Bicyclic Pyrimidines and Bicyclic 3,4-Dihydropyrimidines as Inhibitors of Cellular Proliferation

专利摘要:
The present invention provides bicyclic heterocycles useful for treating cancer and restenosis as well as cell proliferative diseases such as angiogenesis and atherosclerosis. We have found a group of bicyclic compounds that are potent inhibitors of cyclin-dependent kinases (cdk), growth factor-mediated kinases, and non-receptor kinases. The compound is easy to synthesize, can be administered by various routes including oral, and has sufficient bioavailability when used clinically. The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. <Formula I> In the above formula, Z is N or CH, G is N or CH, W is NH, S, SO or SO 2 , R 1 includes phenyl and substituted phenyl, R 2 includes alkyl and cycloalkyl, R 3 includes alkyl and hydrogen, R 8 and R 9 include hydrogen and alkyl.
公开号:KR20010043829A
申请号:KR1020007013279
申请日:1999-05-10
公开日:2001-05-25
发明作者:엘렌 마이라 도브러신；제임스 마리노 햄바이；제임스 버나드 크라머；멜 콘라드 쉬로더；하워드 대니얼 홀리스 쇼왈터；피터 투굿；수전 에이. 트럼프-칼메이어
申请人:로즈 암스트롱, 크리스틴 에이. 트러트웨인；워너-램버트 캄파니；
IPC主号:

专利说明:

Bicyclic Pyrimidines and Bicyclic 3,4-Dihydropyrimidines as Inhibitors of Cellular Proliferation}
Cell cycle kinases are natural enzymes involved in the regulation of the cell cycle (Meijer L., "Chemical Inhibitors of Cyclin-Dependent Kinases", Progress in Cell Cycle Research, 1995; 1: 351-363). Representative enzymes include cyclin-dependent kinases (cdk) cdk1 (also known as cdc2), cdk2, cdk4, cdk5, cdk6, and wee-1 kinases. Increased activity or transient aberrant activity of these kinases has been shown to cause the development of human tumors and other proliferative diseases such as restenosis. Compounds that inhibit cdk by blocking the interaction between cyclin and its kinase partners or by binding to and inactivating kinases inhibit cell proliferation and are therefore useful for the treatment of tumors or other abnormal cell proliferation.
Some compounds that inhibit cdk have demonstrated both antitumor activity before and after the clinic. For example, flavopyridols are flavonoids that have been found to be potent inhibitors for some types of breast and lung cancer cells [Kaur, et al., J. Natl. Cancer Inst., 1992; 84: 1736-1740; Int. J. Oncol., 1996; 9: 1143-1168. This compound is known to inhibit cdk2 and cdk4. Olomoucine [2- (hydroxyethylamine) -6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 and is described in Veesely, et al., Eur. J. Biochem, 1994; 224: 771-786, known to inhibit the proliferation of about 60 different human tumor cell lines used by the National Cancer Institute (NCI), which examines new cancer therapies [Abraham , et al., Biology of the Cell, 1995; 83; 105-120.
Tyrosine kinases are also enzymes that catalyze the transfer of terminal phosphates of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. Tyrosine kinases are an integral part of growth factor receptors and are essential for the propagation of growth factor signal transduction that results in cell proliferation, differentiation and migration. Growth factor receptors are also known as receptor tyrosine kinases (RTKs). Deviation regulation of growth factors or their cognate receptors plays an important role in the development of proliferative diseases. For example, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are included as important mediators of tumor advanced angiogenesis. Solid tumors rely on new angiogenesis (angiogenesis) to obtain growth nutrients from existing blood vessels and provide metastatic conduits. Thus, inhibitors of FGF and VEGF RTK as well as other tyrosine kinases are useful reagents for the prevention and treatment of such enzyme dependent proliferative diseases.
Despite the progress made so far, it is orally bioavailable and used to treat various human tumors and other proliferative diseases such as restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesion, macular degeneration, and atherosclerosis. Research into useful small molecular weight compounds has continued.
<Summary of invention>
The present invention provides bicyclic heterocycles useful for the treatment of cell proliferative diseases such as cancer, atherosclerosis, restenosis, angiogenesis, diabetic retinopathy, psoriasis, and endometriosis. We have found a group of bicyclic pyrimidine analogs that are potent inhibitors of cyclin-dependent kinases (cdk) and tyrosine kinases. The compounds are easy to synthesize, can be administered by a variety of routes including oral and parenteral and have little or no toxicity.
The compounds of the present invention are the compounds of formula I and their pharmaceutically acceptable salts.
In the above formula,
The dotted line represents any double bond;
Z is N or CH;
G is N or CH;
W is NH, S, SO, or SO ₂ ;
X is O, S, or NR ¹⁰ ;
R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
In a preferred embodiment, the present invention provides compounds of II, III, and IV in chemistry.
Wherein R ¹ , R ² , R ³ , W, R ⁸ , and R ⁹ are as defined above.
Further preferred compounds are those of the above formula, wherein W is NH. Preferred compounds are also compounds wherein R ¹ is substituted alkyl, phenyl, or pyridyl.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds within the scope of the present invention are inhibitors of cyclin-dependent kinases such as cdk2, cdc2, and cdk4. In addition, some of the compounds of the present invention are growth factor-mediated tyrosine kinases, including but not limited to c-Src, including platelet derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). Inhibits receptor tyrosine kinase. As inhibitors of cyclin-dependent as well as growth factor-mediated and non-receptor tyrosine kinases, the compounds of the present invention may be used for the vascular smooth muscle cell proliferation associated with cancer, psoriasis, and atherosclerosis, diabetic retinopathy and angiogenesis, postoperative It is useful for the control of proliferative diseases such as vascular stenosis and restenosis.
A further embodiment of the invention is a method of treating a subject suffering from a disease due to cell proliferation. This method inhibits proliferation and vascular smooth muscle proliferation, and / or cell migration of tumorigenic cells of epithelial origin by administering a therapeutically effective amount of a compound of formula I to a subject in need thereof.
A further embodiment of the invention is a method of treating a subject having a disease caused by a DNA tumor virus, such as herpes virus.
The present invention relates to a bicyclic heterocycle that inhibits cyclin-dependent kinase and tyrosine kinase enzymes and can be used as is for the treatment of cell proliferative diseases such as angiogenesis, atherosclerosis, restenosis, and cancer.
We have discovered a new class of compounds that are potent inhibitors of cyclin-dependent kinases (cdk) and tyrosine kinases and are useful for treating subjects suffering from diseases caused by abnormal cell proliferation. Compounds within the scope of the present invention are inhibitors of cyclin-dependent kinases such as cdc2, cdk2, and cdk4, and tyrosine kinases such as PDGF _r , FGF _r , and c-Src. As inhibitors of these kinases, the compounds of the present invention are useful for the control of proliferative diseases such as cancer, psoriasis, and atherosclerosis, postoperative vascular stenosis and angiogenesis, diabetic retinopathy, and vascular smooth muscle proliferation associated with restenosis. Do.
Compounds of the present invention include the compounds of formula I and their pharmaceutically acceptable salts.
<Formula I>

In the above formula,
The dotted line represents any double bond;
Z is N or CH;
G is N or CH;
W is NH, S, SO, or SO ₂ ;
X is O, S, or NR ¹⁰ ;
R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
Particularly preferred group of compounds of formula (I) are those wherein X is O.
Another preferred group of compounds is that W is NH.
A preferred group of compounds of formula (I) are those wherein X is O or NHR ¹⁰ and R ³ is H or substituted aryl.
Also preferred is a compound of formula (I) wherein both R ⁸ and R ⁹ are hydrogen.
Another preferred group of compounds of Formula (I) are those wherein X is O and R ² is Et, Pr, i-Pr, i-Bu, i-pentyl, or cycloalkyl. A particularly preferred group of compounds is a compound wherein X is O and R ² is cyclopentyl or ethyl.
Another preferred group of compounds of formula (I) are those wherein X is O, W is NH, and R ¹ is alkyl, substituted alkyl, phenyl, or substituted phenyl, pyridyl or substituted pyridyl. Preferred R ¹ substituted phenyl groups include (substituted or unsubstituted) 4-piperidinyl, 4- (2-diethylaminoethoxy), 4-pyrrole, 4-pyrazole, and 4- (4-methyl piperazine-1 -Day) is included. Particularly preferred groups of compounds include those in which X is O and R ¹ is hydroxy, alkoxy, NR ⁴ R ⁵ , or T (CH ₂ ) _m QR ⁴ (where R ⁴ and R ⁵ , T, m, and Q are All of which are as defined above). More preferred groups of compounds are those in which X is O and R ¹ is NR ⁴ R ⁵ or T (CH ₂ ) _m QR ⁴ , wherein R ⁴ and R ⁵ , T, m, and Q are all as defined above. Phenyl substituted by
Another preferred group of compounds of Formula (I) are those wherein X is NH.
More preferred compounds of the invention are pyrimido [4,5-d] pyrimidines of the formula I, wherein Z is N.
Particularly preferred compounds provided by the present invention have the formulas II, III, and IV.
<Formula II>

<Formula III>

<Formula IV>

Wherein R ¹ , R ² , R ³ , W, R ⁸ , R ⁹ , and X are as defined above.
Further preferred compounds have the above formula wherein W is NH. Also preferred is a compound wherein R ¹ is alkyl, substituted phenyl or pyridyl.
Further preferred compounds of the invention are compounds of formula V.
Wherein R ² is as defined above and Ar is phenyl, substituted phenyl, or heteroaryl. Ideally, R ² is alkyl such as ethyl, isopropyl, propyl, butyl, or isopentyl or cycloalkyl such as norbornyl, cyclopentyl, cyclohexyl, or adamantyl. Most preferred Ar groups are phenyl, preferably phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxycarbonylmethyl, carboxy, carboxymethyl, ethoxycar Selected from carbonyl, 2-carboxyethyl, 2-ethoxycarbonylethyl, NR ⁴ R ⁵ , and O (CH ₂ ) _0-6 NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are as defined above Is phenyl substituted with one, two, or three groups. Another preferred Ar group is pyridyl and thiazolyl, for example pyridyl and thiazolyl, optionally substituted with alkyl, halo, phenyl, hydroxyphenyl, or alkoxyphenyl, respectively, for example 3-pyridyl, 2- Thiazolyl.
Other preferred compounds have the general formula (VI).
Wherein alkyl, Ar, aryl, heteroaryl, R ² and X are as defined above. Particularly preferred compounds of formula VI are X is O or NHCOR ⁴ , for example NHCO alkyl and NHCONH alkyl. Preferred aryl groups are phenyl and substituted phenyl. Preferred heteroaryl groups are pyridyl and substituted pyridyl.
Compounds of formula (I), wherein W is S, SO, or SO ₂ , are particularly useful as intermediates to compounds where W is NH, and these compounds also exhibit inhibitory activity against cyclin-dependent kinases and tyrosine kinases.
Unless stated otherwise, the following definitions apply throughout this specification.
"Alkyl" refers to a straight or branched chain hydrocarbon group of 1 to 10 carbon atoms (unless stated otherwise), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl , tert-butyl, n-pentyl, iso-pentyl, n-hexyl and the like.
"Halo" includes fluoro, chloro, bromo and iodo.
"Alkenyl" refers to a straight and branched chain hydrocarbon group having 2 to 10 carbon atoms, having 1 or 2 double bonds, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexene-1 -Yl, 6-octadien-1-yl and the like.
"Alkynyl" refers to a straight and branched chain hydrocarbon group having 2 to 10 carbon atoms, having 1 or 2 triple bonds, including ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, 3,6-octadien-1-yl and the like.
"Cycloalkyl" refers to monocyclic or polycyclic hydros such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl and cyclopentyl Speaks Carbyl. Such groups may be substituted with groups such as hydroxy, keto and the like. Also included are rings in which carbon is replaced by 1 to 3 heteroatoms. Such groups are termed “heterocyclyl” and refer to cycloalkyl groups having one or more heteroatoms selected from O, S, or NR ₂ , such as oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, And morpholine.
"Alkoxy" refers to the above-mentioned alkyl group bonded through oxygen, and examples include methoxy, ethoxy, isopropoxy, tert-butoxy and the like. Alkoxy also refers to polyethers such as —O— (CH ₂ ) ₂ —O—CH ₃ and the like.
An "alkanoyl" group is alkyl, ie C ₁ -C ₉ -C (O)-, linked via carbonyl. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
"Acyl" refers to an alkyl or aryl (Ar) group, ie RC (O)-, bonded via a carbonyl group. For example, acyl includes C ₁ -C ₁₀ alkanoyl, including substituted alkanoyl, wherein the alkyl moiety may be substituted by NR ⁴ R ⁵ or a carboxy or heterocyclic group. Typical acyl groups include acetyl, benzoyl and the like.
The above-mentioned alkyl, alkenyl, alkoxy, and alkynyl groups are preferably NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, phenyl, substituted phenyl, thio C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, hydroxy, carboxy, C ₁ -C ₁₀ alkoxycarbonyl, halo, nitrile, cycloalkyl, and 1-2 hetero selected from nitrogen, substituted nitrogen, oxygen, and sulfur Optionally substituted by 1 to 3 groups selected from 5- or 6-membered carbocyclic rings or heterocyclic rings with atoms. "Substituted nitrogen" refers to nitrogen having C ₁ -C ₁₀ alkyl or (CH ₂ ) _n Ph where n is 0, 1, 2, or 3. Perhalo and polyhalo substitutions are also included.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methylsulfanylmethyl, meth Methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2- (4-methylpi Ferrazinyl) ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanietinyl, 4- (1-piperazinyl) -3- (butynyl), 3-phenyl-5-hexynyl, 3-di Ethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl and the like.
Typical substituted alkoxy groups include 2-aminoethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. This includes.
Examples of substituted alkyl, alkenyl, and alkynyl groups also include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentin-1-yl, 4-morpholinobutyl, 4-tetrahydropyridinylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl and the like Included.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have 4 to 9 ring atoms, of which 1 to 4 are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 to 2 heteroatoms in the 5 or 6 membered aromatic ring. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 2,4,6- Tribromophenyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl, 1-naphthyl, 4,7-dichloro-2-naphthyl, pyrrole, Pyrazole, imidazole, thiazole and the like. Particularly preferred heteroaryl groups are pyridyls.
Preferred Ar groups are phenyl and alkyl, alkoxy, thio, thioalkyl, hydroxy, -COOR ⁷ , amino of the formula -NR ⁴ R ⁵ , CONR ⁴ R ⁵ , and T (CH ₂ ) _m QR ⁴ or T (CH ₂ ) _m CO ₂ R ⁴ [where m is 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, wherein R ⁴ and R ⁵ are as described above and R ⁷ is H, alkyl or substituted alkyl, for example methyl, 2- Aminoethyl, trichloroethyl, diphenylmethyl, etc.). It is phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of Alkyl and alkoxy groups may be substituted as described above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
The compounds of the present invention will be named according to the following positional designations.


Those skilled in the art will recognize that compounds defined by the above formulas may exist in tautomeric forms. For example, the 2-keto compound can be tautomerized with 2-enol as follows when R ² is hydrogen.

Similarly, 2-imino compounds can be tautomerized to 2-amino compounds as follows.

2-thione can be tautomerized with thiols as follows.

All tautomeric forms of compounds of Formulas (I) through (IV) are considered to be within the scope of the present invention and are included.
The compounds of the present invention may exist in solvated forms, including hydrated forms as well as unsolvated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are included within the scope of the present invention.
Compounds of formula (I) may further form pharmaceutically acceptable formulations comprising salts, solvates and N-oxides, such as acid additions and / or basic salts. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All such forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of compounds of formula I include aliphatic mono- and dicarboxylic acids, phenyl-substituted salts as well as salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus, and the like. Salts derived from organic acids such as alkanoic acid, hydroxy alkanoic acid, alkanedioic acid, aromatic acid, aliphatic and aromatic sulfonic acid and the like are included. Thus, such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromide, iodides, Acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suverate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitro Benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also examples include salts of amino acids such as arginate, gluconate, galacturonate and the like (see, eg, Berge, et al., "Pharmaceutical Salts", J. of Pharmaceutical Science, 1977; 66: 1-19).
Acid addition salts of basic compounds are prepared by producing salts in conventional manner by contacting the free base form with a sufficient amount of the desired acid. The free base form can be regenerated by contacting the salt form with the base and separating the free base in conventional manner. The free base form differs somewhat from its individual salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salt is equivalent to the individual free base thereof.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine (e.g., such as Berge et al. See literature).
Base addition salts of acidic compounds are prepared by salt formation in conventional manner by contacting the free acid form with a sufficient amount of the desired base. The free acid form can be regenerated by contacting the salt form with the acid and separating the free acid in conventional manner. The free acid form is somewhat different from its individual salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salt is equivalent to its individual free acid.
Compounds of the invention include cancer (eg, leukemia and lung cancer, breast cancer, prostate cancer, and skin cancers such as melanoma) and other proliferative agents, including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis It is useful for the treatment of diseases. In order to use a compound of the present invention in the treatment of cancer, a cancer patient is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising the compound of the present invention.
Another embodiment of the invention is a method of treating a subject suffering from a disease due to vascular smooth muscle cell proliferation. Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration. The method includes inhibiting vascular smooth muscle cell proliferation, and / or migration by administering an effective amount of a compound of Formula I to a subject in need thereof.
The compounds of the present invention can be formulated and administered in a variety of oral and parenteral dosage forms, including transdermal and rectal administration. Those skilled in the art will recognize that the following dosage forms include, as active ingredients, a compound of formula (I) or a corresponding pharmaceutically acceptable salt or solvate thereof.
Another embodiment of the invention is a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. In preparing pharmaceutical compositions with the compounds of the present invention, the pharmaceutically acceptable carrier may be a solid or a liquid. Solid dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can function as diluents, flavors, binders, preservatives, tablet disintegrants, or capsule forming agents.
In the case of powders, the carrier is a finely divided solid such as talc or starch mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Formulations of the present invention preferably contain from about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Preferred forms for oral use are capsules, which include the formulation of the active ingredient with the encapsulating agent as a carrier to provide a capsule in which the other carrier-containing or -free active ingredient is surrounded and bound by the carrier. Similarly, cachets and narcotic tablets are included. Tablets, powders, capsules, pills, cachets, and glycosides can be used in solid dosage forms suitable for oral administration.
In the preparation of suppositories, low melting waxes such as mixtures of fatty acid glycerides or cocoa butter are first melted and the active ingredient is homogeneously dispersed therein by stirring. The molten homogeneous mixture is then poured into molds of conventional size, cooled and solidified.
Liquid formulations include solutions such as water or water / propylene glycol solutions, suspensions, and emulsions. For parenteral injection, liquid formulations may be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding the desired suitable colorants, flavors, stabilizers and thickeners. Suspension solutions suitable for oral use can be prepared by dispersing the finely divided active component in water and mixing with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.
Also included are solid dosage forms which are converted to liquid dosage forms for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. Waxes, polymers, particulates and the like can be used to prepare sustained release dosage forms. In addition, osmotic pumps can be used to deliver the active compound uniformly over a long period of time.
Pharmaceutical formulations of the invention are preferably in unit dosage form. In this form, the formulation is subdivided into unit dosage forms containing the active ingredient in an appropriate amount. The unit dosage form can be made up of a packaged formulation containing the amount of the formulation, such as packaged tablets, capsules and powders, in a container or ampoule. In addition, the unit dosage form may be a capsule, tablet, casein, or glycosides per se, or may be any suitable number in packaged form.
A therapeutically effective amount of a compound of Formula (I) and / or (II) is typically from about 1 mg to about 100 mg per kg of body weight per day. Typical adult dosages will be from about 50 mg to about 800 mg per day. The amount of active ingredient in the unit dosage form can vary or can be altered or adjusted from about 0.1 mg to about 500 mg, preferably from about 0.5 mg to 100 mg, depending on the particular use and potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired. A subject in need of treatment with a compound of Formula (I) and / or (II) may be administered one or multiple doses of about 1 to about 500 mg per day for 24 hours.
Compounds of the present invention can bind to inhibit the activity of proteins having the ability to phosphorylate other proteins such as cdk, PDGFr, FGFr, c-src, and EGFr-FL. cdk forms a complex with cyclin, which complexes phosphorylates a major protein allowing the cell to progress through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995; 1: 351-363). The compounds of the present invention inhibit such phosphorylation and can therefore be used as antiproliferative agents for the treatment of cancer and / or restenosis and other proliferative diseases.
Because of their inhibitory activity against cdk and other kinases, the compounds of the present invention also become useful research materials for the mechanism of action of these kinases in vitro and in vivo.
Although the form of this invention comprises a preferable embodiment now in this specification, there are many other possibilities. It is not intended to refer to all possible equivalent or detailed forms of the invention. It will be understood that the terminology used herein is for the purpose of description rather than of limitation, and those skilled in the art will recognize that various changes are possible within the spirit or scope of the invention.
The following compounds illustrate certain embodiments provided by the present invention, with the compounds described below being among the preferred embodiments.
1-methyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- On;
1-methyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one ;
1-isopropyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-isopropyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one (exo);
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- {4- [4- (2-amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -1-cyclopentyl-3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one;
1-methyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
1-isopropyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
1-cyclopentyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one (exo);
1-cyclopentyl-7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-methanesulfonyl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-fluoro-3-methyl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-cyclopentyl-7- (4-piperazin-1-yl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro- Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro- Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- (pyridin-4-ylamino) -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one;
3- (2-Chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5-d] pyridine Midin-2 (1H) -one;
3- (2,6-dichloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one;
3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one;
7- [3- (carboxy) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
7- [3- (N-dimethylaminopropyl-carboxamide) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
7- [3- (N-dimethylaminopropyl-carboxamide) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyri Mido [4,5-d] pyrimidin-2 (1H) -one;
7- [3- (carboxy) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- [4- (2-ethylamino-ethoxy) -phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
3- (2,6-dichloro-3-hydroxy-phenyl) -7- [4- (2-ethylamino-ethoxy) -phenylamino] -1-methyl-3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2 (1H) -one;
7- [4- (carboxamide) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine- 2 (1H) -one;
7- [4- (carboxamide) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- (3-hydroxymethyl-phenylamino) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
3- (2,6-dichloro-phenyl) -7- (4-morpholin-4-yl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-7- (4-morpholin-4-yl-phenylamino) -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-3-hydroxy-phenyl) -7- (3-hydroxymethyl-phenylamino) -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- [4- (3-carboxypropyl) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- [4- (3-carboxypropyl) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- [4- (formyl-phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
3- (2,6-dichloro-3-hydroxy-phenyl) -7- [4- (formyl-phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
1-methyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one ( Exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine-2 (1H) -On (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine-2 ( 1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (dimethylamino) piperidin1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H) -one (exo);
7- [4- (4-aminoacetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- {4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -1-cyclopentyl-pyrimido [4,5-d] pyrimidine- 2 (1H) -one;
1-methyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-isopropyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H )-On;
1-cyclopentyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H )-On;
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4, 5-d] pyrimidin-2 (1H) -one (exo);
1-cyclopentyl-7- (4-methylsulfonyl-phenylamino) -pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-fluoro-3-methyl-phenylamino) -pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -1-cyclopentyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-piperazin-1-yl-phenylamino) -pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -pyrimido [4,5-d] pyrimidine- 2 (1H) -one;
7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -1-cycloheptyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (pyridin-4-ylamino) pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1- [7- (4-fluoro-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -3-methyl-urea;
1-isopropyl-3- (7-phenylamino-pyrimido [4,5-d] pyrimidin-2-yl) -urea;
1- {7- [4- (3-aminomethyl-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-isopropyl-urea ;
1-isopropyl-3- [7- (4-piperazin-1-yl-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -urea;
1- {7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-isopropyl-urea;
N- {7- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butyramid ;
N- [7- (4-piperazin-1-yl-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -isobutyramid;
N- {7- [4- (4-acetyl-piperazin-1-yl) phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butyramid;
3-methyl-N- [7- (pyridin-4-ylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -butyramid;
1-isopropyl-3- [7- (pyridin-4-ylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -urea;
N- {7- [4- (3-Aminomethyl-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butyra mid;
3-Methyl-N- {7- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2-yl} -butyramid;
1- {7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-yl} -3 Isopropyl-urea;
1- [7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5- d] pyrimidin-2-yl] -3-ethyl-urea;
1- {3- (2-Chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2-yl} -3-ethyl-urea;
1-tert-butyl-3- [7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyri Mido [4,5-d] pyrimidin-2-yl] -urea;
1-tert-butyl-3- {3- (2-chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) phenylamino] -3,4-di Hydro-pyrimido [4,5-d] pyrimidin-2-yl] -urea;
1-tert-butyl-3- [3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrid Midin-2-yl] -urea;
1- [3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-yl] -3-ethyl-urea;
1-tert-butyl-3- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2-yl] -urea;
1- [3- (2-Chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine- 2-yl] -3-ethyl-urea;
1- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4,5-d] pyri Midin-2-yl] -3-ethyl-urea;
1-tert-butyl-3- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2-yl] -urea;
1- (2-benzyloxyethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine-2 (1H) -one;
1- (thiophen-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine- 2 (1H) -one;
1- (thiophen-2-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
1- (tetrahydrofuran-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
1- (hexa-2,4-dien-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3- d] pyrimidin-2 (1H) -one;
1- (prop-2-yn-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
1- [3- (dimethylamino) prop-1-yl] -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3 -d] pyrimidin-2 (1H) -one;
1- (3-hydroxyprop-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
1- (pyridin-4-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine- 2 (1H) -one;
1- (3,5-dimethylhept-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine-2 (1H )-On;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
3- (2,6-dichloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] Pyrimidin-2 (1H) -one;
3- (2-methyl-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] Pyrimidin-2 (1H) -one;
7- [4- (4-aminoacetyl-piperazin-1-yl) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrido [ 4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (2-benzyloxyethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (thiophen-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (thiophen-2-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (tetrahydrofuran-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (hexa-2,4-dien-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H )-On;
1- (prop-2-yn-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1- [3- (dimethylamino) prop-1-yl] -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 ( 1H) -one;
1- (3-hydroxyprop-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1- (pyridin-4-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (3,5-dimethylhept-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1-cyclopentyl-7- (4-piperazin-1-ylphenylamino) pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (3-aminopyrrolidin-1-yl) phenylamino] -1-cyclopentylpyrido [4,3-d] pyrimidin-2 (1H) -one;
2- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-8H-pyrido [4,3-d] pyrimidin-7-one;
8-cyclopentyl-2- [4- (hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -phenylamino] -8H-pyrido [4,3-d] pyrimidine-7- On;
2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-8H-pyrido [4,3-d] pyrimidin-7-one;
N- {2- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-pyrido [4,3-d] pyrimidin-7-yl} -2, 2-dimethyl-propionamide;
N- {2- {4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -8-cyclopentyl-pyrido [4,3-d] -Pyrimidin-7-yl} -2,2-dimethyl-propionamide;
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- [4- (2-diethylaminoethoxy) phenylamino] -1-isopropyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- (4-diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine -2,4-dione; And
7- (pyridin-4-ylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione.
Compounds of formula I, wherein Z is N or CH, can be prepared according to the synthesis schemes summarized in Schemes 1-3. Although the following schemes often dictate a particular structure, those skilled in the art find that this method is widely applicable to similar compounds of formula I, given the proper consideration of the protection and deprotection of reactive functional groups by standard methods in the art of organic chemistry. You will know. For example, to prevent unwanted side reactions, hydroxy groups typically need to be converted to ethers or esters during chemical reactions at other sites of the molecule. The hydroxy protecting group is easily removed to provide the free hydroxy group. Amino groups and carboxylic acid groups are similarly derivatized to prevent unwanted side reactions. Conventional protecting groups and methods for combining and dividing them are described in Greene and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, (2nd Ed., 1991), McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.
Scheme 1 shows a process for the preparation of bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines of the present invention. This synthesis starts with 4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile or 4-chloro-6- (methylthio) -3-pyridinecarbonitrile which is readily prepared from conventional reactants. Substitution of the 4-chloro group with an amine in a solvent such as tetrahydrofuran (THF) in the presence of a tertiary amine such as triethylamine gives the corresponding 4-amino-2- (methylthio) -5-pyrimidinecarbonitrile or 4 -Amino-6- (methylthio) -3-pyridinecarbonitrile is provided. The amines used may be anhydrides or aqueous solutions with methyl or ethyl amines, or cyclopentylamines. The use of aqueous ammonium hydroxide solution provides the corresponding primary amine at position 4. Reducing the cyano group with a conventional reducing agent such as LAH provides the corresponding aminomethyl analog. Cyclization is achieved by reaction with a reagent such as 1,1'-carbonyldiimidazole (CDI). Oxidation of the methylthio group with an oxidizing agent such as oxaziridine in a solvent such as chloroform at room temperature provides a methyl sulfoxide derivative. Substitution of the sulfoxide with an amine (H ₂ NR ¹ ) forms the corresponding 7-amino-3,4-dihydro-bicyclic pyrimidine. The temperature required for replacement depends on the amine used. Aromatic, secondary, and tertiary amines typically require higher temperatures than primary aliphatic or benzyl amines. When using aromatic amines such as aniline, the reaction is usually carried out with amines as solvents at high temperatures (eg 80-150 ° C.).
Bicyclic 3,4-dihydropyrimidines are readily oxidized upon reaction with oxidizing agents such as potassium tert-butoxide and oxygen to provide the corresponding bicyclic pyrimidines of the present invention.
Scheme 1a illustrates a typical process for the preparation of bicyclic pyrimidines of formula I wherein R ² is H and X is NHR ¹⁰ . Suitably substituted 2-methylthio-5-aminomethyl-4-amino-pyrimidine is first reacted with cyanogen bromide to cyclize to dihydropyrimido pyrimidine. Methylthio groups are oxidized to sulfoxides by reaction with an oxidizing agent such as oxaziridine or perbenzoic acid. The methylsulfoxide moiety is readily replaced by reaction with an amine (R ¹ NH ₂ ) to give 7-amino-3,4-dihydro bicyclic pyrimidine with an amino group in the 2-position. Such dihydro pyrimidines are readily converted to the corresponding aromatic pyrimidines by oxidation using conventional oxidants such as potassium tert-butoxide and oxygen. 2-amino dihydropyrimidines and 2-amino pyrimidines are useful biological agents and also function as intermediates in which 2-amino groups are derivatized by standard methods such as alkylation or acylation, such that X is NHR ¹⁰ , for example It provides a compound of formula (I).
Schemes 1b and 1c describe conventional methods for preparing bicyclic pyrimidines of formula I, wherein G is C. In Scheme 1b, reacting 2-methylthio-4-halo-5-cyano pyrimidine with alkyl malonate in the presence of a base such as sodium hydride provides a pyrimidyl malonate derivative. The reaction of the pyrimidyl malonate intermediate with an alkyl or cycloalkyl halide in the presence of a base such as sodium carbonate or triethylamine allows the insertion of R ² groups such as alkyl and cycloalkyl. 5-cyano groups, such as pyrimidyl malonate intermediates, are easily reacted with a reducing agent to be reduced to amino methyl groups, which then replace one of the alkoxy groups in the malonate moiety to effect ring closure to give the corresponding dihydro pyridopi Limidine is provided. Decarboxylation of the residual malonate carboxyl group is readily carried out by reaction with a base such as alkali hydroxide, giving 2-methylthio-5,6-dihydropyridopyrimidine. The methylthio group is oxidized to sulfoxide and then easily replaced by reaction with an amine (R ¹ NH ₂ ) to provide 2-amino-5,6-dihydropyridopyrimidine. Further oxidation by reaction with alkali metal alkoxides and oxygen Fully aromatic 7-hydroxy-pyridopyrimidine is provided.
Scheme 1c shows a conventional conversion of 7-hydroxy pyridopyrimidine, prepared as mentioned above, to the 7-substituted amino compound of formula I (X = NHR ¹⁰ ). Reacting the 7-hydroxy compound with the phosphorus oxy halide first provides the corresponding 7-halo pyrido pyrimidine. 7-halo groups are readily substituted by reaction with amines such as ammonia to give 7-amino compounds, which are derivatized by standard methods such that X is NHR ¹⁰ , for example Pyridopyrimidine of the formula (I) is provided.
In Scheme 2, R ² is for example H or alkyl such as ethyl Slightly different processes for the preparation of compounds of the invention starting with suitably substituted pyridyl or pyrimidyl aldehydes are described. All reactions in Scheme 2 are carried out by known methods. Condensation of aldehydes with N-substituted amines (H ₂ NR ³ ) provides imine. Imines are reduced to secondary amines, which are converted to the main sulfoxide intermediates after cyclization. Substantially reacting the sulfoxide group with any primary amine is readily replaced by Compounds of the invention are provided.
Preferred groups of the compounds of the invention have the structure of formula (I) wherein R ³ is aryl such as di-, tri-, or tetra-substituted phenyl. They are readily prepared by any of the above methods, for example by reacting suitably substituted aniline with pyridyl or pyrimidyl aldehyde as described in Scheme 2. Conventional anilines that can be used for the reaction are Wherein the substituents are phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxycarbonylmethyl, carboxy, carboxymethyl, ethoxycarbonyl, 2 -Carboxyethyl, 2-ethoxycarbonylethyl, NR ⁴ R ⁵ , and O (CH ₂ ) _0-6 NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are as defined above.
As mentioned above, a preferred group of compounds of the present invention have the structure of formula I, wherein X is NR ¹⁰ as well as X is O. Conventional compounds of the present invention are prepared according to Scheme 3 starting with reduced imines (where R ² is H) described in Scheme 2. As mentioned above, the reduced imine is cyclized by reaction with cyanogen bromide and the 7-methylthio group is oxidized to the corresponding sulfoxide. The methylsulfoxide group is replaced by reaction with a primary amine (H ₂ NR ¹ ), and X is derivatized by NHR ¹⁰ , by derivatization of a 2-amino group by reaction with an alkylating agent or acylating agent (eg alkyl isocyanate or acyl halide). E.g Provided are compounds of the invention of formula (I).
All compounds of the present invention are readily purified by standard methods if desired. Typical purification steps used include chromatography on a solid support such as silica gel or alumina. Elution is usually carried out using conventional solvents such as acetone, ethyl acetate, tetrahydrofuran, ethanol, triethylamine, and mixtures of these solvents. Other purification methods, such as crystallization from conventional solvents such as methanol, ethanol, diethyl ether, ethyl acetate and the like, can likewise be used. Often in such crystallization solvents such as ethanol solvates as well as hydrates are used and all such solvates and hydrates are within the scope of the present invention.
The above detailed reaction schemes are further illustrated by the following detailed examples, which are for illustrative purposes and should not be construed as limiting or limiting the invention in any way. Those skilled in the art will recognize that modifications and variations are possible without departing from the spirit and scope of the invention.
Preparation Examples 1-10 and Examples 1-47 are specific embodiments of conventional schemes shown in Scheme 1 above.
<Production example 1>
4-hydroxy-2- (methylthio) -5-pyrimidinecarbonitrile
To a 5 ° C. solution of 119 g (703 mmol) of ethyl (ethoxymethylene) cyanoacetate just distilled in 800 ml of methanol was added 108 g (599 mmol) of 2-methyl-2-thiosudourea. A sodium methoxide solution prepared by dissolving 35.6 g (1.55 mol) of sodium metal in 800 ml of methanol was added to this mixture. This solution was allowed to warm to room temperature and stirred for 6 hours. After standing overnight, the solvent was removed under reduced pressure, and the residue was dissolved in 1.5 L of water with stirring at 50 ° C., and the solution was filtered hot. The filtrate was acidified to pH 2 with concentrated HCl and left overnight at room temperature. The precipitated product was collected and dried to give 48.3 g (48%) of the title compound which was used directly in the next step.
<Production example 2>
4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile
A mixture of 48.3 g (289 mmol) of 4-hydroxy-2- (methylthio) -5-pyrimidinecarbonitrile and 150 ml of phosphorus oxychloride was heated to reflux for 3 hours. The reaction mixture was cooled to rt, filtered and the filtrate was concentrated to dryness. The residue was partitioned between dichloromethane and ice water. The organic phase was washed with water, dried over magnesium sulfate and concentrated to give a residue, which was diluted with 750 ml of hexane. The stirred mixture was heated to reflux and the hot hexane solution was decanted from the insoluble material. Upon cooling to room temperature, crystals formed which collected 32 g (60%) of the title compound.
<Production example 3>
4- (cyclopentylamino) -2- (methylthio) -5-pyrimidinecarbonitrile
To a 0 ° C. solution of 10.0 g (53.9 mmol) of 4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile in 100 ml of dichloromethane, 9.0 ml (64.6 mmol) of triethylamine were added followed by cyclopentylamine 6.4 ML (64.6 mmol) was added dropwise. The reaction mixture was stored at 0-10 ° C. for 16 h, diluted with 100 mL of hexanes and filtered. The filtrate was chromatographed on silica gel eluting with ethyl acetate / dichloromethane / hexanes 1: 4: 5 to give 4.6 g (36%) of product. The filtered solid containing both the product and triethylamine hydrochloride was resuspended in 50 ml of dichloromethane and chromatographed as above to give 7.2 g (57%) of additional product. Melting point: 119 to 122 ° C.
Calcd for C ₁₁ H ₁₄ N ₄ S: C, 56.38; H, 6.02; N, 23.91.
Found: C, 56.48; H, 5.99; N, 24.12.
<Production example 4>
4- (isopropylamino) -2- (methylthio) -5-pyrimidinecarbonitrile
To a 0 ° C. solution of 20.0 g (107.7 mmol) of 4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile in 200 mL of dichloromethane, 18.0 mL (129.3 mmol) of triethylamine was added, followed by 11.0 ML (129.3 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 30 minutes. The obtained precipitate of triethylamine hydrochloride was filtered off. The filtrate was chromatographed on a single column of silica gel eluting with dichloromethane. Pure fractions were combined, concentrated, suspended in hexanes and filtered to give 13.7 g (61%) of product. The impure fraction containing both product and triethylamine hydrochloride was diluted with ethyl acetate, washed twice with water and once with brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate: hexanes 1: 9 to give 3.6 g (16%) of additional product. Melting point: 121.0 to 122.5 ° C.
Calcd for Ci ₉ H ₁₂ N ₄ S: C, 51.90; H, 5.81; N, 26.90.
Found: C, 51.80; H, 5. 82; N, 26.73.
<Production example 5>
4- (bicyclo [2.2.1] hept-2-ylamino) -2- (methylthio) -5-pyrimidinecarbonitrile (exo)
9.0 mL (64.6 mmol) of triethylamine was added to a 0 ° C. solution of 10.0 g (53.9 mmol) of 4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile in 100 mL of dichloromethane, followed by exo-2-amino. 7.0 ml (59.3 mmol) of norbornane were added dropwise. The reaction mixture was stirred at 0 ° C for 2 h. The obtained precipitate of triethylamine hydrochloride was filtered off. The filtrate was washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was back extracted twice with dichloromethane. The combined organic phases were concentrated and the residue was purified by filtration through a short column of silica gel eluting with dichloromethane to give 8.9 g (64%) of the title compound.
Calcd for C ₁₃ H ₁₆ N ₄ S: C, 59.97; H, 6. 19; N, 21.52.
Found: C, 59.70; H, 6.08; N, 21.41.
<Production example 6>
4- (methylamino) -2- (methylthio) -5-pyrimidinecarbonitrile
Methylamine gas was bubbled through a 5 ° C. solution of 4-chloro-2- (methylthio) -5-pyrimidinecarbonitrile (14.5 g, 78.1 mmol) in 800 mL of diethyl ether for 15 minutes. The reaction mixture was allowed to warm to rt, stopped overnight and filtered. The solid was effectively washed with diethyl ether followed by 50 ml of water and dried to give 12.0 g (81%) of the title compound. Melting point: 189 to 190 ° C.
Calcd for C ₇ H ₈ N ₄ S: C, 46.65; H, 4. 47; N, 31.09.
Found: C, 46.79; H, 4. 60; N, 31.26.
<Production example 7>
5- (aminomethyl) -4- (cyclopentylamino) -2- (methylthio) pyrimidine
5.0 g of 4- (cyclopentylamino) -2- (methylthio) -5-pyrimidinecarbonitrile in 250 ml of tetrahydrofuran in a stirred 0 ° C. suspension of 1.7 g (44.8 mmol) of LAH in 70 ml of tetrahydrofuran 21.3 mmol) was added dropwise. The reaction was allowed to slowly warm up to room temperature overnight. The mixture was cooled back to 0 ° C. and treated with saturated ammonium sulfate solution until no foaming occurred. After stirring for an additional 15 minutes, the gray solid was filtered off and washed four times with hot ethyl acetate. The combined organic washes were concentrated and the residue was chromatographed on silica gel eluting with methanol / hexanes / chloroform 1: 1: 8 to give 4.0 g (79%) of the title compound. Melting point: 58-60 ° C .;
Calcd for C ₁₁ H ₁₈ N ₄ S: C, 55.43; H, 7.61; N, 23.51.
Found: C, 55.45; H, 7.56; N, 23.49.
<Production example 8>
5- (aminomethyl) -4- (isopropylamino) -2- (methylthio) pyrimidine
15.5 g of 4- (isopropylamino) -2- (methylthio) -5-pyrimidinecarbonitrile in 500 ml of tetrahydrofuran in a stirred 0 ° C. suspension of 5.9 g (156.3 mmol) of LAH in 200 ml of tetrahydrofuran ( 74.4 mmol) was added dropwise. The reaction was allowed to slowly warm up to room temperature overnight. The mixture was recooled to 0 ° C. and treated with saturated ammonium sulphate solution until no more foam was present. After stirring for an additional 15 minutes, the gray solid was filtered off and washed six times with hot ethyl acetate. The combined organic washes were concentrated and the residue was eluted with acetonitrile / dichloromethane / triethylamine 60: 38: 2 followed by acetonitrile / dichloromethane / methanol / triethylamine 60: 33: 5: 2. Purification by chromatography on a 15 cm Biotage silica gel column twice gave 12.9 g (82%) of the title compound as a yellow oil.
Mass Spectrum (CI) (m + 1) / z 213.
<Production example 9>
5- (aminomethyl) -4- (bicyclo [2.2.1] hept-2-ylamino) -2- (methylthio) pyrimidine (exo)
To a stirred 0 ° C. suspension of 2.5 g (65.3 mmol) of LAH in 100 ml tetrahydrofuran was added 4- (bicyclo [2.2.1] hept-2-yl-amino) -2- (methylthio) in 375 ml tetrahydrofuran. A solution of 8.5 g (32.6 mmol) of) -5-pyrimidinecarbonitrile was added dropwise. The reaction was slowly warmed to room temperature overnight. The mixture was recooled to 0 ° C. and treated with saturated ammonium sulphate solution until no more foam was present. After stirring for an additional 15 minutes, the gray solid was filtered off and washed four times with hot ethyl acetate. The combined organic washes were concentrated and the residue was purified by chromatography on silica gel eluting with methanol / dichloroform 1: 9 then 2: 8 to give 5.8 g (68%) of the title compound.
Calcd for C ₁₃ H ₂₀ N ₄ S: C, 59.06; H, 7.62; N, 21.19.
Found: C, 58.94; H, 7.86; N, 21.04.
<Production example 10>
5- (aminomethyl) -4- (methylamino) -2- (methylthio) pyrimidine
30.0 g of 4- (methylamino) -2- (methylthio) -5-pyrimidinecarbonitrile in 1.5 L of tetrahydrofuran to a stirred 0 ° C. suspension of 17.0 g (448 mmol) of lithium aluminum hydride in 500 ml of tetrahydrofuran. (166 mmol) was added dropwise. The reaction was allowed to slowly warm up to room temperature overnight. The mixture was recooled to 0 ° C. and treated with saturated ammonium sulfate solution (80-100 mL) until no foaming. After stirring for an additional 15 minutes, the gray solid was filtered off, washed three times with hot tetrahydrofuran and once with hot ethyl acetate. The combined organic washes were concentrated and the residue was chromatographed on silica gel eluting with triethylamine / methanol / chloroform 0.5: 25: 75 to afford the title compound to give 21.6 g (70%) of solidified oil.
Mass spectrum (CI) (m + 1) / z 185.
<Example 1>
1-cyclopentyl-7-methanesulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
1,1′-carbonyldiimidazole in a 0 ° C. solution of 4.2 g (17.6 mmol) of 5- (aminomethyl) -4- (cyclopentylamino) -2- (methylthio) pyrimidine in 100 ml of tetrahydrofuran 3.4 g (21.1 mmol) was added. The solution was stirred at 0 ° C. for 30 min and then heated under mild reflux overnight. The mixture was concentrated to a solid residue, which was stirred for 4 hours as a suspension in chloroform. The powdered solids were combined and dried to give 2.6 g of product contaminated with about 5% imidazole. The filtrate was chromatographed on silica gel eluting with ethyl acetate / dichloromethane 6: 4 to give 1.6 g of product contaminated with about 10% imidazole. A small portion was crystallized from chloroform to give an analytically pure sample of the title compound. Melting point: 179 to 182 ° C.
Calcd for C ₁₂ H ₁₆ N ₄ OS: C, 54.52; H, 6. 10; N, 21.19.
Found: C, 54.42; H, 6. 11; N, 21.29.
<Example 2>
1-isopropyl-7-methanesulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
1,1'-carbonyldiimidazole in a 0 ° C. solution of 12.0 g (56.5 mmol) of 5- (aminomethyl) -4- (isopropylamino) -2- (methylthio) pyrimidine in 300 ml tetrahydrofuran 11.0 g (67.8 mmol) was added. The solution was stirred at 0 ° C. for 30 min and then heated under mild reflux overnight. The mixture was concentrated to a solid residue, which was dissolved in dichloroform and washed twice with 1N HCl, water, saturated solution of sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate and concentrated. The crude solid residue was crystallized from chloroform / hexanes to give 9.7 g (72%) of the title compound. Melting point: 175.0 to 176.5 ° C.
Calcd for C ₁₀ H ₁₄ N ₄ OS: C, 50.40; H, 5.92; N, 23.51.
Found: C, 50.35; H, 5. 90; N, 23.54.
<Example 3>
1-bicyclo [2.2.1] hept-2-yl-7-methanesulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one (exo)
0 ° C. solution of 4.6 g (17.6 mmol) of 5- (aminomethyl) -4- (bicyclo [2.2.1] hept-2-yl-amino) -2- (methylthio) pyrimidine in 100 mL tetrahydrofuran To 3.7 g (22.7 mmol) of 1,1'-carbonyldiimidazole was added. The solution was stirred at 0 ° C. for 30 minutes and at room temperature for 2 hours and then heated under mild reflux for 48 hours. The mixture was diluted with brine and extracted with diethyl ether. The organic phase was concentrated and the residue was purified by chromatography on silica gel eluting with methanol / dichloromethane 5:95 then 10:90 to give 2.2 g (85%) of the title compound. Melting point: 133 to 134 ° C.
Calcd for C ₁₄ H ₁₈ N ₄ OS: C, 57.91; H, 6. 25; N, 19.29.
Found: C, 57.61; H, 6.09; N, 19.12.
<Example 4>
7-methanesulfanyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
1,1'- in a 0 ° C. solution of 21.2 g (152.2 mmol) of 5- (aminomethyl) -4- (methylamino) -2- (methylthio) pyrimidine in 900 ml of tetrahydrofuran and 100 ml of dimethylformamide 3.4 g (21.1 mmol) of carbonyldiimidazole were added. The solution was stirred at 0 ° C. for 1 h and then heated under mild reflux for 10 h. The mixture was cooled, the solids collected, washed with diethyl ether and dried to give 18.6 g (78%) of the title compound. Melting point: 263 to 265 ° C.
Calcd for C ₈ H ₁₀ N ₄ OS: C, 45.70; H, 4.79; N, 26.65; S, 15.25
Found: C, 46.15; H, 4.59; N, 26.62; S, 15.51.
<Example 5>
1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
To a room temperature solution of 3.7 g (14.0 mmol) of 1-cyclopentyl-7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 40 ml of chloroform. 4.4 g (1.8 mmol) of 3-phenyl-2- (phenylsulfonyl) -oxaziridine were added. The reaction mixture was stirred for 3 hours, filtered and washed with chloroform / hexane 1: 1 to give 2.85 g (73%) of the title compound. Melting point: 235-236 ° C. (decomposition).
C ₁₂ H ₁₆ N ₄ O ₂ Calcd for S: C, 51.41; H, 5.75; N, 19.98.
Found: C, 50.43; H, 5.55; N, 19.52.
<Example 6>
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
Room temperature solution of 7.0 g (29.4 mmol) of 1-isopropyl-7-methanesulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 80 mL of dichloroform. To this was added 9.2 g (35.2 mmol) of 3-phenyl-2- (phenylsulfonyl) oxaziridine. The reaction mixture was stirred overnight, diluted with 40 mL of hexane, filtered and washed with chloroform / hexane 1: 1 to afford 6.4 g (85%) of the title compound. Melting point: 218-219 ° C. (decomposition).
Calcd for C ₁₀ H ₁₄ N ₄ 0 ₂ S: C, 47.23; H, 5.55; N, 22.03.
Found: C, 46.88; H, 5.40; N, 21.56.
<Example 7>
1-bicyclo [2.2.1] hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one (exo)
1-bicyclo [2.2.1] hept-2-yl-7-methanesulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 20 ml of chloroform. To 2.0 g (6.9 mmol) of room temperature solution was added 2.1 g (8.3 mmol) of 3-phenyl-2- (phenylsulfonyl) oxaziridine. The reaction mixture was stirred overnight, 200 mg (0.76 mmol) of 3-phenyl-2- (phenylsulfonyl) oxaziridine was added and stirred overnight. The reaction mixture was applied to the column and chromatographed on a 4 × 15 cm Biotage Silica gel column by eluting with a gradient of methanol / chloroform 2:98 followed by 4:96 followed by 8:92 to give the title compound 1.1. g (51%) was obtained. Melting point: 220-222 ° C. (decomposition).
Mass spectrum (CI) (m + 1) / z 307 and 264.
<Example 8>
7-methanesulfinyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
9.0 g (42.8 mmol) of 7-methanesulfanyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 100 ml of chloroform was added to 3 12.5 g (47.8 mmol) of -phenyl-2- (phenylsulfonyl) oxaziridine were added. The reaction mixture was stirred for 6 hours, and further 3.1 g (11.9 mmol) of 3-phenyl-2- (phenylsulfonyl) oxaziridine was added and stirred overnight. The reaction mixture was left at 0 ° C. overnight, filtered and dried in vacuo at 75 ° C. to give a constant weight of 9.7 g (100%) of the title compound. Melting point: 225 to 228 ° C (decomposition).
Mass spectrum (CI) (m + 1) / z 227.
<Example 9>
1-cyclopentyl-7- (4-methoxyphenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
300 mg (1.07 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one, 527 mg of p-anisidine ( 4.28 mmol), and a solution of 1.5 ml of dimethyl sulfoxide were heated at 130 ° C. for 30 minutes, cooled and diluted with ethyl acetate. The mixture was washed three times with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residual solid was washed with chloroform / ethyl acetate / ethanol / triethylamine 9: 1: 0.1: 0.1 followed by chloroform and suspended in 150 ml of chloroform / methanol (7: 3). The suspension was diluted with 20 mL of hexane, stirred for 3 h and filtered to give 88 mg (24%) of the title compound as an off-white powder. Melting point: 247 to 249 ° C. (decomposition).
Calcd for Ci ₈ H ₂₁ N ₅ 0 ₂ : C, 63.70; H, 6. 24; N, 20.63.
Found: C, 63.45; H, 6.04; N, 20.62.
<Example 10>
1-cyclopentyl-7- [4- (piperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
1- (4-aminophenyl) piperidine 377 mg (2.14 mmol), 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( A solution of 300 mg (1.07 mmol) of 1H) -one, 745 mg (3.21 mmol) of camphorsulfonic acid, and 2 ml of p-dioxane was heated to 130 ° C. for 1 hour in a sealed tube. The mixture was cooled down and diluted with chloroform. The solution was washed twice with saturated aqueous sodium bicarbonate and once with aqueous sodium chloride followed by brine. The organic phase was dried over magnesium sulfate and concentrated to leave a dark green residue, which was dissolved in chloroform and chromatographed on silica gel eluting with ethyl acetate / ethanol / triethylamine 9: 1: 0.5. The product fractions were combined and concentrated to leave a residue which was dissolved in chloroform. Most of the chloroform was removed by boiling while diluting the solution with ethyl acetate. After cooling to form crystals, they were collected to give 101 mg (24%) of the title compound. Melting point: 254-277 ° C. (decomposition).
Calcd for C ₂₂ H ₂₈ N ₆ O: C, 67.32; H, 7. 19; N, 21.41.
Found: C, 67.10; H, 7.06; N, 21.58.
<Example 11>
1-cyclopentyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
2.0 g (7.1 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 32 ml of acetonitrile and 1- To 2.7 g (14.3 mmol) of (4-aminophenyl) -4-methylpiperazine was added 2.75 mL (35.7 mmol) of trifluoroacetic acid. The mixture was heated at 85 ° C overnight. The cooled reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution and once with brine. The combined aqueous phases were back extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The dark solid residue was stirred in 30 mL of dichloromethane / ethyl acetate (1: 1) for 2 hours, filtered, washed with ethyl acetate and dried to give 2.3 g (80%) of the title compound. Melting point: 236-239 ° C. (decomposition).
Calcd for C ₂₂ H ₂₉ N ₇ O: C, 64.84; H, 7. 17; N, 24.06.
Found: C, 64.55; H, 7.00; N, 24.00.
General preparation of other 1-cyclopentyl-7- (substituted phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -ones
200 mg (0.71 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 3.2 ml of acetonitrile and substituted aniline To 2 equivalents of solution was added trifluoroacetic acid. The mixture was heated at 85 ° C. overnight, cooled to rt, diluted with ethyl acetate or dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate and concentrated to leave a residue, which was further processed as described above to give a compound of formula (I).
The following specific compounds of the invention were prepared according to the above general methods.
<Example 12>
1-cyclopentyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
Prepared from 222 mg (1.43 mmol) of 1- (4-aminophenyl) -4 (pyrazol-1-yl) piperidine and 165 μl (2.1 mmol) of trifluoroacetic acid. After heating, a heavy precipitate formed. The cooled reaction mixture was diluted with 4 ml of ethyl acetate and filtered. The solid was washed with ethyl acetate and dried to give 275 mg (79%) of the trifluoroacetate salt of the title compound. Melting point: 256-258 ° C. (decomposition).
Calcd for C ₂₂ H ₂₈ N ₆ 0 ₂ C ₂ HF ₃ 0 ₂ : C, 53.99; H, 4.53; N, 20.03.
Found: C, 53.82; H, 4.52; N, 20.05.
<Example 13>
1-cyclopentyl-7- {3-methyl-4- [2- (diethylamino) ethoxy] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -on
Prepared from 317 mg (1.43 mmol) of 3-methyl-4- [2- (diethylamino) -ethoxy] aniline and 165 μl (2.1 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane and stirred for several hours. The solids were combined, washed with ethyl acetate and dried to give 210 mg (67%) of the title compound. Melting point: 175 to 177 ° C.
Calcd for C ₂₄ H ₃₄ N ₆ 0 ₂ : C, 65.73; H, 7.81; N, 19.16.
Found: C, 65.42; H, 7.73; N, 19.17.
<Example 14>
1-cyclopentyl-7- [4- (pyrrole-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
Prepared from 226 mg (1.43 mmol) of 1- (4-aminophenyl) pyrrole and 165 μl (2.1 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane / acetonitrile and stirred for several hours. The solids were combined, washed with ethyl acetate and dried to give 90 mg (32%) of the title compound. Melting point> 200 ° C. (decomposition).
Calcd for C ₂₁ H ₂₂ N ₆ O.0.33 H ₂ O: C, 66.31; H, 6.00; N, 22.09.
Found: C, 66.35; H, 5.92; N, 21.94.
<Example 15>
1-cyclopentyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On
Prepared from 274 mg (1.43 mmol) of 1- (4-aminophenyl) -4-hydroxypiperidine and 330 μl (4.3 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane / acetonitrile and stirred for several hours. The solids were combined, washed with ethyl acetate and dried to give 140 mg (47%) of the title compound. Melting point> 200 ° C. (decomposition).
Calcd for C ₂₂ H ₂₈ N ₆ O ₂ .0.5 H ₂ O: C, 63.29; H, 7.00; N, 20.13.
Found: C, 63.27; H, 6.65; N, 19.99.
<Example 16>
1-cyclopentyl-7- [4- (3-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On
Prepared from 274 mg (1.43 mmol) of 1- (4-aminophenyl) -3-hydroxypiperidine and 330 μl (4.3 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane and stirred for several hours. The solids were combined, washed with ethyl acetate and dried to give 135 mg (42%) of the title compound. Melting point> 200 ° C. (decomposition).
Calcd for C ₂₂ H ₂₈ N ₆ 0 ₂ .0.15 CH ₂ Cl ₂ : C, 63.16; H, 6. 77; N, 19.95.
Found: C, 63.18; H, 6. 66; N, 19.97.
<Example 17>
1-cyclopentyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -on
Prepared from 313 mg (1.43 mmol) of 1- (4-aminophenyl) -4- (dimethylamino) piperidine and 275 μl (3.75 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane and stirred for several hours. The solids were combined, washed with ethyl acetate and dried to give 80 mg (24%) of the title compound. Melting point> 200 ° C. (decomposition).
Calcd for C ₂₄ H ₃₃ N ₇ 0 ₂ .0.23 CH ₂ Cl ₂ : C, 63.95; H, 7.41; N, 21.54.
Found: C, 63.99; H, 7. 38; N, 21.28.
<Example 18>
1-cyclopentyl-7- [4- (3,5-dimethylpiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On
Prepared from 292 mg (1.43 mmol) of 1- (4-aminophenyl) -3,5-dimethylpiperazine and 165 mL (2.1 mmol) of trifluoroacetic acid. The crude residue was purified by chromatography on a 1.2 × 7 cm Biotage silica gel column eluting with acetonitrile / ethyl acetate / methanol / triethylamine 50: 40: 5: 5. The product fractions were combined and concentrated to leave a residue, which was crystallized from dichloromethane / ethyl acetate to give 16 mg (5%) of the title compound. Melting point> 200 ° C. (decomposition).
C ₂₃ H ₃₁ N ₇ O.0.15 CH ₂ Cl ₂ .0.01 Calcd for C ₄ H ₈ O ₂ : C, 64.01; H, 7. 27; N, 22.53.
Found: C, 63.98; H, 7.06; N, 22.60.
<Example 19>
1-cyclopentyl-7- [4- (2-hydroxymethylpiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On
Prepared from 294 mg (1.43 mmol) of 1- (4-aminophenyl) -2-hydroxymethylpiperidine and 330 μl (4.3 mmol) of trifluoroacetic acid. The crude residue was purified by chromatography on a 1.2 × 7 cm Biotage silica gel column eluting with ethyl acetate / dichloromethane 3: 2. The product fractions were combined and concentrated to give 130 mg (43%) of the title compound. Melting point: 200-221 ° C.
Calcd for C ₂₃ H ₃₀ N ₆ 0 ₂ : C, 65.38; H, 7. 16; N, 19.89.
Found: C, 65.13; H, 7. 15; N, 19.87.
<Example 20>
1-cyclopentyl-7- {4- [4- (3-hydroxypropyl) piperidin-1-yl) phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -on
Prepared from 335 mg (1.43 mmol) of 1- (4-aminophenyl) -4- (3-hydroxypropyl) piperidine and 330 μl (4.3 mmol) of trifluoroacetic acid. The crude residue was suspended in ethyl acetate / dichloromethane and stirred for several hours. The solids were combined and crystallized from ethyl acetate / dichloromethane. The impure product was dissolved in ethyl acetate / ethanol / triethylamine 9: 2: 1 and then further purified through a silica gel column eluting with the same solvent to afford 31 mg (10%) of the title compound. Melting point> 230 ° C.
Calcd for C ₂₅ H ₃₄ N ₆ 0 ₂ : C, 65.67; H, 7.51; N, 18.31.
Found: C, 65.50; H, 7. 40; N, 18.30.
<Example 21>
1-cyclopentyl-7- [4- (2-morpholin-1-yl) ethyl) piperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one
Prepared from 500 mg (1.43 mmol) of 1- (4-aminophenyl) -4- (2- (1-morpholine) ethyl)) piperidine and 275 μl (4.3 mmol) trifluoroacetic acid. The crude residue was dissolved in 15 mL of dichloromethane and the solution was concentrated to 5 mL, then diluted with 15 mL of ethyl acetate to precipitate a solid. The suspension was stirred for 2 hours, filtered and washed with ethyl acetate. The brown powder was dissolved in dichloromethane and filtered through a silica gel short column with methanol / chloroform 1: 9. The filtrate was concentrated to a pink powder, which was dissolved in 20 ml of dichloromethane and three drops of methanol. The solution was diluted with 30 ml of ethyl acetate and concentrated to 30 ml under a stream of nitrogen with gentle stirring. The pale powder which precipitated was filtered and dried to give 54 mg (11%) of the title compound. Melting point: 218-220 ° C.
Calcd for C ₂₂ H ₂₈ N ₆ O ₂ .0.1 CH ₂ Cl ₂ .0.1 H ₂ O: C, 65.41; H, 7. 70; N, 19.00.
Found: C, 65.70; H, 7. 74; N, 19.37.
General preparation of 1-isopropyl-7- (substituted phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
Trifluoro in a solution of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one and substituted aniline 2 equivalents in acetonitrile Roacetic acid was added. The mixture was heated at 85 ° C. overnight, cooled to rt, diluted with ethyl acetate or dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate and concentrated to leave a residue, which was further processed as described above to give a compound of formula (I).
The following specific compounds of the invention were prepared according to the above general methods.
<Example 22>
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 400 mg (1.57 mmol), 1- in 6.4 ml of acetonitrile. Prepared from 600 mg (3.14 mmol) of (4-aminophenyl) -4-methylpiperazine and 605 μl (7.85 mmol) of trifluoroacetic acid. The reaction mixture was heated at 85 ° C for 48 h. After operation, the crude residue was triturated in ethyl acetate / dichloromethane and filtered. The solid was redissolved in dichloromethane and ethyl acetate was added to maintain a volume of 5 ml while the solvent was evaporated under a stream of nitrogen. The suspension was filtered and the solid was washed with ethyl acetate / dichloromethane and dried to give 470 mg (78%) of the title compound. Melting point: 234-237 ° C. (decomposition).
C ₂₀ H ₂₇ N ₇ O.0.15 C ₄ H ₈ O ₂ .05 Calcd for CH ₂ Cl ₂ : C, 62.17; H, 7. 15; N, 24.58.
Found: C, 62.01; H, 7.06; N, 24.57.
<Example 23>
7- [4- (4-hydroxypepyridin-1-yl) phenylamino] -1-isopropyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- On
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 200 mg (0.79 mmol), 1- in 3.2 ml of acetonitrile. Prepared from 302 mg (1.57 mmol) of (4-aminophenyl) -4-hydroxypiperidine and 182 μl (2.36 mmol) of trifluoroacetic acid. After operation, the crude residue was triturated in ethyl acetate / dichloromethane and filtered. The filtrate was further concentrated to give a second crystal product. The two products were combined and dried to give 45 mg (13%) of the title compound. Melting point> 120 ° C. (decomposition).
C ₂₀ H ₂₆ N ₆ 0 ₂ .0.3 C ₄ H ₈ 0 _2. Calcd for 0.5 H ₂ O: C, 60.93. H, 7.09; N, 20.11.
Found: C, 60.95; H, 6. 82; N, 20.35.
<Example 24>
7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -1-isopropyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one; Compound with trifluoroacetic acid
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 400 mg (1.57 mmol), 1- in 5 ml of acetonitrile. Prepared from 690 mg (3.14 mmol) of (4-aminophenyl) -4- (dimethylamino) piperidine and 605 μl (7.86 mmol) of trifluoroacetic acid. After heating the reaction mixture overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with 6 ml of ethyl acetate and filtered. The solid was washed twice with ethyl acetate and once with ethyl acetate / dichloromethane and dried to give 389 mg (38%) of the trifluoroacetate salt of the title compound. Melting point: 215-217 ° C. (decomposition).
C ₂₂ H ₃₁ N ₇ O.2.0 C ₂ HF ₃ O ₂ .0.1 C ₄ H ₈ O _2. Calcd for 0.25 H ₂ O: C, 48.72; H, 5. 31; N, 15.06.
Found: C, 48.67; H, 5. 15; N, 15.05.
<Example 25>
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one; Compound with trifluoroacetic acid
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 200 mg (0.79 mmol), 1- in 3.2 ml of acetonitrile. Prepared from 250 mg (1.57 mmol) of (4-aminophenyl) pyrazole and 182 μl (2.36 mmol) of trifluoroacetic acid. After heating the reaction mixture overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with ethyl acetate and filtered. The solid was washed with ethyl acetate and dried to give 315 mg (86%) of the trifluoroacetate salt of the title compound. Melting point: 249 to 252 ° C. (decomposition).
Calcd for Ci ₈ H ₁₉ N ₇ 0C ₂ HF ₃ 0 ₂ : C, 51.84; H, 4. 35; N, 21.16.
Found: C, 51.94; H, 4. 37; N, 21.02.
<Example 26>
1-isopropyl-7- {4- [4- (3- (morpholin-1-yl) propyl) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one
1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 200 mg (0.79 mmol), 1- in 3.2 ml of acetonitrile. Prepared from 477 mg (1.57 mmol) of (4-aminophenyl) -4- (3- (1-morpholine) propyl)) piperidine and 303 μl (3.93 mmol) of trifluoroacetic acid. After operation, the crude residue was triturated in ethyl acetate / dichloromethane and filtered. The solid was washed with ethyl acetate and dried to give 140 mg (33%) of the title compound. Melting point: 203 to 205 ° C (decomposition).
C ₂₇ H ₃₉ N ₇ O ₂ .0.1 C ₄ H ₈ O _2. Calcd for 0.25 H ₂ O: C, 64.92; H, 8.01; N, 19.34.
Found: C, 65.14; H, 7.96; N, 19.27.
<Example 27>
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d ] Pyrimidine-2 (1H) -one (exo)
1-bicyclo [2.2.1] hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)-in 4.0 ml of acetonitrile. To a suspension of 300 mg (0.98 mmol) and 374 mg (1.96 mmol) of 1- (4-aminophenyl) -4-methylpiperazine was added 377 μl (4.90 mmol) of trifluoroacetic acid. The mixture was heated at 85 ° C overnight. The cooled reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate and concentrated. The dark solid residue was triturated in 4 mL of dichloromethane / ethyl acetate 1: 1, filtered, washed with ethyl acetate and dried to give 266 mg (63%) of the title compound. Melting point: 251 to 254 ° C. (decomposition).
Calcd for C ₂₄ H ₃₁ N ₇ O: C, 66.49; H, 7. 21; N, 22.61.
Found: C, 66.14; H, 7. 16; N, 22.22.
<Example 28>
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one; Compound with trifluoroacetic acid
300 mg (1.32 mmol) and 1- (7-methanesulfinyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 5 ml of acetonitrile. To a solution of 507 mg (2.65 mmol) of 4-aminophenyl) -4-methylpiperazine was added 510 μl (6.6 mmol) of trifluoroacetic acid. After heating the reaction mixture to 85 ° C. overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with 2 ml of ethyl acetate and filtered. The solid was washed three times with ethyl acetate / acetonitrile and dried to give 560 mg (84%) of the trifluoroacetate salt of the title compound. Melting point: 234-235 ° C. (decomposition).
C ₁₈ H ₂₃ N ₇ O. 2.0 C ₂ HF ₃ O ₂ calcd for: C, 45.44; H, 4.33; N, 16.77.
Found: C, 45.49; H, 4. 35; N, 16.77.
<Example 29>
7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H)- On; Compound with trifluoroacetic acid
400 mg (1.77 mmol) and 1- (7-methanesulfinyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 6 ml of acetonitrile. To a solution of 680 mg (3.53 mmol) of 4-aminophenyl) -4-hydroxypiperidine was added 408 μl (5.3 mmol) of trifluoroacetic acid. After heating the reaction mixture at 85 ° C. overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with 2 ml of ethyl acetate and filtered. The solid was washed with ethyl acetate and recrystallized from acetonitrile to give 565 mg (51%) of the trifluoroacetate salt of the title compound. Melting point: 228-229 ° C. (decomposition).
C ₁₈ H ₂₂ N ₆ O ₂ .2.0 C ₂ HF ₃ O _2. Calcd for C ₂ H ₃ N: C, 46.23; H, 4. 36; N, 15.72.
Found: C, 46.55; H, 4. 48; N, 15.52.
<Example 30>
7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On; Compound with trifluoroacetic acid
400 mg (1.77 mmol) and 1- (7-methanesulfinyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 6 ml of acetonitrile. To a solution of 775 mg (3.53 mmol) of 4-aminophenyl) -4- (dimethylamino) piperidine was added 680 μl (8.8 mmol) of trifluoroacetic acid. After heating the reaction mixture at 85 ° C. overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with 6 ml of ethyl acetate and filtered. The solid was washed with ethyl acetate and recrystallized from acetonitrile followed by acetonitrile / dichloromethane / trifluoroacetic acid to give 202 mg (17%) of the trifluoroacetate salt of the title compound. Melting point: 190-191 ° C. (decomposition).
C ₂₀ H ₂₇ N ₇ O. 2.0 C ₂ HF ₃ O ₂ .H ₂ O. 0.3 C ₂ H ₃ N. Calcd for 0.2 CH ₂ Cl ₂ : C, 45.39; H, 4.96; N, 15.59.
Found: C, 45.37; H, 5. 12; N, 15.42.
<Example 31>
1-methyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one; Compound with trifluoroacetic acid
200 mg (0.88 mmol) and 1- (7-methanesulfinyl-1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 3.2 ml of acetonitrile. To a solution of 281 mL (1.77 mmol) of 4-aminophenyl) pyrazole, 204 μl (2.65 mmol) of trifluoroacetic acid were added. After heating the reaction mixture at 85 ° C. overnight, a heavy precipitate formed. The cooled reaction mixture was diluted with 2 ml of ethyl acetate and filtered. The solid was washed with ethyl acetate to give 356 mg (93%) of the trifluoroacetate salt of the title compound. Melting point: 250-251 ° C. (decomposition).
Calcd for Ci ₆ H ₁₅ N ₇ 0C ₂ HF ₃ 0 ₂ : C, 49.66; H, 3. 70; N, 22.52.
Found: C, 49.70; H, 3. 60; N, 22.18.
1-alkyl-7-[(substituted) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one of 1-alkyl-7-[(substituted) Method of oxidation to phenylamino] -pyrimido [4,5-d] pyrimidin-2 (1H) -one
Potassium tert in a room temperature solution of 1-alkyl-7-[(substituted) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in THF or DMSO 4 equivalents of butoxide were added. Oxygen air was injected and the solution was stirred overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic phase was dried over magnesium sulfate and concentrated to leave a residue which was triturated in a suitable solvent and the precipitated product was collected. Further purification can be carried out by standard methods to afford compounds of formula (I).
<Example 32>
1-cyclopentyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido- [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 in 6 mL THF ( Prepared from 150 mg (0.37 mmol) of 1H) -one and 165 mg (1.47 mmol) of potassium tert-butoxide. The dark orange semisolid was triturated in diethyl ether and the yellow powders were combined and dried to give 100 mg (67%) of the title compound. Melting point: 220-225 ° C. (decomposition).
Calcd for C ₂₂ H ₂₇ N ₇ O: C, 65.16; H, 6.71; N, 24.18.
Found: C, 65.22; H, 6.55; N, 23.78.
<Example 33>
1-cyclopentyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine- in 1.5 mL DMSO- Prepared from 60 mg (0.15 mmol) of 2 (1H) -one and 66 mg (0.58 mmol) of potassium tert-butoxide. The crude semisolid residue was triturated in 15 mL of diethyl ether / hexane (2: 1), and the orange amorphous solid was collected and dried to give 20 mg (30%) of the title compound. Melting point> 185 ° C (decomposition).
MS (CI) (m + 1) / z 407.
<Example 34>
1-cyclopentyl-7- {3-methyl-4- [2- (diethylamino) ethoxy] -phenylamino} pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- {3-methyl-4- [2- (diethylamino) ethoxy] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyridine in 3.0 mL DMSO Prepared from 70 mg (0.16 mmol) of midin-2 (1H) -one and 72 mg (0.58 mmol) of potassium tert-butoxide. The crude semisolid residue was dissolved in a mixture of tert-butyl methyl ether and hexanes. The solution was slowly evaporated to 1 mL and then diluted with 2 mL diethyl ether / hexanes (1: 3). The precipitated solids were collected and dried to give 17 mg (24%) of the title compound. Melting point> 95 ° C. (decomposition).
MS (CI) (m + 1) / z 437 and 232.
<Example 35>
1-cyclopentyl-7- [4- (3-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- [4- (3-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine- in 4.0 mL THF- Prepared from 75 mg (0.18 mmol) of 2 (1H) -one and 82 mg (0.73 mmol) of potassium tert-butoxide. The semisolid residue was triturated in diethyl ether and the orange amorphous solid was collected and dried to give 35 mg (45%) of the title compound. Melting point> 135 ° C. (decomposition).
C ₂₂ H ₂₆ N ₆ O ₂ .0.15 Calcd for C ₂ H ₁₀ O.0.75 H ₂ O: C, 62.96; H, 6. 78; N, 19.49.
Found: C, 62.98; H, 6. 54; N, 19.47.
<Example 36>
1-cyclopentyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)-in 5.0 mL THF- From 100 mg (0.20 mmol) and 115 mg (1.02 mmol) of potassium tert-butoxide. The semisolid residue was triturated in diethyl ether and the orange amorphous solid was collected and dried to give 31 mg (40%) of the title compound. Melting point> 135 ° C. (decomposition).
C ₂₀ H ₁₉ N ₇ O · Calcd for _{0.1 C 2 H 10 O · 0.5} H 2 O: C, 62.85; H, 5. 43; N, 25.15.
Found: C, 63.09; H, 5. 30; N, 25.04.
<Example 37>
1-cyclopentyl-7- (4-methoxyphenylamino) pyrimido [4,5-d] pyrimidin-2 (1H) -one
By reacting 1-cyclopentyl-7- (4-methoxyphenylamino) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one according to the general method described above The title compound was obtained.
MS (CI) (m + 1) / z 338.
<Example 38>
1-cyclopentyl-7- [4- (piperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-cyclopentyl-7- [4- (piperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 according to the general method described above (1H) -one was reacted to give the title compound.
MS (CI) (m + 1) / z 391.
<Example 39>
1-cyclopentyl-7- [4- (2- (morpholin-1-yl) ethyl) piperidin-1-yl) phenylamino] -pyrimido [4,5-d] pyrimidine-2 (1H )-On
1-cyclopentyl-7- [4- (2- (morpholin-1-yl) ethyl) piperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4 in 2.0 mL THF , 5-d] pyrimidin-2 (1H) -one was prepared from 37 mg (0.07 mmol) and 33 mg (0.29 mmol) of potassium tert-butoxide. The semisolid residue was triturated in diethyl ether and the orange amorphous solid was collected and dried to give 11.8 mg (32%) of the title compound. Melting point> 140 ° C. (decomposition).
MS (CI) (m + a) / z 504.
<Example 40>
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine- in 10 ml of tetrahydrofuran- Prepared from 2 (1H) -one 200 mg (0.52 mmol) and potassium tert-butoxide 235 mg (2.10 mmol). The semisolid was triturated in 14 ml of diethyl ether / hexane (1: 1) and the powders were combined and dried to give 135 mg (68%) of the title compound. Melting point: 228-229 ° C. (decomposition).
Calcd for C ₂₀ H ₂₅ N ₇ 0 .0.03 C ₆ H ₁₄ .0.5 H ₂ 0: C, 61.98; H, 6.81; N, 25.07.
Found: C, 61.95; H, 6.73; N, 25.04.
<Example 41>
7- {4- [4- (dimethylamino) piperidin-1-yl) phenylamino} -1-isopropyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one
7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino] -1-isopropyl-3,4-dihydro-pyrimido [4,5-d in 7 ml tetrahydrofuran ] Prepared from 200 mg (0.31 mmol) of pyrimidin-2 (1H) -one, 211 mg (1.88 mmol) of trifluoroacetic acid and potassium tert-butoxide. The reaction mixture was stirred for 48 hours, the operation was carried out as described in the general method and then the reaction was repeated for 72 hours. After working, the semisolid was triturated in diethyl ether, the powders were combined and dried to give 24 mg (18%) of the title compound. Melting point> 100 ° C. (decomposition).
Calcd for C ₂₂ H ₂₉ N ₇ 0H ₂ 0 0.1 CH ₂ Cl ₂ : C, 61.16; H, 7. 25; N, 22.59.
Found: C, 61.11; H, 6.98; N, 22.49.
<Example 42>
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H in 10 mL tetrahydrofuran) Prepared from 150 mg (0.32 mmol) of tri-acetic acid and 218 mg (1.94 mmol) of potassium tert-butoxide. The reaction mixture was stirred for 48 hours, 50 mg (0.44 mmol) of potassium tert-butoxide were added and the reaction continued for 72 hours. After working, the semisolid was triturated in diethyl ether, the powders were collected and dried to give 86 mg (73%) of the title compound. Melting point: 243 to 247 ° C. (decomposition).
C ₁₈ H ₁₇ N ₇ O. 0.75 H ₂ O. 0.15 Calcd for C ₄ H ₁₀ O: C, 60.05; H, 5. 42; N, 26.36.
Found: C, 60.19; H, 5. 36; N, 26.09.
<Example 43>
1-isopropyl-7- {4- [4- (3- (morpholin-4-yl) propyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H) -on
1-isopropyl-7- {4- [4- (3- (morpholin-4-yl) propyl) pyridin-1-yl] phenylamino} -3,4-dihydro in 10 ml tetrahydrofuran Prepared from 100 mg (0.20 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one and 88.5 mg (0.79 mmol) of potassium tert-butoxide. The reaction mixture was stirred overnight, 88.5 mg (0.79 mmol) of potassium tert-butoxide was added and the reaction continued for 48 hours. After working, the semisolid was suspended five times in diethyl ether and evaporated to dryness to give 87 mg (85%) of the title compound. Melting point> 95 ° C. (decomposition).
Calcd for C ₁₈ H ₁₇ N ₇ O.0.8 H ₂ O.0.1 C ₄ H ₁₀ O: C, 64.09; H, 7.77; N, 19.10.
Found: C, 64.02; H, 7. 50; N, 19.08.
<Example 44>
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine-2 (1H) -ON, EXO
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido in 10 ml tetrahydrofuran Prepared from [4,5-d] pyrimidin-2 (1H) -one, exo 200 mg (0.46 mmol), and 207 mg (1.84 mmol) of potassium tert-butoxide. The reaction mixture was stirred for 48 hours. After operation, the semisolid was triturated in diethyl ether / hexanes, the powders were combined and dried to give 140 mg (70%) of the title compound. Melting point> 210 ° C. (decomposition).
Calcd for C ₂₄ H ₂₉ N ₇ 0.0.5 H ₂ O: C, 65.43; H, 6. 86; N, 22.26.
Found: C, 65.29; H, 6. 74; N, 21.90.
<Example 45>
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 in 12 ml tetrahydrofuran Prepared from 250 mg (0.50 mmol) of (1H) -one, 336 mg (2.99 mmol) of trifluoroacetic acid and potassium tert-butoxide. The reaction mixture was stirred for 48 hours. After working, the semisolid was triturated in diethyl ether, the powders were combined and dried to give 110 mg (61%) of the title compound. Melting point: 259-260 ° C. (decomposition).
Calcd for C ₁₈ H ₂₁ N ₇ O.0.4 H ₂ O: C, 60.29; H, 6. 13; N, 27.34.
Found: C, 60.54; H, 5.99; N, 27.05.
<Example 46>
7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -1-methyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one
7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -1-methyl-3,4-dihydro-pyrimido [4,5-d] in 20 mL tetrahydrofuran Prepared from 170 mg (0.26 mmol) of pyrimidin-2 (1H) -one, 233 mg (2.07 mmol) of trifluoroacetic acid and potassium tert-butoxide. After the reaction mixture was stirred for 6 days, the operation was carried out as described in the general method, including back extracting the combined aqueous phases with chloroform. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The semisolid was triturated in diethyl ether / hexanes and the powders were combined and dried to give 64 mg (60%) of the title compound. Melting point: 198-202 ° C. (decomposition).
Calcd for C ₂₀ H ₂₅ N ₇ O.1.7 H ₂ O: C, 58.58. H, 6.98; N, 23.91.
Found: C, 58.73; H, 6.71; N, 23.92.
<Example 47>
1-methyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one
1-methyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) in 15 ml of tetrahydrofuran Prepared from 200 mg (0.46 mmol), trifluoroacetic acid and 309 mg (2.76 mmol) of potassium tert-butoxide. The reaction mixture was stirred overnight. After working, the semisolid was triturated in diethyl ether, the powders were combined and dried to give 102 mg (65%) of the title compound. Melting point> 290 ° C (decomposition).
C ₁₆ H ₁₃ N ₇ O. 0.4 H ₂ O. 0.2 Calcd for C ₄ H ₁₀ O: C, 59.11. H, 4.67; N, 28.72.
Found: C, 59.42; H, 4. 39; N, 28.46.
Examples 48-65 are specific embodiments of the general scheme shown in Scheme 2.
<Example 48>
5-[(3,5-Dimethoxy-phenylimino) -methyl] -2-methylsulfanyl-pyrimidin-4-ylamine
4.36 g (23.7 mmol) and 3,5-dimethoxyaniline 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (prepared as described in WO 98/33798) in 165 ml of water To 3.65 g (23.7 mmol) of suspension 4.5 ml of glacial acetic acid was added. The reaction was stirred at 25 ° C. overnight and filtered. The filter pad was washed with water and the filtrate was dried in vacuo to give 7.02 g (96%) of the title compound which was used for the next step.
MS (APCI) (m + 1) / z 305.1.
<Example 48a>
{5-[(3,5-Dimethoxy-phenylimino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine
4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (5.0 g, 25.09 mmol, in J. Med. Chem., 1998: 41 (17): 3276-3292 in water (190 mL) 5 ml of glacial acetic acid was added to a stirred suspension of 3,5-dimethoxyaniline (3.84 g, 25.09 mmol). The reaction mixture was stirred at ambient temperature for 24 hours and the suspension was filtered. The insoluble product was dried on a filter to give 7.79 g (92%) of the title compound. Melting point: 100-105 ° C.
Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ O, probe = 450 ° C.) (M + 1) / z 333.1.
Calcd for C ₁₆ H ₂₀ N ₄ 0 ₂ S ₁ : C, 57.81; H, 6.06; N, 16.85.
Found: C, 57.63; H, 6.06; N, 16.86.
<Example 49>
5-[(3,5-Dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-ylamine
18.2 mL (18.2 mmol) of a 1 M lithium aluminum hydride (LAH) solution in tetrahydrofuran cooled to 5 ° C., 5-[(3,5-dimethoxy-phenylamino) -methyl] -2-methyl in 94 mL of dry THF A solution of 5.55 g (18.3 mmol) of sulfanyl-pyrimidin-4-ylamine was added for 20 minutes. The reaction was stirred at 5 ° C. for 1.5 h, then quenched by the slow addition of 0.72 ml of water, 3.0 ml of 25% NaOH, and 1.66 ml of additional water in order. The reaction mixture was filtered through Celite and the filter pad was washed well with THF. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed three times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 5.10 g (91%) of the title compound.
Calcd for _{C 14 H 18 N 4 O 2} S: C, 54.88; H, 5.92; N, 18.29; S, 10.47.
Found: C, 54.92; H, 5.93; N, 18.32; S, 10.68.
<Example 49a>
{5- [4- (3,5-Dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine
{5-[(3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine (5.91 g, in dry THF (100 mL) at 5 ° C. 17.78 mL) of a 1 M solution of LAH in THF was added dropwise for 20 minutes. The reaction mixture was stirred at 5 ° C. for 1 hour and then quenched by dropwise addition of 0.8 ml of water, 3.2 ml of 25% NaOH, and 1.8 ml of water. The reaction mixture was partitioned between 1/2 saturated brine and EtOAc. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with a 1% to 3% methanol solvent gradient in dichloromethane to give 5.4 g (91%) of the title compound. Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ O, probe = 450 ° C.) (M + 1) / z 335.2.
Calcd for C ₁₆ H ₂₂ N ₄ 0 ₂ S ₁ : C, 57.46; H, 6.63; N, 16.75.
Found: C, 57.75; H, 6. 62; N, 16.52.
<Example 50>
3- (3,5-Dimethoxy-phenyl) -7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
A solution of 5.0 g (16.3 mmol) of 5-[(3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-ylamine in 55 ml of dimethylformamide cooled to 5 ° C. To this was added 1.63 g (40.8 mmol) of sodium hydride as a 60% mineral oil suspension. The ice bath was removed and the reaction stirred for 1 hour. Then, 7.94 g (48.9 mmol) of 1,1'-carbonylimidazole was added to the reaction. After the mixture was stirred for an additional 2.5 hours, the mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated solution of ammonium chloride. The dichloromethane layer was washed twice with saturated solutions of saturated sodium chloride, water and sodium chloride, respectively. The dichloromethane solution was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform / methanol (10: 0.25 v / v) to give 3.24 g (60%) of the title compound.
MS (APCI) (m + 1) / z 333.2.
<Example 50a>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
{5- [4- (3,5-Dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine (6.42) in dichloromethane (120 mL) at 5 ° C. g, 19.2 mmol) and diisopropylethylamine (4.96 g, 38.39 mmol) were added dropwise for 10 minutes with 10 ml of a 20% solution of phosgene in toluene. The reaction mixture was warmed to ambient temperature and stirred for 4 hours. The mixture was washed with 1/2 saturated NaHCO ₃ and water, then dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography eluting with a solvent gradient of 1% to 3% methanol in dichloromethane to give 5.96 g (86%) of the title compound. Melting point: 134 to 136 ° C. Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ O, probe = 450 ° C.) (M + 1) / z 361.2.
Calcd for C ₁₇ H ₂₀ N ₄ 0 ₃ S: C, 56.65; H, 5.59; N, 15.54.
Found: C, 56.49; H, 5.54; N, 15.33.
<Example 51>
3- (3,5-Dimethoxy-phenyl) -7-methylsulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
2.0 g of 3- (3,5-dimethoxy-phenyl) -7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 450 ml of chloroform To a solution of (6.02 mmol) was added 1.73 g (6.62 mmol) of trans-2- (phenylsulfonyl) -3-phenyloxaziridine. The reaction was stirred at rt overnight then concentrated in vacuo. The residue was eluted with chloroform and chromatographed on silica gel eluting with chloroform / methanol (10: 0.25 v / v) solution, finally with chloroform / methanol (9: 1 v / v) to give 1.87 g (85) of the title compound. %) Was obtained. Melting point: 220-222 ° C.
C ₁₅ H ₁₆ N ₄ O ₄ S.0.30 H ₂ O.0.10 Calcd for ₃ : C, 49.59; H, 4. 60; N, 15.32; S, 8.77; H ₂ O, 1.48.
Found: C, 49.62; H, 4. 34; N, 15.20; S, 8.87; H ₂ O, 1.42.
<Example 51a>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one
3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methylsulfanyl-3,4-pyrimido [4,5-d] pyrimidine-2 in dichloromethane (100 mL) at ambient temperature 3-phenyl-2- (phenylsulfonyl) oxaziridine (4.88 g, 18.69 mmol, PD 0191006, [Org. Synth., 1987; 66: 203] in a solution of (1H) -one (5.61 g, 15.57 mmol) -210] were added in portions. The reaction mixture was stirred overnight and then washed with brine and water. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a solvent mixture of 3% methanol in dichloromethane to give 4.6 g (78%) of the title compound. Melting point: 167-169 ° C.
Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ 0, probe = 450 ° C.) (M + 1) / z 377.1.
Calcd for C ₁₇ H ₂₀ N ₄ 0 ₃ S: C, 54.24; H, 5. 36; N, 14.88.
Found: C, 53.95; H, 5. 27; N, 14.51.
<Example 52>
7- (4-Diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- On
0.2261 g of 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-pyrimido [4,5-d] pyrimidin-2 (1H) -one in 10 ml of dry dioxane ( 0.65 mmol) and 0.103 g (0.71 mmol) of diethylaminobutylamine were warmed to 60 ° C. and stirred overnight. 0.306 g (2.13 mmol) of diethylaminobutylamine and 0.1658 g (0.71 mmol) of camphorsulfonic acid were added to the reaction mixture. The reaction mixture was stirred at 60 ° C. for an additional 18 hours. The reaction solution was concentrated in vacuo and the residue was partitioned between saturated solution of ethyl acetate and sodium bicarbonate. The ethyl acetate layer was washed with a saturated solution of sodium bicarbonate followed by water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to give 0.173 g (62%) of the title compound. Melting point: 203 to 207 ° C.
Calcd for C ₂₂ H ₃₂ N ₆ 0 ₃ : C, 61.66; H, 7.53; N, 19.61.
Found: C, 61.31; H, 7. 32; N, 19.23.
<Example 53>
7- (4-diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -on
3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 in acetonitrile (6 mL) A mixture of (1H) -one (0.5 g, 1.33 mmol), 4-diethylaminobutylamine (0.38 g, 2.66 mmol), and trifluuroacetic acid (0.31 g, 2.66 mmol) at 90 ° C. in a sealed tube Heated for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 1N HCl. The solution was made basic with 50% NaOH and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by radial chromatography eluting with a solvent mixture of ethyl acetate / methanol / ethyl (89: 10: 1 v / v / v) to give 0.34 g (56%) of the title compound. Melting point: 83 to 85 ° C.
Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ O, probe = 450 ° C.) (M + 1) / z 458.2.
Calcd for C ₂₄ H ₃₆ N ₆ 0 ₃ : C, 63.13; H, 7.95; N, 8.41.
Found: C, 62.85; H, 7. 84; N, 18.06.
<Example 53a>
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one
3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 in acetonitrile (6 mL) (1H) -one (0.5 g, 1.33 mmol), 4- (2-diethylaminoethoxy) aniline (0.55 g, 2.66 mmol, Helv. Chim. Acta, 1960; 43: 1971-1979) and tree A mixture of fluoroacetic acid (0.46 g, 3.98 mmol) was heated at 100 ° C. for 18 hours in a sealed tube. The solvent was removed under reduced pressure and the residue was dissolved in water. The solution was made basic with 1N NaOH and extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was suspended in ether (20 mL), triethylamine (0.27 g, 2.66 mmol), and BOC ₂ O (0.32 g, 1.46 mmol) were added and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with hexanes and cooled to 0 ° C. The insoluble product was collected by filtration and washed with hexane to give 0.56 g (81%) of the title compound. Melting point: 139 to 141 ° C.
Mass spectrum (APCI, 80/20 CH ₃ CN / H ₂ O, probe = 450 ° C) (m + 1) / z 521.3
Calcd for C ₂₈ H ₃₆ N ₆ 0 ₄ 0.19 CF ₃ CO ₂ H: C, 62.86; H, 6.73; N, 15.50.
Found: C, 62.85; H, 6.65; N, 15.56.
3-aryl-7- (substituted alkylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one and 3-aryl-1-alkyl-7- ( General experiment for the parallel synthesis of substituted alkylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -ones
Argonaut Technologies' Quest 210 in a 10 ml reactor in 3-ml (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido in 5 ml of dry dioxane 0.100 g (0.287 mmol) of [4,5-d] pyrimidin-2 (1H) -one or 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methane in 4 ml of dry dioxane 0.100 g (0.266 mmol) of finyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one and 0.0753 g (0.3157 mmol) of camphorsulfonic acid in 2 ml of dry dioxane. Added. To the reaction mixture was added a solution of 2.7-3.3 equivalents of amine (R ¹ NH ₂ ) in ¹ ml of dioxane. The reaction mixture was shaken at 65 ° C. for 18 hours and then cooled to room temperature. Dioxane was evaporated under a stream of nitrogen and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed twice with a dilute solution of sodium bicarbonate and then once with water. The ethyl acetate layer was dried over magnesium sulfate and concentrated to dryness using a nitrogen stream. The residue was subjected to silica gel chromatography to give the title compound.
<Example 54>
3- (3,5-Dimethoxy-phenyl) -7- {2-[(pyridin-4-ylmethyl) -amino] -ethylamino} -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one
Using this general method, 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- One was reacted with 0.1423 g (0.941 mmol) of N- (4-picoli) ethylenediamine. Chromatography eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) followed by ethyl acetate / ethanol / triethylamine (9: 3: 2 v / v / v) This gave 0.0162 g (13%) of the title compound. HPLC = 92% pure.
MS (APCI) (m + 1) / z 436.2.
<Example 54a>
3- (3,5-Dimethoxy-phenyl) -7- [3- (4-methyl-piperazin-1-yl) -propylamino] -3,4-dihydro-1H-pyrimido [4,5 -d] pyrimidin-2 (1H) -one
Using this general method, 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- One was reacted with 0.1234 g (0.785 mmol) of 3- (4-methyl-piperazin-1-yl) -propylamine. The residue was eluted with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) followed by ethyl acetate / ethanol / triethylamine (9: 3: 2 v / v / v). Phase chromatography gave 0.0443 g (35%) of the title compound. HPLC = 92% pure.
MS (APCI) (m + 1) / z 442.2.
<Example 54b>
3- (3,5-Dimethoxy-phenyl) -7- [4- (4-methyl-piperazin-1-yl) -butylamino] -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one
Using this general method, 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- One and 0.1354 g (0.791 mmol) of 4- (4-methyl-piperazin-1-yl) -butylamine were reacted. The residue was eluted with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) followed by ethyl acetate / ethanol / triethylamine (9: 3: 2 v / v / v). Phase chromatography gave 0.0401 g (31%) of the title compound. HPLC = 99% pure.
MS (APCI) (m + 1) / z 456.2.
<Example 54c>
3- (3,5-Dimethoxy-phenyl) -7- [5- (4-methyl-piperazin-1-yl) -pentylamino] -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one
Using this general method, 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- One was reacted with 0.1475 g (0.805 mmol) of 5- (4-methyl-piperazin-1-yl) -pentylamine. The residue was eluted with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) followed by ethyl acetate / ethanol / triethylamine (9: 3: 2 v / v / v). Phase chromatography gave 0.0322 g (24%) of the title compound. HPLC = 97% pure.
MS (APCI) (m + 1) / z 470.2.
<Example 55>
7- (3-Diethylamino-propylamino) -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- On
Using this general method, 3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- One and 0.1121 g (0.861 mmol) of diethylaminopropylamine were reacted. The residue was chromatographed eluting with acetonitrile / ethanol / triethylamine (8: 1: 0.5 v / v / v) to afford 0.0476 g (40%) of the title compound. HPLC = 89% pure.
MS (APCI) (m + 1) / z 415.2.
<Example 56>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7- {2-[(pyridin-4-ylmethyl) -amino] -ethylamino} -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one
Using the above general method, 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one and 0.1317 g (0.871 mmol) of N- (4-picolyl) ethylenediamine were reacted. The residue was chromatographed on silica gel eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to afford 0.0307 g (25%) of the title compound. HPLC = 87% pure.
MS (APCI) (m + 1) / z 464.2.
<Example 57>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7- [3- (4-methyl-piperazin-1-yl) -propylamino] -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one
Using the above general method, 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one and 0.1142 g (0.726 mmol) of 3- (4-methyl-piperazin-1-yl) -propylamine were reacted. The residue was chromatographed on silica gel eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to afford 0.0712 g (57%) of the title compound. HPLC = 96% pure.
MS (APCI) (m + 1) / z 470.2.
<Example 58>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7- [4- (4-methyl-piperazin-1-yl) -butylamino] -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one
Using the above general method, 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one and 0.1253 g (0.732 mmol) of 4- (4-methyl-piperazin-1-yl) -butylamine were reacted. The residue was chromatographed on silica gel eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to afford 0.0527 g (41%) of the title compound. HPLC = 94% pure.
MS (APCI) (m + 1) / z 484.3.
<Example 59>
3- (3,5-Dimethoxy-phenyl) -1-ethyl-7- [5- (4-methyl-piperazin-1-yl) -pentylamino] -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one
Using the above general method, 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 0.1365 g (0.745 mmol) of (1H) -one and 5- (4-methyl-piperazin-1-yl) -pentylamine were reacted. The residue was chromatographed on silica gel eluting with ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to afford 0.041 g (31%) of the title compound. HPLC = 98% pure.
MS (APCI) (m + 1) / z 498.3.
<Example 60>
7- (3-diethylamino-propylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -on
Using the above general method, 3- (3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (0H) -one and 0.1038 g (0.797 mmol) of diethylaminopropylamine were reacted. The residue was chromatographed on silica gel eluting with acetonitrile / ethanol / triethylamine (8: 1: 0.5 v / v / v) to afford 0.0719 g (61%) of the title compound. HPLC = 81% pure.
MS (APCI) (m + 1) / z 443.2.
<Production example 11>
2-Chloro-3,5-dimethoxy-benzoic acid
12 g (52.0) 2-chloro-3,5-dimethoxy-benzoic acid methyl ester (prepared according to the method of [TR Kasuri and EM Abraham, Indian Journal of Chemistry, 1973; 11: 1099-1104]) in 40 ml of methanol 60 ml (60 mmol) of 1N potassium hydroxide solution were added to the solution. After stirring at room temperature overnight, methanol was removed in vacuo and the residue suspended in 800 mL of water. The aqueous layer was extracted three times with diethyl ether and acidified to pH 3 with concentrated hydrochloric acid. The white solid obtained was filtered, washed well with water and air dried to give 9.82 g (87%) of the title compound.
MS (APCI) (m + 1) / z 217.
<Production example 12>
(2-Chloro-3,5-dimethoxy-phenyl) -carbamic acid, tert-butyl ester
To a solution of 9.57 g (44.18 mmol) of 2-chloro-3,5-dimethoxy-benzoic acid and 4.78 g (47.3 mmol) of triethylamine in 250 ml of toluene was added 13.57 g (49.3 mmol) of diphenylphosphoryl azide. . The reaction was refluxed for 4 hours. To the reaction was added 3.63 g (49.0 mmol) of tert-butanol. The reaction was refluxed overnight and then concentrated in vacuo. The residue was partitioned between cold citric acid 1N solution and ethyl acetate. The ethyl acetate layer was washed twice with cold 1N solution of citric acid, water, and saturated sodium bicarbonate solution, respectively. The ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, silica gel was added and concentrated to dryness. The residue was subjected to silica gel chromatography eluting with hexane / diethyl ether (9: 1 v / v) to give 8.14 g (64%) of the title compound. Melting point: 94.5-95.5 ° C.
Calcd for Ci ₃ H ₁₈ N0 ₄ Cl: C, 54.26; H, 6. 31; N, 4.87; Cl, 12.32.
Found: C, 54.20; H, 6. 17; N, 4.90; Cl, 12.08.
<Production example 13>
2-chloro-3,5-dimethoxy-phenylamine
To 6.01 g (0.021 mmol) of (2-chloro-3,5-dimethoxy-phenyl) -carbamic acid tert-butyl ester was added 15 ml of trifluoroacetic acid. The reaction was stirred at rt for 3 h and then concentrated in vacuo. The residue was made basic with a saturated solution of sodium bicarbonate and then extracted three times with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and concentrated in vacuo to give 3.98 g of the title compound which was used in the examples below.
MS (APCI) (m + 1) / z 188.
<Example 61>
{5-[(2-Chloro-3,5-dimethoxy-phenylimino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine
To 3.78 g (20.2 mmol) of 2-chloro-3,5-dimethoxy-phenylamine in 110 ml of toluene was added 3.97 g (20.15 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. Added. The reaction vessel was equipped with a Dean-Stark trap and the reaction was warmed to reflux. After 3 hours, 2 drops of concentrated sulfuric acid were added to the reaction. The reaction was refluxed overnight and then concentrated in vacuo to give 7.36 g (93%) of the title compound, which was used in the examples below. Melting point: 196.5 to 198.5 ° C.
MS (APCI) (m + 1) / z 367.0.
<Example 62>
{5-[(2-Chloro-3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine
{5-[(2-chloro-3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine in 200 mL of dry THF cooled to 5 ° C. To 6.96 g (18.97 mmol) suspension was added 18.97 mL (18.97 mmol) of a 1M solution of LAH in THF. After stirring for 1 hour, the cold reaction was quenched by the addition of 0.8 ml of water, 3.0 ml of 25 NaOH, and 1.7 ml of water in sequence. The reaction was filtered through celite, the filter pad was washed well with THF and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, silica gel was added and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane / ethyl acetate (2: 1 v / v) to give 5.15 g (74%) of the title compound. Melting point: 116.5 to 118.5 ° C.
Calcd for C ₁₆ H ₂₁ N ₄ 0 ₂ ClS: C, 52.10; H, 5. 74; N, 15.19; Cl, 9.61; S, 8.69.
Found: C, 52.45; H, 5.67; N, 14.99; Cl, 9.38; S, 8.66.
<Example 63>
3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On
{5-[(2-chloro-3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -ethyl-amine in 7 mL of dry DMF cooled to 5 ° C. To 1.00 g (2.71 mmol) of solution 0.271 g (6.78 mmol) of sodium hydride was added as a 60% mineral oil suspension. The ice bath was removed and the reaction stirred for 1 hour. Then, 1.32 g (8.13 mmol) of 1,1'-carbonyldiimidazole was added to the reaction. After stirring for an additional 2 hours, the reaction was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated solution of ammonium chloride. The aqueous layer was extracted twice with dichloromethane. The dichloromethane layer was combined, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, silica gel was added and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with dichloromethane / ethyl acetate (9: 0.5 v / v) to give 0.7507 g (70%) of the title compound. Melting point: 189-191 ° C.
Calcd for C ₁₇ H ₁₉ N ₄ 0 ₃ ClS: C, 51.71; H, 4. 85; N, 14.19.
Found: C, 51.95; H, 4.81; N, 13.88.
<Example 64>
3- (2-Chloro-3,5-dimethoxy-phenyl) -1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On
3- (2-Chloro-3,5-dimethoxy-phenyl) -1-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine- in 7 ml of chloroform To a solution of 0.7457 g (1.89 mmol) of 2 (1H) -one, 0.5428 g (2.08 mmol) of trans-2- (phenylsulfonyl) -3-phenyloxaziridine was added. The reaction was stirred at rt overnight then concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with ethyl acetate / ethanol (9: 1 v / v) to give the title compound 0.697 (90%).
Calcd for C ₁₇ H ₁₉ N ₄ 0 ₄ ClS.0.06 CH ₂ Cl ₂ : C, 49.26; H, 4.63; N, 13.47.
Found: C, 49.58; H, 4.69; N, 13.08.
<Example 65>
3- (2-Chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -1-ethyl-3,4-dihydro-pyrimido [4.5-d] -pyri Mydin-2 (1H) -on
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -1-ethyl-3,4-dihydro-pyrimido in 4 ml of dry dioxane [ A solution of 0.1074 g (0.2614 mmol) of 4,5-d] pyrimidin-2 (1H) -one, 0.113 g (0.784 mmol) of diethylaminobutylamine, and 0.067 g (0.287 mmol) of camphorsulfonic acid was heated to 60 ° C. Warmed. After stirring overnight, the reaction was concentrated in vacuo and the residue dissolved in dichloromethane. The dichloromethane solution was extracted three times with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with ethyl acetate / ethanol / triethylamine (9: 1: 0.5 v / v / v) to afford 0.106 (82%) of the title compound.
MS (APCI) (m + 1) / z 491.1.
Examples 66-67 are as described in Scheme 3.
<Example 66>
3- (3,5-dimethoxy-phenyl) -7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-ylamine
25.0 g (81.6 mmol) of 5-[(3,5-dimethoxy-phenylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-ylamine in 125 ml of dry dimethylformamide cooled to 5 ° C To the solution was added portionwise a solution of 10.1 g (95.5 mmol) of cyanogen bromide in 25 ml of dry dimethylformamide. After the cyanogen bromide solution was added, the ice bath was removed and the reaction was allowed to warm to room temperature for 30 minutes. The reaction was warmed at 80 ° C. for 4 h and then added to 500 mL 1N NaOH. The aqueous suspension was extracted with dichloromethane (7 x 150 mL). The dichloromethane layer was combined and concentrated in vacuo. The residue was dissolved in dichloromethane, extracted three times with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, silica gel was added and concentrated in vacuo. The residue was first eluted with ethyl acetate and then silica gel chromatography eluting with ethyl acetate / ethanol (9: 1 v / v) to give a slightly impure product. This product was first eluted with chloroform and again silica gel chromatography eluting with chloroform / methanol (9: 0.5 v / v) to give 7.34 g (24%) of the title compound. Melting point: 198 to 204 ° C.
Calcd for C ₁₅ H ₁₇ N ₅ 0 ₂ S.0.30 CHCl ₃ : C, 50.04; H, 4.75; N, 19.07; S, 8.73.
Found: C, 50.11; H, 4.59; N, 19.18; S, 8.91.
<Example 67>
3- (3,5-dimethoxy-phenyl) -7-methanesulfinyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-ylamine
2.00 g (6.04) of 3- (3,5-dimethoxy-phenyl) -7-methylsulfanyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-ylamine in 50 ml of chloroform (6.04) to a solution of 1.73 g (6.64 mmol) of trans-2- (phenylsulfonyl) -3-phenyloxaziridine in 20 ml of chloroform. The reaction was stirred at rt overnight then concentrated in vacuo. The residue was dissolved in dichloromethane, silica gel was added and concentrated in vacuo. The residue was first subjected to silica gel chromatography eluting with ethyl acetate followed by ethyl acetate / ethanol / triethylamine (9: 2: 1 v / v / v) to give 1.4306 g (68%) of the title compound.
C ₁₅ H ₁₇ N ₅ O ₃ S.0.25 EtOAc. Calcd for 0.25 H ₂ O: C, 51.37; H, 5. 26; N, 18.73.
Found: C, 51.15; H, 5. 23; N, 18.44.
<Production example 14>
Ethyl 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate
4.4 mL of isopropylamine in a 0 ° C. solution of 10.0 g (43.0 mmol) of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate and 7.2 mL (51.6 mmol) of triethylamine in 100 mL of dichloromethane (51.6 mmol) was added. The reaction solution was stirred at 0 ° C. for 2 hours and then warmed to room temperature. The reaction mixture was diluted with ethyl acetate and washed twice with aqueous HCl, twice with water, once with saturated solution of sodium bicarbonate, and with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 11.1 g (quantitative) of the title compound as an oil which solidified on standing. Melting point: 159 to 160 ° C.
Mass spectrum (CI) (m + 1) / z 256.
<Production example 15>
4- (Isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid
A solution of 0.8 g (20.6 mmol) of sodium hydroxide in 30 ml of water in a solution of 5.0 g (19.6 mmol) of ethyl 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate in 20 ml of ethanol. Was added. The reaction suspension was stirred overnight at room temperature. The reaction solution was diluted with 100 mL of water and washed twice with diethyl ether. The aqueous phase was neutralized with 20.6 mL 1N HCl. The precipitate was filtered off, washed twice with water and dried in vacuo at 70 ° C. to give 4.0 g (90%) of the title compound. Melting point: 202 to 203 ° C. (decomposition).
Calcd for Ci ₉ H ₁₃ N ₃ S0 ₂ : C, 47.56; H, 5.77; N, 18.49.
Found: C, 47.38; H, 5. 70; N, 18.29.
<Production example 16>
N-allyl-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide
To 3.5 mL (15.4 mmol) of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid, 9.0 mL (123.2 mmol) of thionyl chloride are added and the reaction mixture is stirred at 50 ° C. for 1 hour. Heated to, cooled to room temperature and concentrated. The residue was suspended twice in anhydrous toluene and concentrated to give 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid chloride as a colorless solid.
To 0 ° C. suspension of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid chloride in 10 ml of tetrahydrofuran 3.5 ml (46.2 mmol) and 20 ml of tetrahydrofuran are added It was. The reaction suspension was briefly warmed to room temperature and then stored at 0 ° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated solution of sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound 2.1 (51%). Melting point: 159 to 161 ° C.
Calcd for C ₁₂ H ₁₈ N ₄ SO: C, 54.11; H, 6.81; N, 21.03.
Found: C, 54.42; H, 6. 69; N, 21.13.
<Production example 17>
N- (4-methoxybenzyl) -4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide
In 30 mL of tetrahydrofuran 4- in an 0 ° C. suspension of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid chloride (prepared as in Example 16, above) 6.0 ml (46.3 mmol) of methoxybenzylamine and 30 ml of tetrahydrofuran were added. The reaction suspension was briefly warmed to room temperature and then stored at 0 ° C. overnight. The reaction mixture was diluted with dichloromethane and washed with 1N HCl and water. The combined aqueous phases were washed with dichloromethane. The combined organic phases were washed with saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. The residue was crystallized from ethyl acetate / hexanes to give 3.27 g (61%) of the title compound. Melting point: 176 to 177 ° C.
Calcd for C ₁₇ H ₂₂ N ₄ SO ₂ : C, 58.94; H, 6. 40; N, 16.17.
Found: C, 58.87; H, 6. 34; N, 16.26.
<Example 68>
3-allyl-7- (imidazol-1-yl) -1-isopropyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione
1.5 g (5.63 mmol) of N-allyl- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide were added to a 0 ° C. suspension of 563 mg (14.1 mmol) of sodium hydride (60% dispersion). Was added and the reaction mixture was stirred for 15 minutes. To the reaction mixture was added 2.7 g (16.9 mmol) of 1,1'-carbonyldiimidazole in small portions. The reaction mixture was stirred at rt overnight, diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, and brine. The combined aqueous phases were washed with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica eluting with ethyl acetate / hexanes 4: 6. The single component fractions were combined and crystallized from dichloromethane / hexanes to give 457 mg (26%) of the title compound. Melting point: 158 to 160 ° C.
Calcd for C ₁₅ H ₁₆ N ₆ 0 ₂ : C, 57.68; H, 5. 16; N, 26.91.
Found: C, 57.57; H, 4. 90; N, 26.98.
The combined component fractions were also collected and crystallized as above to give 782 mg (44%) of the title compound, which was analytically pure.
<Example 69>
7- (imidazol-1-yl) -1-isopropyl-3- (4-methoxybenzyl) -1H-pyrimido [4,5-d] pyrimidine-2,4-dione
To a 0 ° C. suspension of 865 mg (21.6 mmol) sodium hydride (which is a 60% dispersion) N- (4-methoxybenzyl) -4- (isopropylamino) -2- (methylthio) pyrimidine-5-carbox 3.0 g (8.66 mmol) of mead were added and the reaction mixture was stirred for 1 h. To the reaction mixture was added 4.2 g (26.0 mmol) of 1,1'-carbonyldiimidazole in small portions. The reaction mixture was stirred at 50 ° C. for 5 hours, concentrated to dryness and dissolved in 300 mL of 6N HCl. The solution was washed with diethyl ether and made basic with a 50% aqueous solution of sodium hydroxide while maintaining the solution temperature below 40 ° C. The suspension was cooled to 15 ° C., the precipitate was filtered off, washed with water and dried in vacuo at 65 ° C. to give 3.1 g (91%) of the title compound. Melting point: 148-150 ° C. (decomposition).
Calcd for C ₂₀ H ₂₀ N ₆ 0 ₃ : C, 61.22; H, 5. 14; N, 21.42.
Found: C, 60.92; H, 5. 25; N, 21.17.
<Example 70>
3-allyl-1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -1H-pyrimido [4,5-d] pyrimidine-2,4-dione
3-allyl-7- (imidazol-1-yl) -1-isopropyl-1H-pyrimido [4,5-d] pyrimidin-2,4-dione 300 mg (0.96 mmol) and 1- (4 A mixture of 551 mg (2.88 mmol) of -aminophenyl) -4-methylpiperazine was heated at 180 ° C. for 2 hours. The reaction mixture was cooled down, dissolved in chloroform and silica gel chromatography eluting with methanol / chloroform 4:96. The resulting material was crystallized from methanol / water to give 251 mg (60%) of the title compound. Melting point: 176 to 177 ° C.
Calcd for C ₂₃ H ₂₉ N ₇ 0 ₂ H ₂ 0: C, 60.91; H, 6.89; N, 21.62.
Found: C, 60.79; H, 6. 80; N, 21.54.
<Example 71>
1-isopropyl-3- (4-methoxybenzyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -1H-pyrimido [4,5-d] pyrimidine-2 , 4-dione
700 mg (1.78 mmol) of 7- (imidazol-1-yl) -1-isopropyl-3- (4-methoxybenzyl) -1H-pyrimido [4,5-d] pyrimidine-2,4-dione ) And 1.02 g (5.35 mmol) of 1- (4-aminophenyl) -4-methylpiperazine were heated at 180 ° C. for 2 hours. The reaction mixture was cooled down, dissolved in chloroform and chromatographed on silica eluting with methanol / chloroform 5:95. The obtained material was crystallized from methanol / water to give 530 mg (58%) of the title compound. Melting point: 215 to 216 ° C.
Calcd for C ₂₈ H ₃₃ N ₇ 0 ₃ : C, 65.22; H, 6. 45; N, 19.02.
Found: C, 65.28; H, 6. 41; N, 19.00.
<Example 72>
3-allyl-7- [4- (2-diethylaminoethoxy) phenylamino] -1-isopropyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione
3-allyl-7- (imidazol-1-yl) -1-isopropyl-1H-pyrimido [4,5-d] pyrimidin-2,4-dione 200 mg (0.64 mmol) and 4- (2 A mixture of 400 mg (1.92 mmol) of diethylaminoethoxy) aniline was heated at 180 ° C. for 3 hours. The reaction mixture was cooled down, dissolved in chloroform and chromatographed on silica eluting with methanol / chloroform 4:96. The oily substance obtained was left to crystallize partially and the mixture was triturated with diethyl ether / hexanes and filtered to give 106 mg (36%) of the title compound. Melting point: 90 to 96 ° C.
Calcd for C ₂₄ H ₃₂ N ₆ 0 ₃ : C, 63.70; H, 7.13; N, 18.57.
Found: C, 63.39; H, 7. 15; N, 18.36.
<Example 73>
7- [4- (2-diethylaminoethoxy) phenylamino] -1-isopropyl-3- (4-methoxybenzyl) -1H-pyrimido [4,5-d] pyrimidine-2,4 Dion
700 mg (1.78 mmol) of 7- (imidazol-1-yl) -1-isopropyl-3- (4-methoxybenzyl) -1H-pyrimido [4,5-d] pyrimidine-2,4-dione ) And a mixture of 1.1 g (5.35 mmol) of 4- (2-diethylaminoethoxy) aniline were heated at 180 ° C. for 4 hours and then cooled. To the reaction mixture was added 357 mg (3.6 mmol) of succinic anhydride, 1 ml of chloroform, and 3 ml of dimethylformamide. The reaction mixture was heated at 50 ° C. for 2 hours, cooled and diluted with chloroform. The mixture was washed with saturated solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica eluting with methanol / chloroform 5:95 to give a yellow solid crystallized from methanol / water to give 590 mg (61%) of the title compound. Melting point: 139 to 141 ° C.
Calcd for C ₂₉ H ₃₆ N ₆ O ₄ : C, 65.39; H, 6.81; N, 15.78.
Found: C, 65.35; H, 6.83; N, 15.70.
As mentioned above, the compounds of the present invention are potent inhibitors of cyclin-dependent kinases and tyrosine kinases and are therefore useful for the treatment and prevention of atherosclerosis and other cell proliferative diseases such as cancer. This compound is low in toxicity. This compound showed good inhibitory activity against various cyclin-dependent kinases and all assays were generally used to measure this activity. For example, a conventional potency assay is to measure the inhibitory activity against cyclin D dependent kinase 4 enzyme (cdk4 / D). Compounds of formula (I) of the present invention generally exhibit IC ₅₀ values ranging from about 0.04 μM to less than 40 μM. The potency assay of cdk 4 was performed as follows.
Cyclin-Dependent Kinase 4 (cdk4) Effect Assay
Enzyme potency assays and response assessments were performed for IC ₅₀ measurements (Tables 1 and 2) in 96 well filter plates (Millipore MADVN6550). Total volume was 25 μM ATP containing 0.25 μCi of 20 mM TRIS (tri [hydroxymethyl] aminomethane), 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl ₂ , [ ³² P] ATP 0.1 cd containing 20 ng of cdk4, 1 μg of retinoblastoma, and a suitable dilution of the compound of the invention. All components other than ATP were added to the wells and the plate was placed on a plate mixer for 2 minutes. The reaction was initiated by the addition of [ ³² P] ATP and the plate was incubated at 25 ° C. for 15 minutes. 0.1 ml of 20% trichloroacetic acid (TCA) was added to terminate the reaction. This plate was then held at 4 ° C. for at least 1 hour to allow substrate to precipitate. The wells were then washed five times with 0.2 ml of 10% TCA and ³² P coalescing was measured with a beta plate counter (Wallac, Gettysburg, MD).
Cyclin-dependent kinase potency assay (cdk2 / cycline E, cdk2 / cyclin A, cdc2 / cyclin B)
at pH 7.4, 12 mM ATP, enzyme containing 0.25 μCi of 20 mM TRIS (tri [hydroxymethyl] aminomethane), 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl ₂ , [ ³² P] ATP enzymatic potency assay for IC ₅₀ measurements in 20 ng of cdk2 / cyclinE, cdk2 / A, or cdc2 / cyclinB), 1 μg of retinoblastoma, and 0.1 ml total volume of appropriate dilution of certain compounds of the invention, and Response assessments were performed in 96 well filter plates (Millipore MADVN6550). All components other than ATP were added to the wells and the plate was placed on a plate mixer for 2 minutes. The reaction was initiated by the addition of [ ³² P] ATP and the plate was incubated at 25 ° C. for 15 minutes. The reaction was terminated by addition of 0.1 ml 20% TCA. The plate was kept at 4 ° C. for at least 1 hour to allow the substrate to precipitate. Wells were then washed five times with 0.2 ml of 10% TCA and ³² P coalescence was measured with a beta plate counter (Warracks, Gettysburg, Maryland).
When measured for cdk2 / E, the compounds of the present invention typically exhibit IC ₅₀ values ranging from about 0.9 μM to less than 40 μM. Against cdk2 / A, the compound exhibited an IC ₅₀ value in the range of about 0.5 μM or more but less than 40 μM and, against cdk2 / B, an IC ₅₀ value in the range of about 5 μM or more and less than 40 μM. Efficacy assays were performed as described above, and specific data for the compounds of the present invention are shown in Table 1 below.

Table 2 shows data for specific pyrimido [4,5-d] pyrimidines (double bonds at 3,4-position).

In addition, some compounds of the present invention showed good inhibitory activity against the cdk6 / D ₂ and cdk6 / D ₃ enzymes. This potency assay was performed in a similar manner as described for cdk4 above by using a shortly suitable cdk6 kinase enzyme.
In addition, the compounds of formula (I) showed good inhibitory activity against certain growth factor receptor tyrosine kinase enzymes, including fibroblast growth factor (FGF) and platelet derived growth factor (PDGF). The range of compounds of the invention in IC ₅₀ inhibition to FGF tyrosine kinases was typically at least about 0.3 μM and less than 50 μM. Against PDGF tyrosine kinase, the compounds of the present invention exhibited an IC ₅₀ of at least about 0.02 μM and less than 50 μM. Assays used to measure this activity were performed as follows:
PDGF and EGF Receptor Tyrosine Kinase Assays
The total length of cDNA for mouse PDGF-β and human FGF-1 (flg) receptor tyrosine kinase was obtained from J. Escobedo and described in J. Escobedo. Biol. Chem., 1991; 262: 1482-1487. PCR primers were designed to amplify fragments of DNA encoding intracellular tyrosine kinase domains. The fragment was inserted into a Baculovirus vector, co-transfected with AcMNPV DNA, and the recombination virus was isolated. Infection of SF9 insect cells with virus overexpressed the protein and the cell lysate was used for potency assays. Efficacy assays were performed in 96-well plates (100 μl / incubation / well) and the conditions were optimized so that coalescence from γ ³² P-ATP to ³² P glutamate-tyrosine copolymer substrate was measured. Briefly, 25 mM Hepes, pH 7.0, 150 mM NaCl, 0.1% Triton X-100, 0.2 mM PMSF, 0.2 mM Na ₃ VO ₄ , 10 mM MnCl ₂ , and 750 μg / ml poly (4: 1) glutamate The reaction was initiated by adding tyrosine followed by 82.5 μl of incubation buffer containing 2.5 μl of inhibitor and 5 μl of enzyme lysate (7.5 μg / μl FGF-TK or 6.0 μg / μl PDGF-TK). After incubation at 25 ° C. for 10 minutes, 10 ml of γ ³² P-ATP (0.4 μCi and 50 μM ATP) was added to each well and the samples were incubated at 25 ° C. for an additional 10 minutes. The reaction was terminated by the addition of 100 μl of 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphate and the material precipitated on a glass fiber mat (manufactured by Wallak). The filter was washed three times with 15% TCA containing 100 mM sodium pyrophosphate and the radioactivity remaining on the filter was counted with a Wallac 1250 betaplate reader. Nonspecific activity was defined as radioactivity remaining on the filter, and the samples were incubated with buffer only (without enzyme). Specific enzyme activity (enzyme and buffer) was defined as total activity minus nonspecific activity. The concentration of the compound that inhibits specific activity at 50% (IC ₅₀ ) was determined based on the inhibition curve and the general results are shown in the table below.


The Src (translational genes of the Rous sarcoma retrovirus) family of protein kinases, all containing the SH2 region, are used in a number of cellular signaling pathways. For example, Src may be a growth factor receptor signal; Integrin-mediated signals; It is used for T- and B-cell activity and osteoclast activity. The Src SH2 region is associated with several major receptors and nonreceptor tyrosine kinases such as PDGF, EGF, HER2 / Neu (tumor forming gene form of EGF), FGF, focal adhesion kinase, p 130 protein, and tyrosine kinase containing p68 protein. It is known to be combined. In addition, pp60c-Src has been shown to be used for the regulation of DNA synthesis, mitosis, and other cellular activities.
Thus, compounds that inhibit the binding of the protein containing the SH2 region to the homologous phosphorylated protein, so as to inhibit the binding of the protein containing the SH2 region to homologous phosphorylated protein, may cause It may be useful to be used in the treatment of proliferative diseases such as cancer, osteoporosis, inflammation, allergies, restenosis, and cardiovascular disease, which rely on signal transduction involving proteins containing SH2 regions that bind to polyylated proteins. will be.
Some compounds of the invention were evaluated by measuring their ability to inhibit cellular Src protein kinase (c-Src) in a standard potency assay. Compounds of the invention generally exhibited IC ₅₀ values ranging from about 0.4 to about 50 μM. Efficacy assays were performed as follows:
C-Src kinases were purified from baculovirus infected insect cell lysates using antipeptide monoclonal antibodies directed against the N-terminal amino acid (amino acids 2-17) of c-Src. 150 mM NaCl, 50 mM Tris pH 7.5, 1 mM DTT, 1% NP-40, 2 mM EGTA, 1 mM sodium vanadate, 1 mM PMSF, 1 μg / μl leupetin, pepstatin, and afro To a suspension of insect cell lysate buffer consisting of tinine was added an antibody covalently bound to 0.65 μm latex beads. Insect cell lysates containing c-Arc were incubated with these beads while rotating at 4 ° C. for 3-4 hours. After incubation of the lysate, the beads were washed three times in lysis buffer, resuspended in lysis buffer containing 10% glycerol and frozen. These latex beads were dissolved and washed three times in potency assay buffer (Tris 40 mM, pH 7.5, 5 mM μg Cl ₂ ) and suspended in the same buffer. 10 μl of reaction component c-Src beads, 10 μl of 2.5 mg / ml poly GluTyr substrate, 5 μM ATP containing 0.2 μCi labeled ³² P-ATP in Millipore 96-well with 0.65 μm polyvinylidene membrane bottom, 5 μl of DMSO containing inhibitor or as solvent control, and buffer were added and the final volume was made to 125 μl. The reaction was initiated at room temperature by the addition of ATP and after 10 minutes 125 μl of 30% TCA, 0.1 M sodium pyrophosphate was added to ice for 5 minutes. The plates were then filtered and wells washed with two 250 mL portions of 15% TCA, 0.1 M pyrophosphate each. The filter was then punched out, counted with a liquid scintillation counter, and the data examined for inhibitory activity against known inhibitors such as erbstatin. This method is described in J. Med. Chem., 1994; 37: 598-609. Tables 5 and 6 describe the c-Src inhibitory concentrations (IC ₅₀ ) for representative compounds of the present invention.

Compounds of formula (I) are useful for the treatment of cell proliferative diseases associated with angiogenesis and have been evaluated by in vitro potency assay of human umbilical vein endothelial cells. The following assay was used to determine the anti-proliferative effect of the compounds of the present invention on human umbilical vein endothelial cells, the results are shown in Table 7.
Assay of Proliferation Effect of Human Umbilical Vein Endothelial Cells (HUVEC)
96 well tissue culture plates seeded 100 μL cells in all wells of rows A to G, leaving column H blank. HUVEC [Clonetics, San Diego, CA, USA] was grown in endothelial cell growth medium (EGM medium, manufactured by Clonetics) containing 2% fetal calf serum. Cell seed density for HUVEC was 20,000 per ml. C6 cells (ATCC Cat. No. CCL-107) in F10 medium [Hemes, a nutrient mixture] supplemented with 600 ml of 15% horse serum, 2.5% fetal calf serum, and 6.0 ml of 200 mM glutamine per 600 ml of medium. Seed at 6000 / ml. A90 cells (Suny, Buffalo, NY) were also seeded at 6000 / ml, but they were grown in RPMI 1640 (Roswell Park Memorial Institute) with 10% fetal bovine serum. Unless stated otherwise, tissue culture media and components are from Gibco. Cells were incubated at 37 ° C., 5% CO ₂ , and 100% relative humidity for 16 to 24 hours.
Compounds of the present invention were prepared by dissolving them in DMSO at a concentration diluted from 5 mM to 50 μM in EGM medium. 100 μl of compound was applied to dual wells in column 1 of pre-prepared cell plates. Column 100 of column 1 was fed with 100 μl of EGM medium. Compounds in column 1 were diluted in plates using the associated 2-fold dilutions.
Plates were incubated as above for an additional 4 days and then stained with Sulphorhodamine B. Staining was performed as follows: The medium was removed from the plate and cells were fixed for 30 min at 4 ° C. using 10% trifluoroacetic acid. After fixation, the plate was washed five times with distilled water, and then 100 μl of sulforhodamine B was added to each well. Sulphodamine B was dissolved in 1% acetic acid at a concentration of 0.075%. After staining, excess dye was removed from the wells and the plate washed four times with 1% acetic acid. After the plates were air dried, the binding dye was dissolved in 100 μl of unbuffered 10 mM TRIS base. Absorbance was measured at 540 nM with a 96 well plate reader using a reference filter wavelength of 630 nM. The concentration of compound required for 50% inhibition of cell proliferation (IC ₅₀ ) was determined by measuring absorbance. Sulphodamine B and TRIS are products of Sigma Chemical Company. Acetic acid and trichloroacetic acid are from Mallinckrodt AR.
In addition, compounds of formula (I) were evaluated by several standard in vivo cell culture assays, which showed good inhibitory activity against tyrosine kinase enzymes.
The compounds of the present invention may be formulated in a conventional manner to provide a conventional dosage form for oral, parenteral (subcutaneous, intravenous, and intramuscular), transdermal, sustained release such as slow release skin patches or creams as well as osmotic pumps. It can be provided for delivery to a mammal in a variety of ways including sex delivery devices, suppositories, and oral seals. The following examples further illustrate how the compounds are readily formulated.
<Example 75>
50 mg tablet formulation
Per tablet Per 10,000 tablets 0.050 g2-cyclopentyl-7- {3-methyl-4- [2- (diethylamino) -ethoxy] phenylamino} -3,4-dihydro-1H-pyrimido- [4,5-d] pyrid Midin-2-one500 g 0.080 gLactose800 g 0.010 gCorn Starch (For Mix)100 g 0.008 gCorn Starch (For Paste)80 g 0.148 gsub Total1480 g 0.002 gMagnesium Stearate (1%)20 g 0.150 gSum1500 g
Pyrimidopyrimidine, lactose, and corn starch (for the mix) were mixed uniformly. Corn starch (for paste) was suspended in 600 ml of water and heated with stirring to form a paste. This paste was used to granulate the mixed powder. The wet particles were passed through a hand screen 8 times and dried at 80 ° C. The dry particles were then passed through screen 16 times. This mixture was lubricated with 1% magnesium stearate and compressed into tablets in a conventional tableting machine. In addition to the compounds of the present invention, these tablets are useful for the treatment of breast cancer, prostate cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, melanoma, esophageal cancer, brain cancer, Kaposi's sarcoma, and lymphoma. Certain associated diseases to be treated include small cell lung cancer, lower human bladder cancer, and human colorectal cancer.
<Example 76>
Preparation of Oral Suspension
ingredientamount 1-cyclopentyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-1H-pyrimido [4,5-d] pyrimidine- 2-on500 mg Sorbitol solution (70% N.F)40 ml Sodium benzoate150 mg saccharin10 mg Cherry flavor50 mg Sufficient amount of distilled water100 ml
Sorbitol solution was added to 40 ml of distilled water, and pyrido pyrimidine was suspended therein. Saccharin, sodium benzoate, and flavoring agent were added and dissolved. The volume was adjusted to 100 ml with distilled water. Each 1 ml of syrup contained 5 mg of the compound of the present invention.
<Example 77>
Preparation of Parenteral Solutions
1-cyclopentyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine- with stirring in a solution of 700 ml of propylene glycol and 200 ml of water for injection 20.0 g of 2 (1H) -one were suspended. After completion of the suspension, the pH was adjusted to 5.5 with hydrochloric acid and the volume was adjusted to 1000 ml with water for injection. The formulation was sterilized and filled with 5.0 ml ampoules each containing 2.0 ml (which represents 40 mg of the compound of the invention) and sealed under nitrogen.
<Example 78>
suppository
400 mg of 1-cyclopentyl-7- [4- (piperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one and 600 mg of thiobroma oil The mixture was stirred uniformly at 60 ° C. The mixture was cooled and cured in a tapered mold to yield 1 g of suppository.
<Example 79>
Sustained release formulations
1-cyclopentyl-7- [4- (3-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2- On 500 mg was converted to the hydrochloride salt and placed in an Oros osmotic pump controlling the release for the treatment of atherosclerosis.
<Example 80>
Skin patch formulation
1-cyclopentyl-7- {3-methyl-4- [2- (diethylamino) -ethoxy] phenylamino} -pyrimido [4,5-d] pyrimidin-2 (1H) -one 50 mg Was mixed with 50 mg of propylene glycol monolaurate in a polydimethylsiloxane adhesive. This mixture was layered on an elastic film made of an adhesive composition of polybutene, polyisobutylene, and propylene glycol monolaurate. The layers were placed in between two layers of polyurethane film. The release liner is adhered to the adhesive surface and peeled off before sticking to the skin surface. Propylene glycol monolaurate functions as a penetration-enhancing agent.

权利要求:
Claims (43)
[1" claim-type="Currently amended] Compounds of formula (I) and pharmaceutically acceptable salts thereof.
<Formula I>

In the above formula,
The dashed line represents any double bond,
Z is N or CH;
G is N or CH;
W is NH, S, SO, or SO ₂ ;
X is O, S, or NR ¹⁰ ;
R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
[2" claim-type="Currently amended] The compound of claim 1, wherein Z and G are both N, W is NH, and R ⁸ and R ⁹ are both hydrogen.
[3" claim-type="Currently amended] The chemical formula of claim 2 wherein Compound having a structure of.
[4" claim-type="Currently amended] The compound of claim 3, wherein R ¹ is phenyl or substituted phenyl, pyridyl or substituted pyridyl.
[5" claim-type="Currently amended] The compound of claim 4, wherein R ² is alkyl, substituted alkyl, or unsubstituted or substituted cycloalkyl.
[6" claim-type="Currently amended] 1-methyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- [4- (pyrazol-1-yl) phenylamino] pyrimido [4,5-d] pyrimidin-2 (1H) -one ( Exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine-2 (1H) -On (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] pyrimido [4,5-d] pyrimidine-2 ( 1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine- 2 (1H) -one (exo);
7- [4- (4-aminoacetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- {4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -1-cyclopentyl-pyrimido [4,5-d] pyrimidine- 2 (1H) -one;
1-methyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-isopropyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-cyclopentyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4,5-d] pyrimidine-2 (1H )-On;
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} pyrimido [4, 5-d] pyrimidin-2 (1H) -one (exo);
1-cyclopentyl-7- (4-methanesulfonyl-phenylamino) pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-fluoro-3-methyl-phenylamino) pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -1-cyclopentyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-piperazin-1-yl-phenylamino) -pyrimidin [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- [4- (5-methyl-hexahydro-pyrrole [3,4-c] pyrrol-2-yl) -phenylamino] -pyrimido [4,5-d] pyrimidine-2 (1H) -one;
7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -1-cycloheptyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one; And
1-cyclopentyl-7- (pyridin-4-ylamino) pyrimido [4,5-d] pyrimidin-2 (1H) -one
Compound selected from.
[7" claim-type="Currently amended] The chemical formula of claim 2 wherein Compound having a structure of.
[8" claim-type="Currently amended] 8. The compound of claim 7, wherein R ¹ is alkyl, pyridyl, or phenyl, each optionally substituted with hydroxy, alkoxy, NR ⁴ R ⁵ , or T (CH ₂ ) _m QR.
[9" claim-type="Currently amended] 1-methyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-methyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H)- On;
1-methyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
1-isopropyl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one ;
1-isopropyl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-isopropyl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- [4- (pyrazol-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- [4- (4-hydroxypiperidin-1-yl) phenylamino] -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one (exo);
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (dimethylamino) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one (exo);
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- {4- [4- (2-amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -1-cyclopentyl-3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one;
1-methyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
1-isopropyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
1-cyclopentyl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
1-bicyclo [2.2.1] hept-2-yl-7- {4- [4- (3-morpholin-4-ylpropyl) piperidin-1-yl] phenylamino} -3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one (exo);
1-cyclopentyl-7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-methanesulfonyl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- (4-fluoro-3-methyl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -On;
1-cyclopentyl-7- (4-piperazin-1-yl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
1-cyclopentyl-7- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro- Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro- Pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (4-diethylamino-butylamino) -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
7- (pyridin-4-ylamino) -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- (pyridin-4-ylamino) -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-cyclopentyl-3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one;
3- (2-Chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one;
7- [4- (2-Diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5-d] pyridine Midin-2 (1H) -one;
3- (2,6-dichloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one; And
3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one
Compound selected from.
[10" claim-type="Currently amended] The chemical formula of claim 2 wherein Compound having a structure of.
[11" claim-type="Currently amended] 1- [7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyrimido [4,5- d] pyrimidin-2-yl] -3-ethyl-urea;
1- {3- (2-Chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2-yl} -3-ethyl-urea;
1-tert-butyl-3- [7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -3,4-dihydro-pyri Mido [4,5-d] pyrimidin-2-yl] -urea;
1-tert-butyl-3- {3- (2-chloro-3,5-dimethoxy-phenyl) -7- [4- (2-diethylamino-ethoxy) -phenylamino] -3,4- Dihydro-pyrimido [4,5-d] pyrimidin-2-yl] -urea;
1-tert-butyl-3- [3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrid Midin-2-yl] -urea;
1- [3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-yl] -3-ethyl-urea;
1-tert-butyl-3- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2-yl] -urea;
1- [3- (2-Chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine- 2-yl] -3-ethyl-urea;
1- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4,5-d] pyri Midin-2-yl] -3-ethyl-urea;
3-Methyl-N- {7- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2-yl} -butyramid;
1- {7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2-yl} -3 Isopropyl-urea; And
1-tert-butyl-3- [3- (2-chloro-3,5-dimethoxy-phenyl) -7- (4-diethylamino-butylamino) -3,4-dihydro-pyrimido [4 , 5-d] pyrimidin-2-yl] -urea
Compound selected from.
[12" claim-type="Currently amended] The chemical formula of claim 2 wherein Compound having a structure of.
[13" claim-type="Currently amended] 1- [7- (4-fluoro-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -3-methyl-urea;
1-isopropyl-3- (7-phenylamino-pyrimido [4,5-d] pyrimidin-2-yl) -urea;
1- {7- [4- (3-aminomethyl-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-isopropyl-urea ;
1-isopropyl-3- [7- (4-piperazin-1-yl-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -urea;
1- {7- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-isopropyl-urea;
N- {7- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butylamide;
N- [7- (4-piperazin-1-yl-phenylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -isobutyramid;
N- {7- [4- (4-acetyl-piperazin-1-yl) phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butyramid;
3-methyl-N- [7- (pyridin-4-ylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -butyramid;
1-isopropyl-3- [7- (pyridin-4-ylamino) -pyrimido [4,5-d] pyrimidin-2-yl] -urea; And
N- {7- [4- (3-Aminomethyl-pyrrolidin-1-yl) -phenylamino] -pyrimido [4,5-d] pyrimidin-2-yl} -3-methyl-butyra mid
Compound selected from.
[14" claim-type="Currently amended] The compound of claim 1, wherein W is S, SO, or SO ₂ .
[15" claim-type="Currently amended] The chemical formula of claim 1 wherein Compound having a structure of.
[16" claim-type="Currently amended] 1-isopropyl-7- [4- (4-methylpiperazin-1-yl) phenylamino] -1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- [4- (2-diethylaminoethoxy) phenylamino] -1-isopropyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- (4-diethylamino-butylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione;
7- [4- (2-diethylamino-ethoxy) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine -2,4-dione; And
7- (pyridin-4-ylamino) -3- (3,5-dimethoxy-phenyl) -1-ethyl-1H-pyrimido [4,5-d] pyrimidine-2,4-dione
Compound selected from.
[17" claim-type="Currently amended] The compound of claim 1, wherein Z is N, G is CH, W is NH, and R ⁸ and R ⁹ are both hydrogen.
[18" claim-type="Currently amended] 18. The chemical formula of claim 17, wherein Compound having a structure of.
[19" claim-type="Currently amended] 2- [4- (3-amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-8H-pyrido [4,3-d] pyrimidin-7-one;
8-cyclopentyl-2- [4- (hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -phenylamino] -8H-pyrido [4,3-d] pyrimidine-7- On;
2- [4- (4-acetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-8H-pyrido [4,3-d] pyrimidin-7-one;
N- {2- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -8-cyclopentyl-pyrido [4,3-d] pyrimidin-7-yl} -2, 2-dimethyl-propionamide; And
N- {2- {4- [4- (2-Amino-4-methyl-pentanoyl) -piperazin-1-yl] -phenylamino} -8-cyclopentyl-pyrido [4,3-d] -Pyrimidin-7-yl} -2,2-dimethyl-propionamide
Compound selected from.
[20" claim-type="Currently amended] The compound of claim 1, wherein Z is CH, G is N, W is NH, and R ⁸ and R ⁹ are both hydrogen.
[21" claim-type="Currently amended] The chemical formula of claim 20 wherein Compound having a structure of.
[22" claim-type="Currently amended] 1- (2-benzyloxyethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (thiophen-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (thiophen-2-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (tetrahydrofuran-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (hexa-2,4-dien-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H )-On;
1- (prop-2-yn-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1- [3- (dimethylamino) prop-1-yl] -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 ( 1H) -one;
1- (3-hydroxyprop-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1- (pyridin-4-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidin-2 (1H) -one;
1- (3,5-dimethylhept-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] pyrido [4,3-d] pyrimidine-2 (1H) -On;
1-cyclopentyl-7- (4-piperazin-1-ylphenylamino) pyrido [4,3-d] pyrimidin-2 (1H) -one; And
7- [4- (3-aminopyrrolidin-1-yl) phenylamino] -1-cyclopentylpyrido [4,3-d] pyrimidin-2 (1H) -one
Compound selected from.
[23" claim-type="Currently amended] The chemical formula of claim 20 wherein Compound having a structure of.
[24" claim-type="Currently amended] 1- (2-benzyloxyethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine-2 (1H) -one;
1- (thiophen-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine- 2 (1H) -one;
1- (thiophen-2-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
1- (tetrahydrofuran-2-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
1- (hexa-2,4-dien-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3- d] pyrimidin-2 (1H) -one;
1- (prop-2-yn-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
1- [3- (dimethylamino) prop-1-yl] -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3 -d] pyrimidin-2 (1H) -one;
1- (3-hydroxyprop-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
1- (pyridin-4-ylmethyl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d] pyrimidine- 2 (1H) -one;
1- (3,5-dimethylhept-1-yl) -7- [4- (4-methylpiperazin-1-yl) phenylamino] -3,4-dihydro-pyrido [4,3-d ] Pyrimidin-2 (1H) -one;
3- (3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine-2 (1H )-On;
3- (2-chloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
3- (2,6-dichloro-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] Pyrimidin-2 (1H) -one;
3- (2-methyl-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] pyrimidine -2 (1H) -one;
3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -7- (pyridin-4-ylamino) -1-ethyl-3,4-dihydro-pyrido [4,3-d] Pyrimidin-2 (1H) -one;
7- [4- (4-aminoacetyl-piperazin-1-yl) -phenylamino] -3- (3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro-pyrido [ 4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-chloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrido [4,3-d] pyrimidin-2 (1H) -one;
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2-methyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4-dihydro -Pyrido [4,3-d] pyrimidin-2 (1H) -one; And
7- [4- (4-Aminoacetyl-piperazin-1-yl) -phenylamino] -3- (2,6-dimethyl-3,5-dimethoxy-phenyl) -1-ethyl-3,4- Dihydro-pyrido [4,3-d] pyrimidin-2 (1H) -one
Compound selected from.
[25" claim-type="Currently amended] Vascular smooth muscle associated with a disease selected from the group consisting of atherosclerosis, postoperative vascular stenosis, restenosis, diabetic retinopathy and angiogenesis in cancer, psoriasis and mammals, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) A method for controlling a proliferative disease selected from the group consisting of proliferation.
<Formula I>

R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
[26" claim-type="Currently amended] A method of inhibiting a cyclin-dependent kinase comprising contacting a cyclin-dependent kinase with a compound of formula (I).
<Formula I>

R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
[27" claim-type="Currently amended] The method of claim 26, wherein the cyclin-dependent kinase is cdc2.
[28" claim-type="Currently amended] The method of claim 26, wherein the cyclin-dependent kinase is cdk2.
[29" claim-type="Currently amended] The method of claim 26, wherein the cyclin-dependent kinase is cdk4 or cdk6.
[30" claim-type="Currently amended] A method of inhibiting said growth factor-mediated tyrosine kinase, comprising contacting the growth factor-mediated kinase with a compound of formula (I) and a pharmaceutically acceptable salt thereof.
<Formula I>

In the above formula,
The dotted line represents any double bond;
Z is N or CH;
G is N or CH;
W is NH, S, SO, or SO ₂ ;
X is O, S, or NR ¹⁰ ;
R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
[31" claim-type="Currently amended] 31. The method of claim 30, wherein said growth factor-mediated tyrosine kinase is platelet derived growth factor (PDGF).
[32" claim-type="Currently amended] 31. The method of claim 30, wherein said growth factor-mediated tyrosine kinase is fibroblast growth factor (FGF).
[33" claim-type="Currently amended] 31. The method of claim 30, wherein said growth factor-mediated tyrosine kinase is vascular endothelial growth factor (VEGF).
[34" claim-type="Currently amended] A method of inhibiting non-receptor tyrosine kinase comprising contacting a non-receptor tyrosine kinase with a compound of formula (I) and a pharmaceutically acceptable salt thereof.
<Formula I>

In the above formula,
The dotted line represents any double bond;
Z is N or CH;
G is N or CH;
W is NH, S, SO, or SO ₂ ;
X is O, S, or NR ¹⁰ ;
R ¹ , R ² , and R ¹⁰ are H, (CH ₂ ) _n Ar, COR ⁴ , (CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocyclyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl, wherein n is 0, 1, 2, or 3, and (CH ₂ ) _n Ar, (CH ₂ ) _n heteroaryl, Alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, alkyl, phenyl, substituted phenyl, (CH ₂ ) _n hetero Aryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , aldehyde, nitrile , Nitro, heteroaryloxy, T (CH ₂ ) _m QR ⁴ , , C (O) T (CH ₂ ) _m QR ⁴ , NHC (O) T (CH ₂ ) _m QR ⁴ , T (CH ₂ ) _m C (O) NR ⁴ NR ⁵ , or T (CH ₂ ) _m CO ₂ R ⁴ , wherein each m is independently 1 to 6, T is O, S, NR ⁴ , N (O) R ⁴ , NR ⁴ R ⁶ Y, or CR ⁴ R ⁵ , and Q is O, S , NR ⁵ , N (O) R ⁵ , or NR ⁵ R ⁶ Y, and substituted with up to 5 groups selected from &lt; RTI ID = 0.0 &gt;
If there is a dotted line, there is no R ³ ;
In the absence of a dashed line, R ³ represents not only R ² as defined above but also OH, NR ⁴ R ⁵ , COOR ⁴ , OR ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , T (CH ₂ ) _m QR ⁴ , Wherein T and Q are as defined above;
R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₆ alkyl, substituted alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, N (C ₁ -C ₆ alkyl) _{1 or 2} , ( CH ₂ ) _n Ar, independently selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, heterocyclyl, and heteroaryl, or R ⁴ and R ⁵ together with the nitrogen attached thereto are optionally nitrogen, substituted nitrogen Form a ring of 3 to 7 carbon atoms containing 1, 2, or 3 heteroatoms selected from the group consisting of, oxygen, and sulfur;
When R ⁴ and R ⁵ together with the nitrogen bonded thereto form a ring, the ring is optionally OH, OR ⁴ , NR ⁴ R ⁵ , (CH ₂ ) _m OR ⁴ , (CH ₂ ) _m NR ⁴ R ⁵ , T- (CH ₂ ) _m QR ⁴ , CO-T- (CH ₂ ) _m QR ⁴ , NH (CO) T (CH ₂ ) _m QR ⁴ , T- (CH ₂ ) _m CO ₂ R ⁴ , or T (CH ₂ ) _m is substituted with 1 to 3 groups selected from CONR ⁴ R ⁵ ;
R ⁶ is alkyl;
R ⁸ and R ⁹ are independently H, C ₁ -C ₃ alkyl, NR ⁴ R ⁵ , N (O) R ⁴ R ⁵ , NR ⁴ R ⁵ R ⁶ Y, hydroxy, alkoxy, thiol, thioalkyl, halo , COR ⁴ , CO ₂ R ⁴ , CONR ⁴ R ⁵ , SO ₂ NR ⁴ R ⁵ , SO ₃ R ⁴ , PO ₃ R ⁴ , CHO, CN, or NO ₂ ;
In the absence of a dashed line, R ⁹ is further carbonyl, thiocarbonyl, imine and substituted imines, oximes and oxime ethers;
Y is a halo counter-ion.
[35" claim-type="Currently amended] 34. The method of claim 33, wherein said non-receptor tyrosine kinase is selected from the transgenes of Loose sarcoma retrovirus (Src) family.
[36" claim-type="Currently amended] A method of inhibiting serine kinase in a mammal comprising administering an amount of the compound of claim 1 to inhibit serine kinase.
[37" claim-type="Currently amended] A method of treating a subject with a disease caused by vascular smooth muscle proliferation comprising administering to the subject a therapeutically effective amount of a compound of claim 1.
[38" claim-type="Currently amended] A method of treating a subject with cancer comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
[39" claim-type="Currently amended] A method of inhibiting angiogenesis in a mammal comprising administering an anti-angiogenically effective amount of the compound of claim 1.
[40" claim-type="Currently amended] The method of claim 39, wherein the disease state caused by angiogenesis is selected from human cancer, macular degeneration, diabetic retinopathy, surgical adhesion, and psoriasis.
[41" claim-type="Currently amended] A method of inhibiting wee-1 kinase in a mammal comprising administering an amount of the compound of claim 1 to inhibit wee-1 kinase.
[42" claim-type="Currently amended] 7- [3- (carboxy) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
7- [3- (N-dimethylaminopropyl-carboxamide) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
7- [3- (N-dimethylaminopropyl-carboxamide) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyri Mido [4,5-d] pyrimidin-2 (1H) -one;
7- [3- (carboxy) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- [4- (2-ethylamino-ethoxy) -phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one;
3- (2,6-dichloro-3-hydroxy-phenyl) -7- [4- (2-ethylamino-ethoxy) -phenylamino] -1-methyl-3,4-dihydro-pyrimido [ 4,5-d] pyrimidin-2 (1H) -one;
7- [4- (carboxamide) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine- 2 (1H) -one;
7- [4- (carboxamide) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5- d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- (3-hydroxymethyl-phenylamino) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one;
3- (2,6-dichloro-phenyl) -7- (4-morpholin-4-yl-phenylamino) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H )-On;
3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-7- (4-morpholin-4-yl-phenylamino) -3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-3-hydroxy-phenyl) -7- (3-hydroxymethyl-phenylamino) -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one;
7- [4- (3-carboxypropyl) -phenylamino] -3- (2,6-dichloro-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine -2 (1H) -one;
7- [4- (3-carboxypropyl) -phenylamino] -3- (2,6-dichloro-3-hydroxy-phenyl) -1-methyl-3,4-dihydro-pyrimido [4,5 -d] pyrimidin-2 (1H) -one;
3- (2,6-dichloro-phenyl) -7- [4- (formyl-phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 1H) -one; and
3- (2,6-dichloro-3-hydroxy-phenyl) -7- [4- (formyl-phenylamino] -1-methyl-3,4-dihydro-pyrimido [4,5-d] Pyrimidin-2 (1H) -one
Compound selected from.
[43" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

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同族专利:

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公开号 | 公开日

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CA2329703C|2005-12-20|

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DE69939168D1|2008-09-04|

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WO1999061444A2|1999-12-02|

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HK1039483A1|2004-06-18|

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AT402177T|2008-08-15|

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AP200001964A0|2000-12-31|

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CA2329703A1|1999-12-02|

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HU0102514A3|2002-03-28|

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EE200000706A|2002-06-17|

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US7501425B1|2009-03-10|

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NO20005928D0|2000-11-23|

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EA003640B1|2003-08-28|

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IS5687A|2000-10-27|

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SK17532000A3|2002-08-06|

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BR9911590A|2001-02-13|

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IL139599D0|2002-02-10|

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GEP20033093B|2003-04-10|

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CN1138778C|2004-02-18|

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HRP20000799A2|2001-06-30|

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YU73300A|2003-08-29|

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NZ508268A|2004-02-27|

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EA200001171A1|2001-06-25|

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AU4073499A|1999-12-13|

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JP2002516327A|2002-06-04|

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HU0102514A2|2001-11-28|

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TR200003429T2|2001-07-23|

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ES2310039T3|2008-12-16|

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BG104960A|2001-10-31|

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EP1080092B1|2008-07-23|

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PL344248A1|2001-10-22|

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EP1080092A2|2001-03-07|

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ID27589A|2001-04-12|

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NO20005928L|2000-11-23|

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WO1999061444A3|2000-02-03|

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AU763839B2|2003-07-31|

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CN1302301A|2001-07-04|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-05-26|Priority to US8670898P

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1999-03-25|Priority to US12615899P

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1999-03-25|Priority to US60/126,158

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1999-03-25|Priority to US60/086,708

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1999-05-10|Application filed by 로즈 암스트롱, 크리스틴 에이. 트러트웨인, 워너-램버트 캄파니

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1999-05-10|Priority to PCT/US1999/010187

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2001-05-25|Publication of KR20010043829A

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2003-08-21|First worldwide family litigation filed

优先权:

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申请号 | 申请日 | 专利标题

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US8670898P| true| 1998-05-26|1998-05-26|

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US12615899P| true| 1999-03-25|1999-03-25|

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US60/126,158|1999-03-25|

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US60/086,708|1999-03-25|

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PCT/US1999/010187|WO1999061444A2|1998-05-26|1999-05-10|Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation|