacle.
Background of invention
The association area general introduction
Cell-cycle kinases be naturally occurring participation Cycle Regulation enzyme (Meijer L. " Chemical Inhibitors of Cyclin-Dependent Kinases; " Progressin Cell Cycle Research (cell cycle progress), 1995; 1:351-363).Typical enzyme comprises serine/threonine kinase, for example cell cycle protein dependent kinase (cdk) cdk1, cdk2, cdk4, cdk5, cdk6, and the Tyrosylprotein kinase that participates in Cycle Regulation.
Shown that these kinase whose active increases or activity or regulating effect temporarily can develop into human tumor and other proliferative disorders unusually.Cause the inhibition of cell proliferation by the interaction between retardance cyclin and its kinases mating partner or by combining the compound that this kinases of deactivation also suppresses cdk, thereby can be used for treating the cell of tumour or other abnormality proliferations.
The compound of verified some inhibition cdk has the preclinical phase anti-tumor activity.For example, flavopiridol is a kind of flavonoid, has held itself out to be strong inhibitor (Kaur etc., J.Natl Cancer Inst. (National Cancer Institute magazine), the 1992:84:1736-1740 of some type mammary cancer and lung carcinoma cell; Int.J.Oncol. (international oncology magazine), 1996; 9:1143-1168).Shown that this compound suppresses cdk2 and cdk4.Olomoucine (2-(hydroxyethylamino)-6-benzylamine-9-methyl purine) is strong cdk2 and cdk5 inhibitor (Vesely etc., Eur.J.Biochem. (european journal of biological chemistry) 1994,224:771-786), shown and suppressed the propagation (Abraham etc., Biology of the Cell. (cytobiology) 1995:83:105-120) that National Cancer Institute (NCI) is used to screen about 60 kinds of different human tumor cell lines of new novel remedies for cancer.Occurred purvalanol class cdk inhibitor recently, it is stronger olomoucine derivative (Gray N.S. etc., Science. (science) 1998:281:533-538).
It is necessary that Tyrosylprotein kinase is that growth factor signal transduction is propagated, cause the advancing of cell cycle, cell propagation, break up and divide a word with a hyphen at the end of a line.Tyrosylprotein kinase comprises the cell surface growth factor receptor tyrosine kinase, and for example FGFr and PDGFr, and nonreceptor tyrosine kinase comprise c-Src and lck.The inhibition of verified these enzymes causes antitumor and anti-angiogenesis activity (Hamby etc., Pharmacol.Ther. (pharmacology and therapy) 1999:82 (2-3): 169-193).
It is known (WO 98/33798) that some inhibition cdk and somatomedin mediate kinase whose pyrido [2,3-d] pyrimidine.U.S. Patent No. 5,733,913 and 5,733,914 have described also [2,3-d] pyrimidine of 6-aryl-pyridine.
Although obtained certain progress, but the research about small molecular weight compounds is also continuing, but these compounds are oral biological utilisations, can be used for treating multiple human tumor and other proliferative disorders, comprise restenosis, vasculogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration and atherosclerosis.The invention provides such compound, their pharmaceutical preparation and their purposes in the treatment proliferative disorders.
Summary of the invention
The invention provides novel pyrido [2,3-d] pyrimidine-2, the 7-diamine compound, they serve as the inhibitor of the Tyrosylprotein kinase of Cycle Regulation kinases, for example cell cycle protein dependent kinase and somatomedin mediation.Thereby these compounds can be used for treating the cell proliferation obstacle, for example atherosclerosis and restenosis; Cancer; Vasculogenesis; Virus infection comprises dna virus, as bleb, and RNA viruses, as HIV; Fungi infestation; Type i diabetes, diabetic neuropathy and retinopathy; Multiple sclerosis; Glomerulonephritis; Neurodegenerative disease comprises Alzheimer; Autoimmune disorders, for example psoriasis, rheumatoid arthritis and lupus; Organ-graft refection and host are to the graft disease; Gout; Polycystic kidney disease; And inflammation, comprise inflammatory bowel disease.
Therefore, the invention provides pyrido [2,3-d] pyrimidine with the general structure of formula I Wherein: R 2, R 7, R 13, R 14And R 15Be hydrogen independently, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,-OR 9,-NR 9COR 10,-COR 10,-(CH 2) nSO 2R 11,-(CH 2) nR 11, or-(CH 2) nR 12, replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,
-OR 9,-NR 9COR 10,-COR 10,-(CH 2) nSO 2R 11,-(CH 2) nR 11R 5Be halogen, cyano group, nitro ,-R 9,-NR 9R 10Or-OR 9R 6Be halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-CO 2R 9,-COR 9,-CONR 9R 10,
-NR 9COR 10、-SO 2NR 9R 10、-SO 2R 9、-SO 3R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、
-PO (NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl are alternatively by-R 9Replace; R 8Be H ,-CO 2R 13,-COR 13,-CONR 13R 14,-CSNR 13R 14,-C (NR 13) NR 14R 15,-SO 3R 13,-SO 2R 13,-SO 2NR 13R 14,-PO 3R 13R 14,-POR 13R 14,-PO (NR 13R 14) 2R 9And R 10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively that substituting group is selected from by halogen, amino, one or the group formed of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R 9And R 10Constitute ring with the nitrogen that they connected with 3-7 member, wherein at the most four can be selected from
Figure A0180404800231
O, S and NR 20, R wherein 20Be hydrogen, low alkyl group or-the CO low alkyl group; R 11Be heteroaryl or heterocyclic radical; R 12Be cycloalkyl, heterocyclic radical, aryl or heteroaryl; N is 0,1,2 or 3; And pharmacy acceptable salt, ester, acid amides and prodrug.The present invention also provides composition, comprises formula I compound and pharmaceutically acceptable carrier, thinner or vehicle.The present invention also is provided for suppressing cell cycle protein dependent kinase and somatomedin mediates kinase whose method.The present invention also provides treatment to suffer from the method that is caused the curee of disease by cell proliferation.This method comprises curee's administration of needs being treated by the formula I compound that will treat significant quantity, suppresses tumorigenic cell propagation and the vascular smooth muscle propagation and/or the cell migration of epithelial origin.The present invention also provides treatment to suffer from the method that is caused the curee of disease by DNA tumour virus, for example simplexvirus, comprises the compound administration with formula I.
The compound that detailed description of the invention is contained by the present invention be by above-mentioned general formula I described those, and pharmacy acceptable salt, ester, acid amides and prodrug.Except formula I compound, the present invention also provides preferred formula II compound:
Figure A0180404800232
R wherein 5, R 6, R 7And R 8Be defined suc as formula I, R 16, R 17And R 18Be as above about (CH 2) nR 12Substituting group is defined, preferably be independently hydrogen, halogen, amino, one or dialkyl amido, hydroxyl, low alkyl group, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10Perhaps R 16It is the carbocylic radical that contains 3-7 member; wherein 2 members are the heteroatomss that are selected from oxygen and nitrogen at the most; wherein this carbocylic radical be unsubstituted or by 1,2 or 3 as defined above group replace, but preferably be independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group formed of dialkyl amido, aryl, heteroaryl, aralkyl, heteroaralkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle alkylsulfonyl or heterocycle sulphonyl alkyl.
Preferably formula II compound is, wherein R 5Be hydrogen or low alkyl group; R 6Be hydrogen, low alkyl group, cyano group or halogen; R 17And R 18Be independently hydrogen, halogen, amino, one or dialkyl amido, hydroxyl, low alkyl group, lower alkoxy, aminocarboxyl, one or dialkyl amino carbonyl ,-SO 2NR 9R 10Or-NR 9COR 10R 16Be optional substituted N-piperidines, N-piperazine or N-tetramethyleneimine, for example wherein ring substituents is selected from-R 9,-NR 9R 10,-OR 9, NR 9COR 10And COR 10
In addition, the present invention also provides preferred formula III compound:
Figure A0180404800241
R wherein 2, R 5And R 6Be defined suc as formula I; And R 19Be hydrogen, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, lower alkylcarbonyl ,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, R wherein 9And R 10Be as defined above, or aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl are replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or (CH 2) n-contain 3-7 member's carbocylic radical, wherein 2 members are the heteroatomss that are selected from oxygen and nitrogen at the most, and wherein this carbocylic radical is unsubstituted or is independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group replacement of the group formed of dialkyl amido, aryl, heteroaryl, aralkyl, heteroaralkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle alkylsulfonyl or heterocycle sulphonyl alkyl by 1,2 or 3; R 21Be hydrogen, low alkyl group or the low alkyl group that replaced by the phenyl of phenyl or replacement.
Preferably the formula III compound is, wherein R 5Be hydrogen or low alkyl group, R 6Be hydrogen or halogen, R 2Be optional substituted phenyl, R 21Be hydrogen or methyl, R 19Be optional substituted low alkyl group, cycloalkyl or (CH 2) n-carbocylic radical.
One group of especially preferred pyrido [2,3-d] pyrimidine is formula IV:
Figure A0180404800251
R wherein 5, R 6, R 16, R 17, R 18, R 19And R 21Be as defined above.Preferred formula IV compound is R wherein 21Be those of hydrogen or methyl.
Another organizes especially preferred The compounds of this invention is formula V:
Figure A0180404800261
R wherein 5, R 6, R 16, R 17, R 18, R 19And R 21Be as defined above.Preferred formula V compound is R wherein 21Be those of hydrogen or methyl.
Most preferred The compounds of this invention has formula VI R wherein 5, R 6, R 17And R 18Be as defined above, R 22And R 23Be hydrogen or alkyl independently.
" alkyl " among the present invention, " low alkyl group " and " (C 1-C 10) alkyl " expression has the straight or branched alkyl of 1 to 10 carbon atom, is preferably C 1-C 6Alkyl.Usually, alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, decyl, octyl group and 3-methyl amyl.These groups for example can be by halogen, C 1-C 3Replacements such as alkyl, amino, alkylamino, dialkyl amido, hydroxyl, alkoxyl group.Example comprises chloromethyl, 2-amino-ethyl and 3-dimethyl-aminopropyl.
" thiazolinyl ", " low-grade alkenyl " and " (C 2-C 10)-thiazolinyl " expression has the straight or branched alkyl of 1 to 10 carbon atom and 1 or 2 non-conterminous pair of key.The example of thiazolinyl includes but not limited to 3-butenyl and 1-methyl-3-pentenyl.
" alkynyl ", " low-grade alkynyl " and " (C 2-C 10)-alkynyl " expression has the straight or branched alkyl of 1 to 10 carbon atom and one three key.Typical alkynyl comprises 2-propynyl and 1,1-dimethyl-3-butynyl.The thiazolinyl and the alkynyl that replace comprise 4,4-two bromo-pentenyl and 3-amino-5-hexin base.
" alkoxyl group " among the present invention, " lower alkoxy " or " (C 1-C 10) alkoxyl group " expression has the straight or branched alkoxyl group of 1 to 10 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, 2-amyl group, isopentyloxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methyl pentyloxy.
Term " alkyloyl " expression is by the alkyl of carbonyl moiety bonding.Example comprises ethanoyl and pentanoyl." aminoalkanoyl radical " expression is by the amino alkyl that replaces.Example comprises glycyl and the amino caproyl of 3-." alkylamino alkyloyl " represents that wherein amine is by C 1-C 10The aminoalkanoyl radical that alkyl replaces comprises methylamino-ethanoyl and 4-(isobutyl amino)-capryloyl." dialkyl amido alkyloyl " expression N, the dibasic aminoalkanoyl radical of N-, for example diisopropylaminoethyl ethanoyl.
Halogen among the present invention is represented fluorine, chlorine, bromine and iodine.
Unsubstituted aromatic carbocyclic represented in term " aryl ", has single ring (for example phenyl), a plurality of ring (for example biphenyl) or a plurality of condensed ring, and wherein at least one is aromatics (for example 1,2,3,4-tetralyl, naphthyl, anthryl or phenanthryl).The aryl that term " aryl of replacement " expression is replaced by 1 to 4 substituting group, substituting group be selected from alkyl, O-alkyl and S-alkyl ,-OH ,-SH ,-CN, halogen, 1, the 3-dioxolanyl ,-CF 3,-NO 2,-NH 2,-NHCH 3,-N (CH 3) 2,-NHCO-alkyl ,-(CH 2) mCO 2H ,-(CH 2) mCO 2-alkyl ,-(CH 2) mSO 3H ,-the NH alkyl ,-N (alkyl) 2,-(CH 2) mPO 3H 2,-(CH 2) mPO 3(alkyl) 2,-(CH 2) mSO 2NH 2With-(CH 2) mSO 2The NH-alkyl, wherein alkyl is as defined above, m is 0,1,2 or 3.Some examples of the aryl that replaces are aminomethyl phenyl, isopropyl phenyl, chloro-phenyl-, 2-bromo-3-trifluoromethyl-4-nitro-5-aminophenyl, 4-bromo biphenyl, 3-kharophen naphthyl, 3-dimethylamino anthryl, 3,4-dimethoxy phenanthryl and 2, the inferior biphenyl of 8-dibromo-1-base.
" heteroaryl " represents one or more 5-, 6-or 7-unit aromatics ring system, contains at least 14 heteroatoms that are selected from nitrogen, oxygen or sulphur at the most.This class heteroaryl for example comprises thienyl, furans, thiazolyl, imidazolyl, (different) oxazolyl, tetrazyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, (different) quinolyl, naphthyridinyl, phthalimidyl, benzimidazolyl-, benzoxazolyl." heteroaryl of replacement " can be replaced by 1,2,3 or 4 group of as above being mentioned about " aryl of replacement ", and for example 2,3,4,6-4 chloro pyridine base and 2-methoxyl group-3-trifluoromethyl thiophene-4-base.
Term " heterocyclic radical " expression has the non-aromatic ring of 5-, 6-or 7-annular atoms, and wherein 1 to 4 is selected from nitrogen, oxygen or sulphur.The example of heterocyclic radical comprises morpholino base, piperidino-(1-position only), piperazinyl, pyrrolidyl and tetrahydro-thienyl.This class group can be replaced about the described identical group of the heteroaryl that replaces with top.
" carbocylic radical " or " cycloalkyl " is non-aromatics ring system or the condensed ring with 3-to 7-ring carbon member.Example comprises cyclopropyl, cyclobutyl and suberyl.These rings can be replaced by one or more substituting groups of as above mentioning about aryl, for example alkyl, halogen, amino, hydroxyl and alkoxyl group.The typical carbocylic radical that replaces comprises 2-chlorine cyclopropyl, 2,3-diethoxy cyclopentyl and 2,2,4,4-ptfe ring hexyl.Carbocylic radical can contain 1 or 2 heteroatoms that is selected from oxygen, sulphur and nitrogen, and this class ring system is called as " heterocyclic radical " or " heterocycle ".Example comprises piperidyl, piperazinyl, pyrrolidyl, pyranyl, tetrahydrofuran base He alkyl dioxin.These heterocyclic radicals can for example be obtained 3,5-lupetazin-1-base, 3 by 4 substituting groups replacements of mentioning about aryl at the most, 3-diethyl piperazine-1-base, 3,3,4,4-tetramethylpyrrolidi-e base, 3-chloro-2-alkyl dioxin and 3,5-dihydroxyl morpholino base.They can also carry ketone group, for example 3-keto piperidine base.
Term " cancer " includes but not limited to following tumor type: mammary gland, ovary, uterine cervix, prostate gland, testis, oesophagus, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, gland cancer, bone, colon, adenoma, pancreas, Tiroidina, follicular carcinoma, undifferentiated cancer, papillary carcinoma, spermocytoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract, kidney, marrow sample obstacle, lymph sample obstacle, He Jiejinshi, the hair cell cancer, cheek chamber and pharynx (mouth) cancer, lip, tongue, mouthful, pharynx, small intestine, colon, rectum, large intestine, brain and the central nervous system leukemia of unifying.
Formula I to VI compound can exist pharmacy acceptable salt, ester, acid amides and prodrug.Term used herein " pharmacy acceptable salt, ester, acid amides and prodrug " refers to carboxylate salt, amino acid addition salt, ester, acid amides and the prodrug of The compounds of this invention, they are being suitable for contacting with patient tissue in the medical judgment scope reliably, can not cause toxicity, hormesis, transformation reactions etc., with rational interests/risk than matching, desired use to them is effectively, and the possible zwitterionic form of The compounds of this invention.Term " salt " refers to the nontoxic relatively inorganic and organic acid addition salt and the alkali salt of following formula compound.These salt can be during the final compound isolation and purification preparation on the spot, perhaps preparation like this, the free alkali form that makes purifying compounds separately for example with the organic or inorganic acid-respons that is fit to, separate the salt that is generated again.Representational salt comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, Lactobionate and lauryl sulfonate etc.If the following formula compound has one or more acidic-groups, then it can generate salt by the reaction with alkali.These salt can comprise the positively charged ion based on basic metal and alkaline-earth metal, for example sodium, lithium, potassium, calcium, magnesium etc., and mineral alkali, for example ammonium, quaternary ammonium and other amine positively charged ions comprise tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, ethamine etc.Pharmacy acceptable salt is that the medical chemistry those skilled in the art know (for example referring to Berge S.M. etc., " Pharmaceutical Salts. " J Pharm.Sci. (pharmaceutical science magazine), 1977:66:1-19 quotes at this as a reference).
The example of the pharmaceutically acceptable nontoxic ester of The compounds of this invention comprises C 1-C 6Alkyl ester, wherein alkyl is to replace or unsubstituted straight or branched hydrocarbon.Ester also comprises C 5-C 7Cycloalkyl ester and aralkyl ester, for example benzyl and trityl.C 1-C 4Alkyl ester is preferred, for example methyl, ethyl, 2,2,2-three chloroethyls and the tertiary butyl.The ester of The compounds of this invention can prepare according to ordinary method, for example by the reaction of acid with alcohol.
The example of the pharmaceutically acceptable acid amides of The compounds of this invention comprises from ammonia, C 1-C 6Kiber alkyl amine and C 1-C 6Dialkylamine deutero-acid amides, wherein alkyl is a straight or branched.Under the situation of secondary amine, amine can also be 5-or the 6-unit heterocyclic form that contains 1 nitrogen-atoms.From ammonia, C 1-C 3Kiber alkyl amine and C 1-C 2Dialkylamine deutero-acid amides is preferred.The acid amides of The compounds of this invention can prepare according to the ordinary method that the medical chemistry technician knows.
Term " prodrug " refers to the compound that is converted into the following formula parent compound in the body rapidly, for example hydrolysis in blood or gastric juice.Talking out of prodrug referring to Higuchi T. and Stella V., " Pro-drugs as Novel Delivery Systems; " Vol.14, A.C.S.Symposium Series and Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and PergamonPress, 1987, the two is all quoted at this as a reference.
Representative compounds of the present invention is as shown in table 1 below.Table 1
Figure A0180404800311
Table 1 (continuing)
Figure A0180404800321
Table 1 (continuing)
Figure A0180404800331
Table 1 (continuing)
Figure A0180404800341
Table 1 (continuing)
Figure A0180404800361
Figure A0180404800371
The representative compounds of the present invention that is contained by formula I includes but not limited to compound and pharmaceutically acceptable acid or base addition salt, ester or amide analogue and the prodrug in the table 1.
The compounds of this invention can exist not solvation form and solvation form, comprises hydrated form.In general, comprise that the solvation form of hydrated form is equivalent to not solvation form, also plan to be contained by the scope of the invention.
Some formula I compound has one or more chiral centres, thereby can have independent steric isomer and composition thereof.Can there be more than one rotamerism type in other compounds.The present invention includes all optically-actives and geometrical isomer and form and composition thereof.The racemic mixture of The compounds of this invention is split as independent isomer by conventional process easily, and for example chromatography, Steppecd crystallization and classical Split Method use the acid and the salt of optically active.Independent isomer can also comprise chirality hydrogenolysis etc. by the synthetic preparation of chirality, uses commercial available chiral catalyst.
The compounds of this invention can be used for treating cancer (for example leukemia and lung, mammary gland, prostate gland and skin cancer, for example melanoma) and other hyperplasias, includes but not limited to psoriasis, HSV, HIV, restenosis and atherosclerosis.In order to utilize The compounds of this invention treatment cancer, the pharmaceutically acceptable composition to the cancer patients gives to treat significant quantity wherein comprises The compounds of this invention.
Further the invention embodiment is the method that treatment suffers from the patient of the disease that is caused by vascular smooth muscle cell proliferation.Compound in the scope of the invention suppresses vascular smooth muscle cell proliferation effectively and divides a word with a hyphen at the end of a line.This method need be by curee's administration that formula I to the VI compound of significant quantity is treated needs, and the inhibition vascular smooth muscle is bred and/or divided a word with a hyphen at the end of a line." curee " used herein and " patient " are Mammalss, and for example the people still also comprises horse, ox, sheep and companion animals, for example dog and cat.
The compounds of this invention can be mixed with multiple oral and parenteral dosage forms administration, comprises transdermal and rectal administration.To be that following dosage forms can comprise the pharmacy acceptable salt of formula I compound or corresponding formula I compound or solvate as active ingredient by what those skilled in the art admitted.
Further the invention embodiment is a pharmaceutical composition, comprises formula I to VI compound and pharmaceutically acceptable carrier, thinner or vehicle.Contain the pharmaceutical composition of The compounds of this invention about preparation, pharmaceutically acceptable carrier both can be a solid, also can be liquid.Solid preparation comprises pulvis, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials, and they can also serve as thinner, correctives, tackiness agent, sanitas, tablet disintegrant or encapsulating material.
In pulvis, carrier is the solid of fine pulverizing, for example talcum or starch, and the active ingredient of it and fine pulverizing forms mixture.In tablet, active ingredient and carrier with necessary bond property by suitable mixed, are pressed into desired shape and size.
Preparation of the present invention preferably contains has an appointment 5% to about 70% or above active compound.The carrier that is fit to comprises magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Preferred mouthful is capsule with formulation, comprises the preparation of active compound and encapsulating material, and the latter provides a kind of like this capsule as carrier, wherein active ingredient and or do not have other carriers to be surrounded by this carrier, thereby association with it.Similarly, comprise cachet and lozenge.Can utilize tablet, pulvis, capsule, pill, cachet and lozenge as the solid dosage that is fit to oral administration.
About preparation suppository, at first melt low melt wax, the mixture of glycerin fatty acid ester or theobroma oil for example is by stirring with the active ingredient homodisperse wherein.Uniform mixture after will melting then is poured in the mould of suitable size, cooling, thus solidify.
Liquid preparation comprises solution, suspension and emulsion, for example water or water/propylene glycol solution.About parenteral injection, liquid preparation can be mixed with in the solution of the polyoxyethylene glycol aqueous solution, isotonic saline solution, 5% D/W etc.The aqueous solution that is fit to mouthful usefulness can prepare like this, and active ingredient is water-soluble, adds tinting material, correctives, stablizer and the thickening material that is fit to as required.The aqueous suspensions that is fit to mouthful usefulness can prepare like this, and the active ingredient of fine pulverizing is dispersed in the water, mixes with cohesive material, and is for example natural or synthetic is gummy, resin, methylcellulose gum, Xylo-Mucine or other suspension agents of knowing.
Also comprise such solid preparation, they are tending towards being converted into soon before use the liquid preparation that is used for oral administration.This class I liquid I formulation comprises solution, suspension and emulsion.These preparations can also contain tinting material, correctives, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent etc. except active ingredient.Can utilize preparation slow release formulations such as wax, polymkeric substance, particulate.And, can adopt osmotic pump even release of active compounds in long-time.
Pharmaceutical preparation of the present invention is preferably unit dosage.In this class formulation, preparation is subdivided into the unitary dose that contains an amount of active ingredient.Unit dosage can be the preparation of band packing, and packing contains the preparation of discontinuous quantity, for example tablet, capsule and be packaged in bottle or ampoule in pulvis.And unit dosage can be capsule, tablet, cachet or a lozenge itself, and perhaps it can be the form of any these packings of proper amt.
The treatment effective dose of formula I compound generally will be from about 1 to about 100mg/kg body weight every day.Typical adult's dosage will be from about 50 to about 800mg every days.According to the application-specific and the effectiveness of active ingredient, the amount of active ingredient in unit dose formulations can not wait from about 0.1 to about 500mg, is preferably about 0.5 to 100mg.If necessary, composition can also contain other consistency therapeutical agents.The curee who needs formula I compounds for treating is given the dosage of about 1 to about 500mg every day, in 24 hours, divide the single or multiple administration.
The compounds of this invention can with the protein bound with other protein abilities of phosphorylation, and suppress its activity, for example cdks, PDGFr, FGFr, c-Src and EGFr.Cdks and cyclin generate title complex, and the key protein matter of these title complex phosphorylations permission cells process cell cycles (Meijer L., Progress in Cell Cycle Research (cell cycle progress), 1995:1:351-363).The compounds of this invention suppresses this phosphorylation, therefore can be used for the treatment of cancer and/or restenosis and other hyperplasias as antiproliferative.
Because they are active to cdks and other kinase whose inhibition, The compounds of this invention or useful tool are used for external and these kinase whose mechanisms of action of the interior research of body.
The preparation of The compounds of this invention and purposes further describe in following detailed embodiment.Embodiment plans to set forth specific invention embodiment, never plans to limit the scope of specification sheets or claims.The compounds of this invention is to utilize commercial available raw material and reagent to be prepared by the synthetic method that the organic chemistry filed technician knows.
Reactive functional groups in the molecule that the experience of may deriving between the synthesis phase of The compounds of this invention is reacted is to avoid undesirable side reaction.Usually will get up with the radical protection that is fit to such as functional groups such as hydroxyl, amino and acidic groups, remove easily when needed.The purposes of blocking group commonly used fully is described in the Protective Groups in OrganicSnthesis of Green and Wuts, John Wiley and Sons, New York, New York (2 NdEdition.1991) in.Typical hydroxy-protective group comprises into ether group, for example benzyl, and aryl, for example tertbutyloxycarbonyl (Boc), formyl radical and ethanoyl.The amido protecting group comprises benzyl, aryl, for example ethanoyl, and trialkylsilkl.The carboxylic acid group is normally protected by the ester that is converted into easy hydrolysis, for example three chloroethyls, the tertiary butyl, benzyl etc.
As mentioned above, some The compounds of this invention has one or more chiral centres, thereby can have independent optically active isomer and geometrical isomer and composition thereof.For example, compound 106 has two asymmetric centers, and has cis-configuration.The present invention includes the independent R or the S isomer of all such geometrical isomers, enantiomer and RS racemic modification and chipal compounds.Isomer that all are independent and composition thereof all comprises in the present invention.Independent isomer is prepared by chirality is synthetic easily, is perhaps prepared by conventional disassemble technique well known to those skilled in the art.
The preparation of The compounds of this invention is set forth among the flow process 1-4.The synthetic of Compound I (embodiment 15) is depicted in the flow process 1; What but should admit is that generalized flowsheet can be applicable to all The compounds of this invention.Each step shown in the flow process further is set forth among the following detailed embodiment.
In the flow process 1, make the reaction of 2-methylthio group-4-halo-5-carbalkoxy pyrimidine and ammonium hydroxide, obtain corresponding 4-aminoderivative.By with LiAlH 4This ester of reaction reduction obtains 5-methylol analogue, is oxidized to 5-formyl radical derivative then.The 5-formyl radical is converted into unsaturated group (acrylate), and latter's cyclisation generates pyrido [2,3-d] pyrimidine.Pyridopyrimidine is converted into crucial intermediate, 2-methylthio group pyrido [2,3-d] pyrimidin-7-yl amine just, the easy oxidation of the latter obtains 2-methanesulfinyl analogue.By with amine R 2NH 2Reaction replace the 2-methanesulfinyl easily, obtain formula I compound of the present invention.By with isocyanic ester, for example R 19The reaction of N=C=O, the 7-amino on the Pyridopyrimidine ring is converted into urea easily.Flow process 1
Figure A0180404800421
Reactant has following meanings shown in the flow process 1:
(a) NH 3(b) LAH; (c) MnO 2(d) Ph 3PCHCO 2Et; (e) DBU; (f) POCl 3(g) NH 3(h) (±)-trans-2-(benzenesulfonyl)-3-phenyl oxaza propane; (i) 4-(4-Boc-piperidines) aniline; (j) NaH. tertiary butyl isocyanic ester; (k) HCl
Flow process 2 be set forth in the 7-position have urea functional group Pyridopyrimidine substitute synthetic.This class urea is by the prepared in reaction of isocyanic ester and 7-aminopyridine and pyrimidine in flow process 1, and flow process 2 is utilized carbonyl dimidazoles, obtains intermediate imidazoles thing.Easy and the amine R of imidazoles thing 19NH 2Reaction obtains corresponding urea.Flow process 2 is set forth this method by showing synthesizing of compound 51, and is described in more fully among the embodiment 32.
Flow process 2
Figure A0180404800431
Condition: (a) NaH. carbonyl dimidazoles; (b) cyclopentamine; (c) HCl
Formula I compound also can wherein have been described synthetic (embodiment 45) of compound 4 according to flow process 3 preparations.Make 4-amino-2-methylthiopyrimidine-5-formaldehyde and Diethylaminoethyl reactive magnesium, obtain corresponding 5-(2-hydroxyethyl)-pyrimidine.The oxidized methyl ketone analogue that obtains of alcohol.Make the reaction of methyl ketone and cyanogen methyl-phosphorous acid diethyl ester, cyclisation is 5-methyl-7-aminopyridine and pyrimidine.Further as flow process 1 or 2 reactions, obtain The compounds of this invention, for example compound 4.
Flow process 3
Condition: (a) MeMgBr; (b) MnO 2(c) (EtO) 2P (O) CH 2CN
Formula I compound can also wherein have been described the synthetic of compound 12 (embodiment 40) according to flow process 4 preparations.In this flow process, the 2-methylthio group of pyrimidine at first is oxidized to corresponding methanesulfinyl analogue.By with amine R 2NH 2Reaction displacement methanesulfinyl.As flow process 1 derivatize 5-formaldehyde, cyclisation obtains corresponding 2-(R then 2NH) the 7-aminopyridine and the pyrimidine of Qu Daiing.With 7-amino as acrylated or other derivatizes as described in the flow process 1-3.Flow process 4
Condition: (a) (±)-trans-2-(benzenesulfonyl)-3-phenyl oxaza propane (oxaziridine); (b) 4-(4-Boc-piperidines)-aniline; (c) (EtO) 2P (O) CH 2CN
Any formula I-VI compound of the present invention can wherein have been set forth the synthetic of compound 1,51,4 and 12 respectively according to flow process 1-4 preparation.Organic chemistry filed technician will recognize that raw material can be different, and can adopt other step to be prepared as the compound that the present invention is contained, as what following specific embodiment proved.
Open in this application all articles and reference, comprise that patent all quotes at this as a reference.
Following detailed embodiment further sets forth invention, and they are not interpreted as in scope or mentally invention are limited to wherein described specific procedure.Raw material and various intermediate can obtain from commercial source, prepare from the synthetic method that commercial available organic compound prepares or utilization is known.
Embodiment 1
4-amino-2-methylthio group-pyrimidine-5-carboxylic acid's ethyl ester
(15.0g adds the 25mL triethylamine in 200mL tetrahydrofuran solution 65mmol), add the 35mL ammonium hydroxide aqueous solution then to the 4-of room temperature chloro-2-methylthio group-pyrimidine-5-carboxylic acid's ethyl ester.After at room temperature stirring 1.5 hours, add other 30mL ammonium hydroxide aqueous solution, continue to stir 1 hour.Reaction mixture is concentrated in a vacuum, between ethyl acetate and saturated sodium bicarbonate aqueous solution, distribute.With organic layer salt water washing, through dried over mgso, filter, concentrate in a vacuum.Add ethyl acetate and hexane, filter and collect the gained solid, obtain 10.84g (79%) 4-amino-2-methylthio group-pyrimidine-5-carboxylic acid's ethyl ester.
Embodiment 2
(4-amino-2-methylthio group-pyrimidine-5-yl)-methyl alcohol
(13.36g, 250mL tetrahydrofuran solution 63mmol) are added drop-wise in the 250mL tetrahydrofuran (THF) suspension of lithium aluminium hydride (3.82g 100mmol) of room temperature with 4-amino-2-methylthio group-pyrimidine-5-carboxylic acid's ethyl ester.After 30 minutes, reaction is cooled to 0 ℃, adds Virahol, reduce until bubbling.To react with 15mL water, 15mL 15%NaOH and the quencher of 50mL water, mixture will be stirred 1 hour.Remove by filter white precipitate, wash with ethyl acetate.Filtrate is concentrated in a vacuum, add 3: 1 hexanes: ethyl acetate.Collect solid, with 3: 1 hexanes: ethyl acetate was washed, and uses hexane wash then.Solid is dissolved in ethyl acetate, and solution is through dried over mgso.Filtration concentrates then in a vacuum, obtains 8.14g (76%) (4-amino-2-methylthio group-pyrimidine-5-yl)-methyl alcohol.
Analytical calculation value C 6H 9N 3OS:
C，42.09；H，5.30；N，24.54.
Measured value: C, 42.31; H, 5.24; N, 24.27.
Embodiment 34-amino-3-methylthio group-pyrimidine-5-formaldehyde
To (4-amino-2-methylthio group-pyrimidine-5-yl)-methyl alcohol (8.14g, add in 1L chloroformic solution 48mmol) manganese oxide (33.13g, 381mmol).Suspension at room temperature stirred spend the night, filter by C salt then, with the washing of 300mL chloroform.Concentrated filtrate obtains 8.14g (quantitative yield) 4-amino-2-methylthio group-pyrimidine-5-formaldehyde in a vacuum.mp185-187℃。Document mp=183-184 ℃, JOC, 1958:23:1738.
Analytical calculation value C 6H 7N 3OS:
C，42.59；H，4.17；N，24.83.
Measured value: C, 42.84; H, 4.21; N, 24.73.
Embodiment 4
3-(4-amino-2-methylthio group-pyrimidine-5-yl) ethyl propenoate
To the 4-of room temperature amino-2-methylthio group-pyrimidine-5-formaldehyde (4.08g, add in 100mL tetrahydrofuran solution 24.14mmol) (ethoxycarbonyl methylene radical) triphenyl phosphorane (10.80g, 31mmol).Reaction mixture was heated 3 hours under refluxing, at room temperature stir then and spend the night.Concentrated reaction mixture in a vacuum, resistates be through purification by flash chromatography, and with 1: 1 ethyl acetate: the hexane wash-out obtained 4.30g (75%) 3-(4-amino-2-methylthio group-pyrimidine-5-yl) ethyl propenoate; Mp is softening down at 108 ℃.
Analytical calculation value C 10H 13N 3O 2S:
C，50.19；H，5.48；N，17.56
Measured value: C, 50.22; H, 5.45; N, 17.24
Embodiment 5
2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones
(368mg, 3mL N 1.53mmol) add 380 μ L 1 in the N-diisopropylethylamine solution, the 8-diazabicylo is [5.4.0] 11 carbon-7-alkene also to the 3-of room temperature (4-amino-2-methylthio group-pyrimidine-5-yl) ethyl propenoate.Reaction mixture was heated 3 hours under refluxing, be cooled to room temperature then, concentrate.Resistates is used eluent ethyl acetate through purification by flash chromatography.Partial concentration contains the part of product in a vacuum, and solids removed by filtration obtains 134mg (45%) 2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones, mp 269-271 ℃.
Analytical calculation value C 8H 7N 3OS:
C，49.73；H，3.65；N，21.75.
Measured value: C, 49.67; H, 3.46; N, 21.49.
Embodiment 6
7-chloro-2-methylthio group-pyrido [2,3-d] pyrimidine
The 10mL phosphoryl chloride suspension of 1.0g (5.2mmol) 2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 5) was heated 1 hour under refluxing.With the cooling of gained solution, concentrate, obtain solid, with the cold water development, filter, obtain the 1.05g crude product.Recrystallization from acetonitrile obtains 0.76g (69%) product, mp 201-203 ℃.
MS (APCI) M+1: calculated value 212.0; Measured value 212.0.
Analytical calculation value C 8H 6Cl 1S 1N 3:
C，45.39；H，2.86；N，19.85.
Measured value: C, 45.53; H, 2.90; N, 19.74.
Embodiment 7
2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
To heat 65 hours down at 40 ℃ with the 200mL Virahol suspension sealing of the saturated 2.95g of ammonia (13.9mmol) 7-chloro-2-methylthio group-pyrido [2,3-d] pyrimidine (embodiment 6).Use ammonia saturated once more suspension, heated other 18 hours down at 40 ℃.Solid collected by filtration, water development obtains 1.98g (74.2%) product, mp＞250 ℃.
MS (APCI) M+1: calculated value 193.1; Measured value 193.0.
Analytical calculation value C 8H 8N 4S 1:
C，49.98；H，4.19；N，29.14.
Measured value: C, 50.14; H, 4.22; N, 29.04.
Embodiment 8
2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine
With 10.63g (55.3mmol) 2-methylthio group-pyrido [2; 3-d] the 300mL methylene dichloride of pyrimidin-7-yl amine (embodiment 7) and 300mL methyl alcohol suspension handle with 18.06g (69.1mmol) (±)-trans-2-(benzenesulfonyl)-3-phenyl oxaza propane, and stirring is spent the night.Suspension is filtered,, be concentrated into about 25mL, dilute with ethyl acetate to remove small amount of solid.Solid collected by filtration obtains 9.27g (80.5%) product, 180 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 209.0; Measured value 209.1
Embodiment 9
N 2-phenyl-pyrido [2,3-d] pyrimidine-2, the 7-diamines
With the 2mL dimethyl sulfoxide (DMSO) suspension of 0.44g (2.1mmol) 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine (embodiment 8) and 0.39mL (4.2mmol) aniline 100 ℃ of following heated overnight.Cooling gained solution is poured in the water.In suspension, add ethyl acetate, solid collected by filtration.Solid with 0% to 20% ethanol/methylene gradient elution during 30 minutes, obtains 0.14g (29%) product, mp 225-260 ℃ through purification by flash chromatography.
MS (APCI) M+1: calculated value 238.1: measured value 238.1.
Analytical calculation value C 13H 11N 50.18H 2O:
C，64.92；H，4.76；N，29.12.
Measured value: C, 65.26; H, 4.75; N, 28.76.
Embodiment 10
The 1-tertiary butyl-3-(2-phenylamino-pyrido [2,3-d] pyrimidin-7-yl)-urea
To refrigerative 0.1022g (0.431mmol) N in ice bath 2-phenyl-pyrido [2,3-d] pyrimidine-2 adds 0.019g (0.47mmol) 60% sodium hydride in the 2mL dimethyl formamide solution of 7-diamines (embodiment 9).To in ice bath, handle with 0.054mL (0.47mmol) tert-butyl isocyanate by refrigerative gained solution then.Solution is taken advantage of cold stirring 15 minutes, at room temperature stirred then 1 hour.Solution is poured in the frozen water, obtains solid, the filtration collection, use hexane wash, obtain 0.0849g (57.8%) product (compound 45), 227 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 337.2; Measured value 337.1.
Analytical calculation value C 18H 20N 6O 10.27H 2O:
C，63.35；H，6.07；N，24.63.
Measured value: C, 63.73; H, 5.82; N, 24.20.
Embodiment 11
4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester
The 75mL methylene dichloride suspension of 7.5g (36mmol) 1-(4-nitrophenyl)-piperazine and 6.94mL (40mmol) ethyl-di-isopropyl-amine is handled with 8.69g (40mmol) tert-Butyl dicarbonate, at room temperature stirred and spend the night.Gained solution is washed with saturated sodium bicarbonate aqueous solution, wash with water then, dry (sal epsom) concentrates.The gained material with 10% to 30% ethyl acetate/hexane gradient elution during 10 minutes, obtains 8.62g (77.5%) product, mp 136-140 ℃ through purification by flash chromatography.
MS (APCI) M+1: calculated value 308.2; Measured value 308.2.
Embodiment 12
4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
Adding hydrogen to initial pressure in the 50mL tetrahydrofuran (THF) suspension of 1.46g (4.8mmol) 4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (embodiment 11) and 1g Raney nickel is 54.5psi.Reaction was shaken 14 hours, filter then.Concentrated filtrate obtains 1.29g (97%) product, is solid.
MS (APCI) M+1: calculated value 278.2; Measured value 278.2.
Analytical calculation value C 15H 23N 3O 2:
C，64.96；H，8.36；N，15.15.
Measured value: C, 65.22; H, 8.58; N, 14.58.
Embodiment 13
4-[4-(the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 9, replace aniline, obtain 0.0744g (36.0%) product, mp 219-220 ℃ with 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (embodiment 12).
MS (APCI) M+1: calculated value 422.2; Measured value 422.2.
Analytical calculation value C 22H 27N 7O 20.5H 2O:
C，61.38；H，6.56；N，22.77.
Measured value: C, 61.34; H, 6.30; N, 22.47.
Embodiment 14
4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, use 4-[4-(the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (embodiment 13) replacement N 2-phenyl-pyrido [2,3-d] pyrimidine-2, the 7-diamines obtains 0.3354g (67.9%) product (compound 79), 225 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 521.3; Measured value 521.2.
Analytical calculation value C 27H 36N 8O 3:
C，62.29；H，6.97；N，21.52.
Measured value: C, 62.33; H, 6.81; N, 21.43.
Embodiment 15
The 1-tertiary butyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl] urea
To 0.100g (0.192mmol) 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } add 2mL 4M hydrogenchloride/diox in the 2mL methyl alcohol suspension of piperazine-1-carboxylic acid tert-butyl ester (embodiment 14), obtain solution.Suspension at room temperature stirred spend the night, dilute with ether then.Filter collection of material, obtain 0.0941g (93.4%) product (compound 1), 215 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 421.2; Measured value 421.1.
Analytical calculation value C 22H 28N 8O 12.10 HCl1.51 H 2O:
C, 50.40; H, 6.37; N, 21.37; Cl (altogether) .14.20
Measured value: C, 50.40; H, 6.18; N, 21.03; Cl (altogether) .14.33.
Embodiment 16
4-{4-[7-3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester
In embodiment 14, replace tert-butyl isocyanate, obtain 0.1463g (70.4%) product (compound 80), 241 ℃ of mp (decomposition) with NSC 87419.
MS (APCI) M+1: calculated value 547.3: measured value 547.4
Analytical calculation value C 29H 38N 8O 30.28H 2O:
C，63.13；H，7.04；N，20.31.
Measured value: C, 63.14; H, 6.81; N, 20.25.
Embodiment 17
1-cyclohexyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl)-urea
In embodiment 15, use 4-{4-[7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester (embodiment 16) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2-base) amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.0871g (81.4%) product (compound 9), 200 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 447.3; Measured value 447.3.
Analytical calculation value C 24H 30N 8O 12.55 HCl2.82 H 2O:
C, 48.83; H, 6.52; N, 18.98:Cl (altogether), 15.31.
Measured value: C, 48.83; H, 6.18; N, 18.89; Cl (altogether), 15.37.
Embodiment 18
N 2-(4-fluoro-3-methyl-phenyl)-pyrido [2,3-d] pyrimidine-2, the 7-diamines
In embodiment 9, replace aniline, obtain 0.2025g (39.2%) product, be solid with 4-fluoro-3-monomethylaniline.
MS (APCI) M+1: calculated value 270.1; Measured value 270.0.
Embodiment 19
The 1-tertiary butyl-3-[2-(4-fluoro-3-methyl-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 10, use N 2-(4-fluoro-3-methyl-phenyl)-pyrido [2,3-d] pyrimidine-2,7-diamines (embodiment 18) replaces N 2-phenyl-pyrido [2,3-d] pyrimidine-2, the 7-diamines obtains 0.0656g (47.9%) product (compound 46), 230 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 369.2: measured value 369.1.
Analytical calculation value C 19H 21F 1N 6O 1:
C，61.94；H，5.75；N，22.81.
Measured value: C, 61.82; H, 5.73; N, 22.75.
Embodiment 20
1-(4-chloro-phenyl)-3-[2-(4-fluoro-3-methyl-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 19, replace tert-butyl isocyanate, obtain 0.050 (37%) product (compound 47), mp＞250 ℃ with 4-chloro-phenyl-isocyanic ester.
MS (APCI) M+1: calculated value 423.1: measured value 423.1.
Analytical calculation value C 21H 16F 1Cl 1N 6O 10.23H 2O:
C，59.07；H，3.89；N，19.68.
Measured value: C, 59.09; H, 3.97; N, 19.65.
Embodiment 21
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea
To 0.145g (0.277mmol) the 1-tertiary butyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl] add 0.19mL (1.11mmol) ethyl-di-isopropyl-amine in the 5mL methylene dichloride suspension of urea (embodiment 15).Suspension is cooled off in ice bath, handle with 0.024mL (0.33mmol) Acetyl Chloride 98Min..Suspension at room temperature stirred spend the night, filter then.Use the washed with dichloromethane solid.Merging filtrate and washing lotion wash with water, and dry (sal epsom) concentrates.Material with 0% to 5% ethanol/methylene gradient elution during 30 minutes, obtains 0.0674g (51.8%) product (compound 5), mp 206-208 ℃ (decomposition) through purification by flash chromatography.
MS (APCI) M+1: calculated value 463.3: measured value 463.3.
Analytical calculation value C 24H 30N 8O 20.40H 2O:
C，61.36；H，6.61；N，23.85.
Measured value: C, 61.38; H, 6.37; N, 23.98.
Embodiment 22
4-{4-[7-(3-sec.-propyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester
In embodiment 14, replace tert-butyl isocyanate, obtain 0.909g (69.9%) product, be solid with n-Isopropyl isocyanate.
MS (APCI) M+1: calculated value 507.3; Measured value 507.4.
Embodiment 23
1-sec.-propyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl] urea
In embodiment 15, use 4-{4-[7-(3-sec.-propyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester (embodiment 22) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester, obtain 0.0287g (27.9%) product (compound 48), 190 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 407.2: measured value 407.1.
Analytical calculation value C 21H 26N 8O 12.05 TFA0.84 H 2O:
C，46.00；H，4.57；N，17.10.
Measured value: C, 46.00; H, 4.65; N, 17.09.
Embodiment 24
Cis-3,5-dimethyl-1-(4-nitro-phenyl)-piperazine
With 6.74g (47.8mmol) 4-fluoro-oil of mirbane and 10.91g (95.5mmol) cis-2, the suspension of 6-dimethyl-piperazine heated 1 hour down at 45 ℃.With the reaction mixture cooling, shake with methylene dichloride and water.With organic layer drying (sal epsom), concentrate, obtain 11.62g (＞100%) product, be solid.
Embodiment 25
Cis-2,6-dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
With cis-3,5-dimethyl-1-(4-nitro-phenyl)-piperazine (embodiment 24) replaces 1-(4-nitrophenyl)-piperazine, obtains 14.87g (92.8%) product, is solid in embodiment 11.
Embodiment 26
4-(4-amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
With cis-2,6-dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (embodiment 25) replaces 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, obtains 5.03g (64.7%) product, is solid in embodiment 12.
Embodiment 27
4-[4-(the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
With 4-(4-amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 26) replaces aniline, obtains 0.6463g (59.8%) product, 245 ℃ of mp (decomposition) in embodiment 9.
MS (APCI) M+1: calculated value 450.3; Measured value 450.3.
Embodiment 28
4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, use 4-[4-(the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 27) replaces N 2-phenyl-pyrido [2,3-d] pyrimidine-2, the 7-diamines obtains 0.1828g (74.9%) product, is solid.
MS (APCI) M+1: calculated value 549.3; Measured value 549.4.
Embodiment 29
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidine-7 base }-urea
In embodiment 15, use 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 28) replaces 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.0910g (92.9%) product (compound 49), 245 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 449.3; Measured value 449.2.
Embodiment 30
4-{4-[7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 28, replace tert-butyl isocyanate, obtain 0.1156g (60.8%) product, be solid with NSC 87419.
MS (APCI) M+1: calculated value 575.3; Measured value 575.3.
Embodiment 31
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-urea
In embodiment 15, use 4-{4-[7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 30) replaces 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.1022g product (compound 50), 228 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 475.2; Measured value 475.2.
Embodiment 32
4-{4-[7-(3-cyclopentyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester
To refrigerative 0.150g (0.36mmol) 4-[4-in ice bath (the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-add 0.022g (0.54mmol) 60% sodium hydride in the 2mL dimethyl formamide solution of piperazine-1-carboxylic acid tert-butyl ester (embodiment 13).With refrigerative solution stirring 15 minutes, use 0.088g (0.54mmol) carbonyl dimidazoles to handle then.With other 30 minutes of refrigerative solution stirring, use 0.071mL (0.72mmol) cyclopentamine to handle then.Gained solution was at room temperature stirred 1 hour, join in the cold water then.Solid collected by filtration obtains first material.Contain filter liquor with dichloromethane extraction then,, concentrate, obtain second batch of material extraction liquid drying (sal epsom).Merge 2 batches of materials,,, obtain 0.1159g (60.4%) product, be solid with 0% to 5% ethanol/methylene gradient elution during 30 minutes through purified by flash chromatography.
MS (APCI) M+1: calculated value 533.3; Measured value 533.4.
Embodiment 33
1-cyclopentyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, use 4-{4-[7-(3-cyclopentyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester (embodiment 32) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.0937g (80.8%) product (compound 51), mp 210-213 ℃ (decomposition).
MS (APCI) M+1: calculated value 433.2; Measured value 433.2.
Analytical calculation value C 23H 28N 8O 12.49 HCl1.65 H 2The O0.1 diox:
C, 50.02; H, 6.21; N, 19.94; Cl (altogether), 15.71.
Measured value: C, 49.89; H, 5.81; N, 19.74; Cl (altogether), 14.74.
Embodiment 34
1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethanol
During 20 minutes, in by the 150mL tetrahydrofuran (THF) suspension of ice bath refrigerative 5.0g (29mmol) 4-amino-2-methylthio group-pyrimidine-5-formaldehyde (embodiment 3), add the diethyl ether solution (69.4mmol) of 23.2mL3.0M methylmagnesium-bromide.At 0 ℃ after following 1 hour, add other 23.2mL 3.0M Diethylaminoethyl magnesium solution, make suspension return to room temperature, stirring is spent the night.To react with the quencher of 100mL saturated aqueous ammonium chloride, between water and ethyl acetate, distribute.With organic layer drying (sal epsom), concentrate, obtain 5.24g (96%) product, mp 140-142 ℃.
MS (APCI) M+1: calculated value 186.1; Measured value 185.9.
Embodiment 35
1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethyl ketone
In embodiment 3, replace (4-amino-2-methylthio group-pyrimidine-5-yl)-methyl alcohol, in toluene, react, obtain 3.74g (72%) product, be solid at 80 ℃ with 1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethanol (embodiment 34).
MS (APCI) M+1: calculated value 184.0; Measured value 183.9.
Embodiment 36
1-(4-amino-2-methanesulfinyl-pyrimidine-5-yl)-ethyl ketone
In embodiment 8, replace 2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 9.57g (88%) product, be solid with 1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethyl ketone (embodiment 35).
MS (APCI) M+1: calculated value 200; Measured value 200.
Embodiment 37
4-[4-(5-ethanoyl-4-amino-pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 13, replace 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 4.04g (65%) product, be solid with 1-(4-amino-2-methanesulfinyl-pyrimidine-5-yl)-ethyl ketone (embodiment 36).
MS (APCI) M+1: calculated value 413; Measured value 413.
Embodiment 38
4-[4-(7-amino-5-methyl-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
Under 0 ℃, in the 10mL tetrahydrofuran (THF) suspension of 0.58g (14.6mmol) 60% sodium hydride, drip 2.58g (14.56mmol) (cyanogen methyl) diethyl phosphonate.Reaction mixture was stirred 5 minutes down at 0 ℃, at room temperature stirred then 20 minutes.Mixture is cooled to 0 ℃ then, with 2g (4.85mmol) 4-[4-(5-ethanoyl-4-amino-pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (embodiment 37) processing.Mixture at room temperature stirred spend the night, water and saturated aqueous ammonium chloride are handled then.Filter and collect the gained solid,, obtain 1.069g (80%) product with the ether washing.
MS (APCI) M+1: calculated value 436; Measured value 436.
Embodiment 39
4-{4-[7-(3-cyclohexyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, use 4-[4-(7-amino-5-methyl-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (embodiment 38) replaces 4-[4-(7-amino-pyridine also [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.199g (42%) product, be solid.
MS (APCI) M+1: calculated value 561; Measured value 561.
Embodiment 40
1-cyclohexyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, use 4-{4-[7-(3-cyclohexyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester (embodiment 39) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain product (compound 12), be solid, 238 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 461; Measured value 461.
Embodiment 41
5-methyl-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 38, replace 4-[4-(5-ethanoyl-4-amino-pyrimidine-2--amino)-phenyl with 1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethyl ketone (embodiment 35)]-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.97g (85%) product, be solid.
MS (APCI) M+1: calculated value 207; Measured value 207.
Embodiment 42
2-methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 8, replace 2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 0.85g (83%) product, be solid with 5-methyl-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine (embodiment 41).
MS (APCI) M+1: calculated value 223; Measured value 223.
Embodiment 43
4-[4-(7-amino-5-methyl-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 13, replace 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 0.33g (20%) product, be solid with 2-methanesulfinyl-5-methyl-pyrido [2,3-d] pyrimidin-7-yl amine (embodiment 42).
MS (APCI) M+1: calculated value 436; Measured value 436.
Embodiment 44
4-{4-[7-(the 3-tertiary butyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, use 4-[4-(7-amino-5-methyl-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (embodiment 43) replacement N 2-phenyl-pyrido [2,3-d] pyrimidine-2, the 7-diamines obtains 0.17g (45%) product, is solid.
MS (APCI) M+1: calculated value 535; Measured value 535.
Embodiment 45
The 1-tertiary butyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido-[2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, use 4-{4-[7-(the 3-tertiary butyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester (embodiment 44) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.070g (72%) product (compound 4), be solid, mp 230-232 ℃ (decomposition).
MS (APCI) M+1: calculated value 435; Measured value 435.
Embodiment 46
6-fluoro-2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones
The 20mL tetrahydrofuran solution of 1.74g (10.33mmol) (diethoxy-phosphoryl)-fluoro-ethyl acetate is cooled to-78 ℃, drips the hexane solution of 12.9mL (20.65mmol) 1.6M n-Butyl Lithium.After stirring 30 minutes under-78 ℃, solution is handled with 1.74g (10.33mmol) 4-amino-2-methylthio group-pyrimidine-5-formaldehyde (embodiment 3), make solution be warmed to room temperature, stirring is spent the night.To react with saturated aqueous ammonium chloride and handle, use water treatment then.Solid collected by filtration with the ether washing, obtains 2.01g (92%) product.
MS (APCI) M+1: calculated value 212; Measured value 212.
Embodiment 47
7-chloro-6-fluoro-2-methylthio group-pyrido [2,3-d] pyrimidine
In embodiment 6, replace 2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones, obtain 1.86g (85%) product, be solid with 6-fluoro-2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 46).
MS (APCI) M+1: calculated value 230,232; Measured value 230,232.
Embodiment 48
6-fluoro-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 7, replace 7-chloro-2-methylthio group-pyrido [2,3-d] pyrimidine, obtain 0.29g (90%) product, be solid with 7-chloro-6-fluoro-2-methylthio group-pyrido [2,3-d] pyrimidine (embodiment 47).
MS (APCI) M+1: calculated value 211; Measured value 211.
Embodiment 49
6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 8, replace 2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 0.26g (95%) product, be solid with 6-fluoro-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine (embodiment 48).
MS (APCI) M+1: calculated value 227; Measured value 227.
Embodiment 50
4-[4-(7-amino-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 27, replace 2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine, obtain 0.040g (63%) product, be solid with 6-fluoro-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine (embodiment 49).
MS (APCI) M+1: calculated value 468; Measured value 468.
Embodiment 51
4-{4-[7-(3-cyclohexyl-urea groups)-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, use 4-[4-(7-amino-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 50) replaces 4-[4-(7-amino-pyridine also [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.10g (74%) product, be solid.
MS (APCI) M+1: calculated value 593; Measured value 593.
Embodiment 52
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea
In embodiment 15, use 4-{4-[7-(3-cyclohexyl-urea groups)-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 51) replaces 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.060g (75%) product (compound 52), be solid, mp 227-229 ℃.
MS (APCI) M+1: calculated value 493; Measured value 493.
Embodiment 53
4-{4-[7-(3-cyclopentyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 32, use 4-[4-(7-amino-5-methyl-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (embodiment 43) replaces 4-[4-(7-amino-pyridine also [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.18g (55%) product, be solid.
MS (APCI) M+1: calculated value 547; Measured value 547.
Embodiment 54
1-cyclopentyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, use 4-{4-[7-(3-cyclopentyl-urea groups)-5-methyl-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester (embodiment 53) replacement 4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester, obtain 0.08g (70%) product (compound 53), mp234 ℃ (decomposition).
MS (APCI) M+1: calculated value 447; Measured value 447.
Embodiment 55
4-(4-{7-[3-(3-hydroxyl-propyl group)-urea groups]-pyrido [2,3-d] pyrimidine-2--amino }-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 32, replace cyclopentamine, replace sodium hydride, obtain 0.1295g (52.2%) product, be solid with sodium tert-butoxide with 3-amino-1-propyl alcohol.
MS (APCI) M+1: calculated value 523.3; Measured value 523.2.
Embodiment 56
1-(3-hydroxyl-propyl group)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 55, obtain 0.1077g product (compound 81), be solid, 183 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 423.2; Measured value 423.1.
Embodiment 57
4-{4-[7-(3-cyclohexyl-3-methyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain 0.1932g (72.7%) product, be solid with N-methylcyclohexyl amine.
MS (APCI) M+1: calculated value 561.3; Measured value 561.2.
Embodiment 58
1-cyclohexyl-1-methyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 57, obtain 0.1645g product (compound 65), be solid, 177 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 461.3; Measured value 461.2.
Embodiment 59
4-(4-{7-[3-((S)-1-methylol-3-methyl-butyl)-urea groups]-pyrido [2,3-d] pyrimidine-2--amino }-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain 0.1048g (39.1%) product, be solid with (S)-(+)-leucinol.
MS (APCI) M+1: calculated value 565.3; Measured value 565.3.
Embodiment 60
1-((S)-1-methylol-3-methyl-butyl)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 59, obtain 0.0802g product (compound 83), be solid, 185 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 465.3; Measured value 465.2.
Embodiment 61
4-[4-(7-{[1-(4-methyl-piperazine-1-yl)-formyl radical]-amino }-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with N methyl piperazine.
MS (APCI) M+1: calculated value 548.3; Measured value 548.3.
Embodiment 62
4-methyl-piperazine-1-carboxylic acid [2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-acid amides
In embodiment 15, replace the product of embodiment 61, obtain 0.1194g product (compound 84), be solid, 200 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 448.3; Measured value 448.2.
Embodiment 63
4-(4-{7-[(1-morpholine-4-base-formyl radical)-amino]-pyrido [2,3-d] pyrimidine-2--amino }-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with morpholino.
MS (APCI) M+1: calculated value 535.3; Measured value 535.2.
Embodiment 64
Morpholine-4-carboxylic acid [2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-acid amides
In embodiment 15, replace the product of embodiment 63, obtain 0.1132g product (compound 85), be solid, 190 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 435.2; Measured value 435.2.
Embodiment 65
4-{4-[7-(3,3-dipropyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl } piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with dipropyl amine.
MS (APCI) M+1: calculated value 549.3; Measured value 549.3.
Embodiment 66
3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-1,1-dipropyl-urea
In embodiment 15, replace the product of embodiment 65, obtain 0.1278g product (compound 86), be solid, 190 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 449.3; Measured value 449.2.
Embodiment 67
4-[4-(7-{[1-(4-Boc-piperazine-1-yl)-formyl radical]-amino)-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with the Boc-piperazine.
MS (APCI) M+1: calculated value 634.3; Measured value 634.3.
Embodiment 68
Piperazine-1-carboxylic acid [2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-acid amides
In embodiment 15, replace the product of embodiment 67, obtain 0.0342g product (compound 87), be solid, 220 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 434.2; Measured value 434.2.
Embodiment 69
4-(4-{7-[3-((R)-1-methylol-2-methyl-propyl group)-urea groups]-pyrido [2,3-d] pyrimidine-2--amino }-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with (R)-valerian ammonia alcohol.
MS (APCI) M+1: calculated value 551.3; Measured value 551.3.
Embodiment 70
1-((R)-1-methylol-2-methyl-propyl group)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 69, obtain 0.0639g product (compound 88), be solid, 200 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 451.3; Measured value 451.2.
Embodiment 71
4-(4-{7-[3,3-pair-(2-hydroxyl-ethyl)-urea groups]-pyrido [2,3-d] pyrimidine-2--amino }-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 55, replace 3-amino-1-propyl alcohol, obtain product, be solid with diethanolamine.
MS (APCI) M+1: calculated value 553.3; Measured value 553.2.
Embodiment 72
1,1-pair-(2-hydroxyl-ethyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 71, obtain 0.0916g product (compound 89), be solid, 185 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 453.2; Measured value 453.2.
Embodiment 73
6-bromo-2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones
In the 130mL DMF solution of 5.00g (25.9mmol) 2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 5), add 5.00g (28.1mmol) N-bromine succinimide.The gained suspension at room temperature stirred spend the night, concentrate.Solid is developed with hot water, used washed with isopropyl alcohol, obtain 5.59g (79.4%) product, be solid, mp 266-270 ℃.
Embodiment 74
6-bromo-7-chloro-2-methylthio group-pyrido [2,3-d] pyrimidine
In embodiment 6, replace the product of embodiment 73, obtain 2.73g (97.2%) product, be solid.
MS (APCI) M+1: calculated value 289.9; Measured value 289.8.
Embodiment 75
6-bromo-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 7, replace the product of embodiment 74, obtain 2.09g (82.9%) product, be solid.
MS (APCI) M+1: calculated value 271.0; Measured value 270.8.
Embodiment 76
6-bromo-2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 8, replace the product of embodiment 75, obtain 1.81g (81.9%) product, be solid, 245 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 287.0; Measured value 286.8.
Embodiment 77
4-[4-7-amino-6-bromo-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 13, replace the product of embodiment 76, obtain 1.40g (44.4%) product, be solid.
MS (APCI) M+1: calculated value 500.1; Measured value 500.0.
Embodiment 78
4-{4-[6-bromo-7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, replace the product of embodiment 77, obtain 0.1160g (46.4%) product, be solid.
MS (APCI) M+1: calculated value 625.2; Measured value 625.1.
Embodiment 79
1-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-cyclohexyl-urea
In embodiment 15, replace the product of embodiment 78, obtain 0.0886g (77.0%) product (compound 55), be solid, 195 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 525.2; Measured value 525.1.
Analytical calculation value C 24H 29Br 1N 8O 11.64H 2O1.83HCl:
C，46.37；H，5.53；N，18.02；Cl，10.44.
Measured value: C, 46.53; H, 5.34; N, 17.73; Cl, 10.15.
Embodiment 80
4-{4-[6-bromo-7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, replace the product of embodiment 77, obtain 0.2571g (42.9%) product, be solid.
MS (APCI) M+1: calculated value 599.2; Measured value 599.2.
Embodiment 81
1-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-the 3-tertiary butyl-urea
In embodiment 15, replace the product of embodiment 80, obtain 0.0481g product (compound 91), be solid.
MS (APCI) M+1: calculated value 499.2; Measured value 499.0.
Embodiment 82
4-{4-[6-bromo-7-(3-methyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 32, replace product and the methylamine of embodiment 77, obtain 0.170g (29.9%) product, be solid.
MS (APCI) M+1: calculated value 557.2; Measured value 557.1.
Embodiment 83
1-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-methyl-urea
In embodiment 15, replace the product of embodiment 82, obtain 0.0963g (69%) product (compound 93), be solid.
MS (APCI) M+1: calculated value 457.1: measured value 457.1.
Analytical calculation value C 19H 21Br 1N 8O 13HCl3H 2O:
C，36.76；H，4.87；N，18.05；Cl，17.13；H 2O，8.71.
Measured value: C, 36.49; H, 4.35; N, 17.52; Cl, 15.79; H 2O, 8.12.
Embodiment 84
4-[4-(7-amino-6-bromo-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 27, replace the product of embodiment 76, obtain 2.10g (63.1%) product, be solid.
MS (APCI) M+1: calculated value 528.2; Measured value 528.2.
Embodiment 85
4-{4-[6-bromo-7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, replace the product of embodiment 84, obtain 0.1725g (72.6%) product, be solid.
MS (APCI) M+1: calculated value 627.2; Measured value 627.2.
Embodiment 86
1-{6-bromo-2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea
In embodiment 15, replace the product of embodiment 85, obtain 0.1593g (96.0%) product (compound 94), be solid, 202 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 527.2; Measured value 527.2.
Analytical calculation value C 24H 31Br 1N 8O 12.55HCl1.70H 2O:
C，44.28；H，5.72；N，17.21；Cl，13.89
Measured value: C, 44.28; H, 5.72; N, 17.09; Cl, 12.49
Embodiment 87
4-{4-[6-bromo-7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, replace the product of embodiment 84, obtain 0.1750g (70.7%) product, be solid.
MS (APCI) M+1: calculated value 653.3; Measured value 653.3.
Embodiment 88
1-{6-bromo-2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea
In embodiment 15, replace the product of embodiment 87, obtain 0.1614g (95.4%) product (compound 95), be solid, 198 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 553.2: measured value 553.2.
Analytical calculation value C 26H 33N 8O 1Br 12.76HCl2.02H 2O:
C，45.22；H，5.81；N，16.23；Cl，14.17.
Measured value: C, 45.23; H, 5.82; N, 16.08; Cl, 13.53.
Embodiment 89
N 2-(4-fluoro-phenyl)-pyrido [2,3-d] pyrimidine-2, the 7-diamines
In embodiment 9, replace the 4-fluoroaniline, obtain 1.1529g (45.2%) product, be solid, mp 245-248 ℃.
MS (APCI) M+1: calculated value 256.1; Measured value 255.9.
Embodiment 90
1-[2-(4-fluoro-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(3-morpholine-4-base-propyl group)-urea
In embodiment 32, replace product and the 3-morpholine-4-base propylamine of embodiment 89, obtain 0.1465g (58.6%) product (compound 96), be solid, mp 253-256 ℃.
MS (APCI) M+1: calculated value 426.2; Measured value 426.1.
Analytical calculation value C 21H 24F 1N 7O 2:
C，59.28；H，5.69；N，23.04.
Measured value: C, 59.18; H, 5.66; N, 23.04.
Embodiment 91
1-[2-(4-fluoro-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl) urea
In embodiment 32, replace product and the 2-hydroxyl-ethamine of embodiment 89, obtain 0.0811g (40.3%) product (compound 97), be solid, mp 238-240 ℃.
MS (APCI) M-1: calculated value 343.1: measured value 343.1.
Analytical calculation value C 16H 15F 1N 6O 2:
C，56.14；H，4.42；N，24.55.
Measured value: C, 55.82; H, 4.52; N, 24.15.
Embodiment 92
1-(2-amino-ethyl)-3-[2-(4-fluoro-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl] urea
In embodiment 32, replace product and the quadrol of embodiment 89, obtain 0.1000g (49.3%) product (compound 98), be solid, mp 217-220 ℃.
MS (APCI) M+1: calculated value 342.1: measured value 3420
Analytical calculation value C 16H 16F 1N 7O 10.2H 2O:
C，55.71；H，4.79；N，28.42
Measured value: C, 55.72; H, 4.57; N, 28.07.
Embodiment 93
1-(2-dimethylamino-ethyl)-3-[2-(4-fluoro-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 32, replace product and the 2-dimethylamino-ethamine of embodiment 89, obtain 0.0778 (35.8%) product (compound 99), be solid, mp 251-255 ℃.
MS (APCI) M+1: calculated value 370.2; Measured value 370.0.
Analytical calculation value C 18H 20F 1N 7O 1:
C，58.53；H，5.46；N，26.54.
Measured value: C, 58.39; H, 5.51; N, 26.26.
Embodiment 94
3,3-dimethyl-1-(4-nitro-phenyl)-piperazine
Replace 2 in embodiment 24,2-dimethyl-piperazine obtains 29.43g (88.4%) product, is solid.
MS (APCI) M+1: calculated value 236; Measured value 236.
Embodiment 95
2,2-dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 11, replace the product of embodiment 94, obtain 38g (93%) product, be solid.
MS (APCI) M+1: calculated value 336; Measured value 336.
Embodiment 96
4-(4-amino-phenyl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 12, replace the product of embodiment 95, obtain 27g (78%) product, be solid.
MS (APCI) M+1: calculated value 306; Measured value 306.
Embodiment 97
4-[4-(7-amino-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 50, replace the product of embodiment 96, obtain 0.4346g (59.0%) product, be solid.
MS (APCI) M+1: calculated value 468.2; Measured value 468.3.
Embodiment 98
4-{4-[7-(3-cyclohexyl-urea groups)-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, replace the product of embodiment 97, obtain 0.170g (31.2%) product, be solid.
MS (APCI) M+1: calculated value 593.2; Measured value 593.4.
Embodiment 99
1-cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea
In embodiment 15, replace the product of embodiment 98, obtain 0.040g product (compound 100), be solid.
MS (APCI) M+1: calculated value 493.3; Measured value 493.2.
Embodiment 100
4-[4-(7-amino-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 50, replace the product of embodiment 12, obtain 0.2017g (29.7%) product, be solid.
MS (APCI) M+1: calculated value 440.2; Measured value 440.2.
Embodiment 101
4-{4-[7-(3-cyclohexyl-urea groups)-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, replace the product of embodiment 100, obtain 0.2036g (78.6%) product, be solid.
MS (APCI) M+1: calculated value 565.3; Measured value 565.3.
Embodiment 102
1-cyclohexyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 101, obtain 0.1084g (96.0%) product (compound 11), be solid.
MS (APCI) M+1: calculated value 465.2; Measured value 465.2.
Analytical calculation value C 24H 29F 1N 8O 12.75HCl3.5H 2O:
C，45.91；H，5.10；N，17.85；Cl，15.53；H 2O，10.04.
Measured value: C, 46.20; H, 5.86; N, 17.45; Cl, 15.22; H 2O, 8.97.
Embodiment 103
4-{4-[7-(the 3-tertiary butyl-urea groups)-6-fluoro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, replace the product of embodiment 50, obtain 0.070g (17.9%) product, be solid.
MS (APCI) M+1: calculated value 567.3; Measured value 567.3
Embodiment 104
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea
In embodiment 15, replace the product of embodiment 103, obtain 0.0585g product (compound 102), be solid.
MS (APCI) M+1: calculated value 467.3; Measured value 467.3.
Embodiment 105
1-[4-(4-nitro-phenyl)-piperazinyl]-ethyl ketone
In the 100mL dichloromethane solution of 5.0g (24.1mmol) 1-(4-nitro-phenyl)-piperazine, add 5.04mL (28.9mmol) di-isopropyl-ethamine.Solution is cooled off in ice bath, handle, at room temperature stir and spend the night with 1.89mL (26.5mmol) Acetyl Chloride 98Min..To react continuous water, 0.5M HCl, saturated sodium bicarbonate and salt water washing,, concentrate, obtain 5.91g (98.5%) product, be solid through dried over mgso.
MS (APCI) M+1: calculated value 250.1; Measured value 250.0.
Embodiment 106
1-[4-(4-amino-phenyl)-piperazine-1-yl]-ethyl ketone
In embodiment 12, replace the product of embodiment 105, obtain 4.35g (84.1%) product, be solid.
MS (APCI) M+1: calculated value 220.1; Measured value 220.1.
Embodiment 107
1-{4-[4-(the 7-amino-pyridine is [2,3-d] pyrimidine-2--amino also)-phenyl]-piperazine-1-yl }-ethyl ketone
In embodiment 9, replace the product of embodiment 106, obtain 0.1829g (50.1%) product, be solid.
MS (APCI) M+1: calculated value 364.2; Measured value 364.2.
Analytical calculation value C 19H 21N 7O 11.0H 2O:
C，59.46；H，6.11；N，25.55.
Measured value: C, 59.51; H, 6.03; N, 25.28.
Embodiment 108
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-(3-morpholine-4-base-propyl group)-urea
In embodiment 32, replace product and the 3-morpholine-4-base-propylamine of embodiment 107, obtain 0.0338g (22.6%) product (compound 103), be solid, mp 222-225 ℃ (decomposition).
MS (APCI) M+1: calculated value 534.3: measured value 534.2.
Analytical calculation value C 27H 35N 9O 30.5H 2O:
C，59.76；H，6.69；N，23.25.
Measured value: C, 59.74; H, 6.53; N, 23.35.
Embodiment 109
6-chloro-2-methylthio group-8H-pyrido [2,3-d] pyrimidin-7-ones
In embodiment 74, replace N-chloro-succinimide, obtain 0.3700g (31.4%) product, be solid, mp 264-266 ℃ (decomposition).
MS (APCI) M+1: calculated value 228.0; Measured value 227.9.
Embodiment 110
6,7-two chloro-2-methylthio group-pyrido [2,3-d] pyrimidines
In embodiment 6, replace the product of embodiment 109, obtain 0.6534g (86.5%) product, be solid.
MS (APCI) M+1: calculated value 246.0; Measured value 245.8.
Embodiment 111
6-chloro-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 7, replace the product of embodiment 110, obtain 0.38g (63%) product, be solid.
MS (APCI) M+1: calculated value 227.0; Measured value 226.9.
Embodiment 112
6-chloro-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In embodiment 8, replace the product of embodiment 111, obtain 0.2328g (57.1%) product, be solid, mp 260-262 ℃.
MS (APCI) M+1: calculated value 243.0; Measured value 242.9.
Embodiment 113
4-[4-(7-amino-6-chloro-pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 27, replace the product of embodiment 112, obtain 0.22g (49%) product, be solid.
MS (APCI) M+1: calculated value 484.2; Measured value 484.2.
Embodiment 114
4-{4-[7-(the 3-tertiary butyl-urea groups)-6-chloro-pyrido [2,3-d] pyrimidine-2--amino]-phenyl }-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 10, replace the product of embodiment 113, obtain 0.0995g (39.2%) product, be solid.
Embodiment 115
The 1-tertiary butyl-3-{6-chloro-2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea
In embodiment 15, replace the product of embodiment 114, obtain 0.0995g product (compound 104), be solid, 205 ℃ (decomposition).
MS (APCI) M+1: calculated value 483.2; Measured value 483.2.
Embodiment 116
Methyl-(2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl)-amine
In embodiment 7, replace methylamine, obtain 1.46g (30.0%) product, be solid.
MS (APCI) M+1: calculated value 207.1; Measured value 206.9.
Embodiment 117
(2-methanesulfinyl-pyrido [2,3-d] pyrimidin-7-yl)-methyl-amine
In embodiment 8, replace the product of embodiment 116, obtain 1.31g (83.4%) product, be solid, 185 ℃ of mp.
MS (APCI) M+1: calculated value 223.1; Measured value 223.0
Embodiment 118
4-[4-(7-methylamino--pyrido [2,3-d] pyrimidine-2--amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 13, replace the product of embodiment 117, obtain 0.4934g (62.9%) product, be solid.
MS (APCI) M+1: calculated value 436.2; Measured value 436.2.
Embodiment 119
4-{4-[7-(3-cyclohexyl-1-methyl-urea groups)-pyrido [2,3-d] pyrimidine-2-base]-phenyl }-piperazine-1-carboxylic acid tert-butyl ester
In embodiment 16, replace the product of embodiment 118, and use acetonitrile, do not use alkali, obtain 0.8535g (78.8%) product, be solid as solvent.
MS (APCI) M+1: calculated value 561.3; Measured value 561.3.
Embodiment 120
3-cyclohexyl-1-methyl isophthalic acid-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
In embodiment 15, replace the product of embodiment 119, obtain 0.2548g (36.0%) product (compound 70), be solid.mp?169-175℃。
MS (APCI) M+1: calculated value 461.3: measured value 461.2.
Analytical calculation value C 25H 32N 8O 10.25H 2O:
C，64.56；H，7.04；N，24.09.
Measured value: C, 64.57; H, 7.01; N, 23.98.
Embodiment 121
3-cyclohexyl-1-[2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-1-methyl-urea
Utilize the universal method of synthetic embodiment 120, obtain 0.1366g (95.6%) product (compound 106), be solid.170 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 489.3; Measured value 489.3.
Analytical calculation value C 27H 36N 8O 13.32H 2O2.69HCl:
C，50.16；H，7.07；N，17.33；Cl，14.75.
Measured value: C, 50.36; H, 6.98; N, 16.97; Cl, 15.07.
Embodiment 122
3-cyclohexyl-1-ethyl-1-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
Utilize the universal method of synthetic embodiment 120, obtain 0.118g (94%) product (compound 107), be solid.
MS (APCI) M+1: calculated value 475.3: measured value 475.3.
Analytical calculation value C 26H 34N 8O 13.0HCl0.3 ether:
C，53.89；H，6.65；N，18.48.
Measured value: C, 53.75; H, 6.96; N, 18.57.
Embodiment 123
The 3-tertiary butyl-1-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-1-ethyl-urea
Utilize the universal method of synthetic embodiment 15, obtain 0.022g (56%) product (compound 108), be solid.
MS (APCI) M+1: calculated value 477.3; Measured value 477.3.
Embodiment 124
1-methyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
Utilize the universal method of synthetic embodiment 40, obtain product (compound 64), be solid, mp 204-206 ℃ (decomposition).
MS (APCI) M+1: calculated value 393; Measured value 393.
Embodiment 125
1-ethyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
Utilize the universal method of synthetic embodiment 40, obtain product (compound 28), be solid.mp?220-222℃。
MS (APCI) M+1: calculated value 407; Measured value 407.
Embodiment 126
1-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-propyl group-urea
Utilize the universal method of synthetic embodiment 40, obtain product (compound 111), be solid, mp 223-225 ℃.
MS (APCI) M+1: calculated value 421; Measured value 421.
Embodiment 127
N, N-dimethyl-N '-[5-methyl-2-[[4-(1-piperazinyl) phenyl]-amino]-pyrido [2,3-d]-pyrimidin-7-yl-sulphonamide
Utilize the universal method of synthetic embodiment 40, but be to use dimethylamino SULPHURYL CHLORIDE rather than NSC 87419, obtain product (compound 71), be solid, mp 228-230 ℃ (decomposition).
MS (APCI) M+1: calculated value 443; Measured value 443.
Embodiment 128
7-amino-2-methylthio group-pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
In the 10mL tetrahydrofuran solution of 4-amino-2-methylthio group-pyrimidine-5-formaldehyde (embodiment 3), add 0.126mL (1.18mmol) ethyl cyanacetate.Solution is cooled to-10 ℃, handles with 2.36mL (2.36mmol) titanium tetrachloride.In this solution, slowly add 0.52mL (4.72mmol) N-methylmorpholine.Reaction is gone through be warmed to room temperature in 2 hours, between ethyl acetate and saturated aqueous ammonium chloride, distribute.Concentrate organic phase, obtain solid,, obtain 0.30g (96%) product, be solid with the ether development.
MS (APCI) M+1: calculated value 265.1; Measured value 264.9.
Embodiment 129
7-amino-2-chloro-pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
In the 50mL chloroform suspension of embodiment 128 products, slowly add SULPHURYL CHLORIDE, add 2 ethanol then.To react and at room temperature stir 16 hours, be poured in the ether, collect solid, obtain 0.50g (98%) product.
MS (APCI) M+1: calculated value 253.1; Measured value 253.1.
Embodiment 130
7-amino-2-[4-(4-tertbutyloxycarbonyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
Embodiment 12 products and embodiment 129 product De dioxane solutions were heated 1.5 hours under refluxing.Reaction is poured in the hexane/ethyl acetate (1: 1), collects solid.Through purification by flash chromatography, use methylene dichloride as eluent, obtain 0.08g (16%) product, be solid.
MS (APCI) M+1: calculated value 494.2; Measured value 494.1.
Embodiment 131
2-[4-(4-tertbutyloxycarbonyl-piperazine-1-yl)-phenylamino]-7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
In embodiment 10, replace the product of embodiment 130, obtain 0.05g (48%) product, be solid.
Embodiment 132
7-(the 3-tertiary butyl-urea groups)-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
In embodiment 15, replace the product of embodiment 131, obtain 0.036g product (compound 113), be solid, mp＞300 ℃.
Embodiment 133
1-[6-fluoro-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-sec.-propyl-urea
Utilize the universal method of synthetic embodiment 52, but be to use 1-(4-amino-2-methylthio group-pyrimidine-5-yl)-ethyl ketone (embodiment 35), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (embodiment 12) and n-Isopropyl isocyanate as reagent, obtain product (compound 114), be solid, 208 ℃ of mp (decomposition).
MS (APCI) M+1: calculated value 439.2; Measured value 439.3.
Embodiment 134
1-cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea
Utilize the universal method of synthetic embodiment 17, but be to use 4-(4-amino-phenyl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (embodiment 96) obtains 0.95g (100%) product (compound 115), is solid.
MS (APCI) M+1: calculated value 475.6; Measured value 475.3
Analytical calculation value C 26H 34N 8O 13HCl1H 2O:
C，51.96；H，6.37；N，18.64；Cl，17.69；H 2O，2.99.
Measured value: C, 52.00; H, 6.41; N, 18.53; Cl, 16.51; H 2O, 3.06
Embodiment 135
6-methyl-2-methylthio group-pyrido [2,3-d] pyrimidin-7-yl amine
In the 300mL tetrahydrofuran (THF) suspension that is cooled to oily dispersed system 10 ℃, 2.18g (54mmol) 60% sodium hydride, add 10.2g (53.4mmol) (1-cyano group-1-methyl-methyl)-diethyl phosphonate (Synthesis (synthesizing), 1975:516).In the refrigerative suspension, add 4.30g (25.4mmol) 4-amino-2-methylthio group-pyrimidine-5-formaldehyde (embodiment 3), will react and at room temperature stir 22 hours.With the gained solution concentration, filter, obtain solid, with the tetrahydrofuran (THF) washing, be dissolved in the 1N citric acid, regulate pH to 8 with 50% sodium hydroxide and carry out redeposition.Solid collected by filtration obtains 1.1g (21%) product, mp 268-270 ℃.
MS (APCI) M+1: calculated value 207.3; Measured value 207.0.
Embodiment 136
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea
Utilize the universal method of synthetic embodiment 31, but be to use embodiment 135 products, obtain 0.14g (42%) product (compound 116), be solid as raw material.
MS (APCI) M+1: calculated value 589.6; Measured value 589.3
Analytical calculation value C 27H 36N 8O 12.5HCl1.5H 2O:
C，53.80；H，6.73；N，18.01；Cl，14.11；H 2O，4.06
Measured value: C, 53.44; H, 6.89; N, 18.46; Cl, 14.60; H 2O, 4.48.
Embodiment 137
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea
Utilize the universal method of synthetic embodiment 29, but be to use embodiment 135 products, obtain 0.26g (89%) product (compound 117), be solid as raw material.
MS (APCI) M+1: calculated value 463.6; Measured value 463.3.
Analytical calculation value C 25H 36N 8O 12.4HCl1.75H 2O:
C，51.62；H，6.91；N，19.26；Cl，14.63；H 2O，5.42.
Measured value: C, 51.23; H, 6.55; N, 18.92; Cl, 14.73; H 2O, 5.10.
Embodiment 138
The 1-tertiary butyl-3-[6-methyl-2-(4-piperazine-1-yl)-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea
Utilize the universal method of synthetic embodiment 15, but be to use embodiment 135 products, obtain 1.02g (100%) product (compound 118), be solid as raw material.
MS (APCI) M+1: calculated value 435.3; Measured value 435.3.
Analytical calculation value C 23H 30N 8O 15HCl1.75H 2O:
C，42.60；H，5.98；N，17.28；Cl，27.34；H 2O，4.86.
Measured value: C, 42.03; H, 6.04; N, 16.81; Cl, 22.95; H 2O, 4.72.
Embodiment 139
1-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-3-sec.-propyl-urea
Utilize the universal method of synthetic embodiment 33, but be to use embodiment 135 products as raw material, and use 4-(4-aminophenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and Isopropylamine are as reagent, obtain 0.130g (100%) product (compound 119), be solid.
MS (APCI) M+1: calculated value 449.3: measured value 449.3.
Analytical calculation value C 24H 32N 8O 13HCl1.75H 2O:
C，48.90；H，6.58；N，19.01；Cl，16.04；H 2O，5.35.
Measured value: C, 49.03; H, 6.63; N, 18.70; Cl, 16.03; H 2O, 5.19.
Embodiment 140
1-cyclopropyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea
Utilize the universal method of synthetic embodiment 33, but be to use embodiment 135 products as raw material, and use 4-(4-aminophenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and cyclopropylamine are as reagent, obtain 0.099g (100%) product (compound 120), be solid.
MS (APCI) M+1: calculated value 447.3; Measured value 447.3.
Analytical calculation value C 24H 30N 8O 1
C，49.83；H，6.19；N，19.37；Cl，18.39；H 2O，3.89.
Measured value: C, 49.76; H, 6.23; N, 18.92; Cl, 15.66; H 2O, 3.06.
Embodiment 141
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-ethyl-pyrido [2,3-d] pyrimidin-7-yl }-urea
Utilize the universal method of synthetic embodiment 137, but be to use (1-cyano group-propyl group)-diethyl phosphonate, obtain 0.34g (95%) product (compound 121), be solid as raw material.
MS (APCI) M+1: calculated value 477.3: measured value 477.3.
Analytical calculation value C 26H 26N 8O 12.5HCl1H 2O:
C，53.26；H；7.05；N，19.11；Cl，15.18；H 2O，3.07.
Measured value: C, 53.63; H, 7.31; N, 18.46; Cl, 15.32; H 2O, 3.48.
Embodiment 142
Basically prepare following compounds according to embodiment 1-141 is described with program shown in the flow process 1-4:
(a) the 1-tertiary butyl-3-[2-(3-chloro-4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 2);
(b) the 1-tertiary butyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 3);
(c) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea (compound 6);
(d) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea (compound 7);
(e) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-methyl-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea (compound 8);
(f) 1-[2-(3-chloro-4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-3-cyclohexyl-urea (compound 10);
(g) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea (compound 13);
(h) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea (compound 14);
(i) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea (compound 15);
(j) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-methyl-pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea (compound 1 6);
(k) 1-(2-hydroxyl-ethyl)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 1 7);
(l) 1-[2-(3-chloro-4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea (compound 18);
(m) 1-[6-fluoro-2-(4-piperazine-1-yl)-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea (compound 19);
(n) 1-(2-hydroxyl-ethyl)-3-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 20);
(o) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea (compound 21);
(p) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea (compound 22);
(q) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea (compound 23);
(r) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-methyl-pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea (compound 24);
(s) 1-ethyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 25);
(t) 1-[2-(3-chloro-4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-3-ethyl-urea (compound 26);
(u) 1-ethyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 27);
(v) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea (compound 29);
(w) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea (compound 30);
(x) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea (compound 31);
(y) 1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-methyl-pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea (compound 32);
(z) the 1-tertiary butyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 33);
(aa) 1-cyclohexyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 34);
(bb) 1-ethyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidine 7-yl]-urea (compound 35);
(cc) 1-(hydroxyl-ethyl)-3-[2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 36);
(dd) the 1-tertiary butyl-3-[6-fluoro-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 37);
(ee) 1-cyclohexyl-3-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 38);
(ff) 1-ethyl-3-[6-fluoro-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 39);
(gg) 1-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea (compound 40);
(hh) the 1-tertiary butyl-3-[5-methyl-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 41);
(ii) 1-cyclohexyl-3-[5-methyl-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 42);
(jj) 1-ethyl-3-[5-methyl-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 43);
(kk) 1-(2-hydroxyl-ethyl)-3-[5-methyl-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 44);
(ll) 1-cyclohexyl-3-[6-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 54);
(mm) 1-cyclohexyl-3-[6-cyano group-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 56);
(nn) 1-cyclohexyl-3-[6-chloro-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 57);
(oo) 1-cyclohexyl-3-[6-fluoro-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 58);
(pp) 1-cyclohexyl-3-[6-bromo-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 59);
(qq) 1-cyclohexyl-3-[6-chloro-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 60);
(rr) 1-sec.-propyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 61);
(ss) 1-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 63);
(tt) 1-(4-hydroxyl-cyclohexyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 66);
(uu) 1-(4-amino-cyclohexyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 67);
(vv) 1-(2-dimethylamino-ethyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 68);
(ww) 1-(3-morpholino-4-base-propyl group)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea (compound 69);
(xx) 1-cyclohexyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-thiocarbamide (compound 72);
(yy) N-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-ethanamide (compound 73);
(zz) 4-[7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-benzsulfamide (compound 74);
(aaa) 1-cyclohexyl-3-{2-[4-(1-piperazine-1-base-formyl radical)-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)-piperazine-1-yl]-phenylamino-pyrido [2,3-d] pyrimidin-7-yl)-3-cyclohexyl-urea (compound 77); With
(ddd) 1-(2-{4-[4-(2-amino-3-methyl-butyryl radicals)-piperazine-1-yl] phenylamino }-pyrido [2,3-d] pyrimidin-7-yl)-3-cyclohexyl-urea (compound 78).
Embodiment 143
Biological assay
As mentioned above, The compounds of this invention is strong cdks inhibitor, therefore can be used for atherosis and other cell proliferation obstacles of treatment and prevention of arterial, resembles by this class cdk enzyme cancers mediated.When being used for measuring cdk those skilled in the art traditionally and suppressing active standard test method and estimate, these compounds comprise cdkcdk1/ cell periodic protein B, cdk2/ cyclin A, cdk2/ cyclin E and cdk4/ cyclin D to the excellent inhibition activity of a large amount of cdk enzyme performances.Typical assay method is following carrying out.
Cell cycle protein dependent kinase 4 (cdk4) assay method
About IC 50The enzyme assay of mensuration and kinetics evaluation carries out in 96-hole filter plate (Millipore MADVN6550).Cumulative volume is 0.1mL, contains the TRIS that ultimate density is 20mM (three [methylol] aminomethane), pH 7.4,50mM NaCl, 1mM dithiothreitol (DTT), 10mM MgCl 2, contain 0.25 μ Ci [ 32P] 25 μ m ATP, 20ng cdk4,1 μ g retinoblastoma and the suitable The compounds of this invention of dilution of ATP.In aperture, add all components except that ATP, flat board is placed on reaches 2 minutes on the dull and stereotyped mixing machine.Add [ 32P] ATP begins reaction, with flat board 25 ℃ of down insulations 15 minutes.Add 0.1mL 20% trichoroacetic acid(TCA) (TCA) termination reaction.Flat board was kept 1 hour down at 4 ℃ at least, make the substrate precipitation.Then aperture is washed 5 times with 0.2mL 10%TCA, (Wallac Inc., Gaithersburg MD) measure to utilize β plate count device 32P mixes.
Cell cycle protein dependent kinase 1 and 2 (cdk1/ cell periodic protein B, cdk2/ cyclin A, cdk2/ cyclin E) assay method
About IC 50The enzyme assay of mensuration and kinetics evaluation carries out in 96-hole filter plate (Millipore MADVN6550), cumulative volume is 0.1mL, the TRIS (three [methylol] aminomethane) that contains 20mM, pH 7.4,50mM NaCl, 1mM dithiothreitol (DTT), 10mM MgCl 2, contain 0.25 μ Ci[ 32P] 12mM ATP, 20ng enzyme (cdk1/B, cdk2/A or cdk2/E), 1 μ g retinoblastoma and the suitable The compounds of this invention of dilution of ATP.In aperture, add all components except that ATP, flat board is placed on reaches 2 minutes on the dull and stereotyped mixing machine.Add [ 32P] ATP begins reaction, with flat board 25 ℃ of down insulations 15 minutes.Add 0.1mL 20%TCA termination reaction.Flat board was kept 1 hour down at 4 ℃ at least, make the substrate precipitation.Then aperture is washed 5 times with 0.2mL 10%TCA, (Wallac Inc., Gaithersburg MD) measure to utilize β plate count device 32P mixes.
The protein kinase assay method of cell cycle protein dependent kinase 5/p25 proline(Pro)-orientation
The source of enzyme: the reorganization cdk5-p25 complex body that the insect cell sf9-of recombinant baculovirus-infection expresses
Purpose: estimate ability for the cdk5/p25 phosphorylation of reagent thing inhibition of histone H1.
Method: with p25 (or GST-p25) combined enzyme agent of the cdk5/Glu-mark of baculovirus-insect cell His-mark enzyme dilution buffer liquid (EDB:50mM Tris-HCl[pH 8.0], 10mM NaCl, 10mM MgCl 2, 1mM DTT) in to be diluted to concentration be 50ng/20 μ L.Then 20 μ L are supplied the final cdk5/p25 enzyme prepared product of reagent thing (being diluted among the EDB) sample and 20 μ L to merge, at room temperature placed 5 minutes.Then to adding the EDB solution of 25 microlitre substrates for reagent thing/enzyme prepared product, contain 115 μ L/mL histone h1s, 30 μ MATP (no vanadate) and 30 μ Ci/mL γ- 33P ATP (Amersham) shook under 30 ℃ 45 minutes.The sample that adds the final prepared product of 50 μ L in 100mL 150mM phosphoric acid places to reach 30 minutes on ice to promote precipitation.To precipitate then by 96-hole phosphorylated cotton filter plate and filter, use the 75mM phosphoric acid washing subsequently 3 times.20 μ L flicker cocktail is accepted in every hole then, utilize the β of Trilux rolling counters forward flat board to launch ( 33P filter agreement).Relatively this (does not exist for the reagent thing with contrast for sample; 0% suppresses) and baseline values (do not have enzyme, do not supply the reagent thing; 100% inhibition) β emission is to measure the inhibition percentage of histone h1 phosphorylation.
Said determination about representative The compounds of this invention the results are shown in the following table 2.The IC that The compounds of this invention showed 50Value is extremely＞5 μ M of 0.027 μ M to cdk1/B, is extremely＞5 μ M of 0.010 μ M to cdk2/A, is extremely＞5 μ M of 0.020 μ M to cdk2/E, is that 0.004 μ M is to＞5 μ M to cdk4/D.Generally speaking compounds effective is a compound 9, and it shows the IC of 0.027 μ M, 0.010 μ M, 0.020 μ M, 0.005 μ M respectively to cdk1/B, cdk2/A, cdk2/E and cdk4/D 50Value.Table 2: to the restraining effect of Cdk: IC 50Sequence Table <110> head of university of nagasaki <120> nucleic acid probe comprising the nucleic acids and the use of the screening method of the probe <130> U2001P165 <160> 4 <210> 1 <211> 39726 <212> Nucleic Acid <213> human chromosome <400> 1 tttgatgatg ggttctgcct ttgccatttc agacacattt tctataaatc aagctagctg 60 aatctacagc tctggagggt tttttttttt ttttttttga gacagaatct cgctctgtca 120 cccaggctgg agtgcactga tgtgatcttg ggtcactgca acctctgcct cccggcttca 180 agagattctc ctacctaagc ctgccaagta gctgggatta caggcgtgca ccaccacgct 240 cagctaattt ttgtagtttt agtagagagg ggatttcgcc atattggcca ggctggtttc 300 aaactcctga cctcaagtga tctgcccacc tcggcctccc aaagtgctgg gattacaggc 360 gtgagccacc agacctggcc tctgggtttt tttttttttt tttgagacag agccttacta 420 tgtcacccag gctggagtgc agtggcgcga tctcagctca ctgcaacctc cgcctcccgg 480 gttcaagcga ttcttctgtc tcagcctccc gagtagctgg gactacaggt gcccgccacc 540 acgcccagct aatttttgta tttttagtag agacagggtt tcaccgtgtt agccgggatg 600 gtcttgatct cctgaccttg tgatctgccc gctttggcct cccaaagtgc tgggattaca 660 ggcgtgagcc accgtgtccg gccaacgccc agctaatttt ttgtagagat gaggtttcgt 720 tgcccagtct ggtcttcaac tcctgccctc cagtgatcca cccacctcgg catcccaaag 780 tgctgggatt ataggcttca gccaccacgc ccagcccttt tagtatttat tgagcaacta 840 ctgggtacaa actctttgtc attcctccac tagcaagagc agtgatttca tgagctgctt 900 ttcagccttt gttttcatct gtaaaatagg atatcttctc tttgaggggc aacaaggggt 960 aggtgtgggt gggtgagcta taaaccctaa tcctcaccca ggaggaggtg cagccacctt 1020 tctggccact ggctggagac ctcccccttt ccccatactc ctccttccac tccctgatcc 1080 aagcactgcc agaacccagc attctctcac tttctcttcc tccgttttga atcagtaggt 1140 tcagaagtgc ttggcttgat atgaagctgg gggtgcatcc aacaaaatca gatgcctaga 1200 gaaggagcag gattggggtg ggagagagaa gacagataat tgggttgagg aacctggggg 1260 catcctgaag gaggtgccca gtgggcagtt gctttgtgct gggcccaggg ccaggttata 1320 cgtactttga atattttatc ttcatagcta tcccatttgg tgaggctcaa agagcgaaaa 1380 tgacattcct ggtaaatggc cctgctgcag tttgaatttg tatccatctg actccaggtc 1440 acgtaagctc tttttgtttt tgagacggag tctcgccctg tagcccaggc tggagtgcaa 1500 tggcgggatc tcagcttact gcaacttcca cctgccaggt tcaagcgatt ctcctgcctc 1560 agcctccctt gtagctggga ttacaggcac gtgccaccac gcccagctaa tcctttgtat 1620 ctttagtaga gacggggttt caccatgttg gccaggctgt tctcgaaccc ctgaccttgt 1680 gatccgccct cctcggcctc ccaaagtgct gggattacag gcatgagcca ctgagcctgg 1740 tcataaggtc tcttatactt ttatttattt atttattgga gccagagtct cactctgtca 1800 cccaggctga agtgcaatgg catgaacatg gctcactgca gcctccacat cctgggctca 1860 agcgatcctc ccacctcagc ctgccaagta gctgggacta tgggtgcgaa tcatacacca 1920 ccatgccagg ataatttgtt tgtttgtttg tttgtttttt taaatggagt ttcgccttgt 1980 ggaccagggt ggagtgaaat ggcgcgatct cagctcactg caacctcagc ctcttgggtt 2040 caagcgattc tcctgcctca gccccccgaa tagctgggat tacaggtgtg tgccaccaca 2100 tccggctaat tttgtatttt tagtagagac ggggtttcac cacattggtc aggctggtct 2160 caaactcctg acctcatgtg acccacctgc cttggcctcc caaagtgctg ggattacaga 2220 tgtgagccac agcgcctggc ctactttttg tattttttgt agagacaagg tttagccata 2280 ttgcccaggc tggtcttgaa ctcctgggct caagcgatcc gtctgcctca gccttccaaa 2340 gtgctgggac taaaggcgtg caccactgta cctggcctct tatgctttgt aaagcattgt 2400 ctggcaccaa aggctgtttg ttcctcaaac atcttgaatc ctttttggga ggatctgagt 2460 tttgtacaac tcatttggtc cgttattgaa accacaattc tgtctgatgg agacacaggc 2520 ttggagagga gaggagggga tagatcaggc atcatgaaat gtttctggag cactcactct 2580 gagcttcacg gtctgggctt gttcactgga ggtcagagag tatatgtcct tagtcttgtt 2640 ggaagtgact gtccaactgg atgagaccag atttagaagc cattagttac taccaggact 2700 cagggaaaaa tggctgcctg taggggtggg aagactacca ggaggaggag tcttctaaac 2760 tggatgaatg gagtctgccc aggggaaaag gcagagtgac tggcatgagc ataggctgga 2820 caggatgtgg cttgtcctgg cactgggcag ttgggggaag tgagagcagg agggcaggga 2880 ttagtggcca ccataccaag cttcagaagg aggtttaaga agaagaaaac ttaaaggtgg 2940 atgcttgagt ccttcgggct ggggctgggc gtacaggctc aggttagcga caggacctgg 3000 tatttggggc aggaaggaga ctgctggagg gctgcctggt ctcagatgtg gtcaggcctt 3060 ccttgatctt aagttgaaaa ctgattcaat tttggggaaa tccgtgggtg gggagaggaa 3120 ggaaacagct cctagaccca tcagaaggca tggtcctggt gttcaccagc tatgttcagg 3180 attaattacc aaaggcctcc atgcctctcc caagacctaa ctgtttagtc agaaggcaga 3240 tgctgttcct gttcagtggg aacaaggagc tggaactagg atgggagttt gtctctgggc 3300 aagtcatgct tcctttctag aagatgggga taacaataat acccatctca gaggagtaaa 3360 tgagtatcct gcagggtagc tggaacagag gaggataagc tacaactgtt attgtaacaa 3420 caggcagagc ccttgctgga gttgtgtttc taggggagga accagtgtct tctggacaca 3480 gaagagtgag ctttctactg ctcagatgcc atcacgtcat tatcctcctc cctcaccttc 3540 catggctgct tactgccttc cagataaagc ttcaactctt taacttaacc aaccaagccc 3600 tgaagggtga ggctctgtgt ctgccccatc cttggttgag cctctttctg cactcattac 3660 ctctgccccg gcacatacac tagacatgct tgttgtggtc agttcctctg aagcctggtg 3720 tttctctgga ctctgctgga atctctgcct cttccccttc ttgcctggct attcctgaat 3780 atcctccagg actctctctg gatgttgctt cctcaaggat acccctgagt tagtttcaag 3840 ggcattctca gcttctccag cacccttggc ttctctctca gtactcagtt ctctgccttg 3900 ttattacctg tctgcttttt ccacaaggct gtgacgggga gccccaaaat atttatggaa 3960 ttaatgaatg aaaaggggtg gttctaagaa aaaagagatc actgtacatt ggccaaatgt 4020 cccaacaggt atctattata tctcaccagg gtaggaatta tcagtaacca agatttacag 4080 atgaggaaac tcagcccaag gtagagtccc tctgcctgtc attcaaattt ctgggcacct 4140 gtgtgtaagc accatgctgg gcttttcaca ggcagtatgt gtagggtgga caggctgaga 4200 gcaagcacgt gaggcccatc ataccaggtg agagttaagg tgctgacacc ttgcatgagg 4260 gcttagtctc ttggacctca attcttcgta gggctggtga agggtcatag gaacgactgt 4320 atgtgaagtg cccaggacag tgtccagtac actagtacag acccagcaag tgtttactga 4380 ttcttatctc agtcctaagg atgggagtca caggcccaga aaaggtccct ggattgagac 4440 aaccagccag aggagagctg agtgtacatc ccaggccccc accctacagg gacacagtcc 4500 tctcccttct gcccccactc aaggagtcag tgtccttgtg agaatctatg gcgctgtgga 4560 tcttctcaac ctagtgctgg cacacatgag atgcttggcc agggcctgcc agatggggag 4620 gctggagatg ggtcggctgt gattgagacc tctgtggcca agttttactc taagaggcag 4680 gtaaggccct caggggttat cccagagaag tctgagaggt tttccctggg gtcctggtct 4740 tctcccccag acctgtcagc aagcagttca tccccagctg ccaatctcct tttggccctc 4800 agtcttccag aggagctggg aggtgggaga gaggggttct gcagggcagt gttgttcaga 4860 ggtgagcttt ggaagaaact gttgtctcaa ccctattttc acaccatagc acctttattt 4920 aactgtcttt tcccgaggcc aggatctcat cttttgtttc cccagcactc agcacactgc 4980 ctggaatgca ggaaatggtt gctgaatgaa gcgatgaatt acatttcagc actcatcaag 5040 tgctcagcct ataactaagt ctgagtgtag gctgctaaca cttagacctt taccttacag 5100 aatcttcgca gccagtgctg tgcattggaa gttgcagatg gggaaactga ggctcaggac 5160 tgttaagtga ctagttcaag gcaggtctca ggccctcagg atggttagtg gcaaagtaaa 5220 ggactgggag gagcattgat gaattggggc aattggcaga ggagtaactg tcagtcaaaa 5280 tgattggctc aaattattag gtgtgaagaa ggaaccagtc agagcttgcc tgttgagtcg 5340 aattgcccag atgggattag cagggtgagt gaccctagca gaacaaagag ctggcccttg 5400 taggtataga ctcgactttt ctctggttgg tcccaacaca tagacaacta ccaacctgac 5460 tttgcacctg agaatcttca gggtacctca gactcttcaa cagaaggagc ctccctgagg 5520 tcacagccct ctcatcagtc ccgttccagt gggcactttc cctctaacaa agcccacttg 5580 ctgtcttggc agggtctgca tccggcactt gcagacatgt gctaagggcc tgttgacttg 5640 ggagcctcca tcactggact gtgggccttg gagagcaaaa gggtaagagc atctcgagct 5700 ccacgcctgc tgggccagtc gctggctgaa ggcaggggaa ggatggagtt tagctggcca 5760 gcactaatgt cacacagggc aacgccaaaa atggcctttc tcccaggtgg gctcaaagtt 5820 aacagaaggc agtgagtaaa cagtccactg gggcaataac tatgcacatt tactaagcca 5880 tgggaagaat agtagtcacg tggccctcga gggcggtgcc ctcagcttga gatggagtta 5940 actccaaatc taatcacaga aggctttctg gaggaggcgg aatttttatg gcggccggat 6000 ccggctttct ctgaacagcg agaaggcgct tagcgcccta gggaccaggt aactcctgag 6060 gtgagcttct tggtggggat caagcccagg gggcgacgga gtccgggctg ggggaagggc 6120 ccgaggggct ggagtcgcaa gttcaggccc agcttgggct ccctgtcccg cccttccgct 6180 gtcttggggg attggacgcc acgcggtcgt gctagattcg gtgctgcggg cccggtgcag 6240 gatgcaggcc gtgaggcccc aggccgaggg ctgcgccagc gggcttgtcc cggccagccg 6300 ggcggtcccg tgtcccggcg cagctccgct ggggtccaga tgcccggccc tcaggggcga 6360 ggcgcgcact ccccggggaa ccgggctgcg gagcaggcgg cccgctctgg gcggcggtgg 6420 cacgagaggg ccatctgcct gggtgccgag aactgcagcg tccgcggtgc gaggcgcggc 6480 ccgtcccgtc ccggccccca gcccggcgcg cacgcacata cccacgccgg ccggcgcccg 6540 ctgcccgagc ccccgtgcca ggcccagacc ttgactaggc gcgggaggcg gtgcagggac 6600 tagaggaccc cctcccccgg cgttcccctc gccccgcccg aggctgcgag gacccctggg 6660 ctcgggggtg gtgagggagc ttcgtcccgg ctgggcccgg gctggggact cggcctccct 6720 gggcgggggc cgcacggctg caggccgagg tgcggacgcg ctgtcaggct gcagcccggc 6780 tcggtgccgg gggtgggctc agcgctgggg tcgcctggct tcgttccccc gcggaggcca 6840 cggccgggcg agcagtgccg gggcgggtaa cccgacccgg ctccccagag ccgctcaccc 6900 cgcacggccc ggcaagggga gggagaggga tggggggagg gggaagggaa ggggtggtgg 6960 gtgaggggct gtgggcaccg cagggccgag tccccggccc gtctgcgctg ctgtagggcg 7020 gctgcccgcg gcacccggga cgatccagcc tctgcctcgc gggcgtcgag cctgagacag 7080 gagggagccc tggggctgca caggcttggc tcagggaggc agacccgagc tgctgcctcc 7140 attttgtttc ctgctcagct tggtctgtgg tggtggtggt ggtggtggtg tgggtttggg 7200 gtgcggccgg gtagggggtt cgcctgcggc cgcgtctgct cggggcctga ggcctcgaag 7260 accccagccc aagcccccag gtgagccctg cggcaggagg ggggttgcct tggcctcggg 7320 ccgaacccag cgggctgagg gcaggtgccc agtggatggg gagcctgggc tgtaacctaa 7380 gatggaggcc gggactgacg cgggcccgag cagggctggc gggacgatcg gacaggcctc 7440 agccgcgcca ggtgccgcct gggttggggt tcgagacgcg tagggtgcgg gagccgtgtg 7500 cggcccgagg ccagcgccgt gccccgaggt aggtgagggg atcggaatgc cacccacgac 7560 gcccgcaggc cccgacactc caaggaggcg cgcgaggccc ctggggagcc cgcctcaggc 7620 cccgcccggg cagccgggcc ggcccgtagg ccccggccgc gagcgggcgc gcagggggag 7680 gggagggggc ggcagcggca gctccgctga ttgggcggcg ctctcacaag cccgacttca 7740 cccgccctga accccgaaga gtgagagaag ggaacgcgcg cgctcggtgg gggaaggggt 7800 gcgcgcgcac tcggggccca gccgcacgcg ggccggcgcg aggcgctcgg tcgcacgcgc 7860 ggccgcgggg gcgcgcgcgg tgggggtgtg aggaggagga ggcggcggcg gaataggccg 7920 gggcaggtcg cgctcgctgc cttctcccct gaagagagac gcggggggag gggggtgcgg 7980 cgagcggccc cgctctctcc ccaccgctcc gctcgcaccc cagtgtaatg agggtcaccc 8040 cctcccccca gctggcccgg gagggggcgc ggggcacggt aactagtgcg ctggggtggg 8100 cggcgggcag gcgcgaggag aagggaggga ggagggtggc cgggcgggga agatggtggt 8160 ggccgtaagg tgaggggctc gggggagggc caggcgcgat gcggggttgg tggccggcgg 8220 cgctgcagcc gccggcctcc tccccctccc cctcctccat cactaccagc cgggctcagg 8280 cctagctggc cgggctgccg cgaacttcct cccggcgcgg cccgtgcccc gccggccgcc 8340 tgcgaacacc tcggcctccg cctcccctca ggtagcaggc tgcggggcgc ggggccggct 8400 gccctcccgc agcaaacttt gcttgctgct gaatattgat gagagcgatc ggctcggctg 8460 ggaggtgctg ccgcggctgc gggaaggagc gcggcccggg caggcggcgg cggcgtcggc 8520 agcagccatg tttttcgagc tgtagcagct gctgctaccc tgactgggct tcgctggccg 8580 cctcggtttc tccctctgcc gggtccaggc ctcttcgccc tgcagctgcg gatccagcag 8640 gcctgcattc aggaaggcga gctctggggt gcagccgcct cggccggctc gcctgcggcc 8700 tgcgcaccgc cgctgcaaag gctccggcgc tggctgggcg cagggtgcag cgctattgtg 8760 accgctgcgc cctagcgagc caggaagggg ggggtacctt tttgtgcagg gtccaggagc 8820 ccccctcgga ccccgcagcc ttttgctttt gagagatcca gctgctcgac ccctggcgag 8880 ggagggggag gactagtcct gtttgagaat tgggaatttt gacgggcaga ggggttttaa 8940 ttttagttca tcccaagtgt ccaccagtct acagaggagg aaaaagagac gggctgtttc 9000 tatgtagcag gatcggccca gcttcgggaa aatggagttt tcagaggctc atcgaggcca 9060 ttttttcatc tccagtcggg ggaacttttt ctgcccatgg aagtgcagca gaaaggcata 9120 gaggccacta ggccttgaag tggctgccat tttaaagagt cgagtcagat ggcctattaa 9180 ctcagattaa ttgctgtgct tttggattcc aggttgatgc cggcccagga tggatcagac 9240 ctgtgaacta cccagaagaa attgtctgct gcccttttcc aatccagtga atttagatgc 9300 ccctgaagac aaggacagcc ctttcggtaa tggtcaatcc aatttttctg agccacttaa 9360 tgggtgtact atgcagttat cgactgtcag tggaacatcc caaaatgctt atggacaaga 9420 ttctccatct tgttacattc cactgcggag actacaggat ttggcctcca tgatcaatgt 9480 agagtattta aatgggtctg ctgatggatc agaatccttt caagaccctg aaaaaagtga 9540 ttcaagagct cagacgccaa ttgtttgcac ttccttgagt cctggtggtc ctacagcact 9600 tgctatgaaa caggaaccct cttgtaataa ctcccctgaa ctccaggtaa aagtaacaaa 9660 gactatcaag aatggctttc tgcactttga gaattttact tgtgtggacg atgcagatgt 9720 agattctgaa atggacccag aacagccagt cacagaggat gagagtatag aggagatctt 9780 tgaggaaact cagaccaatg ccacctgcaa ttatgagact aaatcagaga atggtgtaaa 9840 agtggccatg ggaagtgaac aagacagcac accagagagt agacacggtg cagtcaaatc 9900 gccattcttg ccattagctc ctcagactga aacacagaaa aataagcaaa gaaatgaagt 9960 ggacggcagc aatgaaaaag cagcccttct cccagccccc ttttcactag gagacacaaa 10020 cattacaata gaagagcaat taaactcaat aaatttatct tttcaggatg atccagattc 10080 cagtaccagt acattaggaa acatgctaga attacctgga acttcatcat catctacttc 10140 acaggaattg ccatttgtaa gcagtttttg gtacaactta aatatataca tatatgtata 10200 tatacaggcc acttaaaggg aaacttgtaa caaatttgtt tttggttgct tatcagttca 10260 cagctgaaat cctattgcta atcataagct ttgggcaaaa ttttactttg atttttaaat 10320 ttatctctgt tgtatgaatt tggttgtttt aagctttttc caaataactc ttcattgaga 10380 gtaggctaat gcttttaaag gcatttgatt gagttcaggt ttaatttctc aagttggagg 10440 tatacatata tgattaaaaa aaaaaaaaaa agatgggttt tggcctgcca gcaccatgag 10500 tgcaggtgaa ccaatttagt acttggagtc ctgttgctat atgtggcaga ttattttttt 10560 acttgatgac ttgactctta cttcaggttg aagggcattt tgaacacaga ttaaagtggc 10620 taagatgaag ttttcttgga cattgtcaaa atctaaatta ggctagtttt tctgaactac 10680 ctgttttgaa ggtatagcat cctgtgcttt tgataactgc caccattagc tctttttttt 10740 ttttttgagg tggagtctca ctctgttgcc aggctggagt gcagtggttg atcactgcaa 10800 cctctgcctc ttgggttcaa gcaattctcc tgcctcaccc tcccgagtag ctgggattac 10860 tggtacccat caccacgccc ggctaatttt tgtatcacca ttagctcttg aagtttttct 10920 agttttgttt tgttttattt tattttattt taacagaacc ctaactaaga caaagtttta 10980 tatttattta ttgtttagag actggccttg tcatgttgcc caggctggcg tcgggactcc 11040 tgggctcatt cgatcctcct gcatcagcta gaactacagt agtttcagat tttgaagtgt 11100 gtatgtgtat gtgtgatatg tatatattcc gtgtgtatag aaatggagag tatcttattt 11160 gagttgttgt tttcagtaat gctgtcaagt attgttagag ggtgataaat gataacattt 11220 gtttttattt gagcttatga agaatttctt gactttctag ctaaatgatc agttcacttc 11280 tcttagcctc aattttattg cgtctaaatt ccagaagttc ttgattgcta taagattcct 11340 tcagctttaa atattaatat ttgatattga ttttgtttct gcccaaacac attgtttggt 11400 caccgccggt aatgttagca aagagaattt tttttggcca acaaatgtct cataccacat 11460 tcagttttta taagaaaaac ttttatggta tgttgttatt ctgagttcat taaacattcg 11520 ctttacctta tatccctgct gttctttaaa gttacagagg gagaatgtgg gtgtgtcact 11580 tttgtttctg ttgatttgta tcttaattat gccttggtac tccttggttt cttggcaatt 11640 gcagatttaa aaaaatttgc tttagtggtt atcttgagtc tgaattgtcc tacacattag 11700 ggtgggtagg ctgttttgaa aacctattgg cagctcagac aaatcctttt tcttgggttc 11760 acgttgaaat ttattttata tatatatcgt gtctttgttt ttgcacataa atttaaatct 11820 gagaatggag atagatgttt ctctagaagc atacaaatag aattgtaaac ctgtttctcg 11880 tcaaagagat gttagtggag tattggttct attaaaaaaa aaatgaaggc tgagtgtggt 11940 ggctcacacc tgtagtccca gcactttggg aggctgaggt ggacagatca cctgaggtca 12000 ggagtttgag accagtctgg ccaacatggt gaaactccgt ctctacaaaa attagccggg 12060 cgtgatggtg ggcaactgta atcccagcta ctcgagaggc tgaggcagga gaatcgcttg 12120 aacccaggag gcagaggttg cagtgagcca agattgcgcc attgcactcc atactgggaa 12180 ataagagtga aactctgtct caaaaaaaaa aacaacaaaa aaacaaacaa acaaacaaac 12240 aaaaaactga aaatattgga gcctttagat agtaggttac atgtctaaaa tgggagttag 12300 caaatgtata aatgtagaag tttttttttc agggagaaat tgaaattgct caaagacttt 12360 atcaccttga agaagcaagt atgtagttta tttatttttt tgagacacag tcatgctgtc 12420 acccaggctg gagtgtagtg gcgcgatctc agctcacttc aaccacctcc tcctgggttc 12480 aagcgattct cccacctcag cctcccgagt agctgggact acaggtgtgc accaccatgc 12540 ctgactactt tttgtatttt tattagagac gaggtttcac catgtgggcc aggctggtct 12600 tgaactcctg acctcaggtg atccgcccac cttggcctcc caaagtgctg ggattacagg 12660 cgtgagccac cgtacccatc ccctaattta ttattttagg aatttggttc aaagttgtga 12720 ttgaaatcta ttgcctttat ttttgccttt gatattttta aactgaagac attttttttt 12780 ttgagacgaa gtttcactct tgttgcccag gctggagtgc aatggcatga tctcggctca 12840 ctgcaatctc cgccttctgg gttcaagcag ttctcctgcc tcagccttct gagtagctgg 12900 gattacaggt gcgcaccacc accccagcta atttttgtat ttttagtaga gatggggttt 12960 taccatgttg gcccagctgg tctcgaactc ctgacctcag gtgatccacc cgcctcagcc 13020 tcccaaagtg ctgggattac aggtgtgagc cacggagccc ggcctcagac tgaggactta 13080 aaaagtgagg tcagggtggg catggtggct cacgcctgta atcccagcac tttgggaggc 13140 tgaggcgggt ggatcacctg agatgaggat ttcaagacca gcctggccaa catggcaaaa 13200 ccccgtctct actaaaaata caaaaaatta gctaggcatg gtggcaggag cctgtaatct 13260 cagctatttg ggaggctgag gcaggagaat cacttgaacc cgggaggctg aggttgcagt 13320 gagctgagat cgccccattg cactctagcc tgggcaacaa gagcgaaact ccctctcaag 13380 aaaaaaaaaa accatcctgg ccgacatggt gaaaccccgt ctctactaaa aatacaaaaa 13440 ttagctgggc gtggtggcag gctcgggagg ttgaggcagg agaatcactt gaacccggga 13500 ggcggaggtt gcagtgagcc gagattgtgc cactgcactc cagccttgag acagagggag 13560 actccatctc aaaaaaaaaa aaaaaaagcg gtcaatctta gaatgcaaag ttaggtaagc 13620 aatacagctt gagaaaagtg taattaaaaa taacttttct atgtagtcat gtgatattaa 13680 tgtattcaac ttgttcacag ttgatttaag ttattgatat agtaggtatt gttactatgc 13740 tgggaatttt agaaaatcct tagcaaattg ctatttgtct ctttttgtct gtaattttgg 13800 ctgggcttgg tggctaacac ctgtaattct agcaagttgg gaagccgaga caaaaggatt 13860 gcttggggcc cagagtttga aactagactg ggcaacatag tgagatcctg tctctacact 13920 cagttggttg tggtggtatg cctgtagtcc cagctactca ggaggctgag gcagtagtag 13980 gatcacttga ggccagaagt ttgagactgc agtgagccat gatcatgcca ctgcattcca 14040 gcctaggcaa cagagcaaga tcctgtcaaa aaaaaaaaaa aaggagaaaa ttctcttggc 14100 agtgggtaag agtagttatt agggttgtag atttcctgtc tggaattaga gaaagaaggg 14160 tcatattttc tgttattttg tgtatctacc tctaagtgga ctgtttgcct cttgtcacga 14220 attagtagcc tcttcagttt accatcatgt gctcttattt tctctgcata cagtgaagtg 14280 attgtcatta caatttataa tcctgacctg gtacttttat atttaattgg gctgatattt 14340 tctaattctt cccagtgtac aaaggtttta tgctttgttg ttgttgttga gacaggctag 14400 gtgctttgga tgtggagaat taaatgagca tggcattttc agaggatact tgttggagat 14460 tgcttgggta ggatggatgt agtcagctaa tggggcctag aaattcagac tgaagcattt 14520 ggtattgatg tgatgggaac tggcagccct tgagagattt tagctgagaa gtgatgtaaa 14580 atctgtttgg aagactttga gtagaggaga ttagaggcaa ggttaggatg tagggtatgt 14640 tgcaatagta attaagactt aagaatcggc ccagtggcat gtacctgtag tcctagctac 14700 tctggaggcc gaggcaggag gatcacttga ggctgcaatt agctgtgatt gtgcctgtga 14760 atagccactg cactccaacc taggcaatat aatgagattc tgtctcttaa aaaaaaaatg 14820 agcacagtga gtactctaaa gaaagggggt aaatctaaaa gattatttca aagggagaaa 14880 attggcagct ttttgggggc tacctgatct ggaggcagat tggagtctgg atttgaggaa 14940 tggagagaga tgaggcagat gatgtctaag gcttatagtt ttgctgcctg agacaaaaat 15000 gattcctcag aggttccttc ctcttctcta cccatcatcc cacaattttc tactccctcc 15060 ttagctatct tggaagaaaa ttgatctctt cacacctgag gttctgctct ctctccgatt 15120 ccctcctggc tgggtgacct tttttgtttg tttttgtttt tgttttgaga cagagtctca 15180 ctctgtcacc caggctggag tgcagtgggg cgatctcggc tcactgcaac ctctgcctcc 15240 caggttcaag caattctctg cctcagcctc tggagtagct gggattacag gcgcccgcca 15300 ccgcaaccag ctaattttta tatttttagt agagacgggg tttcaccatc ttggccaggc 15360 tggtcttgaa ctcctgacct cgtgatccac ccgccttggc ctcccaaagt gctgggatta 15420 caggcgtgag ccaccgcgcg cagccttttt tttttttttt tttttttttt ttttaagatg 15480 aattcttgct ctgttgccca ggctggagtg cagtggtgtg accttagccc acggcaacct 15540 ccatctcctg ggttcaagag attcttgtgc ctcagcctcc caagtagctg ggattgcagg 15600 cgccctccac catgcttggc taatttttgt atttttagca gagagaggtt tcaccatgtt 15660 ggccaggctg gtctcgaacc cctgacctca agtgatccac ctgcttcagt ctttcaaagt 15720 gctggaatta caggtgtgag ccaccacgac ctgcatacca cttctcaaac agtccttttt 15780 tgcgtccttg ttctcttttt cttcctcttt ctctgcagtc tcattcactt tcattgattc 15840 tgctgctact ccactctatg aaactctctt ctgaactgac ttcaaaccaa caaattctac 15900 ttgtcaacta agctgctcct ctaccttgtg ttatattcac ctaaaatgta atattatttc 15960 cttttttatt tttcctttgg acagggtctt tctctgtcac ccaggctgta gtgcagtggt 16020 gccatctcgg ctcactgcaa cctctgcctt ctgggttcaa gtgattctcc tgcctcagcc 16080 tcctaagtag ctgggactac aggcgcccac caccatgcct ggctaatttt tgtattttta 16140 gtagagacag ggttttgcca tgttggccat gctggtctca aactcctgac ctcaagtgat 16200 acgcctgcct ctgcttccca aagtgctggg attacaggca tgagccactg cgcccagcct 16260 attattttca ttttgaaccc atctctttta ttgccaaaca cgcatttact tctgtgttca 16320 tgatgacatc attatcctat tcatctcaaa gctggaaacc ttgcagtcaa tcatttaaat 16380 gattaaaata catttgagta cctcttgagc caggcactgc cagtataata aaaaataaaa 16440 aaattaaaaa aaggaaagag atagtttgct tttaaggaac ttcactgtgt ggcaaaaact 16500 agtgtaaaca atgacaatac agaatactaa gtggtctggt aggtgttatg tatgcagtac 16560 tttgggagtg tggaggaagg catgcctaga ataatcaggg aggacttcac agagtggtta 16620 tttatagttt aagcagagac ataccagtaa gagggaatag catatgcaag tggccagaaa 16680 tccttggcta gctatctggg aggagtgggg ttgtcaggag ataaaggtat aaagataggc 16740 ttatatgccg tgctgtatag ttgaatgttt ttactattac aaaattttac agatgccctc 16800 agtttctccc tttattcatt tttctatgac atctttattg ttggtcttca tttagtcttt 16860 ccttccagtc tatcctgtgt aaaattactt cctacttcca aaatgagaaa tactgggtct 16920 ctacttaaat ttgtaaccta aatgcctcac acctcatttt ctgaacaaat aaagcccaaa 16980 ttcagtgtcc tttttgatag gatcctgtcc tgacctttcc aaatctgatg ctagagcctt 17040 gtgtaccctg agttcagcca aactgaactc ttaatggtcc cttgctccat actctcccct 17100 tgctcatgcc tttattctcc tggtctgatt catctttgca tcttaacagt gtatagcatg 17160 gtgccttctt tttactgggg acatatcgag ttaatgaatg aatgatgcta ttacagaggt 17220 acagtttggg aaggggagtg agtacatttt agaaaggtga taagtggatt gtcagccttc 17280 atcattttca atggaccaaa ttactaaaac tttacaggtt ggttggtttt ttttcttttt 17340 tcatttcctc atgtactcaa tttctaaggc tttttgaatt tgagcttcct aatatctcat 17400 gcattaattt ttttctccat tctcaacttt cactctttta attaaggata ataatttttt 17460 tttttgagat ggagtcttgc tctgttgcac aggttcgagg gcagtggtgc gatcttggct 17520 cactgcaatc tccgtctgcc gtgttcaagc aattctcctg cctcagcctc ctgagtagct 17580 gggattacag gtgcatgcca ccacgcctgg ctaatttttg tatttttaga agagatgggg 17640 tttcaccacg ttggttaagc tggtcttgaa ctcctgacct tatggtccgc ctgcctcagc 17700 ctcccaaagt gctgggatta caggcatgag ccactgagcc tggccaagga taataaatta 17760 taatggtttt aggttggaca tctctgactg catactgcac tgtgtttact ggaagaagtc 17820 ccttaatgtc tctaaggccc atttcctcag ttctaaatta cggctagtac cttcattgga 17880 gggttgttaa gtctatgata caagataact tttttttttt tttttttttg agacagagtc 17940 tctatcgccc aggctggagt gcaaaatggc acgatcttgg ctcactgcaa cctccacctc 18000 atgggttcaa gttgattctc ctgcctcagc ctcccaagta gcttggatta taggcatgcg 18060 ccaccatgcc cgactaattt tgtgttttta gtagagatgg ggttcaccac gttggccagg 18120 ctggtcgaac tcctgacctc aggtgatcga cccacctcgg cctcccaaag ttgctaggat 18180 tacaggtgtg agccatctct cctggccatg atacaagata atttatatga agtaatacac 18240 tgctggttct gaagtaggtg tgcagtaagt gatgcctact gctgcatgcc aagagtcaaa 18300 tgtatatttg aaagagttgt gaatttcaag aaagatattt ttgagttttt ttttttttct 18360 ttctgagaca gggtcttgta ctgtttccca ggctagagtg cagtggcctg atcttggctc 18420 ctggctgggc ccaagtgatc caccgccctc agccttccaa cgtattggga ttacgggaat 18480 gagccactgc atttggctaa gtttttgttt tttttttctc tatttttcca aacttatttg 18540 attagtaaga taaagacatt aactgctgtt gacagtttcc atttttaatt agtaatcagg 18600 agcatttgtt gtatttttgt ttgataatca gaataattta atttgtgcaa taggatcaat 18660 agctttctgt attccaactg ttaagtggtg taagtttatt acattgttgc tttttgcagg 18720 ttgtcctttg ttctagatag aaatgtttaa tttattcttc ctggttttca ggggagccca 18780 ttgaaaggag atccagtctc tgaaatttag tggtaggata ataacaattg aacagttact 18840 tttgaatcta atttaaataa tctcaattgt agccttttaa agcaattcct atgaaccttt 18900 ttgaatttag aaaagtaata cttggccggg cgcggtggtt cacatctata atcccagcac 18960 tttgggaggc tgagggggtg gattatctga ggtcaggagt tcaagaccag cctggccaac 19020 gtagtgaaac cctgtctcta ctgaaaatac aaaaaaaaat tagctgggtg tggtggcacg 19080 tgcctgtagt cccagctact caggaggctg atgcaggagg atcgcttgaa cccaggaggc 19140 agaggttgca gtaagctggg attgtgccac tgcactccag cctgggtgac agagtgagac 19200 tttgtctcaa aaaaaaaaaa aaaaaagtca aacttaaaaa tggaatataa aaatctcttg 19260 atttttgtca gttttcatat actccctcat ttacactctt aatattctat tagaaattgt 19320 ctcttctctc tacacacccc tttttttccc ttttggttaa tatgttaaga catcttttca 19380 tatgagcatg taacatgtaa caagattttt tttttttttt ttggacagtg tctcgctctg 19440 ttgctcaggc tggagtctag tagtatgatc acaactcact gcagtttaga cctcctgtgt 19500 taaagtgatt ctcctacttt agcctcatga gtagttggga ctacaggccc atgccaccac 19560 gcctggctaa ttaaagaaaa aattatttgg tagagacagg gtcttgctat gttgcccagg 19620 ctggtcttga atttctggct tcaggcaatt ctcctactct gcatgagcca cctcagccgc 19680 gaatattttc ttattatgaa atttttgttt agataaatgt tgattcacat gcagttgtaa 19740 caaattccat ggccaggctg ggcgtggtgg ctcacgcctg taatcccagc actttgggag 19800 gctgaggtgg atcacctgag gttgggagtc caagaccagc ctgaccaaca tggagaaacc 19860 ccgtctctac taaaaataca aaattagcca ggcgtgatgg tgcgtgcttg taatcccagc 19920 tacttgggag gctgaggcag aagaatcact tgaacccggg aggcggaggt tgtagtgagc 19980 caagatcgtg ccattgcact ccagcctggg ctagaagagc gaaactccat ctcaaaaaaa 20040 aaaaaaaaaa aatcaggaaa ttccatgggc taggcacagt gacttatgcc tgtaatccca 20100 gcgttttgga aggctgaggt tggaggattg cttgagccca ggagtttgag gctacagtga 20160 acactgactg tgccactgca ctccagcctg ggtgaccctg tctcttaaaa aaaaaaaaga 20220 atacagagag gtcccttgta tattttgcct ggttttgcaa tggtaatatt ttgcaaaaaa 20280 tatctaatac cacacaacca gaatattgat gttgatgtac ttcaccaatc gttttttttt 20340 tttttttttg agtcggagtc tccatctgat gcccaggcta gagtgcagtg gctcaatctc 20400 ggctcactgc aacctccacc tcctgggttc aagcaattct cctgcctcag cctcctgagt 20460 agctgggact acaggcgtgt gctatgacgc ccagctagtt tttgtatttt tagtagagac 20520 ggtgtttcac cgtgttatcc agggtggtct caatctcccg accttgtgat ccgcccgcct 20580 cagcctccca aagtgttggg attacaggct tgagccaccg cgtccagcca gtcttactta 20640 ggcattgacg ttcatgtaat ttatccatct tattcagatg tccttaaatt ttatcttttt 20700 ccttaaaaga aatctgtatt tctatcagga cattctggat gtccccagtt ttactggtag 20760 tctttcattg tgtgtatatt aagttctttg tttttatcac ctgtataggt tagtatatcc 20820 atgactcccg tcaactttct aaatgttcgc tgggtgcagt ggctcatgcc tgtaatccca 20880 gcactttggg aggctgaggc ggctggatca cctgaggtca gtagttcgag accagtctgg 20940 ccaacatggt gaaaccccgt gtctactaaa aataaaaaaa aaattagctg gatatggtgg 21000 gtcatgcctg taatcctagc tactcgggag gctgaggttg gagaatcgct tgaacccagg 21060 aggcggaagt tgcagtgagc tgagatcgcg ccgctgcact ctagcctggg tgacagagta 21120 tgtctctgtc tcaaaaaaaa aaaaaaagtt gctaaacatt tctaatacca taaggatccc 21180 tgctgttgcc agccgtttta aaactacatc catcgtcttc ttggcaacct tccatctctt 21240 tttcgtatgt gacagcgtct tgctctgccg cccaggctgg agtgcagtag ttgcatctca 21300 gctcactgca ccctctgtgt cccaggctta agcgatcctc ccacctcagc ctcctgatta 21360 gctgcgacta caggcacttg ccaccatgcc ccactaattt ttgtatgttt ttgtagagat 21420 ggggttttac catgttgctc aagctcgtct tgaactcgtg agctcaagca atccgcctgc 21480 cttggcctcc caaatggctg ggattacagg caggagccac catgcctggc ctagcccctc 21540 catctctagc ctttgtcagt tactaaactt tttttcctga agttttgtca tttcacaaat 21600 gttagataaa catgagtcat acagtatgca gccttttggg attgtctttt tttcccttag 21660 cataatttcc aggggattca tctaagttgt tgactaaatc aatagttgtt ttttttgttt 21720 gttttttttt tgagacggag tttcactctt gtggaccagg ctggagtgca atggcatgat 21780 cttggctcac tgcaacctcc gcctcccagg ttcaagcgat tctcctgcct cagcctcctg 21840 agcagttggg attataggcc cctgccacca cacccagcta atttttgtat ttttagtaga 21900 gatggggttt caccatgttg gtcagggtag tcttgaactc ctggcctcaa gtgatctacc 21960 tgcattggcc tcccaaagtg ctgggattac aggtgtgagc cactgcgcac ggccctagtt 22020 ttttcctttt tatcactaag taatattcca tgatacaaat ataccatggt ttgcttgacc 22080 gttcacctgt tgaaggacat ctggggcaat gctagctttt ggtaattaag gtaaaagtac 22140 tatttatgtt catttatggg gttttgtgtg actgtaagtt ttcacttctc tgggataaat 22200 accagtagaa caattgcagt attatatggt aatggcatgt taagtttttt ttttttcctg 22260 agagggagtt tcgatcttgt tgcccaggct ggagtgcaat tgcgcgatct tggctcgctg 22320 caacctctgc ctcctgggtt caagcgattg tcctttctca gcctcgcatg tagctgggat 22380 tataggtgtc aaccaccaca cccagctcat ttttgtattt ttagtagaga tggggtttca 22440 ctgtgtttgc caggctggtc ccaaactctt gaccccaggt gatccaccct cctcagcctc 22500 ccaaagtgct gggattacag gcgtgagcca cggcgccccg ccaatgttca gttgtttttt 22560 tgtttttttg agacaatctc tctctgtcac ccaggctgga gggcagtggc gcgatcctgg 22620 ctcactgcaa cctctgcctc ccggattcaa gcgattatcc cgcctcaggc tcctgagtag 22680 ctgggaccac aggtgcacac caccacacca ggctaatttt tttattttta gtagagacgg 22740 ggtttcacca tgttgggtca ggctggtctc gaactcctga cctcaggtga tccacccacc 22800 tcggcctccc gaagtgctgg gattacaggt gtgagccacc acgcctggcc caatgttcag 22860 ttttataaga aactaccaag ctgttttccc tagtgtctgt accatttaca ttctcactag 22920 cagtatatga gtgatccagt ttcttttatt ttttgttttt tgagacggag tctcgccctg 22980 ttgcccaggc tgaagtgcag tggcacgatc tcggctcact gcaacctctg cttcccggct 23040 tcaagtgatt ctcctgcatc agcctcccaa gtagctggga ttacaggcat gtgcaccatg 23100 cctggctaat tttttgtatt tttagtagag atagggtttc accatgttgg ccaggctggt 23160 ctcgaactcc tgacctcagg taatccaccc atcttggctt cccaaagtcc tgggatttca 23220 ggcatgagcc attgcacctg gccgagtgct tcagtttcta tgcatcctca ccagcatttg 23280 gtgtggtcac tattttaatt ttagccattc gtgtagatat gtagtaatgt ctcatctcat 23340 tatgttttgt tttttttttt gagacggaat gttgctcttg ttgcccagac tggagtgcag 23400 tgatgccatc tcggttcact gcaacctcca cctgctgagt tcaagcaatt ctcgtgcgtc 23460 agcctctgga gtagctggga ttataggtgt gcatcaccat gcctggctaa tttttgtatt 23520 ttttagtaga catggggttt caccacgttg gccaggctgt tcttgaactc ctgacctcag 23580 gtgagctgcc cacctcggcc tcccaaagtg ctgggattac agttttgtat ggtggattcc 23640 atgcagagag agttttttct gtagtctaga ttagcagtcc ccagcctttt tggcaccagg 23700 gaccaaattc ctgggaaaca gtttttccac aggtgggagt gggatggttt ggggatgaaa 23760 cttttccacc ttagattatc acgcattagt tagaatctca taagaagcgc gcaacctaga 23820 tcccttgcat ttgcagttca caatagggtt catgatcctc tgagaatcta atgccacccc 23880 <210> 2 <400> 2 <210> 3 <400> 3 <400> 4 <210> 5 <400> 5 <210> 6 <211> 275 <400> 6 ...50(ΜM) Compound Cdk1 / B Cdk2 / A Cdk2 / E Cdk4D 55> 5> 5> 5 0.300 64> 5> 5> 5> 5 65> 5> 5> 5> 5 70 1.448 0.697 0.530 0.017 71> 5> 5 > 5> 579> 5 1.066> 5> 580 0.461 0.092 0.230 0.460 81 2.610 1.560 3.250 0.399 0.305 0.315 0.055 0.500 83 84> 5> 5> 5> 585> 5> 5> 5> 586> 5> 5 > 5> 587> 5> 5> 5> 588 89 0.418 0.043 0.055 0.025> 5> 5> 5> 591> 5> 5> 5 93 0.070> 5> 5> 5> 594> 5 95 0.101> 5 0.310 96 6.365 1.108 1.550> 597 0.862 0.278 0.345> 5 table 2: Cdk inhibition: IC50(ΜM) Compound Cdk1 / B Cdk2 / A Cdk2 / E Cdk4D 98 0.442 0.157 0.140 1.050 99 1.810 1.012 0.410> 5 100 0.265 0.153 0.415 0.035 102 3.130 3.590 4.500 0.165 103> 5> 5> 5> 5 104> 5> 5> 5 0.185 106 0.350 0.440 107 1.728 1.950 1.650 2.425 2.035 3.050 0.067 0.019 108 111> 5> 5> 5> 5113> 5> 5> 5 3.000 114> 5> 5> 5> 5115 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 still is the inhibitor of growth factor receptor tyrosine kinase FGFr and PDGFr and the inhibitor of nonreceptor tyrosine kinase c-Src.Some The compounds of this invention have been estimated via measuring the standard test method that suppresses the Tyrosylprotein kinase ability.These assay methods are following carrying out:
PDGF and FGF receptor tyrosine kinase assay method
The full-length cDNA of mouse PDGF-β and people FGF-1 (flg) receptor tyrosine kinase obtains from J.Escobedo, is as J.Biol.Chem.1991; The described preparation of 262:1482-1487.The PCR primer is designed to the dna fragmentation of amplification coding intracellular tyrosine kinase domain.This fragment is inserted baculovirus vector,, separate recombinant virus with AcMNPV DNA cotransfection.With this virus infection SF9 insect cell,, use cell lysates to measure with overexpression protein.Mensuration is carried out (100 μ L/ insulation/hole) in the flat board of 96-hole, condition is optimized, to measure from γ 32P-ATP is in glutaminate-tyrosine multipolymer substrate 32P mixes.In brief, add 82.5 μ L insulation damping fluid, contain 25mM Hepes (pH7.0), 150mM NaCl, 0.1%Triton X-100,0.2mM PMSF, 0.2mM Na to every hole 3VO 4, 10mM MnCl 2With 750 μ g/mL Poly (4: 1) glutaminate-tyrosine, add 2.5 μ L inhibitor+5 μ L enzyme lysates (7.5 μ g/ μ LFGF-TK or 6.0 μ g/ μ L PDGF-TK) then, with initiation reaction.After 10 minutes, add 10mL γ in insulation under 25 ℃ to every hole 32P-ATP (0.4 μ Ci adds 50 μ M ATP) is incubated other 10 minutes with sample down at 25 ℃.Add 100 μ L, 30% trichoroacetic acid(TCA)s (TCA) that contain the 20mM trisodium phosphate, make species precipitate on glass fiber mats (Wallac), with termination reaction.Filter with the 15%TCA washing that contains the 100mM trisodium phosphate 3 times, is counted the radioactivity that is retained on the filter in Wallac 1250 β plate readers.Non-specific activity is defined as being retained in after sample and the insulation of independent damping fluid (not having enzyme) radioactivity on the filter.Specific enzymes activity (enzyme is with damping fluid) is defined as gross activity and deducts non-specific activity.Be determined at the inhibition % under the 50 μ M, about more effective compound, based on suppressing the concentration (IC that the curve determination compound suppresses 50% activity specific 50).
The C-Src kinase assay
Use is oriented to the anti-peptide monoclonal antibody of-terminal amino acid (amino acid 2-17) of c-Src from the insect cell lysate purifying C-Src kinases of baculovirus infection.Add and the covalently bound antibody of 0.65 μ m latex beads in insect cell dissolving damping fluid, this damping fluid comprises 150mM NaCl, 50mM Tris pH7.5,1mM DTT, 1%NP-40,2mMEGTA, 1mM vanadic acid sodium, 1mM PMSF, respectively is leupeptin, pepstatin and the Trypsin inhibitor,Trasylol of 1 μ g/mL.To contain the proteic insect cell lysate of c-Src and these beads and be incubated 3 to 4 hours down, simultaneously rotation at 4 ℃.When the lysate insulation finishes, bead is washed 3 times in the dissolving damping fluid, be resuspended in the dissolving damping fluid that contains 10% glycerine, freezing.These latex beads are melted, measuring damping fluid (40mM Tris pH7.5,5mM MgCl 2) the middle cleaning 3 times, be suspended in the identical damping fluid.In being the Millipore 96-hole flat board of 0.65 μ mpolyvinylidine film, the bottom adds reactive component: 10 μ Lc-Src beads, 10 μ L 2.5mg/mL polyGluTyr substrates, contain 0.2 μ Ci mark 32The 5 μ M ATP of P-ATP, contain inhibitor or as 5 μ L DMSO and appropriate amount of buffer solution of solvent control, making cumulative volume is 125 μ L.At room temperature add ATP and begin reaction, add 125 μ L30%TCA, 0.1M trisodium phosphate after 10 minutes, place to reach quencher in 5 minutes on ice.Filter flat board then, aperture washs with 15%TCA, the 0.1M pyrophosphate salt of two parts of 250-mL.The punching press filter is counted in liquid scintillation counter then, checks the inhibition activity of data, compares with known inhibitor, for example erbstatin.This method also is described in J.Med.Chem. (pharmaceutical chemistry magazine), 1994; Among the 37:598-609.
The tyrosine-kinase enzyme inhibition activity of the representative The compounds of this invention of estimating in the said determination method sees Table 3.
Table 3: to the restraining effect of Tyrosylprotein kinase: the inhibition % under 50 μ L is (if measure IC 50[μ M] is in bracket) compound PDGFr FGFr1 94.4 (0.593) 93.79 89.811 (0.131) (0.284) 45 21.9 67.446 17.5 19.547 10.555 (0.033) (0.151) 70 (0.536) (1.15) 80 18.6117 (0.081) (0.061)
As mentioned above, the present invention also provides pharmaceutical composition, comprises the The compounds of this invention that is mixed with carrier, thinner or vehicle.The following example is set forth by exemplary composition provided by the invention.
Embodiment 144
Use the following ingredients preparation to be used for the pharmaceutical composition of the form of hard gelatin capsules of oral administration:
Amount (mg/ capsule) active compound 250 starch powders 200 Magnesium Stearates 10 amount to 460
Mentioned component is mixed, be filled in the hard capsule by the amount of 460mg.Typical activeconstituents is 1-isobutyl--3-[2-{ (2-chloro-4-piperazine-1-yl)-phenylamino }-pyrido [2,3-d] pyrimidin-7-yl]-urea.With this compound administration every day 2 to 4 times, be used for the treatment of postoperative restenosis.
Embodiment 144a
Be used for the composition components amount 1-isopropyl of oral suspension-3-[5-methyl-6-bromo-2-(3-ethylpyridine 500mg-4-base is amino)-pyrido [2; 3-d] pyrimidine-7-yl]-urea sorbitol solution (70%NF) 40mL Sodium Benzoate 150mg asccharin 10mg cherry flavouring 50mg distilled water is appropriate, adds to 100mL
In 40mL distilled water, add sorbitol solution, pyrrolopyrimidine is suspended wherein.Add asccharin, Sodium Benzoate and correctives, dissolving.With the distilled water adjusted volume to 100mL.Every milliliter of syrup contains the 5mg activeconstituents.
Embodiment 144b tablet, every contains 60mg active component active component 60mg starch 45mg microcrystalline cellulose 35mg polyvinylpyrrolidone (10% aqueous solution) 4mg sodium carboxymethyl starch 4.5mg dolomol 0.5mg talcum 1.0mg and amounts to 150mg
Make activeconstituents, starch and Mierocrystalline cellulose by No.45 order US sieve, thorough mixing.With polyvinylpyrrolidonesolution solution and gained powder mixes, then by No.14 order US sieve.Particle is dry under 50 ℃ to 60 ℃, sieve by No.18 order US.Add sodium starch glycolate, Magnesium Stearate and the talcum that passes through No.60 order US sieve in advance to particle then, it is in blocks to mix back compacting on pelleter, the heavy 150mg of sheet.
The typical activity composition that is used for above-mentioned preparation is embodiment 40 compounds (compounds 12).This composition is particularly suitable for treating diabetic retinopathy.
Embodiment 144c
100mg compound 77 is dissolved in 250mL 0.9% sodium chloride aqueous solution, and the pH that regulates this solution is to about 7.0, and preparation is fit to the parenteral composition by drug administration by injection.This preparation is particularly suitable for treating mammary cancer.
Embodiment 144d
The preparation of suppository
With 500mg 1-normal-butyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-mixture of urea and 1500mg theobroma oil is 60 ℃ of even fusion down.With mixture at gradually thin mould internal cooling to 24 ℃.Every suppository will heavily about 2g, can administration every day 1 to 2 time, be used for the treatment of virus infection, for example bleb and HIV.
Embodiment 144e
Topical formulations becomes component (mg) 1-cyclohexyl-3-{[2-(4-morpholine-1-base-phenylamino)] 20-5; 6-two fluoro-pyrido [2,3-d] pyrimidine-7-yls }-urea propane diols 100 white petrolatum 500 cetostearyl alcohol 50 tristerin 100PEG 100 stearate 100Ceteth-20 50 sodium dihydrogen phosphates 80 totals 1000
The compounds of this invention and other composition are mixed together evenly, make thickness suspension.This suspension evenly is coated on the polymeric film of tackiness agent backing, and is cut into 2-inch square.This patch can be applied to be suffered from the psoriasic patient skin.
Embodiment 144f
Sustained release preparation
With 500mg hydrochloric acid 7-acetylaminohydroxyphenylarsonic acid 6-bromo-2-[4-(2-diethylamino ethoxy)-phenylamino] pyrido [2,3-d] pyrimidine places in the osmotic pump tablet, to curee's oral administration, is used for the treatment of and prevention of restenosis.
Now complete, clear, succinctly and exactly the present invention and preparation and mode and the method for using it have been described, the affiliated any technician in field can be prepared and use it.Be understandable that preamble is described preferred implementation of the present invention, can improve therein, and do not deviate from as claimed in claim the spirit or scope of the present invention.In order to spell out and the claimed subject matter of an invention that is considered as clearly, following claim is summed up this specification sheets.

Claims (21)

1, formula I compoundAnd pharmaceutically acceptable salt, ester, acid amides and pro-drug, wherein: R2、R 7、R 13、R 14And R15Be hydrogen independently, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、   -(CH 2) nCO 2R 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11、-COR 9、-CONR 9R 10、-SO 3R 9、   -SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、   -NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively9、-NR 9R 10、   -OR 9、-NR 9COR 10、-COR 10、-(CH 2) nSO 2R 11、-(CH 2) nR 11, or-(CH2) nR 12, replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、-(CH 2) nCO 2R 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11、   -COR 9、-CONR 9R 10、-SO 3R 9、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively9、-NR 9R 10、   -OR 9、-NR 9COR 10、-COR 10、-(CH 2) nSO 2R 11、-(CH 2) nR 11； R 5Be halogen, cyano group, nitro ,-R9、-NR 9R 10Or-OR9； R 6Be halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、-CO 2R 9、-COR 9、-CONR 9R 10、   -NR 9COR 10、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、-PO(NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl, alternatively by-R9Replace; R8Be H ,-CO2R 13、-COR 13、-CONR 13R 14、-CSNR 13R 14、-C(NR 13)NR 14R 15、-SO 3R 13、   -SO 2R 13、-SO 2NR 13R 14、-PO 3R 13R 14、-POR 13R 14、-PO(NR 13R 14) 2； R 9And R10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively, substituting group selects free halogen, amino, one or the group that forms of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R9And R10Form the ring with 3-7 member together with nitrogen that they connect, wherein at the most four can be selected fromO, S and NR20, R wherein20Be hydrogen, low alkyl group or-the CO low alkyl group; R11Heteroaryl or heterocyclic radical; R12Cycloalkyl, heterocyclic radical, aryl or heteroaryl; And n is 0,1,2 or 3.
2, formula II compound And pharmacy acceptable salt, ester, acid amides and prodrug, wherein: R 7, R 13, R 14And R 15Be hydrogen independently, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,-OR 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11, or-(CH 2) nR 12, replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,-OR 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11R 5Be halogen, cyano group, nitro ,-R 9,-NR 9R 10Or-OR 9R 6Be halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-CO 2R 9,-COR 9,-CONR 9R 10,-NR 9COR 10, or low-grade alkenyl or low-grade alkynyl are alternatively by-R 9Replace; R 8Be H ,-CO 2R 13,-COR 13,-CONR 13R 14,-CSNR 13R 14,-C (NR 13) NR 14R 15,-SO 3R 13,-SO 2R 13,-SO 2NR 13R 14,-PO 3R 13R 14,-POR 13R 14,-PO (NR 13R 14) 2R 9And R 10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively, substituting group be selected from by halogen, amino,
One or the group formed of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R 9And R 10Constitute ring with the nitrogen that they connected with 3-7 member, wherein at the most four can be selected from O, S and NR 20, R wherein 20Be hydrogen, low alkyl group or-the CO low alkyl group; R 11Be heteroaryl or heterocyclic radical; R 12Be cycloalkyl, heterocyclic radical, aryl or heteroaryl; N is 0,1,2 or 3; R 16, R 17And R 18Be independently hydrogen, halogen, amino, one or dialkyl amido, hydroxyl, low alkyl group, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10Perhaps R 16It is the carbocylic radical that contains 3-7 member; wherein 2 members are the heteroatomss that are selected from oxygen and nitrogen at the most, and wherein this carbocylic radical is unsubstituted or is independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group replacement of the group formed of dialkyl amido, aryl, heteroaryl, aralkyl, heteroaralkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle alkylsulfonyl or heterocycle sulphonyl alkyl by 1,2 or 3.
3, formula III compoundAnd pharmaceutically acceptable salt, ester, acid amides and pro-drug, wherein: R2Be hydrogen, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、   -(CH 2) nCO 2R 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11、-COR 9、-CONR 9R 10、-SO 3R 9、   -SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、   -NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively9、-NR 9R 10、   -OR 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11, or-(CH2) nR 12, replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、-(CH 2) nCO 2R 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11、   -COR 9、-CONR 9R 10、-SO 3R 9、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively9、-NR 9R 10、   -OR 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11； R 5Be halogen, cyano group, nitro ,-R9、-NR 9R 10Or-OR9； R 6Be halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、-CO 2R 9、-COR 9、-CONR 9R 10、   -NR 9COR 10、-SO 2NR 9R 10、-SO 2R 9、-SO 3R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl, alternatively by-R9Replace; R9And R10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively, substituting group selects free halogen, amino, one or the group that forms of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R9And R10Form the ring with 3-7 member together with nitrogen that they connect, wherein at the most four can be selected fromO, S and NR20, R wherein20Be hydrogen, low alkyl group or-the CO low alkyl group; R11Heteroaryl or heterocyclic radical; R12Cycloalkyl, heterocyclic radical, aryl or heteroaryl; N is 0,1,2 or 3; And R19Hydrogen, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyl alkyl, amino carbonyl, one or dialkyl amino carbonyl, lower alkylcarbonyl ,-SO3R 9、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、   -POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、   -NR 9SO 2R 10Or aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl are replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyl alkyl, amino carbonyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO3R 9、-SO 2R 9R 10、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or (CH2) n-contain 3-7 member's carbocylic radical, wherein 2 members are the hetero atoms that are selected from oxygen and nitrogen at the most, and wherein this carbocylic radical is unsubstituted or by 1,2 or 3, is independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group replacement of the group that forms of dialkyl amido, aryl, heteroaryl, aralkyl, heteroarylalkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle sulfonyl or heterocycle sulphonyl alkyl; And R21Hydrogen, low alkyl group or by the low alkyl group of the phenyl substituted of phenyl or replacement.
4, formula IV compound And pharmacy acceptable salt, ester, acid amides and prodrug, wherein: R 5Be halogen, cyano group, nitro ,-R 9,-NR 9R 10Or-OR 9R 6Be halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-CO 2R 9,-COR 9,-CONR 9R 10,-NR 9COR 10,-SO 2R 9R 10,-SO 2R 9,-SO 3R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl are alternatively by-R 9Replace; R 9And R 10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively that substituting group is selected from by halogen, amino, one or the group formed of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R 9And R 10Constitute ring with the nitrogen that they connected with 3-7 member, wherein at the most four can be selected from O, S and NR 20, R wherein 20Be hydrogen, low alkyl group or-the CO low alkyl group; R 11Be heteroaryl or heterocyclic radical; R 16, R 17And R 18Be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,
-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、
-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,
-OR 9,-NR 9COR 10,-COR 10,-(CH 2) nSO 2R 11,-(CH 2) nR 11R 19Be hydrogen, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, lower alkylcarbonyl ,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10Or aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl are replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyalkyl, aminocarboxyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO 3R 9,-SO 2R 9R 10,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or (CH 2) n-contain 3-7 member's carbocylic radical, wherein 2 members are the heteroatomss that are selected from oxygen and nitrogen at the most, and wherein this carbocylic radical is unsubstituted or is independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group replacement of the group formed of dialkyl amido, aryl, heteroaryl, aralkyl, heteroaralkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle alkylsulfonyl or heterocycle sulphonyl alkyl by 1,2 or 3; And R 21Be hydrogen, low alkyl group or the low alkyl group that replaced by the phenyl of phenyl or replacement.
5, formula V compoundAnd pharmaceutically acceptable salt, ester, acid amides and pro-drug, wherein: R5Be halogen, cyano group, nitro ,-R9、-NR 9R 10Or-OR9； R 6Be halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、-CO 2R 9、-COR 9、-CONR 9R 10、   -NR 9COR 10、-SO 2NR 9R 10、-SO 2R 9、-SO 3R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl, alternatively by-R9Replace; R16、R 17And R18Be independently selected from hydrogen, halogen, cyano group, nitro ,-R9、-NR 9R 10、-OR 9、   -(CH 2) nCO 2R 9、-(CH 2) nSO 2R 11、-(CH 2) nR 11、-COR 9、-CONR 9R 10、-SO 3R 9、   -SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、   -NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively9、-NR 9R 10、   -OR 9、-NR 9COR 10、-COR 10、-(CH 2) nSO 2R 11、-(CH 2) nR 11； R 9And R10Be hydrogen independently, or low alkyl group, replaced by 3 groups at the most alternatively, substituting group selects free halogen, amino, one or the group that forms of the phenyl of dialkyl group alkyl, hydroxyl, lower alkoxy, phenyl or replacement, perhaps R9And R10Form the ring with 3-7 member together with nitrogen that they connect, wherein at the most four can be selected fromO, S and NR20, R wherein20Be hydrogen, low alkyl group or-the CO low alkyl group; R11Heteroaryl or heterocyclic radical; R19Hydrogen, or low alkyl group, low-grade alkenyl or low-grade alkynyl, they are replaced by 5 groups at the most separately alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyl alkyl, amino carbonyl, one or dialkyl amino carbonyl, lower alkylcarbonyl ,-SO3R 9、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、   -POR 9R 10、-PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、   -NR 9SO 2R 10Or aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl, wherein each aryl, heteroaryl or cycloalkyl are replaced by 5 groups at the most alternatively, substituting group be independently selected from halogen, amino, one or dialkyl amido, hydroxyl, lower alkoxy, cyano group, nitro, carboxyl, carboxyl alkyl, amino carbonyl, one or dialkyl amino carbonyl, alkyl-carbonyl ,-SO3R 9、-SO 2R 9R 10、-SO 2NR 9R 10、-SO 2R 9、-SR 9、-PO 3R 9R 10、-POR 9R 10、   -PO(NR 9R 10) 2、-NR 9COR 10、-NR 9CO 2R 10、-NR 9CONR 9R 10、-NR 9SO 2R 10, or (CH2) n-contain 3-7 member's carbocylic radical, wherein 2 members are the hetero atoms that are selected from oxygen and nitrogen at the most, and wherein this carbocylic radical is unsubstituted or by 1,2 or 3, is independently selected from by halogen, hydroxyl, low alkyl group, trifluoromethyl, lower alkoxy, amino, one or the group replacement of the group that forms of dialkyl amido, aryl, heteroaryl, aralkyl, heteroarylalkyl, assorted arylsulfonyl, assorted fragrant sulphonyl alkyl, Heterocyclylalkyl, heterocycle sulfonyl or heterocycle sulphonyl alkyl; And R21Hydrogen, low alkyl group or by the low alkyl group of the phenyl substituted of phenyl or replacement.
6, formula VI compound
Figure A0180404800101
And pharmacy acceptable salt, ester, acid amides and prodrug, wherein: R 5Be halogen, cyano group, nitro ,-R 9,-NR 9R 10Or-OR 9R 6Be halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-CO 2R 9,-COR 9,-CONR 9R 10,-NR 9COR 10,-SO 2NR 9R 10,-SO 2R 9,-SO 3R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2, or low-grade alkenyl or low-grade alkynyl are alternatively by-R 9Replace; R 17And R 18Be independently selected from halogen, cyano group, nitro ,-R 9,-NR 9R 10,-OR 9,-(CH 2) nCO 2R 9,-(CH 2) nSO 2R 11,-(CH 2) nR 11,-COR 9,-CONR 9R 10,-SO 3R 9,-SO 2NR 9R 10,-SO 2R 9,-SR 9,-PO 3R 9R 10,-POR 9R 10,-PO (NR 9R 10) 2,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 9R 10,-NR 9SO 2R 10, or heterocycle, by 3 groups replacements at the most, substituting group is independently selected from-R alternatively 9,-NR 9R 10,-OR 9,-NR 9COR 10,-COR 10,-(CH 2) nSO 2R 11,-(CH 2) nR 11R 22And R 23Be hydrogen or alkyl independently.
7, compound is selected from:
The 1-tertiary butyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 1-tertiary butyl-3-[2-(3-chloro-4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 1-tertiary butyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 1-tertiary butyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea;
1-{2-[4 (4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea;
1-{2-[4 (4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluorine pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-picoline [2,3-d] pyrimidin-7-yl also }-the 3-tertiary butyl-urea;
1-cyclohexyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[2-(3-chloro-4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-cyclohexyl-urea;
1-cyclohexyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluorine pyrido [2,3-d] pyrimidin-7-yl }-3-cyclohexyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-picoline [2,3-d] pyrimidin-7-yl also }-3-cyclohexyl-urea;
1-(2-hydroxyl-ethyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[2-(3-chloro-4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea;
1-[6-fluoro-2-(4-piperazine-1-yl)-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea;
1-(2-hydroxyl-ethyl)-3-[5-methyl-2-(4-piperazine-1-base phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluorine pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-methyl-pyrido [2,3-d] pyrimidin-7-yl }-3-(2-hydroxyl-ethyl)-urea;
1-ethyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[2-(3-chloro-4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-ethyl-urea;
1-ethyl-3-[6-fluoro-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-ethyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-chloro-phenylamino] pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-3-ethyl-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-5-picoline [2,3-d] pyrimidin-7-yl also }-3-ethyl-urea;
The 1-tertiary butyl-3-(2-phenylamino-pyrido [2,3-d] pyrimidin-7-yl)-urea;
The 1-tertiary 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-sec.-propyl-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea;
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea;
1-cyclopentyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea;
1-cyclopentyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-cyano group-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-chloro-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-fluoro-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-bromo-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-chloro-5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-sec.-propyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-ethyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-methyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-1-methyl-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-(4-hydroxyl-cyclohexyl)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-(4-amino-cyclohexyl)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-(2-dimethylamino-ethyl)-3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-(3-morpholino-4-base-propyl group)-3-[2-(4-piperazine-1-base phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
3-cyclohexyl-1-methyl isophthalic acid-[2-(4-piperazine-1-base-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]-sulphonamide;
1-cyclohexyl-3-[5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-thiocarbamide;
N-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-ethanamide;
4-[7-(3-cyclohexyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino]-benzsulfamide;
1-cyclohexyl-3-{2-[4-(1-piperazine-1-base-formyl radical)-phenylamino]-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)-piperazine-1-yl] phenylamino }-pyrido [2,3-d] pyrimidin-7-yl)-3-cyclohexyl-urea; With
1-(2-{4-[4-(2-amino-3-methyl-butyryl radicals)-piperazine-1-yl] phenylamino }-pyrido [2,3-d] pyrimidin-7-yl)-3-cyclohexyl-urea.
8, compound is selected from:
The 1-tertiary butyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-ethyl-3-[2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-(hydroxyl-ethyl)-3-[2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 1-tertiary butyl-3-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-ethyl-3-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[6-fluoro-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-ethyl)-urea;
The 1-tertiary butyl-3-[5-methyl-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-cyclohexyl-3-[5-methyl-2-(pyridin-4-yl amino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-ethyl-3-[5-methyl-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea; With
1-(2-hydroxyl-ethyl)-3-[5-methyl-2-(pyridin-4-yl amino) pyrido [2,3-d] pyrimidin-7-yl]-urea.
9, compound is selected from:
4-{4-[7-(the 3-tertiary butyl-urea groups)-pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester;
4-{4-[7-3-cyclohexyl-urea groups)-and pyrido [2,3-d] pyrimidine-2--amino] phenyl }-piperazine-1-carboxylic acid tert-butyl ester;
1-(3-hydroxyl-propyl group)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-((S)-1-methylol-3-methyl-butyl)-3-[2-(4-piperazine-1-base phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
4-methyl-piperazine-1-carboxylic acid [2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-acid amides;
Morpholine-4-carboxylic acid [2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-acid amides;
3-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-1,1-dipropyl-urea;
Piperazine-1-carboxylic acid [2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-acid amides;
1-((R)-1-methylol-2-methyl-propyl group)-3-[2-(4-piperazine-1-base phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1,1-pair-(2-hydroxyl-ethyl)-3-[2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-the 3-tertiary butyl-urea;
1-[6-bromo-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-methyl-urea;
1-{6-bromo-2-[4-(cis-3.5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-the 3-tertiary butyl-urea;
1-{6-bromo-2-[4-(cis-3.5-dimethyl-piperazine-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-morpholine-4-base-propyl group)-urea;
1-[2-(4-fluoro-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-(2-hydroxyl-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-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea;
The 1-tertiary butyl-3-{2-[4-(cis-3.5-dimethyl-piperazine-1-yl)-phenylamino]-6-fluoro-pyrido [2,3-d] pyrimidin-7-yl }-urea;
1-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-3-(3-morpholine-4-base-propyl group)-urea;
The 1-tertiary butyl-3-{6-chloro-2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea;
3-cyclohexyl-1-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-1-methyl-urea;
3-cyclohexyl-1-ethyl-1-[2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
The 3-tertiary butyl-1-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-1-ethyl-urea;
1-[5-methyl-2-(4-piperazine-1-base-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-3-propyl group-urea;
7-(the 3-tertiary butyl-urea groups)-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester;
1-[6-fluoro-5-methyl-2-(4-piperazine-1-base-phenylamino) pyrido [2,3-d] pyrimidin-7-yl]-3-sec.-propyl-urea;
1-cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazine-1-yl)-phenylamino]-pyrido [2,3-d] pyrimidin-7-yl }-urea;
1-cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea;
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea;
The 1-tertiary butyl-3-[6-methyl-2-(4-piperazine-1-yl)-phenylamino)-pyrido [2,3-d] pyrimidin-7-yl]-urea;
1-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-picoline [2,3-d] pyrimidin-7-yl also }-3-sec.-propyl-urea;
1-cyclopropyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl)-phenylamino]-6-methyl-pyrido [2,3-d] pyrimidin-7-yl }-urea; With
The 1-tertiary butyl-3-{2-[4-(cis-3,5-dimethyl-piperazine-1-yl) phenylamino]-6-ethyl-pyrido [2,3-d] pyrimidin-7-yl }-urea.
10, pharmaceutical composition comprises the compound that is selected from claim 1 that is mixed with pharmaceutically acceptable carrier, thinner or vehicle.
11, be used to control the method for Mammals proliferative disorders, be selected from the group of forming by cancer, psoriasis, the vascular smooth muscle propagation relevant with a kind of obstacle, latter's obstacle is selected from the group of being made up of atherosclerosis, postoperative angiostenosis and restenosis, and this method comprises the compound according to claim 1 of described Mammals being given to treat significant quantity.
12, the method that suppresses the cdk enzyme comprises the cdk enzyme is contacted with the compound that is selected from claim 1.
13, the method for claim 12, wherein said cdk is cdk1.
14, the method for claim 12, wherein said cdk is cdk2.
15, the method for claim 12, wherein said cdk is cdk4.
16, suppress the method for the Tyrosylprotein kinase of somatomedin-mediation, comprise the kinases that makes described somatomedin-mediation and contact with the compound that is selected from claim 1.
17, the method for claim 16, the Tyrosylprotein kinase of wherein said somatomedin-mediation are platelet derived growth factor (PDGF).
18, the method for claim 16, the Tyrosylprotein kinase of wherein said somatomedin-mediation are fibroblast growth factor (FGF).
19, treatment suffers from the method by the curee of vascular smooth muscle cell proliferation associated diseases, comprises the compound that is selected from claim 1 of described curee being given to treat significant quantity.
20, treatment suffers from the curee's of cancer method, comprises the compound that is selected from claim 1 of described curee being given to treat significant quantity.
21, treatment suffers from the curee's of cancer method, is selected from mammary cancer, large cell carcinoma, pancreas, colon, melanoma, lung and leukemia, and this method comprises the compound that is selected from claim 1 of described curee being given to treat significant quantity.
CN01804048A 2000-01-25 2001-01-23 Byrido [2,3-d] pyrimidine-2, 7-diamine kinase inhibitors Pending CN1395578A (en)

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