WO2013064919A1

WO2013064919A1 - Quinazoline derivatives with hsp90 inhibitory activity

Info

Publication number: WO2013064919A1
Application number: PCT/IB2012/054649
Authority: WO
Inventors: Raffaella Amici; Andrea Colombo; Stephen Martin Courtney; Ciro Mercurio; Christian Aldo Georges Napoleon Montalbetti; Annalisa MORTONI; Mario Varasi
Original assignee: Dac Srl
Priority date: 2011-11-03
Filing date: 2012-09-07
Publication date: 2013-05-10
Also published as: ITTO20111013A1; WO2013064919A9

Abstract

Compounds of general formula (I): or a stereoisomer, tautomer, polymorph, hydrate, solvate, or a pharmaceutically acceptable salt thereof, wherein R is as defined herein, are useful for the treatment of diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity such as proliferative diseases, e.g. cancers, viral and fungal infections, neurodegenerative or inflammatory diseases or conditions. The invention also relates to the preparation of these compounds as well as to pharmaceutical compositions comprising them.

Description

QUINAZOLINE DERIVATIVES WITH HSP90 INHIBITORY ACTIVITY Field of the invention

The present invention relates to new compounds having Hsp90 inhibitory activity and to the use of these compounds in medicine, in particular for the treatment of diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity such as proliferative diseases, e.g. cancers, viral and fungal infections, neurodegenerative or inflammatory diseases or conditions. The invention also relates to the preparation of these compounds as well as to pharmaceutical compositions comprising them. In particular, the invention relates to 2-amino-7,8-dihydro-6H- quinazolin-5-one oximes and stereoisomer, tautomer, polymorph, hydrate, solvate, or a pharmaceutically acceptable salt thereof.

Background of the invention

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone involved in the conformational maturation of numerous client proteins implicated in diverse cellular functions. Moreover, Hsp90 plays a key role in the stress response and protection of the cell against the effects of mutation (A. Kamal et al. Naiwre 2003, 425, 407-410).

Hsp90 protein (http://onlinelibrarv.wiley.eom/doi/ l 0.1002/cmdc.20090001 1 /fu.lD consists of three distinct domains (Pearl L.H. et al. Adv. Protein Chem. 2001 , 54, 157-186): the C-terminal domain, which has a role in the homodimerisation process, the middle domain that is involved in the ATPase cycle and in the binding with co-chaperone and client proteins, and finally, the N-terminal ATP binding domain (Chaudhury et al. ChemMedChem. 2006, 1, 1331-1340).

The function of Hsp90 is regulated by a pocket in the N-terminal region of the protein that binds and hydrolyzes ATP (Richter K.et al. J Cell Physiol. 2001 , 188 (3), 281-90). Occupancy of this pocket by high affinity ligands prevents the Hsp90 client proteins from achieving their mature functional conformation.

Protein clients of Hsp90 are mostly kinases, steroid receptors, transcriptional factors involved in driving multistep malignancy and mutated oncogenic proteins required for the transformed phenotype. Examples include Her2, Raf-1 , Akt, Cdk4, cMet, mutant p53, ER, AR, mutant BRaf, Bcr-Abl, Fit- 3, Polo-1 kinase, HIF-1 alpha, and hTERT {Trends Mol. Med. 2004, 10, 283-290; Trends Mol. Med. 2002, 8, S55-S61 ; Expert Opin. Biol. Ther. 2002, 2, 3-24). Furthermore, elevated Hsp90 expression has been documented in different tumor types as well as a correlation between the high expression of Hsp90 and poor disease prognosis (Becker B et al. Experimental Dermatology 2004, 13, 27-32; Pick E. et al. Cancer Res. 2007, 67(7), 2932-7; Zagouri F. et al. BMC Cancer 2008, 8, 312; Li C.F. et al. Clin Cancer Res 2008, 14, 7822-7831 ; Flandrin P et al. Cell Stress and Chaperones 2008, 13, 357-364; Wu X. et al. British Journal of Cancer 2009, 100, 334-43; Diehl MC. et al. Cancer Biol Ther. 2009, 8(20), 1952-6; Kang G.H. et al. Histopathology 2010, 56, 694-701).

Hsp90 represents therefore an emerging target in cancer treatment due to its important roles in regulating key proteins in cell growth, survival, and differentiation pathways (Whitesell L et al. Nat Rev Cancer. 2005, 5(10), 761-72; Trepel J. et al. Nature Reviews Cancer 2010, 10, 537-549 ). The involvement of Hsp90 in several relevant cellular processes such as signal transduction produced by steroid hormones, nitric oxide and calcium, as well as protein trafficking, innate immunity, muscle contraction and cell motility, viral infections etc. (Taipale M. et al. Nature Reviews Molecular Cell Biology 2010, 11, 515-528) opens the possibility of the medical use of Hsp90 inhibitors in the treatment of viral and fungal infections, inflammatory conditions and neurodegenerative diseases (Solti D.B. et al. Drug Discovery Today 2008, 13 (1-2) 38-43).

The following (non exhaustive) selection of references strongly demonstrates the involvement and relevant role of Hs$90 in different pathologies and the potential benefit by inhibiting it:

1. cancer [Isaacs JS et al. Cancer Cell 2003, (3), 213-7; Bagatell R. et al. Mol Cancer Ther. 2004, (8), 1021-30; Bauer S. et al. Cancer Res 2006, 66, 9153-61 ; Peng C. et al. Cell Cycle 2007, 6,

2227-31; Whitesell L. et al. Nat Rev Cancer. 2005, (10), 761-72; Rodina A. et al. Nat Chem Biol 2007, 3, 498-507; Shimamura, T. et al. Cancer Res. 2008, 68, 5827-5838; Banerji U. Clin Cancer Res. 2009, 15(1), 9-14; D Mahalingam et al. British Journal of Cancer 2009, 100, 1523- 1529; Caldas-Lopes, E. et al. Proc. Natl Acad. Sci. USA 2009, 106, 8368-8373; Porter J.R. et al., Current Opinion in Chemical Biology 2010, 14 (3), 412-420; Richardson P.G. et al. Br. J. Haematol. 2011, 152(4), 367-79)];

2. neurodegenerative diseases [Dou F. et al. Proc Natl Acad Sci USA 2003, 100, 721-726; Waza M. et al. Nat. Med. 2005, 11, 1088-1095; Dickey C.A. et al. /. Clin. Invest. 2007, 1 17, 648-658; Lou W. et al. Proc Natl Acad Sci USA 2007, 104, 9511-9516; Luo W. et al. Molecular Neurodegeneration 2010, 5, 24-32]; 3. inflammatory conditions [Dello Russo C. et al. J. Neurochem. 2006, 99, 1351-1362; Poulaki V. et al. FASEB J. 2007, 21, 2113-2123; Rice J. W. et al. Arthritis Rheum. 2008, 58, 3765-3775; Yun J. et al. J. Immunol. 2011, 186, 563-575];

4. viral and fungal infections [Cowen L.E. et al. Science 2005, 309, 2185-2189; Chase G. et al. Virology 2008, 377 431-439; Cowen L.E. et al. Proc Natl Acad Sci USA 2009, 106(8), 2818-

2823].

In the last years numerous Hsp90-specific inhibitors belonging to distinct chemical classes such as benzoquinone ansamycins (e.g. geldanamycin derivatives), radicicol derivatives, purine-scaffold- based inhibitors, dihydroxyphenylpyrazoles, and small peptides have been identified (Porter J.R. et al., Curr Opin in Chemical Biology 2010, 14, (3), 412-420; Gao Z. et al. Curr Opin Drug Discov Devel. 2010, 13(2), 193-202).

Several Hsp90 inhibitors are currently being tested in human in multiple clinical trials, and first evidences of clinical responses have been reported (Modi S. et al. J Clin Oncol. 2007, 25(34), 5410-7; Banerji U. Clin Cancer Res. 2009, 15(1), 9-14; Trepel et al. Nature Reviews Cancer 2010, 10, 537-549; Sequist L.V. et al. J Clin Oncol. 2010, 28(33), 4953-60; Richardson P.G. et al. Br J Haematol. 2010, 150(4), 428-37; Richardson P.G. et al. Br J Haematol. 2010, 150(4), 438-45; Lancet J.E. et al. Leukemia 2010, 24(4), 699-705; Modi S. et al. Clin Cancer Res. 2011, 17(15), 5132-9.

However, issues regarding poor solubility and pharmacokinetic characteristic, as well as peculiar toxicity profiles have emerged during these trials. It is thus still desired to identify novel inhibitors with improved characteristics.

WO 2006113498 and WO 2007041362 relate respectively to 2-aminoquinazolin-5-one and 2- amino-7,8-dihydro-6H-pyrido[4,3-d] pyrimidin-5-one compounds which are Hsp90 inhibitors.

WO 2009097578 relates to 2-amino-7,8-dihydro-6H-pyrido[4,3-d] pyrimidin-5-one O-alkyl oxime derivatives as Hsp90 inhibitors, useful for the treatment and prevention of diseases such as cancer, inflammation, inflammatory bowel disease, psoriasis, arthritis, and transplant rejection.

Despite these developments, there is still need for effective agents for said diseases.

WO 2008142720, in the name of the present Applicant, discloses 2-amino-7,8-dihydro-6H- quinazolin-5-one oximes derivatives as Hsp90 inhibitors comprising 2-amino-7-biphenyl-2-yl-4- methyl-7,8-dihydro-6H-quinazolin-5-one oximes

wherein R is (C4)heterocyclyl(C2-C3)alkyl. The 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8- dihydro-6H-quinazolin-5-one oxime derivatives of general formula

wherein R is C3-C5 heterocyclyl or (C3-C5)heterocyclyl(Ci-C5)alkyl were not disclosed in this patent application.

Now, we have found that compounds of general formula (I), described below, are highly potent Hsp90 inhibitors with improved activity and metabolic stability and are thus useful in therapy for treatment of proliferative diseases such as cancer, viral and fungal infections, neurodegenerative or inflammatory diseases or conditions.

Summary of the Invention

Accordingly, a first object the present disclosure provides compounds endowed with a potent Hsp90 inibitory activity and improved cellular activity of general formula (I) or a stereoisomer, tautomer, polymorph, hydrate, solvate or a pharmaceutically acceptable salt thereof:

(I)

wherein:

R is hydrogen or A-B; A is a bond or C 1-C5 alkylene;

B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl, wherein the C3-C5 heterocyclyl and the C₆-C8 heterobicyclyl may be optionally substituted by one or two substituents selected from halogen, C1-C5 alkyl optionally substituted by aryl, -C(0)R1, -S0₂R2 or -C(0)NR3R4;

Rl, R2, R3 and R4 are independently hydrogen, C 1-C5 alkyl or aryl;

provided that when R is hydrogen, the configuration of 7-(4-fluoro-2-pyiridin-3-yl-phenyl) is (S). The compounds of the invention have Hsp90 inhibitory activity and are therefore useful for the treatment of diseases and conditions, which are mediated by excessive or inappropriate Hsp90 activity, e.g. proliferative diseases such as cancers, viral or fungal infections, neurodegenerative or inflammatory diseases or conditions.

The present invention also relates to methods of synthesizing the compounds of formula (I) as defined above prepared through a process consisting of standard synthetic transformation.

In another embodiment, the invention provides compounds of general formula (I) as defined above as well as their stereoisomers, tautomers, polymorphs, hydrates, solvates or pharmaceutically acceptable salts, for use in medicine.

In another embodiment, the invention provides the use of a compound of general formula (I) as defined above as well as their stereoisomers, tautomers, polymorphs, hydrates, solvates or pharmaceutically acceptable salts, in the manufacture of a medicament for treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity. Such treatment comprises administering to the patient a therapeutic effective amount of a compound of formula (I) as defined above.

In another embodiment, the invention provides a compound of general formula (I) as defined above or the use of a compound of general formula (I) as defined above as well as their stereoisomers, tautomers, polymorphs, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is administered combined with another agent used in the treatment of cancer, or inflammation or neurodegenerative disease, or viral or fungal infections.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of general formula (I) as defined above as well as their stereoisomers, tautomers, polymorphs, hydrates, solvates or pharmaceutically acceptable salts, together with a pharmaceutically acceptable excipient; which optionally further includes an additional agent useful in the treatment of cancer, or inflammation or neurodegenerative disease, or viral or fungal infections.

The present invention is also providing a method for treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity as defined above which comprises administering to an animal or human subject in need thereof an effective amount of a compound of formula (I) as defined above as well as their stereoisomers, tautomers, polymorphs, hydrates, solvates or pharmaceutically acceptable salts.

Detailed Description of the Invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

The term "C₁-C5 alkyl" refers to a fully saturated straight or branched saturated hydrocarbon chain having one to five carbon atoms. The "C₁-C5 alkyl" is preferably a straight or branched C₁ -C3 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and the like.

The term "C ₁-C5 alkylene" refers to C₁-C5 alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond and having one to five carbon atoms. The "C₁-C5 alkylene" is preferably a C₁-C3 alkylene. Examples include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.

The term "C3-C5 heterocyclyl" refers to a non aromatic, saturated or partially unsaturated ring system having at least one heteroatom chosen from N, O or S , which may be the same or different. C_x heterocyclyl and C_x-C_y heterocyclyl are typically used wherein X is the minimum and Y is the maximum number of carbon atoms in the ring assembly. Examples include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, dihydrofuran, tetrahydrofuran, tetrahydrothiopyran, pyran, dihydropyran, tetrahydropyran, thiazolidine, pyrazolidine, oxazolidine, isoxazolidine, imidazolidine and the like. The term "C₆-C₈ heterobicyclyl" refers to a saturated or partially unsaturated fused, spiro and bridged bicyclic ring having one or more heteroatoms within the ring selected independently from N, O, or S. C_x-C_y heterobicyclyl are typically used wherein X is the minimum and Y is the maximum number of carbon atoms in the ring assembly. Examples include, but a not limited to, quinuclidine, 6-azabicyclo[3.1.1]heptanes, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane and the like.

The term "halogen" refers to fluoro, chloro, bromo or iodo.

The term "hydroxy protecting group" unless otherwise indicated, includes e.g. oxy-tetrahydro-2H- pyrane, acetyl, benzyloxycarbonyl, and various hydroxy protecting groups familiar to those skilled in the art as described in T. W. Greene, (Greene, T.W.; Wuts, P.G.M. "Protective Groups in Organic Synthesis", John Wiley & Sons Inc., 2007) or in ocienski ( ocienski, P.J. "Protecting Groups", George Thieme Verlag, 2003).

The term "aryl" refers to a ring system having from 6 to 14 ring carbon atoms and containing up to three rings, at least one of which has aromatic character. Suitable aryl groups include, but are not limited to benzene, biphenyl, naphthalene, indanyl, indenyl, and the like.

The term "pharmaceutically acceptable salts" refers to the relatively non-toxic mineral and organic acid-addition salts, and the base-addition salts, of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds.

In particular, the acid-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed. The resulting salts are, salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3- phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate, succinate; organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2- hydroxyethane sulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p- chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids, dihydrogenophosphate, 2-naphtalenesulfonates, para-toluenesulfonates. The invention also relates to pharmaceutically acceptable salts with organic or inorganic bases. In particular, the basic-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or inorganic base and isolating the salt thus formed. The resulting salts are, for example, metal salts, particularly alkali metal salts, alkaline-earth metal salts and transition metal salts (such as sodium, potassium, calcium, magnesium, zinc, aluminum), or salts obtained with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine, ethyl diamine), or with basic amino-acids, or with osamines (such as meglumine), or with aminoalcohols (such as 3- aminobutanol, 2-aminoethanol, choline, ethanolamine, diethanolamine) and other well known basic addition salts.

Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.

Unless otherwise specified, when referring to the compounds of formula (I) per se as well as to any pharmaceutical composition thereof or to any therapeutic treatment comprising them, the present invention includes all of the isomers, stereoisomers and their admixtures, tautomers, racemic forms, enantiomers, diastereoisomers, epimers, as well as their crystalline forms, including their polymorphic forms, hydrates, solvates, . mixtures thereof and pharmaceutically acceptable salts of the compounds of the invention.

It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the drawn structure, whether existing in equilibrium or predominantly in one form.

The present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers and/or diastereoisomers thereof, as well or as mixtures of these in all proportions. Compounds containing a stereogenic center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.

Likewise, the polymorphs, hydrates or solvates of the compounds of formula (I) as defined above are included within the scope of, and suitable for use in, the present invention. The term "polymorph" refers to substances that have the same chemical formula but different crystal structures.

The term "hydrate" refers to a solvate comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.

The term "solvate" refers to a molecular complex comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., EtOH). In a preferred embodiment, the invention provides derivatives of formula (la)

(la)

wherein R is as defined above.

In the compounds of the present invention of general formula (I) or (la), it is preferred that:

A is a bond or C 1 -C3 alkylene.

Other preferred compounds of the present invention of general formula (I) or (la) include those in which B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl, wherein the C3-C5 heterocyclyl and the C₆-C₈ heterobicyclyl may be optionally substituted by one or two substituents selected from halogen; C 1-C3 alkyl optionally substituted by phenyl; -C(0)R1 ; -S0₂R2; or -C(0)NR3R4; more preferably B is azetidine, pyrrolidine, piperidine, piperazine, morpholine, or 8- azabicyclo[3.2.1]octane, each of said groups optionally substituted by one or two substituents selected from halogen; C 1-C3 alkyl optionally substituted by phenyl; -C(0)R1 ; -S0₂R2; or - C(0)NR3R4;

wherein Rl, R2, R3 and R4 are independently hydrogen, C 1-C3 alkyl or phenyl.

Specific, non limiting examples of compounds of formula (I) are shown in the following list:

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime; 2-Amino-7-(4-fluoro-2^yridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2- azetidin- 1 -yl-ethyl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2- azetidin- 1 -yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2- pyrrolidin- 1 -yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2- moφholin-4-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-oae 0-(2- piperazin-l-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2^yridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4- methyl-piperazin- 1 -yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4- isopropyl-piperazin- 1 -yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4- acetyl-piperazin-l-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3- azetidin- 1 -yl-propyl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3- azetidin-l-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3- pyrrolidin- 1 -yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3- piperidin- 1 -yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[3- (3,3-difluoro-azetidin-l-yl)-propyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[3- (3,3-difluoro-pyrrolidin-l-yl)-propyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3- piperazin-l-yl-propyl)-oxime; 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- azetidin-3 -yl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- azetidin-3 -ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2- azetidin-3-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- methyl-azetidin-3-yl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- methyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- isopropyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- benzyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- acetyl-azetidin-3-yl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- acetyl-azetidin-3 -yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- benzoyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- methylaminocarbonyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- dimethylaminocarbonyl-azetidin-3 -yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- methanesulfonyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- piperidin-4-yl-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- piperidin-4-yl-oxime; 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7,8-dihydro-6H-quinazolin-5-one O- piperidin-4-ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7,8-dihydro-6H-quinazolin-5-one O- piperidin-4-yl-ethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7 , 8 -dihydro-6H-quinazolin- 5 -one 0-(3- piperidin-4-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(l- methyl-piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(l- isopropyl-piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl -4-methyl-7,8-dihydro-6H-quinazolin-5-One 0-[2-(l- acetyl-piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- methyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- isopropyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- benzyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l- acetyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one o-(i- benzoyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl i-4-methyl-7,8-dihydro-6H-quinazolin-5-one o-

((lS,3R,5R)-8-methyl-8-aza-bicyclo[3.2.1]o occtt--33--yyll))--ooxxiimmee;;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl )-4-methyl-7,8-dihydro-6H-quinazolin-5-one o- piped din-3-ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl )-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(S)-l- pyrrolidin-3-ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl )-4-methyl-7 , 8-dihydro-6H-quinazol in- 5 -one 0-(R)-l- pyrrolidin-3-ylmethyl-oxime; 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-m 0-((S)-2- pyrrolidin-2-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-((R)- 2-pyrrolidin-2-yl-ethyl)-oxime;

and their stereoisomers, tautomers, pharmaceutically acceptable salts.

The present invention also relates to processes for preparing the compounds of general formula (I) as defined above according to the following methods that can be carried out according to methods well known to a person skilled in the art. The following processes are given for representative purposes.

A further object of the present invention is represented by the process for preparing the compounds of formula (I) and the pharmaceutically acceptable salts thereof which process comprises reacting a compound of formula (II)

(Π)

with a compound of formula (III):

Y— A-X

(III)

wherein A is as defined above for general formula (I), Y is B or a suitable hydroxy protecting group, wherein B is as defined above for general formula (I), and X is a halogen such as chloro, bromo or iodo or a suitable leaving group such as mesyl or tosyl group to give the compounds of the present invention (I) or a compound that is converted into a compound of the present invention (I) by standard methods well known to those skilled in the art; and, if desidered, converting a compound of general formula (I) to another compound of formula (I) or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I). In the case Y is a suitable hydroxy protecting group, the formed intermediate can be converted into a compound of formula (I) wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl by conventional methods of deprotection and organic functional group conversion. The compounds of the present invention prepared as described above can be optionally and conveniently converted into other compounds of the present invention by operating according to well known synthetic conditions, the following being examples of possible conversions:

a) converting a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-Cg heterobicyclyl into a compound of formula (I) wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl substituted by a C₁-C5 alkyl group optionally substituted by aryl by conventional methods of alkylation of an amino group;

b) converting a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C6-C₈ heterobicyclyl into a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl substituted by C(0)R1, wherein Rl is as defined above by conventional methods of acylation of an amino group;

c) converting a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl into a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl substituted by S0₂R2 wherein R2 is as defined above by conventional methods of conversion of an amino group into a sulfonamide group;

d) converting a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl into a compound of formula (I), wherein B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl substituted by -C(0)NR3R4, wherein R3 and R4 are as defined above by conventional methods of conversion of an amino group into a carbonyldiimino group.

Typically, the reaction of a compound of formula (II) with a compound of formula (III) is conducted in an organic solvent such as polar aprotic solvents, for instance, dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride or tetrabutylammonium hydroxide and it may be necessary to heat the reaction mixture, for example, to between about 50 and 100°C. Depending on the nature of the compounds of the formula (I) to be obtained, the methodologies presented may be adapted by a person skilled in the art by selecting the appropriate starting materials, in which the nature of the substituents A, B and X may be modified.

The compound of formula (II) may be prepared according to the procedure described in WO 2008142720.

Compounds of general formula (III) are well known and are either readily available or may be prepared by standard methods known to those skilled in the art.

If the compounds of formula (I) prepared according to the process described above are obtained as mixture of isomers, their separation using conventional techniques into the single isomers of formula (I), is within the scope of the present invention. Conventional techniques for racemate resolution include, for instance, partitioned crystallization of diasteroisomeric salt derivatives or preparative chiral HPLC. Homochiral compounds of general formula (I) may also be prepared according to the same procedure described above starting from the corresponding enantiopure compound (II). Preferably, homochiral compounds of general formula (I) are prepared according to the same procedure described above starting from the corresponding enantiopure compound (II). Oxime (II) can be resolved into enantiomers by conventional techniques well known in the art, for instance by enantioselective lipase-catalyzed hydrolysis of the corresponding acetate in an organic solvent and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, or by treating with a suitable organic solvent. Any suitable solvent known to those skilled in the art can be used for the process of the present invention. Suitable solvents include, but are not limited to, halogenated hydrocarbons, such as dichloromethane, chloroform; heterocyclic solvents, such as tetrahydrofuran, N- methylpyrrolidone; ketones such as acetone or methyl ethyl ketone; alcohols, such as methanol, ethanol, propanol, wo-propanol, butanol, tert-butanol; or a solvent polarized due to the presence of an electron withdrawing group, for instance, esters, such as ethyl acetate, butyl acetate; nitriles, such as acetonitrile; ethers, such as diethyl ether; and the like.

As it will be appreciated by the person skilled in the art, when, during the syntheses of compounds of formula (I) certain functional groups could give rise to unwanted side reactions, these groups need to be properly protected before the reactions take place and then deprotected at the end of the reactions according to conventional techniques well known in organic chemistry. A thorough discussion for protection/deprotection steps is provided for example in Greene and Wuts (Greene, T.W.; Wuts, P.G.M. "Protective Groups in Organic Synthesis", John Wiley & Sons Inc., 2007) or in Kocienski ( ocienski, P.J. "Protecting Groups", George Thieme Verlag, 2003).

The compounds of formula (I), as defined above, are useful in therapy for the treatment of diseases, which are mediated by excessive or inappropriate Hsp90 activity such as proliferative diseases, e.g. cancers, viral or fungal infections, inflammatory and neurodegenerative diseases and conditions. More specifically, the compounds of this invention are useful for the preparation of a medicament for the treatment of a variety of diseases such as defined above.

The inhibiting activity and the potency of selected compounds are determined through an in vitro assay that evaluates the ability of the invention compounds to interfere with Hsp90 activity. A representative assay for determining Hsp90 inhibitory activity is described in Example 55. Furthermore cell growth inhibitory activity assay described in Example 56 shows an enhancement of antiproliferative activity.

In another aspect, the present invention provides methods for inhibiting Hsp90 activity and provides a method for treating diseases and conditions caused by and/or associated with an alterated Hsp90 activity such as viral or fungal infections, inflammatory diseases, neurodegenerative and proliferative diseases such as cancer in a human or animal subject in need of such treatment. Such method comprises administering to a human or animal an amount of a compound of formula (I) or a composition comprising a compound of formula (I) effective to reduce or prevent such viral or fungal infections, inflammatory diseases or conditions, neurodegenerative diseases or cellular proliferation in the subject.

The invention also provides the compounds of general formula (I) for use in medicine, especially for treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity; in the treatment of viral or fungal infections, neurodegenerative or inflammatory diseases or conditions and proliferative diseases such as cancer.

In a further aspect there is provided the use of a compound of general formula (I) in the manufacture of a medicament for treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity; preferably for the treatment of proliferative diseases such as cancer, viral and fungal infections, inflammatory diseases or conditions or neurodegenerative diseases. Cancers which may be treated using the compounds of general formula (I) include lung and bronchus; oral cavity and pharynx; larynx; breast; pancreas; small intestine, colon and rectum; thyroid; esophagus, stomach; liver and intrahepatic bile duct; kidney or renal pelvis; urinary bladder, female genital tract (including cervix, uterus, and ovaries); prostate; melanomas, multiple myeloma; brain; acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma, and villous colon adenoma.

The compounds of general formula (I) may be employed alone as a sole therapy or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. Active agents, that can be formulated with a compound of the invention or alternatively, can be administered in a combined method of treatment depend on the disease state to be cured and are, for instance, gamma globulin, immune globulin and monoclonal antibody products, antibiotics and antimicrobial products; antitumor agents (chemotherapeutics, for instance, Paclitaxel and Carboplatin); and the like. The term "antitumor agent" is meant to comprise both a single antitumor drug and "cocktails", i.e. a mixture of such drugs, according to clinical practice. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In particular, in cancer therapy the compounds of the invention can be administered alone or in association with an antitumor agent as herebelow defined, as well as combination with chemotherapy, surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) and the use of at least one other cancer treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) and at least one other pharmaceutical active agent, preferably an anti-neoplastic agent. The compound(s) of formula (I) and the other pharmaceutical active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutical active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The compounds of formula (I) and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemo therapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (I) thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in a unitary pharmaceutical composition including both compounds or separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti- neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms. The compounds of the present invention may be administered in combination with another agent useful in the treatment of cancer and examples of such agents include agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins and/or radionuclides; biological response modifiers (e.g., interferons and interleukins; adoptive immunotherapy agents; hematopoietic growth factors); agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines;' inhibitors of angiogenesis and the like.

Numerous other examples of chemotherapeutic compounds and anticancer therapies suitable for co-administration with the 2-amino-7,8-dihydro-6H-quinazolin-5-one oxime compounds of the invention are known to those skilled in the art.

In certain embodiments, anticancer agents to be used in combination with compounds of general formula (I) comprise agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to, radiation; kinase inhibitors (e.g., Epidermal Growth Factor Receptor [EGFR] kinase inhibitor, Vascular Endothelial Growth Factor Receptor [VEGFR] kinase inhibitor, Fibroblast Growth Factor Receptor [FGFR] kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR] I kinase inhibitor, and Bcr-Abl kinase inhibitors such as STI-571 [Gleevec or Glivec]); antisense molecules; antibodies [e.g., Herceptin and Rituxan]; anti-estrogens [e.g., raloxifene and tamoxifen]; anti-androgens [e.g., flutamide, bicalutamide, finasteride, amino- glutethamide, ketoconazole and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan (Camptosar), CPT-I1, fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone, Mylotarg, VP- 16, cisplatinum, 5-FU, Doxrubicin, Taxotere or Taxol]; cellular signaling molecules; ceramides, cytokines; and staurosparine; and the like.

Preferred anticancer agents for use in combination with compounds of general formula (I) include irinotecan, topotecan, gemcitabine, gefitinib, vatalanib, sunitinib, sorafenib, erlotinib, dexrazoxane, gleevec, herceptin, 5-fluorourdcil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab and topoisomerase I inhibitors.

The compounds of the present invention may also be used to treat other conditions mediated by Hsp90, for example viral conditions such as hepatitis B, hepatitis C and herpes simplex; inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, type I diabetes, Lupus erythmatosus, psoriasis and inflammatory bowel disease; cystic fibrosis; angiogenesis- related diseases such as diabetic retinopathy, haemangiomas and endometriosis. In addition the compounds may be used to treat neurodegenerative diseases which may be mediated by Hsp90, for example scrapie or its human equivalent, Creuzfeldt-Jakob disease (CJD), Huntington's disease or Alzheimer's disease or to protect normal cells against chemotherapy-induced toxicity. Another use for the compounds of the invention is to resensitise previously resistant fungal strains to antifungal agents such as azoles or echinocandins.

The compound of general formula (I) may be administered in combination with another agent useful in the treatment of inflammatory, or neurodegenerative disease, an anti-viral agent, an antifungal agent or an agent useful for treating any of the diseases or conditions listed above.

The compounds of formula (I) of the present invention, suitable for administration to human or for veterinary medicine, can be administered by the usual routes in a variety of dosage forms containing the active ingredient along with pharmaceutically acceptable carriers and excipients. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. In yet another aspect of the invention, there is provided a pharmaceutical composition comprising at least a compound of general formula (I) together with a pharmaceutically acceptable excipient. The composition may further include one or more additional anti-cancer agent such as those listed above or, alternatively, another anti-inflammatory, anti-viral or anti-fungal agent or an agent useful for treating any of the diseases or conditions listed above.

All the pharmaceutical preparations comprising a compound of general formula (I) can be used as pharmaceuticals in human or veterinary medicine.

The pharmaceutical compositions, which are useful for administering the compounds of formula (I) according to this invention, can be administered by a variety of routes including oral, parenteral (including intramuscular, intravenous, subcutaneous, intra-arterial, intraperitoneal, intrasternal, intraarticular, by injection or infusion), transmucosal (including buccal, sublingual, nasal, transurethral, intravaginal and rectal), topical, transdermal, ocular or intravitreal route, by inhalation or aerosolization, permucous or percutaneous or using any other route of administration, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.

The pharmaceutical compositions will thus be presented in the form of both solid forms such as tablets, plain or coated tablets, sugar or film coated tablets, capsules, wafer capsules, gel capsules, pills, cachets, sachets, lozenges, dragees, powders, granules, bolus; liquid forms such as solutions, syrups, elisirs, emulsions or suspensions; in the form of aerosol, suppositories, rectal capsules, past, creams, ointments, gels, drops, transdermal patch, multi-dose bottles, electuary, ocular implants, reservoir implants, directly into tumor masses or using any other route of administration. The compositions of the invention may be obtained by conventional procedure using conventional pharmaceutical excipient, well known in the art. A person skilled in the art is aware of a whole variety of such excipients suitable to formulate a pharmaceutical composition. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art. Excipients include, by way of illustration and not limitation, diluents, fillers, agglutinants, disintegrants, disintegration inhibitors, absorption accelerators, adjuvant, binders, carriers, suspensing/dispersing agents, film formers/coatings, adhesives, antiadherents, wetting agents, lubricants, glidants, preservatives, sorbents, surface active agents, substances added to mask or counteract a disagreeable taste or odor, flavorings, colorants, fragrances, aromatising agents, sweeteners and substances added to improve appearance of the composition. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The pharmaceutical compositions of the invention may contain a compound of formula (I) as the active substance, in association with one or more pharmaceutically acceptable excipients and/or carrier, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. A sustained-release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxcylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids, such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.

The solid oral forms, e.g. tablets, dragees, capsules, pills, powders, granules, may contain, together with the active compound, diluents, e.g., lactose, starches, sucrose and the like. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants, e.g. magnesium or calcium salts, sodium stearate and the like. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. The solid oral formulations may be also in the form of sustained release formulations that can be prepared in conventional manner, for instance, by applying an enteric coating to tablets and granules.

Liquid oral preparations can be formulated e.g. as aqueous or oily suspensions or solutions, emulsions, syrups or elixir, or can be presented as freeze dried product to be regenerated by addition of water or a suitable vehicle before use. Said liquid preparations can contain conventional additives such as wetting agents, suspending agents, emulsifying agents, cyclodextrins; and, if desired, conventional sweetening, flavoring, perfuming agents and dyes. Pharmaceutical compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, in the form of sterile, aqueous, isotonic, saline solutions, Ringer's solution, isotonic sodium chloride solution, isotonizing agents, a pH adjuster, fixed oils, including synthetic mono- or di- glycerides, anti-oxidants, buffers, solubilizers; stabilizers; preservatives; carboxymethylcellulose and suitable mixtures thereof; fatty acids and injectable organic esters; suspending agents; thickening agents and, if desired, a suitable amount of lidocaine hydrochloride. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, suspending and dispersing agents.

Advantageously, it is possible to include a surfactant or a wetting agent in the composition with the aim of easing the uniform distribution of the compound of the invention.

Pharmaceutical preparations which are suitable for rectal or vaginal administration, e.g. suppositories, enemas, may be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as natural or synthetic triglycerides, cocoa butter, polyethylene glycol, paraffin hydrocarbons, polyoxyethylene, sorbitan fatty acid esters surfactants, lecithin, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound and the like. Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically- acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, e.g. edetic acid, disodium edentate; preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, see, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. The above described components for pharmaceutical composition administered are merely representative. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. In general, the above compositions may be prepared in a conventional manner using conventional excipients. Further materials as well as processing techniques and the like are set out in Part 5 of Remington 's Pharmaceutical Sciences, 20^th Edition, 2000, Merck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. Compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.

Compounds of general formula (I) may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. A determination of the optimal range for each individual being however within the skill of the art.

The agents to be employed in combination with the compounds of general formula (I) will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 47th Edition (1993), or such therapeutically useful amounts as would be known to one of ordinary skill in the art.

The compounds of formula (I) of the present invention are contained in the above said pharmaceutical compositions in an amount which is effective for the disease to be prevented or treated. The compounds of general formula (I) and the other agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on a variety of factors including the disorder being treated, the severity of the disorder and the response of the patient; activity of the specific compound employed; the specific composition employed, the age, body weight, conditions of the patient, general health, sex and diet of the individual being treated; the time and route of administration, the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; the severity of the illness being treated and like factors well known by those skilled in the art.

If desired, the effective daily dose may be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response by the practitioner who is treating any particular patient.

The compounds of the present invention may be employed alone as a sole therapy or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. The combination can be administered as separate compositions (simultaneous, sequential) of the individual components of the treatment or as a single dosage form containing both agents When the compounds of this invention are in combination with others active ingredients, the active ingredients may be separately formulated into single-ingredient preparations of one of the above- described forms and then provided as combined preparations, which are given at the same time or different times, or may be formulated together into a two- or more- ingredient preparation.

With the aim to better illustrate the present invention, without posing any limitation to it, the following examples are now given.

EXPERIMENTAL PART

1. COMPOUND SYNTHESIS

Method

Unless otherwise indicated, all the starting reagents and solvents (HPLC purity) were found to be commercially available and were used without any prior purification.

The following abbreviation can be used in the description of the experimental procedures:

Boc anhydride (di-tert-butyldicarbonate); Boc (tert-butoxycarbonate); CDC1₃ (deuterated chloroform); CH₃CN (acetonitrile); DCM (dichlorometane); DMF (dimethylformammidee);

DMSO-d₆ (deuterated dimethyl sulfoxide); Et₂0 (diethyl ether); EtOAc (ethyl acetate); g (grams); h (hours); Ή (proton); HC1 (hydrochloric acid); H₂0 (water), HPLC/UPLC (High/Ultra

Performance Liquid Chromatography); Hz (Hertz); IC₅₀ (inhibitory concentation causing 50% reduction of the measured activity); i-PrOH (isopropyl alchol); K₂C0₃ (potassium carbonate);

KOH (potassium hydroxide); LC-MS (Liquid Chromatography associated with Mass Spectrum);

M (molarity); MeOH (methanol); mg (milligrams); MHz (MegaHertz); min (minutes); mL (milliliters); mmol (millimoles); Na₂S0₄ (sodium sulfate); NaBH₃CN (sodium cyanoborohydride); NaBH₄ (sodium borohydride); NaCl (sodium chloride); NaHC0₃ (sodium hydrogen carbonate); NaOH (sodium hydroxide); nBuOH (normal butanol); NH₄C1 (ammonium chloride); NH₄COOH (ammonium formate); NH4OH (ammonium hydroxide); NMR (Nuclear Magnetic Resonance); RT (room temperature); rt (retention time in minutes); s (seconds); TEA (triethylammine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μΐ (microliters). Nomenclature of compounds described in this invention was obtained using AutoNom 2000 (Automatic Nomenclature) for Simix. This software is based on standardized IUPAC nomenclature. Other compounds, intermediates and starting materials were cited using the standard IUPAC nomenclature.

Except where otherwise indicated, all temperatures are expressed in °C (degrees centigrade).

Ή-NMR spectra were recorded on a Brucker 300 MHz. Chemical shifts are expressed in parts of million (ppm, δ units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sxt (sextet), m (multiplet), bs (broad signal).

LC-MS analysis were recorded using one of the following methods:

METHOD A:

Waters Acquity UPLC, Micromass ZQ 2000 single quadrupole (Waters). Column: Fenomenex^® Kinetex UPLC C18 (50 x 2.1 mm, 1.7 μπι). Mobile phase: phase A: H₂O/CH₃CN 95/5 + 0.1% TFA; phase B: H₂0/CH₃CN 5/95 + 0.1% TFA; flow rate: 0.5 mL/min. Detection: UV (DIODE array) among 210 e 400 nm; ESI positive mode. Full scan from 100-2000 m/z.

Gradient: 0-0.3 min (A: 95%, B: 5%), 0.3-1.5 min (A: 0%, B: 100%), 1.5-2.0 min (A: 0%, B: 100%), 2.0-2.4 min (A: 95%, B: 5%).

METHOD B:

Waters HPLC, Micromass ZQ 2000 single quadrupole (Waters). Column: XBridge C8 (50 x 4.6 mm, 3.5 μπι). Mobile phase: phase A: H₂0 + 0.1% TFA; phase B: CH₃CN + 0.1% TFA; flow rate: 2.0 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C. Gradient: 0-1.0 min (A: 95%, B: 5%), 1.0-8.0 min (A: 0%, B: 100%), 8.0-8.1 min (A: 90%, B 10%), 8.1-8.5 (A: 95%, B: 5%), 8.5-9.5 (A: 95%, B: 5%).

METHOD C: Waters Acquity HPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Acquity Atlantis C 18 (50 x 2.1 mm, 3 μιη). Mobile phase: phase A: H₂0 + 0.1% TFA; phase B: CH₃CN + 0.1%) TFA; flow rate: 0.3 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

Gradient: 0-0.2 min (A: 95%, B: 5%), 0.2-5.0 min (A: 0%, B: 100%), 5.0-6.0 min (A: 0%, B: 100%), 6.0-6.1 min (A: 95%, B: 5%), 6.1-7.0 min (A: 95%, B: 5%).

METHOD D:

Waters Acquity UPLC, Micromass ZQ 2000 Single quadrupol (Waters).). Column: Acquity UPLC-BEH CI 8 (50 x 2.1 mm, 1.7 μιη). Mobile phase: phase A: H₂0 r/MeOH 95/5 + 0.1% formic acid; phase B: H₂0 r/MeOH 5/95 + 0.1% formic acid; flow rate: 0.6 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

Gradient: 0-0.25 min (A: 95%, B: 5%), 0.25-3.3 min (A: 0%, B: 100%), 3.3-4.0 min (A: 0%, B: 100%), 4.0-4.1 min (A: 95%, B: 5%), 4.1-5.0 min (A: 95%, B: 5%).

METHOD E:

Waters Acquity UPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Acquity UPLC- BEH CI 8 (50 x 2.1 mm, 1.7 μπι). Mobile phase: phase A: H₂0 /CH₃CN 95/5 + 0.1% TFA; phase B= H₂0 /CH₃CN 5/95 + 0.1% TFA; flow rate: 0.6 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

Gradient: 0-0.5 min (A: 95%, B: 5%), 0.5-6.0 min (A: 0%, B: 100%), 6.0-7.0 min (A: 0%, B: 100%), 7.0-7.1 min (A: 95%, B: 5%), 7.1-8.5 min (A: 95%, B: 5%).

METHOD F:

Waters Acquity HPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Gemini CI 8 (50 x 2.0 mm, 5.0 μπι). Mobile phase: phase A: H₂0 (NH₃ f 9.5)/CH₃CN 95/5; phase B: H₂0 (NH₃ f 9.5)/CH₃CN 5/95; flow rate: 0.35 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

Gradient: 0-0.5 min (A: 95%, B: 5%), 0.5-2.0 min (A:90%, B: 10%), 2.0-7.0 min (A: 0%, B: 100%), 7.0-9.0 min (A: 0%, B: 100%), 9.0-9.1 min (A: 90%, B: 10%), 9.1-12.0 min (A: 90%, B: 10%).

METHOD G:

Waters Acquity UPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Acquity UPLC- BEH CI 8 (50 x 2.1 mm, 1.7 μιη). Mobile phase: phase A: H₂0 /CH₃CN 95/5 + 0.1% TFA; phase B: H₂0 /CH₃CN 5/95 + 0.1% TFA; flow rate: 0.6 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

METHOD H:

Waters Acquity HPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Ascentis Express C18 (30 x 2.1 mm, 2.7 μπι). Mobile phase: phase A: H₂0 /CH₃CN 95/5 + 0.1% TFA; phase B: H₂0 /CH₃CN 5/95 + 0.1% TFA; flow rate: 0.7 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C.

Gradient: 0-1.0 min (A: 95%, B: 5%), 1.0-7.5 min (A: 0%, B: 100%), 7.5-8.5 min (A: 0%, B: 100%), 8.5-8.6 min (A: 95%, B: 5%), 8.6-9.5 min (A: 95%, B: 5%).

METHOD I:

Waters Acquity HPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Gemini CI 8 (50 x 2 mm, χ5μιη). Mobile phase: phase A= NH₄COOH 10 mM f 5; phase B = MeOH; flow rate: 0.25 mL/min. Detection: UV at 254 nm or BPI with ESI positive mode at 3.2KV, 25V, 350 °C. Gradient: 0-0.1 min (A: 80%, B: 20%), 0.1-17.0 min (A: 27.5%, B: 72.5%), 17.0-38.0 min (A: 27.5%, B: 72.5%), 38.0-39.1 min (A: 80%, B: 20%), 39.1-40.0 min (A: 80%, B: 20%).

METHOD L:

Waters Acquity HPLC, Micromass ZQ 2000 Single quadrupol (Waters). Column: Fenomenex ® Kinetex UPLC C18 (50 x 2.1 mm, 1.7 μπι). Mobile phase: phase A: H₂0 /CH₃CN 95/5 + 0.1% TFA; phase B: H₂0 /CH₃CN 5/95 + 0.1% TFA; flow rate: 0.5 mL/min. Detection: UV (DIODE array) among 200 e 400 nm; ESI positive mode with full scan from 100-2000 m/z.

Gradient: 0-0.3 min (A: 95%, B: 5%), 0.3-3.3 min (A: 0%, B: 100%), 3.3-3.9 min (A: 0%, B: 100%), 3.9-4.4 min (A: 95%, B: 5%).

METHOD M:

Agilent LC-MS, serie 1200, single quadrupol (Agilent). Column: Zorbax Eclipse Plus CI 8 (50 x 4.6 mm, 5 μπι). Mobile phase: phase A: H₂0 + 0.1% formic acid; phase B: methanol; flow rate: 1.2 mL/min. Detection: UV (DIODE array) among 200 e 400 nm. Gradient: 0-3.5 min (A: 90%, B: 10%), 3.5-5.0 min (A: 5%, B: 95%), 5.0-5.5 min (A: 90%, B: 10%), 5.5-7.0 min (A: 90%, B: 10%).

METHOD N: Chiral Column

Waters Alliance HPLC. Column: Chiralcel ® OD-H (150 x 4.6 mm, 5 μπι). Mobile phase: phase A: n-hexane + 0.1% TEA; phase B: -PrOH + 0.1% TEA; flow rate: 0.4 mL/min. Detection: UV at 260 nm.

Isocratic gradient: A: 45%, B: 55% for 25 min.

METHOD O:

Agilent LC-MS, HP1100, single quadrupol (Agilent). Column: Atlantis C18 (2.1 x 100 mm, 3 μπι). Mobile phase: phase A: H₂0 /0.1% formic acid; phase B: acetonitrile/0.1% formic acid; flow rate: 0.6 mL/min. Detection: UV (DIODE array) at 215 nm.

Gradient: 5-100% B in 7 min.

The reactions were monitored by thin layer chromatography (TLC) using Merck plates 0.2 mm (60F-254) and spotting reaction products with UV light at 254 nm. Flash chromatography purifications were performed on Merck silica gel 60 (0.04-0.063 mm).

Intermediate 1 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyI-7,8-dihydro-6H- quinazolin-5-one oxi - Rif. ( ) 89

This compound was prepared as described in WO 2008142720.

Intermediate 2: (E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro- 6H-quinazolin-5-one O-acetyl oxime

Acetyl chloride (0.982 mL, 13.76 mmol) is added dropwise to the solution of (E)-2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (5 g, 13.76 mmol) in anhydrous DMF (100 mL) and TEA (2.88 mL, 20.64 mmol) maintaining the internal temperature between 0-5 °C.

The reaction is stirred overnight at RT. Acetyl chloride (0.3 mL, 4.22 mmol) and TEA (0.6 mL, 4.30 mmol) were added for three times leaving the reaction at RT for 1 h after each addition. The organic solvent is evaporated under reduced pressure. The crude is washed with H₂0 and filtered. The solid is washed with MeOH, filtered and dried under vacuum to yield the title compound (5.18 g, 12.78 mmol, Yield: 93%) as white solid.

LC-MS: method A, rt=0.98 min; (ES+), M+H⁺=406

Ή-NMR (DMSO-d₆) δ ppm: 8.58 (dd, J=4.7, 1.8 Hz, 1 H); 8.55 (dd, J=2.3, 0.9 Hz, 1 H); 7.79 (dt, J=7.9, 2.3 Hz, 1 H); 7.71 (dd, J=8.8, 5.9 Hz, 1 H); 7.46 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.33 (td, 1 H); 7.13 (dd, J=9.5, 2.8 Hz, 1 H); 7.01 (s, 2 H); 2.55-3.26 (m, 5 H); 2.52 (br s, 3 H); 2.16 (s, 3 H) Intermediate 3 : (S,E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro- 6H-quinazolin-5-one oxime (e.e.~80%)

Intermediate 4 : (R,E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8- dihydro-6H-quinazolin-5-one O-acetyl oxime (e.e.~80%)

Lipase acrylic resin from Candida Antarctica (0.3 g) is added to the solution of (E)-2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-acetyl oxima (0.2 g, 0.493 mmol) (Intermediate 2) in THF (20 mL) e nBuOH (0.034 mL, 0.37 mmol). The suspension is stirred at 30°C for 36 h. The suspension is filtered and a mixture of DCM and aceton (4: 1, 200 mL) is added to the solution. The organic solvent is removed under vacuum and the crude is purified by flash column chromathography (eluent DCM/MeOH from 99/1 to 95/5). Two fractions were obtained: Intermediate 4: (R,E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-acetyl oxime (0.073 g, 0.180 mmol, Yield: 73%) as light yellow solid.

Chiral HPLC: method N, rt=l 6.695 min; enantiomeric ratio: S/R=7/93.

LC-MS: method A, rt=1.00 min; (ES+), M+H⁺=406

Intermediate 3: (S,E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (0.060 g, 0.165 mmol, Yield: 67%) as white solid.

Chiral HPLC: method N, rt=l 0.646 min; enantiomeric ratio: S/R=9/l .

LC-MS: method A, rt=0.92 min; (ES+), M+H⁺=364

Intermediate 5: N-Boc-4-iodopiperidine

f T 1 T I .

— — ^N~^"if^{0 ~ *} ^ ⁰†'

STEP A:

Boc anhydride (4.4 g, 20.17 mmol) is added at 0°C to the solution of 4-hydroxypiperidine (2 g,

19.77 mmol) in DCM (70 mL) and TEA (2.81 mL, 20.17 mmol). The reaction is stirred for 3 h.

Additional Boc anhydride (1.377 mL, 5.93 mmol) is added and the solution is stirred for 1 h. The reaction mixture is washed with H₂0 and The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography

(eluent petroleum ether/EtOAc from 9/1 to 1/1) to yield the expected compound (2.72 g, 13.51 mmol, Yield: 68%) as light yellow oil.

LC-MS: method A, rt=1.74 min; (ES+), M+H⁺=202.1

Ή-NMR (DMSO-i , δ (ppm): 4.66 (d, J=4.4 Hz, 1 H); 3.51-3.72 (m, 3 H); 2.84-3.05 (m, 2 H);

1.61-1.78 (m, 2 H); 1.39 (s, 9 H); 1.16-1.33 (m, 2 H)

STEP B:

Imidazole (1.196 g, 17.57 mmol), triphenylphospine (3.72 g, 14.19 mmol) and iodine (3.60 g, 14.19 mmol) are added at 0°C to the solution of N-Boc-4-hydroxypiperidine (2.72 g, 13.51 mmol) in CH₃CN (113 mL). The reaction is stirred at 0°C for 30 min and then for 5 days at RT. The organic solvent is removed at reduced pressure and the residue is dissolved in DCM. The organic phase is washed with a solution of tiosulfate and then with brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent petroleum ether/EtOAc from 100/0 to 95/5) to yield the title compound (2.76 g, 8.87 mmol, Yield: 66%) as light yellow oil..

Ή-NMR (DMSO-i ₆) δ (ppm): 4.60 (tt, J=8.5, 4.1 Hz, 1 H); 3.39-3.53 (m, 2 H); 3.08-3.24 (m, 2 H); 1.96-2.12 (m, 2 H); 1.79-1.96 (m, 2 H); 1.40 (s, 9 H)

Example 1: (R)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

STEP A:

Lipase acrylic resin from Candida Antarctica (1.5 g) is added to the solution of (E)-2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-acetyl oxime (5/95 S/R) (1.26 g, 3.11 mmol) (Intermediate 4) in anhydrous THF (100 mL) and nBuOH (0.142 mL, 1.554 mmol). The mixture is stirred under orbital shaking at 30°C for 40 h. As chiral HPLC showed an enantiomeric ratio of 1/99 (S/R), the enzyme is filtered and a mixture of DCM and acetone (4: 1, 200 mL) is added to the obtained solution.The organic solvent is evaporated to dryness and the residue is purified by flash column chromatography (eluent: DCM 100% to DCM/MeOH 98/2) to obtain the title compound (0.715 g, 1.764 mmol, Yield: 56.7%) as light yellow solid.

Chiral HPLC: method N, rt=l 6.09 min, 1/99 S/R.

LC-MS: method A, rt=0.99 min; (ES+), M+H⁺=406

STEP B:

1M NaOH (3.53 mL, 3.53 mmol) is added to the solution of (R,E)-2-amino-7-(4-fluoro-2-pyridin- 3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-acetyl oxime (0.715 g, 1.764 mmol) in MeOH (45 mL). The mixture is stirred at RT for 15 min and then evaporated under reduced pressure. The residue is washed with H₂0, filtered and dried overnight under vacuum to give the title compound (0.59 g, 1.624 mmol, Yield: 92%>) as white solid.

Chiral HPLC: method N, rt =13.55 min, 1/99 S/R. LC-MS: method C, rt =1.71 min; (ES+) MH⁺: 364.18

Ή-NMR (DMSO-i e) δ (ppm): 10.91 (br. s., 1 H); 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.3, 0.9 Hz, 1 H); 7.77 (dt, J=7.9, 2.1 Hz, 1 H); 7.68 (dd, J=8.9, 6.0 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.7, 2.9 Hz, 1 H); 7.10 (dd, J=9.7, 2.9 Hz, 1 H); 6.65 (s, 2 H); 3.01-3.12 (m, 1 H); 2.99 (dd, J=15.3, 12.0 Hz, 1 H); 2.79-2.92 (m, 1 H); 2.54-2.68 (m, 2 H); 2.45 (s, 3 H)

Example 2 : (S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

80% e.e 96% e.e.

STEP A:

Acetyl chloride (0.357 mL, 5.00 mmol) is added dropwise to the solution (S,E)-2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (9/1 S/R) (Intermediate 3) (1.397 g, 3.84 mmol) in anhydrous DMF (20 mL) and TEA (0.804 mL, 5.77 mmol) maintaining the internal temperature between 0-5 °C.

The reaction is stirred at RT. After 1 h, an extra amount of acetyl chloride (0.273 mL, 3.84 mmol) and TEA (0.536 mL, 3.84 mmol) is added stirring the reaction overnight at RT. The organic solvent is evaporated under reduced pressure. The crude is washed with H₂0, filtered and dried under vacuum. The solid is triturated in the minimum amount of MeOH and, after filtration, a white solid is obtained.

Chiral HPLC (method N) of the mother liquor: S > 98%.

Chiral HPLC (method N) of the solid: 63/37 S/R.

Mother liquor is concentrated under reduced pressure to yield (S,E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-acetyl oxime (S > 98%, 0.94 g, 2.319 mmol, Yield: 60%).

LC-MS: method A, rt=0.98 min; (ES+), M+H⁺=406

Chiral HPLC: method N, rt=l 5.919 min.

STEP B: 1M NaOH (10 mL, 10 mmol) is added to the solution of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3- yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-acetyl oxime (0.940 g, 2.319 mmol, S>98%) in MeOH (60 mL). The mixture is stirred at RT for 15 min and then evaporated under reduced pressure. The residue is washed with H₂0, filtered and dried under vacuum to give (S,E)- 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (0.710 g, 1.954 mmol, Yield: 84%) as white solid.

Chiral HPLC: method N, it =10.83 min, S/R = 98/2.

LC-MS: method C, rt =1.71 min; (ES+) MH⁺: 364.18

Ή NMR (DMSO-ife) δ (ppm): 10.91 (br. s., 1 H); 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.3, 0.9 Hz, 1 H); 7.77 (dt, J=7.9, 2.1 Hz, 1 H); 7.68 (dd, J=8.9, 6.0 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.7, 2.9 Hz, 1 H); 7.10 (dd, J=9.7, 2.9 Hz, 1 H); 6.65 (s, 2 H); 3.01-3.12 (m, 1 H); 2.99 (dd, J=15.3, 12.0 Hz, 1 H); 2.79-2.92 (m, 1 H); 2.54-2.68 (m, 2 H); 2.45 (s, 3 H)

Example 3: 2-Amino-7^(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

STEP A:

Sodium hydride (60% mineral oil dispersion) (39.6 mg, 0.991 mmol) is added under nitrogen to a soluzion of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-one oxime (Intermediate 1) (0.30 g, 0.826 mmol) in DMF (10 mL). After 10 min, 2-(2- bromoethoxy)tetrahydro-2H-pyrane (0.152 mL, 0.991 mmol) is added and the mixture is heated at 60°C for 4 h. The suspension is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH 95/5) to give the expected compound (0.28 lg, 0.572 mmol, Yield: 69%).

LC-MS: method A, rt=l .23 min; (ES+), M+H⁺= 492.3

STEP B:

4M HC1 in dioxane (0.712 mL, 2.85 mmol) is added to the solution of (E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-2-(tetrahydro-2H-pyran-2- yloxy)ethyl oxime (0.280 g, 0.570 mmol) in DCM (6 mL). The reaction is stirred at room temperature for 4 h and then evaporated to dryness. The residue is treated with H₂0, basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH 95/5) to give the expected compound (0.227 g, 0.557 mmol, Yield: 98%). LC-MS: method A, rt=0.96 min; (ES+), M+H⁺= 408.2

STEP C:

(E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-2- hydroxyethyl oxime (0.227 g, 0.557 mmol), TEA (0.078 mL, 0.557 mmol) and methansulfonyl chloride (70.2 mg, 0.613 mmol) in DCM (10 mL) are stirred at RT for 1 h. Additional methansulfonyl chloride (70.2 mg, 0.613 mmol) and TEA (0.078 mL, 0.557 mmol) are added and the reaction is stirred for 3 h.

The mixture is diluted with DCM and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH from 95/5 to 9/1) to give the expected compound (0.186 g, 0.382 mmmol, Yield: 69%).

LC-MS: method A, rt=l .05 min; (ES+), M+H⁺= 486.2

STEP D:

Azetidine (0.305 g, 5.34 mmol) is added to the solution of 2-(2-amino-7-(4-fluoro-2-pyridin-3-yl- phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)ethyl metansulfonate (0.098 g, 0.202 mmol) in anhydrous DMF (3 mL). The reaction is heated at 50°C for 4 h in a sealed vessel. The mixture is diluted with EtOAc-Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 98/2/0.1 to 95/5/0.5) to give the title compound (0.0415 g, 0.093 mmol, Yield: 46%) as white solid.

LC-MS: Method E, rt=1.44 min; (ES+) MH⁺: 447.27

Ή-NMR (DMSO-dg) δ (ppm): 8.57 (dd, 1 H); 8.52 (dd, 1 H); 7.76 (ddd, 1 H); 7.67 (dd, 1 H); 7.45 (ddd, 1 H); 7.31 (ddd, 1 H); 7.10 (dd, 1 H); 6.75 (s, 2 H); 3.97 (t, 2 H); 3.07 (t, 4 H); 2.81-3.04 (m, 2 H); 2.55-2.67 (m, 5 H); 2.46 (s, 3 H); 1.93 (quin, 2 H)

Example 4: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(2-pyrrolidin-l-yl-ethyl)-oxime

Sodium hydride (60% mineral oil dispersion) (0.035 g, 0.88 mmol) is added at RT to the solution of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.28 mmol) and l-(2-chloroethyl)-pyrrolidine hydrochloride (0.056 g, 0.33 mmol) in DMF (4 mL) in a sealed vessel. The reaction mixture is heated overnight at 80°C and then cooled to RT. The mixture is diluted with EtOAc (2 x 20 mL) and washed with H₂0, brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The beige-orange residue is purified by flash column chromatography (eluent MeOH/DCM 2:20) to give the title compound (0.070 g, Yield 55%) as white solid.

LC-MS: method O, rt=2.44 min; (ES+), M+H⁺= 461

^LH-NMR (MeOD) δ (ppm): 8.54 (1 H, dd, J=4.9, 1.5 Hz); 8.50 (1 H, d, J=1.5 Hz); 7.81 (1 H, d, J=6.1 Hz); 7.57 (1 H, dd, J=8.8, 5.5 Hz); 7.49 (1 H, dd, J=7.6, 5.2 Hz); 7.22 (1 H, td, J=8.5, 2.7 Hz); 7.03 (1 H, dd, J=9.3, 2.9 Hz); 4.26 (2 H, t, J=5.8 Hz); 3.14-3.23 (1 H, m); 2.95-3.02 (2 H, m); 2.83 (2 H, t, J=5.8 Hz); 2.57-2.76 (6 H, m); 2.54 (3 H, s); 1.75-1.91 (4 H, m)

Example 5 : 2- Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(2-morpholin-4-yl-ethyl)-oxime

This compound is synthesized following the experimental procedure of Example 4, using N-(2- chloroethyl)morpholine instead of l-(2-chloroethyl)-pyrrolidine hydrochloride. The title compound is obtained as white solid (0.056 g, Yield 50%)

LC-MS: method O, rt=2.35 min; (ES+), M+H⁺= 477

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (1 H, dd, J=4.8, 1.5 Hz); 8.52 (1 H, d, J=1.8 Hz); 7.76 (1 H, d, J=7.7 Hz); 7.67 (1 H, dd, J=8.8, 5.9 Hz); 7.45 (1 H, dd, J=7.7, 4.8 Hz); 7.31 (1 H, td, J=8.6, 2.9 Hz); 7.11 (1 H, dd, J=9.5, 2.9 Hz); 6.79 (2 H, s); 4.14 (2 H, t, J=5.9 Hz); 3.54 (4 H, t, J=4.6 Hz); 2.96-3.05 (2 H, m); 2.88 (1 H, t, J=12.3 Hz); 2.54-2.63 (4 H, m); 2.45 (3 H, s); 2.39 (4 H, br. s) Example 6: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-

STEP A:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.330 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, N-Boc-4-(2-bromoethyl)piperazine (161 mg, 0.550 mmol) is added and the mixture is heated at 50°C for 1.5 h. The suspension is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The beige-orange residue is purified by flash column chromatography (eluent DCM/MeOH from 99/1 to 95/5) to give the expected compound (0.111 g, 0.193 mmol, Yield: 70%).

LC-MS: method A, rt=1.60 min; (ES+), M+H⁺= 576.5

'H-NMR (DMSO-</₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.2Q, 0.73 Hz, 1 H): 7.76 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.66 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.31 (td, J=8.73, 2.79 Hz, 1 H); 7.1 1 (dd, J=9.68, 2.93 Hz, 1 H); 6.76 (s, 2 H); 4.15 (t, J=5.87 Hz, 2 H); 3.24-3.28 (m, 4 H); 2.94-3.08 (m, 2 H); 2.82-2.94 (m, 1 H); 2.54-2.66 (m, 4 H); 2.45 (s, 3 H); 2.32-2.39 (m, 4 H); 1.39 (s, 9 H)

STEP B:

4M HC1 in dioxane (1 mL, 4.0 mmol) is added to the solution of N-Boc-4-(2-(2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)ethyl)piperazine (0.103 g, 0.179 mmol) in DCM (4 mL). The reaction mixture is left at RT for 6 h. The obtained precipitate is filtered and washed with DCM. It is then dissolved in H₂0, basified with NH₄OH and extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (0.050 g, 0.105 mmol, Yield: 59%).

LC-MS: method D, rt=1.77 min; (ES+ MH⁺: 476.07

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.84, 1.61 Hz, 1 H); 8.52 (dd, J=2.20, 0.73 Hz, 1 H); 7.76 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.66 (dd, J=8.80, 5.87 Hz, 1 H); 7.46 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.31 (td, J=8.58, 2.79 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.76 (s, 2 H); 4.13 (t, J=6.02 Hz, 2 H); 2.95-3.09 (m, 2 H); 2.82-2.94 (m, 1 H); 2.74-2.81 (m, 4 H); 2.56-2.68 (m, 5 H); 2.45 (s, 3 H); 2.35-2.45 (m, 4 H)

Example 7: 2-Amino-7-(4-fluoro-2-pyridin-3-yI-phenyI)-4-methyI-7,8-dihydro-6H- quinazolin-5-one 0-[2-(4-methyl-piperazin-l-yl)-ethyl]-oxime

STEP A:

A solution of tetrabromomethane (1.58 g, 4.7 mmol) in DCM (10 mL) is added dropwise (30 min) to the solution of N-Boc-piperazin-4-ethanol (1 g, 4.34 mmol) and triphenylphosphine (1.23 g, 4.7 mmol) in DCM (10 mL) at 0°C. The reaction is left at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (1 g, 3.38 mmol, Yield 78%) as colourless oil.

^[H-NMR (CDCI₃) δ (ppm): 3.41-3.47 (m, 6H); 2.81 (t, J=6.00 Hz, 2H); 2.48 (t, J=6.00 Hz, 4H); 1.46 (s, 9H)

STEP B:

Sodium hydride (60% mineral oil dispersion) (19.16 mg, 0.82 mmol) in anhydrous DMF (5 mL) is added at 0°C under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.25 g, 0.684 mmol) in anhydrous DMF (5 mL). After 5 min, N-Boc-4-(2-bromoethyl)piperazine (0.24 g, 0.82 mmol) dissolved in anhydrous DMF (5 mL) is added and the mixture is stirred at RT for 3 h. Ice is added to the suspension and the mixture is extracted with DCM (3 x 10 mL). The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure to give the expected compound (0.395 g, 0.677 mmol, Yield: 99%) as light brown solid.

Ή-NMR (CDCI₃) δ (ppm): 8.60-8.61 (m, 1H); 8.55 (m, 1H); 7.58-7.61 (m, 1H); 7.33-7.42 (m, 1H); 7.13-7.19 (m, 1H); 6.95 (dd, J=2.70, 9.00 Hz, 1H); 5.02 (s, 2H); 4.25 (t, J=6.00 Hz, 2H); 3.43 (t, J=6.00 Hz, 4H); 2.83-3.22 (m, 6H); 2.58 (s, 3H); 2.50-2.54 (m, 1H); 2.45 (t, J=3.00 Hz, 4H); 1.46 (s, 9H)

STEP C:

4M HC1 in dioxane (2 mL, 8.0 mmol) is added to the solution of N-Boc-4-(2-(2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)piperazine (0.395 g, 0.677 mmol) in DCM (4 mL) and the reaction mixture is stirred at RT for 5 h. The organic solvent is removed under reduced pressure to give the desired compound (0.347 g, 0.677 mmol, Yield: 100%) as light brown solid.

STEP D:

The solution of 4-(2-(2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-ylideneaminoxy)ethyl)piperazine (130 mg, 0.273 mmol) and formaldehyde (9 mg, 0.3 mmol) in MeOH (5 mL) is stirred at RT for 6 h. After cooling at 0°C, NaBH₃CN (20 mg, 0.327 mmol) is added. The reaction mixture is stirred at RT for 20 h. Cold H₂0 is added and the precipitate is filtered off and then purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.024 g, 0.0489 mmol, Yield: 18%) as brown solid. LC-MS: method M, rt=2.89 min; (ES+) MH⁺: 490.2

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.7, 1.5 Hz, 1 H); 8.52 (d, J=1.5 Hz, 1 H); 7.76 (dt, J=8.1, 1.8 Hz, 1 H); 7.66 (dd, J=8.8, 5.9 Hz, 1 H) 7.45 (dd, J=7.5, 5.1 Hz, 1 H); 7.31 (td, J=8.7, 2.6 Hz, 1 H); 7.11 (dd, J=9.7, 2.9 Hz, 1 H); 6.75 (s, 2 H); 4.13 (t, J=6.2 Hz, 2 H); 2.80-3.15 (m, 3 H); 2.55-2.68 (m, 8 H); 2.45 (s, 3 H) 2.34-2.43 (m, 2 H); 2.25-2.33 (m, 2 H); 2.14 (s, 3 H)

Example 8: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazol -5-one 0-[2-(4-isopropyl-piperazin-l-yl)-ethy]-oxime

2-Iodopropano (42.8 mg, 0.378 mmol) is added to a suspension of 4-(2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)ethyl)piperazine

(120 mg, 0.252 mmol), prepared as described in Step C of Example 7, and K₂C0₃ (51 mg, 0.378 mmol) in DMF (4 mL) at 0°C. The reaction mixture is stirred at RT for 20 h before adding cold H₂0. The precipitate is filtered off and then purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.038 g, 0.0735 mmol, Yield: 34%) as brown solid. LC-MS: method M, rt=3.17 min; (ES+) MH⁺: 518.2.

^LH-NMR (DMSO-d₆) δ ppm 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.52 (d, J=1.8 Hz, 1 H); 7.76 (dt, J=7.7, 2.0 Hz, 1 H); 7.66 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (dd, J=7.8, 4.8 Hz, 1 H); 7.31 (td, J=8.7, 2.6 Hz, 1 H); 7.10 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.12 (t, J=5.9 Hz, 2 H); 2.80-3.12 (m, 3 H); 2.53-2.68 (m, 5 H); 2.45 (s, 3 H); 2.34-2.43 (m, 8 H); 0.95 (d, J=6.5 Hz, 6 H)

Example 9: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazol -5-one 0-[2-(4-acetyl-piperazin-l-yl)-ethyl]-oxime

Acetyl chloride (9.8 mg, 0.126 mmol) is added to the solution of 4-(2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)ethyl)piperazine (70 mg, 0.126 mmol), prepared as described in Step C of Example 7, and TEA (19 mg, 0.189 mmol) in DMF (4 mL) at 0°C. The mixture is stirred at RT for 2 h before adding cold H₂0. The precipitate is filtered off and then purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.042 g, 0.081 mmol, Yield: 64%) as brown solid.

LC-MS: method M, rt=4.21 min; (ES+) MH⁺: 518.2

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (d, J=1.8 Hz, 1 H); 7.77 (dt, J=7.9, 1.9 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.46 (dd, J=7.9, 4.7 Hz, 1 H); 7.31 (td, J=8.6, 2.8 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.75 (s, 2 H); 4.16 (t, J=5.9 Hz, 2 H); 3.34-3.46 (m, 4 H); 2.80-3.10 (m, 3 H); 2.62 (t, J=5.9 Hz, 2 H); 2.54-2.69 (m, 2 H); 2.46 (s, 3 H); 2.38-2.44 (m, 2 H); 2.35 (t, J=5.1 Hz, 2 H); 1.98 (s, 3 H)

Example 10 : 2- Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(3-azetidin-l-yl-propyl)-oxime

STEP A:

Sodium hydride (60% mineral oil dispersion) (26.4 mg, 0.660 mmol) is added at 0°C under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro- 6H-quinazolin-5-one oxime (Intermediate 1) (0.2 g, 0.550 mmol) in anhydrous DMF (8 mL). After 2 min, 2-(3-bromopropoxy)tetrahydro-2H-pyrane (147 mg, 0.660 mmol) is added and the mixture is heated at 60°C for 2 h. The suspension is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.253 g, 0.5 mmol, Yield: 91%).

LC-MS: method A, rt=l .28 min; (ES+), M+H⁺= 506.3

Ή-NMR (DMSO-i ₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.35, 0.88 Hz, 1 H); 7.76 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.58 Hz, 1 H); 7.45 (ddd, J=7.63, 4.70, 0.88 Hz, 1 H); 7.31 (td, J=8.80, 2.93 Hz, 1 H); 7.1 1 (dd, J=9.54, 2.79 Hz, 1 H); 6.74 (s, 2 H); 4.39-4.62 (m, 1 H); 4.11 (t, J=6.31 Hz, 2 H); 3.59-3.78 (m, 2 H); 3.32-3.48 (m, 2 H); 2.77-3.13 (m, 3 H); 2.55-2.69 (m, 2 H); 2.45 (s, 3 H); 1.87 (quin, J=6.46 Hz, 2 H); 1.27-1.79 (m, 6 H) STEP B:

4M HC1 in dioxane (0.4 mL, 1.6 mmol) is added to the solution of 2-amino-7-(4-fluoro-2-pyridin- 3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-3-(tetrahydro-2H-pyran-2- yloxy)propyl oxime (0.24 g, 0.475 mmol) in DCM (4 mL). The reaction is stirred at RT for 4 h. The precipitate is filtered off, washed with DCM and dissolved in H₂0. The solution is basified with NH₄OH and the precipitate is filtered off, washed with H₂0 and dried under vacuum at 40°C to give the expected compound (0.114 g, 0.27 mmol, Yield: 57%).

LC-MS: method A, rt=1.01 min; (ES+), M+H⁺= 422.3

Ή-NMR (DMSO-t/₆) δ (ppm): 8.58 (dd, J=4.70, 1.76 Hz, 1 H); 8.54 (dd, J=2.35, 0.88 Hz, 1 H); 7.79 (ddd, J=8.00, 1.98, 1.76 Hz, 1 H); 7.68 (dd, J=8.80, 5.87 Hz, 1 H); 7.47 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.32 (td, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.79 (br. s., 2 H); 4.10 (t, J=6.46 Hz, 2 H); 3.46 (t, J=6.46 Hz, 3 H); 2.95-3.14 (m, 2 H); 2.80-2.95 (m, 1 H); 2.54-2.68 (m, 2 H); 2.46 (s, 3 H); 1.77 (quin, J=6.46 Hz, 2 H)

STEP C:

The mixture of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-3-hydroxypropyl oxime (0.105 g, 0.249 mmol), TEA (0.052 mL, 0.374 mmol) and methansulfonyl chloride (0.024 mL, 0.299 mmol) in DCM (15 mL) is stirred at RT for 3 h. During this period additional methansulfonyl chloride (0.010 mL, 0.125 mmol) and TEA (0.021 mL, 0.149 mmol) are added. The mixture is diluted with DCM and washed with 5% di NaHC0₃. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH from 98:2 to 95:5) to give the expected compound (0.104 g, 0.208 mmol, Yield: 84%).

LC-MS: method A, rt= 1.12 min; (ES+), M+H⁺= 500.2

STEP D

Azetidine (0.298 g, 5.25 mmol) is added to the solution of (E)-3-(2-amino-7-(4-fluoro-2-pyridin- 3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)propyl methansulfonate (0.237 g, 0.475 mmol) in anhydrous CH₃CN (4 mL). The reaction is heated at 60°C for 5 h in a sealed vessel. The mixture is diluted with EtOAc-Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 96/4/0.4 to 95/5/0.5) to give the title compound (0.099 g, 0.215 mmol, Yield: 45%) as yellow solid.

LC-MS: method E, rt=l .53 min; (ES+) MH⁺: 461.22

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.2, 0.7 Hz, 1 H); 7.77 (ddd, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, 1 H); 7.31 (dd, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.03 (t, J=6.6 Hz, 2 H); 3.03 (t, J=6.7 Hz, 4 H); 2.95-3.02 (m, 1 H); 2.81-2.95 (m, 1 H); 2.55-2.66 (m, 3 H); 2.44 (s, 3 H); 2.33 (t, J=7.0 Hz, 2 H); 1.91 (quin, J=6.9 Hz, 2 H); 1.58 (quin, J=6.7 Hz, 2 H)

Example 11: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -(3-pyrrolidin-l-yl-propyl)-oxime

Tetrabutylammonium hydroxide (0.077 g, 0.297 mmol) is added to a suspension of (E)-2-amino- 7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime

(Intermediate 1) (0.090 g, 0.248 mmol) in THF (5 mL). To the obtained solution l-(3- iodopropyl)pyrrolidine (0.148 g, 0.619 mmol) is added before refluxing for 8 h. The organic solvent is evaporated to dyness and the residue is dissolved in DCM and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by two flash column chromatographies (the first eluent DCM/MeOH/NH₄OH from 98/2/0.2 to 80/20/2 and the second one DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (0.0582 g, 0.123 mmol, Yield: 50%) as beige solid.

LC-MS: Method B, rt = 3.61 min; (ES+) MH⁺: 475.05

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.35, 0.88 Hz, 1 H); 7.77 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.68 (dd, J=8.80, 5.58 Hz, 1 H); 7.45 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.31 (td, J=8.66, 2.93 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.75 (s, 2 H); 4.07 (t, J=6.46 Hz, 2 H); 2.95-3.09 (m, 2 H); 2.82-2.95 (m, 1 H); 2.53-2.67 (m, 4 H); 2.53-2.55 (m, 4 H); 2.45 (s, 3 H); 1.75-1.87 (m, 2 H); 1.58-1.75 (m, 4 H)

Example 12 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(3-piperidin-l- -propyl)-oxime

l-(3-Chloropropyl)piperidine (0.08 g, 0.495 mmol) in DMF (1 mL) is added under nitrogen to a suspension of sodium hydride (60% mineral oil dispersion) (23.11 mg, 0.578 mmol) and (E)-2- amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.15 g, 0.413 mmol) in DMF (2 mL). The reaction is stirred overnight at RT. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH 9:1) to give the title compound (0.03 g, 0.061 mmol, Yield: 15%) as yellow solid.

LC-MS: method E, rt=2.65 min; (ES+) MH⁺: 489.27

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.20, 0.73 Hz, 1 H); 7.76 (ddd, J=7.92, 2.35; 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.31 (td, J=8.66, 2.93 Hz, 1 H); 7.10 (dd, J=9.68, 2.93 Hz, 1 H); 6.73 (s, 2 H); 4.05 (t, J=6.46 Hz, 2 H); 2.81-3.11 (m, 3 H); 2.54-2.67 (m, 2 H); 2.45 (s, 3 H); 2.18-2.35 (m, 6 H); 1.75 (m, J=7.04, 7.04, 6.90, 6.60 Hz, 2 H); 1.28-1.58 (m, 6 H)

Example 13: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-[3-(3,3-difluor -azetidin-l-yl)-propyl]-oxime

l-(3-Bromopropyl)-3,3-difluoroazetidina (0.132 g, 0.617 mmol) is added at RT under nitrogen to a suspension of sodium hydride (60% mineral oil dispersion) (24.66 mg, 0.617 mmol) and (E)-2- amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.179 g, 0.493 mmol) in DMF (5 mL). The reaction is stirred at 60°C for 4 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by two flash column chromatographies (eluent DCM/MeOH/NH₄OH 98/2/0.2) to give the title compound (0.024 g, 0.048 mmol, Yield: 8%) as yellow solid.

LC-MS: method C, rt =2.53 min; (ES+) MH⁺: 497.20

'H-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.35, 0.59 Hz, 1 H); 7.77 (ddd, J=8.00, 1.98, 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.31 (td, J=8.58, 2.79 Hz, 1 H); 7.11 (dd, 1 H); 6.74 (s, 2 H); 4.05 (t, J=6.46 Hz, 2 H); 3.53 (t, J=12.47 Hz, 4 H); 2.81-3.16 (m, 3 H); 2.54-2.67 (m, 4 H); 2.45 (s, 3 H); 1.66 (m, J=6.79, 6.79, 6.68, 6.46 Hz, 2 H)

Example 14: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-[3-(3,3-difluoro-pyrrolidin-l-yl)-propyl]-oxime

l-(3-Bromopropyl)-3,3-difluoropyrrolidine (0.035 g, 0.153 mmol) in DMF (1 mL) is added at RT under nitrogen to a suspension of sodium hydride (60% mineral oil dispersion) (7.37 mg, 0.184 mmol) and (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-one oxime (Intermediate 1) (0.056 g, 0.153 mmol) in DMF (1 mL). The reaction is stirred at 60°C for 2 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 97/3/0.3) to give the title compound (0.040 g, 0.078 mmol Yield: 51) as light yellow solid.

LC-MS: method C, rt =1.83 min; (ES+) MH⁺: 511.09

'H-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.35, 0.88 Hz, 1 H); 7.77 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.31 (td, J=8.66, 2.93 Hz, 1 H); 7.1 1 (dd, J=9.68, 2.64 Hz, 1 H); 6.74 (s, 2 H); 4.07 (t, J=6.46 Hz, 2 H); 2.85-3.14 (m, 3 H); 2.84 (t, J=13.50 Hz, 2 H); 2.53-2.72 (m, 6 H); 2.45 (s, 3 H); 2.04-2.33 (m, 2 H); 1.77 (m, 2 H)

Example 15: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(3-piperazin-l-yl-propyl)-oxime; trifluoroacetate

This compound is synthesized following the experimental procedure of Example 4, using l-(3- chloro-propyl)-piperazine instead of 1 -(2-chloroethyl)-pyrrolidine hydrochloride. The crude is purified by preparative HPLC to give the title compound (0.02 g, Yield 15%) as a white solid. LC-MS: method O, rt=2.24 min; (ES+), M+H⁺= 490

Ή-NMR (MeOD) δ (ppm): 8.78 (2 H, br. s); 8.29 (1 H, d, J=7.6 Hz); 7.88 (1 H, br. s); 7.67 (1 H, dd, J=8.9, 5.5 Hz); 7.32 (1 H, td, J=8.5, 2.7 Hz); 7.13 (1 H, dd, J=9.0, 2.9 Hz); 4.26 (2 H, t, J=5.8 Hz); 3.55 (8 H, br. s); 3.16-3.30 (4 H, m); 3.01-3.10 (1 H, m); 2.93 (1 H, d, J=16.5 Hz); 2.68-2.76 (3 H, m); 2.66 (1 H, s); 2.13-2.21 (2 H, m)

Example 16: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-azetidin-3-yl-oxime

STEP A:

Sodium hydride (60% mineral oil dispersion) (0.594 g, 14.86 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-one oxime (Intermediate 1) (4.5 g, 12.38 mmol) in anhydrous DMF (100 mL). After 10 min, 2 N-Boc-3-iodoazetidine (4.56 g, 16.10 mmol), dissolved in anhydrous DMF (10 mL), is added and the mixture is heated at 50°C for 2 h. The suspension is diluted with EtOAc/Et₂0 (2/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 98/2/0.2 a 94/6/0.6) to give the expected compound (4.21 g, 8.12 mmol, Yield: 66%).

STEP B:

TFA (9.65 mL, 130 mmol), diluted in DCM (10 mL), is added to a ice-cooled solution of (E)-N- Boc-3-(2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)azetidina (4.21 g, 8.12 mmol) in DCM (81 mL). The mixture is stirred at RT for 4 h. The reaction is evaporated to dryness and the residue is dissolved in H₂0, basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (3.35 g, 8.01 mmol, Yield: 99%).

LC-MS: method E, rt=1.33 min; (ES+) MH⁺: 419.39

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.8, 1.6 Hz, 1 H); 8.54 (dd, J=2.2, 0.7 Hz, 1H); 7.78 (dt, J=7.8, 1.9 Hz, 1 H); 7.69 (dd, J=8.8, 5.9 Hz, 1 H); 7.46 (ddd, J=7.8, 4.9, 0.7 Hz, 1 H); 7.32 (td, J=8.7, 2.9 Hz, 1H); 7.11 (dd, J=9.5, 2.8 Hz, 1H); 6.77 (s, 2 H); 4.91 (quin, 1 H); 3.48-3.68 (m, 4H); 2.81-3.15 (m, 3H); 2.55-2.70 (m, 2 H); 2.43 (s, 3H)

Example 17: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-(l-methyl-azetidin-3-yl)-oxime

The mixture of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-azetidin-3-yl oxime (0.061 g, 0.146 mmol) (Example 16), formaldehyde (0.012 mL, 0.16 mmol) and NaBH₃CN (10.99 mg, 0.175 mmol in MeOH (2 mL) is stirred at RT for 4 h. The reaction is evaporated to dryness and the residue is dissolved in DCM and washed with H₂0. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 90/10/0.2) to give the title compound (0.035 g, 0.081 mmol, Yield: 56%) as white solid.

LC-MS: method E, rt=1.39 min; (ES+) MH⁺: 433.09 Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.69, 1.76 Hz, 1 H); 8.54 (dd, J=2.35, 0.88 Hz, 1 H); 7.78 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.68 (dd, J=8.80, 5.87 Hz, 1 H); 7.46 (ddd, J=7.92, 4.69, 0.88 Hz, 1 H); 7.32 (td, J=8.66, 2.93 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.77 (s, 2 H); 4.71 (quin, J=6.02, 5.82 Hz, 1 H); 3.47-3.66 (m, 2 H); 2.78-3.17 (m, 4 H); 2.55-2.70 (m, 3 H); 2.43 (s, 3 H); 2.28 (s, 3 H)

Example 18: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-isopropyl-azetidin-3-yl)-oxime

2-Iodopropano (0.017 mL, 0.172 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.06 g, 0.143 mmol) and TEA (0.04 mL, 0.287 mmol) in DMF (2 mL). The reaction is stirred at RT for 4 days and at 50°C for 4 h. The mixture is diluted with H₂0 and extracted with DCM. The organic phase is washed with H₂0 and brine. It is then dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 95/5/0.2) to give the title compound (0.02 g, 0.043 mmol, Yield: 30%) as white solid.

LC-MS: method F, rt=6.80 min; (ES+) MH⁺: 461.24

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.54 (dd, J=2.20, 0.73 Hz, 1 H); 7.78 (ddd, J=8.07, 1.91, 1.76 Hz, 1 H); 7.68 (dd, J=8.95, 5.72 Hz, 1 H); 7.45 (ddd, J=7.63, 4.70, 0.59 Hz, 1 H); 7.31 (td, J=8.58, 2.79 Hz, 1 H); 7.1 1 (dd, J=9.54, 2.79 Hz, 1 H); 6.77 (s, 2 H); 4.67 (quin, J=5.80 Hz, 1 H); 3.46 (t, J=6.75 Hz, 2 H); 2.81-3.14 (m, 5 H); 2.55-2.70 (m, 3 H); 2.43 (s, 3 H); 0.86 (d, J=6.16 Hz, 6 H)

Example 19: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-benzyl-azetidin-3-yl)-oxime

Benzyl bromide (0.022 mL, 0.184 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.07 g, 0.167 mmol) and TEA (0.07 mL, 0.502 mmol) in DCM (2 mL) and DMF (0.5 mL). The mixture is stirred overnight at RT. The reaction is diluted with H₂0 and extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 95/5/0.2) to give the title compound (0.029 g, 0.057 mmol, Yield: 34%) as white solid

LC-MS: method E, rt=2.83 min; (ES+) MH⁺: 509.30

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.69, 1.76 Hz, 1 H); 8.55 (dd, J=2.35, 0.88 Hz, 1 H); 7.78 (ddd, J=8.00, 1.98, 1.76 Hz, 1 H); 7.68 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.19-7.39 (m, 6 H); 7.1 1 (dd, J=9.68, 2.93 Hz, 1 H); 6.78 (s, 2 H); 4.77 (quin, J=5.92, 5.72 Hz, 1 H); 3.62 (s, 2 H); 3.51 (t, J=6.90 Hz, 2 H); 2.84-3.16 (m, 5 H); 2.55-2.72 (m, 2 H); 2.43 (s, 3 H)

Example 20 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-(l-acetyl-azetidin-3-yl)-oxime

Acetyl chloride (0.014 mL, 0.201 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.07 g, 0.167 mmol) and TEA (0.047 mL, 0.335 mmol) in DCM (2 mL). The reaction mixture is stirred for 2 h at RT before adding H₂0 and extracting with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH 95/5) to give the title compound (0.050 g, 0.108 mmol, Yield: 64%) as white solid.

LC-MS: method E, rt=1.74 min; (ES+) MH⁺: 461.17

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dt, J=5.0, 1.5 Hz, 1 H); 8.54 (d, J=1.5 Hz, 1 H); 7.75-7.84 (m, 1 H); 7.62-7.75 (m, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.26-7.38 (m, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.82 (s, 2 H); 4.83-5.00 (m, 1 H); 4.26-4.45 (m, 1 H); 3.99-4.18 (m, 2 H); 3.72-3.89 (m, 1 H); 2.82-3.20 (m, 3 H); 2.55-2.70 (m, 2 H); 2.42 (s, 3 H); 1.76 (d, J=1.5 Hz, 3 H) Example 21 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazoli

Benzoyl chloride (0.018 mL, 0.158 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.055 g, 0.131 mmol) and TEA (0.037 mL, 0.263 mmol) in DCM (2 mL) and DMF (few drops). The reaction mixture is stirred for 1 h at RT before adding H₂0 and extracting with DCM. The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 98/2/0.2) to give the title compound (0.04 g, 0.077 mmol, Yield: 59%) as white solid.

LC-MS: method E, rt=3.21 min; (ES+) MH⁺: 523.35

Ή-NMR (DMSO-d₆) δ (ppm): 8.56 (dd, J=4.55, 1.32 Hz, 1 H); 8.54 (dd, J=2.35, 0.88 Hz, 1 H); 7.77 (ddd, J=8.07, 1.91, 1.76 Hz, 1 H); 7.68 (dd, J=8.51, 5.87 Hz, 1 H); 7.60-7.65 (m, 2 H); 7.40- 7.57 (m, 4 H); 7.31 (td, J=8.66, 2.93 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.81 (s, 2 H); 4.87- 5.08 (m, 1 H); 4.4 -4.64 (m, 1 H); 4.18-4.39 (m, 2 H); 3.83-4.18 (m, 1 H); 2.84-3.19 (m, 3 H); 2.55-2.72 (m, 2 H); 2.40 (s, 3 H)

Example 22: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-methylaminocarbonyl-azetidin-3-yl)-oxime

2,5-Dioxopyrrolidin-l-yl methylcarbammate (0.054 g, 0.313 mmol) is added to the solution of di (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- azetidin-3-yl oxime (Example 16) (0.109 g, 0.260 mmol) and TEA (0.073 mL, 0.521 mmol) in DCM (10 mL). The reaction mixture is stirred for 2 h at RT before diluting with DCM and washing with H₂0 and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is triturated with Et₂0 and then purified by flash column chromatography (eluent DCM/MeOH 9/1) to give the title compound (0.06 g, 0.126 mmol, Yield: 48%) as beige solid.

LC-MS: method E, rt=1.66 min; (ES+) MH⁺: 476.17

Ή-NMR (DMSO-de) δ (ppm): 8.38-8.72 (m, 2 H); 7.77 (dt, J=7.78, 1.83 Hz, 1 H); 7.69 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (dd, =7.48, 4.55 Hz, 1 H); 7.31 (td, J=8.58, 2.79 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.80 (s, 1 H); 6.22 (q, J=1.00 Hz, 1 H); 4.76-5.05 (m, 1 H); 3.91-4.13 (m, 2 H); 3.67-3.91 (m, 2 H); 2.83-3.19 (m, 2 H); 2.57-2.77 (m, 2 H); 2.54 (d, J=1.00 Hz, 3 H); 2.41 (s, 3 H)

Example 23: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-(l-dimethylaminocarbonyl-azetidin-3-yl)-oxime

Dimethylcarbamoyl chloride (0.026 mL,0.287 mmol) is added to the solution of di (E)-2-amino-7-

(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.1 g, 0.239 mmol) and TEA (0.067 mL, 0.478 mmol) in DCM (10 mL). The reaction is stirred for 2 h at RT. The organic phase is evaporated to dryness and the crude is diluted with H₂0 and basified with NH₄OH. The precipitate is filtered off and then crystallized with Et₂0 to give the title compound (0.075 g, 0.153 mmol, Yield: 64%) as beige solid.

LC-MS: method E, rt=l .96 min; (ES+) MH⁺: 490.23

'H-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.70, 1.76 Hz, 1 H); 8.54 (dd, J=2.35, 0.59 Hz, 1 H); 7.78 (ddd, J=8.07, 1.91, 1.76 Hz, 1 H); 7.68 (dd, J=8.95, 5.72 Hz, 1 H); 7.45 (ddd, J=7.63, 4.70, 0.59 Hz, 1 H); 7.31 (td, J=8.51, 2.93 Hz, 1 H); 7.1 1 (dd, J=9.54, 2.79 Hz, 1 H); 6.80 (s, 2 H); 4.89 (tt, J=6.64, 4.22 Hz, 1 H); 4.03-4.20 (m, 2 H); 3.80-3.99 (m, 2 H); 2.85-3.16 (m, 3 H); 2.75 (s, 6 H); 2.58-2.72 (m, 2 H); 2.42 (s, 3 H)

Example 24: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-methansulfonyl-azetidin-3-yl)-oxime

Methansulfonyl chloride (0.026 mL,0.330 mmol) is added to a suspension of di (E)-2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 16) (0.115 g, 0.275 mmol) and TEA (0.077 mL, 0.55 mmol) in DCM (10 raL). The reaction mixture is stirred for 2 h at RT. The organic phase is evaporated to dryness and the crude is diluted with H₂0 and basified with NH₄OH. The precipitate is filtered off and triturated with Et₂0. The crude is then purified by flash column chromatography (eluent DCM/MeOH 97/3) to give the title compound (0.07 g, 0.141 mmol, Yield: 56%) as beige solid.

LC-MS: method E, rt=1.94 min; (ES+) MH⁺: 497.09

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.84, 1.61 Hz, 1 H); 8.54 (dd, 1 H); 7.78 (ddd, J=8.00, 1.98, 1.76 Hz, 1 H); 7.69 (dd, J=8.66, 5.72 Hz, 1 H); 7.46 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.32 (td, J=8.58, 2.79 Hz, 1 H); 7.1 1 (dd, J=9.54, 2.79 Hz, 1 H); 6.82 (s, 2 H); 4.94 (tt, J=6.60, 4.84 Hz, 1 H); 4.11 (t, J=7.92 Hz, 2 H); 3.92 (dd, J=8.51, 4.40 Hz, 2 H); 3.03-3.19 (m, 2 H); 3.01 (s, 3 H); 2.82-3.00 (m, 1 H); 2.54-2.77 (m, 2 H); 2.44 (s, 3 H)

Example 25: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- qu

STEP A:

Sodium hydride (60% mineral oil dispersion) (0.016 g, 0.396 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-one oxime (Intermediate 1) (0.12 g, 0.33 mmol) in anhydrous DMF (5 mL). After 5 min, N- Boc-3-(bromomethyl)azetidina (0.099 g, 0.396 mmol) is added and the mixture is heated at 60°C for 2 h. After cooling, additional sodium hydride (60% mineral oil dispersion) (0.007 g, 0.165 mmol) and N-Boc-3-(bromomethyl)azetidina (0.2 g, 0.8 mmol) are added. The reaction is then heated at 60°C for 2 h. The suspension is diluted with EtOAc/Et₂0 (2/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.103 g, 0.193 mmol, Yield: 59). LC-MS: method A, it = 1.35 min; (ES+), M+H⁺: 533.3

STEP B:

TFA (0.087 mL, 1.07 mmol) is added to the solution of (E)-N-Boc-3-((2-ammo-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)methyl)azetidine (0.095 g, 0.178 mmol) in DCM (4 mL). The reaction is stirred overnight at RT. The reaction is evaporated to dryness and the residue, dissolved in H₂0, is basified with NH₄OH. The precipitate is filtered off, washed with H₂0 and dried. The solid is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (0.013 g, 0.029 mmol, Yield: 17%).

LC-MS: method E, rt=1.46 min; (ES+) MH⁺: 433.2

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, 1 H); 8.53 (dd, 1 H); 7.77 (ddd, 1 H); 7.62-7.72 (m, 1 H); 7.41-7.50 (m, 1 H); 7.32 (ddd, 1 H); 7.1 1 (dd, 1 H); 6.77 (s, 2 H); 4.19 (d, 2 H); 3.73 (t, 2 H); 3.51 (dd, 2 H); 2.79-3.11 (m, 5 H); 2.55-2.69 (m, 2 H); 2.44 (s, 3 H)

Example 26: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

STEP A:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.33 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-flUoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, N-Boc-3-(bromoethyl)azetidina (0.087 g, 0.33 mmol) is added and the mixture is heated at 60°C for 1 h. The suspension is diluted with EtOAc/Et₂0 (2/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.131 g, 0.240 mmol, Yield: 87%).

LC-MS: method A, rt = 1.33 min; (ES+), M+H⁺= 547.4 Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.20, 0.73 Hz, 1 H); 7.77 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.87 Hz, 1 H); 7.46 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.31 (td, J=8.66, 2.64 Hz, 1 H); 7.10 (dd, J=9.54, 2.79 Hz, 1 H); 6.75 (s, 2 H); 4.02 (t, J=6.02 Hz, 2 H); 3.82-3.97 (m, 2 H); 3.39-3.55 (m, 2 H); 2.79-3.11 (m, 3 H); 2.54-2.65 (m, 3 H); 2.45 (s, 3 H); 1.88 (q, J=7.04 Hz, 2 H); 1.34 (s, 9 H)

STEP B:

4M HC1 in dioxane (500 μΐ,, 2.0 mmol) is added to the solution of (E)-N-Boc-3-((2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)azetidine (0.122 g, 0.223 mmol) in DCM (3 mL). The reaction is stirred at RT for 1.5 h. The reaction is evaporated to dryness and the residue, dissolved in H₂0, is basified with NH₄OH and extracted with EtOAc The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (0.02 g, 0.045 mmol, Yield: 20%) as beige solid.

LC-MS: method D, rt=1.79 min; (ES+) MH⁺: 447.3

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.70, 1.47 Hz, 1 H); 8.53 (d, J=1.76 Hz, 1 H); 7.77 (ddd, J=8.07, 1.91, 1.76 Hz, 1 H); 7.67 (dd, J=8.80, 5.87 Hz, 1 H); 7.46 (dd, J=7.34, 4.99 Hz, 1 H); 7.31 (td, J=8.58, 2.79 Hz, 1 H); 7.11 (dd, J=9.68, 2.64 Hz, 1 H); 6.75 (s, 2 H); 4.00 (t, J=6.46 Hz, 2 H); 3.54-3.68 (m, 2 H); 2.79-3.21 (m, 4 H); 2.57-2.77 (m, 4 H); 2.46 (s, 3 H); 1.81-1.93 (m, 2 H)

Example 27: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- qu

STEP A:

Sodium hydride (60% mineral oil dispersion) (0.355 g, 8.87 mmol) is added under nitrogen, in portions of about 30 mg each, to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.4 g, 1.102 mmol) in anhydrous DMF (20 mL). After each portion of sodium hydride, N-Boc-4-iodopiperidine (Intermediate 5) (2.76 g, 8.87 mmol; about 0.208 g of iodo-derivative for each addition) in DMF (2.6 mL) is added. After 8 h all the additons are concluded (12 in total). The suspension is diluted with EtOAc and washed with saturated solution of NH₄C1 and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 97/3) to give the expected compound (0.434 g, 0.795 mmol Yield: 72%) as yellow solid.

LC-MS: method A, rt=1.37 min; (ES+), M+H⁺: 547.3

STEP B:

4M HC1 in dioxane (2.269 mL, 9.08 mmol) is added to the solution of (E)-N-Boc-3-((2-amino-7- (4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)piperidine (0.434 g, 0.795 mmol) in DCM (20.7 mL). The reaction is stirred at RT for 5.5 h. The reaction is evaporated to dryness and the residue, washed with DCM, is filtered off. The solid, dissolved in the minimal amount of H₂0, is basified with NH₄OH. The precipitate is filtered off and dried under vacuum to give the title compound (0.296 g, 0.664 mmol, Yield: 84%) as white solid.

LC-MS: method E, rt=l .45 min; (ES+) MH⁺: 447.22

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.3, 0.9 Hz, 1 H); 7.77 (ddd, J=8.0, 2.0, 1.8 Hz, 1 H); 7.68 (dd, J=8.8, 5.9 Hz, 1 H); 7.46 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.6, 2.8 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.72 (s, 2 H); 3.89-4.20 (m, 1 H); 2.82-3.16 (m, 6 H); 2.55-2.70 (m, 3 H); 2.45 (s, 3 H); 1.71-1.97 (m, 2 H); 1.28-1.58 (m, 2 H)

Example 28: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazoIin-5-one 0-(l -methyl-piperidin-4-yl)-oxime

(E)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O- piperidin-4-yl oxime (0.1 g, 0.224 mmol) (Example 27), formaldehyde (0.018 mL, 0.246 mmol) and NaBH₃CN (0.017 g, 0.269 mmol) in MeOH (3 mL) are stirred overnight at RT. The reaction is evaporated to dryness and the residue is dissolved in DCM and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 95/5/0.5) to give the title compound (0.065 g, 0.141 mmol, Yield: 63%) as light yellow solid.

LC-MS: method G, rt=3.10 min; (ES+) MH⁺: 461.27

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.3, 0.9 Hz, 1 H); 7.77 (dt, J=7.6, 2.3 Hz, 1 H); 7.68 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.9, 5.0, 0.9 Hz, 1 H); 7.32 (td, J=8.7, 2.9 Hz, 1 H); 7.1 1 (dd, J=9.7, 2.9 Hz, 1 H); 6.72 (s, 2 H); 3.88-4.13 (m, 1 H); 2.81-3.14 (m, 3 H); 2.54-2.69 (m, 4 H); 2.44 (s, 3 H); 2.15 (s, 3 H); 2.01-2.13 (m, 2 H); 1.78-1.96 (m, 2 H); 1.51-1.74 (m, 2 H)

Example 29: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-(l-isopropyl-piperidin-4-yl)-oxime

2-Iodopropane (0.027 mL, 0.269 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-yl oxime (0.1 g, 0.224 mmol) (Example 27) and TEA (0.062 mL, 0.448 mmol).) in DMF (3 mL). The reaction is stirred overnight at 60°C. The mixture is diluted with H₂0 and extracted with DCM. The organic phase is dried over Na S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 95/5/0.5) to give the title compound (0.014 g, 0.029 mmol, Yield: 13%) as light yellow solid.

LC-MS: method I, rt =13.24 min; (ES+) MH⁺: 489.33

Ή-NMR (CDC1₃) δ (ppm): 8.62 (dd, J=4.8, 1.6 Hz, 1 H); 8.57 (dd, J=2.2, 0.7 Hz, 1 H); 7.56-7.65 (m, 1 H); 7.39-7.47 (m, 1 H); 7.36 (ddd, J=7.8, 4.9, 0.7 Hz, 1 H); 7.18 (td, J=8.5, 2.6 Hz, 1 H); 6.96 (dd, J=9.1, 2.6 Hz, 1 H); 4.94 (s, 2 H); 3.97-4.26 (m, 1 H); 3.20 (ddd, J=17.6, 4.4, 2.3 Hz, 1 H); 2.98-3.12 (m, 1 H); 2.91 (dd, J=15.8, 12.0 Hz, 1 H); 2.68-2.83 (m, 4 H); 2.61 (s, 3 H); 2.58 (dd, J=17.6, 12.0 Hz, 1 H); 2.27-2.42 (m, 2 H); 1.91-2.09 (m, 2 H); 1.65-1.86 (m, 2 H); 1.06 (d, J=6.5 Hz, 6 H)

Example 30 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-benzyl-piperidin-4-yl)-oxime

Benzyl bromide (0.017 mL, 0.140 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-il oxime (0.057 g, 0.128 mmol) (Example 27) and TEA (0.053 mL, 0.383 mmol) in DCM (2 mL). The reaction mixture is stirred at RT for 3 days. Additional benzyl bromide (7.58 μΐ, 0.064 mmol) is added and the reaction is stirred for 24 h. The reaction mixture is diluted with DCM and washed with H₂0. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NF^OH from 100/0/0 to 98/2/0.2) to give the title compound (0.055 g, 0.102 mmol Yield: 80%) as light yellow solid.

LC-MS: method E, it = 2.76 min; (ES+) MH⁺: 537.26

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.84, 1.61 Hz, 1 H); 8.54 (dd, J=2.35, 0.88 Hz, 1 H); 7.77 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.67 (dd, J=8.95, 5.72 Hz, 1 H); 7.45 (ddd, J=7.85, 4.77, 0.88 Hz, 1 H); 7.27-7.37 (m, 5 H); 7.19-7.27 (m, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.72 (s, 2 H); 3.90-4.20 (m, 1 H); 3.46 (s, 2 H); 2.79-3.13 (m, 2 H); 2.55-2.68 (m, 5 H); 2.44 (s, 3 H); 2.11- 2.24 (m, 2 H); 1.79-1.96 (m, 2 H); 1.47-1.71 (m, 2 H)

Example 31 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-(l-acetyl-piperidin-4-yl)-oxime

Acetyl chloride (0.016 mL, 0.224 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-yl oxime (0.1 g, 0.224 mmol) (Example 27) and TEA (0.047 mL, 0.336 mmol) in DCM (3 mL). The reaction mixture is stirred for 24 h at RT before adding H₂0 and extracting with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 97/3/0.3) to give the title compound (0.088 g, 0.180 mmol, Yield: 80%) as light yellow solid.

LC-MS: method E, rt=1.98 min; (ES+) MH⁺: 489.12 Ή-NMR (DMSO-d₆) δ ( pm): 8.35-8.77 (m, 2 H); 7.77 (d, J=7.6 Hz, 1 H); 7.62-7.73 (m, 1 H); 7.44 (dd, J=7.3, 5.0 Hz, 1 H); 7.31 (td, J=8.6, 2.5 Hz, 1 H); 7.1 1 (dd, J=9.5, 2.8 Hz, 1 H); 6.75 (s, 2 H); 4.17-4.42 (m, 1 H); 3.63-3.82 (m, 1 H); 3.46-3.63 (m, 1 H); 2.80-3.26 (m, 5 H); 2.55-2.68 (m, 2 H); 2.45 (s, 3 H); 2.00 (s, 3 H); 1.72-1.97 (m, 2 H); 1.33-1.72 (m, 2 H)

Example 32: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5

Benzoyl chloride (0.015 mL, 0.129 mmol) is added to a suspension of di (E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-yl oxime (0.046 g, 0.103 mmol) (Example 27) and TEA (0.043 mL, 0.309 mmol) in DCM (2 mL). The reaction mixture is stirred overnight at RT before extracting with DCM. The organic phase is washed with ¾0 and brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is triturated with i-PrOH to give the title compound (0.035 g, 0.064 mmol, Yield: 62%) as white solid.

LC-MS: method E, rt=3.25 min; (ES+) MH⁺: 551.24

1H-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.54 (dd, J=2.35, 0.59 Hz, 1 H);

7.78 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.68 (dd, J=8.80, 5.58 Hz, 1 H); 7.36-7.49 (m, 6 H); 7.32

(td, J=8.66, 2.93 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.74 (s, 2 H); 4.23-4.46 (m, 1 H);

3.34-4.01 (m, 4 H); 2.80-3.19 (m, 3 H); 2.55-2.70 (m, 2 H); 2.45 (s, 3 H); 1.91 (bs, 2 H); 1.64 (bs, 2 H)

Example 33 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-piperidin-4-ylmethyl-oxime

This compound is synthesized following the experimental procedure of the Example 26, using N- Boc-4-bromomethyl-piperidine instead of N-Boc-3-(2-bromoethyl)azetidine. A beige solid is obtained (0.080 g, Yield 18%).

LC-MS: method O, rt=2.53 min; (ES+), M+H⁺= 461

'H-NMR (MeOD) δ (ppm): 8.97 (1 H, s); 8.90 (1 H, d, J=5.5 Hz); 8.63 (1 H, d, J=8.2 Hz); 8.16 (1 H, dd, J=7.8, 6.0 Hz); 7.74 (1 H, dd, J=8.9, 5.5 Hz); 7.38 (1 H, td, J=8.5, 2.7 Hz); 7.20 (1 H, dd, J=8.9, 2.7 Hz); 4.06-4.17 (2 H, m); 3.42 (2 H, d, J=11.3 Hz); 3.22-3.29 (2 H, m); 2.95-3.14 (4 H, m); 2.72-2.83 (4 H, m); 2.1 1 (1 H, br. s); 1.96 (2 H, d, J=14.0 Hz); 1.52-1.65 (2 H, m)

Example 34 : 2- Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-piperidin-4-yl-ethyl-oxime

STEP A:

N-Boc-4-(2-bromoethyl)piperidin (0.289 g, 0.991 mmol), dissolved in anhydrous DMF (3 mL), is added dropwise to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8- dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.3 g, 0.826 mmol) and sodium hydride (60% mineral oil dispersion) (0.043 g, 1.073 mmol) in anhydrous DMF (6 mL). The reaction is heated at 60°C for 5 h. The mixture is diluted with EtOAc and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent petroleum ether/EtOAc 9/1) to give the expected compound (0.21 g, 0.365 mmol, Yield: 44%).

LC-MS: method A, rt=1.45 min; (ES+), M+H⁺: 575.3

STEP B:

TFA (0.45 mL, 5.85 mmol) is added to the solution (E)-N-Boc-4-(2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylidenaminoxy)ethyl)piperidine (0.21 g, 0.365 mmol) in DCM (8 mL). The reaction is stirred at RT for 6 h. The rmixture is diluted with DCM and washed with 1M K₂C0₃. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is triturated with Et₂0 to give the title compound (0.15 g, 0.316 mmol, Yield: 86%). LC-MS: method E, rt=1.67 min; (ES+) MH⁺: 475.18

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.7, 1.8 Hz, 1 H); 8.52 (dd, J=2.2, 0.7 Hz, 1 H); 7.76 (dt, J=7.9, 2.3 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.6, 2.8 Hz, 1 H); 7.1 1 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.07 (t, J=6.6 Hz, 2 H); 2.81- 3.10 (m, 5 H); 2.54-2.67 (m, 2 H); 2.45 (s, 3 H); 2.35-2.48 (m, 2 H); 1.48-1.65 (m, 4 H); 1.31-1.47 (m, 1 H); 1.02 (qd, J=11.7, 3.5 Hz, 2 H)

Example 35: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-[2-(l-methyl-piperidin-4-yl)-ethyI]-oxime

STEP A:

A solution of tetrabromomethane (874 mg, 2.6 mmol) in DCM (10 mL) is slowly added dropwise to the solution of N-Boc-piperidm-4-ethanol (550 mg, 0.0023 mmol) and triphenylphosphine (681 mg, 2.6 mol) in DCM (10 mL) at 0°C. The reaction is stirred at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (0.59 g, 2 mmol, Yield: 84%) as colourless oil.

STEP B:

Sodium hydride (60% mineral oil dispersion) (7.8 mg, 0.328 mmol) is added at 0°C under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro- 6H-quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, N-Boc-4-(2-bromoethyl)piperidine (96 mg, 0.328 mmol) dissolved in anhydrous DMF (5 mL) is added and the mixture is stirred at RT for 3 h and then at 50°C for 1 h. The mixture is diluted with H₂0 and extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure to give the expected compound (0.120 g, 0.208 mmol, Yield: 76%). STEP C:

4M HC1 in dioxane (2 mL, 8.0 mmol) is added to the solution of N-Boc-4-(2-(2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)piperidine (0.120 g, 0.209 mmol) in DCM (4 mL). The reaction mixture is stirred at RT for 5 h. The organic solvent is removed under reduced pressure to give the desired compound (0.100 g, 0.195 mmol, Yield: 94%).

STEP D:

The solution of 4-(2-(2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-ylideneaminoxy)ethyl)piperidine (145 mg, 0.302 mmol) and formaldehyde (10 mg, 0.335 mmol) in MeOH (10 mL) is stirred at RT for 6 h. After cooling at 0°C, NaBH₃CN (22.7 mg, 0.362 mmol) is added. The reaction mixture is stirred at RT for 20 h. Cold H₂0 is added and the precipitate is filtered off. The solid is purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.027 g, 0.0563 mmol, Yield: 18) as dark solid.

LC-MS: method M, rt=3.16 min; (ES+) MH⁺: 489.2

Ή-NMR (DMSO-d₆) δ (ppm): 8.58 (d, J=3.81 Hz, 1 H); 8.53 (s, 1 H); 7.76 (dt, J=7.85, 1.94 Hz, 1 H); 7.66 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (dd, J=7.63, 4.69 Hz, 1 H); 7.31 (td, J=8.66, 2.64 Hz, 1 H); 7.11 (dd, J=9.68, 2.93 Hz, 1 H); 6.73 (s, 2 H); 4.07 (t, J=6.60 Hz, 2 H); 2.77-3.1 1 (m, 3 H); 2.54-2.77 (m, 4 H); 2.45 (s, 3 H); 2.13 (s, 3 H); 1.80 (t, J=10.42 Hz, 2 H); 1.58-1.69 (m, 2 H); 1.54 (q, J=6.75 Hz, 2 H); 1.25-1.35 (m, 1 H); 1.01-1.23 (m, 2 H)

Example 36: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazol -5-one 0-[2-(l-isopropyl-piperidin-4-yl)-ethyl]-oxime

2-Iodopropane (42.8 mg, 0.378 mmol) is added to a suspension of 4-(2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylidenaminoxy)ethyl)piperidine (118 mg, 0.248 mmol), prepared as described in Step C of Example 35, and K₂C0₃ (51 mg, 0.372 mmol) in DMF (4 mL) at 0°C. The reaction is stirred at RT for 20 h. The mixture is diluted with cold H₂0 and the precipitate is filtered off. The solid is purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.038 g, 0.0736 mmol, Yield: 29%) as dark solid.

LC-MS: method M, rt=3.28 min; (ES+) MH⁺: 517.2

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.52 (dd, J=2.3, 0.6 Hz, 1 H); 7.76 (dt, J=8.0, 1.9 Hz, 1 H); 7.66 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.7, 2.6 Hz, 1 H); 7.1 1 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.07 (t, J=6.6 Hz, 2 H); 2.82- 3.10 (m, 3 H); 2.54-2.81 (m, 5 H); 2.45 (s, 3 H); 1.96-2.19 (m, 2 H); 1.59-1.70 (m, 2 H); 1.54 (q, J=6.8 Hz, 2 H); 1.02-1.20 (m, 3 H); 0.95 (d, J=6.5 Hz, 6 H)

Example 37: 2-Amino-7-(4-fluoro-2-pyridin-3-yI-phenyl)-4-methyl-7,8-dihydro-6H-

Acetyl chloride (12.3 mg, 0.157 mmol) is added to the solution of 4-(2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylidenaminoxy)ethyl)piperidine (75 mg, 0.157 mmol), prepared as described in Step C of Example 35, and TEA (24 mg, 0.237 mmol) in DMF (4 mL) at 0°C. The reaction is stirred at RT for 2 h. The reaction mixture is diluted with cold H₂0 and the precipitate is filtered off. The solid is purified by flash column chromatography (eluent DCM/MeOH) to give the title compound (0.032 g, 0.062 mmol, Yield: 38) as brown solid. LC-MS: method E, rt=2.25 min; (ES+) MH⁺: 517.32

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.7, 1.5 Hz, 1 H); 8.53 (d, J=1.8 Hz, 1 H); 7.77 (dt, J=7.8, 1.8 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (dd, J=7.8, 4.8 Hz, 1 H); 7.31 (td, J=8.7, 2.6 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.21-4.43 (m, 1 H); 4.09 (t, J=5.7 Hz, 2 H); 3.62-3.91 (m, 1 H); 2.79-3.13 (m, 4 H); 2.55-2.60 (m, 3 H); 2.45 (s, 3 H); 1.97 (s, 3 H); 1.39- 1.78 (m, 5 H); 0.75-1.33 (m, 2 H)

Example 38: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(3-piperidin-4-yl-propyl)-oxime

STEP A:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.33 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (10 mL). After 5 min, N-Boc-4-(3-bromopropyl)piperidine (0.101 g, 0.330 mmol) is added and the mixture is stirred at 60°C for 2 h. The mixture is diluted with EtOAc/Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.101 g, 0.172 mmol, Yield: 62%).

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, 1 H); 8.52 (dd, 1 H); 7.76 (ddd, 1 H); 7.67 (dd, 1 H); 7.45 (ddd, 1 H); 7.31 (ddd, 1 H); 7.10 (dd, 1 H); 6.74 (s, 2 H); 4.02 (t, 2 H); 3.79-3.97 (m, 2 H); 2.82- 3.09 (m, 3 H); 2.55-2.70 (m, 4 H); 2.45 (s, 3 H); 1.53-1.71 (m, 4 H); 1.31-1.45 (m, 1 H); 1.39 (s, 9 H); 1.12-1.31 (m, 2 H); 0.79-1.05 (m, 2 H)

STEP B:

4M HC1 in dioxane (300 μΐ, 1.2 mmol) is added to the solution of N-Boc-4-(2-(2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)propyl)piperidine (0.101 g, 0.172 mmol) in DCM (5 mL) and the reaction mixture is stirred at RT for 3 h. The organic solvent is removed under reduced pressure and the residue is dissolved in H₂0 and basified with NH₄OH. The precipitate is filtered off and the solid is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) (0.018 g, 0.037 mmol Yield: 22%).

LC-MS: method E, rt=l .87 min; (ES+) MH⁺: 489.25

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, 1 H); 8.53 (dd, 1 H); 7.76 (ddd, 1 H); 7.67 (dd, 1 H); 7.40-7.51 (m, 1 H); 7.31 (ddd, 1 H); 7.11 (dd, 1 H); 6.74 (s, 2 H); 4.01 (t, 2 H); 2.79-3.11 (m, 5 H); 2.54-2.68 (m, 3 H); 2.45 (s, 3 H); 1.46-1.70 (m, 4 H); 1.14-1.43 (m, 5 H); 0.93-1.14 (m, 2 H) Example 39: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin- -one 0-((l S,3R,5R)-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl)-

(lR,3R,5S)-8-Methyl-8-azabiciclo[3.2.1]ottan-3-yl methansulfonate (0.230 g, 1.049 mmol) dissolved in anhydrous DMF (2 mL) is added dropwise to the solution of (E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.15 g, 0.413 mmol) and sodium hydride (60% mineral oil dispersion) (0.017 g, 0.413 mmol) in anydrous DMF (2 mL). The mixture is stirred at 60°C for 5 h. H₂0 is added and the mixture is evaporated to dryness. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 98/2) and then with preparative HPLC to give the title compound (0.015 g, 0.031 mmol, Yield: 8%) as light yellow solid

LC-MS: method H, rt=4.94 min; (ES+) MH⁺: 487.31

^LH-NMR (DMSO-d₆) 5 (ppm): 9.93 (bs, 1 H); 8.58 (dd, 1 H); 8.53 (dd, 1 H); 7.78 (dt, 1 H); 7.67 (dd, 1 H); 7.48 (ddd, 1 H); 7.32 (td, 1 H); 7.12 (dd, 1 H); 6.80 (bs, 2 H); 4.32-4.62 (m, 1 H); 3.92 (bs, 2 H); 2.95-3.12 (m, 2 H); 2.79-2.95 (m, 1 H); 2.66 (d, 3 H); 2.53-2.64 (m, 3 H); 2.46 (s, 3 H); 2.09-2.25 (m, 3 H); 1.83-2.08 (m, 4 H)

Example 40: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-piperidin-3-ylmethyl-oxime

This compound is synthesized following the experimental procedure of Example 26, using N-Boc- 3-bromomethyl-piperidine instead of N-Boc-3-(2-bromoethyl)azetidine. The title compound is obtained (0.003 g, Yield 15%) as yellow-orange solid.

LC-MS: method O, rt=2.75 min; (ES+), M+H⁺= 461 Ή-NMR (MeOD) 6 (ppm): 8.97 (1 H, br. s); 8.87-8.94 (1 H, m); 8.62 (1 H, br. s); 8.17 (1 H, br. s); 7.74 (1 H, br. s); 7.38 (1 H, d, J=2.0 Hz); 7.21 (1 H, dd, J=9.1, 2.2 Hz); 4.15-4.24 (1 H, m); 4.12 (1 H, br. s); 3.41-3.49 (1 H, m); 3.23 (1 H, br. s); 3.00 (1 H, br. s); 2.91-2.97 (1 H, m); 2.80- 2.85 (1 H, m); 2.76 (3 H, br. s); 2.31 (1 H, br. s); 1.96 (3 H, d, J=16.6 Hz); 1.35-1.42 (2 H, m); 1.29 (1 H, s); 0.87-1.00 (1 H, m)

Example 41 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q ochloride

STEP A:

Tetrabromomethane (0.906 g, 2.73 mmol) and triphenylphosphine (0.717 g, 2.73 mmol) are added under nitrogen to the solution (S)-N-Boc-3-(bromomethyl)pyrrolidine (0.5 g, 2.484 mmol) in anhydrous DCM (10 mL) at 0°C. The reaction is stirred at 0°C for 5 h. During this period of time additional tetrabromomethane (0.906 g, 2.73 mmol) is added. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent DCM 100%) to give the expected compound (0.433 g, 1.64 mmol, Yield: 66%).

Ή-NMR (CDC1₃) δ (ppm): 3.59 (dd, J=10.86, 7.34 Hz, 1 H); 3.49 (ddd, J=l 1.15, 8.22, 4.11 Hz, 1 H); 3.40 (d, J=6.75 Hz, 2 H); 3.28-3.37 (m, 1 H); 3.11 (dd, J=11.00, 7.48 Hz, 1 H); 2.45-2.73 (m, 1 H); 1.98-2.14 (m, 1 H); 1.64-1.79 (m, 1 H); 1.47 (s, 9 H)

STEP B:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.330 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, (S)-N-Boc-3-(bromomethyl)pyrrolidine (0.087 g, 0.330 mmol) is added and the reaction is heated overnight at 80°C. The mixture is diluted with EtOAc/Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.124 g, 0.227 mmol, Yield: 82%).

LC-MS: method A, rt=l .81 min; (ES+), M+H⁺= 547.4

Ή-NMR (CDCI₃) δ (ppm): 8.76-8.99 (m, 1 H); 8.30-8.49 (m, 1 H); 8.10-8.25 (m, 1 H); 7.51 (dd, J=8.95, 5.43 Hz, 1 H); 7.35 (dd, J=7.92, 2.64 Hz, 1 H); 7.00 (dd, J=8.51, 2.64 Hz, 1 H); 4.19-4.32 (m, 1 H); 3.92-4.19 (m, 1 H); 3.27-3.62 (m, 3 H); 2.95-3.27 (m, 5 H); 2.81 (s, 3 H); 2.48-2.72 (m, 3 H); 1.94-2.10 (m, 1 H); 1.59-1.78 (m, 1 H); 1.47 (s, 9 H)

STEP C:

4M HC1 in dioxane (2 mL, 8.0 mmol) is added to the solution of (3S)-N-Boc-3-(((E)-2-amino-7- (4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)methyl)pyrrolidine (0.1 15 g, 0.210 mmol) in DCM (3 mL). The reaction is stirred at RT for 3 h. The precipitate is filtered off, washed with DCM and dried under vacuum to give the title compound desiderato (0.077g, 0.138 mmol, Yield: 65%) as tri-hydrochloride salt.

LC-MS: method D, rt=l.76 min; (ES+) MH⁺: 447.45

Ή-NMR (DMSO-d₆) δ (ppm): 9.25 (bs, 2 H); 8.68-8.87 (m, 2 H); 8.22 (d, J=8.51 Hz, 1 H); 7.82 (ddd, J=7.34, 6.02, 1.03 Hz, 1 H); 7.75 (dd, J=8.80, 5.87 Hz, 1 H); 7.39 (td, J=8.58, 2.79 Hz, 1 H); 7.21 (dd, J=9.54, 2.79 Hz, 1 H); 4.14 (dd, J=10.86, 6.16 Hz, 1 H); 4.09 (dd, J=10.86, 7.04 Hz, 1 H); 3.04-3.33 (m, 5 H); 2.83-3.04 (m, 2 H); 2.61-2.82 (m, 3 H); 2.58 (s, 3 H); 1.92-2.1 1 (m, I H); 1.53-1.75 (m, 1 H)

Example 42: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(R)-l-pyrrolidin-3-ylmethyl-oxime, tri-hydrochloride

STEP A:

Tetrabromomethane (0.906 g, 2.73 mmol) and triphenylphosphine (0.717 g, 2.73 mmol) are added under nitrogen to the solution (R)-N-Boc-3-(bromomethyl)pyrrolidine (0.5 g, 2.484 mmol) in anhydrous DCM (10 mL) at 0°C. The reaction is stirred at 0°C for 5 h. During this period of time additional tetrabromomethane (0.906 g, 2.73 mmol) is added. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent DCM 100%) to give the expected compound (0.485 g, 1.84 mmol, Yield: 74%).

Ή-NMR (CDC1₃) δ (ppm): 3.60 (dd, J=l 1.00, 7.48 Hz, 1 H); 3.50 (ddd, J=l 1.15, 8.22, 4.11 Hz, 1 H); 3.40 (d, J=7.04 Hz, 2 H); 3.28-3.38 (m, 1 H); 3.11 (dd, J=11.00, 7.48 Hz, 1 H); 2.45-2.74 (m, 1 H); 1.97-2.17 (m, 1 H); 1.65-1.88 (m, 1 H); 1.47.(s, 9 H)

STEP B:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.330 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one Oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, (R)-N-Boc-3-(bromomethyl)pyrrolidine (0.087 g, 0.330 mmol) is added and the reaction is heated overnight at 80°C. Additional sodium hydride (60% mineral oil dispersion) (11.0 mg, 0.275 mmol) and (R)-N-Boc-3-(bromomethyl)pyrrolidine (0.174 g, 0.660 mmol) are added under nitrogen and the the reaction is heated overnight at 80°C. The mixture is diluted with EtOAc/Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.130 g, 0.238 mmol, Yield: 86%).

LC-MS: method A, rt=l .81 min; (ES+), M+H⁺= 547.4

Ή-NMR (CDC13) δ (ppm): 8.66-8.95 (m, 2 H); 8.17-8.34 (m, 1 H); 7.91-8.15 (m, 1 H); 7.48 (dd, 1 H); 7.32 (dd, 1 H); 4.17-4.34 (m, 1 H); 4.10 (d, 1 H); 2.92-3.62 (m, 8 H); 2.82 (s, 3 H); 2.44- 2.76 (m, 3 H); 1.90-2.12 (m, 1 H); 1.58-1.82 (m, 1 H); 1.47 (s, 9 H)

STEP C:

4M HC1 in dioxane (2 mL, 8.0 mmol) is added to the solution of (3R)-N-Boc-3-(((E)-2-amino-7- (4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)methyl)pyrrolidine (0.115 g, 0.210 mmol) in DCM (3 mL). The reaction is stirred at RT for 3 h. The precipitate is filtered off, washed with DCM and dried under vacuum to give the title compound (0.036 g, 0.064 mmol, Yield: 29%) as tri-hydrochloride salt.

LC-MS: method D, rt=l .76 min; (ES+) MH⁺: 447.48 Ή-NMR (DMSO-d₆) δ (ppm): 9.29 (bs, 2 H); 8.61-8.92 (m, 2 H); 8.23 (d, J=6.75 Hz, 1 H); 7.81- 7.91 (m, 1 H); 7.75 (dd, J=8.80, 5.58 Hz, 1 H); 7.40 (td, J=8.58, 2.79 Hz, 1 H); 7.22 (dd, J=9.54, 2.79 Hz, 1 H); 4.14 (dd, J=10.86, 6.46 Hz, 1 H); 4.09 (dd, J=11.44, 7.63 Hz, 1 H); 3.04-3.36 (m, 5 H); 2.85-3.04 (m, 2 H); 2.61-2.85 (m, 3 H); 2.58 (s, 3 H); 1.91-2.12 (m, 1 H); 1.56-1.76 (m, 1 H) Example 43: 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-((S)-2-pyrrolidin-2-yl-ethyl)-oxime

STEP A:

4-Methylmorfoline (0.441 g, 4.36 mmol) is added under nitrogen to the solution of (S)-2-(N-Boc- pyrrolidin-2-yl)acetic acid (1.0 g, 4.36 mmol) in anhydrous THF (10 mL). The reaction is cooled with an ice bath and isobuthyl chloroformate (0.596 g, 4.36 mmol) is added dropwise in 10 min. After 10 min, the white precipitate is filtered off and the solid is washed with anhydrous THF (5 mL). To the solution NaBH₄ (0.224 g, 5.93 mmol), dissolved in H₂0 (3 mL), is added dropwise cooling the reaction with an ice bath. The reaction is stirred for 1 h. The organic solvent is evaporated under reduced pressure and the residue is dissolved in EtOAc and washed with 5% citric acid, 5% di NaHC0₃ and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent petroleum ether/EtOAc 7/3) to give the expected compound (0.875 g, 4.06 mmol, Yield: 93%).

Ή-NMR (DMSO- ) δ (ppm): 3.11-3.82 (m, 5 H); 1.57-2.05 (m, 6 H); 1.40 (s, 9 H)

STEP B:

Tetrabromomethane (0.847 g, 2.55 mmol)) and triphenylphosphine (0.67 g, 2.55 mmol) are added under nitrogen to the solution of (S)-N-Boc-2-(2-hydroxyethyl)pyrrolidine (0.5 g, 2.322 mmol) in anhydrous THF (10 mL) at 0°C. The reaction is stirred at RT for 4 h. During this period of time additional tetrabromomethane (0.847 g, 2.55 nimol) is added. The precipitate is filtered off and the solution is evaporated to dryness. The crude is purified by flash column chromatography (eluent petroleum ether/EtOAc from 9/1 to 8/2) to give the expected compound that is used in the next step without further purification.

STEP C:

Sodium hydride (60% mineral oil dispersion) (13.21 mg, 0.330 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, (S)-N-Boc-3-(bromoethyl)pyrrolidine (0.092 g, 0.330 mmol) is added and the reaction is heated at 60°C for 45 min. The mixture is diluted with EtOAc/Et₂0 (1/1) and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 98/2 to 95/5) to give the expected compound (0.098 g, 0.175 mmol, Yield: 64%).

LC-MS: method A, rt= 1.35 min; (ES+), M+H⁺: 561.4

*H-NMR (DMSO- ) δ (ppm): 8.57 (ddd, J=4.77, 2.42, 1.61 Hz, 1 H); 8.47-8.53 (m, 1 H); 7.76 (dt, J=7.92, 1.91 Hz, 1 H); 7.68 (ddd, J=8.66, 5.87, 2.79 Hz, 1 H); 7.44 (dd, J=7.78, 4.84 Hz, 1 H); 7.23-7.37 (m, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.75 (s, 2 H); 3.90-4.24 (m, 2 H); 3.61-3.89 (m, 1 H); 3.12-3.25 (m, 2 H); 2.79-3.12 (m, 3 H); 2.55-2.68 (m, 2 H); 2.46 (d, 3 H); 1.51-2.06 (m, 6 H); 0.92-1.43 (m, 9 H)

STEP D:

4M HC1 in dioxane (2 mL, 8.0 mmol) is added to the solution of (2S)-N-Boc-2-(2-((E)-2-ammino- 7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)ethyl)pyrrolidine (0.092 g, 0.164 mmol) in DCM (4 mL). The reaction is stirred at RT for 3 h. The reaction is evaporated to dryness and the residue is dissolved in DCM, washed with H₂0 and basified with NH₄OH. The aqueous phase is extracted with EtOAc The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 95/5/0.5 to 90/10/1) to give the title compound (0.044 g, 0.095 mmol, Yield: 58%).

LC-MS: method D, rt=2.31 min; (ES+) MH⁺: 461.40 'H-NMR (DMSO-d₆) 6 (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.20, 0.73 Hz, 1 H); 7.76 (ddd, J=8.00, 1.98, 1.76 Hz, 1 H); 7.67 (dd, J=8.66, 5.72 Hz, 1 H); 7.45 (m, J=7.81, 4.88, 0.99, 0.99 Hz, 1 H); 7.31 (td, J=8.66, 2.64 Hz, 1 H); 7.11 (dd, J=9.54, 2.79 Hz, 1 H); 6.74 (s, 2 H); 4.10 (t, J=6.60 Hz, 2 H); 2.77-3.13 (m, 5 H); 2.55-2.77 (m, 4 H); 2.45 (s, 3 H); 1.48-1.97 (m, 5 H); 1.08-1.32 (m, 1 H)

Example 44 : 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-((R)-2-pyrrolidin-2-yl-ethyl)-oxime

STEP A:

4-Methylmorfoline (0.240 mL, 2.181 mmol) is added under nitrogen to the solution of (R)-2-(N- Boc-pyrrolidin-2-yl)acetic acid (0.5 g, 2.181 mmol) in anhydrous THF (8 mL). The reaction is cooled with an ice bath and isobuthyl chloroformate (0.283 mL, 2.18 mmol) is added dropwise in 10 min. After 10 min, the white precipitate is filtered off and the solid is washed with anhydrous THF (6 mL). To the solution NaBH₄ (0.1 12 g, 2.97 mmol), dissolved in H₂0 (3 mL), is added dropwise cooling the reaction with an ice bath. The reaction is stirred for 1 h. The organic solvent is evaporated under reduced pressure and the residue is dissolved in EtOAc and washed with 5% citric acid, 5% di NaHC0₃ and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent petroleum ether/EtOAc 7/3) to give the expected compound (0.47 g, 2.18 mmol, Yield: 100%).

STEP B:

Methansulfonyl chloride (0.081 mL, 1.047 mmol) is added at 0°C to the solution of (R)-N-Boc-2- (2-hydroxyethyl)pyrrolidine (0.205 g, 0.952 mmol) and TEA (0.279 mL, 2.0 mmol) in DCM (3 mL). The reaction is stirred at RT for 1 h and then washed with H₂0. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The crude (0.278 g, 0.948 mmol) is used in the next step without further purification.

LC-MS: method A, rt=l .32; (ES+), M+H⁺: 394.0

STEP C:

Sodium hydride (60% mineral oil dispersion) (0.037 g, 0.921 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-one oxime (Intermediate 1) (0.279 g, 0.768 mmol) in anhydrous DMF (2 mL). After 5 min, (R)- N-Boc-2-(2-(methylsulphonyloxy)ethyl)pyrrolidine (0.270 g, 0.921 mmol), dissolved in anliydroys DMF (2 mL), is added and the reaction is stirred overnight at RT. The mixture is diluted with EtOAc and washed with H₂0 and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH NH₄OH 98/2/0.2) to give the expected compound (0.164 g, 0. 293 mmol, Yield: 38%) as white solid.

LC-MS: method L, rt = 2.02 min; (ES+), M+H⁺=561.2

STEP D:

4M HC1 in dioxane (1 mL, 4,0 mmol) is added to the solution of (2R)-N-Boc-2-(2-((E)-2-amino- 7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylidenaminoxy)ethyl)pyrrolidine (0.164 g, 0.293 mmol) in DCM (10 mL). The reaction is stirred at RT for 3 h. The mixture is evaporated to dryness and the residue is partitioned between DCM and 1M NaOH. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH OH from 98/2/0.2 to 95/5/0.5) to give the title compound (0.068 g, 0.148 mmol, Yield: 51%) as white solid.

LC-MS: method E, rt=l .59 min; (ES+) MH⁺: 461.35

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (d, J=1.8 Hz, 1 H); 7.76 (dt, J=7.9, 1.9 Hz, 1 H); 7.67 (dd, J=8.5, 5.9 Hz, 1 H); 7.45 (dd, J=7.8, 4.8 Hz, 1 H); 7.31 (td, J=8.6, 2.8 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.10 (t, J=6.6 Hz, 2 H); 2.77-3.11 (m, 5 H); 2.55-2.76 (m, 3 H); 2.45 (s, 3 H); 1.51-1.85 (m, 5 H); 1.07-1.33 (m, 1 H)

Example 45: (R)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(2-azetidin-l-yl-ethyl)-oxime

STEP A:

A solution of 2-(2-bromoethoxy)tetrahydro-2H-pyrane (0.121 g, 0.578 mmol) in anhydrous DMF (2 mL) is added dropwise under nitrogen to the solution of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3- yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 1) (0.21 g, 0.578 mmol) and sodium hydride (60% mineral oil dispersion) (0.028 g, 0.693 mmol) in anhydrous DMF (4 mL). The reaction is stirred at RT for 2 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (0.3 g, 0.6 mmol, Yield: 100%) is used in the next step without further purification. LC-MS: method A, rt= 1.13 min; (ES+), M+H⁺: 492.1

STEP B:

The mixture of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-2-(tetrahydro-2H-pyran-2-yloxy)ethyl oxime (0.284 g, 0.578 mmol) and 4M HCl in dioxane (0.723 mL, 2.89 mmol) in DCM (15 mL) and anhydrous dioxane (7.5 mL) is stirred at RT for 4 h. The solution is basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is triturated with i-PrOH 1. The precipitate is filtered off and dried under vacuum to give the expected compound (0.22 g, 0.540 mmol, Yield: 93%).

LC-MS: method A, rt = 0.92 min; (ES+), M+H⁺: 407.9

STEP C:

The mixture of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-2-hydroxyethyl oxime (0.22 g, 0.54 mmol), TEA (0.226 mL, 1.620 mmol) and methansulfonyl chloride (0.084 mL, 1.080 mmol) in anhydrous DCM (20 mL) and DMF (1 n L) is stirred at RT for 2 h. The mixture is diluted with DCM and washed with H₂0 and brine. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude (0.32 g, 0.659 mmol) is used in the next step without further purification.

LC-MS: method A, rt=1.01 min; (ES+), M+H⁺: 486.0

STEP D

Azetidine (0.364 mL, 5.4 mmol) is added to the solution of (R)-2-(2-amino-7-(4-fluoro-2-pyridin- 3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)ethyl methansulfonate (0.262 g, 0.540 mmol) in anhydrous CH₃CN (10 mL). The reaction is heated under MW irradiation at 50°C for 2.5 h in a sealed vessel. The organic phase is concentrated under reduced pressure and the crude is purified by flash column chromatography (eluent DCM/MeOH/NHUOH 95/5/0.5) to give the title compound (0.045 g, 0.101 mmol, Yield: 19%) as beige solid.

Chiral HPLC: method N, rt =11.75 min, 98/2 R/S

LC-MS: method E, rt = 1.42 min; (ES+) MH⁺: 447.19

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.52 (dd, 7=2.3, 0.9 Hz, 1 H); 7.76 (dt, J=7.6, 2.3 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.8, 4.9, 0.7 Hz, 1 H); 7.31 (td, J=8.7, 2.9 Hz, 1 H); 7.1 1 (dd, J=9.4, 2.9 Hz, 1 H); 6.75 (s, 2 H); 3.97 (t, J=5.7 Hz, 2 H); 3.08 (t, J=6.7 Hz, 4 H); 2.76-3.03 (m, 3 H); 2.54-2.69 (m, 4 H); 2.46 (s, 3 H); 1.93 (quin, J=6.9 Hz, 2 H)

Example 46: (S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

STEP A: A solution of 2-(2-bromoethoxy)tetrahydro-2H-pyrane (0.132 g, 0.619 mmol) in anhydrous DMF (5 mL) is added dropwise under nitrogen to the solution of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3- yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 2) (0.225 g, 0.619 mmo) and sodium hydride (60% mineral oil dispersion) (0.03 g, 0.743 mmol) in anhydrous DMF (2.5 mL). The reaction is stirred at RT for 2 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (0.35 g, 0.7 mmol) is used in the next step without further purification.

LC-MS: method A, rt=1.10 min; (ES+), M+H⁺: 492.1

STEP B:

The mixture of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-2-(tetrahydro-2H-pyran-2-yloxy)ethyl oxime (0.304 g, 0.619 mmol) and 4M HCl in dioxane (2.322 mL, 9.29 mmol) in DCM (15 mL) and anhydrous dioxane (7.5 mL) is stirred at RT for 2 h. The solution is basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is triturated with isopropyl ether. The precipitate is filtered off and dried under vacuum to give the expected compound (0.245 g, 0.601 mmol, Yield: 97%) as white solid.

LC-MS: method A, rt=0.90 min; (ES+), M+H⁺: 408.1

STEP C :

The mixture of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-2-hydroxyethyl oxime (0.24 g, 0.589 mmol), TEA (0.246 mL, 1.767 mmol) and methansulfonyl chloride (0.091 mL, 1.178 mmol) in anhydrous DCM (20 mL) and DMF (1 mL) is stirred at RT for 2 h. The mixture is diluted with DCM and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude (0.33 g, 0.659 mmol) is used in the next step without further purification.

LC-MS: method A, rt=l .0 min; (ES+), M+H⁺: 486.0

STEP D

Azetidine (0.404 mL, 6.0 mmol) is added to the solution of (S)-2-(2-amino-7-(4-fluoro-2-pyridin- 3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)ethyl methansulfonate (0.291 g, 0.6 mmol) in anhydrous CH CN (5 mL). The reaction is heated under MW irradiation at 50°C for 2.5 h in a sealed vessel. The organic phase is concentrated under reduced pressure and the crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 96/4/0.4) to give the title compound (0.088 g, 0.197 mmol, Yield: 33%) as beige solid.

Chiral HPLC: method N, rt =11.142 min, 99/1 S/R

LC-MS: method E, rt=l .42 min; (ES+) MH⁺: 447.24

Ή-NMR (DMSO-de) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.52 (dd, J=2.3, 0.9 Hz, 1 H); 7.76 (ddd, J=7.8, 2.3, 1.6 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.7, 2.9 Hz, 1 H); 7.10 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 3.97 (t, J=5.9 Hz, 2 H); 3.08 (t, J=7.0 Hz, 4 H); 2.80-3.04 (m, 3 H); 2.55-2.70 (m, 4 H); 2.46 (s, 3 H); 1.93 (quin, J=6.9 Hz, 2 H)

Example 47: (S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyI-7,8-dihydro-6H- q

STEP A:

A solution of 2-(2-bromopropoxy)tetrahydro-2H-pyrane (0.146 mL, 0.826 mmol) in anhydrous DMF (5 mL) is added dropwise under nitrogen to the solution of (S,E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 2) (0.3 g, 0.826 mmol) and sodium hydride (60% mineral oil dispersion) (0.04 g, 0.991 mmol) in anhydrous DMF (5 mL). The reaction is stirred at RT for 2 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (0.5 g, 0.99 mmol) is used in the next step without further purification.

LC-MS: method A, rt = 1.16 min; (ES+), M+H⁺: 506.2.

STEP B: The mixture of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-2-(tetrahydro-2H-pyran-2-yloxy)propyl oxime (0.418 g, 0.826 mmol)) and 4M HCl in dioxane (0.826 mL, 3.3 mmol) in DCM (20 mL) and anhydrous dioxane (10 mL) is stirred overnight at RT. The solution is basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The residue is triturated with isopropyl ether. The precipitate is filtered off and dried under vacuum to give the expected compound (0.35 g, 0.83 mmol, Yield: 100%) as white solid.

LC-MS: method A, rt = 0.94 min; (ES+), M+H⁺: 422.1

STEP C:

The mixture of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-2-hydroxypropyl oxime (0.348 g, 0.826 mmol), TEA (0.345 mL, 2.478 mmol) and methansulfonyl chloride (0.128 mL, 1.652 mmol) in anhydrous DCM (20 mL) and DMF (0.3 mL) is stirred at RT for 2 h. The mixture is diluted with DCM and washed with H₂0. The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude (0.44 g, 0.886 mmol) is used in the next step without further purification.

LC-MS: method A, rt=1.04 min; (ES+), M+H⁺: 500.1

STEP D

Azetidine (0.557 mL, 8.26 mmol) is added to the solution of (S, E)-2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)propyl

methansulfonate (0.291 g, 0.6 mmol) in anhydrous CH₃CN (6 mL). The reaction is heated under microwave irradiation at 50°C for 1 h in a sealed vessel. The organic phase is concentrated under reduced pressure and the crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 99/1/0.1 to 95/5/0.25) to give the title compound (0.08 g, 0.174 mmol, Yield: 20%) as beige solid.

Chiral HPLC: method N, rt =10.89 min, 99/1 S/R

LC-MS: method E, rt=l .54 min; (ES+) MH⁺: 461.25

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.7, 1.8 Hz, 1 H); 8.53 (dd, 1 H); 7.77 (dt, J=7.9, 2.3 Hz, 1 H); 7.67 (dd, J=8.9, 5.7 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.6, 2.8 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.03 (t, J=6.5 Hz, 2 H); 3.04 (t, J=7.0 Hz, 4 H); 2.80-3.03 (m, 3 H); 2.54-2.70 (m, 2 H); 2.44 (s, 3 H); 2.34 (t, J=7.0 Hz, 2 H); 1.77-2.02 (m, 2 H); 1.58 (quin, J=6.9 Hz, 2 H)

Example 48: (R)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- q

STEP A:

A solution of 2-(2-bromopropoxy)tetrahydro-2H-pyrane (0.195 mL, 1.101 mmol) in anhydrous DMF (2 mL) is added dropwise under nitrogen to the solution of (R,E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 1) (0.4 g, 1.101 mmol) and sodium hydride (60% mineral oil dispersion) (0.053 g, 1.321 mmol) in anhydrous DMF (6 mL). The reaction is stirred at RT for 2 h. The mixture is diluted with H₂0 and extracted with EtOAc. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (0.6 g, 1.18 mmol) is used in the next step without further purification. LC-MS: method A, rt=l .15 min; (ES+), M+H⁺: 506.2

STEP B:

The mixture of 4M HC1 in dioxane (1.101 mL, 4.40 mmol) and (R,E)-2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-2-(tetrahydro-2H-pyran-2- yloxy)propyl oxime (0.557 g, 1.101 mmol) in DCM (20 mL) and anhydrous dioxane (10 mL) is stirred at RT for 4 h. The solution is basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is triturated with isopropyl ether. The precipitate is filtered off and dried under vacuum to give the expected compound (0.43 g, 1.020 mmol, Yield: 93%) as white solid.

LC-MS: method A, rt=0.95 min; (ES+), M+H⁺: 422.1 STEP C:

The mixture of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-2-hydroxypropyl oxime (0.43 g, 1.020 mmol), TEA 0.427 mL, 3.06 mmol) and methansulfonyl chloride (0.158 mL, 2.040 mmol) in anhydrous DCM (20 mL) and DMF (1 mL) is stirred at RT for 2 h. The mixture is diluted with DCM and washed with H₂0. The organic phase is washed with brine, dried over Na₂S04, filtered and concentrated under reduced pressure. The crude (0.5 g, 1.001 mmol) is used in the next step without further purification.

LC-MS: method A, rt=1.05 min; (ES+), M+H⁺: 500.1

STEP D

Azetidine (0.675 mL, 10.01 mmol) is added to the solution of (R,E)-2-(2-amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminoxy)propyl

methansulfonate (0.5 g, 1.001 mmol) in anhydrous CH₃CN (10 mL). The reaction is heated under microwave irradiation at 50°C for 1 h in a sealed vessel. The organic phase is concentrated under reduced pressure and the crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 96/4/0.4 to 95/5/0.5) to give the title compound (0.024 g, 0.052 mmol, Yield: 5%) as beige solid.

Chiral HPLC: method N, rt=12.30 min, 98/2 R/S.

LC-MS: method E, rt=1.53 min; (ES+) MH⁺: 461.21

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.53 (dd, J=2.3, 0.9 Hz, 1 H); 7.77 (dt, J=7.9, 2.3 Hz, 1 H); 7.67 (dd, J=8.8, 5.9 Hz, 1 H); 7.45 (ddd, J=7.9, 4.8, 0.7 Hz, 1 H); 7.31 (td, J=8.7, 2.6 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.74 (s, 2 H); 4.03 (t, J=6.5 Hz, 2 H); 3.03 (t, J=6.9 Hz, 4 H); 2.81-2.99 (m, 2 H); 2.54-2.68 (m, 3 H); 2.44 (s, 3 H); 2.33 (t, J=7.0 Hz, 2 H); 1.92 (quin, J=6.9 Hz, 2 H); 1.58 (quin, J=6.7 Hz, 2 H)

Example 49 : (S)-2-Amino-7-(4-fluoro-2-py ridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-methyl-azetidin-3-yl)-oxime

STEP A: N-Boc-3-iodoazetidine (0.461 g, 1.628 mmol), dissolved in anhydrous DMF (10 mL), is added dropwise under nitrogen to the solution of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 2) (0.455 g, 1.252 mmol) in anhydrous DMF (10 mL). Sodium hydride (60% mineral oil dispersion) (0.06 g, 1.503 mmol) is added and the mixture is heated at 50°C for 1 h. The suspension is diluted with EtOAc/Et₂0 (2/1) and washed with H₂0. The organic phase is dried over a₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 99/1/0.1 to 97/3/0.3) to give the expected compound (0.580 g, 1.118 mmol, Yield: 89%) as white solid.

LC-MS: method A, rt=1.16 min; (ES+), M+H⁺: 519.2

STEP B:

TFA (1 mL, 12.98 mmol), diluted in DCM (2 mL), is added dropwise to the ice-cooled solution of (S,E)-N-Boc-3-(2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin- 5-ylidenaminoxy)azetidina (0.58 g, 1.118 mmol) in DCM (10 mL). The reaction is stirred overnight at RT. The reaction is evaporated to dryness and the residue is dissolved in H₂0, basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent DCM/MeOH/NH₄OH from 98/2/0.1 to 92/8/0.5) to give the expected compound (0.320 g, 0.765 mmol, Yield: 68%) as light yellow solid.

LC-MS: method A,

(ES+), M+H⁺: 419.1

STEP C:

The mixture of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-azetidin-3-yl oxime (0.22 g, 0.526 mmol), formaldehyde (0.043 mL, 0.578 mmol) and NaBH₃CN (0.04 g, 0.631 mmol) in MeOH (10 mL) is stirred at RT for 1 h. The reaction is evaporated to dryness and the residue is dissolved in DCM and washed with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by preparative HPLC to give the title compound (0.047 g, 0.109 mmol, Yield: 21%) as white solid.

Chiral HPLC: method N, rt=l 1.53 min, 98.5/1.5 S/R

LC-MS: method E, rt=1.38 min; (ES+) MH⁺: 433.19 ^-NMR (DMSO-de) δ (ppm): 8.58 (dd, J=4.8, 1.6 Hz, 1 H); 8.54 (dd, J=2.2, 0.7 Hz, 1 H); 7.78 (ddd, J=7.8, 2.3, 1.6 Hz, 1 H); 7.69 (dd, J=8.7, 6.0 Hz, 1 H); 7.46 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.32 (td, J=8.5, 2.9 Hz, 1 H); 7.11 (dd, J=9.7, 2.9 Hz, 1 H); 6.78 (s, 1 H); 4.70 (quin, J=5.9 Hz, 1 H); 3.46-3.61 (m, 2 H); 2.84-3.18 (m, 5 H); 2.54-2.71 (m, 3 H); 2.43 (s, 3 H); 2.27 (s, 3 H)

Example 50: (R)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-methyl-azetidin-3-yl)-oxime

STEP A:

N-Boc-3-iodoazetidine (0.567 g, 2.003 mmol), dissolved in anhydrous DMF (2.5 mL), is added dropwise under nitrogen to the solution of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 1) (0.56 g, 1.541 mmol) in anhydrous DMF (10 mL). Sodium hydride (60% mineral oil dispersion) (0.074 g, 1.849 mmol) is added and the mixture is heated at 50°C for 1 h. The suspension is diluted with EtOAc. The organic phase, after washing with H₂0 and brine, is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude (0.9 g, 1.73 mmol) is used in the next step without furter purification.

LC-MS: method A, rt=1.18 min; (ES+), M+H⁺: 519.2

STEP B:

TFA (1.187 mL, 15.41 mmol), diluted in DCM (5 mL), is added dropwise to the ice-cooled solution of (R,E)-N-Boc-3-(2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro- 6H-quinazolin-5-ylidenaminoxy)azetidina (0.799 g, 1.541 mmol) in DCM (10 mL). The reaction is stirred at RT for 6 h. The reaction is evaporated to dryness and the residue is dissolved in H₂0, basified with NH₄OH and then extracted with DCM. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude (0.645 g, 1.54 mmol) is used in the next step without further purification.

LC-MS: method A, rt=0.84 min; (ES+), M+H⁺=419.1

STEP C:

The mixture of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one O-azetidin-3-yl oxime (0.645 g, 1.541 mmol), formaldehyde (0.13 mL, 1.695 mmol) and NaBH₃CN (0.1 16 g, 1.849 mmol) in MeOH (30 mL) is stirred at RT for 1 h. The reaction is evaporated to dryness and the crude is purified by preparative HPLC to give the title compound (0.174 g, 0.402 mmol, Yield: 26%) as light yellow solid.

Chiral HPLC: method N, rt=12.90 min, 98/2 R/S.

LC-MS: method E, rt=1.38 min; (ES+) MH⁺: 433.22

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (dd, J=4.8, 1.6 Hz, 1 H); 8.54 (dd, J=2.3, 0.9 Hz, 1 H); 7.78 (dt, J=7.9, 2.3 Hz, 1 H); 7.68 (dd, J=8.8, 5.6 Hz, 1 H); 7.46 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.31 (td, J=8.7, 2.9 Hz, 1 H); 7.11 (dd, J=9.5, 2.8 Hz, 1 H); 6.78 (s, 2 H); 4.69 (quin, 1 H); 3.44-3.56 (m, 2 H); 2.80-3.16 (m, 5 H); 2.55-2.76 (m, 2 H); 2.43 (s, 3 H); 2.25 (s, 3 H)

Example 51: (S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l-acetyl-azetidin-3-yl)-oxime

Acetyl chloride (0.02 mL, 0.287 mmol) is added to a suspension of di (S,E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 49-Step B) (0.1 g, 0.239 mmol) and TEA (0.067 mL, 0.478 mmol) in DCM (3 mL). The reaction mixture is stirred for 2 h at RT before diluting with DCM and ishing with H₂0. The organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 96/4) to give the title compound (0.089 g, 0.193 mmol, Yield: 81 %) as white solid.

Chiral HPLC: method N, rt=18.03 min, 99/1 S/R

LC-MS : method E, rt= 1.75 min; (ES+) MH⁺: 461.19

Ή-NMR (DMSO-d₆) δ (ppm): 8.55-8.60 (m, 1 H); 8.54 (dd, J=2.3, 0.6 Hz, 1 H); 7.74-7.83 (m, 1 H); 7.69 (ddd, J=8.5, 5.6, 2.1 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.32 (td, J=8.7, 2.6 Hz, 1 H); 7.11 (dd, J=9.7, 2.9 Hz, 1 H); 6.82 (s, 2 H); 4.86-5.03 (m, 1 H); 4.34 (dd, J=9.5, 6.6 Hz, 1 H); 3.97-4.19 (m, 2 H); 3.71-3.97 (m, 1 H); 2.83-3.20 (m, 3 H); 2.56-2.77 (m, 2 H); 2.42 (s, 3 H); 1.76 (d, J=1.5 Hz, 3 H)

Example 52 : (R)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one 0-(l -acetyl-azetidin-3-yl)-oxime

Acetyl chloride (8.16 μΐ, 0.115 mmol) is added to the suspension of di (R,E)-2-amino-7-(4-fluoro- 2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl oxime (Example 50-Step B) (0.040 g, 0.096 mmol) and TEA (0.040 g, 0.096 mmol) in DCM (2 mL). The reaction mixture is stirred for 1 h at RT before diluting with DCM and washing with H₂0. The organic phase is dried over Na₂S04, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 96/4) to give the title compound (0.029 g, 0.063 mmol, Yield: 66%) as light yellow solid.

Chiral HPLC: method N, rt=23.291 min, 98/2 R S

LC-MS: method E, rt=1.73 min; (ES+) MH⁺: 461.18

Ή-NMR (DMSO-d₆) δ (ppm): 8.57 (ddd, J=4.7, 1.5, 0.6 Hz, 1 H); 8.54 (dd, J=2.3, 0.6 Hz, 1 H); 7.74-7.83 (m, 1 H); 7.69 (ddd, J=8.6, 5.9, 2.2 Hz, 1 H); 7.45 (ddd, J=7.8, 4.8, 0.9 Hz, 1 H); 7.32 (td, J=8.7, 2.9 Hz, 1 H); 7.1 1 (dd, J=9.5, 2.8 Hz, 1 H); 6.82 (s, 2 H); 4.80-5.03 (m, 1 H); 4.27-4.44 (m, 1 H); 3.95-4.19 (m, 2 H); 3.70-3.94 (m, 1 H); 2.82-3.17 (m, 3 H); 2.54-2.73 (m, 2 H); 2.42 (s, 3 H); 1.76 (s, 3 H)

Example 53: (S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- qu

STEP A:

Sodium hydride (60% mineral oil dispersion) (0.969 g, 24.22 mmol) is added under nitrogen in portions of about 90 mg each to the solution of (S,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)- 4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 2) (1.1 g, 3.03 mmol) in anhydrous DMF (45 mL). Every 10 min after the addition of each portion of sodium hydride, N-Boc-4- iodopiperidine (Intermediate 5) (7.54 g, 24.22 mmol; about 0.65 g of iodo-derivative for each addition followed by 30 min stirring before adding new portion of sodium hydride) in DMF (8 mL) is added. After 8 h all the additons are concluded (12 in total). The mixture is diluted with EtOAc and washed with saturated solution of NH₄C1. The aqueous phase is extracted with EtOAc and the organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 97/3) to give the expected compound (0.61 g, 1.1 16 mmol, Yield: 37%) as yellow solid.

LC-MS: method A, rt=1.25 min; (ES+), M+H⁺: 547.2

STEP B:

4M HC1 in dioxane (1 mL, 4.0 mmol) is added to the solution of (S,E)-N-Boc-3-((2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)piperidine (0.597 g, 1.092 mmol) in DCM (20 mL). The reaction is stirred at RT for 4 h and then evaporated to dryness. The solid, dissolved in the minimal amount of H₂0, is basified with NH₄OH. The precipitate is filtered off and purified by flash column chromatography (eluent DCM7MeOH/NH₄OH 95/5/0.5) to give the title compound (0.47 g, 1.053 mmol, Yield: 96%) as light yellow solid.

Chiral HPLC chirale: method N, rt=14.32 min, S>99%

LC-MS: method E, rt=1.46 min; (ES+) MH⁺: 447.16

Ή-ΝΜΡν (CDC1₃) δ (ppm): 8.63 (dd, J=4.8, 1.6 Hz, 1 H); 8.58 (dd, J=2.3, 0.6 Hz, 1 H); 7.63 (dt, J=7.6, 2.1 Hz, 1 H); 7.33-7.48 (m, 2 H); 7.19 (td, J=8.4, 2.9 Hz, 1 H); 6.97 (dd, J=9.1, 2.6 Hz, 1 H); 5.00 (br. s, 2 H); 4.21-4.35 (m, 1 H); 2.70-3.29 (m, 8 H); 2.59 (s, 3 H); 2.55 (dd, J=17.3, 12.0 Hz, 1 H); 2.03-2.18 (m, 2 H); 1.69-1.91 (m, 2 H)

Example 54 : (R)-2- Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dih dro-6H- quinazolin-5-one O-piperidin-4-yl-oxime

STEP A:

Sodium hydride (60% mineral oil dispersion) (0.494 g, 12.35 mmol) is added under nitrogen in portions of about 40 mg each to the solution of (R,E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)- 4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Example 1) (0.561 g, 1.544 mmol) in anhydrous DMF (25 mL). Every 10 min after the addition of each portion of sodium hydride, N- Boc-4-iodopiperidine (Intermediate 5) (3.84 g, 12.35 mmol); about 0.32 g of iodo-derivative for each addition followed by 30 min stirring before adding new portion of sodium hydride) in DMF (4 mL) is added. After 8 h all the additons are concluded (12 in total). The mixture is diluted with EtOAc and washed with saturated solution of NH₄C1. The aqueous phase is extracted with EtOAc and the organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude is purified by flash column chromatography (eluent DCM/MeOH from 100/0 to 97/3). The solid is triturated with isopropyl ether to give the title compound (0.26 g, 0.476 mmol, Yield: 31) as white solid.

LC-MS: method A, rt=1.25 min; (ES4 ), M+H⁺: 547.1

STEP B:

4M HC1 in dioxane (1 mL, 4.0 mmol) is added to the solution of (R,E)-N-Boc-3-((2-amino-7-(4- fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- ylideneaminoxy)ethyl)piperidine (0.26 g, 0.476 mmol) in DCM (10 mL). The reaction is stirred at RT for 4 h. The reaction is evaporated to dryness. The solid, dissolved in the minimal amount of H₂0, is basified with NH₄OH. The precipitate is filtered off and purified by flash column chromatography (eluent DCM/MeOH/NH₄OH 95/5/0.5) to give the title compound (0.16 g, 0.358 mmol, Yield: 75%) as white solid.

Chiral HPLC: method N, rt=l 5.27 min, R>94%.

LC-MS: method E, rt=l .45 min; (ES+) MH⁺: 447.08

'H-NMR (DMSO-d₆) δ (ppm): 8.58 (dd, J=4.8, 1.6 Hz, 1 H); 8.54 (dd, J=2.2, 0.7 Hz, 1 H); 7.77 (dt, J=7.9, 2.3 Hz, 1 H); 7.68 (dd, J=8.8, 5.9 Hz, 1 H); 7.46 (ddd, J=7.8, 4.8, 0.6 Hz, 1 H); 7.32 (td, J=8.5, 2.9 Hz, 1 H); 7.1 1 (dd, J=9.7, 2.9 Hz, 1 H); 6.74 (s, 2 H); 4.06-4.26 (m, 1 H); 2.82-3.14 (m, 4 H); 2.55-2.78 (m, 5 H); 2.45 (s, 3 H); 1.87-1.99 (m, 2 H); 1.46-1.66 (m, 2 H)

Example 55 - Assay For Determining Hsp90 Inhibitory Activity

The representative assay for determining Hsp90 Inhibitory Activity was carried out as described in the literature (Schilb A. et al. J. Biomol. Screen. 2004, 9, 569-577; Kim J. et al. J. Biomol. Screen. 2004, 9, 375-381). In the present case a Tamra-Geldanamicin ligand was used as a fluorescent tracer for the Hsp90 ATPase domain, whereby small molecule inhibitors of the Hsp90 ATPase function displace the ligand out of its binding site. This displacement is measured bi fluorescence changes. Using this assay format the following inhibition data were obtained as shown in Table 1.

As evident from comparison with the reference HSP90 inhibitors of the prior art (Table 2), the compounds of the invention showed a significant enhancement of activity.

The reference HSP90 inhibitors marked with (*) are those disclosed in the patent application WO 2008142720.

Table 1

oxime

Tabella 2

Example Geldanamicin binding assay

Structure

Nbr IC_5O( )

Example 56-Cell growth

CellTiter-Glo® Luminescent Cell Viabiliti Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantitation of the present ATP, which indicates the presence of metabolicalli active cells. The homogeneous assay procedure involves addition of a single reagent (CellTiter-Glo® Reagent) directli to the cells, which leads to cell lisis and generation of a luminescent signal proportional to the amount of the ATP and the number of cells present in culture. The assay relies on the properties of a proprietari thermostable luciferase (Ultra-Glo^® recombinant luciferase), which generates a luminescent signal.

K562, A549 and HCT-1 16 cells, in exponential growth, were incubated for 72 h with different concentrations of the inhibitors. After 72 h, a volume of CellTiter-Glo® Reagent equal to the volume of cell culture medium was added. The content was mixed for 2 min to induce cell lisis. The luminescence was recorded after further 10 min at room temperature in order to obtain a stable luminescent signal.

The IC50 was calculated using GrafPad Software.

The obtained results are illustrated in Table 3.

As evident from comparison with the reference HSP90 inhibitors of the prior art, the compounds of the invention showed a significant enhancement of cell growth inhibitory activity (Table 4). The reference HSP90 inhibitors marked with (*) are those disclosed in the patent application WO 2008142720.

Table 3

Example HCT116 A549 K562

Structure

Nbr ICso(uM) ΙΟ₅₀(μΜ) ICso(uM)

(S)-2-Amino-7-(4- fluoro-2-pyridin-3-yl- phenyl)-4-methyl-7,8-

0.099 0.111 0.136 dihydro-6H-quinazolin- 5-one 0-(3-azetidin-l- yl-propyl)-oxime

(R)-2-Amino-7-(4- fluoro-2-pyridin-3-yl- phenyl)-4-methyl-7,8-

2.458 3 706 3.668 dihydro-6H-quinazolin- 5-one 0-(3-azetidin-l- yl-propyl)-oxime

2-Amino-7 -(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-

0.111 0.1 1 1 0.22 quinazolin-5-one 0-(l- isopropyl-azetidin-3-yl)- oxime

2-Amino-7-(4-fIuoro-2- pyridin-3-yl-phenyl)-4- methyl-7, 8 -dihydro-6H-

0.265 0.174 0.39 quinazolin-5-one 0-(l- methansulfonyl-azetidin- 3-yl)-oxime

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- ^N'°^~C^NH

methyl-7,8-dihydro-6H- 0.17 0.268 0.189 quinazolin-5-one 0- piperidin-4-il-oxime

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7, 8 -dihydro-6H-

32 0.297 0.193 0.394 quinazolin-5-one 0-(l- benzoyl-piperidin-4-yl)- oxime

2-Amino-7-(4-fluoro-2- pyridin-3 -yl -phenyl) -4- methyl-7,8-dihydro-6H-

39 quinazolin-5-one 0- . 0.086 0.04 0.088 ((l S,3R,5R)-8-methyl-8- aza-biciclo[3.2. l]oct-3- yl)-oxime

Table 4

Example 57-Metabolic stability in mouse hepatic microsomes

Experimental procedure

The test compound was dissolved in DMSO at the final concentration of 1 μΜ and pre-incubated for 10 min at 37°C in potassium phosphate buffer pH 7.4 together with mouse hepatic microsomes (Xenotech) at the final concentration of 0.5 mg/ml.

After the pre-incubation the reaction was started by adding the cofactor mixture (NADP, G6P, G6P-DH); aliquots were taken at time 0 and 30 min, added to acetonitrile in order to stop the reaction. After centrifugation the supernatant was separated and analyzed by LC-MS/MS.

A control sample without cofactor was always studied in parallel in order to check the chemical stability of the test compound.

Two reference compounds of known metabolic stability 7-ethoxycoumarin and propranolol were present each time to access the validity of the experiment. A fixed concentration of verapamil was added in each sample as internal standard for the LC- MS/MS analysis.

Data analysis

The percentage of the compound remaining after 30 min incubation period is calculated according the following equation: [area at time 30 min]/ [area at time 0 min]* 100%.

Sample analysis

HPLC conditions

Samples were analyzed on an Acquity UPLC (Waters) coupled with a Sample Organizer and interfaced with a triple quadrupole Premiere XE (Waters). Eluents were:

Phase A: 95% H₂0, 5% CH₃CN + 0.1 % HCOOH

Phase B: 5% H₂0, 95% CH₃CN + 0.1 % HCOOH

Column: Acquity BEH CI 8 50x2.1 mm 1.7 μιη at 40°C. Flow 0.45 ml/min, alternatively Acquity BEH CI 8 50x1 mm 1.7 μπι at 40°C. Flow 0.2 ml/min,

Chromatographic method is reported below.

Table 5 Chromatographic method

MS method

Samples were analyzed in MRM (Multiple Reaction Monitoring) ESI Pos mode.

MS Conditions: Capillary Voltage 3.4kV, Source Temp. 1 15°C, Desolvation Temp. 450°C,

Desolvation gas 900 1/h, Cell Pressure 3.3 10-3 mbar.

Cone Voltage and Collision Energy were optimized for each compound. The acquisition of each compound was performed together with the internal standard verapamil. The obtained results are illustrated in the following Table 6. The reference HSP90 inhibitor marked with (*) is the one disclosed in the patent application WO 2008142720 which differs from the compounds of the present application through one structural element.

As evident from comparison with the reference HSP90 inhibitor of the prior art, the compounds of the invention showed a significant enhancement in metabolic stability.

Table 6

Example

Name Structure Remaining in mouse Nbr

Rif (^*) 90 5.39

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-

43 37.04

quinazolin-5-one 0-((S)- 2-pyrrolidin-2-yl-ethyl)- oxime

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-

44 26.65

quinazolin-5-one 0-((R)- 2-pyrrolidin-2-yl-ethyl)- oxime

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-

3 methyl-7,8-dihydro-6H- 27.56

quinazolin-5-one 0-(2- azetidin- 1 -yl-ethyl)-

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H- 42.3 quinazolin-5-one 0- piperidin-4-yl-oxime

2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-

22.16 quinazolin-5-one 0-( 1 - benzoyl-piperidin-4-yl)-

oxime

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, polymorph, hydrate, solvate, or a pharmaceutically acceptable salt thereof:

(I)

wherein:

R is hydrogen or A-B;

A is a bond, or Cj-C₅ alkylene;

B is a C3-C5 heterocyclyl or a C₆-C₈ heterobicyclyl, wherein the C3-C5 heterocyclyl and the C₆-C₈ heterobicyclyl may be optionally substituted by one or two substituents selected from halogen, C1-C5 alkyl optionally substituted by aryl; -C(0)R1 ; -S0₂R2; or -C(0)NR3R4;

Rl, R2, R3 and R4 are independently hydrogen, C 1-C5 alkyl, or aryl;

provided that when R is hydrogen, the configuration of 7-(4-fluoro-2-pyiridin-3-yl-phenyl) is (S).

A compound according to claim 1 of general formula (la)

(la)

wherein R is as defined in claim 1. A compound according to claims 1-2, wherein:

A is a bond, or C1-C3 alkylene.

A compound according to claims 1-3 wherein:

B is a C3-C5 heterocyclyl or a C₆-Cs heterobicyclyl, wherein the C3-C5 heterocyclyl and the C₆-Cg heterobicyclyl may be optionally substituted by one or two substituents selected from halogen; C 1-C3 alkyl optionally substituted by phenyl; -C(0)R1; -S0₂R2; or -C(0)NR3R4; preferably B is azetidine, pyrrolidine, piperidine, piperazine, morpholine or 8-azabicyclo[3.2.1]octane, each of said groups optionally substituted by one or two substituents selected from halogen; C 1-C3 alkyl optionally substituted by phenyl; -C(0)R1 ; -S0₂R2 or -C(0)NR3R4;

Rl, R2, R3 and R4 are independently hydrogen, C 1-C3 alkyl, or phenyl.

A compound according to claim 1 selected from:

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- one oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2-azetidin-l-yl-ethyl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- one 0-(2-azetidin-l-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2-pyrrolidin- 1 -yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2-piperazin- 1 -yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4-methyl-piperazin- 1 -yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4-isopropyl-piperazin- 1 -yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(4-acetyl-piperazin- 1 -yl)-ethyl]-oxime; 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3-azetidin- 1 -yl-propyl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- one 0-(3-azetidin-l-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3 -pyrrolidin- 1 -yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3-piperidin-l-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[3-(3,3-difluoro-azetidin-l-yl)-propyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[3-(3,3-difluoro-pyrrolidin-l-yl)-propyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3-piperazin-l-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-yl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-azetidin-3-ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(2-azetidin-3-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl^henyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-methyl-azetidin-3-yl)-oxime;

(S)-2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5- one 0-(l-methyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -isopropyl-azetidin-3 -yl)-oxime;

2-Amino-7-(4-fluoro-2^yridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l -benzyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-acetyl-azetidin-3-yl)-oxime; (S)-2-Amino-7-(4-fluoro-2-pyridm-3-yl-phenyl)-4-me^^

one 0-( 1 -acetyl-azetidin-3 -yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-benzoyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-methylaminocarbonyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -dimethylaminocarbonyl-azetidin-3 -yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-methanesulfonyl-azetidin-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-yl-oxime;

(S)-2-Amino-7-(4-fluoro-2rpyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolm-5- one O-piperidin-4-yl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-ylmethyl-oxime;

2-Amino-7-(4-fluoiO-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin-4-yl-ethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(3-piperidin-4-yl-propyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(l-methyl-piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-(l-isopropyl-piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-[2-( 1 -acetyl -piperidin-4-yl)-ethyl]-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -methyl -piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -isopropyl-piperidin-4-yl)-oxime; 2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -benzyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-( 1 -acetyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(l-benzoyl-piperidin-4-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-((l S,3R,5R)-8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-piperidin- 3 -ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(S)-l-pyrrolidin-3 -ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-(R)-l-pyrrolidin-3-ylmethyl-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-((S)-2-pyrrolidin-2-yl-ethyl)-oxime;

2-Amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one 0-((R)-2-pyrrolidin-2-yl-ethyl)-oxime;

and their stereoisomers, tautomers, pharmaceutically acceptable salts.

6. A process for the preparation of a compound as claimed in any one of claims 1 to 5, the process comprising:

a) reacting a compound of formula (II)

(Π) with a compound of formula (III):

Y— A-X

(III)

wherein A is as defined in claim 1, Y is B or a suitable hydroxy protecting group, wherein B is as defined in claim 1, and X is a halogen or a suitable leaving group to give the compounds of formula (I) or a compound that is converted into a compound of formula (I) by standard methods well known to those skilled in the art;

b) optionally resolving an individual stereoisomer of a compound of formula (I) from a mixture of stereoisomers;

c) optionally resolving an individual stereoisomer of a compound of formula (II) from a mixture of stereoisomers;

d) optionally converting a compound of general formula (I) to another compound of formula (I) or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I).

7. A compound as claimed in any one of claims 1 to 5 for use in medicine; preferably for use in treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity; more preferably for use in the treatment of proliferative diseases, preferably cancer, viral and fungal infections, neurodegenerative or inflammatory diseases or conditions; more and more preferably for use in the treatment of hepatitis B, hepatitis C and herpes simplex; inflammatory conditions and diseases; cystic fibrosis; angiogenesis- related diseases; neurodegenerative diseases; to protect normal cells against chemotherapy- induced toxicity; for resensitising previously resistant fungal strains to antifungal agents; cancer of lung, bronchus, oral cavity, pharynx, larynx, breast, pancreas, small intestine, colon, rectum, thyroid, esophagus, stomach, liver, intrahepatic bile ducts, kidney, renal pelvis, urinary bladder, female genital tract, prostate, melanomas, multiple myeloma, brain, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, non-Hodgkin lymphoma or villous colon adenoma.

8. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for treating diseases and conditions which are mediated by excessive or inappropriate Hsp90 activity; preferably for the treatment of proliferative diseases, preferably cancer, viral and fungal infections, inflammatory or neurodegenerative diseases or conditions; more and more preferably for the treatment of hepatitis B, hepatitis C and herpes simplex; inflammatory conditions and diseases; cystic fibrosis; angiogenesis-related diseases; neurodegenerative diseases; to protect normal cells against chemotherapy- induced toxicity; for resensitising previously resistant fungal strains to antifungal agents; cancer of lung, bronchus, oral cavity, pharynx, larynx, breast, pancreas, small intestine, colon, rectum, thyroid, esophagus, stomach, liver, intrahepatic bile ducts, kidney, renal pelvis, urinary bladder, female genital tract, prostate, melanomas, multiple myeloma, brain, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, non-Hodgkin lymphoma or villous colon adenoma.

9. A compound according to claims 1 to 5 or the use as claimed in claim 8, wherein the compound is administered combined with another agent used in the treatment of cancer, or inflammation or neurodegenerative disease, or viral or fungal infections.

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 5 together with a pharmaceutically acceptable excipient, which optionally includes an additional agent as defined in claim 9.