HK1064675B - Irreversible inhibitors of tyrosine kinases - Google Patents
Irreversible inhibitors of tyrosine kinases Download PDFInfo
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- HK1064675B HK1064675B HK04107693.1A HK04107693A HK1064675B HK 1064675 B HK1064675 B HK 1064675B HK 04107693 A HK04107693 A HK 04107693A HK 1064675 B HK1064675 B HK 1064675B
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Description
The present invention is a divisional application of Chinese patent application with application number 97194458.X, application date 1997, 8.4, entitled "irreversible inhibitor of tyrosine kinase".
Technical Field
The present invention relates to compounds which are irreversible inhibitors of tyrosine kinases. The invention also relates to methods of treating cancer, atherosclerosis, restenosis, endometriosis or psoriasis and to pharmaceutical compositions comprising compounds which are irreversible inhibitors of tyrosine kinases.
Background
Cancer is considered a disease of the intracellular signaling system or signaling mechanism. The cells receive a number of instructions from outside the cell that direct whether the cell will proliferate. The purpose of the signaling system is to take these or other signals from the cell surface, introduce them into the cell, and then transmit these signals to the nucleus, cytoskeleton, and transport and protein synthesis structures.
The most common cause of cancer is a series of defects, which can be defects in these proteins (when mutated), or defects in the regulation of the amount of proteins within the cell, thereby overproducing or underproducing the protein. Usually, there are important lesions within the cell that result in a constitutive state whereby the nucleus receives proliferative signals, while in fact these signals are not present. This may occur through a variety of mechanisms. Sometimes cells will start to produce the true growth factors of their own receptors in the absence of a response, the so-called autocrine loop mechanism. Mutations in cell surface receptors, which typically transmit signals into the cell via tyrosine kinases, can result in the kinases being activated in the absence of ligands and transmitting signals that are not, in fact, present. Alternatively, many surface kinases can be overexpressed on the cell surface, resulting in an exaggerated response to a weak signal. There are many levels within a cell at which mutations or overexpression can lead to the same false signal production within the cell, and there are many other kinds of signaling defects involved in cancer. The present invention is directed to cancers that are caused by the three mechanisms described above involving cell surface receptors of the epidermal growth factor receptor tyrosine kinase family (EGFR). The family consists of EGF receptor (Erb-B1), Erb-B2 receptor, and mutants of its constitutively active oncoprotein Neu, Erb-B3 receptor, and Erb-B4 receptor. In addition, other physiological processes that pass through members of the EGF family of receptors may also be treated with the compounds of the invention described below.
EGFR has two important ligands, Epidermal Growth Factor (EGF) and transforming growth factor alpha (TGF α). This receptor has only a very weak function in adults, but appears to be involved in the disease progression of most cancers, particularly colon and breast cancers. Closely related Erb-B2, Erb-B3 and Erb-B4 receptors have a class of Heregulins as their major ligands, and overexpression and mutation of the receptors have been clearly demonstrated to be major risk factors for poorly predicted breast cancer. In addition, it has been shown that all four members of the receptor family form heterodimeric signaling complexes with other members of the family, resulting in synergistic signaling if more than one member of the family is overexpressed in a malignant tumor. Overexpression of more than one family member has been shown to be quite common in human malignancies.
In addition to cancer, restenosis is also a disease caused by unwanted cell proliferation. Restenosis involves the proliferation of vascular smooth muscle cells. Restenosis is a major clinical problem associated with coronary angioplasty and other medical procedures. Restenosis typically occurs in patients who undergo balloon angioplasty to clear an occluded coronary artery in order to treat heart disease caused by arterial occlusion within about 0 to about 6 months with an incidence of about 30% -50%. The resulting restenosis can cause substantial patient cost in terms of disease and health care.
The process of restenosis is triggered by injury to blood vessels, including arteries and veins, followed by release of prothrombin, vasoactive and mitogenic factors. Injury to the endothelium and deep blood vessels leads to platelet aggregation, thrombosis, inflammation, and activation of macrophages and smooth muscle cells. These events cause the production and release of growth factors and cytokines, which in turn promote their own synthesis and release from the target cell. Thus, a self-sustaining process involving growth factors such as EGF, Platelet Derived Growth Factor (PDGF) or Fibroblast Growth Factors (FGFs) is initiated. Therefore, irreversible inhibitors of signaling pathways, in particular tyrosine kinases such as EGF, PDGF, FGF or src tyrosine kinases, are highly desirable.
There is currently no good treatment for proliferative skin diseases psoriasis. Treatment with anticancer agents such as methotrexate is common, and the drug has very serious side effects and is not very effective at the toxic limit doses that must be used. TGF α is believed to be a major growth factor overproduced in psoriasis, since psoriasis is produced in 50% of transgenic mice overexpressing TGF α. This indicates that good inhibitors of EGFR signalling may be useful as anti-psoriatic agents, preferably, but not necessarily, by topical administration.
Irreversible tyrosine kinase inhibitors have a very significant advantage over reversible inhibitors, since irreversible inhibitors inhibit tyrosine kinases for a long time, which is limited only by the normal rate of receptor resynthesis (also known as recovery).
Additional information on the role of src tyrosine kinase in physiological processes involved in cancer and restenosis may be found in the following references, all of which are incorporated herein by reference.
Benjamin c.w. and Jones D.a, "platelet-derived growth factor stimulates the association of the growth factor receptor binding protein-2 with Src in vascular smooth muscle cells", JBC, 1994; 269: 30911-30916.
Kovalenko M et al, "selective platelet-derived growth factor receptor kinase blockers reverse cis-trans formation", Cancer Res, 1994; 54: 6106-6114.
Schwartz r.s. et al, "The resistance paramigm Revisted: another suggestion for cellular mechanisms ", J Am col Cardio, 1992; 20: 1284-1293.
Libby p, et al, "chain model of restenosis-a specific case of the progression of arteriosclerosis", Circulation, 1992; 86: 47-52.
Other information on the effect of EGF tyrosine kinase on cancer and restenosis in biological processes can be found in the following references, which are incorporated herein by reference.
Jonathan Blay and Morley d.hollenberg, "heterologous modulation of EGF receptor function in cultured aortic smooth muscle cells", Eur J Pharmacal, Mol PharmacolSect, 1989; 172(1): 1-7.
Information on the in vivo anti-tumor activity of antibodies against EGF or EGFR may be found in the following references, which are incorporated herein by reference.
Modjtahedi h., eclles s., Box g., Styles J., Dean C, "immunotherapy of human tumor xenografts overexpressing EGF receptors with rat antibodies that block growth factor-receptor effects", Br J Cancer, 1993; 67: 254-261.
Kurachi h., Morishige k.i., amediya k., Adachi h., Hirota k., Miyake a., Tanizawa O, "importance of transforming growth factor α/epidermal growth factor receptor autocrine growth mechanism in ovarian Cancer cell lines in vivo", Cancer Res, 1991; 51: 5956-5959.
Masui h., moroyamat, Mendelsohn J, "mechanism of anti-epidermal growth factor receptor monoclonal antibody in mice with different isotype profiles" cancer res, 1986; 46: 5592-5598.
Rodeck u., Herlyn m., herlyn.d., Molthoff c., Atkinson b., Varello m., Steplewski z., Koprowski h., "modulation of tumor growth by an epidermal growth factor receptor monoclonal antibody", Cancer Res, 1987; 47: 3692-3696.
Guan e., Zhou t., Wang J., Huang p., Tang w., Zhao m., cheny., Sun Y, "growth inhibition of human nasopharyngeal carcinoma in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies", Internat J Cell Clon, 1989; 7: 242-256.
Masuih, kawamoto t., Sato j.d., Wolf b., Sato g., Mendelsohn J, "growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies," Cancer Res, 1984; 44: 1002-1007.
In addition, the following documents also clearly show the antitumor activity of protein tyrosine kinase inhibitors. These documents are incorporated herein by reference.
Buchdinger e., Trinks u., Mett h., Regenass u., Muller m., Meyer t., McGlynn e., pinana l.a. traxler p., Lydon n n.b. "4, 5-diphenylaminophthalamide: a protein tyrosine kinase inhibitor with selectivity for epidermal growth factor receptor signaling pathway and in vivo antitumor activity, Proc NatlAcad Sci USA, 1994; 91: 2334-2338.
Buchdinger e., Mett h., Trinks u., Regenass u., Muller m., Meyer t., Beilstein p., Wirz b., Schneider p., Traxler p., Lydon n. "4.5-bis (4-fluorophenylamino) phthalic amide: a selective inhibitor of the epidermal growth factor receptor signaling pathway having potent in vivo Mdd antitumor activity, clinical cancer Research, 1995; 1: 813-821.
Compounds that are reversible inhibitors of tyrosine kinases are described in the following patent documents: US5,457,105, 5,475,001 and 5,409,930, and PCT applications WO9519774 and WO 9519970. The compounds disclosed in the present invention have a structure different from that of the tyrosine kinase inhibitors described in the above documents, and the compounds of the present invention are irreversible inhibitors of tyrosine kinase.
Disclosure of Invention
The present invention provides compounds having the following formula I and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
wherein X is-D-E-F, Y is-SR4Halogen, -OR4、-NHR3Or hydrogen, or X is-SR4Halogen, -OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or does not have
E isOrIs composed ofOr
With the proviso that when E isOrIs not provided withOr
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH, -NH2or-N-B, A and B independently being hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl、-(CH2)n-N-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an imidazolyl group;
Z1、Z2or Z3Independently of one another hydrogen, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from Z1、Z2、Z3Or a monocyclic heteroaryl group, and R5Each of (C) above1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; and
n is 1-4, and p is 0 or 1.
In a preferred embodiment of the compounds of the formula I, Z1And Z2Is hydrogen, Z3Is halogen.
In another preferred embodiment of the compounds of formula I, Z3Is bromine.
In another preferred embodiment of the compounds of formula I, bromine is located at the 3-or meta-position of the phenyl ring.
In another preferred embodiment of the compounds of formula I, Z1Is hydrogen, Z2Is F, Z3Is Cl.
In another preferred embodiment of the compounds of formula I, Z1Is hydrogen, Z2Is F, Z3Is Cl, wherein Z2At the 4-position of the phenyl ring and Z3 at the 3-position of the phenyl ring.
In another preferred embodiment of the compounds of formula I,
x isIs a hydrogen atom, and is,or
x is hydrogen and Y is
In another preferred embodiment of the compounds of formula I, Y is-D-E-F, -D-E-F is
Or
In another preferred embodiment of the compounds of formula I, X is-D-E-F, -D-E-F is
Or
In another preferred embodiment of the compounds of formula I, R2Is hydrogen.
In another preferred embodiment of the compounds of formula I, Y is-D-E-F and X is-O- (CH)2)n-a morpholino group.
In another preferred embodiment of the compounds of formula I, R5Is carboxyl, (C)1-C6) Alkoxycarbonyl or C1-C6An alkyl group.
In another preferred embodiment of the compounds of formula I, Y is-D-E-F and X is-O- (CH)2)n-a morpholino group.
In another preferred embodiment of the compounds of formula I, Y is-D-E-F and X is-O- (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]。
In another preferred embodiment of the compounds of formula I, Y is-D-E-F, Xis-O- (CH)2)n-an imidazolyl group.
In another embodiment, the present invention provides a compound of formula II below and pharmaceutically acceptable salts, esters, amides and prodrugs thereof,
wherein Q is
Or
p is 0 or 1;
x is-D-E-F, Y is-SR4、-OR4、-NHR3Or hydrogen, or X is-SR4、-OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or none;
e isOr
Or
With the proviso that when E isOrIs not provided with
Or
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH, -NH2OrA and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an imidazolyl group;
E1、E2or E3Independently of one another, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl radical, - (A)CH2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from E1、E2、E3Or a monocyclic heteroaryl group, and each is (C)1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; and
n is 1-4, and p is 0 or 1.
In a preferred embodiment of the compounds of the formula II, E1And E2Is hydrogen, E3Is halogen.
In another preferred embodiment of the compound of formula II, halogen is bromine.
In another preferred embodiment of the compounds of formula II, bromine is located at the 3-or meta-position of the phenyl ring.
In another preferred embodiment of the compounds of the formula II, E1Is hydrogen, E2Is chlorine, E3Is fluorine.
In another preferred embodiment of the compounds of formula II, Q is
In another preferred embodiment of the compounds of formula II, Q is
In another preferred embodiment of the compounds of formula II, Q is
In another preferred embodiment of the compounds of formula II, Q is
In another preferred embodiment of the compounds of formula II, X is
In another preferred embodiment of the compounds of formula II, X is
In another embodiment, the present invention provides a compound of formula III below and pharmaceutically acceptable salts, esters, amides and prodrugs thereof,
wherein Q is
Or
p is 0 or 1;
x is-D-E-F, Y is-SR4、-OR4、-NHR3Or hydrogen, or X is-SR4、-OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or none;
e isOr
F isOr
With the proviso that when E isOrIs not provided with
Or
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH, -NHzOrA and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an imidazolyl group;
E1、E2or E3Independently of one another, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonyl radicalAlkyl radical, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyrazinyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from E1、E2、E3Or a monocyclic heteroaryl group, and each is (C)1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; and
n is 1 to 4.
In another preferred embodiment of the compounds of formula III, Q is
In another preferred embodiment of the compounds of formula III, Q is
In another preferred embodiment of the compounds of formula III, X is
In another preferred embodiment of the compounds of the formula III, E1And E2Is hydrogen, E3Is bromine.
In another preferred embodiment of the compounds of the formula III, E1Is hydrogen, E2Is chlorine, E3Is fluorine.
In another preferred embodiment of the compounds of formula III, X is
In another preferred embodiment, Q is 6-substituted benzothieno [3, 2-d ] pyrimidin-4-yl.
The invention also provides pharmaceutically acceptable compositions comprising a compound of formula I, II or III.
The present invention also provides a method of treating cancer comprising administering to a cancer patient a therapeutically effective amount of a compound of formula I, II or III.
The present invention also provides a method of treating or preventing restenosis which comprises administering to a patient suffering from restenosis or at risk of restenosis a therapeutically effective amount of a compound of formula I, II or III.
The present invention also provides a method of treating psoriasis comprising administering to a patient with psoriasis a therapeutically effective amount of a compound of formula I, II or III.
The present invention also provides a method of treating atherosclerosis comprising administering to a patient with atherosclerosis a therapeutically effective amount of a compound of formula I, II or III.
The present invention also provides a method of treating endometriosis comprising administering to a patient with endometriosis a therapeutically effective amount of a compound of formula I, II or III.
The present invention also provides a method of irreversibly inhibiting a tyrosine kinase, which comprises administering to a patient in need of tyrosine kinase inhibition a tyrosine kinase inhibiting amount of a compound of formula I, II or III.
The present invention provides the following compounds:
n- [4- (3-bromo-phenylamino) -pyrido [4, 3-d ] -pyrimidin-7-yl ] -N- (3-morpholin-4-yl-propyl) -acrylamide;
n- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] -pyrimidin-6-yl ] -N- (3-morpholin-4-yl-propyl) -acrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -acrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -N- [ 3-morpholinopropyl ] acrylamide;
3- [4- (3-bromo-phenylamino) -quinazolin-7-yl-carbamoyl ] acrylic acid;
3- [4- (3-bromo-phenylamino) -quinazolin-7-yl-carbamoyl ] acrylic acid ethyl ester;
but-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-7-yl ] amide;
n- [4- [ (3-bromo-phenylamino) -6- (3-morpholin-4-yl-propylamino) -quinazolin-7-yl ] -acrylamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -acrylamide;
n- [4- (3-methyl-phenylamino) -quinazolin-7-yl ] -acrylamide;
n- [4- (3-chloro-phenylamino) -quinazolin-7-yl ] -acrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] methacrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] ethenylsulfonamide;
n- [4- [ (3-chloro-phenyl) amino ] -quinazolin-6-yl ] -acrylamide;
n- [4- (3-methyl-phenylamino) -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3- (trifluoromethyl) phenyl) amino ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [3- (4-morpholino) -propoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-methylphenyl) amino ] -7- [3- (4-morpholino) -propoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-methylphenyl) amino ] -7- [3- (4, N-methyl-1, N-piperazinyl) -propoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [3- (4, N-methyl-1, N-piperazinyl) -propoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [3- (1, N-imidazolyl) -propoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [4- (N, N-dimethyl-amino) butoxy ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -N- [ 3-morpholinopropyl ] acrylamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] methacrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] ethenylsulfonamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -E-but-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -4, 4, 4-trifluoro-E-but-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -propynamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -but-2-ynylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [4, 3-d ] pyrimidin-7-yl ] -acrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide;
n- [4- [ (3-methyl-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -N-methacrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] methacrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] ethenylsulfonamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 2-d ] pyrimidin-6-yl ] acrylamide;
n- [4- [ (3-bromo-phenylamino) -benzo [ b ] thieno [3, 2-d ] pyrimidin-8-yl ] -acrylamide;
n- [4- [ (3-bromo-phenylamino) -benzo [ b ] thieno [3, 2-d ] pyrimidin-6-yl ] -acrylamide;
n- [4- [ (3-bromo-phenylamino) -benzo [ b ] thieno [3, 2-d ] pyrimidin-7-yl ] -acrylamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] but-2, 3-dienamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] -E, 4-oxopent-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] -E, 4-ethoxy-4-oxobut-2-enamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] penta-2, 4-dienamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -N- (2-N, N-dimethylamino) ethyl) acrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] E-but-2-enamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] cinnamamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -E, 3-chloro-acrylamide;
n- [4- [ (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] propynamide;
n- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4- (3- (N, N-dimethylamino) propoxy-4-oxobut-2-enamide trifluoracetate;
3- [4- (3-bromo-phenylamino) -quinazolin-6-yl-carbamoyl ] acrylic acid (Z);
n- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4- (3- (N, N-dimethylamino) propylamino-4-oxobut-2-enamide;
4- [ (3-bromo-phenyl) amino ] -6- (ethylenesulfonyl) pyrido [3, 4-d ] pyrimidine;
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] pyrrole-2, 5-dione;
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] prop-2-en-1-one;
4- (3-bromophenylamino) -quinazolin-6-yl acrylate;
n- [4- [ (3-bromophenyl) amino ] -P-vinyl-pyrido [3, 4-d ] pyrimidin-6-yl ] -phosphonamide methyl ester;
4- (3-bromophenylamino) -quinazolin-7-yl acrylate;
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] but-3-en-2-one;
4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinazolin-6-yl acrylate;
n- [4- (3-bromophenylamino) -7- (3-morpholin-4-yl-propoxy) -pyrido [3, 2-d ] pyrimidin-6-yl ] -acrylamide;
penta-2, 3-dienoic acid [4- (3-bromophenylamino) -quinazolin-6-yl ] amide;
propane-1, 2-diene-1-sulfonic acid [4- (3-bromophenylamino) -quinazolin-6-yl ] amide;
n- [4- [ (3-bromophenyl) amino ] -6-quinazolinyl ] -P- (1, 2-allenyl) phosphonamide methyl ester;
n- [1- (3-bromophenylamino) -9H-2, 4, 9-triazafluoren-7-yl ] -acrylamide;
n- [4- (3-bromophenylamino) -9H-1, 3, 9-triazafluoren-6-yl ] -acrylamide;
n- [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -acrylamide;
n- (4-phenylmethylamino-quinazolin-6-yl) -acrylamide;
(S) -N- [4- (1-phenylethylamino) -quinazolin-6-yl ] -acrylamide;
(R) -N- [4- (1-phenylethylamino) -quinazolin-6-yl ] -acrylamide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
n- [4- (3-chloro-4-fluoro-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide;
n- [4- (3-chloro-4-fluoro-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -N-methyl-acrylamide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5- (4-methylpiperazin-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] thiadin-6-yl ] -amide;
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methylpiperazin-1-yl) -ethyl ester;
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (2-imidazol-1-yl) -ethyl ester;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-morpholin-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] amide };
(3-chloro-4-fluorophenyl) - {6- [2- (3-dimethylaminopropoxy) ethanesulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-chloro-4-fluorophenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) butylamino ] -ethanesulfonyl } -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-chloro-4-fluorophenyl) - [6- (5-morpholin-4-yl-pent-1-en-1-sulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
(3-chloro-4-fluorophenyl) - (6-vinylsulfinyl-pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
2-morpholin-4-yl-ethyl 3- [4- (1-phenylethylamino) quinazolin-6-ylcarbamoyl ] acrylate;
but-2-enedioic acid (4-imidazol-1-yl-butyl) -amide [4- (1-phenyl-ethylamino) quinazolin-6-yl ] -amide;
4- [4- (1-phenylethylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 3-diethylaminopropyl ester;
penta-2-enedioic acid 5- { [2- (4-methylpiperazin-1-yl) ethyl ] -amide }1- { [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide };
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
7-imidazol-1-yl-hept-2-ynoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester;
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-imidazol-1-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
(3-bromo-phenyl) - {6- [2- (3-dimethylamino-propoxy) -ethanesulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-bromo-phenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) -butylamino ] -ethanesulfonyl } -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-bromo-phenyl) - [6- (5-morpholin-4-yl-pent-1-en-1-sulfonyl) -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
(3-bromo-phenyl) - (6-ethylene-sulfinyl) -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin 6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
penta-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
(3-chloro-4-fluoro-phenyl) - {6- [2- (3-dimethylamino-propoxy) -ethanesulfonyl ] -quinazolin-4-yl } -amine;
(3-chloro-4-fluoro-phenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) -butylamino ] -ethanesulfonyl } -quinazolin-4-yl } -amine;
but-2-enedioic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester;
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-imidazol-1-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
penta-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
2-morpholin-4-yl-ethyl 3- [4- (1-phenylethylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] acrylate;
but-2-enedioic acid (4-imidazol-1-yl-butyl) -amide [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4- [4- (1-phenylethylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 3-diethylaminopropyl ester;
penta-2-enedioic acid 5- { [2- (4-methylpiperazin-1-yl) ethyl ] -amide }1- { [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide };
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-imidazol-1-yl-hept-2-ynoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
but-2-enedioic acid (4- (3-chloro-4-fluorophenylamino) -7-fluoroquinazolin-6-yl ] -amide (3-dimethylaminopropyl) amide;
but-2-enedioic acid (7-chloro-4- (3-chloro-4-fluorophenylamino) quinazolin-6-yl ] -amide (3-dimethylaminopropyl) amide;
n- [4- [3- (bromophenyl) amino ] -5-fluoro-7- [3- (4-morpholino) propoxy ] quinazolin-6-yl ] -acrylamide; and
n- [4- [ (3- (chloro-4-fluorophenyl) amino ] -5-fluoro-7- [1, N-imidazolyl) propoxy ] quinazolin-6-yl ] -acrylamide.
Detailed Description
The present invention provides a compound of formula I and pharmaceutically acceptable salts, esters, amides and prodrugs thereof,
wherein X is-D-E-F, Y is-SR4Halogen, -OR4、-NHR3Or hydrogen, or X is-SR4Halogen, -OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or none;
e isOr
F isOr
With the proviso that when E isOrIs not provided withOr
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituent is selected from-OH, -NH-2OrA and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an N-imidazolyl group;
Z1、Z2or Z3Independently of one another hydrogen, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl radical、-(CH2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from Z1、Z2、Z3Or a monocyclic heteroaryl group, and each is (C)1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; r13Is hydrogen or halogen; and
n is 1-4, and p is 0 or 1.
In another embodiment, the present invention provides a compound of formula II below and pharmaceutically acceptable salts, esters, amides and prodrugs thereof,
wherein Q is
p is 0 or 1;
x is-D-E-F, Y is-SR4、-OR4、-NHR3Or hydrogen, or X is-SR4、-OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or none;
e isOrIs composed ofOr
With the proviso that when E isOrIs not provided with
Or
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of each otherIs hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituent is selected from-OH, -NH-2OrA and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an imidazolyl group;
E1、E2or E3Independently of one another, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinyl cycloalkyl, sulfinyl cycloalkyl,3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and R5Is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from E1、E2、E3Or a monocyclic heteroaryl group, and each is (C)1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; and
n is 1-4, and p is 0 or 1.
In another embodiment, the present invention also provides a compound of formula III below and pharmaceutically acceptable salts, esters, amides and prodrugs thereof,
wherein Q is
Or
p is 0 or 1;
x is-D-E-F, Y is-SR4、-OR4、-NHR3Or hydrogen, or X is-SR4、-OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or none;
e isOrF isOr
With the proviso that when E isOrIs not provided with
Or
R1Is hydrogen, halogen, C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH, -NH2OrA and B are independently hydrogen, C1-C6Alkyl group, (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl, - (CH)2)n-N-imidazolyl or- (CH)2)n-an imidazolyl group;
E1、E2or E3Independently of one another, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-C1-C6Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, (C)1-C6) Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl may have 1-3 substituents independently selected from E1、E2、E3Or a monocyclic heteroaryl group, and each is (C)1-C6) The alkyl group being optionally substituted by-OH, -NH2or-NAB substitution, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; and
n is 1 to 4.
The term "alkyl" refers to a straight or branched chain hydrocarbon group. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl.
The term "alkoxy" refers to an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups are methoxy, ethoxy, t-butoxy, propoxy and isobutoxy.
The term "halogen" includes chlorine, fluorine, bromine and iodine.
The term "alkenyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds.
The term "cycloalkyl" refers to a cyclic hydrocarbon group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkoxy" refers to a cycloalkyl group attached to an oxygen atom.
The term "perfluoroalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms.
The term "acyl" refers to a group obtained by removing a hydroxyl group (-OH) from an organic acid.
The term "acyloxy" refers to an acyl group attached to an oxygen atom.
The term "thioalkyl" refers to an alkyl group attached to a sulfur atom.
The term "sulfinylalkyl" refers to a sulfinyl group attached to an alkyl group.
The term "sulfonylalkyl" refers to a sulfonyl group attached to an alkyl group.
The term "thiocycloalkyl" refers to a cycloalkyl group attached to a sulfur atom.
The term "sulfinylcycloalkyl" refers to a sulfinyl group attached to a cycloalkyl group.
The term "sulfonylcycloalkyl" refers to a sulfonyl group attached to a cycloalkyl group.
The term "mercapto" refers to the-SH group.
The term "alkoxycarbonyl" refers to an alkoxy group attached to a carbonyl group.
The term "cycloalkyloxycarbonyl" refers to a cycloalkoxy group attached to a carbonyl group.
The term "cycloalkenyl" refers to cyclic hydrocarbon groups having one or more carbon-carbon double bonds.
The term "alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds.
The term "monocyclic heteroaryl" refers to a heterocyclic aryl compound having only one ring structure. The cyclic compound is aromatic and contains one or more heteroatoms. Examples of heteroatoms include, but are not limited to: nitrogen, oxygen, sulfur and phosphorus. Examples of monocyclic heteroaryls include, but are not limited to: pyridine, thiophene and imidazole.
The symbol "-" represents a covalent bond.
The compounds of formulae I, II and III are irreversible inhibitors of tyrosine kinases, particularly EGF tyrosine kinase. A therapeutically effective amount of a compound of formula I, II or III may be administered to a patient with cancer, a patient with restenosis or a patient at risk for restenosis, a patient with psoriasis, a patient with atherosclerosis or a patient with endometriosis. One skilled in the art will readily identify patients with cancer, restenosis, psoriasis, atherosclerosis or endometriosis, or patients likely to have restenosis. The term "patient" refers to animals such as dogs, cats, cattle, sheep, and also includes humans.
The compounds of the invention can be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (powders, ointments or drops), or as an oral or nasal spray. The compounds may be administered alone or as part of a pharmaceutically acceptable composition comprising a pharmaceutically acceptable excipient. It is noted that more than one compound of formula I, II, III may be administered simultaneously or sequentially.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the dispersion, and by the use of surfactants.
These compositions may also contain various adjuvants, such as preservatives, wetting agents, emulsifying agents, dispersing agents. Prevention of the action of microorganisms can be ensured by various bactericides and fungicides, and examples thereof are parabens, chlorobutanol, phenol, sorbic acid, and the like. Likewise, the compositions may also include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof, capsules, tablets and pills, the dosage forms may also contain buffering agents.
Solid compositions of a similar type may also employ excipients such as lactose, and high molecular weight polyethylene glycols and the like as fillers in soft-filled and hard-filled capsules.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, especially cottonseed, groundnut, corn germ, olive, castor, and sesame oils, glycerol, tetrahydroxyfuranol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, bentonite, agar-agar, and tragacanth, or mixtures of these materials and the like.
Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary temperatures and liquid at body temperatures and therefore melt in the rectum or vagina and release the active ingredient.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also within the scope of the present invention.
As used herein, the term "pharmaceutically acceptable salts, esters, amides, and prodrugs" refers to carboxylic acid salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are pharmaceutically suitable for use in contact with the tissues of patients without toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their function, and if possible, zwitterionic forms of the compounds of the present invention. The term "salt" refers to both inorganic and organic acid addition salts of the compounds of the present invention that are relatively non-toxic. These salts may be prepared in situ during the final isolation and purification of the compound or alternatively by reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt formed. Representative salts include hydrobromide, hydrochloride, sulfate, sulfite, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and the like. They may contain cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see, e.g., S.M. Berge et al, "drug salts" J Pharm Sci, 1977; 66: 1-19, which is incorporated herein by reference).
Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include C1-C6Alkyl esters, wherein the alkyl group is a linear or branched group. Acceptable esters also include C5-C7Cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl esters. Preferably C1-C4An alkyl ester. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable non-toxic amides of the compounds of the invention include those consisting of ammonia, C1-C6Alkyl primary amine, C1-C6Secondary dialkylamines, wherein the alkyl group is a straight or branched chain group. In the case of secondary amines, the amines may also be in the form of 5-or 6-membered heterocyclic rings containing one nitrogen atom. Preferably from ammonia, C1-C3Alkyl primary amine, C1-C2Secondary dialkylamines. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to those compounds that are rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. For a detailed discussion, reference may be made to the following documents: t.higuchi and v.stella, "prodrugs as new delivery systems" vol.14 of the a.c.s.symposium Series, and Bioreversible Carriers in Drug Design, ed.edward b.roche, American Pharmaceutical Association and pergamon Press, 1987, all of which are incorporated herein by reference.
The compounds of the invention are administered to the patient at a dose of about 0.1 to 1000 mg/day. For an average adult human weighing about 70kg, about 0.01-100 mg/day/kg body weight is sufficient. Of course, the particular dosage employed may vary. For example, the dosage may vary depending on a variety of factors including the requirements of the patient, the severity of the condition being treated, and the pharmaceutical activity of the compound employed. How to determine the optimal dosage for a particular patient is well known to those skilled in the art.
The compounds of the invention exist in different stereoisomeric forms depending on the presence of their asymmetric centers. It is understood that all stereoisomeric forms of the compounds and mixtures thereof, including racemic mixtures thereof, form part of the present invention.
In addition, the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms for purposes of the present invention.
The compounds of formula I, II or III of the present invention can be produced synthetically or biologically.
The following examples illustrate specific embodiments of the invention, but are not intended to limit the invention to the specification and claims.
General synthetic route
Amino-linked alkylated Michael acceptor side chains
The amine is acylated by an acid in the presence of a coupling agent such as EDAC, or by an acid chloride. Amines are prepared by reduction of the corresponding nitro compound, substitution of the halogen with an amine or ammonia equivalent, or direct incorporation during synthesis when pyrido [4, 3-d ] pyrimidine is used. The 2-haloalkylsulfonyl halide forms a vinylsulfonamide when treated with an acyl amine and an excess of a tertiary amine base.
C/N means that a carbon or nitrogen atom is present at that position.
- - -means a single bond or no bond.
O-linked alkylated Michael acceptor side chains
The hydroxyl group is acylated with an acid in the presence of a coupling agent such as EDAC, or by an acid chloride. The hydroxy compound is prepared by dissociation of the corresponding methyl ether compound. 3-methylthioalkanoic acids or their acid chlorides can be used for the acylation of oxygen, followed by S-alkylation or oxidation and alkali or heat elimination.
Ar and R represent aryl groups, and R represents an organic group exemplified herein.
Carbon-linked alkylated Michael acceptor side chains
Stille and Suzuki coupling reactions can be used to couple the side chain to an appropriate substituted quinazoline/pyridopyrimidine/pyrimidopyrimidine/tricyclic ring. These materials can be prepared as aryl halides by methods well known in the art, as aryl triflates by triflation of the above-mentioned hydroxy compounds, as aryl stannanes by reaction of the above-mentioned triflates with hexamethyldistannane, or as aryl boronic acids by conversion of aryl iodides to aryl organometalates followed by treatment with boronates and hydrolysis. Alternatively, aryl iodides may be converted to aryl zinc species, which are then coupled to an active halogen.
Sulfur-linked alkylated Michael acceptor side chains
The active halogen in pyridopyrimidines and pyrimidopyrimidines can be replaced by suitable 2-hydroxythiolates, which in turn are oxidized to sulfones, and then the water is removed by treatment with methanesulfonyl chloride and several equivalents of a base. For quinazolines and the claimed tricyclic compounds, either an active halogen such as fluorine can be used in the sequence described for pyridopyrimidines, or an acyl iodide precursor can be metallated, quenched with sulfur or a suitable sulfur electrophilic reactant, and the aryl thiol formed then used to open the terminal epoxide to give a 2-hydroxy thioether which can be converted to a vinyl sulfone by the oxidation and water elimination processes described previously.
Hydrazino-linked alkylated Michael acceptor side chains
The active halogen and moderately substituted quinazolines in pyridopyrimidines and pyrimidopyrimidines may be substituted with (N-alkyl) hydrazines. Alternatively, the amino derivative of the desired cyclic nucleus can be diazotized and then reduced to hydrazine. The terminal nitrogen of the hydrazine can then be acylated, sulfonylated, or phosphorylated by methods well known to those skilled in the art.
hydroxylamino-O-linked alkylated Michael acceptor side chains
The active halogen and moderately substituted quinazolines in pyridopyrimidines and pyrimidopyrimidines may be substituted with a suitable O-protected (N-alkyl) hydroxylamine. Alternatively, nitro derivatives of the desired cyclic nucleus can be synthesized and then reduced to hydroxylamine under suitable mild reducing conditions. The oxygen of the hydroxylamine may then be acylated, sulfonylated, or phosphorylated by methods well known to those skilled in the art.
methyleneamino-N-linked alkylated Michael acceptors
The active halogen and the moderately substituted quinazolines in pyridopyrimidines and pyrimidopyrimidines may be cyanide-substituted, preferably under catalysis by copper or nickel salts. Alternatively, the amino derivative of the desired cyclic nucleus may be diazotized and then converted to the nitrile as described above. In some cases, nitrile functions may be introduced into the heterocycle at an early stage of the synthesis, either by itself or via a carboxylic acid or anhydride, both of which are readily converted to nitrile compounds by those skilled in the art. The reduction of the nitrile to the methylene amine can then be achieved by nitrogen acylation, sulfonylation, or phosphorylation by methods well known to those skilled in the art.
Methyleneoxy-O-linked alkylated Michael acceptor side chains
The methylol compound may be incorporated into a suitable heterocyclic compound in a variety of ways well known to those skilled in the art. For example, iodoquinazolines may be carbonylated in a Heck reaction followed by NaBN4Reduced to the desired precursor. Aminopyrido-pyrimidines may be diazotized, converted to nitriles, partially reduced to imines, hydrolyzed, and the aldehyde formed reduced to the hydroxymethyl compound. The oxygen of the hydroxymethyl compound is then acylated, sulfonylated, or phosphorylated by methods well known to those skilled in the art.
Bridged ethylene-linked alkylated Michael acceptor side chains
If desired, Michael addition of the cuprate obtained from iodoquinazoline via organozincate to divinyl ketone, or a suitable mono masked derivative, followed by unmasking of the second unsaturated functionality, will give the desired type of compound. The aldehyde derived from a pyridopyrimidine or pyrimidopyrimidine as previously described can be reacted (homologate) to the desired compound by a variety of techniques, such as those illustrated by those skilled in the art.
aminomethyl-C-linked alkylated Michael acceptor side chains
Amino heterocycles of the type described by this application can be alkylated via the various double bond masked equivalents of 1-bromo-but-3-en-2-one and subsequently deblocked by unsaturation by methods well known to those skilled in the art.
hydroxymethyl-C-linked alkylated Michael acceptor side chains
Hydroxy heterocycles prepared from methoxy-heterocycles as described above can be alkylated by the various double bond masked equivalents of 1-bromo-but-3-en-2-one and then subjected to unsaturated unmasking by methods well known to those skilled in the art. Alternatively, alkylation of phenol can be accomplished with chloroacetic acid, which is converted to the acid chloride, and Stille coupling of the acid halide to the appropriate alkenyl stannane.
Thiomethyl-C-linked alkylated Michael acceptor side chains
Suitable mercapto-heterocycles can be prepared by substitution of an activated halogen on the heteroaromatic ring, which can be alkylated by the various double bond masked equivalents of 1-bromo-but-3-en-2-one. The unsaturated unmasking is then carried out by methods well known to the person skilled in the art. Alternatively, alkylation of the thiol can be accomplished with chloroacetic acid, which is converted to the acid chloride, and Stille coupling of the acid halide to the appropriate alkenyl stannane.
Example 1
N- [4- (3-bromo-phenylamino) -pyrido [4, 3-d]Pyrimidin-7-yl]-N- (3-morpholin-4-ylpropyl) -propane
Alkeneamides
General procedure a:
acylation of 7-amino-4- [ (3-bromophenyl) amino ] -pyrido [4, 3-d ] pyrimidine can be carried out according to methods well known to those skilled in the art [ J Med Chem, 1995: 3780] to obtain N- [4- (3-bromo-phenylamino) -pyrido [4, 3-d ] pyrimidin-7-yl ] -N- (3-morpholin-4-ylpropyl) -acrylamide. For example, acylation with acrylic acid can be achieved by using standard condensation reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (EDAC) or by using acryloyl chloride and a tertiary base such as diisopropylethylamine as an acid scavenger.
The N-alkylation of the-acrylamide can then be carried out by methods known to those skilled in the art. For example, treatment with standard reagents such as sodium hydride converts the amide to its monoanion, which is subsequently substituted with a suitable halide such as N- (3-chloropropyl) morpholine or N- (4-chlorobutyl) morpholine to give the desired alkylated amide.
General procedure B:
n- [4- (3-bromo-phenylamino) -pyrido [4, 3-d ] pyrimidin-7-yl ] -N- (3-morpholin-4-ylpropyl) -acrylamide may also be prepared by: 7-fluoro-4- [ (3-bromophenyl) amino ] -pyrido [4.3-d ] pyrimidine is treated with N- (3-aminopropyl) morpholine in dimethylsulfoxide and acylated with acrylic acid and a coupling reagent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (EDAC) or acryloyl chloride and a tertiary base such as diisopropylethylamine according to methods well known to those skilled in the art. See, for example, WO9519774a 1.
Example 2
N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-N- (3-morpholin-4-ylpropyl) -propane
Alkeneamides
Stirring 4- [ (3-bromo-phenyl) amino at 0 ℃ under nitrogen]-6- [ (3-morpholinopropyl) amino group]Pyrido [3, 4-d]Pyrimidine (400mg, 0.90mmol) (prepared from 4- [ (3-bromo-phenyl) amino]-6-fluoropyrido [3, 4-d]Pyrimidine and 3-morpholinopropan-1-ylamine), DMAP (40mg) and Et3To a solution of N (excess, 2.0mL) was added acryloyl chloride (1.2 molar equivalents, 1.08mmol, 89. mu.L). After stirring for 1 hour, two more portions of acid chloride (89. mu. each) were added over 2 hoursL), the reaction mixture was stirred at 20 ℃ for 1 hour, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel using methanol/ethyl acetate (1:9) to methanol/ethyl acetate (1:5) as eluents to give N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ]]Pyrimidin-6-yl]N- (3-Morpholinopropyl) -acrylamide (142mg, 32%) as a cream-white powder, mp (dichloromethane/hexane) 178-.
1H NMR[(CD3)2SO]: δ 10.15(s, 1H, NH), 9.15(s, 1H, aromatic), 8.80(s, 1H, aromatic), 8.47(s, 1H,
aromatic), 8.21(br s, 1H, H-2 '), 7.92(br d, J ═ 7.6Hz, 1H, H-6'), 7.41(t, J ═ 8.0Hz, 1H, H-5 '), 7.37(dt, J ═ 8.1Hz, J ═ 1.6Hz, 1H, H-4'), 6.25(m, 2H, CH), 2, c, H2CHCO，CH2CHCO)，5.66(m，1H，CH2CHCO)，3.98(t，J＝7.5Hz，2H，CH2NRCO), 3.46(t, J ═ 4.5Hz, 4H, morpholinomethylene), 2.29(t, J ═ 7.1Hz, 2H, CH)2CH2CH2NRCO)，2.24(br s，4H，
Morpholinomethylene), 1.73 (quintet, J ═ 7.2Hz, 2H, CH)2CH2CH2).
13C NMR：δ 164.84，156.69，155.80，151.83，150.05，143.01，140.02，130.51，129.27，127.88，126.76，124，32，121.19，120.82，113.02，66.02(×2)，55.05，53.02(×2)，45.8，24.63。
To C23H25BrN6O2·H2Elemental analysis of O:
calculated values: c, 53.6; h, 5.3; n, 16.3 percent.
Measured value: c, 53.8; h, 5.0; n, 16.3 percent.
Example 3
N- [4- (3-bromo-phenylamino) -quinazolin-7-yl]-acrylamide
To 7-amino-4- (3-bromoanilino) quinazoline (0.158g (0.5mM)) [ J Med Chem 1995: 3482] to an ice-cooled solution of acrylic acid (0.108g) in anhydrous dimethylformamide (DMF, 5.0mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC) (0.288 g). After stirring for 5 minutes, the mixture became a solution and the ice bath was removed. The reaction mixture was stirred at room temperature for a further 3 hours. The reaction mixture was then poured into a mixture of ice and water and made basic by the addition of saturated sodium bicarbonate solution. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give a pale yellow solid. The solid was dissolved in 100mL of methanol, filtered and concentrated in vacuo to about 10 mL. The solid precipitated from the solution was collected and dried under vacuum at 80 ℃ to give 50mg of N- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -acrylamide, mp >265 ℃. Chemical ionization mass spectrometry: m/e 369.
1H NMR(D6-dimethyl sulfoxide): δ 5.86(dd, 1H, J ═ 10.1, J ═ 1.9), 6.36(dd, 1H, J ═ 17.0, J ═ 1.9), 6.51(dd, 1H, J ═ 16.9, J ═ 10.1), 7.30(m, 1H), 7.36(t, 1H, J ═ 8.1), 7.82(dd, 1H, J ═ 9.2, J ═ 2.2), 7.9(d, 1H, J ═ 8.0), 8.25(dd, 1H, J ═ 3.6, J ═ 1.9), 8.50(d, 1H, J ═ 8.9), 8.61(s, 1H), 9.79(s, 1H, -NH), 10.61(s, 1H, -NH).
To C17H13BrN4Elemental analysis of O:
calculated values: c, 55.30; h, 3.55; and N, 15.17.
Measured value: c, 55.49; h, 3.63; and N, 15.26.
Example 4
N- [4- (3-bromo-phenylamino) -quinazolin-7-yl]-N- [ 3-morpholinopropyl group]-acryloyl groupAmines as pesticides
To a solution of 4- [ (3-bromo-phenyl) amino ] -7-fluoroquinazoline (0.60g, 1.89mmol) in Dimethylsulfoxide (DMSO) (10mL) was added 4- (3-aminopropyl) morpholine (7.54mmol, 1.10 mL). The reaction mixture was heated at 110 ℃ for 26 hours, then diluted with water, basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography on grade III alumina eluting with a gradient of ethyl acetate to ethyl acetate/methanol (98: 2) followed by recrystallization from ethyl acetate/hexane afforded 4- [ (3-bromo-phenyl) amino ] -7- [ (3-morpholinopropyl) amino ] -quinazoline (0.65g, 78%) as cream crystals, mp162-162.5 ℃.
1H NMR[(CD3)2SO，200MHz]：δ 9.41(s，1H，NH)，8.43(s，1H，H-2)，8.24(br s，1H，H-2′)，8.18(d，J＝9.2Hz，1H，H-5)，7.87(br d，J＝8.1Hz，1H，H-6′)，7.35-7.18(m，2H，H-4′，5′)，6.88(dd，J＝1.9Hz，J＝9.1Hz，1H，H-6′)，6.65(t，J＝5.3Hz，1H，CH2NH), 6.62(br s, 1H, H-8), 3.60(t, J ═ 4.6Hz, 4H, morpholinomethylene), 3.19(dt, J ═ 6.4Hz, J ═ 5.8Hz, 1H, CH2CH2NH)，2.43-2.33(m，6H，
Morpholinomethylene, CH2CH2CH2NH), 1.75 (quintet, J ═ 6.8Hz, 1H, CH)2CH2CH2).
13C NMR：δ 156.56，154.27，152.41，152.32，141.60，130.15，124.90，123.41，123.31，121.06，119.87，116.51，105.68，102.21，66.13(×2)，55.81，53.31(×2)，40.46，25.14
To the above-mentioned 4- [ (3-bromo-phenyl) amino group under a nitrogen atmosphere]-7- [ (3-morpholinopropyl) amino group]To a solution of (0.10g, 0.230mmol) of quinazoline in anhydrous DMF (5.0ml) were added acrylic acid (0.565mmol, 39. mu.L), triethylamine (100. mu.L) and 1- (3-dimethylaminopropyl) -3-ethylCarbodiimide hydrochloride (EDCI. HCl) (0.565mmol, 108mg) and the reaction mixture was stirred at room temperature for 4 days, to which were added acrylic acid (40. mu.L), triethylamine (100. mu.L) and EDCI. HCl (100mg) daily. Thereafter, DMF was removed in vacuo and the resulting residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Subjecting to silica gel column chromatography, and performing gradient elution with methanol/ethyl acetate/dichloromethane (1:4:5) to methanol/ethyl acetate/dichloromethane (2:4:4) at high RfObtaining N- [4- (3-bromo-phenylamino) -quinazolin-7-yl]-N- [ 3-morpholinopropyl group]Acrylamide (39mg, 35%) as a white powder, mp (ethyl acetate/hexane) 86-88 ℃ (decomposed).
1H NMR[(CD3)2SO，200MHz]: δ 9.96(s, 1H, NH), 8.68(s, 1H, H-2), 8.63(d, J ═ 8.7Hz, 1H, H-5), 8.23(br s, 1H, H-2 '), 7.91(dt, J ═ 7.3Hz, J ═ 2.0Hz, 1H, H-6 '), 7.68-7.58(m, 2H, aromatic), 7.42-7.31(m, 2H, aromatic), 6.18(m, 2H, CH-6 '), and so forth2CHCO，CH2CHCO)，5.63(dd，J＝2.0Hz，J＝10.0Hz，1H，CH2CHCO)，3.90(t，J＝7.1Hz，2H，CH2CH2CH2NCO), 3.51(t, J ═ 4.3Hz, 4H, morpholinomethylene) 2.50(br s, 2H, CH)2CH2CH2NCO), 2.28(br s, 4H, morpholinomethylene), 1.67 (quintet, J ═ 6.5Hz, 2H, CH)2CH2CH2) At low RfNext, the starting material, 4- [ (3-bromo-phenyl) amino group, was recovered]-7- [ (3-morpholinopropyl) amino group]Quinazoline (34%), identical to authentic samples.
Example 5
3- [4- (3-bromo-phenylamino) -quinazolin-7-ylcarbamoyl]Acrylic acid
To a solution of 7-amino-4- (3-bromoanilino) quinazoline (0.158g) [ J Med Chem 1995: 3482] to a solution of tetrahydrofuran (10ml) was added maleic anhydride (0.059 g). The cold solution was stirred for 15 minutes, then the ice bath was removed. The reaction mixture was warmed to room temperature and stirred for an additional 15 hours. The suspension was heated at reflux for 30 minutes and then stirred at room temperature for a further 15 hours. Further, maleic anhydride (0.059g) and tetrahydrofuran (20ml) were added to the reaction solution, and the reaction mixture was refluxed for another 2 hours. After a further 15 hours of treatment at room temperature, the reaction mixture is refluxed for 15 hours. The reaction mixture was filtered and the light brown solid was first recrystallized from dimethylformamide and then from methanol to give 0.036g of the desired product.
1H NMR[(CD3)2SO]: Δ 12.95(br s, 1H, and D)2O exchange), 11.04(br s, 1H, and D2O exchange), 9.81(br s, 1H, and D)2O exchange), 8.62(s, 1H), 8.49(d, J ═ 9.2Hz, 1H), 8.24(s, 1H), 8.17(d, J ═ 1.7Hz, 1H), 7.90(d, J ═ 8.4Hz, 1H), 7, 78(d, J ═ 9.2Hz, 1H), 7.36(t, J ═ 8.1Hz, 1H), 7.30(dd, J ═ 1Hz, 9Hz, 1H), 6.50(d, J ═ 12.1Hz, 1H), 6.37(d, J ═ 11.8Hz, 1H);
CIMS m/z (relative))：411.3(95)，412.3(23)，413.3(100)，414.3(21)
To C18H13BrN4O3Elemental analysis of (2):
calculated values: c, 52.32; h, 3.17; n, 13.56.
Measured value: c, 52.57; h, 3.51; and N, 13.16.
Example 6
3- [4- (3-bromo-phenylamino) -quinazolin-7-ylcarbamoyl]Acrylic acid ethyl ester
To an ice-cooled solution of 7-amino-4- (3-bromoanilino) -quinazoline (0.158g) and monoethyl fumarate (0.216g) in anhydrous dimethylformamide (3ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC) (0.288 g). 7-amino-4- (3-bromoanilino) -quinazoline was prepared according to methods well known to those skilled in the art. See: j Med Chem, 1995: 3482 which is incorporated herein by reference. After stirring at 5 ℃ for 5 minutes, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for a further 15 hours. The reaction mixture was poured into cold water and saturated sodium bicarbonate solution was added to basify the suspension. The solid formed was collected by filtration, washed with water and recrystallized from 50ml of ethanol to give 0.052g of the desired product, mp >260 ℃.
1H NMR[(CD3)2SO]: Δ 10.99(br s, 1H, and D)2O exchange), 9.82(br s, 1H,. and D)2O exchange), 8.62(s, 1H), 8.52(d, J ═ 8.9Hz, 1H), 8.24(s, 2H), 7.90(d, J ═ 8.2Hz, 1H), 7.81(dd, J ═ 1.7Hz, 8.9Hz, 1H), 7.34(m, 2H), 7.26(d, J ═ 15.7Hz, 1H), 6.79(d, J ═ 15.4Hz, 1H), 3.33(q, J ═ 7.0Hz, 14.2Hz, 2H), 1.28(t, J ═ 7.0Hz, 3H);
CIMS m/z (relative))：440(19％)，441(100)，442(37)，443(78).
To C20H17BrN4O3Elemental analysis of (2):
calculated values: c, 54.44; h, 3.88; n, 12.70; br, 18.11.
Measured value: c, 54.32; h, 3.85; n, 12.76; br, 17.89.
Example 7
N- (3-bromo-phenyl) -quinazolin-4-yl-amines
N- (3-bromo-phenyl) -quinazolin-4-yl-amine is prepared according to methods well known to those skilled in the art. See, for example: j Med Chem, 1995: 3482-3487.
Example 8
4- (3-bromo-phenylamino) -6, 7-dimethoxyquinazoline
4- (3-bromo-phenylamino) -6, 7-dimethoxyquinazoline was prepared according to methods well known to those skilled in the art. See, for example: EP 566226 a 1.
Example 9
But-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-7-yl]Amides of carboxylic acids
To an ice-cooled tetrahydrofuran (5ml) solution of 7-amino-4- (3-bromoanilino) -quinazoline (0.158g) (J Med Chem, 1995: 3482) was added dropwise a tetrahydrofuran (5ml) solution of crotonyl chloride (0.105 g). When the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture is filtered off, the yellow solid is filtered off, washed with tetrahydrofuran and recrystallized from 20ml of boiling methanol to yield 0.060g of the desired product, mp >250 ℃.
1H NMR[(CD3)2SO]: Δ 11.44(br s, 1H, and D)2O exchange), 11.04(s, 1H, and D2O exchange), 8.92(s, 1H), 8.78(d, J ═ 9.2Hz, 1H), 8.52(d, J ═ 1.9Hz, 1H), 8.05(t, J ═ 1.8Hz, 1H), 7.91(dd, J ═ 2.1Hz, 9.3Hz, 1H), 7.76(m, 1H), 7.52(m, 1H), 7.45(t, J ═ 8.0Hz, 1H), 6.70(m, 1H), 6.28(dd, J ═ 1.7Hz, 15.1Hz, 1H), 1.92(dd, J ═ 1.6Hz, 6.9Hz, 3H);
CIMS：382(21)，383(100)，384(34)，385(64).
to C18H15BrN4O·1HCl·0.5H2Elemental analysis of O:
calculated values: c, 50.43; h, 4.00; n, 13.07; br, 18.64; cl, 8.27.
Measured value: c, 50.71; h, 4.00; n, 12.98; br, 18.93; cl, 7.51.
Example 10
N- [4- (3-bromo-phenylamino) -6- (3-morpholin-4-yl-propylamino) -quinazolin-7-yl]Amides of carboxylic acids
With thionyl chloride or POCl3Treatment of 6-chloro-7-nitroquinazolin-4-one (Aust JChem, 1995; 48: 227-. Reaction with 3-bromoaniline affords 4- (3-bromophenylamino) -6-chloro-7-nitroquinazoline and 4-chloro-6- (3-bromophenylamino) -7-nitroquinazoline, which are separated by column chromatography. Treatment of the desired 4- (3-bromophenylamino) -6-chloro-7-nitroquinazoline with N- (3-aminopropyl) morpholine followed by reaction of the nitro functional group with iron, for example in acetic acid, affords 7-amino-4- (3-bromo-phenylamino) -6- (3-morpholin-4-yl-propylamino) quinazoline. Acylation was carried out in the same manner as in example 3 to give-acrylamide.
Example 11
N- [4- (3-bromo-phenylamino) quinazolin-6-yl]Acrylamide
To a solution of 6-amino-4- [ (3-bromophenyl) amino ] -quinazoline (2.0g, 6.35mmol) in anhydrous DMF (20ml) under a nitrogen atmosphere was added acrylic acid (12.7mmol, 0.87 ml). The resulting solution was cooled to 0 deg.C and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (7.62mmol, 1.46g) was added. The reaction mixture was stirred at 0 ℃ for 15 minutes, then allowed to warm to room temperature and stirred for a further 2 hours, after which acrylic acid (0.30ml) and (EDCI. HCl) (0.30g) were added. After stirring for a further 2 hours, the reaction was confirmed to be complete by TLC, the solvent was removed under reduced pressure and the residue formed was diluted with saturated sodium bicarbonate and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography over grade III alumina eluting with ethyl acetate/methanol (95:5) and then ethyl acetate/hexane to give a spongy white solid which was recrystallized under high vacuum over several hours to give N- [4- (3-bromophenyl) amino ] quinazolin-6-yl ] -acrylamide (1.06g, 45%) as a cream powder, mp 258-.
1H NMR[(CD3)2SO，200MHz]：δ 10.51(s，1H，CONH)，9.93(s，1H，NH)，8.83(br s，1H，H-5)，8.59(s，1H，H-2)，8.18(br s，1H，H-2′)，7.94-7.78(m，3H，H-6′，8，5′)，7.40-7.27(m，2H，H-7，4′)，6.54(dd，J＝9.8Hz，J＝17.0Hz，1H，CH2CHCO)，6.36(dd，J＝2.1Hz，J＝16.9Hz，1H，CH2CHCO)，5.85(dd，J＝2.0Hz，J＝9.7Hz，1H，CH2CHCO).
Mass spectrum (CI): 371(95,81BrMH+)，370(53，81BrM+)，369(100，79BrMH+)，368(33，79BrM+).
to C17H13BrN4Elemental analysis of O:
calculated values: c, 55.30; h, 3.55; and N, 15.17 percent.
Measured value: c, 55.19; h, 3.34; n, 14.88 percent.
Example 12
N- [4- (N, N-dimethylamino) -quinazolin-6-yl]-acrylamide
6-Nitro-quinazolinone (3.50g, 18.5mmol) was dissolved in pure SOCl containing two drops of DMF2The suspension in (30ml) was refluxed for 3 hours until it was clear. Removing excess SOCl under reduced pressure2Anhydrous benzene was added and evaporated under reduced pressure to remove all traces of SOCl2. The resulting crude 4-chloro-6-nitroquinazoline was dissolved in anhydrous dichloromethane (50ml), washed 2 times with saturated sodium carbonate and then the solution was added to a solution of triethylamine (excess, 7.0ml) in 4-amino-2-bromo-N, N-dimethylbenzylamine (20.3mmol, 4.64g) in isopropanol (60 ml). The resulting reaction mixture was heated under reflux for 3 hours, then concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. Drying the combined organic extracts with anhydrous sodium sulfate, concentrating under reduced pressure, treating with silica gel chromatography, and separating with silica gel column chromatographyMethyl chloride/ethyl acetate (1:1) to methanol/dichloromethane/ethyl acetate (2:9:9) to give 4-N, N-dimethylamino-6-nitroquinazoline (2.56g, 64%) as yellow crystals, mp (dichloromethane) 131-.
1H NMR[(CD3)2SO]，(400MHz)：δ 9.02(d，J＝2.4Hz，1H，H-5)，8.59(s，1H，H-2)，8.47(dd，J＝2.5Hz，J＝9.2Hz，1H，H-7)，7.85(d，J＝9.2Hz，1H，H-8)，3.46(s，6H，N(CH3)2).
Further elution gave 2-bromo-N, N-dimethyl-4- (6-nitroquinazolin-4-yl) benzylamine (0.62g, 8%) as a yellow powder, mp (dichloromethane) 198 ℃.
1H NMR[(CD3)2SO]，(400MHz)：δ 10.47(br s，1H，NH)，9.66(d，J＝2.4Hz，1H，H-5)，8.77(s，1H，H-2)，8.57(dd，J＝9.2Hz，J＝2.5Hz，1H，H-7)，8.21(d，J＝2.0Hz，1H，H-2′)，7.95(d，J＝9.1Hz，1H，H-8)，7.91(dd，J＝8.4Hz，1H，H-6′)′7.49(d，J＝8.5Hz，1H，H-5′)，3.46(s，2H，CH2N(CH3)2)，2.22(s，6H，N(CH3)2).
To C17H16BrN5O20·1.5H2Elemental analysis of O:
calculated values: c, 47.6; h, 4.5; n, 16.3 percent.
Measured value: c, 47.7; h, 4.2; and N, 15.7 percent.
To a refluxing ethanol/water (2:1, 90ml) solution of the above 4-N, N-dimethylamino-6-nitroquinazolinamine (1.20g, 5.50mmol) containing glacial acetic acid (4.0ml) was added iron powder (4 molar equivalents, 1.24g) freshly washed (with 1N hydrochloric acid and then distilled water) in portions. The same reaction procedure as above was repeated, followed by silica gel chromatography eluting with dichloromethane/ethyl acetate (1:1) to methanol/dichloromethane/ethyl acetate (1:4:5) to give 4-N, N-dimethylamino-6-aminoquinazoline (0.87g, 84%) as a light brown powder, mp (dihydrochloride from methanol/diethyl ether) 258-.
1H NMR (dihydrochloride) [ (CD)3)2SO]，(400MHz)：δ 14.8(br s，1H，NH+)，8.65(s，1H，H-2)，7.79(m，2H，H-5，H-8)，7.57(dd，J＝2.1Hz，J＝8.9Hz，1H，H-7)，5.70(br s，3H，NH3 +)，3.55(s，6H，N(CH3)2).
To a stirred DMA (20ml) solution containing the above 4-N, N-dimethylamino-6-aminoquinazoline (0.65g, 3.45mmol), acrylic acid (4 molar equivalents, 13.8mmol, 0.95ml) and pyridine (excess, 1.3ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (2 molar equivalents, 6.90mmol, 1.32g) under nitrogen. The standard procedure described above was followed by silica gel chromatography eluting with methylene chloride/ethyl acetate (1:1) to methanol/methylene chloride/ethyl acetate (1:4:5) to give [4- (N, N-dimethylamino) quinazolin-6-yl ] -acrylamide (350mg, 42%) as a cream powder, mp (methylene chloride/hexane) 204-.
1H NMR[(CD3)2SO]，(400MHz)：δ 10.49(s，1H，CONH)，8.80(d，J＝2.2Hz，1H，H-5)，8.46(s，1H，H-2)，7.88(dd，J＝2.4Hz，J＝9.1Hz，1H，H-7)，7.73(d，J＝9.0Hz，1H，H-8)，6.47(dd，J＝17.0Hz，J＝10.1Hz，1H，CH2CHCO)，6.34(dd，J＝17.0Hz，J＝2.0Hz，1H，CH2CHCO)，5.83(dd，J＝10.1Hz，J＝2.0Hz，1H，CH2CHCO)，3.32(s，6H，N(CH3)2).
Example 13
N- [4- (3-methyl-phenylamino) -quinazolin-7-yl]-acrylamide
To a stirred solution of 7-amino-4- [ (3-methylphenyl) amino ] quinazoline (123mg, 0.49mmol), acrylic acid (0.04ml, 0.58mmol), triethylamine (0.15ml, 1.1mmol) in DMF (1.5ml) at 0 deg.C was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (123mg, 0.64 mmol). The resulting pale yellow mixture was stirred at 25 ℃ for 20 hours and the reaction was stopped with water. The solid was collected and purified by sonication with a mixture of dichloromethane/ethyl acetate/methanol to give the desired product (75mg, 49%) as a yellow solid, mp269.7-270 ℃.
1H NMR[(CD3)2SO]：δ 10.63(s，1H，NH)，9.68(s，1H，NH)，8.58(s，1H，H2)，8.54(d，J＝9.3Hz，1H，H6)，8.25(d，J＝2.2Hz，1H，H8)，7.83(dd，J＝9.0，1.9Hz，1H，H5)，7.71(m，2H，H2′，H6′)，7.32(t，J＝8.3Hz，1H，H5′)，6.99(d，J＝7.1Hz，1H，H4′)，6.56(dd.J＝16.8，10.0Hz，1H，CH＝CH2)，6.40(dd.J＝17.1，5.0Hz，1H，CH＝CH2)，5.9(dd，J＝10.3，2.0Hz，1H，CH＝CH2)，2.39(s，3H，CH3).
Mass spectrum (CI): 305(100, MH)+)，304(31.84，M+).
To C18H16N4O·0.4H2Elemental analysis of O:
calculated values: c, 69.39; h, 5.44; n, 17.94 percent.
Measured value: c, 69.19; h, 5.19; n, 17.67%.
Example 14
N- [4- (3-chloro-phenylamino) -quinazolin-7-yl]-acrylamide
To a stirred solution of 6-amino-4- [ (3-chlorophenyl) amino ] quinazoline (136mg, 0.5mmol) and acrylic acid (108mg, 1.5mmol) in DMF (5ml) at 0 ℃ under a nitrogen atmosphere was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288mg, 1.5 mmol). After 15 minutes, it was stirred at 25 ℃ for 18 hours, then poured into ice water (50ml), and after 1 hour, the precipitate was collected by filtration through a buchner funnel. The residue was rinsed, air dried and dissolved in a small amount of methanol (60ml) at 25 ℃. Concentration to less than 10ml at 25 ℃ under reduced pressure and recrystallisation at 0 ℃ gave N- [4- (3-chloro-phenylamino) -quinazolin-7-yl ] -acrylamide (33mg, 20%) as a pale orange solid, mp296.5-298.5 ℃.
To C17H13ClN4O·0.08CH3OH·0.25H2Elemental analysis of O:
calculated values: c, 61.82; h, 4.20; n, 116.89 percent.
Measured value: c, 69.19; h, 4.23; and N, 116.72 percent.
1H NMR[(CD3)2SO]：δ 10.61(brs，1H，NH)，9.80(s，1H，NH)，8.62(s，1H，H2)，8.50(d，J＝9.0Hz，H5)，8.25(d，J＝2.0Hz，1H，H8)，8.13(t，J＝2.0Hz，1H，H2′)，7.87-7.78(m，2H，H6 & H6′)，7.42(t，J＝8.2Hz，1H，H5′)，7.16(dd，J＝2.2，7.9Hz，1H，H4′)，6.51(dd，J＝10.0，17.1Hz，1H，CH＝CH2)，6.35(dd，J＝1.8，17.1Hz，1H，CH＝CH2)，5.86(dd，J＝1.8，10.1Hz，1H，CH＝CH2).
The mass spectrum (CI)327(32,37ClMH+)，326(25，37ClM+，13C35ClMH+)，325(100，35ClMH+)，322(22，35ClMH+).
example 15
N- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -methacrylamide
To a stirred solution of 7-amino-4- [ (3-bromophenyl) amino ] quinazoline (J Med Chem, 1995; 38: 3482) (150mg, 0.48mmol) in anhydrous DMF (20ml) was added methacrylic acid (200mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (228mg, 2.5 mmol). After the reaction mixture was stirred overnight, EDI.HCl (230mg) and methacrylic acid (200mg) were added thereto. After a further 2 days, the solvent is removed in vacuo, the residue is diluted with saturated sodium bicarbonate, extracted with ethyl acetate, the combined organic extracts are dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel using methanol/dichloromethane/ethyl acetate (5:45:50) to methanol/dichloromethane/ethyl acetate (10:40:50) to give N- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -methacrylamide (43mg, 24%) as a light brown solid, mp (dichloromethane/hexane) 255-.
1H NMR[(CD3)2SO]，(400MHz)δ 10.22(s，1H，CONH)，9.76(s，1H，NH)，8.61(s，1H，H-2)，8.48(d，J＝9.2Hz，1H，H-5)，8.26(m，2H，H-2′，8)，7.92(m，2H，H-6′，6)，7.36(t，J＝8.0Hz，1H，H-5′)，7.30(br d，J＝8.3Hz，1H，H-4′)，5.92(s，1H，CH2C(CH3)CO)，5.63(s，1H，CH2C(CH3)CO)，2.00(s，3H，CH2C(CH3)CO).
To C18H15BrN4Elemental analysis of O:
calculated values: c, 56.4; h, 4.0; n, 14.6 percent.
Measured value: c, 56.1; h, 4.0; n, 14.1 percent.
Example 16
N- [4- (3-bromo-phenylamino) -quinazolin-7-yl]Vinyl-sulfonamides
A solution of 7-amino-4- [ (3-bromophenyl) amino ] quinazoline (J MedChem, 1995; 38: 3482) (500mg, 1.59mmol), triethylamine (0.60ml) and a catalytic amount of dimethylaminopyridine DMAP (THF) (30ml) was reacted with chloroethanesulfonyl chloride (1.6 molar equivalents, 2.54mmol, 265. mu.L) at 25 ℃ for 1 hour with stirring under a nitrogen atmosphere. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, chromatographed on silica gel eluting with methanol/dichloromethane/ethyl acetate (3:47: 50). Recrystallization from dichloromethane/hexane gave N- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] vinyl-sulfonamide (80mg, 12%) as a cream powder, which was decomposed (dec) at mp218 ℃.
1H NNR[(CD3)2SO]，(400MHz)δ 10.73(s，1H，SO2NH)，9.80(s，1H，NH)，8.59(s，1H，H-2)，8.47(d，J＝9.1Hz，1H，H-5)，8.21(br s，1H，H-2′)，7.87(brd，J＝8.0Hz，1H，H-6′)，7.47(d，J＝2.1Hz，1H，H-8)，7.40(dd，J＝9.0Hz，J＝2.2Hz，1H，H-6)，7.36(t，J＝8.0Hz，1H，H-5′)，7.30(br d，J＝8.0Hz，1H，H-4′)，6.93(dd，J＝16.4Hz，J＝9.9Hz，1H，CH2CHSO2)，6.28(d，J＝16.4Hz，1H，CH2CHSO2)，6.15(d，J＝9.9Hz，1H，CH2CHSO2)，
To C16H13BrN4O2Elemental analysis of S:
calculated values: c, 47.4; h, 3.2 percent.
Measured value: c, 47.3; h, 3.5 percent.
Example 17
N- [4- (3-bromo-phenylamino) -quinazolin-7-yl]Propanamides
Propionyl chloride (0.05ml, 0.58mmmol) was added dropwise to a stirred solution of 7-amino-4- [ (3-bromophenyl) amino ] quinazoline (163mg, 0.52mmol) in anhydrous THF (3ml) under a nitrogen atmosphere at 25 ℃. A yellow solid formed immediately. After 1 hour, the solid was collected by filtration through a buchner funnel, washed with ether and dried. Recrystallization from wet methanol gave the desired product (81mg, 38%) as a bright yellow solid, mp282-283 ℃.
1H NMR[(CD3)2SO]：δ 11.4(brs，1H，NH)，10.76(s，1H，NH)，8.90(s，1H，H8)，8.64(d，J＝9.0Hz，1H，H6)，8.42(s，1H，H2)，8.06(s，1H，H2′)，7.80(dd，J＝9.2，1.9Hz，1H，H5)，7.74(d，J＝7.8Hz，1H，H4′)，7.50(d，J＝8.0Hz，1H，H6′)，7.45(t，J＝8.0Hz，1H，H5′)，2.48(q，J＝7.6Hz，2H，CH2)，1.13(t，J＝7.5Hz，3H，CH3).
Mass spectrum (APCI): 373(100,81BrMH+)，372(21，81BrM+)，371(96，79BrMH+).
to C17H15BrO·HCl·0.2H2Elemental analysis of O:
calculated values: c, 49.64; h, 4.02; and N, 13.63 percent.
Measured value: c, 49.48; h, 3.91; and N, 13.57%.
Example 18
N- [4- [ 3-chloro-phenyl) amino]Quinazolin-6-yl]-acrylamide
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1902mg, 1mmol) was added to a stirring solution of 6-amino-4- [ (3-chlorophenyl) amino ] quinazoline (136mg, 0.5mmol), acrylic acid (74mg, 1.0mmol) and pyridine (201mg, 2.5mmol) in THF/DMF (4:1, 2.5ml) at 0 ℃ under a nitrogen atmosphere. After 20 minutes, the reaction mixture was stirred at 25 ℃ for a further 3 hours, then poured into water (12.5ml) and extracted with ethyl acetate (2X 10 ml). The combined extracts were treated with dilute hydrochloric acid (0.5M, 10ml) and the precipitate collected by filtration through a Buchner funnel, washed with water (10ml) and diethyl ether (2X 10ml) and dried in air to give N- [4- [ 3-chloro-phenyl) amino ] quinazolin-6-yl ] -acrylamide hydrochloride (93mg, 48%) as a dark yellow solid, mp223-227 ℃.
To C18H13ClN4O·HCl·1.5H2Elemental analysis of O:
calculated values: c, 52.59; h, 4.41; n, 14.43 percent.
Measured value: c, 52.43; h, 4.37; n, 14.27 percent.
1H NMR[(CD3)2SO]：δ 11.46(brs，1H，NH)，11.05(s，1H，NH)，9.13(d，J＝2.0Hz，1H，H5)，8.90(s，1H，H2)，8.12(dd，J＝2.0，9.0Hz，1H，H7)，7.99(d，J＝9.0Hz，1H，H8)，7.88(t，J＝2.0Hz，1H，H2′)，7.68(dd，J＝6.1，1.0Hz，1H，H6′)，7.51(t，J＝8.0Hz，1H，H5′)，7.37(dd，J＝8.1，1.2Hz，1H，H-4′)，6.63(dd，J＝10.3，17.1Hz，1H，CH＝CH2)，6.37(dd，J＝1.6，17.1Hz，1H，CH＝CH2)，5.87(dd，J＝1.7，10.Hz，1H，CH＝CH2)。
Mass spectrum, Chemical Ionization (CI): 327(8,37ClMH+)，325(37，35ClMH+)，135(100).
example 19
N- [4- (3-methylphenyl) amino]-quinazolin-6-yl]-acrylamide
Isobutyl chloroformate (20.35g, 0.15mol) was added dropwise over 20 minutes to a stirred solution of acrylic acid (10.82g, 0.15mol) and triethylamine (30.19g, 0.30mol) in THF (400ml) at 0 ℃ under a nitrogen atmosphere. The slurry was stirred at this temperature for 30 minutes and then a solution of 6-amino-4- [ (3-methylphenyl) amino ] quinazoline (27.71mg, 107mmol) in DMF (80ml) was added dropwise over 45 minutes. After 4 hours, the mixed anhydride (THF (100ml) from acrylic acid (3.61g, 50mmol), isobutyl chloroformate (6.80g, 50mmol) and triethylamine (10.1g, 100 mmol)) was added in one portion (0 ℃ C.). After 15 minutes, the reaction mixture was stirred at 25 ℃ for 30 minutes and then poured into ice water (1L). Diethyl ether (200ml) was added and the phases were separated. The aqueous layer was extracted with ethyl acetate (500ml), and the combined organic phases were washed with water (500ml) and saturated brine (250 ml). The solution was stirred with anhydrous magnesium sulfate for 2 minutes, filtered, and silica gel (150g) was added. The mixture was stripped to dryness as a sample on a flash silica chromatography column (700g) eluting with acetone/dichloromethane (25% 4L, 35% 8L, 40% 4L). The residue was suspended in ethyl acetate (200ml) by stripping the solvent with the appropriate ingredients, refluxed for 5 min, sonicated at 60 ℃ for 20 min, then collected by filtration through a buchner funnel, washed with ethyl acetate (3 × 25ml) and dried at 75 ℃ for 16 h in a vacuum oven to give N- [4- (3-methylphenyl) amino ] -quinazolin-6-yl ] -acrylamide (11.38g, 35%) as a pale yellow solid, mp247-8 ℃.
To C18H16N4O·0.1H2Elemental analysis of O:
calculated values: c, 70.61; h, 5.33; n, 18.30 percent.
Measured value: c, 70.33; h, 5.19; n, 18.17 percent.
1H NMR[(CD3)2SO]：δ 10.49(brs，1H，NH)，9.76(brs，1H，NH)，8.75(d，J＝2.5Hz，1H，H5)，8.52(s，1H，H2)，7.89(dd，J＝2.0，9.2Hz，1H，H7)，7.77(d，J＝8.9Hz，1H，H8)，7.64-7.60(m，2H，H6′&H2′)，7.26(dt，Jd＝1.4Hz，Jt＝7.5Hz，1H，H5′)，6.94(d，J＝7.2Hz，1H，H4′)，6.53(dd，J＝10.1，16.9Hz，1H，CH＝CH2)，6.34(dd，J＝1.9，16.9Hz，1H，CH＝CH2)，5.84(dd，J＝1.9，10.1Hz，1H，CH＝CH2)2.34(s，3H，Me).
Mass Spectrometry (CI)305(100, MH)+)，304(49，M+).
Example 20
N- [4- [ (3- (trifluoromethyl) phenylamino ] amino]-quinazolin-6-yl]-acrylamide
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (212mg, 1.1mmol) was added to a solution of 6-amino-4- [ (3- (trifluoromethyl) phenyl) amino ] quinazoline (153mg, 0.5mmol), acrylic acid (73mg, 1.0mol) and pyridine (206mg, 2.5mmol) in THF/DMF (4:1, 2.5ml) at 0 ℃ under a nitrogen atmosphere and stirred. After 15 minutes, the reaction mixture was stirred at 25 ℃ for 1 hour, then cooled to 0 ℃ again. Dilute hydrochloric acid (0.5M, 10ml) was added and after 15 minutes the precipitate was collected by filtration through a Buchner funnel. The residue was washed with water (5ml) and diethyl ether (2X 5ml) and dried in a vacuum oven at 75 ℃ overnight to give N- [4- [ (3- (trifluoromethyl) phenylamino ] -quinazolin-6-yl ] -acrylamide hydrochloride (87mg, 45%) as a pale green solid, mp195-199 ℃.
To C18H13F3N4O·HCl·0.5H2Elemental analysis of O:
calculated values: c, 53.54; h, 3.74; n, 13.88 percent.
Measured value: c, 53.70; h, 3.72; n, 13.73%.
1H NMR[(CD3)2SO]：δ 11.59(brs，1H，NH)，10.99(s，1H，NH)，9.17(d，J＝2.0Hz，H5)，8.92(s，1H，H2)，8.12(s，1H，H2′)，8.10(dd，J＝2.0，9.2Hz，1H，H7)，8.04(d，J＝8.0Hz，1H，H6′)，7.98(d，J＝9.0Hz，1H，H8)，7.74(t，J＝7.9Hz，1H，H5′)，7.68(d，J＝7.8Hz，1H，H4′)，6.60(dd，J＝10.1，16.9Hz，1H，CH＝CH2)，6.38(dd，J＝1.6，16.9Hz，1H，CH＝CH2)，5.89(dd，J＝1.6，10.1Hz，1H，CH＝CH2)。
Mass Spectrometry (CI)359(45, MH)+)，134(100).
Example 21
N- [4- [ (3-bromophenyl) amino group]-7- [3- (4-morpholino) propoxy group]-quinazolin-6-yl]-acrylamide
Metallic sodium (27.6mmol, 0.63g) was added to a solution of 3-morpholinopropan-1-ol (22.0mmol, 3.20g) in THF (60ml) under a nitrogen atmosphere. The resulting suspension was stirred at 20 ℃ for 2 hours and then added with a cannula to a solution of 4- [ (3-bromophenyl) amino ] -7-fluoro-6-nitroquinazoline (J Med Chem, 1996 (39): 918) (2.0g, 5.51mmol) in THF (50ml) under a nitrogen atmosphere. Then, the solution was heated under reflux for 24 hours, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on an alumina column, eluting with ethyl acetate/hexane (1:1) to methanol/dichloromethane/ethyl acetate (2:3:5) to give N- [4- [ (3-bromophenyl) amino ] -7- [3- (4-morpholino) propoxy ] -6-nitroquinazoline (1.75g, 65%) as a yellow powder, mp (methanol) 216-.
1H NMR[(CD3)2SO]: δ 10.12(s, 1H, NH), 9.24(s, 1H, aromatic), 8.69(s, 1H, aromatic), 8.19(t, J ═ 1.8Hz, 1H, H-2 '), 7.88(dt, J ═ 1.8Hz, 1H, H-2'), andd＝7.8Hz，Jt1.4Hz, 1H, H-6 '), 7.49(s, 1H, aromatic), 7.38(t, J ═ 8.0Hz, z1H, H-5'), 7.34(dt, J)d＝8.1Hz，Jt＝1.4Hz，1H，H-4′)，4.35(t，J＝6.2Hz，2H，CH2CH2CH2O), 3.58(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.45(t, J ═ 7.0Hz, 2H, NCH)2CH2CH2) Br s, 4H, morpholinomethylene), 1.94 (quintuple, J ═ 6.6Hz, 2H, CH2CH2CH2)。
13C NMR：δ 157.76，157.26，153.76，153.21，140.32，138.86，130.37，126.38，124.26，121.70，121.13，120.72，110.11，107.88，67.87，66.13(×2)，54.42，53.28(×2)，25.30.
To C21H22BrN5O4·0.75H2Elemental analysis of O:
calculated values: c, 50.3; h, 4.7; n, 14.0%.
Measured value: c, 50.3; h, 4.4; and N, 13.8%.
Freshly washed (1N hydrochloric acid with distilled water) iron powder (12mmol, 0.686g) was added portionwise to a refluxing solution of glacial acetic acid (2.0ml) in ethanol/water (2:1, 80ml) of the above nitroquinazoline (1.50g, 3.07 mmol). The resulting suspension was heated under reflux for 20 minutes under vigorous stirring, then cooled, basified by addition of concentrated ammonia, filtered through a pad of celite, the pad was washed with ethanol, the filtrate was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, chromatographed on a III-grade alumina column, washed with dichloromethane/ethyl acetate (1:1) to methanol/ethyl acetate (2:98) to give 6-amino-4- [ (3-bromophenyl) amino ] -7- [ (3-morpholino) propoxy ] -quinazoline (1.08g, 77%) as a light brown powder, mp (ethyl acetate/hexane) 158-.
1H NMR[(CD3)2SO](400 MHz): δ 9.37(s, 1H, NH), 8.40(s, 1H, aromatic), 8.24(t, J ═ 1.9Hz, 1H, H-2 '), 7.86(ddd, J ═ 8.2, 0.8, 1.8Hz, 1H, H-6 '), 7.42(s, 1H, aromatic), 7.30(t, J ═ 8.1Hz, 1H, H-5 '), 7.21(ddd, J ═ 8.2, 1.0, 1.9Hz, 1H, H-4 '), 7.09(s, 1H, aromatic), 5.36(s, 2H, NH, aromatic), 8.24(t, J ═ 1.9Hz, 1H, aromatic), 7.6 ' (t, J ═ 8.1H, aromatic), 7.09(s, 1H, aromatic)2)，4.20(t，J＝6.2Hz，2H，CH2CH2CH(null)2O), 3.59(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.50(t, J ═ 7.3Hz, 2H, NCH)2CH2CH2) Br s, 4H, morpholinomethylene), 1.99 (quintuple, J ═ 6.7Hz, 2H, CH2CH2CH2)。
13C NMR：δ 154.88，151.94，150.19，144.84，141.94，138.50，130.16，124.66，123.02，121.09，119.65，110.42，106.37，100.81，66.45，66.14(×2)，54.77，53.29(×2)，25.50.
To C21H24BrN5O2·0.25H2Elemental analysis of O:
calculated values: c, 54.5; h, 5.3; n, 15.1 percent.
Measured value: c, 54.6; h, 5.5; n, 15.0 percent.
To a stirred solution of the above 6-amino-quinazoline (0.50g, 1.09mmol), acrylic acid (6.54mmol, 449. mu.L) and triethylamine (excess, 2.0ml) in DMF (20ml) under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (3mol, 3.27mmol, 627 mg). The reaction mixture was stirred at 0 ℃ for 15 minutes, then warmed to room temperature and stirred for an additional 2 hours. The solvent was removed under reduced pressure and the resulting residue was diluted with saturated sodium bicarbonate and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on a grade III alumina column, washing with ethyl acetate/hexane (9:1) to methanol/ethyl acetate (2:98) gave N- [4- [ (3-bromophenyl) amino ] -7- [3- (4-morpholino) propoxy ] -quinazolin-6-yl ] -acrylamide (329mg, 59%) as a cream powder, mp (ethyl acetate/hexane) 170 ℃ 172 ℃.
1H NMR[(CD3)2SO]: δ 9.78(s, 1H, CONH), 9.62(s, 1H, NH), 8.89(s, 1H, aromatic), 8.56(s, 1H, aromatic), 8.18(t, J ═ 1.9Hz, 1H, H-2 '), 7.88(br d, J ═ 8.2Hz, 1H, H-6'), 7.34(t, J ═ 8.1Hz, 1H, H-5 '), 7.30(s, 1H, aromatic), 7.27(ddd, J ═ 7.9, 1.4, 0.8Hz, 1H, H-4'), 6.72(dd, J ═ 17.0, 10.2Hz, 1H, CH ═ 7, 1H, and J ═ 7.92CHCO)，6.33(dd，J＝17.0，1.9Hz，1H，CH2CHCO)，5.83(dd，J＝10.2，1.9Hz，1H，CH2CHCO)，4.27(t，J＝6.3Hz，2H，CH2CH2CH2O), 3.58(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.48(t, J ═ 7.1Hz, 2H, NCH)2CH2CH2) Br s, 4H, morpholinomethylene), 1.99 (quintet J ═ 6.7Hz, 2H, CH2CH2CH2)。
13C NMR：δ 163.49，156.68，154.96，153.92，149.19，141.20，131.58，130.19，127.16，126.95，125.52，123.97，121.03，120.52，116.78，108.80，107.28，66.96，66.14(×2)，54.54，53.28(×2)，25.31。
To C24H26BrN5O3·0.5H2Element of OElement analysis:
calculated values: c, 55.3; h, 5.2; and N, 13.4%.
Measured value: c, 55.3; h, 4.9; and N, 13.3 percent.
Example 22
N- [4- [ (3-methylphenyl) amino group]-7- [3- (4-morpholino) propoxy group]-quinazolin-6-yl]-acrylamide
7-fluoro-6-nitroquinazolinone (2.40g, 11.48mmol) containing 2 drops of DMF in pure SOCl2The suspension (25ml) was refluxed for 3 hours until it was clear. Then, excess SOCl was removed in vacuo2To the residue was added anhydrous benzene followed by distillation under reduced pressure to remove all traces of SOCl2To give crude 4-chloro-7-fluoro-6-nitroquinazoline, it was dissolved in anhydrous dichloromethane (50ml) and added to a stirring solution of m-toluidine in isopropanol (30 ml). The reaction mixture was stirred at 20 ℃ for 30 minutes, then hexane (200ml) was added and the product precipitated as the hydrochloride salt. The precipitate was filtered off, washed with hexane and then dissolved in methanol/water (4:1, 150ml) under mild heating. Then, an excess of triethylamine was added to the solution, and water (400ml) was added to precipitate a free base, which was then filtered off, washed with water, and dried under reduced pressure to give 7-fluoro-4- [ (3-methylphenyl) -amino]6-Nitro-quinazoline (3.01g, 88%) as a yellow powder, mp (dichloromethane/hexane) 191 ℃ and 192 ℃.
1H NMR[(CD3)2SO]：δ 10.38(s，1H，NH)，9.62(d，J＝8.1Hz，1H，H-5)，8.67(s，1H，H-2)，7.80(d，J＝12.6Hz，1H，H-8)，7.63(br d，J＝8.2Hz，1H，H-6′)，7.60(br s，1H，H-2′)，7.31(t，J＝7.8Hz，1H，H-5′)，7.03(br d，J＝7.5Hz，1H，H-4′)，2.35(s，3H，ArCH3)。
To C15H11FN4O2Elemental analysis of (2):
calculated values: c, 60.4; h, 3.7; n, 18.8 percent.
Measured value: c, 60.6; h, 3.6; n, 19.0%.
To a solution of 3-morpholinopropan-1-ol (8.40mmol, 1.22g) in THF (40ml) under a nitrogen atmosphere was added sodium metal (11.8mmol, 0.27 g). The resulting suspension was stirred at 20 ℃ for 2h and then added by cannula to a solution of 7-fluoro-4- [ (3-methylphenyl) -amino ] -6-nitroquinazoline (0.70g, 2.35mmol) in THF (30ml) under a nitrogen atmosphere. After the above-mentioned reaction and treatment, chromatography on silica gel eluting with methanol/dichloromethane/ethyl acetate (5:45:50) to methanol/dichloromethane/ethyl acetate (3:7:10) gave 4- [ (3-methylphenyl) amino ] -7- [ (3-morpholino) propoxy ] -6-nitro-quinazoline (0.87g, 88%) as a yellow powder, mp (dichloromethane/hexane) 169-.
1H NMR[(CD3)2SO]: δ 10.00(s, 1H, NH), 9.26(s, 1H, aromatic), 8.62(s, 1H, aromatic), 7.64(br d, J ═ 8.1Hz, 1H, H-6 '), 7.62(br s, 1H, H-2 '), 7.45(s, 1H, aromatic), 7.29(t, J ═ 7.8Hz, 1H, H-5 '), 6.99(br d, J ═ 7.5Hz, 1H, H-4 '), 4.34(t, J ═ 6.1Hz, 2H, CH, aromatic), 7.62(br d, H-2 '), and so forth2CH2CH2O), 3.58(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.46(t, J ═ 7.0Hz, 2H, NCH)2CH2CH2) 2.38(br s, 4H, morpholinomethylene), 2.35(s, 3H, CH)3Ar), 1.94 (quintuple, J ═ 6.6Hz, 2H, CH)2CH2CH2).
To C22H25N5O4Elemental analysis of (2):
calculated values: c, 62.4; h, 6.0; and N, 16.5%.
Measured value: c, 62.2; h, 6.1; and N, 16.5%.
A solution of the above nitroquinazoline (0.71g, 1.68mmol) in methanol/ethyl acetate (2:1, 60ml) was hydrogenated at Pd-C (60psi) for 6h and then filtered through celite. The filtrate was concentrated under reduced pressure to give 6-amino-4- [ (3-methylphenyl) amino ] -7- [ (3-morpholino) propoxy ] -quinazoline, which was used without further treatment. To a stirred solution of this quinazoline (0.7g, 1.8mmol), acrylic acid (6mol, 10.8mmol, 776 μ L), triethylamine (excess, 4.0ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (3mol, 5.38mmol, 1.03 g). The standard procedure described above was followed by chromatography on silica gel eluting with dichloromethane/ethyl acetate (1:1) to methanol/dichloromethane/ethyl acetate (3:7:10) to give N- [4- [ (3-methylphenyl) amino ] -7- [3- (4-morpholino) propoxy ] -quinazolin-6-yl ] -acrylamide (175mg, 22%) as a cream powder, mp (ethyl acetate/ether) 69-72 ℃.
1H NMR[(CD3)2SO](400 MHz): δ 9.60(s, 1H, interchangeable), 9.59(s, 1H, NH), 8.86(s, 1H, H5), 8.48(s, 1H, H2), 7.62(br d, J ═ 8.0Hz, 1H, H-6 '), 7.61(br s, 1H, H-2'), 7.26(s, 1H, H8), 7.25(t, J ═ 7.8Hz, 1H, H-5 '), 6.92(br d, J ═ 7.4Hz, 1H, H-4'), 6.70(dd, J ═ 16.9, 10.2Hz, 1H, CH, etc.)2CHCO)，6.32(dd，J＝16.9，1.9Hz，1H，CH2CHCO)，5.82(dd，J＝10.2，1.9Hz，1H，CH2CHCO)，4.26(t，J＝6.3Hz，2H，CH2CH2CH2O), 3.58(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.48(t, J ═ 7.1Hz, 2H, NCH)2CH2CH2) Br s, 4H, morpholinomethylene), 2.38 (s, 3H, CH)3Ar), 1.99 (quintuple, J ═ 6.7Hz, 2H, CH)2CH2CH2)。
To C25H29N5O3·0.25H2Elemental analysis of O:
calculated values: c, 66.4; h, 6.6; and N, 15.5 percent.
Measured value: c, 66.3; h, 6.9; and N, 15.9 percent.
Example 23
N- [4- [ (3-methylphenyl) amino group]-7- [3- (4, N-methyl-1, N-piperazinyl) propoxy group]-quinazoline-6-
Base of]-acrylamide
To a solution of 3-N- (4-methylpiperazinyl) propan-1-ol (6.71mmol, 1.06g) in THF (15ml) under a nitrogen atmosphere was added sodium metal (10.1mmol, 0.23 g). The resulting suspension was stirred at 20 ℃ for 2h and then added by cannula to a solution of 7-fluoro-4- [ (3-methylphenyl) -amino ] -6-nitroquinazoline (0.50g, 1.68mmol) in THF (20ml) under a nitrogen atmosphere. The dark red solution was heated to reflux for 24 hours, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on alumina eluting with ethyl acetate/hexane (1:1) to ethyl acetate (2:3:5) to give 4- [ (3-methylphenyl) amino ] -7- [3-N- (4-methylpiperazinyl) propoxy ] -6-nitro-quinazoline (0.67g, 91%) as a yellow powder, mp (ether/hexane) 155-.
1H NMR[(CD3)2SO]：δ 10.00(s，1H，NH)，9.26(s，1H，H5，H2H5)，8.61(s，1H，H2)，7.64(br d，J＝8.4Hz，1H，H-6′)，7.62(br s，1H，H-2′)，7.43(s，1H H8)7.29(t，J＝7.8Hz，1H，H-5′)，6.99(br d，J＝7.4Hz，1H，H-4′)，4.32(t，J＝6.0Hz，2H，CH2CH2CH2O)，2，44(t，J＝7.0Hz，2H，NCH2CH2CH2) 2.39-2.28(br s, 8H, piperazinylmethylene), 2.34(s, 3H, CH)3Ar)，2.14(s，3H，CH3N), 1.92 (quintuple, J ═ 6.6Hz, 2H, CH)2CH2CH2).
To CH28N6O3Elemental analysis of (2):
calculated values: c, 63.3; h, 6.5; n, 19.3 percent.
Measured value: c, 63.4; h, 6.8; n, 19.6 percent.
A solution of the above nitroquinazoline (0.61g, 1.40mmol) in methanol/ethyl acetate (2:1, 50ml) was hydrogenated at Pd-C (60psi) for 5h and then filtered through celite. The filtrate was concentrated under reduced pressure and chromatographed on grade III alumina eluting with methanol/ethyl acetate (5:95) to give 6-amino-4- [ (3-methylphenyl) amino ] -7- [3-N- (4-methylpiperazinyl) propoxy ] -quinazoline (361mg) which showed rapid decolorization and could be used without further treatment. To a stirred solution of this quinazoline (0.36g, 0.89mmol), acrylic acid (6mol, 5.53mmol, 366. mu.L), triethylamine (excess, 2.0ml) in DMF (20ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (3mol, 2.66mmol, 511 mg). The standard procedure described above was followed by chromatography on grade III alumina eluting with ethyl acetate to methanol/ethyl acetate (2:98) to give N- [4- [ (3-methylphenyl) amino ] -7- [3-N- (4-methylpiperazinyl) propoxy ] -quinazolin-6-yl ] -acrylamide (65mg, 16%) as a colourless glass, mp (ether/hexane) 60-66 ℃.
1H NMR[(CD3)2SO]：δ 9.60(s，1H，NH)，9.59(s，1H，NH)，8.86(s，1H，H5)，8.48(s，1H，H2)，7.62(br d，J＝8.0Hz，1H，H-6′)，7.62(br s，1H，H-2′)，7.25(t，J＝8.1Hz，1H，H-5′)，7.25(s，1H，H8)，6.92(br d，J＝7.5Hz，1H，H-4′)，6.70(dd，J＝17.0Hz，J＝10.2Hz，1H，CH2CHCO)，6.31(dd，J＝16.9，1.8Hz，1H，CH2CHCO)，5.83(dd，J＝10.2，1.8Hz，1H，CH2CHCO)，4.24(t，J＝6.3Hz，2H，CH2CH2CH2O)，2.47(t，J＝7.1Hz，2H，NCH2CH2CH2) 2.41-2.28(br s, 8H, piperazinylmethylene), 2.33(s, 3H, CH)3Ar)，2.15(s，3H，CH3N), 1.97 (quintuple, J ═ 6.8Hz, 2H, CH)2CH2CH2)。
EI HRMS(M+)C26H32N6O2Calculated values: 460.2587.
measured value: 460.2576.
example 24
N- [4- [ (3-bromophenyl) amino group]-7- [3- (4, N-methyl-1, N-piperazinyl) propoxy group]-quinazolin-6-yl]-
Acrylamide
To a solution of 3-N- (4-methylpiperazinyl) propan-1-ol (8.81mmol, 1.39g) in THF (40ml) under a nitrogen atmosphere was added sodium metal (13.2mmol, 0.30 g). The resulting suspension was stirred at 20 ℃ for 2 hours and then, under nitrogen, it was cannulated to 4- [ (3-bromophenyl) -amino ] -7-fluoro-6-nitroquinazoline [ J Med Chem, 1996 (39): 918] (0.80g, 2.20mmol) in THF (30 ml). The same procedure as in the previous example was followed and chromatography on silica gel eluting with methanol/dichloromethane/ethyl acetate (1:9:10) to methanol/dichloromethane/ethyl acetate (2:3:5) gave 4- [ (3-bromophenyl) amino ] -7- [3-N- (4-methylpiperazinyl) propoxy ] -6-nitro-quinazoline (0.36g, 33%) as a yellow powder, mp (trihydrochloride) (methanol/ether) 233 deg.C (dec).
1H NMR (free base, (CD)3)2SO]：δ 10.12(s，1H，NH)，9.24(s，1H，H5)，8.69(s，1H，H2)，8.19(br s，1H，H-2′)，7.88(br d，J＝7.8Hz，1H，H-6′)，7.47(s，1H，H8)，7.38(t，J＝7.8Hz，1H，H-5′)，7.34(dt，Jd＝8.0，Jt＝1.3Hz，1H，H-4′)，4.33(t，J＝6.1Hz，2H，CH2CH2CH2O)，2.45(t，J＝7.0Hz，2H，NCH2CH2CH2) 2.42-2.29(br s, 8H, piperazinylmethylene), 2.15(s, 3H, CH)3N), 1.92 (quintuple, J ═ 6.7Hz, 2H, CH)2CH2CH2).
To C22H25BrN6O3Elemental analysis of 3 HCl. H2O:
calculated values: c, 42.0; h, 4.8; n, 13.4; cl, 16.9%.
Measured value: c, 42.1; h, 4.5; n, 13.3; cl, 16.9%.
Freshly washed (1N hydrochloric acid, then distilled water) iron powder (4 molar equivalents, 0.138g) was added portionwise to a refluxing solution of the above nitroquinazoline (0.31g, 0.62mmol) in ethanol/water (2:1, 50ml) containing glacial acetic acid (1.0 ml). The resulting suspension was heated under reflux for 20 minutes under vigorous stirring, then cooled, basified by addition of concentrated ammonia, filtered through a pad of celite, the pad was washed with ethanol, the filtrate was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, chromatographed on a III-grade alumina column, washed with methanol/ethyl acetate (5;95) to give 6-amino-4- [ (3-bromophenyl) amino ] -7- [ (3-N- (4-methylpiperazinyl) propoxy ] -quinazoline (238mg, 82%) as a cream-colored powder, mp (dichloromethane) 171-.
1H NMR[(CD3)2SO]：δ 9.36(s，1H，NH)，8.38(s，1H，H2)，8.22(t，J＝1.9Hz，1H，H-2′)，7.86(ddd，J＝8.2，0.8，1.9Hz，1H，H-6′)，7.40(s，1H，H5)，7.30(t，J＝8.0Hz，1H，H-5′)，7.20(ddd，J＝8.3，1.0，1.9Hz，1H，H-4′)，7.09(s，1H，H8)，5.34(s，2H，NH2)，4.19(t，J＝6.2Hz，2H，CH2CH2CH2O), 2.49 (ambiguous t, J ═ 7Hz, 2H, NCH)2CH2CH2)，2.43-2.29(br s，8H，
Piperazinyl methylene), 2.16(s, 3H, CH)3N), 1.97 (quintuple, J ═ 6.8Hz, 2H, CH)2CH2CH2).
To C22H27BrN6O·1.25H2Elemental analysis of O:
calculated values: c, 53.5; h, 6.0; n, 17.0%.
Measured value: c, 53.5; h, 5.7; n, 17.0%.
To a stirred solution of acrylic acid (6mol, 2.84mmol, 195. mu.L), triethylamine (excess, 1.0ml) in DMA (20ml) was added the above aminoquinazoline (233mg, 0.47mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (3mol, 1.42mmol, 273mg) under nitrogen. The standard procedure described above was followed by chromatography on grade III alumina eluting with ethyl acetate/hexane (1:1) to methanol/ethyl acetate (2:98) to give N- [4- [ (3-bromophenyl) amino ] -7- [3-N- (4-methylpiperazinyl) propoxy ] -quinazolin-6-yl ] -acrylamide (145mg, 58%) as a cream powder, mp (dichloromethane/ether/hexane) 105-.
1H NMR[(CD3)2SO]：δ 9.78(s，1H，CONH)，9.61(s，1H，NH)，8.89(s，1H，H5)，8.56(s，1H，H2)，8.17(t，J＝1.9Hz，1H，H-2′)，7.87(br d，J＝8.5Hz，1H，H-6′)，7.34(t，J＝8.1Hz，1H，H-5′)，7.28(s，1H，H8)，7.27(br dt，Jd＝8Hz，Jt＝1Hz，1H，H-4′)，6.72(dd，J＝17.0，10.3Hz，1H，CH2CHCO)，6.32(dd，J＝17.0，1.9Hz，1H，CH2CHCO)，5.83(dd，J＝10.2，1.9Hz，1H，CH2CHCO)，4.26(t，J＝6.3Hz，2H，CH2CH2CH2O)，2.47(t，J＝7.1Hz，2H，NCH2CH2CH2) 2.42-2.27(br s, 8H, piperazinylmethylene), 2.15(s, 3H, CH)3N), 1.98 (quintuple, J ═ 6.7Hz, 2H, CH)2CH2CH2).
To C25H29BrN6O2·0.5H2Elemental analysis of O:
calculated values: c, 56.2; h, 5.7; and N, 15.7 percent.
Measured value: c, 56.3; h, 5.6; and N, 15.5 percent.
Example 25
N- [4- [ (3-bromophenyl) amino group]-7- [3- (1, N-imidazolyl) propoxy group]-quinazolin-6-yl]-acrylamide
To a suspension of sodium hydride (5.50mmol, 220mg, 60% dispersion in mineral oil) prewashed with hexane in THF (20ml) was added a solution of 3-N- (imidazolyl) propan-1-ol (4.84mmol, 0.61g) in THF (30ml) via cannula. The resulting suspension was stirred under nitrogen at 20 ℃ for 2 hours during which the desired sodium alkoxide was partially precipitated from solution, and then solid 4- [ (3-bromophenyl) -amino ] -7-fluoro-6-nitroquinazoline was added to the suspension [ JMed Chem, 1996 (39): 918] (0.80g, 2.20mmol) to give a dark red solution, which is heated under reflux for 24 hours, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with dichloromethane/ethyl acetate (1:1) to methanol/dichloromethane/ethyl acetate (3:7:10) to give 4- [ (3-bromophenyl) amino ] -7- [3-N- (imidazolyl) propoxy ] -6-nitro-quinazoline (524mg, 51%) as a yellow powder, mp (dichloromethane/hexane) 212-.
1H NMR[(CD3)2SO]：δ 10.16(s，1H，NH)，9.30(s，1H，H5)，8.70(s，1H，H2)，8.19(t，J＝1.6Hz，1H，H-2′)，7.88(dt，Jd＝7.8Hz，Jt1.5Hz, 1H, H-6 '), 7.63(s, 1H, imidazolylmethylene), 7.48(s, 1H, H8), 7.39(t, J ═ 7.9Hz, 1H, H-5'), 7.35(dt, J)d＝8.0Hz，Jt1.6Hz, 1H, H-4'), 7.21(s, 1H, imidazolylmethylene) 6.90(s, 1H, imidazolylmethylene), 4.22(t, J ═ 6.0Hz, 2H, CH2CH2CH2)，4.18(t，J＝6.8Hz，2H，CH2CH2CH2) 2.26 (quintuple, J ═ 64Hz, 2H, CH)2CH2CH2)
To C20H17BrN6O3Elemental analysis of (2):
calculated values: c, 51.2; h, 3.6; n, 17.9 percent.
Measured value: c, 51.0; h, 3.6; and N, 17.6%.
Freshly washed (1N hydrochloric acid with distilled water) iron powder (4mol, 0.241g) was added portionwise to a refluxing solution of glacial acetic acid (0.7ml) in ethanol/water (2:1, 60ml) of the above 6-nitroquinazoline (0.51g, 1.08 mmol). The same reactions and treatments as in the previous examples were carried out using a column of grade III alumina, eluting with methanol/ethyl acetate (5:95) to give 6-amino-4- [ (3-bromophenyl) amino ] -7- [3-N- (imidazolyl) propoxy ] -quinazoline (389mg, 82%) as an off-white powder, mp (dichloromethane/ether) 178-.
1H NMR[(CD3)2SO]: δ 9.37(s, 1H, NH), 8.38(s, 1H, H2), 8.22(t, J ═ 1.8Hz, 1H, H-2 '), 7.86(br d, J ═ 8.1Hz, 1H, H-6 '), 7.66(s, 1H, imidazolylmethylene), 7.40(s, 1H, H5), 7.30(t, J ═ 8.1Hz, 1H, H-5 '), 7.23(s, 1H, imidazolylmethylene), 7.21(br d, J ═ 7.7Hz, 1H, H-4 '), 7.06(s, 1H, H8), 6.90(s, 1H, imidazolylmethylene), 5.45(s, 2H, NH, 1H, imidazolyl methine), 7.21(s, 1H, H-6.1H, and H-4 ')2)，4.28(t，J＝7.1Hz，2H，CH2CH2CH2)，4.10(t，J＝5.8Hz，2H，CH2CH2CH2) 2.27 (quintuple, J ═ 6.5Hz, 2H, CH)2CH2CH2).
To C20H19BrN6O·0.5H2Elemental analysis of O:
calculated values: c, 53.6; h, 4.5; n, 18.7 percent.
Measured value: c, 53.6; h, 4.5; n, 18.6 percent.
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] -7- [3-N- (imidazolyl) propoxy ] -quinazoline (383mg, 0.87mmol), acrylic acid (6mol, 5.23mmol, 359. mu.L), pyridine (excess, 1.0ml) in DMA (20ml) under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (5mol, 4.36mmol, 838 mg). The standard procedure described above was followed by chromatography on grade III alumina eluting with ethyl acetate/hexane (1:1) to methanol/ethyl acetate (5:95) to give N- [4- [ (3-bromophenyl) amino ] -7- [3-N- (imidazolyl) propoxy ] -quinazolin-6-yl ] -acrylamide (9mg, 2%) as a cream powder, mp (dichloromethane/ether/hexane) 235-.
1H NMR[(CD3)2SO]: δ 9.79(s, 1H, CONH), 9.60(s, 1H, NH), 8.88(s, 1H, H5), 8.55(s, 1H, H2), 8.18(t, J ═ 1.9Hz, 1H, H-2 '), 7.87(ddd, J ═ 8.2, 1.8, 1.0Hz, 1H, H-6 '), 7.64(s, 1H, imidazolylmethylene), 7.34(t, J ═ 8.0Hz, 1H, H-5 '), 7.28(br dt, J ═ 8.0Hz, 1H, H-5 '), and 7.28(br dt, J ═ 8.0Hz, 1H, H-5 ')d＝8.0Hz，Jt1.2Hz, 1H, H-4'), 7.27(s, 1H, H8), 7.21(t, J ═ 1.3Hz, 1H, imidazolylmethylene), 6.89(br s, 1H,
imidazolylmethylene), 6.73(dd, J ═ 17.0, 10.2Hz, 1H, CH)2CHCO)，6.34(dd，J＝17.0，1.8Hz，1H，CH2CHCO)，5.85(dd，J＝10.2，1.8Hz，1H，CH2CHCO)，4.22(t，J＝6.9Hz，2H，CH2CH2CH2)，4.14(t，J＝6.0Hz，2H，CH2CH2CH2) 2.27 (quintuple, J ═ 6.4Hz, 2H, CH)2CH2CH2)。
To C23H21BrN6O2·0.75H2Elemental analysis of O:
calculated values: c, 54.5; h, 4.5; and N, 16.6%.
Measured value: c, 54.5; h, 4.4; n, 16.2 percent.
Example 26
N- [4- [ (3-bromophenyl) amino group]-7- [4- (N, N-dimethylamino) butoxy]-quinazolin-6-yl]-propylene
Amides of carboxylic acids
To a suspension of sodium hydride (11.0mmol, 440mg, 60% dispersion in mineral oil) prewashed with hexane in THF (20ml) was added a solution of 4- (N, N-dimethylamino) butan-1-ol (8.80mmol, 1.03g) in THF (30ml) via cannula. The resulting suspension was stirred under nitrogen at 20 ℃ for 2 hours, and then 4- [ (3-bromophenyl) -amino ] -7-fluoro-6-nitroquinazoline was added to the suspension by cannula [ JMedChem, 1996 (39): 918-928] (0.80g, 2.20mmol) in THF (30 ml). The resulting dark red solution was heated to reflux overnight. The same procedure as before was followed by chromatography on grade III alumina eluting with ethyl acetate to methanol/ethyl acetate (5:95) to give 6-amino-4- [ (3-bromophenyl) amino ] -7- [4- (N, N-dimethylamino) butoxy ] -quinazoline (310mg, 33%). As a light brown powder, mp (dichloromethane/hexane) 155-.
1H NMR[(CD3)2SO](400 MHz): δ 9.36(s, 1H, NH), 8.39(s, 1H, aromatic), 8.23(t, J ═ 2.0Hz, 1H, H-2 '), 7.86(br d, J ═ 8.0Hz, 1H, H-6 '), 7.41(s, 1H, aromatic), 7.30(t, J ═ 8.1Hz, 1H, H-5 '), 7.20(ddd, J ═ 8.2Hz, J ═ 0.8Hz, J ═ 1.8Hz, 1H, H-4 '), 7.09(s, 1H, aromatic), 5.32(s, 2H, NH, H-4 '), 7.09(s, 1H, aromatic), c2)，4.17(t，J＝6.2Hz，2H，CH2CH2CH2CH2O)，2.47(t，J＝7.3Hz，2H，NCH2CH2CH2CH2)，2.15(s，6H，N(CH3)2) 1.84 (quintuple, J ═ 6.4Hz, 2H, CH)2CH2CH2CH2) 1.62 (quintuple, J ═ 6.9Hz, 2H, CH)2CH2CH2CH2).
To C20H24BrN5O·0.5H2Elemental analysis of O:
calculated values: c, 54.7; h, 5.7; and N, 15.9 percent.
Measured value: c, 54.3; h, 5.8; and N, 15.8 percent.
To a stirred solution of the above 6-aminoquinazoline (276mg, 0.64mmol), acrylic acid (6 molar equivalents, 3.85mmol, 264. mu.L), triethylamine (excess, 1.0ml) in DMA (10ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (3 molar equivalents, 1.92mmol, 369mg) under a nitrogen atmosphere. The standard procedure described above was followed by chromatography on grade III alumina eluting with ethyl acetate/hexane (1:1) to methanol/ethyl acetate (3:97) to give N- [4- [ (3-bromophenyl) amino ] -7- [4- (N, N-dimethylamino) butoxy ] -quinazolin-6-yl ] -acrylamide (98mg, 32%) as a cream powder, mp (dichloromethane/ether) 112-.
1H NMR[(CD3)2SO](400 MHz): δ 9.77(s, 1H, CONH), 9.62(s, 1H, NH), 8.88(s, 1H, aromatic), 8.56(s, 1H,
aromatic, 8.17(t, J ═ 1.9Hz, 1H, H-2 '), 7.87(ddd, J ═ 8.2Hz, J ═ 1.8Hz, J ═ 1.0Hz, 1H, H-6 '), 7.34(t, J ═ 8.0Hz, 1H, H-5 '), 7.29(s, 1H, aromatic), 7.27(ddd, J ═ 8.2Hz, J ═ 1.8Hz, J ═ 1.0Hz, 1H, H-4 '), 6.71(dd, J ═ 17.1Hz, J ═ 10.2Hz, 1H, CH, H-2 '), and so on2CHCO)，6.32(dd，J＝17.0Hz，J＝1.9Hz，1H，CH2CHCO)，5.82(dd，J＝10.2Hz，J＝1.9Hz，1H，CH2CHCO)，4.24(t，J＝6.6Hz，2H，CH2CH2CH2CH2O)，2.27(t，J＝7.2Hz，2H，NCH2CH2CH2CH2)，2.12(s，6H，N(CH3)2) 1.85 (quintuple, J ═ 6.9Hz, 2H, CH)2CH2CH2CH2) 1.60 (quintuple, J ═ 7.4Hz, 2H, CH)2CH2CH2CH2)。
To C23H26BrN5O2·1.25H2Elemental analysis of O:
calculated values: c, 54.5; h, 5.7; and N, 13.8%.
Measured value: c, 54.5; h, 5.3; and N, 13.7%.
Example 27
N- [4- [ (3-bromo-phenyl) amino group]-quinazolin-6-yl]-N- [ 3-morpholinopropyl group]Acrylamide
A stirred solution of N- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -acrylamide (1.78g, 4.82mmol), morpholine (excess, 4.0ml) and p-toluene sulphonic acid (catalytic amount) in THF (50ml) was heated at 50 ℃ for 4h, concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with methanol/dichloromethane/ethyl acetate (15:40:45) to give N- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -3-morpholinopropylamide (1.86g, 78%) as a cream powder, mp (ethyl acetate) 184-.
1H NMR[(CD3)2SO]：δ 10.37(s，1H，CONH)，9.91(s，1H，NH)，8.72(d，J＝1.9Hz，1H，H-5)，8.58(s，1H，H-2)，8.17(t，J＝2.1Hz，1H，H-2′)，7.86(m，2H，H-7，6′)，7.78(d，J＝8.9Hz，1H，H-8)，7.35(t，J＝8.0Hz，1H，H-5′)，7.29(dt，Jt＝1.2Hz，Jd8.0Hz, 1H, H-4'), 3.40(t, J ═ 4.6Hz, 4H, morpholinomethylene), 2.69(t, J ═ 6.6Hz, 2H, NCH2CH2CONH)，2.58(t，J＝6.6Hz，2H，NCH2CH2CONH), 2.44(br s, 4H, morpholinomethylene).
13C NMR：δ 170.24，157.18，152.86，146.48，141.13，136.87，130.21，128.39，127.01，125.74，124.21，121.03，120.79，115.40，111.46，66.09(×2)，54.04，53.00(×2)，33.66.
To C21H22BrN5O2Elemental analysis of (2):
calculated values: c, 55.3; h, 4.9; and N, 15.3 percent.
Measured value: c, 55.1; h, 5.2; and N, 15.2 percent.
To a stirred solution of the above amide (0.85g, 1.86mmol) in THF (30ml) at 0 deg.C under nitrogen was added dropwise BH3DMS (2 molar equivalents, 372. mu.L, 10M solution). The resulting solution was warmed to 25 ℃ and stirred for 2 hours1N hydrochloric acid (40ml) was added to stop the reaction. Then, the reaction mixture was stirred at 50 ℃ for 2 hours, basified with saturated sodium carbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, chromatographed on silica gel, eluting with methanol/dichloromethane/ethyl acetate (3:8:8) to give N- [4- [ (3-bromo-phenyl) amino group]-6- [ (3-morpholinopropyl) amino group]Quinazoline (130mg, 16%) as a yellow glass (about 90% pure, NMR). The product was used without purification.
1H NMR[(CD3)2SO]：δ 9.40(s，1H，NHAr)，8.37(s，1H，H-2)，8.17(t，J＝1.9Hz，1H，H-2′)，7.91(br d，J＝8.2Hz，1H，H-6′)，7.54(d，J＝9.0Hz，1H，H-8)，7.34(t，J＝8.0Hz，1H，H-5′)，7.27(m，2H，H-4′，7)，7.16(d，J＝2.2Hz，1H，H-5)，6.25(t，J＝5.1Hz，1H，CH2NH), 3.59(t, J ═ 4.5Hz, 4H; morpholinomethylene), 3.22(q, J ═ 6.0Hz, 1H, CH)2NH)，2.45(t，J＝6.9Hz，2H，CH2CH2CH2NH), 2.39(br s, 4H, morpholinomethylene), 1.82 (quintet, J ═ 7.0Hz, 2H, CH2CH2CH2)。
To a stirred solution of the above amine (133mg, 0.30mmol), acrylic acid (4 molar equivalents, 1.20mmol, 83. mu.L) and triethylamine (excess, 0.50ml) in DMF (5.0ml) under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (2.0mol, 0.60mmol, 115 mg). The standard procedure described above was followed by silica gel chromatography eluting with ethyl acetate/dichloromethane (1:1) to methanol/dichloromethane/ethyl acetate (3:7:10) to give N- [4- [ (3-bromophenyl) amino ] - - -quinazolin-6-yl ] -N- [ 3-morpholinopropyl ] acrylamide (39mg, 26%) as a cream powder, mp (dichloromethane/hexane) 171-.
1H NMR[(CD3)2SO]：δ 9.86(s，1H，NH)，8.70(s，1H，H-2)，8.52(d，J＝2.0Hz，1H，H-5)，8.20(t，J＝1.9Hz，1H，H-2′)，7.91(br d，J＝8.6Hz，1H，H-6′)，7.89(d，J＝8.9Hz，1H，H-8)，7.79(dd，J＝8.8Hz，J＝2.1Hz，1H，H-7)，7.38(t，J＝7.9Hz，1H，H-5′)，7.33(dt，Jd＝8.4Hz，Jt＝1.7Hz，1H，H-4′)，6.22(dd，J＝16.7，2.3Hz，1H，CH2CHCO)，6.05(br s，1H，CH2CHCO)，5.61(br d，J＝8.8Hz，1H，CH2CHCO)，3.87(t，J＝7.4Hz，2H，CH2NRCO), 3.49(t, J ═ 4.5Hz, 4H, morpholinomethylene), 2.28(t, J ═ 7.1Hz, 2H, CH)2CH2CH2NRCO)，2.27(br s，4H，
Morpholinomethylene), 1.69 (quintet, J ═ 7.3Hz, 2H, CH)2CH2CH2)·DEI HRMS(M+).
To C24H26BrN5O2The calculated value of (a): 497.1249.
measured value: 497.1250.
example 28
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]Propanamides
Propionyl chloride (0.05ml, 0.58mmol) was added dropwise to a solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (157mg, 0.5mmol) in dry THF (3ml) under a nitrogen atmosphere at 25 ℃. A yellow solid formed immediately. After 45 minutes, the solid was collected by filtration, washed with ether and dried. Recrystallization from wet methanol gave the desired product (97mg, 47%), mp265-266 ℃.
1H NMR[(CD3)2SO]：δ 11.3(brs，1H，NH)，10.53(s，1H，NH)，9.02(s，1H，H5)，8.88(s，1H，H2)，8.00-7.97(m，2H，H7，H2′)，7.89(d，J＝9.1Hz，1H，H8)，7.71(d，J＝7.8Hz，1H，H6′)，7.50(d，J＝8.3Hz，1H，H4′)，7.45(t，J＝8.1Hz，1H，H5′)，2.45(q，J＝7.3Hz，2H，CH2)，1.15(t，J＝7.5Hz，3H，CH3).
Mass spectrum (CI): 373(84,81BrMH+)，372(43，81BrM+)，371(100，79BrMH+)，370(28，79BrM+).
to C17H15N4BrO·HCl·0.5H2Elemental analysis of O:
calculated values: c, 49.00; h, 4.11; and N, 13.45%.
Measured value: c, 48.89; h, 3.97; and N, 13.36 percent.
Example 29
N- [4- [ (3-bromo-phenyl) amino group]-quinazolin-6-yl]-methacrylamide
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (J MedChem, 1995; 38: 3482) (0.50g, 1.59mmol) in THF (20ml) under a nitrogen atmosphere was added dropwise triethylamine (excess, 1.0ml), catalytic amounts of DMAP and methacryloyl chloride (1.1 molar equivalent, 1.75mmol, 171. mu.L). The reaction mixture was stirred at 25 ℃ for 1.5 hours, during which time methacryloyl chloride (50 μ L each) was added twice. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (1:1) to methanol/dichloromethane/ethyl acetate (5:45: 50). Recrystallization from ethyl acetate gave N- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -2-methylacrylamide (195mg, 32%) as a cream powder, mp 244-.
1H NMR[(CD3)2SO]：δ 10.15(s，1H，CONH)，9.90(s，1H，NH)，8.80(br s，1H，H-5)，8.60(s，1H，H-2)，8.20(br s，1H，H-2′)，7.97(br d，J＝8.6Hz，1H，H-7)，7.89(br d，J＝7.7Hz，1H，H-6′)，7.80(d，J＝8.9Hz，1H，H-8)，7.35(t，J＝8.0Hz，1H，H-5′)，7.30(br d，J＝7.5Hz，1H，H-4′)，5.94(s，1H，CH2C(CH3)CO)，5.62(s，1H，CH2C(CH3)CO)，2.02(s，3H，CH2C(CH3)CO).13C NMR：δ 166.71，157.17，153.07，146.69，141.09，139.93，136.62，130.23，128.24，128.11，125.73，124.11，121.04，120.66，120.51，115.19，113.28，18.60.
To C18H15BrN4Elemental analysis of O:
calculated values: c, 56.4; h, 4.0; n, 14.6 percent.
Measured value: c, 56.1; h, 3.9; n, 14.5 percent.
Example 30
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]-vinyl sulfonamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (JMedChem, 1995; 38: 3482) (0.30g, 0.95mmol) in THF (20ml) under a nitrogen atmosphere was added dropwise triethylamine (3.5 molar equivalents, 3.33mmol, 245. mu.L), a catalytic amount of DMAP and chloroacetyl chloride (1.2 molar equivalents, 1.14mmol, 119. mu.L). The reaction mixture was stirred at 25 ℃ for 1 hour, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, chromatographed on silica gel, eluting with methanol/dichloromethane/ethyl acetate (3:47: 50). Recrystallization from dichloromethane/hexane gave N- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -vinylsulfonamide (210mg, 542%) as a cream powder, mp217 deg.C (dec).
1H NMR[(CD3)2SO]：δ 10.31(s，1H，SO2NH)，9.96(s，1H，NH)，8.60(s，1H，H-2)，8.20(d，J＝2.0Hz，1H，H-5)，8.14(br s，1H，H-2′)，7.85(br d，J＝7.9Hz，1H，H-6′)，7.81(d，J＝8.9Hz，1H，H-8)，7.67(dd，J＝8.9，2.1Hz，1H，H-7)，7.37(t，J＝8.0Hz，1H，H-5′)，7.32(br d，J＝8.1Hz，1H，H-4′)，6.90(dd，J＝16.4，9.8Hz，1H，CH2CHSO2)，6.17(d，J＝16.4Hz，1H，CH2CHSO2)，6.06(d，J＝9.8Hz，1H，CH2CHSO2).
13C NMR：δ 157.18，153.47，147.17，140.83，136.02，135.48，130.25，129.03，128.44，127.77，126.08，124.60，121.18，121.03，115.43，114.01.
To C16H13BrN4O2Elemental analysis of S:
calculated values: c, 47.4; h, 3.2; and N, 13.8%.
Measured value: c, 47.7; h, 3.1; and N, 13.8%.
Example 31
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]-E-but-2-enamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (316mg, 1.0mmol) in THF (6ml) at 0 deg.C under a nitrogen atmosphere was added trans-crotonyl chloride. Upon addition, a yellow solid formed. After 2.5 h, the solid was collected by filtration through a Buchner funnel and sonicated with ethyl acetate to give the title compound (216mg, 52%), mp 279 and 281 ℃.
1H NMR[(CD3)2SO]：δ 11.55(brs，1H，NH)，10.78(s，1H，NH)，9.17(d，J＝1.9Hz，1H，H5)，8.97(s，1H，H2)，8.12(dd，J＝9.1，2.0Hz，1H，H7)，8.05(t，J＝1.9Hz，1H，H2′)，7.99(d，J＝9.0Hz，1H，H8)，7.76(dd，J＝8.1，2.0Hz，1H，H6′)，7.58(dd，J＝8.6，1.7Hz，1H，H4′)，7.52(t，J＝8.1Hz，1H，H5′)，7.03-6.94(m，1H，[(CO)CH＝]，6.34(dd，J＝15.1，1.7Hz，1H，CH＝CHCH3)，1.98(dd，J＝6.8，1.4Hz，3H,CH3
Mass spectrum (CI): 385(89,81BrMH+)，384(51，81BrM+)，383(100，79BrMH+)，382(37，79BrM+).
to C18H15N4Elemental analysis of BrO & HCl:
calculated values: c, 51.51; h, 3.84; and N, 13.35%.
Measured value: c, 51.29; h, 3.52; and N, 13.13%.
Example 32
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]-4, 4, 4 trifluoro-E-but-2-enamide
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (158mg, 0.5mmol) and 4, 4, 4-trifluorobut-2-enoic acid (153mg, 1.1mmol) in THF/DMF (4:1, 2.5ml) at 0 ℃ under a nitrogen atmosphere was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (192mg, 1.0 mmol). After 1 hour, water (10ml) was added and after 15 minutes the precipitate was collected by filtration through a buchner funnel. The residue was washed with water (2X 5ml) and diethyl ether (10ml) and air dried. The solid was suspended in ethyl acetate (10ml), rapidly refluxed, sonicated for 10 minutes, and the solid collected by filtration through a buchner funnel, washed with ethyl acetate (5ml) and dried in a vacuum oven at 75 ℃ for 1.5 hours to give N- [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -4, 4, 4 trifluoro-but-2-enamide 0.4 hydrochloride (76mg, 33%) as a pale yellow solid, mp273-278 ℃.
To C18H13BrF3N4Elemental analysis of O.0.4 HCl:
calculated values: c, 47.85; h, 2.77; and N, 12.40%.
Measured value: c, 47.89; h, 2.66; and N, 12.27%.
1H NMR[(CD3)2SO]：δ 11.09(brs，1H，NH)，10.43(s，1H，NH)，8.90(s，1H，H2)，8.70(s，1H，H5)，8.11(s，1H，H2′)，7.97(dd，J＝2.5，9.2Hz，1H，H7)，7.87(d，J＝9.0Hz，1H，H8)，7.81(d，J＝6.9Hz，1H，H6′)，7.41-7.33(m，2H.H5′＆ H4′)，7.11(d，J＝16.4Hz，1H，CH＝CHCF3)，7.03(dq，Jd＝16.4Hz，Jq＝6.4Hz，1H，CH＝CHCF3).
Mass Spectrometry (CI)439 (78)81BrM+)，437(100 79BrM+).
Example 33
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]-propynylamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (158mg, 0.5mmol) and propiolic acid (0.08ml, 1.1mmol) in DMF (1.5ml) at 0 ℃ under a nitrogen atmosphere was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (200mg, 1.04 mmol). The resulting solution was stirred at 0 ℃ for 30 minutes and the reaction was stopped with water. The fine solid formed was collected by filtration through a buchner funnel, then dissolved in methanol and purified by preparative TLC on silica gel eluting with 10% methanol/chloroform. The title compound was isolated as a yellow solid (21mg, 12%), mp >310 ℃.
1H NMR[(CD3)2SO]：δ 11.18(brs，1H，NH)，9.94(s，1H，NH)，8.75(s，1H，H5)，8.59(s，1H，H2)，8.15(s，1H，H2′)，7.85-7.79(m，3H，H7，H8，H6′)，7.37-7.28(m，2H，H5′，H4′)，4.53(s，1H，CH).
Mass spectrum (CI): 369(47,81BrMH+)，368(24，81BrM+)，367(50，79BrMH+)，366(13，79BrM+)，91(100).Calculated for C17H11N4BrO：
to C17H11BrN4Elemental analysis of O:
calculated values: c, 55.61; h, 3.02; and N, 15.26%.
Measured value: c, 55.40; h, 2.84; and N, 15.18 percent.
Example 34
N- [4- (3-bromo-phenylamino) -quinazolin-6-yl]-but-2-ynylamides
To a solution of 2-butynoic acid (196mg, 2.3mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (385mg, 2.0mmol) in DMF (5ml) stirred at 25 ℃ for 20 minutes was added 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (316mg, 1.0 mmol). The resulting solution was stirred at 25 ℃ under nitrogen for 14 h, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (206mg, 1.0mmol) and 2-butynoic acid (82mg, 1.0mmol) were added. After 8h, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (197mg, 1.0mmol) and 2-butynoic acid (93mg, 1.0mmol) were added to the reaction mixture. After stirring at 25 ℃ for a further 12 hours, the reaction was stopped with water. The yellow precipitate formed was collected and then sonicated with acetone and then triethylamine and purified by preparative TLC on silica gel eluting with 1:1 ethyl acetate/acetone. The desired product was isolated as a yellow solid (20mg, 4.7%), mp > 281-.
1H NMR[(CD3)2SO]：δ 10.97(brs，1H，NH)，9.93(s，1H，NH)，8.76(s，1H，H5)，8.57(s，1H，H2)，8.14(s，1H，H2′)，7.84-7.76(m，3H，H7，H8，H4′)，7.34(t，J＝8.1Hz，1H，H5′)，7.29(d，J＝7.8Hz，1H，H6′)，2.09(s，3H，CH3).
Mass spectrum (APCI): 383(100,81BrMH+)，382(23，81BrM+)，381(95，79BrMH+).
to C18H13BrN4O·0.3HCl·0.6C3H6Elemental analysis of O:
calculated values: c, 55.69; h, 3.99; and N, 13.12%.
Measured value: c, 55.67; h, 3.96; and N, 12.93 percent.
Example 35
N- [4- (3-bromo-phenylamino) -pyrido [4, 3-d]Pyrimidin-7-yl]-acrylamide
To a stirring mixture of 7-amino-4- [ (3-bromophenyl) amino ] -pyrido [4, 3-d ] pyrimidine [ J Med Chem, 1995: 3780] (140mg, 0.46mmol), DMAP (14mg) and triethylamine (excess, 2.0ml) was added dropwise to a solution of acryloyl chloride (4.8 molar equivalents, 182. mu.L). Then, the reaction mixture was stirred at 20 ℃, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with methanol/dichloromethane/ethyl acetate (5:45:50) to give N- [4- (3-bromo-phenylamino) -pyrido [4, 3-d ] pyrimidin-7-yl ] -acrylamide (12mg, 7%) as a cream powder, mp (dichloromethane/hexane) 215-.
1H NMR[(CD3)2SO]：δ 11.15(s，1H，CONH)，10.25(s，1H，NH)，9.67(s，1H，H5)，8.71(s，1H，H2)，8.40(s，1H，H8)，8.21(t，J＝1.9Hz，1H，H-2′)，7.88(dt，Jd＝7.6Hz，Jt＝1.5Hz，1H，H-6′)，7.38(t，J＝7.7Hz，1H，H-5′)，7.36(dt，Jd＝7.7Hz，Jt＝1.5Hz，1H，H-4′)，6.68(dd，J＝17.1，10.2Hz，1H，CH2CHCO)，6.39(dd，J＝17.0，1.8Hz，1H，CH2CHCO)，5.86(dd，J＝10.1，1.8Hz，1H，CH2CHCO).
Example 36
N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-acrylamide
A suspension of 6-fluoropyrido [3, 4-d ] pyrimidin-4 (3H) -one (U.S. patent application 08/358,352, 1994) (1.65g) in thionyl chloride (50ml) was heated under reflux with a few drops of dimethylformamide until a clear solution was obtained (20 min) and then treated for an additional 30 min. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane and washed with aqueous sodium carbonate. The solvent was dried off to give crude 4-chloro-6-fluoropyrido [3, 4-d ] pyrimidine, which was dissolved in 2-propanol (50ml) containing 3-bromoaniline (2.1 g). The mixture was heated under reflux for 15 minutes to give a precipitate which was then dissolved by addition of triethylamine. After addition of water, the solution was concentrated and cooled to give 4- [ (3-bromo-phenyl) amino ] -6-fluoropyrido [3, 4-d ] pyrimidine (2.29g), mp (methanol) 219.5-221 ℃.
A mixture of 4- [ (3-bromo-phenyl) amino ] -6-fluoropyrido [3, 4-d ] pyrimidine (0.48g) and 4-methoxybenzylamine (10.3g) in ethanol (50ml) was heated to 100 ℃ for 5 days. The resulting product was chromatographed on silica gel eluting with dichloromethane, ethyl acetate (3:1) to give 4- [ (3-bromo-phenyl) amino ] -6- [ (4-methoxyphenyl) methylamino ] pyrido [3, 4-d ] pyrimidine (0.18g), mp (aqueous methanol), 178-179.5 ℃. 0.10g of this product was dissolved in 5ml of trifluoroacetic acid, heated under reflux for 1 hour, and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and aqueous ammonia and the crude product was chromatographed on alumina eluting with dichloromethane: methanol (97:3) to give 6-amino-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidine (0.040g), mp (dichloromethane) 241.5-242 ℃.
Triethylamine (22.5mmol, 1.61ml), catalytic amount of DMAP (45mg) and acryloyl chloride (4.50mmol, 366. mu.L) were added to a solution of 6-amino-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidine (J Med Chem, 1996; 39: 1823) (455mg, 1.50mmol) in anhydrous THF (50ml) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour, acryloyl chloride (100. mu.L) was added, the reaction mixture was allowed to warm to room temperature, and stirred for an additional 1 hour, treated as in the previous example, and subjected to silica gel column chromatography eluting with methanol/ethyl acetate (5:95) to give N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide (20mg, 37%) as a cream powder, mp (ethyl acetate/methanol) 238-.
1H NMR[(CD3)2SO]：δ 11.07(s，1H，CONH)，10.33(s，1H，NH)，9.05(s，1H，H5 or H2)，9.03(s，1H，H2 orH5)，8.66(s，1H，H8)，8.18(br s，1H，H-2′)，7.89(brd，J＝7.6Hz，1H，H-6′).7.40-7.33(m，2H，H-4′，5′)，6.70(dd，J＝17.0，10.2Hz，1H，CH2CHCO)，6.41(dd，J＝1.2，16.9Hz，1H，CH2CHCO)，5.87(dd，J＝1.2，10.1Hz，1H，CH2CHCO).
13C NMR：δ 163.35，156.82，154.13，150.87，147.92，141.64，140.40，131.25，130.26，127.86，126.49，124.76，121.30，121.02，120.97，103.43.
To C16H12BrN5Elemental analysis of O.1.25H 2O:
calculated values: c, 51.3; h, 3.4; n, 18.7 percent.
Measured value: c, 51.1; h, 3.1; n, 18.4 percent.
Example 37
N- [4- (3-methyl-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-acrylamide
To a stirred solution of 6-amino-4- [ (3-methylphenyl) amino ] pyrido [3, 4-d ] pyrimidine (prepared from m-toluidine and 4-chloro-6-fluoropyrido [3, 4-d ] pyrimidine, as described in the preceding example, followed by p-methoxybenzylamine and trifluoroacetic acid) (140mg, 0.56mmol), DMAP (14mg) and triethylamine (excess, 0.5ml) was added acryloyl chloride (2.7 molar equivalents, 123. mu.L) dropwise over 3 hours under a nitrogen atmosphere at 0 ℃. Then, the reaction mixture was stirred at 20 ℃ for 1 hour, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with methylene chloride/ethyl acetate (1:1) to methanol/methylene chloride/ethyl acetate (2:48:50) to give N- [4- (3-methyl-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide (41mg, 24%) as cream powder, mp (ethyl acetate/hexane) 221-.
1H NMR[(CD3)2SO]：δ 11.03(s，1H，CONH)，10.18(s，1H，NH)，9.02(s，1H，H5 or H2)，9.01(s，1H，H2 orH5)，8.59(s，1H，H8)，7.63(m，2H，H-2′，6′)，7.29(m，1H，H-5′)，6.89(br d，J＝7.5Hz，1H，H-4′)，6.69(dd，J＝17.0，10.2Hz，1H，CH2CHCO)，6.37(dd，J＝17.0，1.9Hz，1H，CH2CHCO)，5.85(dd，J＝10.2，1.9Hz，1H，CH2CHCO)，2.35(s，3H，CH3Ar)。
To C17H15N5Elemental analysis of O:
calculated values: c, 66.9; h, 5.0; and N, 22.9 percent.
Measured value: c, 67.3; h, 5.2; and N, 22.9 percent.
Example 38
N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-N-methyl acrylamide
To a stirred solution of 4- [ (3-bromophenyl) amino ] -6-methylaminopyrido [3, 4-d ] pyrimidine (100mg, 0.3mmol), redistilled acrylic acid (75 μ L, 1.05mmol), pyridine (0.3ml) in THF/DMA (3:2, 1.8ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (294mg, 1.5mmol) in one portion at 0 ℃ under a nitrogen atmosphere. After 30 minutes, the reaction mixture was warmed to 25 ℃ and 3.75 hours, then acrylic acid (25 μ L) was added and the solution was stirred for 3 hours. The reaction was stopped with water, the solid was collected and air dried. Solid in hot dichloromethane: trituration in ethyl acetate collected to give the product (67mg, 56%), mp 215-.
1H NMR[(CD3)2SO]: delta 10.11(s, and D)2O-swap), 9.14(s, 1H), 8.80(s, 1H), 8.45(s, 1H), 8.22(s, 1H), 7.91(br d, J ═ 7.7Hz, 1H), 7.43-7.36(m, 2H), 6.36-6.23(m, 2H), 5.66(dd, J ═ 9.5, 3.0Hz, 1H), 3.44(s, 3H).
CIMS m/z (relative))383(23)，384(100)，385(40)，386(99)，387(20)，
To C17H14N5OBr·0.4H2Elemental analysis of O:
calculated values: c, 52.16; h, 3.81; n, 17.89%.
Measured value: c, 52.25; h, 3.51; n, 17.76 percent.
Example 39
N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-methacrylamide
To 6-amino-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidine (J MedChem, 1996; 39: 1823) (250mg, 0.82mmol), triethylamine (excess, 2.0ml) and DMAP (catalytic amount) in THF (20ml) were added methacryloyl chloride (3X 1.1 molar equivalent, 264. mu.L total) under the same reaction conditions as before, and subjected to column chromatography and preparative thin layer chromatography on silica gel eluting with ethyl acetate/dichloromethane (1:1) to give N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -methacrylamide (18mg, 6%) as a cream powder, mp (dichloromethane/hexane) 177-.
1H NMR[(CD3)2SO]：δ 10.61(s，1H，CONH)，10.29(s，1H，NH)，9.06(s，1H，H5)，8.93(s，1H，H2)，8.67(s，1H，H8)，8.19(t，J＝1.6Hz，1H，H-2′)，7.91(dt，Jd＝7.6Hz，Jt＝1.6Hz，1H，H-6′)，7.38(t，J＝7.9Hz，1H，H-5′)，7.34(dt，Jd＝8.1Hz，Jt＝1.4Hz，1H，H-4′)，6.04(s，1H，CH2C(CH3)CO)，5.64(s，1H，CH2C(CH3)CO)，2.03(s，1H，CH2C(CH3)CO)。
EI HRMS(M+)C17H14BrN5Calculated value of O: 385.0361.
measured value: 385.0360.
example 40
N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]-vinyl sulfonamides
6-amino-4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]A solution of pyrimidine (J Med Chem, 1996; 39: 1823) (250mg, 0.82mmol), triethylamine (0.23ml) and DMAP (catalytic amount) in THF (20ml) was reacted with chloroethanesulfonyl chloride (1.4 molar equivalents, 1.15mmol, 120. mu.L) as before, chromatographed on silica gel, eluted with methanol/dichloromethane/ethyl acetate (2:48:50) and CH2Cl2/ethane recrystallization to give N- [4- (3-bromo-phenylamino) -pyrido [3, 4-d]Pyrimidin-6-yl]Vinylsulfonamide (53mg, 16%) as a emulsifiable powder, mp 261-.
1H NMR[(CD3)2SO]：δ 11.02(s，1H，SO2NH)，10.25(s，1H，NH)，9.02(s，1H，H5)，8.67(s，1H，H2)，8.15(br s，1H，H-2′)，8.00(s，1H，H8)，7.87(dt，Jd＝7.2Hz，Jt＝1.9Hz，1H，H-6′)，7.40(br t，J＝7.9Hz，1H，H-5′)，7.37(br dt，Jd＝7.8Hz，Jt＝1.9Hz，1H，H-4′)，7.07(dd，J＝16.5，9.9Hz，1H，CH2CHSO2)，6.30(d，J＝16.5Hz，1H，CH2CHSO2)，6.09(d，J＝9.9Hz，1H，CH2CHSO2).
13C NMR：δ 156.59，154.34，151.23，147.43，141.54，140.18，137.02，130.36，127.06，126.73，124.88，121.43，121.24，121.07，103.57.
To C15H12BrN5O2S·0.25H2Elemental analysis of O:
calculated values: c, 43.9; h, 3.1; n, 17.0%.
Measured value: c, 44.2; h, 3.0; and N, 16.5%.
EXAMPLE 41
N- [4- (3-bromo-phenylamino) -pyrido [3, 2-d]Pyrimidin-6-yl]-acrylamide
To a stirred DMA (5.0ml) solution of 6-amino-4- [ (3-bromophenyl) amino ] -pyrido [3, 2-d ] pyrimidine (J Med Chem, 1996; 39: 1823) (46mg, 0.15mmol) and acrylic acid (6 molar equivalents, 0.91mmol, 62. mu.L) under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl) (4.0 molar equivalents, 0.61mmol, 116 mg). The reaction mixture was stirred for 48 h and an additional amount of acrylic acid and EDCI. HCl (62. mu.L/116 mg) were added over 12 h, then the previous treatments were performed and chromatographed on silica gel eluting with ethyl acetate dichloromethane (1:1) to methanol/dichloromethane/ethyl acetate (2:48:50) to give N- [4- (3-bromo-phenylamino) -pyrido [3, 2-d ] pyrimidin-6-yl ] -acrylamide (14mg, 26%) as a cream powder, mp (dichloromethane/hexane) 226-.
1H NMR[(CD3)2SO]：δ 11.13(s，1H，CONH)，9.57(s，1H，NH)，8.72(s，1H，H2)，8.69(d，J＝9.1Hz，1H，H8)，8.43(t，J＝1.9Hz，1H，H-2′)，8.30(d，J＝9.1Hz，1H，H7)，7.87(br d，J＝6.9Hz，1H，H-6′)，7.39(t，J＝8.1Hz，1H，H-5′)，7.33(dt，Jd＝8.2Hz，Jt＝1.3Hz，1H，H-4′)，6.68(dd，J＝17.0，10.2Hz，1H，CH2CHCO)，6.43(dd，J＝17.0，1.8Hz，1H，CH2CHCO)，5.91(dd，J＝10.2，1.8Hz，1H，CH2CHCO).
To C16H12BrN5Elemental analysis of O:
calculated values: c, 51.9; h, 3.3; n, 18.9 percent.
Measured value: c, 51.7; h, 3.3; n, 18.8 percent.
Example 42
N- [4- (3-bromo-phenylamino) -benzo [ b ]]Thieno [3, 2-d]Pyrimidin-8-yl]-acrylamide
To a stirred solution of 8-amino-4- [ (3-bromophenyl) amino ] -benzothienopyrimidine (see WO patent application 95/19970, 1995) (100mg, 0.26mmol) and acrylic acid (0.04ml, 0.58mmol) and triethylamine (0.07ml, 0.5mmol) in DMF (1.5ml) at 25 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.66mmol, 127 mg). After 24 h, the reaction mixture was quenched with water, and the light brown precipitate was collected by filtration through a buchner funnel and purified by preparative TLC on silica gel eluting with 10% methanol/chloroform to give the desired product (25mg, 23%) as a brown solid, mp249.0-250.5 ℃.
1H NMR[(CD3)2SO]：δ 10.50(s，1H，NH)，9.86(s，1H，NH)，8.86(d，J＝2.0Hz，1H，H9)，8.79(s，1H，H2)，8.19(s，1H，H2′)，8.17(dd，J＝8.0，1.9Hz，1H，H7)，7.91(dd，J＝8.8，2.2Hz，1H，H6)，7.84(d，J＝8.1Hz，1H，H6′)，7.35(t，J＝8.1Hz，1H，H5′)，7.29(d，J＝8.0Hz，1H，H4′)，6.50(dd，J＝16.9，10Hz，1H，＝CH)，6.33(dd，J＝16.8，2.1Hz，1H，＝CH2)，5.82(dd，J＝10，1.9Hz，1H，＝CH2).
Mass spectrum (APCI): 427(100,81BrMH+)，426(21，81BrM+)，425(93，79BrMH+)。
to C19H13BrN4OS·0.3HCl·0.25C3H6Elemental analysis of O:
calculated values: c, 52.49; h, 3.18; n, 12.19 percent.
Measured value: c, 52.62; h, 3.31; and N, 12.40%.
Example 43
N- [4- (3-bromo-phenylamino) -benzo [ b ]]Thieno [3, 2-d]Pyrimidin-6-yl]-acrylamide
6-amino-4- (3-bromoaniline) benzothieno [3, 2-d ] pyrimidines
2-chloro-3-nitrobenzamide: DMF (3 drops) was added to a mixture of 2-chloro-3-nitrobenzoic acid (0.99g, 4.9mmol), oxalyl chloride (0.47ml, 5.4mmol) in dichloromethane (20ml) at 25 ℃ under nitrogen. After gas formation ceased, all solids dissolved in solution. After 3 hours, the solvent was removed under reduced pressure to give a pale yellow solid which was treated with cold ammonium hydroxide (20 ml). 2-chloro-3-nitrobenzamide (1.02g, 100%) was collected as an off-white solid.
1H NMR[(CD3)2SO]：δ 8.12(brs，1H，NH2)，8.06(dd，J＝8.0，1.7Hz，1H，H4)，7.87(brs，1H，NH2)，7.73(dd，J＝7.8，1.7Hz，1H，H6)，7.63(t，J＝8.1Hz，1H，H5).
2-chloro-3-nitrobenzonitrile: 2-chloro-3-nitrobenzamide (1.02g, 4.9mmol) in P2O5/(TMS)2A solution of O/1, 2-dichloroethane (30ml) was heated at 85 ℃ for 18 hours. After cooling to 25 ℃, filtration through a plug of silica gel (60ml) was performed eluting with 5% methanol/chloroform (400 ml). The combined washings were concentrated under reduced pressure to give 2-chloro-3-nitrobenzonitrile (0.66g, 74%) as an off-white solid.
1H NNR[(CD3)2SO]：δ 8.42(dd，J＝8.1，1.5Hz，1H，H4)，8.33(dd，J＝8.1，1.7Hz，1H，H6)，7.81(t，J＝8.3Hz，1H，H5)。
3-amino-7-nitrobenzothiophene-2-carboxylic acid methyl ester: triethylamine (0.16ml, 1.15mmol) was added dropwise to a solution of 2-chloro-3-nitrobenzonitrile (191mg, 1.05mmol) and methyl thioacetate (0.1ml, 1.1mmol) in DMSO (3ml) under nitrogen at 25 ℃ with stirring. The color of the solution turned dark orange. After 30 minutes, the reaction was stopped with ice water. The solid formed was collected by filtration through a buchner funnel and air dried to give methyl 3-amino-7-nitrobenzothiophene-2-carboxylate (244mg, 92%) as an orange-red solid.
1H NMR[(CD3)2SO]：δ 8.67(dd，J＝8.1，1.0Hz，1H，H6)，8.58(dd，J＝7.8，0.8Hz，1H，H4)，7.72(t，J＝7.8Hz，1H，H5)，7.37(brs，2H，NH2).
Reacting 6-nitrobenzothiopheno [3, 2-d ] pyrimidone: to a mixture of methyl 3-amino-7-nitrobenzothiophene-2-carboxylate (242mg, 0.96mmol) and formamidine acetate (0.51g, 4.9mmol) was heated to 185 ℃, 1.5ml of formamide was added. After heating at 185 ℃ for 1 hour, the reaction mixture was cooled to 25 ℃. The solid was collected and washed with water, then dried. After isolation, 6-nitrobenzothiopheno [3, 2-d ] pyrimidinone (161.5mg, 68%) was obtained as a yellow solid.
1H NMR[(CD3)2SO]：δ 8.72(d，J＝8.1Hz，2H，H7，H9)，8.45(s，1H，H2)，7.91(t，J＝7.8Hz，H8).
4-chloro-6-nitrobenzthieno [3, 2-d ] pyrimidine: anhydrous DMF (5 drops) was added to a mixture of 6-nitrobenzothiopheno [3, 2-d ] pyrimidinone (161mg, 0.65mmol) and oxalyl chloride (0.28ml, 3.2mmol) in 1, 2-dichloroethane (5 ml). The reaction mixture was heated at 85 ℃ for 7.5 hours and then cooled to 25 ℃. The solid was filtered off through a buchner funnel, washed with dichloromethane and air dried. 4-chloro-6-nitrobenzthieno [3, 2-d ] pyrimidine (166mg, 96% crude product) was obtained as a grey solid.
1H NMR[(CD3)2SO]：δ 9.33(s，1H，H2)，8.99(dd，J＝7.9，1.3Hz，1H，H7)，8.87(dd，J＝8.1，1.0Hz，1H，H9)，8.03(t，J＝7.8Hz，1H，H8).
4- ([ 3-bromophenyl ] amino-6-nitrobenzthieno [3, 2-d ] pyrimidine A mixture of 4-chloro-6-nitrobenzthienopyrimidine (166mg, 0.62mmol), m-bromoaniline (0.08ml, 0.73mmol), and m-bromoaniline hydrochloride (144mg, 0.69mmol) in isopropanol (4.5ml) was heated under nitrogen and stirring at 85 deg.C for 7.5 hours, the dark brown solid was collected by filtration through a Buchner funnel, washed with isopropanol, and air dried to give 4- ([ 3-bromophenyl ] amino-6-nitrobenzthieno [3, 2-d ] pyrimidine (145mg, 67%), mp247.0-248.1 deg.C.
1H NMR[(CD3)2SO]：δ 10.21(s，1H，NH)，8.89(s，1H，H2)，8.84(dd，J＝7.6，1.1Hz，1H，H7)，8.75(dd，J＝8.0，0.9Hz，1H，H9)，8.25(s，1H，H2′)，7.92(t，J＝7.8Hz，1H，H8)，7.89(d，J＝6.6Hz，1H，H4′)，7.39-7.31(m，2H，H5′，H6′).
MS(APCI)：403(100，81Br，MH+)，402(17.45，81Br，M+)，401(93.01，79Br，MH+).
To C16H9BrN4O2Elemental analysis of S.HCl:
calculated values: c, 43.90; h, 2.30; n, 12.80 percent.
Measured value: c, 44.00; h, 2.43; and N, 12.48 percent.
6-amino-4- [ (3-bromophenyl) amino ] benzothieno [3, 2-d ] pyrimidine: hydrogenation of a solution of 4- ([ 3-bromophenyl ] amino-6-nitrobenzthieno [3, 2-d ] pyrimidine (160mg, 0.4mmol) in methanol (10ml) was performed with Raney nickel (0.07g) at 25 ℃ for 30 h after completion of the reaction, the solvent was removed under reduced pressure to give a dark brown solid which was recrystallized from wet methanol to give 6-amino-4- [ (3-bromophenyl) amino ] benzothieno [3, 2-d ] pyrimidine (70mg, 43%) as a brown solid, mp217.6-218.8 ℃.
1H NMR[(CD3)2SO]：δ 9.89(s，1H，NH)，8.77(s，1H，H2)，8.19(t，J＝1.9Hz，H2′)，7.85(ddd，J＝8.1，2.9，1.2Hz，1H，H4′)，7.64(dd，J＝7.9，1.0Hz，1H，H9)，7.34(t，J＝7.6Hz，2H，H8，H5′)，7.28(td，J＝8.1，1.5Hz，1H，H6′)，6.95(dd，J＝7.4，1.0Hz，1H，H7)，5.71(brs，2H，NH2).
MS(APCI)：373(100，81Br，MH+)，372(19.5，81Br，M+)，371(96.87，79Br，MH+).
To C16H11BrN4S·0.3HCl·0.7CH3Elemental analysis of OH:
calculated values: c, 49.57; h, 3.51; and N, 13.85 percent.
Measured value: c, 49.47; h, 3.56; n, 13.84 percent.
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] benzothienoquinazoline (130mg, 0.35mmol), acrylic acid (0.05ml, 0.73mmol) and triethylamine (0.1ml, 0.72mmol) in DMF (3ml) at 0 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (144mg, 0.75 mmol). The reaction mixture was gradually warmed to 25 ℃ and after 20 hours, the reaction was stopped with water. The yellow solid formed was collected and purified by sonication with acetone to give the desired product (40mg, 27%), mp 216.4-217.2 ℃.
1H NMR[(CD3)2SO]：δ 10.64(s，1H，NH)，9.84(s，1H，NH)，8.77(s，1H，H2)，8.73(d，J＝1.5Hz，1H，H6)，8.31(d，1H，J＝8.8Hz，H8)，8.20(s，1H，H2′)，7.84(d，J＝8.3Hz，1H，H6′)，7.67(dd，J＝8.6，1.7Hz，1H，H9)，7.34(t，J＝7.8Hz，1H，H5′)，7.28(d，J＝8.1Hz，1H，H4′)，6.50(dd，J＝16.9，10.0Hz，1H，＝CH)，6.34(dd，J＝17.1，1.7Hz，1H，＝CH2)，5.83(dd，J＝10，1.7Hz，1H＝CH2).
Mass spectrum (APCI): 426.7(100,81BrMH+)，425.7(26.28，81BrM+)，424.7(92，79BrMH+).
to C19H13BrN4OS·0.3HCl·0.8H2Elemental analysis of O:
calculated values: c, 52.28; h, 3.62; n, 12.26%.
Measured value: c, 52.42; h, 3.49; n, 12.41 percent.
Example 44
N- [4- (3-bromo-phenylamino) -benzo [ b ]]Thieno [3, 2-d]Pyrimidin-7-yl]-acrylamide
7-nitro-benzo [ b ] thieno [3, 2-d ] -3H-pyrimidin-4-one
2-fluoro-4-nitrobenzoic acid: [25] to a solution of sodium dichromate (3.87g, 13mmol) in acetic acid (20ml) was added 2-fluoro-4-nitrotoluene (1.55g, 10mmol) in portions, followed by addition of concentrated sulfuric acid (10g) dropwise. A strong exotherm (100 ℃) was observed, changing the color from orange to green. The reaction mixture was heated at 90 ℃ for a further 1 hour and cooled to 25 ℃. The reaction mixture was dissolved in water (30ml) and, after cooling at 0 ℃, white crystals formed. The white solid was collected by filtration, washed with cold water, and dried to give 2-fluoro-4-nitrobenzoic acid (0.99g, 53%).
1H NMR(DMSO-d6)δ：8.16(dd，J＝10.0，2.0Hz，1H)，8.10-8.03(m，2H)。
2-fluoro-4-nitrobenzamide: DMF (3 drops) was added to a mixture of 2-fluoro-4-nitrobenzoic acid (0.98g, 5.3mol), oxalyl chloride (0.48ml, 5.5mmol) in dichloromethane (25ml) at 25 ℃ under nitrogen. Gas release! The solid slowly dissolved and after 4 hours the volatiles were removed under reduced pressure. Saturated aqueous ammonia (5ml) was added to the residue, and the mixture was stirred for 10 minutes. The solid was extracted with chloroform (3X 20 ml). The combined organic extracts were washed with water, saturated brine and dried (magnesium sulfate). The solvent was removed under reduced pressure to give 2-fluoro-4-nitrobenzamide (0.83g, 85%) as a pale yellow solid.
1H NMR(DMSO-d6)：δ 8.15(dd.J＝10.0，2.2Hz，1H)，8.06(dd，J＝8.5，2.2Hz，1H)，8.02(brs，1H)，7.88(brs，1H)，7.81(dd，J＝8.3，7.0Hz，1H).
2-fluoro-4-nitrobenzonitrile: under nitrogen, 2-fluoro-4-nitrobenzamide (0.83g, 4.6mmol) and P2O5A mixture of/hexamethyldisiloxane in 1, 2-dichloroethane (20ml) was heated at 100 ℃ for 4 hours. After cooling, the solution was poured into a silica gel plug and washed with hexane (200ml) and then eluted with 5% methanol/chloroform (400 ml). The methanol/chloroform washings were collected and concentrated under reduced pressure to give 2-fluoro-4-nitrobenzonitrile (0.71g, 95%) as an off-white solid.
1H NMR(DMSO-d6)：δ 8.46(dd，J＝9.5，2.0Hz，1H)，8.37-8.22(m，2H).
3-amino-6-nitrobenzothiophene-2-carboxylic acid methyl ester: methyl thioglycolate (0.08ml, 0.85mmol) was added to a solution of 2-fluoro-4-nitrobenzonitrile (145mg, 0.87mmol) and triethylamine (0.14ml, 1.0mmol) in acetonitrile (20ml) under nitrogen at 25 ℃ with stirring. After 3 hours, triethylamine (0.28ml, 2.0mmol) was added to the solution and stirred for a further 16 hours at 25 ℃. The solvent was removed under reduced pressure to give a brown residue which was triturated with chloroform to precipitate methyl 3-amino-6-nitrobenzothiophene-2-carboxylate (103mg, 54%) as a red-brown solid, mp228.5-229.5 ℃.
1H NMR(DMSO-d6)：δ 8.87(d，J＝2.0Hz，1H)，8.32(d，J＝9.0Hz，1H)，8.15(dd，J＝8.8，2.0Hz，1H)，7.26(brs，2H)，3.77(s，3H)。
Mass spectrum (CI): 253(100, MH)+)，252(52，M+)。
7-nitrobenzo [ b ] thieno [3, 2-d ] -3H-pyrimidin-4-one: a mixture of methyl 3-amino-6-nitrobenzothiophene-2-carboxylate (20mg, 0.08mmol) and formamidine acetate (59mg, 0.57mmol) was heated at 190 ℃ for 5 hours, after which the reaction mixture was cooled to 25 ℃. The reaction residue was triturated with water and filtered through a Buchner funnel to give 7-nitrobenzo [ b ] thieno [3, 2-d ] -3H-pyrimidine 4-one (7mg, 36%) as a dark brown solid, mp >320 ℃.
1H NMR(DMSO-d6)：δ 9.21(d，J＝1.7Hz，1H)，8.39(d，J＝8.5Hz，1H)，8.38(s，1H)，8.32(dd，J＝8.8，2.0Hz，1H).
Mass spectrum (CI): 248(100, MH)+)，247(30，M+).
To C10H5BrN3O3Elemental analysis of S:
calculated values: c, 48.58; h, 2.04; n, 17.00 percent.
Measured value: c, 48.19; h, 2.09; n, 16.77%.
To a stirred solution of 7-amino-4- [ (3-bromophenyl) amino ] benzothienopyrimidine (88mg, 0.24mmol), acrylic acid (0.03ml, 0.44mmol) and triethylamine (0.09ml, 0.64mmol) in DMF (3ml) at 0 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84mg, 0.44 mmol). The reaction mixture was gradually warmed to 25 ℃ and after 24 hours the reaction was stopped with water. The light brown precipitate was collected and purified by sonication with propionic acid. After isolation, the desired product (59mg, 37%) was obtained as a beige solid, mp251.0-252.4 ℃.
1H NMR[(CD3)2SO]：δ 10.58(s，1H，NH)，9.92(s，1H，NH)，8.84(s，1H，H2)，8.28-8.24(m，2H，H6，H2′)，7.88(d，1H，J＝6.8Hz，H6′)，7.70(dd，J＝7.6，1.2Hz，1H，H8)，7.65(t，J＝7.6Hz，1H，H9)，7.33(t，J＝8.0Hz，1H，H5′)，7.28(dd，J＝6.9，1.8Hz，1H，H4′)，6.60(dd，J＝16.8，10.0Hz，1H，＝CH)，6.36(dd，J＝17.1，1.9Hz，1H，＝CH2)，5.88(dd，J＝10.3，1.7Hz，1H，＝CH2).
Mass spectrum (APCI): 426.7(100, MH)+)，425.7(18.68，M+).
To C19H13BrN4OS·H2Elemental analysis of O:
calculated values: c, 51.47; h, 3.41; n, 12.64 percent.
Measured value: c, 51.42; h, 3.39; and N, 12.40%.
Example 45
N- [4- [ (3-bromophenyl) amino group]-quinazolin-6-yl]-butadiene-2, 3-dienamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (316mg, 1.0mmol) and 3-butynoic acid (173mg, 2.06mmol) in DMF (5ml) at 0 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (384mg, 2.0 mmol). After 1.5 hours, the reaction was stopped with 0.1M hydrochloric acid solution (10 ml). Filter through buchner funnel, wash with water and then acetone, collect the yellow precipitate. Triethylamine was added to dissolve the solid in acetone. The resulting solution was filtered through 2-inch silica gel, eluting with 50% acetone/dichloromethane. The filtrate was collected and concentrated under reduced pressure to give the title compound (247mg, 56%) as a yellow solid, mp 268-.
1H NMR[(CD3)2SO]：δ 10.39(s，1H，NH)，9.93(s，1H，NH)，8.76(d，J＝2.2Hz，1H，H5)，8.58(s，1H，H2)，8.18(s，1H，H2′)，7.87(dt，J＝9.0，1.9Hz，2H，H7，H8)，7.79(d，J＝8.8Hz，1H，H6′)，7.34(t，J＝7.9Hz，1H，H5′)，7.29(d，J＝8.3Hz，1H，H4′)，6.07(t，J＝6.5Hz，1H，CH＝C＝CH2)，5.49(d，J＝6.6Hz，2H，＝C＝CH2).
Spectrum (APCI): 382.8(88,81BrMH+)，381.8(19，81BrM+)，380.7(100，79BrMH+).
to C18H13BrN4O·0.8H2O·0.8C3H6Elemental analysis of O:
calculated values: c, 55.42; h, 4.42; n, 12.68 percent.
Measured value: c, 55.13; h, 4.17; n, 12.87 percent.
Example 46
N- [4- [ (3-bromophenyl) amino group]-quinazolin-6-yl]-E, 4-oxopent-2-enamide
To a stirred solution of E, 4-oxopent-2-enoic acid (171mg, 1.5mmol) and EDAC & HCl (288mg, 1.5mmol) in THF/DMF (3:1, 4ml) was added 6-amino-4 [ (3-bromophenyl) amino ] quinazoline (0.23g, 0.75mmol) and N-ethyldiisopropylamine (0.26ml, 1.5mmol) at 25 ℃ under a nitrogen atmosphere. The ice bath was removed and the reaction mixture was stirred at 25 ℃ for 4h, before addition of N-ethyldiisopropylamine (0.13ml, 0.75mmol), E, 4-oxopent-2-enoic acid (86mg, 0.75mmol) and EDAC. HCl (144mg, 0.75 mmol). After stirring at 25 ℃ for a further 14 hours, the reaction mixture was added dropwise to stirring cold water (100 ml). The solid was collected, dissolved in methanol (50ml) and silica gel dried (3 g). This was used as the loading material for a silica gel flash column (80g) eluting with 10% methanol in dichloromethane. The pure fractions were concentrated under reduced pressure to give N- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4-oxopent-2-enamide (0.14g, 45%) as a yellow solid, mp 230 ℃ (dec.).
1H NMR[(CD3)2SO]：δ 10.91(s，1H，NH)，9.99(s，1H，NH)，8.87(d，J＝1.9Hz，1H，H5)，8.60(s，1H，H2)，8.17(t，J＝1.9Hz，1H，H2′)，7.85(m，3H，H7，H8，H6′)，7.37(m，2H, H5 ', H4'), 7.15(d, J ═ 15.7Hz, 1H, H3-pentenyl), 6.99(d, J ═ 15.7Hz, 1H, H2-pentenyl |), 2.40(s, 3H, Me).
Mass spectrum (APCI): 412.7(100,81BrMH+)，410.8(98，79BrMH+).
to C19H15BrN4O2Elemental analysis of (2):
calculated values: c, 55.49; h, 3.68; n, 13.62 percent.
Measured value: c, 55.21; h, 3.72; and N, 13.35%.
Example 47
N- [4- [ (3-bromophenyl) amino group]-quinazolin-6-yl]-E, 4-ethoxy-4-oxobut-2-enamide
To a stirred solution of E, 4-ethoxy-4-oxobut-2-enoic acid (216mg, 1.5mmol) and EDAC & HCl (288mg, 1.5mmol) in THF/DMF (3:1, 4ml) was added 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (0.23g, 0.75mmol) and N-ethyldiisopropylamine (0.26ml, 1.5mmol) at 25 ℃ under a nitrogen atmosphere. The ice bath was removed and the reaction mixture was stirred at 25 ℃ for 4h, before addition of N-ethyldiisopropylamine (0.13ml, 0.75mmol), E, 4-ethoxy-4-oxobut-2-enoic acid (108mg, 0.75mmol) and EDAC & HCl (144mg, 0.75 mmol). After stirring at 25 ℃ for a further 14 hours, the reaction mixture was added dropwise to stirring cold water (100 ml). The solid was collected, dissolved in methanol (50ml) and dried on silica gel (3 g). This was used as the loading material for a silica gel flash column (80g) eluting with 10% methanol in dichloromethane. The purified fractions were concentrated under reduced pressure to give N- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4-ethoxy-4-oxobut-2-enamide (0.19g, 58%) as a yellow solid, mp >255 ℃.
1H NMR[(CD3)2SO]：δ 10.93(s，1H，NH)，9.99(s，1H，NH)，8.89(d，J＝1.9Hz，1H，H5)，8.60(s，1H，H2)，8.16(t，J＝1.9Hz，1H, H2 '), 7.85(m, 3H, H7, H8, H6'), 7.33(m, 3H, H5 ', H4', H3-pentenyl), 6.79(d, J ═ 15.4Hz, 1H, H2-pentenyl), 4.24(q, J ═ 7.1Hz. ch)2)，1，29(t，J＝7.1Hz，3H，Me).
Mass spectrum (APCI): 442.8(99,81BrMH+)，440.8(100，79BrMH+).
to C20H17BrN4O3Elemental analysis of (2):
calculated values: c, 55.44; h, 3.88; and N, 12.70%.
Measured value: c, 55.59; h, 3.83; n, 12.67%.
Example 48
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]Penta-2, 4-dienamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidine (160mg, 0.5mmol), 80% trans-2, 4-pentadienoic acid (245mg, 2mmol), and pyridine (0.5ml) in THF/DMA (2:1, 3ml) at 0-5 deg.C under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (490mg, 2.5mmol) in one portion under nitrogen. The cooling bath was removed and the viscous mixture was stirred at 25 ℃. After 23 hours, trans-2, 4-pentadienoic acid (125mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (240mg) and THF/DMA (2:1, 2ml) were further added to the mixture. After stirring for a further 19 hours, the mixture was diluted with water and ethyl acetate. The two-phase mixture was warmed and then filtered through celite through a pad, washing thoroughly with water and hot ethyl acetate. The filtrate was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated to a solid. The solid was dissolved in hot ethyl acetate and the solution was purified by flash column chromatography on silica eluting with ethyl acetate. The product fractions were combined and concentrated to a solid, which was triturated in hot ethyl acetate. After cooling, the solid was collected and dried to give the product (27mg, 13%), mp 210-.
1H NMR[(CD3)2SO]: Δ 11.04(s, 1H, and D)2O exchange), 10.34(s, 1H, and D)2O-swap), 9.04(s, 1H), 9.02(s, 1H), 8.66(s, 1H), 8.17(t, J ═ 1.9Hz, 1H), 7.89(dt, J ═ 7.7, 1.7Hz, 1H), 7.40-7.27(m, 3H), 6.60(dt, J ═ 16.9, 10.6Hz, 1H), 6.53(d, J ═ 15.2Hz, 1H), 5.75(d, J ═ 16.9Hz, 1H), 5.56(d, J ═ 11.1Hz, 1H).
Mass Spectrometry (APCI) m/z (relative))：395.9(89)，396.9(20)，397.9(100)，398.9(20).
To C18H14N5OBr·0.3H2O·0.2C4H8O2Elemental analysis of (2):
calculated values: c, 53.86; h, 3.89; and N, 16.70 percent.
Measured value: c, 54.02; h, 3.77; n, 16.33%.
Example 49
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]-N- (2- (N, N-dimethylamino) ethyl
Based) acrylamide
To a stirred solution of 4- [ (3-bromophenyl) amino ] -6- (2-dimethylaminoethyl) aminopyrido [3, 4-d ] pyrimidine (387mg, 1mmol) and redistilled acrylic acid (0.25ml, 3.6mmol) in pyridine (5ml) at 0-5 deg.C under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (980mg, 5 mmol). After 30 minutes, the cooling bath was removed and the mixture was stirred for 45 minutes. The solution was diluted with 1% aqueous sodium bicarbonate and extracted 4 times with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated to give an oil which was crystallized from ethyl acetate at 5 ℃ overnight to give the product (122mg, 28%), mp >160 ℃ (dec).
1H NMR[(CD3)2SO]: Δ 10.16(s, 1H, and D)2O-swap), 9.15(s, 1H), 8.80(s, 1H), 8.43(s, 1H), 8.22(s, 1H), 7.93(d, J ═ 7.7Hz, 1H), 7.42-7.35(m, 2H), 6.29-6.22(m, 2H), 5.66(dd, J ═ 9.0, 3.5Hz, 1H), 4.05(t, J ═ 7.1Hz, 2H)2.42(t, J ═ 7.1Hz, 2H), 2.11(s, 6H).
Mass Spectrometry (APCI) m/z (relative))：440.9(99)，441.8(23)，442.8(100)，443.9(24).
To C20H21N6Elemental analysis of OBr:
calculated values: c, 54.43; h, 4.80; n, 19.04 percent.
Measured value: c, 54.15; h, 4.65; n, 18.76 percent.
Example 50
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]-E-but-2-enamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] pyrido [3, 4-d ] pyrimidine (32mg, 0.1mmol), trans crotonic acid (35mg, 0.4mmol) in pyridine (0.4ml) at 0-5 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (98mg, 0.5 mmol). The cooling bath was removed and the mixture was stirred at 25 ℃. After 2 hours, the solution was diluted with water and the suspension was stirred for 15 minutes. The solid was collected and dissolved in ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate, dried (magnesium sulfate) and filtered through flash silica gel. The filtrate was concentrated to a solid. It was triturated in hot ethyl acetate. The solid was collected to give the product (11mg, 28%), mp >260 ℃ (dec).
1H NMR[(CD3)2SO]: Δ 10.87(s, 1H, and D)2O exchange), 10.31(s, 1H, and D)2O-swap), 9.03(s, 1H), 9.00(s, 1H), 8.65(s, 1H), 8.17(s, 1H), 7.89(d, J ═ 7.5Hz, 1H), 7.39-7.33(m, 2H), 6.99-6.90(m, 1H), 6.39(dd, J ═ 15.4, 1.7Hz, 1H), 1.91(dd, J ═ 7.0, 1.4Hz, 3H).
Mass Spectrometry (APCI) m/z (relative))：381.8(74)，382.8(27)，383.8(100)，384.8(30)，385.9(10).
To C17H14N5OBr·0.3H2Elemental analysis of O:
calculated values: c, 52.40; h, 3.78; and N, 17.97 percent.
Measured value: c, 52.37; h, 3.65; n, 17.70 percent.
Example 51
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]-cinnamic acid amides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] pyrido [3, 4-d ] pyrimidine (32mg, 0.1mmol), trans-cinnamic acid (60mg, 0.4mmol) in pyridine (0.4ml) at 0-5 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (98mg, 0.5 mmol). The cooling bath was removed and the mixture was stirred at 25 ℃. After 2 hours, the solution was diluted with water and the suspension was stirred for 15 minutes. The solid was collected and dissolved in ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate, dried (magnesium sulfate) and filtered through flash silica gel. The filtrate was concentrated to a solid. It was triturated in hot ethyl acetate. The solid was collected to give the product (23mg, 51%), mp253-256 ℃.
1H NMR[(CD3)2SO: Δ 11.07(s, 1H, and D)2O exchange), 10.36(s, 1H, and D)2O exchange), 9.06(s, 2H; by D2O-Wash-Stack 9.06[ s, 1H ]]and 9.02[s，1H])，8.67(s，1H)，8.19(s，1H)，7.90(d，J＝7.7Hz，1H)，7.72-7.65(m，3H)，7.51-7.34(m，5H)，7.14(d，J＝15.7，1H).
Mass Spectrometry (APCI) m/z (relative))：445.9(97)，446.9(24)，447.9(100)，448.9(26).
To C22H16N5OBr·0.2H2Elemental analysis of O:
calculated values: c, 58.73; h, 3.67; n, 15.57 percent.
Measured value: c, 58.79; h, 3.66; n, 15.37 percent.
Example 52
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]-E, 3-chloropropenamide
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] pyrido [3, 4-d ] pyrimidine (128mg, 0.4mmol) and cis-3-chloroacrylic acid (172mg, 1.6mmol) in pyridine (2ml) at-20 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (392mg, 1.5 mmol). After 4.5 hours, cis-3-chloroacrylic acid (57mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (130mg) were added and the temperature was raised to-10 ℃. After 7 hours total reaction time, the viscous dark mixture was diluted with DMF and the resulting solution was poured into 1:1 ethyl acetate: in water. The resulting mixture was vigorously shaken, and phase separation was carried out. The aqueous layer was extracted 2 more times, then the combined organic extracts were washed 2 times with brine, dried (magnesium sulfate) and filtered through flash silica gel. The filtrate was concentrated to a solid, which was dissolved in warm ethyl acetate. The solution was purified by column chromatography on flash silica eluting with ethyl acetate. The product fractions were combined and concentrated to a solid, which was diluted in 1:1 ethyl acetate: tert-butyl methyl ether. The solid was collected and dried at 0.1mm/25 ℃ to give the product (30mg, 18%), mp165-175 ℃ (dec) and recrystallized from ethyl acetate.
1H NMR[(CD3)2SO]: Δ 11.09(s, 1H, and D)2O exchange), 10.38(s, 1H, and D)2O-swap), 9.04(s, 1H), 9.00(s, 1H), 8.66(s, 1H), 8.16(t, J ═ 1.9Hz, 1H), 7.88(dt, J ═ 7.7, 1.7Hz, 1H), 7.40-7.33(m, 2H), 7.07(d, J ═ 8.0Hz, 1H), 6.77(d, J ═ 8.0Hz, 1H).
Mass Spectrometry (APCI) m/z (relative))；365.8(29)，366.8(36)，367.8(35)，368.8(35)，401.8(82)，402.8(18)，403.8(100)，404.8(20)，405.8(29)。
To C16H11N5OBrCl·0.2H2O·0.2C4H8O2Elemental analysis of (2):
calculated values: c, 47.38; h, 3.08; n, 16.44 percent.
Measured value: c, 47.53; h, 3.15; n, 16.25 percent.
Example 53
N- [4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-yl]-propynylamides
To a stirred solution of 6-amino-4- [ (3-bromophenyl) amino ] pyrido [3, 4-d ] pyrimidine (94mg, 0.3mmol) and propiolic acid (66 μ L, 1.05mmol) in pyridine (1.2ml) at-20 ℃ under nitrogen was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (294mg, 1.5 mmol). After 2.25 hours, propiolic acid (33. mu.L) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (147mg) were added to the cold solution. After 7.5 hours total reaction time, the viscous dark mixture was diluted with DMF and the resulting solution was poured into 1:1 ethyl acetate: in water. The resulting mixture was vigorously shaken, and phase separation was carried out. The aqueous layer was extracted 2 more times, then the combined organic extracts were washed 2 times with brine, dried (magnesium sulfate) and filtered through flash silica gel. The filtrate was concentrated to a solid, which was dissolved in warm ethyl acetate. The solution was purified by column chromatography on flash silica eluting with ethyl acetate. The product fractions were combined and concentrated to a solid, which was diluted 1:1 ethyl acetate: tert-butyl methyl ether. The solid was collected and dried at 0.1mm/25 ℃ to give the product (16mg, 14%), mp >150 ℃ (dec).
1H NMR[(CD3)2SO]: Δ 11.69(s, 1H, and D)2O exchange), 10.31(s, 1H, and D)2O-swap), 9.05(s, 1H), 8.83(s, 1H), 8.68(s, 1H), 8.15(s, 1H), 7.87(d, J ═ 7.2Hz, 1H), 7.40-7.33(m, 2H), 4.54(s, 1H).
Mass Spectrometry (APCI) m/z (relative))：365.8(69)，366.8(28)，367.8(100)，368.9(50)，369.9(14)。
To C16H10N5OBr·0.1H2O·0.1C4H8O2Elemental analysis of (2):
calculated values: c, 52.00; h, 2.93; n, 18.49 percent.
Measured value: c, 51.89; h, 3.78; n, 18.50 percent.
Example 54
N- [4- [ (3-bromophenyl) amino group]Quinazolin-6-yl]-E, 4- (3- (N, N-dimethylamino) propoxy-4-oxo
2-Enoamidotrifluoro-2-acetic acid ester
Reacting 6-amino-4- [ (3-bromophenyl) amino) at 0 deg.C under nitrogen for 15 min]A solution of quinazoline (158mg, 0.5mmol) in THF (10ml) was added dropwise to a stirred solution of fumaric chloride (382mg, 2.5mmol) in THF (10 ml). After 1 hour at 0 ℃, the suspension was allowed to stand and the supernatant decanted. Fresh THF (5ml) was added and the suspension was stirred at 0 deg.CThe suspension was added dropwise to a solution of 3- (N, N-dimethylamino) propan-1-ol (1.18ml, 10mmol) in THF (5 ml). The suspension was stirred at 25 ℃ for a further 1 hour, the solvent was stripped off under reduced pressure and the residue was treated with cold water. The solid was collected by filtration through a buchner funnel, dissolved in a small amount of DMF, taken up on silica gel (2g) and dried. The solid was used as a loading material for flash chromatography on silica gel (50g) eluting with methylene chloride/methanol (2: 1). The best fractions were combined, stripped, dissolved in acetic acid/water (3:2, 2.5ml) and passed through a 0.45 μ filter in Vidac C18218Purification was performed by HPLC on a TP1022 reverse phase HPLC column eluting with a gradient of 10% to 50% aqueous 0.1% TFA/acetonitrile 0.1% TFA over 60 minutes. The purified fractions were combined and lyophilized to give N- [4- [ (3-bromophenyl) amino group]-quinazolin-6-yl]-E, 4- (3- (N, N-dimethylamino) propoxy-4-oxobut-2-enamide Tritrifluoroacetate (51mg, 12%) as a yellow solid, mp 60 ℃.
1H NMR[(CD3)2SO]：δ 11.14(s，1H，NH)，10.85(br s，1H，NH)，9.57(br s，1H，NH)，9.01(d，J＝1.7Hz，1H，H5)，8.79(s，1H，H2)，8.07(s，1H，H2′)，8.02(dd，J＝2.1，9.0Hz，1H，H7)，7.89(d，J＝8.9Hz，1H，H8)，7.78(d，J＝6.5Hz，H6′)，7.43(m，2H，H4′&H5'), 7.34(d, J ═ 15.4Hz, 1H, H3-butenyl), 6.84(d, J ═ 15.4Hz, 1H, H2-butenyl), 4.26(t, J ═ 6.2Hz, 2H, OCH2)，3.19(m，2H，CH2N)，2.81(d，J＝4.6Hz，6H，Me)，2.05(m，2H，CH2)，
Mass spectrum (APCI): 499.8(100,81BrMH+)，497.9(97.79BrMH+)。
to C23H24BrN5O3·3CF3Elemental analysis of COOH:
calculated values: c, 40.15; h, 3.49; and N, 8.07 percent.
Measured value: c, 40.06; h, 3.36; n, 8.25 percent.
Example 55
3- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl]Acrylic acid (Z)
To a solution of 6-amino-4- [ (3-bromophenyl) amino ] -quinazoline (0.78g, 2.5mmol) in DMF (8ml) was added maleic anhydride (0.266g, 2.7mmol) and the mixture was heated in an oil bath at 70 ℃ for 2.5 hours with stirring. The resulting suspension was cooled to room temperature and then diluted with water. The solid was collected and washed sequentially with toluene/DMF (1:1), water and IPA. The solid was dried under vacuum at 60 ℃ for 16 h to give 3- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -acrylic acid (Z) (0.87g, 86%) as a pale yellow powder, mp224-225 ℃ (decomposing with gas volatilization).
1H NMR[(CD3)2SO]：δ 13.00(br s，1H，COOH)，10.85(br s，1H，NH)，9.96(br s，1H，NH)，8.73(d，J＝1.8Hz，1H，H5)，8.54(s，1H，H2)，8.11(br s，1H，Me2NCHO)，7.91-7.75(m，4H)，7.32-7.24(m，2H)，6.46(d，J＝12.0Hz，1H，CH＝CH)，6.35(d，J＝12.0Hz，1H，CH＝CH)，2.84(s，3H，Me 2NCHO)，2.68(s，3H，Me 2NCHO).
Mass spectrum (APCI): 412.8(100,81BrM+)，410.8(96，79BrM+)；413.8(26，81BrMH+)，411.8(24，79BrMH+).
to C18H13BrN4O3Elemental analysis of 0.81 DMF:
calculated values: c, 51.94; h, 3.98; n, 14.26 percent.
Measured value: c, 51.97; h, 3.98; n, 14.40 percent.
Example 56
N- [4- [ (3-bromophenyl) amino group]-quinazolin-6-yl]-E，4-(3-(N，N-dimethylamino) propylamino-4-
Oxobut-2-enamides
A solution of 6-amino-4- [ (3-bromophenyl) amino ] quinazoline (158mg, 0.5mmol) in THF (10ml) was added dropwise to a stirring solution of fumaryl chloride (382mg, 2.5mmol) in THF (10ml) at 0 deg.C under a nitrogen atmosphere over 15 minutes. After 1 hour at 0 ℃, the suspension was allowed to stand and the supernatant decanted. Fresh THF (5ml) was added and the suspension was stirred at 0 ℃ while a solution of 3- (N, N-dimethylamino) propan-1-ylamine (1.26ml, 10mmol) in THF (5ml) was added dropwise. The suspension was stirred at 25 ℃ for a further 1 hour, the solvent was stripped off under reduced pressure and the residue was treated with cold water. The solid was collected by filtration through a buchner funnel, dissolved in boiling methanol (25ml), filtered and the solvent removed under reduced pressure. The residue was then dissolved in acetic acid/water (3:2, 2.5ml) and purified by HPLC on a Vidac C18218TP1022 reverse phase HPLC column eluting with a gradient of 10% to 50% 0.1% aqueous TFA/0.1% TFA in acetonitrile over 60 minutes. The purified fractions were combined and lyophilized to give N- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4- (3- (N, N-dimethylamino) prop-1-ylamino-4-oxobut-2-enamide trifluroacetate (154mg, 37%) as a yellow solid, mp40 ℃.
1H NMR[(CD3)2SO]: δ 11.02(s, 1H, NH), 9.50(br s, 1H, NH), 9.02(d, J ═ 1.7Hz, 1H, H5), 8.82(s, 1H, H2), 8.74(t, J ═ 5.7Hz, 1H, NH), 8.05(s, 1H, H2 '), 8.02(dd, J ═ 2.1, 9.0Hz, 1H, H7), 7.89(d, J ═ 8.9Hz, 1H, H8), 7.76(d, J ═ 7.2Hz, H6'), 7.45(m, 2H, H4 '& H5'), 7.17(d, J ═ 14.9Hz, 1H, H3-butenyl), 7.05(d, J ═ 15.2, H2, NCH 8626H, NH 3, H8626-26 Hz), 7.9H, H3526-butenyl, 7.9H, 3H, H3526-butenyl, 7.9-butenyl2)，3.08(m，2H，CH2N)，2.79(d，J＝4.8Hz，6H，Me)，1.83(m，2H，CH2).
Mass spectrum (APCI): 498.8(100,81BrMH+)，496.9(97，79BrMH+).
to C23H25BrN6O2·3CF3Elemental analysis of COOH:
calculated values: c, 41.49; h, 3.36; n, 10.01 percent.
Measured value: c, 41.44; h, 3.60; n, 10.33%.
Example 57
4- [ (3-bromophenyl) amino group]-6- (ethylenesulfonyl) pyrido [3, 4-d]A pyrimidine;
2-4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidin-6-ylsulfanyl (sulfonyl)]-ethanol;
a solution of 2-mercaptoethanol (1.75ml, 25mmol) and 4- [ (3-bromophenyl) amino ] -6-fluoropyrido [3, 4-d ] pyrimidine (1.6g, 5mmol) in DMSO (10ml) under a nitrogen purge was treated with anhydrous cesium carbonate (3.26g, 10 mmol). The stirred solution was heated at 50 ℃ for 2 hours and then poured into a 2% aqueous solution of hydrochloric acid (180 ml). After stirring the suspension for 15 minutes, the solid was collected, washed with water and dissolved in DMF. The solution was poured into 1:1 water: ethyl acetate, and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate) and filtered through flash silica gel. The filtrate was concentrated to a solid which was triturated in ethyl acetate. The solid was collected to give the first two 1.24g (66%) of product, mp182-185 ℃, the third 98mg (5%), mp179-183 ℃.
1H NMR[(CD3)2SO]: Δ 10.03(s, 1H, and D)2O exchange), 9.10(s, 1H), 8.69(s, 1H), 8.35(s, 1H), 8.22(t, J ═ 1.9Hz, 1H), 7.91(dt, J ═ 7.7, 1.9Hz, 1H), 7.42-7.34(m, 2H), 5.04(t, J ═ 5.5Hz, and D2Oo, 1H), 3.68(dd, J ═ 6.8, 5.7Hz, 2H), 3.36(t, J ═ 6.8Hz, 2H).
Mass Spectrometry (APCI) m/z (relative))：374.8(49)，375.8(10)，376.9(100)，377.8(23)，378.9(63)，379.8(14).
To C15H13N4Elemental analysis of OSBr:
calculated values: c, 47.76; h, 3.47; n, 14.85 percent.
Measured value: c, 47.65; h, 3.38; n, 14.55 percent.
2-4- [ (3-bromophenyl) amino group]-pyrido [3, 4-d]Pyrimidine-6-sulfonyl]-ethanol;
a stirred suspension of 2-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidin-6-yl-sulfanyl ] -ethanol (755mg, 2mmol) in chloroform (30ml) at 0-5 ℃ was treated with m-chloroperbenzoic acid (1.27g, 57-86%). The suspension was slowly warmed to 25 ℃ over 4 hours. After 14.5 and 17.5 hours, respectively, the suspension was treated with another portion of oxidizing agent (720mg ). After a total reaction time of 19.5 hours, the diluted suspension was cooled to 0-5 ℃ and treated with DMSO (2 ml). The cooling was removed and the solution was stirred for 30 minutes. The mixture was then partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic phase was washed with brine, dried (magnesium sulfate), concentrated to reduce volume and purified on flash column chromatography on ethyl acetate. The product fractions were combined, concentrated to a solid, which was crystallized from ethyl acetate to give the product (460mg, 56%), mp 210-. The filtrate was further processed to give 84mg (10%) of a second crop of product, mp 208-209 ℃.
1H NMR(CF3CO2H)：δ 10.96(s，1H)，10.90(s，1H)，10.42(s，1H)，9.47(s，1H)，9.16(d，J＝8.2Hz，1H)，9.05(d，J＝8.2Hz，1H)，8.83(t，J＝8.0，1H)，5.81(t，J＝5.2Hz，2H)，5.43(t，J＝5.2Hz，2H).
Mass Spectrometry (APCI) m/z (relative))：378.7(39)，380.7(45)，408.7(100)，409.7(15)，410.7(97)，411.7(17).
To C15H13N4O3Elemental analysis of SBr:
calculated values: c, 44.02; h, 3.20; n, 13.69 percent.
Measured value: c, 44.09; h, 3.14; and N, 13.44 percent.
4- [ (3-bromophenyl) amino group]-6- (ethylenesulfonyl) pyrido [3, 4-d]A pyrimidine;
to a suspension of 2-4- [ (3-bromophenyl) amino ] -pyrido [3, 4-d ] pyrimidine-6-sulfonyl ] -ethanol (41mg, 0.1mmol) and triethylamine (31 μ L, 0.22mmol) in dichloromethane (0.5ml) at 0-5 deg.C under nitrogen was added dropwise methanesulfonyl chloride (9.3 μ L, 0.12 mmol). After 45 minutes and 1.5 hours, additional methanesulfonyl chloride (9.3. mu.L ) was added, followed by triethylamine (50. mu.L) in one addition. After a total of 2.5 hours of reaction, the cooled solution was quenched with 5% aqueous sodium bicarbonate solution, and then extracted 2 times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and filtered through flash silica gel with heating. The filtrate was concentrated to a solid which was then crystallized from ethyl acetate to give the product (17mg, 44%), mp214-217 ℃.
1H NMR[(CD3)2SO]: Δ 10.64(s, 1H, and D)2Oor), 9.30(s, 1H), 9.25(s, 1H), 8.87(s, 1H), 8.16(s, 1H), 7.89-7.85(m, 1H), 7.39-7.33(m, 2H), 7.17(dd, J ═ 10.0, 16.5Hz, 1H), 6.46(d, J ═ 16.4Hz, 1H), 6.37(d, J ═ 10.0Hz, 1H)
Example 58
N- (3-bromophenyl) -N- [6-2, 5-dihydro-pyrrol-1-yl) -quinazolin-4-yl]-acetamide
Sodium acetate (0.10g, 1.2mmol) was added to a suspension of 3- [4- (3-bromophenylamino) -quinazolin-6-ylcarbamoyl ] acrylic acid (Z) (0.25g, 0.61mmol) in acetic anhydride (5ml) and the mixture was heated at reflux for 30 min. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate, water and brine. The ethyl acetate fraction was dried over magnesium sulfate, filtered, and concentrated to give a pale pink solid. The solid was recrystallized twice from ethyl acetate to give N- (3-bromophenyl) -N- [6- (2, 5-dihydro-pyrrol-1-yl) -quinazolin-4-yl ] -acetamide (0.104g, 39%) as an off-white powder, mp 174-.
1H NMR[CDCl3]：δ 9.24(s，1H，H2)，8.16(d，J＝9Hz，1H，H8)，8.10(d，J＝2Hz，1H，H5)，8.03(dd，J＝9Hz，J＝2Hz，1H，H7)，7.59(t，1H，J＝2Hz，H2′)，7.45(m，1H，H4′)，7.38(m，1H，H6′)，7.27(d，1H，J＝7Hz，H5′)，6.91(s，2H，CH＝CH)，2.15(s，3H，CH3).(79，79BrMH+)；439.7(17，81BrM+)，437.7(19，79BrM+)；470.7(100，81BrM+MeOH)，468.8(95，79BrM+MeOH).
To C20H13BrN4O3Elemental analysis of (2):
calculated values: c, 54.94; h, 3.00; n, 12.81 percent.
Measured value: c, 54.90; h, 2.97; n, 12.61%.
The following compounds can be prepared using the reaction schemes and examples described previously:
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] pyrrole-2, 5-dione;
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] prop-2-en-1-one;
4- (3-bromophenylamino) -quinazolin-6-yl acrylate;
n- [4- [ (3-bromophenyl) amino ] -P-vinyl-pyrido [3, 4-d ] pyrimidin-6-yl ] phosphonamide methyl ester;
4- (3-bromophenylamino) -quinazolin-7-yl acrylate;
1- [4- (3-bromophenylamino) -quinazolin-6-yl ] but-3-en-2-one;
4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinazolin-6-yl acrylate;
n- [4- (3-bromophenylamino) -7- (3-morpholin-4-yl-propoxy) -pyrido [3, 2-d ] pyrimidin-6-yl ] -acrylamide;
penta-2, 3-dienoic acid [4- (3-bromophenylamino) -quinazolin-6-yl ] amide;
propane-1, 2-diene-1-sulfonic acid [4- (3-bromophenylamino) -quinazolin-6-yl ] amide;
n- [4- [ (3-bromophenyl) amino ] -6-quinazolinyl ] -P- (1, 2-allenyl) phosphonamide methyl ester;
n- [1- (3-bromophenylamino) -9H-2, 4, 9-triazafluoren-7-yl ] -acrylamide;
n- [4- (3-bromophenylamino) -9H-1, 3, 9-triazafluoren-6-yl ] -acrylamide;
n- [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -acrylamide;
n- (4-phenylmethylamino-quinazolin-6-yl) -acrylamide;
(S) -N- [4- (1-phenylethylamino) -quinazolin-6-yl ] -acrylamide;
(R) -N- [4- (1-phenylethylamino) -quinazolin-6-yl ] -acrylamide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
n- [4- (3-chloro-4-fluoro-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -acrylamide;
n- [4- (3-chloro-4-fluoro-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -N-methyl-acrylamide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5- (4-methylpiperazin-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methylpiperazin-1-yl) -ethyl ester;
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (2-imidazol-1-yl) -ethyl ester;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-morpholin-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluorophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] amide };
(3-chloro-4-fluorophenyl) - {6- [2- (3-dimethylaminopropoxy) ethanesulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-chloro-4-fluorophenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) butylamino ] -ethanesulfonyl } -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-chloro-4-fluorophenyl) - [6- (5-morpholin-4-yl-pent-1-en-1-sulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
(3-chloro-4-fluorophenyl) - (6-vinylsulfinyl-pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
2-morpholin-4-yl-ethyl 3- [4- (1-phenylethylamino) quinazolin-6-ylcarbamoyl ] acrylate;
but-2-enedioic acid (4-imidazol-1-yl-butyl) -amide [4- (1-phenyl-ethylamino) quinazolin-6-yl ] -amide;
4- [4- (1-phenylethylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 3-diethylaminopropyl ester;
penta-2-enedioic acid 5- { [2- (4-methylpiperazin-1-yl) ethyl ] -amide }1- { [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide };
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
7-imidazol-1-yl-hept-2-ynoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (1-phenyl-ethylamino) -quinazolin-6-yl ] -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester;
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-imidazol-1-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-bromo-phenylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
(3-bromo-phenyl) - {6- [2- (3-dimethylamino-propoxy) -ethanesulfonyl ] -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-bromo-phenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) -butylamino ] -ethanesulfonyl } -pyrido [3, 4-d ] pyrimidin-4-yl } -amine;
(3-bromo-phenyl) - [6- (5-morpholin-4-yl-pent-1-en-1-sulfonyl) -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
(3-bromo-phenyl) - (6-ethylene-sulfinyl) -pyrido [3, 4-d ] pyrimidin-4-yl ] -amine;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-chloro-4-fluorophenylamino) -quinazolin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide;
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
penta-2-enedioic acid 1- { [4- (3-chloro-4-fluoro-phenylamino) -quinazolin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
(3-chloro-4-fluoro-phenyl) - {6- [2- (3-dimethylamino-propoxy) -ethanesulfonyl ] -quinazolin-4-yl } -amine;
(3-chloro-4-fluoro-phenyl) - (6- {2- [4- (4-methylpiperazin-1-yl) -butylamino ] -ethanesulfonyl } -quinazolin-4-yl } -amine;
but-2-enedioic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide (3-dimethylamino-propyl) -amide;
but-2-enedioic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide (3-imidazol-1-yl-propyl) -amide;
4, 4-difluoro-8-morpholin-4-yl-oct-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
8-dimethylamino-4, 4-difluoro-oct-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
6-morpholin-4-yl-hex-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-dimethylamino-hept-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
7-morpholin-4-yl-hept-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-dimethylamino-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-morpholin-4-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5-imidazol-1-yl-pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
5- (4-methyl-piperazin-1-yl) -pent-2-ynoic acid [4- (3-bromo-phenylamino) -quinazolin-6-yl ] -amide;
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2- (4-methyl-piperazin-1-yl) -ethyl ester;
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-imidazol-1-yl-ethyl ester;
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- [ (3-morpholinyl-4-yl-propyl) -amide ];
pent-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- [ (3-diethylamino-propyl) -amide ];
4- [4- (3-bromo-phenylamino) -quinazolin-6-ylcarbamoyl ] -but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
penta-2-enedioic acid 1- { [4- (3-bromophenylamino) -quinazolin-6-yl ] -amide }5- { [3- (4-methyl-piperazin-1-yl) -propyl ] -amide };
2-morpholin-4-yl-ethyl 3- [4- (1-phenylethylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] acrylate;
but-2-enedioic acid (4-imidazol-1-yl-butyl) -amide [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
4- [4- (1-phenylethylamino) -pyrido [3, 4-d ] pyrimidin-6-ylcarbamoyl ] -but-3-enoic acid 3-diethylaminopropyl ester;
penta-2-enedioic acid 5- { [2- (4-methylpiperazin-1-yl) ethyl ] -amide }1- { [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide };
4, 4-difluoro-7-morpholin-4-yl-hept-2-enoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-dimethylamino-4, 4-difluoro-hept-2-enoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
7-imidazol-1-yl-hept-2-ynoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
6-dimethylamino-hex-2-ynoic acid [4- (1-phenyl-ethylamino) -pyrido [3, 4-d ] pyrimidin-6-yl ] -amide;
but-2-enedioic acid (4- (3-chloro-4-fluorophenylamino) -7-fluoroquinazolin-6-yl ] -amide (3-dimethylaminopropyl) amide;
but-2-enedioic acid (7-chloro-4- (3-chloro-4-fluorophenylamino) quinazolin-6-yl ] -amide (3-dimethylaminopropyl) amide;
n- [4- [3- (bromophenyl) amino ] -5-fluoro-7- [3- (4-morpholino) propoxy ] quinazolin-6-yl ] -acrylamide; and
n- [4- [ (3- (chloro-4-fluorophenyl) amino ] -5-fluoro-7- [1, N-imidazolyl) propoxy ] quinazolin-6-yl ] -acrylamide.
Biological method
Tissue culture
A431 human epidermoid carcinoma cells were obtained from American type Culture Collection, Rockville, Md, and stored as monolayers in dMEM (Dulbecco's modified eagle Medium)/F12, 50:50(Gibco/BRL) containing 10% fetal bovine serum. For growth inhibition experiments, 10. mu.L dilutions of the indicated compounds were placed in 24-well Linbro plates (1.7X 1.6cm, flat bottom) and subsequently cells (2X 10) in 2mL of medium were added4). The plates were incubated at 37 ℃ for 72 hours in a humidified atmosphere containing 5% carbon dioxide. Cell growth was measured by cell counting using a Coulter Model AM electron cytometer (Coulter Electronics, Inc., Hialeah, FL).
Purification of epidermal growth factor receptor tyrosine kinase
Human EGF receptor tyrosine kinase was isolated from A431 human epidermoid carcinoma cells by the following method. Cells were grown in dMEM/F12 medium (Gibco/BRL) containing 10% fetal bovine serum in roller bottles. About 109The cells were dissolved in 2 volumes of buffer containing 20mM N- [ 2-hydroxyethyl-]-piperazine-N' - [ 2-ethanesulfonic acid](Hepes) ethylene glycol-bis (. beta. -aminoethyl ether) N, N, N ', N' -tetraacetic acid (EGTA) at pH7.4, 5mM, 1%Triton X-100, 10% glycerol, 0.1mM sodium orthovanadate, 5mM sodium fluoride, 4mM pyrophosphate, 4mM benzamide, 1mM Dithiothreitol (DTT), 80. mu.g/mL aprotinin, 40. mu.g/mL leupeptin, and 1mM phenylmethylsulfonyl fluoride (PMSF). After centrifugation at 25,000 Xg for 10 minutes, the supernatant was applied to a flash Q sepharose column (Pharmacia biotech, Inc., Piscataway, N.J.) and eluted with a linear gradient of 0.1M sodium chloride to 0.4M sodium chloride, 10% glycerol, pH7.4 in 50mM Hepes. The enzyme active fractions were pooled, aliquoted and stored at-100 ℃. Fibroblast Growth Factor Receptor (FGFR), Platelet Derived Growth Factor (PDGF), insulin and c-src tyrosine kinase were made by methods well known in the art. See, for example: fry et al, "discovery strategy for novel tyrosine kinase inhibitors with antitumor activity", anticancer Design, 1994; 9: 331-351.
Tyrosine kinase assay
To IC50The enzyme experiments measured were performed in 96-well filter plates (Millipore MADVN6550, Millipore, Bedford, MA). A total volume of 0.1mL, containing 20mM Hepes, pH7.4, 50. mu.M sodium vanadate, 40mM magnesium chloride, containing 0.5. mu. Ci32P]ATP in 10 μ M Adenosine Triphosphate (ATP), 20 μ g polyglutamic acid/tyrosine (Sigma chemical co., st. louis, MO), 10ng EGF receptor tyrosine kinase and a dilution of a suitable inhibitor. All components except ATP were added to the wells and the plates were incubated at 25 ℃ for 10 minutes with shaking. The reaction is carried out by adding32P]ATP was started and the plates were incubated at 25 ℃ for 10 min. The reaction was stopped by adding 0.1mL of 20% trichloroacetic acid (TCA). The plate was held at 4 ℃ for at least 15 minutes to allow the substrate to precipitate. The wells were then washed 5 times with 0.2mL of 10% TCA and measured with a Wallac beta plate counter (Wallac, Inc., Gaithersburg, Pa.)32And (4) doping P. Experiments using intracellular kinase domains of PDGF, FGF and insulin receptors and those of c-src were performed as described for the EGF receptor, except that 10mM manganese chloride was included in the reaction.
Western blotExperiment of
Preparing an extracting solution: the single cell layer was dissolved in 0.2mL boiling Laemlli buffer (2% sodium dodecyl sulfate, 5% beta-mercaptoethanol, 10% glycerol and 50mM Tris [ hydroxymethyl ] aminomethane (Tris), pH) and the lysate was heated at 100 ℃ for 5 minutes. Proteins in the lysate were separated by polyacrylamide gel electrophoresis and electrophoretically transferred to nitrocellulose. Membranes were washed once in 10mM Tris, pH7.2, 150mM sodium chloride, 0.01% azide (TNA) and blocked overnight in TNA containing 5% bovine serum albumin and 1% ovalbumin. The membrane was blotted with an anti-phosphotyrosine antibody (UBI, 1 μ g/mL blocking buffer) for 2 hours, then washed 2 times with TNA, 1 time in TNA with 0.05% tween-20 detergent and 0.05% ethylphenylpolyethylene glycol (Nonidet P40) detergent, and 2 times with TNA. The membranes were then incubated in blocking buffer containing 0.1. mu.Ciml [125I ] protein A for 2 hours and then washed as described above. After drying the blot, it was placed in a film cassette and exposed to X-AR X-ray film for 1-7 days (Eastman Kodak Co., Rochester, N.Y.). The band intensity was measured with a molecular dynamics laser densitometer.
Autophosphorylation assay
A431 human epidermoid carcinoma cells were grown to about 80% confluence on 6-well plates and then cultured in serum-free medium for 18 hours. Duplicate cells were treated with various concentrations of the indicated compounds to be tested as inhibitors for 15 minutes. Then, the cells were stimulated with 100ng/mL EGF for 5 minutes, and then the extract was obtained as described in Western blot experiment.
Irreversible experimental method
A431 human epidermoid cancer cells were grown to about 80% confluence on 6-well plates and then cultured in serum-free medium for 18 hours. Duplicate cells were treated with 2 μ M of the indicated compound to be tested as irreversible inhibitor for 1 or 2 hours. Then, a group of cells was stimulated with 100ng/mL of EGF for 5 minutes, and then an extract was obtained as described in Western blotting experiment. Another group of cells was washed free of compound with warm serum-free medium, cultured for 2 hours, washed again, cultured for 2 hours again, washed again, and cultured for 4 hours again. Then, the group of cells was stimulated with EGF and an extract was obtained similarly to the first group of cells.
Results
Column 1 of Table 1 shows the IC of various compounds for isolated EGF receptor tyrosine kinase inhibition50Values, column 2 shows the IC of EGF receptor autophosphorylation inhibition stimulated by EGF in A431 cells50The value is obtained. Most compounds of the invention inhibit isolated enzymes with low nanomolar or sub-nanomolar potency, most of which have low nanomolar potency when inhibiting autophosphorylation of cells. Table 2 shows the ability of a431 cells to restore EGF receptor autophosphorylation activity after enzyme inhibition by these compounds was completed by removing them from the culture medium. The cell extract of group 1 (column 2) shows that most of the tested compounds completely inhibited EGF receptor autophosphorylation after the initial 2 hours of culture. Column 3 of table 2 shows the percent recovery of EGF receptor autophosphorylation after washing and culturing in compound-free medium as described in the methods. At least 30 compounds retain 50% or more of their inhibition of kinase activity after such treatment, while at least 23 compounds show 90-100% inhibition of their original enzyme activity. Cells treated with all other test compounds restored EGF-dependent autophosphorylation activity by 86-100%. Reversibility studies in which cultures were performed further showed that the time required to restore 50% activity was 21 hours (table 3). The side chain requirements specific to irreversible interactions are indicated by the fact that: compound 9, which is very similar to compound 3, is fully reversible with the same potential inhibitory activity on the enzyme. Further, the need for conjugated olefins in the side chains is illustrated by comparative compounds 3 and 11 and their saturated analogs 17 and 28. In these cases, the compounds all showed similar potency towards the separating enzyme and were not well differentiated in the autophosphorylation experiments, but were nevertheless differentiatedCompounds 17 and 28 had no inhibitory effect after 8 hours of washing, while irreversible inhibitor compounds 3 and 11 had enzyme inhibition at this time of 89% and 100%.
Table 4 shows that compound 3 retained very high specificity for EGF receptor tyrosine kinase with exposure to other tyrosine kinases and that the active side chain in example 3 did not function indistinguishably from the other enzymes.
Finally, compound 3 was tested for its ability to inhibit proliferation of a431 human epidermoid cancer cells. IC (integrated circuit)50A value of 0.30. + -. 0.09 micromolar indicates its ability to stop tumor growth.
The performance of irreversible inhibitors is more attractive because it helps to overcome or address the problem of potency with a short plasma half-life and/or prolong the need for target inhibition. An intravenous bolus injection at an appropriate dose of irreversible inhibitor will be effective enough to completely destroy the activity of the target present, and the recovery of this activity will depend on the rate of target resynthesis. Since the half-life of EGF receptor recovery in a431 cells is 20 hours, the inhibitor will remain inhibitory to the receptor by once or twice a day administration. This eliminates the need for multiple injections or the use of infusion or osmotic pumps. In addition, since receptor activity is no longer constrained by equilibrium binding conditions, the dosage used to achieve the effect of the irreversible inhibitor in a multiple or continuous mode of administration may be reduced.
TABLE 1
IC of various examples on isolated EGFR kinase Activity50Values and EGFR autophosphorylation in A431 cells
TABLE 1 (continuation)
IC of various examples on isolated EGFR kinase Activity50Value and EGFR autophosphorylation in A431 cellsAcidification
TABLE 2
Restoration of EGF receptor autophosphorylation activity in A431 cells after exposure to 2. mu.M inhibitor
Table 2 (continuation)
Restoration of EGF receptor autophosphorylation activity in A431 cells after exposure to 2. mu.M inhibitor
TABLE 3
Reversibility of EGF receptor autophosphorylation inhibitors in A431 cells treated with 2 μ M Compound 3 or Compound 9 inhibitors for 2 hours
TABLE 4
Example 3 inhibition of different tyrosine kinases IC50(nM) Effect
In vivo data
On day 0, 18-20g of female nude mice (Ncr nu/nu,taconic farm) with tumor fragments (about 30 mg). The tumor used in this study was fibroblast NIH 3T3 transfected with the h-EGF receptor (Decker et al, J Biol Chem, 1990; 265: 7009-. This model is very prone to tumorigenesis with an incidence of 100% and volume doubling within 2 days. The compound of example 3 was administered intraperitoneally every 12 hours on days 3-7 for a total of 10 injections (5 mice per group). The excipient is 6% dimethylacetamide, 50mM lactic acid buffer, pH 4.0. By measuring the length and width of individual tumors, as follows (a × b)2) Calculated mass (in mg) and tumor volume was recorded 3 times per week, where a and b are the length and width of the tumor, respectively. The percentage T/C (treated/control) was calculated as the ratio of the median tumor volume of the treated tumors to the median tumor volume of the control tumors on the particular measurement days.
Treatment with 100 and 30 mg/kg/injection inhibited tumor growth by 40-50% from experiments on days 7,10 and 12. Whereas no activity was observed at 10 and 3 mg/kg/injection. No signs of weight loss, death or clinical toxicity were observed at any dose level.
％T/C
Additive in vivo assay
Several compounds were tested for various tumor xenografts using a similar method as described above, except that there were 6 mice per group and the dosing schedule was as described above. These assays included the h-EGF receptor transfected NIH 3T 3-transfected fibroblast cell model as previously described; a431 human epidermoid carcinoma, which severely overexpresses the EGF receptor; MCF7 human breast cancer, which is sensitive to EGF receptor inhibitors and is known to express EGF receptor and erbB-2 and erbB-3; SK-OV-3 human ovarian cancer which overexpresses erbB-2; AH-125 small cell lung cancer which overexpresses the EGF receptor; murine 16/c Breast cancer.
Example 3
EGFR tumor
Intraperitoneal administration, 2 times daily on days 3-7:
@100mg/kg caused a growth delay of 4 days.
@30mg/kg caused a growth delay of 2.5 days.
Intraperitoneal administration, 2 times daily on days 1-13:
@300mg/kg are inactive.
@190 and 120mg/kg caused a growth delay of 1 day.
@75mg/kg caused a growth delay of 5 days.
Example 11
MCF-7 tumors
Intraperitoneal administration, 2 times daily on days 1-5, 8-12, and 15-19:
@47mg/kg caused a growth delay of 17.4 days.
@28mg/kg caused a growth delay of 22.9 days.
Murine 16/C Breast cancer
The medicine is administered 2 times daily, and the dosage of the medicine is more than 120 mg/kg.
EGFR tumor
Intraperitoneal administration, 2 times daily for 14 days:
@75mg/kg caused a growth delay of 8.7 days.
@47mg/kg caused a growth delay of 6.6 days.
@29mg/kg caused a growth delay of 2.3 days.
@18mg/kg caused a growth delay of 1.8 days.
@150mg/kg is toxic.
@75mg/kg is toxic.
Intraperitoneal administration, 2 times daily on days 3-7, days 10-14, days 17-21, and days 24-28:
@75mg/kg caused a growth delay of 19.9 days.
@150mg/kg is toxic.
Intraperitoneal administration, 1 time per day on days 3-17:
@75mg/kg caused a growth delay of 11.7 days.
Intraperitoneal administration, 1 time daily on days 3-7, 10-14, 17-21:
@75mg/kg caused a growth delay of 5.3 days.
@150mg/kg is toxic.
A431 tumor
Intraperitoneal administration, 2 times daily on days 7-11, 4-18, 21-25:
@28mg/kg caused a growth delay of 28.2 days.
Oral administration, 1 time per day, 7-21 days:
@200mg/kg caused a growth delay of 3.5 days.
@100mg/kg caused a growth delay of 2 days.
SK-OV-3-tumors
Intradermal administration, 2 times daily on days 10-14, days 17-21, and days 24-28:
@30mg/kg caused a growth delay of 1.2 days.
Example 19
EGFR tumor
Intraperitoneal administration, 2 times daily for 14 days:
@124mg/kg caused a growth delay of 11.8 days.
@77mg/kg caused a growth delay of 7.9 days.
@48mg/kg caused a growth delay of 6.4 days.
@200mg/kg is toxic.
SK-OV-3-tumors
Intradermal administration, 2 times daily on days 10-14, days 17-21, and days 24-28:
@30mg/kg caused a growth delay of 1.3 days.
A431 tumor
Subcutaneous infusion (Alzet), days 9-23:
@24 mg/kg/day caused a growth delay of 14 days.
@12 mg/kg/day caused a growth delay of 15 days.
Example 21
Intraperitoneal administration, 2 times daily:
@48mg/kg is toxic.
EGFR tumor
Intraperitoneal administration, 2 times daily for 14 days:
@12.5mg/kg caused a growth delay of 16.8 days.
@6.25mg/kg caused a growth delay of 9.3 days.
@25mg/kg is toxic.
Subcutaneous infusion (Alzet):
@200, 124, 77 and 48 mg/kg/day are toxic.
AH-125 tumor
Subcutaneous infusion (Alzet), days 19-23:
@20.6 mg/kg/day caused a growth delay of 10.0 days.
@10.4 mg/kg/day caused a growth delay of 9.5 days.
@5.5 mg/kg/day caused a growth delay of 9.5 days.
A431 tumor
Subcutaneous infusion (Alzet), days 9-23 and 42-56:
@48 mg/kg/day caused a growth delay of 55 days.
@24 mg/kg/day caused a growth delay of 60 days.
@12 mg/kg/day caused a growth delay of 51 days.
Example 36
EGFR tumor
Intraperitoneal administration, 2 times daily for 7 days:
@48mg/kg caused a growth delay of 10.3 days.
Intraperitoneal administration, 2 times daily for 14 days:
@25mg/kg caused a growth delay of 8.7 days.
@12.5mg/kg caused a growth delay of 3.5 days.
@50mg/kg is toxic.
Subcutaneous infusion (Alzet):
@200, 124, 77 mg/kg/day are toxic.
Example 40
Intraperitoneal administration, 2 times daily:
@48 and 20mg/kg are toxic.
EGFR tumor
@14 days 2 times daily, 10 and 5mg/kg were ineffective.
Subcutaneous infusion (Alzet):
@200, 124, 77 and 48 mg/kg/day are toxic.
Claims (32)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein X is-D-E-F, Y is-SR4Halogen, -OR4、-NHR3Or hydrogen, or X is-SR4、-OR4、-NHR3Or hydrogen, Y is-D-E-F;
d is
Or does not have
E isOr
F isOr
With the proviso that when E is
OrWhen the temperature of the water is higher than the set temperature,
d is notOr
R1Is hydrogen, halogen, or C1-C6An alkyl group;
R2、R3and R4Independently of one another is hydrogen, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH or-NAB, A and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl or- (CH)2)n-an imidazolyl group;
Z1、Z2or Z3Independently of one another hydrogen, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, nitro, C1-C6Perfluoroalkyl, hydroxy, C1-C6Acyloxy, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C3-C8Cycloalkyl), -N (C)3-C8Cycloalkyl radicals2Hydroxymethyl, C1-C6Acyl, cyano, azido, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C3-C8Thiocycloalkyl radical, C3-C8Sulfinylcycloalkyl, C3-C8Sulfonylcycloalkyl, mercapto, C1-C6Alkoxycarbonyl, C3-C8Cycloalkoxycarbonyl, C2-C4Alkenyl radical, C4-C8Cycloalkenyl or C2-C4An alkynyl group; and
R5is hydrogen, halogen, C1-C6Perfluoroalkyl, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH2、-CH＝CH-(C1-C6) Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)nNH2、-(CH2)nNH(C1-C6Alkyl), - (CH)2)n-N-(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, C1-C6Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl has 1-3 substituents independently selected from Z1、Z2、Z3Or a monocyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen, sulfur or phosphorus, and each C1-C6Alkyl is unsubstituted or substituted by-OH or-NAB, wherein A and B are as previously defined, R6Is hydrogen or C1-C6An alkyl group; r13Is hydrogen or halogen; and
n is 1-4, p is 0 or 1;
with the proviso that if R is13Is hydrogen or halogen, p is 0, Y is-NH-CO-F1, wherein F1 is-CH ═ CH2or-C ≡ CH, both unsubstituted or substituted by one or more C1-C6Substituted by alkyl groups, then X cannot be hydrogen, hydroxy or C1-C6An alkoxy group.
2. A compound according to claim 1, wherein Z1And Z2Is hydrogen, Z3Is halogen.
3. A compound according to claim 2, wherein Z3Is bromine.
4. A compound according to claim 3 wherein bromine is located at the 3-position of the phenyl ring.
5. A compound according to claim 1, wherein Z1Is hydrogen, Z2Is fluorine, Z3Is chlorine.
6. A compound according to claim 5, wherein fluorine is in the 4-position and chlorine is in the 3-position of the phenyl ring.
7. A compound according to claim 1, wherein
X isAnd Y is hydrogen, or
X is hydrogen and Y is
8. The compound according to claim 1, wherein Y is-D-E-F, and-D-E-F is
Or
9. The compound according to claim 1, wherein X is-D-E-F, and-D-E-F is
Or
10. A compound according to claim 8, wherein R2Is hydrogen.
11. A compound according to claim 9, wherein R2Is hydrogen.
12. A compound according to claim 8, wherein R2Is- (CH)2)n-N-morpholino.
13. A compound according to claim 9, wherein R2Is- (CH)2)n-N-morpholino.
14. A compound according to claim 8, wherein R5Is carboxyl, C1-C6Alkoxycarbonyl or C1-C6An alkyl group.
15. The compound according to claim 1, wherein Y is-D-E-F and X is-O- (CH)2)n-N-morpholino.
16. The compound according to claim 1, wherein Y is-D-E-F and X is-O- (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]。
17. The compound according to claim 1, wherein Y is-D-E-F and X is-O- (CH)2)n-an imidazolyl group.
18. The compound according to claim 1, wherein said- (CH)2)n-imidazolyl is- (CH)2)n-an N-imidazolyl group.
19. The compound according to claim 1Wherein said-NAB is-NH2。
20. A compound according to claim 1 which is the following:
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] -acrylamide;
3- [4- (3-bromo-phenylamino) -quinazolin-7-yl-carbamoyl ] acrylic acid;
3- [4- (3-bromo-phenylamino) -quinazolin-7-yl-carbamoyl ] acrylic acid ethyl ester;
but-2-enoic acid [4- (3-bromo-phenylamino) -quinazolin-7-yl ] amide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] acrylamide;
n- [4- (3-methyl-phenylamino) -quinazolin-7-yl ] acrylamide;
n- [4- (3-chloro-phenylamino) -quinazolin-7-yl ] acrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] methacrylamide;
n- [4- (3-bromo-phenylamino) -quinazolin-7-yl ] ethenylsulfonamide;
n- [4- [ (3-chloro-phenyl) amino ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-methylphenyl) amino ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3- (trifluoromethyl) phenyl) amino ] -quinazolin-6-yl ] acrylamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] methacrylamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -E-but-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] -4, 4, 4-trifluoro-E-but-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] propynamide;
n- [4- [ (3-bromo-phenyl) amino ] -quinazolin-6-yl ] but-2-ynylamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] but-2, 3-dienamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] -E, 4-oxopent-2-enamide;
n- [4- [ (3-bromo-phenyl) amino ] quinazolin-6-yl ] -E, 4-ethoxy-4-oxobut-2-enamide.
21. The compound of claim 1 selected from
N- [4- [ (3-bromophenyl) amino ] -quinazolin-7-yl ] -N- [ 3-morpholinopropyl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [ (3- (4-morpholino) propoxy ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-methylphenyl) amino ] -7- [ (3- (4-morpholino) propoxy ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-methylphenyl) amino ] -7- [ (3- (4, N-methyl-1, N-piperazinyl) propoxy ] -quinazolin-6-yl) -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [ (3- (4, N-methyl-1, N-piperazinyl) propoxy ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [ (3- (1, N-imidazolyl) propoxy ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -7- [4- (N, N-dimethylamino) butoxy ] -quinazolin-6-yl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -N- [ 3-morpholinopropyl ] -acrylamide;
n- [4- [ (3-bromophenyl) amino ] -quinazolin-6-yl ] -E, 4- (3- (N, N-dimethylamino) propoxy-4-oxobut-2-enamide ] trifluoroacetate.
22. A compound according to claim 1, wherein
X is-D-E-F, F is
Or
R5Is composed of
1, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH- (C)1-C6) Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, C1-C6Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, and each 1, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, -CH ═ CH- (C)1-C6) Alkyl, -1-oxo (C)1-C6) Alkyl radical, C1-C6Alkoxycarbonyl or-N- (C)1-C6) C of alkylcarbamoyl1-C6Alkyl is unsubstituted or substituted by-OH or-NAB, wherein A and B are as defined in claim 1; or
Y is-D-E-F, F is
Or
R5Is composed of
1, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, - (CH)2)n-N-piperidinyl, - (CH)2)n-piperazinyl, - (CH)2)n-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-N-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, -CH ═ CH- (C)1-C6) Alkyl, - (CH)2)n-N-hexahydroazepine, - (CH)2)n-NH2、-(CH2)n-NH(C1-C6Alkyl), - (CH)2)n-N(C1-C6Alkyl radical)2-1-oxo (C)1-C6) Alkyl, carboxyl, C1-C6Alkoxycarbonyl, N- (C)1-C6) Alkylcarbamoyl, and each 1, 1-difluoro (C)1-C6) Alkyl radical, C1-C6Alkyl, -CH ═ CH- (C)1-C6) Alkyl, -1-oxo (C)1-C6) Alkyl radical, C1-C6Alkoxycarbonyl or-N- (C)1-C6) C of alkylcarbamoyl1-C6Alkyl is unsubstituted or substituted by-OH or-NAB, wherein A and B are as defined in claim 1.
23. A compound according to claim 1, wherein
X is-D-E-F;
y is-SR4、-OR4or-NHR3；
R3And R4Is composed of
-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH or-NAB, A and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl or- (CH)2)n-an imidazolyl group; or
Y is-D-E-F;
x is-SR4、-OR4or-NHR3；
R3And R4Is composed of
-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-pyridyl, - (CH)2)n-imidazolyl, - (CH)2)n-N-morpholino, - (CH)2)n-N-thiomorpholino, - (CH)2)n-N-hexahydroazepine or substituted C1-C6Alkyl, wherein the substituents are selected from-OH or-NAB, A and B are independently hydrogen, C1-C6Alkyl, - (CH)2)nOH、-(CH2)n-N-piperidinyl, - (CH)2)n-N-piperazinyl, - (CH)2)n-N1-piperazinyl [ N ]4-(C1-C6) Alkyl radical]、-(CH2)n-N-pyrrolidinyl, - (CH)2)n-N-pyridyl or- (CH)2)n-an imidazolyl group.
24. A compound according to claim 22 or 23, wherein- (CH)2)n-imidazolyl is- (CH)2)n-an N-imidazolyl group.
25. The compound according to claim 22 or 23, wherein the-NAB is-NH2。
26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 and a pharmaceutically acceptable carrier.
27. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment of cancer.
28. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment or prophylaxis of restenosis.
29. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the irreversible inhibition of a tyrosine kinase in a patient.
30. The use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment of psoriasis.
31. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment of atherosclerosis.
32. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment of endometriosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1535196P | 1996-04-12 | 1996-04-12 | |
| US60/015,351 | 1996-04-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1064675A1 HK1064675A1 (en) | 2005-02-04 |
| HK1064675B true HK1064675B (en) | 2009-12-24 |
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