HK1069576B - Substituted bicyclic derivatives for the treatment of abnormal cell growth - Google Patents

Substituted bicyclic derivatives for the treatment of abnormal cell growth Download PDF

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Publication number
HK1069576B
HK1069576B HK05102099.1A HK05102099A HK1069576B HK 1069576 B HK1069576 B HK 1069576B HK 05102099 A HK05102099 A HK 05102099A HK 1069576 B HK1069576 B HK 1069576B
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Hong Kong
Prior art keywords
methyl
yloxy
phenylamino
pyridin
quinazolin
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HK05102099.1A
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Chinese (zh)
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HK1069576A1 (en
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J．C．卡瑟
S．K．巴塔查尔亚
J.莫里斯
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辉瑞产品公司
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Description

Substituted bicyclic derivatives for the treatment of abnormal cell growth
The present invention is a divisional application of chinese patent application 01811470.9 filed 6/14/2001 entitled "substituted bicyclic derivatives for treating abnormal cell growth".
Background
The present invention relates to novel bicyclic derivatives useful for treating abnormal cell growth, such as mammalian cancer. The invention also relates to methods of using such compounds to treat abnormal cell growth in mammals, particularly humans, and to pharmaceutical compositions containing such compounds.
It is known that cells can become cancerous due to the transformation of a portion of their DNA into an oncogene (i.e., a gene that, upon activation, leads to the production of malignant tumor cells). Many oncogenes encode abnormal tyrosine kinase proteins that can cause cellular transformation. Alternatively, overexpression of the normal proto-oncogene tyrosine kinase may also lead to proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are intracellular portions that span the cell membrane and have an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and function as kinases to phosphorylate specific tyrosine residues within proteins, thereby affecting cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. Such kinases are known to be often aberrantly expressed in common cancers such as breast cancer, gastrointestinal cancers such as colon, rectal or stomach cancer, leukemia and ovarian, bronchial or pancreatic cancer. Epidermal Growth Factor Receptor (EGFR) with tyrosine kinase activity has also been shown to be mutated and/or overexpressed in many human cancers, such as brain, lung, squamous cell, bladder, stomach, breast, head and neck, esophagus and thyroid tumors.
Accordingly, it is recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of mammalian cancer cell growth. For example, epistatin, a tyrosine kinase inhibitor, selectively attenuates the growth of transplanted human breast cancer expressing epidermal growth factor receptor tyrosine kinase (EGFR) in athymic nude mice but has no effect on the growth of another cancer that does not express the EGF receptor. Accordingly, the compounds of the present invention are selective inhibitors of certain receptor tyrosine kinases and are useful in the treatment of abnormal cell growth, particularly cancer, in mammals. In addition to receptor tyrosine kinases, the compounds of the invention also exhibit inhibitory activity against a variety of other non-receptor tyrosine kinases (e.g., Ick, src, abl) or serine/threonine kinases (e.g., cyclin-dependent kinases).
Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties. Recently, five European patent documents, namely EP 0566226A 1 (published 1993 at 10/20), EP 0602851A 1 (published 1994 at 6/22), EP 0635507A 1 (published 1995 at 1/25), EP 0635498A 1 (published 1995 at 1/25), and EP 0520722A 1 (published 1992 at 12/30), have indicated that certain bicyclic derivatives, in particular quinazoline derivatives, have anti-cancer properties as a result of their tyrosine kinase inhibitory properties. Also, world patent application WO 92/20642 (26/11/1992) teaches that certain di-mono-and bicyclic aryl and heteroaryl compounds are useful as tyrosine kinase inhibitors in inhibiting abnormal cell proliferation. The world patent applications WO 96/16960 (6.6.1996), WO 96/09294 (6.3.1996), WO 97/30034 (21.8.1997), WO 98/02434 (22.1.1998), WO 98/02437 (22.1.1998), and WO98/02438 (22.1.1998) also indicate that substituted bicyclic heteroaryl derivatives can be used for the same purpose as tyrosine kinase inhibitors. Other patent applications for anticancer compounds are U.S. patent application Ser. Nos. 09/488,350(2000, 1/20), and 09/488,378(2000, 1/20), both of which are incorporated herein by reference in their entirety.
Summary of The Invention
And to pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein: m is an integer of 0 to 3;
p is an integer from 0 to 4;
R1and R2Each independently selected from H and C1-C6An alkyl group;
R3is- (CR)1R2)t(4-to 10-membered heterocyclic ring), wherein t is an integer from 0 to 5, said heterocyclic group optionally being associated with a benzene ring or C5-C8Cycloalkyl fused, said R being3Of a group- (CR)1R2)t-the moiety optionally comprises a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the above R3Groups, including any optionally fused rings indicated above, optionally substituted with 1-5R8Substituted by groups;
R4is- (CR)16R17)m-C≡C-(CR16R17)tR9，-(CR16R17)m-C＝C-(CR16R17)t-R9，-(CR16R17)m-C≡C-(CR16R17)kR13，-(CR16R17)m-C＝C-(CR16R17)kR13Or is- (CR)16R17)tR9Wherein with R9Is through R9Carbon atoms of the group, each k is an integer from 1 to 3, each t is an integer from 0 to 5, and each m is an integer from 0 to 3;
each R is5Each independently selected from halogen atoms, hydroxy groups, -NR1R2，C1-C6Alkyl, trifluoromethyl, C1-C6Alkoxy, trifluoromethoxy, -NR6C(O)R1，-C(O)NR6R7，-SO2NR6R7，-NR6C(O)NR7R1and-NR6C(O)OR7；
Each R is6，R6aAnd R7Independently selected from H, C1-C6Alkyl, - (CR)1R2)t(C6-C10Alkyl), and- (CR)1R2)t(4-to 10-membered heterocyclic ring), wherein t is an integer of O to 5, 1 or 2 ring-forming carbon atoms of the heterocyclic group being optionally substituted with an oxo (═ O) moiety, and the above R6And R7The alkyl, aryl and heterocyclic moieties of the group are optionally independently selected from halogen atoms, cyano, nitro, -NR1R2Trifluoromethyl, trifluoromethoxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy, and C1-C61 to 3 substituents of alkoxy;
or R6And R7Or R is6aAnd R7When it is linked to a nitrogen atom (including the same nitrogen atom or by internal linkage, e.g. by-C (O) or-SO)2Two separate nitrogen atoms close to each other) may together form a4 to 10 membered heterocyclic ring, except for the attachment of R6，R6aAnd R7May include 1 to 3 additional heteroatom moieties in addition to the nitrogen atom(s) selected from N, N (R)1) O, and S, with the proviso that two O atoms, two S atoms or one O and one S atom are not directly attached to each other;
each R is8Independently selected from oxo (═ O), halogen atom, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6Alkoxy radical, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, -C (O) R6，-C(O)OR6，-OC(O)R6，-NR6C(O)R7，-NR6SO2NR7R1，-NR6C(O)NR1R7，-NR6C(O)OR7，-C(O)NR6R7，-NR6R7，-NR6OR7，-SO2NR6R7，-S(O)j(C1-C6Alkyl) where j is an integer from 0 to 2, - (CR)1R2)t(C6-C10Aryl), - (CR)1R2)t(4-to 10-membered heterocycle), - (CR)1R2)qC(O)(CR1R2)t(C6-C10Aryl), - (CR)1R2)qC(O)(CR1R2)t(4-to 10-membered heterocycle), - (CR)1R2)tO(CR1R2)q(C6-C10Aryl), - (CR)1R2)tO(CR1R2)q(4-to 10-membered heterocycle), - (CR)1R2)qS(O)j(CR1R2)t(C6-C10Aryl), and- (CR)1R2)qS(O)j(CR1R2)t(4-to 10-membered heterocycle), wherein j is 0, 1 or 2, q and t are each independently an integer of 0 to 5, and R81 or 2 ring-forming carbon atoms of the heterocyclic moiety of the group are optionally substituted with an oxo (═ O) moiety, and the above R8The alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the group are optionally independently selected from halogen atoms, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6，-C(O)R6，-C(O)OR6，-OC(O)R6，-NR6C(O)R7，-C(O)NR6R7，-NR6R7，-NR6OR7，C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, - (CR)1R2)t(C6-C10Aryl), and- (CR)1R2)t(4-to 10-membered heterocycle), wherein t is 1 to 3 substituents of an integer of 0 to 5;
R9is a non-aromatic monocyclic, fused or bridged bicyclic ring, or a spiro ring, wherein said ring contains 3 to 12 carbon atoms, wherein 0 to 3 carbon atoms are optionally independently selected from N, O, S (O)jWherein j is an integer of O to 2, and-NR1-with the proviso that two O atoms are present,two S (O)jMoiety, one O atom and one S (O)jMoiety, one N atom and one S atom, or one N atom and one O atom, are not directly linked to each other within the ring, and the carbon atoms of the ring are optionally substituted by 1 or 2R8Substituted by groups;
each R is11Independently selected from R8Substituents given in the definitions, except for R11Is not oxo (═ O);
R12is R6，-OR6，-OC(O)R6，-OC(O)NR6R7，-OCO2R6，-S(O)jR6，-S(O)jNR6R7，-NR6R7，-NR6C(O)R7，-NR6SO2R7，-NR6C(O)NR6aR7，-NR6SO2NR6aR7，-NR6CO2R7，CN，-C(O)R6Or a halogen atom, wherein j is an integer of 0 to 2;
R13is-NR1R14OR-OR14；
R14Is H, R15，-C(O)R15，-SO2R15，-C(O)NR15R7，-SO2NR15R7or-CO2R15；
R15Is R18，-(CR1R2)t(C6-C10Aryl), - (CR)1R2)t(4-to 10-membered heterocycle), wherein t is an integer of 0 to 5, 1 or 2 ring-forming carbon atoms of the heterocycle being optionally substituted with an oxo (═ O) moiety, and the above R15The aryl and heterocyclic moieties of the group are optionally substituted with 1-3R8Substituent group substitution;
each R is16And R17Independently selected from H, C1-C6Alkyl, and-CH2OH, or R16And R17Together form-CH2CH2-or-CH2CH2CH2-；
R18Is C1-C6Alkyl, wherein no N or O atom is bonded, or no S (O)pBonded, wherein each carbon atom of j is an integer of 0 to 2 is optionally substituted with R12Substitution;
including not having halogen atoms, SO or SO2Radicals or CH to which N, O or S atoms are attached3(methyl group), CH2The above substituents of the (methylene) or CH (methine) group being optionally substituted by a group selected from hydroxy, halogen, C1-C4Alkyl radical, C1-C4Alkoxy and-NR1R2Is substituted with a group (b).
In a particular embodiment of the invention, R3Is- (CR)1R2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; said heterocycle being optionally substituted with a benzene ring or C5-C8Cycloalkyl fused, said R being3Groups, including the optionally fused rings indicated above, optionally substituted with 1-3R8And (4) substituting the group.
Other embodiments of the compounds of formula 1 include those wherein R is3Is- (CR)1R2)t(4-10 membered heterocyclic) in which t is an integer from 0 to 5, the above-mentioned R3 group being optionally substituted with 1 to 3R8And (4) substituting the group.
Other embodiments of the compounds of formula 1 include those wherein R is3Selected from the following
And
wherein the aboveR3The radical being optionally substituted by 1 to 3R8And (4) substituting the group.
Other embodiments of the compounds of formula 1 include those wherein R is3Is optionally substituted by 1-3R8Group-substituted pyridin-3-yl.
Other embodiments of the compounds of formula 1 include those wherein the moiety of formula 1 is a moiety of formula
Selected from those below:
3-methyl-4- (pyridin-2-yloxy) -phenylamino
3-chloro-4- (pyridin-2-yloxy) -phenylamino
3-methoxy-4- (pyridin-2-yloxy) -phenylamino
4- (pyridin-2-yloxy) -phenylamino
2-methyl-4- (pyridin-2-yloxy) -phenylamino
2-methoxy-4- (pyridin-2-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyridin-3-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (pyridin-3-yloxy) -phenylamino
3-chloro-4- (pyridin-3-yloxy) -phenylamino
3-methoxy-4- (pyridin-3-yloxy) -phenylamino
2-methyl-4- (pyridin-3-yloxy) -phenylamino
2-methoxy-4- (pyridin-3-yloxy) -phenylamino
4- (pyridin-3-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-chloro-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
2-methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
2-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-methyl-4- (pyridin-4-yloxy) -phenylamino
3-chloro-4- (pyridin-4-yloxy) -phenylamino
3-methoxy-4- (pyridin-4-yloxy) -phenylamino
2-methyl-4- (pyridin-4-yloxy) -phenylamino
2-methoxy-4- (pyridin-4-yloxy) -phenylamino
4- (pyridin-4-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-methyl-4- (pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (pyrazin-2-yloxy) -phenylamino
3-chloro-4- (pyrazin-2-yloxy) -phenylamino
2-methyl-4- (pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (pyrazin-2-yloxy) -phenylamino
4- (pyrazin-2-yloxy) -phenylamino
3-chloro-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-chloro-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (pyridazin-3-yloxy) -phenylamino
3-chloro-4- (pyridazin-3-yloxy) -phenylamino
3-methoxy-4- (pyridazin-3-yloxy) -phenylamino
2-methyl-4- (pyridazin-3-yloxy) -phenylamino
2-methoxy-4- (pyridazin-3-yloxy) -phenylamino
4- (pyridazin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-chloro-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
2-methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-methyl-4- (pyridazin-4-yloxy) -phenylamino
3-chloro-4- (pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (pyridazin-4-yloxy) -phenylamino
2-methyl-4- (pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (pyridazin-4-yloxy) -phenylamino
4- (pyridazin-4-yloxy) -phenylamino
3-chloro-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
3-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
3-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
2-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
2-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino,
and 4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C≡C-(CR16R17)tR9Wherein m is an integer of 0 to 3 and t is an integer of 0 to 5.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C≡C-(CR16R17)tR9Wherein m is an integer of 0 to 3, t is an integer of 0 to 5, wherein R9Selected from each optionally substituted by 1 or 2R8Group-substituted 3-piperidinyl and 4-piperidinyl groups.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C＝C-(CR16R17)t-R9Wherein m is an integer of 0 to 3 and t is an integer of 0 to 5.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C＝C-(CR16R17)t-R9Wherein m is an integer of 0 to 3, t is an integer of 0 to 5, wherein R9Selected from 3-piperidinyl and 4-piperidinyl (optionally substituted with 1 or 2R)8Substituted with groups).
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Wherein k is an integer of 1 to 3 and m is an integer of 0 to 3.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Wherein k is an integer of 1 to 3, m is an integer of 0 to 3, wherein R13is-NR1R14Wherein R is14Selected from the group consisting of-C (O) R15，-SO2R15And C (O) NR15R7。
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C＝C-(CR16R17)kR13Wherein k is an integer of 1 to 3 and m is an integer of 0 to 3.
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C＝C-(CR16R17)kR13Of whichk is an integer of 1 to 3, m is an integer of 0 to 3, wherein R13is-NR1R14Wherein R is14Selected from the group consisting of-C (O) R15，-SO2R15And C (O) NR15R7。
Other embodiments of the compounds of formula 1 include those wherein R is4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Or- (C)16R17)m-C＝C-(CR16R17)kR13Wherein k is an integer of 1 to 3, m is an integer of 0 to 3, R13is-NR1R14OR-OR14，R14Is R15，R15Is R18And R is18Is optionally substituted by-OR6，-S(O)jR6，-NR6R7，-NR6C(O)R7，-NR6SO2R7，-NR6CO2R7，CN，-C(O)R6Or C substituted by halogen atoms1-C6An alkyl group.
Particularly preferred compounds of the invention include those selected from the group consisting of:
(±) - [ 3-methyl-4- (pyridin-3-yloxy) -phenyl ] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
(±) - [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
[ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine
[ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
2-fluoro-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
E-2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -acetamide;
[ 3-methyl-4- (pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-ylethynyl } -cyclopropyl) -acetamide;
E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -2-methoxy-acetamide;
n- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
n- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -acetamide;
E-2-ethoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -acetamide;
1-ethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -urea;
piperazine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
(±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
2-dimethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -methanesulfonamide;
isoxazole-5-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
1- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -3-ethyl-urea;
and pharmaceutically acceptable salts, prodrugs and solvates of the above compounds.
The present invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, effective in treating abnormal cell growth. In one embodiment of the method, the abnormal cell growth is a cancer, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing. In another embodiment of the method, the abnormal cell growth is a benign proliferative disease including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis.
The present invention also relates to a method for treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof effective to treat abnormal cell growth in combination with an antineoplastic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones and anti-androgens.
The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human, comprising an amount of a compound of formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of the composition, the abnormal cell growth is cancer, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, neoplasms of the spinal axis, brain stem glioma, pituitary adenoma, or a combination of one or more of. In another embodiment of the pharmaceutical composition, the abnormal cell growth is a benign proliferative disease including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis.
The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human, comprising a compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to treat abnormal cell growth in combination with a pharmaceutically acceptable carrier and an antineoplastic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones and anti-androgens.
The present invention also relates to a method of treatment of a disease associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined above, effective in treating said disease. Such diseases include cancerous tumors such as melanoma; ocular diseases such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization due to proliferative diabetic retinopathy; rheumatoid arthritis; bone loss diseases such as osteoporosis, Paget's disease, hypercalcemia of malignant body fluids, hypercalcemia of tumor metastasis to bone, and glucocorticoid therapy-induced osteoporosis; coronary restenosis; and some microbial infections include those associated with microbial pathogens selected from the group consisting of adenovirus, hantaviruses (hantaviruses), borrelia burgdorferi (borrelia burgdorferi), Yersinia sp, Bordetella pertussis (Bordetella pertussis), and streptococcus.
The present invention also relates to methods (and pharmaceutical compositions) for treating abnormal cell growth in a mammal comprising administering together an amount of a compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more agents selected from the group consisting of anti-angiogenic agents, signal transduction inhibitors and antiproliferative agents effective to treat said abnormal cell growth.
In the methods and pharmaceutical compositions described herein, anti-angiogenic agentsFor example, MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors may be used in combination with the compound of formula 1. Examples of useful COX-II inhibitors include CELEBRETTM(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix-metalloprotease inhibitors are described in WO 96/33172 (published 24/10/1996), WO 96/27583 (published 7/3/1996), European patent application No.97304971.1 (published 8/7/1997), European patent application No.99308617.2 (published 29/10/1999), WO 98/07697 (published 26/2/1998), WO 98/03516 (published 29/1998), WO 98/34918 (published 13/8/1998), WO 98/34915 (published 13/8/1998), WO98/33768 (published 6/8/1998), WO 98/30566 (published 16/7/1998), European patent publication 606,046 (published 13/7/13/1994), European patent publication 931,788 (published 28/7/1999), WO 90/05719 (published 31/5/1990), WO 99/52910 (published 21/10/1999), WO 99/52889 (published 21/10/1999), WO 99/29667 (published 17/6/1999), PCT International application No. PCT/IB98/01113 (published 21/7/1998), European patent application No.99302232.1 (published 25/3/1999), british patent application No. 9912961.1 (published 3/6/1999), U.S. provisional application No.60/148,464 (published 12/8/1999), U.S. patent 5,863,949 (published 26/1999), U.S. patent 5,861,510 (published 19/1/1999), and European patent publication 780,386 (published 25/6/1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no inhibition of MMP-1 activity. More preferably, those that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix-metalloproteases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in combination with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed below:
3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclopentyl) -amino ] propionic acid;
3-exo) -3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
(2R, 3R)1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclobutyl) -amino ] propionic acid;
4- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;
(2R, 3R)1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-1-methyl-ethyl) amino ] -propionic acid;
3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) amino ] -propionic acid;
3-nor-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
3-endo (endo) -3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
and 3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-furan-3-carboxylic acid hydroxyamide;
and pharmaceutically acceptable salts, solvates and prodrugs of said compounds.
A compound of formula 1And pharmaceutically acceptable salts, solvates and prodrugs thereof, may also be used in combination with signal transduction inhibitors, e.g., agents capable of inhibiting EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, e.g. organic molecules or antibodies that bind to the erbB2 receptor, e.g. HERCEPTINTM(Genentech，Inc.Of South San Francisco，California，USA)。
EGFR inhibitors are described, for example, in WO 95/19970 (published 7/27 1995), WO98/14451 (published 4/9 1998), WO 98/02434 (published 1/22 1998), and U.S. Pat. No. 5,747,498 (published 5/5 1998). EGFR-inhibitors include, but are not limited to, monoclonal antibody C225 and anti-EGFR 22Mab (Imclone systems incorporated of New York, New York, USA), compound ZD-1839(AstraZeneca), BIBX-1382(Boehringer Ingelheim), MDX-447 (Metarex Inc. of Annandale, New Jersey, USA), and OLX-103(Merck & Co. of Whitehouse State, New Jersey, USA), VRCTC-310(Ventech Research) and EGF fusion toxin (sergen Inc. of Hopkinton, Massachusettes).
VEGF inhibitors such as SU-5416 and SU-6668(Sugen Inc. of South san Francisco, Calif., USA) can also be used in combination with the compounds of formula 1. VEGF inhibitors are described, for example, in WO 99/24440 (published 20/5/1999), PCT International application PCT/IB99/00797 (published 3/5/1999), WO 95/21613 (published 17/8/1995), WO 99/61422 (published 2/12/1999), U.S. Pat. No. 5,834,504 (published 10/11/1998), WO 98/50356 (published 12/11/1998), U.S. Pat. No. 5,883,113 (published 16/3/1999), U.S. Pat. No. 5,886,020 (published 23/1999), U.S. Pat. No. 5,792,783 (published 11/8/1998), WO 99/10349 (published 4/3/1999), WO 97/32856 (published 12/1997), WO 97/22596 (published 26/1997), WO98/54093 (published 3/12/1998), WO98/02438 (published 22/1998), WO 99/16755 (published 8/4 1999), and WO 98/02437 (published 22/1 1998), all of which are incorporated herein by reference in their entirety. Some other examples of specific VEGF inhibitors are IM862(Cytran inc. of Kirkland, washington, USA); anti-VEGF monoclonal antibodies from Genentech, Inc. of South San Francisco, California, and a synthetic Ribozyme produced by Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).
ErbB2 receptor inhibitors, such as GW-282974(Glaxo Welcome plc) and monoclonal antibodies AR-209(Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1(Chiron) can be administered in combination with The compound of formula 1. Such erbB2 inhibitors include those described in WO 98/02434 (published 22/1/1998), WO99/35146 (published 15/7/1999), WO 99/35132 (published 15/7/1999), WO 98/02437 (published 22/1/1998), WO 97/13760 (published 17/4/1997), WO 95/19970 (published 27/7/1995), U.S. Pat. No. 5,587,458 (published 24/12/1996) and U.S. Pat. No. 5,877,305 (published 2/3/1999), all of which are incorporated herein by reference in their entirety. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. provisional application No.60/117,341, (1/27/1999) and U.S. provisional application No.60/117,346 (1/27/1999), both of which are incorporated herein by reference in their entirety.
Other antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzymatic nimyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following U.S. patent applications: 09/221946 (application 12/28, 1998); 09/454058 (filed on 12/2/1999); 09/501163 (application 1/9/2000); 09/539930 (application 3/31/2000); 09/202796 (applied 5/22/1997); 09/384339 (8/26/1999); and 09/383755 (8/26 of 1999); and the compounds disclosed and claimed in the following U.S. provisional patent applications: 60/168207 (application on 30/11/1999); 60/170119 (application 12/10, 1999); 60/177718 (application on 21/1/2000); 60/168217 (applied for 30/11/1999), and 60/200834 (applied for 1/5/2000). The above-mentioned patent applications and provisional patent applications are incorporated herein by reference in their entirety.
The compounds of formula 1 may also be used with other agents for treating abnormal cell growth or cancer, including but not limited to agents capable of enhancing anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other agents capable of blocking CTLA 4; and antiproliferative substances such as other inhibitors of farnesyl protein transferase, for example as described in the references cited in the "background" section above. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. provisional application 60/113,647 (12/23/1998), which is incorporated herein by reference in its entirety.
"abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that does not rely on normal modulator mechanisms (e.g., no contact inhibition). This includes the following abnormal growth: (1) tumor cells (tumors) that proliferate by expressing a mutant tyrosine kinase or overexpressing a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which abnormal tyrosine kinase activation is present; (4) any tumor that proliferates through receptor tyrosine kinases; (5) any tumor that proliferates through aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation is present.
The term "treating", as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the progression of, or preventing the disease or condition for which the term is used, or one or more symptoms of such disease or condition. The term "therapeutic effect", as used herein, unless otherwise indicated, refers to the therapeutic effect of "treatment" as defined above.
The term "halogen atom", as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine. Preferred halogen atom groups are fluorine and chlorine.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic (including mono-or polycyclic cyclic portions) or branched moieties. It is understood that for the alkyl groups to include a cyclic moiety, they must contain at least three carbon atoms.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a cyclic (one-or multiple-membered) moiety.
The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl groups as defined having at least one carbon-carbon double bond.
The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl groups as defined having at least one carbon-carbon triple bond.
The term "aryl", as used herein, unless otherwise indicated, includes organic groups derived from aromatic hydrocarbons by the removal of one hydrogen atom, such as phenyl or naphthyl.
The term "alkoxy", as used herein, unless otherwise indicated, includes-O-alkyl wherein alkyl is as defined above.
The term "4 to 10 membered heterocyclic", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms selected from O, S and N, wherein the ring system of each heterocyclic group contains from 4 to 10 atoms. Non-aromatic heterocyclic groups include groups containing only 4 atoms in the ring system, but aromatic heterocyclic groups must contain at least 5 atoms in the ring system. Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxprenyl, thiepanyl, oxazepanyl * yl (oxazepinyl), diaza * yl (diazepinyl), thiazepinyl (thiazepinyl), 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, 2, 3-naphthyridinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, 1, 5-naphthyridinyl and furopyridyl. The aforementioned groups derived from the aforementioned compounds may be C-linked or N-linked where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or-3-yl (C-linked).
The term "Me" denotes methyl, "Et" denotes ethyl, and "Ac" denotes acetyl.
In the above-mentioned X1In the definition of (1), (CR) as described above1R2)m-and (CR)16R17)kMoieties and other like moieties for which each subscript (i.e., m, k, etc.) above 1 may be at R1，R2，R16And R17Is different in the definition of (a). Accordingly, - (CR)1R2)m-may comprise-CH where m is 22C(Me)(Et)。
The phrase "pharmaceutically acceptable salts", as used herein, unless otherwise specified, includes salts of acid or base groups that may be present in the compounds of the present invention. The compounds of the present invention, which are basic in nature, are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. The acids that can be used to prepare such pharmaceutically acceptable acid addition salts of the basic compounds of the invention are those from which acid addition salts are formed that are not toxic, i.e. salts comprising pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulfonate salt and pamoate [ i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate) ] salt. The compounds of the present invention comprising a base moiety such as an amino group may form pharmaceutically acceptable salts with various amino acids other than the above-mentioned acids.
The compounds of the present invention, which are acidic in nature, are capable of forming basic salts with a wide variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium and potassium salts of the compounds of the invention.
Some of the functional groups carried by the compounds of the present invention may be substituted with bioisostere groups, i.e., groups that have a similar steric or electronic requirement as the parent group, but which exhibit different or improved physicochemical or other properties. Suitable examples are well known to those skilled in the art and include, but are not limited to, those described in Patini et al, chem. Rev, 1996, 96, 3147-3176, which is incorporated herein by reference.
The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric configurations. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment in which they may be used or are included. The compound of formula 1 may exist as a tautomer. The present invention relates to the use of all such tautomers and their compounds.
The invention also includes isotopically-labeled compounds, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H，3H，13C，14C，15N，18O，17O，35S，18F, and36and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Some isotopically-labelled compounds of the invention, e.g. incorporating moieties such as3H and14those of C such radioisotopes are useful in drug and/or substrate tissue distribution testing. Tritiated, that is,3h, and carbon-14, i.e.,14the C isotopes are particularly preferred because of their ease of preparation and detection. In addition, the heavy isotopes such as deuterium, i.e.,2h substitution may be preferred in some circumstances because it may provide some therapeutic benefit due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula 1 of the present invention and prodrugs thereof can be prepared by carrying out the procedures disclosed in the schemes below and/or in the examples and preparations by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The invention also relates to pharmaceutical compositions containing prodrugs of compounds of formula 1 and methods of treating bacterial infections by administering prodrugs of compounds of formula 1. The compound of formula 1 having a free amino, amido, hydroxyl or carboxyl group may be converted into a prodrug. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently linked through an amide or ester bond to a free amino, hydroxyl, or formate group of the compound of formula 1. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids generally represented by the three letter alphabet, and also include 4-hydroxyproline, hydroxylysine, desmosine (desmosine), isodesmosine (isodemosine), 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Other types of prodrugs are also included. For example, the free carboxyl groups may be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate and phosphoryloxymethyloxycarbonyl groups, as described in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included are carbamate prodrugs of hydroxy and amino groups, such as carbonate prodrugs, sulfonates and sulfates of hydroxy groups. Also included are the derivatization of hydroxyl groups, such as (acyloxy) methyl and (acyloxy) ethyl ethers, where the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and formate functions, or where the acyl group is an amino acid ester as described above. Prodrugs of this type are described in j.med.chem.1996, 39, 10. The free amines may also be derivatized as amides, sulfonamides or phosphoramides. All of these prodrug moieties may be interrupted including but not limited to ether, amine and formate functions.
Scheme 1
Detailed description of the invention
General synthetic methods for preparing the compounds of the present invention are provided in the literature below; U.S. Pat. No. 5,747,498 (published 5/1998), U.S. patent application Ser. No. 08/953078 (published 10/17/1997), WO 98/02434 (published 22/1/1998), WO98/02438 (published 22/1/1998), WO 96/40142 (published 19/1996), WO 96/09294 (published 6/3/1996), WO 97/03069 (published 30/1/1997), WO 95/19774 (published 27/7/1995) and WO97/13771 (published 17/4/1997). Additional methods are described in U.S. patent application Ser. Nos. 09/488,350 (filed on 20/1/2000) and 09/488,378 (filed on 20/1/2000). The above patents and patent applications are incorporated herein by reference in their entirety. Some starting materials may be prepared according to methods well known to those skilled in the art, while some synthetic modifications may be made according to methods well known to those skilled in the art. Standard methods for preparing 6-iodoquinazolinones are provided in Stevenson, t.m., Kazmierczak, f., Leonard, n.j., j.org.chem.1986, 51, 5, p.616. Palladium-catalyzed boronic acid couplings are described in Miyaura, n., Yanagi, t., Suzuki, a.syn.comm.1981, 11, 7, p.513. Palladium-catalyzed Heck couplings are described in Heck et al, Organic Reactions, 1982, 27, 345 or Cabri et al, Acc. chem. Res.1995, 28, 2. Examples of palladium-catalyzed couplings of terminal alkynes with aryl halides are given in: castro et al, J.org.chem.1963, 28, 3136 or Sonogashira et al, Synthesis, 1977, 777. Terminal alkyne synthesis can be performed using appropriately substituted/protected aldehydes as described in the following documents: colvin, e.w.j. et al, chem.soc.perkin trans.i, 1977, 869; gilbert, j.c., et al, j.org.chem., 47, 10, 1982; hauske, j.r. et al, tet.lett., 33, 26, 1992, 3715; ohira, s. et al, j.chem.soc.chem.commun., 9, 1992, 721; trost, b.m.j.amer.chem.soc., 119, 4, 1997, 698; or Marshall, j.a. et al, j.org.chem., 62, 13, 1997, 4313.
Alternatively, the terminal alkyne can be prepared by a two-step process. First, a lithium cation of TMS (trimethylsilyl) is added to an appropriately substituted/protected aldehyde, as described by Nakatani, K.et al, Tetrahedron, 49, 9, 1993, 1901. The intermediate terminal alkyne can then be isolated using base deprotection, such as Malaria, m.; tetrahedron, 33, 1977, 2813; or White, j.d., et al tet.lett., 31, 1, 1990, 59.
The synthesis of starting materials, which are either commercially available or can be prepared by methods well known to those skilled in the art, is not described in detail above.
In the reactions discussed above or the individual reactions detailed in the above scheme design, pressure is not critical unless otherwise indicated. Pressures of about 0.5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressures, i.e., about 1 atmosphere, being preferred for convenience.
Referring to scheme 1 above, wherein R is prepared by dissolving R in an anhydrous solvent, particularly a solvent selected from DMF (N, N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE (dichloroethane), and t-butanol and phenol or mixtures thereof, at a temperature in the range of about 50-150 deg.C4And R5A compound of formula D as defined above and wherein R1，R3And R11The compound of formula 1 can be prepared by coupling the compound of formula E as defined above for 1 to 48 hours. Heteroaryloxyanilines of formula E may be prepared by methods well known to those skilled in the art, for example, reduction of the corresponding nitro intermediates. By Brown, r.k., Nelson, n.a.j.org.chem.1954, p.5149; yuste, r., Saldana, M, Walls, f., tet.lett.1982, 23, 2, p.147; alternatively, the reduction of the aromatic nitro group may be carried out by the method disclosed in WO 96/09294. Such as Dinsmore, c.j. et al, bioorg.med.chem.lett., 7, 10, 1997, 1345; loupy, a. et al, synth. commun., 20, 18, 1990, 2855; or Brunelle, d.j., tet.lett., 25, 32, 1984, 3383, suitable heteroaryloxynitrobenzene derivatives can be prepared from the halonitrobenzene precursors by nucleophilic substitution of the halide with a suitable alcohol. By R1Reductive amination of the parent aniline with CH (O) can produce a compound in which R is1Is C1-C6Alkyl, compounds of formula E. By treating Z therein with a coupling partner, e.g. a terminal alkyne, terminal alkene, vinyl halide, vinyltin hydride, vinyl borane, alkyl borane or an alkyl or alkenyl zinc reagent1Is an activating group, e.g. bromo, iodo, -N2or-OTf (which is-OSO)2CF3) Or precursors of activating groups such as NO2，NH2Or OH, a compound of formula C, a compound of formula D may be prepared. By using a chlorinating agent such as POCl in a halogenated solvent at a temperature in the range of about 60 ℃ to 150 ℃3，SOCl2Or ClC (O) C (O) Cl/DMF the compound of formula B may be treated for about 2 to 24 hours to produce the compound of formula C. From which Z can be removed according to one or more of the methods described in the above-mentioned WO 95/197741As described above and Z2Is NH2、C1-C6Alkoxy or OH compounds of formula A to prepare compounds of formula B.
By the pair R4Standard manipulations of groups can convert any compound of formula 1 to another compound of formula 1. These methods are well known to those skilled in the art and include a) removal of protecting Groups by the methods described in t.w.greene and p.g.m.wuts, "Protective Groups in Organic Synthesis", second edition, John Wiley and Sons, new york, 1991; b) displacement of the leaving group (halide, mesylate, tosylate, etc.) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; c) treatment of phenyl carbamates (or substituted phenyl esters) with primary or secondary amines to form the corresponding ureas as described by Thavonekham, B et al Synthesis (1997), 10, p 1189; d) reduction of propargyl or homopropargyl alcohols or N-BOC protected primary amines to the corresponding E-allylic or E-homoallylic derivatives, such as Denmark, s.e., by treatment with sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al); jones, t.k.j.org.chem. (1982)47, 4595-4597 or vanBenthem, r.a.t.m.; miches, j.j.; speckamp, W.N.Synlett (1994), 368-370; e) alkynes are reduced to the corresponding Z-alkene derivatives by treating the hydrogen and Pd catalyst, e.g. Tomassy, B. et al, Synth. Commun (1998), 28P1201 said, f) treatment of primary and secondary amines with isocyanates, acid chlorides (or other activated formic acid derivatives), alkyl/aryl chloroformates or sulfonyl chlorides to give the corresponding ureas, amides, carbamates or sulfonamides; g) with R1Reductive amination of a primary or secondary amine by CH (O); and h) treating the alcohol with an isocyanate, an acid chloride (or other activated formic acid derivative), an alkylaryl chloroformate or a sulfonyl chloride to give the corresponding carbamate, ester, carbonate or sulfonate ester.
The compounds of the present invention may have asymmetric carbon atoms. Mixtures of diastereomers can be resolved into their respective diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the individual diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered part of the invention.
The compounds of formula 1, which are basic in nature, can form a wide variety of different salts with various inorganic and organic acids. While such salts must necessarily be pharmaceutically acceptable for administration to an animal, it is in fact desirable to initially isolate the compound of formula 1 as a pharmaceutically unacceptable salt from the reaction mixture and then convert the latter to the free base compound, simply by treatment with an alkaline reagent, followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Careful evaporation of the solvent readily affords the desired solid salt. The desired acidic salt can also be precipitated from the organic solvent solution of the free base by adding a suitable mineral or organic acid to the solution.
Those compounds of formula 1 that are acidic in nature are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts are prepared by conventional techniques. Chemical bases useful as reagents for preparing pharmaceutically acceptable basic salts of the invention are those that form non-toxic basic salts with acidic compounds of formula 1. Such non-toxic basic salts include those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, and magnesium, and the like. These salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together a solution of the acidic compound in a lower alkanol and the desired alkali metal alcoholate and then evaporating the resulting solution to dryness in the same manner as described above. In either case, it is preferred to use stoichiometric amounts of the reagents in order to ensure complete reaction and maximum yield of the desired end product. Because a single compound of the invention may include more than one acidic or basic moiety, a compound of the invention may include monovalent, divalent, or trivalent salts in a single compound.
The compounds of the invention are potent inhibitors of the erbB family of oncogene and proto-oncogene protein tyrosine kinases, particularly erbB2, and are therefore all suitable for use as anti-proliferative (e.g. anti-cancer) drugs in mammals, particularly humans. In particular, the compounds of the present invention are useful in the prevention and treatment of various human hyperproliferative diseases such as malignant and benign liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid tumors, liver cancer, sarcoma, glioblastoma, head and neck cancer, and other proliferative conditions such as benign skin hyperplasia (e.g., psoriasis) and benign prostate hyperplasia (e.g., BPH). In addition, it is contemplated that the compounds of the present invention may have activity against leukemia and thyroid malignancies.
The compounds of the present invention may also be useful in the treatment of additional diseases in which aberrantly expressed ligand/receptor interactions or activation or signaling effects associated with various protein tyrosine kinases are implicated. Such diseases may include those in which aberrant function, expression, activation or signaling of erbB tyrosine kinase is implicated in the properties of the neurons, glia, astrocytes, hypothalamus and other glands, macrophages, epithelium, stroma and blastocoel. In addition, the compounds of the invention have therapeutic utility in inflammatory, angiogenic and immune diseases involving identified and unidentified tyrosine kinases that are inhibited by the compounds of the invention.
The in vitro activity of the compound of formula 1 can be determined by the following method.
The c-erbB2 kinase assay is similar to that described previously in Schrang et al, anal. biochem.211, 1993, p 233-239. Nunc MaxiSorp 96-well plates were coated with 100mL of 0.25mg/mL of a PBS (phosphate buffered saline) solution of Poly (Glu, Tyr) 4: 1(PGT) (Sigma Chemical Co., St. Louis, Mo.) per well by incubation at 37 ℃ overnight. Excess PGT was aspirated and the plates were washed three times with wash buffer (0.1% Tween 20PBS solution). The kinase reaction was carried out in 50mL of 50mM HEPES (pH 7.5) containing 125mM sodium chloride, 10mM magnesium chloride, 0.1mM sodium orthovanadate, 1mM ATP, 0.48mg/mL (24 ng/well) of the intracellular domain of c-erbB 2. The intracellular domain of erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GST fusion protein in baculovirus and purified by binding to and elution from glutathione-coated beads. A DMSO (dimethyl sulfoxide) solution of compound was added to a final DMSO concentration of about 2.5%. Phosphorylation was started by adding ATP (adenosine triphosphate) and fixed shaking at room temperature for 6 min. The kinase reaction was stopped by aspirating the reaction mixture followed by washing with wash buffer (see above). Phosphorylated PGT was determined by incubating each well with 50mL of HRP-conjugated PY54(OncogeneScience, inc. union, NY) anti-phosphotyrosine antibody diluted to 0.2mg/mL in blocking buffer (3% BSA and 0.05% Tween 20 in PBS) for 25 minutes. The antibody was aspirated and the plate was washed 4 times with wash buffer. Color signals were presented by adding 50ml of TMB Microwell peroxidase substrate (Kirkegaard and Perry, Gaithersburg, Md.) per wellNumber, and stopped by adding 50ml of 0.09M sulfuric acid per well. Phosphotyrosine was estimated by measuring the absorbance at 450 nm. The control signal is typically 0.6-1.2 absorbance units, with essentially no background signal in wells without PGT substrate, and is proportional to the 10 minute incubation time. Reduction of signal relative to wells without inhibitor identifies the inhibitor and determines the IC corresponding to the concentration of compound required for 50% inhibition50The value is obtained. Compounds exemplified herein corresponding to formula 1 have an IC of < 10 μ M against erbB2 kinase50The value is obtained.
The activity of the compound of formula 1 can be determined in vivo by the amount of test compound that inhibits tumor growth relative to a control. The tumor growth inhibition of the various compounds was determined according to the following literature methods, with slight modifications: corbett T.H., et al, "TumorInduction Relationships in Development of transplantable cancers of the Colon in Rice for Chemotherapy Assays, with aNote on Carbonogen Structure," Cancer Res., 35, 2434-2439(1975) and Corbett T.H., et al, "A Mouse Colon-tuner Model for Experimental therapy," Cancer Chemotherer Rep. (Part 2), "5, 169-186 (1975). Tumors were induced by left-side subcutaneous injection of a suspension of 1-5 million log phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3 ovarian cancer cells) in 0.1ml RPMI 1640 medium. Enough tumor to become palpable (100-150 mm)3Size/5-6 mm diameter), test animals (athymic female mice) are treated with test compound (formulated in 5Gelucire at a concentration of 10-15 mg/ml) by intraperitoneal (ip) or oral (po) routes once or twice daily for 7-10 consecutive days. To determine the antitumor effect, tumors were measured in millimeters on two diameters with a vernier caliper, and the tumor size (mm) was calculated using the following formula3): tumor size (mm)3) Is (long x [ wide ]]2) [2 ] methods according to Geran, R.I., et al, "Protocols for Screening Chemical Agents and Natural products agricultural animals and Other Biological Systems", third edition, Cancer ChemotherRep., 3, 1-104 (1972). Root of herbaceous plantAccording to the formula: inhibition (%) - (TuW)Control-TuWTest of)/TuWControlx 100%, results are expressed as percent inhibition. The spot on the side of the tumor graft (flare) provides a reproducible dose/response effect for various chemotherapeutic substances and the assay (tumor diameter) method is a reliable method to evaluate the tumor growth rate.
The compounds of the present invention (hereinafter "active compounds") can be administered by any method that is capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
The amount of active compound administered will depend on the subject being treated, the severity of the disease or condition, the frequency of administration, the disposition of the compound and the judgment of the clinician. However, effective dosages will range from about 0.001 to about 100mg per kilogram of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a 70kg person, this means about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be administered without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compound may be used as a monotherapy or may comprise one or more other anti-tumour substances, for example selected from, for example, those below: mitotic inhibitors, such as vinblastine; alkylating agents, such as cisplatin, carboplatin, and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytarabine and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European patent application No.239362, for example N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino]-2-thenoyl) -L-glutamic acid; a growth factor inhibitor; a cell cycle inhibitor; insertion antibiotics, such as doxorubicin and bleomycin; enzymes, examplesSuch as interferon; and anti-hormones, e.g. antiestrogens, e.g. NolvadexTM(tamoxifen) or, for example, antiestrogens, for example, CasodexTM(4 '-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline such combined treatment may be achieved by administering the components of the treatment simultaneously, sequentially or separately.
The pharmaceutical compositions may be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, for parenteral injection, such as sterile solutions, suspensions or emulsions, for topical administration, such as ointments or creams, or for rectal administration, such as suppositories. The pharmaceutical compositions may be in unit dosage form suitable for administration of a precise dose at a time. The pharmaceutical compositions may contain conventional pharmaceutical carriers or excipients and, as active ingredient, the compounds of the invention. In addition, it may contain other pharmaceutical or pharmaceutical agents, carriers, adjuvants and the like.
Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents, and if desired, the pharmaceutical compositions may contain additional ingredients such as flavoring agents, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, may be employed with various disintegrants such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting purposes. Solid compositions of similar type to soft and hard filled gelatin capsules may also be used. Preferred materials therefore include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein should be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying agents or suspending agents as well as diluents such as water, ethanol, propylene glycol, glycerin or mixtures thereof.
Methods for preparing various pharmaceutical compositions having specific amounts of active compound are well known or will be apparent to those skilled in the art. See, for example, Remington's pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., fifteenth edition (1975).
Examples and preparations are provided below to further illustrate and exemplify the compounds of the present invention and methods of making such compounds. It will be understood that the scope of the invention is not in any way limited by the scope of the examples and preparations which follow. In the examples below, molecules with one chiral center are present as a racemic mixture, unless otherwise indicated. Those molecules having two or more chiral centers, unless otherwise specified, exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained by methods well known to those skilled in the art.
In the following preparations and examples, reference is made to HPLC chromatography, and unless otherwise indicated, the following general conditions are used. The column used was ZORBAXTMRXC18 column (produced by Hewlett Packard), height 150mm and inner diameter 4.6 mm. The sample was flowed through a Hewlett Packard-1100 system. A gradient solvent method was used, eluting with 100% ammonium acetate/acetic acid buffer (0.2M) to 100% acetonitrile for 10 minutes. The system was then rinsed once for 1.5 minutes with 100% acetonitrile and then for 3 minutes with 100% buffer. The flow rate for this process was kept constant at 3 mL/min.
In the examples and preparations below, "Et" refers to ethyl, "AC" refers to acetyl, "Me" refers to methyl, "ETOAC" or "ETOAc" refers to ethyl acetate, "THF" refers to tetrahydrofuran, and "Bu" refers to butyl.
The method A comprises the following steps: [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl- Synthesis of quinazolin-4-yl) -amine (1):
4- (4-chloro-quinazolin-6-ylethynyl) -piperidine- ] -carboxylic acid tert-butyl ester:
a mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (1.12g, 5.35mmol), 4-chloro-6-iodoquinazoline (1.35g, 4.65mmol), dichlorobis (triphenylphosphine) palladium (II) (0.16g, 0.23mmol), ketone iodide (1) (0.044g, 0.23mmol), and diisopropylamine (0.47g, 4.65mmol) in dry THF (20mL) was stirred at room temperature under nitrogen pressure for 2 hours. After concentration, the residue was dissolved in CH2Cl2(100mL) with NH4Aqueous Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as a brown oil. Purification by silica gel column using 20% EtOAc in hexanes gave 1.63g (94%) of the title compound as a viscous yellow oil:1H NMR(CDCl3)δ1.45(s，9H)，1.67-1.75(m，2H)，1.87-1.92(m，2H)，2.84(m，1H)，3.20-3.26(m，2H)，3.78(br d，2H)，7.88(dd，1H)，7.97(d，1H)，8.26(d，1H)，9.00(s，1H)。
[ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine: 4- (4-chloro-quinazolin-6-ylethynyl) -piperidine-1-carboxylic acid tert-butyl ester (80mg, 0.21mmol) and 3-methyl-4- (pyridin-3-yloxy) -aniline (43mg, 0.21mmol) were mixed together in tert-butanol (1mL) and dichloroethane (1mL) and heated in a sealed vial at 90 ℃ for 20 minutes. The reaction was cooled and HCl (gas) was bubbled for 5 minutes. EtOAC was then added as a yellow precipitate was produced. The precipitate was collected and dried to give the desired product [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine as a yellow solid (96mg, 95%).1H NMR(CDCl3)δ2.01(m，2H)，2.22(m，2H)，2.35(s，3H)，3.20(m，2H)，3.45(m，2H)，7.28(d，1H，J＝8.7Hz)，7.75(dd，3H，J1＝8.7，J2＝8.7Hz)，8.06(dd，J＝8.7)，8.10(dd，J1＝J2＝8.7Hz)，8.17(m，1H)，8.60(d，1H，J＝5.4Hz)，8.80(s，1H)，8.89(s，1H).MS：M+1，436.6。
The method B comprises the following steps: 2-chloro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quina Synthesis of oxazolin-6-yl } -prop-2-ynyl) -acetamide (2):
2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl]-an acetamide: 2-chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 eq) were dissolved in anhydrous THF and diisopropylamine (296 mg; 0.41 mL; 1 eq). To the mixture were added 0.04 equivalent of copper iodide (22mg) and Pd (PPh)3)2Cl2(82 mg). The reaction was stirred overnight (approximately 20 hours) at room temperature under nitrogen. The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. The solution was transferred to a separatory funnel and washed with 1x saturated NH4Cl, brine, Na2SO4Dried and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1: 1 hexanes/EtOAc and the fraction with Rf ═ 0.25 was collected to give 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl]Acetamide as an off-white solid (454 mg; 53%).1H NMR(400MHz；CDCl3)δ4.12(2H，s)，4.40(2H，d，J＝5.2Hz)，7.91-7.93(1H，dd，J＝2，6.8Hz)，8.00(1H，d，J＝8.4Hz)，8.34(1H，d，J＝1.6Hz)，9.03(1H，s)。Irms(M+)：294.0，296.0，298.1。
2-chloro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide: 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl) -acetamide (0.90g, 3.05mmol) and 3-methyl-4- (pyridin-3-yloxy) -aniline (0.61g, 3.05mmol) intThe mixture in BuOH/DCE (5.0/5.0mL) was refluxed under nitrogen for 40 min and concentrated. The residue was dissolved in MeOH (2.0mL) and EtOAc was added with vigorous stirring to precipitate the hydrochloride salt product as a brown solid, which was collected by vacuum filtration, washed with EtOAc and further dried to give 1.24g (82%) of 2-chloro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide: 1HNMR (CD)30D)δ2.27(s，3H)，4.09(s，2H)，4.29(s，2H)，7.07(d，1H)，7.51(m，2H)，7.60(d，1H)，7.70(s，1H)，7.78(d，1H)，8.05(d，1H)，8.32(m，2H)，8.67(s，1H)，8.75(s，1H)；MS m/z(MH+)458.0。
The method C comprises the following steps: 2-dimethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenyl Amino group]-synthesis of quinazolin-6-yl } -prop-2-ynyl) -acetamide (3):
2-dimethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide: to the 2-chloro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino group]-quinazolin-6-yl } -prop-2-ynyl) -acetamide (99mg, 0.20mmol) in MeOH (5mL) A solution of dimethylamine in FHF (2mL, 4.0mmol) was added. The resulting solution was refluxed under nitrogen for 1 hour. After concentration, the residue was further dried, dissolved in MeOH (1.0mL), and treated with HCl gas for 3 minutes. The resulting solution was added to EtOAc with vigorous stirring to precipitate the hydrochloride salt as a yellow solid, which was collected by vacuum filtration, washed with EtOAc, and further dried to yield 110mg (99%) of the title compound.1H NMR(CD3OD)δ2.30(s，3H)，2.96(s，6H)，4.03(s，2H)，4.37(s，2H)，7.27(d，1H)，7.72(dt，1H)，7.81(m，1H)，7.84(d，1H)，8.03(dd，1H)，8.06(d，1H)，8.13(dd，1H)，8.59(d，1H)，8.68(s，1H)，8.81(s，1H)，8.84(s，1H)；MS m/z(MH+)467.3。
The method D comprises the following steps: 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quina Synthesis of oxazolin-6-yl } -prop-2-ynyl) -3-methylurea (4):
1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-methylurea: (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] prepared by Process B]A mixture of phenyl (0.1g, 0.18mmol), methylamine (2.0M in methanol, 1mL, 2mmol) and DMSO (0.5mL) was stirred at 80 ℃ overnight. The solvent was removed in vacuo (GeneVac HT8) and the residue was redissolved in MeOH (ca. 1 mL).HCl gas was bubbled through the solution and EtOAc. The title compound (80mg, 90% yield) was obtained as a yellow solid by filtration.1H NMR(400MHz，CD3OD)δ2.72(3H，s)，2.76(3H，s)，4.19(2H，s)，7.49(1H，d，J＝9Hz)，7.84(1H，d，J＝2Hz)，7.86(1H，d，J＝2Hz)，7.92(1H，d，J＝9Hz)，8.12(2H，m，J＝2Hz)，8.16(1H，d，J＝2.4Hz)，8.60(1H，d，J＝3.2Hz)，8.74(1H，d，J＝1.2Hz)，8.87(1H，s)。LRMS(M+)：473.0，475.0，476.0。
The method E comprises the following steps: 1- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolines -Synthesis of 6-yl } -prop-2-en-1-ol (5):
to a solution of 0.56g (1.47mmol) of 3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino group at 0 deg.C]A solution of-quinazolin-6-yl } -prop-2-yn-1-ol (prepared by method B) in 6mL anhydrous tetrahydrofuran was added 0.73mL of a 65% by weight solution of sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al, 2.35mmol) in toluene in 1mL THF. The reaction was stirred at room temperature for 3 hours. Upon cooling to 0 deg.C again, another 0.73mL of Red-Al solution in 1mL THF was added. After stirring at room temperature for 1 hour, the mixture was quenched by dropwise addition of a 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and evaporated to give 650 mg. Chromatography on 90g of silica gel eluting with 96: 4: 0.1 chloroform/methanol/concentrated ammonium hydroxide gave 268mg of the title compound.1H NMR(d6DMSO)：δ9.79(s，1)，8.57(m，2)，8.35(m，2)，8.01(m，1)，7.80(m，3)，7.41(m，1)，7.29(m，1)，7.07(d，J＝8.7Hz，1)，6.77(d，J＝16.2Hz，1)，6.67(m，1)，5.04(t，J＝5.6Hz，1)，4.23(m，2)，2.23(s，3)。
Method F: [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- [6- (3-morpholin-4-yl-propene) Yl) -quinazolin-4-yl]-synthesis of amine (6):
[ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- [6- (3-morpholin-4-yl-propenyl) -quinazolin-4-yl } -amine: to the direction of0.035g (0.091mmol) of 3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] in 0.5mL of dichloromethane and 1mL of dichloroethane]Suspension of-quinazolin-6-yl } -prop-2-en-1-ol 1mL of thionyl chloride was added. The reaction was heated at 100 ℃ for 1 hour and the solvent was evaporated to give [6- (3-chloro-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) phenyl]-an amine [ MS: m+403.1]It was dissolved in THF and used directly in the following reaction. To [6- (3-chloro-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) phenyl]To the amine solution, 0.10mL of morpholine and 0.044mL of triethylamine were added. The mixture was heated at 85 ℃ for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to give 57mg of material. Purify the product on a silica gel preparation plate with 96: 4: 0.1 chloroform/methanol/concentrated ammonium hydroxide to give 26mg of the title compound;1H NMR(CDCl3)：δ8.71(s，1)，8.33(m，2)，7.94(s，1)，7.80(m，2)，7.69(s，1)，7.58(m，1)，7.20(m，1)，6.94(d，J＝8.7Hz，1)，6.68(d，J＝15.8Hz，1)，6.46(m，1)，3.79(m，4)，3.26(m，2)，2.63(m，4)，2.25(s，3)。
method G: E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]- Synthesis of quinazolin-6-yl } -propenyl) -acetamide (7):
e- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -propenyl) -carbamic acid tert-butyl ester: to a solution of 7.53mL of 65% by weight sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al, 24.2mmol) in toluene in 90 mL of tetrahydrofuran at 0 deg.C was added 5.0 g of solid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid tert-butyl ester. The reaction was stirred at 0 ℃ for 2 hours, quenched with 10% aqueous potassium carbonate and extracted with ethyl acetate. The combined organics were dried and evaporated. The crude product was purified on 115g of silica gel, eluting with 80% ethyl acetate/hexane to give 4.42g of E- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy)-phenylamino group]-quinazolin-6-yl } -propenyl) -carbamic acid tert-butyl ester.1H NMR(CDCl3)＝δ8.66(s，1)，8.24(m，1)，8.03(m，2)，7.77-7.65(m，3)，7.13(m，2)，6.97(d，J＝8.7Hz，1)，6.54(d，1)，6.35(m，1)，4.9(m，1)，3.90(m，2)，2.52(s，3)，1.46(s，9)。
E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-an amine: to 21mL of tetrahydrofuran was added 4.42g of E- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -propenyl) -carbamic acid tert-butyl ester solution 21mL of 2N hydrochloric acid was added. The mixture was heated at 60 ℃ for 3 hours, cooled to room temperature, and basified with 10% aqueous potassium carbonate. Dichloromethane was added to the aqueous mixture and a solid precipitated out. The solid was filtered and dried to give 2.98g of E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-an amine.1H NMR(d6DMSO)：δ8.62(s，1)，8.53(m，1)，8.26(m，2)，7.99 (m，1)，7.89(m，1)，7.77(m，1)，7.30(m，3)，6.67(m，2)，3.44(m，2)，2.47(s，3)。
E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -propenyl) -acetamide: a mixture of 14.4. mu.L (0.25mmol) of acetic acid and 40.3mg (0.33mmol) of dicyclohexylcarbodiimide in 2mL of dichloromethane is stirred for 10 minutes and 100.3mg of E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amine treatment. The reaction was allowed to stir at room temperature overnight. The resulting precipitate was filtered and chromatographed on silica gel, eluting with 6-10% methanol/chloroform to give 106mg of the title compound; mp 254-256 deg.C;1H NMR(d6DMSO)：δ9.88(s，1)，8.58(s，1)，8.48(m，1)，8.20(m，3)，7.95(m，1)，7.83(m，1)，7.71(d，J＝8.7Hz，1)，7.24(m，2)，7.19(d，J＝8.7Hz，1)，6.61(d，J＝16.2Hz，1)，6.48(m，1)，3.90(m，2)。
method H: E-2S-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl) Yl-pyridin-3-yloxy) -phenylamino]Preparation of (8) quinazolin-6-yl) -allyl-amide Preparing:
0.125g (0.31mmol) of E- [6- (3-amino-propenyl) -quinazolin-4-yl in 1mL of dichloromethane while stirring at 0 deg.C]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]Solution of amine (prepared according to method G) 60.3. mu.l (0.34mmol) of Hunig's base was added followed by dropwise addition of 48.2. mu.l (0.34mmol) of 4-chlorophenyl chloroformate solution in 1mL of methylene chloride. The reaction was stirred for 30 minutes and evaporated under reduced pressure. The residue was dissolved in 2mL of dimethyl sulfoxide and 123. mu.l (0.94mmol) of(s) - (+) -2- (methoxymethyl) -pyrrolidine were added uniformly. The reaction was stirred at room temperature for 3 hours. The reaction was quenched with 10% potassium carbonate and extracted with ethyl acetate. The organic layer was washed several times with water and twice with brine. The organic layer was dried over sodium sulfate and reduced to give the crude product. The product was purified on 90g silica gel using 96: 4: 0.1 chloroform: methanol: hydroxylamine as eluent to give 75mg (0.14mmol) of the title compound.1H NMR(d6DMSO)：δ9.83(s，1)，8.56(s，2)，8.21(d，1)，7.95(d，1)，7.80(d，1)，7.50(d，1)，7.25(m，2)，7.01(d，1)，6.63(d，1)，6.53(m，1)，3.95(m，2)，3.40(dd，1)，3.28(s，3)，2.49(s，3)，2.24(s，3)，1.85(m，4)。
The method I comprises the following steps: E-2-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -benzene Radical amino]Preparation of-quinazolin-6-yl } -allyl) -isobutyramide (9):
to 1mL of methylene chloride was added 0.170g (0.42mmol) of E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]Solution of amine (prepared according to method G) 65 microliters (0.47mmol) of triethylamine was added followed by 65 microliters (0.45mmol) of a solution of 2-acetoxyisobutyryl chloride in 1mL of dichloromethane. The reaction was stirred at 0 ℃ for 1 hour. The reaction was terminated by adding 10% potassium carbonate dropwise. The aqueous layer was extracted with dichloromethane and the combined organics were washed with brine, dried over sodium sulfate and evaporated. The crude product was purified over 90g of silica gel using 96: 4: 0.1 chloroformMethanol/hydroxylamine wash to give 2-acetoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -isobutyramide. A solution of this material in 2mL of methanol was treated dropwise with a solution of 41mg (3.02mmol) of potassium carbonate in 0.5mL of water. The solution was stirred at room temperature for 1 hour. The reaction was evaporated and the residue partitioned between water and chloroform. The aqueous layer was extracted twice with chloroform and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give 100mg of the title compound (47%).1H NMR(d6DMSO)：δ9.78(s，1)，8.50(s，1)，8.48(s，1)，8.15(d，1)，7.95(m，2)，7.65(m，3)，7.21(m，2)，6.96(d，1)，6.56(dt，1)，3.92(t，2)，2.46(s，3)，2.1。
Method J: z-cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) - Phenylamino group]Preparation of-quinazolin-6-yl } -allyl) -amide:
z- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-an amine: reacting (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid tert-butyl ester (1g, 2.01mmol) was dissolved in methanol (20ml), palladium carbonate (50mg) was added and the resulting suspension was hydrogenated at 40psi for 8 hours. The suspension was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the Z-olefin compound. The product was dissolved in methanol and HCl (gas) was added. Then evaporating the solvent to obtain Z- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amine hydrochloride. Dissolving the salt in CH2Cl2And with Na2CO3Stirring, filtration and evaporation of the solvent gave about 700mg of free amine.
1H NMR(CD3OD)：δ8.49(s，1)，8.31(s，1)，8.07(m，1)，7.78(s，2H)，7.72(m，1H)，7.67(s，1H)，7.58(d，J＝10.5Hz，1H)，7.25(m，2H)，6.99(m 2H)，5.88(m，1H)，3.95(d，J＝8Hz，2H)，2.47(s，3H)，2.23(s，3H).MS：M+1，399.3
Z-Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -allyl) -amide: reacting Z- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amine (100mg, 0.25mmol) was dissolved in DMF (3ml), HATU (143mg, 0.38mmol) and propanecarboxylic acid (36mg, 0.42mmol) was added and the resulting solution was stirred for 18 h. Water was then added, the reaction mixture was extracted with dichloromethane, the organic extract was washed with brine and Na2SO4And (5) drying. After concentration in vacuo, in preparative HPLC (reverse phase, 5-40% CH)3CN-H2O) to yield 46mg of the title compound.1H NMR(CD3OD): δ 8.77(s, 1H), 8.72(s, 1H), 8.24(s, 1H), 8.00(m 1H), 7.77(m, 3H), 7.55(m, 2H), 7.07(d, J ═ 10Hz, 1H), 6.76(d, J ═ 13Hz, 1H), 5.95(m, 1H), 4.2(br unresolved m, 2H), 2.59(s, 3H), 2.3(s, 3H), 1.59(br unresolved m, 1H), 1.16(br unresolved m, 1H), 0.79(m, 3H). MS: m + 1466.3.
The following examples were prepared using the above method.
TABLE 1
Example number Name (R) Method of producing a composite material LRMS HPLCRT
10 (±) - [ 3-methyl-4- (pyrid-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) amine A 436.0 4.48
11 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-cyclopropyl-urea D 499.0 5.74
12 N- (3- { 7-chloro-4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 492.0 6.07
13 N- (3- { 7-chloro-4- [ 3-methyl-4- (6-methyl-pyridin-3-yl) B 472.2 5.79
Oxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide
14 3-azabicyclo [3.1.0] o-6-hydroxymethyl]Hexane-3-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 555.0 5.19
15 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (2-fluoro-ethyl) -urea D 505.0 5.65
16 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (2-hydroxy-ethyl) -urea D 503.0 4.98
17 3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-ylethynyl } -piperidin-3-ol A 452.0 4.01
18 2- (2-hydroxy-ethylsulfanyl) -N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -phenyl]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 500.0 4.87
19 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2- (2-hydroxy-ethylsulfanyl) -acetamide C 520.0 5.15
20 (±) - [ 3-methyl-4- (pyrid-3-yloxy) -phenyl]- (6-morpholin-2-ylethynyl-quinazolin-4-yl) -amine A 438.0 4.29
21 2-cyano-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 448.9 5.18
22 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -butyramide B 452.0 5.61
23 Pentanoic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 466.0 6.02
24 2-methoxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 454.0 5.24
25 N- (4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -acetamide B 438.1 5.11
26 [6- (4-amino-but-1-ynyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]-amines A 396.1 4.04
27 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methylsulfanyl-acetamide B 4 70.2 5.50
28 3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1-ol B 383.0 4.97
29 [6- (3-methyl-prop-1-ynyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]-amines B 397.3 6.23
30 4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl-1-ol B 397.1 5.17
31 2-methyl-4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -2-ol B 411.0 5.62
32 (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid methyl ester B 440.3 5.61
33 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -methanesulfonamide B 460.0 5.38
34 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 424.1 4.94
35 [ 3-methoxy-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 452.0 4.10
36 2-chloro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 458.0 5.52
37 2-methylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 453.1 4.08
38 2-dimethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 467.3 4.15
39 (±) - (6-piperidin-3-ylethynyl-quinazolin-4-yl) - [4- (pyridin-3-yloxy) -phenyl]-amines A 422.1 4.13
40 [ 3-methoxy-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-quinazolin-4-yl) -amines A 452.1 4.11
41 [ 3-chloro-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 456.1 4.57
42 [ 3-fluoro-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 440.1 4.38
43 (6-piperidin-4-ylethynyl-quinazolin-4-yl) - [4- (pyridin-3-yloxy) -phenyl]-amines A 422.1 4.11
44 2-methoxy-N- (3- {4- [ 3-methoxy-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 470.3 4.87
45 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 474.2 5.48
46 N- (3- {4- [ 3-fluoro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 458.3 5.23
47 [ 3-methyl-4- (pyridin-2-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 436.0 4.52
48 2, 2-dimethyl-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide A 452.3 5.60
49 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide B 466.3 6.01
50 {6- [3- (2-methoxy-ethoxy) -prop-1-ynyl]-quinazolin-4-yl } - [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]-amines B 441.1 6.11
51 2-diethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 495.1 4.45
52 (±) - [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl } -amine A 450.0 4.47
53 [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 450.0 4.39
54 2-methoxy-N- (3- {4- [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 468.0 5.33
55 2- (2-methoxy-ethoxy) -N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 498.3 5.34
56 (±) -tetrahydro-furan-2-carboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide B 480.0 5.45
57 (±) -4, 4-dimethyl-5- {4- [ 3-methyl-4- (pyrid-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -oxazolidin-2-one B 466.0 5.70
58 {6- [4- (2-methoxy-ethoxy) -but-1-ynyl]-quinazolin-4-yl } - [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]-amines B 455.3 6.23
59 4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -piperidin-4-ol A 452.0 3.82
60 1-methyl-4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -piperidin-4-ol B 466..1 4.03
61 (±) - [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ethynyl-quinazolin-4-yl) -amines A 450.0 4.52
62 [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ethynyl-quinazolin-4-yl) -amine A 450.0 4.49
63 2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 468.8 5.38
64 [6- (4-methoxy-but-1-ynyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) -3-phenyl]-amines B 411.2 6.30
65 (±) - [4- (2-amino-pyridin-3-yloxy) -3-methyl-phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 470.0 4.89
66 Cyclopropanecarboxylic acid (4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -amide B 464.3 5.63
67 [4- (2-chloro-pyridin-3-yloxy) -3-methyl-phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 470.0 4.86
68 N- (3- {4- [4- (2-chloro-pyridin-3-yloxy) -3-methyl-phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 488.0 5.84
69 N- (4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -2-methylsulfanyl-acetamide B 484.2 5.64
70 [ 3-amino-4- (pyridin-3-yloxy) -phenyl]- [6- (4-methoxy-but-1-ynyl) -quinazolin-4-yl]-amines B 431.1 6.67
71 (±) -4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-yne-1, 2-diol A 413.1 4.31
72 (±) - [ 3-methyl-4- (pyrid-4-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 434.1 3.88
73 [ 3-methyl-4- (pyridin-4-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 436.1 3.91
74 2-methoxy-N- (3- {4- [ 3-methyl-4- (pyridin-4-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 452.0 4.71
75 2, 2-difluoro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 460.2 5.63
76 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2, 2-difluoro-acetamide B 482.2480.1 5.92
77 R-pyrrolidine-2-carboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide A 479.1 4.22
78 (±) -tetrahydro-furan-3-carboxylic acid (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino ] -phenyl]-quinazolin-6-yl } -prop-2-ynyl) -amide B 500.0 5.39
79 Cyclopropanecarboxylic acid (4- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -amide B 484.0 5.92
80 N- (4- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -2-methylsulfanyl-acetamide B 505.4 5.91
81 1- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-phenyl-urea D 501.1 6.17
82 1-cyclohexyl-3- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 507.2 6.24
83 1- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-cyclohexyl-urea D 528.1 6.49
84 2-hydroxy-N- (4- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -but-3-ynyl) -acetamide A 454.2 4.78
85 E-3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-en-1-ol E 385.1 4.71
86 E- [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- [6- (3-morpholin-4-yl-propenyl) -quinazolin-4-yl]-amines F 454.1 4.14
87 2-methanesulfonyl-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 502.0 5.00
88 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methanesulfonyl-acetamide B 522.0 5.28
89 (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -thiocarbamic acid S-methyl ester B 456.2 6.02
90 (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -thiocarbamic acid S-methyl ester B 476.1 6.29
91 [4- (2-methyl-pyridin-3-yloxy) -phenyl]- [ 6-piperidin-4-ylethynyl-quinazolin-4-yl group]-amines A 436.1 4.24
92 (±) - [4- (2-methyl-pyridin-3-yloxy) -phenyl]- [ 6-piperidin-3-ylethynyl-quinazolin-4-yl group]-amines A 436.0 4.85
93 N- (3- {4- [ 2-methyl-pyridin-3-yloxy)]-phenylamino } -quinazol B 424.1 4.85
Lin-6-yl) -prop-2-ynyl) -acetamide
94 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-oxo-propionamide B 452.1 5.64
95 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-oxo-propionamide B 474.3472.3 5.93
96 N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -malonamic acid ethyl ester B 496.2 5.56
97 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -malonamic acid ethyl ester B 516.0 5.84
98 N- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2, 2, 2-trifluoroacetamide B 506.0 6.76
99 (±) -N- (1-hydroxymethyl-3- {4- [ 3-methyl-4- (pyrid-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 454.1 4.47
100 (±) - [ 3-ethynyl-4- (pyridin-3-yloxy) -phenyl]- [ 6-piperidin-3-ylethynyl-quinazolin-4-yl group]-amines A 446.1 4.33
101 [ 3-ethynyl-4- (pyridin-3-yloxy) -phenyl]- [ 6-piperidin-4-ylethynyl-quinazolin-4-yl group]-amines A 446.1 4.27
102 3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-yn-1-ol B 403.1 5.43
103 (±) -N- (1-hydroxymethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 468.1 4.66
104 (±) -N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -1-hydroxymethyl-prop-2-ynyl) -acetamide b 474.0 4.78
105 2, 2-difluoro-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 474.2 5.83
106 2-methanesulfonyl-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 516.0 5.20
107 2-fluoro-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 441.8 5.27
108 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-fluoro-acetamide B 461.9 5.55
109 2-fluoro-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 456.2 5.47
110 N- (3- {4- [ 3-ethynyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 464.1 5.16
111 2-methoxy-N- (3- {4- [4- (2-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 454.2 5.15
112 [4- (2-chloro-pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 456.1 4.64
113 (±) - [4- (2-chloro-pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 456.0 4.67
114 N- (3- {4- [4- (2-chloro-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 474.0 5.54
115 N- (3- {4- [4- (2-chloro-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 444.0 5.25
116 N- (3- {4- [ 3-ethynyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 434.1 4.88
117 1- (2-chloro-ethyl) -3- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 487.2 5.46
118 (±) - [ 3-fluoro-4- (2-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 454.1 4.57
119 [ 3-fluoro-4- (2-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidines) A 454.1 4.56
-4-ylethynyl-quinazolin-4-yl) -amine
120 N- (3- {4- [ 3-fluoro-4- (2-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 442.1 5.19
121 N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 458.0 5.48
122 [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 470.0 4.78
123 (±) - [ 3-fluoro-4- (6-methyl-pyridin-3-yloxy) -phenyl]- (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine A 470.0 4.80
124 Acetic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino [)]-quinazolin-6-yl } -prop-2-ynyl ester B 425.1 6.34
125 3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-yn-1-ol B 397.2 5.31
126 Acetic acid 3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl ester B 439.1 6.57
127 Acetic acid 3- {4- [ 3-amino-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl ester B 445.1 6.66
128 2-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide A 454.2 4.81
129 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 438.0 5.20
130 R-pyrrolidine-2-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide A 493.0 4.42
131 2- (2-hydroxy-ethylsulfanyl) -N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 513.9 5.07
132 (+ -) -2-methanesulfinyl-N- (3- {4- [ 3-methyl-4- (6-methyl-) B 499.9 4.71
Pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide
133 (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -thiocarbamic acid S-methyl ester B 469.9 6.25
134 (±) -tetrahydro-furan-3-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide B 494.0 5.31
135 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-oxo-propionamide B 465.9 5.87
136 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -malonamic acid ethyl ester B 510.0 5.77
137 (6-piperidin-4-ylethynyl-quinazolin-4-yl) - [4- (pyridin-2-yloxy) -phenyl]-amines A 422.2 3.48
138 (±) - (6-piperidin-3-ylethynyl-quinazolin-4-yl) - [4- (pyridin-2-yloxy) -phenyl]-amines A 422.2 3.51
139 N- (3- {4- [4- (pyridin-2-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 410.1 3.81
140 2-methylamino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 467.0 4.26
141 2-dimethylamino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 481.0 4.26
142 (±) -N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -1-hydroxymethyl-prop-2-ynyl) -acetamide B 488.0 4.99
143 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridine)-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-dimethylamino-ethan C 501.0 4.83
Amides of carboxylic acids
144 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 488.0 5.79
145 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-fluoro-acetamide B 476.0 5.79
146 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2, 2-difluoro-acetamide B 494.0 6.14
147 E-3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-en-1-ol E 405.1 5.04
148 2-methoxy-N- (3- {4- [4- (pyridin-2-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 440.8 4.05
149 1-ethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 467.2 5.36
150 1- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-ethyl-urea D 473.2 5.45
151 1-ethyl-3- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 453.1 5.16
152 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-ethyl-urea D 487.1 5.60
153 (±) -2-hydroxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] amino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide A 454.1 4.79
154 N- (3- {4- [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-oxo-propionamide B 466.1 5.85
155 N- (3- {4- [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 438.1 5.18
156 (±) -2-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide A 468.0 4.98
15 (±) -N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yl) A 48 5.
7 Oxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-hydroxy-propionamide 8.0 32
158 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2- (4-methyl-piperazin-1-yl) -acetamide C 536.2 4.46
159 2- [ bis- (2-methoxy-ethyl) -amino]-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 569.1 5.93
160 2- (2-hydroxy-ethylamino) -N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide C 483.0 4.11
161 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-dimethylamino-acetamide C 487.0 4.65
162 N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methylamino-acetamide C 473.0 4.42
163 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methylamino-acetamide C 487.1 4.60
164 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-hydroxy-acetamide A 474.0 5.13
165 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-isopropyl-urea D 501.8 5.98
166 1-isopropyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 481.0 5.69
167 Morpholine-4-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 509.1 5.27
168 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-morpholin-4-yl-eth-yl C 543.3 5.64
Amides of carboxylic acids
169 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-morpholin-4-yl-acetamide C 522.8 5.37
170 [6- (3-amino-prop-1-ynyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines A 396.3 4.05
171 E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines G 398.2 3.87
172 E- [6- (3-amino-propenyl) -quinazolin-4-yl]- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines G 418.0 4.26
173 2-hydroxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide A 468.1 5.04
174 2-hydroxy-N-(3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide A 482.1 5.24
175 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-hydroxy-isobutyramide A 502.0504.0 5.55
176 [6- (3-amino-prop-1-ynyl) -quinazolin-4-yl]- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines A 416.2 4.25
177 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2- (2, 2, 2-trifluoro-ethylamino) -acetamide C 535.3 5.99
178 1, 1-dimethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 467.3 5.36
179 3- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1, 1-diethyl-urea D 515.0 6.32
180 3- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1, 1-dimethyl-urea D 487.1 5.70
181 E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 440.3 4.74
182 E-2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 470.1 5.05
183 Morpholine-4-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 529.0 5.58
184 Pyrrolidine-1-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 513.0 6.00
185 1- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-methyl-urea D 473.0 5.37
186 1- (3- {4- [ 3-chloro-4- (6-methyl) methyl ester-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-propyl-urea D 501.0 6.03
187 1-tert-butyl-3- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 515.0 6.56
188 2S-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide B 468.0 4.95
189 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (2, 2, 2-trifluoro-ethyl) -urea D 540.7 6.19
190 (±) -azetidine-2-carboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino [ ] -]-quinazolin-6-yl } -prop-2-ynyl) -amide A 465.2 4.21
191 (±) -azetidine-2-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino [ ]]-quinazolin-6-yl } -prop-2-ynyl) -amide A 479.3 4.41
192 (+ -) -Aminocyclobutane-2-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl- A 499.3 4.70
Pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide
193 1-hydroxy-cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide B 480.0 5.20
194 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylaminoBase of]-quinazolin-6-yl } -prop-2-ynyl) -propionamide B 452.1 5.55
195 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -butyramide B 466.1 5.88
196 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide B 466.1 5.88
197 2-ethoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 482.1 5.89
198 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methylsulfanyl-acetamide B 484.0 5.76
199 Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 464.1 5.76
200 Cyclobutanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -prop-2-ynyl) -amide B 478.1 6.07
201 [6- (3-amino-prop-1-ynyl) -quinazolin-4-yl]- [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]-amines A 382.1 4.02
202 Isoxazole-5-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 491.0 5.78
203 N-methyl-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 452.5 5.79
204 2-methoxy-N- (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 481.9 5.86
205 N- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 466.2 5.82
206 2R-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -propan-2-alkynyl) -propionamide B 468.0 4.95
207 E-Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 466.1 5.41
208 E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide G 454.1 5.07
209 E-2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 484.0 5.54
210 E- (±) -2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide G 484.1 5.45
211 E-2-fluoro-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 458.1 5.48
212 2-methoxy-N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -cyclobutyl) -acetamide B 508.0 6.17
213 N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -cyclobutyl) -acetamide B 478.0 5.90
214 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-fluoro-acetamide G 478.0 5.55
215 E-Cyclopropanecarboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yl) G 485.7 5.77
Oxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides
216 [6- (1-amino-cyclobutylethynyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines A 436.0 4.87
217 (±) -2-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 537.1 6.1 3
218 Piperazine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 508.1 4.28
219 3- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1-ethyl-1- (2-hydroxy-ethyl) -urea D 531.0 5.41
220 [6- (1-amino-cyclopropylethynyl) -quinazolin-4-yl]- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-amines A 422.1 5.11
221 E-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-en-1-ol E 399.2 4.93
222 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2- (2-methoxy-ethoxy) -acetamide B 532.0 5.86
223 N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-oxo-propionamide B 486.0 6.17
224 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridine-3-)Oxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2- (2-hydroxy-ethylsulfanyl) -acetamide C 534.0 5.57
225 N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methylsulfanyl-acetamide B 504.0 6.04
226 pyrrolidine-2R-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acyl A 513.4 4.86
Amines as pesticides
227 pyrrolidine-2R-carboxylic acid (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide A 499.0 4.45
228 (±) -2-methanesulfinyl-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 486.1 4.52
229 (±) -2-methanesulfinyl-N- (3- {4- [ 3-chloro-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 506.0 4.81
230 (±) -tetrahydro-furan-3-carboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide B 480.1 5.11
231 2-hydroxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide A 440.3 4.60
232 2-ethoxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -eth-ylAmides of carboxylic acids B 467.9 5.62
233 [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 436.6 4.35
234 Cyclobutanecarboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -prop-2-ynyl) -amide B 464.0 5.78
235 Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 450.0 5.44
236 [ 3-methyl-4- (pyridin-2-yloxy) -phenyl]- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A 436.0 4.64
237 (6-azetidin-3-ylethynyl-quinazolin-4-yl) - [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]Amines as pesticides A 407.9 4.10
238 N- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 481.9 5.96
239 2- [4- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -phenyl]-quinazolin-6-yl } -prop-2-ynyl) -piperazin-1-yl]-ethanol A 495.4 4.10
240 (±) -2-methoxy-N- (1-methyl-3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 467.9 5.57
241 [ 3-methyl-4- (pyridin-3-yloxy)-phenyl radical]- (6-piperidin-3R-ylethynyl-quinazolin-4-yl) -amine A 436.0 4.48
242 [ 3-methyl-4- (pyridin-3-yloxy) -phenyl]- (6-piperidin-3S-ylethynyl-quinazolin-4-yl) -amine A 436.0 4.48
243 (±) - [ 3-methyl-4- (pyrid-3-yloxy) -phenyl]- (6-pyrrolidin-3-ylethynyl-quinazolin-4-yl) -amine A 422.2 4.30
TABLE II
Example number Name (R) Method of producing a composite material LRMS HPLCRT
244 1- (2-methoxy-ethyl) -1-methyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 511.1 5.61
245 (±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 523.1 5.19
246 (±) -3-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolines D 509.1 4.75
-6-yl } -prop-2-ynyl) -amide
247 Cis-and trans-2, 5-dimethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazoline-6-yl } -prop-2-ynyl) -amide D 521.1 6.386.28
248 1-isobutyl-1-methyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 509.1 6.45
249 N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -cyclopropyl) -acetamide B 464.0 5.46
250 2-methoxy-N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -cyclopropyl) -acetamide B 5.76 493.7
251 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide G 474.0 5.53
252 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-methoxy G 504.0 5.67
Cyclopropyl amino amides
253 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-methoxy-acetamide G 489.7 5.52
254 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-ethoxy-acetamide G 504.0 5.89
255 (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid tert-butyl ester B 496.3 7.11
256 2- (R) -hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide B 468.0 5.04
257 Cyclobutanecarboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -prop-2-ynyl) -amide B 498.0500.0 6.36
258 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionyl B 472.0474.0 5.86
Amines as pesticides
259 Cyclopropanecarboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 484.0486.0 6.06
260 N- (3- {4- [ 3-chloro-4- (6)-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide B 486.1488.1 6.17
261 (±) -N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-propionamide B 502.0504.0 6.00
262 (±) -2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide B 482.1 5.73
263 5-oxo-pyrrolidinyl-2R-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 507.1 4.73
264 E-1-hydroxy-cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl alcohol I 482.0 4.65
Acyl) -amides
265 E-2S-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide I 470.1 4.56
266 E-2R-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide I 470.1 4.60
267 E-2-hydroxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide I 456.1 4.51
268 1-cyanomethyl-3- (3- {4-[ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 478.1 5.26
269 1-cyclobutyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 492.8 5.90
270 1, 1, 3-trimethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl D 481.1 6.30
Amino group]-quinazolin-6-yl } -prop-2-ynyl) -urea
271 1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1, 3, 3-trimethyl-urea D 501.1 6.52
272 1-Ethyl-1- (2-hydroxy-ethyl) -3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 511.1 5.20
273 (±) -3-dimethylamino-pyrrolidinyl-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 536.1 4.40
274 Morpholine-4-carboxylic acid (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 523.4 5.58
275 Pendant-6-amino-3-azabicyclo [3.1.0]Hexane-3-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 520.9 4.28
276 3-aza-6-hydroxymethyl-aza D 535.1 4.98
Bicyclo [3.1.0]Hexane-3-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide
277 (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 439.8 4.81
278 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -propenyl) -2-hydroxy-acetamide I 476.0 4.86
279 Piperazine-1-carboxylic acid (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 536.1 4.74
280 1- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3-ethyl-urea D 495.3 6.11
281 Morpholine-4-carboxylic acid (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 537.3 6.02
282 1, 3-dimethyl-1- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 467.1 5.51
283 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -1, 1-dimethyl-prop-2-ynyl) -2-hydroxy-acetamide B 5.025.04 5.74
284 N- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-hydroxy-acetamide B 482.2 5.46
285 E-1, 1-diethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -urea H 497.1 5.72
286 E-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolLIN-6-YL } -allyl) -AMIDES H 495.1 5.40
287 E-1-ethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -ene H 469.1 4.80
Propyl) -urea
288 E-morpholine-4-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides H 511.1 4.75
289 (±) -1-ethyl-1- (2-hydroxy-ethyl) -3- (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 525.1 5.51
290 (±) -1-ethyl-3- (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 481.1 5.68
291 4-methyl-piperazine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 522.3 4.44
292 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -2-cyano-acetamide B 483.1 5.73
293 2-cyano-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridine-3-) B 463.1 5.44
Oxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide
294 E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-methylsulfanyl-acetamide G 486.3 5.33
295 E-5-oxo-tetrahydro-furan-2R-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 510.2 5.58
296 E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -methanesulfonamide G 476.0 5.36
297 (±) -5- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -morpholin-3-one B 466.1 5.22
298 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2S-hydroxy-propionamide I 490.1 5.06
299 E-1-hydroxy-cyclopropanecarboxylic acid (3- {4- [ 3-chloro-4- (6-methyl- I 502.2 5.24
Pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides
300 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-hydroxy-isobutyramide I 504.2 5.24
301 (±) -E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-hydroxy-propionamide I 490.0 5.07
302 2R-amino-N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide A 487.1 4.54
303 2R-amino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -propionamide A 467.2 4.35
304 (±) -4- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-ylethynyl } -oxazolidin-2-one A 452.2 5.40
305 (±) -E-3, 3, 3-trifluoro I 524.1 5.52
-2-hydroxy-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide
306 (±) -E-2-hydroxy-3-methyl-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -butyramide I 498.2 5.49
307 (±) -2-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 557.1 6.42
308 (±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 543.2 5.61
309 (±) -1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (1, 2-dimethyl-propyl) -urea D 529.2 6.87
310 (±) -1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-yne D 529.2 6.89
3- (1, 1-dimethyl-propyl) -urea
311 (±) -1- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (1-hydroxymethyl-propyl) -urea D 531.1 5.41
312 1- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -3- (1-ethyl-propyl) -urea D 529.1 6.63
313 (±) -1-sec-butyl-3- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 515.1 6.32
314 (±) -1- (1, 1-dimethyl-propyl) -3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 509.2 6.60
315 (±) -1- (1-hydroxymethyl-propyl) -3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 511.2 5.13
316 1- (1-ethyl-propyl) D 509.3 6.35
3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -phenyl]-quinazolin-6-yl } -prop-2-ynyl) -urea
317 (±) -1-sec-butyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 495.3 6.07
318 Azetidine-1-carboxylic acid (3- {4- [ 3-methyl-4)- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 479.2 5.46
319 1- (1, 2-dimethyl-propyl) -3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea D 509.2 6.36
320 Piperidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 507.3 6.21
321 E-pyridine-2-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -allyl) -amides G 503.3 6.11
322 E-2-isopropoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 498.3 5.94
323 E-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -benzenesulfonamides G 538.1 6.51
324 E-Ethanesulfonic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -allyl) -amides G 490.3 5.62
325 E-1H-imidazole-4-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 492.3 5.53
326 E-isoxazole-5-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 493.2 5.41
327 E-pyrrolidine-1-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides H 515.2 5.77
328 E-morpholine-4-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -allyl) -amides H 531.1 5.20
329 E-N-(3-{4-[3-Oxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-methylsulfanyl-acetamide G 506.1 5.81
330 E-5-oxo-tetrahydro-furan-2R-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 530.2 5.44
331 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-cyclopropylmethoxy-acetamide G 530.2 6.34
332 (±) -E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -2-hydroxy-3-methyl-butyramide I 518.2 5.73
333 E-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -methanesulfonyl G 496.1 5.72
Amines as pesticides
334 E-2R-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides H 525.2 4.91
335 E-2S-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides H 252.2 4.92
336 E-2-Cyclopropylmethoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 510.3 6.00
337 E-1-isopropyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -urea H 483.2 5.33
338 Azetidine-1-carboxylic acid (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -amide D 499.2 5.73
339 Piperazine-1-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n D 528.2 4.65
Base of]-quinazolin-6-yl } -prop-2-ynyl) -amide
340 2-methoxy-N- (3- { 7-methoxy-4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 498.2 5.47
341 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-7-methoxy-quinazolin-6-yl } -prop-2-ynyl) -2-methoxy-acetamide B 518.2 5.76
342 3- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -1- (2-methoxy-ethyl) -methyl-urea D 531.2 5.92
343 N- (3- { 7-methoxy-4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 468.2 5.21
344 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-7-methoxy-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 488.2 5.50
345 1, 1-diisopropyl group D 553.3 6.79
-3- (3- { 7-methoxy-4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -urea
346 (±) -2-methyl-piperidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -prop-2-ynyl) -amide D 521.3 6.53
347 E-azetidine-2S-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 481.3 4.10
348 E-1-amino-cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 481.3 4.40
349 E-2-amino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -isobutyramide G 483.3 4.12
350 E-5-oxo-pyrrolidine-2R-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 509.2 4.45
351 E-2R-amino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide G 469.3 4.09
352 E-2S-amino-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -propionamide G 469.3 4.09
353 E-5-oxo-pyrrolidine-2R-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 509.2 4.42
354 E-isoxazole-5-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 513.0 5.86
355 E-3- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -1, 1-diethyl-urea H 517.2 6.11
356 E-pyridine-2-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -n]-quinazolin-6-yl } -allyl alcohol G 523.1 6.47
Acyl) -amides
357 N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -methanesulfonamide B 474.2 5.66
358 N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -methanesulfonamide B 494.1 5.93
TABLE II
Example number Name (R) Method of producing a composite material Mass spectrometry RT
359 Z-Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino-]-quinazolin-6-yl } -allyl) -amides J 466.3 4.65
360 Z-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide J 440.3 5.56
361 Z-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -isobutyramide J 468.3 6.75
362 3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl B 454.3 5.93
Amino group]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid methyl ester
363 (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid methyl ester B 474.2476.2 6.20
364 3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -carbamic acid tert-butyl ester B 517.3 7.34
365 E- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -carbamic acid tert-butyl ester G 498.2 7.01
366 3-methyl-pyridine-2-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridine-3-)Oxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides ( 517.2 6.39
367 E-N- (3- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -benzenesulfonamides G 558.2 6.83
368 2-fluoro-N- (3- {4- [ 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 457.2 4.92
369 [ 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenyl]-(6- A 451.5 4.09
Piperidin-4-ylethynyl-quinazolin-4-yl } -amines
370 2-methoxy-N- (3- {4- [ 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 469.3 4.86
371 E-2-methoxy-N- (3- {4- [ 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 471.3 4.71
372 2-methoxy-N- (3- {4- [ 3-methyl-4- (pyrimidin-5-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 455.4 4.79
373 N- (3- {4- [ 3-methyl-4- (pyrimidin-5-yloxy) -phenylamino [ ] -methyl-amino]-quinazolin-6-yl } -prop-2-ynyl) -isobutyramide B 453.1 5.16
374 3-methyl-isoxazole-5-carboxylic acid (3- {4- [ 3-methyl-4- (pyrimidin-5-yloxy) -benzeneRadical amino]-quinazolin-6-yl } -prop-2-ynyl) -amide B 492.1 5.27
375 N- (3- {4- [ 3-methyl-4- (pyrimidin-5-yloxy) -phenylamino [ ] -methyl-amino]-quinazolin-6-yl } -prop-2-ynyl) -methanesulfonamide B 461.1 4.92
376 (±) [ 3-methyl-4- (pyrimidin-5-yloxy) -phenyl]- (6-piperazines) A 437.2 4.016
Pyridin-3-ylethynyl-quinazolin-4-yl } -amines
377 2-methoxy-N-methyl-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -prop-2-ynyl) -acetamide B 468.3 5.52
378 E-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 426.2 5.02
379 E-2-methoxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -acetamide G 456.2 5.27
380 E- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -carbamic acid methyl ester G 442.3 5.60
381 E-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -methanesulfonamide G 462.0 5.29
382 E-Cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -amides G 452.2 5.48
383 E-pyridine-2-carboxylic acid (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -phenyl]-quina G 489.1 6.15
Azolin-6-yl } -allyl) -amides
384 E-1-ethyl-3- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl } -allyl) -urea H 455.3 5.16
Using methods a through J and appropriate starting materials (prepared according to methods well known in the art), the following compounds may be prepared, which are part of the present invention:
Z-2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -acetamide
E-2- (2-Fluoroethoxy) -N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -acetamide
Z-N- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -2-fluoro-acetamide
2-hydroxy-N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-ylethynyl } -cyclopropyl) -acetamide
E-2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -isobutyramide
1-ethyl-3- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-ylethynyl } -cyclopropyl) -urea
1-ethyl-3- [1- (2- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-ylethynyl } -ethyl) -cyclopropyl ] -urea
3-methoxy-azetidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide
N- (3- {7- (2-methoxy-ethoxy) -4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
E-1-methoxy-cyclopropanecarboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -propenyl) -amide
N- (3- {4- [ 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
(±) -E-1- (2-fluoro-ethyl) -3- (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -urea
E-N- [1- (2- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -vinyl) -cyclopropyl ] -methanesulfonamide
(±) -E-tetrahydro-furan-3-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -amide
E-morpholine-4-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -amide
N- [1- (2- {4- [ 3-amino-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -ethyl) -cyclopropyl ] -methanesulfonamide
(±) -E-tetrahydro-furan-2-carboxylic acid (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -allyl) -amide
(±) -ethanesulfonic acid (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide
(±) -pyridine-2-carboxylic acid (1-methyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide
And pharmaceutically acceptable salts, solvates and prodrugs of the above compounds.

Claims (16)

1. A compound of formula 1
Or a pharmaceutically acceptable salt thereof, wherein:
m is an integer of 0 to 3;
p is an integer from 0 to 4;
R1and R2Each independently selected from H and C1-C6An alkyl group;
R3is- (CR)1R2)t(4-to 10-membered heterocyclic ring), wherein t is an integer from 0 to 5, said heterocyclic group optionally being associated with a benzene ring or C5-C8Cycloalkyl fused, said R being3Groups, including any optionally fused rings indicated above, optionally substituted with 1-5R8Substituted by groups;
R4is- (CR)16R17)m-C≡C-(CR16R17)tR9，-(CR16R17)m-C≡C-(CR16R17)kR13Or is- (CR)16R17)tR9Wherein with R9Is through R9Carbon atoms of the group, each k is an integer from 1 to 3, each t is an integer from 0 to 5, and each m is an integer from 0 to 3;
each R is5Each independently selected from halogen atoms, hydroxy groups, -NR1R2，C1-C6Alkyl, trifluoromethyl, C1-C6Alkoxy, trifluoromethoxy;
each R is6，R6aAnd R7Independently selected from H, C1-C6Alkyl, - (CR)1R2)t(C6-C10Alkyl), and- (CR)1R2)t(4-to 10-membered heterocyclic ring), wherein t is an integer of 0 to 5, 1 or 2 ring-forming carbon atoms of the heterocyclic group are optionally substituted by an oxo moiety, and the above R6And R7The alkyl and heterocyclic moieties of the group are optionally independently selected from halogen atoms, cyano, nitro, -NR1R2Trifluoromethyl, trifluoromethoxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy, and C1-C61 to 3 substituents of alkoxy;
or R6And R7Or R is6aAnd R7When attached to the same nitrogen atom, may together form a 4-to 10-membered heterocyclic ring, except that said R is attached6，R6aAnd R7May comprise 1 to 3 further heteroatom moieties selected from N, N (R) in addition to the nitrogen atom of (A)1) O, and S, with the proviso that two O atoms, two S atoms or one O and one S atom are not directly attached to each other;
each R is8Independently selected from halogen atom, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6Alkoxy radical, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, and the above R8The alkyl, alkenyl, alkynyl groups of the group are optionally substituted with 1 to 3 substituents independently selected from halogen atoms, cyano, nitro, trifluoromethyl, trifluoromethoxy;
R9is a non-aromatic monocyclic ring, wherein said ring contains 3 to 12 carbon atoms, wherein 0 to 3 carbon atoms are optionally independently selected from N, O, S (O)jWherein j is an integer of 0 to 2, and-NR1-partial replacement of the heteroatom (S), with the proviso that two O atoms, two S (O)jMoiety, one O atom and one S (O)jMoiety, one N atom and one S atom, or one N atom and one O atom, are not directly linked to each other within the ring, and the carbon atoms of the ring are optionally substituted by 1 or 2R8Substituted by groups;
each R is11Independently selected from R8Substituents given in the definitions;
R12is R6，-OR6，-OC(O)R6，-OC(O)NR6R7，-OCO2R6，-S(O)jR6，-S(O)jNR6R7，-NR6R7，-NR6C(O)R7，-NR6SO2R7，-NR6C(O)NR6aR7，-NR6SO2NR6aR7，-NR6CO2R7，CN，-C(O)R6Or a halogen atom, wherein j is an integer of 0 to 2;
R13is-NR1R14OR-OR14；
R14Is H, R15，-C(O)R15，-SO2R15，-C(O)NR15R7，-SO2NR15R7or-CO2R15；
R15Is R18，-(CR1R2)t(C6-C10Aryl), - (CR)1R2)t(4-to 10-membered heterocycle), wherein t is an integer of 0 to 5, 1 or 2 ring-forming carbon atoms of the heterocycle being optionally substituted with an oxo (═ O) moiety, and the above R15The aryl and heterocyclic moieties of the group are optionally substituted with 1-3R8Substituent group substitution;
each R is16And R17Independently selected from H, C1-C6Alkyl and-CH2OH；
R18Is C1-C6Alkyl, wherein no N or O atom is bonded or S (O)jBonded, wherein each carbon atom of j is an integer of 0 to 2 is optionally substituted with R12Substitution;
including not having halogen atoms, SO or SO2Radicals or CH to which N, O or S atoms are attached3(methyl group), CH2The above substituents of the (methylene) or CH (methine) group being optionally substituted by a group selected from hydroxy, halogen, C1-C4Alkyl radical, C1-C4Alkoxy and-NR1R2Is substituted with a group (b).
2. A compound according to claim 1, wherein R3Is- (CR)1R2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; said heterocycle being optionally substituted with a benzene ring or C5-C8Cycloalkyl fused, said R being3Groups, including the optionally fused rings indicated above, optionally substituted with 1-3R8And (4) substituting the group.
3. A compound according to claim 1, wherein R3Is- (CR)1R2)t(4-to 10-membered hetero)Ring) where t is an integer of 0 to 5, R as described above3The radical being optionally substituted by 1 to 3R8And (4) substituting the group.
4. A compound according to claim 1, wherein R3Selected from the following
And
wherein R is as defined above3The radical being optionally substituted by 1 to 3R8And (4) substituting the group.
5. A compound according to claim 1, wherein R3Is optionally substituted by 1-3R8Group-substituted pyridin-3-yl.
6. A compound according to claim 1, wherein the following moiety of the compound of formula 1
Selected from those of:
3-methyl-4- (pyridin-2-yloxy) -phenylamino
3-chloro-4- (pyridin-2-yloxy) -phenylamino
3-methoxy-4- (pyridin-2-yloxy) -phenylamino
4- (pyridin-2-yloxy) -phenylamino
2-methyl-4- (pyridin-2-yloxy) -phenylamino
2-methoxy-4- (pyridin-2-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
4- (6-methyl-pyridin-2-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyridin-3-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
4- (2-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
4- (6-methyl-pyridin-3-yloxy) -phenylamino
3-methyl-4- (pyridin-3-yloxy) -phenylamino
3-chloro-4- (pyridin-3-yloxy) -phenylamino
3-methoxy-4- (pyridin-3-yloxy) -phenylamino
2-methyl-4- (pyridin-3-yloxy) -phenylamino
2-methoxy-4- (pyridin-3-yloxy) -phenylamino
4- (pyridin-3-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
3-methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-chloro-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
2-methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
2-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
4- (2-methyl-pyridin-4-yloxy) -phenylamino
3-methyl-4- (pyridin-4-yloxy) -phenylamino
3-chloro-4- (pyridin-4-yloxy) -phenylamino
3-methoxy-4- (pyridin-4-yloxy) -phenylamino
2-methyl-4- (pyridin-4-yloxy) -phenylamino
2-methoxy-4- (pyridin-4-yloxy) -phenylamino
4- (pyridin-4-yloxy) -phenylamino
3-methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-chloro-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
2-methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
2-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
3-methyl-4- (pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (pyrazin-2-yloxy) -phenylamino
3-chloro-4- (pyrazin-2-yloxy) -phenylamino
2-methyl-4- (pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (pyrazin-2-yloxy) -phenylamino
4- (pyrazin-2-yloxy) -phenylamino
3-chloro-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
4- (3-methyl-pyrazin-2-yloxy) -phenylamino
3-chloro-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
4- (5-methyl-pyrazin-2-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
4- (6-methyl-pyrazin-2-yloxy) -phenylamino
3-methyl-4- (pyridazin-3-yloxy) -phenylamino
3-chloro-4- (pyridazin-3-yloxy) -phenylamino
3-methoxy-4- (pyridazin-3-yloxy) -phenylamino
2-methyl-4- (pyridazin-3-yloxy) -phenylamino
2-methoxy-4- (pyridazin-3-yloxy) -phenylamino
4- (pyridazin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
4- (6-methyl-pyridazin-3-yloxy) -phenylamino
3-methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-chloro-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
2-methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
4- (6-methyl-pyridazin-4-yloxy) -phenylamino
3-methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-chloro-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
2-methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
4- (3-methyl-pyridazin-4-yloxy) -phenylamino
3-methyl-4- (pyridazin-4-yloxy) -phenylamino
3-chloro-4- (pyridazin-4-yloxy) -phenylamino
3-methoxy-4- (pyridazin-4-yloxy) -phenylamino
2-methyl-4- (pyridazin-4-yloxy) -phenylamino
2-methoxy-4- (pyridazin-4-yloxy) -phenylamino
4- (pyridazin-4-yloxy) -phenylamino
3-chloro-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
3-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
3-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
2-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
2-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino,
and 4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino.
7. A compound according to claim 1, wherein R4Is- (CR)16R17)m-C≡C-(CR16R17)tR9Wherein m is an integer of 0 to 3 and t is an integer of 0 to 5.
8. A compound according to claim 1, R4Is- (CR)16R17)m-C≡C-(CR16R17)tR9Wherein m is an integer of 0 to 3 and t is an integer of 0 to 5, wherein R9Selected from each optionally substituted by 1 or 2R8Group-substituted 3-piperidinyl and 4-piperidinyl groups.
9. A compound according to claim 1, wherein R4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Wherein k is an integer of 1 to 3 and m isAn integer of 0 to 3.
10. A compound according to claim 1, wherein R4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Wherein k is an integer of 1 to 3, m is an integer of 0 to 3, wherein R13is-NR1R14Wherein R is14Selected from the group consisting of-C (O) R15，-SO2R15And C (O) NR15R7。
11. A compound according to claim 1, wherein R4Is- (CR)16R17)m-C≡C-(CR16R17)kR13Wherein k is an integer of 1 to 3, m is an integer of 0 to 3, R13is-NR1R14OR-OR14，R14Is R15，R15Is R18And R is18Is optionally substituted by-OR6，-S(O)jR6，-NR6R7，-NR6C(O)R7，-NR6SO2R7，-NR6CO2R7，CN，-C(O)R6Or C substituted by halogen atoms1-C6An alkyl group.
12. A compound according to claim 1, selected from:
(±) - [ 3-methyl-4- (pyridin-3-yloxy) -phenyl ] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
(±) - [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide
[ 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine
[ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
2-fluoro-N- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
[ 3-methyl-4- (pyridin-3-yloxy) -phenyl ] - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine;
2-methoxy-N- (1- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-ylethynyl } -cyclopropyl) -acetamide;
n- (3- {4- [ 3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
n- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
1-ethyl-3- (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -urea;
piperazine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
(±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
2-dimethylamino-N- (3- {4- [ 3-methyl-4- (pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -acetamide;
isoxazole-5-carboxylic acid (3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -amide;
1- (1, 1-dimethyl-3- {4- [ 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino ] -quinazolin-6-yl } -prop-2-ynyl) -3-ethyl-urea;
or a pharmaceutically acceptable salt of the above compound.
13. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of abnormal mammalian cell growth mediated by erb B2 kinase.
14. The use according to claim 13, wherein the abnormal cell growth is cancer.
15. The use according to claim 14, wherein the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, tumor of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.
16. A pharmaceutical composition for treating abnormal cell growth in a mammal, comprising an amount of a compound of formula 1 as defined in claim 1 effective to treat abnormal cell growth and a pharmaceutically acceptable carrier.
HK05102099.1A 2000-06-22 2005-03-11 Substituted bicyclic derivatives for the treatment of abnormal cell growth HK1069576B (en)

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