MXPA97007980A - Derivatives of 4-aminoquinazoline, compositions that contain them, and use of the mis - Google Patents

Abstract

The present invention relates to certain 4-aminoquinazoline derivatives of the formula (I): and their pharmaceutically acceptable salts, in the R1, Q1, m, n and Z are defined as in the specification, and to the use of the compounds of Formula I and pharmaceutically acceptable salts in the preparation of compositions for the treatment of hyperproliferative disorders and conditions in mammals

Description

DERIVATIVES OF 4-AMINOQUINflZOLINfl, COMPOSITIONS THAT CONTAIN THEM, AND USE THEREOF BACKGROUND OF THE INVENTION This invention relates to 4-a-inoquinazoline derivatives which are useful in the treatment of hyperproliferative diseases such as cancers in mammals. Many of the current treatment regimens for cancer use compounds that inhibit DNA synthesis. Such compounds are generally toxic to cells, but their toxic effect on rapidly dividing tumor cells can be beneficial. Alternative procedures have been explored in relation to anti-cancer agents that act by mechanisms other than the inhibition of DNA synthesis, to improve the selectivity of action against cancer cells. It is known that a cell can become cancerous by virtue of the transformation of a part of its DNA into an oncogene (ie, a gene that, upon activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, over-expression of a normal proto-oncogenic tyrosine kinase can also produce proliferative disorders, sometimes resulting in a malignant phenotype. The receptor quinoae cells are large enzymes that extend over the cell membrane and possess an extracellular binding domain for factorial growth factor such as the epidermal growth factor, a tranemernbrane domain, and a kinase-functional part of the cell to form debris. tyrosine-specific proteins and, therefore, influence cell proliferation. It is known that tale quinaeas are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or eto-cancerous cancer, leukemia and ovarian, bronchial or pancreatic cancer. tico It has also been demonstrated that the epidermal growth factor receptor (EGFR), which possesses tyrosma qumase activity, undergoes a mutation and / or ee-expresses in many human cancers such as brain, lung, squamous cell, and bladder tumors. , gastric, rnarna, head and neck, esophagus, gynecological and thyroid. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth of a human mammary carcinoma transplanted in nude mice atirnicoe, which expresses the epidermal growth factor receptor-thyroid (EGFR) -tiroein qumaea, but has no effect on growth of other carcinomas that do not express the EGF receptor. It has also been shown that various different compounds, such as styrene derivatives, possess tyrosma quimase inhibitory activities. More recently, five European Patent Publications, particularly, EP 0 566 226 A1, published on October 20, 1993, EP 0 602 851 A1, published on June 22, 1994, EP 0 635 507 Al. , published on January 25, 1995, EP 0 635 498 A1, published on January 25, 1995 and EP 0 520 722 A1, published on December 30, 1992, have referred to certain quinazoline derivatives that They have anti-cancer properties from their inhibitory properties of the thymaemae. Also, World Patent Application UO 92/20642, published on November 26, 1992, refers to certain aryl and heteroaryl compounds, bis-nono and bicyclic, as tyrosine kinase inhibitors that are useful in the inhibition of proliferation. abnormal cells The worldwide patent application WO92 / 16960, published on 6 Dunio of 1996, and the application of world patent LJO 95/23141, published on August 31, 1995, refers to certain quamzolmas substituted with phenyla mo as tyrosma qumasa inhibitors that are useful for the same in. European patent application EP 0 414 386 A1, published on February 27, 1991, refers to certain p? R? Do_2,3-d? P? R? M? D? Nas as fungicides, insecticides and acaricides. The pending patent applications together with this PCT / IB95 / G0436 and PCT / IB95 / 07B81, which designate the United States and which are on June 6, 1995 and June 7, 1995, respectively, describe mdolil - and fenilarnino-qumazolines optionally substituted, respectively, which are useful in the treatment of hyperproliferative diseases involving tyrosine receptor kinases. Although the anticancer compounds described above contribute significantly to the art, research in the art continues to obtain better pharmaceutical compounds against cancer.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to substituted heterocyclic aniline derivatives of the formula wherein Z is NR3 R *, where R is hydrogen and R * is O2 or phenyl substituted with (R5) q, or NR3 R * is a group of the formula wherein the dashed line represents an optional double bond; each R5 is independently selected from mono-, di- and tri-f-luoromethyl, halo, nitro, hydroxy, amino, azido, isothiocyan, alkyl (C? -C "), phenyl, thienyl, (C1-C4) alkoxy, benzyloxy, phenoxy, alkenyl (C2-Ce), alkynyl (C2-C &), alkylene (C? -C *) dioxy, cyano, benzoylamino, tnfluoror- nylcarboni lamino, alkanoyl (Ci -CA) arnn, aicanol ( C? -CA), N-rnono- and N, Nd? -alqu? L (C? -Ct, lamino, alkyl (CiCt,) sulfon? Lam? No, tn fluoro ethylsulfonylamino, +? oalqu? lo (C? -C < 4), alkyl (C? -C_,) sulfonyl, and alkyKCi-C «) sulfonyl, μ? rrol-1-? lo, p? er? dm-1-? lo and p? rrol? dm-1-? lo, wherein said phenyl, benzyloxy, phenoxy and benzoylamino may optionally be rnonono-substituted with halo, nitro, + pfluorornet ?, hydroxy or alkyl (C? -Ct,), and where said alkylene (C? -Ci) dioxy is attached at both ends to adjacent carbons of the benzene radical; or doe R51 together with the carbon atoms to which they are attached form a group selected from irnidazolyl, pyrrolo and pyrazolyl; each R6 is independently selected from hydroxy, arnino, N-rnono- and N, Nd? -alqu? l (C? -C ") ammo, sulfo and alkoxyCi-C *) (with the proviso that talee group not are attached to a ring carbon which is directly attached to the ring nitrogen) or each R6 is independently selected from carboxy, hydroxy (C1-C4) alkyl, (C? -C "), amyloalkyl ( C? -C4), rnono-N- and d? -N, N-alkyl (C? -Ci), am? Noalkyl (C? -Ct?), Morph? Noalkyl (C?) Ct,), 4-alkyl (C? -C?,) -piperazm-l-yl-alkylCiCt,), carboxyalkylCiC *), alkoxy (C? -C4 Icarbonyl, sulfoalkyl) (C ? -Ct,), p? R? D? Alkyl (C? -Ct,) and alkyl (C1-C4) 7 which is an integer from 0 to 3, or is 0, 1 or 2; O2 is a bicyclic heterocyclic radical of 9 or 11 links, or a hydrogenated derivative of the earth, which contains one or more nitrogen heteroatoms and which contains, optionally, another he + eroatorno selected from nitrogen, oxygen and sulfur, and O2. it may optionally carry one or two sub-testers independently selected from halogen, hydroxy, oxo, arnino, nitro, carbarnoyl, alky (C? -Ct), alkoxy (C? - "), alkyl (Ci -C") arn? no, di-CalquiKCi -Ct,) ammo, alkane? (C2-C?) animo, alchem (C2 -Ct,) and alk (C2-Ct,); Qi ee Ar ~ Y-X; each Ar is an aryl or heteroaryl, rnonocicyclic or bicyclic ring (for example, phenyl, naphthyl, pyridyl, pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, benznidazolyl, benzoxazolyl, benzothiazolyl, pyranyl, pyrazinyl, thiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, quinazoliml, ptepnyl, quinolinyl or isoquinolinyl), and wherein each Ar group may be optionally substituted with one to two R2 substituents; each X is, independently, C2 alkene (ie, -C = C-), alkyl C2 (ie, -CSC-) or is absent; m is one or two; n is zero, one, doe or three; Y is (CH2) where p is 0-5 and where one or two of the CH2 groups can be replaced, optionally and independently, by oxygen, sulfur, SO2, C = 0, NH or NCH3; each R1 is independently selected from: (a) < rif lororne + io, halo, nitro, hydroxy, ammo, cyano, alkyl (C? -Ct,), alkoxy (Ci-Ct, 1, alkoxy (Ci-Ct, 1-carbonyl, uncle, alkanoiKCi-Ct, loxi, to canoi 1 (Ci -Ct, lamino, carbox, phenoxy, benzoyloxy, carbarnoyl, rnono-N-od? -N, Nd? -aiquil (C? - Ct, Icarbarnoyl, rnono-N- and d? -N, N- alkyl (C? -Ct, lamino, rnono-N- and d? -N, N- (hydroxyalkyl (C2 -Ct, lamino, mono-N and di-N, N- (alkoxy? (C? -C'-lamino, anilino, pyrrolidin-1-yl, p-peridin-1-? Lo, orfolmo, piperazin-l-yl, 4-alk? L (Ci-Ct, 1? Peraz? N -1-1I0, t? Oal it (C? -C * 1 and fe iltio, and any of the above groups eubstituted in the alkyl (C? -C <; 41; and (b) hydroxyalkyl (C2-C ") alkyl (C? -C41, alkoxy? (C? -Ct, 1 -alkoxy (C2-C4I-alkyloxyCi-C * 1, hydroxytioalkylC? -Ct,) alkyl (C? -C_> 1, (C 1 -C 4) alkoxy (C 2 -C 4) alkyl (C 1 -C 1, hydroxyarnino, benzoylamino, mono-N- and di-N, N-alkyl (Ci - Ct, Icarbamoylnamphenylamino, carbamoylmethylamino, alkoxy (C? - Ct, 1 carbomlammo, alkanoyl (CiCt, lamino, carboxymethylene, alkoxy (CiCt, 1 carbonylmethylamino, alkoxy (CiCt, lamino, alkanoyl (Q_ - C4 loxiarnm, phenylalkylKCiCt, lamino, alkyKCi-Ct, Isulfonyl, benzenesulfonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, ureido, alkoxyCi-C *) alky (C? -C'-Icarbonyalkylene, alkyKCi-Ct, Isulfonyl, alkyKCi-Ct-Isulfonyl, alkoxy (C? -Ce,) -thioalkyl (C2-C41, mono-, di- and tri-fluorornetiloxy, alkylene (C? -C? Idioxy, benzyloxy, azido, guanidino, aminocarbonyl, rnono-N and di-N, N-alkyl (Ci-C-laminocarbonyl, phenoxy alkoxy (Ci -CA 1, carboxy-methoxy, alkoxy (C? CA 1 carbonylrhetoxy, carbarnoylrhetoxy, nono-N and d? ~ N, N-alkyl (C? -CA Icarbarnoylrnetoxy, nono-N and d? -N, N- (h? Drox? Alk? (C2 - CA 1 Icarboxamido , nono-N- and d? -N, N- (alkoxy? (C? -CA-alkyl) (C2-CA.sub.11-carboxarnide and bis (alkane (Ci-CA-sulfonylamido and (c) -alkox? (C2 -CA1, +? oalqu? lo (C2 -CA1, alkanoiKC? -CA IOXI, alkyl? (C2 -CA lamino, alkyl (Ci -CA) alk? lene (C? -C Idioxy and alkane? l (C2 -CA lamino wherein each of the above R1 groups of "c" can be + + + + + + + s optionally with one or two substituents independently selected from arnin, halo, hydroxy, alkane, (C2-CA loxi, alkoxy? ? -CA 1, rnono-N- and d? -N, N-alkyl (CI-CA lamino, mono-N- and d? -N, N- (h? Drox? Alqu? L (C2-CA lamino, rnono-N- and d? -N, N- (alkoxy? (C? CA) alkyl (C2-C lamino, alkane? l (C? -C lamino, phenoxy, anilmo,? m? dazol-1-? phenylthio, piperidino, morpholmo, p? peraz? n-1-ylo, 4-alk? l (C? ~ CA lp? peraz? n-l? l, carboxy, alkox? (C? - CA Icarbonilo, carbanoyl, rnono-N- and d? -N, N-alkyl (C? - CA Ic barnoyl , carboxamido, mono-N- and d? -N, N-alk? l (C? -CA Icarboxamido and rnono-N- and d? -N, N- (hydroxyalkyl (C2-CA 1 Icarboxamido; wherein any phenyl radical of a substituent Rl can optionally be substituted with one or two substituents independently selected from halo, nitro, trifluoromethyl, hydroxy, alkoxy (C? -C 1 and alkyl (C? -CA 1, and where Alcan (C? -CA Idioxy is attached, for the extreme ends, to the qumazolma ring, and every 3 is independently selected from the eubs + A uyentee presented earlier in Paragraphs "(a)" and "fbl" of the definition of Rl, with the proviso that: (a) Ql must be in the "5" or "7" position of the quinazoline ring or in these two positions, (b) Ar can not be unsubstituted; (c) the sum of rn + n can not be greater than four, (d) when R * is lH-? ndol-5-? lo, n is zero, rn is one and Ql is a group 2- (fen? what eubet? your? <Jo) -ete -L-ilo that is attached to the "7" position of the quinazolma ring, then (íl Ar can not be 1,1-d? rnet? l-4,4 -d? rnet? ll, 2,3,4-tetrah? dro-naft-l-? lo, and (nor the radical femlo of Q can not have none of the following 13 substitution models, each of which completely and independently defines the sub-constitution on the phenyl radical: 3-n? tro, 4-methox ?, 4-brorno, 3, 4-d? metox ?, 3-brorno, 4-hydroxynet, 2, 3,4,5, 6-penta luoro, 3,5-rnetox ?, 1-arninoethyl, 3-oxo-4-rnethyl, 2- rnetox ?, 3-n? tro-4-rnetilcarbonilarnino or 3-rnetox? -4-benc? loxi; and (when R * is lH-? ndol-5-? lo, n is one, rn is one, Rl is 6-rnetox? and Ql is a 2- (substituted phenol) -eten-1-? which is attached to the "7" position of the qumazoline ring, then (i) Ar can not be 1, ld? met? l-4, 4-d? rnet? ll, 2,3, 4-tetrahydro- naft-l-? lo, and (n 1 the phenyl radical of Ql can not have any of the following 4 substitution models, each of which completely and independently defines the substitution on the phenyl radical; 3-n? tro, 3-Brorno, 4-Brorno or 2,3,4,5,6-pentafluoro, and which are pharmaceutically acceptable compounds. The preferred components of Formula I include the following: (3-Et? N? L-phen l) - (6-p? nd? n-2-? l-qu? nazol? n-4-? ll-arnine; (3-Et? n? l-feml) - (6-p? pd? n-3-? l-qu? nazol? n-4-? l) ~ arnin; (lH-Indol-5-? l) - (6-p? nd? n -3? l-qu? nazole? n-4-? ll-amma; (3-Et? n? l-phen? l) -C6- (2-p? r? d? n-4-? lv? n? l) -qumazole? n- 4-? L] -amine; (lH-Indol-5-? L) - [6- (2-p? R? D? N-4-? Lv? N? L) -qu? Nazole? N-4 -? l_-arnma; (lH-Indol-5-? l) -C7-rnetox? -6- (2-p ? r? d? n-4- l-v? mll-qu? nazolm-4-? l] -arn? na; (3-xxazol-5-? L-phen? L) -C6- (2-p? R? D? N-4-? Lv? N? Ll-qu? Nazolm-4-? 13 -amine, - ( lH-Indol-5-? l) -C6- (2-p? r? d? n-2-? lv? n? l) -qu? nazole? n- 4-? l] -am? na; lH-Indol-5-? l) - (7-methox? -6-p? pd? n -3? l-qu? nazole? n-4-? l) -amine; (3-Et? n? l-phenol) - (7-rnetox? -6-p? r? d? n-2-? l-qu? nazol? n-4-? l) -am? na; (lH-Indol-5 -? l) - (7-methox? -6-?? r? d? n-2-? l-qu? nazolm- L2 4-? L 1-arn? Na; (3-Bromo-) - "in? Ll- (7-rnetox -6-p? Pd? N ~ 2-? L-qu? Na ol? N-4-? L 1 -amina; 4 ~ (lH- Indole-5- larn? O) -6-p? Pd? N-3-? L-qu? Nazol? N-7-ol; (lH-Indol-5-? Ll- (7-rnetox? -6- p? pd? n-2?? let? n? l-qu? nazolm-4-? l 1 -amine; (lH-Indol-5-? ll-_7- (2-rnetox? -etox?) - 6-p? nd? n -3? l-qumazole? n-4-? 1] -ami a; (lH -Indol-5-? L) - { 7-methox? -6-_2- (4-rnetox? -fen? L) -v? N? L] -qu? Nazolm-4-? L.} .arn? na; {.6-C2- (3,4-D? methox? -fen? l) -v? ml] -7-rnetox? -qu? nazolm-4-? l.}. (lH-mdol-5-? l) -amine; (4- {2-C4- (lH-Indol-5? lam? no) -7-rnetox? -qu? nazol? n-6-? l] -v? n? l.).-phenyl? -methanol;. {6-C2- (4-Arn? no-feml) -v? r.? l_-7-methox? -qu? Nazol-4-? l .-- (lH-Ndol-5? l) -amine; (lH-Indol-5? l) -C-methoxy? -6- (2-p? raz? n-2-? lv? n? ll-qumazol? n-4-? l] amine; (lH-Indol-5-? l) - { 7-rnetox? -6-_2- (6-rnet? ll-ox? -p? r? d? n -3? l) -v? n? l] -qu? nazolm-4-? l.}. -arn? na; (6- { 2- [4- (l-Am? No-et? L) -fen? L] -v? Nil.}. -7-rnetox? -qumazole? N-4-? Ll- (lH-mdol-5-? L ) -amine; (lH-Indol-5-? l) -C6- (2-p? r? d? n-2-? lv? ml) -qu? nazole? n-4-? l] 4-amma (lH-Indol-5-? l) - [7-methox? -6- (6-methox? -p? r? d? n -3? ll-L3 Nazolm-4-l] -amine; . { 6-r2- (4-Arn? No-phen? L) -v? N? LJ-7-rnetox? -qu? Nazole? N-4-? L} (lH-? ndol-5-? l -amine; (lH-Indol-5-? l) -C7-? netox? -6- (l-ox? - ?? pd? n -3? ) -qu? nazol? n-4-? l] -anima; and C6- (3-Ammo-phen? let? n? 1 -7-methox? ~? nazol? n-4-? l_- ( 1H-indol .5.? Ll -amine Examples of other compounds of formula I are the following + ee:. {6-_3- (Benc? L-rnet? L-arn? No -prop-l-an? L_ -qu? nazol? n-4-? l. - (lH-mdol-5? l) -amine; (3-Et? n? l-phen? l) - (6 - ?? pd? n -2-? Let?? L-qu? Nazol? N-4-Lll -amina, - (lH-Indol-5-? Ll- (6-p? Pd? N-2-? Let? Ml-qu? nazol? n-4-? l 1 -amine, - (lH-Indol-5-? l) - (7-methox? -6-p? r? d? n-2? let? n? l-qumazol ? n-4-? l) -am? na (3-Et? n? l-fen? l) - (6-p? r? d? n-2-? l-qu? nazol? n-4 -? l) -amine; (3-Et? n? i-phenyl-C6- (4-rne? lsulfan? l-phen? 1 -qu? nazol? n-4-? l-amine; Et? N? L-phen? Ll-C6- (4-tnfluoromet? L-phen? L) -qu? Nazole? N-4-? L] -amine; (3-Et? N? L-phen? L 1 - (7-methoxy? -6-phen? L-qu? Nazole? N-4-? L 1 -amy; (3-Et? N? L-phen? L) - (7-methox? -6- 6-p? Nd? Ne-? L-qu? Nazol? N-4-? Ll-amina; (3-Et? N? L-phen? L) - (7-rnetox? -6-p? R? d? n-2-? l-na? nol? n-4-? ll-amine; (3-Bromo-phen? l) - (6-p? r? d? n-2-? l-qu? nazol? n-4- l) -amine; i 4 E. + e. Ethyl acid 2-E4- (lH-? ndol-5? lammo) -7-rnetox? -qu? nazol? n-6- i] -benzoic acid; ethyl ester of 2-C4-Í 3-et? ml ~ phen? larnin) -7-rnetox? -qu? nazol? n-6-? l] -benzoic acid ester; ethyl ester of 4-C4- (lH-? ndol-5? larn? no) -7-rnetox? -quinazolm-6? l] -benzoic acid ester; 4- (lH-Indol-5-larn? No) -5-?? pd? N-3 ~? L-qu? Nazol? N-7-? L) -arn? Na; (lH-Indol-5-? ll-l 7- (2-metho? -ethox? 1-6-p? r? d? n -3? l-qumazole? n- 4-? l] -amma; (3-Et? N? L ~ phen?) - (6-p-tol? L-qu? Nazole? N-4-? L) -am? Na; (3-Et? Ml-f "in? l) - (6-femyl-qu? nzol? n-4-? ll -amine; (3-Et? n? l-phen? l) -C6- (4-rnet? lsulfan? l-phen? l) -quinazo! m ~ 4-l] -amine; (3-Et? n? l-phen? l) -6- (4-tr? fluorornet? l-phen? l) -qu? nazole? n-4- ? -amine; C6- (4-chloro-phen? ll-qu? nazole? n-4-? l] - (3-et? ml-phen l) -arn? na; 4- (b-chloro- 2,3-d? H? Dro? Ndol-l-? L) -6-phen? L-qu? Nazol? Na; (3-Et? N? L-phen? L) - (7-rnetox? -6-feml-qu? Nazol? N-4-? Ll -amine; 4- (6-chloro-2,3-d? H? Dro? Ndol-l-? L) -7-rnetox? -6 -phen-quinazolma; (3-xxazol-5-? l-feml) - (6-p? r? d? n-3-? l-qu? nazol? n-4-? l) -am? na (lH-Indol-5-? l) -6- (2-p? nd? n-4-et? l) -qu? nazole? n-4-? l -amine; (lH-Indol-5-? l 1 - (6-phen? let? n? l-qu? nazol? n-4-? l -amine; (lH-Indol-5-? l) - (7- rnetox? -6-?? pd? n-3? l-qu? nazol? n-4-? l) -am? na; (3-Et? n? l-phen? l) - (7-methox? -6-p? R? D? N-3-? L-qu? Nazol? N-4-? D-amma; is ethyl + of the acid 4- 4- (lH- ndol-5? larnmol-qu? nazolm-6-L] -benzoic acid; ethyl ester of the acid 2-C4-Í 3-et? n? l-phenylarnino ) -quinazolm-6-l] -benzo-co; ethyl ester of 2-C4- (lH-? ndol-5? larn? no) -qu? nazol? n-6-yl] -benzoic acid ester; (3-Et? N? L-phen? L) - (6-p? R? D? N-2? Let? N? L-qu? Nazol? Na-4-_l) -arn? Na; (IIH-Indol-5-? L) - (6-p? R? Dm-2-? L-qu? Nazole? N-4-? L) -amine; (3-bromo-phen?) - (6-p?? D? N-2-? L-qu? Nazole? N-4-? L) -arn? Na; (lH-Indol-5-? ll- (6-p?? d? n-2? let? n? l-qu? nazole? -4-? l) -amine; ethyl ester of 2-_4- acid lH-? ndol-5? larn? no) -7-rnetox? -qumazole? -6-? l] -benzoic acid; Ethyl ester of the acid 2-C4-Í 3-Et? N? L-phen? Larnmo) -7-rnetox? -qu? Nazolm-6-? L] -benzoic acid; ethyl ester of 4-C4-lh-? ndol-5? larn? no) -7-rnetox? -qui nazolm-6-yl] -benzoic acid ester; (lH-Indol-5-? l) - (7-rnetox? -6-eet? r? l-qu? nazol? n-4-? ll -amine; (lH-Indol-5-? l) -. { 7-methoxy? -6-_2- (3-n? Tro-phen? L) -v? N? L] -qui nazolin? 4-? L} -amine; . { 6-_2- (4-Benzyl) -3-rnetox? -fen? L) -v? N? L] -7-rnetox? -qu? Nazole? N- 4-? L} - (lH-? ndol-5-? l) -am? na; (lH-Indol-5-? l) -. { 7-rnetox? -6-_2- (5,5, B, 8-tetrarnet? L-5,6,7,8-tetrahydro-naphthalene-2? -v? N? L] -qumazole? n-4-? l.}. -am? na; N- (4- { 2-_4- (lH-Indol-5? larn? no) -7-rnetox? -qu? nazol? n- 6-? L] v? N? L.} -2-n? Tro-feml) -acetarn? Da {. 6-_2- (3,5-D? Rnetox? -fen? L) -v n-1-rnetox? -qu? nzol? n-4-? l.} - (lH-indol-5-yl) -amine; (4 ~ £ 2-_4- ((lH-Indole -5-ilarninol-quinazolin-6-yl] -vinyl.} Phenyl-1-amino; (lH-Indol-5-yl) -6- (2-pi azin-2-yl) -quinazolin.4-il] ~ arnin; 5-C4-lH-Indol-5-ilarnino) -quinazolin-6-yl3-lH-pyridin-2-one; (lH-Indol-5-yl-5-yl) -C7-rnetoxy-6- (6-Rethyl-pyridin-3-yl-quinazoli-4-yl] -amine; 5-C4- (lH-Indol.-5-ilarnino) -7-rnetoxy-quinazolin-6-yl] -nicotinarnide; C - (lH-Indol-5-ylamino) -7-methoxy-quinazolin-6-yl] -nicotinotrile; 5- 4- (ÍH-Indol-5-ilarnino) -7-methoxy-quinazolin-6-yl] pyridin-3-yl-methanol; Methyl ester of 5-C4-lH-Indol-5-ylamino) -7-methoxy-quinazolin-6-yl] -nicotinic acid methyl ester; (lH-Indol-5-yl) - (7-rnetoxy-6-quinolin-3-yl-quinazolin-4-ill-arnin; [6- (6-Amino-? iridin-3-yl) -7-methoxy -quinazolin-4-yl] - (1H-indol-5-yl-1 -amine; [6- (6-Dimethyl-pyridin-3-yl) -7-methoxy-quinazolin-4-yl] - (lH-indole -5-yl-1-amino: 5- (6-pyridin-3-yl-quinazolin-4-ylamino) -l, 3-dihydro-indol-2-one; (lH-Indol-5-yl) - (7 -rnetoxy-6-pyrazin-2-yl-quinazolin-4-yl) -amine; (lH-Indol-5-yl) -C7-methoxy-6- (6-rnethyl-? irazin-2-yl) -quinazolin-4 -yl] -amine; L7 [6- (fa-Arn? No - ?? raz? N-2-? L) -7-rnetox? -qu? Nazol? N-4-? L] - (lH-? Ndol-5-ill -ami (1H-Tndol-5-? ll- _6- (2-μ? raz? n-2 ~? lv? ml 1 -quinazo l? n-4-? l) -ami a; This invention also relates to to a method for inhibiting abnormal cell growth in mammals, including humans, that is caused by the mutation or overexpression of a protein tyrosumnamase (e.g., epidermal growth factor receptor tyrosmamamama), which comprises ad inietrate a mammal in need of such inhibition, an effective amount for the inhibition of the tyrosine quimase protein of a compound of the formula I or a pharmaceutically acceptable salt of the same. This invention also relates to a pharmaceutical composition for inhibiting growth. cellular abnormality in mammals, including human beings, that is caused by the mutation or overexpression of a protein tyrosine kinase (for example, the thyrokinin receptor kinase factor) epidermal growth), comprising an effective amount for the inhibition of the tyrosine quimase protein of a compound according to claim 1 or a pharmaceutically acceptable salt of the ism and a pharmaceutically acceptable carrier. This invention also relates to a method for treating or preventing hyperproliferative disorders or conditions such as malignant or benign tumors, other hyperplastic conditions, such as benign skin hyperplasia (eg, psoriasis) and benign hyperplasia of the prostate (e.g., benign prostatic hypertrophy (BPH), leucerniae and lymphoid rnalignidadee) in a mammal, including a human, which comprises administering to a mammal in need of such treatment or prevention an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of such disorder or condition.This invention also relates to a pharmaceutical composition for preventing or treating hyperproliferative disorders or conditions, such as benign or malignant tumors, other hyperplastic conditions, such as benign hyperplasia of the skin (e.g., psoriasis) and benign prostatic hyperplasia (e.g., benign prostatic hypertrophy), leukemias and lymphoid malignancies of a mammal, including a human being, comprising a quantity of and a compound of formula I or a pharmaceutically acceptable salt thereof, which is effective in the prevention or treatment of such a condition or disorder, and a pharmaceutically acceptable carrier. This invention also relates to a method of treating or preventing hyperproliferative disorders or conditions, such as benign or malignant tumors, other hyperplastic conditions, such as benign hyperplasia of the skin (eg, psoriasis), and benign prostatic hyperplasia ( example, benign prosthetic hypertrophy), leukaemias and lmfoidee malignancies in a mammal, including a human, which comprises administering to a mammal in need of such treatment or prevention an effective amount for the inhibition of the protein tyrosine kinase, of a compound of the Formula I or a pharmaceutically acceptable salt thereof. This invention also relates to a pharmaceutical composition for preventing or treating hyperproliferative disorders or conditions, such as benign or malignant tumors, other hyperplastic conditions, such as benign hyperplasia of the skin (eg, psoriasis), and benign hyperplasia of the prostate ( for example, benign prosthetic hypertrophy), leukaemias and lmfoid malignancies in a mammal, including a human, comprising an effective amount for the inhibition of the tyrosma qumase protein of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. Examples of such benign proliferative disorders which can be prevented or treated with the compounds of the formula II and their pharmaceutically acceptable salts are psoriasis., benign prosthetic hypertrophy and restinosis. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, cyclic radicals or combinations thereof. The term "halo", as used herein, unless otherwise indicated, refers to chlorine, fluorine, bromine or iodine. The term "one or more substitutents", as used herein, refers to a number of one to the maximum number of possible substituents based on the number of available binding sites. Compounds of formula I which are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those which form non-toxic acid addition salts, ie, ealee containing pharmacologically acceptable anions, such as the hydrochloride salts, Hydrobromide, hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, ealicylate, citrate, acid citrate, tartrate, pantothenate, bitart ate, ascorbate, succinate, maieate, gentisinate, fumarate, gluconate, glucaronate, saccharate , formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. That is, 1,1'-methylene-bis- (2-hydroxy-3-nagtoate)]. The compounds of the formula I which are acidic in nature can form 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 saltse. The compounds of formula I may contain chiral centers and, therefore, may exist in different enantiomeric forms. This invention relates to all optical isomers (for example, enantiomers or diaeterers) and to other stereoisomers of compounds of formula I, as well as to mixtures of racer and other mixtures thereof, Formula I above includes compounds identical to those represented. This is due to the fact that one or more hydrogen or carbon atoms are replaced by isotopes of them.These compounds are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays. treated with compounds of formula I according to the methods of this invention include, for example, patients who have been diagnosed with lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malane a cutaneous or intraocular, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, cancer colonic cancer, breast cancer, gynecological tumors (eg, uterine sarcomas, fallopian tube carcinoma, endorhene carcinoma, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (for example, cancer of.? '.') thyroid, parathyroid or adrenal glands), "soft tissue sarcomas, urethral cancer, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphocytic, bladder cancer, kidney or kidney cancer ureter (for example, renal cell carcinoma, renal pelvis 1 carcinoma or neoplasm of the central nervous system (for example, primary CNS lmforna, spiral axis tumors, brainstem gliomas, or pituitary adenomas). which can be treated with the pharmaceutically acceptable compounds of formula I and its ealee according to the methods of this invention, also include patients suffering from an abnormal cellular growth, as defined above.This invention also relates to compounds of the formula / II in which Ar, Q, m, Rl and n are as defined previously, with the exception that the Ar group of Ql can not be phenyl. These compounds are useful or intermediates in the synthesis of the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared as described below. In the schemes of reaction and in the disqueion that eiguen,, A, Ql, Q2, Ar, X, Y, Rl to R? , rn, n, o, p, q, and formula I, are as defined previously.

SCHEME 1 I I 1. activate 2. ZH (X is absent) F QUEMÍ-I 2 111 Catalyst Pd (2) base II 9 SCHEME 3 III SCHEME 4 VI (q> zero to three) (C4H,), SnSn < C4H,), PdPPhj il 1. nC4H, Ll, B (0CH,) 3 2. HCl VAT SCHEME 5 VII III (q = zero to three) IIP where Rr SCHEME 6 n VIII IX 1 IB where Or = (R2), OR SCHEME 7 III 1. activate 2. ZH (Rl) ( IB (X is alkene C2 or alkyne C_) SCHEME 8 (R1) XI SCHEME 9 (R1), The E-game illustrates the synthesis of compounds of formula I in which X is absent. In Scheme 1 and throughout this specification, these compounds are referred to as "compounds of the formula IA". As shown in Scheme 1, such compounds are prepared from the analogous compounds having an oxo group in the "4" position of the quinazoline ring, the position in which Z is bound in the final product. Thus, the compounds of the formula IA, of which all have the aryl or heteroaryl radicals of Ql directly attached to the quinazolone ring, are formed by the addition of one or two Ql groups to the quinazolinone nucleus before converting the oxo group in the Z substituent. Referring to Scheme 1, the quinazolinone of formula II is first activated by reacting it with an activating agent, at a temperature of about 60 ° C to about 120 ° C, preferably at the reflux temperature, and then adding a reagent of the formula ZH. Examples of suitable activating agents are the following: triphenylphosphine polymer / carbon tetrachloride in methylene chloride or solvent; phosphorus oxychloride (POCI3) (pure); POCI3 in the presence of pyridine, lutidine or other amine base; phosphorus pentachloride (PCI5); oxalyl chloride (COCI2) using a DMS catalyst; or thionyl chloride (SOCI2) (pure). The reaction with the Z-containing reagent is generally carried out in an alcoholic solvent Ci-Cβ, preferably isopropanol, in a sealed tube, at a temperature from about 68 ° C to about 120 ° C, preferably at about 120 ° C. Before adding the reagent containing Z, the solvent is generally removed from the activation step using a rotary evaporator or, when the agent is actively triphenylphosphine / carbon tetrachloride polymer, by filtration. The compounds of the formula II can be prepared as illustrated in Scheme 2. With reference to scheme 2, the compounds of the formula III are reacted with a compound of the formula IV in the presence of a palladium catalyst (2) and a inorganic base. This reaction, which forms a bond between the aryl or heteroaryl group and the "6" or "7" position of the quinazolinone nucleus, is typically carried out in a solvent such as toluene, benzene or an CiCt alcohol, at a temperature of about the ambient temperature at about the reflux temperature of the reaction mixture. Preferably, it is carried out at the reflux temperature. Examples of catalysts which can be used are diphenylphospane, butadiene palladium dichloride, bis- (tpfen? Lfosf? Na) palladium, palladium acetate and palladium tetrakistriphenylphosphine. Examples of inorganic bases that can be used are sodium hydride, sodium or potassium carbonate and sodium or potassium hydroxide. The above procedure can also be used to add a second Ar group. to the quinazolone nucleus (ie, to prepare a compound of formula II in which a substitute + e Ar is attached to both "6" and "7" positions). Compounds of formula III can be obtained, as shown in Scheme 3, by reacting a compound of formula V with iodine chloride (IC1) in concentrated aqueous hydrochloric acid and ethanol, at a temperature of about - 40 ° C at about 20 ° C, to form the corresponding components of formula VI. The resulting compounds of formula VI can then be converted to the desired starting materials of formula III, by reacting them with HC (= 0) NH 2, in a formamide as solvent, at a temperature of about 120 ° C to about 180 ° C. ° C. Esquernae 4 and 5 illustrate processes for preparing, respectively, compounds of formulas IV and II in which Ar is pipodyl. Analogous methods can be used to prepare the corresponding compounds of formulas II and IV in which Ar represents other heteroaryl groups. Referring to scheme 4, a compound of formula VI, wherein q is zero, one, two or three, is reacted with hexabutyl diethyne ((C4H9)) 3SnSn (C «C9) 3) in the presence of tetraquie tp enylphosphine of palladium, in a polar aprotic solvent such as tetrahydrofuran (THF), dioxane, dimethylformamide (DMF) or ether, preferably THF or toluene, at a temperature of about 20 ° C at about the reflux temperature of the reaction mixture, preferably at about reflux temperature. The compound of formula VII thus formed can then be converted into the corresponding compound of formula IVA by reaction thereof first with N-butyl lithium and trirnetoxy borate (B (0CH) 3) or trusopropoxy borate (B (0CH (CH3)).2) 3) and then with hydrochloric acid. Generally this reaction which can also be used to convert compound of formula VI directly into the corresponding compound of formula IVA, as shown in scheme 4, is generally carried out in a polar aprotic solvent, such as THF, dioxane, ether, DMF or glimene, preferably THF or ether, at a temperature from about -100 ° C to about -40 ° C, preferably at about -78 ° C. Referring to Scheme 5, a compound of formula VII, wherein q is zero, one, two, or three, is reacted with a compound of formula III to form the desired compound of formula IIA in which a pyridyl group substituted or unsubstituted is attached directly to the qumazolmone nucleus. Typically, this reaction is carried out in the presence of a palladium (0) catalyst, such as palladium tetrakisphenylphenylphosphine, in a polar aprotic solvent such as THF, dioxane, ether, glycol or DMF, preferably THF, at a temperature of about 20. ° C at about the reflux temperature of the reaction mixture, preferably at about reflux temperature. The above procedure can also be used to add a second group Ar to the "6" or "7" section of the benzene ring. Scheme 6 illustrates the preferred method for attaching phenyl or natfyl groups to the benzo radical of the quinazolone core. According to this process, this Ar group substituted with zinc of the formula IX, instead of the group Ar substituted with tributyleetane of the formula VII, is coupled to the iodo substituent of the compound of the formula III. The zinc derivative of formula IX is formed by reacting the corresponding compound of formula VIII with tributyl lithium and zinc dichloride at a temperature of about -100 ° C to about -40 ° C, preferably at about -78 ° C. The preferred solvents for this reaction are THF and ether; however, other polar aprotic solvents such as DMF or dioxanes can also be used. The above procedure can also be used to add a second Ar group to the "6" or "7" position of the benzene ring. Compounds of the formula I wherein X is C2 alkene or C2 alkyne, can be prepared as illustrated in Scheme 7. These compounds, referred to in Scheme 7 and throughout this specification as compounds of the formula IB, contain a alkenyl, alkynyl or aiquinyl-Y linking group between each Ar substituent and the benzo radical of the qumazolma ring. According to this procedure, the substituent Z is added before adding the substituent or the Ar constituents. The first reaction illustrated in the scheme, that is, the conversion of the compounds of the formula EII into the composition of formula VIII, is carried out using a procedure similar to that illustrated in Scheme 1 and described above for the formation of compounds of the formula IA from compounde of formula II. After having added the substituy Z in the "4" position of the quinazoline ring, the compound of formula VIII is reacted with a compound of the formula Ar-Y-XH, where X is C2-alkenne or C2-alkyne, to form the desired compound of formula IB. Schemes £) and 9 illustrate examples of those two variations of this procedure, respectively. The starting materials of the formula Ar-Y-XH wherein X is -CH = CH- or -C ^ C-ee can be purchased commercially, can be prepared using literature procedures well known to those skilled in the art or they can be prepared by refluxing a compound of the formula ArBr with a compound of the formula XSnBu3 (in which Bu is butyl) in toluene or benzene as the solvent and in the presence of diphenylphosphine butane palladium dichloride. The starting materials of the formula ZH are commercially available, can be prepared using literature procedures well known to those skilled in the art or can be prepared using procedures described in PCT Patent Application PCT / IB95 / 07881, which designates the United States and which was filed on June 7, 1995. The above patent application is hereby incorporated by reference in its entirety. The starting materials of which the synthesis has not been specifically described above, can be purchased commercially or can be prepared using literature procedures well known to those skilled in the art. The preparation of the compounds of formula I not specifically described in the above experimental section can be performed using combinations of the above-described reactions that will be apparent to those skilled in the art. In each of the reactions discussed or illustrated in Schemes 1-9 above, the pressure is not critical unless otherwise indicated. Generally pressures of about 0.5 atosphere to about 5 atm are acceptable, and for convenience reasons, environmental pressure, i.e. about 1 atmosphere, is preferred. The compounds of formula I, which are basic in nature, can form a wide variety of different salts with various inorganic and organic acids. Although taale ealee must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt, and then simply convert the latter into 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 base compound with a substantially equivalent amount of the selected 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 product is readily 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. Compounds of formula I which are acidic in nature, can form base elasts 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 are prepared by conventional techniques. The chemical bases which are used as reagents for preparing pharmaceutically acceptable base metals of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those derived from pharmacologically cations. acceptable such as sodium, potassium, calcium, magnesium, etc. These salts can be easily prepared by treating the corresponding acid compounds with an aqueous solution containing the pharmacologically acceptable cations and deep-evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower a-cacolics of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometrical quantities of reagents are preferably employed to ensure that the reaction is completed and that maximum yields of the desired final product are obtained. The active compounds of this invention are potent inhibitors of the erbB family of the 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 (for example, against cancer) in rnarníferoe, particularly, in humans. In particular, the compounds of this 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, stomach, ovaries, colorectal system, prostate, pancreas, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck and other hyperplastic conditions such as benign hyperplasia of the skin (eg, psoriasis) and benign hyperplasia of the prostate (eg, BPH). In addition, it is expected that a compound of the present invention may possess activity against a series of leukemias and lymphoid malignancies. The active compounds can also be useful in the treatment of other disorders in which the aberrant expression of ligand / receptor interactions, or cases of activation or signaling related to the various tyrosine kinase proteins, is involved. Such disorders may include those of a neuronal, glial, astrocytal, hypothalmic and other glandular, macrophage, epithelial, oestratic and blastocoelic nature, in which the aberrant functioning, expression, activation or signaling of tyrosine kinases is implicated. erbB. In addition, the compounds of the formula I can have therapeutic utility in inflammatory, angiogenic and in unological disorders involving tyrosine kinases both identified with or not yet identified, which are inhibited by the compounds of the formula I. The in vitro activity of the Active compounds in the inhibition of receptor tyrosine kinase (and, therefore, of the subsequent proliferative response, eg, cancer) can be determined by the following procedure. The activity of the active compounds, in vitro, can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate, for example, random copolymer of Lys3-Gastrin or polyGluTyr (4: 1) (I. Posner et al., 3. Biol. Chern. 267 (29), 20638-20647 [19923] on thyroxene, by the epidermal growth factor receptor kinase, by a test compound with respect to a control. The soluble human EGF receptor, purified by affinity (96 ng), is obtained according to the procedure of GN Gili, Ul. Ueber, Methods in Enzymology 146, 82-88 (1987) from A431 cells (American Type Culture Collection, Rockville, MD) and preincubated in an icrocentrifuge tube with EGF (2 ug / ml) in phosphorylation buffer + vanadate (PBV: HEPES 50 rnM, pH 7.4; 125 mM NaCl; MgCl? 24 rnM; sodium orthovanadate 100 μM), in a total volume of 10 μl, for 20-30 minutes, at room temperature. The test compound dissolved in dimethylsulfoxide (DMSO), is diluted in PBV, 10 μl is mixed with the EGF / EGF receptor mixture and incubated for 10-30 minutes at 30 ° C. The phosphorylation reaction is initiated by the addition of 20 μl of 33p-qtP / substrate mixture (Lys3-Gaetrin 120 μM Ceequence with the single-letter code for amino acids, KKKGPILEEEEEAYGULDF]), 50 mM Hepes pH 7.4, ATP 40 μM, 2 μCi t-_33p] -p? TP) to the EGFr / EGF mixture and incubate for 20 minutes at room temperature. The reaction is stopped by the addition of 10 μl of interruption solution (0.5 M EDTA, pH 8, 2 mM ATP) and 6 μl of 2N HCl. The tubes are centrifuged at 14.G00 rpm, at 4 ° C, for 10 minutes. 35 μl of supernatant from each tube is pipetted onto a 2.5 cm circle of Uhatman P81 paper, washed four times with a large volume of 5% acetic acid, 1 liter per wash, and then air dried. This results in the binding of the substrate to the paper with the loss of free ATP with washing. The [33] incorporated ee is measured by liquid scintillation counting. Incorporation in the absence of the substrate (eg, Lys3-gastpna) is subtracted from all values as a background effect and the percent inhibition is calculated with respect to the controls without the present test compound. Such assays, performed with a dose interval of eneay compound, allow the determination of an approximate IC50 value for the in vitro inhibition of EGFR qumasa activity. The compounds of formula I which were tested using the procedure described above, presented IC50 values in the range of 0.0001-30 μM. The activity of the active compounds, in vivo, can be determined by the amount of inhibition of tumor growth by an eneay compound with respect to a control. The inhibitory effects of tumor growth of various compounds are measured according to the procedures of Corbett T. H., et al. "Tumor Induction Relationships ín Development of Transplantable Cancers of the Colon m Mice for Chemotherapy Assys, with a Note on Carcinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett T. H., et al. "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2) ", 5., 169-186 (1975), with slight modifications, tumors are induced in the left side by sc injection of 1 X 10 6 turnoral cells cultivated in logarithmic fae (MDA breast carcinoma cells -MB-468 human or human head and neck carcinoma HN5) suspended in 0.10 rnl of RPMI 1640. After having left a sufficient time for the tumors to be palpable (with a diameter of 2-3 nm), the test animals (atirnic mice) are treated with the active compound (formulated by dissolving in DMSO, typically at a concentration of 50 to 100 rng / ml, followed by 1: 9 dilution in saline or, alternatively, by 1: dilution: 9 in Pluronium * 1.0% P105 in 0.9% saline) via the intraperitoneal (ip) or oral (po) administration routes, twice a day (ie, every 12 hours), for 5 days In order to determine the antiturn effect, the tumor is measured in millimeters with Verni calipers er along two diameters and the size of the tumors (mg) is calculated using the formula: Tumor weight = (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 Tu ors and Other Biological Syeteme ", Third Edition, Cancer Chemother, Rep., 3, 1-104 (1972) The results are expressed as percentage of inhibition according to the formula: Inhibition (%) = ( TuUeontrol ~ TuUß nt «yo) / TuUe o ntr 1 X 100% The site of the side where tumor implantation occurs provides reproducible dose / response effects for a variety of chemotherapeutic agents and the measurement procedure (tumor diameter) It is a reliable method to evaluate the growth rates of tumors, all compounds of the title of expelled patients of this class, which are compounds of formula I, showed, when tested in the previous test, higher percentages of inhibition values. of 50% at a concentration of 1U μM The administration of the active compounds can be carried out by any method that allows the release of the compounds at the site of action ( r example, carcinogenic cells). These procedures include lae oral route, intraduodenal, parenteral injection (including intravenous, eubcutaneous, mularnuecular, vascular or infusion), topical administration, etc. The amount of the active compound administered will be dependent on the subject to be treated, the severity of the disorder or condition, the rate of administration and the opinion of the corresponding physician. However, an effective dose is in the range of from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg / kg / day, in a single dose or in divided doses. For a 70 kg human being, this could amount from about 0.05 to about 7 g / day, preferably from about 0.2 to about 2.5 g / day. In some cases, lower dose levels than the lower limit of the range mentioned above may be more than adequate, while in other cases higher doses may be used without causing any adverse effect, provided that the higher doses are first divided into several doses. small for administration throughout the day. The pharmaceutical composition can be, for example, in a form suitable for oral admmeration such as a tablet, capeula, pill, powder, sustained-release formulations, solution, suspension, for parenteral administration such as a sterile solution, suspension or emulsion. , for topical administration such as an ointment or cream for rectal administration such as suppository. The pharmaceutical composition may be in unit dosage forms suitable for the single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. Also, may include other medicinal or pharmaceutical agents, vehicles, adjuvants, etc. Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered if desired. Suitable pharmaceutical carriers include diluents or inert fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavors, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, will be used together with various disintegrants such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for the manufacture of tablets. Solid compositions of a similar type can also be pleated in soft and hard filled gelatin capsules. Preferred materials for this include lactose or sugar from the milk 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, dyestuffs or dyes and, if desired, with surfactant or euepeneion 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 Pharmaceutics Sciences, Mack Publishing Company, Easter, Pa., 15Q Edition (1975).

EXAMPLE 1 (lH-Indol-5-yl) - (6-vodo-quinazolin-4-yl) -amine 6-iodo-3H-quinazolin-4-one (50 g, 18.3 rnmoles) was suspended in 60 ml of methylene chloride (CH2Cl2) with several drops of DMF. Oxalyl chloride (6.99 g, 4.83 rnl, 55.1 rnmoles) was added dropwise to the suspension at 0 ° C. The reaction was heated to reflux for 48 hours and then concentrated in vacuo. Pyridine (2.9 g, 2.97 rnl, 36.7 rnmoles) and tert-butyl alcohol (10 ml) was added to dissolve the 4-chloro-6-iodo-quinazoline. 5-arninoindole (2.9 g, 22.0 mmol) was added and the reaction was heated at 60 ° C overnight. The reaction mixture was diluted with chloroform (CHCl3) and washed with brine, saturated aqueous NaHC3 and dried over a2SO4. The organic layer was concentrated in vacuo to a black oil. The crude product was chromatographed on silica gel (2 parts of rnetanol to 1 part of rnetylene chloride (2 MeOH / CH2Cl2)) to provide 2.99 of a white crystalline product. P.F. 261 ° C; LC-MS: 387 (M *); RP18-HPLC TA: 4.12 min.

EXAMPLE 2 (lH-Indol-5-yl) - (eniletinyl-quinazolin-4-yl) -amine (LH-indol-5-yl) - (6-iodo-quinazolin-4-yl) ~ arnin (200 rn, 0.5 rnmoles), 1-ethynylbenzene (158 rnn, 1.5 rnrnols) and diethylamine (189 rng, 2.5 rnrnoles) in 4 rnl of DMF. Copper iodide (16 rng, 0.09 rnrnole) and bis-triphenyl phosphine dichloropalladium (18 mg, 0.025 rnmoles) were added to the reaction. The reaction was sealed under nitrogen, wrapped in an aluminum foil and heated at 60 ° C for 2 hours. The reaction was cooled to room temperature and diluted with chloroform. The mixture was washed with a solution of EDTA IN, saturated aqueous sodium bicarbonate (NaHCO 3) and dried over sodium sulfate (Na 2 SO 3). The organic layer was concentrated in vacuo to yield a brown oil. The crude product was chromatographed on silica gel with 2% rnetanol / chloroform to provide 186 mg (quantitative yield) of the pure product in the form of its free base. The yellow residue was suspended in CHCl3 / MeOH and 2 equivalents of IN HCl / ether was added. The title compound was precipitated with ether to yield 155 rng (69%). P.F. 278-287 ° C (dec.); LC-MS: 361 (M +); RP18-HPLC TA: 5.05 rnin.

EXAMPLE 3 6-Iodo-7-methoxy-3H-quinazolin-4-one 2-ethylcarboxy-5-r-methoxyaniline was dissolved (anthraniline) (10 g, 43 rnrols) in 50 ml of water, 30 ml of ethanol and 4.3 ml of concentrated hydrochloric acid (HCl). The solution was cooled to 20 ° C. A solution of iodine rnonocloride (7.0 g, 43.1 rnrnolee in 7.55 rnl of concentrated HCl and 27 rnl of water) was added rapidly at 5 ° C, to the aniline solution. The reaction was stirred overnight. The reaction was filtered to obtain 29.5 g (96%) of product which was left unchanged in the next step. Dirnetylformamide dimethoxyketal (59.1 g, 496 rnmoles) was added to the product and the solution was heated for 14 hours at 80 ° C. The reaction was concentrated in vacuo, dissolved in rnetanol (100 nmol) and cooled to 0 ° C. Ammonia was bubbled through the solution for 45 minutes. The reaction was stirred at room temperature overnight. 6-Iodo-7-rnetoxy quinazoline was filtered from the reaction as pure product (20.9 g, 84%).

EXAMPLE 4 (lH-Indol-5-yl) - (6-iodo-7-methoxy-quinazolin-4-yl) -amine In a round bottom flask were mixed 6-iodo-7-rnetoxy-3H-quinazolin-4-one (500 g, 1.65 nmrn), triphenyl phosphine polymer (2.75 g, 3 rnmoles / g and carbon tetrachloride (2.53 g, 16.5 mmol) in 3 ml of dichloroethane and the mixture was refluxed for 5 hours, 5-aminoindole (686 mg, 1.65 mmol) was added to the mixture and the mixture was heated at 50 [deg.] C. overnight. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel with 20% MeOH / 1% ammonium hydroxide (NH "0H) / CHCl3 to give 186 mg (28%) of the product as a light yellow solid. 260-267 ° C; PB-MS: 417 (M +); RP18-HPLC TA: 4.28 nil.

EXAMPLE 5 (6-Ethynyl-7-methoxy-quinazolin-4-yl) - (lH-indol-5-yl) -amine The title compound protected with trimethylsilyl was synthesized according to the procedure of Example 2 using (lH-indol-5-yl) - (6-iodo-7-methoxy-quinazolin-4-yl) -amine (90 mg, 0.198 rnmoles), trimethylsilyl acetylene (59 mg, 0.596 mmol) and diethylamine (72 mg, 0.99 mmol) in 2 mmol of DMF. The group . rirnethylelyl was removed by the addition of solid tetra-n-butyl ammonium fluoride hydrate (155 mg). The mixture was stirred for 1 hour and diluted with ethyl acetate. The organic layer was dried over Na 2 O * and concentrated in vacuo to provide a yellow oil. The crude product was chromatogenated on silica gel using 5% MeOH / CH 2 Cl 2 to yield 44 g of product in the form of a free base. The HCl salt was obtained as in the procedure of Example 1 to give 34 g (49%) of the title compound. P.F. 176 ° C; LC-MS: 350 (M +); RP18-HPLC TA: 3.48 rnin.

EXAMPLE 6 (lH-Indol-5-yl) -l7-methoxy-6- (2-pyridin-4-yl-vinyl) -quinazolin-4-yl-amine In a sealed tube under nitrogen, (1H-? Ndol-5-? L) - (6-iodo-7-rnetox? -qu? Nazole? N-4-? L) -amine (80 mg, 0.176 mmol) were mixed. ), 4-v? N? Lp? R? D? Na (22 g, 0.211 rnmoles), palladium acetate (4 rng, 0.001 nrnoles) and triethylamine (74 rng, 103 μl, 0.74 rnmoles) in 1.5 rnl of acetonitrile . The reaction was heated at 100 ° C for 48 hours. The crude product is filtered from the reaction mixture and chromatographed. on silica gel with 10% MeOH / CHCl3 to obtain 60 mg of the product as a free base. The title compound was converted to 56 rng (68%) of its HCl salt as described in Example 2.

P.F. 264-273 ° C (dec.); TS-MS: 394 (M +); RP18-HPLC TA: 3.98 rmn. The compounds of Example 7-18 were obtained according to the procedure of Example 6, starting from (1H-? Ndol-5? L) - (6-iodo-7-rnetox? -qu? Nazolin-4-) ? l) arn? na and rnatepalee starting vinilicoe apropiae.

EXAMPLE 19 (lH-Indol-5-yl) -6- (2-pyridin-2-yl-vinyl) -quinazolin-4-yl-amine The title compound was prepared according to the procedure of Example 6, using (lH-Indol-5-yl) - - (6-iodo-quinazolin-4-yl) -amine (200 mg, 0.52 nmrn) and 2- vinylpyridine (65 ng, 67μl, 0.62 nrnols). P.F. 300 ° C (dec.); PM-MS: 364 (MH *); RP1B-HPLC TA: 3.83 rnin.

EXAMPLE 20 6- (2-Pyridin-4-yl-vinyl) -3H-quinazolin-4-one In a sealed tube under nitrogen, 6-iodoquinazolone (1.36 g, 5.0 mrnol), 4-vinylpyridine (631 mg, 6.0 mmol), palladium acetate (11 mg, 0.05 nrnol) and triethylamine (1.11 g, 1.53 nln, were mixed. 11 mmol) in 7 ml of acetonitrile and the mixture was heated at 100 ° C for 18 hours. The reaction mixture was cooled to room temperature and the product isolated by filtration. The product was washed with acetonitrile and dried in a vacuum oven to provide 536 mg (43%) of a white solid. P.F. 307-309 ° C; TS-MS: 250 (MH *); RP18-HPLC TA: 2.41 rnin.

EXAMPLE 21 (3-Ethynyl-phenyl) -C6- (2-pyridin-4-yl-vinyl) -quinazolin-4-yl-amine The title compound of Example 20 (250 rng, 1.0 mrnol), triphenyl phosphine polymer (1.66 g, 3 rnmol / g resin) and carbon tetrachloride (1.53 g, 10.0 rnrnol) in 3 rnl of dichloroethane were mixed and they were heated at 50 ° C overnight. 3-ethynyl aniline (152 mg, 1.3 mmol) was added and the reaction was continued at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature, the resin was filtered off and the solution was concentrated in vacuo. A yellow solid was obtained which was washed with methanol MeOH and with warm methylene chloride CH2Cl2, and dried to obtain 290 mg (68%) of the product in the form of its free base. 140 mg of the free base was converted to the title compound (166 mg, 39%) following the procedure of Example 2. P.F. 272 ° C (dec.); PB-MS: 349 (MH +); RP18-HPLC TA: 4.86 min.

EXAMPLE 22 (lH-Indol-5-yl) -5- (2-pyridin-4-yl-vinyl) -quina2? lin-4-yl-ami a The composition of the title of example 20 (250 rng, 1.0 mmoles) is active with a procedure analogous to that of the example 21 and mixed with 5-arn? No? Ndol (171 mg, 1.3 rnmolee). The reaction mixture was heated at 60 ° C overnight and deep cooled to room temperature. The filtrate was filtered off and the solution was concentrated in vacuo. The crude residue was chromatographed on silica gel in acetone / 10% ethyl acetate to provide 270 mg (74%) of the product. P.F. 290 ° C (dec.); TS-MS: 364 (MH *); RP18-HPLC TA: 3. 71 rnm.

EXAMPLE 23 (3-Oxazol-5-yl-phenyl) - [6- (2-pyridin-4-yl-vinyl) -quinazolin-4-yl-3-amine The title compound of Example 20 (200 mg, 0.8 mmol) was activated with a procedure analogous to that of Example 21, mixed with 3-oxazolo-an? Lma (128 mg, 0.8 mmol) and heated at 60 ° C for 48 hours. The reaction was cooled to room temperature, the reaction was carried out by filtration and the solution was washed with saturated aqueous NaHCO 3, dried over Na 2 O 2 and concentrated in vacuo. The crude residue was chromatographed on silica gel with 5% MeOH / CH2C_2 and deephoe in chromatography in RP18 HPLC with ammonia acetate (pH 4.5) / aceton? Tplo to produce a yellow residue. The residue was converted to the title compound (34 rnG, 7%) following the procedure of Example 2. P.K 285 ° C (dec.); PB-MS: 392 (M +); RP18-HPLC TA: 4.07 min.

EXAMPLE 24 (lH-Indol-5- l) -. 6- (2-p-ridin-2-yl-vinyl) -quinazolin-4-yl-3-amine In a sealed tube under nitrogen, (1H-? Ndol-5-? L) - (6-iodo-qumazole? N-4-? L) -amina (80 g, 0.176 rnmoles), 4-v. ? n? lp? r? d? na (22 rng, 0.211 mmoles), palladium acetate (4 rng, 0.001 mmol) and tethylaniline (74 mg, 103 μl, 0.74 rnmolee) in 1.5 rnl of acetonitplo. The reaction was heated at 100 ° C for 48 h. The crude product was filtered from the reaction mixture and chromatographed on silica gel with 10% MeOH / CHCl3 to obtain 60 mg of product in the form of free bae. The title component became 56 mg (68%) of its HCl as described in Example 2.

P.F. 264-273 ° C (dec.); T? -MS: 394 (M +); RP18-HPLC TA: 4.98 rnin.

EXAMPLE 25 7-Methoxy-6-pyridin-2-yl-3H-quinazolin-4-one In a flame-dried, three-necked round bottom flask, 2-brornopyridine (3.14 g, 19.9 mmol) was added to 40 rnl of tetrahydrofuran and the solution was cooled to -78 ° C. N-Butyllithium (12.4 rnl, 19.9 mrnol, 1.6 M) was added dropwise and the reaction was stirred for 20 minutes. Zinc chloride (39.7 rnl, 0.5 M, 19.9 rnmoles) was added at 78 ° C, stirring of the mixture was continued for 5 minutes and then warmed to room temperature to produce a clear green solution of zinc intermediate. pyridyl. Phenylenyl phosphinyl butane palladium bischloride was prepared in situ by mixing equinolar amounts of diphenylphosphine palladium benzene (282 mg, 0.66 mmol) and diphenylphosphinyl butane (254 mg, 0.66 mmol) in 40 ml of THF for 20 minutes. 6-Iodo-7-methoxyquinazoline (2.0 g, 6.6 mmol) was added followed by the pyridyl zinc solution and the reaction mixture was heated to reflux for 24 hours. The reaction was concentrated in vacuo and chromatographed on eilice gel with 10% ethanol / CHCl3 to provide 1.83 g (quantitative) of the title compound. bO P.F. 302 ° C (dec.); TS-MS: 254 (MH *); RP18-HPLC TA: 2, 4- rnm.

Example 26 (lH-Indol-5-yl) - (7-methoxy-6-pyridin-2-yl-quinazolin-4-yl) -amine The title compound of Example 25 (300 rn, 1.2 rnrnolee), tpfenylfoephine polymer (1.97 g, 3 rnmolee / g reema) and carbon tetrachloride (1.8 g, 1.14 rnl, 11.8 rnmoles) in 10 rnl dichloroethane were mixed. and they were heated at 85 ° C for 48 hours. The ream was separated by filtration and the solution was added to 5-arnidene dol (156 mg, 1.18 mmol). The solution was refluxed for 16 hours, cooled to room temperature and concentrated in vacuo to yield a yellow residue. The crude product was chromatographed on silica gel using ethyl acetate and gave 25 mg (5%) of the title compound. P.F. 194 ° C (dec.) APC-MS: 368 (MH +); RP18-HPLC TA = 3.66 rnin.

Example 27 (3-bromo-phenyl) - (7-methoxy-6-pyridin-2-yl-quinazolin-4-yl) -amine The title compound of Example 25 (300 rnG, 1.2 mmol), t-phenylphosphine polymer (1.97 g, 3 rnrnols / g resin) and carbon tetrachloride (1.8 g, 1.14 rnl, 11.0 rnrols) in 10 ml of dichloroethane and heated at 85 ° C for 48 hours. The resin was separated by filtration and the solution was added to 3-bromoanamma (156 rng, 1.18 rnmoles). The solution was refluxed for 16 hours, cooled to room temperature and concentrated in vacuo to yield a yellow residue. The crude product was chromatographed on silica gel using ethyl acetate and gave 25 mg (5%) of the title compound. P.F. 231 ° C (dec.); PB-MS: 407 (MH +); RP18-HPLC TA = 4.55 min.

Example 28 (lH-Indol-5-yl) -6- (l-pyridin-2-yl-vinyl) -quinazolin-4-yl) -amine In a selected tube under nitrogen, (lH-? Ndol-5-? L) - (6-iodo-qu? Nazole? N-4-? L) -am? Na (200 mg, 0.517 mmol), -v? n? lp? r? dma (65 mg, 0.621 mmol, palladium acetate (12 mg, 0.005 mmol), triphenyl foefine (27 mg, 0.01 mmol), tetrabutyl ammonium chloride (152 mg, 0.517 mmol) and triethylamine (115 mg, 158 μl, 1.31 mmol) in 1.5 ml of acetonitrile.The reaction was heated at 100 ° C for 48 hours.The crude product of the reaction mixture was filtered and chromatographed on the silica (MeOH / 10% CHCla) to obtain bO of the product in the form of the free base The title compound was converted to 117 rng (63%) of its HCl salt as described in Example 2. PF 30Q ° C (dec.); TS-MS: 364 (M +); RP1B-HPLC TA: 3.83 rnin The compounds of Examples 29-31 were obtained according to the procedure of Example 28 from (1H-? ndol-5-? l) - (6-iodo-qumazole? n-4-? l) -amine and the appropriate starting materials vi ilicoe.

Example 32 (lH-Indol-5-yl) - (6-pyridin-2-yl-quinazolin-4-yl) -amine The title compound of Example 25 was mixed (300 rng, 1.2 rnrols), triphenylphosphine polymer (1.97 g, 3 rnrnoles / g of reein) and carbon tetrachloride (1.8 g, 1.14 rnl, 11. B rnmolee) in 10 ml of dichloroethane and the mixture was heated to reach 85 ° C for 48 hours. The resin was filtered off and the solution was added to 5-aminoindole (156 mg, 1.18 rnmoles). The solution was refluxed for 16 hours, cooled to room temperature and concentrated in vacuo to produce a yellow residue. The crude product was chromatographed on silica gel using ethyl acetate and gave 25 mg (5%) of the title compound. P.F. 272-279 ° C (dec.); APC-MS: 338 (MH +); RP18-HPLC TA = 3.46 rnin.

Example 33 Ethyl ester of 4-C4- (lH-Indol-5-ylamino) -quinazolin-6-yl-3-benzoic acid The catalyst Pd (dp? B) Cl2 was prepared according to the procedure of Example 25 in a round-bottomed flask dried to flame, under nitrogen. (LH-indol-5-yl) - (6-iodo-quinazolin-4-yl) -amine (200 mg, 0.517 mmol) and b4 were added. ethyl ester of 4-c? nc-iodo-benzoic acid (1.6 ml, 0.5 M, 1.1 rnmoles) and the reaction mixture heated to reflux for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (NH4CI) and extracted with ethyl acetate and CH2Cl2. The organic extracts were combined, dried over MgSO 4 and concentrated in vacuo to a yellow oil. The crude mixture was chromatogenated on silica gel using a gradient of CH 2 Cl 2 to 2% MeOH / CH 2 Cl 2 to obtain 78 rng (40%) of the free base. The title compound was obtained according to the procedure of Example 2. P.F. 265-270 ° C (dec.); TS-MS: 409 (MH +); RP18-HPLC TA: 5.21 rnin.

Example 34 Ethyl 2- (4-oxo-3, -dih? Dro-quinazolin-6-yl) -benzoic acid ethyl ester 6-iodo-3H-qumazol-n-4-one (500 rng, 1.83 rnmoles) in 1 rnl of DMF was added and added to 10 ml of anhydrous THF. Palladium tnphenyl phosphine (105 rng, 0.09 rnmolee), 4-cmc-iodine-ethyl benzoate (5.22 rnl 9.7M 3.66 mmolee) were added and the mixture heated to reflux for 24 hours. The reaction was quenched with NH4CI, extracted with CHCl3, dried over MgSO_, and concentrated to obtain yellow oil. The crude residue was chromatogenated on silica gel with ethyl acetate to obtain 357 mg (68%) of the title compound. P.T. 151-158ßC; TS-MS: 295 (MH *); RP18-HPLC TA: 3.57 rnm.

Example 35 Ethyl [4- (3-ethynyl-phenylamino) -quinazolin-6-yl-3-benzoic acid ethyl ester The ethyl ester of 2- (4-oxo-3,4-d? -hydro-qu? Nazole? -6?) Benzoic acid (135 mg, 0.46 mmol) was activated in a procedure analogous to of Example 4 and filtered in a flask containing 3-ethylene nililin (54 rng, 0.46 nmrnols). The yellow mixture is stirred for 24 hours at room temperature. The reaction was washed with saturated aqueous NaHC 3, dried over Na 2 SO 3 and chromatographed on silica gel using 50% ethyl acetate / hexane. Sixty-four milligrams (35%) of the free base were obtained and the title compound was prepared using a procedure analogous to that of Example 2. P.F. 174-177 ° C; TS-MS: 394 (MH +); RT18-HPLC TA: 5.66 nm. Example 36 Ethyl 2- [4-tlH-indol-5-ylamino) -quinazolin-6-yl-3-benzoic acid ethyl ester The ethyl ester of 2- (4-oxo-3,4-d? H? Dro-qumazole? N-6?) Benzoic acid (175 mg, 0.59 mmol) was activated in a single procedure. of Example 4 and filtered in a flask containing 5-arn? no? ndol (19 rn., 0.59 rnrnolee). The yellow mixture was stirred for 24 hours at room temperature. The reaction was washed with saturated aqueous NaHC 3 3, dried over Na 2 O 3 and chromatographed on eilice gel using 50% ethyl acetate / hexane. Fifteen milligrams (18%) of the free bae were obtained and the title compound was prepared using a procedure analogous to that of Example 2. P.F. 212-216 ° C; AP + -MS: 409 (MH +); RT18-HPLC TA: 4.69 rnin.

Example 37 6-Pyridin-3-yl-3H-quinazolin-4-one 6-Iodo-3H-qumazole? N-4-one (4.0 g, 14.7 rnmoles), 3-d? Et? Lborate pyridine (1.72 g, 11.75), potassium hydroxide (2.63 g) were mixed. g, 46.95 rnmolee), tetrabutyl ammonium iodide (2.16 g, 5.87 rnmoles) and tetraqu? s [tnfen? l-foef? na_palad? o (680 rng, 0.586 rnrnolee) in 70 ml of anhydrous THF and the mixture heated to reflux for 24 hours. The reaction was neutralized with 1.83 ml of acetic acid and the product was filtered off in the form of a black precipitate. The precipitate was washed with water and THF and then chromatographed on silica gel using 1% pyridine / 5% MeOH / CH2Cl2. 1.29 g (39%) of a light yellow solid was obtained. P.F. 240-246ßC; TS-MS: 224 (MH +); RP18-HPLC TA: 2.33 rni.

Example 38 (3-Qxazol-5-yl-phenyl) - (6-pyridin-3-yl-quinazolin-4-yl) -amine The title compound was obtained with a procedure analogous to that of Example 4, using 6-pyridin-3-yl-3H-quinazolin-4-one (200 rng, 0.9 rnmoles) and 3-oxazolylaniline (143 mg, 0.9 mmol). (81 mg, 27%). P.F. 309-320 ° C; TS-MS: 366 (MH +).

Example 39 (3-Ethynyl-enyl) - (6-pyridin-3-yl-quinazolin-4-yl) -amine The title compound was obtained with a procedure analogous to that of Example 4, using 6-pyridin-3-yl-3H-qα-inazolin-4-one (200 g, 0.9 rnmoles) and 3-ethynyl aniline (104 g, 0.9 rnmoles) (81 rng, 27%). P.F. 276-282 ° C; PB-M ?: 323 (MH *); RP1B-HPLC TA: 4.22 min.

Example 40 (lH-Indol-5-yl) - (6-pyridin-3-yl-quinazolin-4-yl) -amine The title compound was obtained with a procedure analogous to that of Example 4, using 6-? Iridin-3-yl-3H-quinazolin-4-one (200 mg, 0.9 mmol) and 5-arnino indole (118 mg, 0.9 mmol ) (78 rng, 23%). P.F. 259-265 ° C; PB-MS: 388 (MH +); RP18-HPLC TA: 3.32 rnin, Example 41 7-Methoxy-6-pyridin-3-yl-3H-quinazolin-4-one The title compound was obtained using the procedure of Example 37 from 6-iodo-7-rnetoxy-3H-quinazolin-4-one (1.5 g, 4.96 mmol). Two hundred seventy-eight milligrams (22%) of a light yellow solid was obtained. P.F. 233 ° C; MS: 254 (MH +); RP18-HPLC TA: 2.5 min.

Example 42 (3-Ethyl-phenyl) -7-methoxy-6-pyridin-3-yl-quinazolin-4-yl) -amine The title compound was obtained according to b9 procedure of Example 4 using 7-methox? -6-p? pd? n -3? l-3H-qu na oim-4-one (130 rng, 0.513 immoles) and 3-et? n? l aniline (68 rng, 0.513 rnmolee). Eight milliligrarnoe (10%) of a yellow precipitate were obtained. P.F. 218-26 ° C (dec.); TS-MS: 353 (MH +); RP18-HPLC TA; 4, bl rnin.

Example 43 (lH-Indol-5-yl) - (7-methoxy-6-py? din-3-yl-quinazolin-4-yl) -amine The title compound was obtained according to the procedure of Example 4, using 7-rnetox? -6-p? Pd? N -3? L-3H-qu? Nazolm-4-one (130 rng, 0.513 mrnol) and 5-arn? no? ndol (68 rng, 0.513 rnrnolee). Twenty-eight milligrams (10%) of the free base were obtained. The HCl salt was obtained according to a procedure analogous to that of Example 2. P.F. 222 ° C (dec.); T? -MS: 368 (MH *); RP18-HPLC TA: 3.58 rnin.

Example 44 6-Phenyl-3H-quinazolin-4-one The catalyst was prepared by the addition of bis-benzomethyl (palladium (II) chloride (140 mg, 0.37 mmol) to a solution of bis (diphenylphosphine butane) (157 mg, 0.37 mmol) in 18 ml of toluene. The mixture was stirred at room temperature for 20 minutes.To the catalyst solution, 6-iodo-3H-qumazol-n-4-one (1.0 g, 3.67 mmol), phenyl boronic acid (B96 rng, 7.35 rn oies) were added. , a2 aqueous CO3 1M (3.67 rnl, 7.35 rnmoles) and 9 rnl of ethanol The reaction mixture was heated to reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered through celite, filtered, and the reaction mixture was heated to room temperature. The aqueous layer was washed with saturated aqueous NaHCO 3 and the residue was concentrated on silica gel using 20% hexane / ethyl acetate, and five hundred and ten milliliters were isolated. (63%) of the title compound PB-MS: 223 (H +); RP18-HPLC TA: 3.47 rnin.

Example 45 4- (6-Chloro-2,3-dihydro-indol-l-yl) -6-phenyl-quinazoline The title compound was prepared in a manner analogous to that of the procedure of Example 4, using 6-phenol-3H-qumazole? N-4-one (250 mg, 1124 rnmoles) and 6-chloro-n-dolone ( 172 rng, 1.24 rnmoles). Three hundred and eighty nine milligrams (88%) of a yellow solid was isolated from the reaction mixture.

P. F. 249-255ßC; T. S. M. S: 358, 360 (M +, M + 2 +); RP18-HPLC TA: 6, 59 rmn. Example 46 7-Methoxy-6-phenyl-3H-quinazolin-4-one The title compound was obtained from 6-iodo-7-rnetoxy? -3H-qu? Nazole? N-4-one (5.0 g, 16.55 nmrnols) and boronic acid feml (4.04 g, 33.1 mmolee) using the procedure of Example 44. The crude product (1.42 g, 34%) is evaporated from silica gel chromatography. The crude product is in the eigth reactions. P.F. 258 ~ 262 ° C; TS-MS: 253 (M +); RP18-HPLC TA: 3.67 rnin.

Example 47 4- (6-Chloro-2,3-dihydro-indol-l-yl) -7-methoxy-6-phenyl-quinazoline The title compound was prepared from 7-rnetox? -6-feml-3H-q? Nazol? N-4-one (250 rng, 0.99 mmol) and 6-chloroindoline (152 g, 0.99 mmol), using the procedure of Example 45 (163 rng, 39%). A hundred percent and three milligrams (39%) of the product were obtained after column chromatography and precipitation in the form of the HCl salt. P.F. 2_8-2l9ßC; M.S. (T.S): 388, 390 (rn *, rn * * 2); RP18-HPLC TA: 7.05 min.

Example 48 . { 6-.3- (Benzyl-meth? L -amino) -prop-l-inyl-3-quinazolin-4-yl- (lH-indol-5-yl) -amine The title compound was synthesized according to the procedure of Example 2, using (lH-? Ndol-5? I) - (6-iodo-qu? Nazolm-4-? L) -amine (200 mg, 0.517 nm. ), N-rnetii-n-propargylbenzylamine (246 mg, 1596 mmol) and diethylamine (0.189 mg, 2.59 mmol) in 2 ml of dirnethylformamide (DMF). P.F. 187 ° C (dec.); LC-MS: 418 (mh +); RP18-HPLC TA: 4. 13 min.

Example 49 (3-Ethynyl-phenyl) - (6-pyridin-2-ylethynyl-quinazolin-4-yl) -amine The title compound was synthesized according to the procedure of Example 2, with (3-et? N? L-feml) - (6-iodo-qu? Nazole? N-4-? L) -amine (125 mg, 0.505 rnrnolee), 2-et? N? L-pipdin (66 mg, 0.505 mmol) and diethylamine (72 mg, 0.99 mmol) in 2 ml of DMF.

P.F. 163-69 ° C; LC-MS: 547 (MH *); RP1B-HPLC TA: 3080 rnin.

EXAMPLE 50 (lH-Indol-5-yl) - (6-pyridin-2-ylethynyl-quinazolin-4-yl) -amine The title compound was synthesized according to the procedure of Example 2, using (lH-mdol-5? L) - (6-iodo-qu? Nazolm-4-? L) -amine (125 rng, 0.505 rnrnolee) , 2-et? N? L-pipdin (66 rng, 0.505 rnmoles) and dieilarnma (72 rng, 0.99 rnrnoles) in 2 rnl of DMF. P.F. 189 ° C (dec.); LC-MS: 362 (MH *); RP1B-HPLC TA: 5.13 rnin.

EXAMPLE 51 (lH-Indol-5-yl) - (7-methoxy-6-pyridin-2-ylethynyl-quinazolin-4-yl) -amine The title compound was synthesized according to the procedure of Example 2, using ( lH-mdol-5-? l) - (6-iodo-7-rnetox? -qu? nazole? n-4-? l) -am? na (135 rn., 0.486 rnmolee), 2-ethyl-pyri dune ( 185 rng, 1.45 rnmolee) and diethylamine (605 rng, 8. 27 rnmolee) in 2 rnl of DMF. P.F. 237 ° C (deec); LC-MS: 392 (MH +); RP18-HPLC TA: 4.47 rnin.

EXAMPLE 52 (lH-Indol-5-yl) -7-methoxy-6- (6-methoxy-p? ridin-3-yl) -quinazolin-4-yl-3-amino The title compound was obtained by a procedure analogous to that of example 44, using (lH-mdol-5-yl) - (6-iodo-7-rnetoxy? -qu? Nazole? N-4-? L) -amine ( 250 rng, 0.6 rnrnoles) and acid 3- (2-rnetox? -p? R? D? L) boron? Co (183 ing, 1.2 rnmoles). 172 rng of a light yellow product were obtained after chromatography on silica gel. Eete ee became the title compoteto according to the procedure of example 2. P.F. 266-28Q ° C (deec); AC + -MS: 398 (MH +); RP18-HPLC TA: 4.49 rnm.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - Compound of the formula Wherein Z is NR3 R4, R3 is hydrogen and R * is O2 or phenyl substituted with (R5) q, or NR3 R4 is a group of the formula wherein the dashed line represents an optional double bond; Each R5 is independently selected from mono-, i- and trifluoromethyl, halo, nitro, hydroxy, amino, azido, isothiocyano, CiCi-alkyl, phenyl, thienyl, alkoxy (C_-Ct,), benzyloxy , phenoxy, alkenyl (C 2 -Ce), alkynyl (C 2 -Ce), alkyleneCi-C *) dioxy, cyano, benzoylamino, 25 trifluoro-erilcarbonylamino, alkanoyl (CiCt,) arnino, alkanoyl (C? -Ct,), N-rnonono- and N, N-di-alkoyl (C? -Ct,) amino, alkyl (C1-C4) ) sul foni lamino, tp fl uo rorne ri 1 sul toni lamino, thioalkylCi-C *), alkyl (C1-C4) sul finilo y alq? iKCi- Ct,) euifomlo, p? rrol-1- lo, ?? pend ? n-1- lo y pirróla d? n-1-? wherein said phenyl, benzyloxy, phenoxy and benzoylamino can optionally be ono-euetituidoe with halo, nitro, tnfluorome + yl, hydroxy or alko (C -Ci), and wherein said alkan (C? - C?) D? Ox? eeta joined by the doe extrernoe to adjacent carbone of the benzene radical; or two R5, together with the carbon atoms to which they are attached, form a group selected in. re irní dazolyl, pyrrolo and pyrazolyl; each R6 is selected, independently, between hydroxy, arnmo, N-rnono- and N, Nd? -alqu KCi-C *) am? no, sulfo and alcox? (C? -C4) (with the condition that tamale groups are not bound to a ring carbon that is directly attached to the ring nitrogen) or each R * is independently selected from carboxy, hydrox (C? - C?) alkyl, alkoxy (CiCt, ) alkyl (C? -Ct,), arn? noal? (C? -Ct,), rnono-N- and d? -N, N-alkyl (Ci -Ct,) arnmoalqu? lo (C ? -Ct,), rnorfolino alkyl (C? -Ct,), rnorfolino alkyl (C? -Ci,), 4-alkyl (Ci-Ct,)-??? peraz? N (C? -C "), carbox? Allo (C? -Ct,), alkoxy (C? -Ct, Icarbon lo, eulfoalqu? Lo (C? -Ct,), p? R? D? La? (C? -CA) and (C1-C4) alkyl, which is an integer from 0 to 3, or is 0, 1 or 2, O2 is a 9 or 10-membered bicyclic heteroaryl cyclic radical, or a hydrogenated derivative of the same, containing one or two nitrogen heteroatoms and containing, optionally, another heteroatom selected from nitrogen, oxygen and sulfur, and O2 can optionally carry one or do substituents independently selected from halogen, hydroxy, oxo, arnino, nitro, caloyl, alkyl (C_-C "), alkoxy (C? -C"), alkyl (Ci- CA) arnmo, di. [alkyl (Ci -CA) lamino, alkane? HC-2 -CA) arn? no, alkemloic? -CA) and alquimlo (C2 ~ CA); O1 ee Ar-Y-X; each flr is an aryl or heteroaryl, rnonociclic or bicyclic ring (for example, femlo, naphthyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, benzenednidazolyl, benzoxazolyl, benzothiazolyl, pyranyl, pyrazyl, thiazimyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, quinazolinyl, ptepnyl, quinolyl or leoquinolyl), and wherein each Ar group may be substituted, optionally, with one to three constituents R2; each X ee, independently, alchem C2 (ie *, -C = C ~), alkyne C2Íes say, -C ^ C-) or absent; rn ee one or two; n is zero, one, two or three; Y is (CH2) P where p is 0-5 and where one or two of the CH2 groups can be replaced, optionally and independently, by oxygen, sulfur, O2, C = 0, NH or NCH3; each R1 is independently selected from: (a) trifluoromethyl, halo, nitro, hydroxy, arnino, cyano, alkyl (C? -CA), alkoxy (Ci -CA), alkoxy (C_ -CA) carbon? it, uncle alkanoiKCi -CA) ox ?, alkanoyl (Ci -CA) arnmo, carboxy, phenoxy, benzoyloxy, carbarnoyl, rnono-N- or di-N ^ N-di-alquiKCi-CA) carbanoílo, rnono-N- yd ? -N, N-alkyl (Ci -CAarnino, rnono-N- and d? -N, N- (hydroxalkyl) (C2 -CA) amine, mono-N and d? -N , N- (alkoxy? (C_ -CA) alkyl (C2 ~ CA) arn? No, anilmo, p? Rrol? Dm-1-? Lo, p? Per? D? N-1-1I0, norfolmo, ?????????????????????????????????????????????????????????????????????????????? formerly substituted in the alkyl (CI-CA); and (b) hydrox? alkox? (C2-CA) alkyl (C? -CA), alkox? (C? -CA) -alcox? (C2 ~ CA) -alqu? Lo (C? -C), hydroxythioalkyl (CI-CA) alkyo (C? -CA), alkoxy? (C? -CA) t? Oal? L (C2 -CA) alkyl (C? -CA), hydroxyammon, benxoylanin, mono-N- and d? -N, N-alkyl? (C? -CA) carbamo? Lrnet? Larnmo, carbarnoylrhenethylamino, carbamoyl-rhenylamino, alkox? (C? -CA) carbomlarn ? no, alkanoiKCi-CA) arn? no, carbo irneti lamino, alkox? (C? -CA) carbon? lrnet? lam? no, alkox? (C? -CA) arn? no, alkanoyl (C2 -CA) ox ? arnmo, ilalquiKCi - CA) am? no, alkyl (Ci -CA) sulphilarmno, benzenesulfonarnido, 3-feml? reido, 2-oxop? rrol? dm-l-? lo, 2, 5-d? oxop? r? n? -l, ureido, alkox? (C? -CA) alkyl (Ci -CA) carbomlarn? no, alkyl (Ci-CA) s? lf? n it, al? l (C? - C) eulphonyl, alkoxy (C? -CA) t? Oalkyl (C2-CA), mono-, di- and tn-fluororethyloxy, alkylene (C? -CA) d? Ox? , benzyloxy, azido, guamdino, arninocarbonyl, mono-N and d? -N, N-alkyl (CI-CA) arnmocarbonyl, femlalcox? (C? -CA), carboxymethoxy, alkoxy (Ci- CA) carbon? lrnetox? , carbamoylmethoxy, mono-N and d? -N, N-alkyl? (C? -CAcarbarnoylrhetoxy, mono-N and d? -N, N- (hydroxalkyl (C2-CA)) carboxarn? do , rnono-N- and d? -N, N- (alkoxy? (C? -CA) alkyl (2 ~ CA)) carboxamido and b? s (alkane (C_ -CA) s? lfon? l) arn? do and (c) alkoxy (C2-CA), cyano (C2-CA), alkanoyl (C2-CA) OXI, alkyl (C2-CA) amine, alkyl (C? -CA) ) ammo, alkyKCi -CA) alkylene (C? -CA) d? ox? and alkane? (C2 -CA) arn? no; where each of the above Rl groups of "c" can optionally be optionally substituted with one or two substituents independently selected from amino, halo, hydroxy, alkanoyl (C2 ~ CA) oxy, alkoxy (CI ~ CA), monomer N- and di-N, N-alkyl (C? -CA) arnino, rnono-N- and di-N, N- (hydroxyalkyl (C2-CA) arnino, rnono-N- and di-N, N- ( alkyl (C2-CA-amino, alkanoyl (Ci-CA) arnino, phenoxy, anilino, imidazol-1-yl, phenylthio, piperidino, morpholino,? iperazin-1-yl, 4-alkyl (C? -CA) pi? erazin-1-yl, carboxy, alkoxy (Ci -CA) carbonyl, carbarnoyl, rnono-N- and di-N, N-alkyl (C? -CA) carbarnoyl, carboxarnide, rnono-N- and di-N , N-alkyl (C? -CA) carboxarnide and rnono-N- and di-N, N- (hydroxy (C2-C)) carboxamido, wherein any phenyl radical of a Rl substituent may be optionally substituted with one or two substituents independently selected from halo, nitro, trifluoromethyl, hidoxy, alkoxy (Ci -CA) and alkyloCi -CA), and wherein said alkylene (C_-CAdi dioxy is attached, by the the ends, to the quinazoline ring; and each R2 is independently selected among the sustit.uyenf.es previously presented in paragraphs "(a)" and "(b)" of the definition of Rl; with the proviso that: (a) O1 must be in position "6" or "7" of the quinazoline ring or in these two positions; (b) Ar can not be unsubstituted phenyl; and (c) the sum of rn + n can not be greater than four; (d) when R 4 is lH ~ indol-5-yl, n is zero, m is one and Q 1 is a 2- (substituted phenyl) -tene-1-yl group which is attached to the "7" position of the ring quinazoline, then (i) Ar can not be 1, l-dimethyl-4,4-dirnethyl-l, 2,3,4-tetrahydro-haft-1-yl, and (ii) the phenyl radical of Ql can not have none of the following 13 substitution models, each of which completely and independently defines the substitution of the phenyl radical: 3-n, tro, 4-methox ?, 4-brorno, 3,4-d? metox ?, 3-bromo, 4-hydroxymethyl, 2,3,4,5,6-pentafluorO, 3,5-rnetox ?, 1-amynoetheyl, 3-oxo-4-metho , 2-inetoxy, 3-n? Tro-4-rnet? Lcabon? Lam? No or 3-rnetox? -4-benc? Lox?; and (e) when R < ee iH-mdol-5-? lo, n ee one, rn ee one, Rl ee 6-rnetoxi and Ql ee a 2- (feml substituted) -eten-1-? what is attached to position "7" of the quinazoline ring, then (i) Ar can not be 1, ld? met? l-4, 4-d? met? ll, 2, 3, 4-tetrahydro-naft-1-? lo, and (n) ) the Ql radical can not have any of the following four models of substitution, each of which completely and independently defines the substitution on the phenyl radical; 3-nitrite, 3-bromo, 4-brorno or 2,3,4,5,6-pentafluoro; and pharmaceutically acceptable salts of such compounds.

2. A compote according to claim 1, wherein Z e NR3 and NR3 R4 forms a group of the formula A in which RS ee ammo, or is zero, p is one and the broken line represents a double bond .

3. A compound according to claim 1, wherein said compound contains only one group Q1.

4. A compound according to claim 1, wherein said compound contains two groups Q1.

5. A compound according to claim 1, wherein Ar is substituted femlo. 01

6. - A compound according to claim 1, wherein Ar is optionally substituted pipdma or pyrazine.

7. A compound according to claim 5, wherein Ar is phenyl unsubstituted. B.

A compound according to claim 5, wherein Ar is disubstituted femlo.

9. A compound according to claim 1, selected from the group consisting of; (-et n? l-feml) - (b-p? pd? n-2-? l-qu? nazol? n-4-? l) -amine; (3-et? N? L-phen? L) - (6-p?? D? N -3? L-qu? Nazole? N-4-? L) -arn? Na; (lH-mdol-5-? l) - (6-p? r? dm-3? l-qu? nazolm-4-? l) -amine; (3-et? N? L-phen?) -C6- (2-p? R? D? N-4-? Lv? N? L) ~ qu? Nazol? N-4-? L] -amine; (lH-indole -5-? l) - [6- (2-p? pd? n-4-? l-v? n? l) -qu? nazole? n-4-? l_-arn? na; (lH-mdol-5-? l) - [7-rnetox? -6- (2-?? r? d? n-4-? lv? ml) -qu? nazole? n-4-? l] - amine; (3-oxazol-5-yl-feml) ~ [6- (2-p? R? D? N-4-? L-v? N? L) -qu? Nazolm-4-yl-arnin; (lH-? ndol-5-? l) - [6- (2-p? r? d? n-2-? l-v? n? l) -qu? nazole? n-4-yl 3 -amine; (lH-mdol-5 ~? l) - (-? netox? -6-p?? d? n -3? l-qu? nazole? -4-? l) -arn? na; (3-et? N? L-phen?) - (7-rnetox? ~ 6-p? Pd? N-2-? L-q? Nazolm-4 ~? L) -amine; (1H-β-Ndol-5-? l) - (7-methox? -6 ~? r? d? n-2-? l-qu? nazolm-4-? l) -amine; (3-bromo-phen?) - (7-rnetox? -6-?? pd? N- 2-? 1-qu? Nazole? N-4-? L) -am? Na; 4- (lH-? Ndol-5-? Larn? No) -6 - ?? r? D? -3-? L-qu? Nazol? N-7-ol; (lH-mdol-5-? l) - (7-methox? -6-p? r? d? n-2? let? ml-qu? nazole? n-4-? l) -amine; (lH-? ndol-5 ~? l) - [7- (2-rnetox? -etox?) - 6-p? r? d? n -3? l-qu? nazole? n-4-? ] -amine; (lH-? ndol-5-? l) -. { 7-rnetox? -6- [2- (4-methox? -feml) -v? N? L] -qu? Nazole? N-4-? L} arn? na; . { 6- [2- (3,4-d? Methox? -fen? L) -v? N? L] -7-methox? -qu? Nazole? N-4-? L} - B2 (lH-indol-5-? l) -amine; (4-T2-T4- (1H-indol-5-ylamino) -7-rnetoxy? -qu? Nazole? N-6-? L] -v? N? L.).-Phenyl? -rnetanol; . { 6-C2- (4-arn? No-phenyl) -v? N? L] -7-rnetox? -qu? Nazoi? N-4-? L} - (1H-? ndol-5? l) -amine; (1H-? Ndol-5-? L) - [7-rnetox? -6- (2-p? Raz? N-2-? L-v? Ml) -qu? Nazole? N-4-l-amino; (lH-? ndol-5-? l) -. { 7-rnetox? -6- [2- (6-rnet? L-l-ox? -p? R? D? N -3? L) -vinyl 3 -quinazo1m-4-? L} - mine; (6- {2 ~ (1-arn? Na-et? L) -fen? L3-v? N.].-7-rnetox? -qu? Nazole? N-4-? L) - (lH-? ndol-5-? l) -arni a; (lH-? ndol-5-? l) -C6- (2-p? pd? n-2-? l-v? n? l) -qu? nazole? n-4-yl 3-arn? to; (lH-mdol-5-? l) - [7-rnetox? -6- (6-rnetox? -p ?? -? d? n -3? l) -q-nazole? -4-? L3-arn? Na; . { 6- [2- (4-arn? No-phen?) -v? N? L -7-rnetox? -qu? Na ol? N-4-? L] - (lH-mdol-5-? L ) -amine; (lH-? ndol-5-? l) -C7-rnetox? -6- (l-ox? -p? pd? n -3? l) -qu? nazole? n-4-? l] -arn ? na; and [6- (3-arnino-femletiml) -7-rnetox? -qumazole? n-4-? l3- (lH-? ndol-5-? l) -arni a.

10. The use of a therapeutically effective amount of a compound of claim 1, in the preparation of compositions for treating hyperproliferative diseases in a mammal in need of such treatment.

11. The procedure according to claim 10, wherein the hyperproliferative disease is cancer.

12. The use as recited in claim 11, wherein the disease is brain, lung, cell carcinoma, bladder, gáetpco, pancreatic, breast, head, neck, eeofagic ?, gynecological or thyroid cancer. .

13. The use as mentioned in the claim 10, in which the hyperproliferative disease is not cancerous.

14. - The use of claim 13, wherein said disease is a benign hyperplasia of the skin or prostate.

15. A pharmaceutical composition for the treatment of hyperproliferative diseases in a mammal, comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable carrier. 16.- A component of the formula II wherein Ql, rn, Rl and n ee are defined as in claim 1, with the exception that the Ar group of Ql can not be phenyl.