SA04250294B1 - QUINAZOLINE derivatives as tyrosine kinase inhibitors - Google Patents

Abstract

Abstract: The invention relates to a quinazoline derivative of structural formula I: receptor kinases, particularly tyrosine EGFR kinase.I wherein a, z, X2, X1, w, R1, R2 and b are as indicated in the description; processes for their preparation; Pharmaceutical ingredients they contain and their use in the manufacture of a drug that provides antiproliferative effect. The quinaz.line derivatives of the I structure are expected to be useful in the treatment of diseases such as certain cancers treated with erbB tyrosine.

Description

Quinazoline Derivatives As Tyrosine Kinase Inhibitors Full Description

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The invention relates to certain new quinazoline derivatives or pharmaceutical salts; or 65 is acceptable

pharmacist from him; It has antitumor activity and is therefore useful in the treatment methods of the human body

or object. The invention also relates to processes for manufacturing the aforementioned quinazoline derivatives or pharmaceutical formulations containing them and using them in “dade methods” for example in

Manufacture of drugs for use in the prevention or treatment of solid tumors in warm-blooded organisms, ie

Human.

Many of the current systems are used to treat diseases resulting from the abnormal regulation of reproduction

cellular such as psoriasis and cancer and compounds that inhibit DNA synthesis and cellular reproduction 01 0 to date; The compounds used in these treatments are generally cytotoxic

But their boosting effects on rapidly dividing cells such as tumor cells can be beneficial. Complete

Currently, alternative approaches to these antitumor cytotoxic agents are being developed, for example

(JE) are selected inhibitors of cellular signaling pathways. It is likely that these types of

Reductants are able to show enhanced selectivity against tumor cells and thus are likely to reduce the potential for treatment to have unwanted side effects.

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Normal eukaryotic cells continuously respond to numerous signals from outside that allow communication between cells within an organism. These signals regulate a wide variety of physical responses in Ly cells, including proliferation, differentiation, apoptosis, and locomotion. Extracellular signals take the form of many different forms of soluble Lay factors, including Jal go, growth factors, endocrine factors, and endogenous factors. by binding to receptors across membranes; These splicing fragments integrate this signal from outside the cell into the intracellular signaling pathways; And therefore; Accidental transmission of a signal across the plasma membrane and allowing an individual cell to respond to signals from outside the cell. Many of these signaling processes utilize the ALL process of inserting a phosphate group into proteins used to promote these diverse 0 cellular responses. Alla is regulated by the Ae pene phosphate insertion of target proteins by specific kinases or phosphatases responsible for the regulation of about one-third of all proteins encoded by the mammalian genome. Whereas, the process of introducing a phosphate group represents an important regulatory mechanism in the signal transduction process; It is not surprising that aberrations in these intercellular pathways result in abnormal cellular growth and differentiation and thus induce cellular transformation (which has been

. (Cohen et al, Curr Opin Chem Biol, 1999, 3, 459-465 reviewed in 10 tyrosine kinases convert to synthetically active forms. It has been widely demonstrated that a number of tyrosine kinases and/or when overexpressed They result in transformation in many human cells These mutated and overexpressed forms are present in high proportions in human tumors (reviewed by tyrosine Kolibaba et al, Biochimica et Biophysica Acta, 1997,133, F217-F248 © Kinases play essential roles in the proliferation and differentiation of many tissues.

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= ¢ - These enzymes have been instrumental in the development of new anti-cancer therapies. This family of enzymes is divided into two groups - receptor tyrosine kinases and non-Alin a, for example; EGF receptors and the SRC family, respectively. Based on the results of a large number of studies, including the Human Genome Project; About 90 tyrosine©1004565 enzymes have been identified in the human genome; Of these, OA is of the type of receivers and 7 of the type of non-receivers. These can be divided into Alle 01 subfamily of receptor tyrosine kinases and 10 subfamily of non-receptor tyrosine kinases: et al, Oncogene, 2000,19,5548-5557 (010801AD). The receptors for tyrosine kinases are particularly important in sending mitogenic signals, which facilitate the process of cellular replication. These large glycoproteins that span the cell's plasma membrane possess an extracellular binding domain relative to their binding fragments (such as epidermal growth factor (EGF) of the EGE receptor. Binding of the receptor fragment activates the enzymatic activity of the receptor kinase encoded by the intracellular portion This activity phosphorylates key tyrosine amino acids 0 into target proteins, resulting in aie translocation of JUS signals through the plasma tissues of the cell. Receptor tyrosine kinases, which include erbB2 5 EGFR cerbB4 5 erbB3 5 are often involved in SUSE induction and tumor cell survival (reviewed by 1, 3159, 19, 2000) (Olayioye et al., EMOB is one of the mechanisms by which

- © — This can be achieved by overexpression of the receptor at the protein level; Generally due to gene amplification. This has been observed in several common human cancers (reviewed by breast cancer such as breast cancer) (Klapper et al., Adv. Cancer Res. 2000,77,25) (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al., Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, ed. ,

Salomon et al., Crit. Rev. Oncol. Hematol., 1995, 19, (reviewed in ref. 3 183) and Ley non-small cell lung cancers (NSCLCs), including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265). Reubi et al., Int. J. Cancer, 1990, 45, 269;

Rusch et al., Cancer Research, 1993, 53, 2379; Brabender et al, Clinic. Cancer Res., 2001, (Hendler et al., Cancer Cells, 1989, other lung cancers as well as lung cancers 7, 1850) 0 Bladder cancer or bladder cancer «7, 347; Ohsaki et al., Oncol. Rep., 2000, 7, 603), (Neal et al., Lancet, 1985, 366; Chowetal., Clinic. Cancer Res., 2001, 7, 1957, Zhau et al., (Mukaida et al., Cancer, oesophageal cancer Or esophageal cancer (Mol Carcinog., 3,254) (1991, 68, 142<) or Jie gastrointestinal cancer (Bolen et al., Oncogene Res., 1987, 1, <stomach cancer) or stomach cancer rectal colon 0 149; Kapitanovic et al., Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest., (Visakorpi et al., Histochem. J., 1992, 24, prostate cancer Prostate 0 2001, 19, 554 (Scher et al., J. Natl. Cancer Inst., 2000, 92, 1866), 2000, 32, 73 ML; Kumar et al., 481; or (Konaka et al. 0

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01 - Res., 2001, 61, 2420 (©800©); head and neck cancer (Shiga ef al., Head and neck Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et. al., Neoplasma, pancreatic cancer (2001, 48, 188). and by examining more human tumor tissues for expression of the erbB family of receptor tyrosine kinases; It is expected that its wide reach and importance will be further enhanced in the future.

as a result of dysregulation of one or more of these receptors; It is widely believed that many

Tumors become more aggressive clinically and are therefore associated with a poor prognosis for Aad patients: (Brabender et al, Clin.

Cancer Res., 2001, 7, 1850; Ross et al, Cancer Investigation, Yu et al., Bioessays, 2000, 22.7, 673). One of the receptor tyrosine kinases involved in cellular transformation. These observations include that many tumor cell lines overexpress one or more cerbB receptors and that EGFR or erbB2 upon Lis infection into non-neoplastic WA has the potential to transform these cells. This ability to generate tumors was further confirmed as transgenic mice that overexpress erbB2 spontaneously generated tumors in the mammary gland. In addition, a number of preclinical studies have shown that antiproliferative effects can be induced by eliminating one or more erbB activities by a small partial Glade or

Dominant negatives or inhibitory antibodies (reviewed in: boredom

1 - Mendelsonh et al, Oncogene 2000.19.6550 Thus, it was realized that these receptor tyrosine kinases inhibitors are valuable as an inhibitor of choice for cancer cell proliferation in mammals ibaba et al, Biochimica et Biophysica Acta, s (Yaish et al. al.

Science, 1988, 242, 933, K F217-F248; Al-Obeidi et al, 2000, Oncogene, 19, 5690-5701; Mendelsohn et al., 1997, 133 AH) 19, 6550-6565 .al, 2000, Oncogene, and it was recently approved that the enzyme tyrosine kinases EGER is associated with a small molecule; Iressa (Lad aka gefitinib, 201834) for use in the treatment of late-stage non-small cell lung cancer. in addition to; The results of the use of inhibitory antibodies against erbB2 5s EGFR (0.225 and TRUSTZUMAb anti-32 antibody, respectively) have demonstrated benefit in selected solid tumor clinics (reviewed by: Mendelsohn et al, 2000). Oncogene, 19, 6550-6565 An enlargement and/or activity of erbB receptor tyrosine kinases has been detected and therefore considered to play a role in a number of non-malignant LAL disorders (Jie psoriasis) Ben - Bassart, Curr.

Pharm.

Des. 2000.6.933. Elder et al science, 1989.243.811) and benign prostatic hyperplasia (Kumar etal., Int. benign prostatic hyperplasia (BPH) Nephrol., 2000, 32,73) 17101. and atherosclerosis. and back to Gmail. (Bokemeyer et al.

Kideny Intel. 2000.58.549) restenosis It is therefore expected that inhibitors of the erbB receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders related to excessive cellular LLL.

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Allah reveals the innocence of the Akhtra 2 | For European 117 that there ;- certain derivatives of

4-anilinoquinazolines are receptor tyrosine kinase inhibitors.

International Patent Applications Disclosure Numbers: 77/4697, AT/FFAVA, 773724/17, and

12/771, 12/7714, 197/7034, and 97/7/8444 that certain derivatives of quinazoline° bearing an anilino substitution group at p-position and a substituent at position 1 and/or ha

Inhibitory activity of receptor tyrosine kinases.

European patent application 977097 discloses that derivatives of 4-aminoquinazoline have a substituent

Carrying a fragment containing an aryl ic gana or a hetero-aryl group at position —-1 or not

On the quinazoline ring. The useful compounds were identified in the treatment of hyperproliferative disorders.

International patent applications for AVY To and 98/177384 reveal that there are ?-derivatives

Certain anilino quinazoline substituents at the Vo position are tyrosine aa inhibitors.

115 receptor for vascular endothelial growth factor.

The international application 00/590141 discloses 4-anilinoquinazolines having a substitution at the \o-position A/A; Characterized by the fact that the substitution in position = and/or -1 carries certain ester groups.

The international application 0 70 discloses 6,7-dialkoxy-4-anilinoquinazoline compounds for the treatment of

Cancer or allergic effects.

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The international application 7 discloses the use of certain 4-anilinoquinazoline derivatives as aurora 2 kinase inhibitors. International applications Nos. 17/187511 and 7/1877 disclose the use of a specific ClSe 4-anilinoquinazoline with a substitution at the 7- and/or v= position that has an inhibitory effect on the transmission of

© Signal mediated by tyrosine kinases. IR 17/418487 discloses 4-anilinoquinazoline compounds having a substitution at the -1 and/or –V position by a piperidinyl alkoxy or a pyrrolidinyl alkoxy substituent . It has now become surprisingly clear that certain quinazoline derivatives are substitutable at the 7- position and carry a substituent containing certain substituent alkanoyl groups that have antifungal activity.

Oncology is effective. The compounds of the present invention also have a high cellular capacity; desirable physical properties, in particular solubility; Which could provide advantages in formulating and supplying the compound to patients. Most of the compounds of the present invention have desirable DMPK properties; For example; High bioavailability, high free plasma levels, characteristic half-life, and/or characteristic amount of distribution These properties are expected to provide improved potency in the whole organism and it is possible

1 to reduce inter-patient variability in exposure to the compound compared to other EGFR tyrosine kinase inhibitors such as gefitinib. Moreover; Many of the compounds according to the present invention are inactive or only weakly active in lial 11176.

101- Without wanting to imply that the compounds disclosed in the present invention have pharmaceutical activity only due to the effect of one biological process; The compounds are believed to exert an antitumor effect by inhibiting one or more of the erbB family receptor tyrosine kinases involved in the signal transduction steps leading to the proliferation of tumor cells. Specifically; It is believed that the compounds of the present invention give antitumor ils by inhibiting the enzyme tyrosine -kinases EGFR. In general; The compounds of the present invention have effective inhibitory activity against the enzyme tyrosine 05, the receptor cerbB, for example; by inhibiting the receptor tyrosine kinases EGF, erbB2 and/or cerbB4 while having less potent inhibitory activity against the other 01 kinases; Such as enzymes tyrosine kinases KDR receptor 5 VEGF in addition to Oddly compounds of the current invention have a significantly better ability against the enzyme tyrosine kinases EGFR and more than that against the enzyme kinases erbB2 Atone. Accordingly; It is possible to administer the compound according to the present invention in a dose sufficient to suppress the enzyme tyrosine kinases EGFR while it does not have an effective effect on erbB2 (or other) enzymes of the tyrosine kinases. The selective inhibition of the yo provided by compounds of the present invention could provide therapies for conditions mediated by EGER tyrosine kinases while minimizing unwanted side effects that may be associated with inhibition of other tyrosine kinases.

11- The general description of the invention according to the first aspect of the invention; A quinazoline derivative is provided with the formula (1): HN R!w), “OLY a 0 0 O xX 2 I m is chosen from the hydrogen group” and alkoxy (1-4C)s ¢ hydroxy © and pydroxy - -2( alkoxy (2-4C) - alkoxy (1-3C) » alkoxy 4C) or from a group having the formula: NRT and where 36 is ©0; and 03 are: azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alky!l 1 Whereas, any heterocyclic group within de gene substituting on RY optionally carries substituent groups 1 or "or JY which can be the same or different" is selected from

11 _ - halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C) alkyllamino, and (2-4C)alkanoyl and Whereas, any heterocyclic group within an ali substituent group of RY optionally carries an oxo) asin group 1 ¢ ht b is 1 or Y or ;? each “R?” which can be Jia or vary; is chosen from bromo + chloro «fluoro ; and alkenyl (2 -4C) 5 » alkyl (1 -4C) and alleynyl (2 -4C) ¢ Q' is 0 or 1 or Y or Y or ¢ ¢ each oW which can be the same or different; Selected from: halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1- 01 6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1- bC)alkylsulfinyl, (1 -6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group having the formula : 0s vo and where XB is a direct bond or chosen from 0©; PRY Cua (N(R) 805 «CO

11“ _ - halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1- hydrogen or (1-6C)alkyl, and 6C)alkoxy-(1- 6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1 -6C)alkylamino-(1- 6C)alkyl or N,N-di-[(1- 6C)alkyl]amino-(1-6C)alkyl; X! is chosen from CO £5055 0 36# representing a group with the formula l-(CR"RP) Cua " represents 0 or ps) represents 0 or 1 or ? or © or ? and 0 or 1 or dr dy represent each of the RP SRM SR SR which can are the same or different; are chosen from: hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1 -6C)alkyl]amino 0 and 0 are chosen from cycloalkylene (3 -7C) and cycloalkylene (3-7C) + and where any group of CHy or CH; within the XP group and optionally carried on each group of CH, or CH; mentioned aly or more halogeno or alkyl substituent groups (1-60©) or a substituent group chosen from: hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di -[(1-6C)alkyl]amino vo 2 is selected from: F

1 - - hydroxy, amino, (1-bC)alkylamino, di-[(1-bC)alkyl]Jamino, (1-6C)alkoxy, )1-bC)alkylsulfonyl, (1-bC) alkanesulfonylamino, N-(1-6C)alkyl-(1- 6C)alkanesulfonylamino and a group having the formula: Q5-X°-° where XP is a direct bond or is chosen from 0; 5 SON(R') 5 S055 NR) where R'® Jia : hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl- (1-4C)alkyl, (3- 7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyylyl-(1- 4C)alkyl, 01 provided that when X° direct bond Rco heterocyclyl « and with the proviso that when ©; m and y represent +“ and heterocyclyl Z” and where adjacent carbon atoms in any alkylene chain (2-6C) within substituent group 2 can be optionally separated by entering the chain to a group chosen from of 0; and 5 “COs Ve, 80” 5 “CO ” NR) and ---; and -©<©- where it stands for 7l18 hydrogen or (1-6C) alkyl «

- Yo - inside CH; within group 2; other than group CH; or CH) and where any group of that is CHj and optionally carried on each group of 011 or ¢ heterocyclyl ring or alkyl substituting dc sans (1-6C) or halogeno mentioned by one or more substituent groups : a substituent group chosen from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, ° (1-6C) alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1- 6C)alkylamino, di-[(1-6C)allcylJamino, N-(1-6C)alkylcarbamoyl, N.N -di-[(1- 6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1- 6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N.N-di-[(1- 6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-016C)alkanesulfonylamino optionally bearing a group Substituting Az a Jala heterocyclyl substituting group, and where any group: one or more which can be the same or different”; And then choose from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1 -6C)alkylthio, (1 -6C)alkylsulfinyl, (1- Vo 6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2- 6C )alkanoyloxy and from a group of the formula: 0

101 - - and where X10 is direct bond or selected from 0; “COs and d50; f((l178; R" Cus hydrogen Ji or alkyl (1-4C); and 5l8 represents: halogeno-(1-4C)alkyl, hydroxy (1-4C)alkyl, (1-4C) alkoxy-(1-4C)alkyl, cyano-(1- 4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di -[(1- 4C)alkyl}amino-(1-4C)alkyl ° provided that: when the 4-anilino group in formula 1 is: 4-bromo-2-fluoroanilino or 4-chloro -2-fluoroanilino or stands for hydrogen or (1-3C) alkoxy ; it stands for 0 and 7 is chosen from: hydroxy, amino, (1-6C)allcylamino, di-[(1-6C) )alkyl]amino, (1-6C)alcoxy, (1- Ve 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group thereof Formula 1Q%-X'- or its pharmaceutically acceptable salt; or its pharmaceutically acceptable esters Vo and in a specific embodiment of the present invention provide the quinazoline derivative of Formula 1 as defined above; or dale Pharmacologically acceptable

/ \Y - — in this (Adis) gall the generic expression alkyl” includes all of the straight or branched chain alkyl groups Jie groups : propyl, isopropyl and tert-butyl, and (3 -7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The single-chain branched ‎isopropyl “Je" is specified by the branched chain only; References are to single cycloalkyl groups with cyclopentyl' that are specific to a ring with © atoms only. This symmetrical agreement applies to other general expressions, for example (1-6C)alkoxy includes ethoxy s « methoxy « cyclopentyloxys cyclopropyloxys 0 » and (1-6C)alkylamino includes methylamino « cyclobutylamino « ethylamino and cyclohexylamino » and includes di-[(1-6-Calkyllamino) includes N-cyclobutyl-N-methylamino « dimethylamino and: N-cyclohexyl-N-ethylamino. You should be aware that With the aforementioned compounds of Formula 1 being in Lh gain or racemic ve active forms by one or more carbon atoms other than AB and the invention includes by definition any of the photoactive or racemic forms having the aforementioned activity. The names of chiral compounds (8,5) refer to any standard or racemic mixture, while (R) and (59) refer to specific isomers. in the absence of (RS) or SFR) (9) in the name; It should be understood that the name refers to a standard or racemic mixture; where the standard mixture contains R and 5 isomers in percentages; YYeu

YA - - while the racemic mixture contains # and 5 isomers with a ratio of 04104 (Say) Synthesis of the photoactive forms using standard techniques from organic chemistry that are well known in the field; eg by synthesis from photoactive starting materials or by hydrolysis of the racemic forms. Alles It is possible to evaluate the aforementioned activity using standard test techniques referred to later. The appropriate add for the general groups referred to above includes those which will be explained below. The appropriate value for any one of the "0" groups Je) ex. cyclopropyl « ie cyclopentyl » or cyclohexyl « 0 cycloheptyl 0 or bicyclo[2.2.1]heptyl and the appropriate value for any of the “©” groups (eg “0, 04, 05) when cycloalkenyl Or for the (3-7C) cycloalkenyl Jala group the “Q” group, for example “cyclobutenyl ¢” i.e. cyclohexenyl sf “cyclopentenyl” or cycloheptenyl . It should also be understood that with reference to cycloalkylene (3-7C) used in this document; For me © it denotes (3-7C) a binary cycloalkane bonding group AN 1 that degen lh, Se from a different Gd Gob carbon in the (3-7C) ring cycloalkylene ¢ or can be bonded via a single carbon atom to the (3-70) cycloalkylene ring. Consequently; Reference to cyclopropylene’ group includes “; for example” cycloprop-1,2-ylene and group 0100007110606 of the formula: D

#1 - - however; References to the cycloalklene (3-7C) group as cyclopropyl din are specific to this group only. A similar agreement is chosen for the cycloalkylene (3-7C) groups represented by 0. The appropriate value is for any one of the '0' groups other than '© (eg 0 and 03 Q's (Q%5©) when the group is heterocyclyl ; for the heterocyclyl group within the '0' group is a binary or monocyclic ring with from © to 01 saturated atoms that are non-aromatic (maximally saturating ring systems) or partially saturated (some-retaining ring systems"; but not to the degree of unsaturation) with up to five heteroatoms selected from oxygen +, nitrogen ¢ and sulfur sulfur which, if not otherwise specified; may be crosslinked with 0 carbon or 08 » on Ex: oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1,1- dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl \o decahydroquinolinyl, and specifically Identification: tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyl, thiamorpholinyl 1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrothien -3 -yl, Y

D.07 tetrahydrothiopyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, piperidino, piperidin-4-yl, piperidin-3- yl, piperidin-2-yl or piperazin-1- yl. A nitrogen or sulfur atom within the heterocyclyl group can be oxidized to give the N or 5 oxide analogues; For example: 1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. The appropriate value is for those with substitution groups 1, ¥ oxo or thioxo ¢ on for example; : 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2- 0 oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidiny! or 2,6-dioxopiperidinyl 1 is piperidinyl ; whose group is attached to oxygen in formula 1 via a ring carbon atom. An appropriate value for the 'Q' group when is 'alkyl (1-6C)— heterocyclyl e.g. heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The present invention includes ad a corresponding fit for Laie groups 'Q' is; For example; Unlike the alkyl group (1-6©)-cycloalkyl (3-7C) sf « alkyl (1-6©)- heterocyclyl alkyl (1-6C)-cycloalkenyl (3-7C) exists. Appropriate values for any of 78 sets (8 to "!8); or 17; or assorted daly. combinations of or SX 2 at:-

fluoro, chloro, bromo and iodo; (1-6C) alkyl: methyl. ethyl, propyl, isopropyl and tert- utyl; (2-8C) alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; (2-8C) alkynyl: ethynyl, 2-propynyl and but-2-ynyl; : methoxy, ethoxy, propoxy, isopropoxy and (1-6C)alkoxy: 000 (2-6C)alkenyloxy: vinyloxy and allyloxy; (2-6C) alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C) alkylthio: methylthio, ethylthio and propylthio; for (1-6C) alkylsulfinyl: methylsulfinyl and ethylsulfinyl; (1-6C) alkylsulfonyl: methylsulfonyl and ethylsulfonyl; (1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; A: dimethylamino, dithylamino, N-ethyl-N- di-[(1-6C)alkyljamino: methylamino and diisopropylamino; : methoxycarbonyl, 0107702170017, (1-6C)alkoxycarbonyl: propoxycarbonyl and tert-butoxycarbonyl;

N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and

N-propylcarbamoyl; :: N.,N-dimethyicarbainoyl, N-ethyl-N-

N.N-di-[(1-6C)alkyl]carbamoy!: methylcarbamoyl and N,N-diethylcarbamoyl; (2-6C)alkanoyl: acetyl, propionyl, butyryl and isobuyryl; (2-6C)alkanoyloxy: acetoxy and propionyloxy; (2-6C)alkanoylamino: acetamido and propionamido;

N-(1-6C)alkyl-(2- 6C)alkanoylamino: N- methylacetamido and N- methylpropionamido;

N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl and N-ethylsulfamoyl;

N,N-di-[(1-6C)alkyl]sulfamoyl: N,N-dimethylsulfamoyl, (1-6C)alkanesulfonylamino: methanesulfonylamino and ethanesulfonylamino;

N-(1-6C)alkyl-(1- N-methylmethanesulfonylamino and N- 6C)alkanesulfonylamino: < /td> methylethanesulfonylamino; (3-6C) alkenoylamino: acrylamido, methacrylamido and crotonamido;

N-(1-6C)alkyl-(3- 6C)alkenoylamino: N- methylacrylamido and N- methylcrotonamido;

_No for (3-6C)alkynoylamino: propiolamido; N-(1-6C)alkyl-(3-6C)alkynoylamino:N- methylpropiolamido; aminomethyl, 2-aminoethyl, 1-aminoethyl : : amino-(1-6C)alkyl: 200 S-aminopropyl; ethylaminoethyl and 3-methylaminopropyl; chloromethyl, 2-chloroethyl, 1-chloroethyl } halogeno-(1-6C)alkyl: and 3-chloropropyl; hydroxymethyl, 2-hydroxyethyl, 1- } hydroxy-(1-6C)alkyl: hydroxyethyl and 3-hydroxypropyl; 2-cyanoethyl, 1-cyanoethyl and } cyano-(1-6C)alkyl: 3-cyanopropyl; 1-methylthioethyl and 3- methylthiopropyl; methylsulfonylmethy 1, ethylsulfonylmethyl, (1-6C)alkylsulfonyl-(1-6C)alkyl: 2-methylsulfonylethyl, 1-methylsulfonylethyl and 3-methylsulfonylpropyl; 6C)alkanoylamino-(1-6C)alkyl: 2-acetamidoethyl: i. . | N-methylacetamidomethyl, 2-(N- oe tyr (2 6C)alkanoylamino methylacetamido)ethyl and 2-(N- yh methylpropionamido)ethyl; methoxycarbon ylaminomethyl, (1-6C)alkoxycarbonylamino-(1 - ethoxycarbonylaminomethyl, tert- 6C)alkyl: butoxycarbonylaminomethyl and 2- methoxycarbonylaminoethyl; j 1. i acetoxymethyl, 2-acetoxyethyl and 2- (2-6C)alkanoyl oxy-(1-6C)alkyl: propionyloxyethyl: carbamoylmethyl, 1-carbamoylethyl, 2- } ] carbamoyl-(1-6C)alkyl: carbamoylethyl and 3-carbamoylpropyl;

YY _ (2-6C)alkanoyl-(1-6C)alkyl: acetylmethyl and 2-acetylethyl;

N-(1-6C)alkylcarbamoyl-(1- 6C)alkyl:<td>N- methylcarbamoylmethyl, N- ethylcarbamoylmethyl, N- propylcarbamoyl, 1-(N-methylcarbamoyl)ethyl, 1-(N- ethylcarbamoyl)ethyl, 2 -(N- methylcarbamoyl)ethyl, 2-(N- ethylcarbamoyl)ethyl and 3-(N- methylcarbamoyl)propyl;

N,N-dimethylcarbamoylmethyl, N,N-

N.N-di[(1-6C)alkyl]carbamoyl-(1- diethylcarbamoylmethyl, 2-(N,N- 6C)alkyl: dimethylcarbamoyl)ethyl, and 3-(N,N- dimethylcarbamoyl)propyl; sulfamoylmethyl, 1-sulfamoylethyl, 2- sulfamoyl(1-6C)alkyl: sulfamoylethyl and 3-sulfamoylpropyl;

N-(1-6C)alkylsulfamoyl(1- 6C)alkyl:N-methylsulfamoylmethyl,

N-ethylsulfamoylmethyl, N- propylsulfamoylmethyl, 1-(N- methylsulfamoyl)ethyl, 2-(N- methylsulfamoyl)ethyl and 3-(N- methylsulfamoyl)propyl; and

N,N-dimethylsulfamoylmethyl, N,N- diethylsulfamoylmethyl, N methyl,N- ethylsulfamoylmethyl, 1-(-N,N-

NLN di-(1-6C)alkylsulfamoyl(1- dimethylsulfamoyl)ethyl, 1-(N,N- 6C)alkyl: diethylsulfamoyl)ethyl, 2-(N,N- dimethylsulfamoyl)ethyl, 2-(N,N- diethylsulfamoyl )ethyl and 3-(N,N- dimethylsulfamoyl)propyl.

when ;as defined above 7 in formula 1 is a set of form 7 - 05,; Xs is SONR') and an SO group, appended Q°—and a nitrogen atom appended X'— in Formula 1. The same agreement applies to the other groups identified in this document. For example; When XP is a group of form m “Q-(CRRY) m is group Q° appended to group 7 in Formula 1 and group m (CRYRY) is appended to group X! in Formula 1. As defined above; Adjacent carbon atoms in any alkylene chain (2-6C) are in; For example; Optionally the substituting group RY can be separated by inserting a group into the string such as O ; N(R?) “CON(R®) or .C=C for example (Ja) Insertion of a C=C 0 group into a Jala ethylene chain of a 2-morpholinoethoxy group excites a group of : 4-morpholinobut-2-ynyloxy and; for example” insertion of the J CONH group of the ethylene chain into the fy 3-methoxypropoxy group (eg Jud group .2-(2-methoxyacetamido) ethoxy It is understood that the expression alkylene chain (2-6C) refers to any group: 011.011 and includes, for example, alkylene chains within the allcynyl group (2-8©) alkenyloxy (2-8©) alkenyl » (1 -6C) alkoxy » (1 -6C) alkyl 0 (-2 (8C) and -(2-8C) alkynyloxy when reference is made herein to the CH group, or the CHy bearing Optionally on each mentioned CH; or CH; group or one or more of the 08108600 or (1-6C) alkyl substituent groups; there are appropriately 1 or ¥ of halogeno or substituent groups (1-6C) alkyl © found on each CH group mentioned and there appropriately 1 or ? or of

Yo - - These substituent groups are on every group CH; mentioned.

Where reference is made in this document to group CH, or : 011 which optionally bears on each group CH, or CH; mentioned substitution group as defined in this ABN includes

Appropriate substitution groups formed, for example: hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3- ° piperidinopropoxy and 2-hydroxy-3-morpholiaopropoxy, hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl, 2- hydroxypropionyl and 2-hydroxybutyryl.0 when reference is made herein to “any CH group, or “CH; other than the CH group within a heterocyclyl ¢ group that optionally bears a substituent group”; It is understood that this statement exists only to distinguish between optional substitution groups that can be present in; For example, “JU group CH; in alkyl de sens is one of the substituent groups that can be present on the carbon atoms of the heterocyclyl group of the cade structure. It is understood that” this statement does not exclude ve other substitution groups Being located on the Gd cyclic carbon in a heterocyclyl group, since it was mentioned in this document that the said heterocyclyl group may also optionally carry one or more substituent groups. For example; If a is S35 3-(pynolidin-1 -yl)propoxy here that the CH; or CH; group is within; For example “de gene substitution (R!) other than the CH group; within the heterocyclyl group; which optionally carries 7 hydroxy substitution group” and that any Jala heterocyclyl group, 1 optionally carries

YY

71 - - an alkyl substituent group ¢ and then it is possible that the optional hydroxy substituent group is present on the CH, for the aad) propoxy group, for example a group: .2-hydroxy-3-(pyrrolidin) -1-yl)propoxy Similarly, the methyl Jw alkyl group can be present in the pyrrolidingl ring to give; For example «JOA group:

.3-(3-methylpyrrolidin-1-y)propoxy 0 Equally, the propoxy group can be replaced by a hydroxy group and the pyrrolidinyl ring can be replaced by a methyl group to give; For example; 2-hydroxy-3-(3-methylpyrrolidin-1-yl)propoxy group . to avoid suspicion; When W is 0x0 ¢ the CH in group '0 is replaced by 0 to give C (0) ie sane

ye 0 It is understood that the reference in this document to Q' for being; eg piperidin-4-yl denotes piperidine dds appended to oxygen 8 formula 1. The piperidine ring is also replaced at the VS position by a 77-2-<- group and optionally bears one or more than 17 substituent groups on one or more cyclic carbon atoms of available piperidinyl. It is understood that some of the compounds of Formula 1 may exist in dissolved and insoluble forms;

1 for example; hydrated shapes. It is understood that the invention, Jal, includes all soluble forms that show the inhibitory effect on the enzyme tyrosine kinases of the receptor -etbB. It is also understood that it is possible that some compounds of formula 1 may show multiple forms; The present invention includes all soluble forms that show an inhibitory effect on the enzyme tyrosine kinases of the receptor erbB.

YY

However, it is understood by Lad that the present invention relates to all tautomeric forms of the compounds of the forms of formula 1 that show the inhibitory effect on the enzyme tyrosine kinases of the receptor erbB. The appropriate pharmaceutically acceptable salt is for a compound of formula 1; For example, the “acidic salt of a compound having the formula [” for example (JB) the acidic salt in the presence of an organic or inorganic acid such as citric “trifluoroacetic” sulfuric “hydrobromic” hydrochloric “or maleic acid” or on For example; a salt of a compound of formula 1 which is sufficiently acidic; for example, an alkali earth metal salt “magnesium 5 calcium Jie” or a salt of <ammonium, or a salt with an organic base such as trimethylamine 1 dimethylamine ¢ methylamine » morpholine » piperidine or tris-(2-hydroxyethyl)amine groups .vy. The term 'pharmaceutically acceptable ester' used herein refers to the ester of a quinazoline derivative of formula 1 that hydrolyzes in vivo to leave the parent compound or its pharmaceutically acceptable salt. (Say) Use ester of a 00108201106 derivative of formula 1 that hydrolyzes in vivo of formula 1 to alter or improve the physical or pharmacological form of the present compound; eg, solubility. The appropriate ester groups that can be used to form pharmacologically acceptable “©””-pro-drugs are known as cua eg as discussed in this example: o Pro-drugs as Novel Delivery Systems, 1. Higuchi and V.

Stella, Vol. 14 of the ACS Symposium Series, and in Edward B.

Roche, ed.; Bioreversible Carriers in Drug Design, American Pharmaceutical » Association and Pergamon Press, 1987;

- YA - » Design of Prodrugs, edited by 11. Bundgaard (Elsevier, 1985) and

Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); e A Textbook of Drug Design and Development, edited by Krogsgaard-

Larsen and 11. Bundgaard, Chapter 5 “Design and Application of °

Prodrugs", by H. Bundgaard p. 113-191 (1991); o 11. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); o H. Bundgaard, et al., Journal of Pharmaceutical Sciences , 77, 285 (1988); and oN. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).01 Its formula 1 or its pharmaceutically acceptable salt quinazoline is a pharmaceutically acceptable specific for the ester lla derivative (along hydroxyl pathway; or more precisely; a carboxy group component of an ester group which is hydrolyzed in the ester body in formula 1; where hydroxy is hydrolyzed as Z for example when When it is administered to warm-blooded organisms “I humans or animals to produce 90108201106 mother to the formula like human. ve alkoxy esters Cig I The pharmaceutically acceptable 8-carboxy formula contains the esters group and includes, for example, Crgalkanoyloxymethyl 5 “methoxymethyl esters” eg methyl and “phthalidyl esters “pivaloyloxymethy!l” eg: CageycloalkoxycarbonyloxyC.galkyl esters

- Yq - : eg 1-cyclohexylcarbonyloxyethyl; 13-dioxolen-2-onylmethyl ester

5-methyl-1,3-dioxolen=2-onylmethyl; and C;.salkoxycarbonyloxyethyl esters for example » 1-methoxycarbonyloxyethyl and can be formed at any carboxy group in

compounds of the present invention.

e Pharmaceutical acceptable esters of the hydroxy group in formula 1 or its pharmaceutically acceptable salt include inorganic a-acyloxyalkyl ethers 'phosphate esters (fia) and related compounds; e and aliphatic derived esters Pharmacologically acceptable carboxylic acids, specifically alkanoic, cycloalkanoic ¢ “alkenoic” and alkanedioic acids, in which each alkyl or part of an alkenyl does not have, in a distinctive way, more than 76 0 atoms. carbon; and it can be formed at any hydroxy group in the compounds of the invention (dal) for example (JE) when Z is a hydroxy or contains an hs. hydroxy group Giving the drug; ester is subject to Pharmacologically acceptable breakdown of Ald hydrolyzate in vivo

to give the parent hydroxy / carboxy group in the quinazoline derivative of Formula 1.

Examples of o-acyloxyalkyl ethers that can be used to form a pharmaceutically acceptable ester include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy Vo . A selection of constituent groups includes a pharmaceutically acceptable ester of the hydroxy group in Formula 1 (eg when

: on ) hydroxy is Z

(1-6C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1- 6C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1-4C)alkylcarbamoyl and N-(di- (1-4C) alkylaminoethyl)-N-(1-4C)alkylcarbamoy! (to give carbamates), di-(1-Y.

da 4C)alkylaminoacetyl and carboxyacetyl. Examples of benzoyl substituent groups include: chloromethyl or aminomethyl, (1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholino or piperazino linked © attached to a ring nitrogen atom via a 4c sane methylene bond to the ?- or ¢ position of the benzoyl ring . And there are certain pharmaceutically acceptable esters, esters 10501816, formed by a hydroxy group in the quinazoline derivative of formula 1 (eg when 7 is a hydroxy or contains a pharmaceutically acceptable ¢ or dale group) day Je limitation; pharmaceutically acceptable 0 esters include quinazoline derivatives of formula 1 in which a hydroxy group * of formula 1 forms “phosphoryl (npd is 1) or phosphiryl (npd is 0) ester or its salt Pharmaceuticalally acceptable: (O)npa 1 p of HO (PDI) 0 Another pharmaceutically acceptable Cee ester is a quinazoline derivative of formula 1 in which it forms a hydroxy group in formula 1 (eg when Z is a phosphoryl group ('hydroxy') to give a group of the formula ¢(PD1) where npd is 1. and includes of gall the argument useful for preparing Those esters are compounds containing a group of formula (PDI) in which any or all of the -011 groups in (PDI) are protected independently of a

0*1 - phenyl or phenyl ¢ (these compounds are also important in their own right) alkyl—(1-4C) way or ? from 1 via LASS. Those phenyl (alkyl (1-4C)) alkoxy (1 -4C) and halo “nitro” alkyl (1-4C) groups are replaced separately. Selected from For Formula 1 containing quinazoline Pharmacologically acceptable derivative esters It is possible to prepare For Formula 1 in the presence of a phosphorylating agent Quinazoline is made by derivatization reaction (PDI) © group or leaving group chloro example; contains dae properly protected (protection is terminated; de gana is considered ); This is followed by oxidation (if necessary) and removal of dialkylaminocs by phosphoramidite. Suitable phosphorylating agents are well known and include; For example; Vehicles: which are being protected; For example: -[1 Nulawah (1-60)]-11,21-01; For example, phosphoramidite 0 -di-tert-butyl N,N-diethylphosphoramidite of Formula 1 can form an acceptable salt of a quinazoline derivative 4 ester and it is understood that the combination of these salts forms part of the present invention. where the salts are pharmaceutically ester of a pharmaceutically acceptable group required; It is achieved by well-known traditional techniques that are well-accepted pharmaceutically for those with regular experience in this field. And so on, for example; Compounds containing a vo group have the formula (001); It can ionize (partially or completely) to form salts in the presence of a pharmaceutically acceptable number of ester if it contains an appropriate cal prodrug of antiions. As a functional matter, the HO-P- of formula 1 contains the set (211); There are two quinazoline derivatives and each can be a suitable salt in the presence of a suitable anti-ion. The suitable salts are basic salts such as the alkali metal salt for example (PDI) of a group with the formula ©

_ “name-_ sodium; or salt of an alkali earth metal, calcium Jie, or magnesium; or an organic amine salt; for example” Triethylamine ¢ or tris (2-hydroxyethyl)amine groups and then; for example » The group may form mono (PD1) - R (di-sodium salt). It includes Ame Bana compounds, for example; quinazoline derivatives of formula I or its pharmaceutically acceptable salts 0 or esters. accepted (Liana where; unless otherwise stated; QR s 82 ; 5 and 2 have any of the meanings previously defined or in Paragraphs (f) to (nnnn) (f) R ' selected from (2-4C)- hydroxy © alkoxy (1-4C) © hydroxy + hydrogen alkoxy(2-4C)— alkoxy(1-3C) « alkoxy or a group having the formula: Q* -X'- 01 where XO is 0' and © is: azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2) -4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl and where any heterocyclyl de gana within a substituent group on C optionally bears 1 7 or 0 1 .From the substitution groups, which can be the same or different, are selected from: halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, )-1 4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoy], and where a heterocyclic alkyl group within an RY substituent optionally carries a 1-oxo substituent;

YY _ (x) R' chosen from alkoxy (1-3C)s alkoxy (2-4C)— hydroxy « alkoxy (1-4C) — alkoxy (2-3C) ¢ R ! (¢) selected from Jey )alkoxy (1-3C)s hydrogen specifically R' is isopropyloxys ethoxy ¢” methoxy Jie alkoxy (1 -3C) ¢ © (q) ke R' 3 for hydrogen ¢ R' (Ua) is methoxy ¢ (v) each wR can be the same or different; are chosen from chloro « fluoro ¢ alkenyl (2-40) « alkyl (1-4C) »bromo and allcynyl (2-4C) ¢ (z) each R? which can be identical or different; la lial is made from chloro ¢ fluoro ¢ ethynyl 3 » bromo 0 ; RPS 0 which can be the same or different; is chosen from chloro » fluoro ¢ bromo ¢ (bb ) b is a 0? or © and one of 8 is a meta position (7) on the anilino group in formula 1; b (= z) Vo is 1 - JY ¥ and one of RZ which can be the same or different. be as defined in which of (c) to (1) Def (dd) b is a 0? or “ and one of RP is a meta-position (77) on an adsorbent group. In formula 1 it is a halogeno; and when b is a 0 JY and “© (AY) groups which can be the same or different as defined in any of “|(c) to (i) above;

i d vs - (woo) 5 is 1 or ? and all 82; which can be similar or different; from fluoro; chloro or bromo and us 82 at position (7-) and the other 12 at position ortho (2-) or para (4-) on anilino ¢ (g) 5 group is 1 or ¥ and one 82 at the meta (-7) position on the anilino group M and it is from chloro or (Jeg) bromo specifically chloro); and when Yb is from the other group R? it is chosen from bromo 3 chloro ¢ fluoro ; (hh) the anilino group is selected at position -; On the quinazoline ring in formula I of; 3-chloro-4-fluomanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluorcanilino, 2-fluoro-5- chloroanilino, 3-bromoanilino and 3-ethynilino 1 (i) (da) The anilino group is chosen at the - position on the quinazoline ally in formula I of 3-chloro-4-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroaniuno, 3- bromoanilino, 3-methylanilino and 3-ethynylanilino \o (j) the anilino group at the — ¢ position on the quinazoline ring in Formula 1 is 3-chloro-4-fluomanilino ¢ (kk) the anilino group at position — ; on the quinazoline ring in formula 1 is aay leg) 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino specification is the anilino group Is ¢ (3-chloro-2-fluoroanilino (11) 0 0 selected from piperidin-3-yl and piperidin-4-yl ?

-Yo-

¢ piperidin-4-yl is Q' m) a): which can be the same or different; selected from W n(all 0); and from a group having the formula halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy; o represents a direct bond or represents 0; and "l8 represents X* where halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl : which can be isomorphic or different; selected from oW (oo) all halogeno, hydroxy, oxo, (1-6C)alkyl and (1-6C)alkoxy

0 (pw) WK which can be the same or different; selected from halogeno; (in particular, hydroxy, (1-3C)alkyl and (1-3C)alkoxy “(fluoro ¢ (qq) - stands for 001 or each ow which can be the same or different; it is defined in either (0d) up to (p p);

co (s s) - represents 0 and » is as defined in either (n 1 represents 80 or 8” piperidin-d-yl (pl) 01 is n) until ( pw); “CO Jia X' (MM) (CO, standing for X’ (tat)

© (s s) Xp is an array of the formula:

1.) .) dislocated)., with, on

where “ is 0 or 0 and “ is 0 or 1 or ?; or JY; Woo is a © or

Ja 7- or JF a

Both RZ L and 4 L8 RS, which can be different or the same; They are chosen from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino | 0

and were selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene ¢

Whereas, any of the CH group, or the CH group within the XP group which is optionally carried on each

Said group of CHy or CH; one or more halogeno or substituent group

“(1-6C)alkyl CH; Which is attached to two carbon atoms or any CH group, that is Cua 1 group.

It is attached to a carbon atom within substituent group 7, optionally bearing on each group of

: substitution group chosen from CH; or CH,

hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and adsorbent[1n(1-60)]-tal

(xx)©© selected from a set of the form (CRVR™) q= (QF) m= - and a set of <1 _ of the form -f (Thr28l08) -« (07); where « is zero or gs is TY

Jf p rthco RY (RP (RZ) each as previously defined;

(y) X is a group with the form -05-; For example, Jie (3 -7C) cycloalkylene

¢ cyclopropylidene

(choose from sx) oa

1 _ cyclopropylene, cyclopbutylene, cyclopentylene, cyclohexylene, methylene-(3-6C)cycloalkylene, (3-6C)cycloalkylene-methylene-, ethylene-(3-6C)cycloalkylene and (3-6C) cycloalkylene-ethylene-, and where any group of CH, or CHy within XP which optionally bears on each group of CH, O or CH; mentioned one or more halogeno or -6C) 1) an alkyl substituent group or de sens a la lial substitution of the alkylamine « (1 -6C) alkoxy «amino » hydroxy (-1 di-[(1- 6C)alkyl]amino 5 (6C; (If) “2 is a group having the formula -and (CRPRP) is 1-7-” or ; (more specifically 1 or 6 0 each of RP 5 RZ which can be the same or different; selected from hydrogen and alkyl (1 -6C); and where any combination of CH? or XP J3ls CHP which optionally bears Each group of CH, or CH; mentioned has one or more halogeno substituent groups; and where any group of CH, which is attached to two carbon atoms or any group of CH; vo is Attached to a carbon atom within the substituent group XP is optionally bearing on each group a CH, or CH; substituent group chosen from: hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di -[(1-6C)alkyl]amino (bbb) XP is a group with the formula -and (3l08!28)-; and b is 1 ; * or ; Both RY are fond of which can be the same or different; They are selected from hydrogen

YA —

alkyl (1 -6©) and

and where any group of CH? or CH? within X2 which is optionally carried on each group of

18108600 or MTA mentioned one or more CH replacement groups,

And where any CH group, which is attached to two carbon atoms, or any CH group; M, which is attached to a carbon atom within the substituent group XP is optionally carried on each group of

¢ alkoxy (1 -6©) and » hydroxy substituent group chosen from CH; or CH,

X2 (zzz) is a group with the formula -and (CR'RY) -(stlbztttle)-

;) 1 or; Especially 1? or? (Most specifically, 0 is Q

Both the RZ and the RP fondness, which can be the same or different; They were tested for hydrogen 0 and (©6- 1) alkyl ¢ and “182” selected from:

,. amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino

And where any group of CH or als CH is an XP group, which is optionally carried on each

A group of CH or CH; mentioned one or more substituting groups of halogeno ¢

And where any CH, de seme that is attached to two carbon atoms or any group CH; vo that is attached to a carbon atom within substituent group 7 is optionally carried on each group of

: substitution group chosen from CH; or CH,

hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino = (CRPR) is a group with the formula -and XP (dd) ;)1 or; In particular 1 and specifically (4 JY YO) is g

- 4 s each from 2 to 8 and 3 to 8; which can be the same or different; are selected from hydrogen and (©6- 1) “alkyl” provided that at least one of the BRP JR?22 groups is a (©6- 1) alkyl ; and wherein any group of CH or Jala CH? is an XP group which optionally bears on each of it a group of CH, or CH; mentioned one or more halogeno substitution groups; And where any group, CH, which is attached to two carbon atoms, or any group, CH, is attached to a carbon atom within the substituent group XP, optionally bearing on each group of “(1-6C) alkoxy” hydroxy substituent group has been her choice of CH; or CH; (wooo) © oo is a group of the form -(088)- (CRVRPCHy)~ - —(CH,CRRP)- «—(CR”R”CH,CH,) 0 ru -(c pettet)- each of the Rothleg arcs, which can be the same or different; are chosen from a hydrogen and (©6- 1) alkyl; and where any group of CH? or CHP within the © group that bears Lots) on each group of CHy or CHy mentioned one or more halogeno substituent groups; and where any group 0112 which is attached to two carbon atoms or which group CH3 ve is attached to an atom Carbon within the de pene substitution X2 optionally bears on each of 2 or 0113 substituent groups selected from: hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C) )alkyl]amino - «(CRPRPCHp)= The formula -(80j)- ld _ (zzzz)© is a group “—(CH,CH,CR''R")~ 5 =(CH,CR' R")~ «—(CR"'R”CH,CH,)

YY.

_ Watt each of (R135 (R12) and which Say to be the same or different; selected from “alkyl (1-6C) 5 hydrogen” provided that at least one of the “Ag” or ARP groups 362 is a subdivided alkyl (1-6C) group; where any group of CH or CHy is within a 2© group; which optionally bears on each © a group of CH, or CH; that is mentioned by one or more halogeno substituent groups, and where any CH group that is attached to two carbon atoms or any CH group that is attached to a carbon atom within substituent group 7 is optionally carried on each group of CH, or CH; substituent group chosen from : hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino ¢ 0 (zzzz) XP is a group J of the formula -(08.080)- —(CRVRVCHy)- - “—(CRR"CH,CH.) -(Rtah tetrah) - 5 -(Tet tet tet) - all of RP;RZ which can be the same or different; selected from hydrogen and (©6- 1) “alkyl” provided that at least one of the groups of JR?3l18 in © is a group (©60- 1) the alkyl is divided; vo preferably choose the group of iso-propyl, iso-butyl, sec-butyl and tert- (alkyl butyl ¢ and where any group of CH or CH inside (X2 de gene) which optionally bears on each group of CH, or CH; for which one or more substituent groups of fluoro or chloro ¢ is indicated and where any group of CH, which are attached to two carbon atoms or to any CHy group © _ be attached to a carbon atom within substituent group 72 optionally bearing on each M group

1 - - of CH, or f [ a substitution group chosen from alkoxy (1 -3C) ¢ hydroxy ; (hhh) XP is a group with the formula -.011-» —CH,CH,CH,~ “—CH,;CH,~ - =(CR"R"'CH,)~ « —(CR"R") R - where each of the RP 5 RY? which can be the same or different is selected from hydrogen ; Eh “alkyl (1-40)- alkoxy(1-4C) 5 alkyl (1-4C)— hydroxy « alkyl (1-4C) provided that both R” sR”? are not from hydrogen ¢ z (L) i i) X2 is a de gene of the form: 011 -:01.011- “—(CHR'®)= - “—(CH,CHR'®)~ 5 =( CH2C(R'™);)= «—(C(R'*),CH;)~ «—(CHR'*CH,) where all *for 8 ; which can be the same or different are selected from: (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1- 01 4C)alkylamino-( 1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl and where 87 were chosen from: hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy , (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1 -4C)alkyl, (1-4C)alkylamino- (1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl Ve )© Y J) X2 is a group having «—(CHR'")~ “—CH,CHy~ “—CHy=4apall ~ —(CH,CHR'**)— 5 —(CHR'**CH,) where SRI selected from : hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, ( 1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alky]l, Y. «¢

_ $Y _ : selected from SRP and where hydrogen, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, )1- 3C)alkoxy- (1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alky! and di-[(1- 4QC)alkyl]-amino-(1-4C)alkyl; - (CHR) -CH,CH;~ is a group of the form -Z01-"; XP (dd 8) © «—(CH,CHR'®)= 5 =(CH,C(R'%), )~ «=(C(R'"**),CH,) «—(CHR'*CH.) ; alkyl (1-4C) where all 87 “that can be the same or different are amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino; : and where the L was chosen from —(CHR'CHp)~ has the formula -(01807)- degre se ©“ (J J J) «—(CH,CHR'®)~ 5 =(CH.C(R'™);)~ «—(C(R"*),CH,) 0 (Ali ( 1-40) alkyl that can be the same or different is RS Cua (1)); di-[(1-4C)alkyl]-amino (particularly R12b is selected from (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularly di-[(1-3C)alkyl] -Vo amino); - «(CHR®)= «~CHpCH,~ Formula -.011- le dc gene is X2 m m) a) —(CH,CHR'?)- 5 =(CHR''CH ,): Choose from SR? where l

© hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C) alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alky]l (0 n 0) X* is a group with the formula: 2-017 «=(CHR'*)=-CH,CH,~ - =(CH,C(R'**))~ «—(C(R'**),CH;) «(CHR'*CH ,) and -(h for tahih)- 0 where every RP that can be the same or different is (1-4C) alkyl ; (xx)x2 is a group with the formula - (0111807-(W0 01187 ) “—(C(R”),CH,) -(F(79L11:©08©)-5 (CHCHR'™)~ (specifically X2) for -(0187)-); where every RI? that can be the same or different is an alkyl (1-4C); (pg)x2 is a group of the formula -? (CH ) -; Jig Cus? or 1 and specifically and stands for Yo) and in particular stands for 1; (qq) 2 is chosen from: yoy, amino, (1-6C)alkylamino, di -[(1-6C)alkyl]amino, (1-6C)alkoxy, )1- 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1- 6C) alkanesulfonylamino 1 and a group with the formula Q6-X9- where X° is a direct bond or chosen from 0 R'® Cus SON(R')5 50, « N(R) is:

- Yes hydrogen or (1-6C)alkyl, and 96 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3- 7C)cycloalkenyl, (3-7C) cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1- 4C)alkyl, direct bond heterocyclyl and Co X° provided that

0, provided that “um and and are zeros; and then 7 is heterocyclyl ; and where any heterocyclyl group in 2 is a fully saturated monocyclic heterocyclyl group of 0 + or -17 and containing 1 or ? From heterogeneous atoms selected from nitrogen «oxygen and sulfur ¢

and where any group of CH, or CH; within group 2; Unlike the CH group, it is inside a ring

heterocyclyl 01 » which is optionally carried on each group of 0117 or which was mentioned one

One or more halogeno or (1-6C) alkyl substituent groups or substituent groups are

hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2- choose from)

6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-

6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-

6C)alkyl]jcarbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1- Vo

6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-

6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-

6C) alkanesulfonylamine

and where any heterocyclyl group within a Z-substituted group optionally carries one or more

© (eg 1 ? or “) are substitution groups that can be the same or different

- e; - : which are selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alky], (2-6C)alkenyl, (2-6C)alkynyl , (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1- 6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (2 -6C)alkanoyl, (2- 6C)alkanoyloxy ° and from a group having the formula: 10-8 where 87 represents: (N(R) 80, 0; CO where © represents a direct bond or is chosen from ‎ hydrogen or (1-4C)alkyl, and R18 is hatogeno-(1-4C)alkyl, hydroxy-(1- 4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1- 4C)alkyl, amino-(1-4C)alkyl, N- 01 (1-4C)alkylamino-(1-4C)alky! and N,N-di-[(1-4C)alkyl}amino-(1- 4C)alky}; : selected from Z y ua) ua) and its group hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C )alkoxy : of formula Q6-X9- Vo : is RY where N(R) 5 0 where © is a direct bond or is selected from hydrogen or (1 -6C)alkyl, and 96 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3- 7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1- 4C) )alkyl, « heterocyclyl Q° direct bond; It represents X° provided it is vo

Provided that em m and q are all 1; then Z is a heterocyclyl Cus i.e. the heterocyclyl group in 7 is a non-aromatic monocyclic fully or partially saturated with a group lg heterocyclyl 4; 0 1 contains 1 heterocycle selected from nitrogens oxygen 335 another heterocycle selected from oxygen © nitrogeny and sulfur ¢ and where any combination of CH, or CH; within group 2; Other than the CH group; within the heterocyclyl ring ¢ which optionally bears on each CHy or 13 group mentioned one or more halogeno or alkyl substituent groups (©6- 1) or substituent groups that are Choice of : hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, 1 (1-6C)alkoxy, (1-6C)alkylthio, (1- 6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1- 6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1) - 6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N- (1-6C)alkylsulfamoyl, N,N-di-[(1- 6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1- \o 6C) alkanesulfonylamino and where any heterocyclyl group within de gene substituent Z optionally carries one or more Je (eg YO or “) substituent groups which may be the same or different and which are chosen from:

- M halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, ( 1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2 - 6C)alkanoyloxy 0 and from a group having the formula: -X10-R18 where 09 is a direct bond or chosen from 0; NR") 580; «CO where RY is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, )1 - 4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1- 01 4C)alkyl and N,N-di-[(1-4C)alkyl}amino-(1-4C)alkyl; [(1-6C)alkyl]amino, (1-6C)alkoxy and from a group with the formula: Q6-X9- vo where © is a direct bond or is chosen from © N(R) where “8 is hydrogen or -6C)alkyl 1) and “© is: (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3- 7C)cycloalkenyl-( 1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, ¥.

fA - - and provided that pom and and are all zeros; and then Z is heterocyclyl ¢ and where any heterocyclyl group in 7 is chosen from: tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl , homopiperidinyl, piperazinyl° and such heterocyclyl group may be a carbon or dais ya nitrogen of the group appended to H and where any group of .611 or Jala CH;group 2; other than the CH group, inside the heterocyclyl ring ; which optionally carries on each group of CH, or CH; mentioned one or more halogeno or (1-6C) alkyl substituent groups or a substituent group chosen from ; hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)aikylsulfinyl, (1-6C)alkylsulfonyl, (1- 6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1- 6C) )alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1- Vo 6C)alkyl-(2-6C)alkanoylamino, N-(1- 6C)alkylsulfamoyl, N,N-di-[(1- 6C)alkyl}sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1- 6C)alkanesulfonylamino and where any A heterocyclyl group within a substituent group Z optionally bears one or more Ske) x. For example 0 ? OR 0 of the substitution groups that can be the same or different 0l

_ $4 _ Which is chosen from: halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alky], (2-6C)alkenyl, (2-6C)alkynyl, ( 1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2 -6C)alkanoyl, (2- 6C)alkanoyloxy ° and from a group with the formula: -X10-R18 | where 309 is a direct bond or chosen from 0 RY Cun NR") 580; "CO is : hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, 01 (1-4C)alkoxy-(1-4C)alkyl, cyano -(1-4C)alkyl, amino-(1-4C)alkyl, N-(1- 4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino -(1-4C)alkyl; (pl) 7 selected from : hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and from the group vo has the formula: Q6-X9-, where X° represents a direct bond and represents co heterocyclyl “and provided that am is m and y are all or and then 2 is a heterocyclyl (preferably carbon bonded to 6l); © - and where any group of 011 or 11© is within group 7; It is tested by:

—— Ov —— azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, within the CH ring, other than the Z group inside group CH; or CHy and where any combination of the mentioned one is CH; ; which optionally bears on each of the 0117 or © heterocyclyl or substituent groups chosen (1-6C) alkyl or halogeno substitution groups or more than one Jala heterocyclyl group and where any group is 1 alkoxy (1 and (60- + hydroxy) from one or more (FF 7 0 0) groups (eg Goss) substitution 2 bearing : substitutions that can be the same or different and which are chosen from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-6C)alkyl, (2- 01 6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1- 6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoyl hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-U) 27 M selected from BY (6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N -[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, 00 di -[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyljamino, N-[(1- 4C)alkoxy-(2-6C)alkyl]-N -[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2- 6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4 -dioxanyl Y.

YY

oy - - and from a group with the formula: Q6-X9- : X9 dus is chosen from © 5 R16 Cua « N(R16) is : hydrogen or (1-4C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3- 7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-( 1- ° 4C)alkyl, and where any heterocyclyl group in 0 is chosen from: tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro- 1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl 01 and that heterocyclyl group can be a carbon or a nitrogen attached to the group appended to h provided that pom and are all zeros; then 2 is a heterocyclyl ¢ and preferably one of the heterocyclic groups mentioned above that 1 can be represented by 05; (preferably the heterocyclyl group of the carbon attached to ); and where any group of 011 or CH; within group 2; other than the CH group, within the heterocyclyl ring » which optionally bears on each of the 011 or CH; mentioned one or more 18108600 or (1-6C) alkyl substituent groups or a substituent group chosen from :

- oy - hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1- 6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1- 6C)alkyl]carbamoyl , (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1- 6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N -di-[(1- ° 6C)alkyl}sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1- 6C)alkanesulfonylamino, substitution 7 optionally bearing one or more de gene Jala heterocyclyl de sana and where any of the substitution groups that can be the same or different (TY) (eg: which is chosen from and from a group having the formula: -X10-R18 5,LeR" Cus (N(R') 50; “CO where 29 is direct bond or chosen from 0; hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(14C)alkyl , (1- on 4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1- \ o 4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; (vvv) Z is selected from amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1- 6C)alkylJamino, N -[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2- 6C)alkyl]-N-(1-6C)alkylarnino, di- [hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2- 6C)alkyljamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N- [hydroxy-(2-6C)alkyl]-amino, 0

oY _ - y azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl and homopiperazin-1-yl, and where any combination of .11 © or CH; within a Z group which optionally loads on JS a group of 0117 or CH of which one or more fluoro-substituted groups are mentioned or from which a fluoro-substituted group is selected from: hydroxy, cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, Cus Which Jala heterocyclyl substituent group Z optionally carries one or more Je) eg 0 ? or ?) from substituent groups that can be the same or different 0 and are chosen from: halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl , )1- 4C)alkylanuno and di-[(1-4C)alkyl]amino, and provided that em are all zeros; Then Z is one of the heterocyclyl groups mentioned above (Say represented by 27 pyrrolidin-1-yl Jie or piperidino Vo (preferably the sum of « + m + eq least 1 (s s s) 2 selected from : hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl gay 0 group has the formula:

06-9 where X9 is 0; and 0 is : (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, wherein any ‎heterocyclyl group represented by 96 is preferably selected from tetrahydrofuran-2-yl, ° tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl and tetrahydropyranyl and provided that om m and q are all yellow; And then 7 is chosen from: tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and oxepanyl Camp 0 any group of CHy or CHy within group 2; Which optionally bears on each group of CH, or CH; mentioned one or more fluoro substituent groups or from a substituent group chosen from: hydroxy, cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, vo and where any heterocyclyl group within the Z substituent Optionally bear one or more (eg 0?(FS) substitution groups that can be the same or different and are chosen from: halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di- [(1-4C)alkyl]amino; 0 |

- eh - : its selection from SZ (xx) hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2- 6C) alkylamine, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1 -6C)alkylamino,

N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]}-amino, di-[(1-4C) )alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2- ° 6C)alkyl]-amino, (1-6C )alkoxy, hydroxy-(2-6C)alkoxy and (1 -4C)alkoxy-(2-6C)alkoxy, 1; be at least 9+ ptm and where the sum of: (z) 2 was selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino, (1-6C)alkoxy, hydroxy-(2- 6C)alkoxy and (1-4C)alkoxy-(2-6C )alkoxy, \;1 is at least 0 + ptm and is the sum of: z z) 2 selected from a) and is hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy); -methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N- methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N -methylamino, N-(2- hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N- methylamino, N-(2-methoxyethyl)-N- ethylamino, pyrrolidin-1-yl, piperidino, piperazin-Y.

ov -— - 1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl and where other than the heterocyclyl group within the Z substituent optionally carries one or two substituent groups which can be the same or different and which are chosen from: fluoro, chloro, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkoxy, provided that om m and q are all or and then 7 counts as one from Cle sane enral16:00_which was mentioned above and which can be represented by 7; Like: tetrahydrofuranyl! or piperidino, the 017117011010-1-7 and (preferably the sum of 0 + m + and at least 1); yl, morpholino, homopiperidin-1-yl, \ homopiperazin-1-yl. Whereas, any heterocyclyl group within a Z-substituted group optionally bears one or more (eg 1;1" or ) substituent groups which can be the same or different and which are chosen from fluoro, chloro, cyano, hydroxy, amino, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C) alkylcarbamoyl, N,N-di- [(1- 4C)alkyl]carbamoyl, acetyl, propionyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyacetyl, aminoacetyl, methylaminoacetyl, ethylaminoacetyl, dimethylaminoacetyl and N-methyl-N-ethylaminoacetyl Y

AH - (preferably the sum of qt ptm is at least 1); (CCG) 2 selected from: Z Jala hydroxy, (1-4C)alkoxy, tetrahydrofuranyl and tetrahydropyranyl and optionally carrying one or more of replacement groups; Which can be the same or different are chosen from (1-4C)alkoxy ° by (1-40) fluoro, chloro, hydroxy, and provided that qos pom are all 6 and then choose 7 of tetrahydrofuranyl and tetrahydropyranyl (preferably sum: 0 + 0 qT at least 6 Z (2229) is Je) hydroxy or (1-4C)alkoxy specifically Z is for ('hydroxy ¢ 0) and the sum of " + m + 0 is at least 1 (e ha e) 2 as defined in either (qqq) through (dddd) above; Cua “36 selected from: “—(CR””R”CH,)~ “—(CR”’R”)~ “~CH,CH,~ -(Talaat Ammo)- and Je) (3-6C)cycloalkenylene eg ¢(cyclopropylidene Jie cyclopropylene vo where JS from RPS RZ which can be the same or different; both are chosen from alkyl (1-4C)— alkoxy )1 -3©( « alkyl (14©)- hydroxy « alkyl (1-4C) ¢ hydrogen ¢ provided that “8 and a are not both from hydrogen” and where l is 60; (wooo) and 2 is as done Defined in any of (qqq) through (dddd) above; z 7

- OA -— - “(CHR')~ “—CH,CHy~ “CHy~ Selected from a set of formula aX expression X2 specifically (leg) “—(CHCHR')= 5 = (CH ,.C(R'™),)~ - —(CHR'*CH,) «(((CHR'*)-(e); alkyl (1-4C) which can be the same or different; choose from RZ JS where « alkyl (1-40)- alkoxy (1-3C) 5 alkyl (1-4C)~ hydroxy | 0 : selected from SRP Cua hydroxy, amino, (1-4C)alkyl , (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl , amino-(1 -4C)alkyl, (1-4C)alkylamino- (1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl (CO) is XN and where 0 « (I-4Cjalkoxy and hydroxy (zzzzzz) 2) was chosen from - -(01807)- “—CH;CH;~ “CHy~ selected from a group of formula 2 “as = ) (CHCHR™)=5 ~(CH,C(R™))- «—(C(R'*),CH,) —(CHR'*CH,) (((CHR™*)=(e ) The X2 selection phrase ¢ alkyl (1-4C) can be the same or different; selected from SHRP where each vo: was selected from RPP and where hydroxy, amino, (1- 4C)alkyl, (1-4C)alkoxy, (1 -4C)alkylamino and di-[(1-4C)atkyl]- amino.

- 08 - (hhhh) X XZ is : z hydroxy-(2-4C)alkanoyl, for example hydroxyacetyl, 2-hydroxypropionyl or 3- hydroxypropionyl. Specifically: 2-7<-1 is 2-hydroxypropionyl? 0 (mi X' = X-Z (bh) is (1-4C)alkoxy-(2-4C)alkanoyl + ie (methoxyacetyl, 2-methoxypropionyl or 3-methoxypropionyl (yy j) 2 XX choose from: amino-(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl and di-[(1-4C)alkyl]amino- (2- 4C)alkanoyl Ve eg 362-2- The expression for Jie di-[(1-4C)alkyl]aminoacetyl : (dimethylaminoacetyl ¢ (kkkk) 72-2 was selected from: tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, yo is attached to a carbonyl group in formula 1; via a carbon ring” and where group The heterocyclyl within -762 Z- optionally bears 1 or ?substituted groups” that can be the same or different. They are chosen from: fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C). )alkoxy and (2-4C)alkanoyl

- and 04 (L L L L) -2 -2 is selected from: tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl ) eg Z- X2- ¢(tetrahydrofuran -2-yl or tetrahydropyran-2-yl (MMMM) -365 -2 is chosen from: pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and ° homopiperazinyl where heterocyclic cyclyl 32 is attached in formula 1 via a carbon ring; and where X'- Jala heterocyclyl ic game 2) optionally holds | or? of substitution groups” which can be the same or different; chloro » fluoro pp »¢ alkoxy (1-4C) « alkyl (1-4C) » hydroxy 0 and alkanoyl (2-4C); (NNN)-L-7 is selected from: pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, homopiperidin-1-yl and homopiperazin-1-yl, and where heterocyclyl within -32 Z- optionally bearing (Yd) groups of 1-substituted which can be the same or different; aby chosen from chloro « fluoro ¢ alkoxy (1-4C) « alkyl (1-4C) » hydroxy and alkanoyl (2-4C); A particular embodiment AT of the present invention is the quinazoline derivative of formula 1 where: a is chosen from alkoxy(1-3C) « alkoxy (2-4C) = hydroxy » alkoxy (1-4C) -(2-40) alkoxy or from a group with the formula: Q2-X3- Y.YY.

1 - - where XB is ©; And QF is : azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alky!, piperazino-(2) -4C)alkyl or morpholino-(2-4C)alkyl, and where any heterocyclyl group within a substituent group on RY optionally carries STA m* of the substituent groups; which can be the same or different; alkylsulfinyl (1-4C) « alkoxy (1-4C) ¢ alkyl (1-4C) » amino 0 hydroxy « halogeno » camino [alkyl (1-4C)] - di « alkylamino (1-4C) ) and an alkanoyl (2-4C) « ung in any heterocyclyl de seme within a substituent group on RY optionally bearing 1 substituent group 0x0 ; #5 J stands for oF each R* which can be the same or different; Selected from bromo 6 chloro « fluoro and allcynyl (2-4C); that piperidin-4-yl ¢ represents a zero or a 1 (preferably a zero); 10 all 7's which can be the same or different; is selected from halogeno (specifically alkyl (1-3C) “hydroxy” ( fluoro and alkoxy(1-3C); X! is a CO 2 selected from ic gene has the formula “(CHR™)~ “-CH,CH,~ ¢-CH,~ - “=(CH,CHR™)= 5 =(CH,C(R'*);)~ « =(C(R'*),CH;) ~(CHR'**CH,) guest i

~My - ¢ alkyl (1-4C) which can be the same or different; Selected from RP each Gua 1-( « alkyl (1-4C)~ amino ¢ alkyl )1-40(- alkoxy (1-3C) « alkyl (1-4C)— hydroxy face Ges) alkyl (1-4C)- di-[(1-3C)alkyl]-amino 5 alkyl (1-4C)~alkylamino (4C “( alkyl (1-4C) 1”) limitation represents (1-4C) « alkoxy (1 4c) ¢ alkyl (1-4C) camino “hydroxy” was selected from R%m and where alkoxy (1-3C) “alkyl 0 hydroxy is transcribed- [ alkyl (1-4C)] = di » alkylamino 1-)] - diy alkyl (1-4C)alkylamino (1-4C) « alkyl (1-4C)~ amino « alkyl (1-40)- 1-) camino select 2 to be selected from any ( and alkyl (1-4©)- amino— ] alkyl (40 «alkoxy (1 -4C) ¢ hydroxy was selected from Z ); di-[(1-3C)alkyl]-amino slkylamino 40 or -362 -2 is selected “alkoxy (2-4©)- alkoxy (1 -4C)s alkoxy (240©)- hydroxy 00 and piperidinyl » pyrrolidinyl » azetidinyl » tetrahydropyranyl ¢ tetrahydrofuranyl from the “ring carbon atom Z- X*- cyclic carbon atom to which a morpholinyl is attached

Cle Ghana; optionally bearing one or more 7 Jala heterocyclyl and where any group ¢ chloro 6 fluoro substitution; which may be the same or different; selected from ¢ alkanoyl (2-4C) and alkoxy(1-4C) « alkyl (1-4C) ¢« hydroxy Vo provided that: 4-bromo-2-fluoroanilino or 4-chloro-2 - is an anilino when it is the ;- tv then m group (“alkoxy (1-3C)” is RY and a pharmaceutically acceptable fluoroanilino thereof. ester or a pharmaceutically acceptable salt thereof; or

~My _

in this form; the dad specific to Z is a chosen group of hydroxy ¢

and (1-40) alkoxy (eg Z is methoxy « hydroxy or ethoxy ].

in this form; the; The anilino group in Formula 1 was chosen from:

3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5- chloroanilino, 3-bromoanilino and 3-ethynylanilino. °

The aniline de sexe is still in particular:

3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino : for formula 1 where quinazoline is a 3 ke derivative, another particular form of the present invention is (2-40©)-alkoxy(1-3C) « alkoxy (2-4C)~ hydroxy « alkoxy (1-4C) C is chosen from its formula: dc sana or from alkoxy 0

; Q2-X3-

: where © is ©0; and 0 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino- (2-4C)alkyl,

\ or 0 substitution group on 1 optionally carries Jala heterocyclyl and where any group Vo 1-) camino ¢ hydroxy « halogeno which can be the same or different; are chosen from oF or 1 -([ = di ¢ alkylamino (1 -4C) ¢ alkylsulfinyl (1 -4C) ¢” alkoxy (1 -4C) ¢ alkyl (4C” alkanoyl (2-4C) and “amino [ alkyl (4C ic gana 1) within substituent group !8 optionally carries heterocyclyl de sane and where any (2-40)- hydroxy « alkoxy (1-4C) is selected from R' specifically Je) oxo replace ov.

alkoxy and (1-30) alkoxy (2-4C) alkoxy « and specifically alkoxy(1-4C) R' ;

d is 10? or © (more specifically b is 1; more specifically b is ?); Each p that can be the same or different is chosen from fluoro ; bromo ¢ chloro and allcynyl (2-4C);

©1 0 is piperidin-4-yl ;

a is zero or 1 (preferably zero);

WS which can be the same or different are chosen from halogeno (specifically alkyl(1-3C) « hydroxy ¢ ( fluoro) and alkoxy (1-3C) ¢

for is “CO

06 enr is a group with the form - and (CRY) (CRIRY).

© is 1 10 or ¥ (more specifically 1 or ¥ and especially 1);

All RPS RP RT that can be the same or different are selected from a hydrogen f (-1! alkyl (6C ¢) so they are selected from ¢ di-[(1-4C)alkyl]amino alkylamino (1 -4C) “amino is chosen from (1-4C)5 alkoxy (2 -4C)~ hydroxy « alkoxy (1 -4C) « hydroxy

alkoxy (2 -4C)— alkoxy 00” or Z-X? is a Z selected from azetidinyl “tetrahydropyranyl ¢ tetrahydrofuranyl” piperidinyl “pyrrolidinyl” and “morpholinyl” daa 2-2 related BL a ring carbon atom ¢

- 0 - and where any heterocyclyl de sexe is inside Z; Optionally carries one or two replacement assemblies; which may be the same or different; chosen from chloro « fluoro ; alkoxy(1-4C) © alkyl (1-4C) « hydroxy and alkanoyl (2-4C); da that: ° when the 4 - anilino group in formula 1 is: 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R! is (1-30) calkoxy and then a is 00 ?;] or a pharmaceutically acceptable salt or a pharmaceutically jade ester thereof. chloro-4-fluoroanilino, sf 3-chloro-2-fluoroanilino 3- 01 0 3 bromoanilino and 3-ethynylanilino & 0 and particularly in this embodiment; ;- the aniline group in the formula is chosen from: 3-chloro -4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino and 3- bromoanilino. | 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino Preferably the anilino group is 3-chloro-2-fluoroanilino. Another particular embodiment of the present invention is the quinazoline Gide of Formula 1 where : a is chosen from alkoxy(1-3C) « alkoxy (2-4C)—hydroxy 1 alkoxy (1-4C) -(-2 alkoxy )46 | © or from a group having the formula:

Q2-X3- where © is ©; and QF is : azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2- 4C) alkyl | morpholino-(2-4C)alkyl, oo and where any heterocyclyl group within a substituent group on 8 optionally carries a Y Jo of which can be the same or different; It is chosen from «amino » hydroxy 1 halogen )-1 camino [alkyl (1 -4C)] - di «alkylamino (1-4C) © alkoxy (1-4C) « alkyl (4C) (and specifically a Selected from from alkoxy (2-4C)- hydroxy « alkoxy (1-4C) and (©1-3) aay Jes 6 alkoxy (2-4C)— alkoxy defining alkoxy(1-4C) RY For example isopropyloxy + ethoxy ¢ methoxy Jud 0 Still in particular l is methoxy (¢ -011:00 group in Formula 1 is chosen from: 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5- chloroanilino, 3-bromoanilino and 3-ethynylanilino 1 © ve is 1 or ??; i All 82 that can be the same or different are chosen from 0 bromo + chloro + fluo and ethynyl ¢ a is piperidin-4-yl ¢ a is zero or 1 (preferably zero);

ny - ~ all 77a that can be the same or different are chosen from a halogeno (specifically alkoxy (1-3C)s alkyl (1-3C) « hydroxy ) fluoro ; X's is (CO x? chosen from a set of the formula “—(C(R'*),CH;) ”—(CHR'**CHy)~ —(CHR'#)~ “—(CH,CHR'?)~ 5 =(CH,CR™)2)~ 0 . where RUS which can be the same or different is 1 1-4( any Je) alkyl defining alkyl (1-3C) ); Cua ag is selected from di-[(1-3C)alkyl]- nino alkylamino (1-4C) camino (specifically 7l is selected from alkylamino (1-4C) and yl]-amino 10-0 ' and in particular ¢(amino — [ alkyl (1-3C)] - di©.2 is chosen from -)s alkoxy (2-4C)~ hydroxy « alkoxy (1 -4C) + hydroxy 1 1 alkoxy(2-4C)— alkoxy(4C) or 72-2 is selected from “pyrrolidinyl » azetidinyl » tetrahydropyranyl 0;tetrahydrofuranyl p10 morpholinyls ; which are attached to X' via a cyclic carbon atom ring carbon atom \o ¢ and where any Jala heterocyclyl group 7 optionally bears one or two substituent groups which can be the same or different chosen from chloro fluoro alkoxy (1- 4C) « alkyl (1-40) ¢ hydroxy and alkanoyl (2-4C); or a pharmaceutically acceptable salt or a fishingly acceptable ester thereof.

- 8+ - in this form; A particular value of Z is a de gene chosen from hydroxy ¢ and (-1 alkoxy )4© (eg Z is methoxy © hydroxy or (ethoxy . In this model; - a particular anilino group in formula 1 is chosen from: 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3- ethynylanilino. In particular; the anilino group is: 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of Formula 1 where RY: is selected from: (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy 01 or from a group having the formula: i Q2-X3- where X3 is for 0 and 03 are: Vo and where any heterocyclyl group within a substituent group on R! optionally bears 1- or Y or (Y which can be the same or different; chosen from “amino » hydroxy ¢ halogeno )- 1 amino [alkyl (1-4C)] - di 1 alkylamino (1-4C) « alkoxy (1-4C) « alkyl (4c) »

- 14 - º (specifically !1 is chosen from 1-)s5 alkoxy (2-4C)= hydroxy « alkoxy (1-4C) alkoxy (2-4C) alkoxy (30 ; specifically 18 alkoxy(1-4C); for example ethoxy » methoxy; isopropyloxy » and still in particular l is ¢(methoxy); - J aniline group Formula 1 is chosen from: 3-bromo-2-fluoroanilino, 3.chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoapilino and Z is hydroxy or alkoxy (1-4C) » (specifically A is hydroxy; methoxy or ethoxy + in particular Z is aay les 1 methoxy hydroxy 0 in particular Z is hydroxy ); Q ' is piperidin-4-yl ¢ a is zero or 1 (preferably zero); WS which can be different Salles; choose from alkyl (1-3C) ¢ hydroxy and (©1-30) alkoxy ¢ XI 10 is a “CO* chosen from a group of the formula (~(CH,CHR'®)~ 5 —(CHR'*)~ where H is (1-40) alkyl (and specifically alkyl (1-3C); in particular “(methyl RI? Cua) is chosen from di-[(1-3C)alkyl [-amino 5 alkylamino (1-4C) camino (specifically RZ) is selected from:

- and 0 amino - [alkyl (1-30©)[ - disalkylamino (1-3C) and in particular [alkyl (1-3C)] = di - camino and specifically still 182” is a methylamino In particular dimethylamino (¢ or a pharmaceutically acceptable salt; or a pharmaceutically acceptable ester thereof. © In this embodiment, 4 - a particular group 0 in Formula 1 is chosen from: 3-bromo-2-fluoroanilino, 3 .chloro-2-fluoroanilino, 3-bromoanilino and 3- ethynylanilino. Still specifically, the aniline group is: 3-chloro-2-fluoroanilin or 3-bromo-2-fluoroanilino. 0 Another particular embodiment of the present invention je of the inazoline derivative or of formula 1 where: R' is an alkoxy (1-4C) on methoxy ES ¢ sp ¢ isopropyloxy " Specifically methoxy (¢ z;?- group 0 in formula 1 is chosen from: 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro- 5- chloroanilino, 3-bromoanilino and 3-ethynylanilino; \o Q' is piperidin-4-yl ¢ a is zero or 1 (preferably zero); all W which can be the same or different 0 is chosen from hydroxy + (1-30) alkyl and (©1-3) alkoxy ¢

1 - - L is “CO Z-X? It is chosen from tetrahydropyranyl ¢ tetrahydrofuranyl ¢ cobblestone” the amalgamation of piperidinyl ¢ and octamom (specifically 7-32 is tetrahydrofuranyl or of pyrrolidiny! where .2-2 is attached to a birr via a ring carbon atom “oo” and where any heterocyclyl group within Z optionally carries one or two substituent groups that can be the same or different. Its choice of hydroxy « chloro » fluoro methoxy ¢ methyl and acetyl ¢ or an acceptable ester or an ester from it. Formula I is chosen for this HY 3_bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino | 0 and in particular “the aniline group is selected from: 3_bromo- 2-fluoroanilino and 3-chloro-2-fluomanilino. Another particular embodiment of the invention Mall is a quinazoline derivative of the formula Ib Pee i A 0” te i Bb Plus Yo $

17 - R' was chosen from bromo R® ¢ alkoxy (1 -3C)s hydrogen or chloro (specifically i chloro ( ; m is yellow; 1 or ? (more specifically a is a zero) all 177 that can be the same or different are chosen from halogeno ¢ hydroxy (specifically oo alkyl (1-4C)) fluoro and alkoxy (1-4C) ¢ xX? is chosen from a set of the formula -:011- —CH,CH,CH,~ “—CH;CHy— - ~(CH,CR'R””)~ 5 =(CR"'R"CH,)~ «—(CR""R") where RPS RY JS which can be the same or different is chosen from hydrogen 5).1 alkyl (4C ( Specifically “8 is “CH”, and in particular 1 is ~(CHR'™) 00 - where #8 is an alkyl (1-4C) ); : 7 is chosen from: E hydroxy, amino, ( 1-6C) Ikylamino, hydroxy-(2-6C)allcylaraino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1 6C)alkylJamino, N-[ hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, ‎N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)allcylamino, di- [hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1 -4C)alkoxy-(2-6C)alkyl ]-N-[hydroxy-(2- Vo 6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1 -4C)alkoxy-(2-6C)alkoxy, azetidiu-1-yl, pymolidin-1-yl, piperidino, piper-azin-1-yl, morpholino, homopiperidin- | 1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3 - yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl yo and group 7-75 is chosen from:

VY - tetrahydrofuranyl, 1 3-dioxolanyl, tetrahydropyranyl, 1 ,A-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which is represented by a 7-322 carbonyl group in formula 10 of the heterocyclyl where cyclic carbon road linkage; oo or ? of groups 1 within 722-7 optionally bearing heterocyclyl and where any “hydroxy†group “chloro†fluoro substitution; that can be the same or different chosen from ¢ alkanoy! (2-4C)s alkoxy (1-4C) © alkyl (1-4C) is a pharmaceutically acceptable thereof. ester or a pharmaceutically acceptable salt or : in an embodiment of formula 15 2 chosen from 0 hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N- methyl-N-ethylamino, dithylamino, N-(2 -hydroxyethyl)-N-methylamino, N-(2- hydroxyethyl)-N-ethyl : ino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N- methylamino, N-( 2-me] oxy tne, pyrrolidin-1-yl, piperidino, piperazin- Vo 1-yl, morpholino, tra drofurany! and terdhydropyranyl; Substitution groups” 1 or 1 in 7 optionally bear heterocyclyl i.e. Cus group

Na - a which can be the same or different is Ja from ro « fluoro e (1-4C) « hydroxy » of i y j . alkoxy (1-4C)s alkyl in another embodiment in formula 18 db is methoxy Jie alkoxy (1 -3C) fla Jil . In another embodiment in the formula R' db is chosen from hydroxy ¢ alkoxy (1-4C) -(2-40) alkoxy (2-40(- alkoxy(1 -3C)s alkoxy © ; a are 40 2 selected from hydroxy « alkoxy (2 -4C)~ hydroxy ¢ alkoxy (1-4C) and (1-40) sles + 2 40(- alkoxy specifically 2 selected from alkoxy (1-4C)s hydroxy ; in particular 7 is a hydroxy or methoxy (particularly hydroxy ); and X2 has any of the meanings defined above relating to quinazoline of the formula bl 0 > A particular embodiment Al of the present invention is a quinazoline derivative of the formula lc a . IL y N ml » and where: ve #l8 was selected from alkoxy(1-3C)s alkoxy (2-3C)~ hydroxy ¢ alkoxy (1-3C) -(-2 alkoxy (3C) (and specifically methoxy R'™ (¢ m) was chosen from the set It has the formula “—(CH,CHR'?)~ 5 ~(CHR'®)~ Ras is a (©1-4) Jeg) alkyl specifically (©1-3) «alkyl In particular, R'?® Thiho ¢ (methyl) was selected from the alkylamine (1-4C) amino and di-[(1-3C)alkyl]-amino Ye (specifically SRP selected from :

Vo - - camino — [alkyl (1-3C)] - di salkylamino (1-3C) and specifically (1-3C)] _ di camino — [ alkyl and still on aay Determination methylamino R'% and in particular: dimethylamino (¢ z! la lial from (1-4C)s alkoxy (2-4C)—hydroxy 1 alkoxy (1-4C) + hydroxy Je g)alkoxy (2-40)- specifically alkoxy !2 hydroxy or alkoxy (1 -4C) ¢ for example hydroxy or 0 ( methoxy or de gana #tebra2 which Selected from tetrahydrofuranyl piperidinyl 3 » pyrrolidinyl tetrahydropyranyl « where T is attached to a carbonyl group via a ring carbon atom ¢ and where heterocyclyl 4c sane Jah !2 optionally carries one or two groups substitution; which can be identical 0 or different chosen from fluoro; “alkoxy (1-4C) 0 alkyl (1-4C) ¢ hydroxy” chloro and alkanoyl(2-4C); or A pharmaceutically acceptable salt, or an ester that is acceptable to fish from. specifically de for hydroxy ) . 1 in this form; fhe XP 3 is preferably a group of formula (CHR')- where R'? is a Jeg) alkyl (1-4C) and specifically alkyl (1-3C); particularly methyl (¢). Another example of Formula 1 compounds is the quinazoline derivative of formula 11d a ml t m Id

vi - - where: li represents (1-4C) alkoxy ; XP & its choice oo group Ld formula follows “~CHCHy~ -(y)v - —(CH,CHR'?)~ 5 =(CHR*CH,) oo where SRP selected from: (1-3C)alkyl, hydxoxy-(1-3C)alkyl and (1 -3C)alkoxy-(1-3C)alkyl ; and 272 were selected from hydroxy, (1-3C)alkozy, hydroxy-(2-3C)alkoxy, (1 -3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3- yl, 1 ,3-dioxolanyl, tetrahydropyranyl and 1,4- dioxanyl; Which heterocyclyl group within 22-47” optionally carries a 1 or ? from replacement groups; which may be the same or different selected from hydroxy « chloro ¢ fluoro « alkoxy (1-3C) » alkyl (1-3C) and (©2-3) alkanoyl ¢ or a pharmaceutically acceptable salt edie Or an ester that is pharmaceutically acceptable. In form in form old “18 selected from methoxy Jie alkoxy (1-3C) ” 00 in form a) in form XP dd selected from a group of form -011-) - SR? Cua «—(CHR'*)~ «—CH,CH, chosen from (©3- 1) hydroxy « alkyl -(©3- 1) alkyl and (30- 1) alkyl )1 - 3C)- alkoxy ) for example R? is (methyl in the AT form of formula dd 762 chosen from a group having the formula -q0- - § —(CHRP) where RZ? is an alk (1-3C) ( eg methyl ( 1 1 2

VY - - for XP Jia selected from -0117- and -(:11)011© -; Specifically 20" is -(:01)011 —" in another embodiment in the formula dd 72 chosen from hydroxy and (30- 1) alkoxy (particularly hydroxy ). 1 º © in another embodiment in the form for 1; ZX group selected from: hydroxymethyl, methox | methyl, (S)-1-hydroxyethyl, (R)-1 -hydroxyethyl, (S)-1- methoxyethyl, (R)-1 methoxyethy]: specifically the group “22-72” is: 1 -hydroxyethyl, more particularly (S)-1 -hydroxyethyl or (R)-1-hydroxyethyl. Selected from : hydroxymethyl, methoxymethyl, (5)-1 -hydroxyethyl, (R)-1-hydroxyethyl, (S)-1- methoxyethyl, (R)-1-methoxyethyl. Specifically in this model 22 -2029 is: 1-hydroxyethyl 0; specifically le 3 for (S)-1-hydroxyethyl or (R)-1-hydroxyethyl. A specific compound of the present invention; for example (Jad) is The quinazoline derivative of Formula 1 was chosen from: N-(3-chloro-2-fluorophenyl)-7-( {1- [(dimethylamino)acetyl]pipendin-4-yl}oxy)-6- methoxyquinase olin -4-amine; 00 L.L

-VA-

N-(3-chloro-2-fluorophenyl)-6-m ethoxy-7-({1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl } oxy)quinazolin-4-amine;

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1 -(methoxyacetyl)piperidin-4-ylJoxy} which is nazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino] -6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2- °oxoethanol;< /1i>

N-(3-chloro-2-fluorophenyl)-7-{ [1 -(ethoxyacetyl)piperidin-4-yljoxy } -6- methoxyquinazolin-4-a mine;

N-(3-chloro-2-fluorophenyl)-6-methoxy-7 - {[1-(3-methoxypropanoyl)piperidin-4- ylJoxy}quinazolin-4-ami ne; 01 3-[4-({4-[3 —chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl} oxy)piperidin-1-y}]-3- oxopropan-1-ol; (2S)-1-[4-({4-[3 -chloro-2-fluoroanilino]-6-methoxyquin azolin-7-yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2 S,3S)- 1 -[4-({4-[3-chloro-2-fluoroanilino]-6-me thoxyquinazolin-7-yl}oxy)piperidin- \o 1-y1]-3-methyl- 1-oxoperita n-2-ol; & 4-[4-({4- [3-chloro-2-fluoroanilino]-6-metho} Fy quinazotin-7-yl}oxy)piperidin-1-yl]-2- methyl-4-oxobutan-2- 0 1,

-ve-

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[ 1 ~(tetrahydrofuran-2-ylcarbonyl)piperidin- 4-ylloxy }quinazoli n-4; mine; 1 1 0 3-[4-({4-[3-chloro-2-fliroanilino]-6-met hg iyquinazolin-7-yl}oxy)piperidin- 1-71[-2,2- dimethyl-3-oxopr opani ol; : 3 (3R,5S)-1-acetyl-5-{[4-( {4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl } ° oxy)piperidin-1-yl]carbonyl }pyrrolidin-3-ol; and

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-( {1- [(4-methylpiperazin-1- yl)acetyl]piperidin-4-yl}oxy)quinase olin-4-amine; Or a pharmaceutically acceptable salt or an acceptable ester of it. quinazoline is a derivative of “Jha” and there is another specific compound of the present invention; For example 0 for the format [ was chosen from:

N-(3-Chloro-2-fluorophenyl)-6-m ethoxy-7-{[1 -(methoxyacetyl)piperidin-4- ylJoxy}quinazolin-4- amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-2-oxoethanol; \o

N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperid in-4-ylJoxy}-6-methoxyquinazolin-4-amine;

—- .m-(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- yl }oxy)piperidin-1- yl]-1-oxopropan-2 -ol; and 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl} oxy)piperidin-1-yl1}-2,2- dimethyl-3-oxopropan-1- ol; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)pipendin-L-°yl]-3,3-dimethyl-1-0 xobutan-2-ol;

N-(3-chloro-2-fluorophenyl)-6-m ethoxy-7-[1-(1-methyl-L-prolyl)piperidin-4- yl]oxy} quinazolin -4-amine;

N-(3-chloro-2-fluorophényl)-6-metho xy-7-({1-[(2S)-tetrahydrofuran-2- ylcarbonyl]piperidin -4-yl}oxy)quinazolin-4-amine; 01 (2R)-1-[4-({4-[ 3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yl]-1-oxopropan-2-ol;

N-(3-c chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxy propanoyl]piperidin-4- yl }oxy)quinazolin-4-amine; 3

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1- [(2R)-2-methoxypropanoyl]piperidin-4 - \o yl}oxy)quinazolin-4-amine; (2R)-3-[4-({4-[3-chloro- 2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan- 1-ol;

- 1m - (2S)-1- (4-({4-[(3-chlor¢ ET } oxy)piperidin-1- yl]-1-oxopropan-2-ol; |

{4-[3-bromoanilino]-6-methoxyquinazolin-7-yl} oxy)piperid in-1-yl}-1- (-4[ -1-(25) oxopropan-2-ol; (2S)-1-[4-({4-[3-b romo-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin -1- ° yl]-1-oxopropan-2- ol;(2R)-1-[4-({4-[3-bro mo-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1 - yl]-1-oxopropan -2-ol; and (2R)-1-[4-({4-[3-bromoanilino]-6-methoxyq vinazolin-7-yl }oxy)piperidin-1-yl]-1-oxopropan -2-ol;01 or a pharmaceutically acceptable salt or ester thereof. In a particular embodiment of the present invention, a quinazoline derivative of formula “I” described herein is provided; or a pharmaceutically acceptable salt thereof. A quinazoline derivative of Formula J or a pharmaceutically acceptable salt or ester pharmaceutically acceptable Vo thereof shall be prepared using any method known to be applicable to the preparation of chemical compounds. Suitable processes include, for example, those shown In international applications, numbers of 7787 54 A vaio 4 llala 17745 48 YA 1774 4, 4 4, Av 1774 4 and Y Y va ; ;

AY - - 35/7741, 17/7074, 44 57/748, 1/1344 and US Patent No. 7? 0? ; and European patents, OTT 0 OY VYY numbers, and the numbers and numbers of those operations; when used in the preparation of a quinazoline derivative of the formula ]; Loa bg is given as another feature of the present invention and is illustrated by the following illustrative process variables which are such unless otherwise indicated; What's the XP XR? GR Fa and 2 are any of the previously defined meanings. The necessary starting materials can be obtained using nll procedures in organic chemistry. The preparation of these starting materials in combination with the process variables is described for the following illustration and within the accompanying examples. Aly the necessary starting materials may be obtained by 1 procedures corresponding to those shown and which are within the normal skill range of an expert in organic chemistry. Process A: For the preparation of compounds of formula 1 where A “CO Jig” by conjugation; traditionally in the presence of a suitable base; Quinazoline has the formula IT or its salt: mm HN 1 2 N 0 01 HN 11 Vo YY.

AY - - a where 8 and 12 bsas Wy can have any of the meanings ll Boas in this document; Except that any function group al must protect when necessary; with an acid of formula JI 0 a reactive derivative of which: Z-X2-COOH 1 where 7 and 2 can have any of the meanings defined earlier in this document; Except that any job group is protected when necessary; or process B: by carrying out a reaction in a conventional manner in the presence of a suitable base; a quinazoline derivative having formula II or 0 its salt; As defined earlier in this document in relation to the operation off) with a compound of the formula TV Z-X2-X1-L1 7 where .1 is a transposable group of l 7 or any of the meanings defined earlier in this document ; Except that any functional de gana is protected when necessary; Process C: Yo for the preparation of these quinazoline derivatives has the formula | where 7 binds to x? by nitrogen ¢ and the reaction ¢ is carried out conventionally in the presence of a suitable base; for a compound of formula Vv i | YY. i 1

- 2m - HN R! Ww), SN J a +0 N aq Vv where 1 is a shiftable group; and Whereas a £ the bras Xs X's Wy QU shall have any of the meanings previously defined in this cA) except that any functional group is protected when necessary; with a compound of formula dus ZH 27 as then previously defined herein (da ll © except that any functional group is protected where necessary; or process (d): for the preparation of these 00108201106 derivatives bearing mono = alkylamino de sans ( 1-6C) di ¢ Amineralization of a quinazoline derivative of formula T containing an N-H group is done with formaldehyde or (2-6C)alkanolaldehyde (eg, acetaldehyde 0 arn0 to 102m0:m); or process (e): to produce these quinazoline derivatives of formula 1 where RY is hydroxy ; a quinazoline derivative of formula 1 is fission where RY is (1-6C ) alkoxy group ; or

AO - - process (f): to produce these 6-derivatives having dye 1 where 18 is attached to the quinazoline ring of 0© seed; by conjugating a compound of formula V1 HN HO (W), SN / Qt 0 N } 1-N xx ) V1 0 | and where L can have Xs X's WR and 2 Q'sbsas have any of the meanings previously defined herein except that any functional group is protected where necessary; With a compound having the formula R'OH, where the R"O group is one of the oxygen-bonded groups as specified earlier in this document for (Se) R' for example RI" 1 for alkoxy (1-6C) or -07-0)); except that any functional group is protected at yg pall 0 and that thereafter, as necessary (and in whatever order) (convert a quinazoline derivative of formula (J)I into another quinazoline derivative of formula I (9) removal of any protecting group by conventional methods; (c) formation of a pharmaceutically acceptable salt or ester. The specific conditions for the above reactions are as follows: } Y 7 'a Ct v

- M - Reaction conditions for the process (a) The coupling reaction proceeds suitably in the presence of an appropriate coupling agent {8 dis amide or a suitable peptide coupling agent; Such as the coupling agent ferronium# for example: 1 0 1 ‎O-(7-azabenzotriazol-1 H1)-N,NN! rn hexafluoro-phosphate ‎(HATU) or O-(1H-Benzotriazol-1 yD)-N,NN! JN'-tetramethyl uronium tetrafluoroborate ° (TBTU); di 5— 5 amide as dicyclohexylcarbodiimide; Optionally in the presence of a catalyst such as dimethylaminopyridine or .4-pyrrolidinopyridine the coupling reaction is suitably carried out in the presence of an appropriate base. The proper rule is; 0 for example; In an organic amine base such as: pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di- isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0Jundec-7-ene | or for example a metal carbonate alkaline earth metal carbonate or ' for example: sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate yo The reaction is suitably carried out in the presence of a suitable inert solvent or suitable inert diluent; For example, an ester such as ethyl acetate or a Jie halogenated solvent: F

AY - - tetrahydrofuran or Jia ether 0 methylene chloride, chloroform or carbon tetrachloride 1,4-dioxan, or an aromatic solvent such as toluene or Jie N,N-dimethylformamide, N ,N-dimethylacetamide, N-methylpyrrolidin-2-one The reaction is suitably carried out at a temperature of 0°C to 171°C; In particular 1 at or near ambient temperature. “Reactive derivative” of an acid of formula (IID) means a carboxylic acid derivative that reacts with quinazoline of formula II to give the corresponding amide 0. A suitable reactive derivative of (J carboxylic acid) is formula (111) in acyl ha ide; for example J; acyl chloride formed by the reaction of an acid and an organic chloride a § thionyl chloride; and anhydride 0 mixed” or for example; whic Formed by the reaction of acid and abut chloroformate Jie chloroformate; or an active ester 1 ester formed by acid Jeli and a phenol such as pentafluorophenol or N-hydroxybenzotriazole; or acyl azide ¢ For example; azide formed by acid reaction and Jie azide diphenylphosphoryl azide i.e. cyanide Jie acyl cyanide formed by acid reaction and diethylphosphoryl cyanide Jie cyanide 0. The reaction of these reacted derivatives of carboxylic acid is known With amines (such as a compound of the formula (IT) well in this respect” for example”) they can be reacted in the presence of a base such as those described previously; and in suitable solvents (Je) those described previously. temperature was previously described.

AA = - Prepare the starting material for the process (1) (Sa obtain 00108201106 of the formula IT using appropriate procedures, eg as shown in the reaction diagram: 1)® 1 R Or HN R!0 2 0-um 0 Pg—0 N lla (ii) Deprotect HN .R hoe, (Ww), Ho 1 N (Ww), Q L , 01 OH Cay Pg (+) Id (iia) iy Mohr 1 HN R o 2 Deprotect i \ Pg'N Q (iv) Inf ° Reaction scheme 1 Cua a, 82 Q's, and wh wa is as defined in this document before; except that any functional group is protected if necessary; any protection group will be removed using conventional methods; and 78 is a protection group 71 i is a suitable hydroxy group; and 13 is a suitable amino protecting group and 13 is a suitable displacement group.

AY - - Remarks on reaction diagram (1): Step (1): Suitable hydroxy protection groups that are represented by Pg are well known in this field and include those identified earlier in this AEBS For example, a minor alkanoyl group (Jie is an acetyl group; or a benzyl group. E. The 13 displaceable group is appropriate; for example, “Jil” is a halogeno (specifically chloro) and alkylthio, arylthig alkylsulfinyl, arylsulfinyl, alkylsulfonyl, and alkoxy, aryloxy, arylsulfonyl, alkylsulfonyloxy or arylsulfor by group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, mefh ylthio, methanesulfonyl, methanesulfon yloxy or toluene-4-sulfonyloxy 01 The displacement group 13 assigned is chloro . The reaction is suitably carried out in the presence of an acid. Suitable acids eg 0 include hydrogen chloride gas (which It dissolves appropriately in a suitable solvent, Jie (diethyl ether or dioxane or hydrochloric acid 1). Alternatively, a quinazoline derivative of the formula dla can be reacted where 13 is a halogeno (eg For example, chloro with aniline in the presence of an acid or a base. in this interaction; The susceptibility of the leaving group 0p18108_0 to the displacement 3a results in the formation of acid 1113 in situ and autocatalysis of the reaction.

In dln form, a quinazoline of formula lla can be reacted with aniline in the presence of a suitable base. The appropriate rule is; (JB) is an organic amino base; eg: pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0Jundec-7 -ene ° or alkali earth metal carbonate or alkali earth metal carbonate for example sodium carbonate or potassium carbonate or cesium carbonate or calcium carbonate or alkali metal hydride 0 hydride eg sodium hydride sodium hydride » alkali metal fluoride cesium Jie alkali metal fluoride fluoride 00 ¢ or calkali metal disilazide eg; sodium hexamethyldisilazide .The above reactions are suitably carried out in Presence of a suitable inert solvent or diluent, for example an alcohol or esters such as isopropanol ¢ ethanol “methanol” ie “ethyl” acetate or a halogenated solvent tetrachloride “methylene chloride (fie halogenated) or carbon ether as tetrahydrofuran or 1,4-dioxary toluene solvent (fie AE; Or No, a neutral bipolar solvent, such as: | i N,N-dimethylformamide, NN-dimethy acetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide or acetonitrile The reaction is appropriately carried out at a temperature ranging from zero to You m for example» Suitable from Ee to 88°C or preferably at or near 0°C - reflux of solvent on application.

41 - - Aniline and a compound with the formula Ila are commercially available or can be prepared using traditional methods. Step (?): Remove the protection using well known methods. For example (Jaa) when Pg is a 0 benzyl group, it can be removed by treating compound of formula 115 with a suitable acid such as trifluoroacetic acid. Alternatively, it is possible to remove Ala de gene from benzyl The catalytic hydrogenation method using a metal (JE) by hydrogenation in the presence of palladium on a similar hos. carbon catalyst. When Pg is an acetyl Jie sia alkanoyl group, it can be removed by hydrolysis Under basic conditions, for example using “ammonia” and appropriately as a methanolic ammonia solution. Step (a): The appropriate amino protecting groups “Pg; for example” are: -tert- butoxycarbonyl (BOC) LF is a suitable displaceable group; for example as described above for halogeno Jie dP 5 (specifically chloro or bromo); or a group: alkylsulfonyloxy ( specifically (methanesulfonyloxy or arylsulfonyloxy 4c gene (and specifically toluene-4-sulfonyloxy or 4-nitrophenylsulfonyloxy). The reaction of a compound of formula 0 with a compound of formula 82 is suitably carried out in the presence of a base suitable. Appropriate rules include those listed above Led related to step (1);

Potassium carbonate cesium fluoride Jie The_reaction is properly carried out in the presence of a suitable inert solvent; For example; Dipolar neutral solvent Jie : N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide © The above reaction is suitably carried out at a temperature of 0 to 0C For example; suitably from 50 to Av. C. or preferably at or near the reflux temperature of the solvent on application. Step (?b): As an alternative to Step (3a); The compound of formula llc is conjugated to the alcohol of formula Te 0 - using Jeli conjugation Mitsunobu. Suitable Mitsunobu reaction conditions are well known and include for example; on the reaction in the presence of tertiary phosphine and a di-alkylazodicarboxylate in an organic solvent of 0 THF or appropriately in dichloromethane and at a temperature ranging from -0 C to +00 for example Example k is from 0 C to 1 C but is appropriate at or near 3 temperature A 3 1 A suitable tertiary phosphine Vo includes — or more specifically a 0 includes di- alkylazodicarboxylate on diethyl azodicarboxylate (DEAD) or, appropriately, di- tert-butyl azodicarboxylate (DTAD) and the details of the Mitsunobu reactions are shown in reference:

1-ay-Tet.

Letts., 31, 699, (1990); The Mitsunobu Reaction, D.L.Hughes, Organic Reactions, V.42, 335-656 and Progress in the Mitsunobu Reaction, D.L.Hughes, Organic, 1992 Preparations and Procedures International, 1996, V.28, 127-164. Compounds with formula 114 Tes are commercially available or can be prepared using conventional methods. Step oo (¢): removal of a protecting group (Pg; aminod) using well known methods. For example. When it is 08, it is a BOC group by treatment with a suitable acid such as trifluoroacetic or hydrochloric acid. As an alternative method to that shown in the reaction diagram Say) reacted the aniline in step 1 (Ve) with a deprotected variant of the compound having the formula [la (which means that Ja Pg hydrogen ) To directly give the compound of formula Tle, a compound of formula [1] can be prepared according to the reaction scheme ?: (W), Pg! (=) OH 12 12 R! R' XN ile (W ), IN a 7 7 0 01 day HO (i) Ig Ih 2 IC J z 0 H,N Il reaction diagram Y a 'Villa

Where 18, 12, 0, 1177, uh, uh, 13, and 0 are as previously defined; Except for the protection of any functional group if necessary and where any existing protection group has subsequently been removed in a conventional way. Conditions in the interaction diagram? Step (1) This is coupling under Mitsunobu conditions as previously mentioned in step (QV) reaction diagram 1.

Step ?: The reaction is carried out conventionally in the presence of an acid. Suitable acids include; For example; hydrogen chloride gas (suitably dissolved in a suitable solvent such as diethyl ether or dioxane ) or hydrochloric acid. The reaction is suitably carried out in a suitable inert solvent;

LS 0 is given in step 1 of the reaction diagram? appropriately Jb, protection group, Pg!, on site by acidic conditions during #aniline coupling sole; For example when Pg is tert-butoxycarbonyl in the form of “py” the protecting group can be removed using conventional methods following the reaction. Quinazoline of formula Tg is available commercially or can be prepared using conventional methods.

Vo quinazoline derivatives of formula [1] can be prepared according to the reaction scheme oF where RY is the alkoxy (2-60)-heterocyclyl; Cua the heterocyclyl group is nitrogen attached to an alkoxy group (2-6C):

{qo - - ymm mom HN ! , HN HN b qq Sy (ii) 00 : (iv) vs Ww) Ww) ; 5 y TS 2 sq m Q R J 1 OH lio º from what oe 4 0 00 ] TRY, Hq for Oe HN AN HN dha timh N 0 ) HO.

Ce N wn thm" 12-0 p. Lax 0 7 Hao 7 0 lk | ij i The reaction diagram v where for 18, 18, 0, 77, 32, 11, 12, e, and 0 are as previously defined; except for the protection of any a functional group if required al) and where any existing Alen group Las has yet to be removed by conventional methods. Example chloro Jie halogeno The reaction with the compound of formula Tj can be carried out under Cag ka corresponding to that used in process (b) mentioned herein The compound of formula II; can be prepared by conventional methods such as those mentioned In International Application No. 0 0 32/087071 for obtaining a compound of formula Ij bearing compounds 0.3-dihaloanilines, analogous methods can be used to prepare compounds of formula I} by conjugating 4-chloro-6-hydroxy- 7- Methoxyquinazoline with the appropriate aniline

º step?: conditions corresponding to process (b) mentioned in this document step ?: fission of a methoxy group under standard conditions for these reactions; By treating the compound of formula IIm with pyridinium hydrochloride at an elevated temperature; ranging for example from 11 to VAC m; It is more appropriate to inform We M. © Step 10 Conjugation under Mitsunobu conditions as already mentioned in Step (b) of the reaction diagram 1. Step +: Deprotection to remove the Riles amine group Pg! when Pg' is a tert - butoxycarbonyl; By treating the compound of 1 (Ilo) with a suitable trifluoroacetic acid Jie i . acid 0 The reaction conditions for process (b) include a suitable displaceable LY group for example a halogeno such as chloro . The reaction takes place in the presence of an appropriate base appropriately; In the presence of suitable acids for example » as an organic amine base Jie : pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di- isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0Jundec-7- ene Vo for example - an alkali or an alkaline earth metal carbonate such as sodium carbonate or potassium carbonate or cesium carbonate or

qv - - calcium carbonate ¢ or alkali metal hydride sodium hydride i alkali metal hydride or sodium hexamethyldisilazide Ji alkali metal disilazide . The reaction is suitably carried out in the presence of a suitable inert solvent or suitable diluent; as a halogenated solvent such as: methylene chloride, chloroform or carbon tetrachloride © in tetrahydrofuran Jie ether or 1,4-dioxane and an aromatic solvent toluene Jie aromatic; or a dipolar non-proton donor solvent: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide 0 The reaction is appropriately conducted at a temperature of 0 to op To and at an appropriate ambient temperature. when Z is hydroxy ; The hydroxy group is suitably protected during the reaction with the compound of formula 1. Suitable protecting groups are known; For example, Jel is the acetyl Jie alkanoyl group. The protecting group can be removed following reaction with a compound of formula IT 1 by conventional methods; Such as alkali hydrolysis in the presence of a suitable base, sodium hydroxide Jie. Compounds of Formula 17 are commercially available, known in the art, or can be prepared by standard processes known in the art. ! Y Y ve |

-0 W8 - Reaction conditions for process (z) The suitable displaceable group represented by 12 includes eg halogeno, chloro Jie ¢ sulfonyloxy group, bromo, sulfonyloxy methyl group, or toluene-4-sulfonyloxy . chloro is a specific group 1. } 0 reaction is performed appropriately if there is 1 event; As one of the rules mentioned in the context of process (b): 0 : : 1 the reaction is suitably carried out in the presence of a suitable inert solvent or suitable diluent; As a halogenated solvent such as: methylene chloride, chloroform or carbon tetrachloride » and ether such as: ethyl acetate Jia esters ¢ tetrahydrofuran or 1,4-dioxane 01 ¢ and an aromatic solvent toluene Jie or a non-dipolar non-proton donor solvent such as : N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. ambient temperature appropriately.

Preparation of process starting materials (c) The compound of formula V used as “aaah” for example may be prepared by reacting suitably in the presence of a suitable base and a quinazoline of formula dl or a salt thereof; as above determined in the off process) with a compound of formula Va L2-X2-X1-L5 Va °

where XD and 72 are as previously defined and 12 and 1 are suitable shiftable groups; Provided that '1 is more metamorphic than 2'. Where appropriate displaceable groups represented by both 12 and 15 include ; for example » halogeno as chloro .

The reaction is carried out in the presence of an appropriate base and an inert solvent or diluent: appropriately; As previously specified; For the reaction of quinazoline of formula V with a compound of D compounds of formulas ZH and 78 are commercially available, known in the art, or can be prepared by standard processes known in the art. appropriately In process model (C); Quinazoline of the formula [

0 of quinazoline of formula IT by reacting quinazoline of formula [1] with a compound of formula “Va” and then reacting the product directly with a compound of formula ZH without separating the compound of formula 7. This allows The reaction is by preparing quinazoline having the formula [ in one reaction vessel starting with quinazoline having II pall :

‎; YY

11.1. - - Reaction conditions for process (D) (I) has the formula quinazoline in an NH derivative to an alkyl group using process (D) to introduce (Say amino 2-62 or when carrying the group ¢ alkylamine ( 1-6C) or amino is Z when amine reductive treatment conditions are considered appropriate. The alkylamine (1-6C) or said substituent group having quinazoline is known in the art. For example, to produce 0 derivatives, the corresponding compound containing methyl << formula 1 containing __ group may react with 10021061706 ... in the presence of a suitable reducing agent. The reducing agent is N-H group formic acid, an suitable alkali metal Jie hydride”; for example, in an alkali reducing agent or alkali metal borohydride 6 lithium aluminum hydride such as aluminum hydride sodium s,s cyano and sodium borohydride Jie suitably; metal borohydride 1, sodium hydride, boro methyl, sodium hydrides, Ji, and tri hydride. tetrahydrofuran Jie The reaction is suitably carried out in a suitable solvent or diluent; 1 methylene s lithium aluminum hydride stronger reducing such as Jal gal diethyl ethers

Jie Weaker reduction Jal gal ethanol 5 methanol Jie or a proton donor solvent chloride The reaction proceeds as sodium triacetoxyborohydride and sodium cyanoborohydride “acetic acid 51 hydrogen chloride Jie is suitable under acidic conditions in the presence of a suitable base

111 - - A buffer solution can be used to maintain the pH at the desired level during the reaction. when the reducing agent is acid 200018 ; The reaction is appropriately carried out using an aqueous solution of formic acid. The reaction is carried out, at a temperature ranging from; For example, Jal from -01 to -001 pm; range from zero | 0 m appropriately; or at or close to 0 ambient temperature. A 1

Quinazoline derivatives having formula 1 containing a group (le) NH for example » Laie 7 is an amino or (1-6C) can be prepared using (saa) the mentioned methods Lad was previously mentioned in this document. For example; By conjugating a compound of formula [1] with an amino acid

Optionally protected suitable using operation (a) followed by removing any Ales collection

0 Reaction conditions for the process (e) The fission reaction can be suitably carried out by any known procedure for this transformation. A particularly suitable fission reaction is the treatment of a quinazoline derivative of formula “I where R! is the alkoxy (1-6C) Ae sane of the alkali metal halide lithium iodide Jie alkali metal halide ; In an inventory of .2,4,6-collidine (2,4,6-trimethylpyridine) it was discovered that the use of 2,4,6-collidine 1 provides Gili cleavage of a de alkoxy group (1-6C C6 position on the quinazoline ring. The reaction may be carried out in the presence of a suitable inert solvent or a suitable dilute ole as previously specified herein. appropriately The reaction can be carried out with only -2,4,6 collidine without the need for additional solvents/diluents. The reaction is carried out appropriately

01011 - - at a temperature of; For example; From 01 to VV. C and it is preferable to perform it at high temperatures ranging from, for example; 101 to ea 171 is approximately the same as 101 m. Reaction conditions for the process (f) The reaction is appropriately conducted under Mitsunobu conditions as already mentioned in the context of step 0 (“b) in reaction diagram 1. Preparation of process starting materials (f) The compound of which Formula VI used as a starting material; For example; fission of a quinazoline derivative of formula I where (eg Jia R' is methoxy) using the aforementioned process (a). Alternatively, the compound of formula VI can be prepared 0 using conventional procedures, for example (Ji when XD represents ShyCO) Prepare the compound of formula VI using the method shown in the reaction diagram Prt ye Fe) »Filled "0 Ho XN HO 1 I "jur mm jo sn- OL) calculate how much INQ lj Vib Vie Ww (if) Po (iv) OH GL HN HO SN (v) Deprotect w) 2 1 m ( ) ohm 00--- 00060068 ye (vi) 22-000 Vid Interaction diagram (¢) ( ) for

- 1 —

where R, 182, 01 Xs Ws, E, E, and P2 are as previously specified; Except for the protection of the Ay group

functional if necessary; And where any existing protection group was removed later in a traditional way.

Reaction diagram conditions ¢

Step: (1) fission of the methoxy group under conditions corresponding to those mentioned in step (3) in

) interaction diagram?.

Step (Y): ic gana Pg is a suitable hydroxy protection as previously determined, for example

alkanoyl is like acetyl . Group Pg can be introduced under standard conditions; with a compound reaction

.806116 anhydride with formula VIb

Step 7: Coupling under Mitsunobu conditions as already mentioned in the context of step (b) in Diagram 0 - Reaction 1.

Step (4): Deprotection to remove the protecting group Pg for example “Jha when Pg represents acetyl

by alkaline hydrolysis into alcohol; Using a solution of methanolic ammonia, for example.

Step (©): WY is the place of go protection group mY p when Pg' represents -tert

Jie with a suitable acid (VIA) for example by treating the compound having the formula butoxycarbonyl . trifluoroacetic acid 00

- 1016 -

Step (1): Conjugation with acid Z-XP-COOH using the aforementioned method for process (a).

(Sa) obtaining a quinazoline derivative of formula (1) from the previous operations in the form of a base

free Alternatively, it may be obtained in the form of a salt or an acidic addition salt. at will

In obtaining the free base from the salt of the compound of formula (I), the salt can be treated with a suitable base Jie alkali or sodium carbonate Jie “alkaline earth metal carbonate” or

potassium, sodium hydroxide, calcium carbonate, or potassium carbonate

hydroxide” or by treatment with ammonia using a solution of M methanolic A, for example

,. methanol in (¢V) ammonia Jie eg

The protective groups used in the foregoing Ella may generally be selected from any group .1 mentioned in the art or known to the skilled chemist as being suitable for the protection of the said te pls; And can

introduced in the traditional way. Protection groups can be removed by any method ni as mentioned in

field or known to a skilled chemist to be suitable for removing said protection group; is chosen

These methods are such that the protecting group is removed with the least perturbation of the groups in the molecule.

Here are specific examples of protection groups for illustration; where 'small', as in 1 small alkyl group, indicates that the group to which this expression applies contains 1 to ;

Preferably carbon atoms. It should be noted that there are other examples besides those mentioned. is done as follows

Show specific examples of ways to remove protection suites; Nor are they the only examples of them.

The use of protection suites and removal methods not specifically mentioned falls under

field of invention.

101 - : - the carboxy protecting group may be the residue of an aliphatic alcohol aryl aliphatic constituent of the ester » or rssh silanol of the ester (preferably the said alcohol or 1001 contains 1 to 0 carbon atom). Examples include carboxy protecting groups of straight or branched-chain (1-2C) alkyl groups (isopropyl, and tert-butyl Jie) and small 0-alkyl small alkoxy groups (eg methoxymethyl “, ¢ (isobutoxymethyl 5 methyl ethoxy and acetoxymethyl, propionyloxymethyl, Ji) ' lower acyloxy-lower alkyl (butyryloxymethyl and pivaloyloxymethyl | ; lower alkoxycarbonyloxy-lower groups

alkyl (eg ¢ (1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl z and Je) aryl-lower alkyl groups eg benzyl, 4-methoxybenzyl, 2-nitrobenzyl, ¢ (4-nitrobenzyl, benzhydryl and phthalidyl 0 and tri(lower alkyl)silyl groups (eg ¢ (trimethylsilyl and tert-butyldimethylsilyl) tri(lower alkyl)silyl-lower alkyl groups (eg ¢ (trimethylsilylethyl) and (2-6C)alkenyl (eg (allyl) methods specifically suitable for removing carboxyl protecting | groups include “ on

example; Fission catalyzed by an acid, base, metal, or enzyme. 1 Examples of hydroxy protecting groups include lower moiety groups (such as tert-butyl), small alkenyl groups (such as allyl), small alkanoyl groups (such as acetyl), and alkoxycarbonyl groups small tert-butoxycarbonyl (Sis)) and allyloxycarbonyl Jia groups (5 ya alkenyloxycarbonyl) and aryl-lower alkoxycarbonyl groups (such as 2-benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, (nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl | 0 ; and tri(lower alkyl)silyl groups

- 11,1 - and benzyl (as aryl-lower alkyl 5 (trimethylsilyl and tert-butyldimethylsilyl) (as substituted with benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and di-4-anisylmethyl and furylmethyl and (triphenylmethyl : Jia) lower alkenyloxycarbonyl ( tert-butoxycarbonyl Jia) lower alkoxycarbonyl ° : Ju) aryl-lower alkoxycarbonyl groups ( allyloxycarbonyl benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl and 4- ¢ (nitrobenzyloxycarbonyl trimethylsilyl Jia) trialkylsilyl ? and pivaloyloxymethyl Jia) lower alkanoyloxyalkyl benzylidene 5 (methylidene eg Je) alkylidene y ¢ (and tert-butyldimethylsilyl 0) are substituted. And groups that include, for example, the decomposition of amino s hydroxy, suitable methods for the removal of protecting groups “2-nitrobenzyloxycarbonyl Jie aqueous catalyst with an acid, base, metal or enzyme for groups: and the decomposition of groups such as benzyl Jia Sle gana hydrogenation: 1H2-01005©02710«708700. For example; A protecting group can be removed: by acid-catalyzed hydrolysis using an amino of the tert-butoxycarbonyl group. trifluoroacetic acid

111 - - The reader should refer to <Advanced Organic Chemistry, 4th Edition by J.

March 1992 published by John Wiley & Sons for a general guide to reaction conditions and reagents” and to Protective Groups in Organic Synthesis, 2nd Edition by <T.

Green et al. published by John Wiley & Son as a general guide to protection groups. It should be noted that several cyclic substituent groups can be introduced into the compounds of the present invention with standard aromatic substitution reactions; or produced with conventional modifications to the functional group either before or immediately after the aforementioned operations; This is included in the dle side of the invention. These interactions and modifications include; For example (JE) introduction of a substituent group by an aromatic substitution reaction, reduction of substituents, alkylation of substitution groups, and oxidation of substitution groups. The 0 reagents and reaction conditions for these procedures are known in the chemical field. Specific examples of aromatic substitution reactions include the introduction of a nitro group using Concentrated nitric acid and the introduction of an acyl group using acyl halide and Lewis acid 'for example (such as aluminum trichloride under Friedel Crafts conditions) the introduction of a 4-alkyl group using alkyl halide and 2610 Lewis (eg aluminum trichloride under 0 Friedel and insert ¥ halogeno 4c gana 1). When a pharmaceutically acceptable salt of a quinazoline derivative of formula “I” is desired as an acidic addition salt, it ( Say obtained by reacting said quinazoline derivative, for example, with a suitable acid by an appropriate procedure.

#11 - - Laie is desired to obtain a pharmaceutically acceptable ester of a quinazoline derivative of formula 1 as an acidic addition salt; It can be obtained Jelly derivative Saal quinazoline as JBN with an appropriate acid by an appropriate procedure as stated in the context of defining pharmaceutically acceptable esters.

0 as stated in this document; Some Gy compounds of the present invention may contain one of several chiral centers; Thus it may exist as stereoisomers (when '0 is piperidin-3-yl ). The stereoisomers can be separated by conventional methods; such as chromatographic separation or partial crystallization. The enantiomers can be isolated by separating the racemes by partial crystallization; For example; or decomposition or ©1101. Dimers can be isolated by separation based on the different physical properties of E

0 as partial crystallization, HPLC, or flash chromatography. alternatively Certain stereoisomers can be obtained by chiral synthesis from chiral starting materials under conditions that do not cause racemic Lala formation or sugar conformation; or by derivation with a chiral detector. When isolating a specific stereoisomer; it is fitting to isolate it suitably free from other holograms; As if it contains less than 271 and less than 701 specifically; and less than 75 by weight more specifically

1 of the other stereoisomers. In the preceding section relating to the preparation of quinazoline (Fide) having the formula ld "inert" denotes a solvent that does not react with starting materials, reagents, intermediates or products in such a way as to adversely affect the amount of product required. YY.

101.84 - - Those skilled in this field are aware that in some cases, to obtain the compounds of the invention by an alternative or more appropriate method; The individual steps of the aforementioned process may be performed in a different order and/or the individual reactions may be performed at different stages in the overall method (ie the chemical reactions may be carried out on different intermediates than those related to a particular reaction above). © Certain intermediates used in the processes are novel and thus constitute another feature of the present invention. According to one aspect of the present invention; A quinazoline derivative of which is given the formula; As previously defined “a dua stands for 7 and each BR? is the same or different; stands for halogeno (more specifically a variant of fluoro or chloro ); and where the R? groups are located in the ortho (2-) and meta (3) positions on the “aniline ring” or a salt thereof. A compound of formula I is considered a specific compound for compounds that have The formula (Il where the anilino group is:

aay les 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino The specification The anilino group is 3-chloro-2-fluoroanilino . in an embodiment of the compound of formula [1]; or salt thereof; !8 represents alkoxy (1 -4C); It represents zero or 1; and 17, when present, represents a ring carbon atom in “Q!” and is selected from:

alkoxy (1 -4C)s hydroxys alkyl (1 -4C) 01 (preferably W being a zero); Q'y stands for piperidin-4-yl ; The anilino group is: 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Specifically, a degraded group is represented in 3-chloro-2-fluoroanilino. The intermediate compound of formula 11 may take the form of the salt of the intermediate compound. These salts should not be pharmaceutically acceptable. For example, Jad might be

101 - - It is useful to prepare an intermediate compound in the form of a pharmaceutically unacceptable salt, where these salts are Bada - for example - in the manufacture of a compound of formula 1. It is preferable that the salts of the compound of formula [1] be pharmaceutically acceptable; As defined above from Cus a quinazoline derivative of Formula 1. oo Biological tests

The inhibitory activities of compounds in assays for non-cell-dependent protein tyrosine kinases as performed in cell-dependent proliferation assays were evaluated prior to evaluation of in vivo activity in exograft studies. Examinations of inserting a phosphate group into protein tyrosine kinases

Ye This assay measures the ability of a test compound to inhibit the insertion of a phosphate group on an enzyme-dependent polypeptide-containing tyrosine by the tyrosine kinases EGFR, erbB2, or erbB4. The erbB4 5 erbB2 ys EGFR fragments were transcribed into Recombinant cell (accession numbers 7400588 5 X03363 and 1.07868, respectively) and genotyped in a viral system

Yo Membership/601. Cytolysis yields were prepared from these cells by treating them with ice-cooled lysis solution (0 mM hydroxyethylpiperizine-N'-2-ethanesulfonic acid (HEPES) at a pH of 7.5 1500 mM From 701 (NaCl) from ZY « glycerol from V,0 (Triton X-100 mM) from 1 MgCl mM from:

7,0

11010 - - ethylene glycol-bis(B-aminoethyl ether) N'N' N',N'-tetraacetic acid (EGTA) plus protease inhibitors; Then purified by centrifugation. The formational kinase activity of these proteins resulting from genetic recombination was determined by their ability to insert a phosphate group on the synthetic peptide (made of: co-polymer of Glutamic Acid, Alanine and Tyrosine ° in proportions of 7: ?: 0. (1 on Towards specification, immunoblotting plates consisting of Maxisorb™ AT eye synthetic peptide (17 μg of peptide) were covered in 100 μl of phosphate-buffered saline (PBS) and placed in Incubation at 4 C. all night). or 2 by incubation in peptide-coated dishes for 100 minutes at room temperature in 100 mM HEPES at pH 0.4 at room temperature; and trisphosphate (ATP) at a concentration (Km) of the corresponding enzyme; 10 mM of MnCl, 11 mM of 14:70, and 71 mM of di-DL-thio-erythritol ¢ ( DTT) 5 70.1 of Triton X-100 01 with test compound in DMSO (final concentration 727.5). The reaction was terminated by removing the test liquid components and then Jue the plates with PBS-T (phosphate-buffered saline with 70.8 Tween 01). The immobile phospho-peptide product of the reaction was detected by immunoblotting. These plates were incubated for 0 min at room temperature with antibody primary antibodies

- 1101 -

Phosphotyrosine generated in mice (4G10) from Biotechnology 51816 ml). after washing

(Jalil) Plates were treated with a goat anti-mouse secondary antibody conjugated with

Spicy watercress peroxidase (NXA931) (HRP) from sad (Amersham) +1 min at

room temperature. after more washing; HRP activity was measured in each eye of the dish

](6) ethylbenzthiazolinesulfonate =F] - dim ss JT by colorimetric scale using salt crystals 0

di ammonium MABTS™ (Roche) as enzyme subject.

The color evolution and enzymatic activity were thus calculated by measuring the absorbance at £00 nm at

Molecular Devices ThermoMax microplate reader expressing kinase inhibition

For a specific compound as the value of ICs, this was determined by calculating the concentration of the compound required to obtain 01 inhibition by Jo. To introduce a phosphate group in this test 0 and then calculate the extent of introducing a group

Phosphate from the positive comparative values (the transporter plus ATP) and the negative (the transporter minus it).

(ATP

(b) EGFR-derived KB cell dendritic assay

This assay measures the ability of a test compound to inhibit AS in KB cells (naso-pha-rangeal eo carcinoma) obtained from American Type Culture Collection

.((ATCC)

SKB cells were incubated in Dulbecco's modified Eagle's medium (DMEM) containing

0 Fetal Calf Serum, 7 mM of “Glutamine” and “Non-Essential Amino Acids”.

In an aerobic incubation unit containing CO, at a ratio of 797.5. Cells were harvested from storage flasks

1101” - - using Trypsin/ethylaminediaminetetraacetic acid (EDTA). Cell density was measured using a hematocyte counter; and calculation of viability using pre-cultured trypan blue solution at a density of 01 #1.75" cells per eye from a plate of 976 eyes in DMSO containing 58 serum taken from a plant pad; and 1 mL JY go. of glutamine and 0 non-essential amino acids at VY m at 77.5 pH of 00.2 and allowed to settle for 2 hours after adhesion to the plate, cells were treated with or without EGF (final concentration 8 unit/ ml); and with or without using compound in a range of concentrations in dimethylsulfoxide (DMSO) (final ratio (70) before incubating for 0 days after the incubation period; the number of cells was determined by adding 50 μL of: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 01 (storage rate o mg/mL) for 2 h. Then MTT solution was replenished and dried. Gently plate to dry and lyse cells by adding 100 μl of DMSO. Absorption rate of lysed cells was read at 46© nm using a Devices ThermoMax 201600127 microplate reader. Kinase inactivation of a given compound was expressed as a mO value of 10. 1 “This was determined by calculating the concentration of the compound required to obtain a Jon ratio inhibition of reproduction. The extent of reproduction was calculated from the positive (transporter plus ATP) and negative (transporter minus ATP ml) values.

105 - - (2) Phospho-012cell assay© copy;? The final immunofluorescence assay measures the ability of the test compound to inhibit the introgression of a 2-phosphate deaminase into the cell line derived from 1077 (cancer breast tumor) obtained by transfection with 14077 cells with the full-length erbB2 gene using standard methods to obtain a cell lineage oe that genetically overexpressed the full-length wild-type erbB2 protein (hereinafter referred to as UE-copy cells) YE-copy cells were transduced incubated in Growth's Medium (Dulbecco's Modified Eagle's Medium) free of phenol red (DMEM) containing Fetal Calf Serum 701 and 7 mM of β-glutamine and V,Y mg/mL of G418 in an aerobic incubation unit containing CO, at 0 rar at STV cells were harvested from 775 storage flasks by washing them once in PBS (phosphate-buffered saline); hydrogen number of 8” V, Gibco No. 10010-015) and harvested with ¥ mL of trypsinic acid (0.7 6 mg/mL)/ethylaminediaminetetraacetic +A) acid (EDTA) solution. mg/mL. Cells were resuspended in Growth medium. Cell density was measured using a hematocyte counter; Calculate the shall potential using trypan blue 1 solution before again in Growth's medium and culture them at a density of 1 7 01 * cells per eye of the dish (in 00 μL) in dishes composed of AT transparent eye Bottom (Packard No. 6005182). After three days; Growth's medium was removed from the cells and replaced with 100 μL of Assay medium (free from phenol red (DMEM) containing ¥ de M of glutamine; 71 mg/mL of 6418) with or without the use of a LerbB inhibitor compound (sale) vy. dishes were transferred to the incubation unit for ; hours; Then add 01 μl of formaldehyde solution YY.

- Haa - by 7710 in PBS to each eye and leave the plate at room temperature for 1 min. The fixation solution was removed with a multichannel pipette; add 100 µL of PBS to each eye and remove it with a multichannel pipette; Then add 100 µL of PBS to each eye. The dishes were sealed and stored beyond 2 weeks at 4 C. 0 Immunostaining was performed at room temperature. Plates were washed once with Yoo μL of 035/Tween 01 (made by adding 1 sachet of Zorour 785/Tween Gila ¢Sigma) No. (P3563) to IL of 11:0 double distilled) using a dishwashing unit; Then add 0010 μl of blocking solution (75% skimmed milk powder dried by Marvel (Nestle) at 755/Tween 10); and incubate for 10 minutes. The 0 blocking solution was removed using a dishwashing unit and 70.5 μl of X-100 1:660/sec Yo, then 1 000 1 μl of the blocking solution was added again and incubated for 11 minutes. After removing the blocking solution using a dishwashing unit; Yo was added μL of rabbit polyclonal anti-phospho-ErbB2 IgG antibody (phospho-adhesive peak ¢SantaCruz «Tyr 1248 No. 50-12352-8]); Dilute You:1 in blocking solution to each eye and incubate for 2 hours. Said primary antibody solution was then removed from the eyes using a dishwashing unit; Then perform due operations with 706 µL of 785/Tween 01 using a dishwashing unit. μL of secondary anti-rabbit IgG secondary antibody from goat Alexa-Fluor 488 (Molecular Probes; no. 8-11008) was then added; and diluted at a ratio of 1:7560 in blocking solution to each eye. Starting from this step © Lad after if possible » The plates were protected from exposure at this point by being sealed with black backing tape. The plates were incubated for £0 min; Then remove the body lotion

YY. .

1101 - - secondary antagonist from eyes; Then perform two Jue operations with Yoo μL of 035/Tween 01 using a dishwashing unit. 100 μl of PBS was added to each plate; It was incubated for 10 minutes and then removed using a dishwasher. 100 μl of PBS was then added to each plate; without placing it in incubation for a long time; Remove it using the dishwashing unit ©. 50 µL of PBS was then added to each eye; The dishes were re-sealed tightly with black support tape and stored for 2 days at C before analysis. The blinking signal in each eye was measured using the Acumen Bioscience instrument (Acumen Explorer) [], which is a plate reader that can be used to quickly measure the features of X-ray images. The instrument was set to measure the number of scaling elements above a preset cut-off value of 0 and this provided a measure of the state of the phosphate group insertion of the 082© protein. JB flicker dose response data obtained from each compound were transferred to an appropriate software package (such as Origin) to perform curve fit analysis. Inhibition of erbB2-related phosphate group insertion was expressed as a value of 10. This was determined by calculating the concentration Compound required to obtain 756% inhibition of the phosphate group insertion signal related to 0132.ae d) In vivo xenograft test This assay measures the ability of a test compound to inhibit the growth of a LoVo tumor (adenomatous carcinoma of the colon rectum). (ATCC) in female Swiss mice without a thymus (Alderley Park) of the genotype (nulnu) Female Swiss mice without a thymus (of the genotype (nulnu) were bred 0 and kept at Alderley Park in Negative Pressure Insulators (PFI Systems Ltd.) Housed

- 19 -

The rats are kept in a barrier for the duration of the cycle of light cada fe and provided with sterile food and water according to their desire. Then execute

All procedures were performed on mice aged at least 2 weeks old. Taste types were created

Exogenous LoVo Tumor Cell (Adenocarcinoma of Os rectum then obtained from

(ATCC) into the hind flank of dala rats by subcutaneous injections of Ve XY of 0 cells freshly cultured in 100 μL of serum-free medium per

animal. on the fifth day of transplantation; Phthrans were randomly assigned into seven groups before being treated

with a compound or a vector and then administered once daily at a rate of 1,101 [Ja] gm of body weight. Then evaluate

Twice weekly tumor volume was measured by a two-sided Vernier thickness gauge using

The equation is (length x width) x length(1a x width) * (TH) where length is the longest diameter 0 through the tumor; The width represents the corresponding orthogonal line. Growth inhibition was calculated by the study bank

By comparing mean changes in tumor size between control and treated groups; and evaluation

The statistically significant difference between the two groups using the Student's t-test

Although the pharmacological properties of the formula 1 compounds vary according to the structural formula; As is

expected The efficacy of compounds of Formula 1 can be shown at the following concentrations or doses in one or more tests vo of the above (a), (b), and (c) and:

Test A: ICs - in the range of 1 = 0.000 micromolar for example;

Test B: 0 and 1 - in the range of 1,000 - 0 micromolar for example;

Test C: ICs in the range of 0.09 - 1 μM for example;

(J) test: activity in the range of 100 - 100 mg/kg/day for example;

Money

#1108 - - No Pharmacologically Unacceptable Toxicity was observed in Test (D) at the effective dose of the compounds of the present invention then tested. Accordingly; Serious toxic effects are not expected when a compound of the formula or a pharmaceutically acceptable salt thereof as previously defined is administered; within the dosage ranges specified below. For example; Using Test A (for inhibition of phosphorylation of protein kinase M0 tyrosine (EGFR) and Test B (the aforementioned KB cell assay), the representative compounds mentioned in the examples herein yield results of 10:0 shown in the table (a) Next: Example Compound | 16 (nanomolar) Test 0) (Inhibition | ICs (nanomolar) Test (b) (Introduction Test of a tyrosine kinase assembly of a KB cell derived from EGFR (protein phosphorylation ee. a 1) In accordance with the AT side of the invention; a pharmaceutical composition comprising a quinazoline derivative of formula I or a pharmaceutically acceptable salt or an ester thereof 0 is provided as Previously defined in terms of a pharmaceutically acceptable carrier or diluent

The compositions of the invention may take a form suitable for oral administration (as tablets or lozenges

hard or softgel capsules, oily or aqueous suspensions, emulsions, powders or granules

for dispersion, syrup or elixirs); or for topical administration (such as creams, ointments, gels, or

aqueous or oily solutions or suspensions); or for administration by inhalation (as a finely divided powder or 0 liquid aerosol); Or for administration by blowing (as a finely divided powder) or for administration by a third party route

Enteric (as a sterile aqueous or oily solution for intravenous, subcutaneous, or intravenous dose administration).

intramuscularly or as a suppository to administer the dose into the rectum).

The compositions of the invention can be obtained by conventional procedures using pharmaceutically acceptable excipients

known in this field. Thus formulations designed for oral administration may contain; 0 for example; One or more coloring, sweetening, flavoring and/or preservatives.

The amount of active ingredient that is combined with one or more excipients to obtain a form varies

A single dose is necessarily based on the host being treated and the particular route of administration. for example

“JE The oral formulation given to humans generally contains between 1.6 mg

to 16 g of active agent (appropriately 15 to 100 mg; OS 1 1 to 10 mg) compounded with an appropriate amount of excipients varying from about 79 to

Approx. 798 by weight of the total formula.

The dosage size of the quinazoline derivative for therapeutic or prophylactic purposes of Formula 1 varies considerably

normal according to the nature and unity of cases; the age and sex of the animal or patient and the method of administration; According

known principles of medicine.

Lal

171 - - when a quinazoline derivative of Formula 1 is used for therapeutic or prophylactic purposes; It is generally given with a daily dose ranging from eg 70.1 mg/kg to 7975 mg/kg body weight; It can be given in divided doses if needed. in general; Low doses are given when a non-enteric route of administration is followed. like this for example; Done

0 Generally if given by intravenous infusion; The dose ranges from 1091 mg/kg to 1000 mg/kg of body weight. likewise; if given by inhalation; Dosage ranges from 0.06 mg/kg to TO mg/kg body weight for example. Oral administration is preferred; Especially in the form of tablets. Typical unit dosage forms contain from 1.5 mg to 8 g of the compound of the invention.

0 It has been found that the compounds of the present invention have anti-HEAD properties as anti-cancer properties that are believed to arise from their inhibitory activity of the receptor tyrosine kinases of the erbB family, specifically the inhibition of the enzyme tyrosine kinases of the receptor “dX ( erbBl) EGF Certain compounds according to the present invention have activity against EGF receptor tyrosine kinases greater to aa large compared to other tyrosine kinases; Such as erbB2, VEGF, or .KDR

vo compounds with sufficient effectiveness against the enzyme tyrosine kinases of the receptor “EGF”, and then they can be used in sufficient quantity to inhibit the enzyme tyrosine kinases of the receptor “EGF while showing little activity” or less effective against the enzyme tyrosine kinases. receptor (EGF) and may be useful for the effective treatment of tumors derived from, for example, EGF. Ga Therefore, the compounds of the present invention are believed to be useful in the treatment of diseases or medical conditions to which they contribute.

tyrosine kinases Y. of the receptor erbB (especially the enzyme tyrosine kinase of the receptor (EGF) i.e. can

1171 - - Using compounds to induce inhibitory activity of the enzyme tyrosine kinase of the receptor © in warm-blooded organisms in need of this treatment. Thus the compounds of the present invention provide a method for treating malignant cells characterized by inhibition of one or more ALLY tyrosine kinases erbB2 receptors. Specifically, the compounds of the invention can be used to produce an antiproliferative, apoptotic, and/or antiviral effect Invasion is contributed wholly or partly by 18 tyrosine inhibition of the 032© receptor. specially; The compounds of the present invention are believed to be useful in the prevention or treatment of such tumors that are affected by inhibition of one or more of the tyrosine kinases of the EGF Jie receptor cerbB2, erbB2 and/or erbB4 (in particular EGF receptor tyrosine kinases are involved in the signal transduction steps that cause the proliferation and survival of these tumor cells. According to lI the compounds of the present invention are believed to be useful in the treatment of psoriasis and/or benign prostatic hyperplasia (BPH) BPH) and/or atherosclerosis and/or cancer by providing an antiproliferative effect; specifically in the treatment of cancerous tumors affected by the LerbB2 receptor tyrosine kinase enzyme These tumors, benign or malignant, may affect any tissue; including non-plastic tumors Jie leukemia, multiple myeloma or lymphoma; as well as solid tumors Jie 1 carcinomas of the bile duct, bone, bladder, brain/0175, breast, colon rectum, endometriosis, stomach, head and neck tumors, liver, lung (specifically non-small cell carcinoma), neuron And the esophagus, ovaries, pancreas, prostate, kidney, skin, testis, thyroid, uterine drum, and vulva. According to this aspect of the invention; A quinazoline derivative of Formula I or a pharmaceutically acceptable salt thereof, Y. or 4a ester (UY ana), is provided for use as a drug. YY.

- 177 -

Gy for another aspect of the invention; A quinazoline derivative of the formula © or an acceptable salt thereof is provided

A pharmaceutically acceptable ase or ester for use in producing an antiproliferative effect in an organism

Warm-blooded like humans.

sho or a salt thereof oI having the formula quinazoline for another aspect of the invention; A pharmaceutically acceptable iy derivative is provided as previously specified; In the manufacture of a drug for use in the production of a pharmaceutical grade 4a ester or 0

Anti-proliferative effect on an all-blooded organism such as humans.

According to another aspect of the invention; A method for producing an antiproliferative effect in a subject is provided

blood (lal) as a human being; in dala to this treatment; Contains a therapeutically effective amount of Gide

quinazoline of formula “I or a pharmaceutically acceptable salt thereof or ester thereof as 0 as previously specified; to the said object.

FP for another aspect of the invention; The use of a quinazoline derivative of Formula I or a salt thereof is provided

pharmaceutically acceptable or ester 40 pharmaceutically acceptable; As previously specified; in the manufacture of a drug for use in

Prevention or treatment of these affected tumors by inhibiting Jie cerbB2 ified tyrosine kinases.

erbB2 l/s EGFR tyrosine kinases and/or 4 (specifically EGFR) involved in

ve steps of signal transduction that lead to tumor cell proliferation.

According to another aspect of this clad of the invention; A method for preventing or treating these is provided

tumors in the warm-blooded organism to which the invention deals; As a human being affected by one or more inhibitions

of tyrosine kinases of the erbB2 receptor family s/s EGFR tyrosine kinases Jie cerbB2 and/or

le) erbB4 specifically (EGFR) involved in the translocation steps of the signal that leads to

- 1170 -

to proliferation and/or survival of the WA tumor. It involves administering an effective amount of a quinazoline derivative of the formulation

3 Or a salt of it is acceptable as a fish for a long time, or an ester of it is acceptable as a fish for news, as previously specified.

i for another feature of this aspect of the invention; Provide a compound of Formula 1 or an acceptable salt thereof

Pharmaceutical or ester of it is pharmaceutically acceptable for use in the prevention or treatment of these tumors in organism 0 of LAL blood, such as humans affected by the inhibition of tyrosine kinases of the cerbB2 receptor such as tyrosine

EGFR kinases and/or erbB2 and/or erbB4 (specifically EGFR) involved in steps

Accidental transduction of a signal that leads to tumor cell proliferation.

Ga for another aspect of the invention; The use of a quinazoline derivative of formula “J” or a salt thereof is provided

Pharmaceutically acceptable or ester of it Pharmaceutical acceptable as coda’ previously coda’ in manufacturing a drug for use in 0 providing an inhibitory effect of EGFR kinases amily and/or erbB2 and/or le) erbB4 specifically

(EGFR) in an all-blooded organism such as humans.

According to another feature of this other aspect of the invention; A method to provide an enzyme inhibitory effect is provided

EGFR kinase and/or erbB2 and/or aay le) erbB4 selection (EGFR) in a hematopoietic organism

Warm as a man” involves administering a therapeutically effective amount of a quinazoline derivative of formula I or a pharmaceutically acceptable die 0 salt or an acceptable ester thereof (lana as previously determined; to the said organism.

Gay for another aspect of the invention; A compound of the formula is provided [; or a pharmaceutically acceptable die-salt

:© -_ of it is acceptable (Liana) as previously determined; in providing an inhibitory effect on the enzyme EGFR kinases

and/or 62 and/or erbB4 (specifically EGFR) in a warm-blooded organism ¢ such as human 0

a

-YY¢-

clad Fp is another of the invention; The use of a quinazoline derivative of Formula I or a salt thereof is provided

Pharmaceutical acceptable or ester of it is pharmaceutically acceptable as previously specified; in the manufacture of a drug for use in

Providing an inhibitory effect on the EGFR kinase enzyme in a warm-blooded organism such as a human.

According to another feature of this aspect of the invention; A method to provide an enzyme inhibitory effect is provided

tyrosine kinases EGFR© in a warm-blooded organism such as humans” includes administration of an effective amount

therapeutically from a quinazoline derivative of formula 1; Or a pharmaceutically acceptable salt thereof, or an acceptable ester thereof

pharmacists, as previously specified; to the said object.

According to another feature of this aspect of the invention; A compound of formula fof is supplied as an acceptable salt

Pharmaceutical or aie ester is pharmaceutically acceptable for use in providing a selective inhibitory effect of the tyrosine kinases EGFR 0 in warm-blooded organisms such as humans.

The term 'selective inhibitory effect of tyrosine kinases EGFR' indicates that the quinazoline derivative

Which has formula 1 more potent against the enzyme tyrosine kinases of the EGF receptor compared to kinase enzymes:

the other. specially; Some of the compounds according to the invention are more potent against the enzyme kinase

of the EGF receptor compared to other kinase enzymes, Jie cerbB, tyrosine kinases of the vo 32 receptor. For example; bie increases the activity of selective EGFR kinase GE, of the invention vs

EGF receptor kinases at least © times; preferably at least 10 times; comparison

with its inhibition activity against the ctyrosine kinases erbB, as determined by the relative ICsp values in

appropriate tests. For example; Comparing the value of the ICs from the KB cell test (Measurement of Effectiveness

Activation of the enzyme (EGFR tyrosine kinases) with a value of 16:0 from a phospho-cell test - erbB2 copy

— Ye-

;? Measuring the inhibitory activity of the enzyme (erb-B2 tyrosine kinases) for a specific test compound, as previously.

mention it.

According to another aspect of the present invention; The use of a quinazoline derivative of formula 1 or

a pharmaceutically acceptable salt thereof or aie ester that is pharmaceutically acceptable; As previously specified; In the manufacture of drug 0 for use in the provision of cancer treatment (as selected cancer from leukemia, leukemia and myeloma

multiple or lymphangioma; Cancerous tumors of the bile duct, bone, bladder, brain/0815 and breast

colon, rectum, endometrium, stomach, head and neck, liver and lung tumors (in particular

Select non-small cell carcinoma), nerve cell, esophagus, ovary, and pancreas

the prostate, the kidneys, the skin, the testis, the thyroid, the uterine motility, and the vulva in a warm-blooded being; Like a human.

id for another feature of this side of AY (cp) a way to treat a cancer is provided (as a selective cancer

from leukemia, multiple myeloma or lymphoma; And carcinomas of the bile duct

Bones, bladder 5 ONS pall, breast, colon, rectum, endometrium, stomach, head tumors

neck, liver, lung (specifically non-small cell carcinoma), nerve cell, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterine

And the vulva is in a being of all blood, such as a human being; need this treatment; Include quantity

Active Ladle of a quinazoline derivative having the formula ]© or a pharmaceutically acceptable salt thereof or ester

of it is pharmaceutically acceptable as previously determined; to the said object.

f

IY - - Ga for the AT side of the invention; Provide a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or: __ of it, pharmaceutically acceptable; In the treatment of cancer (selected eg from leukemia, multiple myeloma or lymphoma; carcinomas of the bile duct, bone, bladder, brain/breast, colon, rectum, endometrium, stomach, head and neck, liver, lung tumors Je)6 in particular non-small cell carcinoma_LAY ) and the nerve cell, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterine drum and vulva in a warm-blooded being like a human. As already mentioned; The amount of dose required for the treatment or prevention of a particular disease may necessarily vary depending on among the factors (sal) the host being treated, the method of administration, the severity of the disease being treated. Anti-proliferative therapy / tyrosine kinases inhibitory effect / anti-cancer therapy may be used previously specified as a single therapy or may include, in addition to the compound of the invention, conventional surgery, radiotherapy or chemotherapy This chemotherapy may include one or more of the following classes of antitumor agents: (1) oe antiproliferative/antineoplastic drugs and terminator combinations as used in medical oncology; such as L Ji) alkyl insertion agents cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, zs¢ (busulphan and nitrosoureas) antimetabolites Ae) antimetabolites example; Folic acid antagonists, cantifolates, such as Jie fluoropyrimidines: Y Y 00

- 10171 - -fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea: Jie anthracyclines (such as antitumour antibiotics and antitumor antibiotics adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin °

Jie vinca alkaloids Ji) antimitotic agents Jill anti Jal se ¢ (vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere etoposide and teniposide, such as epipodophyllotoxins (such as topoisomerase and inhibitors) ¢ (amsacrine, topotecan and camptothecin tamoxifen, (as antioestrogens Jie cytostable factors) 0 oestrogen receptor downregulators ¢ (toremifene, raloxifene, droloxifene and iodoxyfene

Ji) antiandrogens and antiandrogens + fulvestrant (fis) 4d in a controlled manner or LHRH and antagonists (bicalutamide, flutamide, nilutamide and cyproterone acetate (as progestogens) and (goserelin, leuprorelin and buserelin Jie) LHRH auxiliaries anastrozole, letrozole, vorazole and (such as aromatase inhibitors (megestrol acetate 0 ¢ finasteride) as 5a-reductase and inhibitors ( exemestane «metalloproteinase inhibitors Jie]) agents that inhibit cell invasion (7) ¢(urokinase plasminogen and inhibitors of activator receptor function marimastat Jie F

0170 - - (?) Inhibitors of growth factor function; As inhibitors including anti-growth factor and growth factor receptor antibodies (such as the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225)), © and farnesyl transferase ¢ inhibitors MEK inhibitors, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, and other inhibitors of the epidermal growth factor family, for example, Jie, tyrosine kinase inhibitors such as: N-(3-chloro-4) -fluorophenyl)-7-methoxy-6-( 3-morpholinopropoxy)quinazolin-4-amine ‎(gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyetho xy)quinazolin-4 - amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- 01 mocpholi nopropoxy)quinazolin-4-amine (CI 1033)), such as inhibitors of the platelet derived growth factor family; eg hepatocyte growth factor family inhibitors; (0) Sal anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor (eg 0 anti-VEGF-J™ bevacizumab antibody [Avastin] compounds such as those disclosed in international patent applications No. 1-il9, Yo-l9, 7/318, 18/177504.), compounds acting by other mechanisms (such as linomide), and inhibitors of ¢ (angiostatin integrin vB3a) function.

- 1" -

(7) Combretastatin ad jie fle damaging agents and compounds disclosed in applications

International patents:

Tah 5 Ktmkt / AYYYE 5 [E1710 No CBO “Night”

("") treatment modalities that do not impede the expression of the gene; such as those directed at the aforementioned targets o such as 2503 1518; therapeutic modalities that do not inhibit the expression of the anti-tras gene

(A) Genetic therapies including, for example, Goh to replace stray genes Jie 53m

Ion or BRCAI ion or BRCA2 or GDEPT methods (prodrug and enzyme directed therapy)

toward the gene); Such as those that use cytosine deaminase, i.e. thymidine kinase, or a bacterial enzyme.

nitroreductase ¢ and methods for increasing patient tolerance to chemotherapy or radiation therapy; such as gene therapy MDR-0; And

(9) Immunotherapy methods; They include, for example, ways both outside and inside the body to increase immunity

of tumor cells in patients; Transmission of infection with cytokines such as:

interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor;

ways to reduce oT cell energy and ways to use infected immune cells; Such as dendritic cells transmissible (Leal) infection with coytokine and methods using transfused tumor cell strains

Infection with cytokines and methods using homologous antibodies.

flavopiridol (as CDK) cell cycle inhibitors which include e.g. inhibitors (01)

cell cycle checkpoint inhibitors (such as checkpoint kinase) and

- 1101 -

aurora kinase and other kinase enzymes involved in mitosis and regulation of cytokinesis

(eg cytokinesis resulting from mitosis) and 'histone deacetylase' inhibitors

Communication therapy can be implemented by administering doses of the individual treatment components at the same time or together

sequentially or separately. These joint products utilize compounds of the invention in the aforementioned 0 dosage range and the other pharmaceutically active agent in the specified de all range.

According to this aspect of the invention; A pharmaceutical product containing a quinazoline derivative is supplied

Formula 1 as aforementioned” and additional antineoplastic agent; It has also been previously identified for the treatment of cancer

the contact.

Although compounds of Formula 1 are primarily of interest as therapeutic agents for use in warm-blooded organisms (including humans); They are useful when inhibition of the effects of enzymes is required

Tyrosine protein kinase for the receptor 03©. Thus, Audi has shown these compounds their usefulness as pharmacological measures

For use in the development of new biological tests and in the search for new pharmacological agents.

The invention is illustrated below with the following non-restrictive examples which are JUS except in Aa

otherwise stipulate: (1) temperatures are expressed in degrees Celsius (C); yo operations are performed at room temperature or ambient temperature at a degree ranging from YA to

ta Yo

(Y) Organic solutions were dried using magnesium sulfur or sodium sulfate ¢ and

Evaporate the solvent using a rotary evaporator at low pressure (01 (01) 7000-7000 Pa; 6.0

fo 10 mm Hg) at a bath temperature of ©0

boredom

YY - - (©) chromatography refers to flash chromatography on silica gel; Thin layer chromatography (TLC) was applied in silica gel dishes; (¢) with a dale image after reaction set-up and then TLC and/or analytical LCMS; and then (1) 0 of the end products with satisfactory nuclear magnetic resonance (NMR) and/or mass spectrometry data; (3) Results are specified for eda purposes and do not necessarily represent results obtained with an elaborate progression of the process; preparations were repeated if more material was required; (7) when stated NMR data takes the form of major diagnostic proton delta values given in parts per million” in terms of tetramethylsilane (TMS) as an internal scale; specified at an operating frequency (0 NMR (YOO) or 000MHz); using: perdeuterio dimethyl sulfoxide (DMSO-d6) as a solvent; Unless otherwise indicated; The following abbreviations were used: is singular; double td; ;: iq ASE quadruple :0: multiple; 5: Amplitude ¢ (A) Chemical symbols in their usual sense: SST units and symbols are used Vo (9) Solvent ratios are specified by volume: volume (vol/vol); (01) mass spectrometry is measured ( MS) using LC-MS electronic sprayer of Waters type or Micromass 8 Positive or negative ion mode; m/z values determined Generally not specified

10'17 - - only the ions denoting the original mass; and the mass ion is specified as (0411; except in Als text otherwise; (WY) when describing the synthesis aly corresponding to that given in the preceding example; the quantities used are millimolar equivalents of those used in the preceding example; (OY) oe When purifying the compounds with 1.0045 mass-induced preparatives, the following conditions were used: Column: 01 Xan YY (5 Sie © “ThermoHypersil Keystone B-Basic y mm mm) Sequencing material: V,0 min; graded from 7780 to 795 acetonitrile in water (buffer solution; 7 g/L of (00110):00; pH equal to AS - flow rate: Yo ml/min (VY) Melting points measured using a Buchi B-545 automated melting point instrument; (V5) Where not otherwise stated, compounds containing an asymmetrically substituted carbon are not dissolved; and

- YY - The following abbreviations were used: (Ve)

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-Tetramethyluronium Hexafluoro-

Phosphate

N,N-d imethylformamide: uronium tetrafluoroborate;

176 - - Example No. 1 N-(3-Chloro-2-nuorophenyl)-7-({1 -[(dimethylamino)acetyl]piperidin-4-yl} oxy)-6- methoxyquinazo lin -4-amine HN “ — “© Lajo p 9 N 0 ke mers / 0 001 (NN-Dimethylaminoacetyl chloride hydrochloride mg) was added in amounts to a solution of: (N- 3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride : You) mg +,0V mmol) and V+ +) micro diisopropylethylamine (Jd in methylene 0 YO chloride) ml) at safram. The reaction mixture was stirred for 2 hours to room temperature. The reaction mixture was prepared with a saturated sodium bicarbonate solution (Je YO), dried (+B50O11), filtered, and evaporated. The remaining materials were purified by column chromatography and sequentially separated by increasing polar mixtures of methylene chloride/methanol (0/100) to ¢(V+/%+) then methylene chloride/methanol (90/01). (ammoniadly) the portions containing the desired product yo were collected and evaporated under low pressure to obtain the product mentioned in the title as a white foam (© 11 dg; to %).

- 1011© - 11111111 Spectrum: (DMSO dg) 1.50-1.65 (m, 111): 1.65-1.80 (m, 1H); 1.95-2.15 (m, 2H); 2.25 (s, 6H); 3.10-3.50 (m) , 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H); 4.90 (m, 1H), 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s, 1H); 8.40 (s, 1H); 9.65 (s, 1H);

Mass Spectrum: (M+H)+ 488. Then prepare o

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride used as a starting material is as follows: To a suspension of (Je 5.0) dioxane In HCl was added; molar of as is (CAS Jaw No. N0162364-72-9) 7-(benzyloxy)-4-chloro-6-methoxyquinazoline 0 3-chloro-2-fluoroaniline mol ) and 1.7 g (10) (1) mentioned in 13354/17098; Example No. 80 ml). The reaction mixture was heated at YY acetonitrile (ev mol) in + YY g; ¥Y,41) and the resulting precipitate filtered (Je 0 (acetonitrile) for 1 hour to settle overnight. Added: and dried under reduced pressure to obtain (Je 500 XY) acetonitrile and wash it with 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyqu inazolin-4-amine Vo hydrochloride (727 g Ao , £0) as a beige solid.

Y Yve

117 - - Spectrum: (DMSO de) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 111 1H), 8.38 (s, 1H) ), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410. A solution of: 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyqu inazolin-4-amine hydrochloride ° was heated. VAY aa 54 ° (0 mol) in (J Yeu ) trifluoroacetic acid at Av 1 for 1 hour. The reaction mixture was evaporated to dryness and the remaining materials were re-dissolved in methanol (100 mL). This solution was added dropwise to a saturated aqueous solution of sodium bicarbonate while stirring WL (sO). The precipitate obtained by filtration was collected and washed with acetonitrile and dried it under 0 low pressure. The resulting solids were then purified by hot crushing (100 m) using a mixture of butanone (Ja *000) and MeOH (100 mL); filtered and dried to: 4-[3-chloro-2-fluoroanilino]- 6-methoxyquinazolin-7-ol as solid Osh cream) £0 g; 077 NMR Spectrum: (DMSO dg): 3.98 (s, 3H), 7.10 (s, 1H), 7.25-7.30 (m, 1H ), 7.40-7.50 pounds (m, 1H), 7.50-7.60 (m, 1H), 7.80 (s, 1H), 8.30 (s, 1H), 9.55 (s, 1H), 10.32 (s, 1H) ; Mass Vo Spectrum: (M+H)+ 320. 4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (0 90 mg 1.016 mmol) was dissolved in DMA ) + 7 ml). Added: 7,0

111 - - (ane 47 1( tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate 1.070 mmol) cesium fluoride (, 17 vol. 0.966 mmol) 0 and heating the mixture Galo quantities were added to the reaction mixture after YA for an hour; 1 hour. The solvent was evaporated; the residue was fractionated between a saturated 48k sodium bicarbonate solution (50 (do, xY) EtOAc + © ml). The organics were collected; Chromatograph and sequentially separate it with increasing polar mixtures of EtOAc / methylene chloride (0/100 to 1/001). The fractions containing the desired product were collected and evaporated under 0 reduced pressure to obtain: tert-butyl 4-({ 4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} ox y)piperidine-1- carboxylate | as colorless foam (cane YOV) 7495); 'H NMR Spectrum: (DMSO-de): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), (m, 2H), 3.75-3.92 (m , 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), Ve 3.20-3.45 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+503.7.55-7.70 (Je 0+) trifluoroacetic acid was added to a solution of:

- 010 - tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} His y)piperidine-1- carboxylate (Je V) triethylsilane and (Je 1 ( methylene chloride mmol) in 0.49 can YOU) h. The reaction mixture was evaporated under reduced pressure, the sads were re-dissolved, and the solution stirred in molars of 1. This solution was then treated with residual (de©) EtOAc at 0 to yield a precipitate (Je 04) diethylether followed by more (Jo 1) diethylether/HCI white. The resulting solids were collected after centrifugation and dried under reduced pressure: to obtain

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride Ve mg.Vou) as a white solid 111 NMR Spectrum: (DMSO -d6): 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 3.15-3.50 (m, 4H), 4.15 (s, 3H), 5.02 (m, 1H), 7.48 (m, 1H) ), 7.60-7.85 m, 3H), 8.35 (s, 1H), 8.85 (s, 1H), 9.56 (bs, 2H); Mass Spectrum : (M+H)+ 403. 1 Example No. Vo

N-(3-Chloro-2-nuorophenyl)-6-met hoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4- yl}oxy)quina zolin-4-amine

- 11794 - 0 ma am required N 0 T : stirred

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine dihydrochloride 2-(2-methoxyethoxy)acetyl chloride 5 (Jo +,£¢) diisopropylethylamines mg) Yr +) 0 methylene h. Y.0 ml) was added for q ) methylene chloride in PEN 0 0)

Aqueous Yo)¥ M sodium hydroxide organic matter using Jug 5 (Jo Y+) chloride Then purify the product by flash column chromatography and sequentially separate it 0. (J Ye. ) and water (Ja to obtain a re-deposited foam (Z4Y) methylene chlorides (ZY) methanol to obtain the product mentioned in the title as a solid (Ja Y+) diethylether by stirring at 0 g) 0 ) White 1H NMR Spectrum : (DMSO YL 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t) , J=7Hz; 2H), 3.60 (t, J=9Hz, 2H). 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H). 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (brs, 1H); Mass Spectrum: (M+H)+ 519; \o M. 111 to 011 Melting point:

- 16 and - (7) Example No

N-(3-Chloro-2-fluorophenyl)-6-me thoxy-7-{[1-(methoxyacetyl)piperidin-4- ylJoxy}quinazolin-4-a mine

L.L

Comprising 0 : g) to a solution of +, YE) HATU has been added

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride o g) +,+°%) methoxyacetic acid and (Js + ,¥V) diisopropylethylamine 5 mg (YO) and the mixture was stirred at room temperature for 0.¥ h. (Je 4) methylene chloride in sodium hydroxide ml) and washing the organic matter with (01) methylene chloride product purified by flash column chromatography (Je Yr) and water (do Yr molar; TY) aqueous to obtain foam added 0 4V) methylene chloride s (% ¥) methanol B Lali and its separation 0 to obtain the product given in the title (Jo 71( diethylether re-deposited by stirring in g); 00 as a white solid 1H NMR Spectrum: (DMSO ds 373K) 1.73 (m) , 2H), 2.02 (m, 2H), 3.37 (s, 3H), 3.41 (m, 2H), 3.77 (m, 2H), 3.98 (s, 3H), 4.09 (s, 2H), 4.85 (m, 1H), 7.26 (m, 1H), 7.30 (s, 1H), 7.39 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.34 (br s, lH);

Spectrum: (M+H)+ 475.

11 - - Example No. Using the Silas procedure for that mentioned in Example No. ; Conjugate: N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine ,3 dihydrochloride °b carboxylic acid to obtain the appropriate On compounds shown in Table 1: Table 1 No. and Notes 3-hydroxypropanoy!HO 0 0 : [1] a OH HO [v] 0 7 , 0

- 067 - 0 print 0 0 0 0 0 (TF [01]

N

= 0

Oh

= 0) 0 00

SAN [1] 0 0 0 A [1] OL om M [

Oh

- VEY - : Notes 1 in table piperidin - in nitrogen group B 1 Refer to the carbonyl group binding position in table . 4-yl : [1 ] ° 2-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yl}-2-oxoethanol g) ; ), 4.11 (s, 2H), 4.84 (m, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 0 1H), 7.50-7.67 (m, 2H), 7.82 (s , 1H), 8.38 (s, 1H), 9.31 (br s, 1H); Mass Spectrum: (M+H)" 461. : [¥]

N-(3-Chloro-2-fluorophenyl)-7- {[ | -(ethoxyacetyl)piper idin-4-yl]oxy}-6- methoxyquinazolin-4-amine \o g); 0 Ao) as a white solid

- Yee - 1H NMR Spectrum: (DMSO dg 373K) 1.18 (t, J=8Hz, 3H), 1.74 (m, 2H), 2.03 (m, 2H), 3.41 (m, 2H), 3.52 (q, J= 8Hz, 2H), 3.79 (m, 2H), 3.98 (s, 3H),4.12 (s, 2H), 4.84 (m, 1H), 7.23 (m, 1H), 7.32 (s, 1H), 7.42 (m , 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.30 (brs, 1H) 11 to 101 m Melting point: :[

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7- {[1-(3-methox ypropanoyl)piperidin-4- ylJoxy}quinazolin-4-amine g); +1100)

IH NMR Spectrum: (DMSO dg 373K) 1.73 (m, 2H), 2.01 (m, 2H), 2.62 (t, J=9Hz, 2H), 01 3.28 (s, 3H), 3.41 (m, 2H), 3.60 (t, J=9Hz, 2H), 3.79 (m, 2H), 3.97 (s, 3H), 4.82 (m, 1H), 7.24 (m, 1H). 7.30 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum : (M+H) M. VAS Melting Point: 185 to : [ ¢ ] Vo 3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7- yl }oxy)piperidin-1-yl]-3-oxopropan-1-ol (g); 00 WY)

- Y¢o - 1H NMR Spectrum: (DMSO ds 373K) 1.72 (m, 2H), 2.01 (m, 2H), 2.62 (t, J=8Hz, 2H), 3.40 (m, 2H), 3.71 (m, 2H), 3.80 (m, 2H), 3.96 (s, 3H), 4.13 (t, J=5Hz, 1H), 4.83 (m, 1H), 7.28 (m, 1H), 7.31 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 475 M. 177 to 118 M. Melting point: f (25)-2-hydroxypropanoic acid following the coupling reaction between [©]

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride methylene chloride The product was then purified by an illuminated column chromatogram; and sequentially separated using (La) (94.1/€,1) to obtain a foam. The methanol was reconstituted in ammonia / 0 solution: to obtain (eV) diethylether by stirring by stirring in (2S) -1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl} oxy)piperidin-1- yl]-1-oxopropan-2-ol um). 111 to 0117 g) (melting point: +, 8Y) was obtained as a white amorphous solid m); 191 to YAS (melting point: acetonitrile) was obtained on a re-crystalline solid Crystallization of the product vo 480 was carried out by a flash chromatography column and sequentially separated by FY (oo) following reaction [1] (L) (1/54) to obtain methanol in ammonia / methylene chloride solution using : To obtain (Je Yo) diethylether foam that has been re-deposited by stirring in

- Yen - (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl} oxy)piperidin-1-yl]-1-oxopropan-2- ol

PEN Ye £) as a white solid 111 NMR Spectrum: (DMSO de) 0.78 (d, J=7Hz, 3H), 0.91 (t, J=7Hz, 3H), *1.21 (m, 1H), 1.44 (m , 1H), 1.61 (m, 3H), 2.05 (m, 2H), 3.40 (m, 2H), 3.79 (m, 1H), 3.95 (s, 3H), 4.00° (m, 1H), 4.28 (m , 1H), 4.43 (m, 1H), 4.93 (m, 1H), 7.29 (m, 1H), 7.36 (s, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)+ 517 Melting Point: 116 to 118 M. [Vv] \ After the coupling reaction, the product was purified by a flash chromatography column and eluted with methylene chlorides (£¢) methanol (£97) to yield a foam that was re-deposited by stirring in (JaY +) diethylether to obtain: 4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yl]-2- methyl-4-oxobutan-2-0l \o As a white solid (777 g); NMR Spectrum: (DMSO de) 1.20 (s, 6H), 1.54-1.77 (m, 2H), 2.04 (m, 2H), 2.49 (s, 2H), 3.30 (m, 1H), 3.45 (m, 1H), 3.86 (m, 1H), 3.96 (s, 3H), 4.00 (m, 1H), 4.88 (s, 1H), (1H, m), 7.28 (m, 1H), 7.35 (s, 1H), 7.47 (m, 1H), 7.54 (m, 1H), 7.83 (s, 1H), 8.40 491 Y 0.0 A

- 051 - (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)+ 503 Melting Point: 197 to 194 C. [A] After the coupling reaction + ligands the product with a flash chromatography column and sequentially separate it using methylene chloride/ammonia solution in methanol (L/4A) to obtain: mL) to obtain 71 diethylether foam re-deposited by stirring in 0

N-(3-chloro-2-fluorophenyl)-6-methoxy-7- {[ 1-(tetrahydrofuran -2-ylcarbonyl)piperidin- 4-ylloxy}quinazolin-4-amine

TPES 70 (as white solid (DMSO dg 373K) 1.73 (m, 2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 0 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.33 (br s, 1H);

Spectrum: (M+H)” 501 Melting point: 154 to 700 C. [4] After the coupling reaction » the product was purified by a flash chromatography column and eluted by methylene chlorides (74) 0 methanol (£91) to yield on a foam that was re-deposited by stirring in 71 (diethylether mL) to obtain:

:- YEA - 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-y! }oxy)piperidin-1-yl]-2,2- dimethyl-3-oxopropan -1-ol

Ap ,V ¢ 3 as a white solid 111 NMR Spectrum : (DMSO de) 1.10 (s, 6H), 1.64 (m, 2H), 2.03 (m, 2H), 3.39 (m, 2H), 3.45 (m, 2H), 3.95 (s, 3H), 3.98 (m, 2H), 4.54 (t, J=6Hz, 1H). 4.91 (1H, m), 7.29 ° (m, 1H), 7.35 (s, lH), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.64 (br 5, 1H); Mass Spectrum : (M+H)+ 503 M 111 to 111 Melting Point: : 1 0 1 (3R,5S)-1-Acetyl-5-{[4-({4-[3) -chloro-2-fluoroa nilino]-6-methoxyquinazolin-7- 01 yl}oxy)piperidin-1-yl]carbonyl } pyrrolidin-3-ol g); 1) 1H NMR Spectrum: (DMSO ds 373K) 1.65 -1.87 (m, 3H), 1.93 (s, 3H), 2.04 (m, 3H), 3.44-3.64 (m, 4H), 3.81 (m, 2H), 3.98 (s, 3H), 4.28-4.39 (m , 1H), 4.71 (m, 1H), 4.89 (m, 2H), 7.23 (m, 1H), 7.32 (s, 1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.39 (s, 1H), \o 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 558 Melting Point: 87 to 87 C.

- 1694 - — “Following the coupling reaction” the product was purified by flash chromatography and sequentially separated [VY] to obtain a foam that was re-deposited into (79597) methylene chloride (77(methanol: ml) to obtain +) diethylether by stirring In(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl} oxy)piperidin-1-yl]-1-oxobutan-2-ol ° as a white solid; FEN oY. A) 1H NMR Spectrum: (DMSO dg 373K) 0.91 (t, J=9Hz, 3H), 1.52 (m, 1H), 1.70 (m, 3H), 2.05 (m, 2H), 3.40 (m, 2H), 3.84 (m, 2H), 3.94 (s, 3H), 4.28 (m, 1H), 4.40 (m, 1H), 4.88 (m, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.42 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 489 01 M. 167 to 157 Melting Point: After the coupling reaction + then purification and sequencing of the product by flash column chromatography [1] (L) (94/7 ) to obtain methanol in ammonia / methylene chloride solution using: to obtain (Jo 71) diethylether foam re-deposited by stirring in

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tet rahydrofuran-2- Vo ylcarbonyl]piperidin-4-y1} oxy)quinazolin-4-amine g ); oY £Y) as a white solid

- Yo. —— 1H NMR Spectrum: (DMSO dg 373K) 1.73 (m, 2H), 1.99 (m, 2H). 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7THz, 1H). 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)" 501 to 1994 CE 158 Melting Point: 0 Product purified by flash column chromatography and sequentially separated 0 following coupling reaction [VY] to yield (Y/4A) (L) methanol in ammonia / methylene chloride solution plainly: to obtain (Je 71) diethylether on a foam that was re-deposited by stirring in

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-tet rahydrofuran-2- ylcarbonyl]piperidin-4-yl }oxy)quinazolin-4-amine 0.1

PES 0.1 7 as a white solid 1H NMR Spectrum: (DMSO dg 373K) 1.73 (m, 2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m , 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 ¢ (br s, 1H); Mass Spectrum: (M+H)+ 501 Vo m. 094 to 197 Melting Point: Product purified by flash column chromatography and sequentially separated 0 after coupling reaction [Y¢ ] sale) to obtain TM Foam (£4V,0) methylene chloride (%~Y,®) methanoles

- Yo) - : to obtain (Jo 71( diethylether) precipitate it by stirring in (25)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyqui nazolin-7-yl } oxy)piperidin-1- yl]-3,3-dimethyl-1-oxobutan-2-0 1 : g) as white solid; PEARY 1H NMR Spectrum: (DMSO dg 373K) 0.94 (s, 9H), 1.72 (m, 2H), 2.03 (m, 2H), 3.49 ° (m, 2H), 3.90 (m, 2H), 3.96 (s, 3H), 4.17 (m, 1H), 4.24 (m, 1H), 4.86 (m, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.29 (br s, 1H);

Mass Spectrum: (M+H)+ 517 M 7016 to 006 Melting Point: [1 0] 01 7-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin- 4-yl} oxy)-N-(3-chloro-2- fluorophenyl)-6-methoxyquinazolin-4-amine 1H NMR Spectrum: (DMSO + CD;COOD): 1.33-1.46 (m, 1H); 1.50-1.62 (m, 1H): 1.62-1.74 (m, 3H); 1.75-1.85 (m, 1H); 2.00-2.18 (m, 2H); 2.02 (s, 3H); 2.62-2.71 (m, 1H); 2.92-3.00 (m, 1H); 3.13 (dd, 1H); 3.30-3.43 (m, 1H); 3.47-3.57 (m, 1H); 3.80-3.98 \o (m, 3H); 4.02 (s, 3H); 4.39 (d, 1H); 4.93 (bs, 1H); 7.41 (dd, 1H); 7.49 (s, 1H); 7.58 (dd, 1H); 7.68 (dd, 1H); 8.11 (s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)+ 556

- ov_ : [V1]

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[ 1-(tetrahyd rofuran-3 -ylcarbonyl)piperidin- 4-ylloxy}quinazohn-4-amine 1H NMR Spectrum: (DMSO + CD; COOD: 11.64-1.74 (m, 1H); 1.74-1.84 (m, 1H); 2.01-2.17 (m, 4H); 3.33-3.55 (m, 3H); 3.66-3.80 (m, 3H); 3.80-3.99 (m, 3H); 4.03 (s, 3°H); 3.93 (bs, 1H); 7.41 (dd, 1H); 7.48 (s, 1H); 7.58 (dd, 1H); 7.67 (dd, 1H); 8.12- (s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)" 501. Product purified by flash column chromatography and eluted with Saal following a coupling reaction [ \Vv] to yield a re-deposited foam (£90) methylene chlorides (#2) methanol : mL) to obtain 01( diethylether by stirring in 1 0-{[4-({4- 3 -chloro-2-fluoroanilino]-6-methoxyquinazolin-7-y 1} oxy)piperidin-1- yl ]carbonyl}cyclopropanol as a white solid (5 to g); ), 3.54 (m, 2H), 3.96 (s, 3H), 4.00 (m, 2H), 4.87 (m, 1H), 5.90 (s, 1H), 7.25 (m, Vo 1H), 7.31 (s, 1H) ), 7.40 (m, 1H), 7.58 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); ¢{Mass Spectrum: (M+H)" 487 to 78 m.‎ 1777 Melting point:‎

10 - Example No. ° N-(3-chloro-2-fluorophenyl)-6-me thoxy-7-{[(3S)-1-(methoxyacetyl)piperidin-3- ylJoxy}qu inazolin- 4-amine HN' g Cl 7 0 ml. 0 0 17 4 (HATU g) has been added to a solution of: N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)- piperidin-3-yloxy]quinazolin- 4-amine dihydrochloride (YO) mg) (a> +,+©£) methoxyacetic acidy (Je +,¥V) diisopropylethylamine sy in (Je 4) methylene chloride, and the mixture was stirred at room temperature for 7.5 hours. 0 (Jo 01) methylene chloride was added and the organic matter was washed with sodium hydroxide matthe ¥ mol (Je 01 and water (Ye ml). The product was purified by a flash chromatography column and sequentially separated by ( 74Y) methylene chlorides (ZY) methanol to obtain a foam that was re-deposited by stirring in (oY +) diethylether to obtain the product mentioned in the title as a white solid ((p= YY ¢

- A - 1H NMR Spectrum: (DMSO dg 373K) 1.60 (m, 1H), 1.88 (m, 2H), 2.10 (m, 1H), 3.32 (s, 3H), 3.51 (m, 2H), 3.62 (m, 1H), 3.87 (m, 1H), 3.98 (s, 3H), 4.02 (d, J=14Hz, 1H), 4.12 (d, J=14Hz, 1H), 4.66 (m, 1H), 7.26 (m, 1H), 7.33 (s, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 7.83 (s, 1H), 8.40 (s, 1H), 9.34 (br s, 1H); Mass Spectrum : (M+H)+ 475. : oo

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)- piperidin-3-yloxy]quinazolin-4-amine dihydrochloride used as a starting material was prepared as follows: (Y,VY) added Diethylazodicarboxylate g) dropwise into a mixture of : <p>€,Y4) tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate 0 and (p> 0 ) 4-chloro-6-methoxyquinazolin-7- ol and (p>©,1Y) triphenylphosphine in YO)methylene chloride mL). Then the solution was heated to 66°C. and stir it for how long? hours. after cooling; The mixture was filtered, purified by flash chromatography, and eluted using: to yield (1/01/81) isohexane/acetone/triethylamine tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7). -yl)oxy]piperi dine-1-carboxylate M Mass Spectrum: (M+H)" 394 was used directly; (aa ¥, 74) as a colorless oil: to a suspension of (Je 1, +) dioxane AHCI was added; molar of tert-butyl (35)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperi dine-1-carboxylate during (Je 0+) acetonitrile in (Je+,4A) 3-chloro-2-fluoroaniliney (g)V,Y)) stirred. The reaction mixture was heated to 88 °C and left at this temperature overnight. © evaporated

- Yoo - solvent and purification of the residue by column chromatography and sequencing it with polar mixtures increasing from 0/20 (to obtain Y/4V) (L) methanol in ammonia except methylene chloride: on N -(3-chloro-2-fluorophenyl)-6-methoxy-7-[(35)- piperidin-3-yloxy]quinazolin-4-amine dihydrochloride ° g); VY) as solid 1H NMR Spectrum: (DMSO dg) 1.56 (m, 2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m,1H), 3.20 (m, 1H), 3.95 ( s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s , 1H), 9.63(s, 1H); Mass Spectrum: (M+H)+ 403.01 6 Example No. 2-[(3S)-3-({4-[3-chloro-2-fluoro anilino]-6-methoxyquinazolin-7-yl}oxy )piperidin-1- y1]-2-oxoethanol

SE

Ol

L

For that mentioned in Example No. ©; Paired with: Silas using the action of 0

You - - N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)- piperidin-3-yloxy]quinazolin-4-amine dihydrochloride Yo. ) mg) glycolic acid (° p g). Then, the product was purified by a flash chromatography column and sequentially separated with (AY) methylene chloride (77 methanol %) to obtain a foam.

E Re-deposited by stirring in (JY 0 ) diethylether to obtain the product mentioned in the title as a white solid (° LY g); NMR Spectrum: (DMSO dg 373K) 1.59 (m, 1H), 1.87 (m, 2H), 2.09 (m, 1H), 3.40-111 : (m, 4H), 3.86 (m, 1H), 3.98 (s, 3H), 4.04-4.18 (m, 2H), 4.66 (m, 1H), 7.24 (m, 1H), 3.60 (s, 1H), 7.40 (m, 1H), 7.60 (m, 1H ), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass 7.31 Spectrum: (M+H)+ 461.01 Ex 77 N-(3-Chloro-2-fluorophenyl)-6-me thoxy-7-({(3S)-1-[(4) -methylpiperazin-1- ylacetyl]piperidin-3 -yl}oxy)quinazolin-4-amine HN | Cl 9 Se (re

—- AA - : µl) to a solution of £V) Chloroacetyl chloride was added

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)- piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (de V+) methylene chloride µL) in YVY) diisopropylethylamine 5 mg (YO +): The mixture was stirred at ambient temperature for one hour. sodium b(774_mg) was added and the solution was stirred for 1 hour before 1-Methylpiperazine was purified by column (J01) and (de10M; Y) hydroxide in ammonia/methylene chloride solution flash chromatography and sequencing with diethylether to obtain a foam that was re-deposited by stirring in (Y/4Y) (L) methanol ¢ (PEN 8 mL) to obtain the product mentioned in the title As a white solid 1 ) 01 'H NMR Spectrum: (DMSO dg) 1.42-1.67 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.48 (m, 9H), 2.18 (s, 3H), 2.82-3.05 (m, 1H), 3.20-4.02 (m, 8H), 4.68 (m, 1H), 7.30 (m, 1H), 7.34 (s, 1H), 7.44-7.60 (m, 2H), 7.82 (m, 1H), 8.38 (s, 1H), 9.64 (m, 1H);

Spectrum: (M+H)+ 543 C 171 to 101 Melting Point: ve

A Example No

N-(3-Chloro-2-fluorophenyl)-6-me thoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl] piperidin-4-yl}o xy)quinazolin-4-amine

- 108 - Malak —0 Sy F —N N Baltam Rata 0: Using a procedure similar to that mentioned in Example No. 7 - Interaction

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride aaa¥ YA) 1-Methylpiperazine µL then £€V) chloroacetyl chloride (mg) with Yor) 0 ¢ (p>0) purified to obtain the product mentioned in the title as a white solid Cad gg 'H NMR Spectrum: (DMSO dg) 1.57 (m, 1H), 1.72 (m, 1H) ), 1.96-2.12 (m, 2H), 2.15 (s, 3H), 2.27-2.48 (m, 8H), 3.08-3.52 (m, 4H), 3.86-4.04 (m, 2H), 3.95 (s, 3H ), 4.90 (m, 1H,), 7.30 (m, 1H), 7.37 (s, 1H), 7.47-7.58 (m, 2H), 7.83 (s, 1H), 8.38 (s, 1H), 9.63 (s , 1H); Mass Spectrum: (M+H)+ 543 01 (7) Example No. (2R)-1-[4-({4-[3-Chloro-2-fluoro anilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol

YY ou

- Yod - (Process A).

HN’§ “Ci 0 0

A

Oh

A hydrochloride salt suspension was stirred from: N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)q uinazolin-4-amine can ¢ AY) ° A molene and then prepared by a process corresponding to that mentioned in Example No. (1) in -1 (Je £4) methyl-2-pyrrolidinone and cooled in an ice/water bath. Triethylamine (£,Y) was added filling 77.17 mM “(dso and 11”ds ,5(N,N-diisopropylethylamine mmol) and can) ,0) D-(-)-lactic acid 16.7 mmol) ; Then HATU 0,YY (can lar 1 mmol) was added in amounts such that the internal temperature was less than 11°C. The reaction mixture was stirred at 0 room temperature overnight and partitioned between a solution of saturated Ale sodium bicarbonate (EtOAc) ethyl acetate (NaHCq;) and the combined organic layers of saturated aqueous ammonium chloride (twice). ); 1075 of aqueous brine (twice) and brine (once); dried with anhydrous sodium sulfate; filtering and evaporation. The remaining material was purified by column chromatography and eluted using dichloromethane in methanol (a) ve (6/87) The fractions containing the desired product were evaporated to a gum that was pulverized with

- Yl. - acetonitrile crystallization of the solid thereafter from (Bale): 1) isohexane / diethylether (00,1 can 7,17) to obtain the product mentioned in the title in the form of a white powder 111 NMR Spectrum (DMSO dg ) 1.20 (d, 3H). , 4.35-4.55 (m, 1H), 4.80-5.00 (m, 2H), 7.27(dd, 1H); 7.34 (s, 1H); 7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.63 (s, 1°H); Mass Spectrum: (M+H)+ 475 to 851.6 C.184 Melting Point: 01 eg No.

N-(3-Chloro-2-fluorophenyl)-6-m ethoxy-7-({1-[(2R)-2-(methylamino) propanoyl] piperidin -4-yl} oxy)quinazolin-4-amine ( Operation a) peel 0

QO,

A .l 8 0 : thawed

YYeo

111 - - tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyq uinazolin-7- yl}oxy)piperidin-1 -yl]-1-methyl-2-oxoethyl } methy Icarbamate (¥,YY) g; Lala, 7 mmol) in (Je Y +) acetonitrile and treated with; Molar of HCI in ca (T,A) dioxane 5.7 mmol) at 80 °C for ¾ minutes. The reaction mixture 0 was fractionated between saturated sodium bicarbonate and P200181. Jue the organic layers with brine (once); and dried using sodium sulfate; filtering and evaporation. The remaining materials were purified by column chromatography and eluted using dichloromethane in (¢V) methanol (8/97). The portions containing the desired product were evaporated to obtain a gum which was pulverized with (iY) isohexane/ diethylether to obtain the product mentioned in the title in the form of 0 white powder. )00, (LAE) cand 'H NMR Spectrum : (DMSO dg + CD;C0,D) 1.35 (d, 3H), 1.61 -1.81 (m, 2H), 1.98-2.15 (m, 2H ), 2.48 (s, 3H), 3.26-3.51 (m, 2H), 3.65-3.79 (m, 1H), 3.92 (s, 3H), 3.84 - 4.08 (m, 1H), 4.32 - 4.42 (m , 1H), 4.85 - 4.99 (m, 1H), 7.20 - 7.29 (m, 1H), 7.36 (s, 1H), 7.42 - (m, 2H), 7.81 (s, 1H), 8.35 (s, 1H); Mass Spectrum : (M+H)" 488 7.54 ve The starting material is prepared:

tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-flucroanilino]-6-methoxyq uinazolin-7-yl} oxy)piperidin-1-yl]}-1 methyl-2-oxoethyl methyl carbamate

as follows:

f

The hydrochloride salt of the compound was conjugated: N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine aa ,0(00,£ m) mol) with N-tert-butoxycarbonyl-N-methyl-D-alanine according to the method mentioned in Example No. 4. The product was purified using a chromatogram F column and separated: (L) (7/94) to obtain methanol in dichloromethane sequentially with 0 tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyq uinazolin-7- yl} oxy)piperidin-1 -yl]-1-methyl-2-oxoethyl} methy lcarbamate as foam. 1H NMR Spectrum : (CDCI3) 1.29 (d, 3H), (1.48) (s, 9H), 1.75 -1.89 10 AV, reg ) (m, 1H), 1.89 - 2.04 (m, 2H), 2.07 - 2.22 (m, 1H), 2.75 (s, 3H), 3.26 - 3.42 (m, 1H), 3.50 01 - 3.85 (m, 2H ), 4.02 (s, 3H),3.91 -4.28(m, 1H), 4.65 - 4.93 (m, 1H), 5.10 - 5.21 (m, 1H),7.05 (s, 1H), 7.13 - 7.21 (m, 2H) ), 7.28 - 7.33 (m, 2H), 8.44- 8.54 (m, 1H), 8.69 (s, 1H); Mass Spectrum: (M+H)+ 11 588 Example No

N-(3-Chloro-2-fluorophenyl)-7-( {1-[(2R)-2-(dimethylamino)propanoyl]piperidin-4- \o yl}ox y)-6-methoxyquinazolin-4-amine

YY.

11” - - (Process d) “cl aug 7 0 z 0 : A solution was treated with a mixture of: N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2R)-2-(methyla mino)propanoyl] piperidin-4-yl}oxy)quinazolin-4-amine (0 g; 0.17 mmol (Example No. +, Y) paraformaldehyde 5 Ve g 0.1 mmol) Yor A can "°) 45lY magnesium sulfates mmol) in (Je©) methanol using ; molar of hydrogen chloride in YOV) dioxane μl (0.17 mmol) were added (aa +,Y1) Sodium cyanoborohydride 0,17; mmol) and the mixture was heated to 1 4 for * hours. The reaction mixture was fractionated between saturated sodium bicarbonate 5 cthyl acetate 0. Jue organics were degassed with a solution (gale) and dried with sodium sulfate; filtered and evaporated. The residue was purified by column chromatography and eluted with ammonia/dichloromethane in methanol (L 17/) The parts containing the desired product were evaporated to obtain a gum that was pulverized (VV) isohexane/ diethylether to obtain the product mentioned in the title in the form of a white powder (11 g AY)?

- 116 - 'H NMR Spectrum: (DMSO dg + CD3C0,D) 1.18 - 1.25 (m, 3H), 1.52 - 1.80 (m, 2H), 1.95 -2.15 (m, 2H), 2.48 (s, 6H), 3.18 - 3.54 (m, 2H), 3.73 - 3.91 (m, 1.5H), 3.92 (s, 3H), 4.00 - 4.14 (m, 1.5H), 4.83 - 4.95 (m, 1H), 7.21 - 7.29 (m , 1H), 7.35 (s, 1H), 7.41 - 7.55 (m, 2H), 7.80 (s, 1H), 8.35 (s, IH); Mass Spectrum : (M+H)+ 502.1" Example No

N-(3-Chloro-2-fluorophenyl)-6-m ethoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4- yl} oxy)quinazolin-4-amine (Process A) ,

Cl

HN

0S

No N 0 / : mg dmmol) to a solution of YAO (solid TBTU) added 1

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine ml + bitter mmol) and oY ) DIPEA mg; 06 mmol); and Yoo ) methylene chloride mmol) at +,00 cana 0V) (S)-(-)-2-methoxypropionoic acid ml) while being stirred. The resulting solution was stirred at room temperature overnight; dilute it (1 ml); and water (©xY) p) Y)sodium hydroxide and washed it with “(Ja 01) methylene chloride— 00

- Yio - using Al (gle), filtering and fumigation. (MgSO) was purified and dried “(de ©): silica chromatogram and sequentially separated by increasing polar mixtures to obtain the compound mentioned in (1/01-01/7) methylene chloride/ methanol; Yes ) Title as a white solid 1H NMR Spectrum: 1.34 (d, 3H), 1.64-1.72 (m, 2H), 2.04-2.07 (m, 2H), 3.20 (s, 3H), 3.25-3.47° (m, 2H), 3.86-3.97 (m, 2H), 4.03 (s, 3H), 4.21-4.23 (m, 1H), 4.88-4.91 (m, 1H), 7.28(dd, 1H), 7.33 (s, 1H) , 7.47 (dd, 1H), 7.51 (dd, 1H), 7.92 (s, 1H), 8.38 (s, 1H), 9.67 (s, 1H); Mass Spectrum : (M+H)+ 489. : Obtained

N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine 01 pH by hydrotreatment at pH 1) hydrochloride (Example No. di from salt and aqueous_bed extraction using ©010010:006080 Organic matter 58 was dried and concentrated to obtain free amine as white foam; magnesium sulfate using 111 NMR Spectrum: (B01901)) 1.78- 1.85 (m, 211+ INH), 2.18 (m, 2H), 2.80 (m, 2H), 3.22 (m, 2H), 4.03 (s, 3H), 4.61 (m, 1H), 7.03 (s, 1H) , 7.15 (m, 2H), 7.29 (s, 1H), 7.31 Vo (m, 1H), 8.50 (m, 1H), 8.69 (s, INH); Mass Spectrum: (M+H)+ 403.

YYeo

- Yi - 11 Example No

N-(3-Chloro-2-fluorophenyl)-6-m ethoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4- yl}oxy)qui nazolin-4-amine (Process A ) (R)-(+)-2-methoxypropionic acid using VY and then repeating the method mentioned in Example No. mmol) to obtain the compound mentioned in the title as a white solid 02 (ana ov) ¢ ( LAY ) HT 1H NMR Spectrum: 1.24 (d, 3H), 1.57-1.67 (m, 2H), 2.04-2.09 (m, 2H), 3.22 (s, 3H), 3.22-3.47 (m, 2H), 3.87 -3.97 (m, 2H), 3.97 (s, 3H), 4.22-4.27 (m, 1H), 4.92-4.95 (m, 1H), 7.27-7.30 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.60 (dd, 1H), 7.82 (s, 1H), 8.37 (s, 1H), 9.67 (s, 1H); Mass Spectrum : (M+H)+ 489.1 Ex. 1 2R)-2-Amino-3-[4-({4-[3-chloro-2-fluo roanilino]-6-methoxyquinazolin-7- yl} oxy)piperidin-1-yl]-3-0xopropan-1-ol

ly - - (process 1( Cl HN 0 fermentant H,N HO) V4 TBTU (4) mg; VAY mM (Use) was added to a solution of: N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine (ana © ) ° ara mmol)e; 5 A) DIPEA 4 ,; ode except mmol) and YA (N-(tert-butoxycarbonyl)-D-serine (mg VY mmol) in methylene chloride 9 ml). The resulting solution was stirred at room temperature overnight; diluted with (Y+) methylene chloride ml); washed with 148011 (7 p) (7 »© elas (de )© ml); dried (MgSO) and evaporated. The resulting foam was dissolved in (Je©) methylene chloride 0 and treated with trifluoroacetic acid (©mL). Leave the resulting solution to settle at room temperature for an hour; It was concentrated and purified with a mass-induced preparative 10148 to obtain the compound mentioned in title (47,5 7); H NMR Spectrum: 1.58-1.72 (m, 2H), 2.01 -2.08 (m, 2H), 3.24-3.44 (m, 2H), 3.80-4.03 (m, 4H), 3.95 (s, 3H), 4.77 (m, 1H), 4.91 -4.94 (m, 1H), 7.27(dd, 1H), 7.35 (s, 1H), 7.47

- VIA - (dd, 1H), 7.51(dd, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.67 (s, 1H); Mass Spectrum : (M-+H)+ 490 : 11 Example (2S)-2-Amino-3-[4-({4-[3-chloro -2-fluoroanilino]-6-methoxyquinazolin-7- yl}oxy)piperidin-1-y 1 ]-3-oxopropan-1-ol . Then repeat the method mentioned in Example No. 26, but using millimoles) to obtain the product 0.771 cana YA) N(tert-butoxycarbonyl)-L-serine ° mentioned in Title (777); 111 NMR Spectrum: 1.58-1.73 (m, 2H), 2.01-2.08 (m, 2H), 3.24-3.44 (m, 2H), 3.80- 4.00 (m, 4H), 3.97 (s, 3H), 4.74 (m, 1H), 4.93-4.96 (m, 1H), 7.28 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.82 (s, 1H), 8.37 (s, 1H) , 9.67 (s, 1H); Mass Spectrum: (M-+H)+ 490.0111 Example No. (2S)-3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl1]-2-(di methylamino)-3-oxopropan-1-ol

1194 - - (Process D) Cl for each HN 0 N > f for N ml “\f7_7 HO added NaCNBH; solid YAY) mg; 1.114 mmol) to a solution of : (2S)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-me thoxyquinazolin-7- yl } oxy)piperidin-1-yl]-3-oxopropan-1-ol ° VOU) volume 0.707 mmol; Example number YO) sodium acetate trihydrate “(V0 mg; 2.0 mM YY (de of 06Nr10e00)(aqueous) VAL) acetic acids (Jo Y,0) mg Ye V mmol) at Zero - © M. The resulting solution was left to warm to room temperature and stirred for one hour. The mixture was then evaporated and the remaining solid was purified by flash chromatography on silica gel 00 and sequentially separated by increasing polar mixtures of dichloromethane in methanol (L) 0/001 ( = 15/85). The fractions containing the desired product were collected and evaporated to obtain the compound mentioned in the title as a white solid (775); NMR Spectrum: 1.52-1.69 (m, 2H), 1.94-2.07 (m, 2H), 2.28-2.30 (2 x s, 6H), 3.15-111 (m, 2H), 3.53-3.76 (m, 4H) ), 3.94 (s, 3H), 4.02 (m, 1H), 4.49 (m, 1H), 4.92-4.94 (m, 3.22 1H), 7.27(dd, 1H), 7.34 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.38 (s, 1H), Vo (s, 1H); Mass Spectrum: (M+H)+ 518 9.65

- YY. — 117 Example No. (2R)-3-[4-({4-[3-Chloro-2-fluoroanilin 0]-6-methoxyquinazolin-7-y1} oxy)piperidin-1- yl]-2-( dimethyla mino)-3-oxopropan-1-ol (Process D): Using 11 the process mentioned in Example No. (2R)-2-amino-3-[4-({4-[3) was repeated -chloro-2-t7uoroanilino]-6-methoxyqu inazolin-7- yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol ° to obtain the compound mentioned in the title (1 mg afammol 3 Ex. Yo.) (777); , 2H), 3.53-3.74 (m, 4H), 3.94 (s, 3H), 4.04 (m, 1H), 4.47 (m, 1H), 4.91 (m, 1H), 7.26 (dd, 1H), 7.35 ( s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.66 01 (s, 1H); Mass Spectrum: (M+H)+ 518. (VA) Example No. (2S)-1-(4-{[4-[3-Chloro-2-fluoroanilino]-6-(2-pyrrolidin-1) -ylethoxy)quinazolin-7-ylJoxy}pip eridin-1-yl)-1-oxopropan-2-ol

111 - - (Process B) Cl p Jr M Na Ol OH VT) (S)-(-)-2-Acetoxyproprionyl chloride C (se a AY) added to a solution of : N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-( 2-pyrrolidin-1- ° ylethoxy)quinazolin-4-amine trihydrochloride Yas YY) _mM (se Ge VY “de VV) Triethylamines (J se in 01 ( methylene chloride ml) while being stirred at 10 C. The resulting solution was left to warm to room temperature and stirred for To min. The resulting yellow solution was diluted with methylene (V+) chloride (0 mL) and washed with water (XV © mL); desiccation, desiccation (MSOs), and evaporation. The resulting foam was dissolved in 1 (THF ml) and 1 (pyrrolidine ml) added. The mixture was heated at 71 °C for 7 hours; evaporation and purification of the remaining materials by chromatography, flashing on silica gel and sequentially separating them using ammonia/dichloromethane in methanol (L) (2/42) The parts containing the desired product were collected and evaporated to obtain the product mentioned in heading 1 as a white solid.) 99 0.0 g; 69,7#?

- 1171 - 1111118 Spectrum: (DMSO-dg): § 1.20 (d, 3H), 1.52-1.82 (m, 6H), 1.86-2.08 (m, 4H), 3.24-3.50 (m, 4H), 3.74-3.86 (m, 2H), 4.28 (m, 2H), 4.45 (m, 1H), 4.89-4.95 (m, 3H), 7.27 (dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H), 7.53 (dd, 1H), 7.87 (s, 1H), 8.38 (s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)" 558. Prepared

N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-( 2-pyrrolidin-1- ylethoxy)quinazolin-4-amine trihydrochloride is as follows: (1) used as prefix 0 9 cl 0 0 be 0838 “en _ aN x a on f a(gs aN - how much Tod what » = ham -_ ham 7: ml) to pending (©) 1,2-Dichloroethane 1,77 g 0) 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6 was then added while stirred; (WO03 /082831 mol; prepared as in reference example ¥ from heating (Je V0) DMF mmol) in 01 can V,Y4) potassium carbonate and adding (©+) methylene chloride 1 h. The reaction mixture was diluted with £A suspension obtained at 7 + 0 M for

EE e dried (50p11) and evaporated to dryness to obtain (Je Ye X 9 ml) and washed with water as brown oil used unrefined; (77000 g; YLT) ; Mass Spectrum: (M+H)+ 382.

Y.¥A) © ml; 17.8 mmol) to a solution of 5.1 g (4.446 pyrrolidine) was added and the resulting pale brown solution (cali ml) was added and heated during 1 DMF (1.79 mmol) in at 0 um for two hours. The reaction mixture was evaporated to dryness using a rotary evaporator under a brown foam (7000 aa 7,1) high pressure to obtain;

Mass Spectrum : (M+H)" 7 pyridinium mmol) to a pure solution of LY 0 g (intermediate compound M was added within minutes. Reaction mixture was stirred 1710 mmol) at ?011 aa 1) hydrochloride 0 h. The reaction mixture was cooled to room temperature and the precipitate was suspended 171 m sad at PH in water (©mL) and the resulting black precipitate was removed by filtration. Concentrated aqueous pH and evaporation of the resulting solution to dryness. Using 1 ammonia filtrate and sequentially separating it with silica gel, the resulting beige solid was purified by flash chromatography (-19//85). RF/001 (Ag) methanol in dichloromethane of increasing polarity from Lida, yo Collect the portions containing the desired product and evaporate them to obtain a “pale green foam” (Ze 17,1 g)

Mass Spectrum: (M+H)" 403.

1176 - - (+,0Y)) Di-tert-butylazodicarboxylate added g; 7.48 mmol) to a solution of ? 0 ) collected; 0.74 mmol); 1 (4) 4-hydroxy-1-tert-butoxycarbonylpiperidine s mg; 1 mmol) 0) triphenylphosphine gathered YEA mM (Je 10) THF (Iso) at 0 um while stirred within minutes. Leave The resulting yellow solution was warmed to room temperature C and then heated at Ve C for 1 h. The reaction mixture was concentrated, the remaining material was purified by flash chromatography on silica gel, and sequentially separated with increasing polar mixtures of methylene methanol s® ammonia chloride (La) (100/zero-0/©). The fractions containing the desired product were collected and evaporated to obtain a pale green oil (1 8c; 77#) ¢ Mass Spectrum: (M+H)+586 Addition of 1 JTFA (mL) to a solution of (ads YY. ) Y bkd mmol) in 1 methylene (chloride mL) while stirring at Dla has © minutes. The resulting yellow solution was left to warm to room temperature and stirred for 1 hour.The reaction mixture was evaporated to dryness and the remaining materials were re-dissolved in 100 (methylene chloride mL).10 (000 mL) ethyl ether was added, followed by a solution of HCL in (Je Y ) dioxane ) ¢ mol). The resulting thick white precipitate 10 was collected by filtration; It was washed with diethyl ether (7*7 (Je) and dried to constant weight to obtain: N-(3 -chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-( 2-pyrrolidin-1). (-ylethoxy)quinazolin-4-amine trihydrochloride 1) ( as a white solid and then used without purification A) ¢ , + C 101 10 Mass Spectrum: (M+H)+ 486

- A - Example No. 19 (28)-1-(4-{[4-[3-Chloro-2-fluoroanilin ol-6-(2-methoxyethoxy)quinazolin-7- ylJoxy}piperidin-1 -yl) -1- oxopropan-2-ol (process A) cl \ HN 0 OC no 0 μml _ OH o 1,075 (aaa 0 ) added TBTU mmol) to a solution of : N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin -4-yloxy)quinazolin-4-amine dihydrochloride YA ) mg; iad millimoles); vv) L-(+)-lactic acid mg; £8 mmol) and DIPEA vd), ml; 975 mmol) in V+ (methylene chloride ml) while stirred. The resulting solution was stirred at room temperature for 2 hours and then diluted with methylene chloride (01 ml). This solution was washed with NaOH (7p) (de © XY), dried (MgS04) », filtered and evaporated. The residue was purified by chromatography and flashed on silica gel and eluted using ammonia/ methylene chloride in (¢V)methanol (3°/°(Vo for J of the product mentioned in the title as a white solid) $y 2, (ada AQ %( ¢

- 1756 -

IH NMR Spectrum: (01150-0) : 51.21 (d, 3H), 1.64-1.72 (m, 2H), 1.86-2.07 (m, 2H), 3.37-3.46 (m, 2H), 3.77-3.92 (m , 5H), 4.27 (m, 2H), 4.46 (m, 1H), 4.90-4.92 (m, 3H), 7.29 (dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H). 7.52 (dd, 1H), 7.86 (s, 1H), 8.38 (s, 1H), 9.63 (s, 1H); Mass Spectrum: (M+H)+ 519. Hah then preparation: ‎N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin -4-yloxy)quinazolin-4- The amine dihydrochloride (intermediate compound 1 in the following reaction diagram) used as a starting material is as follows: al Cl Cl F F F with a label for . HN °\m HN > OL) — oO Tol N N HN 0 N “ : b) simulates n Cl 0 )Cl 0 ) HN HN UO — Ma 7 0 HO 6 | 10 ADDED: Vee) 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6 g YOY mmol) solid to a clear liquid of 70.7 aa 7 ( pyridinium hydrochloride mmol) at 6/19 m in 10 minutes. The reaction mixture was stirred at 1071 °C for 2 hours and then cooled to A

1/9 - - room temperature. The mixture was suspended in (Ja Fo)ele and the resulting precipitate was collected by filtration; It was washed with diethylether 5 (Js)© mL and dried to constant weight in a low-pressure oven at 200 to obtain 01 beige solid. eV) g” (IVY Mass Spectrum: (M+H)” 306 © Added V VV) Acetic anhydride mg; 5 mmol) and a NaOH solution (£1 mg; ara mmol) ) in 9 water (Ja to a suspension of Yo. (Yo.) mg; , mmol) in THF (©mL) while stirred at -10 O. The resulting two-phase mixture was stirred at room for 2 hours The organic phase was kept, dried (1/850 B) and evaporated to dryness The resulting beige foam was pulverized with acetonitrile (¥ ml), cooled to 0 C and the 0 - precipitate collected by filtration and dried to constant weight at 560 m low-pressure furnace to obtain a beige solid of 4. (777 mg (ATA Mass Spectrum : 11711 348.0.58 cana ¥1 8 mmol) Di-tert-butylazodicarboxylatedslial (8 mmol) solid to solution from 4 mg; 7 mmol); 0.58 ana 0 ( triphenylphosphine mmol) and A4 (4-hydroxy-1-tert-butoxycarbonylpiperidine Vo? 1.44 cana mmol) in V+) THF ml) while being stirred at room temperature within ½ minutes The resulting yellow solution was stirred at room temperature for 2 hours and concentrated to obtain a yellow foam which was then dissolved in (pV) NH, in MeOH (0 ml) and stirred for an hour. The solution was concentrated and purified by flash chromatography on silica gel (and separated by Gals with a mixture of 0014-MeOH in a ratio of 0/30) to obtain

0/8 - - over 1 YA) A mg; 1 (1 as a beige foam; 489 Mass Spectrum : (M+H)" VY cae V1) Di-tert-butylazodicarboxylatedslis), + mmol) solid to a solution of A (V0) mg 74 mM mol) triphenylphosphine s (141 g; VY mmol) and 177 cane 00) 2-methoxyethanol mM THE 3 (Use (7 mL) while stirred at da 0 room temperature during © minutes. The resulting yellow solution was stirred at room temperature for 2 hours and then concentrated to a yellow foam that was dissolved in 1014 (Je 1) and treated with (Je 1) trifluoroacetic acid and stirred for 1 hour. The solution was concentrated and purified with LCMS N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(pi peridin-4-yloxy)quinazolin-4- amine dihydrochloride (7)1 as a white solid A+) Mg 799); .447.13 Mass Spectrum: (M+H)" Ex. -2-hydroxypropanoyl]piperidin-4-yl} oxy) quinazolin-6 -ol Cl 10 HN HO 2 a N 0 N OH vo

1179 - - solid lithium iodide 7.11 (g; 059.8 mmol) was added to (Je©) 2,4,6-collidine at VT m. The resulting yellow solution was heated at 171 °C for 1 hour. Compound: (2S)-1-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyqu inazolin-7-yl} oxy)piperidin-1-yl}-1-oxopropan -2-ol (0 °) °g; 7.17 mmol; Example No. ([0]E) Solid within 10 minutes. The resulting solution was stirred at 11 °C for 11 hours to obtain a dark brown yellow precipitate. The liquid was clarified and the solid was purified with a mass-induced preparative LCMS to obtain Product stated in title as a brown solid (0 px for (d, 3H), 1.61-1.77 (m, 2H), 1.95-2.08 (m, 2H), 51.21 :(and 01150-0) ' H NMR Spectrum: (m, 2H), 3.86-3.92 (m, 2H), 4.47 (m, 1H), 4.91 (m, 1H), 7.26 (m, 1H), 7.32 (s, \-3.41 3.51 1H), 7.45 (m, 1H), 7.53 (m, 1H), 7.70 (s, 1H), 8.33 (s, 1H), 9.45 (s, 2H), Mass Spectrum: (M+H) 461. Ex. 71 (2S)-1-[4-({4-[3-Chloro-2-fluoroanilin o0]-6-isopropoxyquinazolin-7-yl}oxy)piperidin-1- yl]-1-oxoprop an-2-ol Vo ‎YY. |

- Y.A. - (operation and).

Cl > HN 0

Oe

Oh

mmol) solid to a solution of 134 mg; YY 5 ( Di-tert-butylazodicarboxylatedila) mM 154 mg (YT4) triphenylphosphine mM) 58 Ja 14 ( 2-propanol) was dissolved in The yellow solution was stirred ia ml) at 1 (THE 3 mol) 0: the product was heated to room temperature and 4-[3-chloro-2-fluoroanilino]-7 was added. ({1-[(2 S)-2-hydroxypro panoyl]piperidin-4- yl} oxy)quinazolin-6-ol h; 1 for 2 Av for a mixture at AJ CHa A then (Y 0 mmol; Example No. 0 VY mg; Yo.) mass-induced preparation for LCMS Residue pulp <a) purification, cooling, and evaporation. Ye ¢ 08 Compound in title as white solid (5 l mg no

IH NMR Spectrum: )0001:(: 51.37 (d, 3H), 1.43 (d, 6H), 1.61 -1.72 (m, 2H), 1.95- 2.07 (m, 2H), 3.38-3.50 (m, 2H), 3.78-3.88 (m, 2H), 4.49 (m, 1H), 4.66 (m, 1H), 4.82 (m, 1H), 7.15 (m, 3H), 7.31 (s, 1H), 8.52 (s, 1H) , 8.69 (s, 1H); Mass Spectrum: (M+H)" 503. Vo

YAY - - Example No. YY (25)-1-[4-({4-[(3-Chloro-4-fluo roanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-0x opropan-2-ol (Process A) Cl º 2 HN | 0 HO. 0 SO: H — N . 0 added 15 cane HATU (V4) mmol) to a solution of : N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride 0 mg 457 mmol); L-(+)-lactic acid (5 mg; 0.9 mmol) and <- methyl ¢Jar,V0) morpholine 0 1.74 mmol) in (Je 01) DMF while being stirred at room temperature After 2 hours, the mixture was evaporated to dryness, the remaining material was purified by column-on-silica chromatography, and sequentially separated by increasing polar mixtures of methanol [dichloromethane (01/-1/95). containing the desired product into a gum that was pulverized using (Je 01( diethylether) and the resulting material was collected by filtering and dried under high pressure to obtain the product mentioned in the title in the form of a white powder. (cana OFT) 775); l

YAY - - NMR Spectrum: (DMSO dg) 1.1-1.3 (m, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H). 3.0- yra (m, 2H + H,0) 3.7 - 4.1 (m, 2H), 3.95 (s, 3H), 4.43 (m, 1H), 4.95 (m, 2H), 7.32 (s, 3.60 1H), 7.47 (dd, 1H), 7.7-7.8 (m, 1H). 7.83 (s, 1H), 8.0-8.1 (m, 1H), 8.58 (s, 1H), 9.87 (bs, 1H); Mass Spectrum: (M+H)+ 475 ° Then prepare: ‎N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine ‎hydrochloride The starting material used is as follows: Di-tert-butylazodicarboxylatedilal ( 64 g VE mmol) methylene (Js 01( 0 chloride) is slowly reduced to a suspension of ¢a>), +) 4- Chloro-6-methoxyquinazolin-7-ol 7 mM ede as listed in ISBN 70040414879; Example 1 'Preparation of starting materials') 5,4-hydroxy-1-tert-butoxycarbonylpiperidine (44gm; 7.14mmol) triphenylphosphine (/A/gm; V,Y¢ mmol ) in methylene chloride (+© ml) during its stirring at © m in a nitrogen atmosphere. Leave the mixture to warm to room temperature for VA 1 hour. The reaction mixture was filtered, purified by silica flash chromatography, and separated by Lad with increasing polar mixtures of 11 4/70 (Triethylamine/ ethyl acetate/ isohexane followed by 0/44/1). The fractions containing the desired product were collected and evaporated under low pressure for:

- YAY - tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine- 1 -carboxylateas «( 879, g; Yo) white 1 ala as 1H NMR Spectrum: (DMSO dg) 1.40 (s, 9H), 1.5-1.7 (m, 2H), 1.9-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.60 -3.80 (m, 2H), 3.95 (s, 3H), 4.92 (m, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.83 (s, 1H); Mass Spectrum : (M+H)+ 394 ° : To a suspension of (Je V) dioxane in HCI was added; Molar of tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate acetonitrile mg in 1 mmol ©, #*( 3-chloro-4-fluoroaniline ) and 1544 cama 1 ) ml). The reaction mixture was stirred and heated at 70 °C for ; hours. The resulting precipitate (01) was filtered and dried under low pressure to obtain acetonitrile and washed with Gale 0.

N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride

Mass Spectrum: (M+H)+ 403. (peo 17)

YY Example No. (2R)-1-[4-({4-[3-Chloro-4-fluor oanilino}-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-ox0 propan -2-ol

- YAS - (Operation A) 0 or 0 | HN

O.L

0 : Paired

D-Lactic acid was coupled with N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride ° to obtain the product mentioned in the title; Using conditions such as those in Example No. 'H NMR Spectrum: (DMSO de) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.50 (m, 2H + H,0), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.8 (m, 2H), 7.32 (s, 1H). 7.45 (dd, 1H), 7.7-7.85 (m, 2H), 8.1 (dd, 1H), 8.5 (s, 1H), 9.55 (s, 1H); mass

Spectrum : (M+H)+ 475 1 C 17.7 Melting Point:

Ye No. Jha 2S)-1-[4-({4-[3-Bromoanilino}- 6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-o

YYo

- da - (operation a) o LL

I | HN Br 0 0 N Paired

N-(3-Bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)q uinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid ° to obtain the product mentioned in YY using Method similar to that given in the address number example in the form of white powder; 111 NMR Spectrum: (DMSO d¢) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.60 (m, 2H + H,0), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.13 (s , 1H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H) + 01 501,503. : preparation a

N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quin azolin-4-amine hydrochloride used as a starting material is as follows.

- YAR - : tert-Buty!l 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carbo xylate (starting material preparation) YY was conjugated with A method similar to that mentioned in Example No. 3-bromoaniline: for the preparation of N-(3-Bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride M '"H NMR Spectrum: (DMSO de): 1.8-2.1 (m, 2H), 2.1-2.3 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.88 (m, 1H), 7.38 -7.52 (m, 2H), 7.6 (s, 1H), 7.8 (d, 1H), 8.05 (s, 1H), 8.5 (s, 1H), 8.87 (s, 1H), 9.2 (bs, 2H), 11.7 (s, 1H); Mass Spectrum: (M+H)+ 431.

Yo Example No. (2R)-1-[4-({4-[3-Bromoanilino}- 6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-o 00 for 1 | HN Br 0 2 0 : Paired

N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)q uinazoline-4-amine hydrochloride to obtain YY using a method similar to that in Example No. D-lactic acid and then conjugate it with On the product mentioned in the title in the form of a white powder;

- YAY - '"H NMR Spectrum: (DMSO dg) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H + 1120(, 3.7) - 4.1 (m, 2H), 3.95 (s, 3H), 4.43 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.15 (s, 1H), 8.5 (s, 1H), 9.5 (s, 1H); -[5-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-ox0 propan-2-ol (Process A) cl

HO

"8 | HN' g 0 7 : Paired

N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine hydrochloride to obtain YY using a method similar to that in Example No. L-(+ )-lactic acid B ¢ The product mentioned in the title is in the form of a white powder

- YAA - ; IH NMR Spectrum: (DMSO mL 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.60 (m, 2H + H,0), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.3- 7.45 (m, 3H), 7.7 (d, 1H), 7.85 (s, 1H ), 8.5 (s, 1H), 9.95 (s, 1H); Mass Spectrum : (M+H)+ 475. : Then prepare 0

N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride used as a starting material is as follows. : tert-butyl 4-[ conjugate (4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carbo xylate 01

VY to those mentioned in Example No. Alles using the 2-fluoro-S-chloroaniline method with compound: (preparation of starting materials) to prepare

N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride : For Vo

N-(5-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride

Y Y 00

- YAY - 111 NMR Spectrum: (DMSO dg) 1.8-2.1 (m, 2H), 2.1-2.35 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.8-5.0 (m , 1H), 7.4-7.55 (m, 2H), 7.55-7.75 (m, 2H), 8.45 (s, 1H), 8.82 (s, 1H), 9.22 (bs, 2H), 11.94 (s, 1H); Mass Spectrum: (M+H)+ 403.

YV Example No. (2R)-1-[4-({4-[5-Chloro-2-fluor oanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-0x0 propan -2-ol (idee)© cl

HO.

YAY

0 7

N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine hydrochloride to obtain product YY using a method similar to that in Example No. D-lactic acid of the title in the form of a white powder; m, 2H + H,0), 3.7 - 4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.45 (m, 3H), 7.7 (dd, 1H), 7.8 (s, 1H), 8.4 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+475.7.0

- 1094 and -

YA Example No. (2S)-1-[4-({4-[3-Ethynylanilino]-6-met hoxyquinazolin-7-yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol (Operation A) The Ls 0 : Paired

N-(3-Ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy )quinazolin-4-amine ° hydrochloride

YY using a method similar to that in Example No. Lo(+)-lactic acid is combined with ¢ to obtain the product in the title as a white powder 111 NMR Spectrum: (DMSO dg) 1.2 (d, 3H) ), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 (m, 2H + H;0), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 01 (m, 2H), 7.2 (d, 1H), 7.33 (s, 1H), 7.39 (dd, 1H), 7.83 (s, 1H) , 7.89 (d, 1H), 7.97 (s, 1H), 8.5 (s, 1H), 9.48 (s, 1H); Mass Spectrum: (M+H)+ 447.

- 191 - : Then preparation

N-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)qu inazolin-4-amine hydrochloride used as a starting material is as follows: : hull then conjugate tert-butyl 4-[(4 -chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carbo xylate (prepare YY using a method similar to that in Example No. 3-ethynylaniline with compound: starting materials) to prepare

N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride 01 : To obtain

N-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)qu inazolin-4-amine hydrochloride 1H NMR Spectrum : (DMSO dg) 1.85-2.1 (m, 2H),2.1-2.3 (m) , 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.25 (s, 1H), 4.8-4.95 (m, 1H), 7.39 (d, 1H), 7.47 (dd, 1H), 7.6 (s, 1H), 7.8 Vo (d, 1H), 7.89 (s, 1H), 8.5 (s, 1H), 8.83(s, 1H), 9.22 (bs, 2H), 11.68 (s, 1H); mass

Spectrum: (M+H)+ 375.

- 1097 -

Ya Example No. (2R)-1-[4-({4-[(3-Ethynylanilin 0]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl}-1- oxopropan- 2-01 (Operation A): Paired

N-(3-Ethynylphenyl)-6-methoxy-7-(piperidi n-4-yloxy)quinazolin-4-amine hydrochloride ° to obtain YA using a method similar to that in Example No. D-lactic acid B ¢ Product mentioned in title as white powder 111 NMR Spectrum: (DMSO de) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 ( m, 2H + H,0), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.2 ( d, 1H), 7.33 (s, 1H), 7.39 (dd, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 7.97 (s, 1H), 1 8.48 (s, 1H), 9.47 ( s, 1H); Mass Spectrum : (M+H)+ 447.01 Example No. (25)-1-[4-({4-[3-Bromo-2-fluoro anilino]-6-methoxyquinazolin-7-yl} oxy) piperidin-1-yl]-1-oxopropan-2-ol

YY.

- 197 - (Operation A).

HO cL A 0

N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin- 4-yloxy)quinazolin-4-amine hydrochloride

YY using a process similar to that described in Example No. Lo(+)-lactic acid was combined with 0 ¢ to obtain the product mentioned in the title in the form of a white powder 'H NMR Spectrum: (DMSO dg) 1.2 ( d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 (m, 2H + H,0), 3.7 -4.1 (m, 2H), 3.95 (s, 3H ), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.21 (dd, 1H), 7.32 (s, 1H), 7.48-7.65 (m, 2H), 7.8 (s, 1H), 8.37 ( s, 1H), 9.6 (s, 1H); .Mass Spectrum: (M+ H)" 521 01 : Starting material prepared

N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)qu inazolin-4-amine hydrochloride is as follows: TAMM 161-8071 4-[(4-chloro) -6-methoxyquinazolin-7-yl)oxy]piperidine-1-carbo xylate Vo A process similar to that of olastultert-butyl (3-bromo-2-fluorophenyl)carbamate is paired with: (preparation of starting materials) to prepare YY and then describe it in Example No

- 10956 -

N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride : on N-(3-bromo-2-fluorophenyl)-6- methoxy-7-(piperidin-4-y loxy)quinazolin-4-amine hydrochloride ° 'H NMR Spectrum: (DMSO dg) 1.85-2.1 (m, 2H),2.1 -2.32 (m, 2H), 3.0-3.35 ( m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H), 7.5-7.65 (m,2H), 7.75 (dd, 1H), 8.45 (s, .Mass Spectrum: (M+ H)" 447.12 ¢1H), 8.8(s, 1H), 9.15 (bs, 2H), 11.86 (s, 1H): Prepared

Triethylamine is a starting material. The tert-butyl (3-bromo-2-fluorophenyl)carbamate 0 (Use 1 mg; €Y'A) 3-bromo-2-fluorobenzoic acid was added to a stirred solution of (de 007 (mmol 567 “Ja 1 (Diphenyl phosphoryl azide ml)) then 10 (tert-butanol) is added and the reaction mixture is heated in reflux overnight. Then the toluene is purified The solution is evaporated Until drying and azeotropic extraction of 0 from ethyl _residuals using flash chromatography by sequential separation of silica using 1. Particles containing the desired product were collected and evaporated (0/10) i-hexane/ acetate as a white solid tert. -butyl (3-bromo-2-fluorophenyl)carbamate For (pet) 'H NMR Spectrum (CDCI3) 1.5 (s, 9H), 6.4 (s, 1H), 7.1-7.25 (m, 1H), 7.7 (dd, 1H)

:-Yo-

YY Example No. (2R)-1-[4-({4-[3-Bromo-2-fluoro anilino}-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-oxopropan -2-ol (Process A).

Ho ro ll 0 7

N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride °

YY A process similar to that described in Example No. pladiuly D-LACTIC ACID paired with B to obtain the product mentioned in the title as a white powder; 'H NMR Spectrum: (DMSO dg) 1.2 (d, 3H) , 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 (m, 2H + H,0), 3.7 - 4.1 (m, 2H), 3.95 (s, 3H), 4.45 ( pent, 1H), 4.8-5.0 (m, 2H), ¢7.22 (dd, 1H), 7.32 (s, 1H), 7.48-7.65 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H ), 9.62 (s, 1H) 01

Mass Spectrum : (M+H)+ 475 79 Example No. (28)-1-[4-({4-[(4-Chloro-2-fluo roanilino]-6-methoxyquinazolin-7-yl} oxy) piperidin-1-yl]-1-0xopropan-2-ol

- 10957 - (Operation A).

F Ci

SS} is inclined on 0 2

N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine hydrochloride

VY using a process similar to that described in Example No. L-(+)-lactic acid and then combined with B to give the product mentioned in the title as a white powder; 111 NMR Spectrum: (DMSO dg) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 (m, 2H + H30), 3.7-4.1 (m, 2H), 3.93 (s, 3H), 4.44 ( pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H), 7.8 (s, 1H), 8.33 (s, 1H), 9.5 (s, 1H); Mass ¢Spectrum : (M+H) + 475 01 M. 159 Melting Point: The starting material has been prepared.

N-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4- yloxy)quinazolin-4-amine hydrochloride as follows: 10

Voile (aa0) 4-[(4-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7- ol 4413) DMA mmol; Which were prepared as described in the international application D Lala 1/1100) in: ml). (001) added

- 199 - g; 776 mmol) 1060( tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate M with stirring. 0 mmol is done); the mixture is heated to 61056 an Vid) cesium fluoride s and (eV eo) EtOAc and (Jo Yoo) are dried by evaporation of the solvent; And the fractionation of the remaining substance between water and drying it on 0. (Ja Yoo) mL) and brine (001*7) organic matter using water and evaporates to give MgSO, © tert-butyl 4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin- 7-yl}ox y)piperidine- 1-carboxylate 4 Ved 'an YeYY) 111 NMR Spectrum: (DMSO-d¢): 1.4 (d, 9H), 1.5-1.7 (m, 2H), 1.8-2.1 (m , 2H), 3.1-3.3 (m, 2H), 3.65-3.85 (m, 2H), 3.91 (s, 3H), 4.75-4.9 (m, 1H), 7.3 (s, 1H), 7.32 (dd, 1H) ), 01 7.54 (dd, 1H), 7.57 (dd, 1H), 7.80 (s, 1H), 8.32 (s, 1H), 9.5 (s, 1H); Mass Spectrum: .(M+H) +503. To a solution of (Ja 001) dioxane in hydrogen chloride a solution of 4 M of: was added by stirring it from tert-butyl 4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin -7-yl 1 oxy)piperidine-1- Vo carboxylate a Ve The reaction mixture was heated at (Je 001 (acetonitrile mmol) in 0464 7 evaporate 9 for an hour after that it was concentrated at 7 volume. Then Collecting the resulting precipitate by filtration, washing it with: and drying it under low pressure to obtain acetonitrile.

N-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine 0 hydrochloride

TA v cp as a 7 white solid

111 NMR Spectrum: (DMSO-d6): 1.90-2.10 (m, 2H), 2.10-2.32 (m, 2H), 3.00-3.35 (m, 4H), 4.02 (s, 3H), 4.90 (m, 1H) , 7.36-7.50 (m, 1H), 7.50-7.70 (m, 3H), 8.48 (s, 1H), 8.80(s, 1H), 9.30(bs, 2H), 11.90 (bs, 1H); Mass Spectrum: (M+H)+ 403.

VY Example No. (2R)-1-[4-({4-[4-chloro-2-fluoroanilino}-6-methoxyquinazolin-7-yl} oxy)piperidin-1- °yl]-1-0x0 propan-2-ol (Process A) 0 | HN

TOC

Oh

0

N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine hydrochloride 01

YY ©0-18011_using a process identical to that described in the example. ACID is paired with ¢ to give the product mentioned in the title as a white powder.

IHNMR Spectrum : (DMSO de) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1- 3.55 (m, 2H + H,0), 3.7 - 4.1 (m , 2H), 3.93 (s, 3H), 4.43 (pent, 1H), 4.80-4.98 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H), 7.8 (s, 1H) ), 8.35 (s, 1H), 9.5 (s, 1H); Mass Vo «Spectrum: (M+H)+ 475 M. 18 Melting Point at

- Y44 - ve Example No

N-(3-chloro-2-fluorophenyl)-6-m ethoxy-7-{[1-(1 -methyl-L-prolyl)piperidin-4- yl]oxy}quinazoli n-4-amine (Process A ).

HN Cl 0 m Nam 0 °

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine hydrochloride using a process similar to that described in Example No. ? N-methyl-L- proline has been conjugated with B to give the product mentioned in the title in the form of a white powder; ), 01 3.05- 3.25 (m, 2H), 3.25-3.65 (m, 1H + 1120), 3.75-4.2 (m, 2H), 3.95 (s, 3H), 4.75-5.0 (m, 1H), -7.2 7.4 (m, 2H), 7.4-7.6 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.65 (s, 1H);

Spectrum: (M+H)+ 514 M. VAY Melting point at

Yer -— - Example No. Yo (25)-1-[4-({4-[3-chloro-2-fluor oanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1- yl]-1-0x0 propan-2-ol (ie) HN LL, F 66 1 N 2 E OH N-(3-Chl oro-2-fluorophenyl) -6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine (0.15 pra O00) mmol) and 0005 cana (1 A) 4-dimethylaminopyridine mmol) are stirred in diisopropylethylamine s (Je Y,0) acetonitrile ( 17 fill; 101 mmol) was added. The mixture was cooled to +0"C and a solution of: 1.91"de 1 ( (8)-(-)-2-acetoxypropionyl chloride 0 mmol) in acetonitrile (0 © mL) was added. drop by drop. Then it is stirred at this temperature for a period of +0 hours. Water was added (1.0 potassium hydroxides (Je) + 1 ml of 259 w/w solution in cl) and the mixture was stirred at Room temperature overnight The materials are separated and the organic matter is diluted with 0. (de Y,0) ethyl acetate Water is added followed by acid 86806 vol. (de YY) 10 The mixture is stirred and fractionated The organic materials are dried using magnesium “sulphate” and filtered and concentrated under reduced pressure to give the product mentioned in heading YY (0 milligrams; 47 7) as a white solid;

- Yu) - 'H NMR Spectrum: (DMSOdg) 1.19 (d, 3H), 1.48- 1.75 (m, 2H), 1.94-2.13 (m, 2H), 3.21 -3.53 (m, 2H), 3.93 (s, 3H), 3.78 - 4.06 (m, 2H), 4.40 - 4.52 (m, 1H), 4.83 - 4.99 (m, 2H), 7.28 (dd, 1H), 7.33 (s, 1H), 7.42 -7.55 (m, 2H), 7.81 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum: (M+H)+ 475. 1 Example No. °

N-(3-Chloro-2-fluorophenyl)-6-m ethoxy-7-{[1-(3 -methoxypropanoyl)piperidin-4- yl]oxy}quinazol in-4-amine (Process B)

LS

0

O — 0 \

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin -4-yloxy)quinazolin-4-amine except for the subsequent addition of water Yo No. Jud using a process identical to that described in The materials are separated directly and cf AY) is extracted upon completion of the potassium hydroxide reaction to give the product mentioned in the title; Yo the product and its separation as described in Example No. 1H NMR Spectrum: (DMSOde) 1.59 (m, 1H ); 1 69 (m, 1H); 2.04 (m, 2H); 2.61 (t, 2H); \o 3.21 (s, 3H); 3.26 (m, 1H); 3.41 (m, 1H); 3.57 (t, 2H); 3.77 (m, 1H); 3.95 (m, 4H); 4.90 (m, 1H); 7.29 (m, 1H); 7.35 (s, 1H); 7.48 (m, 1H); 7.53 (m, 1H); 7.83 (s, 1H); 8.39 (s, 1H); 9.63 (s, 1H). Mass Spectrum: (M+H)+ 489.

— A. Example No. YY Pharmaceutical Compositions The following shows representative pharmaceutical dosage forms of the invention as specified herein (the active substance is referred to as “compound X” which can be prepared for use in the treatment or prophylaxis of all 0 human.re rer 0

TR xs

ES Ask Me

VY, ns Croscarmellose sodium

Y,Yo Weight/Jo (Maize Wi Paste Size) Memmi Baling || esr Xess a lan sens fewer di mola mitts salted by 1 molar Hydrochloric acid volum / volume (to adjust the pH to 1 Polyethylene glycol 0 aq To reach the TT, the above formulations can be prepared using traditional procedures well known in the pharmaceutical field.For example, Tablet 1 can be prepared by mixing the ingredients together and pressing the mixture into a tablet.

Claims (1)

0 07! _ Claims: (I) has the formula quinazoline derivative 1 - 1 2 HN v R! (W), AN J AH N C ~N AH Y where: ¢ RY is selected from a set of: hydrogen, hydroxy, (1 -4.C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3 C)alkoxy-(2- 4C)alkoxy 1 or from a group having the formula: v A took place + where 36 is ©; and 03 are: azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, 01 piperazino-(2-4C)alkyl or morpholino-(2) -4C)alkyl 11 Whereas, any heterocyclic group within a !1 substituent group carries ++ which can be symmetric or different oF SY or optionally 1 yp substituent groups choose from; pls 0" — 0;?. 7 halogeno, hydroxy, amino, (1 -4C)alkyl, (1-4C)alkoxy, (1 -4C)alkylsulfonyl, (1- Ve 4C)alkylamino, di-[(1-4C)alkyl]amino, and ( 2-4C)alkanoyl Vi VY Whereas, any heterocyclic group within a substituent group on 18 carries ¢ and 1 de gana substitution optionally VA or JY and 1 ab | 4 : which can sway or vary; Selected from RTS 0 fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl 2 JY a 1 a 01 aQ 7" or ;;" ? - all 77; which can sway or vary; Selected from: halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, v¢ (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1 -6C) )allcylsulfinyl, (1- ve 6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2- 1 6C)alkanoyloxy vy group has the formula: (wg YA Y4 my To galaxy and where “for is a direct bond or is chosen from 0; NR)” 8025 “COs” where 1 is tertiary: is halogeno-(1-6C)alkyl, hydroxy- (1- vy “to hydrogen or (1-6C)alkyl, and 6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-( 1 -6C)alkyl, N- YY (1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]Jamino-(1-6C)alkyl ve YY.” —- R~ ¢S0, 5 CO selected from X' Yo XP VY represents an array with the format: vv ) 7 ) since tabaj YA where “ stands for 0 or 11 and what stands for 0 or 1 or JY SY ? and w stands for 0 or 1 or ? or “Ya” and £0 each of 82, 83, 84 and 85 which can be the same or different; It is selected from: hydrogen, (1-6C)alkyl, amino, (1 -6C)alkylamino and di-[(1-6C)alkyl]amino i). (3-7C)cycloalkylene and (3-7C)cycloalkenylene are selected from EY and where any group of CHa or CHy within the XP group and optionally bears EE on each group of 11© or CHy mentioned by one or more of the 6 groups Substitute: halogeno £1 or (©1-6) alkyl or hydroxy substituent group chosen ; camino ¢ cyano 55 and (©1-6) alkyl (1-60©)[- di_salkylamino (1-6C) « alkoxy [ tamino 4 4 7 to choose from: hydroxy, amino, (1-6C)alkylamino, di-[(1 -6C)alkyl]amino, (1-6C)alkoxy, (1- or 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1 -6C)alkyl-(1- 2 6C)alkanesulfonylamino oY and a group has the formula: OF z turk o¢ - 7.1 - 00 where 7 is direct bond or is chosen from 0 N(R')5 and 50,5 SONR') 01 where RY is: hydrogen or (1-6C)alkyl, and CO is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1- ov) 4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or oA heterocyclyl-(1-4C)alkyl; oq « heterocyclyl direct bond RKO X° provided that when it represents 0 « heterocyclyl Z and m f + ¢ and represent em, provided that when it represents 11 7 Whereas, adjacent carbon atoms in any Jala alkylene chain (2-6C) group “+ substituent 2” can be optionally separated by entering the chain for a group chosen from 4 of ©0; and 5 -C=C-y «-C=C —3 «COs ¢« N(R"); "8025 "COs where 7 a 8 8 hydrogen ~~ 6 or alkyl (1-6C)" 1 and where any group of 032 or CH; is within a <Z group other than the group CH, vy is within a heterocyclyl ring ¢ and optionally carried on each group of CH, 4 CH A which Said one or more halogeno substituent groups or (1-6C) 4 alkyl substituent group or substituent group to be selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-bC)alkenyl, (2- Ve 6C)alkynyl, (1-6C)alkoxy, (1 -6C)alkylthio, (1-6C)alkylsulfinyl, (1 - except 6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl}jamino, N-(1- to 6C)alkylcarbamoyl, N.N-di-[(1 -6C) )alkyl]carbamoyl, (2-6C)alkanoyl, (2- vy - Y.V - 6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)al kyl-(2-6C)alkanoylamino, vi N-(1-6C)alkylsulfamoyl, N.N-di-[(1-6C) )allcyl]sulfamoyl, (1- ve 6C)alkanesulfonylamino and N-(1-6C)alkyl-(1 -6C)alkanesulfonylamino vi optionally carries Az within a heterocyclyl substituent group except where any group: or Different; And selected from Bilas one or more substituent groups which can VA halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1- va 6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1- A 6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1- AY 6C)alkyl ]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy AY and from a group of the formula: AY mcg; NR')5 S025 and where “8 does not represent a direct bond or is chosen from and Roh AO is: RY where AR hydrogen or (1-4C)alkyl, and R'8 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, AY (1-4C)alkoxy -(1-4C)alkyl, cyano-(1-4C)alkyl, amino-( 1-4C)alkyl, N-(1- AA 4C)alkylamino-(1-4C)alkyl and N,N-di-[ (1-4C)alkyl]amino-(1 -4C)alkyl Ad provided that: q. 4-bromo-2-fluoroanilino or is an I of formula 4-anilino when the AY group is + and 2 a +” hydrogen or (1-3C)alkoxy JiR! g 4-chloro-2-fluoroanilino qy : .selected from AY YA - - α hydroxy, amino, (1 -6C)alkylamino, di-[(1 -6C)allcyljamino, (1-6C)alkoxy, (1- at 6C)alkylsulfonyl, (1 -6C) alkanesulfonylamine, N-(1-6C)alkyl-(1- Ae 6C)atkanesulfonylamino an qy and a group having the formula ¢QS-X°-aA or its pharmaceutically acceptable salt; Or the accepted 5 esters Catch Lanya. =v 1 a quinazoline derivative of formula 1, salt or ester pharmaceutically acceptable die according to claimant Y) 10 R! Cua are: (1-4C)allcoxy, hydroxy-(2-4C)alkoxy and (1 -3C)allcoxy-(2-3C)alcoxy Y . 1 0 7 ?- a quinazoline derivative of formula 1, a salt, or © _ is a pharmaceutically acceptable form of it; According to X of claimant))(¢ where R' is an alkoxy. (1-3C) 1 ?- a quinazoline derivative of formula 1, salt or pharmaceutically Jee ester (dia) according to Y of claim (1), where L18 is methoxy .1©—a quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt or © thereof in accordance with any " - of the foregoing claim; where b is for 1; or ? and all 82 that can be y the same or different from fluoro chloro or bromo 5 where R? is at position (-3) - .no - R? the other ¢ at position (-4) ortho (2-) or para on an anilino group having formula 1°. z -1 1 is a quinazoline derivative of formula 1 or a pharmaceutically acceptable salt or ester thereof according to any Among the claims are numbers from 1-5, where the anilino group is chosen at position 3 - on the quinazoline ring in formula 1 of: 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino , 3-chloro-2-fluoroanilino, 2- ¢ ;fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino ° —V 1 a quinazoline derivative of formula 1, salt, or ester pharmaceutically acceptable of it according to any of the claims Nos. 1-5, where the anilin group is chosen at the -0 position on the quinazoline ally in a compound having formula 1 of: 3_chloro-2-bromoanilino, 3-chloro-2 -fluoroanilino, 3-ethynylanilino and 3-: bromoanilino. © 01 “8- A quinazoline derivative of formula 1 or a salt or pharmacologically J sie ester of which Li, of any ". of the foregoing claims, where: x2 v is a group of the form -n (continued) -(tllrtli)- ; -© is a JY) ?; © both RP and R75 who They can be the same or different; they are chosen - 01. - 1 from hydrogen and (1-6C)alkyl » and 182 were selected from: amino, (1-6C)alkylamino and di-{(1 -6C)alkyl]amino for A Whereas, any group of CH or CH within the XP group that optionally bears 4 on each group of .11© or CHy mentioned has one or more of the 0 groups substituted by a halogeno ; 1 Whereas, any CH group that is attached to two carbon atoms or any VY group (CH; 35) attached to a carbon atom within the XP substituent group optionally carries NY on each group of CHy or de gene CH;substitution selected from : droxy, amino, (1-6C)alkoxy, (1 -6C)alkylamino and di-[(1-6C)alkyllamino. Vi 1 4— a quinazoline derivative It has formula 1 or a pharmaceutically acceptable salt or ester of which Ls, for any One of the claims are numbers from VY where: “© is a group of the form = (CR?) — g 3 is 10 7 ? or les) specifically 1 or oY and especially 1); SO from RY, RE which can be the same or different; are selected from hydrogen 1 and (©6- 1) 1 alkyl, provided that at least one of the groups “a or 1 a in 162 is a (©6- 1) alkyl ; A Whereas any group of CH? or Jala CHP is group 76©2; which optionally carries 8 on each group of CHy or CHy mentioned and one or more of the halogeno substituting 0 groups “ 7110 - - 1 Whereas, any group 1127© that is attached to two carbon atoms or any Y group CHy is attached to a carbon atom within substituent group 7 optionally carries a 0 on each group of CH OR : 011 substituent group chosen from: hydroxy, and (1-6C)alkoxy 04 1 + )= a quinazoline derivative of formula 1 or a pharmaceutically acceptable salt or ester thereof according to any Y of Claims numbers 1-7; where: “360 phrase_ a group_ has the form -.01-; —(CHR'®)- —CH;CH;~ - ‎«~(CH,CHR'®)~ 5 —(CH,C(R'*))~ «~(C(R'*), CH,)~ «—(CHR'*CH,) ¢ © where every l is 8; which can be the same or different is (1-4C)alkyl . 1 ) = a quinazoline derivative having formula 1 or a salt or pharmacologically sia ester thereof according to any “- of the previous claims, where: 8 7 is selected from: hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1-6C)alkoxy, 5 hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy 1 a and a group with the formula : A thick 4 where X® is the heterocyclyl bond Q° 55 ile ¢ 117 - - 0 and provided that q 5p oem are all 1; then 7 is a heterocyclyl 1 ¢ VY and where any group of CHp or CH; is within group 7; Unlike the group CH;Jala VY is a heterocyclyl ring ¢ and optionally bears on each de gana of CH, or CH; 04 mentioned one or more halogeno substituent groups or (1-4C)VO alkyl substituent group or labial substituent of hydroxy ¢ (1-4C)alkoxy 1 ¢ VY and where any heterocyclyl group within de gene substitution Z optionally carries one or more vA substitution groups that can be the same or different and that V4 is selected from: Y chlorinated (1-40) halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1- 4C)alkyl] Jamino 7 and (2-4C)alkanoyl. VY 1-1 is a quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt or ester thereof according to any “- of the foregoing claims where: Y 2 represents a hydroxy or (1-4C)alkoxy ¢ ; - at least gtptm sum .1 71” - - VY 1 is a quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt or ester thereof according to any “Claims 1-7; where: xX?Y is ld dc gana Formula -.,01-» “—(CHR'*)- “—CH,CH,— - (~(CH,CHR'%)~ 5 ~(CH,C(R'*) );)~ “=(C(R'*)2CHa)~ “—(CHR'®CH,) 0 where RPS can be the same or different is (1-4C) alkyl Z. 1 represents a hydroxy or (1-4C) alkoxy ¢ —V&¢ quinazoline derivative of Formula 1 or a pharmaceutical salt or Joe ester thereof according to any of the foregoing claims where: Q' is piperidin-4-yl “Juda + or 1 Wy©”; is selected from the hydroxy “halogeno” and (1-3C) alkoxy ¢ (1-3C) alkyl. 1 - A quinazoline derivative of formula 1 or a pharmaceutically acceptable salt or ester thereof pursuant to any Y of the foregoing claims where X!CO represents quinazoline Gide -11 -1 of formula 1 according to Claim 1 has formula 18. mg l HN” a R WwW), ~ N F Y 0 J J xX N 0 N Ib + where ¢ l was selected from (1-3C) alkoxy hydrogen ¢ ¢ chloro sl bromo as 5 0 is 1 0 or ?; + Each SW can be the same or different being selected from halogeno “hydroxy A (specifically (1-4C) alkyl “(fluoro) and (1-4C) alkoxy ¢ and © is chosen from a group of the formula —CH,CH,CHy~ ~CH;CH;~ «~CHy= - "6 (tll) - -(ytnut tay) - and -(a mauri) - where each #*for 8 RPS that can be the same or different is chosen from hydrogen yy and (©14) alkyl ¢ M, 2 to be chosen from: hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy- y¢ (2-6C)alkylamino, di-[(1-6C)alkyl]Jamino, N- [hydroxy-(2-6C)alkyl]-N-(1- yo 6C)alkylamino, N-[(1 -4C)alkoxy-(2-6C)allcyl]-N-(1-6C)alkylamino, di- 75 [hydroxy-(2-6¢)alkyl}-amind, di-[(1 -4C)alkoxy-(2-6C)alkyl}amino, N-[(1-ba 4C)alkoxy-(2) -6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, YA hydroxy-(2-6C)alkoxy, (1 -4C)alkoxy-(2-6C) alkoxy, azetidin-1-yl, pyrrolidin-1- ~~ Y4 yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin- 0 1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl , 1,3-dioxolanyl, 71 tetrahydropyranyl and 1,4-dioxanyl YY - 10 - : : And group 2-762 is selected from YY tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1 4-dioxanyl, oxepanyl, vi pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and Yo homopiperazinyl v1 which It is represented by 7312 with a carbonyl group in the heterocyclyl where YY 7X2 is bonded within the heterocyclyl and where any Bish carbon oils group of “lb of formula YA” or of the substituent groups; which can be Identical or Different 1 Optionally Carrying YA : Then Selection from Yo chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl 1 or acceptable salt 79 pharmacologists; or an ester acceptable to catch Ly from it —VV 1 a quinazoline derivative of formula 1 or a salt or ester acceptable dua from which aa of any From the previous claims, where p is 0. YA is a quinazoline derivative of formula 1 aa of claim No. 1 of formula p1: a HN' g Cl x 0 SN J 2 _“ ° N 0 N 2 lc - YY - where : ARM 8 to choose from: (1-3C)alcoxy, hydroxy-(2-3C)alkoxy and (1-3C)alkoxy-(2-3C)alcoxy 7 2 are chosen from a group with the formula ~(CHR'*)~ R- (0110777) - : and where “82 selected from alkyl (1-4C) is R12 where VY amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino A : selected from 27 4 hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy 01 choice of: 25 heterocyclyl or group 2722# is group 11 Cua tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl 2.60 VY bonded to a carbonyl group via a ring carbon atom “ 16 and where the heterocyclyl group within a optionally bears one or two of the _substituted Ve groups; Which can be the same or different selected from: fluoro, chloro, hydroxy, patol (1-40) (1-4C)alkoxy and (2-4C)alkanoyl; 1 pharmaceutically acceptable of it. ester or pharmaceutically acceptable salt; or VY 1 4- A quinazoline derivative has the formula I according to claim No. YA, where 7! is the Y term for hydroxy, that is, methoxy. - 11 - 00 1 a quinazoline derivative of formula 1 or a pharmaceutically acceptable salt or ester thereof in accordance with Y of claim 1 where: The 4-anilino group on ring 6 in formula 1 is selected from: 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3- ¢ bromoanilin and 3-ethynylaniline ° R 1 is chosen from: No (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1 -3C)allcoxy-(2-4C)alkoxy or of A group has the formula: q sprout dus Ve © is ©; And QF is: azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1 -yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, 1 piperazino-(2-4C)alkyl or morpholino-(2) -4C) alkyl, VY within a substituent group on 8 optionally bearing heterocyclyl, and where any VY group: or ? or » which could be the same or different; It is selected from 1 - 04 halogeno, hydroxy, amino, (1 -4C)alkyl, (1-4C)alkoxy, (1 -4C)alkylamino and ve di-[(1-4C)alkyl]amino, 1 ; (1-4C) alkoxy or hydroxy representing Z VY piperidin-4-yl is ©! 1; 8 or 0 is 4 : which can be the same or different is chosen from OW SY for 0 - YYA - hydroxy, (1-3C)alkyl and (1-3C)alcoxy 7 for no is 00; YY «=(CH,CHR'?")~ chosen from a group of formula - (0117) free 3X?YY¢ (1-4C) alkyl is R'* where YE : and where 2120 is selected from Yo amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino v1 Pharmaceutically acceptable of it according to ester of formula 1 or salt or quinazoline derivative -71 1 id of formula 1 of claim number 1 HN Cl R 0 ~N F I y for ON 0 N 2 Where: + (1-40) alkoxy and “c represents --(0187)- -011:011:- “=CHp~ has been selected from a set of formula 22” 0-) whose engine is =(CHR"CH,) ~~ : Then select it from R!? Cus 7 (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl A YY eo 71109 - - 4 and 22 selected from : hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1 -3C)alkoxy-(2-3C)alkoxy, 01 tetrahydrofuran-2 -yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl lL and 1,4-dioxanyl, VY VY and where any heterocyclyl group within "72-72 optionally carries 1 or ? of 4 substituent groups; which can be the same or different selected from: fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; Ve 0 or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable ester thereof.—VY 1 a quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt or ester thereof pursuant to paid XY Protection No. 1? where 72 is hydroxy .— YY 1 is a quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt or ester thereof according to ¥ of claim No. YY where 72 is the hydroxy derivation of (1-3C) alkyl .—Y¢ 1 A quinazoline derivative having formula 1 or a pharmaceutically acceptable salt or ester thereof according to OY of claim number YY where: R" v represents (1-3C) alkoxy ¢ 8 and group 72- was selected 72 of: --YY. - hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)- 8 1-methoxyethyl and (R)-1-methoxyethyl. 1 Pharmaceutical Acceptable thereof according to ester of formula 1, salt or quinazoline derivative —Yo 1 where: YY of claim number ¢ methoxy of 1 .3-hydroxyethyl and group “-72 72 represents ¢ Selected from: 1 of formula 1 according to claim No. quinazoline derivative 71-1 N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl) ]piperidin-4-yl} oxy)- ¥ 6-methoxyquinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1- r [(2-methoxyethoxy)acetyl] piperidin-4-yl} oxy)quinazolin-4-amine; N-(3- t chloro-2-fluorophenyl)-6-methoxy-7-{|1-(methoxyacetyl)piperidin-4-©ylJoxy}quinazolin-4 -amine; 2-[4-({4-[3-chloro-2-ftuoroanilmo]-6- 1 methoxyquinazolin-7-yl} oxy)pipendin-1-yl]-2-oxoethanol; N-(3-chloro) -2- 7 fluorophenyl)-7- {[1-(ethoxyacetyl)pipendin-4-yl}oxy ( -6-methoxyquinazolin-4- A amine; N-(3-chloro-2-fluorophenyl)-6-methoxy- 7-{[1-(3- 1 methoxypropanoyl)piperidin-4-yljoxylquinazolin-4-amine; 3-[4-({4-[3-chloro- Ve 2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)pipendin-1-yl]-3-oxopropan-1- 11 ol; (25)-1-[4-({4-[3-chloro-2-fluoroanilino}-6-methoxyquinazolin-7- VY ْ - YY) - yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (25,3S)-1-[4-({4-[3-chloro-2- vw fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-3-methyl-1- V oxopentan-2-ol; 4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- Vo yl} oxy)piperidin-1-yl}-2-methyl-4-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)- 1 6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yljoxy} quinazolin- VY 4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino}-6-methoxyquinazolin-7- yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan- 1-ol; (3R,5S)-1-acetyl-5-{[4- 1 ({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-ve yl]carbonyl} pyrrolidin-3-ol; and N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1- 7 [(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl} oxy)quinazolin-4-amine YY It is pharmaceutically acceptable ester or WY aaa or acceptable salt YY -717 1 A quinazoline derivative of formula 1 is selected from: ‎N-(3-Chloro-2-fluorophenyl)-6-methoxy-7- {[ 1 -(methoxyacetyl)piperidin-4- v ylloxy} quinazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6- 1 methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-2-oxoethanol; N-(3-chloro-2- t fluorophenyl)-7- {[1-(ethoxyacetyl)piperidin-4-yl]oxy } -6-methoxyquinazolin-4- ° amine; (25)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- 1 yl} oxy)pipendin-1-yl]-1-oxopropan-2-ol; 3-[4-({4-[3-chloro-2-fluoroanilino]-6- v methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol ; A (25)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- 1 yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan -2-ol; N-(3-chloro-2- 01 fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4- 1 yl]oxy}quinazolin-4-amine; N-(3-chloro-2-fluofophenyl)-6-methoxy-7-({1- VY [(25)-tetrahydrofuran-2-ylcarbonyl]pipendin-4-yl} oxy)quinazolin-4-amine; VY (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- 0 yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol; N-(3-chloro-2-fluorophenyl)-6- Ve methoxy-7-({1-[(25)-2-methoxypropanoyl]piperidin-4-yl} oxy)quinazolin-4- 1 amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2- VY methoxypropanoyl]piperidin-4-yl} oxy)quinazolin-4-amine; (2R)-3-[4-({4-[3- YA chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-2- '4 (dimethylamino)-3 -oxopropan-1-ol; (25)-1-[4-({4-[(3-chloro-4-fluoroanilino]-v.6-methoxyquinazolin-7-yl} oxy)piperidin- 1-yl]-1-oxopropan-2-ol ; (25)-1-[4- 5 ({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-1-vy oxopropan-2-ol; (25) -1-[4-({4-[3-bromo-2-fluoroanilino]-6- vy methoxyquinazolin-7-yl} oxy)pipendin-1-yl]-1-oxopropan-2-ol; (2R)- 1-[4-({4- ve [3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl}-1- ve oxopropan-2-ol; and (2R) -1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7- vi yl} oxy)piperidin-1-yl}-1-oxopropan-2-ol; vy YA or a pharmaceutically acceptable salt thereof. : is a 1 quinazoline of formula 1 according to claim No. Bide - YA) 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-y1} oxy)piperidin -1- Y yl]-2-oxoethanol v or a pharmaceutically acceptable salt thereof.‎8 : 1 of Claim No. lig 1 is a quinazoline derivative with the formula 1*-1 )25-1-[4-)114-3 -chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)Y pipendin-1-yl}-1-oxopropan-2-ol v; Or a pharmaceutically acceptable salt thereof : is a 1 of claim I having the formula quinazoline derivative —¥” 1 (25)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7- Y yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol, 1 ; Or a pharmaceutically acceptable salt thereof : is 1 of formula 1 according to claim No. quinazoline derivative ©1 -1 (2R)-1-[4-({4-[3-bromo-2-fluoroanilino] -6-methoxyquinazolin-7- y yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol, ¥ ; or a pharmaceutically acceptable salt thereof. ) YY —YY 1 quinazoline derivative having formula I according to any of the claims numbers of YV=Y “or a pharmaceutically acceptable salt thereof. 1 ‘””- a medicinal composition comprising a quinazoline derivative Having the formula “I or a salt or ester” - a pharmaceutically acceptable salt thereof; according to any of the preceding claims; in association with a pharmaceutically acceptable diluent or _carrier. —Y¢1 A quinazoline derivative of formula I 0 pharmaceutically acceptable salt or ester thereof; according to “any of the Claims Numbers FV) for use as a remedy. —vo 1 use a quinazoline derivative of formula <I or a pharmaceutically acceptable salt or ester (Ade " as defined in any Claims 1-1 in the manufacture of a remedy for use Y in producing an anti-proliferative effect in warm-blooded organisms such as humans. Any of the protective elements Numbers 1-7 in the manufacture of a treatment for use 1 in the prevention or treatment of those tumors that are sensitive to the inhibition of enzymes tyrosine kinases EGFR Y involved in the signal transduction steps that lead to the proliferation of Wa tumor. F YYo - - 1 1 use of a quinazoline derivative of formula “I or a pharmaceutically acceptable salt or ester thereof; Y as defined in any of Claims Numbers 1-1 in the manufacture of a treatment for use in providing an effective effect in inhibiting the enzyme tyrosine kinases EGFR in hematopoietic organisms; - Hot Bie human. 1 8- Using a quinazoline derivative having the formula “I 0 is a pharmaceutically acceptable salt or ester thereof; As defined in any of Claims 71-1 in the manufacture of a remedy © for use in the treatment of cancer in warm-blooded organisms such as humans. 1 1 4*- A process for the preparation of a quinazoline derivative of Formula 1 as defined in Clause 7 Claim 1 comprising: 0” Process (a): ; To prepare compounds of formula 1 where X' represents CO by conjugating quinazoline of formula [1] or its salt: 2 HN R 1 (W), NN J N 1 0 01 HN II V where 'bsas Wy REyR' can have any of the meanings defined earlier in this document A; Except that any functional group is protected at ib yg ual with an acid of formula 4 CIT or a reactive derivative thereof: 01 z 11 COOH 2-22 11 where L 7 X25 can have any Of the meanings previously specified in this document; Except 1 that any job group is protected when necessary; 0 or 04 Operation B: Vo performs a reaction; traditionally in the presence of a suitable base; a quinazoline derivative of formula 1 11 or its salt; As specified earlier in this document in relation to the operation off) with a compound of 11 of formula AV vel 17 Z-x*-X'-L! 14 where 11 is a displaceable group of l 7 and any of the meanings previously defined 0 in this document; Except that any functional de gana is protected when necessary; YY process (Hz) YY preparation of these quinazoline derivatives having formula 1 where 7 bonds to 3 via nitrogen YY ¢ and performs a reaction to a compound of formula ?: and Lal - YYV - d" 2 HN R (W), NN pe N D Q Alith Vv Yo where 12 is the ALG group of displacement; and where WRI can have SR, XP, YT, H, and © have any of the meanings previously defined herein; except that any Yv functional group is protected where necessary; with a compound of formula “ZH where 7 as then specified by YA previously in this document, except that any functional group is protected where necessary; or YA Process (D): ©0 for the preparation of these quinazoline derivatives bearing a mono- or (di-6C) 1) group alkylamino 1; the amine reductive treatment of a quinazoline analogue derivative of formula I FY containing a group 17-71 is done with formaldehyde or (©2-6) alkanol aldehyde; or _process (e): ve Production These quinazoline derivatives have formula 1 where a is hydroxy; yo is cleaved. A quinazoline derivative of formula 1 Cus !1 is a (1-6C) alkoxy group; or © _process (f): gay vv these quinazoline derivatives of formula 1 R' Gus bond to the quinazoline ring of an oxygen atom oxygen 4 ¢ by conjugating a compound of formula VI - M778 - 2 v4 HN HO (W), XN p Q +0 N l any ah 171, 2, h, 5, 01 Which of the given meanings does XP X's WHR? Whereas 0 can have a prefix in this document; Except that any job group is protected when necessary; with £) is one of the groups R"O ic gana where "R"OH is a compound of formula EY (eg RY defined earlier herein for the associated LS oxygens £ F or -02-0); except that any alkoxy functional group (1-6C) is RI" ; eg protected as necessary ald to and so that thereafter and as necessary (and in whatever order) £1 to the derivative of I Has the formula quinazoline Derivative conversion 0 ty Has the formula 1; Al quinazoline p Removed any protecting group by conventional methods; (b) £4 Pharmaceutical acceptable. (7) O. The specific conditions for the above reactions are as follows. 51 YY.. :1] has the formula quinazoline derivative 6 -1 2 HN R! (w), bit Y J Q 0 N HN II; 1; and © and w as defined in claim No. WR ay YF; or its salt. halogeno wll020; which can be the same or different; 06 ¢ of formula 1 as defined in quinazoline is a pharmaceutical product comprising a derivative of ?1-1 and an additional antitumor agent for use in 37-1 any of the Claims Numbers of "Combined Therapy". Anticancer. Has formula 1 as defined in any of the claim numbers. Quinazoline derivative -47 1 0 psoriasis for use in the treatment of psoriasis 1-7? Y