Title of Invention

SUBSTITUTED BICYCLIC COMPOUNDS OF FORMULA I

Abstract The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and solvates thereof, wherein A,X,R1,R3 and R4 are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals with administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compound of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
8B
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"SUBSTITUTED BICYCLIC COMPOUNDS OF FORMULA I"
PFIZER PRODUCTS, INC., a corporation organized under the laws of the State of Connecticut, United States of America, of Eastern Point Road, Groton, Connecticut 06340, United States of America,
The following specification particularly describes the invention and the manner in which it is to be performed:


5 (SUBSTITUTED BICYCLIC-eERIVATIVEST USEFUL AS ANTlCANCER7reEttf§ Background of the Invention
This invention relates to nove-bieyelic derivatives-that-are usefulln the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially
10 humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (ij., a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic
15 tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such-as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to
20 phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. 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 common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor
25 receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a
30 tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular
35 cancer, in mammals. In addition to receptor tyrosine kianses, the compounds of the present invention can also display inhibitory activity against a variety of other non-receptor tyrosine kinases (eg: Ick, src, abl) or serine/threonine kinases (e.g.: cyclin dependent kinases).
Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently, five European patent publications,
40 namely 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), refer to certain bicyclic derivatives,
2

5 in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996),
10 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), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose.
Summary of the Invention
15 The present invention relates to compounds of the formula 1

and to pharmaceutical^ acceptable salts and solvates thereof, wherein: X is N or CH;

wherein said group is optionally substituted with 1 to 3 R6 groups;
A represents a fused 5, 6 or 7-membered ring optionally containing 1 to 4 20 heteroatoms which may be the same or different and which are selected from -N(R1)-, O, and S(0)j, wherein j is an integer from 0 to 2, the fused ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused wherein the R1 group attached to the nitrogen is absent if a double bond includes the foregoing optional nitrogen moiety -N(R1)-, with the proviso that the fused ring does not form part of a purine and 25 that the fused ring does not contain two adjacent O or S(0)j atoms, and wherein the carbon atoms of the A moiety are optionally substituted with 1 to 3 R5 groups; each R1 and R2 is independently H or CrC6 alkyl; R3 is -(CR1R2)m-R8 wherein m is 0 or 1; or R1 and R3 are taken together to form a group of the formula

5 R4 is -(CR1R2)m-C=C-(CR1R2),R9, -C-(CR1R2)rR9, -C=NOR12, or -X1-R12
wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and X1 is a divalent group derived
from azetidine, oxetane or a C3-C4 carbocyclic group; r
or R4 is -(CR1R2)m-CsC-(CR1R2)kR13 or -(CR1R2)m-C=C-(CR1Ra)kR13 wherein k is an integer from 1 to 3 and m is an integer from 0 to 3;
10 or R4 is -(CR1R2)tR9, wherein t is an integer from 0 to 5 and the attachment point to R9 is
through a carbon atom of the R9 group;
each R6 is independently selected from halo, hydroxy, -NR1R2, Ci-C6 alkyl, trifiuoromethyi, C,-C6 alkoxy, trifluoromethoxy, -C(0)R6, -C02R6, -NR6C(0)R1, -C(0)NR6R7, -S02NR6R7, -NR6C(0)NR7R1, and -NR6C(0)OR7;
15 each R6 and R7 is independently selected from H, C1C6 alkyl, -(CR1R2),(C6-Ci0 aryl),
and -(CR1R2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (=0) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR1R2,
20 trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and CrC6 alkoxy;
R8 is independently selected from -(CR1R2MC6-C10 aryl) and -(CR1R2),(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (=0) moiety, and each of the
25 foregoing R8 groups is optionally substituted with 1 to 5 R10 groups;
R9 is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(0)j wherein j is an integer from 0 to 2, and -NR12-, provided that two O atoms, two S(0)j moieties, an O
30 atom and a S(0)j moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 to 2 R11 groups;
^. each R10 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, d-C6 alkoxy, C1C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
35 -C(0)R6, -C(0)OR6, -OC(0)R6, -NR6C(0)R7, -NR8CONRV, -NR6C(0)OR7, -C(0)NR6R7, -NR6R7, -NR6OR7, -S02NR6R7, -S(O)d-C6 alkyl) wherein j is an integer from 0 to 2, -(CR1R2),(C6-Cio aryl), -(CR1R2),(4-10 membered heterocyclic), -(CR1R2)qC(O)(CR1R2),(C6-C10 aryl), -(CR1R2)„C(0)(CR1R2),(4-1Q membered heterocyclic), -(CR1R2),O(CR1R2)q(C6-C,0 aryl), -(CR1R2),O(CR1R2)q(4-10 membered heterocyclic), -(CR1R2)qS(O)j(CR1R2),(C6-C10 aryl), and
40 -(CR1R2)qS(O)j(CR1R2)t(4-10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of

5 the foregoing R10 groups are optionally substituted with an oxo (=0) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R10 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C(0)R6, -C(0)OR6, -OC(0)R6, -NR6C(0)R7, -C(0)NR6R7, -NR6R7, -NR60R7, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -{CR1R2),(C6-C10 10 aryl), and -(CR1R2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
each R11 is independently selected from -R12, -OR1, -NR1R2, -NR6C(0)R7, -NR6C(0)NR7R1, -NR6C(0)OR7, and -NR6S02NR7R1, or R11 replaces two hydrogen atoms on a carbon to form an oxo (C=0) group;
R12 is R6, -C(0)R6 or -S02R6, -C(0)NR6R7, -S02NR6R7, or -C02R6;
15 R13is-NR1R12or-OR12;
and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2
(methylene), or CH (methine) group which is not attached to a halogeno, SO or S02 group or
to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halo,
CrC4 alkyl, CrC4 alkoxy and -NR1R2.
20 In a specific embodiment of the present invention, the A moiety of the compounds of
formula 1 is selected from

wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
__r-


5 Other specific embodiments of the compounds of formula 1 include those wherein A
is selected from

wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 Rs
groups as substituents.
10 Other specific embodiments of the compounds of formula 1 include those wherein A
is selected from -

wherein the above AjTioieties bear an R4 group as a substituent and optionally bear 1
to 3 R5 groups as substituents.
15 Other specific embodiments of the compounds of formula 1 include those wherein A

is selected from


5 wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5
groups as substituents.
Other specific embodiments of the compounds of formula i include those wherein A is
10 wherein the above A moieties bear an R4 group as a substituent and optionally bear 1
to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula I include those wherein R4 is -(CR1R2)m-OC-(CR1R2)tR9 wherein m is an integer from 0-3 and t is an integer from 0-5..
Other specific embodiments of the compounds of formula 1 include those wherein R4 15 is -{CR1R2)m-C=C-(CR1R2)t-R9 and m is an integer from 0 to 3 and t is an integer from 0-5.
Other specific embodiments of the compounds of formula 1 include those wherein R4 -(CR1R2)ri,-CsC-(CR1R2)kR13 or - Other specific embodiments of the compounds of formula 1 include those wherein R4 20 is is -C=NOR12, or -X1-R12 wherein X1 is a divalent group derived from azetidine, oxetane or a C3-C4 carbocyclic group; or R4 is -(CR^^R9, wherein the attachment point to R9 is through a carbon atom of R9.
Other specific embodiments of the compounds of formula 1 include those wherein R8 is selected from -(CR1R2),(phenyl), -(CR1R2)t(pyridyl), -(CR1R2),(pyrimidinyl), -(CR1R2),(indolyl), 25 -(CR1R2)t(indazolyl) and -(CR1R2),(benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R8 groups is optionally substituted with 1 to 5 R10 groups.
Other specific embodiments of the compounds of formula 1 include those wherein R9
is a 4 to 10 membered heterocyclic group having 1 to 3 hetero moieties as indicated in formula
1 above and wherein said R9 is optionally substituted with 1 to 2 R11 groups.
30 Preferred compounds include those selected from the group consisting of:
Acetic acid 3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allyl ester;
(1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(4-methyl-piperazin-1-yl)- prop-1-ynyl]-
quinazolin-4-yl}-amine;
(1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-35 amine;
4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol; (1-Benzenesulfonyl-1H-indol-5-yl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;

5 [6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(1-benzenesulfonyMH-
indoJ-5-y1)-amine;
1-Methyl-4-{4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]- quinazolin-6-ylethynyl}-piperidin^4-ol;
1 -[4-(1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-4-methyl-pent-1 -yn-3-ol;
10 4-{4-[4-(1 -Phenyl-ethoxy)-phenylamino]-quinazolin-6-ylethynyl}-tetrahydro-pyran-4-ol;
1 -[4-(1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-4,4-dimethyl-pent-1 -yn-3-0I;
4,4-Dimethyl-1-{4-[4-(1-phenyl-ethoxy)-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol;
3-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;
15 1-Methyl-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol; 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-
ol;

20 2-one;

S-^-CI-Benzyl-IH-indazol-S-ylaminoJ-quinazolin-Q-yiethynyll^^-dimethyl-oxazolidin-
4-Amino-1 -[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]- pent-1 -yn-3-ol; 4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]~4-methyl-pent-1-yn-

3-OI;
3^2-[4-(3-Methyl-4-phenoxy-phenylamino)-quina*oIin-6-yl]-ethyl}-piperidin-3-ol;
25 and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
In accordance with the present invention, the most preferred compounds include those selected from the group consisting of:
(+)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(R)-ylethynyl-quinazolin-4-yl)-amine;
(-)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(S)-ylethynyl-quinazolin-4-yl)-amine;
30 3-(SH4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-
carboxylic acid methylamide;
3-(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide;
(3-Methyl-4-phenoxy-phenyl)-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl)-amine;
35 3-[4-(5-Methyl-6-phenoxy-pyridin-3-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
(-)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol; (+)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol; 4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol; {6-[1-(2-Methoxy-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-40 phenyl)-amine;
[4-(2-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

5 [4-(3-Fluoro-phenoxy)«3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;
(6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine; 3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;
3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-10 ol;
4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;
(3-Chloro-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;
3-(4-(3-Methy}-4"phenoxy-phenyiamino)-quinazoHn-6-y)ethynyi]-8-aza-
bicyclo[3.2.1 ]octan-3-ol;
15 (3-Chloro-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;
3-[4-(3-Methyl-4-phenoxy-phenyIamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol;
and the pharmaceutical^ acceptable salts and solvates of the foregoing compounds.
Other preferred compounds include those selected from the group consisting of:
20 N-{3-[4-(3-ChlorcH4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;
N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide; (3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-€-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;
4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-25 1-carboxylic acid Diethylamide;
{6-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-4-ol; N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-30 acetamide;
N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-methyl-prop-2-ynyl}-acetamide;
N-{1,1 -Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-
acetamide;
35 4-[4-(1 -Benzenesulfonyi-1 H-indol-5-ylamino)-quinazolin-6-yIethynyl]-1 -methyl-
piperidin-4-ol;
3-[4-(1-BenzenesulfonyMH-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(3-Bromo-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(4-Benzenesulfonyi-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol,
40 3-[4-(4-Cyclohexyloxy-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
2-Methyl-4-[4-(3-methy|-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol; 2-Amino-4-[4-(3-methy|-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-1-ol;

5 3-[4-(3-Methyl-4-phenylsulfanyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
and the pharmaceutical^ acceptable salts and solvates of the foregoing compounds. Other preferred compounds of the present invention include those selected from the group consisting of:
3-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-€-ylethynyl]-piperidin-3-ol;
10 3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
(3-Methyl-4-phenoxy-phenyl)-[6-(1-methyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine;
(3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)-quinazolin-4-yl]-amine;
3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;
15 3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-Oxo-5-(4-pyrrolidin-1 -yl-butyl)-1,2,3,5-tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylic acid benzylamide;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
This invention also relates to a method for the treatment of abnormal cell growffrirTa
■^ nn ■ " """•
20 mammal, including a human, comprising administering to said mammal an amount of a
,__„—...—__————■ — ——-————-■*
thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the
abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic
cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine
25 cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin"s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft
30 tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method,
35 said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof that is efifective in treating abnormal
40 cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell

5 cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula % as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is
10 effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uteYine cancerTovalrian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the
15 fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin"s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the
20 bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy
25 or restinosis.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with a pharmaceutically
30 acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of preparing a compound of the formula 1

NR1R3

5 signal for controls is typically 0.6-1.2 absorbance units, with essentially no background in wells without the PGT substrate and is proportional to the time of incubation for 10 minutes. Inhibitors were identified by reduction of signal relative to wells without inhibitor and ICS0 values corresponding to the concentration of compound required for 50% inhibition are determined.
10 The activity of the compounds of formula 1, in vivo, can be determine by the amount
of inhibition of tumor growth by a test compound relative to a control. The tumor growth inhibitory effects of various compounds are measured according to the method of Corbett T.H., 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.,
15 35, 2434-2439 (1975) and Corbett T.H., et al., "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2)", 5, 169-186 (1975), with slight modifications. Tumors are induced in the left flank by subcutaneous (sc) injection of 1-5 million log phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3 ovarian carcinoma cells) suspended in 0.1 ml RPMI 1640 medium. After sufficient time has elapsed for the tumors to
20 become palpable (100-150 mm3 in size/5-6 mm in diameter) the test animals (athymic female mice) are treated with test compound (formulated at a concentration of 10 to 15 mg/ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) route of administration once or twice daily for 7 to 10 consecutive days. In order to determine an anti-tumor effect, the tumor is measured in millimeters with a Vernier caliper across two diameters and the tumor size (mm3) is calculated
25 using the formula: Tumor size (mm3) = (length x [width]2)/2, according to the methods of Geran, R.I., 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). Results are expressed as percent inhibition, according to the formula: Inhibition (%) = (TuWcontroi - TuWtestJ/TuWeontrai x 100%. The flank site of tumor implantation provides
30 reproducible dose/response effects for a variety of chemotherapeutic agents, and the method of measurement (tumor diameter) is a reliable method for assessing tumor growth rates.
Administration of the compounds of the present invention (hereinafter the "active compound(s)") can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection
35 (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage
40 is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels
21-

5 below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compound may be applied as a sole therapy or may involve one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors,
10 for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fiuorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-{N-(3,4-dihydro-2-methyl-4-oxoquina20lin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors;
15 intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™ (4"-cyano-3-(4-fluorophenylsuiphonyl)-2-hydroxy-2-methyl-3"-(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
20 The pharmaceutical composition may, for example, be in a form suitable for oral
administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of
25 precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose
30 solutions. Such dosage forms can be suitably buffered, if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various
35 disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight
40 polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents,

coloring matters or dyes and, if desired, emulsifying agents of suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof:
Method of preparing various pharmaceutical composition with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington"s Pharmaceutical Sciences, Mack Publishing Company, Easter, P.a., 15th Edition (1975).
Accordingly, there is provided a substituted bicyclic compound of formula 1
MR1ff

1 or a pSiarmaeetrtfcalfy acceptable salt or solvate thereof, wherein:
the A moiety Is

wherein the above A moiety bears an R* groap as a substituent and optioraaliy bears 1 to 3 Rs groups as substituenis;
each R1 and RE is Independently H or CrCg alkyl;
ff is -(Cf^PrVR* wherein m fe 0 or 1;
wherein said group is optionally substituted with 1 to 3 Ft5 groups;
or rf and R9 afe taken together to form a gnoifi of the fcHrmila


iriuorarriethyt, teflucwwieiftoxy, Ct-Cg ailkyl, CrG* sltenyi, CrC« alkynyl, hydros, and Cj-Cg alkoxy;
H8 is teteeted from -fgRWMptewyf), -{GR1R^#yridyf» HCRWMpyM*tj% ^CfiW)»f>fo!ytJ, ^CHWjpclazQjyf} awl ^CR"R^i^rrtitajly!}, wherein t is an integer from 0 to 5, and each of the feregoing ft8 groups Is optionally substituted with 1 to 5 R16 groups;
eacn fiM Is independently selected from hafo, cyano, nttr©* -triHuoromeflhoxy, trifluoromothy), aado, hydroxy, Ct-C6 ataxy, CrQm aiiyl, Ca-Oe aBtenyl, CrGs alkynyf, -G(0)R8. ■CfOJOfi®, -OC(0)R*, -Nft6C|d)RVNrfiC{Oj^R1R7t -NflfiC{0J0R?> -G(CPRV, -NR^f, ■Nfi*QRTf -BtVIFftf, -S{0)|(GrCs alkyl} wherein | fs an integer from 0 to 2, -(CR1R8MC*-C» «& -Re( -OC(0)R*( 4IRsC{Q}ff, -CttyNHW, -NRsFf, -NRfoR*. GfCt a!M, Cz-Ce atayl. CrCs alkynyf, - R12 is R6, Rf3fe -KRfR12 or-OR,s;and wharein any of the above-mentioned subsftusertts comprising a CHS{mafiyt}, CH* (methylene), or CH {methJrte) group which is not attached tea halogerso, SO or S02 group octet a N, O or S atom oplonally bears cm said group a sufasiituent selected from hydroxy, halo, Ct-C* alfcyl, CrC« alkoxy and -NRW.
Accordingly, there is also provided a pharmaceutical composition for the treatment of abnormal cell growth in a mammal comprising an amount of a compound as claimed in claim 1 in the range of 0 to 99.90% that is effective in treating abnormal cell growth, and a pharmaceutical^ acceptable carrier.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be 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 following examples molecules with a single chiral 15 center, unless otherwise noted, exist as a racemic mixture. Those molecules with- two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Where HPLC chromatography is referred to in the preparations and examples below, 20 the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX™ RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samples are run on a Hewlett Packard-1100 system. A gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes. The system then proceeds on a wash cycle with 25 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate over this period is a constant 3 ml / minute.
In the following examples and preparations, "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, and "Bu" means butyl.
Preparation of 3-methvl-4-phenoxynitrobenzene
30 Sodium hydride (95% dry powder) (83,62 g, 3.31 moles, 1.3 eq.) was charged under
nitrogen atmosphere to a clean and dry 12 L four neck flask equipped with a condenser, a dropping funnel, a mechanical stirrer and two nitrogen inlet-outlet bubblers (Caution: sodium hydride is pyrophoric, avoid.contact with water or moisture). The reaction flask was cooled to 0 °C (ice bath) then anhydrous DMF (1280 mL) was carefully added using a dropping funnel. 35 The reaction mixture was stirred for 30 minutes at 0 °C, then a solution of phenol (263.5 g, 2.8 moles, 1.1 eq.) in anhydrous DMF (1280 mL) was added using a dropping funnel over 2 hours (Caution: exothermic, vigorous hydrogen evolution). After complete addition, the reaction mixture was stirred for 40 minutes at 0 °C (the reaction mixture turned to a white slurry), then a solution of 3-methy!-4-fluoronitrobenzene (390.0 g, 2.51 moles, 1.0 eq.) in anhydrous DMF 40 (dimethylformamide)(1280 mL) was added dropwise over 1 hour. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 15-22 hours (dark-

5 brown viscous solution) until all the starting material was converted to the phenoxynitrotoluene (TLC, 2% ethyl acetate in hexanes). Again the reaction mixture was cooled to 0 °C (ice bath), then carefully quenched with cold water (5000 mL) over 2 hours (Caution: exothermic, hydrogen evolution; first 100 ml water was added over 90 minutes). The reaction mixture was stirred for 1h, then transferred to a two 50 L carboys, each containing 40 L of water. The
10 contents was stirred and left at room temperature for 24 hours to afford the phenoxynitrotoluene, as a yellow solid. The yellow solid was filtered, washed with excess of water and air dried to afford 3-methyl-4-phenoxynitrobenzene (552 g, 96% yield). The crude 3-methyl-4-phenoxynitrobenzene was found to be pure by 1H and 13C NMR spectra, and used as such in the next reaction; m p 51-52 °C; FT-IR (cm"1): 1582, 1509, 1480, 1339, 1242, 1204,
15 1091 and 796; 1H NMR (300 MHz, CDCI3) 6 2.41 (s, 3 H), 6.78 (d, 1 H, J = 8.7 Hz), 7.02-7.08 (m, 2 H), 7.19-7.29 (m, 1 H), 7.38-7.46 (m, 2 H), 7.99 (dd, 1 H, J = 9.15 Hz, 2.7 Hz); 13C NMR (75.45 MHz, CDCI3) 16.22, 115.93, 119.11, 123.17, 124.9, 126.79, 129.53, 130.28, 142.66, 155.44 and 161.4.
Preparation of 3-methvl-4-phenoxvaniline hydrochloride
20 To a stirred solution of 3-methyl-4-phenoxynitrobenzene (2) (548 g, 2.39 moles, 1.0
eq.) in methanol (5 L) was added 10% Pd/C (100 g, 50% wet, 46.98 mmol, 0.02 eq.). Then the reaction mixture was stirred under a hydrogen atmosphere (60-80 psi) for 15-16 hours at room temperature in a 2 gallon Parr hydrogenator. The progress of the reaction was monitored by TLC (50% ethyl acetate in hexanes, sm Rf = 0.69, pr Rf = 0.47, UV visible).
25 Then the reaction mixture was filtered through Celite, and the solid was washed with excess methanol. The filtrate was concentrated under reduced pressure to give 3-methyl-4-phenoxyaniline as a pale brown viscous liquid (451.0 g, 95%). The 3-methyl-4-phenoxyaniline was found to be pure by 1H and 13C NMR spectra, and used as such in the next reaction
To a cooled (0 °C) and stirred solution of 3-methyl-4-phenoxyaniline (451.0 g, 2.26
30 moles, 1.0 eq.) in anhydrous ether (12 L) was bubbled dry HCI gas for 40-90 minutes until all the starting material was converted to the aniline hydrochloride salt. The off-white solid was filtered, washed with ether and dried in a vacuum oven for 6 hours at 60 °C to afford 3-methyl-4-phenoxyaniline hydrochloride (511.8 g, 96%); m p 173-174 °C; FT-IR (cm"1): 3058, 3019, 2840, 2573, 1485, 1253, 1223 and 691; 1H NMR (300 MHz, CDCI3) 5 2.22 (s, 3 H), 6.81-6.9
35 (m, 3 H), 7.04-7.11 (m, 1 H), 7.25-7.37 (m, 3 H), 7.43 (d, 1H,J = 2.4 Hz), 10.45 (S, 3 H); 13C NMR (75.45 MHz, CDCI3) 16.03, 118.01, 119.9, 122.12, 123.35. 124.78, 126.13, 129.93, 131.89, 155.5 and 156.96; APCI (negative FAB) 200.3 (100%); Anal. Calcd for C13H14CINO: C, 66.24; H, 5.99; N, 5.94. Found: C, 60.05; H, 6.01; N, 5.98.
Examples of other amines prepared by the above methods are:
40 3-Chloro-4-phenoxy-phenylamine
3-Methoxy-4-phenoxy-phenylamine

5 4-Phenoxy-3-trifiuoromethyl-phenylamine
3-Fluoro-4-phenoxy-phenylamine
5-Amino-2-phenoxy-benzonitrile
4-(2-Methoxy-phenoxy)-3-methyl-phenylamine
4-(3-Methoxy-phenoxy)-3-methyl-phenylamine
10 4-(4-Methoxy-phenoxy)-3-methyl-phenylamine
4-(2-Fluoro-phenoxy)-3-methyl-phenylamine
4-(3-Fluoro-phenoxy)-3-methyl-phenylamine
4-(4-Fluoro-phenoxy)-3-methyl-phenylamine
4-(2-Methyl-phenoxy)-3-methyl-phenylamine
15 4-(3-Methyl-phenoxy)-3-methyl-phenylamine
4-(4-Methyl-phenoxy)-3-methyl-phenylamine
4-(2,6-Difluoro-phenoxy)-3-methyl-phenylamine
3,5-Dichloro-4-phenoxy-phenylamine
3-Methyl-4-phenylsulfanyl-phenylamine
20 4-phenylsulfanyl-phenylamine
4-Cyclohexyloxy-3-methyl-phenylamine
4-Cyclopentyloxy-3-methyl-phenylamine
4-Cyclobutyloxy-3-methyl-phenylamine
2-Fluoro-4-phenoxyamine
25 4-Fluoro-2-phenoxyamine
3-Bromo-4-phenoxy-phenylamine
4-(2-Chloro-phenoxy)-3-methyl-phenylamine
4-(2-Methoxy-phenoxy)-3-methyl-phenylamine
4-(2-Ethyl-phenoxy)-3-methyl-phenylamine
30 4-(2-Trifluoromethyl-phenoxy)-3-methyl-phenylamine
1-(5-amino-2-phenoxy-phenyl)-ethanone
(+/-)-4-Benzenesu!finyl-3-methyl-phenylamine, (+/-) 4-Benzenesulfinyl-phenylamine, 4-Benzenesulfonyl-3-methyl-phenylamine, 4-Benzenesulfonyl-phenylamine were prepared from 3-Methyl-4-phenylsulfanyl-phenylamine and 4-phenylsulfanyl-phenylamine by oxidation 35 methods known to those skilled in the art. 3-Ethvl-4-phenoxv-phenvlamine
To a solution of 1-(5-amino-2-phenoxy-phenyl)-ethanone ( 0.5 g, 2.20 mmol) in THF
(15 ml) was added sodium borohydride(O.4 g, 10.5 mmol ) and AICI3 (anhydrous) (0.803g,
6.02 mmol ) under nitrogen. The resulting reaction mixture was heated under reflux for 4
40 hours. The mixture was then cooled and iced-water added. The resultant mixture was
extracted with EtOAc and dried over Na2S04. Removal of the solvent afforded a brownish

5 residue which was chromatographed with 4 : 1 hexane / EtOAc to afford (15 mg, 10%) product 3-ethyl-4-phenoxy-phenylamine.
3-Hvdroxv-4-Phenoxv-phenvlamine
3-methoxy-4-phenoxynitrobenzene(2 g, 8.15 mmol) was treated with 48% HBr (20 ml) and HOAc ( 20 ml), The reaction mixture was heated to 110 °C for 24 hours and then the 10 reaction mixture was poured into ice and extracted with EtOAc, the organic layer was washed with brine, dried over Na2S04. Removal of the solvent provided a brownish residue 5-Nitro-2-phenoxy-phenol which was taken to next step without further purification, (almost quantitative yield). 1H NMR(CDCI3): 5 7.91(d,1H, 2.7 Hz), 7.72(dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.43(t, 2 H, J = 7.9 Hz), 7.28(d, 1 H, 7.9 Hz), 7.10(d, 1H, J = 8.3 Hz), 6.78(d, 2H, J= 8.9 15 Hz).
Ethoxv-4-phenoxy-phenvlamine
To a solution of 5-m"tro-2-phenoxy-phenol (500 mg,2.16 mmol ) in acetone( 20 ml) was added bromoethane (0.353g , 3.26 mmol ) and potassium carbonate (0.447 g, 3.26 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and then 20 the reaction was heated to 50 °C for 4 hours. Water was added and aqueous layer extracted with EtOAc (3 x 30 ml), the organic layer washed with brine and dried over Na2S04. Removal of the solvent provided( 0.3 g, 53%) 3-ethoxy-4-pheoxy-nitrobenzene. The product was subjected to hygrogenation over %Pd-C in methanol to afford (0.1 g, 38% ) of 3-Ethoxy-4-phenoxy-phenylamine. M/z, 230.0, 1H NMR(CDCI3): 7.91(d,1H, 2.7 Hz), 7.72(dd, 1H, J1 = 8.8 25 Hz, J2 = 2.4 Hz), 7.43(app t, 2 H, J = 7.9 Hz), 7.28(d, 1 H, 7.9 Hz), 7.10(d, 1H, J = 8.3 Hz), 6.78(d, 2H, J= 8.9 Hz), 4.17 (dd, 2H, J1 = 13. 9 HZ, J2 = 7.1 Hz), 1.42(t, 3H, J = 7.1 Hz).
3-lsopropoxy-4-phenoxy-phenylamine was also prepared by the above alkylation protocol.
3-Phenyl-1 H-indazol-6-vlamine
30 To a solution of 2-chloro-5-nitro-benzophenone(1.0 g) in THF (tetrahydrofuran) (15
ml) was added anhydrous hydrazine(120 mg). The resulting reaction mixture was kept stirring at room temperature for 2-4 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc, washed with water and brine, dried over Na2S04. Removal of the solvent afforded (0.8 g, 88%) product 6-Nitro-3-phenyl-1 H-indazole(5 ). 6-Nitro-3-phenyMH-indazole 35 was hydrogenated over H2/Pd and gave 0.5 g of 3-phenyl-1 H-indazol-6-ylamine (71.5%). M/z: 210.0. 1H NMR(CD3OD): 7.86(d, 2H, J = 7.9 Hz), 7.47( t, J = 8.1 Hz), 7.35(t, 3H, J = 8.7 Hz), 7.01 (d, 1H, J =8.7 Hz).
General Procedure for the Addition of 1-Lithio-2-trimethvlsilvlacetvlene to a
Carbonvl
40 A cold (-78 °C), stirred solution of (trimethylsilyl)acetylene (1.2 eq) in anhydrous THF
was treated with nBuLi (1.2 eq) under nitrogen (In the case of BOC-protected amino

I
5 aldehydes containing a free NH, the amount of (trimethylsilyl)acetylene and n-BuLi is
doubled.). The colorless solution was stirred for 30 to 40 minutes, followed by the addition of
carbonyl compounds (1.0 eq) in anhydrous THF. The reaction was warmed up to room
temperature, stirred for 2 to 4 hours, and quenched with water. After removal of THF, the
residue was partitioned between ether or EtOAc and water. The separated organic layer was
10 washed with brine, dried over sodium sulfate, and concentrated to give the crude TMS
protected propargyl alcohol. Subsequently, a mixture of the crude propargyl alcohol (1.0 eq)
and K2C03 (2.0 eq) in methanol was stirred at room temperature for 0.5 to 1 hour. The solids
was filtered off and washed with ether. The filtrate was concentrated, dissolved in ether,
washed with water and brine, and dried over sodium sulfate. Solvent removal gave the crude
15 terminal acetylene product, which was purified by distillation or chromatography (Ethyl
Acetate/Hexanes). Overall yields for this procedure range from 62-97%.
Examples of terminal alkynes prepared by above method are:
3-Ethynyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
4-Ethynyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
20 3-Ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
endo-a-3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl ester
exo-p-3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
2-(1-Hydroxy-prop-2-ynyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
25 1-Cyclobutyl-prop-2-yn-1-ol
Pent-1-yn-3-ol
4-Amino-pent-1 -yn-3-ol
1 -(3-Aza-bicyclo[3.1,0]hex-6-yl)-prop-2-yn-1 -ol
4-Ethynyl-tetrahydro-pyran-4-ol
30 (4-Ethynyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester
2-(1-Hydroxy-prop-2-ynyl)-piperidine-1-carboxylic acid tert-butyl ester 3-(1-Hydroxy-prop-2-ynyl)-piperidine-1-carboxylic acid tert-butyl ester 4-Ethynyl-1-methyl-piperidin-4-ol
(2-Hydroxy-but-3-ynyl)-methyl-carbamic acid tert-butyl ester
35 (2-Ethynyl-2-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester
R and S-3-Ethynyl-1-aza-bicyclo[2.2.2]octan-3-ol General Procedure Homologating Aldehydes to Terminal Alkynes To a cold (-78 °C), stirred solution of LDA (lithium diisopropylamide) (1.3 eq) in anhydrous THF was added a solution of (trimethylsilyl)diazomethane in hexane (1.3 eq) 40 dropwise under nitrogen (In the case of BOC-protected amino aldehydes containing a free NH, the amount of (trimethylsilyl)diazomethane and LDA is doubled.). After 1 hour, aldehyde

5 (1.0 eq) in anhydrous THF was introduced and cooling bath was removed. The reaction was stirred at rt for 1to 2 hours, quenched with water, concentrated, and partitioned between ether and water. The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude product, which was purified by distillation or chromatography (Ethyl Acetate/Hexanes). Overall yields for this procedure range from 37-10 72%.
Examples of terminal alkynes prepared by this method are:
4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester
3{S)-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester
3(R)-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester
15 2-Ethynyl-piperidine-1 -carboxylic acid tert-butyl ester
3-Ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester
3-Ethynyl-azetidine-1-carboxylic acid tert-butyl ester
(4-Ethynyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester
[1-(tert-Butyl-dimethyl-silanyloxymethyl)-prop-2-ynyl]-carbamic acid tert-butyl ester
20 4-Prop-2-ynvl-piperazine-1-carboxylic acid tert-butyl ester
To a solution of N-t-butoxycarbonypiperazine (5.0 g, 26.8 mmol) in acetone (40 ml) was added potassium carbonate (3.70g, 26.8 mmol). Propargy\ bromide (2.39 mi, 26.8 mmol) in acetone (10 ml) was added dropwise to the above reaction mixture. The resultant mixture was allowed to stir at room temperature for overnight. Water was added, the aqueous layer 25 extracted with ether and combined organic layer washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester which as crude material is taken on into a Pd coupling reaction with the appropriate anilinoquinazoline.
Examples of terminal alkynes prepared by this method are:
30 1-Prop-2-ynyl-pyrrolidine
3-Methyl-4-prop-2-ynyl-p(perazine-1 -carboxylic acid tert-butyl ester
3,5-Dimethyl-4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester
1 -Methyl-4-prop-2-yny|-piperazine
4-Prop-2-ynyl-morpholine
35 (3-Prop-2-ynyl-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol
1 -Prop-2-ynyl-piperidin-4-ol
1 -Prop-2-ynyl-piperidin-3-ol
1 -Prop-2-ynyl-pyrrolidin-3-ol
(1 -Prop-2-ynyl-piperidin-4-yl)-methanol
40 (1 -Prop-2-ynyJ-piperidin-3-yl)-methanoJ
(1-Prop-2-ynyl-piperidin-2-yl)-methanol

5 (1 -Prop-2-ynyl-pyrrolidin-2-yl)-methanol
2-(1-Prop-2-ynyl-piperidin-4-yl)-ethanol
2-(4-Prop-2-ynyl-piperazin-1-yl)-ethanol
4,4-Dimethoxy-1-prop-2-ynyl-piperidine
1-Prop-2-ynyl-piperidin-4-ylamine
10 2-(Methyl-prop-2-ynyl-amino)-ethanol
4-Prop-2-ynyl-piperazine-1-carboxylic acid methylamide
1 -(4-Prop-2-ynyl-piperazin-1 -yl)*ethanone
4-Prop-2-ynyl-piperazine-1-carboxamide
1-Methanesulfonyl-4-prop-2-ynyl-piperazine
15 2-Chloro-N-prop-2-vnvl-acetamide
Propargyl amine (250 mg; 0.34 ml; 4.6 mmol) was dissolved in dichloromethane (10
ml) and cooled to 0° C. Chloro-acetyl chloride (256 mg; 0.18 ml; 2.3 mmol) was added to this
solution dropwise and the solution was stirred for 30 minutes and allowed to warm up to room
temperature. The solution was washed with 2 x H20, dried over Na2S04 and the solvent
20 removed. 2-Chloro-N-prop-2-ynyl-acetamide (385 mg) was obtained as white crystals. 1H
NMR (400 MHz; CDCI3) S 2.27 (1H, m), 4.07 (2H, s), 4.09 (2H, q, J = 2.5 Hz), 6.78 (1H, br s).
Examples of terminal acetylenes prepared by the above method are:
N-Prop-2-ynyl-acetamide
N-Prop-2-ynyl-propionamide
25 Cyclopropanecarboxylic acid prop-2-ynylamide
2,2-Dimethyl-N-prop-2-ynyl-propionamide
N-Prop-2-ynyl-methanesulfonamide
N-Methyl-N-prop-2-ynyl-acetamide
N-( 1 -Methyl-prop-2-ynyl)-acetamide
30 N-(1,1-Dimethyl-prop-2-ynyl)-acetamide
2-Methoxy-N-prop-2-ynyl-acetamide 2-/tert-Butoxvcarbonvlamino)-2-methvl-1-propanol
A mixture of 2-amino-2-methyl-1-propanol (8.9 g, 0.1 mol), di-tert-butyldicarbonate
(22.0 g, 0.1 mol), and Na2C03 (21.0 g, 0.2 mol) in water/THF (150/150 mL) was refluxed for 1
35 hour. After removal of THF, the residue was partitioned between ether (200 mL) and water
(150 mL). The separated organic layer was washed with brine (100 mL), dried over sodium
sulfate, and concentrated to give 17.97 g (95%) of 2-(tert-butoxycarbonylamino)-2-methyl-1-
propanol as waxy, white solid: 1H NMR (CDCI3) 5 1.23 (s, 6H), 1.41 (s, 9H), 3.56 (s, 2H).
2-(tert-butoxvcarbonvlamino)-2-methvl propionaldehyde
40 To a solution 2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol (5.7 g, 30.0 mmol) in
triethylamine (42 mL) was added a mixture of sulfur trioxide pyridine complex (14.3 g, 90.0

5 mmol) in anhydrous DMSO (dimethylsulfoxide) (50 mL) at room temperature. The reaction was stirred for 1 hour under nitrogen and concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give crude 2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde as yellow oil. Purification by distillation afforded 4.90 g (87%) of waxy, white solid: 1H NMR (CDCI3) 5 10 1.30 (s, 6H), 1.41 (s, 9H), 4.97 (br, 1H), 9.40 (s, 1H).
4.4-Dimethvl-5-trimethvlsilylethvnvl-2-oxazolidinone
A cold (-78 °C), stirred solution of (trimethylsilyl)acetylene (4.42 g, 45.0 mmol) in
anhydrous THF (20 mL) was treated with nBuLi (18 mL, 45.0 mmol) under nitrogen. The
colorless solution was stirred for 30 minutes and followed by the addition of 2-{tert-
15 butoxycarbonylamino)-2-methyl propionaldehyde (2.80 g, 15 mmol) in anhydrous THF (20
mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched
with water. After removal of THF, the residue was partitioned between ether (150 mL) and
water (100 mL). The separated organic layer was washed with brine (100 mL), dried over
sodium sulfate, and concentrated to give the crude 4,4-Dimethyl-5-trimethylsilylethynyl-2-
20 oxazolidinone (100%) as yellow oil which was carried to the next step.
4.4-Dimethvl-5-ethvnvl-2-oxazolidinone
A mixture of 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (15.0 mmol) and K2C03 (4.1 g, 30.0 mmol) in methanol (30.0 mL) was stirred at room temperature for 30 min. The solid was filtered off and washed with ether. The filtrate was concentrated, dissolved in 25 ether (100 mL), washed with water (50 mL) and brine (50 mL), and dried over sodium sulfate. Solvent removal afforded 1.10 g (53%) of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone as a yellow oil: 1H NMR (CDCI3) S 1.37 (s, 3H), 1.39 (s, 3H), 2.68 (s, 1H), 4.82 (s, 1H), 6.00 (brs, 1H).
Preparation of 4-Ethvnyl-4-hvdroxv-tetrahvdro-pvran-2-carboxylic acid amide
4-Oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester: ZnCI (0.63 g, 4.6
30 mmol) was dissolved in anhydrous THF (15 mL) and added to a solution of 1-methoxy-3-
(trimethylsilyloxy)-1,3-butadiene (7.94 g, 46.0 mmol) and ethyl glyoxalate (7.05 g, 69.0 mmol)
in toluene (30 mL) at room temperature. After stirring for 30 minutes, water (30 mL) and TFA
(trifluoracetic acid) (2 mL) were added and the mixture was stirred vigorously for 20 min. After
concentration, the residue was partitioned between EtOAc (200 mL) and water (100 mL). The
35 separated organic layer was washed with brine, dried over sodium sulfate, and concentrated
to give 8.0 g (100%) of brown oil which was carried to the next step without further purification.
1H NMR (CDCI3) 6 1.30 (t, 3H), 2.85 (d, 2H), 4.26 (q, 2H), 5.00 (t, 1H), 5.48 (d, 1H), 7.39 (d,
1H).
4-Oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester: A mixture of 4-oxo-3,4-
40 dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and Pd/C (10%, 0.20 g.) in
EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered

5 through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCI3) 5 1.29 (t, 3H), 2.40 (d, 1H), 2.58 - 2.75 (m 3H), 3. 79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).
4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester: A cold (-78 °C), stirred solution of (trimethylsilyl)acetylene (1.80 g, 18.24 mmol) in
10 anhydrous THF (30 mL) was treated with nBuLi (7.3 mL in hexane, 18.24 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 15.2 mmol) in anhydrous THF (30 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2 x 60 mL).
15 The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 2.50 g (61%) of yellow oil: 1H NMR (CDCI3) 8 0.17 (s, 9H), 1.30 (t, 3H), 1.76-1.90 (m, 3H), 2.25 (m, 1H), 3.66 (tt, 1H), 4.11 -4.21 (m, 2H), 4.24 (q, 2H).
4-Ethynyl-4-hydroxy-tetrahydro-pyran-2-carboxylic acid amide: 4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.50 g, 9.25 mmol) was
20 dissolved in MeOH (20 mL) in a pressure reaction tube and NH3 gas was passed through the solution for 10 minutes with stirring. The tube was tightly capped and the reaction was stirred for 3 days. After solvent removal, 1.53 g (97%) of yellow oil was obtained: 1H NMR (CD3OD) 8 1.48 (t, 1H), 1.70 (td, 1H), 1.85 (d, 1H). 2.30 (d, 1H), 3.04 (s, 1H), 3.29 (s, 1H), 3.71 (t, 1H), 3.98 (d, 1H),4.06(dt, 1H).
25 Preparation of 2-(te/t-Butvl-dimethvl-sHanvloxvmethvl)-4-ethvnvl-tetrahydro-
pyran-4-ol
2-Hydroxymethyl-tetrahydro-pyran-4-ol: To a cooled (0 °C), stirred suspension of LiAIH4 (3.42 g, 90.0 mmol) in anhydrous THF (50 mL) was added dropwise a solution of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (5.17 g, 30.0 mmol). After stirring for 1
30 hour, the reaction was quenched by the slow, sequential addition of water (3.4 mL), 15%
NaOH (3.4 mL), and water (10.0 mL). The inorganic salt was filtered off and extracted with
EtOAc repeatedly since the product was absorbed on the solid. Solvent removal afforded
2.42 g (61%) of yellow oil. The crude mixture was carried to the next step without purification.
2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol: To a solution of
35 2-hydroxymethyl-tetrahydro-pyran-4-ol (2.42 g, 18.3 mmol), DMAP (4-dimethylaminopyridine) (90 mg, 0.74 mmol), and Et3N (2.04 g, 20.1 mmol) in anhydrous CH2CI2 (50 mL) was added te/f-butyldimethylsilyl chloride (2.76 g, 18.3 mmol) at room temperature. After stirring overnight, the reaction solution was quenched with brine (30 mL) and the separated aqueous layer was extracted with CH2CI2 (40 mL). The combined organic extract was dried over
40 sodium sulfate and concentrated. Purification by silica gel column using 30% EtOAc in hexane gave 2.27 g (50%) of colorless oil: 1H NMR (CDCI3) 8 0.04 (s, 6H), 0.88 (s, 9H), 1.21

5 (m, 1H), 1.43 (m, 1H), 1.82 (dt, 1H), 2.00 (dt, 1H), 3.35 (m, 1H), 3.51 (q, 1H), 3.66 (q, 1H), 3.79 (m, 1H), 4.01 (m, 1H).
2-(fert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one: A solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (2.27 g, 9.21 mmol) in anhydrous DMSO/Et3N (15/13 mL) was treated with sulfur trioxide pyridine complex (7.33 g, 46.1 mmol) 10 portionwise at room temperature. After stirring for 1 hour, the reaction was concentrated and the residue was partitioned between EtOAc (100 mL) and water (50 ml). The separated organic layer was washed with brine (70 mL), dried over sodium sulfate, and concentrated. Purification by silica gel column using 10 - 20% of EtOAc in hexane afforded 1.48 g (66%) of colorless oil: "H NMR (CDCI3) 6 0.05 (s, 6H), 0.88 (s, 9H), 2.32 (dt, 1H), 2.41 (m, 2H), 2.58 (m,
15 1H), 3.62 (m, 2H), 3.70 (d, 2H), 4.31 (m, 1H).
2-(terf-Butyl-dimethyl-silanyloxymethyl)-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol: A cold (-78 °C), stirred solution of (trimethylsilyl)acetylene (1.01 g, 10.3 mmol) in anhydrous THF (25 mL) was treated with nBuLi (4.12 mL in hexane, 10.3 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2-
20 (tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one (1.48 g, 6.06 mmol) in anhydrous THF (25 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 1.75 g (84%) of yellow oil: 1H NMR (CDCI3) 5 0.05 (s, 6H), 0.16 (s, 9H),
25 0.89 (s, 9H), 1.43 (m, 1H), 1.78 (td, 1H), 1.83 (d, 1H), 1.94 (d, 1H), 3.52 - 3.70 (m, 4H), 4.00 (m1H).
2-(te/f-Butyl-dimethyl-silanyloxymethyl)-4-ethynyl-tetrahydro-pyran-4-ol: A
mixture of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol (1.75 g, 5.1 mmol) and K2C03 (1.4 g, 10.2 mmol) was stirred at room temperature for 30
30 minutes. After concentration, the residue was partitioned between EtOAc (50 mL) and water (30 mL) and the separated aqueous layer was extracted with EtOAc. The combined organic extract was dried over sodium sulfate and concentrated to give 1.33 g (96%) of light yellow oil: "H NMR (CDCI3) 5 0.05 (s, 6H), 0.88 (s, 9H), 1.50 (m, 1H), 1.78 (m, 1H), 1.84 (d, 1H), 2.01 (m, 1H), 2.55 (s, 1H), 3.55 - 3.70 (m, 4H), 4.00 (m, 1H).
35 6-lodo-4-quinazolinone
A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) and formamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxed for 20 hours. After cooling to 0°C, the solid product was collected by filtration. Further drying in vacuo provided 6-iodo-4-quinazolinone (22.0 g, 81%) as a grey crystalline solid. 1H NMR (400 MHz; DMSO-d6) 5:
40 12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS: 272.9 (MH+).
16

5 6-iodo-4-chloroquinazoline (12): To a stirred solution of DMF (6.3 mL) in DCE (20
mL) cooled to 0°C was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was 10 quenched cautiously with H2O. CH2CI2 was added and the bilayer transferred to a separatory
funnel. The aqueous layer was extracted with CH2CI2 (2x50 mL) and the combined organic layers dried (Na2SC«4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1HNMR (CDCI3, 400 MHz): 6: 9.05 (s,
15 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).
6-iodo-4-phenoxvquinazoline (13): A suspension of NaH (washed free of mineral oil) in DMF (40 mL) was cooled to 0°C and a solution of phenol (5.65 g, 60 mmol) in DMF (20 mL) was added dropwise. Upon completion of addition, 6-iodo-4-chloroquinazoline (14.6 g, 50.3 mmol) was added as a solid in small portions. The cooling bath was moved and the
20 reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water (200 mL), diluted with EtOAc (300 mL) and transferred to a separatory funnel. The organic layer was washed with dilute aqueous NaOH, water and brine and dried over Na2SC>4. Filtration of the solids and removal of the solvent provided quinazoline 13 (17.2
g, 98%) as a yellow solid. 1H NMR (400 MHz; CDCI3): 8: 8.74 (d, 1H), 8.14 (s, 1H), 8.12 (dd,
25 1H), 7.71 (d, 1H), 7.49 (dd, 2H), 7.32 (t, 1H), 7.22 (m, 2H).
Method A: (1 -Benzenesulf onvl-1 H-indol-5-vlH6-(3-imidazoM -vl-prop-1 -vnvl)-quinazolin-4-vn-amine MS)..
(1-Benzenesulfonvl-1H-indol-5-vl)-(6-iodo-quinazolin-4-vl)-amine (14): 6-iodo-4-
chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00
30 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was
heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling
the solids were filtered and rinsed with CH2CI2 and placed under high vacuum to remove any
excess solvent. Quinazoline 14 (3.23g, 75%) was obtained as a yellow solid. 1H NMR (DMSO d6; 400 MHz): 5: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 35 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz, 0.6 Hz).
(1-Benzenesulfonvl-1H-indol-5-vl)-r6-(3-imidazol-1-vl-prop-1-vnvl)-quinazolin-4-yll-amine (15): Quinazoline 14 (150 mg, 0.28 mmol), 1-N-2-propynylimidazole (200 mg, 1.89 mmol), Pd(OAc)2 (4 mg, 0.016 mmol) and PPh3 (9 mg, 0.033 mmol) were mixed in NEt3
(1.25 mL) and DMF (0.5 mL). The mixture was heated at 80°C under N2 for 16 hours. Upon

5 cooling the black suspension was concentrated under reduced pressure and the residue dissolved in MeOH. Silica gel (1g) was added and the methanol removed in vacuo. The resulting silica gel was placed atop a silica gel (40g) column which was then eluted with 200 mL 50:1 CtyCfe."MeOH, the 300 mL 25:1 CH2CI2 to provide alkyne 15 (72 mg, 51%) as a
yellow foam. 1H NMR (CDCI3; 400 MHz): 6: 8.95 (br, 1H, NH), 8.63 (s, 1H), 8.62 (s, 1H), 8.24
10 (s, 1H), 7.96 (d, 1H, J=1.7 Hz), 7.84 (m, 3H), 7.71 (m, 2H), 7.51 (m, 3H), 7.41 (m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.55 (d, 1H, J=3.5 Hz), 5.01 (s, 2H).
Method A": (3-Methyl-4-phenoxv-phenvlH6-(3-piperazin-1-vl-prop-1-vnvl)-
QUinazolin-4-yll-amine
(6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine: The 4-chloro-6-iodo-
15 quinazoline (5.0 g, 17.2 mmol) and the 3-methyl-4-phenoxyaniline (17.2 mmol) were mixed together in 1 : 1 dichloroethane and t-butanol (50 ml). The reaction mixture was heated at 90 °C for 4hours whereupon a yellow precipitate was observed. The reaction was cooled down and the precipitate was collected and afforded (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine. ( 8.0 g, 94%). M/z, 454. 1H NMR (CD3OD): 5: 9.12(s, 1H), 8.83(s, 1H),
20 8.39(d, 1H, J = 8.8 Hz), 7.63(d, 1H, J = 8.8 Hz), 7.55 (d, 1H, J = 2.1 Hz), 7.35(dd,1H, J1 = J2 = 8.5 Hz), 7.28(t, 2H, J = 8.1 Hz,), 7.05 (t, J = 8.5 Hz), 6.87(d, 1H, J = 8.1 Hz), 3.81(s, 3H).
i3-methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1-yl-prop-1-ynyl)-quinazoHn-4-yl]-amine: The 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester ( 2.37g, crude) and (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine (800 mg, 1.76 mmol) , Pd(OAc)2
25 (23,7 mg, 0.105 mmol,), PPh3(55.3 mg,0.21 mmol) in E^N ( 8ml) and DMF (3 ml) were mixed together. The resulting reaction mixture was heated at 80°C for overnight. After cooling, methylene chloride was added to the reaction mixture and the dark mixture was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel (1: 1 hexane + ethyl acetate) to give product 2. 2 was
30 dissolved in methyene chloride and HCI gas was bubbled through for 5 minutes, precipitate was collected and afforded (400 mg , 46.7 %) product {3-methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1 -yl-prop-1 -ynyl)-quinazolin-4-yl]-amine.
M/z, 450, 1H NMR (DMSO), 6 (ppm), 9.52(s, 1H), 8.84(s, 1H), 8.20(dd, 1H, J1 = 8.7 Hz, J2 = 1.3 Hz), 7.99 (d, 1H, J = 2.5 Hz), 7.60(dd, J1 = 8.7 Hz, J2 = 2.7 Hz), 7.36(app t, 2H,
35 J= 8.5 Hz), 7.11(t, 1H, J = 7.5 Hz), 6.92(d, 1H,J= 8.8 Hz), 6.91 (d, 1H, J = 7.9 Hz). 3.55 (br, 4H), 3.44(br, 4H), 3.30(s, 2H), 2.19(S. 3H).
Method B: (6-Cvclobutvl-quinazolin-4-vlM4-phenoxv-phenvnamine (17). 6-cyclobutyI-4-phenoxyquinazoline(16): To a stirred solution of naphthalene (3.85 g, 30 mmol) in dry THF (tetrahydrofuran)(20 mL) at room temperature was added finely cut
40 lithium metal (0.21 g, 30 mmol) in small portions. The mixture turned dark green and stirring

5 was continued for 2 hours. A solution of ZnCl2 (33 mL of a 0.5 M solution in THF, 16.5 mmol) was then added dropwise via syringe imparting a black color. After 3 hours, stirring was discontinued and the fine Zn dust was allowed to settle. The supernatant (-40 mL) was removed with a dry pipet and replaced with fresh THF (10 mL). Cyclobutyl bromide (2.0 g, 14.8 mmol) was then added and the resulting dark mixture allowed to stir at room temparature 10 for 16 hours. Stirring was again stopped and the supernatant organozinc reagent used immediately in the next reaction.
To a solution of 6-iodo-4-phenoxyquinazoline (1.75 g, 5.03 mmol), Pd2(dba)3
[tris(dibenzylideneacetamide)dipalladium(0)] (90 mg, 0.1 mmol) and trifurylphosphine (185 mg,
0.8 mmol) in THF (10 mL) was added cyclobutyl zinc prepared as above. The resulting
15 mixture was stirred for 6 hours, then diluted with THF (30 mL) and quenched with saturated
NH4CI solution (40 mL). The two layers were separated and the organic layer washed with
water and brine then dried (Na2SC>4). Removal of the solids and removal of the solvent in
vacuo provided a brown oil. Purification by silica gel chromatography eluting with 1:1
EtOAc:hexanes provided 6-cyclobutyl-4-phenoxyquinazoline (0.78 g, 56%) as a yellow oil. 1H
20 NMR (400 MHz: CDCI3): 8: 8.71 (s, 1H), 8.14 (s, 1H), 7.92 (d, 1H), 7.78 (dd, 1H), 7.50 (t, 2H),
7.31 (t, 1H), 7.25 (d, 2H), 3.78 (m, 1H), 2.43 (m, 2H), 2.25 (m, 2H), 2.11 (m, 1H), 1.92 (m, 1H).
(6-Cvclobutvl-quinazolin-4-vlM4-phenoxy-phenvl)amine (17): Quinazoline 16 (50
mg, 0.18 mmol) was combined with 4-phenoxyaniline (67 mg, 0.36 mmol) in phenol (0.45 g).
25 The mixture was heated at 100°C for a total of 17 hours. Excess phenol was removed by
distillation under reduced pressure to provide a residue which was triturated with CH2CI2 to
provide the desired quinazoline 17 (20 mg, 30%) as a yellow solid. 1H NMR (DMSO d6, 400 MHz): 5: 9.76 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 7.77 (d, 2H), 7.69 (m, 2H), 7.36 (t, 2H), 7.11 (t, 1H), 7.03 (d, 2H), 6.98 (d, 2H), 3.69 (m, 1H), 2.35 (m, 2H), 2.23 (m, 2H), 2.01 (m, 1H), 1.86 30 (m, 1H).
Method C; cis- and trans-3-f4-(1-Benzenesulfonvl-1H-indol-5-vlamino)-guinazolin-6-vn-cvclobutanecarboxvHc acid ethyl ester (19a/19b).
cis- and trans-3-(4-Phenoxv-quinazolin-6-vl)-cvclobutanecarboxvlic acid ethyl ester (18a.b): To a solution of naphthalene (1.92 g, 15 mmol) in dry THF under N2 was
35 added finely cut Li metal (104 mg, 15 mmol) in small portions resulting in a green mixture which was stirred for 2 hours. Zinc Chloride (16 mL of a 0.5M solution in THF, 8 mmol) was then added dropwise via syringe and the mixture stirred at room temperature for 3 hours. Stirring was stopped and the supernatant removed and replaced with a solution of ethyl-3-iodocyclobutane-1-carboxylate (790 mg, 3 mmol). The resulting suspension was stirred for 20
40 hours when stirring was stopped and the remaining Zn metal allowed to settle. The remaining

5 solution was then transferred to a dry flask containing quinazoline 13 (520 mg, 1.5 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and tri-2-furylphosphine (56 mg, 0.24 mmol). The mixture was
stirred at room temperature for 16 hours. The mixture was concentrated, and the residue taken up in EtOAc (30 mL) and washed with saturated aqueous NH4CI, brine and H2O and
dried (Na2S04). The solvent was removed in vacuo and the resulting residue purified by
10 silica gel chromatography to provide cyclobutyl esters 1|a and jBb as a mixture of cis and trans isomers (300 mg, 57%). LRMS: 349.2 (MH+). HPLC: 7.31 min (28%); 7.44 min (72%).
cis- and trans-3>f4-: Esters 18a and 18b (300 mg, 0.86 mmol) were combined with 5-amino-1-phenylsulfonylindole (270 mg, 1.0 mmol) and phenol (1.0 g).
15 The mixture was heated to 100°C for 48 hours. The excess phenol was removed by distillation and the residue dissolved in CH2CI2, transferred to a separatory funnel and washed with H20 and brine. The organic layer was dried (Na2S04) and the solvent removed to provide a dark residue which was purified by preparative TLC eluting with EtOAc to provide esters 19a and 19b (0.20 g, 44%) as a waxy solid. LRMS: 527.2 (MH+). HPLC: 7.54 min (16%); 7.64 min
20 (84%).
Method D: cis- and trans-f3-r4-f1-Benzenesulfonvl-1H-indoi-5-vlamino)-quinazolin-6-v^-cvclobutvn-methanol(20a.b):
To a cold (-78°C), stirred solution of ethyl esters 19a/19b (70 mg, 0.13 mmol) in anhydrous toluene (5 mL) was added 0.78 mL of DIBAL-H (diisobutylaluminum hydride) (1 M
25 in toluene) dropwise via syringe. The reaction was then warmed up to 0°C, stirred for 3 hours, then quenched by dilution with aqueous NH4CI. The mixture was transferred to a separatory funnel and extracted with ethyl acetate. The organic layer was dried (Na2S04), the solids removed and the remaining filtrate concentrated to provide an oil which was purified by preparative TLC (elute w/ ethyl acetate) to give 7 mg (11 %) of alcohols 20a/20b as a yellow
30 solid: MS m/z (MH+) 485.2; HPLC 5.97 min.
Method E: cis- and trans-f3-r4-(1-Benzenesulfonvl-1H-indol-5-vlamino)-quinazolin-6-vn-cvciobutyn-PvrroHdin-1-vi-methanone (21a. b)
The ethyl esters 19a/l9b (60 mg, 0.11 mmol) were dissolved in methanol (5 mL) and refluxed for 1 hour to convert the ethyl ester to methyl ester. After removal of methanol, the
35 residue was dissolved in pyrrolidine (5 mL) and heated at reflux for 20 hours. Removal of pyrrolidine gave a oily, brown product mixture which was purified by preparative TLC (ethyl acetate elution) to give 22 mg (36 %) of amides 21 a/21 b as a waxy, yellow solid: MS m/z (MH+) 552.2; HPLC 6.447 min.

5 Method F: 4[4-(1-Benzvl-1H-indol-5-vlamino)-quinazolin-6-vlethvnvri-1-methvl-
piperidin-4-ol (23).
1-Methvl-4-(4-phenoxv-quinazolin-6-vlethvnvl)-piperidin-4-ol (22): To a 100 mL round bottom flask under nitrogen were added, quinazoline 13 (1.32 g, 3.80 mmol), 4-ethynyl-1-methyl-piperidin-4-ol (1.06 g, 7.6 mmol), Pd(OAc)2 (51mg, 0.23 mmol), PPh3 (120 mg, 0.46
10 mmol) and triethylamine (18 mL). The flask was equipped with a reflux condenser and the mixture heated to 100°C for 16 hours. The dark solution was then cooled and the triethylamine removed under reduced pressure. The resulting residue was diluted with EtOAc (75 mL) and H2O (25 mL) and transferred to a separatory funnel. The organic layer was
washed successively with H2O (2x25 mL) and the combined aqueous washes back extracted
15 with EtOAc (25 mL). The combined organic layers were dried (MgS04) and the solvent removed under reduced pressure. The resulting black foam was purified on silica gel (50 g) eluting with 250 mL 30:1 CH2CI2:MeOH, then 400 mL 30:1:1 CH2Cl2:MeOH:NEt3 to provide
the desired product as a yellow foam (930 mg, 68%). 1H NMR: (CDCI3; 400 MHz) 5: 871 (s, 1H), 8.36 (d, 1H, J=1.9 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.80 (dd, 1H, J=8.7 Hz, 1.9 Hz), 7.45 (t,
20 2H, J=8.3 Hz), 7.31 (m, 1H), 7.21 (m, 2H), 2.72 (br, 2H), 2.47 (br, 2H), 2.31 (s, 3H), 2.09 (m, 2H), 2.00 (m, 2H).
4-r4-(1-Benzvl-1H-»ndol-5-vlamino)-quinazolin-6-vlethvnvn-1-methvl-piperidin-4-ol (23): In a 1 mL Wheaton vial quinazoline 22 (80 mg, 0.22 mmol) was combined with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridinium hydrochloride (5 mg, 0.04 mmol) and
25 phenol (104 mg, 1.11 mmol). The vial was capped and heated at 100°C for 16 hours. After cooling the contents of the Wheaton vial were solvated in a minimal amount of EtOAc and placed atop a silica gel (5g) column. Elution of the column with 1:1:0.1 Hexanes:EtOAc/NEt3
removed high Rf impurities. The desired product 23 (Rf 0.05,10:1 CH2Cl2:MeOH) was eluted off with 10:1 CH2CI2:MeOH and gave a yellow solid (65 mg, 60%). 1H NMR (DMSO d6; 400
30 MHz): 5: 9.88 (s, 1H, NH), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1.7 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.50 (d, 1H, J=3.1 Hz), 7.42 (d, 1H, J=8.9 Hz), 7.35 (dd, 1H, J=8.9 Hz, 1.9 Hz), 7.31-7.18 (m, 6H), 6.48 (dd, 1H, J+3.1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (br, 2H), 2.67 (br, 2H), 2.47 (s, 3H), 1.92 (br, 2H), 1.82 (br, 2H). LRMS: 488.2 (MH+), 126.1.
Method G: Acetic acid 3-f4-(1-benzenesulfonvl-1H-indol-5-vlamino)-quinazolin-35 6-vn-allvl ester (27).
3-(4-Phenoxv-quinazolin-6-vl)-acrvlic acid methyl ester (24): A pressure bottle was charged with quinazoline 13 (3.5 g, 10.0 mmol), methyl acrylate (6.0 g, 70.0 mmol), Pd(OAc)2 (140 mg, 0.62 mmol), PPh3 (320 mg, 1.22 mmol), DMF (4mL) and NEt3 (15 mL).
The tube was purged with nitrogen, sealed and heated at 110°C with stirring for 3 hours. The

5 mixture was cooled and diluted with EtOAc and transferred to a separatory funnel then washed with H2O and brine and dried (MgSO^. After filtration the filtrate was concentrated
under reduced pressure to provide a yellow solid which was recrystallized (EtOAc) to yield
ester 24 as a pale yellow solid (2.2g, 72%). 1HNMR (CDCI3: 400 MHz): 8 8.76 (s, 1H), 8.47
(s, 1H), 8.08 (d, 1H), 8.06 (d, 1H), 7.87 (dd, J-16 Hz, 1Hz), 7.48 (t, 2H), 7.35 (t, 1H), 7.25 (m, 10 2H), 6.60 (d, J=16 Hz, 1 Hz), 3.83 (s, 3H).
3-(4-Phenoxv-Quinazolin-6-vl)-prop-2-en-1-ol (25): To a solution of ester 24 (1.35 g, 4.41 mmol) in toluene (60 mL) under N2 at -78°C was added DIBAL-H (8.8 mL of a 1M
solution in toluene, 8.8 mmol) dropwise. The reaction was then warmed to 0°C and stirred for
30 minutes, then quenched with 30 mL of saturated Rochelle"s salt and the mixture stirred
15 overnight. The bilayer was transferred to a separatory funnel and the organic layer washed
with H2O and brine and dried (MgSC>4). After filtration the organic layer was concentrated
under reduced pressure to provide a yellow oil which was purified by silica gel chromatography eluting with 1:1 hexanes:EtOAc, then EtOAc. The allylic alcohol 25 (900 mg, 73%) was
isolated as a pale yellow oil. 1H NMR (CDCI3; 400 MHz): 5: 8.72 (s, 1H), 8.27 (s, 1H), 7.66
20 (m, 2H), 7.62 (m, 1H), 7.47 (m, 3H), 7.34 (m, 1H), 7.24 (m, 2H), 6.82 (dd, 1h), 6.56 (m, 1H), 4.41 (dd, 1H).
Acetic acid 3-(4-phenoxv-quinazolin-6-vH-aHvl ester (26): To alcohol 25 (900 mg, 3.23 mmol) and pyridine (0.8 mL, 10 mmol) in dry CH2CI2 (15 mL) at 0°C was added acetyl
chloride (0.3 mL, 4.2 mmol). The resulting mixture was stirred for 2 hours, the diluted with 25 CH2CI2 (10 mL) and 5% HCI (10 mL). The mixture was transferred to a separatory funnel and the organic layer washed with H2O and brine. The organic layer was dried (Na2S04), solids filtered and the solvent removed in vacuo to provide the desired acetate 26 as a yellow waxy solid (1.04 g, 100%).1H NMR (CDCI3; 400 MHz): 5: 8.72 (s, 1H), 8.30 (d, 1H, J=1.7 Hz),
7.98 (m, 2H), 7.49 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 6.84 (d, 1H, J=16.0 Hz), 6.46 (m, 1H), 30 4.79 (dd, 2H, J=6.2 Hz, 1.2 Hz), 2.11 (s, 3H).

5 Acetic acid 3-f4-(1-benzenesulfonvl-1H-indol-5-vlamino)-quinazolin-6-vn-allvl
ester (27). A mixture of ester 26 (630 mg, 1.97 mmol) and 5-amino-1-phenylsulfonylindole in phenol (3.0 g) was heated at 100°C for 20 hours. Excess phenol was removed by distillation and the resulting brown oil was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes then ethyl acetate. Quinazoline 27, (430 mg, 43%) was obtained as an off-10 white waxy solid. 1H NMR (CDCI3; 400 MHz): 5: 8.61 (s, 1H), 7.92 (m, 3H), 7.82 (m, 4H),
7.51 (m, 2H), 7.43 (m, 3H), 6.74 (d, 1H), 6.62 (d, 1H), 6.45 (dt, 1H), 4.74 (dd, 2H), 2.09 (s, 3H).
Method G": 3-r4-(1-Benzvl-1H-indazol-5-ylamino)-ouinazolin-6-vll-acrvlic acid methyl ester (28) and 3-f4-(4-Phenoxv-phenvlamino)-Quinazolin-6-vn-prop-2-en-1-ol
15 (29). An identical procedure to that used to transform intermediate 26 into 27 was used to convert 4-phenoxyquinazoline intermediates 24 and 25 into their respective 4-arylaminoquinazoline derivatives 28 and 29 respectively.
Method H: (6-f3-(6-Amino-3-aza-bicvclof3.1.01hex-3-vD-propenvn-quinazolin-4-yJM1 -benzenesulfonyl-1 H-indol-5-yl)-amine (30).
20 A mixture of palladium acetate (6 mg, 0.027 mmol) and P(C6H4-m-S03Na)3 (30 mg,
0.053 mmol) in water (0.3 mL) was stirred at room temperature for 1 hour, followed by the addition of allylic acetate 16 (150 mg, 0.30 mmol) and (1a,5a,6a)-6-t-butyloxycarbonylamino-3-azabicyclo[3.1.0]hexane (prepared as in Brighty, et. al. Synlett 1996, pp.1097-1099.) (71 mg, 0.36 mmol) in CH3CN (3 mL). The resulting reaction mixture was stirred at 50°C for 1.5 hours,
25 taken up in ethyl acetate (10 mL), and washed with aqueous NH4CI and water. The separated organic layer was dried over Na2S04 and concentrated to provide a brown oil. Purification by preparative TLC (ethyl acetate elution) yielded 31 mg of yellow solid. The BOC-protected product obtained was dissolved in methanol (5 mL)and deprotected by passing HCI gas through the solution with stirring. After concentration and drying under high vacuum, amine 30
30 was obtained as its HCI salt (18 mg, 11 %): MS m/z (MH+) 537.2; HPLC 4.423 min.
Method I: 4-f4-(4-Phenoxv-phenvlamino)-ouinazolin-6-vlethvnvn-tetrahvdro-pyran-4-ol hydrochloride (32).
4-(4-Chloro-quinazolin-6-vlethvnvl)-tetrahvdro-pyran-4-ol (31). A mixture of 4-ethynyl-4-hydroxytetrahydropyran (70 mg, 0.55 mmol), 4-chloro-6-iodoquinqzoline (145 mg,
35 0.50 mmol), bis(triphenyiphosphine)palladium(ll) chloride (24 mg, 7 mol %), copper (I) iodide (6.6 mg, 7 mol %), and diisopropylamine (56 mg, 0.55 mmol) in anhydrous THF (5 mL) was purged with N2 and stirred for 2 hours under N2 atmosphere. After dilution with ethyl acetate (30 mL), the mixture was washed with aqueous NH4CI, H20, and brine, dried over Na2S04, and concentrated to give the product as yellow solid. Crystallization from ethyl acetate/hexane

5 afforded 0.13 g (90%) of a tan solid: 1H NMR (CD3OD) 8 1.88 (m, 2H), 2.04 (m, 2H), 3.73 (m, 2H), 3.91 (m, 2H), 8.04 (s, 1H), 8.05 (S, 1H), 8.36 (s, 1H), 9.00 (S, 1H).
4-r4-(4-Phenoxv-Dhenvlamlno)-quinazolin-6-vlethvnvn-tetrahvdro-pyran-4-ol hydrochloride (32). A mixture of 4-(4-Chloro-quinazolin-6-ylethynyl)-tetrahydro-pyran-4-ol (43 mg, 0.15 mmol) and 4-phenoxyaniline (28 mg, 0.15 mmol) in 2 mL of t-BuOH/1,2-
10 dichioroethane (1:1) was heated at 90°C with stirring in a reaction vial for 1 hour. The reaction was cooled, diluted with CH2CI2 and the product was collected by filtration to provide 52 mg (73%) of 22 as a yellow solid: 1H NMR (CD3OD) 8 1.86 (m, 2H), 2.02 (m, 2H), 3.74 (m, 2H), 3.92 (m, 2H), 7.05 (m, 4H), 7.15 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H), 7.69 (d, J=6.8Hz. 2H), 7.81 (d, J=7.2Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.75 (s, 2H); HPLC: 6.36 min.
15 Method J: (3-Methoxv-4-phenoxv-DhenvlW6-piperidin-4-vlethvnvl-Quinazolin-4-
vD-amine
4-{4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid te/f-butyl ester: A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol), 4-chloro-6-iodoquinazoline (1.35 g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(ll)
20 (0.16 g, 0.23 mmol), copper(l) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperature under nitrogen for 2 hours. After concentration, the residue was dissolved in CH2CI2 (100 mL), washed with aqueous NH4CI and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 20% EtOAc in hexane afforded 163 g (94%)
25 of sticky, yellow oil: 1H NMR (CDCI3) S 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).
(3-Methoxy-4-phenoxy-phenyl)- 30 (131 mg, 0.304 mmol) and 3-methoxy-4-phenoxyaniline hydrochloride (77 mg, 0.306 mmol) in ,BuOH/CICH2CH2CI (1.0 /1.0 mL) was heated in a tightly capped reaction vial at 90 °C for 30 minutes. After cooling, the yellow mixture was diluted with MeOH and HCI gas was passed through the mixture for 10 minutes. After stirring for 2 hours, EtOAc was added to precipitate more solid which was collected by suction filtration, rinsed with EtOAc, and further dried to
35 give 105 mg (66%) of yellow solid: 1H NMR (CD3OD) 8 1.93 - 2.02 (m, 2H), 2.18 - 2.24 (m, 2H), 3.12 - 3.21 (m, 2H), 3.41 - 3.47 (m, 2H), 3.81 (s, 3H), 6.87 (d, 2H), 7.02 (t, 1H), 7.06 (d, 1H), 7.27 (t, 2H), 7.33 (dd, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 8.06 (d, 1H), 8.79 (s, 1H), 8.83 (s, 1H); MS m/z(MH+) 451.3.

5 Method K; (3-Methvl-4-Dhenoxv-Phenvn-f6-(1 -propvl-piperidin-3-vlethvnvn-
quinazolin-4-yll-amine
(3-Methyl-4-phenoxy-phenyl)-[6-{1-propyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine: (3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine (114 mg, 0.2 mmol) and propionaldehyde (116 mg, 2.0 mmol) were dissolved in MeOH/H20 (5 / 0.5
10 mL) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and followed by the addition of NaBH3CN (13 mg, 0.2 mmol) over a period of 1 hour. After stirring for another hour, the reaction was concentrated and the residue was partitioned between CH2CI2 (30 mL) and saturated Na2C03 (20 mL). The separated organic layer was dried over sodium sulfate and concentrated. Purification by preparative TLC using 10 %
15 MeOH in EtOAc gave the free base product which was converted to HCI salt to yield 42 mg (38%) of yellow solid: 1H NMR (CD3OD) 8 1.03 (t, 3H), 1.78 - 1.87 (m, 4H), 2.01 - 2.08 (m, 2H), 2.28 (s, 3H)t 2.96 (t, 1H), 3.07 - 3.19 (m, 3H). 3.31 (br, 1H), 3.59 (d, 1H), 3.80 (d, 1H), 6.94 (m, 3H), 7.09 (t, 1H), 7.34 (t. 2H), 7.53 (d, 1H), 7.63 (s, 1H), 7.80 (d, 1H), 8.05 (dd, 1H), 8.73 (s, 1H), 8.75 (S, 1H); MS mfz (MH+) 477.1.
20 Method K": f6-M-(2-Amino-ethvl)-piperidin-3-vlethvnvn-quinazolin-4-vlM3-
methvl-4-phenoxv-phenvH-amine
{6-[1-{2-Amino-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine: (3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine (114 mg, 0.2 mmol) and tert-butyl N-(2-oxoethyl)carbamate (320 mg, 2.0 mmol)
25 were dissolved in MeOH/H20 (5 / 0.5 mL) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and followed by the addition of NaBH3CN (13 mg, 0.2 mmol) over a period of 1 hour. After stirring for another hour, the reaction was concentrated and the residue was partitioned between CH2CI2 (30 mL) and saturated Na2C03 (20 mL). The separated organic layer was dried over sodium sulfate and concentrated.
30 Purification by silica gel column using 5% MeOH in EtOAc gave the free base which was dissolved in MeOH. HCI gas was passed through the solution for 5 min and the deprotected product precipitated as HCI salt. The mixture was diluted with EtOAc and the solid was collected by suction filtration, rinsed with EtOAc, and further dried to afford 83 mg (71%) of yellow solid: 1H NMR (CD3OD) 8 1.71 - 1.82 (br, 2H), 2.0 - 2.12 (br, 2H), 2.27 (s, 3H), 3.00 (t,
35 1H), 3.03 - 3.19 (br, 2H). 3.40 (br. 1H), 3.50 (s, 2H), 3.62 (br d, 1H), 3.70 (m, 1H), 3.89 (br d, 1H), 6.93 (m, 3H), 7.08 (t, 1H), 7.33 (t, 2H), 7.52 (d, 1H), 7.64 (s, 1H), 7.79 (d, 1H), 8.05 (d, 1H), 8.75 (s, 1H), 8.77 (s, 1H); MS m/r (MH+) 476.1.

5 Method L: 3-l2-r4-f3-Methvl-4-phenoxv-phenvlamino)-quinazolin-6-vn-ethvlV
piperidin-3-ol:
3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol:
A mixture of 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol dihydrochloride (100 mg, 0.19 mmol) and Pd/C (10%, 6 mg) was shaken in a Parr bottle with
10 hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated to small volume and added dropwise into EtOAc with stirring. The solid was collected by suction filtration, rinsed with EtOAc, and further dried to yield 89 mg (89%) of yellow solid: 1H NMR (CD3OD) 8 1.69 (dt, 1H), 1.81(br d, 1H), 1.95 (t, 3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d, 1H), 3.31(br, 1H), 6.94 (m, 3H), 7.08 (t, 1H), 7.34 (t,
15 2H), 7.55 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.58 (S, 1H), 8.73 (s, 1H); MS m/z (MH+) 455.2.
Method M; N-(3-r4-(3"Methvl-4-phenoxv-phenvlamino)-ouinazolin-6-vn-prop-2-vnvl)-2-morpholin-4-vl-acetam
2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide: 2-Chloro-N-
20 prop-2-ynyl-acetamide (385mg; 2.93 mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 ml; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (-20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2CI2. This solution was
25 transferred to a separatory funnel and washed with 1 x saturated NH4CI, brine, dried over Na2S04 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1:1 hex/EtOAc and collecting fractions with an Rf = 0.25. This yielded the 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCI3) 5 4.12 (2H, s), 4.40 (2H, d, J = 5.2 Hz), 7.91-
30 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). Irms (M+): 294.0, 296.0, 298.1.
2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide: A solution of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (50 mg; 0.17mmol) and 3-methyl-4-phenoxyaniline (36 mg; 0.9 equiv.) in 1,2-
35 dichloroethane (1 ml) and f-butanol (1 ml) was heated at 87° C for 30 minutes. The mixture was then cooled to room temperature and diluted with ethyl acetate to further facilitate precipitation. The solution was then filtered to give the coupled product as a yellow powder (73 mg; 90%). 2.28 (3H, s), 4.10 (2H, s), 4.30 (2H, s), 6.93 (3H, d), 7.09 (1H, t), 7.34 (2H, t), 7.50-7.53 (1H, dd, J = 2.6, 6 Hz), 7.63 (1H, d, J = 2.4 Hz), 7.78 (1H, d, J = 8 Hz), 8.06-8.08
40 (1H, dd, J = 1.4, 7.2 Hz), 8.68 (1H, d, J = 1.2 Hz), 8.75 (1H, s). lrms(M+): 457.0, 4.59.1; (M-): 455.7, 419.6

5 N-[3-t4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-
morpholin-4-yl-acetamide: To a solution of 2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide (63 mg; 0.12 mmol) in toluene (10 ml) was added 3 equivalents of morpholine (31 mg) and the mixture heated at reflux overnight. The reaction was cooled to room temperature and the morpholine salts were filtered out and
10 the solvent removed from the filtrate. The residue was redissoived in CH2CI2 with a small amount of methanol and HCI gas was bubbled through the solution for 2-3 minutes. The solution was then concentrated to 2-3 ml, diluted with ethyl acetate and filtered to obtain N-{3-t4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamide as a yellow/brown solid (65 mg; 94%). 1H NMR (400 MHz; CD3OD) 8 2.27 (3H, s), 3.21 (2H,
15 m), 3.56 (2H, m), 3.87 (2H, m), 4.04 (2H, m), 4.09 (2H, s), 4.36 (2H, s), 6.93 (3H, d, J = 8.4),
7.09 (1H, t, J = 7.4 Hz), 7.34 (2H, t. J = 8 Hz), 7.54 (1H, dd), 7.65 (1H, s), 7.82 (1H, d, J = 8.8
Hz), 8.06 (1H, d, J = 8.4 Hz), 8.76 (1H, s), 8.80 (1H, s). Irms(M+): 508.0; (M-): 506.0.
Method N; (3-Methvl-4-phenoxv-phenvlM6-piperidin-4-vlethvnvl-pvridof3.4-dlpvrimidin-4-vil-amine
20 4,6-Dichloro-pyrido[3,4-d]pyrimidine: DMF (0.1 ml) was added to 6-chloro-3H-
pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed by dropwise addition of thionyl chloride (10 ml). The flask was fitted with a condenser and a drying tube and the contents heated to reflux for -20 minutes whereupon the solids dissolved. The heating was continued for a further 1h and then cooled. Toluene was added to wash the sides of the flask and the
25 solvents were evaporated in vacuo. Azeotroping with toluene was repeated twice and the crude so obtained was taken through to the next step.
(6-Chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine: The 4,6-dichloro-pyrido[3,4-d]pyrimidine obtained from the previous reaction was taken up in dioxane (50 ml), the 3-methyl 4-phenoxy aniline hydrochloride (2.8 g, 12 mmol) was added
30 and the contents heated to an external bath temperature of -80 °C for 3 hours, whereupon yellow precipitation occurred. Further dioxane (20 ml) was added and the contents heated at ~75°C for 12 hours. The solution was then filtered and the yellow solid placed under vacuum to provide the desired (6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine hydrochloride (3.6g, -100%). 1H NMR (CD3OD; 400MHz) 6 9.05 (s, 1H), 8.87 (s, 1H),
35 8.64 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.58 (dd, J= 8.7, 2.5 Hz, 1H),7.35 (dd, J=8.7, 7.5 Hz, 2H),
7.10 (t, J=7.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 3H), 2.29 (s, 3H). MS m/z (MH+): 363.2
(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin-4-
yl)-amine: A flame dried pear shaped flask was charged with the (6-chloro-pyrido[3,4-
d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine hydrochloride (200 mg, 0.5 mmol) , the
40 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (314 mg, 1.5 mmol), Pd(PhCN)2CI2
(19mg, 0.05 mmol), 1,4-bis (diphenylphosphino)butane (32 mg, 0.075 mmol) and Cul (4.8 mg,

5 0.025 mmol). Dioxane (5ml) was added and to this stirred suspension under Ar was added diisopropylamine (0.32 ml, 2.28 mmol) whereupon a lot of the solid dissolved. The flask (fitted with a condenser) was then placed in a preheated oil-bath and heated at a bath temperature of 104 °C for 14 hours at which point LC/MS indicated disappearance of starting material. The reaction mixture was then filtered through a plug of silica, concentrated and chromatographed
10 using a gradient elution of 20-80% EtOAc-hexanes to give the desired coupled product as a
solid (165 mg, 62%). The solid was taken up in CH2CI2 (and sparing amounts of MeOH to
help in dissolution), HCI (g) was bubbled through, followed by addtition of ether whereupon
solid precipiated out which was filtered and placed under vacuo to give the desired (3-methyl-
4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin-4-yl)-amine as a
15 dihydrochloride salt. 1H NMR (CDCI3; 400 MHz) 5 9.12 (s, 1H), 8.85(s, 1H), 8.68 (s, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.58 (dd, J= 8.7, 2.5 Hz, 1H),7.34 (dd, J=8.3, 7.5 Hz, 2H), 7.10 (app t, J=7.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 3H), 3.42 (m, 2H), 3.19 (m, 3H), 2.29 (s, 3H), 2.22 (m, 2H), 2.0 (m, 2H). MS m/z (MH+): 436.3.
Method O; 4-Amino-4-methvl-1-r4-(3-methvl-4-phenoxv-phenvlamino)-quinazolin-6-vn-20 pent-1-vn-3-ol
5-(4-Chloro-quinazolin-6-ylethynyl)-4,4-dimethyl-oxazolidin-2-one: A mixture of
4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4-chloro-6-iodoquinazoline (1.63
g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(ll) (200 mg, 0.28 mmol), copper
iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30
25 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2CI2 (80 mL), washed with aqueous NH4CI and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCI3) 5 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (brs, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J
30 = 8.8 Hz), 8.38 (d, 1H, J = 2.0 Hz), 9.05 (s, 1H).
4-Amino-4-methyl-1-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol: A solution of 5-(4-Chloro-quinazolin-6-ylethynyl)-4,4-dimethyl-oxazolidin-2-one (151 mg, 0.5 mmol) and 3-methyl-4-phenoxyaniline hydrochloride (130 mg, 0.55 mmol) in tBuOH/CICH2CH2CI (1:1, 2.0 mL) was heated in a tightly capped reaction vial at 90 °C for 30
35 minutes. After cooling, the yellow mixture was diluted with EtOAc to precipitate more solid which was collected by suction filtration, rinsed with EtOAc, and further dried to give 215 mg (86%) of yellow solid. This material (215 mg, 0.43 mmol) was immediately combined with KOH (0.51 g, 9.0 mmol) in MeOH/H20 (9/3 mL) and refluxed for 20 hours. After cooling, the reaction was neutralized with 0.60 g (10.0 mmol) of AcOH and concentrated. The residue was
40 suspended in CH2CI2 and purified on a silica gel column using 20% MeOH in CH2CI2. The purified free base was converted to HCI salt to afford 46 mg (22%) of yellow solid: 1H NMR

5 (CD3OD) 5 1.49 (s, 3H), 1.52 (s, 3H), 2.28 (s, 3H), 4.64 (s, 1H), 6.93 (m, 3H), 7.09 (t, 1H), 7.34 (m, 2H), 7.55 (dd, 1H), 7.65 (d, 1H), 7.83 (d, 1H), 8.13 (dd, 1H), 8.77 (s, 1H), 8.87 (s, 1H); MS m/z (MH+) 439.2.
The following examples were prepared using the methods described above. In the Table below, the term "min" refers to minutes. Example numbers in the following table do not 10 correspond to compound numbers referred to in the preceding experimental section,
TABLE

Example Method
to
Prepare IUPAC name LRMS (MH+) HPLC Retention time (min)
1 I 2-Methyl-4-[4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-but-3-
yn-2-ol 396.1 6.88
2 G" 3-[4-(4-Phenoxy-phenyiamino)-quinazolin-6-yl]-(E)-prop-2-en-1 -ol 370.1 6.06
3 B (6-Cyclobutyl-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine 368.2 8.35
4 B (6-Cyclopropyl-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine 354.2 7.62
5 I 1-Methoxy-2-methyl-4-[4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-but-
3-yn-2-ol 426.1 6.66
6 I 4-[4-(4-Phenoxy-phenylamino)-
quinazolin-6-yl]-2-pyridin-4-yl-but-3-
yn-2-ol 459.0 6.56
7 I 1 -[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-cyclohexanol 436.1 7.80
8 G N-Methyl-3-[4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-
acrylamide 397.2 5.81
9 G" 3-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-(E)-prop-2-en-1 -ol 368.2 6.20
10 G" N,N-Diethyl-3-[6-(3-hydroxy-(E)-propenyl)-quinazolin-4-ylamino]-benzamide 377.2 4.28
11 I 4-[4-(4-Benzyloxy-phenylamino)-quinazolin-6-ylethynyl]-1 -methyl-piperidin-4H3l 465.1 4.88
12 i 4-[4-(1 -Benzenesulfonyl-1 H-indol-5-
ylamino)-quinazolin-6-
ylethynyl]-1-methyl-piperidin-4-ol 538.2, 445.0 4.86
13 I 4-[4-(4-Benzyl-phenylamino)-quinazolin-6-ylethynyl]-1 -methyl-piperidin-4-ol 449.2, 356.2 5.11
14 I 1 -Methyl-4-[4-(4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-4-ol 451.2, 143.2 4.89
15 B 3-(6-Cyclobutyl-quinazolin-4-ylamino)-N, N-diethyl-benzamide 375.3 6.24

16 B (4-Benzyl-phenyl)-(6-cyclobutyl-quinazolin-4-yl)-amine 366.3 8.49
17 B (6-Cyclobutyl-quinazolin-4-yl)-(1H-indol-5-yl)-amine 315.3 5.63
18 B (4-Benzyloxy-phenyl)-(6-cyclobutyl-quinazolin-4-yl)-amine 382.2 7.98
19 G" 3-[4-{1H-lndol-5-ylamino)-quinazolin-6-yl]-(E)-prop-2-en-1 -ol 317.3 3.66
20 G" 3-[4-(4-Benzyloxy-phenylamino)-quinazolin-6-yll-(E)-prop-2-en-1 -ol 384.3 5.85
21 I 4-[4-(4-Phenoxy-phenylamino)-
quinazolin-6-ylethynyl]-tetrahydro-
pyran-4-ol 438.1 6.34
22 I 4-[4-(1 -Benzenesuifonyl-1 H-indol-5-
ylamino)-quinazolin-6-yl]-2-
methyl-but-3-vn-2-ol 483.2 6.55
23 I 4-[4-(1H-lndol-5-ylamino)-quinazolin-6-yl]-2-methvl-but-3-yn-2-ol 343.2 4.61
24 I 4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-2-methyl-but-3-yn-2-ol 394.2 7.06
25 C 3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-cyclobutanecarboxylic acid ethyl ester 440.2 7.93/7.83
26 B (1-Benzenesulfonyl-1 H-indol-5-yl)-(6-cyclobutyl-quinazolin-4-yl)-amine 455.2 7.80
27 1 4-[4-(4-Pnenoxy-pnenylamino)-
quina2olin-6-yl]-2-pyridin-3-yl-but-3-
yn-2-ol 459.2 6.64
28 1 4-[4-(1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-2-pyridin-3-yl-but-3-yn-2-ol 546.2 6.27
29 G" 3-[4-(l-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-(E)-prop-2-en-1-ol 457.2 5.80
30 G" 3-[4-(l-Benzyl-1H-indol-5-ylamino)-quinazolin-6-yl]-(E)-prop-2-en-1-ol 407.3 5.72
31 G" 3-[4-( 1-Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl]-( E)-prop-2-en-1 -ol 408.2 5.15
32 1 4-[4-(i -Benzyl-1 H-indol-5-ylamino)-
quina2olin-6-ylethynyl]-1-methyl-
piperidin-4-ol 488.2 4.84
33 1 4-[4-(4-Benzyl-phenylamino)-
quinazolin-6-ylethynyl]-tetrahydro-
pyran-4-ol 525.1 6.11
34 1 4-[4-(1 -Benzenesulfonyl-1 H-indol-5-
ylamino)-quinazolin-6-ylethynyl]-
tetrahvdro-pyran-4-ol 436.2 6.56
35 A (1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-imidazol-1 -yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 505.2 5.80
36 1 5-Methoxy-3,5-dimethyl-1 -|4-(4-
phenoxy-phenylamino)-quinazolin-6-
yl]-hex-1-yn-3-ol 468.3 8.01
37 1 1 -{4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-5-methoxy-3,5- 466.3 8.21

dimethyl-hex-1 -yn-3-ol
38 I 1 -[4-( 1 -Benzenesulfonyl-1 H-indol-5-
yiamino)-quinazolin-6-yl]-5-
methoxy-3,5-dimethyl-hex-1-yn-3-ol 555.2 7.55
39 I 4-[4-(4-Benzyl-phenylamino)-
quinazolin-6-yl]-2-pyridin-3-yl-but-3-
yn-2-ol 457.4 6.79
40 I 4-[4-(4-Benzyl-phenylamino)-
quinazolin-6-yl]-2-pyridin-4-yl-but-3-
yn-2-ol 457.3 6.71
41 A (1 -Benzenesulfonyl-1 H-indol-5-yl)-[6-(3-d/methylamino-prop-1 -ynyiy quinazolin-4-yl]-amine 482.2 5.16
42 G Acetic acid 3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-(E)-allvl ester 499.2 7.01
43 C 3-[4-(l -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutanecarboxylic acid ethyl ester 527.2 7.54/7.64
44 I 1-Methyl-4-{4-[1-(propane-2-sulfonyl)-1 H-indol-5-ylamino]-quinazolin-6-ylethynyl>-piperidin-4-ol 504.3 4.41
45 H {6-[3-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl(1a,5a,6a))-propenyl]-quinazolin-4-yl}-(1 -benzenesulfonyl-1 H-indol-5-yl)-amine 537.2 4.42
46 I 2-Methyl-4-{4-[1-(propane-2-sulfonyl)-
1H-indol-5-ylamino]-quinazolin-6-yl}-
but-3-yn-2-ol 449.2 6.11
47 I 4-[4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl]-2-methyl-but-3-yn-2-ol 410.3 6.63
48 I N,N-Diethyl-3-[6-(3-hydroxy-3-methyl-but-1 -ynyl)-quinazolin-4-ylamino]-benzamide 403.3 5.06
49 I 4-[4-(1 -Benzenesulfonyl-1 H-indol-5-
ylamino)-quinazolin-6-yl]-2pyridin-4-yl-
but-3-yn-2-ol 546.3 6.26
50 D {3-[4-( 1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutyl}-methanol 485.2 5.97
51 A (1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(2-methoxy-ethylamino)-prop-1 -ynyl]-quinazolin-4-yl}-amine 512.2 5.11
52 A (1 -Benzenesulfonyl-1 H-indol-5-yl)-{6-[3-(2-piperidin-1-yl-ethylamino)-prop-1 -ynyl]-quinazolin-4-yl}-amine 563.2 5.23
53 E {3-[4-(l -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-cyclobutyl}-pyrrolidin-1 -yl-methanone 552.2 6.45/6.64
54 A (1 -Benzenesulfonyl-1 H-indol-5-yl)-[6-(3-morpholin-4-yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 524.2 6.45
55 A (1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-{1,1 -dioxo-1 &-thiomorpholin-4-yl)- 572.2 6.36



89 I 4,4-Dimethyl-1-{4-[1-(propane-2-sulfonyl)-1 H-indol-5-ylamino]-quinazolin-6-yl}-pent-1 -yn-3-ol 477.2 7.12
90 i 1 -[4-(1 -Benzenesulfonyl-1 H-indol-5-
ylamino)-quinazolin-6-yl]-4,4-dimethy1-
pent-1-yn-3-ol 511.2 7.51
91 I 1 -[4-(4-Benzyloxy-phenylamino)-
quinazolin-6-yl]-4,4-dimethyl-pent-1-
yn-3-ol 438.2 7.74
92 I 4,4-Dimethyl-1 -{4-[4-(1 -phenyl-
ethoxy)-phenylamino]-quinazolin-6-yl}-
pent-1-yn-3-ol 452.3 7.95
93 3-[4-(1 -Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yIethynyl]-piperidin-3-ol 475.2 4.42
94 N,N-Diethyl-3-[6-(3-hydroxy-piperidin-
3-ylethynyl)-quinazolin-4-ylamino]-
benzamide 444.3 3.74
95 3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yiethynyl]-piperidin-3-ol 437.2 4.97
96 3-[4-(4-Benzyloxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 451.3 4.94
97 3-l4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 471.2 5.38
98 3-[4-(4-Benzyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 435.2 5.16
99 3-[4-(1H-lndol-5-ylamino)-quinazolin-6-ytethynyl]-piperidin-3-ol 384.2 3.22
100 I 3-[4-(1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-1-cyclobutyl-prop-2-yn-1 -ol 509.1 7.21
101 I 1 -Cyclobutyl-3-{4-[1 -(propane-2-sulfonyl)-1 H-indol-5-ylamino]-quinazolin-6-yl}-prop-2-yn-1 -ol 475.2 6.81
102 I 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -cyclobutyl-prop-2-yn-1 -ol 456.2 8.11
103 I 1 -Cyclobutyl-3-[4-(3-methyl-4-
phenoxy-phenylartiino)-quinazolin-6-
yl]-prop-2-yn-1-ol 436.2 7.95


104 I 3-[4-( 1 -Benzyl-1 H-indazol-5-ylamino)-
quinazolin-6-yl]-1-cyclobutyl-prop-2-
yn-1-ol 460.2 6.69
105 I 1 -Cyclobutyl-3-[4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
yn-1-ol 422.2 7.59
106 J 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -pyrrolidin-2-yl-prop-2-yn-1 -ol 451.2 5.26
107 I 3-[4-(1 -BenzenesulfonyM H-indol-5-
ylamino)-quinazolin-6-ylethynyl]-1-
methyl-piperidin-3-ol 538.2 4.92
108 J 3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
pyrrolidin-3-ol 437.2 5.08
109 J 3-[4-(1 -Benzyl-1 H-indol-5-ylamino)-
quinazorin-6-yl]-1-pyrrolidin-2-yl-prop-
2-yn-1-ol 474.2 5.00
110 I 5-[4-(4-Benzyl-phenylamino)-
quinazolin-6-ylethynyl]-4,4-dimethyl-
oxazolidin-2-one 449.2 7.03
111 I 4,4-Dimethyl-5-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-oxazolidin-2-one 465.2 7,7
112 I 5-[4-(3-Chloro^4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
4,4-dimethyl-oxazolidin-2-one 485.1 7.34
113 I 5-[4-(1 -Benzyl-1 H-indazol-5-ylamino)-
quinazolin-6-ylethynyl]-4,4-dimethyl-
oxazolidin-2-one 489.2 6.00
114 I 5-[4-( 1 -Benzyl-1 H-indol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one 488.2 6.58
115 I 5-[4-(1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one 538.1 6.21
116 J 3-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
pyn-olidin-3-ol 457.1 5.27
117 J 3-[4-(1 -Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol 461.2 4.31
-*-


118 J 3-{4-[1 -(Propane-2-sulfonyl)-1 H-indol-
5-ylamino]-quinazolin-6-ylethynyl}-
pyrrolidin-3-ol 476.1 4.35
119 J 3-[4-(3-Benzyloxy-phenylamino)-quinazolin-6-ylethynyf]-pyrrolidin-3-ol 437.2 4.85
120 J 3-[4-(3-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrroiidin-3-ol 423.2 4.87
121 J 3-[4-(1-Benzyl-1 H-indol-5-ylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol 460.0 4.81
123 J 3-[4-(1-Benzenesulfonyl-1H-indol-5-
ylamino)-quinazolin-6-ylethynyl]-
pyrrolidin-3-ol 510.2 4.82
124 J 3-[4-(1 -Benzyl-1 H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 474.2 4.92
125 J 3-(4-[3-Methyl-4-(pyridin-2-
ylmethoxy)-phenylamino]-quinazolin-
6-ylethynyl}-piperidin-3-ol 466.2 4.14
126 J 3-{4-[1 -(Propane-2-sulfonyl)-1 H-indol-
5-ylamino]-quinazolin-6-ylethynyl}-
piperidin-3-ol 490.1 4.46
127 J 3-[4-(4-Phenoxy-phenylamino)-
quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-
2-yn-1-ol 437.2 5.08
128 J 3-[4-(1 -Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol 475.2 4.45
129 J 3-{4-[1 -(Propane-2-sulfonyl)-1 H-indol-5-ylamino]-quinazolin-6-yl}-1-pyrrolidin-2-yl-prop-2-yn-1 -ol 490.2 4.52
130 J 3-[4-(4-Benzyloxy-phenylamino)-
quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-
2-yn-1-ol 451.2 4.99
131 J 3-[4-(1 -Benzenesulfonyl-1 H-indol-5-
ylamino)-quinazolin-6-yl]-1-pyn*olidin-
2-yl-prop-2-yn-1-ol 524.2 4.94
132 0 4-Amino-1 -[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1 -yn-3-ol 459.1 5.41
133 J 3-[4-{3-Fluoro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]- 455.2 5.19

piperidin-3-ol
134 J 3-[4-(4-Phenoxy-3-trifluoromethyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 505.1 5.61
135 J 4-Amino-1-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-pent-1-yn-3-ol 498.1 4.82
136 J 3-{4-[4-(3-Methoxy-phenoxy)-3-
methyl-phenylamino]-quinazolin-6-
ylethyny!}-piperidin-3-ol 481.2 5.15
137 J 3-[4-(3-Methyl-4-m-tolyloxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 465.1 5.56
138 J 3-{4-[4-(2-Methoxy-phenoxy)-3-
methyl-phenylamino]-quinazolin-6-
ylethynyl}-piperidin-3-ol 481.1 4.94
139 J 3-[4-(3-Methyl-4-o-tolyloxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 465.2 5.50
140 L 3-{2-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-ethyl}-
piperidin-3-ol 455.2 4.93
141 J 3-{4-[3-Chloro^4-(pyridin-2-
ylmethoxy)-phenylamino]-quinazoiin-
6-ylethynyl}-piperidin-3-ol 486.0 4.38
142 J 3-[4-(5-Methyl-6-phenoxy-pyridin-3-
ylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 452.0 4.70
143 L 3-{2-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol 439.2 4.81
144 I 5-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
4,4-dimethyl-oxazolidin-2-one 481.2 6.64
145 I 1-Methyl-3-[4-(3-methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 465.2 5.34
146 L 3-{2-[4-(1 H-lndol-5-ylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol 388.3 2.86
147 ! 3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-1 -methyl-piperidin-3-ol 481.1 4.96


148 I 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-1 -methyl-piperidin-3-ol 485.1 5.48
149 J Endo-a-3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 497.1 5.47
150 J Endo- a-3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 493.2 4.95
151 J Endo- cc-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 477.2 5.29
152 J Exo-B-3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 497.1 5.35
153 J Exo- B-3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
8-
aza-bicyclo[3.2.1 ]octan-3-ol 493.2 4.86
154 J Exo- B-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 477.2 5.21
155 J Exo- p-3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 463.2 4.96
156 J (-)-3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 451.2 5.22
157 J (+)-3-[4-(3-Methyl~4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 4512 5.22
158 J Endo-a-3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1 ]octan-3-ol 463.2 5.02
159 J 4-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-4-ol 467.2 4.77
160 J 4-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-4-ol 471.1 5.26
161 J 4-[4-(3-Methyl-4-phenoxy- 451.2 5.09

pheny!amino)-quinazolin-6-ylethynyl]-piperidin-4-ol
162 I 4-[4-(1-Benzenesulfonyl-1H-indol-5-
ylamino)-quinazolin-7-
ylethynyl]-tetrahydro-pyran-4-ol 525.1 6.02
163 I 4-[4-(4-Phenoxy-phenylamino)-
quinazolin-7-ylethynyl]-tetrahydro-
pyran-4-ol 438.1 6.25
164 J 1 -(3-Aza-bicyclo[3.1.0]hex-6-yl(1 a, 5a, 6a))-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-yn-1-ol 479.1 5.73
165 J 1-(3-Aza-bicyclo[3.1.0]hex-6-yl(1a, 5a, 6a))-3-[4-(3-methyM-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-yn-1-ol 463.1 5.16
166 J 1-(3-Aza-bicyclo[3.1.0]hex-6-yl(1a, 5a, 6a))-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-yn-1 -ol 449.0 4.89
167 J 3-[4-(4-Phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol 437.2 5.09
168 J 3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-7-y!ethynyl]-
piperidin-3-ol 467.2 4.97
169 J 3-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-7-ylethynyl]-
piperidin-3-ol 471.1 5.48
170 J 3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-7-ylethynyl]-
piperidin-3-ol 451.2 5.35
171 0 4-Amino-1 -[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1 -yn-3-ol 455.2 4.91
172 0 4-Amino-4-methyl-1-[4-(3-methyM-
phenoxy-phenylamino)-quinazolin-6-
yl]-pent-1-yn-3-ol 439.2 5.26
173 J 3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 369.2 4.11
174 J 3-t4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 397.1 4.43
175 J [6-(4-Amino-tetrahydro-pyran-4- 451.2 5.43

ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
176 J [6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(4-phenoxy-phenyl)-amine 437.2 5.15
177 J [6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine 467.2 5.00
178 J (3-Methoxy-4-phenoxy-phenyl)-(6-piperidin-2-ylethynyl-quinazolin-4-yl)-amine 451.0 5.25
179 J (3-Methyl-4-phenoxy-phenyl)-(6-piperidin-2-ylethynyi-quinazolin-4-yl)-amine 435.0 5.71
180 J (4-Phenoxy-phenyl)-(6-piperidin-2-ylethynyl-quinazolin-4-yl)-amine 421.2 5.32
181 J (3-Chloro-4-phenoxy-phenyl)-(6-
piperidin-2-ylethynyl-quinazolin-4-yl)-
amine 455.0 5.84
182 J 3-[4-(4-Phenoxy-phenylamino)-
quinazolin-6-yl]-1-piperidin-2-yl-prop-
2-yn-1-ol 451.2 5.16
183 J 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -piperidin-2-yl-prop-2-yn-1 -ol 465.2 5.44
184 J 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -piperidin-2-yl-prop-2-yn-1 -ol 485.1 5.58
185 J 3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-€-yl]-1 -piperidin-2-yl-prop-2-yn-1 -ol 4812 5.05
186 J (4-Phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine 421.2 5.27
187 J (3-Methoxy-4-phenoxy-phenyl)-(6-
piperidin-3-ylethynyl-quinazolin-4-yl)-
amine 451.2 5.21
188 J (3-Chloro-4-phenoxy-phenylH6-
piperidin-3-ylethynyl-quinazolin-4-yl)-
amine 455.0 5.79
189 J 3-[4-(4-Phenoxy-phenylamino)- 451.0 5.00

quinazolin-6-yl]-1-piperidin-3-yl-prop-2-yn-1-ol
190 J 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-piperidin-3-yl-prop-2-yn-1 -ol 465.0 5.26
191 J 3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-piperidin-3-yl-prop-2-yn-1 -ol 481.0 4.86
192 J 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -piperidin-3-yl-prop-2-yn-1 -ol 485.0 5.34
193 I 1 -Methyl-4-[4-(3-methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-4-ol 465.0 5.18
194 I 4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-1 -methyl-piperidin-4-ol 485.0 5.34
195 I 4-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
1-
methyl-piperidin-4-ol 481.0 4.81
196 I N, N-Diethyl-3-f6-(4-hydroxy-
tetrahydro-pyran-4-ylethynyl)-
quinazolin-4-ylaminol-benzamide 445.3 4.66
197 A (3-{3-[4-( 1 -Benzenesulfonyl-1 H-indol-5-ylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 550.3 5.38
198 I 4-{4-[1 -(Propane-2-sulfonyl)-1 H-indol-
5-ylamino]-quinazolin-6-ylethynyl}-
tetrahydro-pyran-4-ol 491.2 5.66
199 I 4-[4-(1H-lndol-5-ylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol 385.2 4.22
200 A 1 -Methyl-3-[4-(4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 451.3 5.04
201 J 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1 -pyrrolidin-2-yl-prop-2-yn-1 -ol 471.0 5.40
202 I 1 -[4-( 1 -Benzenesulfbnyl-1 H-indol-5-
ylamino)-quinazolin-6-yl]-pent-1-yn-3-
ol 430.1 7.57
203 I 1 -{4-(1 -(Propane-2*sulfonyl)-1 H-indol-5-ylamino]-quinazolin-6-yl}-pent-1-yn-3-ol 449.2 6.28
204 I 1 -[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 430.1 7.57

205 I 1 -[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 410.2 7.39
206 I 1 -[4-(1 -Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl]-pent-1 -yn-3-ol 434.2 6.16
207 I 1 -[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-pent-1 -yn-3-ol 396.2 7.04
208 I 3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol 469.1 5.32
209 J 3-{4-[4-(4-Methoxy-phenoxy)-3-
methyl-phenylamino]-quinazolin-6-
ylethynyl}-piperidin-3-ol 481.2 5.10
210 J 4-Amino-1 -[4-(3-methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 425.2 5.13
211 J 4-Amino-1 -[4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 410.3 4.86
212 J 4-Amino-1-[4-(3-chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 445.2 5.27
213 J 4-Amino-1 -(4-11 -(propane-2-sulfonyl)-
1H-indol-5-y!amino]-quinazolin-6-yl}-
pent-1-yn-3-ol 464.1 4.37
214 J 4-Amino-1-{4-[4-(3-fIuoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol 443.2 5.25
215 J 3^4-[4-(4-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol 469.2 5.28
216 J 3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol 469.2 5.22
217 J 3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 467.2 4.85
218 J 3-{4-[1 -(3-Fluoro-benzyi)-1 H-indazol-
5-ylamino]-quinazolin-6-ylethynyl}-
piperidin-3-ol 493.2 4.23
219 J 3--{4-[1-(3-Methoxy-benzyl)-1 H-
indazo!-5-ylamino]-quinazolin-6-
ylethynyl}-piperidin-3-ol 505.11 4.41
220 J 3-{4-[1 -(3-Methyl-benzyl)-1 H-indazol-
5-ylamino]-quinazolin-6-ylethynyl}-
piperidin-3-ol 489.2 4.70
221 J 3-{4-[1 -(2-Fluoro-benzyl)-1 H-indazol-
5-ylamino]-quinazolin-6-ylethynyl}-
piperidin-3-ol 493.2 4.47
222 J 2-Chloro-N,N-diethyl-4-[6-(3-hydroxy-
piperidin-3-ylettiynyl)-quinazolin-4-
ylaminol-benzamide 478.2 4.08
223 J 3-[4-(3-Bromo-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 516.0 5.41

224 J 3-[4-(3,5-Dichloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 506.1 5.64
225 J 3-[4-(3-Methyl-4-phenylsulfanyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 467.2 5.64
226 J 3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
pyrrolidin-3-ol 453.2 4.76
227 J 4-Amino-1 -[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol 441.2 4.78
228 J 1 -[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-pent-1-
yn-3-ol 426.2 6.83
229 J 3-[4-(4-Benzenesulfinyl-3-methyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 483.1 4.08
230 J 3-[4-(4-Benzenesulfonyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 485.1 4.49
231 J 3-[4-(4-Benzenesulfinyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol 469.1 3.89
232 J 3-[4-(4-Benzenesulfonyl-3-methyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 499.1 4.65
233 J 3-[4-(4-Cyclopentyloxy-3-methyl-
phenylamino)-quinazoiin-6-ylethynyl]-
Piperidin-3-ol 443.2 5.30
234 J 3-[4-(4-Cyclobutoxy-3-methyl-
phenylamino)-quinazolin-6-yiethynyl]-
piperidin-3-ol 429.2 4.97
235 J 5-[6-(3-Hydroxy-piperidin-3-ylethynyl)-
quinazolirM-ylamino]-2-phenoxy-
benzonitrile 462.2 4.86
236 J 3-[4-(4-Cyclohexyloxy-3-methyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 457.3 5.62
237 J 3-[4-(4-Phenylamino-phenylamino)-quinazolin-6-ylethynyl1-piperidin-3-ol 436.2 4.58
238 J 3-[4-(3-Phenyl-1H-indazol-6-ylamino)-quinazolin-6-yiethynyl]-piperidin-3-ol 461.2 3.86
239 4-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-2-
methyl-but-3-yn-2-ol 410.2 7.22
240 4-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-2-
methyl-but-3-yn-2-ol 430.1 7.39
241 4-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-2-
methyl-but-3-yn-2-ol 426.2 6.67
242 [6-(3-Methyl-but-1-ynyl)-quinazolin-4-ylH3-methyl-4-phenoxy-phenyl)-amine 394.2 9.08
243 (3-Methoxy-4-phenoxy-phenyl)-[6-(3- 410.2 8.47

methyl-but-1-ynyl)-quinazolin-4-yl]-amine
244 I (3-Chloro-4-phenoxy-phenyl)-[6-(3-
methyl-but-1-ynyl)-quinazolin-4-yl]-
amine 414.1 9.21
245 J 3-[4-(4-Benzyl-3-methyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 449.2 5.37
246 J [6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-ylH3-methyl-4-phenoxy-phenyl)-amine 395.2 5.13
247 J (6-(3-Amino-3-methyl-but-1-ynyl)-
quinazolin-4-yl]-(4-phenoxy-phenyl)-
amine 409.2 5.45
248 J [6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenylj-amine 425.2 5.04
249 J [6-(3-Amino-3-methyl-but-1-ynyl)-
quinazolin-4-yl]-(3-chloro-4-phenoxy-
phenyl)-amine 429.1 5.56
250 J [6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-(4-phenoxy-phenyl)- amine 367.2 4.78
251 J [6-(3-Amino-prop-1 -ynyl)-quinazolin-
4-yl]-(3-methyl-4-phenoxy-phenyl)-
amine 381.2 5.09
252 J [6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine 397.2 4.72
253 J {6-(3-Amino-prop-1 -ynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine 401.1 5.28
254 J [6-(3-Methylamino-prop-1 -ynyl)-quinazolin-4-yl]-(4-phenoxy-phenyl)-amine 381.2 5.05
255 J [6-(3-Methylamino-prop-1 -ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyD-amine 395.2 5.32
256 J (3-Methoxy-4-phenoxy-phenyl)-[6-(3-methylamino-prop-1-ynyl)-quinazolin-4-yl]-amine 411.2 4.87
257 J (3-Chloro-4*phenoxy-phenyl)-[6-(3-
methylamino-prop-1-ynyl)-quinazolin-
4-yl]-amine 415.1 5.45
258 A [6-(3-Dimethylamino-prop-1-ynyl)-
quinazolin-4-yl]-(3-methyl-4-phenoxy-
phenyl)-amine 409.3 5.94
259 J 3-[4-(3-Ethyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 465.2 5.54
260 J 3-[4-(3-Methyl-4-p-tolyloxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 465.2 5.52
261 J 3-[4-(3-Hydroxy-4-phenoxy-
phenylamino)-quinazolin-€-ylethynyl]-
piperidin-3-ol 453.1 4.34

262 J 2-Amino-4-[4-(3-methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-but-3-
yn-1-ol 411.2 4.95
263 J 2-Amino-4-[4-(3-methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-but-3-
yn-1-ol 427.1 4.60
264 J 3-[4-(3-Ethoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 481.1 5.59
265 J 3-[4-(3-lsopropoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 495.2 5.40
266 J 3-(4-(2-Fluoro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 455.2 4.9
267 J 3-[4-(4-Fluoro-2-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 455.2 4.61
268 J 3-[4-(4-Pyridin-2-ylmethyl-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 436.2 3.59
269 J 2-Amino-1 -[4-(3-methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
cyclohexanol 465.1 5.45
270 J 2-Amino-1 -[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-cydohexanol 481.2 5.10
271 J 1 -Methylamino-4-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yl]-but-3-yn-2-ol 425.2 5.08
272 J 4-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-1-
methylamino-but-3-yn-2-ol 441.2 4.76
273 A" (3-Methyl-4-phenoxy-phenyl)-[6-(3-piperazin-1 -yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 450.0 5.25
274 A (3-Methyl-4-phenoxy-phenyl)-[6-(3-pyrrolidin-1 -yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 435.0 5.95
275 A" (3-Methoxy-4-phenoxy-phenyl)-[6-(3-piperazin-1 -yl-prop-1 -ynyl)- quinazolin-4-ayl]-amine 466.3 4.95
276 I 3-[4-(3-Methyl-4-phenoxy-phenylamino)- 277 J 3-{4-[4-(2,6-Difluoro-phenoxy)-3-
methyl-phenylamino]-quinazolin-6-
ylethynyl}-piperidin-3-ol 487.0 5.22
278 A" {6-[3-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl(1a, 5a, 6a))-prop-1 -ynyl]-quinazolin-4-ylM3-methyl-4-phenoxy-phenyl)-amine 462.3 5.38
279 A (3-Methyl-4-phenoxy-phenylH6-{3-morpholin-4-yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 451.0 7.27


280 A (3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl(1 a, 5a, 6a))-methanol 477.3 5.70
281 A" (3-Methyl-4-phenoxy-phenyl)-{6-[3-(2-methyl-piperazin-1 -yl)-prop-1 -ynyl]-quinazolin-4-yl}-amine 464.1 5.49
282 A" {6-[3-(2,6-Dimethyl-piperazin-1-yl)-prop-1-ynyl]-quinazolin-4-yl}- (3-methyl-4-phenoxy-phenyl)-amine 478.3 5.57
283 A (3-Methyl-4-phenoxy-phenyl)-{6-[3-(4-methyl-piperazin-1 -yl)-prop-1 -ynyl]-quinazolin-4-yl}-amine 464.0 5.60
284 A 1 -{3-{4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-4-ol 465.0 5.45
285 A 1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-pyrrolidin-3-ol 451.3 5.38
286 K (3-Methyl-4-phenoxy-phenyl)-t6-( 1 -
methyl-piperidin-3-ylethynyl)-
quinazolin-4-yl|-amine 449.5 5.86
287 A (1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-pyrrolidin-2-yl)-methanol 465.3 5.51
288 A (1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quina20lin-6-yl]-prop-2-
ynyl)-piperidin-2-yl)-methanol 479.1 5.58
289 A (1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-3-yl)-methanol 478.9 5.59
290 A 2-(Methyl-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-amino)-ethanol 439.1 5.45
291 A" 3-Methyl-2-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylamino}-butan-l -ol 467.4 5.72
292 A (3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)- quinazolin-4-yl]-amine 439.3 5.33
293 A 4-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
tetrahydro-pyran-4-ol 452.1 6.76
294 A 4-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
tetrahydro-pyran-4-ol 471.9 6.94
295 K 4-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
tetrahydro-pyran-4-ol 467.9 6.23
296 A 4-Methyl-2-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylamino}-pentan-1-ol 481.0 5.99
297 A" 3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylaminoVpropane-1,2-diol 495.0 4.94

298 A 1 -{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidine-2-carboxylic acid methyl ester 493.3 7.90
299 K (3-Methyl-4-phenoxy-phenyl)-[6-( 1 -
propyl-piperidin-3-ylethynyl)-
quinazolin-4-yl]-amine 477.1 6.24
300 A" {6-[3-(4-Amino-piperidin-1 -yl)-prop-1 -ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-am ine 464.3 5.10
301 K" {6-[1-(2-Amino-ethyl)-piperidin-3-
ylethynyl]-quinazolin-4-yl}-(3-methyl-4-
phenoxy-phenyl)-amine 478.1 5.84
302 A 1 -{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidine-2-carboxylic acid methyl ester 509.0 7.37
303 A (1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-4-yl)-methanol 479.3 5.40
304 A (1 -{3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-4-yl)-methanol 495.3 4.99
305 A {6-[3-(4,4-Dimethoxy-piperidin-1-yl)-prop-1 -ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine 509.2 7.33
306 A {6-[3-(3-Dimethylamino-pyrrolidin-1-
yl)-prop-1-ynyl]-quinazolin-4yl}-(3-
methyl-4-phenoxy-phenyl)-amine 478.3 5.85
307 A 2-(1-{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-4-yl)-ethanol 493.1 5.50
308 K" {6-[1-(2-Amino-propyl)-piperidin-3-
ylethynyl]-quinazolin-4-yl}-(3-methyl-4-
phenoxy~phenyl)-amine 492.4 6.28
309 K 2-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1 -yl}-ethanol 479.3 5.66
310 J 3-[4-(4-Bromc-2-fluoro-phenylamirio)-quinazolin-6-ylethynyl]-piperidin-3-ol 442.9, 440.9 4.26
311 J 3-[4-(4-Bromo-2,6-difluoro-
phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol 460.9, 459.1 4.24
312 K {6-[1-(2-Methoxy-ethyl)-piperidin-3-
ylethynyl]-quinazolin-4-yl}-(3-methyl-4-
phenoxy-phenyl)-amine 493.1 6.05
314 J 6-Hydroxymethyl-3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-piperidin-3-ol 424.2 8.64
315 A" {6-[3-(2,5-Diaza-bicyclo[2.2.1 ]hept-2-
yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-
methoxy-4-phenoxy-phenyl)-amine 478.2 4.92
316 A {6-[3-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-yl(1a, 5a, 6a))-prop-1 -ynyl]-quinazolin-4-yl}-(3- 506.1 5.28

methoxy~4-phenoxy-phenyl)-amine
317 J 5-Hydroxy-5-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-2-carboxylic acid amide 494.0 5.11
318 A 2-(4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazin-1 -yl)-ethanol 494.4 5.17
319 A 2-(4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-€-yl]-prop-2-ynyl}-piperazin-1 -yl)-ethanol 510.1 4.89
320 J 3-Hydroxymethyl-4-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-piperidin-4-ol 481.0 4.94
321 J 3-Hydroxymethyl-4~[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol 497.0 4.63
322 A 1 -{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-piperidin-4-one 463.1 7.17
323 J (3-Methyl-4-phenoxy-phenyl)-[6-(3-thiomorpholin-4-yl-prop-1 -ynyl)-quinazolin-4-yl]-amine 467.3 8.06
324 J 5-Hydroxymethyl-3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-pyrrolidin-3-ol 466.9 5.04
325 J 5-Hydroxymethyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol 482.9 4.72
326 A 1 -{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-4-one oxime 478.3 6.43
327 J 2-Hydroxymethyl-3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-tetrahydro-pyran-3-ol 482.0 6.13
328 A 4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid ethyl ester 522.1 7.78
329 A 4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid ethyl ester 538.3 7.16
330 J 4-Hydroxy-4-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidine-2-carboxylic acid amide 496.1 4.70
331 J 4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-4-hydroxy-pyrrolidine-2-carboxylic acid amide 500.2 5.21
332 J 4-Hydroxy-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidine-2-carboxylic acid amide 480.3 5.03
333 A N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2- 459.0 6.85

ynyl}-methanesulfonamide
334 A 1 -(4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazin-1 -yl)-ethanone 492.3 6.39
335 I 4-Hydroxy-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-2-carboxylic acid amide 495.3 5.90
336 J 4-Hyd roxy-4-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-2-carboxylic acid amide 511.1 5.49
337 J 4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-4-hydroxy-tetrahydro-pyran-2-carboxylic acid amide 515.2 6.09
338 A N-{3-[4-(3-Methoxy-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-methanesulfonamide 475.1 6.40
339 A {6-[3-(4-Methanesulfonyl-piperazin-1~
yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-
methyl-4-phenoxy-phenyl)-amine 528.1 7.08
340 A 4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylJ-piperazine-1-carboxylic acid methylamide 507.3 6.12
341 A 4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pipera2ine-1-carboxylic acid methylamide 523.2 5.64
342 A {6-[3-(4-Methanesulfonyl-piperazin-1-
yl)-prop-1-ynyl]-quinazolin-4-ylH3-methoxy-4-phenoxy-phenyl)-amine 544.1 6.54
343 J 2-Hydroxymethyf-4-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
ylethynyl]-tetrahydro-pyran-4-ol 482.3 5.85
344 J 2-Hydroxymethyl-4-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol 498.3 5.43
345 J 4-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-ylethynyl]-
2-hydroxymethyl-tetrahydro-pyran-4-ol 502.2 6.04
346 A {6-[3-(1,1 -Dioxo-1 &-isothiazolidin-2-yl)-prop-1 -ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine 485.3 7.30
347 A {6-{3-(1,1 -Dioxo-1 &-isothiazolidin-2-
yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-
methoxy-4-phenoxy-phenyl)-amine 501.3 6.69
348 I N-{3-[4-(4-Phenoxy-phenylamino)-
quinazolin-6-yl]-prop-2-ynyl}-
acetamide 409.0 6.03
349 I N-{3-[4-(3-Chloro-4-phenoxy-
phenylamino)-qutnazolin-6-yl]-prop-2-
ynyl}-acetamide 442.9 6.55
350 A {6-[3-(1,1 -Dioxo-1 &-thiomorpholin-4- 515.2 6.40

yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine
351 A 4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylamino}-piperidine-1 -carboxylic acid ethyl ester 536.6 6.04
352 A 4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynylamino}-piperidine-1 -carboxylic acid ethyl ester 552.3 5.97
353 J N-{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-isobutyramide 451.3 7.09
354 J [4-(2-Fluoro-phenoxy)-3-methyl-
phenyl]-(6-piperidin-3-ylethynyl-
quinazolin-4-yl)-amine 453.4 5.55
355 J [4-(3-Fluoro-phenoxy)-3-methyl-
phenyl]-(6-piperidin-3-ylethynyl-
quinazolin-4-yl)-amine 453.4 5.75
356 I N-Methyl-N-{3-(4-(4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynylVacetamide 423.3 6.53
357 I N-Methyl-N-{3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yl]-prop-2-ynyl}-acetamide 437.3 6.86
358 I N-{3-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-N-methyl-acetamide 457.3 7.05
359 I 2,2-Dimethyl-N-{3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yll-prop-2-ynyl}-propionamide 465.0 7.57
360 J (3-Methyl-4-phenoxy-phenyl)-(6-
pyrrolidin-3-ylethynyl-quinazolin-4-yl)-
amine 421.3 5.43
361 J [4-(2-Fluoro-phenoxy)-3-methyl-
phenyl]-(6-pyrrolidin-3-ylethynyl-
quinazolin-4-yl)-amine 439.0 5.39
362 J (3-Chloro-4-phenoxy-phenyl)-(6-
pyrrolidin-3-ylethynyl-quinazolin-4-yl)-
amine 441.0 5.61
363 J (3-Methoxy-4-phenoxy-phenyl)-(6-
pyrrolidin-3-ylethynyl-quinazolin-4-yl)-
amine 437.1 5.06
364 I 2-Chloro-N-{3-[4-(3-methyl-4-
phenoxy-phenylamino")-quinazolin-6-
yn-prop-2-ynyl}-acetamide 457.0 7.00
365 I Cyclopropanecarboxylic acid {3-[4-(3-
methyl-4-phenoxy-phenylamino)-
quinazolin-6-yfl-prop-2-ynyl}-amide 449.1 6.97
366 I N-{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl)-propionamide 437.1 6.74
367 I 2-Methoxy-N-(3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yll-prop-2-ynyl}-acetamide 453.2 6.69

368 M N-{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-2-morpholin-4-yl-acetamide 508.0 6.49
369 A" 1 -{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-2-carboxylic acid methyl ester 508.0 5.66
370 A 4-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid amide 493.5 5.87
371 J (-)-(3-Methyl-4-phenoxy-phenyi)-(6-
piperidin-3(S)-ylethynyl-quinazolin-4-
yl)-amine 435.1 5.61
372 A" 4-Aminomethyl-1-{3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yl]-prop-2-ynyl^pyrrolidin-3-ol 480.3 4.95
373 J 4-Hydroxy-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidine-2-carboxylic acid methylamide 494.0 5.18
374 N (3-Methyl-4-phenoxy-phenyl)-(6-
piperidin-3-ylethynyl-pyrido[3,4-
d]pyrimidin-4-yl)-amine 436.3 5.40
375 N (3-Methyl-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-pyrido[3,4-d]pyrimidin-4-yl)-amine 436.3 5.32
376 J (3-Methoxy-4-phenoxy-phenyl)-(6-
piperidin-4-ylethynyl-quinazolin-4-yl)-
amine 451.3 5.17
377 J (3-Chloro-4-phenoxy-phenyl)-(6-
piperidin-4-ylethynyl-quinazolin-4-yl)-
amine 455.0 5.73
378 J (3-Methyl-4-phenoxy-phenyl)-(6-
piperidin-4-ylethynyl-quinazolin-4-yl)-
amine 435.1 5.56
379 A 3(S)-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide 492.3 7.15
380 I 3(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide 509.4 6.65
381 I N-{1,1 -Dimethyl-3-[4-(3-methyM-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2,2,2-trifluoro-acetamide 505.0 8.15
382 J (+)-{3-Methyl-4-phenoxy-phenyl)-(6-
piperidin-3(R)-ylethynyl-quinazolin-4-
yl)-amine 435.3 5.61
383 I N-f 1,1 -Dimethyl-3-f4-(3-methyl-4- 451.2 7.00 |

phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide
384 I N-{3-[4-(3-Chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-1,1-
dimethyl-prop-2-ynyl}-acetamide 471.1 7.22
385 J [4-(2-Chloro-phenoxy)-3-methyl-
phenyl]-(6-piperidin-3-ylethynyl-
quinazoiin-4-yl)-amine 469.0 5.97
386 J [4-(2-Methoxy-phenoxy)-3-methyl-
phenyl]-(6-piperidin-3-ylethynyl-
quinazolin-4-yl)-amine 465.1 5.31
387 J [3-Methyl-4-(2-trifluoromethyl-
phenoxy)-phenyl]-(6-piperidin-3-
ylethynyl-quinazolin-4-yl)-amine 503.0 6.17
388 J [4-(2-Ethyl-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine 463.0 6.38
389 J (6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine 407.3 5.31
390 I N-{1-Methyl-3-[4-(3-chloro-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-acetamide 456.9 6.84
391 I N-{1 -Methyl-3-[4-(3-methyl-4-
phenoxy-phenylamino)-quinazolin-6-
yl]-prop-2-ynyl}-acetamide 437.1 6.65
392 I N-{3-[4-(3-Methyl-4-phenoxy-
phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-acetamide 422.8 6.36
5
Utilizing method I and the appropriate starting materials (prepared according to
methodology known in the art), the following compounds (and pharmaceutically acceptable salts and solvates thereof), which are part of the present invention, may be prepared:
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-azetidin-1-yl}-10 ethanone
1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-azetidin-1-yl}-ethanone
1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-azetidin-1-yl}-
ethanone
15 [6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-
phenyl)-amine
[6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-azetidin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-20 phenyl)-amine
[6-(1-Methanesulfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine

5 [6-(1-MethanesuIfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-
phenyl)-amine
[6-(1-Methanesulfonyl-pyrrolidin-3-ylethynyl)-quinazolin-4-yI]-(3-chloro-4-phenoxy-phenyl)-amine
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl}-10 ethanone
1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl}-ethanone
1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-1-yl}-
ethanone
15 1 -{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1 -yl}-
ethanone
1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1-yl}-ethanone
1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-1-yl}-20 ethanone
[6-(1-Methanesulfonyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-
phenyl)-amine
25 [6-(1-Methanesulfonyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-
phenyl)-amine
5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-2-one
5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-2-one
5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-2-one
30 4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-2-one
4-[4-(3-Methoxy-4-phenoxy-phenyiamino)-quinazolin-6-ylethynyl]-pyrrolidin-2-one
4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]:pyrrolidin-2-one
H2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-4-yl}-
ethanone
35 1-{2-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolirr-6-ylethynyl]-morpholin-4-yl}-
ethanone
1-{2-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-4-yl}-ethanone
[6-(4-Methanesulfonyl-morpholin-2-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-40 phenyl)-amine
[6-(4-Methanesulfonyl-morpholin-2-ylethyny!)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine

5 [6-(4-Methanesulfonyl-morpholin-2-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-
phenyl)-amine
6-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-3-one
6-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-morpholin-3-one
6-[4-(3-Chloro-4-phenoxy-phenylamino)-quina20lin-6-ylethynyI]-morpholin-3-one
10 5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
6-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
6-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
15 6-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperazin-2-one
1-{5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-pyridin-1 -yl}-ethanone
1-{5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-
pyridin-1 -yi}-ethanone
20 1-{5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,4-dihydro-2H-
pyridin-1 -yl}-ethanone
[6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-25 methoxy-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-4-phenoxy-phenyl)-amine
1-{5-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-
pyridin-1 -yl}-ethanone
30 1-{5-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-
pyridin-1 -yl}-ethanone
1-{5-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1 -yl}-ethanone
[6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-ylH3-35 methyl-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-pheny!)-amine
[6-(1-Methanesulfonyl-1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-(3-chloro-
4-phenoxy-phenyl)-amine
40 1-{4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-
pyridin-1 -yl}-ethanone

5 1-{4-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-
pyridin-1-yl}-ethanone
1-{4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-3,6-dihydro-2H-pyridin-1 -yl}-ethanone
[6-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-10 methyl-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-1,2l3I6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine
[6-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-(3-chloro-
4-phenoxy-phenyl)-amine
15 N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-
acetamide
N-{1,1 -Dimethyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide
N-{1,1 -Dimethyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-20 acetamide
N-{1,1 -Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide
N-{1,1 -Dimethyl-3-[4-(3»methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-
ynyl}-methanesulfonamide
25 N-{1,1 -Dimethyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-
methanesulfonamide
N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide
N-{1-Methyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-30 acetamide
N-{1-Methyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide
N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-
methanesulfonamide
35 N-{1-Methyl-3-[4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-
methanesulfonamide
N-{1-Methyl-3-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-methanesulfonamide
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-2-40 one
H3-[4-(3-Methoxy-4-phenoxy-phenyJamino)quinazolin6 -ylprop-2-ynyJ>-piperidJn-2-one

5 1 -{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-2-
one
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-one
1-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-10 one
1-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-pyrrolidin-2-one
Utilizing method J and the appropriate starting materials (prepared according to methodology known in the art), the following compounds (and pharmaceutically acceptable 15 salts and solvates thereof), which are part of the present invention, may be prepared:
(7-Methoxy-6-piperidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine
(3-Chloro-4-phenoxy-phenyl)-(7-methoxy-6-piperidin-3-ylethynyl-quinazolin-4-yl)-
amine
20 (3-Methoxy-4-phenoxy-phenyl)-(7-methoxy-6-piperidin-3-ylethynyl-quinazolin-4-yl)-
amine
[7-(2-Methoxy-ethoxy)-€-piperidin-3-ylethynyl-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
(3-Chloro-4-phenoxy-phenyl)-[7-(2-methoxy-ethoxy)-6-piperidin-3-ylethynyl-quinazolin-25 4-yf]-amine
[7-(2-Methoxy-ethoxy)-6-piperidin-3-ylethynyl-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-amine
3-[7-(2-Methoxy-ethoxy)-4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol
30 3-[7-(2-Methoxy-ethoxy)-4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-
piperidin-3-ol
3-[7-(2-Methoxy-ethoxy)-4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol
3-[7-Methoxy-4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-35 ol
3-[7-Methoxy-4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol
3-[7-Methoxy-4-(3-methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-
3-ol
40 (6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methoxy-4-phenoxy-phenyl)-amine
(3-Methyl-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quinazolin-4-yl)-amine (3-Methoxy-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quinazolin-4-yl)-amine

-74-
5 (3-Chloro-4-phenoxy-phenyl)-(6-morpholin-2-ylethynyl-quina20lin-4-yl)-amine
(3-Methyl-4-phenoxy-phenyl)-[6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine
(3-Methoxy-4-phenoxy-phenylH6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quina2olin-4-
yl]-amine
10 (3-Chloro-4-phenoxy-phenyl)-[6-(1,4,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-
yl]-amine
(S-MethyM-phenoxy-phenyO-ie^l^.S.S-tetrahydro-pyridin-S-ylethynyO-quinazolin^-yl]-amine
(3-Methoxy-4-phenoxy-phenyl)-[6-(1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-15 yl]-amine
(3-Chloro-4-phenoxy-phenyl)-[6-(1,2,5,6-tetrahydro-pyridin-3-ylethynyl)-quinazolin-4-yl]-amine
(3-Methyl-4-phenoxy-phenyl)-[6-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-
yl]-amine
20 (S-Methoxy-^-phenoxy-phenylHS^I^.S.e-tetrahydro-pyridin^-ylethynyO-quinazolin^-
yl]-amine
(3-Chloro-4-phenoxy-phenyl)-[6-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-quinazolin-4-yl]-amine
[6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
25 [6-(3-Amino-3-methyl-but-1-ynyl)-quinazolin-4-yl]-(3-methoxy-4-phenoxy-phenyl)-
amine
[6-(3-Amino-3-methyl-but-1-ynyl)- t6-(3-Amino-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
t6-(3-Amino-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
30 [6-(3-Amino-but-1-ynyl)-quinazolin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine
/

WE CLAIM:
1. A substituted bicyclic compound of the formula 1

i
or a phanmaeeutscally acceptable salt or solvate thereof, wherein:
XssNorGH;
the A moiety is

whereSn the above A moiety Jsears an R* group as a sMbstituent and opiooaBy bears 1 to 3 R! groups as substltuenis;:
each R1 and ff is independently H or C,*Ga alkyft
R3 is -{ORWjuftf wherein m Is Q or 1;
or R1 and H3 are taken together to form a group of the (ormiila

wherein said group is oplionaliy substituted with 1 to 3 Ft1 groups;
R* is ^GR"RVtMMCR"R^R13 or-{CR1R2)«,-C=G-(CR1ift8>itR1* wh©r«* fc is an Integer km 1 to 3 m$ m is an integer from o to 3;
each if is tndepertdscstly setef&o" from halo, hydroxy, -Nfi"R*. C,-Gs alkyl, trffluoremethyl, C,-Cs alfeoxy* irltooraneihoxy, -C(0>R8, -CQsR*, -NR*C£Q}R\ -G(Q)Hf$r?t -SC^NRBR7, •NF^QppFlW,, aitrJ »NRBC{0|0R7;
eadh ft9 and R7 Is irelependantSy selected frcm H and CrGs alkyl, and the aifcyl rootety of the foregoing Rs and R7 groups is optisnally substituted with 1 to 3 subssiluenls independency selected from halo, cyano, Ftitro, *NR R%



A pharmaceutical composition for the treatment of abnormal cell growth in a mammal comprising an amount of a compound as claimed in claim 1 in the range of 0 to 99.90% that is effective in treating abnormal cell growth, and a phanmaceutically acceptable carrier.
5. A method of preparing a compound as claimed in claim 1 which comprises either (a) reacting a compound of the formula 11 or 2 with a compound of the formula 3




wttere i n Z is a leavhg group and A, X, R1 R4 and R3 are as defined above, or (to) reacting a compound of the formula with compound of the formula |

iwharein X, R\ A, R1 and Rs are as deflifted above and Z1 ts an activating group, lo pw intemiedMs of Uie formula I

wherein Z1, X, R1, A, and ft3 are as defined above and Z" is converted to an R* group wfrtch
optionally may be converted to another R* group.
6. A substituted compound of formula 1 as claimed in claim 1 substantially as hereinbefore described with reference to the foregoing examples.

Documents:

858-bom-1999-abstract(19-10-2007).doc

858-bom-1999-abstract(19-10-2007).pdf

858-bom-1999-abstract(amanded)-(19-10-2007).pdf

858-bom-1999-abstract(complete)-(26-11-1999).pdf

858-bom-1999-abstract(granted)-(5-2-2008).pdf

858-bom-1999-assignment(21-5-2009).pdf

858-bom-1999-cancelled pages(19-10-2007).pdf

858-bom-1999-claim(granted)-(19-10-2007).doc

858-bom-1999-claim(granted)-(19-10-2007).pdf

858-bom-1999-claims(complete)-(26-11-1999).pdf

858-bom-1999-claims(granted)-(5-2-2008).pdf

858-bom-1999-correspondence(21-5-2009).pdf

858-BOM-1999-CORRESPONDENCE(23-11-2009).pdf

858-bom-1999-correspondence(ipo)-(21-10-2009).pdf

858-bom-1999-correspondence(ipo)-(7-4-2008).pdf

858-bom-1999-corrospondence(19-10-2007).pdf

858-bom-1999-corrospondence(ipo)-(19-10-2006).pdf

858-bom-1999-description(complete)-(26-11-1999).pdf

858-bom-1999-description(granted)-(5-2-2008).pdf

858-bom-1999-form 13(19-10-2007).pdf

858-bom-1999-form 16(21-5-2009).pdf

858-bom-1999-form 18(24-03-2005).pdf

858-bom-1999-form 1a(19-10-2007).pdf

858-bom-1999-form 2(complete)-(26-11-1999).pdf

858-bom-1999-form 2(granted)-(19-10-2007).doc

858-bom-1999-form 2(granted)-(19-10-2007).pdf

858-bom-1999-form 2(granted)-(5-2-2008).pdf

858-bom-1999-form 2(title page)-(complete)-(26-11-1999).pdf

858-bom-1999-form 2(title page)-(granted)-(5-2-2008).pdf

858-bom-1999-form 3(19-10-2007).pdf

858-bom-1999-form 3(26-11-1999).pdf

858-bom-1999-form 3(30-06-2000).pdf

858-bom-1999-form 5(19-10-2007).pdf

858-bom-1999-petition under rule 137(19-10-2007).pdf

858-bom-1999-petition under rule 138(19-10-2007).pdf

858-bom-1999-power of attorney(10-02-2000).pdf

858-bom-1999-power of authority(19-10-2007).pdf

858-bom-1999-power of authority(21-5-2009).pdf

858-BOM-1999-POWER OF AUTHORITY(23-11-2009).pdf

858-bom-1999-specification(amanded)-(19-10-2007).pdf


Patent Number 214162
Indian Patent Application Number 858/BOM/1999
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 05-Feb-2008
Date of Filing 26-Nov-1999
Name of Patentee PFIZER PRODUCTS, INC.
Applicant Address EASTERN POINT ROAD, GROTON, CONNECTICUT 06340, USA
Inventors:
# Inventor's Name Inventor's Address
1 JOHN CHARLES KATH 252 SHORE ROAD, WATERFORD, CT 06385
2 NORMA JACQUELINE TOM 43 YORKSHIRE DRIVE, WATERFORD, CT 06385
3 ZHENGYU LIU 46 GALLUP LANE, WATERFORD, CT 06385
4 ERIC DAVID COX 507 JUDSON AVENUE, MYSTIC, CT 06355
5 SAMIT KUMAR BHATTACHARYA 200 MICHELLE LANE, APT. 112, GROTON, CT 06340
6 JOEL MORRIS 24 SPRING ROCK ROAD, EAST LYME, CT 06333
PCT International Classification Number C07D 239/94
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/117,346 1999-01-27 U.S.A.