MXPA01007585A - Substituted bicyclic derivatives useful as anticancer agents - Google Patents

Abstract

The invention relates to compounds of 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 compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1).

Description

SUBSTITUTE BIC.CUCOS DERIVATIVES USEFUL AS AGENTS AGAINST CANCER BACKGROUND OF THE INVENTION This invention relates to novel bicyclic derivatives which are useful in the treatment of abnormal growth of cells, such as cancer, in mammals. This invention also relates to a method for using such compounds in the treatment of abnormal growth of cells in mammals, especially in humans, and to pharmaceutical compositions containing such compounds. It is known that a cell can become cancerous by virtue of the transformation of a part of its DNA into an oncogene (i.e., a gene which, upon activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. On the other hand, overexpression of a normal proto-oncogenic tyrosine kinase can also produce proliferative disorders, which sometimes result in a malignant phenotype. Tyrosine receptor kinases are enzymes that traverse the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain and an intracellular portion that functions as a kinase to phosphorylate specific tyrosinein residues in proteins and proteins. , therefore, 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, in gastrointestinal cancers such as colon, rectal or stomach cancer, in leukemia and in ovarian, bronchial or cancer. pancreatic. It has also been shown that the epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and / or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric tumors. , breast, head and throat, esophageal, gynecological and thyroid. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective growth inhibitors of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth, in nude nude mice, of a transplanted human mammary carcinoma expressing epidermal growth factor receptor tyrosine kinase (EGFR), but has no effect on the growth of other carcinomas that do not express the EGF receptors. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal growth of cells, in particle, cancer, in mammals. In addition to receptor tyrosine kinases, the compounds of the present invention may also exhibit inhibitory activity against a variety of different non-receptor tyrosine kinases (e.g., Ick, src, abl) or serine / threonine kinases (e.g., kinase-dependent kinases). cyclin). It has also been shown that various other compounds, such as styrene derivatives, possess tyrosine kinase inhibitory properties. More recently, five publications of European patents, particularly EP 0 566 226 A1 (published on October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published on 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, in particular quinazoline derivatives, as compounds that possess anti-cancer properties that result from their tyrosine kinase inhibitory properties. In addition, the worldwide patent application WO 92/20642 (published on November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in the inhibition of abnormal proliferation of cells. The worldwide patent applications WO 96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98 / 02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998) and WO 98/02438 (published January 22, 1998), and EP 837063 also refer to substituted bicyclic heteroaromatic derivatives such as tyrosine kinase inhibitors that are useful for the same purpose. WO 96/28430 relates to trisubstituted phenyl derivatives.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula 1 1 and to pharmaceutically acceptable salts and solvates thereof, wherein: X is N or CH; A represents a 5, 6 or 7 membered fused ring optionally containing from 1 to 4 heteroatoms which may be the same or different and which are selected from -N (R1) -, O and S (O) j, wherein is an integer from 0 to 2, the condensed ring containing a total of 1, 2 or 3 double bonds including the bond of the pyridine ring or pyrimidine with which it is condensed, in which the group R1 attached to the nitrogen is absent if a double bond includes the optional nitrogen moiety mentioned above -N (R1) -, with the proviso that the fused ring does not form part of a purine and the fused ring does not contain two adjacent O or S (O) j atoms, and wherein the carbon atoms of residue A are optionally substituted with 1 to 3 R5 groups; each R1 and R2 is independently H or C6-C6 alkyl; R3 is - (CR1R2) m -R8, wherein m is 0 or 1; or R1 and R3 are taken together to form a formula group wherein said group is optionally substituted with 1 to 3 R5 groups; R4 is - (CR1R2) mC = C- (CR R2) tR9, - (CR1R2) mC = C- (CR1R2) tR9, -C = NOR12 or -X1-R12, where 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-C carbocyclic group; or R4 is - (CR1R2) mC = C- (CR1R2) kR13 or - (CR1R2) mC = C- (CR1R2) kR13, where k is an integer from 1 to 3 and m is an integer from 0 to 3; or R4 is - (CR R2) tR9, wherein t is an integer from 0 to 5 and the point of attachment to R9 is through a carbon atom of the group R9; each R5 is independently selected from halo, hydroxy, -NR1R2, Ci-Cß alkyl, trifluoromethyl, Ci-C alco alkoxy, trifluoromethoxy, -C (O) R6, -CO2R6, -NR6C (O) RC (O) NR6R7 , -SO2NR6R7, -NR6C (O) NR7R1 and -NR6C (O) OR7; each R6 and R7 is independently selected from H, C? -C6 alkyl, - (CR1R2) t (C6-C? 0 aryl) and - (CR R2) t (4-10 membered heterocycle), wherein t is an integer of 0 to 5, 1 or 2 carbon atoms of the ring of the heterocyclic group are optionally substituted with an oxo moiety (= 0), and the alkyl, aryl and heterocyclic moieties of the groups R6 and R7 above are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR1R2, trifluoromethyl, trifiuoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy and C1-C6 alkoxy; R8 is independently selected from - (CR1R2) t (C6-C10 aryl) and - (CR1R2) t (4- to 10-membered heterocycle); where t is an integer from 0 to 5, 1 or 2 carbon atoms of the ring of! heterocyclic group are optionally substituted with an oxo moiety (= O) and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups; R9 is a non-aromatic monocyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, said ring containing from 3 to 12 carbon atoms, wherein 0 to 3 carbon atoms are optionally replaced with a selected hetero moiety. independently between N, O, S (O) j, where j is an integer from 0 to 2, and -NR12-, with the proviso that two atoms of O, two residues S (O) j, one atom of O and a S (O) j moiety, an N atom and an S atom, or an N atom and an O atom are not directly bonded together within said ring, and in which 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, Ci-Cß alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C (O) R6, -C ( O) OR6, -OC (O) R6, -NR6C (0) R7, -NR6C (O) NR1R7, -NR6C (O) OR7, -C (O) NR6R7, -NR6R7, -NR6OR7, -S02NR6R7, -S (O) j (Ci-Cß alkyl) wherein j is an integer from 0 to 2, - (CR1R2) t (C6-C6 o aryl), - (CR1R2) t (4-10 membered heterocycle), - (CR1CR2) qC (O) (CR1R2) t (aryl C6-C? 0), (CR1CR2) qC (O) (CR1CR2) t (4-10 membered heterocycle), - (CR1CR2) tO (CR1R2) q (aryl C6-C? 0), (CR1CR2) tO (CR1R2) q (4-10 membered heterocycle), - (CR1CR2) qS (0) j (CR R2) t (aryl C6-C? o) and - (CR1CR2) qS (0) j (CR1R2) t (heterocyon of 4-10 members), where j is 0, 1 or 2, each of q and t is independently an integer from 0 to 5, 1 or 2 Ring carbon atoms of the heterocyclic moieties of the above R 0 groups are optionally substituted with an oxo moiety (= 0), and the alkyl, alkenyl, alkynyl, aryl and heterocycle moieties of the above R 10 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (O) R6, -C (O) OR6, -OC (O) R6, -NR6C (O) R7, -C (O) NR6R7, -NR6R7, -NR6OR7, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CR1R2) t (C6-C? 0 aryl) and - (CR1R2) t (4-10 membered heterocycle) ), where t is a whole number from 0 to 5; each R11 is independently selected from -R12, -OR1, -NR1R2, -NR6C (O) R7, -NR6C (O) NR7R1, -NR6C (O) OR7 and -NR6SO2NR7R1, or R11 replaces two hydrogen atoms of one carbon to form an oxo group (C = O); R 2 is R 6, -C (O) R 6 or -SO 2 R 6, -C (O) NR 6 R 7, -SO 2 NR 6 R 7 or -CO 2 R 6; R13 is -NR1R12 or -OR12; and wherein any of the aforementioned substituents comprising a group CH3 (methyl), CH2 (methylene) or CH (methino) which is not bonded to a halogen group, SO or SO2, or a N, O or S atom , optionally carries on said group a substituent selected from hydroxy, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and -NR 1 R 2. In a specific embodiment of the present invention, the A moiety of the compounds of formula 1 is selected from the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. Other specific embodiments of the compounds of formula 1 include those in which A is selected from the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. Other specific embodiments of the compounds of formula 1 include those in which A is selected from the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. Other specific embodiments of the compounds of formula 1 include those in which A is selected from H H carrying the above residues A a group R as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. Other specific embodiments of the compounds of formula 1 include those in which A the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. Other specific embodiments of the compounds of formula 1 They include those in which R4 is - (CR R2) m-C = C- (CR1R2) tR9, where m is an integer from 0 to 3 and t is an integer from 0 to 5.

Other specific embodiments of the compounds of formula 1 include those in which R4 is - (CR1R2) mC = C- (CR1R2) rR9 and m is an integer from 0 to 3 and t is an integer from 0 to 5. Other modalities specific for the compounds of formula 1 include those in which R4 is - (CR R2) mC = C- (CR1R2) k -R13 or - (CR1R2) m- (CR1R2)? R13, where m is a number from 0 to 3 and k is an integer from 1 to 3. Other specific embodiments of the compounds of formula 1 include those in which R 4 is -C = NOR 12 or -X 1 -R 12, wherein X 1 is a divalent derivative group of azetidine, oxetane or a C3-C4 carbocyclic group; or R4 is - (CR1R2) tR9, where the point of attachment to R9 is through a carbon atom of R9. Other specific embodiments of the compounds of formula 1 include those in which R8 is selected from - (CR1R2) t (phenyl), - (CR1R2M pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl) ), (CR1R2) t (indazolyl) and - (CR1R2) t (benzoamidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with from 1 to 5 groups of R10. Other specific embodiments of the compounds of formula 1 include those in which R9 is a 4- to 10-membered heterocyclic group having from 1 to 3 residues as indicated in formula 1 above and wherein said R9 is optionally substituted with 1 or 2 groups R11.

Preferred compounds include those selected from the group consisting of: 3- [4- (1-benzenesulfonyl-1 H -indol-5-ylamino) -quinazolin-6-yl] -alkyl ester of acetic acid; (1-benzenesulfonyl-1 H-mdol-5-yl) -. { 6- [3- (4-methyl-piperazin-1-yl) -prop-1-ynyl] -quinazolin-4-yl} -amine; (1-benzenesulfonyl-1 H -indol-5-yl) - [6- (3-pyrrolidin-1-yl-prop-1-ynyl) -quinazolin-4-yl] -amine; 4- [4- (1-benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-ylenyl] -piperidin-4-ol; (1-Benzenesulfonyl-1H-indol-5-yl) - (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine; [6- (4-amino-tetrahydro-pyran-4-ylethynyl) -quinazolin-4-yl] - (1-benzenesulfonyl-1H-indol-5-yl) -amine; 1 -methyl-4-. { 4- [3-methyl-4- (pyridin-2-ylomethoxy) -phenylamino] quinazolin-6-tranyl} -piperidin-4-ol; 1- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-yl] -4-methyl-pent-1-yn-3-ol; 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-ol; 4,4-dimethyl-1-. { 4- [4- (1-phenyl-ethoxy) -phenylamino] -quinazolin-6-yl} -pent-1-in-3-ol; 3-. { 4- [1- (propane-2-sulfonyl) -1H-indol-5-ylamino] -quinazolin-6-ylethynyl} -pipepdin-3-ol; 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; 5- [4- (1-Benzyl-1 H -indazol-5-ylamino) -quinazolin-6-ylethynyl] -4,4-dimethyl-oxazolidin-2-one; 4-amino-1- [4-. { 3-chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -pent-1-in-3-ol; 4-amino-1 - [4-. { 3-chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -4-methyl-pent-1-yn-3-ol; 3-. { 2- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] ethyl} -piperidin-3-ol; and the pharmaceutically acceptable salts and solvates of the above compounds. According to 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; 3- (S) - [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidine-1-carboxylic acid methylamide; 3- (S) - [4- (3-Methoxy-4-phenoxy-phenylamino) -chenazolin-6-bulletin] -piperidine-1-carboxylic acid methylamine; (3-Methyl-4-phenoxy-phenyl) - (6-pyrrolidin-3-yletinl-quinazolin-4-yl) -amine; 3- [4- (5-Methyl-6-phenoxy-pyridin-3-ylammon) -cynazolin-6-ylenetinyl] -piperidin-3-ol; (-) - 3- [4- (3-Methyl-4-phenoxy-phenylamino) -cynazolin-6-bulletin] -piperidin-3-ol; (+) - 3- [4- (3-Methyl-4-phenoxy-phen-amylamino) -quinazolin-6-iolet] -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-phenyl) -amine; [4- (2-Fluoride-phenoxy) -3-methyl-phenyl] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine; [4- (3-Fluoride-phenoxy) -3-methyl-phenyl] - (6-piperidin-3-eneyl-quinazolin-4-yl) -amine; (6-Azetedin-3-ylethynyl-quinazolin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine; 3-. { 4- [4- (2-Fluoride-phenoxy) -3-methyl-phenylamino] -quinazolin-6-ylethynyl} -pperidin-3-ol; 3-. { 4- [4- (3-Fluoride-phenoxy) -3-methyl-phenylamino] -quinazolin-6-ylethynyl} -piperidin-3-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-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -8-aza-bicyclo [3.2.1] octan-3-ol; (3-chloro-4-phenoxy-phenyl) - (6-piperidin-4-ylethynyl-quinazol-n-4-yl) -amine; 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pyrrolidin-3-ol; 3- [4- (3-Met l-4-phenoxy-phenylamino) -quinazolin-7-ylethynyl] -piperidin-3-ol; and the pharmaceutically acceptable salts and solvates of the above compounds. Other preferred compounds include those selected from the group consisting of: N-. { 3- [4- (3-Chloro-4-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) -cynazolin-6-yl] prop-2-ynyl} -3-aza-bicyclo [3.1. 0] hex-6-yl) methanol; 4- Methylamide. { 3- [4- (3-methoxy-4-phenoxy-phenylamino) -quinazolin-6-yl] prop-2-ynyl} -piperazine-1-carboxylic acid; . { 6- [3- (1, 1-Dioxo-1-thiomorpholin-4-yl) -prop-1-yl] -quinazoin-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} -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-inl} -acetamide; 4- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-ylethynyl] -1-methyl-piperidin-4-ol; 3- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-ylethynyl] -piperidin-3-ol; 3- [4- (3-Bromo-4-phenoxy-phenylamino) -quinazolin-6-bulletin] -piperidin-3-ol; 3- [4- (4-Benzenesulfonyl-3-methyl-femyl-amino) -q-nazolin-6-ylethyl] -piperidin-3-ol; 3- [4- (4-Cyclohexyloxy-3-methyl-phenylamino) -quinazolin-6-bulletin] -piperidin-3-ol; 2-Methyl-4- [4- (3-methyl-4-phenoxyl-phenylamino) -quinnan-6-yl] -but-3-yn-2-ol; 2-Amino-4- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -but-3-yn-2-ol; 3- [4- (3-Methyl-4-phenylsulfanyl-phenylamino) -quinazolin-6-ylethynyl] -piperidin-3-ol; and the pharmaceutically acceptable salts and solvates of the above compounds. Other preferred compounds of the present invention include those selected from the group consisting of: 3- [4- (3-Chloro-4-fluoro-phenylamino) -quinazolin-6-ylenyl] -piperidin-3-ol; 3- [4- (3-Ethynyl-phenylamino) -cynazolin-6-ylenyl] -piperidin-3-ol; (3-Methyl-4-phenoxy-phenyl) - [6- (1-methyl-p -peridin-3-ylethynyl) -cynazolin-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} -pperidin- 3-ol; 3- [4- (4-phenoxy-phenylamino) -quinazolin-6-bulletin] -piperidin-3-ol; 3-Oxo-5- (4-pyrrolidin-1-yl-butyl) -1, 2,3,5-tetrahydro-benzo [4,5] midazo [1,2-a] pyridine-4-benzylamide -carboxylic; and the pharmaceutically acceptable salts and solvates of the above compounds. This invention also relates to a method for treating abnormal growth of cells in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula 1, as defined above, or a salt or pharmaceutically acceptable solvate thereof, which is effective in treating the abnormal growth of cells. In one embodiment of this procedure, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or throat cancer, cutaneous or intraocular melanoma, cancer uterine, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, 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 tissues, 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, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma , spinal cord tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the above cancers. In another embodiment of said methods, said abnormal growth of the cells is a benign proliferative disease that includes, but is not limited to, psoriasis, benign prostatic hypertrophy or restinosis. This invention also relates to a method for treating abnormal growth of cells 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, which is effective in the treatment of the abnormal growth of the cells, in combination with an antitumor agent selected from the group consisting of inhibitors of mitosis, alkylating agents, anti-metabolites, intercalary antibiotics, inhibitors of growth factors, cell cycle inhibitors, enzymes, inhibitors of the topoisomerase, biological response modifiers, antibodies, cytotoxic, antihormones and antiandrogens. This invention also relates to a pharmaceutical composition for the treatment of abnormal growth of cells in a mammal, including a human, comprising an amount of a compound of formula 1, as defined above, or a salt or solvate pharmaceutically acceptable thereof, which is effective in the treatment of abnormal growth of cells, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal growth of cells is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or throat cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, 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, soft tissue sarcoma, cancer of the urethra, cancer of the penis, cancer of the prostate, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, kidney or ureter cancer, renal cell carcinoma, carc Inoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal cord tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the above cancers. In another embodiment of said pharmaceutical composition, said abnormal growth of the cells is a benign proliferative disease that includes, but is not limited to, psoriasis, benign prostatic hypertrophy or restinosis.

The invention also relates to a pharmaceutical composition for the treatment of abnormal growth of cells in a mammal, including a human, comprising an amount of a compound of formula 1, as defined above, or a pharmaceutically acceptable salt or solvate. acceptable thereof, which is effective in the treatment of abnormal cell growth, in combination with a pharmaceutically acceptable carrier and an antitumor agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, factor inhibitors of growth, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones and antiandrogens. The invention also relates to a process for preparing a compound of formula 1 and pharmaceutically acceptable salts and solvates thereof, wherein A, X, R1, R4 and R3 are as defined above, comprising (a) reacting a compound of formula 11 or 2 with a compound of formula 3 Where z is a leaving group and A, X, R1, R4 and R3 are as defined above, or (b) reacting a compound of formula 7 with a compound of formula 3 wherein X, R1, A, R1 and R3 are as defined above and Z1 is an activating group, to provide an intermediate of formula wherein Z1, X, R1, A and R3 are as defined above and Z1 becomes a group R4. "Abnormal growth of cells", as used herein, unless otherwise indicated, refers to the growth of cells that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). . This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by the expression of a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which activation of aberrant tyrosine kinases occurs; (4) any tumor that proliferates by receptor tyrosine kinases; (5) any tumor that proliferates by the aberrant activation of serine / threonine kinase; and (6) benign and malignant cells of other proliferative diseases in which the aberrant activation of serine / threonine kinases occurs. The term "treat", as used herein, unless otherwise indicated, means the reversal, alleviation, inhibition of progress or prevention of the disorder or condition to which that term applies, or of one or more symptoms of the disorder. disorder or condition The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating, as "treating" has just been defined. The term "halo", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine. Preferred halo groups are fluorine, chlorine and bromine. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties (including fused and bridged and spirocyclic bicyclic moieties), or a combination thereof. previous remains. For an alkyl group to have cyclic moieties, the group must have at least three carbon atoms. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond, wherein alkyl is as defined above, and including isomers E and Z of said alkenyl residue. The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond, wherein alkyl is as defined above. The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groups in which alkyl is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen, such as phenyl or naphthyl. The term "4 to 10 membered heterocycle", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing from one to four heteroatoms, each selected from O, S and N , where each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. The non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but the aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanium, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, , 2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl , imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, azabicyl [2.2.2] hexanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolll, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, benzofuranyl, cinoylnyl, nadolzolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazole, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups, when they come from the groups indicated carbon atom if it is a monocyclic ring, and can be linked through a carbon atom or through a nitrogen if it is a bicyclic ring. Certain compounds of formula 1 can have asymmetric centers and, therefore, exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula 1, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula 1, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms or mixtures thereof. The compounds of formula 1 can also exist as tautomers. The invention relates to the use of all such tautomers and mixtures thereof. The present invention also includes isotopically-labeled compounds, which are identical to those mentioned in formula 1, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or number Mass found normally in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 8F, and 36CI respectively. The compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain previously, they can be attached to C or joined to N when this is possible. For example, a pyrrole derivative group can be pyrrol-1-yl (attached to N) or pyrrole-3-yl (attached to C). In addition, a group derived from imidazole can be midazol-1-yl (attached to N) or imidazol-3-yl (attached to C). An example of a heterocyclic group in which 2 ring carbon atoms are substituted with oxo moieties (= o) is 1,1-dioxo-thiomorpholinyl. The phrase "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula 1. Compounds of Formula 1 which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1, are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as acetate salts, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisliate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate , hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, isotopically labeled compounds of the present invention, for example, those in which is incorporated radioactive octopuses such as 3H and 14C, assays for distribution of drugs and / or substrates in tissues are useful. The tritiated isotopes, ie, 3H, and carbon 14, ie, 14C, are particularly preferred for their ease of preparation and detectability. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, can produce certain therapeutic advantages resulting from increased metabolic stability, for example, a longer half-life in vivo or the need for lower doses and, therefore, it may be preferred in some circumstances. The isotopically-labeled compounds of formula 1 of this invention and the prodrugs thereof can generally be prepared by performing the procedures described in the schemes and / or examples and preparations shown below, substituting an isotopically-labeled reagent for an isotopically-labeled reagent already available.

SCHEME 1 salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiode and valerate. As a single compound of the present invention may include more than one acid or basic moiety, the compounds of the present invention may include mono, di or frials in a single compound. The compounds of the present invention which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention. In compounds of formula 1 where terms such as (CR1R2) qo (CR1R2) t are used, R1 and R2 may vary with each repetition of qot above 1. For example, when qot is 2, the terms (CR1R2 ) qo (CR1R2) t can be equivalent to -CH2CH2- or -CH (CH3) C (CH2CH3) (CH2CH2CH3) -, or any number of similar residues within the scope of the definitions of R1 and R2. In addition, as indicated above, all substituents comprising a group CH3 (methyl), CH2 (methylene) or CH (methino) which is not bonded to a halogen, an SO or SO2 group, or an N, O atom or S, optionally carries on said group a substituent selected from hydroxy, C1-C4 alkoxy, and -NR1R2. In the above compounds of formula 1, wherein R4 is - (CR1R2) t-CR1R11R12, the group R12 is preferably linked through a SCHEME 2 2.

DETAILED DESCRIPTION OF THE INVENTION General synthetic procedures that can be referenced to prepare the compounds of the present invention are provided in the US patent. 5,747,498 (issued May 5, 1998), in the patent application of E.U.A. with serial number 08/953078 (filed October 17, 1997), in WO 98/02434 (published January 22, 1998), WO 98/02438 (published January 22, 1998), WO 94/40142 (published December 19, 1996), WO 96/09294 (published March 6, 1996), WO 97/03069 (published January 30, 1997), WO 95/19774 (published on June 27, 1997). July 1995) and WO 97/13771 (published July 17, 1997). The above patents and patent applications are hereby incorporated by reference in their entirety. Certain starting materials can be prepared according to procedures familiar to those skilled in the art and certain synthesis modifications can be made according to procedures familiar to those skilled in the art. In Stevenson, T.M., Karmierczak, F., Leonard, N.J., J. Org. Chem. 1986, 51, 5, p. 616, a conventional method for preparing 6-iodoquinazolinone is provided. In Miyaura, N., Yanagi, T., Suzuki, a. Syn. Comm. 1981, 11, 7, p. 513, palladium-catalyzed boronic acid couplings are described. In Heck et al. Organic Reactions, 1982, 27, 345 or Cabri et al. in Acc. Chem. Res. 1995, 28, 2, Heck couplings catalysed with palladium are described. As examples of the paediated catalyzed coupling of terminal alkynes to aryl halides see: Castro et al. J. Org. Chem. 1963, 28, 3136 or Sonogashira et al., Synthesis, 1977, 777. For the formation of alkyl and cycloalkylinc reagents, those skilled in the art can refer to Rieke, RD, Hanson, MV, Brown, JD, Niu. , QJ, J. Org. Chem., 1996, 61, 8, p. 2726. The chemistry of azetidinyl zinc can be performed using methods found in Billotte, S. Synlett, 1998, 379. Synthesis of terminal alkynes can be performed using appropriately substituted / protected aldehydes as described in: Colvin, E. W. J. et al. Chem. Soc. Perkin Trans. I, 1977, 869; Gilbert, J. C. et al. J. Org. Chem., 47, 10, 1982; Hauske, J. R. et al. Tet. Lett., 33, 26, 1992, 3715; Ohira, S. et al., J. Chem. Soc. Chem. Commun., 9, 1992, 721; Trost. B. M. J. Amer. Chem. Soc, 119, 4, 1997, 698; or Marshall, J. A. et al J. Org. Chem., 62, 13, 1997, 4313. Alternatively, terminal alkynes can be prepared by a two-step process. First, the addition of the lithium anion of TMS (trimethylsilyl) acetylene to an appropriately substituted / protected ketone or aldehyde can be used in: Nakatani, K. et al. Tetrahedron, 49, 9, 1901. Subsequent deprotection can then be used by a base to isolate the intermediate terminal alkyne as in Malacria, M .; Tetrahedron, 33, 1977, 2813; or White, J. D. et al., Tet. Lett, 31, 1, 1990, 59. The preparation of arylamines such as phenoxyanilines, benzyloxyanilines, phenylsulfonylindoles, benzylindoles or benzylindazoles can be carried out by reduction of the corresponding nitro intermediates. The reduction of the aromatic nitro groups can be carried out by the procedures indicated in Brown, R.K., Nelson, N.A. J. Org. Chem. 1954, p. 5149; And you. R., Saldana, M, Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO 96/09294, mentioned above. The nitro-substituted N 1 -phenylsulphonylindoles / indazoles can be prepared by the procedures found in Sundberg, R.J., Bloom, J. D. J. Org. Chem. 1980, 45, 17, p. 3382; Ottoni, O. et al. Tetrahedron, 1998, 54, 13915; or Boger, Dale L. et al; J. Org. Chem. 55, 4, 1990, 1379. The substituted nitro N1-benzylindoles / indazoles can be prepared by procedures found in Makosza, M .; Owczarczyk, Z .; J. Org. Chem., 54, 21, 1989, 5094; Adebayo, Adelaide T.O.M. et al., J. Chem. Soc. Perkin Trans. 1, 1989, 1415; or in WO 98/02434, mentioned above. The benzyloxy-nitrobenzene intermediates can be prepared by procedures found in WO 98/02434, mentioned above. Alternatively, the arylmethoxy or aryloxy nitrobenzene derivatives can be prepared from halo nitrobenzene precursors by nucleophilic displacement of the halide with an appropriate alcohol as described in Dinsmore, C.J. et al., Bioorg. Med. Chem. Lett, 7, 10, 1997, 1345; Loupy, A. et al., Synth. Commun., 20, 18, 1990, 2855; or Brunelle, D. J., Tet. Lett, 25, 32, 1984, 3383. The starting materials, whose synthesis has not been specifically described before, are commercially available or can be prepared using methods well known to those skilled in the art.

In each of the reactions discussed or illustrated in the preceding Schemes, the pressure is not critical unless otherwise indicated. Pressures of about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is preferred for reasons of convenience. When the compound of formula HNR1R3 is an optionally substituted indole or indoline moiety, such compounds can be prepared according to one or more procedures known to those skilled in the art. Such procedures are described in PCT International Patent Application Publication No. WO 95/23141 and in W.C. Sumpter and F.M. Miller, "Heterocyclic Compounds with Nature and Carbazole Systems," in volume 8 of "The Chemistry of Heterocyclic Compounds," Interscience Publishers Inc., New York (1954). Where appropriate, optional substituents may be included before or after the coupling step in Scheme 1. Prior to the coupling step, the primary and secondary amino radicals (other than those of said amine of formula HNR1R3) are preferably protected using a nitrogen protecting group known to those skilled in the art. Such protecting groups and their use are described in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York, 1991. Referring to Scheme 1 above, the compound of formula 1 can be prepared by coupling the compound of formula 2, wherein X, A and R4 are as defined above and Z is a leaving group , such as a substituted phenoxy derivative (such substituents may include halo, cyano, nitro and / or d-Cß alkyl groups) or chloro, with an amine of formula 3, wherein R 1 and R 3 are as defined above, in an anhydrous solvent, in particular a solvent selected from DMF (N, N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE (dichloroethane), f-butanol and phenol, or a mixture of the above solvents, at a temperature inside from the range of approximately 50 to 150 ° C, during the period ranging from 1 hour to 48 hours. The compound of formula 3 can be prepared by procedures known to those skilled in the art, such as nitrile reduction, reduction of imines or enamines, reduction of oximes, primary and secondary amides, reduction of a nitro group or reductive amination of R1NH2 and R3CH (O) or R3NH2 and R1CH (O). The compound of formula 2 can be prepared by the treatment of a compound of formula 4, which is referred to in Scheme 2, wherein Z is an activating group, such as bromine, iodine, -N2 or -OTF (which is -OSO2CF3), or the precursor of an activating group such as NO2, NH2 or OH, with a coupling molecule, such as a terminal alkyne, alkene terminal, vinyl halide, vinyl stannane, vinyl borane, alkyl borane or a reactive alkyl or alkenyl zinc. Alternatively, the compounds of formula 1 can be prepared according to the synthesis indicated in Scheme 2. In scheme 2, a compound of formula 8 in which X is NH can be prepared from a compound of formula 9 in which A and Z1 are as defined above and Z3 is NH2, C6-C6 alkoxy or OH, according to one or more procedures described in WO 95/19774, mentioned above, and a compound of formula 8 in which X is CH, can be prepared from a compound of formula 10, wherein A and Z1 are as defined above, according to the procedure described in WO 95/19774, to which reference has been made above. The compound of formula 8 can be converted to the compound of formula 7 by treating the starting compound with a chlorinating agent, such as POCI3, or CIC (O) C (O) C1 / DMF, in a halogenated solvent, at a temperature ranging from approximately 60 ° C to 150 ° C, during a period ranging from approximately 2 to 24 hours. The compound of formula 7 can be converted to the compound of formula 6 wherein Z is a substituted phenoxy derivative, by treating the starting compound with an appropriate metal phenoxide, such as sodium phenolate, in a solvent, such as DMF or phenol, at a temperature ranging from about 0 ° C to 100 ° C, for a varying period from about 2 to 24 hours. The compound of formula 6 can be reacted with a coupling molecule such as a terminal alkyne, terminal alkene, vinyl halide, vinyl stannane, vinyl borane, alkyl borane or an alkyl or alkenyl zinc reagent, to provide a compound of formula 2 The compound of formula 2 can then be transformed into a compound of formula 1 by coupling with an amine of formula 3. Alternatively, the compound of formula 1 can be prepared by the reaction of a terminal alkyl, terminal alkene, vinyl halide, vinyl stannane, vinyl borane, alkyl borane or an alkyl or alkenyl zinc reagent, with a compound of formula 7 to provide an intermediate of formula 11. Subsequently, intermediate 11 can be coupled with an amine of formula 3 to provide the compound of formula 1 Another alternative method for the synthesis of the derivatives of formula 1 involves the coupling of chloroquinazoline 7 with an amine 3, followed by the subsequent coupling of intermediate 5 with a terminal alkyl, terminal alkene, vinyl halide, vinyl stannane, vinyl borane, alkyl borane or an alkyl or alkenyl zinc reagent. The compounds of the present invention may have asymmetric carbon atoms. The diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by conversion of the enantiomeric mixtures into a diastereomeric mixture by reacting them with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. . All such isomers, including the diastereomeric mixtures and the pure enantiomers, are considered part of the invention.

The compounds of formula 1 which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula 1 from the reaction mixture in the form of a pharmaceutically unacceptable salt, then simply convert the latter from new in the free base compound by treatment with an alkaline reagent, and subsequently converting the last free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol . After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated in a solution of the free base in an organic solvent, by adding an appropriate mineral or organic acid to the solution. The compounds of formula 1 which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1. Such non-toxic base salts include those derived from pharmacologically acceptable cations such like sodium, potassium, calcium, magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of reagents are preferably employed in order to ensure that the reaction is completed and that maximum yields of the desired final product are obtained. As a single compound of the present invention can include more than one acid or basic moiety, the compounds of the present invention can include mono, di or tri-salts in a single compound. The compounds of the present invention are potent inhibitors of the erbB family of oncogenic and proto-oncogenic tyrosine kinase proteins, such as the epidermal growth factor receptor (EGFR), erbB2, HER3 or HER4 and, therefore, are adapted to the therapeutic use as antiproliferative agents (eg, against cancer) in mammals, particularly in humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a variety of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovaries, colorectal, prostate , pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and throat, and other hyperplastic conditions such as benign hyperplasia of the skin (eg, psoriasis) and benign prostatic hyperplasia (eg, BPH). In addition, it is expected that a compound of the present invention possesses activity against a series of leukemias and lymphoid malignancies. The compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression ligand / receptor interactions are involved., or activation or signaling events related to various protein tyrosine kinases. Such disorders may include those of a neuronal, glial, astrocital, hypothalamic and other nature of glandular, macrophage, epithelial, stromal and blastocoelic nature, in which aberrant function, expression, activation or signaling of erbB tyrosine kinases are involved. . In addition, the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunogenic disorders involving identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention.

The in vitro activity of the compounds of formula 1 can be determined by the following procedure. The c-erbB2 kinase assay is similar to that previously described in Schrang et al. Anal Biochem. 211, 1993, p233-239. 96-well Nunc MaxiSorp plates are coated by incubation overnight at 37 ° C with 100 ml per well of 0.25 mg / ml Poly (Glu, Tyr) 4: 1 (PGT) (Sigma Chemical Co., St. Louis, MO) in PBS (phosphate buffered saline). Excess PGT is removed by aspiration and the plate is washed three times with wash buffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 ml of 50 mM HEPES (pH 7.5) containing 125 mM sodium chloride, 10 mM magnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP and 0.48 mg / ml (24 ng / well) of intracellular domain of c-erbB2. The intracellular domain of the erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GST fusion protein in Baculovirus and purified by binding and elution from beads coated with glutathione. The compound is added in DMSO (dimethylsulfoxide) to give a final concentration of DMSO of about 2.5%. Phosphorylation is initiated by the addition of ATP (adenosine triphosphate) and continues for 6 minutes at room temperature with constant agitation. The reaction of the kinase is terminated by aspiration of the reaction mixture and subsequent washing with wash buffer (see above). Phosphorylated PGT is measured by 25 minutes of incubation with 50 ml per well of antiphosphotyrosine antibody PY54 (Oncogene Science Inc. Uniondale, NY) conjugated with HRP, diluted to 0.2 mg / ml in blocking buffer (3% BSA and Tween 20 0.05% in PBS). The antibody is removed by aspiration and the plate washed 4 times with wash buffer. The colorimetric signal is developed by the addition of TMB Microwell Peroxidase Substrate (Kirkegaard and Perry, Gaithersburg, MD), 50 ml per well, and stopped by the addition of 0.09 M sulfuric acid, 50 ml per well. Phosphotyrosine is estimated by measuring the absorbance at 450 nm. The signal for the controls is typically 0.6-1.2 absorbance units, essentially no background values in the wells without the PGT substrate, and is proportional to the 10 minute incubation time. The inhibitors were identified by the reduction of the signal with respect to the wells without inhibitor and the IC50 values corresponding to the concentration of the compound necessary for the 50% inhibition were determined. The activity of the compounds of formula 1, in vivo, can be determined by the amount of inhibition of tumor growth shown by a test compound with respect to a control. The tumor growth inhibitory effects of various compounds are measured according to the procedure of Corbett TH, et al., "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure" , Cancer Res., 35, 2434-2439 (1975) and Corbett TH, et al., "A Mouse Colon-tumor model for Experimental Therapy", Cancer Chemother. Rep. (Part 2) ", 5, 169-186 (1975), with slight modifications.The tumors are induced in the left flank by subcutaneous (sc) injection of 1-5 million tumor cells cultured in logarithmic phase (cells Murine FRE-ErbB2 or human SK-OV3 ovarian carcinoma cells) suspended in 0.1 ml of RPMI 1640 medium. After sufficient time for the tumors to become palpable (100-150 mm3 in size / 5-6 mm in diameter), the test animals (athymic female mice) are treated with test compounds (formulated at a concentration of 10 to 15 mg / ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) administration route, or twice a day, for 7 to 10 consecutive days.To determine the anti-tumor effect, the tumor is measured in millimeters with a Vernier caliber through two diameters and the tumor size is calculated (mm3) using the formula: tumor size (mm3) = (length x [width] 2) / 2, according to the procedures 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). The results are expressed as percentage of inhibition, according to the formula: Inhibition (%) = (TuWcontroi-TuWensayo) / uWcontroi x 100%. The flank site of the tumor implantation provides reproducible dose / response effects for a variety of chemotherapeutic agents, and the measurement procedure (tumor diameter) is a reliable procedure for evaluating tumor growth rates. The administration of the compounds of the present invention (hereinafter, the "active compound (s)") can be carried out by any method that allows the release of the compounds at the site of action. These procedures include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) and topical and rectal administration. The amount of active compound administered will depend on the subject to be treated, the severity of the disorder to condition, the rate of administration, the disposition of the compound and the discretion of the corresponding physician. However, an effective dose is in the range of about 0.001 to about 100 mg per kg of body weight and per day, preferably about 1 to about 35 mg / kg / day, in a single dose or in divided doses. For a 70 kg human, this amount would be from about 0.05 to about 7 g / day, preferably from about 0.2 to about 2.5 g / day. In some cases, dosing levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be employed without causing any untoward side effects, provided that such larger doses are first divided into several doses small for administration throughout the day. The active compound can be applied as a single therapy or it can include one or more antitumor substances, for example, those selected from, for example, inhibitors of mitosis, for example, vinblastine; alkylating agents, for example, cis-platinum, carboplatin and cyclophosphamide; anti-metabolites, for example, 5-fluorouracil, cytosine arabinoside and hydroxyurea or, for example, one of the preferred anti-metabolites described in European Patent Application No. 239362, such as N- (5- [N-] (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino] -2-tenoyl) -L-glutamic acid; inhibitors of growth factors; cell cycle inhibitors; intercalating antiobiotics, for example, adriamycin and bleomycin; enzymes, for example, interferon and anti-hormones, for example, antiestrogens such as Nolvadex ™ (tamoxifen) or, for example, antiandrogens such as Casodex ™ (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy); -2-methyl-3 '- (trifluoromethyl) propionanilide). Such co-treatment can be achieved by means of the simultaneous, sequential or separate dosing of the individual components of the treatment. The pharmaceutical composition can, for example, be in a form suitable for oral administration, such 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 can be in unit dosage forms for the individual administration of precise doses. 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, vehicles, adjuvants, etc. Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms can be conveniently buffered if desired. Suitable pharmaceutical carriers include diluents or fillers, water and various organic solvents. It is desired, the pharmaceutical compositions may contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as citric acid can be used, together with various disintegrants such as starch, alginic acid and certain complex silicates, and with alginating agents such as sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for forming tablets. Solid compositions of a similar type can also be employed in soft and hard filled gelatin capsules. For this, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol , glycerin or combinations thereof. The methods for preparing various pharmaceutical compositions with a specific amount of active compound are known or will be apparent to those skilled in the art. For example, see Remington's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th edition (1975). The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It will 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 center, unless otherwise indicated, they exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise indicated, exist as a racemic mixture of diastereomers. Individual enantiomers / diastereomers can be obtained by methods known to those skilled in the art. When CLAR chromatography is mentioned in the following examples and preparations, the conditions used in general, 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 internal diameter. The samples are operated with a Hewlett Packard-1100 system. A gradient solvent process ranging from 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile for 10 minutes is used. The system then proceeds in a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate during the period is a constant of 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-methyl-4-phenoxynitrobenzene Sodium hydride (95% dry powder) (83.62 g, 3.31 mmol, 1.3 eq.) Was charged under a nitrogen atmosphere in a clean, dry, 12 liter, 4-neck flask equipped with a condenser, a dropping funnel, a mechanical agitator and two nitrogen inlets / outlets (Caution: sodium hydride is pyrophoric, avoid contact with water or moisture). The reaction flask was cooled to 0 ° C (ice bath) and then anhydrous DMF (1280 ml) was carefully added using a dropping funnel. The reaction mixture was stirred for 30 minutes at 0 ° C and then a solution of phenol (263.5 g, 2.8 mmol, 1.1 eq) in anhydrous DMF (1280 ml) was added using a dropping funnel for 2 hours (Caution: exothermic) , vigorous evolution of hydrogen). After the addition was complete, the reaction mixture was stirred for 40 minutes at 0 ° C (the reaction mixture became a white suspension) and then a solution of 3-methyl-4-fluoronitrobenzene was added dropwise over one hour. (390.0 g, 2.51 mmol, 1.0 eq) in DMF (dimethylformamide) anhydrous (1280 ml). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 15-22 hours (dark brown viscous solution) until all of the starting material was converted to phenoxynitrotoluene (TLC, 2% ethyl acetate in hexanes). Again, the reaction mixture was cooled to 0 ° C (ice bath) and then carefully quenched with ice-cold water (5000 ml) for 2 hours (Caution: exothermic, evolution of hydrogen, first 100 ml of water for 90 minutes). The reaction mixture was stirred for 1 hour and then transferred to two 50 I cylinders, each containing 40 I of water. The contents were stirred and left at room temperature for 24 hours to produce the phenoxynitrotoluene, in the form of a yellow solid. The yellow solid was filtered, washed with excess water and air dried to yield 3-methyl-4-phenoxynitrobenzene (552 g, 96% yield). It was determined that the crude 3-methyl-4-phenoxynitrobenzene was pure by the 1 H and 13 C NMR spectra, and was used as such in the next reaction; mp 51-52 ° C; IR-TF (cm "1): 1582, 1509, 1480, 1339, 1242, 1204, 1091, and 796; 1 H NMR (300 MHz, CDCl 3) d 2.41 (s, 3H), 6.78 (d, 1H, J = 8.7 Hz), 7.02-7.08 (m, 2H), 7.19-7.29 (m, 1H), 7.38-7.46 (m, 2H), 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-methyl-4-phenoxyaniline hydrochloride To a stirred solution of 3-methyl-4-phenoxynitrobenzene (2) (548 g, 2.39 mmol, 1.0 eq) in methanol (5 L), 10% Pd was added. C (100 g, 50% humidity, 46.98 mmole, 0.02 eq). Then, the reaction mixture was stirred under a hydrogen atmosphere (413.68-551.58 kPa) for 15-16 hours at room temperature in a Parr 9-liter hydrogenator. The progress of the reaction was monitored by TLC (50% ethyl acetate in hexanes, Rf mp = 0.69, Rf pr = 0.47, visible UV). 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%). It was determined that 3-methyl-4-phenoxyaniline was pure by the 1 H and 13 C NMR spectra, and was 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 mmol, 1.0 eq) in anhydrous ether (12 I), dry HCl gas was bubbled in 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 produce 3-methyl-4-phenoxyaniline hydrochloride (511.8 g, 96%) mp 173-174 ° C; IR-FT (cm "1): 3058, 3019, 2840, 2573, 1485, 1253, 1223, and 691; 1 H NMR (300 M Hz CDCl 3) d 2.22 (s, 3 H), 6.81-6.9 (m, 3 H) , 7.04-7.11 (m, 1H), 7.25-7.37 (m, 3H), 7.43 (d, 1H, J = 2.4 Hz), 10.45 (s, 3H), 3C 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, 156.96, APCI (negative FAB) 200.3 (100%), analysis calculated 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 procedures are: 3-Chloro-4-phenoxy-phenylamine 3-methoxy-4-phenoxy-phenylamine 4-phenoxy-3-trifluoromethyl-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 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-methylene-phenol amine 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 4-phenylsulfanyl-phenylamine 4-cyclohexyloxy-3-methyl-phenylamine 4-cyclopentyloxy-3-methyl-phenylamine 4-cyclobutyloxy-3-methyl-fenllamine 2-fluoro-4-phenoxyamine 4-fiuoro-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 4- (2-trifluoromethyl-phenoxy) -3-methyl-phenylamine 1- (5-amino-2-phenoxy-phenyl) -ethanone The ( ±) -4-benzenesulfonyl-3-methyl-phenylamine, (±) -4-benzenesulfonyl-phenylamine, 4-benzenesulfonyl-3-methyl-phenylamine and 4-benzenesulfonyl-phenylamine, were prepared from 3-methyl-4- phenylsulfanyl-fanylamine and 4-phenylsulfanyl-phenylamine by oxidation processes known to those skilled in the art. 3-ethyl-4-phenoxy-phenylamine To a solution of 1- (5-amino-2-phenoxy-phenyl) ethanone (0.5 g, 2.20 mmol) in THF (15 ml), sodium borohydride (0.4 g, 10.5 g) was added. mmoles) and AICI3 (anhydrous) (0.803 g, 6.02 mmol) under nitrogen atmosphere. The resulting reaction mixture was heated to reflux for 4 hours. The mixture was then cooled and water cooled with ice was added. The resulting mixture was extracted with EtOAc and dried over Na2SO4. Removal of the solvent produced a brownish residue which was chromatographed with 4: 1 hexane / EtOAc to produce (15 mg, 10%) the product 3-ethyl-4-phenoxy-phenylamine. 3-hydroxy-4-phenoxy-phenylamine 3-methoxy-4-phenoxynitrobenzene (2 g, 8.15 mmole) was treated with 48% HBr (20 ml) and HOAc (20 ml). The reaction reaction mixture was heated at 110 ° C for 24 hours and then the reaction mixture was poured onto ice and extracted with EtOAc, the organic layer was washed with brine and dried over Na2SO4. Removal of the solvent gave a brownish residue, 5-nitro-2-phenoxy-phenol, which was carried to the next step without further purification. (Almost quantitative performance). 1 H NMR (CDCl 3): d 7.91 (d, 1H, 2.7 Hz), 7.72 (dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.43 (t, 2H, J = 7.9 Hz), 7.28 (d, 1H, 7.9 Hz), 7.10 (d, 1H, J = 8.3 Hz), 6.78 (d, 2H, J = 8.9 Hz).

Exoti-4-phenoxy-phenylamine To a solution of 5-nltro-2-phenoxy-phenol (500 mg, 2.16 mmole) in acetone (20 ml) was added bromoethane (0.353 g, 3.26 mmol) and potassium carbonate (0.447 g, 3.26 mmoles). The resulting reaction mixture was stirred at room temperature for 2 hours and then the reaction was heated at 50 ° C for 4 hours. Water was added and the aqueous layer was extracted with EtOAc (3 x 30 mL), the organic layer was washed with brine and dried over Na2SO4. Removal of the solvent gave (0.3 g, 53%) 3-ethoxy-4-phenoxy-nitrobenzene. The product was subjected to hydrogenation over% Pd-C in methanol to yield (0.1 g, 38%) of 3-ethoxy-4-phenoxy-phenylamine.

M / Z, 230.0, 1 H NMR (CDCl 3): 7.91 (d, 1 H, 2.7 Hz), 7.72 (dd, 1 H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.43 (t, ap., 2H, J = 7.9 Hz), 7.28 (d, 1 H, 7.9 Hz), 7.10 (d, 1 H, 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-isopropoxy-4-phenoxy-phenylamine was also prepared by the above alkylation protocol. 3-phenyl-1 H-indazol-6-ylamine To a solution of 2-chloro-5-nltro-benzophenone (1.0 g) in THF (tetrahydrofuran) (15 ml), anhydrous hydrazine (120 mg) was added. The resulting reaction mixture was allowed to stir at room temperature for 2-4 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with water and brine and dried over Na 2 S 4. Removal of the solvent produced (0.8 g, 88%) the product 6-nitro-3-phenyl-1 H-indazole (5_). 6-Nitro-3-phenyl-1 H-indazole was hydrogenated over H2 / Pd and gave 0.5 g of 3-phenyl-1H-indazole-6-llamine (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-trimethylsilylacetylene to a carbonyl A stirred and cooled solution (-78 ° C) of (trimethylsilyl) acetylene (1.2 eq.) In anhydrous THF was treated with nBuLi (1.2 eq.) In nitrogen atmosphere (in the case of BOC-protected amino 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 to room temperature, stirred for 2 to 4 hours and quenched with water. After removal of the THF, the residue was partitioned between ether or EtOAc and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated to give the propargyl alcohol protected with crude TMS. Subsequently, a mixture of crude propargyl alcohol (1.0 eq.) And K2CO3 (2.0 eq.) In methanol was stirred at room temperature for 0.5 to 1 hour. The solids were removed by filtration and washed with ether. The filtrate was concentrated, dissolved in ether, washed with water and brine and dried over sodium sulfate. Removal of the solvent gave the crude terminal acetylene product, which was purified by distillation or chromatography (ethyl acetate / hexanes). The total yields for this procedure varied from 62 to 97%. Examples of terminal alkynes prepared by the above procedure are: 3-ethynyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 4-ethynyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyllic ester 3-ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester of tert-butyl acid of endo-a-3-ethynyl-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8- carboxylic Exo-β-3-ethynyl-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 2- (1-hydroxy-prop-2) acid -inyl) -pyrrolidine-1-carboxylic acid 1-cyclobutyl-prop-2-yn-1-ol Pent-1-in-3-ol 4-amino-pent-1-in-3-ol 1- (3-aza -bicyclo [3.1.0] hex-6-yl) -prop-2-yn-1-ol 4-ethynyl-tetrahydro-pyran-4-ol (4-ethynyl-tetrahydro-pyran-4-tert-butyl ester) -yl) -carbamic 2- (1-hydroxy-prop-2-ynyl) -piperidine-1-carboxylic acid tert-butyl ester 3- (1-hydroxy-prop-2-ynyl) tert-butyl ester ) -piperidine-1-carboxyli co-4-ethynyl-1-methyl-piperidin-4-ol tert-butyl ester of (2-hydroxy-but-3-yl) -methylcarbamate Ter-butyl ester of (2-ethynyl-2-hydroxy-cyclohexyl) -carbamic acid R and S-3-ethynyl-1-aza-bicyclo [2.2.2] octan-3-ol General procedure for homologation of aldehydes to terminal alkynes To a stirred and cooled solution (-78 ° C) of LDA (lithium diisopropylamide) (1.3 eq.) in anhydrous THF, a solution of (trimethylsilyl) diazomethane in hexane (1.3 eq.) was added dropwise under a nitrogen atmosphere (in the case of BOC-protected amino aldehydes containing a NH free, the amount of (trimethylsilyl) diazomethane and LDA is doubled). After 1 hour, aldehyde (1.0 eq.) Was introduced into anhydrous THF and the cooling bath was removed. The reaction was stirred at room temperature for 1 to 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). The overall yields for this procedure vary from 37 to 72%. Examples of terminal alkynes prepared by this procedure are: 4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester 3 (S) -etinyl-piperidine-1-carboxylic acid tert-butyl ester Tert-butyl acid ester 3 (R) -etinyl-piperidine-1-carboxylic acid 2-ethynyl-piperidine-1-carboxylic acid tert-butyl ester 3-ethynyl-pyrrolidin-1-carboxylic acid tert-butyl ester 3-ethynyl-azetidine-1-carboxylic acid (4-etinii-tetrahydro-pyran-4-yl) -carbamic acid tert-butyl ester [l- (tert-butyl-dimethyl-silanyloxymethyl) -prop acid tert-butyl ester -2-inil] -carbamic 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester To a solution of N-t-butoxycarbonipiperazine (5.0 g, 26.8 mmol) in acetone (40 mL), potassium carbonate (3.70 g, 26.8 mmol) was added. To the above reaction mixture was added dropwise propargyl bromide (2.39 ml, 26.8 mmol) in acetone (10 ml). The resulting mixture was allowed to stir at room temperature overnight. Water was added, the aqueous layer was extracted with ether and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to yield 4-prop-2-ynyl-piperazine-1-tert-butyl ester. -carboxylic acid in the form of a crude material that was brought into a coupling reaction of Pd with the appropriate anilinoquinazoline. Examples of terminal alkynes prepared by this process are: 1-prop-2-ynyl-pyrrolidine 3-methyl-4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester tert-butyl acid ester 3,5-Dimethyl-4-prop-2-ynyl-piperazine-1-carboxylic acid 1-methyl-4-prop-2-ynyl-piperazine 4-prop-2-ynyl-morpholine (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 (1-prop-2-ynyl-piperidin-3-yl) -methanol (1-propyl) 2-inyl-piperidin-2-yl) -methanol (1-prop-2-ynyl-pyrrolidin-2-yl) -methanol 2- (1-prop-2-ynyl-plperidin-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 2- (methyl-prop-2-ynylamino) -ethanol 4-prop-2-ynyl-piperazine-1-carboxylic acid methylamide 1- (4-prop-2-ynyl-piperazin-1-yl) -ethanone 4- prop-2-inyl-piperazine-1-carboxamide 1-methanesulfonyl-4-pr op-2-inyl-piperazine 2-chloro-N-prop-2-ynyl-acetamide Propargyl amine was dissolved (250 mg, 0.34 ml; 4.6 mmol) in dichloromethane (10 ml) and the solution was cooled to 0 ° C. Chloroacetyl chloride (256 mg, 0.18 ml, 2.3 mmol) was added dropwise to this solution and the solution was stirred for 30 minutes and allowed to warm to room temperature. The solution was washed with 2 x H2O, dried over Na2SO4 and the solvent was removed. 2-Chloro-N-prop-2-ynyl-acetamide (385 mg) was obtained as white crystals. 1 H NMR (400 MHz, CDCl 3) d 2.27 (1 H, m), 4.07 (2 H, s), 4.09 (2 H, q, J = 2.5 Hz), 6.78 (1 H, s a). Examples of terminal acetylenes prepared by the above procedure are: N-prop-2-inyl-acetamide N-prop-2-ynyl-propionamide Prop-2-inylamine of cyclopropanecarboxylic acid 2,2-dimethyl-N-prop-2-ynyl -propionamide N-prop-2-inyl-methanesulfonamide N-methyl-N-prop-2-inyl-acetamide N- (1-methyl-prop-2-ynyl) -acetamide N- (1,1-dimethyl- prop-2-ynyl) -acetamido 2-methoxy-N-prop-2-ynyl-acetamide 2-fterc-butoxycarbonylamino) -2-methyl-1-propanol A mixture of 2-amino-2-methyl-1-propanol ( 8.9 g, 0.1 mole), di-tert-butyl dicarbonate (22.0 g, 0.1 mole) and Na2CO3 (21.0 g, 0.2 mole) in water / THF (150/150 ml) was heated to reflux for 1 hour. After removing the 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 a solid. Waxy white: 1 H NMR (CDCl 3) d 1.23 (s, 6 H), 1.41 (s, 9 H), 3.56 (s, 2 H). 2- (tert-butoxycarbonylamino) -2-methyl propionaldehyde To a solution of 2- (tert-butoxycarbonylamino) -2-methyl-1-propanol (5.7 g, 30.0 mmol) in triethylamine (42 ml), a mixture of Sulfur trioxide and pyridine complex (14.3 g, 90.0 mmol) in anhydrous DMSO (dimethylsulfoxide) (50 ml) at room temperature. The reaction mixture was stirred for 1 hour under a nitrogen atmosphere and concentrated. The residue was dissolved in EtOAc (200 ml), and washed with water (100 ml) and brine (100 ml). It was dried over sodium sulfate and concentrated to give crude 2- (tert-butoxycarbonylamino) -2-methyl propionaldehyde as a yellow oil. Purification by distillation yielded 4.90 g (87%) of a waxy white solid: 1 H NMR (CDCl 3) d 1.30 (s, 6 H), 1.41 (s, 9 H), 4.97 (a, 1 H), 9.40 (s, 1 H). 4. 4-dimethyl-5-trimethylsilylethynyl-2-oxazolidinone A cold stirred solution (-78 ° C) of (trimethylsilyl) acetylene (4.42 g, 45.0 mmol) in anhydrous THF (20 ml) was treated with nBuLi (18 ml, 45.0 mmol) ) under a nitrogen atmosphere. The colorless solution was stirred for 30 minutes and continued by the addition of 2- (tert-butoxycarbonylamino) -2-methyl propionaldehyde (2.80 g, 15 mmol) in anhydrous THF (20 ml). The reaction was warmed to room temperature, stirred for 2 hours and quenched with water. After removing the 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 crude 4,4-dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (100%) as a yellow oil which was led to the next stage. 4. 4-D-methyl-5-ethynyl-2-oxazolidinone A mixture of 4,4-dimethyl-5-tr ymethylsilyl-2-oxazolidinone (15.0 mmol) and K2C? 3 (4.1 g, 30.0 mmol) in methanol (30.0 ml) was stirred at room temperature for 30 minutes. The solid was removed by filtration and washed with ether. The filtrate was concentrated, dissolved in ether (100 ml), washed with water (50 ml) and brine (50 ml) and dried over sodium sulfate. Removal of the solvent afforded 1.10 g (53%) of 4,4-dimethyl-5-ethynyl-2-oxazolidinone as a yellow oil: 1 H NMR (CDCl 3) d 1.37 (s, 3 H), 1.39 (s, 3 H ), 2.68 (s, 1 H), 4.82 (s, 1 H), 6.00 (s, 1 H).

Preparation of 4-ethynyl-4-hydroxy-tetrahydro-pyran-2-carboxylic acid amide 4-Oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester: ZnCl (0.63 g, 4.6 mmole) 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 (trifluoroacetic acid) (2 ml) were added and the mixture was stirred vigorously for 20 minutes. After concentration, the residue was partitioned between EtOAc (200 ml) and water (100 ml). The separated organic layer was washed with brine, dried over sodium sulfate and concentrated to give 8.0 g (100%) of a brown oil which was taken to the next step without further purification. 1 H NMR (CDCl 3) d 1.30 (t, 3 H), 2.85 (d, 2 H), 4.26 (q, 2 H), 5.00 (t, 1 H), 5.48 (d, 1 H), 7.39 (d, 1 H).

Ethyl ester of 4-oxo-tetrahydro-pyran-2-carboxylic acid. A mixture of 4-oxo-3,4-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 stirred in a Parr bottle with hydrogen at 344.73 kPa overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g, (33%) of a yellowish oil: 1 H NMR (CDC) d 1.29 (t, 3 H), 2.40 (d, 1 H), 2.58-2.75 (m, 3 H ), 3.79 (tt, 1 H), 4.23 (q, 2H), 4.28 (m, 1 H), 4.40 (m, 1H). 4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester: A stirred, cold solution (-78 ° C) of (trimethylsilyl) acetylene (1.80 g, 18.24 mmol) in anhydrous THF (30 ml) it was treated with nBuLi (7.3 ml in hexane, 18.24 mmole) under a nitrogen atmosphere. The colorless solution was stirred for 30 minutes and this was continued 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 to room temperature, stirred for 2 hours and quenched with water (30 ml). After removing the THF, the product was extracted with EtOAc (2 x 60 ml). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give 2.50 g (61%) of a yellow oil: 1 H NMR (CDCl 3) d 0.17 (s, 9 H), 1.30 (t, 3 H), 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-triethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.50 g, 9.25 mmol) was dissolved in MeOH (20 ml) in a pressure reaction tube and NH3 gas was passed through the solution during minutes with agitation. The tube was sealed and the reaction was stirred for 3 days. After removal of the solvent, 1.53 g (97%) of a yellow oil was obtained. 1 H NMR (CD 3 OD) d 1.48 (t, 1 H), 1.70 (td, 1 H), 1.85 (d, 1 H), 2.30 (d, 1 H), 3.04 (s, 1 H), 3.29 (s, 1 H ), 3.71 (t, 1H), 3.98 (d, 1 H), 4.06 (dt, 1H).

Preparation of 2- (tert-butyl-dimethyl-silanyloxymethyl) -4-ethynyl-tetrahydro-pyran-4-ol 2-Hydroxymethyl-tetrahydro-pyran-4-ol: To a stirred and cooled suspension (0 ° C) 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 hour, the reaction was quenched by the slow and sequential addition of water (3.4 ml), 15% NaOH (3.4 ml) and water (10.0 ml). The inorganic salt was separated by filtration and extracted repeatedly with EtOAc until the product was absorbed onto the solid. Removal of the solvent produced 2.42 (61%) of a yellow oil. The crude mixture was taken to the next stage without purification. 2- (tert-Butyl-dimethyl-silanyloxymethyl) -tetrahydro-pyran-4-ol: To a solution of 2-hydroxymethyl-tetrahydro-pyran-4-ol (2.42 g, 18.3 mmol), DMAP (4-dimethylaminopyridine) ( 90 mg, 0.74 mmol) and Et 3 N (2.04 g, 20.1 mmol) in anhydrous CH 2 Cl 2 (50 mL) was added tere-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 CH2Cl2 (40 mL). The combined organic extract was dried over sodium sulfate and concentrated. Purification by column of silica gel using 30% EtOAc in hexane gave 2.27 g (50%) of a colorless oil: 1 H NMR (CDCl 3) d 0.04 (s, 6 H), 0.88 (s, 9 H), 1.21 (m , 1H), 1.43 (m, 1 H), 1.82 (dt, 1 H), 2.00 (dt, 1 H), 3.35 (m, 1H), 3.51 (q, 1H), 3.66 (q, 1 H), 3.79 (m, 1H), 4.01 (m, 1H). 2- (tert-Butyl-dimethyl-silanyloxymethyl) -tetrahydro-pyran-4-one: A solution of 2- (fer-butyl-d-methyl-silanyloxymethyl) -tetrahydro-pyran-4-ol (2.27 g, 9.21 mmole) in anhydrous DMSO / EtsN (15/13 ml) was treated with sulfur trioxide and pyridine complex (7.33 g, 46.1 mmoles) in portions 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 column of silica gel using 10-20% EtOAc in hexane yielded 1.48 g (66%) of a colorless oil: H NMR (CDCb) d 0.05 (s, 6H), 0.88 (s, 9H), 2.32 (dt, 1 H), 2.41 (m, 2H), 2.58 (m, 1 H), 3.62 (m, 2H), 3.70 (d, 2H), 4.31 (m, 1H). 2- (tert-Butyl-dimethyl-silanyloxymethyl) -4-trimethylsilaneletyl-tetrahydro-pyran-4-ol: A stirred, cold solution (-78 ° C) 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) in nitrogen. The colorless solution was stirred for 30 minutes and then 2- (ε-butyl-dimethyl-silanyloxymethyl) -tetrahydro-pyran-4-one (1.48 g, 6.06 mmol) in anhydrous THF (25 mL) was added. The reaction was warmed to room temperature, stirred for 2 hours and quenched with water (30 ml). After removing the 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 a yellow oil: 1 H NMR (CDCl 3) d 0.05 (s, 6H), 0.16 (s, 9H), 0.89 (s, 9H), 1.43 (m, 1H), 1.78 (td, 1H), 1.83 (d, 1H), 1.94 (d, 1 H), 3.52-3.70 (m, 4H), 4.00 (m, 1H) ). 2- (tert-Butyl-dimethyl-silanyloxymethyl) -4-ethylnyl-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 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 a light yellow oil: 1 H NMR (CDCl 3) d 0.05 (s, 6H), 0.88 (s, 9H), 1.50 (m, 1H), 1.78 (m, 1H), 1.84 (d, 1 H), 2.01 (m, 1 H), 2.55 (s, 1H), 3.55-3.70 (m, 4H), 4.00 (m, 1 H).6-Iodo-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 heated to reflux for 20 hours. After cooling to 0 ° C, the solid product was collected by filtration. Further drying under vacuum afforded 6-iodo-4-quinazolinone (22.0 g, 81%) as a gray crystalline solid. 1 H NMR (400 MHz, DMSO-d 6) d: 12.38 (br s, 1 H), 8.35 (d, 1 H), 8.05-8.10 (m, 2 H), 7.43 (dd, 1 H). LRMS: 272.9 (MH +). 6-Iodo-4-chloroquinazoline (12): To a stirred solution of DMF (6.3 ml) in DCE (20 ml) cooled to 0 ° C, a solution of oxalyl chloride (60 ml of a solution) was added dropwise. 2 M in DCE). After the addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction is carefully quenched with H2O. CH2Cl2 was added and the bilayer was transferred to a separatory funnel. The aqueous layer was extracted with CH 2 Cl 2 (2 x 50 ml) and the combined organic layers were dried (Na 2 SO 4). The solvent was removed in vacuo to give a yellow solid which was triturated with diethyl ether to remove any remaining impurity. The resulting yellow solid obtained by filtration was found to be pure by NMR. 1 H NMR (CDCl 3, 400 MHz): d 9.05 (s, 1 H), 8.65 (d, 1 H), 8.21 (dd, 1 H), 7.78 (d, 1 H). 6-Iodo-4-phenoxyquinazoline (13): A suspension of NaH (washed without mineral oil) in DMF (40 ml) was cooled to 0 ° C and a solution of phenol (5.65 g, 60 mmol) was added dropwise at DMF (20 ml). After completing the addition, 6-iodo-4-chloroquinazoline (14.6 g, 50.3 mmol) was added in small portions as a solid. The cooling bath was removed and the 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 Na2SO4. Filtration of the solids and removal of the solvent afforded quinazoline 12 (17.2 g, 98%) as a yellow solid. 1 H NMR (400 MHz CDCl 3): d 8.74 (d, 1 H), 8.14 (s, 1 H), 8.12 (dd, 1 H), 7.71 (d, 1 H), 7.49 (dd, 2 H), 7.32 (t, 1H), 7.22 (m, 2H).

Method A: (1-Benzenesulfonyl-1 H-indol-5-p- [6- (3-imidazol-1-yl-prop-1-ynylo-quinazolin-4-yl] -amine (5) 1-Benzenesulfonyl-1 H-indol-5-yl) - (6-iodo-quinazolin-4-yl) -amine 04): 6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE (20 ml) and t-butanol (20 ml). The resulting mixture was heated to reflux under a nitrogen atmosphere for 18 hours to form a bright yellow suspension. After cooling, the solids were filtered and rinsed with CH 2 Cl 2 and placed under high vacuum to remove all excess solvent. Quinazoline 14 (3.23 g, 75%) was obtained as a yellow solid bu. 1 H NMR (DMSO d6; 400 MHz) d: 9.24 (s, 1H, NH), 8.84 (s, 1 H), 8.33 (dd, 1 H, 8.9 Hz, 1.7 Hz), 8.01 (m, 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-Benzenesulfonyl-1 H-indol-5-yl- [6- (3-imidazol-1-yl-prop-1-ynyl) quinazolin-4-yl-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. After cooling, the black suspension was concentrated under reduced pressure and the residue was dissolved in MeOH. Silica gel (1 g) was added and the methanol was removed in vacuo. The resulting silica gel was placed on top of a column of silica gel (40 g) which was then eluted with 200 ml of 50: 1 CH 2 Cl 2: MeOH; and 300 ml of 25: 1 CH2Cl2 to provide the alkyne 15 (72 mg, 51%) as a yellow foam. 1 H NMR (CDCl 3, 400 MHz) d: 8.95 (a, 1 H, NH), 8.63 (s, 1 H), 8.62 (s, 1 H), 8.24 (s, 1 H), 7.96 (d, 1 H, 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-phenoxy-phenyl) - [6- (3-piperazin-1-yl-prop-1-ynyl) -quinazolin-4-yl] -amine (6-Iodo-quinazol-n-4-yl) - (3-methyl-4-phenoxy-pheyp-amine: 4-Chloro-6-iodo-quinazollna (5.0 g, 17.2 mmol) was mixed together. -methyl-4-phenoxyaniline (5.0 g, 17.2 mmol) and 3-methyl-4-phenoxyaniline (17.2 mmol) in 1: 1 dichloroethane and t-butanol (50 mL) The reaction mixture was heated to 90 °. C for 4 hours, after which a yellow precipitate was observed.The reaction was cooled and the precipitate was collected and produced (6-iodo-quinazolin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine (8.0 g, 94%) M / z, 454. 1 H NMR (CD3OD) d 9.12 (s, 1 H), 8.83 (s, 1 H), 8.39 (d, 1 H, J = 8.8 Hz), 7.63 (d, 1 H, J = 8.8 Hz), 7.55 ( d, 1 H, J = 2.1 Hz), 7.35 (dd, 1 H, J1 = J 2 = 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). (3-methyl-4-phenoxy-pheyp- [6- (3-p-piperazin-1-yl-prop-1-ynyl) -quinazolin-4-yl] -amine: The tert-butyl ester of 4-prop-2-ynyl-piperazine-1-carboxylic acid (2.37 g, crude) and (6-iodo-quinazolin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine (800 mg, 1.76 mmole), Pd (OAc) (23.7 mg, 0.105 mmole), PPh3 (55.3 mg, 0.21 mmole) in EtsN (8 ml) and DMF (3 ml) The resulting reaction mixture was heated at 80 ° C for one hour. 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 the product 2. The product 2 was dissolved in methylene chloride and HCl gas was bubbled through it for 5 minutes, the precipitate was collected and produced (400 mg, 46.7%) the product (3- methyl-4-phenoxy-phenyl) - [6- (3-piperazin-1-yl-prop-1-ynyl) -quinazolin-4-yl] -amine, M / z, 450 1 H NMR (DMSO) d (ppm), 9.52 (s, 1 H), 8.84 (s, 1 H), 8.20 (dd, 1 H, J1 = 8.7 Hz, J2 = 1.3 Hz), 7.99 (d, 1 H , J = 2.5 Hz), 7.60 (dd, J1 = 8.7 Hz, J2 = 2.7 Hz), 7.36 (t ap., 2H, J = 8.5 Hz), 7.11 (t, 1H, J = 7.5 Hz), 6.92 ( d, 1 H, J = 8.8 Hz), 6.91 (d, 1H, J = 7.9 Hz), 3.55 (a, 4H), 3.44 (a, 4H), 3.30 (s, 2H), 2.19 (s, 3H) .

Method B: (6-Cyclobutyl-quinazolin-4-yl) - (4-phenoxy-phenylamino (17). 6-Cyclobutyl-4-phenoxyquinazoline (16): To a stirred solution of naphthalene (3.85 g, 30 mmol) in dry THF (tetrahydrofuran) (20 ml) at room temperature, finely chopped lithium metal (0.21 g, 30 mmol) was added. ) in small portions. The mixture turned dark green and stirring was continued for 2 hours. A solution of ZnCl2 (33 ml of a 0.5 M solution in THF, 16.5 mmol) was added dropwise via a syringe imparting a black color, after 3 hours, the stirring was stopped and the fine Zn powder was allowed to settle. The supernatant (~ 40 ml) was removed with a dry pipette and replaced with fresh THF (10 ml). Then, cyclobutyl bromide (2.0 g, 14.8 mmol) was added and the resulting dark mixture was allowed to stir at room temperature for 16 hours. The agitation was stopped again and the organocin reagent of the supernatant was 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 zinc cyclobutyl prepared as above. The resulting mixture was stirred for 6 hours, then diluted with THF (30 ml) and quenched with saturated NH 4 Cl solution (40 ml). The two layers were separated and the organic layer was washed with water and brine and then dried (Na2SO4). Removal of the solids and removal of the solvent in vacuo gave a brown oil. Purification by chromatography on silica gel eluting with 1: 1 EtOAc: hexanes gave 6-cyclobutyl-4-phenoxyquinazoline (0.78 g, 56%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 8.71 (s, 1 H), 8.14 (s, 1 H), 7.92 (d, 1 H), 7.78 (dd, 1 H), 7.50 (t, 2 H), 7.31 (t, 1 H), 7.25 (d, 2H), 3.78 (m, 1 H), 2.43 (m, 2H), 2.25 (m, 2H), 2.11 (m, 1H), 1.92 (m, 1H). (6-Cyclobutyl-quinazolin-4-yl-4-phenoxy-phenyl) amine (17) The quinazoline Iß (50 mg, 0.18 mmol) was combined with 4-phenoxyaniline (67 mg, 0.36 mmol) in phenol (0.45 g). The mixture was heated to 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 CH 2 Cl 2 to provide the desired quinazoline 17 (20 mg, 30%) as a yellow solid. 1 H NMR (DMSO d6, 400 MHz) d: 9.76 (s, 1 H), 8.47 (s, 1 H), 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, 1 H), 2.35 (m, 2H), 2.23 (m, 2H), 2.01 (m, 1H), 1.86 (m, 1H).

PROCEDURE C Cis- and trans- 3- [4- (1-benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-yl] -cyclobutanecarboxylic acid ethyl ester (19a / 19b) Ethyl ester of cis- and trans-3- (4-phenoxy-quinazolin-6-yl) -cyclobutanecarboxylic acid (18a.b) To a solution of naphthalene (1.92 g, 15 mmol) in dry THF under an N2 atmosphere, added finely-cut metallic Li (104 mg, 15 mmol) in small portions, resulting in a green mixture that was stirred for 2 hours. Then zinc chloride (16 ml of a 0.5 M solution in THF, 8 mmol) was added dropwise via syringe and the mixture was stirred at room temperature for 3 hours. The stirring was stopped and the supernatant was removed and replaced with a solution of ethyl 3-iodocyclobutane-1-carboxylate (790 mg, 3 mmol). The resulting suspension was stirred for 20 hours when the stirring was stopped and the remaining Zn metal was allowed to settle. The resulting 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 was taken up in EtOAc (30 ml) and washed with saturated aqueous NH 4 Cl, brine and H 2 O, and dried (Na 2 SO 4). The solvent was removed in vacuo and the resulting residue was purified by chromatography on silica gel to yield the cyclobutyl esters 18a and 18b as a mixture of cis and trans isomers (300 mg, 57%). LRMS: 349.2 (MH +). HPLC: 7.31 min (28%); 7.44 min (72%).

Ethyl cis-trans-3- [4- (1-benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-yl-1-cyclobutanecarboxylic acid ester (19a.b) Esters 18a and 18b (300 mg, 0.86 mmol) were combined with 5-amino-1-phenylsufonylindole (270 mg, 1.0 mmol) and phenol (1.0 g). The mixture was heated at 100 ° C for 48 hours. The excess phenol was removed by distillation and the residue was dissolved in CH 2 Cl 2, transferred to a separatory funnel and washed with H 2 O and brine. The organic layer was dried (Na2S4) and the solvent was removed to provide a dark residue which was purified by preparative TLC eluting with EtOAc to give the esters _L9a and Sfe (0.20 g, 44%) as a waxy solid. LRMS: 527.2 (MH +). HPLC: 7.54 min (16%); 7.64 min (84%).

PROCEDURE D Cis- and trans-. { 3- [4- (1-benzenesulfonyl-1 H -indole-5-ylamino) -quinazolin-6-yl] -cyclobutyl} methanol (20a.b) To a cooled (-78 ° C) and stirred solution of the ethyl esters 19a / 19b (70 mg, 0.13 mmol) in anhydrous toluene (5 ml), 0.78 ml of DIBAL-H (diisobutylaluminum hydride) (1 M in toluene) was added dropwise by means of a syringe. Then, the reaction was warmed to 0 ° C, stirred for 3 hours and then quenched by dilution with aqueous NH 4 Cl. The mixture was transferred to a separatory funnel and extracted with ethyl acetate. The organic layer was dried (Na2SO4), the solids were removed and the remaining filtrate was concentrated to give an oil which was purified by preparative TLC (eluted with ethyl acetate) to give 7 mg (11%) of the alcohols 20a / 20b in the form of a yellow solid: MS m / z (MH +) 485.2; HPLC 5.97 min.

PROCEDURE E Cis- and trans-. { 3- [4- (1-Benzenesulfonyl-1 H -indol-5-ylamino) -quinazolin-6-yl] -cyclobutyl} -pyrrolidin-1-yl-methanone (21a.b) Ethyl esters 19a / 19b (60 mg, 0.11 mmol) were dissolved in methanol (5 ml) and the mixture was heated to reflux for 1 hour to convert the ethyl ester to methyl ester. After removing the methanol, the residue was dissolved in pyrrolidine (5 ml) and heated to reflux for 20 hours. Removal of the pyrrolidine gave a mixture of oily brown product which was purified by preparative TLC (elution with ethyl acetate) to give 22 mg (36%) of 21 a / 21 b amides as a waxy yellow solid: MS m / z (MH +) 552.2; HPLC 6.447 min.

PROCEDURE F 4- [4- (1-Benzyl-1 H-indol-5-yl-amino) -quinazolin-β-iletinin-1-methyl-piperidin-4-ol (23) 1-Methyl-4- (4-phenoxy-quinazolin-6-ylethynyl) -piperidin-4-ol (22) Quinazoline 13 (1.32 g, 3.80 g) was added to a 100 ml round bottom flask under nitrogen. mmoles), 4-ethynyl-1-methyl-piperidin-4-ol (1.06 g, 7.6 mmol), Pd (OAc) 2 (51 mg, 0.23 mmol), PPh3 (120 mg, 0.46 mmol) and triethylamine (18 ml ). The flask was equipped with a reflux condenser and the mixture was heated at 100 ° C for 16 hours. The dark solution was then cooled and the triethylamine was 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 (2 x 25 ml) and the combined aqueous washings were extracted again with EtOAc (25 ml). The combined organic layers were dried (MgSO 4) and the solvent was removed under reduced pressure. The resulting black foam was purified on silica gel (50 g) eluting with 250 ml of 30: 1 of CH 2 Cl 2: MeOH and then 400 ml of 30: 1: 1 of CH 2 Cl 2: MeOH: NEt 3 to provide the desired product in the form of a yellow foam (930 mg, 68%). 1 H NMR (CDCl 3, 400 MHz) d: 8.71 (s, 1 H), 8.36 (d, 1 H, 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, 2H, J = 8.3 Hz), 7.31 (m, 1 H), 7.21 (m , 2H), 2.72 (a, 2H), 2.47 (a, 2H), 2.31 (s, 3H), 2.09 (m, 2H), 2.00 (m, 2H). 4- [4- (1-Benzyl-1 H-indol-5-ylamino) -quinazolin-6-ylethynyl-1-methyl-piperidin-4-ol (23) Quinazoline 22 was combined in a 1 ml Wheaton vial ( 80 mg, 0.22 mmol) with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridinium hydrochloride (5 mg, 0.04 mmol) and 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, it was solvated in a minimal amount of EtAOc and placed on top of a column of silica gel (5 g). The 1: 1: 0.1 hexane: EtOAc / NEt3 column eludon removed high RF impurities. The desired product 23 (Rf 0.05, 10: 1 of CH 2 Cl 2: MeOH) was eluted with 10: 1 CH 2 Cl 2: MeOH and gave a yellow solid (65 mg, 60%). 1 H NMR (DMSO d6; 400 MHz) d: 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), 7.31-7.18 (m, 6H), 6.48 (dd, 1H, J + 3, 1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (a, 2H), 2.67 (a, 2H), 2.47 (s, 3H), 1.92 (a, 2H), 1.82 (a, 2H). LRMS: 488.2 (MH +), 126.1.

PROCEDURE G 3- [4- < 1-Benzenes? Lfonil-1 H-indol-5-ylammon) -q? Inazol? N-6-yl] -alyl ester of acetic acid 3- (4-Phenoxy-quinazolin-6-yl) -acrylic acid methyl ester (24) Quinazoline 13 (3.5 g, 10.0 mmol), methyl acrylate (6.0 g, 70.0 mmol) was introduced into a pressure vessel, Pd (OAc) 2 (140 mg, 0.62 mmol), PPh3 (320 mg, 1.22 mmol), DMF (4 ml) and NEt ^ (15 ml). The tube was purged with nitrogen, sealed and heated at 110 ° C with stirring for 3 hours. The mixture was cooled and diluted with EtOAc and transferred to a separatory funnel, then washed with H2O and brine and dried (MgSO4). After filtration, the filtrate was concentrated under reduced pressure to provide a yellow solid which was recrystallized (EtOAc) to yield the ester 24 as a pale yellow solid (2.2 g, 72%). 1 H NMR (CDCl 3: 400 MHz) d: 8.76 (s, 1 H), 8.47 (s, 1 H), 8.08 (d, 1H), 8.06 (d, 1 H), 7.87 (dd, J = 16 Hz, 1 Hz), 7.48 (t, 2H), 7.35 (t, 1 H), 7.25 (m, 2H), 6.60 (d, J = 16 Hz, 1 H), 3.83 (s, 3 H). 3- (4-Phenoxy-quinazolin-6-yl) -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, DIBAL-H (8.8 ml of a 1M solution in toluene, 8.8 mmol) was added dropwise. After the reaction heated up to 0 ° C and stirred for 30 minutes, then quenched with 30 ml of Rochelle's saturated salt and the mixture was stirred overnight. The bilayer was transferred to a separatory funnel and the organic layer was washed with H2O and brine and dried (MgSO4). After filtration, the organic layer was concentrated under reduced pressure to give a yellow oil which was purified by silica gel chromatography eluting with 1: 1 hexanes: EtOAc and then EtOAc. Allyl alcohol 2§ (900 mg, 73%) was isolated as a pale yellow oil. 1 H NMR (CDCl 3, 400 MHz) d: 8.72 (s, 1 H), 8.27 (s, 1 H), 7.66 (m, 2 H), 7.62 (m, 1 H), 7.47 (m, 3 H), 7.34 (m , 1 H), 7.24 (m, 2H), 6.82 (dd, 1 H), 6.56 (m, 1 H), 4.41 (dd, 1 H). 3- (4-Phenoxy-quinazolin-6-yl) -alkyl ester of acetic acid (26) To alcohol 2_j (900 mg, 3.23 mmol) and pyridine (0.8 ml, 10 mmol) in CH2Cl2 (15 ml) dry at 0 ° C, acetyl chloride (0.3 ml, 4.2 mmol) was added. The resulting mixture was stirred for 2 hours, diluted with CH2Cl2 (10 mL) and 5% HCl (10 mL). The mixture was transferred to a separatory funnel and the organic layer was washed with H2O and brine. The organic layer was dried (Na 2 SO 4), the solids were filtered and the solvent was removed under vacuum to provide the desired acetate 26 in the form of a yellow waxy solid (1.04 g, 100%). 1 H NMR (CDCl 3, 400 MHz) d: 8.72 (s, 1 H), 8.30 (d, 1 H, J = 1.7 Hz), 7.98 (m, 2 H), 7.49 (m, 2 H), 7.30 (m, 1 H) , 7.25 (m, 2H), 6.84 (d, 1 H, J = 16.0 Hz), 6.46 (m, 1H), 4.79 (dd, 2H, J = 6.2 Hz, 1.2 Hz), 2.11 (s, 3H). 3- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-yl] -alkyl ester of acetic acid (27) A mixture of the ester 2j_ (630 mg, 1.97 mmol) and 5-amino-1-phenylsulfonylindole in phenol (3.0 g) was heated at 100 ° C for 20 hours. The excess phenol was removed by distillation and the resulting brown oil was purified by chromatography on silica gel eluting with 1: 1 ethyl acetate: hexanes and then with ethyl acetate. Quinazoline 27 (430 mg, 43%) was obtained as a whitish waxy solid. 1 H NMR (CDCl 3, 400 MHz) d: 8.61 (s, 1 H), 7.92 (m, 3 H), 7.82 (m, 4 H), 7.51 (m, 2 H), 7.43 (m, 3 H), 6.74 (d, 1 H), 6.62 (d, 1 H), 6.45 (dt, 1 H), 4.74 (dd, 2H), 2.09 (s, 3H).

PROCEDURE G '3- [4- (1-Benzyl-1H-indazol-5-ylamino) -quinazolin-6-yl] -acrylic acid methyl ester (28) and 3- [4- (4-phenoxy-fer? ilamino) -quinazolin-6-yl] -prop-2-en-1-ol (29) A procedure identical to that used to transform intermediate 26 into 2Z was used to convert the 4-phenoxyquinazoline derivative intermediates 24 and 25 into their respective 4-arylaminoquinazoline derivatives 23 and 29, respectively.

PROCEDURE H. { 6- [3- (6-Am8no-3-aza-bicyclo [3.1.0lhex-3-yl] -propenyl-quinazolin-4-yl > - (1- Benzenesulfonyl-1 H-indol-5-yl) -amine (30) A mixture of palladium acetate (6 mg, 0.027 mmol) and P (C 6 H 4 -m-S0 3 Na) 3 (30 mg, 0.053 mmol) in water (0.3 ml) was stirred at room temperature for 1 hour, followed by the addition of allyl acetate 16 (150 mg, 0.30 mmol) and (1a, 5a, 6a) -6-t-butyloxycarbonylamino-3-azabicyclo [3.1.0] hexane (prepared as in Brighry et al., Synlett 1996, pp. 1097-1099) (71 mg, 0.36 mmole) in CH3CN (3 ml ). The. The resulting reaction mixture was stirred at 50 ° C for 1.5 hours, taken up in ethyl acetate (10 ml) and washed with aqueous NH 4 Cl and water. The separated organic layer was dried over NaSO4 and concentrated to give a brown oil. Purification by preparative TLC (elution with ethyl acetate) yielded 31 mg of a yellow solid. The BOC-protected product obtained was dissolved in methanol (5 ml) and deprotected by passing HCl gas through the solution with stirring. After concentration and drying under high vacuum, the 3G amine was obtained in the form of its HCl salt (18 mg, 11%): MS m / z (MH +) 537.2; HPLC 4.423 min.

PROCEDURE I 4- [4- (4-Phenoxyphenylamino) -cynazolin-6-ylethynyl-tetrahydropyran-4-ol hydrochloride (32) 4- (4-Chloro-quinazolin-6-ylethynyl) -tetrahydro-pyran-4-ol (31) A mixture of 4-ethynyl-4-hydroxytetrahydropyran (70 mg, 0.55 mmol), 4-chloro-6-iodoquinazoline ( 145 mg, 0.50 mmol), bis (triphenylphosphine) palladium (II) chloride (24 mg, 7% by mole), copper (I) iodide (6.6 mg, 7% by mole) and diisopropylamine (56 mg, 0.55 mmole) 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 NH 4 Cl, H 2 O and brine, dried over Na 2 SO 4 and concentrated to give the product as a yellow solid. Crystallization from ethyl acetate / hexane yielded 0.13 g (90%) as a tan solid: 1 H NMR (CD 3 OD) d: 1.88 (m, 2 H), 2.04 (m, 2 H), 3.73 (m, 2 H), 3. 91 (m, 2H), 8.04 (s, 1H), 8.05 (s, 1H), 8.36 (s, 1H), 9.00 (s, 1H). 4- [4- (4-phenoxy-phenylamino) -quinazolin-6-ylenyl-1-tetrahydro-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-phenoxyanillin (28 mg, 0.15 mmol) in 2 mL of t-BuOH / 1,2-dichloromethane (1: 1) was heated at 90 ° C with stirring in a reaction vial for 1 hour. The reaction was cooled, diluted with CH2CI2, the product was collected by filtration to provide 52 mg (73%) of 32 as a yellow solid: 1 H NMR (CD3OD) d: 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 = 6.8 Hz, 2H), 7.81 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 8.75 (s, 2H); HPLC: 6.36 min.

PROCEDURE J (3-Methoxy-4-phenoxy-phenyl) - (6-piperidin-4-ylethynyl-quinazolin-4-yl) amine 4- (4-Chloro-quinazolin-6-ylethynyl) -piperidine-1-carboxylic acid tert-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 (II) (0.16 g, 0.23 mmol), copper iodide (l) (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 atmosphere for 2 hours. After concentration, the residue was dissolved in CH 2 Cl 2 (100 ml), washed with NH 4 Cl and brine, dried over sodium sulfate and concentrated to give the crude product as a brown oil. Purification by column on silica gel using 20% EtOAc in hexane yielded 1.63 g (94%) of a sticky yellow oil: 1 H NMR (CDCl 3) d 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 (day, 2H), 7.88 (dd, 1H), 7.97 (d, 1H), 8.26 (d, 1H), 9.00 (s, 1H). (3-Methoxy-4-phenoxy-phenyl- (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine A solution of 4- (4-chloro-quinazoline-) ferric-butyl ester 6-ylethynyl) -piperidine-1-carboxylic acid (131 mg, 0.304 mmol) and 3-methoxy-4-phenoxyaniline hydrochloride (77 mg, 0.306 mmol) in fBuOH / CI CH2CH2CI (1.0 / 1.0 ml) was heated in a vial of reaction, tightly capped at 90 ° C for 30 minutes.After cooling, the yellow mixture was diluted with MeOH and HCl gas was passed through the mixture for 10 minutes.After stirring for 2 hours, EtOAc was added to precipitate solid was collected by suction filtration, rinsed with EtOAc and further dried to give 105 mg (66%) of a yellow solid: 1 H NMR (CD3OD) d 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, 1 H), 7.06 (d, 1 H), 7.27 (t, 2H), 7.33 (dd, 1 H), 7.56 (d, 1H), 7.80 (d, 1 H), 8.06 (d, 1 H), 8.79 (s, 1H), 8.83 ( s, 1H); MS m / z (MH +) 451.3.

PROCEDURE K (3-Methyl-4-phenoxy-phenyl) - [6- (1-propyl-piperidin-3-ylethynyl) -quinazolin-4-yl] -amine (3-Methyl-4-phenoxy-phenyl) - [6- (1-propyl-piperidin-3-ylethynyl) -quinazolin-4-yl] -amine They were dissolved (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) in MeOH / H2O (5 / 0.5 ml) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and then NaBH3CN (13 mg, 0.2 mmol) was added 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 Na2CO3 (20 ml). The separated organic layer was dried over sodium sulfate and concentrated. Purification by preparative TLC using 10% MeOH in EtOAc gave the free base of the product, which was converted to the HCl salt to yield 42 mg (38%) of a yellow solid: 1 H NMR (CD3OD) d 1.03 (t, 3H ), 1.78-1.87 (m, 4H), 2.01-2.08 (m, 2H), 2.28 (s, 3H), 2.96 (t, 1 H), 3.07-3.19 (m, 3H), 3.31 (a, 1H) , 3.59 (d, 1H), 3.80 (d, 1H), 6.94 (m, 3H), 7.09 (t, 1H), 7.34 (t, 2H), 7.34 (t, 2H), 7.53 (d, 1H), 7.63 (s, 1 H), 7.80 (d, 1 H), 8.05 (dd, 1 H), 8.73 (s, 1 H), 8.75 (s, 1 H); MS m / z (MH +) 477.1.

PROCEDURE K '. { 6- [1- (2-Amino-ethyl) -piper8din-3-ylethynyl] -quinazolin-4-yi} - (3-methyl-4-phenoxy-phenyl) -amine . { 6- [1- (2-Amino-ethyl) -piperidin-3-yletnyl] -quinazolin-4-yl} - (3-methyl-4-phenoxy-phenyl) -amine They were dissolved (3-methyl-4-phenoxy-phenyl) - (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine (114 mg, 0.2 mmoles) and tert-butyl N- (2-oxoethyl) carbamate (320 mg, 2.0 mmol) in MeOH / H 2 O (5 / 0.51) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and continued by the addition of NaBH 3 CN (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 Na2CO3 (20 ml). The separated organic layer was dried over sodium sulfate and concentrated. Purification by column of silica gel using 5% MeOH in EtOAc gave the free base which was dissolved in MeOH. HCl gas was passed through the solution for 5 minutes and the deprotected product precipitated in the form of the HCl salt. The mixture was diluted with EtOAc and the solid was collected by suction filtration, rinsed with EtOAc and dried adduction to yield 83 mg (71%) of a yellow solid: 1 H NMR (CD3OD) d 1.71-1.82 (a, 2H ), 2.0-2.12 (a, 2H), 2.27 (s, 3H), 3.00 (t, 1 H), 3.03-3.19 (a, 2H), 3.40 (a, 1 H), 3.50 (s, 2H), 3.62 (day, 1H), 3.70 (m, 1 H), 3.89 (day, 1H), 6.93 (m, 3H), 7.08 (t, 1 H), 7.33 (t, 2H), 7.52 (d, 1 H) ), 7.64 (s, 1H), 7.79 (d, 1 H), 8.05 (d, 1H), 8.75 (s, 1 H), 8.77 (s, 1 H); MS m / z (MH +) 476.1.

PROCEDURE L 3-. { 2- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] ethyl} -piperidin-3-ol 3-. { 2- [4- (3-Met l-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 stirred in a Parr flask with hydrogen at 344.73 Kpa overnight and filtered through a pad of Celite. The filtrate was concentrated to a small volume and added dropwise in EtOAc with stirring. The solid was collected by suction filtration, rinsed with EtOAc and further dried to yield 89 mg (89%) of a yellow solid: 1 H NMR (CD3OD) d 1.69 (dt, 1H), 1.81 (da, 1H), 1.95 (t, 3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d, 1 H), 3.31 (a, 1 H) , 6.94 (m, 3H), 7.08 (t, 1 H), 7.34 (t, 2H), 7.55 (d, 1 H), 7.66 (d, 1 H), 7.78 (d, 1 H), 8.02 (d , 1 H), 8.58 (s, 1 H), 8.73 (s, 1 H); MS m / z (MH +) 455.2.

PROCEDURE M N-. { 3- [4- (3-Metii-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} -2- morpholin-4-yl-acetam 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide 2-chloro-N-prop-2-ynyl-acetamide (385 mg, 2.93 mmol) was dissolved ) and 4-chloro-6-iodoquinazoline (850 mg, 1 equiv.) 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) 2CI2 (82 mg). The reaction was stirred. at room temperature under a nitrogen atmosphere overnight (~ 20 hours). The solvent was then removed in vacuo and the residue was dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1 x saturated NH 4 Cl and brine, dried over Na 2 SO 4 and the solvent was removed in vacuo. The product was purified by silica gel chromatography, eluting with 1: 1 hex / EtOAc and the fractions were collected with Rf = 0.25. This produced 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide as an off-white solid (454 mg, 53%). 1 H NMR (400 MHz, CDCl 3): d 4.12 (2H, s), 4.40 (2H, d, J = 5.2 Hz), 7.91-7.93 (1H, dd, J = 2, 6.8 Hz), 8.00 (1H, d , J = 8.4 Hz), 8.34 (1 H, d, J = 1.6 Hz), 9.03 (1 H, s). LRMS (M +): 294.0, 296.0, 298.1. 2-Chloro-N-. { 3- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynu} -acetamide A solution of 2-chloro-N- [3- (4-chloro-quinazolin-6-yl) -prop-2-ynyl] -acetamide (50 mg, 0.17 mmol) and 3-methyl-4-phenoxyaniline ( 36 mg, 0.9 equiv.) In 1,2-dichloroethane (1 ml) and f-butanol (1 ml), it 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. Then, the solution was 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 (1 H, t), 7.34 (2H, t), 7.50-7.53 (1 H, dd, J = 2.6, 6 Hz), 7.63 (1 H, d, J = 2.4 Hz), 7.78 ( 1 H, d, J = 8 Hz), 8.06-8.08 (1 H, dd, J = 1.4, 7.2), 8.68 (1 H, d, J = 1.2 Hz), 8.75 (1 H, s). LRMS (M +): 457.0, 459.1; (M-) 455.7, 419.6.

N-. { 3-f4- (3-methy1-4-phenoxy-phenylamino) -quinazolin-6-ip-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), 3 equivalents of morpholine (31 mg) were added and the mixture was heated to reflux overnight. The reaction was cooled to room temperature, the morpholine salts were removed by filtration and the solvent was removed from the filtrate. The residue was redissolved in CH2Cl2 with a small amount of methanol and HCl gas was bubbled through the solution for 2-3 minutes. Then, the solution was concentrated to 2-3 ml, diluted with ethyl acetate and filtered to obtain N-. { 3- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-inl} -2-morpholin-4-yl-acetamide as a yellow / brown solid (65 mg, 94%). ? NMR (400 MHz, CD3OD) d 2.27 (3H, s), 3.21 (2H, 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 (1 H, t, J = 7.4 Hz), 7.34 (2H, t, J = 8 Hz), 7.54 (1H, dd), 7.65 (1H, s), 7.82 (1 H, d, J = 8.8 Hz), 8.06 (1 H, d, J = 8.4 Hz), 8.76 (1 H, s), 8.80 (1 H, s). LRMS (M +): 508.0; (M-): 506.0.

PROCEDURE N (3-Methyl-4-phenoxy-phenyl) - (6-piperidin-4-ylethynyl-pyrido [3,4-d] pyrimidin-4-yl) -amine 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 the dropwise addition of thionyl chloride (10 ml). The flask was equipped with a condenser and a drying tube and the contents were heated to reflux for -20 minutes, after which the solids were dissolved. Heating was continued for an additional 1 hour and then cooled. Toluene was added to wash the sides of the flask and the solvents were evaporated in vacuo. The azeotropic evaporation with toluene was repeated twice and the obtained crude product was taken to the next stage. (6-Chloro-pyrido [3,4-d1-pyrimidin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine The 4,6-dichloro-pyrido [3,4-d] pyrimidine obtained from from the above reaction was taken up in dioxane (50 ml), 3-methyl-4-phenoxy-aniline hydrochloride (2.8 g, 12 mmol) was added and the contents were heated to an external bath temperature of ~80 ° C. for 3 hours, after which the precipitation of a yellow material occurred. Additional dioxane (20 ml) was added and the contents warmed to ~75 ° C for 12 hours. Then, the solution was filtered and the yellow solid was placed in vacuo to give the hydrochloride of (6-chloro-pyrido [3,4-d] pyrimidin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine desired (3.6 g, -100%). ? NMR (CD3OD, 400 MHz) d 9.05 (s, 1 H), 8.87 (s, 1 H), 8.64 (s, 1 H), 7.69 (d, J = 2.5 Hz, 1 H), 7.58 (dd, J = 8.7, 2.5 Hz, 1 H), 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 In a flame-dried heart flask was introduced the (6-Chloro-pyrido [3,4-d] pyrimidin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine hydrochloride (200 mg, 0.5 mmol), the tert-butyl ester of 4-ethynyl-piperidine-1-carboxylic acid (314 mg, 1.5 mmol), Pd (PhCN) 2CI2 (19 mg, 0.05 mmol), 1,4-bis (diphenylphosphino) butane (32 mg, 0.075 mmol) and Cui (4.8 mg, 0.025 mmol). Dioxane (5 ml) was added and to this stirred suspension under Ar atmosphere was added diisopropylamine (0.32 ml, 2.28 mmole), after which a large amount of solid was dissolved. Then, the flask (equipped with a condenser) was placed in a preheated oil bath and heated to a bath temperature of 104 ° C for 14 hours, after which the LC / MS indicated the disappearance of the starting material. Then, the reaction mixture was filtered through a pad of silica, concentrated and chromatographed using gradient elution of 20-80% EtOAc-hexanes to give the desired coupled product as a solid (165 mg, 62%). The solid was collected in CH2Cl2 (and small amounts of MeOH to aid dissolution), HCl (g) was bubbled through it, followed by the addition of ether, and then a solid precipitated which was filtered and placed under vacuum to give ja (3-methyl-4-phenoxy-phenyl) - (6-piperidine -4-Ileoynyl-pyrido [3,4-d] pyrimidin-4-yl) -amine desired in the form of the dihydrochloride salt. 1 H NMR (OD CD, 400 MHz) d 9.12 (s, 1 H), 8.85 (s, 1 H), 8.68 (s, 1 H), 7.70 (d, J = 2.5 Hz, 1 H), 7.58 (dd, J = 8.7 , 2.5 Hz, 1H), 7.34 (dd, J = 8.3, 7.5 Hz, 2H), 7.10 (t ap., 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 (, 2H), 2.0 (m, 2H). MS m / z (MH +): 436.3.

PROCEDURE OR 4-Amino-4-methyl-1- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6- »p-pent-1-n-3-pi - (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-iodoquinazollna (1.63 g, 5.60 mmol), dichlorobis (triphenylphosphine) palladium (II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol) and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 ml) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH 2 Cl 2 (80 ml), washed with aqueous NH 4 Cl and brine, dried over sodium sulfate and concentrated to give the crude product as a brown oil. Purification by column of silica gel using 50-70% EtOAc in hexane yielded 1.22 g (72%) as a yellow solid. 1 H NMR (CDCl 3) d 1.49 (s, 3 H), 1.53 (s, 3 H), 5.14 (s, 1 H), 5.57 (s, 1 H), 7.95 (dd, 1 H), 8.04 (d, 1 H, J = 8.8 Hz), 8.38 (d, 1H, J = 2.0 Hz), 9.05 (s, 1 H). 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 'BuOH / CICH.CH .CI (1: 1, 2.0 ml) was heated in a sealed reaction vial at 90 ° C for 30 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 a yellow solid. This material (215 mg, 0.43 mmol) was immediately combined with KOH (0.51 g, 9.0 mmol) in MeOH / H2O (9/3 ml) and heated to reflux for 20 hours. After cooling, the reaction was neutralized with 0.60 g (10.0 mmol) of AcOH and concentrated. The residue was suspended in CH2Cl2 and purified on a silica gel column using 20% MeOH in CH2Cl2. The purified free base was converted to HC1 salt to yield 46 mg (22%) of yellow solid. ? NMR (CD3OD) d 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 procedures described above. In the chart shown below, the term "min" refers to minutes. The numbers of examples in the following table do not correspond to the compound numbers mentioned in the previous experimental section.

PICTURE Using the procedure I and the appropriate starting materials (prepared according to the methodology known in the art), the following compounds (and pharmaceutically acceptable salts and solvates thereof), which are part of the present invention, can be prepared. 1-. { 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -zetidin-1-yl} -etanone 1-. { 3- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -zetidin-1-yl} -etanone 1-. { 3- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -zetidin-1-yl} -etanone [6- (1-metsulfonyl-azetidin-3-ylethynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [6- (1-metsulfonyl-azetidin -3-ylethynyl) -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine [6- (1-metsulfonyl-azetidin-3-ylethynyl) -quinazolin-4-yl] - (3-Chloro-4-phenoxy-phenyl) -amine [6- (1-Metsulfonyl-pyrrolidin-3-ylethynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [6- (1-Metsulfonyl-pyrrolidin-3-ylethynyl) -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine [6- (1-metsulfonyl-pyrrolidin-3-ylethyl) ) -quinazolin-4-yl] - (3-chloro-4-phenoxy-phenyl) -amine 1-. { 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pyrrolidin-1-yl} -etanone 1-. { 3- [4- (3-Methoxy-4-phenoxy-phenamino) -quinazolin-6-ylethynyl] -pyrrolidin-1-yl} -etanone 1-. { 3- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pyrrolidin-1-yl} -etanone 1-. { 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidin-1-yl} -etanone 1-. { 3- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidin-1-yl} -etanone 1-. { 3- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidin-1-yl} -etanone [6- (1-methanesulfonyl-piperidin-3-ylethynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [6- (1-methanesulfonyl-piperidin-3-yl-ethyl) ) -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine [6- (1-methanesulfonyl-piperidin-3-ylethynyl) -quinazolin-4-yl] - (3-chloro-4) -phenoxy-phenyl) -amine 5- [4- (3-Methy-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 4- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pyrrolidin-2-one 4- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazo! 6-ylethynyl] -pyrrolidin-2-one 4- [4- (3-Chloro-4-phenoxy-phenylamino) -cynazolin-6-ylethynyl] -pyrrolidin-2-one 1-. { 2- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-tranyl] -morpholin-4-yl} -etanone 1-. { 2- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ynynyl] -morpholin-4-yl} -etanone 1-. { 2- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -morpholin-4-yl} -etanone [6- (4-methanesulfonyl-morpholin-2-ylethynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [6- (4-methanesulfonyl-moryolin-2-ylethynyl ) -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine [6- (4-methanesulfonyl-morpholin-2-ylethynyl) -qulnazoln-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) -chinazolin-6-ylethynyl] -morpholin-3-one 5- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pperazin-2-one 5- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-) iletinyl] -piperazin-2-one 5- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperazin-2-one 6- [4- (3-MetiI-4-phenoxy) phenylamino) -quinazolin-6-ylethynyl] -piperazin-2-one 6- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperazin-2-one 6- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperazin-2-one 1 -. { 5- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolln-6-ylethynyl-3, 4-dihydro-2H-pyridin-1-yl} -etanone 1-. { 5- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,4-dihydro-2H-pyridin-1-yl} -etanone 1-. { 5- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,4-dihydro-2H-pyridin-1-yl} -etanone [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-methoxy-4-phenoxy-phenyl) -amine [6- (1- Methanesulfonyl-1, 4,5,6-tetrahydro-pyridin-3-ylethynyl) -quinazolln-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} -etanone 1-. { 5- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,6-dihydro-2H-pyridin-1-yl} -etanone 1-. { 5- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,6-dihydro-2H-pyridin-1 -ll} -etanone [6- (1-methanesulfonyl-1, 2,5,6-tetrahydro-pyridin-3-ylethynyl) -cynazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [ 6- (1-Methanesulfonyl-1, 2,5,6-tetrahydro-pyridin-3-ylethynyl) -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine [6- (1 - Methanesulfonyl-1, 2,5,6-tetrahydro-pyridin-3-ylethynyl) -quinazolln-4-yl] - (3-chloro-4-phenoxy-phenyl) -amine 1-. { 4- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,6-dihydro-2H-pyridin-1-yl} -etanone 1-. { 4- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,6-dihydro-2H-pyridin-1-yl} -etanone 1-. { 4- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -3,6-dihydro-2H-pyridin-1-yl} -etanone [6- (1-methanesulfonyl-1, 2,3,6-tetrahydro-pyridin-4-ylethynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [ 6- (1-Methanesulfonyl-1, 2,3,6-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 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) -quinazoln-6-yl] -prop-2-ynyl} -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 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} -acetamide N-. { 1-Methyl-3- [4- (3-chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} -acetamide N-. { 1-Met.l-3- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} ~ methanesulfonamide 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-one 1-. { 3- [4- (3-Methoxy-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} -piperidin-2-one 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-phenamino) -quinazolin-6-yl] -prop-2-ynyl} -pyrididin-2-one 1-. { 3- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} -pyrrolidin-2-one Using the procedure J and the appropriate starting materials (prepared according to the methodology known in the art), the following compounds (and pharmaceutically acceptable salts and solvates thereof) which form part of the present invention: (7-Methods-6-piperidin-3-ylethynyl-quinazolin-4-yl) - (3-methyl-4-phenoxy-phenyl) -amine (3-Chloro-4-phenoxy-phenyl) - (7 -methoxy-6-piperidin-3-ylenyl-quinazolin-4-yl) -amine (3-methoxy-4-phenoxy-phenyl) - (7-methoxy-6-piperidin-3-ylethynyl-quinazole) 4-yl) -amine [7- (2-Methoxy-ethoxy) -6-piperidin-3-ylethynyl-quinazolin-n-yl] - (3-methyl-4-phenoxy-phenyl) -amine (3-Chloro-4-phenoxy) -phenyl) - [7- (2-methoxy-ethoxy) -6-piperidin-3-ylethynyl-quinazolin-4-yl] -amine [7- (2-methoxy-ethoxy) -6-piperidin-3-ylethynyl -quinazolin-4-yl] - (3-methoxy-4-phenoxy-phenyl) -amine 3-r7- (2-Methoxy-ethoxy) -4- (3-methyl-4-phenoxy-phenylamino) -q-nazolin -6-Ilethynyl] -piperidin-3-ol 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-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 (6-Azetidin-3-ylethynyl) -quinazolin-4-yl) - (3-methoxy-4-phenoxy-phenyl) -amine (3-Methyl-4-phenoxy-phenyl) - (6-morpholin-2-ylethynyl-quinazolin-4-) il) -amine (3-Methoxy-4-phenoxy-phenyl) - (6-morpholin-2-ylethynyl-quinazolin-4-yl) -amine (3-Chloro-4-phenoxy-phenyl) - (6-morpholin-2-ylethynyl) -quinazolin-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-phenyl) - [6- (1, 4,5,6-tetrahydro-pyridin-3-ylethynyl) -quinazolin-4-yl] -amine (3-Chloro-4-phenoxy-phenyl) - [6- ( 1, 4,5,6-tetrahydro-pyridin-3-ylenyl] -quinazolin-4-yl] -amine (3-Methyl-4-phenoxy-phenyl) - [6- (1, 2.5.6 -tetrahydro-pyridin-3-ylethynyl) -quinazolin-4-yl] -amine (3-methoxy-4-phenoxy-phenyl) - [6- (1, 2,5,6-tetrahydro-pyridin-3-ylethynyl) -quinazolin-4-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 (3-Methoxy-4) -phenoxy-phenyl) - [6- (1, 2,3,6-tetrahydro-pyridin-4-ylethynyl) -quinazolin-4-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-lyl) -quinazolin-4-) il] - (3-methyl-4-phenoxy-phenyl) -amine [6- (3-Amino-3-methyl-but-1-ynyl) -quinazolin-4-yl] - (3-methoxy-4-phenoxy) -phenyl) -amine [6- (3-Amino-3-methyl-but-1-lnyl) -quinazolin-4-yl] - (3-chloro-4-phenoxy-phenyl) -amine [6- (3-Amino-but -1-inyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine [6- (3-Amino-but-1-ynyl) -quinazolin-4-yl] - (3 -methyl-4-phenoxy-phenyl) -amine [6- (3-Amino-but-1-ynyl) -quinazolin-4-yl] - (3-methyl-4-phenoxy-phenyl) -amine.

Claims (35)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula 1 i or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N or CH; A represents a 5, 6 or 7 membered fused ring optionally containing from 1 to 4 heteroatoms which may be the same or different and which are selected from -N (R1) -, O and S (O) j, where j is an integer from 0 to 2, the condensed ring containing a total of 1, 2 or 3 double bonds including the bond of the pyridine ring or pyrimidine with which it is condensed, wherein the group R1 attached to the nitrogen is absent if a the double bond includes the optional nitrogen moiety mentioned above -N (R1) -, with the proviso that the fused ring does not form part of a purine and the fused ring does not contain two adjacent O or S (O) j atoms, and wherein the carbon atoms of residue A are optionally substituted with 1 to 3 R5 groups; each R 1 and R 2 is independently H or C C β alkyl; R3 is - (CR1R2) m -R8, wherein m is 0 or 1; or R1 and R3 are taken together to form a formula group said group being optionally substituted with 1 to 3 R5 groups; R4 is - (CR1R2) mC = C- (CR1R2) tR9, - (CR1R2) mC = C- (CR1R2) tR9, -C = NOR12 or -X1-R12, where 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; or R4 is - (CR1R2) mC = C- (CR1R2) kR13 or - (CR1R2) mC = C- (CR R2) kR13, where k is an integer from 1 to 3 and m is an integer from 0 to 3; or R4 is - (CR1R2) tR9, where t is an integer from 0 to 5 and the point of attachment to R9 is through a carbon atom of the group R9; each R 5 is independently selected from halo, hydroxy, -NR 1 R 2, C 1 -C 6 alkyl, trifluoromethyl, C 1 -C 6 alkoxy, trifluoromethoxy, -C (O) R 6, -CO 2 R 6, -NR 6 C (O) R 1, -C (O ) NR6R7, -SO2NR6R7, -NR6C (O) NR7R1 and -NR6C (O) OR7; each R6 and R7 is independently selected from H, d-Cß alkyl, - (CR1R2) t (C6-C10 aryl) and - (CR1R2) t (4-10 membered heterocycle), wherein t is an integer of 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo moiety (= O), and the alkyl, aryl and heterocyclic moieties of the above groups R6 and R7 are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR1R2, trifluoromethyl, trifluoromethoxy, Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy and Ci-Cß alkoxy; R8 is independently selected from - (CR1R2) t (Ce-Cι aryl) and - (CR''R2t (4- to 10-membered heterocycle), where t is an integer from 0 to 5, 1 or 2 carbon atoms of the heterocyclic group ring are optionally substituted with an oxo moiety (= O) and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups; R9 is a non-aromatic monocyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, said ring containing from 3 to 12 carbon atoms, wherein from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S (O) j, wherein j is a integer from 0 to 2, and -NR12-, with the proviso that two atoms of O, two residues S (O) j, an atom of O and a residue (SO) j, an atom of N and an atom of S, or an N atom and an O atom are not directly bonded together within said ring, and wherein the carbon atoms of said atom are optionally substituted with 1 to 2 R11 groups; each R10 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, atcoxy CrC6, alkyl dC-io, alkenyl C2-C6, alkynyl C2-C6, -C (0) R6, -C (0) OR6, -OC (0) R6, -NR6C (0) R7, -NR6C (0) NR1R7, -NR6C (O) OR7, -C (O) NR6R7, -NR6R7, -NR6OR7, -SO2NR6R7, -S (0 ) j (C -Cß alkyl) where j is an integer from 0 to 2, - (CR1R2) t (aryl Ce-Cio), - (CR1R2) t (4-10 membered heterocycle), - (CR1R2) qC (O) (CR1R2) t (aryl C6-C? 0), of 4-10 members), - (CR 1'oR2 \) tO (CR1R2) q (aryl C? -C10), - (CR1R2) tO (CR1R2) q (4-10 membered heterocycle), - (CR1R2) qS (O) j ( CR1R2) t (aryl C6-C? 0) and - (CR1R2) qS (O) j (CR1R2) t (heterocycle of 4-10 members), where j is 0, 1 or 2, each of q and t is independently an integer of 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the above R10 groups are optionally substituted with an oxo moiety (= O), and the alkyl, alkenyl, alkynyl, aryl and heterocycle moieties of the above R10 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (O) R6, -C (O) OR6, -OC (O) R6, -NR6C (O) R7, -C (0) NR6R7, -NR6R7, -NR6OR7, C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CR1R2) t (C6-C6aryl aryl) and - (CR1R2) t (4-10 membered heterocycle), where t is an integer from 0 to 5; each R11 is independently selected from -R12, -OR1, -NR2R, -NR6C (O) R7, -NR6C (O) NR7R1, -NR6C (O) OR7 and -NR6SO2NR7R1, or R11 replaces two hydrogen atoms of a carbon to form an oxo group (C = O); R12 is R6, -C (O) R6 or -SO2R6, -C (O) NR6R7, -S02NR6R7 or -C02R6; R13 is -NR1R12 or -OR12; and wherein any of the aforementioned substituents comprising a group CH3 (methyl), CH2 (methylene) or CH (methino) which is not bonded to a halogen group, SO or SO2, or a N, O or S atom, optionally carries on said group a substituent selected from hydroxy, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and -NR 1 R 2.

2. - The compound according to claim 1, further characterized in that the rest A is selected from among the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents.

3. The compound according to claim 1, further characterized in that the rest A is selected from among the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents.

4. The compound according to claim 1, further characterized in that the rest A is selected from among the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents.

5. The compound according to claim 1, further characterized in that the rest A is selected from among the A residues carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents. 35

6. - The compound according to claim 1, further characterized in that the rest A is the rest A carrying a R4 group as a substituent and optionally carrying from 1 to 3 R5 groups as substituents.

7. The compound according to claim 5, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) tR9, where m is an integer from 0 to 3 and t is an integer from 0 to 5 8.

The compound according to claim 6, further characterized in that R4 is - (CR1R2) mC = C- (CR1R) tR9, where m is an integer from 0 to 3 and t is an integer from 0 to 5.

The compound according to claim 5, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) tR9, where m is an integer from 0 to 3 and t is an integer of 0 to 5.

The compound according to claim 6, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) tR9, where m is an integer from 0 to 3 and t is an integer of 0 to 5.

11. The compound according to claim 5, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) kR13 or - (CR1R2) mC = C- (CR1R2) kR13, where m is an integer from 0 to 3 and k is a whole number from 1 to 3; and q is an integer from 1 to 5.

12. The compound according to claim 6, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) kR13 or - (CR1R2) mC = C- (CR1R2) kR13, where m is an integer of 0 a 3 and k is an integer from 1 to 3.

13. The compound according to claim 5, further characterized in that R 4 is -C = NOR 12 or -X 1 -R 12, wherein X 1 is a divalent group derived from azetidine, oxetane or a C3-C4 carbocyclic group; or R4 is - (CR1R2) tR9, wherein the point of attachment to R9 is through a carbon atom of R9.

14. The compound according to claim 6, further characterized in that R4 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 - (CR1R2) tR9, wherein the point of attachment to R9 is through a carbon atom of R9.

15. The compound according to claim 7, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl), (CR1R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

16. The compound according to claim 8, further characterized in that R8 is selected from - (CR1R2) (phenyl), - - (CR1 ^ D2NMindoliio), (CR1R2) t (indazolyl) and - (CR1R2) t ( benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

17. The compound according to claim 9, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), where t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

18. The compound according to claim 10, further characterized in that R8 is selected from - (CR R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl) , - (CR1R2) t (indolyl), (CR1R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

19. The compound according to claim 11, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl), (CR R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

20. The compound according to claim 12, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl), (CR1R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

21. The compound according to claim 13, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl), (CR1R2) t (indazolyl) and - (CR1R2) t (benzoimidazolyl), wherein t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

22. The compound according to claim 14, further characterized in that R8 is selected from - (CR1R2) t (phenyl), - (CR1R2) t (pyridyl), - (CR1R2) t (pyrimidinyl), - (CR1R2) t (indolyl), (CR1R2) t (indazolyl) and - (CR ^ Mbenzoimidazolyl), where t is an integer from 0 to 5 and each of the above R8 groups is optionally substituted with 1 to 5 R10 groups.

23. The compound according to claim 16, further characterized in that the variable m in the group R4 is 0, t in the group R8 is an integer between 0 and 2 and, R9 is a heterocyclic group of 4 to 10 members having 1 to 3 hetero residues as recited in claim 1, said R9 being optionally substituted with 1 or 2 R groups.

24. The compound according to claim 20, further characterized in that R4 is - (CR1R2) mC = C- (CR1R2) kR13, where m is 0 and k is an integer of 1 or 2.

25.- The compound of conformity with claim 22, further characterized in that R4 is - (CR1R2) tR9, wherein the point of attachment to R9 is through a carbon atom of R9; t is an integer from 0 to 2, and R9 is a 4- to 10-membered heterocyclic group having 1 to 3 hetero residues as recited in claim 1, said R9 being optionally substituted with 1 to 2 R11 groups.

26. The compound according to claim 1, further characterized in that it is selected from the group consisting of: 3- [4- (1-benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-yl] -alyl ester of acetic acid; (1-benzenesulfonyl-1 H-indol-5-yl) -. { 6- [3- (4-methyl-piperazin-1-yl) -prop-1-ynyl] -quinazolin-4-yl} -amine; (1-Benzenesulfonyl-1 H -indol-5-yl) - [6- (3-pyrrolidin-1-yl-prop-1-ynyl) -quinazolin-4-yl] -amine; 4- [4- (1-benzenesulfonyl-1 H-indol-5-llamino) -quinazolin-6-ylethynyl] -piperidin-4-ol; (1-benzenesulfonyl-1H-indol-5-yl) - (6-piperidin-4-ylethynyl-quinazol-n-4-yl) -amine; [6- (4-Amino-tetrahydro-pyran-4-ylethynyl) -quinazolin-4-yl] - (1-benzenesulfonyl-1 H-indol-5-yl) -amine; 1-methyl-4-. { 4- [3-methyl-4- (pyridin-2-ylmethoxy) -phenylaminoj-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; 4-. { 4- [4- (1-Phenyi-ethoxy) -phenylamino] -quinazolin-6-ylethynyl} -tetrah¡dro-piran-4-ol; 1- [4- (1-Benzenesulfonyl-1 H -indol-5-ylamino) -quinazolin-6-yl] -4,4-dimethyl-pent-1-yn-3-ol; 4,4-dimethyl-1-. { 4- [4- (1-phenyl-ethoxy) -phenylamino] -quinazolin-6-yl} -pent-1-in-3-ol; 3- . { 4- [1-propane-2-sulfonyl) -1 H -indole-5-ylamine] -quinazolin-6-ylethynyl} -piperidin-3-ol; 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; 5- [4- (1-Benzyl-1 H -indazol-5-ylamino) -quinnolin-6-ylethynyl] -4,4-d-methyl-oxazolidin-2-one; 4-amino-1 - [4- (3-chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -pent-1-in-3-ol; 4-amino-1- [4- (3-chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -4-methyl-pent-1-yn-3-ol; 3-. { 2- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolln-6-yl-ethyl} -piperidin-3-ol; and the pharmaceutically acceptable salts and solvates of the above compounds.

27. The compound according to claim 1, further characterized in that it is selected from the group consisting of: (+) - (3-Methyl-4-phenoxy-phenyl) - (6-piperidin-3 (R) -ylethynyl) -quinazolin-4-yl) -amine; (-H 3 -Methyl-4-phenoxy-phenyl) - (6-piperidin-3 (S) -i-ethynyl-quinazolin-4-yl) -amine; 3- (S) - [4- (3-Methylene-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidine-1-carboxylic acid methylamide; 3- (S) - [4- (3-Methoxy-4-phenoxy-phenylamino) -cynazolin-6-ylethynyl] -piperidine-1-carboxylic acid methylamide; (3-Methyl-4-phenoxy-phenyl) - (6-pyrrolidin-3-ylethynyl-quinazolin-4-yl) -amine; 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-ylenyl] -tetrahydro-pyran-4-ol; . { 6- [1- (2-Methoxy-ethyl) -piperidin-3-ylethyll] -quinazolin-4-yl} - (3-methyl-4-phenoxy-phenyl) -amine; [4- (2-Fluoro-phenoxy) -3-methyl-phenyl] - (6-piperidin-3-ylethynyl-quinazolin-4-yl) -amine; [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-polypeptide} -piperidin-3-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-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -8-aza-bicyclo [3.2.1] octan-3-ol; (3-Chloro-4-phenoxy-phenyl) - (6-piperidin-4-ylethynyl-quinazolin-4-yl) -amine; 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -pyrrolidin-3-ol; 3- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-7-ylethynyl] -piperidin-3-oi; and the pharmaceutically acceptable salts and solvates of the above compounds.

28. The compound according to claim 1, further characterized in that it is selected from the group consisting of: N-. { 3- [4- (3-Chloro-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-ynyl} -acetamide; N-. { 3- [4- (3-Methyl-4-phenoxy-phenylamino) -cynazolin-6-yl] -prop-2-inl} -acetamida; (3- { 3- [4- (3-Methyl-4-phenoxy-phenylamino) -qulnazolin-6-yl] -prop-2-ynyl} -3-aza-bicyclo [3.1.0] hex -6-yl) -methanol; 4- Methylamide. { 3- [4- (3-methoxy-4-phenoxy-phenylamino) -quinazolin-6-yl] -prop-2-inl} -piperazine-1-carboxylic acid; . { 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-phenoxyl-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-inl} -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; 4- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-ylethynyl] -1-methyl-piperidin-4-ol; 3- [4- (1-Benzenesulfonyl-1H-indol-5-ylamino) -quinazolin-6-ylethyl] -piperidin-3-ol; 3- [4- (3-Bromo-4-phenoxy-phenylamino) -quinazolin-6-ylethynyl] -piperidin-3-ol; 3- [4- (4-Benzenesulfonyl-3-methyl-phenamino) -quinazolin-6-ylethynyl] -piperidin-3-ol; 3- [4- (4-Cithohexyloxy-3-methyl-phenylamino) -quinnolin-6-ylethynyl] -piperidin-3-ol; 2-Methyl-4- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -but-3-yn-2-ol; 2-Amino-4- [4- (3-methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -but-3-yn-1-ol; 3- [4- (3-Methyl-4-phenylsulfonyl-phenylamino) -quinazolin-6-ylethynyl] -piperidin-3-ol; and the pharmaceutically acceptable salts and solvates of the above compounds.

29. The compound according to claim 1, further characterized in that it is selected from the group consisting of: 3- [4- (3-Chloro-4-fluoro-phenylamino) -quinazolin-6-ylethynyl] -pperidine- 3-ol; 3- [4- (3-Ethynyl-phenylamino) -quinazolin-6-ylenyl] -piperidin-3-ol; (3-Methyl-4-phenoxy-phenyl) - [6- (1-methyl-p-perpentin-3-ylethynyl) -quinazolin-4-yl] -amine; (3-Methyl-4-phenoxy-phenyl) - [6- (2-piperidin-3-yl-ethyl) -quinazol-n-4-yl] -amine; 3-. { 2- [4- (3-Methyl-4-phenoxy-phenylamino) -quinazolin-6-yl] -ethyl} -piperidin-3-ol; 3-. { 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-a3pyridine-4-carboxylic acid benzylamide; and the pharmaceutically acceptable salts and solvates of the above compounds.

30. The use of a compound as claimed in claim 1, in the manufacture of a medicament for the treatment of abnormal growth of cells in a mammal.

31. - The use as claimed in claim 30, wherein said abnormal growth of the cells is cancer.

32. The use as claimed in claim 31, wherein said cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, head or throat cancer, cutaneous or intraocular melanoma, uterine cancer, cancer of ovaries, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, 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, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary necrosis of the CNS, spinal cord tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the above cancers.

33. The use of a compound as claimed in claim 1, in combination with an anti-tumor agent selected from the group consisting of inhibitors of mitosis, alkylating agents, anti-metabolites, intercalating antibiotics, inhibitors of growth factors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic, anti-hormones and anti-androgens, in the manufacture of a medicament for the treatment of abnormal growth of cells in a mammal . 34.- A pharmaceutical composition for the treatment of abnormal growth of cells in a mammal, characterized in that it comprises an amount of a compound according to claim 1 that is effective in the treatment of abnormal growth of cells, and a pharmaceutically vehicle acceptable. 35.- A process for preparing a compound according to claim 1, characterized in that it comprises (a) reacting a compound of the formula 11 or 2 with a compound of the formula l? wherein Z is a leaving group and A, X, R1, R4 and R3 are as defined above, or (b) reacting a compound of formula 7 with a compound of formula __ wherein X, R1, A, R1 and R3 are as defined above, and Z1 is an activating group, to provide an intermediate of formula wherein Z1, X, R1, A and R3 are as defined above, and Z1 becomes a group R4 which can optionally be converted to another group R4.