Substituted bicyclic derivatives for the treatment of abnormal cell growth

专利摘要:
The present invention relates to a compound of formula 1 and pharmaceutically acceptable salts, prodrugs and solvates thereof. The present invention also relates to a method for treating abnormal cell growth in mammals by administering a compound of Formula 1 and to a pharmaceutical composition for treating the disorder containing the compound of Formula 1. The present invention also relates to a process for preparing the compound of formula (1). Formula 1 Wherein R 1 , R 3 , R 4 , R 5 , R 11 , m and p are as defined herein.
公开号:KR20030016303A
申请号:KR1020027017489
申请日:2001-06-14
公开日:2003-02-26
发明作者:캐스존찰스；바타차리아사미트쿠마르；모리스조엘
申请人:화이자 프로덕츠 인코포레이티드；
IPC主号:

专利说明:

SUBSTITUTED BICYCLIC DERIVATIVES FOR THE TREATMENT OF ABNORMAL CELL GROWTH}
[2] Cells can be cancerous because some of their DNA is transformed into oncogenes (ie, genes that, when activated, cause malignant tumor cell formation). Many oncogenes encode proteins that are abnormal tyrosine kinases that can induce cell transformation. Alternatively, overexpression of normal proto-oncogene tyrosine kinases can also cause proliferative disorders, often malignant phenotypes.
[3] Receptor tyrosine kinases span the cell membrane and act as kinases for phosphorylate specific tyrosine residues in proteins and thus extracellular for growth factors such as epithelial growth factors, membrane metastasis regions, and intracellular parts that affect cell proliferation. It is an enzyme with a binding region. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr and VEGFR. It is known that such kinases are frequently aberrantly expressed in gastrointestinal cancers such as breast cancer, colon, rectum or stomach cancer, leukemia, and common human cancers such as ovarian, bronchial or pancreatic cancer. In addition, epidermal growth factor receptor (EGFR) with tyrosine kinase activity is mutated and / or overexpressed in many human cancers such as brain, lung, scale cells, bladder, stomach, breast, head and neck, esophagus, gynecological and thyroid tumors. Has been found.
[4] Thus, it was recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of mammalian cancer cell growth. For example, the tyrosine kinase inhibitor erbstatin selectively attenuates the growth of transplanted human breast carcinomas expressing epidermal growth factor receptor tyrosine kinase (EGFR) in thymus-free mice, but does not express EGF factor. There is no effect on the growth of other carcinomas. Thus, compounds of the invention that are selective inhibitors of specific receptor tyrosine kinases are useful for the treatment of abnormal cell growth in mammals, particularly cancer. In addition to receptor tyrosine kinases, the compounds of the present invention may also exhibit inhibitory activity against various other non-receptor tyrosine kinases (eg lck, src, abl) or serine / threonine kinases (eg cyclin dependent kinases).
[5] Various other compounds, such as styrene derivatives, have also been found to have tyrosine kinase inhibitory properties. More recently, five European patent publications, EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (Published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992) for certain bicyclic derivatives. , In particular, quinazoline derivatives have anticancer properties due to their tyrosine kinase inhibitory properties. International patent application WO 92/20642 (published November 26, 1992) also mentions that certain bis- and bicyclic aryl and heteroaryl compounds are tyrosine kinase inhibitors useful for inhibiting abnormal cell proliferation. International Patent Application W0 96/16960, published June 6, 1996, WO 96/09294, published March 6, 1996, WO 97/30034, published August 21, 1997 , WO 98/02434 published January 22, 1998, WO 98/02437 published January 22, 1998, and WO 98/02438 published January 22, 1998. Substituted bicyclic heteroaromatic derivatives are also mentioned as useful tyrosine kinase inhibitors for the same purpose. Other patent applications that refer to anticancer compounds are US Patent Application Nos. 09 / 488,350 (filed Jan. 20, 2000) and 09 / 488,378 (filed Jan. 20, 2000), which are herein incorporated by reference. All are cited for reference.
[6] Summary of the Invention
[7] The present invention relates to compounds of formula 1 and pharmaceutically acceptable salts, solvates and prodrugs thereof:
[8]
[9] Where
[10] m is an integer from 0 to 3;
[11] p is an integer from 0 to 4;
[12] Each of R ¹ and R ² is independently selected from H and C ₁ -C ₆ alkyl;
[13] R ³ is — (CR ¹ R ² ) _t (4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, wherein the heterocyclic group is optionally fused to a benzene ring or a C ₅ -C ₈ cycloalkyl group , Wherein the-(CR ¹ R ² ) _t -moiety of the R ³ group optionally comprises a carbon-carbon double bond or a triple bond, wherein t is an integer from 2 to 5 and comprises the above-mentioned optional fused ring Said R ³ groups are optionally substituted with 1 to 5 R ⁸ groups;
[14] R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _t R ⁹ ,-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , -(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ ,-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k -R ¹³ , or-( and CR ¹⁶ R ¹⁷⁾ _t R ^9, provided herein is the point of attachment to the R ⁹ is through a carbon atom of the R ⁹ group, each k is an integer from 1 to 3, each t is an integer from 0 to 5, Each m is an integer from 0 to 3;
[15] R ⁵ is halo, hydroxy, -NR ¹ R ² , C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ -C ₆ alkoxy, trifluoromethoxy, -NR ⁶ C (O) R ¹ ,- C (O) NR ⁶ R ⁷ , -S0 ₂ NR ⁶ R ⁷ , -NR ⁶ C (O) NR ⁷ R ¹ , and -NR ⁶ C (O) OR ⁷ ;
[16] R ⁶ , R ^6a and R ⁷ are each H, C ₁ -C ₆ alkyl,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl), and-(CR ¹ R ² ) _t (4-10 membered) Heterocyclic), wherein t is an integer from 0 to 5, wherein one or two ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (= 0) moiety and wherein the R ⁶ and R ⁷ groups Alkyl, aryl and heterocyclic moieties of halo, cyano, nitro, -NR ¹ R ² , trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C _2- Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkynyl, hydroxy, and C ₁ -C ₆ alkoxy; or
[17] R ⁶ and R ⁷ , or R ^6a and R ^7, may be attached to a nitrogen atom (the same nitrogen atom or two separate nitrogen atoms which are in close proximity to one another via, eg, -C (O) or -SO ₂ -via interconnection). When attached, R ⁶ , R ^6a and R ⁷ may include one to three additional hetero moieties selected from N, N (R ¹ ), O and S in addition to the nitrogen to which they are attached, wherein two O atoms, 2 S atoms or O and S atoms may together form a 4 to 10 membered heterocyclic ring that is not directly attached to each other;
[18] R ⁸ is oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₁₀ alkyl, C _2- C ₆ alkenyl, C ₂ -C ₆ alkynyl, -C (O) R ⁶ , -C (O) OR ⁶ , -OC (O) R ⁶ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ NR ⁷ R ¹ , -NR ⁶ C (O) NR ¹ R ⁷ , -NR ⁶ C (O) OR ⁷ , -C (O) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ 0R ⁷ , -SO ₂ NR ⁶ R ⁷ , -S (O) _j (C ₁ -C ₆ alkyl), where j is an integer from 0 to 2,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl) ,-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic),-(CR ¹ R ² ) _q C (O) (CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl),-(CR ¹ R ² ) _q C (O) (CR ¹ R ² ) _t (4-10 membered heterocyclic),-(CR ¹ R ² ) _t O (CR ¹ R ² ) _q (C ₆ -C ₁₀ aryl),- (CR ¹ R ² ) _t O (CR ¹ R ² ) _q (4 to 10 membered heterocyclic),-(CR ¹ R ² ) _q S (O) _j (CR ¹ R ² ) _t (C ₆ -C ₁₀ Aryl), and-(CR ¹ R ² ) _q S (O) _j (CR ¹ R ² ) _t (4-10 membered heterocyclic) (where j is 0, 1 or 2, and q and t are each independent) Is an integer of 0 to 5) And one or two ring carbon atoms of the heterocyclic moiety of the R ⁸ group are optionally substituted with an oxo (═O) moiety and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the R ⁸ group Halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ , -OC (O) R ⁶ , -NR ⁶ C (O) R ⁷ , -C (O) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ 0R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Independently from alkynyl,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl), and-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic), where t is an integer from 0 to 5 Optionally substituted with one to three substituents selected;
[19] R ⁹ is a non-aromatic monocyclic ring, fused or bridged bicyclic ring, or spirocyclic ring, wherein the ring contains 3 to 12 carbon atoms, wherein 0 to 3 carbon atoms are N, 0, S ( O) j (where j is an integer from 0 to 2) and -NR ¹ -optionally substituted with a hetero residue independently selected from two O atoms, two S (O) _j residues, an O atom and S (O ) _j residues, N and S atoms, or N and O atoms are not directly attached to each other in the ring, and the carbon atoms of the ring are optionally substituted with 1 or 2 R ⁸ groups;
[20] R ¹¹ is independently selected from substituents defined in R ⁸ , except oxo (═O);
[21] R ¹² is R ⁶ , -OR ⁶ , -OC (O) R ⁶ , -OC (O) NR ⁶ R ⁷ , -OCO ₂ R ⁶ , -S (O) _j R ⁶ , -S (O) _j NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ C (O) NR ^6a R ⁷ , -NR ⁶ S0 ₂ NR ^6a R ⁷ , -NR ⁶ CO ₂ R ⁷ , CN, -C (O) R ⁶ , or halo, wherein j is an integer from 0 to 2;
[22] R ¹³ is —NR ¹ R ¹⁴ or —OR ¹⁴ ;
[23] R ¹⁴ is H, R ¹⁵ , -C (O) R ¹⁵ , -S0 ₂ R ¹⁵ , -C (O) NR ¹⁵ R ⁷ , -SO ₂ NR ¹⁵ R ⁷ , or -C0 ₂ R ¹⁵ ;
[24] R ¹⁵ is R ¹⁸ ,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl),-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic), where t is an integer from 0 to 5 , One or two ring carbon atoms of the heterocyclic group are optionally substituted with oxo (═O) residues, and the aryl and heterocyclic residues of the R ¹⁵ groups are optionally substituted with one to three R ⁸ substituents;
[25] R ¹⁶ and R ¹⁷ are each independently selected from H, C ₁ -C ₆ alkyl and —CH ₂ OH, or R ¹⁶ and R ¹⁷ together are —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — ;
[26] R ¹⁸ is C ₁ -C ₆ alkyl but each carbon which is not bonded to an N or O atom, or S (O) _j , where j is an integer from 0 to 2, is optionally substituted with R ¹² ;
[27] Any such substituent comprising a CH ₃ (methyl), CH ₂ (methylene), or CH (methine) group not attached to a halogeno, SO or SO ₂ group or to an N, O or S atom may be hydroxy, halo, C Optionally substituted with _1- C ₄ alkyl, C ₁ -C ₄ alkoxy and —NR ¹ R ² .
[28] In certain embodiments of the invention, R ³ is-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic) where t is an integer from 0 to 5; The heterocyclic group is optionally fused to a benzene ring or a C ₅ -C ₈ cycloalkyl group, wherein the R ³ group comprising the optional fused ring is optionally substituted with 1 to 3 R ⁸ groups.
[29] Other specific embodiments of compounds of Formula 1 are wherein R ³ is-(CR ¹ R ² ) _t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5, wherein said R ³ group is optionally 1 to Substituted with three R ⁸ groups.
[30] In certain other embodiments of compounds of Formula 1, R ³ is selected from:
[31]
[32] Wherein the R ³ groups are optionally substituted with 1 to 3 R ⁸ groups.
[33] Another particular embodiment of a compound of Formula 1 is that R ³ is pyridin-3-yl, optionally substituted with one to three R ⁸ groups.
[34] Another particular embodiment of a compound of Formula 1 is a structural moiety of a compound of Formula 1 Is selected from the group consisting of:
[35] 3-methyl-4- (pyridin-2-yloxy) -phenylamino
[36] 3-chloro-4- (pyridin-2-yloxy) -phenylamino
[37] 3-methoxy-4- (pyridin-2-yloxy) -phenylamino
[38] 4- (pyridin-2-yloxy) -phenylamino
[39] 2-methyl-4- (pyridin-2-yloxy) -phenylamino
[40] 2-methoxy-4- (pyridin-2-yloxy) -phenylamine
[41] 3-Chloro-4- (6-methyl-pyridin-2-yloxy) -phenylamino
[42] 3-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
[43] 3-methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
[44] 2-methoxy-4- (6-methyl-pyridin-2-yloxy) -phenylamino
[45] 2-Methyl-4- (6-methyl-pyridin-2-yloxy) -phenylamino
[46] 4- (6-Methyl-pyridin-2-yloxy) -phenylamino
[47] 3-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
[48] 3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
[49] 3-Chloro-4- (2-methyl-pyridin-3-yloxy) -phenylamino
[50] 2-methoxy-4- (2-methyl-pyridin-3-yloxy) -phenylamino
[51] 2-Methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino
[52] 4- (2-Methyl-pyridin-3-yloxy) -phenylamino
[53] 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
[54] 3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino
[55] 3-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
[56] 2-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino
[57] 2-methoxy-4- (6-methyl-pyridin-3-yloxy) -phenylamino
[58] 4- (6-Methyl-pyridin-3-yloxy) -phenylamino
[59] 3-methyl-4- (pyridin-3-yloxy) -phenylamino
[60] 3-chloro-4- (pyridin-3-yloxy) -phenylamino
[61] 3-methoxy-4- (pyridin-3-yloxy) -phenylamino
[62] 2-methyl-4- (pyridin-3-yloxy) -phenylamino
[63] 2-methoxy-4- (pyridin-3-yloxy) -phenylamino
[64] 4- (pyridin-3-yloxy) -phenylamino
[65] 3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
[66] 3-Chloro-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
[67] 3-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
[68] 2-Methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
[69] 2-methoxy-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino
[70] 4- (2-Methyl-pyrimidin-5-yloxy) -phenylamino
[71] 3-Methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
[72] 3-Chloro-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
[73] 3-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
[74] 2-Methyl-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
[75] 2-methoxy-4- (4-methyl-pyrimidin-5-yloxy) -phenylamino
[76] 4- (4-Methyl-pyrimidin-5-yloxy) -phenylamino
[77] 3-methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
[78] 3-Chloro-4- (2-methyl-pyridin-4-yloxy) -phenylamino
[79] 3-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
[80] 2-Methyl-4- (2-methyl-pyridin-4-yloxy) -phenylamino
[81] 2-methoxy-4- (2-methyl-pyridin-4-yloxy) -phenylamino
[82] 4- (2-Methyl-pyridin-4-yloxy) -phenylamino
[83] 3-methyl-4- (pyridin-4-yloxy) -phenylamino
[84] 3-chloro-4- (pyridin-4-yloxy) -phenylamino
[85] 3-methoxy-4- (pyridin-4-yloxy) -phenylamino
[86] 2-methyl-4- (pyridin-4-yloxy) -phenylamino
[87] 2-methoxy-4- (pyridin-4-yloxy) -phenylamino
[88] 4- (pyridin-4-yloxy) -phenylamino
[89] 3-Methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
[90] 3-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
[91] 3-Chloro-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
[92] 2-Methyl-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
[93] 2-methoxy-4- (2-methyl-pyrimidin-4-yloxy) -phenylamino
[94] 4- (2-Methyl-pyrimidin-4-yloxy) -phenylamino
[95] 3-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
[96] 3-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
[97] 3-Chloro-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
[98] 2-methyl-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
[99] 2-methoxy-4- (6-methyl-pyrimidin-4-yloxy) -phenylamino
[100] 4- (6-Methyl-pyrimidin-4-yloxy) -phenylamino
[101] 3-methyl-4- (pyrazin-2-yloxy) -phenylamino
[102] 3-methoxy-4- (pyrazin-2-yloxy) -phenylamino
[103] 3-chloro-4- (pyrazin-2-yloxy) -phenylamino
[104] 2-methyl-4- (pyrazin-2-yloxy) -phenylamino
[105] 2-methoxy-4- (pyrazin-2-yloxy) -phenylamino
[106] 4- (pyrazin-2-yloxy) -phenylamino
[107] 3-Chloro-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
[108] 3-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
[109] 3-methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
[110] 2-methoxy-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
[111] 2-Methyl-4- (3-methyl-pyrazin-2-yloxy) -phenylamino
[112] 4- (3-Methyl-pyrazin-2-yloxy) -phenylamino
[113] 3-Chloro-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
[114] 3-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
[115] 3-methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
[116] 2-methoxy-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
[117] 2-Methyl-4- (5-methyl-pyrazin-2-yloxy) -phenylamino
[118] 4- (5-Methyl-pyrazin-2-yloxy) -phenylamino
[119] 3-Chloro-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
[120] 3-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
[121] 3-methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
[122] 2-methoxy-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
[123] 2-Methyl-4- (6-methyl-pyrazin-2-yloxy) -phenylamino
[124] 4- (6-Methyl-pyrazin-2-yloxy) -phenylamino
[125] 3-methyl-4- (pyridazin-3-yloxy) -phenylamino
[126] 3-chloro-4- (pyridazin-3-yloxy) -phenylamino
[127] 3-methoxy-4- (pyridazin-3-yloxy) -phenylamino
[128] 2-methyl-4- (pyridazin-3-yloxy) -phenylamino
[129] 2-methoxy-4- (pyridazin-3-yloxy) -phenylamino
[130] 4- (pyridazin-3-yloxy) -phenylamino
[131] 3-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
[132] 3-Chloro-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
[133] 3-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
[134] 2-methyl-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
[135] 2-methoxy-4- (6-methyl-pyridazin-3-yloxy) -phenylamino
[136] 4- (6-Methyl-pyridazin-3-yloxy) -phenylamino
[137] 3-methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
[138] 3-Chloro-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
[139] 3-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
[140] 2-Methyl-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
[141] 2-methoxy-4- (6-methyl-pyridazin-4-yloxy) -phenylamino
[142] 4- (6-Methyl-pyridazin-4-yloxy) -phenylamino
[143] 3-methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
[144] 3-Chloro-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
[145] 3-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
[146] 2-Methyl-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
[147] 2-methoxy-4- (3-methyl-pyridazin-4-yloxy) -phenylamino
[148] 4- (3-Methyl-pyridazin-4-yloxy) -phenylamino
[149] 3-methyl-4- (pyridazin-4-yloxy) -phenylamino
[150] 3-chloro-4- (pyridazin-4-yloxy) -phenylamino
[151] 3-methoxy-4- (pyridazin-4-yloxy) -phenylamino
[152] 2-methyl-4- (pyridazin-4-yloxy) -phenylamino
[153] 2-methoxy-4- (pyridazin-4-yloxy) -phenylamino
[154] 4- (pyridazin-4-yloxy) -phenylamino
[155] 3-chloro-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
[156] 3-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
[157] 3-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
[158] 2-methoxy-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino
[159] 2-methyl-4- (1-methyl-1H-pyrazol-4-yloxy) -phenylamino, and
[160] 4- (1-Methyl-1H-pyrazol-4-yloxy) -phenylamino.
[161] Other aspects specific embodiments of the compounds of formula (1) is ^{R 4 - (CR 16 R 17} ) m -C≡C- (CR 16 R 17) t R 9 ( where, m is an integer from 0 to 3, t is 0 To an integer of 5 to 5).
[162] Other aspects specific embodiments of the compounds of formula (1) is ^{R 4 - (CR 16 R 17} ) m -C≡C- (CR 16 R 17) t R 9 ( where, m is an integer from 0 to 3, t is 0 To an integer from to 5), and R ⁹ is selected from 3-piperidinyl and 4-piperidinyl, each of which is substituted with one or two R ⁸ groups.
[163] In certain other embodiments of compounds of Formula 1, R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , wherein m is an integer from 0 to 3, and t is It is an integer of 0 to 5).
[164] In certain other embodiments of compounds of Formula 1, R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , wherein m is an integer from 0 to 3, and t is An integer from 0 to 5), wherein R ⁹ is selected from 3-piperidinyl and 4-piperidinyl, optionally substituted with 1 to 2 R ⁸ groups.
[165] Another particular embodiment of the compound of formula (1) R ⁴ is _{^{- (CR 16 R 17) m}} -C≡C- (CR 16 R 17) k R 13 ( wherein, k is an integer of 1 to 3 and m is from 0 to It is an integer of 3).
[166] Another particular embodiment of the compound of formula (1) R ⁴ is _{^{- (CR 16 R 17) m}} -C≡C- (CR 16 R 17) k R 13 ( wherein, k is an integer of 1 to 3 and m is from 0 to Is an integer of 3), wherein R ¹³ is -NR ¹ R ¹⁴ , wherein R ¹⁴ is selected from -C (O) R ¹⁵ , -S0 ₂ R ^15, and C (O) NR ¹⁵ R ⁷ .
[167] In certain other embodiments of compounds of Formula 1, R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is 0 to It is an integer of 3).
[168] In certain other embodiments of compounds of Formula 1, R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is 0 to Is an integer of 3), wherein R ¹³ is -NR ¹ R ¹⁴ , wherein R ¹⁴ is selected from -C (O) R ¹⁵ , -S0 ₂ R ^15, and -C (O) NR ¹⁵ R ⁷ .
[169] Other aspects specific embodiments of the compounds of formula (1) R ⁴ is _{^{- (CR 16 R 17) m}} -C≡C- (CR 16 R 17) k R 13 or _{^{- (CR 16 R 17) m}} -C = C- ( CR ¹⁶ R ¹⁷ ) _k R ¹³ (where k is an integer from 1 to 3 and m is an integer from 0 to 3), R ¹³ is —NR ¹ R ¹⁴ or —OR ¹⁴ , R ¹⁴ is R ¹⁵ , R ¹⁵ is R ¹⁸ , R ¹⁸ is -OR ⁶ , -S (O) _j R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ CO ₂ R ⁷ , CN, —C (O) R ⁶ or C ₁ -C ₆ alkyl optionally substituted with halo.
[170] Particularly preferred compounds of the invention include those selected from the group consisting of and pharmaceutically acceptable salts, prodrugs and solvates thereof:
[171] (±)-[3-methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine;
[172] 2-methoxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amides
[173] (±)-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine;
[174] 2-methoxy-N- (3- {4- [3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamide
[175] [3-Methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine
[176] [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine;
[177] 2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamide;
[178] 2-Fluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamide;
[179] E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- Acetamide;
[180] [3-Methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine;
[181] 2-methoxy-N- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclopropyl) Acetamide;
[182] EN- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-methoxy-acetamide ;
[183] N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamide ;
[184] N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamide ;
[185] E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamide;
[186] E-2-ethoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- Acetamide;
[187] 1-ethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -Urea;
[188] Piperazine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amides;
[189] (±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -amide;
[190] 2-dimethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amides;
[191] E-N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -methanesulfonamide;
[192] Isoxazole-5-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amides; And
[193] 1- (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Ynyl) -3-ethyl-urea.
[194] The invention also relates to a mammal, including a human, comprising administering to the mammal a compound of Formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to treat abnormal cell growth. A method of treating abnormal cell growth. In one embodiment of the method, the abnormal cell growth is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric 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, Esophageal cancer, Small intestine cancer, Cancer of the endocrine system, Thyroid cancer, Parathyroid cancer, Adrenal cancer, Soft tissue sarcoma Cancer, Penile Cancer, Prostate Cancer, Chronic or Acute Leukemia, Lymphocytic Lymphoma, Bladder Cancer, Renal or Urinary Tract Cancer, Renal Cell Carcinoma, Renal Carcinoma, Central Nervous System Tumor (CNS), Primary CNS Lymphoma, Spinal Cord Tumor, Brainstem Nerve Glioma, pituitary adenoma, or cancer including but not limited to combinations of one or more of the above cancers. In another embodiment of the method, said abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hyperplasia or stenosis.
[195] The present invention also provides a mammal with a compound of Formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to treat abnormal cell growth, including mitosis inhibitors, alkylating agents, anti-metabolites, septal antibiotics, Administering with an anti-tumor agent selected from the group consisting of growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones and anti-androgens It relates to a method of treating abnormal cell growth in a mammal.
[196] The present invention also provides a human, comprising an amount of a compound of Formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, in an amount effective to treat abnormal cell growth. It relates to a pharmaceutical composition for treating abnormal cell growth of a mammal comprising. In one embodiment of the composition, the abnormal cell growth is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric 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, Esophageal cancer, Small intestine cancer, Cancer of the endocrine system, Thyroid cancer, Parathyroid cancer, Adrenal cancer, Soft tissue sarcoma Cancer, Penile Cancer, Prostate Cancer, Chronic or Acute Leukemia, Lymphocytic Lymphoma, Bladder Cancer, Renal or Urinary Tract Cancer, Renal Cell Carcinoma, Renal Carcinoma, Central Nervous System Tumor (CNS), Primary CNS Lymphoma, Spinal Cord Tumor, Brainstem Nerve Glioma, pituitary adenoma, or cancer including but not limited to combinations of one or more of the above cancers. In other embodiments of the composition, the abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hyperplasia or stenosis.
[197] The present invention also provides an effective amount of a compound of Formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in a mammal for treating abnormal cell growth, including mitosis inhibitors, alkylating agents, anti-metabolites, With an anti-tumor agent selected from the group consisting of septal antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones and anti-androgens, The present invention relates to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human.
[198] In addition, the present invention comprises administering to a mammal a compound of Formula 1 as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to treat the disorder, angiogenesis of a mammal, including a human It relates to a method of treating a disorder associated with. The disorder is a cancerous tumor such as melanoma; Eye disorders such as age-related macular degeneration, putative ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; Rheumatoid arthritis; Bone loss disorders such as osteoporosis, Paget's disease, malignant humoral hypercalcemia, hypercalcemia from tumors metastasized to bone, and osteoporosis induced by glucocorticoid treatment; Coronary artery stenosis; And microbial pathogens selected from adenoviruses, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and Group A Streptococcus Certain microbial infections, including those associated with.
[199] The present invention also includes compounds of formula (1), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and anti-angiogenic agents, signal transduction inhibitors and antiproliferative agents in an amount effective to treat abnormal cell growth together. To a method for treating abnormal cell growth in a mammal (and a pharmaceutical composition therefor).
[200] Anti-angiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase II) inhibitors It can be used with the compound of formula 1 in the methods and pharmaceutical compositions described above. Examples of useful COX-11 inhibitors include CELEBREX ^™ (alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application 97304971.1 ( European Patent Application No. 99308617.2 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998), WO 98/03516 (1998) Published January 29), WO 98/34918 published August 13, 1998, WO 98/34915 published August 13, WO 98/33768, August 1998 Published 6, WO 98130566 published 16 July 1998, European Patent Publication 606,046 published 13 July 1994, European Patent Publication 931,788 published 28 July 1999 ), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999). ), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (July 21, 1998) European Patent Application No. 99302232.1 (filed May 25, 1999), British Patent Application No. 9912961.1 (filed June 3, 1999), US Provisional Application No. 601148,464 (8 1999) US Patent No. 5,863,949 (published January 26, 1999), US Patent No. 5,861,510 (published January 19, 1999), and European Patent Publication No. 780,386 (June 1997) Published May 25, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity that inhibits MMP-1. More preferably, other matrix-metalloproteinases (ie, MMP-1, MMP-3, MMP-4., MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP -11, MMP-12 and MMP-13) selectively inhibits MMP-2 and / or MMP-9.
[201] Some specific examples of MMP inhibitors useful for use with the compounds of the present invention include AG-3340, RO 32-3555, RS 13-0830, and the compounds listed below and their pharmaceutically acceptable salts, solvates and precursors The drug is:
[202] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid;
[203] 3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
[204] (2R, 3R) 1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
[205] 4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
[206] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid;
[207] 4- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
[208] 3- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;
[209] (2R, 3R) 1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
[210] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid;
[211] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid;
[212] 3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
[213] 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; And
[214] 3- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamide.
[215] Compounds of Formula 1, and pharmaceutically acceptable salts, solvates and prodrugs thereof, may also inhibit epidermal growth factor receptor (EGFR) responses such as molecules that are signal transduction inhibitors such as EGFR antibodies, EGF antibodies, and EGFR inhibitors. Drugs that can be used; VEGF (vascular endothelial growth factor) inhibitors; And organic molecules or antibodies that bind to the erbB2 receptor, for example erbB2 receptor inhibitors such as HERCEPTIN ^™ (Genentech, Inc., San Francisco, CA, USA).
[216] EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), WO 98/14451 (community on April 9, 1998), WO 98/02434 (January 22, 1998). And U.S. Patent 5,747,498, issued May 5, 1998. EGFR-inhibitors are monoclonal antibody C225 and anti-EGFR 22 Mab (ImClone Systems Incorporated, New York, NY), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc., Annandale, NJ), and OLX-103 (Merck, Whitehouse Station, NJ, USA) Merck & Co.), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc., Hopkinton, Mass.). It is not limited.
[217] VEGF inhibitors such as SU-5416 and SU-6668 (Sugen Inc., San Francisco, CA, USA) may also be combined with the compound of Formula 1. VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), PCT International Application No. PCT / IB99 / 00797 (filed May 3, 1999), WO 95/21613 (1995). Published August 17, 1999, WO 99/61422 published December 2, 1999, US Patent 5,834,504 issued November 10, 1998, WO 98/50356 published 11 November 1998 Published May 12, US Patent No. 5,883,113 issued March 16, 1999, US Patent No. 5,886,020 issued March 23, 1999, US Patent No. 5,792,783 (August 11, 1998) Published), WO 99/10349 published March 4, 1999, WO 97/32856 published September 12, 1997, WO 97/22596 published June 26, 1997 Published), WO 98/54093 published December 3, 1998, WO 98/02438 published January 22, 1998, WO 99/16755 published April 8, 1999 And WO 98/02437, published January 22, 1998, all of which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors include IM862 (Cytran Inc., Kirkland, WA); Anti-VEGF monoclonal antibodies of Genentech Incorporated, San Francisco, CA; And synthetic ribozymes from angiozyme, Ribozyme (Boulder, Colorado) and Chiron (Emeryville, CA).
[218] ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome plc), and monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc., Woodland, TX) and 2B-1 ( Chiron) can be administered with a compound of formula (I). Such erbB2 inhibitors are disclosed in WO 98/02434 published January 22, 1998, WO 99/35146 published July 15, 1999, WO 99/35132 published July 15, 1999 ); WO 98/02437, published January 22, 1998, WO 97/13760, published April 17, 1997, WO 95/19970, published July 27, 1995, US patent 5,587,458, issued December 24, 1996, and US Pat. No. 5,877,305, issued March 2, 1999, each of which is incorporated herein by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in US Provisional Application No. 60 / 117,341 filed Jan. 27, 1999 and US Provisional Application No. 60 / 117,346 filed Jan. 27, 1999 Which are hereby incorporated by reference in their entirety.
[219] Other antiproliferative agents that can be used with the compounds of the present invention include the following US patent applications: 09/221946, filed Dec. 28, 1998; 09/454058, filed December 2, 1999; 09/501163, filed February 9, 2000; 09/539930, filed March 31, 2000; 09/202796, filed May 22, 1997; 09/384339, filed August 26, 1999; And compounds disclosed and claimed in 09/383755, filed August 26, 1999; And U.S. Provisional Patent Application: 60/168207, filed November 30, 1999; 60/170119, filed December 10, 1999; 60/177718, filed Jan. 21, 2000; Inhibitors of the enzyme farnesyl protein transferase comprising compounds disclosed and claimed in 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1, 2000) And inhibitors of receptor tyrosine kinase PDGFr. Each of the above patent applications and provisional patent applications is hereby incorporated by reference in their entirety.
[220] Compounds of formula (1) may also contain drugs that can potentiate anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other drugs that can block CTLA4; And antiproliferative agents such as other farnesyl protein transferase inhibitors, such as the farnesyl protein transferase inhibitors described in the references cited above in the "Background" section. Particular CTLA4 antibodies that may be used in the present invention include those described in US Provisional Application No. 60 / 113,647, filed December 23, 1998, which is incorporated herein by reference in its entirety.
[221] "Abnormal cell growth" herein refers to cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition) unless otherwise indicated. These include (1) tumor cells (tumors) that proliferate by expression of mutated tyrosine kinases or overexpression of receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumor proliferated by receptor tyrosine kinase; (5) any tumor proliferated by aberrant serine / threonine kinase activation; And (6) abnormal growth of malignant cells and aspects of other proliferative diseases in which aberrant serine / threonine kinase activation occurs.
[222] "Treatment" herein means to reverse, alleviate, inhibit or prevent the progression of the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition, unless otherwise indicated. By "treatment" is meant herein the action of "treatment" as defined above.
[223] The term "halo" herein includes fluoro, chloro, bromo or iodo unless otherwise indicated. Preferred halo groups are fluoro and chloro.
[224] The term "alkyl" herein includes saturated monovalent hydrocarbon radicals having straight, cyclic (including monocyclic or polycyclic moieties) or branched moieties unless otherwise indicated. It is understood that when the alkyl group contains a cyclic moiety it must contain at least 3 carbon atoms.
[225] The term “cycloalkyl” herein includes saturated monovalent hydrocarbon radicals having cyclic (including monocyclic or polycyclic) moieties unless otherwise indicated.
[226] The term "alkenyl" herein includes alkyl groups as defined above having one or more carbon-carbon double bonds unless otherwise indicated.
[227] The term "alkynyl" herein includes alkyl groups as defined above having one or more carbon-carbon triple bonds unless otherwise indicated.
[228] The term "aryl" herein includes organic radicals derived from aromatic hydrocarbons by removing one hydrogen, for example phenyl or naphthyl, unless otherwise indicated.
[229] As used herein, the term "alkoxy" includes —0-alkyl groups where alkyl is as defined above unless otherwise indicated.
[230] As used herein, the term “4 to 10 membered heterocyclic”, unless otherwise indicated, includes aromatic and non-atom containing at least one heteroatom selected from O, S and N and having from 4 to 10 atoms in the ring system thereof. Aromatic heterocyclic groups. Non-aromatic heterocyclic groups include groups having only 4 atoms in the ring system, but aromatic heterocyclic groups must have at least 5 atoms in the ring system. Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo residues. An example of a four-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 include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl , Piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazinyl, diazepinyl, thiazinyl, 1,2,3,6-tetrahydro Pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, ditianyl, dithiolinyl , Dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] Heptanyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pi Rollyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnaolinyl, indazolyl, indolinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, fr Terridinyl, furinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. . The groups may be C-attached or N-attached as possible when derived from the compounds listed above. For example, the group derived from pyrrole may be pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached).
[231] The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl.
[232] In the definition of X ¹ ,-(CR ¹ R ² ) _m -and (CR ¹⁶ R ¹⁷ ) _k residues, and other similar residues as indicated are ^{1 in} the definition of R ¹ , R ² , R ¹⁶ and R ¹⁷ . May vary for repetition of the above subscripts (ie, m, k, etc.). Thus,-(CR ¹ R ² ) _m -may comprise -CH ₂ C (Me) (Et)-, where m is 2.
[233] The phrase “pharmaceutically acceptable salt (s)” herein includes salts of acidic or basic groups which may be present in the compounds of the invention, unless otherwise indicated. Compounds of the present invention that are basic in nature are capable of forming a wide range of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of the basic compounds are non-toxic acid addition salts, ie salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate , Sulfates, unsulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, bitartrates, ascorbates, succinates, Maleate, gentisinate, fumarate, gluconate, glucuronate, saccharide, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ Namely, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salt. . Compounds of the present invention comprising basic residues such as amino groups can form pharmaceutically acceptable salts with various amino acids in addition to the above acids.
[234] Compounds of the invention that are acidic in nature are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular the calcium, magnesium, sodium and potassium salts of the compounds of the invention.
[235] Certain functional groups contained within the compounds of the present invention may be substituted for biostereomeric groups, ie groups that have similar spatial or electronic requirements for parent groups but exhibit different or improved physicochemical or other properties. Suitable examples are well known in the art and described in Patini et al., Chem. Rev, 1996, 96, 3147-3176, and the residues described in the references cited therein.
[236] The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and stereoisomers, and mixtures thereof, of the compounds of the present invention, and to all pharmaceutical compositions and methods of treatment that can use or contain them. Compounds of formula 1 may also exist as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.
[237] In addition, the present invention also provides the same isotopically-labeled compounds as described in Formula 1, except that one or more atoms are replaced with atoms having an atomic weight or mass number that is different from the atomic weight or mass number commonly found in nature, and pharmaceuticals thereof And acceptable salts, solvates and prodrugs. Examples of isotopes that may be incorporated in the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively. , ¹⁷ O, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or the prodrugs that contain the isotopes and / or other isotopes of other atoms are within the scope of the present invention. The incorporation of certain isotopically-labeled compounds of the invention, such as ³ H and ¹⁴ C, with ground radioactive isotopes, is useful for drug and / or matrix tissue distribution assays. Tritium, ie ³ H and carbon-14, ie ¹⁴ C isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, i.e. ² H, has several therapeutic advantages due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore is desirable in some cases. Do. Isotopically labeled compounds of Formula 1 and prodrugs thereof of the present invention are generally prepared by the following schemes and / or examples and preparations by replacing readily obtainable isotopically labeled reagents with non-isotopically labeled reagents. It can be prepared by performing the disclosed procedure.
[238] The present invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula 1 and methods of treating bacterial infections via prodrug administration of compounds of formula 1. Compounds of formula (I) having free amino, amido, hydroxy or carboxyl groups can be converted to prodrugs. Prodrugs include compounds in which the amino acid residue, or polypeptide chains of two or more (eg, 2, 3 or 4) amino acid residues are bound to the free amino, hydroxy or carboxylic acid groups of the compound of formula 1 via amide or ester linkages. . Amino acid residues include, but are not limited to, 20 natural amino acids typically represented by the three-letter symbol, and also 4-hydroxyproline, hydroxylicin, democin, isodemosin, 3-methylhistidine, norvaline, beta -Alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amido or alkyl esters. Free hydroxy groups include groups including, but not limited to, hemisuccinate, phosphate esters, dimethylaminoacetate and phosphoryloxymethyloxycarbonyl as outlined in Advanced Drug Delivery Reviews , 1996 , 19 , 115 Can be derivatized. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Acyl groups may be alkyl esters optionally substituted with groups including but not limited to ether, amine and carboxylic acid functional groups, or of hydroxy groups as (acyloxy) methyl and (acyloxy) ethyl ether, wherein the acyl group is the amino acid ester Derivatization is also included. Prodrugs of this type are described in J. Med. Chem. 1996 , 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of the prodrug moieties may comprise groups including but not limited to ether, amine and carboxylic acid functional groups.
[239]
[1] The present invention relates to novel bicyclic derivatives useful for the treatment of abnormal cell growth in mammals, such as cancer. The invention also relates to methods of using said compounds in the treatment of abnormal cell growth in mammals, in particular humans, and pharmaceutical compositions containing said compounds.
[240] General synthetic methods that may be referenced to prepare compounds of the present invention are described in U.S. Patent No. 5,747,498, issued May 5, 1998, U.S. Patent Application 08/953078, filed Oct. 17, 1997, WO 98/02434 published 22 January 1998, WO 98/02438 published 22 January 1998, WO 96/40142 published 19 December 1996, WO 96 / 09294 (published March 6, 1996), WO 97/03069 (published January 30, 1997), WO 95/19774 (published July 27, 1995) and WO 97/13771 Issue, published April 17, 1997. Additional procedures are mentioned in US Patent Application Serial Nos. 09 / 488,350 (filed Jan. 20, 2000) and 09 / 488,378 (filed Jan. 20, 2000). The above patents and patent applications are incorporated herein by reference in their entirety. Certain starting materials may be prepared according to methods familiar to those skilled in the art and certain synthetic modifications may be made according to methods familiar to those skilled in the art. Standard procedures for preparing 6-iodoquinazolinone are described 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. in Acc. Chem. Res. 1995, 28, 2]. For examples of palladium catalyzed coupling of terminal alkynes to aryl halides, see: Castro et. al. J. Org. Chem. 1963, 28, 3136. or Sonogashira et. al. Synthesis, 1977, 777. Terminal alkyne synthesis can be carried out using suitably substituted / protected aldehydes as described in: 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.
[241] Alternatively terminal alkynes can be prepared by a two step procedure. First, the lithium anion of TMS (trimethylsilyl) acetylene is described by Nakatani, K. et. al. Tetrahedron, 49, 9, 1993, 1901, to appropriately substituted / protected aldehydes. Later, Malacria, M .; Tetrahedron, 33, 1977, 2813; Or in White, J. D. et. al. Tet. Left., 31, 1, 1990, 59, may be used to isolate the intermediate terminal alkyne by deprotection with base.
[242] Starting materials for which the synthetic method is not specifically described above may be commercially available or may be prepared using methods known to those skilled in the art.
[243] In each of the reactions discussed or illustrated in the above schemes, the pressure is not critical unless otherwise indicated. Pressures from about 0.5 atm to about 5 atm are generally acceptable, and ambient pressure, ie, about 1 atm, is preferred for convenience.
[244] With reference to Scheme 1 above, the compound of formula 1 may be prepared by adding a compound of formula D, wherein R ⁴ and R ⁵ are as defined above, in anhydrous solvents, in particular DMF (N, N-dimethylformamide), DME ( A compound of formula E for a period of 1 to 48 hours at a temperature of about 50 to 150 ° C. in a solvent selected from ethylene glycol dimethyl ether), DCE (dichloroethane) and t-butanol, and phenol, or a mixture of said solvents R ¹ , R ³ and R ¹¹ are as defined above). Heteroaryloxyanilines of formula E can be prepared by methods known to those skilled in the art, such as by reduction of the corresponding nitro intermediates. Reduction of aromatic nitro groups is described by Brown, RK, Nelson, NAJ Org. Chem. 1954, p. 5149; Yuste, R., Saldana, M, Walls, F., Tet. Lett. 1982, 23, 2, p. 147; Or by the method outlined in WO 96/09294. Suitable heteroaryloxy nitrobenzene derivatives are described in Dinsmore, CJ et. al., Bioorg. Med. Chem. Left., 7, 10, 1997, 1345; Loupy, A. et. al., Synth. Commun., 20, 18, 1990, 2855; Or Brunelle, DJ, Tet. Lett., 25, 32, 1984, 3383, can be prepared by nucleophilic substitution of halides with a suitable alcohol from halo nitrobenzene precursors. Compounds of formula E, wherein R ¹ is a C ₁ -C ₆ alkyl group, can be prepared by reductive amination of the parent aniline with R ¹ CH (O). The compound of formula D is a compound of formula C wherein Z ¹ is an activating group such as bromo, iodo, -N ₂ or -OTf (which is -OSO ₂ CF ₃ ), or a precursor of the activating group such as NO ₂ , NH ₂ or OH) can be prepared by treating with a coupling partner such as terminal alkyne, terminal alkene, vinyl halide, vinyl stannane, vinylborane, alkyl borane or alkyl or alkenyl zinc reagent. The compound of formula C is prepared by reacting the compound of formula B with a chlorinating agent such as POCl ₃ , SOCl ₂ or ClC (O) C (O) Cl / DMF in a halogenated solvent at a temperature of about 60 ° C. to 150 ° C. for about 2 to 24 hours. By treatment for a period of time. Compounds of formula B may be prepared according to one or more procedures described in WO 95/19774 cited above from compounds of formula A wherein Z ¹ is as above and Z ² is NH ₂ , C ₁ -C ₆ alkoxy or OH. Can be prepared accordingly.
[245] Any compound of formula 1 may be converted to another compound of formula 1 by standard manipulation for the R ⁴ group. Such methods are known to those skilled in the art and a) protecting groups by methods outlined in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991. Removal of; b) transfer of leaving groups (halides, mesylates, tosylates, etc.) to the primary or secondary amines to form secondary or tertiary amines, thioethers or ethers, respectively; c) Thavonekham, B et. al. Synthesis (1997), 10 , p1189], treating phenyl (or substituted phenyl) carbamate with primary or secondary amines to form the corresponding urea; d) Denmark, SE; Jones, TKJ Org. Chem. (1982) 47, 4595-4597 or van Benthem, RATM; Michels, JJ; Propargyl or homopropargyl alcohol or N-BOC protection by treatment with sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) such as Speckamp, WN Synlett (1994), 368-370] Reduced primary amines to the corresponding E-allylic or E-holyaryl derivatives; e) Tomassy, B. et. al. Synth. Commun. (1998), 28, p1201] reduction of alkyne to the corresponding Z-alkene derivatives by treatment with hydrogen gas and a Pd catalyst; f) treating primary and secondary amines with isocyanates, acid chlorides (or other activated carboxylic acid derivatives), alkyl / aryl chloroformates or sulfonyl chlorides to obtain the corresponding ureas, amides, carbamates or sulfonamides; g) reductive amination of primary or secondary amines with R ¹ CH (O); And h) treating the alcohol with isocyanates, acid chlorides (or other activated carboxylic acid derivatives), alkyl / aryl chloroformates or sulfonyl chlorides to obtain the corresponding carbamate, ester, carbonate or sulfonic acid esters.
[246] Compounds of the invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into individual diastereomers on the basis of their physicochemical differences by methods known to those skilled in the art, such as by chromatography or fractional crystallization. Enantiomers convert a diastereomer mixture into a diastereomeric mixture by reacting the enantiomeric mixture with a suitable optically active compound such as an alcohol, separating the diastereomers and converting the individual diastereomers into the corresponding pure enantiomers (e.g., Hydrolysis). All such isomers, including individual diastereomeric mixtures and pure enantiomers, are contemplated as part of the present invention.
[247] Compounds of formula 1 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although the salts must be pharmaceutically acceptable for administration to animals, in practice, the compounds of formula (I) are initially freed from the reaction mixture as pharmaceutically unacceptable salts and then simply treated with an alkaline agent. It is often desirable to convert back to the base compound and then to convert the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of base compounds of the present invention are readily prepared by treating the base compound with an substantially equal amount of selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding the appropriate inorganic or organic acid to the solution.
[248] Compounds of formula 1 that are acidic in nature are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular the sodium and potassium salts. All the salts are prepared by conventional techniques. The chemical base used as a reagent to prepare the pharmaceutically acceptable base salt of the present invention is to form a nontoxic base salt with the acidic compound of formula (1). The non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium and magnesium. The salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation followed by evaporation to dryness of the resulting solution, preferably under reduced pressure. Alternatively, the salt may be prepared by mixing the lower alkanol solution of the acidic compound with the desired alkali metal alkoxide and then evaporating to dryness the resulting solution in the same manner as above. In both cases, stoichiometric amounts of reagent are preferably used to ensure completion of the reaction and maximum yield of the desired final product. Since a single compound of the present invention may contain one or more acidic or basic residues, the compounds of the present invention may include mono-, di or tri-salts in a single compound.
[249] The compounds of the present invention are potential inhibitors of the erbB family of tumorigenic and prototypogenic protein tyrosine kinases, in particular erbB2, and thus both mammalian, in particular human, for therapeutic use as antiproliferative agents (eg anticancer agents). Is adapted. In particular, the compounds of the present invention can be used in the liver, kidney, bladder, breast, stomach, ovary, rectal colon, prostate, pancreas, lung, vulva, thyroid, hepatic carcinoma, sarcoma, glioblastoma, malignant and benign tumors of the head and neck. It is useful in the prevention and treatment of human hyperproliferative disorders and other proliferative conditions such as benign hyperproliferation of the skin (eg psoriasis) and benign proliferation of the prostate (eg BPH). In addition, the compounds of the present invention may have activity against a wide range of leukemias and lymphocyte malignancies.
[250] In addition, the compounds of the present invention may be useful for the treatment of additional disorders involving aberrant expression ligand / receptor interactions or activation or signaling events associated with multiple protein tyrosine kinases. Such disorders may include neurons, glia, astrocytes, hypothalamus, and other gland, macrophage, epithelial, epilepsy, and blastocyst properties to which aberrant function, expression, activation or signaling of erbB tyrosine kinase is involved . In addition, the compounds of the present invention may have therapeutic utility in inflammation, angiogenesis and immunological disorders associated with both identified and yet unidentified tyrosine kinases inhibited by the compounds of the present invention.
[251] The ex vivo activity of the compound of formula 1 can be determined by the following procedure.
[252] The c-erbB2 kinase assay has previously been described in Schrang et. al. Anal. Biochem. 211,1993, p233-239. Nunc MaxiSorp 96-well plates were prepared from 0.25 mg / mL Poly (Glu, Tyr) 4: 1 (PGT) (Sigma Chemical Co., St. Louis, MO) in PBS (phosphate buffered saline). Coat by incubating overnight at 37 ° C. with 100 mL / well. The expression PGT is removed by aspiration and the plates are washed three times with wash buffer (0.1% Tween 20 in PBS). Kinase reactions were performed at 50 mM HEPES pH 7.5 containing 125 mM sodium chloride, 10 mM magnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP, 0.48 mg / mL (24 ng / well) c-erbB2 intracellular region. in mL. The intracellular region of erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GST fusion protein in baculovirus and bound and eluted to glutathione coated beads. Compounds in DMSO (dimethylsulfoxide) are added to bring the final DMSO concentration to about 2.5%. ATP (adenosine triacid) is added to initiate phosphorylation and run for 6 minutes with constant shaking at room temperature. The kinase reaction is terminated by aspirating the reaction mixture followed by washing with wash buffer (see above). 50 mL / well HRP-conjugated PY54 (Oncogene Science Inc., Uniondale, NY) diluted to 0.2 mg / mL in blocking buffer (3% BSA and 0.05% Tween 20 in PBS) ) Phosphorylated PGT is measured by incubation with antiphosphotyrosine antibody for 25 minutes. The antibody is removed by aspiration and the plate is washed four times with wash buffer. Colorimetric signal is expressed by the addition of 50 mL / well of TMB Microwell Peroxidase Substrate (Kirkegaard and Perry, Gaithersburg, Md.) And 0.09M sulfuric acid 50 mL / well It is stopped by the addition of wells. Phosphotyrosine is evaluated by measurement of absorbance at 450 nm. The control signal is typically 0.6-1.2 absorbance units with essentially no background in wells without a PGT substrate and is proportional to the incubation time for 10 minutes. Inhibitors were identified by a decrease in signal to wells without inhibitors, and determined IC ₅₀ values corresponding to the concentration of compound required for 50% inhibition. Compounds exemplified herein corresponding to compounds of Formula 1 have IC ₅₀ values of less than 10 μM for erbB2 kinase.
[253] In vivo activity of the compound of formula 1 can be determined by the amount of inhibition of tumor growth by the test compound against the control. The tumor growth inhibitory effects of various compounds are described in Corbett TH, et al., "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure", Cancer Res., 35, 2434 -2439 (1975) and Corbett TH, et al., "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2) ", 5, 169-186 (1975)]. Tumors were cultured from 1 million to 5 million log phases suspended in 0.1 ml RPMI 1640 medium. Induced in the left flank by subcutaneous (sc) injection of tumor cells (muran FRE-ErbB2 cells or human SK-OV3 ovarian carcinoma cells) Tumors are facilitated (diameter of 100 to 150 mm ³ / diameter of 5 to 6 mm) After a sufficient time to become), the test animals (females without thymus) are combined with the test compound (concentration of 10-15 mg / ml in 5 Gelucire) once or twice a day 7-10 Treatment is by intraperitoneal (ip) or oral (po) route administration for consecutive days of days.To determine anti-tumor effects, Geran, RI, et al. "Protocols for Screening Chemical Agents and Natural Products Against" Animal Tumors and Other Biological Systems ", Third Edition, Cancer Chemother. Rep., 3, 1-104 (1972)] according to the method of Both measured with vernier (Vernier) Caliper in millimeters in two diameters and the tumor size (mm ³⁾ is a formula: computes using the tumor size (mm ³⁾ = (length × [width] ²⁾ / 2. Results are expressed as% inhibition according to the formula:% inhibition = (TuW _control- TuW _test ) / TuW _control x 100% The flank position of tumor transplantation provides a reproducible dose / response effect for various chemotherapeutic agents. The measurement (tumor diameter) method is a reliable method for obtaining tumor growth rate.
[254] Administration of the compounds of the present invention (hereinafter referred to as “active compound (s)”) can be carried out by a method that allows for delivery of the compound to the site of action. The methods include oral route, duodenal route, extra-intestinal injection (including intravenous, subcutaneous, intramuscular, intraarterial, or infusion), local, and rectal administration.
[255] The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of a predetermined physician. However, effective dosages are about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, it is in an amount of about 0.05 to about 7 g / day, preferably about 0.2 to about 2.5 g / day. In some cases, the dosage level is preferably below the lower limit of the range, but in other cases 1 Much larger doses can be used without causing any detrimental side effects, as long as they are first divided into several smaller doses for the administration over a day.
[256] The active compound may be used alone or as one or more other anti-tumor substances, for example mitosis inhibitors such as vinblastine; Alkylating agents such as cis-platin, carboplatin and cyclophosphamide; Anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or for example N- (5- [N- (3,4-dihydro-2-methyl-4- One of the preferred anti-metabolites disclosed in European Patent Application No. 239362, such as oxoquinazolin-6-ylmethyl) -N-methylamino] -2-tenoyl) -L-glutamic acid; Growth factor inhibitors; Cell cycle inhibitors; Septal antibiotics such as adriamycin and bleomycin; Enzymes such as interferon; And anti-hormones, for example anti-estrogens such as Nolvadex ^™ (tamoxifen), or for example Casodex ^™ (4′-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2 And -androgens such as -methyl-3 '-(trifluoromethyl) propionanilide). The combined treatment can be achieved by simultaneous, continuous, or separate administration of the individual components of the treatment.
[257] Pharmaceutical compositions may be, for example, in forms suitable for oral administration such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, or forms suitable for extracorporeal injection, such as sterile solutions, suspensions or emulsions, topical such as ointments or creams. It may be in a form suitable for administration or in a form suitable for rectal administration such as suppositories. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise administration. Weak compositions include conventional pharmaceutical carriers or excipients and compounds of the present invention as active ingredients. It may also include other medical or pharmaceutical reagents, carriers, adjuvants and the like.
[258] Exemplary extra enteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. The dosage form can be suitably buffered if desired.
[259] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical composition may, if desired, contain additional ingredients such as seasonings, binders, excipients, and the like. Thus for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrating agents such as starch, alginic acid and certain complex silicates and binders such as sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and activity are often useful for tablet applications. Solid compositions of a similar type can also be used in soft and hard filled gelatin capsules. Preferred materials therefor include lactose or lactose and high molecular weight polyethylene glycols. If aqueous suspensions or elixirs are desired for oral administration, the active compounds may be formulated with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying or suspending agents with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof. Can be combined together.
[260] Methods of preparing various pharmaceutical compositions having specific amounts of active compounds will be known or apparent to those skilled in the art. See, eg, Remington's Pharmaceutical Sciences , Mack Publishing Company, Easter, Pa., 15th Edition (1975).
[261] The following examples and preparations further illustrate the compounds of the present invention and methods of making the compounds. It is understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the examples below, molecules with a single chiral center are present as racemic mixtures unless otherwise indicated. Molecules having two or more chiral centers exist as racemic mixtures of diastereomers unless otherwise indicated. Single enantiomers / diastereomers may be obtained by methods known to those skilled in the art.
[262] When HPLC chromatography is referred to in the following preparations and examples, the general conditions used are as follows unless otherwise indicated. The column used is a ZORBAX ^™ RXC18 column (Hewlett Packard) with a 150 mm distance and a 4.6 mm inner diameter. Samples flow on a Hewlett Packard-1100 system. The gradient solvent method is used with a flow from 100% ammonium acetate / acetic acid buffer (0.2M) to 100% acetonitrile over 10 minutes. The system then proceeds with 100% acetonitrile for 1.5 minutes on the wash cycle followed by buffer solution for 3 minutes. The flow rate over this period is a constant 3 mL / minute.
[263] In the following examples and preparations, "Et" means ethyl, "AC" means acetyl, "Me" means methyl, "ETOAC" or "ETOAc" means ethyl acetate, " THF "means tetrahydrofuran and" Bu "means butyl.
[264] Method A: Synthesis of [3-methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine (1):
[265] 4- (4-Chloro-quinazolin-6-ylethynyl) -piperidine-1-carboxylic acid tert-butyl ester:
[266] 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol) in anhydrous THF (20 mL), 4-chloro-6-iodoquinazoline (1.35 g, 4.65 mmol), dichloro A mixture of bis (triphenylphosphine) palladium (II) (0.16 g, 0.23 mmol), copper (I) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) was prepared at room temperature. Stirred under nitrogen for 2 h. After concentration, the residue was dissolved in CH ₂ Cl ₂ (100 mL), washed with aqueous NH ₄ Cl and brine, dried over sodium sulphate and concentrated to give the crude product as a brown oil. Purification by silica gel column using 20% EtOAc in hexanes gave 1.63 g (94%) of the title compound as a yellowish yellow oil: ¹ H NMR (CDCl ₃ ) δ 1.45 (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).
[267] [3-Methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine:
[268] 4- (4-Chloro-quinazolin-6-ylethynyl) -piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.21 mmol) and 3-methyl-4- (pyridin-3-yloxy) -Phenylamine (43 mg, 0.21 mmol) was mixed in tert-butanol (1 mL) and dichloroethane (1 mL) and heated in a sealed glass jar at 90 ° C. for 20 minutes. The reaction was cooled and bubbled through HCl (gas) for 5 minutes. Then EtOAC was added and a yellow precipitate occurred. 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)- The amine was obtained as a yellow solid (96 mg, 95%). ¹ H NMR (CDCl ₃ ) δ 2.01 ((m, 2H), 2.22 (m, 2H), 2.35 (s, 3H), 3.20 (m, 2H), 3.45 (m, 2H), 7.28 (d, 1H , J = 8.7 Hz), 7.75 (dd, 3H, J1 = 8.7, J2 = 8.7 Hz), 8.06 (dd, J = 8.7), 8.10 (dd, J1 = J2 = 8.7 Hz); 8.17 (m, 1H) , 8.60 (d, 1H, J = 54 Hz), 8.80 (s, 1H), 8.89 (s, 1H) .MS: M + 1, 436.6.
[269] Method B: 2-Chloro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) Synthesis of Acetamide (2):
[270] 2-Chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide:
[271] 2-chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 equiv) were dried with THF and diisopropylamine (296 mg 0.41 mL; 1 equivalent). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd (PPh ₃ ) ₂ Cl ₂ (82 mg). The reaction was stirred at room temperature overnight under nitrogen atmosphere (about 20 hours). The solvent was then removed in vacuo and the residue dissolved in CH ₂ Cl ₂ . This solution was transferred to a separatory funnel and washed with 1 × saturated NH ₄ Cl, brine, dried over Na ₂ SO ₄ and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1: 1 hexanes / EtOAc and collecting the fragments with Rf = 0.25. 2-Chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide was obtained as a greyish white solid (454 mg; 53%). ¹ H NMR (400 MHz; CDCl ₃ ) δ 4.12 (2H, s), 4.40 (2H, d, J = 5.2 Hz), 7.91-7.93 (1H, dd, J = 2, 6.8 Hz), 8.00 (1H, d, J = 8.4 Hz), 8.34 (1H, d, J = 1.6 Hz), 9.03 (1H, s). lrms (M ⁺ ): 294.0, 296.0, 298.1.
[272] 2-Chloro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamide :
[273] ^t 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide (0.90 g, 3.05 mmol) in BuOH / DCE (5.0 / 5.0 mL) And a mixture of 3-methyl-4- (pyridin-3-yloxy) -phenylamine (0.61 g, 3.05 mmol) was refluxed under nitrogen for 40 minutes and concentrated. The residue was dissolved in MeOH (2.0 mL) and added to EtOAc with vigorous stirring to precipitate the HCl salt product as a tan solid which was collected by vacuum-filtration, rinsed with EtOAc and further dried to give 2-chloro-N- (3 Obtain 1.24 g (82%) of-{4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamide ¹ H NMR (CD ₃ 0D) δ 2.27 (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.
[274] Method C: 2-dimethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino j-quinazolin-6-yl} -prop-2- Synthesis of Inyl) -acetamide (3):
[275] 2-dimethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amides:
[276] 2-Chloro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop- in MeOH (5 mL) To a solution of 2-ynyl) -acetamide (99 mg, 0.20 mmol) was added a solution of dimethylamine (2 mL, 4.0 mmol) in THF. The resulting solution was refluxed under nitrogen for 1 hour. After concentration, the residue was further dried, dissolved in MeOH (1.0 mL) and treated with HCl gas for 3 hours. The resulting solution was added to EtOAc with vigorous stirring to precipitate the HCl salt product as a yellow solid which was collected by vacuum filtration, rinsed with EtOAc and further dried to give 110 mg (99%) of the title compound. ¹ H NMR (CD30D) δ 2.30 (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, 1 H), 8.84 (s, 1 H); MS m / z (MH ⁺ ) 467.3.
[277] Method D: 1- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) Synthesis of 3-Methyl-urea (4):
[278] 1- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Methyl-urea:
[279] (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl prepared by Method B A mixture of) -carbamic acid phenyl ester (0.1 g, 0.18 mmol), methyl amine (2.OM methanol solution, 1 mL, 2 mmol) and DMSO (0.5 mL) was stirred at 80 ° C. overnight. The solvent was removed under vacuum (GeneVac HT-8) and the residue was redissolved in MeOH (about 1 mL). HCl gas was bubbled through the solution and EtOAc to precipitate the desired product. The title compound (80 mg, 90% yield) was obtained by filtration as a yellow solid. ¹ H NMR (400 MHz, CD ₃ 0D) δ 2.72 (3H, s), 2.76 (3H, s), 4.19 (2H, s), 7.49 (1H, d, J = 9 Hz), 7.84 (1H, d, J = 2 Hz), 7.86 (1H, d, J = 2 Hz), 7.92 (1H, d, J = 9 Hz), 8.12 (2H, m, J = 2 Hz), 8.16 (1H, d, J = 2.4 Hz), 8.60 (1H, d, J = 3.2 Hz), 8.74 (1H, d, J = 1.2 Hz), 8.87 (1H, s). LRMS (M ⁺ ): 473.0, 475.0, 476.0.
[280] Method E: 3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-en-1-ol (5) synthesis:
[281] 3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-en-1-ol:
[282] 3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-yn-1-ol in 6 mL of dry tetrahydrofuran (Prepared by Method B) A 65 wt% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (Red-AI, 2.35 mmol) in 1 mL of THF at 0 ° C. in 0.56 g (1.47 mmol) solution. 0.73 mL was added. The reaction was stirred at rt for 3 h. After recooling to 0 ° C., 0.73 mL of a Red-Al solution in 1 mL of additional THF was added. After stirring for 1 hour at room temperature, the mixture was quenched by dropwise addition of 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate, filtered and evaporated to give 650 mg. Chromatography on 90 g silica gel eluting with 96: 4: 0.1 chloroform / methanol / condensed ammonium hydroxide gave 268 mg of the title compound. ¹ H NMR (d ₆ DMSO): δ 9.79 (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 = 8.7 Hz, 1), 6.77 (d, J = 16.2 Hz, 1), 6.67 (m, 1), 5.04 (t, J = 5.6 Hz, 1 ), 4.23 (m, 2), 2.23 (s, 3).
[283] Method F: [3-Methyl-4- (pyridin-3-yloxy) -phenyl]-[6- (3-morpholin-4-yl-propenyl) -quinazolin-4-yl] -amine (6 Synthesis of):
[284] [3-Methyl-4- (pyridin-3-yloxy) -phenyl]-[6- (3-morpholin-4-yl-propenyl) -quinazolin-4-yl] -amine:
[285] 3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ene in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride To a suspension of 0.035 g (0.091 mmol) of -1-ol was added 1 mL of thionyl chloride. The reaction was heated at 100 ° C. for 1 hour and the solvent was evaporated to [6- (3-chloro-propenyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy)- Phenyl] -amine [MS: M ⁺ 403.1] was obtained and dissolved in THF and used directly in the next reaction. 0.10 mL of morpholine and triethyl in a solution of [6- (3-chloro-propenyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amine 0.044 mL of amine was added. The mixture was heated at 85 ° C. for 16 h, cooled to rt and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were evaporated to dryness to yield 57 mg of material. The product was purified on silica gel prep plate eluting with 96: 4: 0.1 chloroform / methanol / conc. Ammonium hydroxide to give 26 mg of the title compound; ¹ H NMR (CDCl ₃ ): δ 8.71 (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 = 8.7 Hz, 1), 6.68 (d, J = 15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26 (m, 2), 2.63 (m, 4), 2.25 (s, 3).
[286] Method G: EN- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamide (7 Synthesis of):
[287] E- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -carbamic acid tert-butyl ester:
[288] To 7.53 mL of a 65 wt% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al, 24.2 mmol) in 90 mL tetrahydrofuran at 0 ° C. (3- {4- [3-chloro- 5.0 g of 4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tent-butyl ester was added as a solid. The reaction was stirred at 0 ° C. for 2 h, quenched with 10% aqueous potassium carbonate and extracted with ethyl acetate. The combined organics were dried and evaporated. The crude was purified on 115 g silica gel eluting with 80% ethyl acetate / hexanes to afford E- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino 4.42 g of] -quinazolin-6-yl} -allyl) -carbamic acid tert-butyl ester were obtained. ¹ H NMR (CDCl ₃ ): δ 8.66 (s, 1), 8.24 (m, 1), 8.03 (m, 2), 7.77-7.65 (m, 3), 7.13 (m, 2), 6.97 (d, J = 8.7 Hz, 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).
[289] E- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine.
[290] E- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -ca in 21 mL tetrahydrofuran To a solution of 4.42 g of chest acid tert-butyl ester was added 21 mL of 2N hydrochloric acid. The mixture was heated at 60 ° C. for 3 h, cooled to rt and basified with 10% aqueous potassium carbonate. Methylene chloride was added to the aqueous mixture to precipitate a solid. The solid was filtered and dried to afford E- [6- (3-amino-propenyl) -quinazolin-4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl] 2.98 g of amine were obtained. ¹ H NMR (d ₆ DMSO): δ 8.62 (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).
[291] E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamide.
[292] A mixture of 14.4 μL (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol) of dicyclohexylcarbodiimide in 2 mL of methylene chloride was stirred for 10 minutes and E- [6- (3-amino-propenyl) -quinazolin- 4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine was treated with 100.3 mg. The reaction was stirred at rt overnight. The precipitate formed was filtered and chromatographed eluting with 6-10% methanol / chloroform to give 106 mg of the title compound; mp 254-256 ° C; ¹ H NMR (d ₆ DMSO): δ 9.88 (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 = 8.7 Hz, 1), 7.24 (m, 2), 7.19 (d, J = 8.7 Hz, 1), 6.61 (d, J = 16.2 Hz, 1), 6.48 (m, 1 ), 3.90 (m, 2).
[293] Method H: E--2S-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]- Quinazolin-6-yl} -allyl) -amide (8):
[294] E- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] in 1 mL of dichloromethane To a stirred solution of 0.125 g (0.31 mmol) of amine (prepared according to Method G) was added 60.3 μL (0.34 mmol) of Hunig's base at 0 ° C., followed by 4-chlorophenyl chloroformate in 1 mL of dichloromethane. 48.2 μL (0.34 mmol) of the solution was added dropwise. The reaction was stirred for 30 minutes and evaporated under reduced pressure. The residue was dissolved in 2 mL of dimethyl sulfoxide and 123 μL (0.94 mmol) of (S)-(±) -2- (methoxymethyl) -pyrrolidine was added neat. The reaction was stirred at rt for 3 h. 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 sulphate and reduced to afford crude material. This material was purified on 90 g silica gel using 96: 4: 0.1 chloroform: methanol: ammonium hydroxide as eluent to yield 75 mg (0.14 mmol) of the title compound. ¹ H NMR (ds DMSO): δ 9.83 (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).
[295] Method I: E-2-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3 yloxy) -phenylamino] -quinazolin-6-yl} -allyl ) -Isobutyramide (8):
[296] E- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] in 1 mL of dichloromethane To a solution of 0.170 g (0.42 mmol) of amine (prepared according to Method G) was added 65 μL (0.47 mmol) of triethylamine at 0 ° C., followed by 65 μL (0.45 mmol of 2-acetoxyisobutyryl chloride in 1 mL of dichloromethane) ) Solution was added. The reaction was stirred at 0 ° C for 1 h. The mixture was quenched by dropwise addition of 10% potassium carbonate. The aqueous layer was extracted with dichloromethane and the combined organics were washed with brine, dried over sodium sulfate and evaporated. The crude material was purified on 90 g silica gel eluting with 96: 4: 0.1 chloroform / methanol / ammonium hydroxide to give 2-acetoxy-N- (3- {4- [3-methyl-4- (6-methyl-) Pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -isobutyramide was obtained. A solution of this material in 2 mL of methanol was treated by dropwise addition of a solution of 41 mg (3.02 mmol) of potassium carbonate in 0.5 mL of water. The solution was stirred at rt for 1 h. The reaction was evaporated and the residue partitioned between water and chloroform. The aqueous layer was extracted twice with chloroform and the combined organics were washed with brine, dried over sodium sulfate and evaporated to give 100 mg (47%) of the title compound. ¹ H NMR (d ₆ DMSO): δ 9.78 (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.
[297] Method J: Z-cyclopropanecarboxylic acid (3- (4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amide Synthesis of
[298] Z- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine:
[299] (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert- A solution of butyl ester (1 g, 2.01 mmol) was dissolved in methanol (20 ml), palladium in carbon (50 mg) was added and the resulting suspension was hydrogenated at 40 psi for 8 hours. The suspension was then filtered through a pad of celite and the filtrate was concentrated in vacuo to afford a Z-alkene compound. It was dissolved in methanol and HCl (g) was added. The solvent was then evaporated to Z- [6- (3-amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]- The amine was obtained as its hydrochloride salt. The salt was dissolved in CH ₂ Cl ₂ , stirred with Na ₂ CO ₃ , filtered and the solvent was evaporated to yield about 700 mg of free amine.
[300] ¹ H NMR (CD ₃ 0D): δ 8.49 (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 = 10.5 Hz, 1H), 7.25 (m, 2H), 6.99 (m, 2H), 5.88 (m, 1H), 3.95 (d, J = 8 Hz, 2H), 2.47 (s, 3H), 2.23 (s, 3H). MS: M + 1, 399.3
[301] Z-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amide
[302] Z- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine (100 mg, 0.25 mmol) was dissolved in DMF (3 ml), HATU (143 mg, 0.38 mmol) and cyclopropane carboxylic acid (36 mg, 0.42 mmol) were added and the resulting solution was stirred for 18 hours. Water was then added, the reaction mixture was extracted with methylene chloride and the organic extracts were washed with brine and dried over Na ₂ S0 ₄ . After concentration in vacuo, the crude material was purified on preparative HPLC (reverse phase, 5-40% CH ₃ CN-H ₂ 0) to give 46 mg of the title compound. ¹ H NMR (CD ₃ OD): 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 = 10 Hz, 1H), 6.76 (d, J = 13 Hz, 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 + 1 466.3.
[303] The following examples were prepared using this method.
[304] Example NumberdesignationWayLRMSHPLCRT 10(±)-[3-methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA436.04.48 111- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Cyclopropyl-ureaD499.05.74 12N- (3- {7-chloro-4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -AcetamideB492.06.07 13N- (3- {7-chloro-4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -AcetamideB472.25.79 14Exo-6-hydroxymethyl-3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy)- Phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideD555.05.19 151- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- (2-fluoro-ethyl) -ureaD505.05.65 161- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- (2-hydroxy-ethyl) -ureaD503.04.98 173- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-ylethynyl} -piperidin-3-olA452.04.01
[305] Example NumberdesignationWayLRMSHPLCRT 182- (2-hydroxy-ethylsulfanyl) -N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -acetamideC500.04.87 19N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- (2-hydr Roxy-ethylsulfanyl) -acetamideC520.05.15 20(±)-[3-methyl-4- (pyridin-3-yloxy) -phenyl]-(6-morpholin-2-ylethynyl-quinazolin-4-yl) -amineA438.04.29 212-cyano-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetyl amidesB448.95.18 22N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -butyramideB452.05.61 23Pentanoic acid (3- (4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB466.06.02 242-methoxy-N- (3- (4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetyl amidesB454.05.24 25N- (4- (4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -acetamideB438.15.11 26[6- (4-Amino-but-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amineA396.14.04 27N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methylsulfanyl- AcetamideB470.25.50 283- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-yn-1-olB383.04.97
[306] Example NumberdesignationWayLRMSHPLCRT 29[6- (3-Methoxy-prop-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amineB397.36.23 304- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-yn-1-olB397.15.17 312-Methyl-4- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-yn-2-olB411.05.62 32(3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid methyl esterB440.35.61 33N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -methanesulfonamideB460.05.38 34N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB424.14.94 35[3-methoxy-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA452.04.10 362-Chloro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB458.05.52 372-Methylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesC453.14.08 382-dimethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesC467.34.15 39(±)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-[4- (pyridin-3-yloxy) -phenyl] -amineA422.14.13
[307] Example NumberdesignationWayLRMSHPLCRT 40[3-methoxy-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4- quinazolin-4-yl) -amineA452.14.11 41[3-Chloro-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA456.14.57 42[3-Fluoro-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA440.14.38 43(6-piperidin-4-ylethynyl-quinazolin-4-yl)-[4- (pyridin-3-yloxy) -phenyl] -amineA422.14.11 442-methoxy-N- (3- {4- [3-methoxy-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- AcetamideB470.34.87 45N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methoxy-acet amidesB474.25.48 46N- (3- {4- [3-fluoro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methoxy- AcetamideB458.35.23 47[3-Methyl-4- (pyridin-2-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA436.04.52 482,2-dimethyl-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- PropionamideA452.35.60 49N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -isobutyramideB466.36.01 50{6- [3- (2-methoxy-ethoxy) -prop-1-ynyl] -quinazolin-4-yl}-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -AmineB441.16.11 512-diethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- AcetamideC495.14.45
[308] Example NumberdesignationWayLRMSHPLCRT 52(±)-[3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA450.04.47 53[3-Methyl-4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA450.04.39 542-methoxy-N- (3- {4- [3-methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB468.05.33 552- (2-methoxy-ethoxy) -N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop 2-ynyl) -acetamideB498.35.34 56(±) -tetrahydro-furan-2-carboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -amideB480.05.45 57(±) -4,4-dimethyl-5- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -oxazolidine-2 -OnB466.05.70 58{6- [4- (2-methoxy-ethoxy) -but-1-ynyl] -quinazolin-4-yl}-[3-methyl-4- (pyridin-3-yloxy) -phenyl]- AmineB455.36.23 594- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -piperidin-4-olA452.03.82 601-Methyl-4- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -piperidin-4-olB466.14.03 61(±)-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA450.04.52
[309] Example NumberdesignationWayLRMSHPLCRT 62[3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA450.04.49 632-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB468.85.38 64[6- (4-Methoxy-but-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amineB411.26.30 65(±)-[4- (2-Chloro-pyridin-3-yloxy) -3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA470.04.89 66Cyclopropanecarboxylic acid (4- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -amideB464.35.63 67[4- (2-Chloro-pyridin-3-yloxy) -3-methyl-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA470.04.86 68N- (3- {4- [4- (2-Chloro-pyridin-3-yloxy) -3-methyl-phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Methoxy-acetamideB488.05.84 69N- (4- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -2-methylsulfanyl-acet amidesB484.25.64 70[3-Chloro-4- (pyridin-3-yloxy) -phenyl]-[6- (4-methoxy-but-1-ynyl) -quinazolin-4-yl] -amineB431.16.67 71(±) -4- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-yn-1,2-diolA413: 14.31 72(±)-[3-methyl-4- (pyridin-4-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA434.13.88
[310] Example NumberdesignationWayLRMSHPLCRT 73[3-Methyl-4- (pyridin-4-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA436.13.91 742-methoxy-N- (3- {4- [3-methyl-4- (pyridin-4-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesB452.0-4.71 752,2-difluoro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -AcetamideB460.25.63 76N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2,2-difluoro Rho-acetamideB482.2,480.15.92 77R-pyrrolidine-2-carboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amidesA479.14.22 78(±) -tetrahydro-furan-3-carboxylic acid (3- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -amideB500.05.39 79Cyclopropanecarboxylic acid (4- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -amideB484.05.92 80N- (4- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -2-methylsulfanyl-acet amidesB505.45.91 811- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3-phenyl-ureaD501.16.17 821-cyclohexyl-3- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -ureaD507.26.24 831- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3-cyclohexyl-ureaD528.16.49
[311] Example NumberdesignationWayLRMSHPLCRT 842-hydroxy-N- (4- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -but-3-ynyl) -acetamideA454.24.78 85E-3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-en-1-olE385.14.71 86E- [3-Methyl-4- (pyridin-3-yloxy) -phenyl]-[6- (3-morpholin-4-yl-propenyl) -quinazolin-4-yl] -amineF454.14.14 872-methanesulfonyl-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- AcetamideB502.05.00 88N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methanesulfonyl- AcetamideB522.05.28 89(3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -thiocarbamic acid S-methyl esterB456.26.02 90(3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -thiocarbamic acid S-methyl esterB476.16.29 91[4- (2-Methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA436.14.24 92(±)-[4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA436.04.85 93N- (3- {4- [4- (2-Methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB424.14.85 94N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-yl} -prop-2-ynyl) -2-oxo-propionamideB452.15.64
[312] Example NumberdesignationWayLRMSHPLCRT 95N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-oxo-propionamideB474.3,472.35.93 96N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -malanoic acid ethyl esterB496.25.56 97N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -malanoic acid ethyl esterB516.05.84 98N- (1,1-dimethyl-3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- 2,2,2-trifluoro-acetamideB506.06.76 99(±) -N- (1-hydroxymethyl-3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB454.14.47 100(±)-[3-ethynyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA446.14.33 101[3-Ethynyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA446.14.27 1023- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-yn-1-olB403.15.43 103(±) -N- (1-hydroxymethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -acetamideB468.14.66 104(±) -N- (3- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -1-hydroxymethyl-prop-2 -Inyl) -acetamideB474.04.78 1052,2-Difluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop 2-ynyl) -acetamideB474.25.83
[313] Example NumberdesignationWayLRMSHPLCRT 1062-Methanesulfonyl-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB516.05.20 1072-Fluoro-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesB441.85.27 108N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-fluoro-acet amidesB461.95.55 1092-Fluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB456.25.47 110N- (3- {4- [3-ethynyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methoxy- AcetamideB464.15.16 1112-methoxy-N- (3- {4- [4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesB454.25.15 112[4- (2-Chloro-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA456.14.64 113(±)-[4- (2-Chloro-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA456.04.67 114N- (3- {4- [4- (2-Chloro-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methoxy-acet amidesB474.05.54 115N- (3- {4- [4- (2-Chloro-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB444.05.25 116N- (3- {4- [3-ethynyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB434.14.88
[314] Example NumberdesignationWayLRMSHPLCRT 1171- (2-Chloro-ethyl) -3- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -ureaD487.25.46 118(±)-[3-fluoro-4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA454.14.57 119[3-Fluoro-4- (2-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA454.14.56 120N- (3- {4- [3-Fluoro-4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesB442.15.19 121N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB458.05.48 122[3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA470.04.78 123(±)-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA470.04.80 124Acetic acid 3- (4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl esterB425.16.34 1253- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-yn-1-olB397.25.31 126Acetic acid 3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl esterB439.16.57 127Acetic acid 3- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl esterB445.16.66
[315] Example NumberdesignationWayLRMSHPLCRT 1282-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideA454.24.81 129N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB438.05.20 130R-pyrrolidine-2-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop- 2-ynyl) -amideA493.04.42 1312- (2-hydroxy-ethylsulfanyl) -N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6- Japanese} -prop-2-ynyl) -acetamideC513.95.07 132(±) -2-methanesulfinyl-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -acetamideB499.94.71 133(3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -thiocarbamic acid S -Methyl esterB469.96.25 134(±) -tetrahydro-furan-3-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -amideB494.05.31 135N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Oxo-propionamideB465.95.87 136N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -malanoic acid Ethyl esterB510.05.77 137(6-piperidin-4-ylethynyl-quinazolin-4-yl)-[4- (pyridin-2-yloxy) -phenyl] -amineA422.23.48
[316] Example NumberdesignationWayLRMSHPLCRT 138(±)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-[4- (pyridin-2-yloxy) -phenyl] -amineA422.23.51 139N- (3- {4- [4- (Pyridin-2-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB410.13.81 1402-Methylamino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideC467.04.26 1412-dimethylamino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideC481.04.26 142(±) -N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -1-hydroxymethyl- Prop-2-ynyl) -acetamideB488.04.99 143N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Dimethylamino-AcetamideC501.04.83 144N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Methoxy-acetamideB-488.05.79 145N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Fluoro-acetamideB476.05.79 146N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2, 2-difluoro-acetamideB494.06.14 147E-3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-en-1-olE405.15.04 1482-methoxy-N- (3- {4- [4- (pyridin-2-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB440.84.05 1491-ethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -UreaD467.25.36
[317] Example NumberdesignationWayLRMSHPLCRT 1501- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3-ethyl-ureaD473.25.45 1511-ethyl-3- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -ureaD453.15.16 1521- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Ethyl-ureaD487.15.60 153(±) -2-hydroxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -propionamideA454.14.79 154N- (3- {4- [3-Methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Oxo-propionamideB466.15.85 155N- (3- {4- [3-Methyl-4- (2-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acetamideB438.15.18 156(±) -2-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -propionamideA468.04.98 157(±) -N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -2-hydroxypropionamideA488.05.32 158N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- (4-Methyl-piperazin-1-yl) -acetamideC536.24.46 1592- [bis- (2-methoxy-ethyl) -amino] -N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quina Zolin-6-yl} -prop-2-ynyl) -acetamideC569.15.93
[318] Example NumberdesignationWayLRMSHPLCRT 1602- (2-hydroxy-ethylamino) -N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop 2-ynyl) -acetamideC483.04.11 161N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-dimethylamino-acet amidesC487.04.65 162N- (3- {4- [3-Chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-methylamino-acet amidesC473.04.42 163N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Methylamino-acetamideC487.14.60 164N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Hydroxy-acetamide-A474.05.13 1651- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Isopropyl-ureaD501.85.98 1661-isopropyl-3- (3- [4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -ureaD481.05.69 167Morpholin-4-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD509.15.27 168N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Morpholin-4-yl-acetamideC543.35.64 169N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Morpholin-4-yl-acetamideC522.85.37 170[6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineA396.34.05
[319] Example NumberdesignationWayLRMSHPLCRT 171E- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineG398.23.87 172E- [6- (3-Amino-propenyl) -quinazolin-4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineG418.04.26 1732-hydroxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -isopart TyramideA468.15.04 1742-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -isobutyramideA482.15.24 175N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Hydroxy-isobutyramideA502.0,504.05.55 176[6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineA416.24.25 177N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- (2,2,2-trifluoro-ethylamino) -acetamideC535.35.99 1781,1-dimethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -ureaD467.35.36 1793- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -1, 1-diethyl-ureaD515.06.32 1803- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -1, 1-dimethyl-ureaD487.15.70
[320] Example NumberdesignationWayLRMSHPLCRT 181E-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamideG440.34.74 182E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- AcetamideG470.15.05 183Morpholin-4-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD529.05.58 184Pyrrolidine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -amideD513.06.00 1851- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Methyl-ureaD473.05.37 1861- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- Profile-UreaD501.06.03 1871-tert-butyl-3- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -ureaD515.06.56 1882S-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -propionamideB468.04.95 1891- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- (2,2,2-trifluoro-ethyl) -ureaD540.76.19 190(±) -azetidine-2-carboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesA465.24.21 191(±) -azetidine-2-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-ynyl) -amideA479.34.41
[321] Example NumberdesignationWayLRMSHPLCRT 192(±) -azetidine-2-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-ynyl) -amideA499.34.70 1931-Hydroxy-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -amideB480.05.20 194N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -propionamideB452.15.55 195N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -butyr amidesB466.15.88 196N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -isobutyr amidesB466.15.88 1972-Ethoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB482.15.89 198N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Methylsulfanyl-acetamideB484.05.76 199Cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amide -B464.15.76 200Cyclobutanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB478.16.07
[322] Example NumberdesignationWayLRMSHPLCRT 201[6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amineA382.14.02 202Isoxazole-5-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesB491.05.78 203N-Methyl-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -AcetamideB452.55.79 2042-methoxy-N- (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -acetamideB481.95.86 205N- (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB466.25.82 2062R-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -propionamideB468.04.95 207E-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG466.15.41 208E-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -propionamideG454.15.07 209E-2-ethoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- AcetamideG484.05.54 210E- (±) -2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -Allyl) -propionamideG484.15.45
[323] Example NumberdesignationWayLRMSHPLCRT 211E-2-fluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- AcetamideG458.15.48 2122-methoxy-N- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclobutyl) AcetamideB508.06.17 213N- (1- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclobutyl) -acetamideB478.05.90 214E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-fluoro-acetamideG478.05.55 215E-cyclopropanecarboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG485.75.77 216[6- (1-Amino-cyclobutylethynyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineA436.04.87 217(±) -2-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4 (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6 -Yl} -prop-2-ynyl) -amideD537.16.13 218Piperazine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD508.14.28 2193- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -1- Ethyl-1- (2-hydroxy-ethyl) -ureaD531.05.41 220[6- (1-Amino-cyclopropylethynyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amineA422.15.11 221E-3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-en-1-olE399.24.93
[324] Example NumberdesignationWayLRMSHPLCRT 222N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- (2-methoxy-ethoxy) -acetamideB532.05.86 223N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Oxo-propionamideB486.06.17 224N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- (2-hydroxy-ethylsulfanyl) -acetamideC534.05.57 225N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Methylsulfanyl-acetamideB504.06.04 226Pyrrolidine-2R-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -amideA513.44.86 227Pyrrolidine-2R-carboxylic acid (3- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideA499.04.45 228(±) -2-methanesulfinyl-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB486.14.52 229(±) -2-methanesulfinyl-N- (3- {4- [3-chloro-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB506.04.81 230(±) -tetrahydro-furan-3-carboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -amideB480.15.11 2312-hydroxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesA440.34.60
[325] Example NumberdesignationWayLRMSHPLCRT 2322-Ethoxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amidesB467.95.62 233[3-Methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA436.64.35 234Cyclobutanecarboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB464.05.78 235Cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB450.05.44 236[3-Methyl-4- (pyridin-2-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA436.04.64 237(6-Azetidin-3-ylethynyl-quinazolin-4-yl)-[3-methyl-4- (pyridin-3-yloxy) -phenyl] -amineA407.94.10 238N- (1,1-dimethyl-3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- 2-methoxy-acetamideB481.95.96 2392- [4- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -piperazine- 1-yl] -ethanolA495.44.10 240(±) -2-methoxy-N- (1-methyl-3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -acetamideB467.95.57 241[3-Methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3R-ylethynyl-quinazolin-4-yl) -amineA436.04.48 242[3-Methyl-4- (pyridin-3-yloxy) -phenyl]-(6-piperidin-3S-ylethynyl-quinazolin-4-yl) -amineA436.04.48
[326] Example NumberdesignationWayLRMSHPLCRT 243(±)-[3-methyl-4- (pyridin-3-yloxy) -phenyl]-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl) -amineA422.04.30
[327] Example NumberdesignationWayLRMSHPLCRT 2441- (2-Methoxy-ethyl) -1-methyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -ureaD511.15.61 245(±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -amideD523.15.19 246(±) -3-hydroxy-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6 -Yl} -prop-2-ynyl) -amideD509.14.75 247Cis- 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) -amideD521.16.38,6.28 2481-isobutyl-1-methyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro Ph-2-inyl) -ureaD509.16.45 249N- (1- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclopropyl) -acetamideB464.05.46 2502-methoxy-N- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclopropyl) AcetamideB5.76493.7
[328] Example NumberdesignationWayLRMSHPLCRT 251E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -propionamideG474.05.53 252E-N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-methoxy-propionamideG504.05.67 253E-N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-methoxy-acetamideG489.75.52 254E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-ethoxy-acetamideG504.05.89 255(3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert- Butyl-esterB496.37.11 2562- (R) -hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -propionamideB468.05.04 257Cyclobutanecarboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB498.0,500.06.36 258N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -propionamideB472.0,474.05.86 259Cyclopropanecarboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideB484.0, 486.06.06
[329] Example NumberdesignationWayLRMSHPLCRT 260N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -isobutyr amidesB486.1,488.16.17 261(±) -N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -2-methoxy-propionamideB502.0,504.06.00 262(±) -2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro P-2-ynyl) -propionamideB482.15.73 2635-Oxo-pyrrolidine-2R-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro Ph-2-ynyl) -amideB507.14.73 264E-1-hydroxycyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amidesI482.04.65 265E-2S-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- PropionamideI470.14.56 266E-2R-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- PropionamideI470.14.60 267E-2-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- AcetamideI456.14.51 2681-cyanomethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -ureaD478.15.26
[330] Example NumberdesignationWayLRMSHPLCRT 2691-cyclobutyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -ureaD492.85.90 2701,1,3-trimethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop 2-inyl) -ureaD481.16.30 2711- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -1, 3,3-trimethyl-ureaD501.16.52 2721-ethyl-1- (2-hydroxy-ethyl) -3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -ureaD511.15.20 273(±) -3-dimethylamino-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6 -Yl} -prop-2-ynyl) -amideD536.14.40 274Morpholin-4-carboxylic acid (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-ynyl) -amideD523.45.58 275Exo-6-amino-3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl Amino] -quinazolin-6-yl} -prop-2-ynyl) -amideD520.94.28 276Exo-6-hydroxymethyl-3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -Phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -amideD535.14.98
[331] Example NumberdesignationWayLRMSHPLCRT 277(3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -ureaD439.84.81 278E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-hydroxy-acetamideI476.04.86 279Piperazine-1-carboxylic acid (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -amideD536.14.74 2801- (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Ynyl) -3-ethyl-ureaD495.36.11 281Morpholin-4-carboxylic acid (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -amideD537.36.02 2821,3-Dimethyl-1- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -ureaD467.15.51 283N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -1,1-dimethyl-prop-2 -Ynyl) -2-hydroxy-acetamideB5.02,5.045.74 284N- (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Ynyl) -2-hydroxy-acetamideB482.25.46 285E-1,1-diethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl ) -UreaH497.15.72
[332] Example NumberdesignationWayLRMSHPLCRT 286E-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- amidesH495.15.40 287E-1-ethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -ureaH469.14.80 288E-morpholine-4-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideH511.14.75 289(±) -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) -ureaD525.15.51 290(±) -1-ethyl-3- (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Prop-2-ynyl) -ureaD481.15.68 2914-Methyl-piperazin-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-ynyl) -amideD522.34.44 292N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2- Cyano-acetamideB483.15.73 2932-cyano-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB463.15.44 294EN- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-methylsulfanyl-acet amidesG486.35.33
[333] Example NumberdesignationWayLRMSHPLCRT 295E-5-oxo-tetrahydro-furan-2R-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Allyl) -amideG510.25.58 296E-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -methanesulfonamideG476.05.36 297(±) -5- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -morpholin-3-oneB466.15.22 298E-N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2S-hydroxy-propionamideI490.15.06 299E-1-hydroxycyclopropanecarboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amidesI502.25.24 300EN- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-hydroxy-isobutyr amidesI504.25.24 301(±) -EN- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-hydro Roxy-propionamideI490.05.07 3022R-amino-N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -PropionamideA487.14.54 3032R-amino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -PropionamideA467.24.35
[334] Example NumberdesignationWayLRMSHPLCRT 304(±) -4- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -oxazolidin-2-one 452.25.40 305(±) -E-3,3,3-trifluoro-2-hydroxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl Amino] -quinazolin-6-yl} -allyl) -propionamideI524.15.52 306(±) -E-2-hydroxy-3-methyl-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -allyl) -butyramideI498.25.49 307(±) -2-methoxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -amideD557.16.42 308(±) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin- 6-yl} -prop-2-ynyl) -amideD543.25.61 309(±) -1- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -3- (1,2-dimethyl-propyl) -ureaD529.26.87 310(±) -1- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -3- (1,1-dimethyl-propyl) -ureaD529.26.89 311(±) -1- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -3- (1-hydroxymethyl-propyl) -ureaD531.15.41 3121- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -3- (1-ethyl-propyl) -ureaD529.16.63
[335] Example NumberdesignationWayLRMSHPLCRT 313(±) -1-sec-butyl-3- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -ureaD515.16.32 314(±) -1- (1,1-dimethyl-propyl) -3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazoline -6-yl} -prop-2-ynyl) -ureaD509.26.60 315(±) -1- (1-hydroxymethyl-propyl) -3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazoline -6-yl} -prop-2-ynyl) -ureaD511.25.13 3161- (1-ethyl-propyl) -3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -ureaD509.36.35 317(±) -1-sec-butyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -ureaD495.36.07 318Azetidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD479.25.46 3191- (1,2-Dimethyl-propyl) -3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Prop-2-ynyl) -ureaD509.26.36 320Piperidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -amideD507.36.21 321E-pyridine-2-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG503.36.11
[336] Example NumberdesignationWayLRMSHPLCRT 322E-2-isopropoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) AcetamideG498.35.94 323E-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -benzenesulfonamideG538.16.51 324E-ethanesulfonic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG490.35.62 325E-1H-imidazole-4-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amidesG492.35.53 326E-isoxazole-5-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG493.25.41 327E-pyrrolidine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- amidesH515.25.77 328E-morpholine-4-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideH531.15.20 329EN- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-methylsulfanyl-acet amidesG506.15.81 330E-5-Oxo-tetrahydro-furan-2R-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Allyl) -amideG530.25.44
[337] Example NumberdesignationWayLRMSHPLCRT 331EN- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-cyclopropylmethoxy- AcetamideG530.26.34 332(±) -EN- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-hydro Roxy-3-methyl-butyramideI518.25.73 333E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -methanesulfonamideG496.15.72 334E-2R-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6- Il} -allyl) -amideH525.24.91 335E-2S-hydroxymethyl-pyrrolidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6- Il} -allyl) -amideH525.24.92 336E-2-cyclopropylmethoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl ) -AcetamideG510.36.00 337E-1-isopropyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- UreaH483.25.33 338Azetidine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD499.25.73 339Piperazine-1-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl )-amidesD528.24.65
[338] Example NumberdesignationWayLRMSHPLCRT 3402-methoxy-N- (3- {7-methoxy-4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}- Prop-2-ynyl) -acetamideB498.25.47 341N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -7-methoxy-quinazolin-6-yl} -prop-2- Inyl) -2-methoxy-acetamideB518.25.76 3423- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -1- (2-methoxy-ethyl) -1-methyl-ureaD531.25.92 343N- (3- {7-methoxy-4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB468.25.21 344N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -7-methoxy-quinazolin-6-yl} -prop-2- Inyl) -acetamideB488.25.50 3451,1-Diisopropyl-3- (3- {7-methoxy-4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6- Il} -prop-2-ynyl) -ureaD553.36.79 346(±) -2-methyl-piperidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6- Yl-prop-2-ynyl) -amideD521.36.53 347E-azetidine-2S-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG481.34.10 348E-1-amino-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- amidesG481.34.40
[339] Example NumberdesignationWayLRMSHPLCRT 349E-2-Amino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -isopart TyramideG483.34.12 350E-5-oxo-pyrrolidine-2R-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -Allyl) -amideG509.24.45 351E-2R-amino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -propion amidesG469.34.09 352E-2S-amino-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -propion amidesG469.34.09 353E-5-oxo-pyrrolidine-2R-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -Allyl) -amideG509.24.42 354E-isoxazole-5-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amide -G513.05.86 355E-3- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -1,1-di Ethyl-ureaH517.26.11 356E-pyridine-2-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG523.16.47 357N- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -methanesulfone amidesB474.25.66
[340] Example NumberdesignationWayLRMSHPLCRT 358N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -methanesulfone amidesB494.15.93
[341] Example NumberdesignationWaymassspecRT 359Z-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideJ466.34.65 360Z-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamideJ440.35.56 361Z-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -isobutyramideJ468.36.75 3623- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid methyl esterB454.35.93 363(3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid methyl esterB474.2,476.26.20 3643- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl esterB517.37.34 365E- (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -carbamic acid tert-butyl esterG498.27.01 3663-Methyl-pyridine-2-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- amidesG517.26.39 367E-N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -benzenesulfonamideG558.26.83
[342] 3682-Fluoro-N- (3- {4- [3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB457.24.92 369[3-Methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl) -amineA451.54.09 3702-methoxy-N- (3- {4- [3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Inyl) -acetamideB469.34.86 371E-2-methoxy-N- (3- {4- [3-methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) AcetamideG471.34.71 3722-methoxy-N- (3- {4- [3-methyl-4- (pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl)- AcetamideB455.44.79 373N- (3- {4- [3-Methyl-4- (pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -isobutyramideB453.15.16 3743-Methyl-isoxazole-5-carboxylic acid (3- {4- [3-methyl-4- (pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -amide-B492.15.27 375N- (3- {4- [3-Methyl-4- (pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -methanesulfonamideB461.14.92 376(±)-[3-methyl-4- (pyrimidin-5-yloxy) -phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl) -amineA437.24.016 3772-methoxy-N-methyl-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -acetamideB468.35.52 378E-N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamideG426.25.02
[343] 379E-2-methoxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -acetamideG456.25.27 380E- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -carbamic acid methyl esterG442.35.60 381E-N- (3- {4- [3-Methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -methanesulfonamideG462.05.29 382E-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG452.25.48 383E-pyridine-2-carboxylic acid (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amideG489.16.15 384E-1-ethyl-3- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -ureaH455.35.16
[344] Methods A to J and suitable starting materials (prepared according to methodologies known in the art) can be used to prepare the following compounds and pharmaceutically acceptable salts, solvates and prodrugs thereof which are part of the present invention:
[345] Z-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- Acetamide
[346] E-2- (2-Fluoro-ethoxy) -N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6 -Yl} -allyl) -acetamide
[347] Z-N- (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -2-fluoro-acetamide
[348] 2-hydroxy-N- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclopropyl) Acetamide
[349] E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl)- Isobutyrylamide
[350] 1-ethyl-3- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} -cyclopropyl)- Urea
[351] 1-ethyl-3- [1- (2- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -ethyl)- Cyclopropyl] -urea
[352] 3-methoxy-azetidine-1-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro Ph-2-ynyl) -amide
[353] N- (3- (7- (2-methoxy-ethoxy) -4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Prop-2-ynyl) -acetamide
[354] E-1-methoxy-cyclopropanecarboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amides
[355] N- (3- {4- [3-Methyl-4- (2-methyl-pyrimidin-5-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -acet amides
[356] (±) -E-1- (2-fluoro-ethyl) -3- (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl Amino] -quinazolin-6-yl} -allyl) -urea
[357] EN- [1- (2- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -vinyl) -cyclopropyl]- Methanesulfonamide
[358] (±) -E-tetrahydro-furan-3-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Allyl) -amide
[359] E-morpholine-4-carboxylic acid (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -allyl) -amide
[360] N- [1- (2- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -ethyl) -cyclopropyl]- Methanesulfonamide
[361] (±) -E-tetrahydro-furan-2-carboxylic acid (3- {4- [3-chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl } -Allyl) -amide
[362] (±) -ethanesulfonic acid (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -pro Ph-2-ynyl) -amide
[363] (±) -pyridine-2-carboxylic acid (1-methyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -Prop-2-ynyl) -amide

权利要求:
Claims (21)
[1" claim-type="Currently amended] A compound of Formula 1, a pharmaceutically acceptable salt, solvate or prodrug thereof:
Formula 1

Where
m is an integer from 0 to 3;
p is an integer from 0 to 4;
Each of R ¹ and R ² is independently selected from H and C ₁ -C ₆ alkyl;
R ³ is — (CR ¹ R ² ) _t (4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, wherein the heterocyclic group is optionally fused to a benzene ring or a C ₅ -C ₈ cycloalkyl group , Wherein the-(CR ¹ R ² ) _t -moiety of the R ³ group optionally comprises a carbon-carbon double bond or a triple bond, wherein t is an integer from 2 to 5 and comprises the above-mentioned optional fused ring Said R ³ groups are optionally substituted with 1 to 5 R ⁸ groups;
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _t R ⁹ ,-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , -(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ ,-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k -R ¹³ , or-( and CR ¹⁶ R ¹⁷⁾ _t R ^9, provided herein is the point of attachment to the R ⁹ is through a carbon atom of the R ⁹ group, each k is an integer from 1 to 3, each t is an integer from 0 to 5, Each m is an integer from 0 to 3;
R ⁵ is halo, hydroxy, -NR ¹ R ² , C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ -C ₆ alkoxy, trifluoromethoxy, -NR ⁶ C (O) R ¹ ,- C (O) NR ⁶ R ⁷ , -S0 ₂ NR ⁶ R ⁷ , -NR ⁶ C (O) NR ⁷ R ¹ , and -NR ⁶ C (O) OR ⁷ ;
R ⁶ , R ^6a and R ⁷ are each H, C ₁ -C ₆ alkyl,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl), and-(CR ¹ R ² ) _t (4-10 membered) Heterocyclic), wherein t is an integer from 0 to 5, wherein one or two ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (= 0) moiety and wherein the R ⁶ and R ⁷ groups Alkyl, aryl and heterocyclic moieties of halo, cyano, nitro, -NR ¹ R ² , trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C _2- Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkynyl, hydroxy, and C ₁ -C ₆ alkoxy; or
R ⁶ and R ⁷ , or R ^6a and R ⁷ , when attached to the same nitrogen atom, are selected from N, N (R ¹ ), O and S in addition to the nitrogen to which R ⁶ , R ^6a and R ⁷ are attached thereto; May include 1 to 3 additional hetero moieties, but two O atoms, two S atoms or O and S atoms may together form a 4 to 10 membered heterocyclic ring that is not directly attached to each other;
R ⁸ is oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₁₀ alkyl, C _2- C ₆ alkenyl, C ₂ -C ₆ alkynyl, -C (O) R ⁶ , -C (O) OR ⁶ , -OC (O) R ⁶ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ NR ⁷ R ¹ , -NR ⁶ C (O) NR ¹ R ⁷ , -NR ⁶ C (O) OR ⁷ , -C (O) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ 0R ⁷ , -SO ₂ NR ⁶ R ⁷ , -S (O) _j (C ₁ -C ₆ alkyl), where j is an integer from 0 to 2,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl) ,-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic),-(CR ¹ R ² ) _q C (O) (CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl),-(CR ¹ R ² ) _q C (O) (CR ¹ R ² ) _t (4-10 membered heterocyclic),-(CR ¹ R ² ) _t O (CR ¹ R ² ) _q (C ₆ -C ₁₀ aryl),- (CR ¹ R ² ) _t O (CR ¹ R ² ) _q (4 to 10 membered heterocyclic),-(CR ¹ R ² ) _q S (O) _j (CR ¹ R ² ) _t (C ₆ -C ₁₀ Aryl), and-(CR ¹ R ² ) _q S (O) _j (CR ¹ R ² ) _t (4-10 membered heterocyclic) (where j is 0, 1 or 2, and q and t are each independent) Is an integer of 0 to 5) And one or two ring carbon atoms of the heterocyclic moiety of the R ⁸ group are optionally substituted with an oxo (═O) moiety and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the R ⁸ group Halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ , -OC (O) R ⁶ , -NR ⁶ C (O) R ⁷ , -C (O) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ 0R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Independently from alkynyl,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl), and-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic), where t is an integer from 0 to 5 Optionally substituted with one to three substituents selected;
R ⁹ is a non-aromatic monocyclic ring, fused or bridged bicyclic ring, or spirocyclic ring, wherein the ring contains 3 to 12 carbon atoms, wherein 0 to 3 carbon atoms are N, 0, S ( O) j (where j is an integer from 0 to 2) and -NR ¹ -optionally substituted with a hetero residue independently selected from two O atoms, two S (O) _j residues, an O atom and S (O ) _j moieties, N and S atoms, or N and O atoms are not directly attached to each other in the ring, and the carbon atoms of the ring are optionally substituted with 1 or 2 R ⁸ groups;
R ¹¹ is independently selected from substituents defined in R ⁸ , except oxo (═O);
R ¹² is R ⁶ , -OR ⁶ , -OC (O) R ⁶ , -OC (O) NR ⁶ R ⁷ , -OCO ₂ R ⁶ , -S (O) _j R ⁶ , -S (O) _j NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ C (O) NR ^6a R ⁷ , -NR ⁶ S0 ₂ NR ^6a R ⁷ , -NR ⁶ CO ₂ R ⁷ , CN, -C (O) R ⁶ , or halo, wherein j is an integer from 0 to 2;
R ¹³ is —NR ¹ R ¹⁴ or —OR ¹⁴ ;
R ¹⁴ is H, R ¹⁵ , -C (O) R ¹⁵ , -S0 ₂ R ¹⁵ , -C (O) NR ¹⁵ R ⁷ , -SO ₂ NR ¹⁵ R ⁷ , or -C0 ₂ R ¹⁵ ;
R ¹⁵ is R ¹⁸ ,-(CR ¹ R ² ) _t (C ₆ -C ₁₀ aryl),-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic), where t is an integer from 0 to 5 , One or two ring carbon atoms of the heterocyclic group are optionally substituted with oxo (═O) residues, and the aryl and heterocyclic residues of the R ¹⁵ groups are optionally substituted with one to three R ⁸ substituents;
R ¹⁶ and R ¹⁷ are each independently selected from H, C ₁ -C ₆ alkyl and —CH ₂ OH, or R ¹⁶ and R ¹⁷ together are —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — ;
R ¹⁸ is C ₁ -C ₆ alkyl but each carbon which is not bonded to an N or O atom, or S (O) _j , where j is an integer from 0 to 2, is optionally substituted with R ¹² ;
Any such substituent comprising a CH ₃ (methyl), CH ₂ (methylene), or CH (methine) group not attached to a halogeno, SO or SO ₂ group or to an N, O or S atom may be hydroxy, halo, C Optionally substituted with _1- C ₄ alkyl, C ₁ -C ₄ alkoxy and —NR ¹ R ² .
[2" claim-type="Currently amended] The method of claim 1,
R ³ is-(CR ¹ R ² ) _t (4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5; Wherein said heterocyclic group is optionally fused to a benzene ring or a C ₅ -C ₈ cycloalkyl group, wherein said R ³ group comprising said optional fused ring is optionally substituted with 1 to 3 R ⁸ groups.
[3" claim-type="Currently amended] The method of claim 1,
R ³ is — (CR ¹ R ² ) _t (4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, and the R ³ group is optionally substituted with 1 to 3 R ⁸ groups.
[4" claim-type="Currently amended] The method of claim 1,
R ³ is selected from:

Wherein the R ³ groups are optionally substituted with 1 to 3 R ⁸ groups.
[5" claim-type="Currently amended] The method of claim 1,
R ³ is pyridin-3-yl optionally substituted with one to three R ⁸ groups.
[6" claim-type="Currently amended] The method of claim 1,
Structural moiety of the compound of formula 1 A compound selected from the group consisting 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) -phenylamine
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" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _t R ⁹ , wherein m is an integer from 0 to 3 and t is an integer from 0 to 5;
[8" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _t R ⁹ , wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and R ⁹ is Compound selected from 3-piperidinyl and 4-piperidinyl, each substituted with one or two R ⁸ groups.
[9" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , wherein m is an integer from 0 to 3 and t is an integer from 0 to 5;
[10" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _t -R ⁹ , where m is an integer from 0 to 3 and t is an integer from 0 to 5, wherein R ⁹ is selected from 3-piperidinyl and 4-piperidinyl, optionally substituted with 1 to 2 R ⁸ groups.
[11" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is an integer from 0 to 3.
[12" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is an integer from 0 to 3, wherein R ¹³ is -NR ¹ R ¹⁴ , wherein R ¹⁴ is selected from -C (O) R ¹⁵ , -S0 ₂ R ^15, and C (O) NR ¹⁵ R ⁷ .
[13" claim-type="Currently amended] The method of claim 1,
R ⁴ is — (CR ¹⁶ R ¹⁷ ) _m —C═C— (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is an integer from 0 to 3. 3.
[14" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ , wherein k is an integer from 1 to 3 and m is an integer from 0 to 3, wherein R ¹³ is -NR ¹ R ¹⁴ , wherein R ¹⁴ is selected from -C (O) R ¹⁵ , -S0 ₂ R ^15, and -C (O) NR ¹⁵ R ⁷ .
[15" claim-type="Currently amended] The method of claim 1,
R ⁴ is-(CR ¹⁶ R ¹⁷ ) _m -C≡C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ or-(CR ¹⁶ R ¹⁷ ) _m -C = C- (CR ¹⁶ R ¹⁷ ) _k R ¹³ where k is an integer from 1 to 3 and m is an integer from 0 to 3), R ¹³ is -NR ¹ R ¹⁴ or -OR ¹⁴ , R ¹⁴ is R ¹⁵ , R ¹⁵ is R ¹⁸ , and R ¹⁸ is -OR ⁶ , -S (O) _j R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C (O) R ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ CO ₂ R ⁷ , CN, -C ( O) R ⁶ or C ₁ -C ₆ alkyl optionally substituted with halo.
[16" claim-type="Currently amended] The method of claim 1,
Compounds selected from the group consisting of: and pharmaceutically acceptable salts, prodrugs and solvates thereof:
(±)-[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) -acet amides
(±)-[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- Inyl) -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- Inyl) -acetamide;
2-Fluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) -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;
EN- (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 )-amides;
(±) -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) -acet amides;
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; and
1- (1,1-dimethyl-3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 -Ynyl) -3-ethyl-urea.
[17" claim-type="Currently amended] A method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of the compound of claim 1 effective to treat abnormal cell growth.
[18" claim-type="Currently amended] The method of claim 17,
The abnormal cell growth is cancer.
[19" claim-type="Currently amended] The method of claim 18,
The cancer may be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin 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, endometrium Carcinoma, cervical carcinoma, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or Acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal carcinoma, tumor of central nervous system (CNS), primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, or one of the above cancers The method selected from the above combinations.
[20" claim-type="Currently amended] The mammal has a compound of claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to treat abnormal cell growth. Mitosis inhibitors, alkylating agents, anti-metabolites, septal antibiotics, growth factor inhibitors, cells Mammalian, comprising administration with an anti-tumor agent selected from the group consisting of cycle inhibitors, enzymes, tooisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones and anti-androgens Method of treating abnormal cell growth.
[21" claim-type="Currently amended] A pharmaceutical composition for the treatment of abnormal cell growth in a mammal, comprising an amount of the compound of claim 1 effective to treat abnormal cell growth, and a pharmaceutically acceptable carrier.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-06-22|Priority to US21313600P

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2000-06-22|Priority to US60/213,136

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2001-06-14|Application filed by 화이자 프로덕츠 인코포레이티드

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2001-06-14|Priority to PCT/IB2001/001046

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2003-02-26|Publication of KR20030016303A

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2006-01-25|Application granted

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2006-01-25|Publication of KR100545537B1

优先权:

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申请号 | 申请日 | 专利标题

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US21313600P| true| 2000-06-22|2000-06-22|

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US60/213,136|2000-06-22|

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PCT/IB2001/001046|WO2001098277A2|2000-06-22|2001-06-14|Substituted bicyclic derivatives for the treatment of abnormal cell growth|