WO2021198191A1 - Quinazolinone derivatives and uses thereof for treating a cancer - Google Patents

Quinazolinone derivatives and uses thereof for treating a cancer Download PDF

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Publication number
WO2021198191A1
WO2021198191A1 PCT/EP2021/058179 EP2021058179W WO2021198191A1 WO 2021198191 A1 WO2021198191 A1 WO 2021198191A1 EP 2021058179 W EP2021058179 W EP 2021058179W WO 2021198191 A1 WO2021198191 A1 WO 2021198191A1
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Prior art keywords
quinazolin
methyl
methoxy
group
halogen
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PCT/EP2021/058179
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French (fr)
Inventor
Laurène MEYNIEL-SCHICKLIN
Peter Machin
Eric Meldrum
Benoît De Chassey
Fabrice Guillier
Christine Massardier
Jérôme AMAUDRUT
Christian Montalbetti
David Cousin
Jean-Laurent Paparin
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Enyo Pharma
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Publication of WO2021198191A1 publication Critical patent/WO2021198191A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine, in particular quinazolinone derivatives and their uses for treating a cancer.
  • Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Among the most common cancers, lung cancers account for 1.69 million deaths per year, colorectal cancer for 774 000 deaths per year, and breast cancer for 571 000 deaths per year.
  • cancer Many treatment options exist nowadays for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy and palliative care.
  • the choice of the best treatment depends on the type, location and grade of the cancer as well as the patient's health and preferences.
  • cancers especially in late stage and/or metastatic cancers that remains resistant to treatment.
  • ICD immunogenic cell death
  • DAMPs damage-associated molecular patterns
  • TME tumour microenvironment
  • DAMPs include the exposure of CALR, PDIA3, HSP70 and HSP90 on the membrane surface and the release of HMGBl and ATP from the dying cells.
  • Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells.
  • the induction of ICD contributes to long-lasting protective antitumour immunity. Therefore, ICD induction has emerged as novel cancer therapies.
  • ICD inducers such as anthracyclines (doxorubicin, idarubicin and mitoxantrone), all the chemical PP1/GADD34 inhibitors (tautomycin, calyculin A and salubrinal), cardiac glycosides (CGs, digoxin, digitoxin, ouabain and lanatoside C), oxaliplatin, bleomycin (BLM, an antitumour antibiotic glycopeptide), cyclophosphamide (CTX), and shikonin (SK), have been widely studied.
  • anthracyclines doxorubicin, idarubicin and mitoxantrone
  • tautomycin calyculin A and salubrinal
  • cardiac glycosides CGs, digoxin, digitoxin, ouabain and lanatoside C
  • oxaliplatin bleomycin
  • BLM an antitumour antibiotic glycopeptide
  • CX cyclophosphamide
  • the present invention thus relates to a compound for use for treating a cancer having the following formula (I): wherein:
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR 6 R 7 with R 6 and R 7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano;
  • R 2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, and a (Ci- Ce)alkyloxy optionally substituted by at least one halogen;
  • R 3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy hydroxy
  • R 3 may form with R 2 a dioxolanyl; and R 4 represents a hydrogen or a (Ci-C 6 )alkyloxy; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
  • Y represents a nitrogen or a -CR 2 group, preferably a -CR 2 group, in which R 2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C 6 )alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluoromethoxy, a (Ci-C 6 )alkyl optionally substituted by a halogen, preferably a methyl or a trifluoromethyl, more preferably R 2 is a hydrogen or a halogen, preferably a fluorine, and even more preferably R 2 is a hydrogen.
  • R 2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C 6 )alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluo
  • R 3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C 6 )alkyloxy, preferably a methoxy, a (Ci-C 6 )alkyl, preferably an isopropyl, a -NR 6 R 7 with R 6 and R 7 being a methyl, and - a halogen, preferably a chlorine.
  • n 0.
  • a compound for use of formula (I) is such that X represents an oxygen atom.
  • Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, and a phenyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a fluorine or a chlorine, and a (Ci-C 6 )alkyl, preferably a methyl;
  • n 0;
  • Y represents a -CR 2 group in which R 2 is a radical selected in the group consisting of a hydrogen and a halogen; R 3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a methoxy, an isopropyl, and a -NR 6 R 7 with 5 and R 7 being a methyl; and R 4 represents a hydrogen.
  • a compound for use of formula (I) is such that X represents a -NR 5 group with R 5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group, preferably a methyl.
  • Ri represents an unsubstituted phenyl, a phenyl substituted by a methyl, a methyloxy, a pyridinyl, a benzothiazolyl, a thiazolyl substituted by a phenyl, and a cyclohexyl;
  • n 0;
  • Y represents a -CR 2 group in which R 2 is a radical selected in the group consisting of a hydrogen and a halogen; R 3 represents a radical selected in the group consisting of a methoxy and a halogen, preferably a chlorine; and R 4 represents a hydrogen.
  • a compound of formula (I) for use is selected in the group consisting of:
  • Example #135 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one; - Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
  • a compound of formula (I) for use is selected in the group consisting of: - Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
  • Example#25 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one; and - Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one.
  • a further object is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined above and an acceptable pharmaceutical excipient for use for treating a cancer.
  • the present invention also provides a new compound of formula (I): wherein:
  • a -NR5 group with R5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group,
  • Ri represents a 5-10 membered ring selected in a group consisting of: a pyridinyl, a phenyl, and
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano;
  • R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C 6 )alkyl substituted by at least one halogen, a (Ci-C 6 )alkyloxy substituted by at least one halogen;
  • R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (C
  • R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen; with the proviso that the compound of formula (I) is not a compound selected in the group consisting of:
  • Y represents a -CR2 group in which R2 is a hydrogen.
  • R3 represents a (Ci-C6)alkyloxy or a halogen, preferably a methoxy or a chlorine, more preferably a methoxy.
  • a new compound of formula (I) is such that:
  • X represents an oxygen atom
  • Ri represents a pyridinyl optionally substituted by at least a (Ci-C 6 )alkyl, preferably a methyl.
  • a new compound of formula (I) is such that:
  • X represents a -NR5 group with R5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group; and Ri represents a phenyl optionally substituted by at least a halogen, a (Ci-C 6 )alkyl, preferably a methyl, or a (Ci-C 6 )alkyloxy, preferably a methoxy.
  • the present invention further provides a new compound of formula (I) selected in the group consisting of:
  • Example #98 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
  • a further object of the invention is a new compound of formula (I) according to the invention, for use as a drug.
  • the present invention also relates to a pharmaceutical composition comprising a new compound of formula (I) according to the invention.
  • C 1 -C 6 can also be used with lower numbers of carbon atoms such as C 1 -C 2 . If, for example, the term C 1 -C 6 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C 1 -C 3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms.
  • alkyl refers to a saturated, linear or branched aliphatic group.
  • (Ci- C 6 )alkyl more specifically means methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl.
  • the “alkyl” is a methyl.
  • alkylene refers to an “alkyl” group as above defined substituted on both terminals.
  • a “(Ci-C 6 )alkylene” more specifically means a methylene (-CH 2 -), an ethylene (-CH 2 -CH 2 -), a propylene (-CH 2 -CH 2 -CH 2 -), a butylene (- CH2-CH2-CH2-CH2-), a propylene (-CH2-CH2-CH2-CH2-), and a hexylene (-CH2-CH2- CH 2 -CH 2 -CH 2 -).
  • a “(Ci-C 6 )alkylene” is a methylene (-CH 2 -).
  • alkoxy or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond.
  • (Ci-C 6 )alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, or hexyloxy
  • the “alkoxy” or “alkyloxy” is a methoxy, an ethoxy, a propoxy, an isopropyloxy, more preferably a methoxy.
  • cycloalkyl corresponds to a saturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms of carbons. It also includes fused, bridged, or spiro- connected cycloalkyl groups.
  • cycloalkyl includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclohexyl.
  • heterocycloalkyl corresponds to a saturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen, oxygen, or sulphur atom, preferably at least one nitrogen atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups.
  • heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydr
  • the heterocycloalkyl group is azetidinyl and pyrrolidinyl.
  • aryl corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms.
  • the term “aryl” includes phenyl, naphthyl, or anthracenyl.
  • the aryl is a phenyl.
  • heteroaryl refers to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom.
  • heteroaryl further includes the “fused arylheterocycloalkyl” and “fused aryl cycloalkyl”.
  • fused arylheterocycloalkyl and fused arylcycloalkyl correspond to a bicyclic group in which an aryl as above defined is bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons.
  • the aryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl.
  • Examples of such mono- and poly cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl
  • halogen corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine or a chlorine.
  • a (Ci-C 6 )alkyl substituted by at least one halogen may include a fluromethyl (-CFEF), a difluoromethyl (-CHF2), or a trifluormethyl (-CF3).
  • stereoisomers are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space.
  • the stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers.
  • the stereoisomers include diastereoisomers and enantiomers.
  • the “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.
  • a tautomer of the compound of formula (I) can be represented by the following formula: in which X, n, Ri, Y, R3, and R4 are such as defined herein.
  • COR refers to C(0)-R and CO2R refers to C(0)-0-R.
  • the “pharmaceutically salts” include inorganic as well as organic acids salts.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like.
  • Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002.
  • the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate.
  • the “pharmaceutically salts” also include inorganic as well as organic base salts.
  • suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt.
  • suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2 -hydroxy ethyl)amine.
  • the salt is selected from the group consisting of sodium and potassium salt.
  • treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease, in particular a cancer.
  • amelioration or eradication of the disease, or symptoms associated with it refers to the amelioration or eradication of the disease, or symptoms associated with it.
  • this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.
  • the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage.
  • the term “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
  • the terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule.
  • active principle As used herein, the terms "active principle”, “active ingredient” and “active pharmaceutical ingredient” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.
  • the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.
  • the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease, particularly a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
  • pharmaceutically acceptable excipient refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.
  • the inventors have demonstrated the therapeutic interest of the compounds of formula (I) of the invention. Indeed, the inventors have shown that the compounds according to the present invention are capable of inducing ICD, more specifically have a Calreticulin EC50 lower than 12 mM, thereby demonstrating the therapeutic interest of such compounds in therapies, more particularly in cancer therapies.
  • the present invention thus relates to a compound having the following formula (I) or a pharmaceutical composition comprising such a compound for use for treating a cancer: wherein:
  • a -NR5 group with R5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group,
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano;
  • R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, and a (Ci- Ce)alkyloxy optionally substituted by at least one halogen;
  • R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy hydroxy
  • R 3 may form with R 2 a dioxolanyl; and R4 represents a hydrogen or a (Ci-C 6 )alkyloxy; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
  • Y represents a -CR2 group with R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen.
  • R2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C 6 )alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluoromethoxy, a (Ci-C 6 )alkyl optionally substituted by a halogen, preferably a methyl, and a trifluoromethyl, more preferably R2 is a hydrogen, or a halogen, preferably a fluorine, and even more preferably R2 is a hydrogen.
  • R2 is a hydrogen or a fluorine.
  • R2 is a hydrogen.
  • Y represents a nitrogen
  • R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by at least one radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy optionally substituted by a halogen, o a halogen, and o a hydroxy a (Ci-C 6 )alkyl and a (Ci-C 6 )alkyloxy optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a -NH-CO 2 -R 7 with R 7 being a (Ci-C 6 )al
  • R 3 represents a radical selected in the group consisting of a cycloalkyl, a (Ci-C 6 )alkyloxy, a -NR 5 R 5 with R 5 and 5 being independently a hydrogen or a (Ci- Ce)alkyl, a heterocycloalkyl optionally substituted by a (Ci-C 6 )alkyl, said (Ci-C 6 )alkyl is optionally substituted by a (Ci-C 6 )alkyloxy, a (Ci-C 6 )alkyl, a halogen, and a (Ci-C 6 )alkyl, and a (Ci-C 6 )alkyloxy optionally substituted by a halogen.
  • R 3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C 6 )alkyloxy, preferably a methoxy, a (Ci-C 6 )alkyl, preferably an isopropyl, a -NR 6 R 7 with 5 and R 7 being a methyl, and a halogen, preferably a chlorine.
  • R 3 may form with R 2 a dioxolanyl.
  • n 0.
  • R 4 represents a hydrogen or a (Ci-C 6 )alkyloxy. In a preferred embodiment, R 4 represents a hydrogen or a methoxy. In an even more preferred embodiment, R 4 represents a hydrogen.
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR 6 R 7 with R 6 and R 7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano.
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a pyridinyl optionally substituted by a (Ci-C 6 )alkyl, preferably a methyl
  • a thiazolyl optionally substituted by a phenyl
  • a benzothiazolyl a benzoxazole optionally substituted by a (Ci-C 6 )alkyl, preferably a methyl, and a cyclohexyl.
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a compound of formula (I) for use for treating a cancer is selected in the group consisting of: - Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
  • Example #134 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one; - Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
  • a compound of formula (I) for use for treating a cancer is selected in the group consisting of:
  • a compound of formula (I) for use for treating a cancer is such that X represents:
  • X represents an oxygen atom
  • a preferred compound of formula (I) for use is such that:
  • Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, a phenyl, a benzoxazolyl, and a thiazolyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a florine, a chlorine, or a bromine, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, preferably a methyl or a trifluoromethyl, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, preferably a trifluoromethoxy, a nitro, and a cyano;
  • Y represents a nitrogen or a -CR 2 group in which R 2 is a radical selected in the group consisting of a hydrogen and a halogen, preferably a fluorine; R 3 represents a radical selected in the group consisting of a heterocycloalkyl, preferably an azetidinyl or a pyrrolidinyl, a (Ci-C 6 )alkyloxy, preferably a methoxy, a (Ci-C 6 )alkyl, preferably an isopropyl, a halogen, preferably a chlorine, and a -NR 6 R 7 with 5 and R 7 being a methyl; and R 4 represents a hydrogen.
  • R 2 is a radical selected in the group consisting of a hydrogen and a halogen, preferably a fluorine
  • R 3 represents a radical selected in the group consisting of a heterocycloalkyl, preferably an azetidinyl or a pyrrolidinyl
  • a more preferred compound of formula (I) for use is such that:
  • X represents an oxygen atom
  • Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, and a phenyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a florine or a chlorine, and a (Ci-C 6 )alkyl, preferably a methyl;
  • Y represents a -CR 2 group in which R 2 is a radical selected in the group consisting of a hydrogen and a halogen; R 3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a methoxy, an isopropyl, and a -NR 6 R 7 with 5 and R 7 being a methyl; and R 4 represents a hydrogen.
  • a particular compound of formula (I) for use is selected in the group consisting of:
  • Example #75 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
  • X represents a -NRs group with Rs being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group, preferably a methyl.
  • X represents a -NH- group, a -N(03 ⁇ 4)- group, a -N(CH2-CH2-OH)-, or a -N(CH2-CH2- NEE)- group, preferably a -N(03 ⁇ 4)- group.
  • a preferred compound of formula (I) for use is such that:
  • X represents a -NRs group with Rs being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group;
  • Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, a phenyl, a benzothiazolyl, a cyclohexyl, and a thiazolyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a (Ci-C 6 )alkyl, preferably a methyl a (Ci-C 6 )alkyloxy, preferably a methoxy, and a phenyl;
  • Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C 6 )alkyloxy, preferably a methoxy, and a halogen, preferably a chlorine; and R4 represents a hydrogen.
  • a more preferred compound of formula (I) for use is such that:
  • X represents a -NR5 group with R5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group;
  • Ri represents an unsubstituted phenyl, a phenyl substituted by a methyl, a methyloxy, a pyridinyl, a benzothiazolyl, a thiazolyl substituted by a phenyl, and a cyclohexyl;
  • Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of a methoxy and a halogen, preferably a chlorine; and R4 represents a hydrogen
  • X represents a -NR5 group with R5 being a methyl
  • Ri represents a phenyl
  • Y represents a -CR2 group in which R2 is a hydrogen; R 3 represents a radical selected in the group consisting of a methoxy, anda chlorine; and R4 represents a hydrogen.
  • a particular compound of formula (I) for use is selected in the group consisting of:
  • X represents a methylene group (-CEE).
  • a preferred compound of formula (I) for use is such that:
  • X represents a methylene group
  • Ri represents a phenyl
  • Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C 6 )alkyloxy, preferably a methoxy, and R4 represents a hydrogen.
  • a particular compound of formula (I) for use is: Example #121. 6-methoxy-2-(2- phenylethyl)-3H-quinazolin-4-one.
  • X represents a sulfur atom or a sulfone group.
  • a preferred compound of formula (I) for use is such that:
  • X represents a sulfur atom or a sulfone group
  • Ri represents a phenyl
  • Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C 6 )alkyloxy, preferably a methoxy, and R4 represents a hydrogen.
  • a particular compound of formula (I) for use is: Example#25. 6-methoxy-2- (phenylsulfanylmethyl) -3H-quinazolin-4-one or Example #26. 2-(benzenesulfonylmethyl)-6- methoxy-3H-quinazolin-4-one.
  • the compound has an activity of ICD inducer.
  • the activity can be determined by an assay measuring the Calreticulin release, the ATP secretion or the HMGB 1 release.
  • the assays are well-known by the person skilled in the art.
  • the methods for measuring calreticulin release and HMGB1 release are detailed in the example section.
  • the compound has an EC50 of less than 20 mM in a method measuring the calreticulin release, in particular as detailed in example B.
  • the inventors have also provided new compounds and the stereoisomers, the tautomers, and the pharmaceutical salts thereof of formula (I) as above defined including all the particular and preferred embodiments.
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with R 6 and R7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano;
  • R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C 6 )alkyl substituted by at least one halogen, a (Ci-C 6 )alkyloxy substituted by at least one halogen;
  • R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (C
  • R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen; with the proviso that the compound of formula (I) is not a compound selected in the group consisting of:
  • Y represents a -CR2 group in which R2 is a hydrogen.
  • R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a -NR 6 R 7 with R 6 and R 7 being a methyl, and a halogen, preferably a chlorine.
  • R 3 represents a (Ci-C 6 )alkyloxy or a halogen, preferably a methoxy or a chlorine, more preferably a methoxy.
  • a new compound of formula (I) is such that X represents an oxygen atom, and n, Ri, Y, R 3 , and R 4 are such as above defined.
  • a new compound of formula (I) is such that:
  • X represents an oxygen atom
  • Ri represents a pyridinyl optionally substituted by at least a (Ci-C 6 )alkyl, preferably a methyl.
  • a new compound of formula (I) is such that X represents a -NR 5 group with R 5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group, and n, Ri, Y, R 3 , and R 4 are such as above defined.
  • a new compound of formula (I) is such that:
  • X represents a -NR 5 group with R 5 being a hydrogen or a (Ci-C 6 )alkyl optionally substituted by a hydroxy or an amino group; and Ri represents a phenyl optionally substituted by at least a halogen, a (Ci-C 6 )alkyl, preferably a methyl, or a (Ci-C 6 )alkyloxy, preferably a methoxy.
  • a further object of the invention is a new compound and, the tautomers, the stereoisomers, and the pharmaceutical salts thereof of formula (I): in which :
  • Ri represents a 5-10 membered ring selected in a group consisting of:
  • a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl said 5-10 Unitd ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C 6 )alkyl optionally substituted by at least one halogen, a (Ci-C 6 )alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR 6 R 7 with 5 and R 7 being independently a hydrogen or a (Ci-C 6 )alkyl, and a cyano;
  • R 2 is a radical selected in the group consisting of a hydrogen, a (Ci-C 6 )alkyl substituted by at least one halogen, a (Ci-C 6 )alkyloxy substituted by at least one halogen;
  • R 3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C 6 )alkyl optionally substituted by a (Ci-C 6 )alkyloxy, a hydroxy or a halogen, o a (Ci-C 6 )alkyloxy substituted by a halogen, o a halogen, and o a hydroxy a (Ci-C 6 )alkyloxy
  • R 3 may form with R 2 a dioxolanyl; and It ! represents a hydrogen; with the proviso that such a compound of formula (I) is not 6-methoxy-2-(phenoxymethyl)-3H- quinazolin-4-one.
  • Y represents a -CR2 group in which R2 is a hydrogen.
  • R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a -NR6R7 with 5 and R7 being a methyl, and a halogen, preferably a chlorine.
  • the compound has an activity of ICD inducer.
  • the activity can be determined by an assay measuring the Calreticulin release, the ATP secretion or the HMGB 1 release.
  • the assays are well-known by the person skilled in the art.
  • the methods for measuring calreticulin release and HMGB1 release are detailed in the example section.
  • the compound has an EC50 of less than 20 mM in a method measuring the calreticulin release, in particular as detailed in example B.
  • the present invention relates to a new compound as defined herein, for use as a drug or a medicine.
  • the present invention further relates to a pharmaceutical or veterinary composition comprising a new compound according to the invention.
  • the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient.
  • the present invention relates to the use of a new compound according to the invention as a drug or a medicine.
  • the invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a new compound according to the invention, is administered to said subject in need thereof.
  • the invention also relates to the use of a new compound according to the invention, for the manufacture of a medicine.
  • the invention also relates to a pharmaceutical composition comprising a new compound according to the invention for use as a drug.
  • the compounds for use of formula (I) and the compounds of formula (I) as such according to the present invention can be prepared according to any chemical routes known from a skilled person, such as general synthetic routes presented in the examples. It is thus understood that one skilled in the art of organic chemistry can easily synthesize the compounds of formula (I) using appropriate starting materials, conventional chemicals reactions, standard and literatures procedures, and experimental conditions to synthesize the compounds of formula (I).
  • the inventors have demonstrated the therapeutic interest of the compounds of the invention. Indeed, the inventors have shown that the compounds according to the present invention are capable of inducing ICD.
  • the present invention also concerns:
  • composition comprising a compound of formula (I) as defined above including anyone of the disclosed embodiments, and an additional antitumor drug, for the treatment of cancer or for use in the treatment of cancer; and/or
  • a compound of formula (I) or a pharmaceutical composition comprising such a compound, for treating cancer or for use for treating cancer in combination with radiotherapy, hyperthermia and/or other antitumor therapies, optionally before, simultaneously and/or after surgery (e.g., tumor resection); and/or
  • kits comprising (a) a compound of formula (I) as defined above including anyone of the disclosed embodiments; and (b) an additional antitumor drug as a combined preparation for simultaneous, separate or sequential use, for treating cancer or for use for treating a cancer; and/or
  • a pharmaceutical composition comprising a compound of formula (I) as defined above including anyone of the disclosed embodiments, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the treatment of a cancer; and/or
  • a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition comprising such a compound, and an additional antitumor drug;
  • a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition comprising such a compound; the method further comprises radiotherapy, hyperthermia and/or other antitumor therapies, optionally before, simultaneously and/or after surgery (e.g., tumor resection).
  • cancer refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • the cancer may be solid tumor or hematopoietic tumor. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma.
  • cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis.
  • AML acute myelogenous leukemia
  • the cancer is selected from the group consisting of colorectal, breast, ovarian, pancreatic, gastric, prostate, renal, cervical, myeloma, lymphoma, leukemia, thyroid, endometrial, uterine, bladder, neuroendocrine, head and neck, liver, nasopharyngeal, testicular, small cell lung cancer, non small cell lung cancer, melanoma, basal cell skin cancer, squamous cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, glioblastoma, glioma, sarcoma, mesothelioma, and myelodisplastic syndromes.
  • the administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumoral or parenteral (including subcutaneous, intramuscular, intravenous and/or intradermal).
  • the administration route is parental, oral or topical.
  • the pharmaceutical composition is adapted for one or several of the above-mentioned routes.
  • the pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.
  • the pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances.
  • the formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients.
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
  • compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
  • the treatment with the compound according to the invention or the pharmaceutical composition according to the invention start no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a most preferred embodiment, the treatment starts the day of the diagnosis.
  • the compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses.
  • the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day.
  • the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.
  • the duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists.
  • the amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient.
  • the total compound dose for each administration of the compound according to the invention or of the pharmaceutical composition according to the invention is comprised between 0.00001 and 1 g, preferably between 0.01 and 10 mg.
  • compositions can be adjusted by the man skilled in the art according to the type and severity of the disease, and to the patient, in particular its age, weight, sex, and general physical condition.
  • the compound of the invention can be used in combination with another antitumoral drug or antineoplastic agent.
  • the additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor, and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions.
  • antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor, and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key
  • Antimitotic agents include, but are not limited to, Paclitaxel, Docetaxel and analogs such as Larotaxel (also called XRP9881; Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer- Squibb), Ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131 ; Bristol-Meyer-Squibb), RPR 109881 A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT-287 (TAPESTRY), PG-Paclitaxel (also called CT-2103, PPX, Paclitaxel Poliglumex, Paclitaxel Polyglutamate or XyotaxTM), ABRA
  • Inhibitors of topoisomerases I and/or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as Doxorubicin, Epirubicin, Daunorubicin, Idarubicin and Mitoxantrone.
  • Inhibitors of Topoisomerase I and II include, but are not limited to Intoplicin.
  • the additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes.
  • Non- exhaustive examples thereof include Uracil mustard, Chlormethine, Cyclophosphamide (CYTOXAN(R)), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Cisplatin, Carboplatin, Fotemustine, Oxaliplatin, Thiotepa, Streptozocin, dacarbazine, and Temozolomide.
  • the DNA alkylating agent is
  • Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis.
  • Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly Methotrexate, Floxuridine, Cytarabine, 6-Mercaptopurine, 6- Thioguanine, Fludarabine phosphate, Pentostatine, 5-Fluorouracil, Gemcitabine and Capecitabine.
  • the additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor.
  • the kinase may be selected from the group consisting of intracellular tyrosine or serine/threonine kinases, receptors tyrosine or serine/theonine kinase.
  • the kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR.
  • the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases.
  • the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec, which inhibits Abl, and Iressa and Tarceva, which both inhibit EGFR, Sorafenib (Nexavar, BAY 43-9006) which inhibits Raf, Dasatinib (BMS-354825) and Nilotinib (AMN-107, Tasigna) which also inhibits Abl, Lapatinib which also inhibits EGFR, Temsirolimus (Torisel, CCI-779) which targets the mTOR pathway, Sunitinib (Stuten, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin and Avastin.
  • the anti-EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, clawartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, preferably is Erlotinib or Cetuximab.
  • the ALK inhibitor can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib.
  • the B-raf inhibitor can be selected among Vemurafenib, dabrafenib, regorafenib, and PLX4720.
  • the MEK inhibitor can be selected among Cobimetinib, Trametinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733.
  • the additional drug can also be a checkpoint inhibitor, for instance an antibody targeting PD- 1, PD-L1, CTLA-4 and the like.
  • Hyperthermia is a medical treatment in which is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anti cancer drugs.
  • heat may be delivered. Some of the most common involve the use of focused ultrasound (FTiS or HIFTi), infrared sauna, microwave heating, induction heating, magnetic hyperthermia, infusion of warmed liquids, or direct application of heat such as through sitting in a hot room or wrapping a patient in hot blankets.
  • FiS focused ultrasound
  • HIFTi infrared sauna
  • microwave heating induction heating
  • magnetic hyperthermia infusion of warmed liquids
  • direct application of heat such as through sitting in a hot room or wrapping a patient in hot blankets.
  • the intermediate 3 can undergo a nucleophilic substitution reaction with various anilines 6 (Scheme I, step b) using similar conditions such as those described in Example #1 using an appropriate base and solvent such as K 2 CO 3 in EtOH, or by methods known to one skilled in the art (for example European Journal of Medicinal Chemistry , 2012, 48, 231-243) to provide the 2-(anilinomethyl)-3H-quinazolin-4-one 7.
  • Heterocyclic amines 9 can be be prepared according to Scheme III by nucleophilic substitution of R2 substituted heterocyclic amines 8 onto chloromethylquinazolinone 3 using similar conditions such as those described in Example #1 using an appropriate base and solvent such as K2CO3 in EtOH, or by methods known to one skilled in the art (for example, PCT Int. Appl. 2009, W02009086264).
  • Heterocyclic amines 13 can also be prepared from nucleophilic substitution on haloheterocycle 12 by amimomethylquinazolinone 11.
  • This aminomethylquinazolinone is prepared in 2 steps from chloromethylquinazolinone 3 by first nucleophilic substitution of chloride by azide using sodium azide using an appropriate solvent and temperature (Scheme IV, step a) or by methods known to one skilled in the art (for example A.
  • Substitution R1 on quinazolinone ring can be placed by functionalization of the anthranilic acid. If anthranilic acids 1 are commercially not available they can be prepared by methods known in the art and as described in literature, for example in Organic Preparations and Procedures International, 1981, 13(3-4), 189-96.
  • Substitution R1 on quinazolinone can also be placed by further functionalization of 2- (aminomethyl)-3H-quinazolin-4-one compounds 7, 9 and 13.
  • phenol ether derivatives 26 are prepared using conditions described in Example #28 by reacting phenol dervatives 25 with an appropriate base and solvent such as NaH in DMF or by methods known to one skilled in the art (for example, U.S. Pat. Appl. 2012, US20120094997) (Scheme VIII, step a).
  • thiophenol derivatives 28 are prepared using conditions described in Example #25 by reacting thiophenol dervatives 27 with an appropriate base and solvent such as NaH in DMF or by methods known to one skilled in the art (for example, K. Junwon et al 2014, Bioorganic & Medicinal Chemistry Letters, 24(23), 5473-5477) (Scheme VIII, step b).
  • the thiophenol ether 28 can be further transformed into sulfone 29 by oxidation using m- CPBA in DCM or by methods known to one skilled in the art (for example, R.A. Devender et al, 1986, Indian Journal of Pharmaceutical Sciences, 48(1), 13-15) (Scheme VIII, step c).
  • Heterocyclic ether 31 can also be prepared from heteroaryloxy acetonitriles 32 using conditions described in Example #107 by reacting anthranilic acid derivatives 1 with an appropriate base and solvent such as K 2 CO 3 in EtOH.
  • the heteroaryloxy acetonitriles 32 are itself prepared by phenol alkylation of heterocyclic phenols 30 with chloroacetonitrile 2 with an appropriate base and solvent such as CS2CO3 in ACN, or by methods known to one skilled in the art (for example in PCT Int. Appl.2014, W02014012360).
  • Heterocyclic ether 31 can also be prepared by Nucleophilic substitution reaction onto heterocyclic halide 12 using conditions described in Example #113 by reacting quinazolinone methylene alcohol 35 with an appropriate base and solvent such as NaH in 1,4-dioxane or by methods known to one skilled in the art (for example in PCT Int. Appl.2016, WO2016161176) (Scheme XI, step d).
  • This synthetic route requires protection of the quinazolinone NH by a protecting group such as SEM.
  • NH protected quinazolinone methylene alcohol 35 illustrated in Preparation #9 is then prepared in 3 steps from chloromethylquinazolinone 3 by first substitution of chloride by acetate group (Scheme XI, step a) with an appropriate base and solvent such as CS2CO3 in DMF, or by methods known to one skilled in the art (for example in GB Patent Appl. 1994, GB2271111).
  • Quinazolinone NH is then protected by a protecting group such as SEM by reacting with 2- (trimethylsilyl) ethoxymethyl chloride and an appropriate base and solvent such as DIEA in DCM or by methods known to one skilled in the art (for example N. Kohyama, Y.
  • Heterocyclic ether 31 providing they bear a chloro, bromo or iodo or any group allowing metal catalysed reactions such as triflate, mesilate group as example such as decribed for intermediate 37, can be further functionalized on the aromatic ring of quinazolinone bicyclic system.
  • aniline 38 as illustrated in Example #111 is prepared by pallado-catalyzed reaction between the bromoaryl substrate 37 with cyclic amines 20 in presence of tBuOK as base, X-Phos and Pd 2 dba 3 as source of palladium or by methods known to one skilled in the art (see for example PCT Int. Appl.2011, WO2011045258).
  • Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all 'H NMR data were collected on a Bruker DPX 300MHz equiped with 5mm BB(0)F GRADZ probe, Bruker AVIII 400MHz equiped with 5mm BB(0)F GRADZ probe or Bruker AVIII 500MHz equiped with 5mm BBI GRADZ probe instruments and chemical shifts are quoted in parts per million (ppm).
  • LC/MS was performed on HPLC Agilent 110 series instrument with a PDA detector from 1100 series coupled to Waters ZQ mass spectrometer, UPLC Acquity Waters with a PDA Acquity detector and a SQ Acquity mass spectrometer or a Shimadzu UFLC-XR system coupled to a LCMS-IT-TOF mass spectrometer.
  • LC/MS data is referenced to LC/MS conditions using the method number provided in Table 1.
  • intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include flash chromatography with a solid phase (i.e. silica gel, alumina, etc.) and a solvent (or combination of solvents, i.e.
  • Step B [6-methoxy-4-oxo-3-(2-trimethylsilylethoxymethyl)quinazolin-2-yl] methyl acetate
  • Step C 2-(hydroxymethyl)-6-methoxy-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one
  • Example #1 2-(indolin-l-ylmethyl)-6-methoxy-3H-quinazolin-4-one (illustrative)
  • the compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) and N-methylaniline (CAS RN 100-61-8, 53 pL; 0.49 mmol; 1.10 eq.).
  • Example #27 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one (CAS RN 387346-90-9)
  • Example #28 2- [(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one
  • the compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) and 3-chlorophenol (CAS RN 108-43-0, 0.34 mL; 3.35 mmol; 3.01 eq.).
  • the residue was purified by column chromatography (0 to 25% of EtOAc in DCM) giving 2-[(3- chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (143 mg; 38.5 %) as a white amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) and 3-fluorophenol (CAS RN 372-20-3, 80 pL; 0.88 mmol; 1.99 eq.).
  • the compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) and 3-bromophenol (CAS RN 591-20-8, 0.35 mL; 3.35 mmol; 3.01 eq.).
  • the residue was purified by column chromatography (0 to 25% of EtOAc in cyclohexane) giving 2-[(3- bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (188 mg; 43.5 %) as a white amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 200 mg; 0.45 mmol; 1.00 eq.) and 3 -(trifluorom ethoxy )phenol (CAS RN 827-99-6, 0.17 mL; 1.32 mmol; 3.00 eq.).
  • the compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 200 mg; 0.45 mmol; 1.00 eq.) and 2-methyl-l,3-benzoxazol-4-ol (CAS RN 51110-60-2, 133 mg; 0.89 mmol; 2.00 eq.).
  • the residue was purified by column chromatography (20 to 80% of EtOAc in DCM) giving 6- methoxy-2- [(2-methyl- l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one (18 mg; 12 %) as a beige amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 500 mg; 2.23 mmol; 1.00 eq.) and 3-hydroxy-6-methylpyridine (CAS RN 1121-78-4, 486 mg; 4.45 mmol; 2.00 eq.).
  • the residue was purified by preparative LC-MS (Table 2, conditions 3) (column: X Bridge C 18,30 x 150 mm 5 pm (Waters); flow rate: 42 mL/min; Mobile phase: H2O with 0.1% of AcOH /
  • the compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.) and N,3-dimethylaniline (CAS RN 696-44-6, 90 pL; 0.72 mmol; 1.10 eq.).
  • the residue was purified by column chromatography (5 to 40% of EtOAc in cyclohexane) giving 6-chloro-2-[(N,3- dimethylanilino)methyl]-3H-quinazolin-4-one (114 mg; 55 %) as a white amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.) and N-methyl-p-toluidine (CAS RN 623-08-5, 90 pL; 0.72 mmol; 1.10 eq.).
  • the residue was purified by column chromatography (0 to 30% of EtOAc in cyclohexane) giving 6-chloro-2-[(N,4- dimethylanilino)methyl]-3H-quinazolin-4-one (51 mg; 25 %) as a white amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-(dimethylamino)-3H-quinazolin-4-one (CAS RN 1690569-78-8, 200 mg; 0.84 mmol; 1.00 eq.) and 3-hydroxypyridine (CAS RN 109-00-2, 160 mg; 1.68 mmol; 2.00 eq.).
  • the residue was purified by column chromatography (0 to 5% of MeOH in DCM) then recrystallized in ACN giving 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (12 mg; 5 %) as a yellow amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 400 mg; 1.78 mmol; 1.00 eq.) and 3-hydroxypyridine (CAS RN 109-00-2, 339 mg, 3.56 mmol, 2.00 eq;).
  • reaction mixture was purified by column chromatography (0 to 30% of EtOAc in DCM) preparative chromatography (Table 2, condition 3) (column: X BRIDGE C18, 30 x 100mm 5pm (WATERS); Flow rate: 42 mL/min; Mobile phase: EEO + 0.1% AcOH / ACN + 0.1% AcOH; Gradient: 20-35%; run 30min) giving 6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (9 mg; 2 %) as a white amorphous powder.
  • Example #107 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one 2-(3-Pyridyloxy) acetonitrile (CAS RN 266348-17-8, 305 mg; 2.27 mmol; 3.00 eq.) was dissolved in MeOH (2 mL) and the solution was cooled in an ice bath at 10°C under N2 atm. Sodium methoxide (8 mg; 0.15 mmol; 0.20 eq.) was added and the solution was stirred for 45 min at 10°C.
  • Example #107 The compound was synthesized using the same procedure detailed in Example #107 starting from 2-amino-5-isopropyl-benzoic acid (CAS RN 68701-22-4, 111.34 mg; 0.62 mmol; 1.00 eq.) and 2-(3-pyridyloxy)acetonitrile (CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.) providing after stirring only for 3h at rt 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (80 mg; 43 %) as a beige amorphous powder.
  • 2-amino-5-isopropyl-benzoic acid CAS 68701-22-4, 111.34 mg; 0.62 mmol; 1.00 eq.
  • 2-(3-pyridyloxy)acetonitrile CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.
  • Example #109 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
  • the compound was synthesized using the same procedure detailed in Example #107 starting from 2-amino-4-fluoro-5-methoxybenzoic acid (CAS RN 637347-90-1, 115.03 mg; 0.62 mmol; 1.00 eq.) and 2-(3-pyridyloxy)acetonitrile (CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.) providing 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (41 mg; 22 %) after stirring 2 days at rt and 24h at 40°C as a beige amorphous powder.
  • azetidine hydrochloride (CAS RN 36520- 39-5, 68 mg; 0.73 mmol; 1.30 eq.), tBuOK (189 mg; 1.68 mmol; 3.00 eq.), 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (26.7 mg; 0.056 mmol; 0.10 eq.) and tris(dibenzylideneacetone)dipalladium (0) (51.3 mg; 0.056 mmol; 0.10 eq.) were successively added under Ar. The mixture was heated under microwave for 2h30 at 120°C.
  • reaction mixture was concentrated to dryness and the residue was purified by column chromatography (0 to 5% of MeOH with 0.1% of NH3 in DCM) then purified by column chromatography with amino silica gel (0 to 5% of MeOH in DCM) giving 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H- quinazolin-4-one (29 mg; 17 %) as a white amorphous powder.
  • Example #111 The compound was synthesized using the same procedure detailed in Example #111 starting from 6-bromo-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (preparation #8, 186 mg; 0.56 mmol; 1.00 eq.) and pyrrolidine (CAS RN 123-75-1, 60 pL; 0.73 mmol; 1.30 eq.) after reaction 2 x 3h at 120°C under microwave.
  • Step B 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one
  • Step A 6-methoxy-2-(2-pyridyloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one
  • Step B 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one
  • 6-Methoxy-2-(2-pyridyloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (Example #114, Step A, 72 mg; 0.17 mmol; 1.00 eq.) was dissolved in HC1 4N in 1,4-dioxane (1.1 mL). The reaction mixture was stirred at rt for 15h then at 50°C for 2h. The mixture was poured slowly in 25 mL of a saturated aqueous solution of NaHCC to give a white precipitate.
  • Example #121 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one (CAS RN 2130021-45-1)
  • Example #134 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one
  • reaction mixture was quenched with water and the formed precipitate was filtered and washed with water (3x) and Et 2 0 (3x) providing 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one (147 mg; 51 %) as a white amorphous powder.
  • the compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.), N-methylcyclohexylamine (CAS RN 100-60-7, 95 pL; 0.72 mmol; 1.10 eq.) and K2CO3 (136 mg; 0.98 mmol; 1.50 eq.) in EtOH (3 mL) was stirred at 80°C overnight. Reaction mixture was diluted with H2O and filtered.
  • Step A tert-butyl (2-(phenylamino)ethyl)carbamate (0.134g, 0.568 mmol) was added to a mixture of 6-chloro-2-(chloromethyl)quinazolin-4(3H)-one (0.1 g, 0.437 mmol) and potassium carbonate (0.181 g, 1.310 mmol) in ethanol (2 ml, 0.437 mmol) and the mixture was stirred at 75 °C for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtred and concentrated.
  • Step B HC1 (4M solution in Dioxane) (0.175 ml, 0.699 mmol) was added to a solution of tert-butyl (2-(((6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(phenyl)amino)ethyl)carbamate (0.030 g, 0.070 mmol) in DCM/Dioxane (1:1, 2 mL) and the mixture was left to stir at room temperature overnight. The mixture was concentrated and the residue was dissolved in methanol then loaded on a column packed with SCX. The column was washed with methanol and the compound eluted with 1% MLMeOH.
  • the product was further purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 pm, 19x50 mm column, 20-50% MeCN in Water) to afford 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one (0.013 g, 53.7) as a colourless solid.
  • preparative HPLC Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 pm, 19x50 mm column, 20-50% MeCN in Water
  • Example #143 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one
  • HMGBl derived from pCMV6-AC-GFP plasmid (ref. RG205918, Origene) was amplified by PCR using the following set of primers: Seq ID No 1: forward, 5’- GATATCGAATTCATGGGC AAAGGAGATCCTAAGAAGCCGAGAGGC-3 ’ ; Seq ID No 2: reverse, 5’- TATC AGCTCGAGACTTCATCATCATCATCTTCTTCTTC ATCTTC-3 ’ .
  • the PCR fragment was subsequently digested by EcoRI and Xhol (R3101S and R0146S respectively, New England Biolabs) and inserted between the EcoRI and Xhol sites in the plasmid pBiT3.1-C (ref.
  • the resulting plasmid (pBiT3.1 -HMGBl) was grown in NEBlO-beta competent E. coli (ref. C3019I, New England Biolabs) and purified using the NucleoBond Xtra Midi Kit (ref. 740410, Macherey -Nagel).
  • HMGBl reporter cell line pBiT3.1 -HMGBl was transfected in MDA-MB-231 cells (ref. ATCC HTB-2) using Lipofectamine 2000 reagent (ref. 11668, Invitrogen). Transfected cells were selected for blasticidin resistance (15pg/ml, ref. Al l 13903 Gibco) in medium containing DMEM IX (ref. 1995065, Gibco) with 1% penicillin and streptomycin, and 10% fetal bovine serum.
  • TEC AN Spark 20M spectrofluorimeter
  • Calreticulin derived from pCMV6-AC plasmid (ref. SC320287, Origene) was amplified by PCR using the following set of primers: Seq ID No 3: forward, 5’- GATATCGAATTCATGCTGCTATCCGTGCCGCTGCTGCTCGGCCTCCTCG-3 ’ ; Seq ID No 4: reverse, 5 ’ - T ATC AGCTCGAGACC AGCTCGTCCTTGGCCTGGCCGGGGAC ATCTTCC-3 ’ .
  • the PCR fragment was subsequently digested by EcoRI and Xhol (R3101 S and R0146S respectively, New England Biolabs) and inserted between the EcoRI and Xhol sites in the plasmid pBiT3.1-C (ref. N237A, Promega).
  • the resulting plasmid (pBiT3.1 -Calreticulin) was grown in NEBlO-beta competent A. coli (ref. C3019I, New England Biolabs) and purified using the NucleoBond Xtra Midi Kit (ref. 740410, Macherey -Nagel).
  • Calreticulin reporter cell line pBiT3.1 -Calreticulin was transfected in MDA-MB-231 cells (ref. ATCC HTB-2) using Lipofectamine 2000 reagent (ref. 11668, Invitrogen). Transfected cells were selected for blasticidin resistance (15pg/ml, ref. Al l 13903 Gibco) in medium containing DMEM IX (ref. 1995065, Gibco) with 1% penicillin and streptomycin, and 10% fetal bovine serum.
  • TEC AN Spark 20M spectrofluorimeter
  • EC50 Calreticulin release
  • HMGBl release High-mobility group box 1
  • Table 3 The results on Calreticulin release (EC50) and HMGBl release (High-mobility group box 1) (EC50) are represented in the Table 3 below. Particularly, the results show that the compounds of formula (I) induce calreticulin and HMGBl release. More particularly, EC50 for Calreticulin release are in mM ranges, preferably lower than 12 pM, and more preferably lower than 1 pM, demonstrating thereby an efficicient anticancer effect for the compounds of the present invention. Table 3:

Abstract

The present invention relates to a new class of quinazolinone derivatives of formula (I), and their uses for treating a cancer. The present invention further relates to pharmaceutical compositions comprising compounds of formula (I).

Description

QUINAZOLINONE DERIVATIVES AND USES THEREOF FOR TREATING A CANCER
FIELD OF THE INVENTION
The present invention relates to the field of medicine, in particular quinazolinone derivatives and their uses for treating a cancer.
BACKGROUND OF THE INVENTION
Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Among the most common cancers, lung cancers account for 1.69 million deaths per year, colorectal cancer for 774 000 deaths per year, and breast cancer for 571 000 deaths per year.
Many treatment options exist nowadays for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy and palliative care. The choice of the best treatment depends on the type, location and grade of the cancer as well as the patient's health and preferences. However, there is still an important proportion of cancers, especially in late stage and/or metastatic cancers that remains resistant to treatment.
In the last few decades immunotherapy has become an important part of cancer treatment strategies. Cancer immunotherapy relies on the use of the immune system to treat cancer. Among the diversity of immunotherapy treatments that have been developed over time, immune checkpoint inhibitor therapies are particularly promising. However, the response to immune checkpoint inhibitors can be low.
A novel approach for treating cancer is to use immunogenic cell death (ICD). ICD is defined by chronic exposure of damage-associated molecular patterns (DAMPs) in the tumour microenvironment (TME), which stimulates the dysfunctional antitumour immune system. Important DAMPs include the exposure of CALR, PDIA3, HSP70 and HSP90 on the membrane surface and the release of HMGBl and ATP from the dying cells. Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD contributes to long-lasting protective antitumour immunity. Therefore, ICD induction has emerged as novel cancer therapies.
Some classic ICD inducers, such as anthracyclines (doxorubicin, idarubicin and mitoxantrone), all the chemical PP1/GADD34 inhibitors (tautomycin, calyculin A and salubrinal), cardiac glycosides (CGs, digoxin, digitoxin, ouabain and lanatoside C), oxaliplatin, bleomycin (BLM, an antitumour antibiotic glycopeptide), cyclophosphamide (CTX), and shikonin (SK), have been widely studied.
However, there remains a need to identify further agents that can promote ICD.
SUMMARY OF THE INVENTION
In this context, the inventors have provided quinazolinone derivatives exhibiting an activity of ICD inducer, demonstrating thereby the therapeutic interest of such compounds in cancer therapies. The present invention thus relates to a compound for use for treating a cancer having the following formula (I):
Figure imgf000003_0001
wherein:
> X represents:
• an oxygen atom,
• a methylene group,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with R6 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, and a (Ci- Ce)alkyloxy optionally substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyl and a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a -NH-CCk-Rs with Rs being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen or a (Ci-C6)alkyloxy; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
In a preferred embodiment, Y represents a nitrogen or a -CR2 group, preferably a -CR2 group, in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C6)alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluoromethoxy, a (Ci-C6)alkyl optionally substituted by a halogen, preferably a methyl or a trifluoromethyl, more preferably R2 is a hydrogen or a halogen, preferably a fluorine, and even more preferably R2 is a hydrogen.
In a further preferred embodiment, R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a (Ci-C6)alkyl, preferably an isopropyl, a -NR6R7 with R6 and R7 being a methyl, and - a halogen, preferably a chlorine.
In a further preferred embodiment, n is 0.
In a first aspect, a compound for use of formula (I) is such that X represents an oxygen atom. In a particular embodiment of this first aspect, Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, and a phenyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a fluorine or a chlorine, and a (Ci-C6)alkyl, preferably a methyl;
> n is 0;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a methoxy, an isopropyl, and a -NR6R7 with 5 and R7 being a methyl; and R4 represents a hydrogen.
In a second aspect, a compound for use of formula (I) is such that X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group, preferably a methyl.
In a particular embodiment of this second aspect, Ri represents an unsubstituted phenyl, a phenyl substituted by a methyl, a methyloxy, a pyridinyl, a benzothiazolyl, a thiazolyl substituted by a phenyl, and a cyclohexyl;
> n is 0;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of a methoxy and a halogen, preferably a chlorine; and R4 represents a hydrogen. In a preferred embodiment, a compound of formula (I) for use is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #70. 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one; - Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one; - Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
In an even more preferred embodiment, a compound of formula (I) for use is selected in the group consisting of: - Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one; - Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one; and - Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one.
A further object is a pharmaceutical composition comprising a compound of formula (I) as defined above and an acceptable pharmaceutical excipient for use for treating a cancer. The present invention also provides a new compound of formula (I):
Figure imgf000007_0001
wherein:
> X represents:
• an oxygen atom,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1, preferably equal to 0; Ri represents a 5-10 membered ring selected in a group consisting of: a pyridinyl, a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl substituted by at least one halogen, a (Ci-C6)alkyloxy substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci-C6)alkyloxy, or a - NH-CO2-R8 with R.8 being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen; with the proviso that the compound of formula (I) is not a compound selected in the group consisting of:
- 2-(4-chloro-phenoxymethyl)-6-methoxy-3H-quinazolin-4-one;
- 7-fluoro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one; and
- 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one. and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
In a particular embodiment, Y represents a -CR2 group in which R2 is a hydrogen.
In a further particular embodiment, R3 represents a (Ci-C6)alkyloxy or a halogen, preferably a methoxy or a chlorine, more preferably a methoxy.
In a preferred embodiment, a new compound of formula (I) is such that:
> X represents an oxygen atom; and Ri represents a pyridinyl optionally substituted by at least a (Ci-C6)alkyl, preferably a methyl. In a further preferred embodiment, a new compound of formula (I) is such that:
> X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group; and Ri represents a phenyl optionally substituted by at least a halogen, a (Ci-C6)alkyl, preferably a methyl, or a (Ci-C6)alkyloxy, preferably a methoxy.
More particularly, the present invention further provides a new compound of formula (I) selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one;
- Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one;
- Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
A further object of the invention is a new compound of formula (I) according to the invention, for use as a drug. The present invention also relates to a pharmaceutical composition comprising a new compound of formula (I) according to the invention. DETAILLED DESCRIPTION OF THE INVENTION
Definitions
According to the present invention, the terms below have the following meanings:
The terms mentioned herein with prefixes such as for example C1-C6, can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term C1-C6 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms.
The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(Ci- C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. In a preferred embodiment, the “alkyl” is a methyl. The term “alkylene” refers to an “alkyl” group as above defined substituted on both terminals. For instance, a “(Ci-C6)alkylene” more specifically means a methylene (-CH2-), an ethylene (-CH2-CH2-), a propylene (-CH2-CH2-CH2-), a butylene (- CH2-CH2-CH2-CH2-), a propylene (-CH2-CH2-CH2-CH2-CH2-), and a hexylene (-CH2-CH2-CH2- CH2-CH2-CH2-). Preferably, a “(Ci-C6)alkylene” is a methylene (-CH2-).
The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (Ci-C6)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, or hexyloxy In a preferred embodiment, the “alkoxy” or “alkyloxy” is a methoxy, an ethoxy, a propoxy, an isopropyloxy, more preferably a methoxy.
The term “cycloalkyl” corresponds to a saturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms of carbons. It also includes fused, bridged, or spiro- connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclohexyl.
The term “heterocycloalkyl” corresponds to a saturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen, oxygen, or sulphur atom, preferably at least one nitrogen atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a preferred embodiment, the heterocycloalkyl group is azetidinyl and pyrrolidinyl. The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, naphthyl, or anthracenyl. In a preferred embodiment, the aryl is a phenyl.
The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. As used herein, the term “heteroaryl” further includes the “fused arylheterocycloalkyl” and “fused aryl cycloalkyl”. The terms “fused arylheterocycloalkyl” and “fused arylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined is bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, b-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a preferred embodiment, the “heteroaryl” is pyridinyl, thiazolyl, benzothiazolyl, and benzoxazolyl.
The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine or a chlorine.
The expression “substituted by at least” means that the radical is substituted by one or several groups of the list. For instance, the expression “a (Ci-C6)alkyl substituted by at least one halogen may include a fluromethyl (-CFEF), a difluoromethyl (-CHF2), or a trifluormethyl (-CF3).
The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list.
The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers. In a preferred embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers. The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons. A tautomer of the compound of formula (I) can be represented by the following formula:
Figure imgf000013_0001
in which X, n, Ri, Y, R3, and R4 are such as defined herein.
COR refers to C(0)-R and CO2R refers to C(0)-0-R.
The “pharmaceutically salts” include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a preferred embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. The “pharmaceutically salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt. Representative examples of suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2 -hydroxy ethyl)amine. In a preferred embodiment, the salt is selected from the group consisting of sodium and potassium salt.
As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease, in particular a cancer. In certain embodiments, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other embodiments, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.
As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others. The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule.
As used herein, the terms "active principle", "active ingredient" and "active pharmaceutical ingredient" are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.
As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.
As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease, particularly a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.
Compounds
Compounds for treating a cancer according to the invention
As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds of formula (I) of the invention. Indeed, the inventors have shown that the compounds according to the present invention are capable of inducing ICD, more specifically have a Calreticulin EC50 lower than 12 mM, thereby demonstrating the therapeutic interest of such compounds in therapies, more particularly in cancer therapies.
The present invention thus relates to a compound having the following formula (I) or a pharmaceutical composition comprising such a compound for use for treating a cancer: wherein:
> X represents:
• an oxygen atom,
• a methylene group,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, and a (Ci- Ce)alkyloxy optionally substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyl or a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a -NH-CC -Rs with Rs being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen or a (Ci-C6)alkyloxy; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
In a particular embodiment, Y represents a -CR2 group with R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen. In a preferred embodiment, R2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C6)alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluoromethoxy, a (Ci-C6)alkyl optionally substituted by a halogen, preferably a methyl, and a trifluoromethyl, more preferably R2 is a hydrogen, or a halogen, preferably a fluorine, and even more preferably R2 is a hydrogen. In a further preferred embodiment, R2 is a hydrogen or a fluorine. In an even more preferred embodiment, R2 is a hydrogen.
In a further particular embodiment, Y represents a nitrogen.
In a particular embodiment, R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by at least one radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyl and a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a -NH-CO2-R7 with R7 being a (Ci-C6)alkyl, a -NR5R5 with R5 and 5 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano.
In a preferred embodiment, R3 represents a radical selected in the group consisting of a cycloalkyl, a (Ci-C6)alkyloxy, a -NR5R5 with R5 and 5 being independently a hydrogen or a (Ci- Ce)alkyl, a heterocycloalkyl optionally substituted by a (Ci-C6)alkyl, said (Ci-C6)alkyl is optionally substituted by a (Ci-C6)alkyloxy, a (Ci-C6)alkyl, a halogen, and a (Ci-C6)alkyl, and a (Ci-C6)alkyloxy optionally substituted by a halogen.
In a more preferred embodiment, R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a (Ci-C6)alkyl, preferably an isopropyl, a -NR6R7 with 5 and R7 being a methyl, and a halogen, preferably a chlorine.
In a particular embodiment, R3 may form with R2 a dioxolanyl.
In a particular embodiment, n is 0.
In a particular embodiment, R4 represents a hydrogen or a (Ci-C6)alkyloxy. In a preferred embodiment, R4 represents a hydrogen or a methoxy. In an even more preferred embodiment, R4 represents a hydrogen.
In a particular embodiment, Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with R6 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano.
In a preferred embodiment, Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl optionally substituted by a (Ci-C6)alkyl, preferably a methyl,
• a phenyl optionally substituted by a phenyloxy, a halogen, preferably a fluorine, a chlorine, or a bromine, a (Ci-C6)alkyl optionally substituted by at least one halogen, preferably a methyl or a trifluoromethyl, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, preferably a methoxy or a trifluoromethoxy, a nitro, or a cyano, and
• a thiazolyl optionally substituted by a phenyl, a benzothiazolyl, a benzoxazole optionally substituted by a (Ci-C6)alkyl, preferably a methyl, and a cyclohexyl.
In a more preferred embodiment, Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl or a pyridinyl substituted by a methyl,
• a phenyl or a phenyl substituted by a phenyloxy, a fluorine, a chlorine, a bromine, a methyl, a trifluoromethyl, a methoxy, atrifluoromethoxy, a nitro, or a cyano, and
• a thiazolyl or a thiazolyl substituted by a phenyl, a benzothiazolyl, benzoxazole substituted by a methyl, and a cyclohexyl.
In a more particular embodiment, Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl or a pyridinyl substituted by (Ci-C6)alkyl, preferably a methyl,
• a phenyl or a phenyl substituted by a phenyloxy, a halogen, preferably a fluorine or a chlorine, and
• a thiazolyl.
In a preferred embodiment, a compound of formula (I) for use for treating a cancer is selected in the group consisting of: - Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #70. 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one;
- Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one; - Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one;
- Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
In a more preferred embodiment, a compound of formula (I) for use for treating a cancer is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one; and
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one.
According to the invention, a compound of formula (I) for use for treating a cancer is such that X represents:
• an oxygen atom,
• a methylene group,
• a -NR.5 group with Rs being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group.
In an embodiment, X represents an oxygen atom.
A preferred compound of formula (I) for use is such that:
> X represents an oxygen atom; > n is 0; Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, a phenyl, a benzoxazolyl, and a thiazolyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a florine, a chlorine, or a bromine, a (Ci-C6)alkyl optionally substituted by at least one halogen, preferably a methyl or a trifluoromethyl, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, preferably a trifluoromethoxy, a nitro, and a cyano;
> Y represents a nitrogen or a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen, preferably a fluorine; R3 represents a radical selected in the group consisting of a heterocycloalkyl, preferably an azetidinyl or a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a (Ci-C6)alkyl, preferably an isopropyl, a halogen, preferably a chlorine, and a -NR6R7 with 5 and R7 being a methyl; and R4 represents a hydrogen.
A more preferred compound of formula (I) for use is such that:
> X represents an oxygen atom;
> n is 0; Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, and a phenyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a florine or a chlorine, and a (Ci-C6)alkyl, preferably a methyl;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a methoxy, an isopropyl, and a -NR6R7 with 5 and R7 being a methyl; and R4 represents a hydrogen.
A particular compound of formula (I) for use is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #70. 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
In an embodiment, X represents a -NRs group with Rs being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group, preferably a methyl. In a preferred embodiment, X represents a -NH- group, a -N(0¾)- group, a -N(CH2-CH2-OH)-, or a -N(CH2-CH2- NEE)- group, preferably a -N(0¾)- group.
A preferred compound of formula (I) for use is such that:
> X represents represents a -NRs group with Rs being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group;
> n is 0; Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl, a phenyl, a benzothiazolyl, a cyclohexyl, and a thiazolyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a (Ci-C6)alkyl, preferably a methyl a (Ci-C6)alkyloxy, preferably a methoxy, and a phenyl;
> Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C6)alkyloxy, preferably a methoxy, and a halogen, preferably a chlorine; and R4 represents a hydrogen.
A more preferred compound of formula (I) for use is such that:
> X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group;
> N is O; Ri represents an unsubstituted phenyl, a phenyl substituted by a methyl, a methyloxy, a pyridinyl, a benzothiazolyl, a thiazolyl substituted by a phenyl, and a cyclohexyl;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of a methoxy and a halogen, preferably a chlorine; and R4 represents a hydrogen
An even more preferred compound of formula (I) for use is such that:
> X represents represents a -NR5 group with R5 being a methyl;
> n is 0; Ri represents a phenyl;
> Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a methoxy, anda chlorine; and R4 represents a hydrogen.
A particular compound of formula (I) for use is selected in the group consisting of:
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one; - Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one; and
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one.
In an embodiment, X represents a methylene group (-CEE).
A preferred compound of formula (I) for use is such that:
> X represents a methylene group;
> n is 0; Ri represents a phenyl,
> Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C6)alkyloxy, preferably a methoxy, and R4 represents a hydrogen.
A particular compound of formula (I) for use is: Example #121. 6-methoxy-2-(2- phenylethyl)-3H-quinazolin-4-one.
In an embodiment, X represents a sulfur atom or a sulfone group.
A preferred compound of formula (I) for use is such that:
> X represents a sulfur atom or a sulfone group;
> n is 0; Ri represents a phenyl,
> Y represents a -CR2 group in which R2 is a hydrogen; R3 represents a radical selected in the group consisting of a (Ci-C6)alkyloxy, preferably a methoxy, and R4 represents a hydrogen.
A particular compound of formula (I) for use is: Example#25. 6-methoxy-2- (phenylsulfanylmethyl) -3H-quinazolin-4-one or Example #26. 2-(benzenesulfonylmethyl)-6- methoxy-3H-quinazolin-4-one.
In a particular aspect, the compound has an activity of ICD inducer. The activity can be determined by an assay measuring the Calreticulin release, the ATP secretion or the HMGB 1 release. The assays are well-known by the person skilled in the art. The methods for measuring calreticulin release and HMGB1 release are detailed in the example section. In a very specific aspect, the compound has an EC50 of less than 20 mM in a method measuring the calreticulin release, in particular as detailed in example B.
New compounds of the invention
The inventors have also provided new compounds and the stereoisomers, the tautomers, and the pharmaceutical salts thereof of formula (I) as above defined including all the particular and preferred embodiments.
More particularly, the inventors have provided new compounds and the tautomers and the stereoisomers, and the pharmaceutical salts thereof of formula (I):
Figure imgf000025_0001
wherein:
> X represents:
• an oxygen atom,
• a -NR5 group with Rs being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1, preferably equal to 0; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with R6 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl substituted by at least one halogen, a (Ci-C6)alkyloxy substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci-C6)alkyloxy, or a - NH-CO2-R8 with R8 being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen; with the proviso that the compound of formula (I) is not a compound selected in the group consisting of:
- 2-(4-chloro-phenoxymethyl)-6-methoxy-3H-quinazolin-4-one;
- 7-fluoro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one
- 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one.
In a preferred embodiment, Y represents a -CR2 group in which R2 is a hydrogen.
In a further preferred embodiment, R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a -NR6R7 with R6 and R7 being a methyl, and a halogen, preferably a chlorine.
Preferably, R3 represents a (Ci-C6)alkyloxy or a halogen, preferably a methoxy or a chlorine, more preferably a methoxy.
In a particular embodiment, a new compound of formula (I) is such that X represents an oxygen atom, and n, Ri, Y, R3, and R4 are such as above defined.
In a preferred embodiment, a new compound of formula (I) is such that:
> X represents an oxygen atom; and Ri represents a pyridinyl optionally substituted by at least a (Ci-C6)alkyl, preferably a methyl.
In a further particular embodiment, a new compound of formula (I) is such that X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group, and n, Ri, Y, R3, and R4 are such as above defined.
In a preferred embodiment, a new compound of formula (I) is such that:
> X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group; and Ri represents a phenyl optionally substituted by at least a halogen, a (Ci-C6)alkyl, preferably a methyl, or a (Ci-C6)alkyloxy, preferably a methoxy.
A further object of the invention is a new compound and, the tautomers, the stereoisomers, and the pharmaceutical salts thereof of formula (I):
Figure imgf000027_0001
in which :
> X represents:
• an oxygen atom,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1, preferably equal to 0; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a (Ci-C6)alkyl substituted by at least one halogen, a (Ci-C6)alkyloxy substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy substituted by a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci-C6)alkyloxy, or a - NH-CO2-R8 with R8 being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and It! represents a hydrogen; with the proviso that such a compound of formula (I) is not 6-methoxy-2-(phenoxymethyl)-3H- quinazolin-4-one.
In a preferred embodiment, Y represents a -CR2 group in which R2 is a hydrogen.
In a further preferred embodiment, R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a -NR6R7 with 5 and R7 being a methyl, and a halogen, preferably a chlorine.
Even more particularly, a new compound of formula (I) is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one; - Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one;;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one;
- Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one;
- Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
In a particular aspect, the compound has an activity of ICD inducer. The activity can be determined by an assay measuring the Calreticulin release, the ATP secretion or the HMGB 1 release. The assays are well-known by the person skilled in the art. The methods for measuring calreticulin release and HMGB1 release are detailed in the example section. In a very specific aspect, the compound has an EC50 of less than 20 mM in a method measuring the calreticulin release, in particular as detailed in example B.
Accordingly, the present invention relates to a new compound as defined herein, for use as a drug or a medicine. The present invention further relates to a pharmaceutical or veterinary composition comprising a new compound according to the invention. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of a new compound according to the invention as a drug or a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a new compound according to the invention, is administered to said subject in need thereof. The invention also relates to the use of a new compound according to the invention, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising a new compound according to the invention for use as a drug.
The compounds for use of formula (I) and the compounds of formula (I) as such according to the present invention can be prepared according to any chemical routes known from a skilled person, such as general synthetic routes presented in the examples. It is thus understood that one skilled in the art of organic chemistry can easily synthesize the compounds of formula (I) using appropriate starting materials, conventional chemicals reactions, standard and literatures procedures, and experimental conditions to synthesize the compounds of formula (I).
Therapeutic applications
As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds of the invention. Indeed, the inventors have shown that the compounds according to the present invention are capable of inducing ICD.
The present invention also concerns:
- a compound of formula (I) as defined above including anyone of the disclosed embodiments or a pharmaceutical composition comprising such compound for treating or for use for treating a cancer; and/or
- a pharmaceutical composition comprising a compound of formula (I) as defined above including anyone of the disclosed embodiments, and an additional antitumor drug, for the treatment of cancer or for use in the treatment of cancer; and/or
- a compound of formula (I) or a pharmaceutical composition comprising such a compound, for treating cancer or for use for treating cancer in combination with radiotherapy, hyperthermia and/or other antitumor therapies, optionally before, simultaneously and/or after surgery (e.g., tumor resection); and/or
- a kit comprising (a) a compound of formula (I) as defined above including anyone of the disclosed embodiments; and (b) an additional antitumor drug as a combined preparation for simultaneous, separate or sequential use, for treating cancer or for use for treating a cancer; and/or
- the use of a compound of formula (I) as defined above including anyone of the disclosed embodiments or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the treatment of a cancer; and/or
- the use of a pharmaceutical composition comprising a compound of formula (I) as defined above including anyone of the disclosed embodiments, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the treatment of a cancer; and/or
- the use of a compound of formula (I) as defined above including anyone of the disclosed embodiments, for the manufacture of a medicament, a medicine or a drug for the treatment of a cancer in combination with radiotherapy, hyperthermia and/or other antitumor therapies, optionally before, simultaneously and/or after surgery (e.g., tumor resection); and/or
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein; - a method for inducing ICD, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutical composition comprising such a compound; in a particular aspect the subject has a cancer and the ICD induction by the compound promotes cancer treatment;
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition comprising such a compound.
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition comprising such a compound, and an additional antitumor drug;
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition comprising such a compound; the method further comprises radiotherapy, hyperthermia and/or other antitumor therapies, optionally before, simultaneously and/or after surgery (e.g., tumor resection).
The term “cancer”, as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. The cancer may be solid tumor or hematopoietic tumor. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis. In a particular aspect, the cancer is selected from the group consisting of colorectal, breast, ovarian, pancreatic, gastric, prostate, renal, cervical, myeloma, lymphoma, leukemia, thyroid, endometrial, uterine, bladder, neuroendocrine, head and neck, liver, nasopharyngeal, testicular, small cell lung cancer, non small cell lung cancer, melanoma, basal cell skin cancer, squamous cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, glioblastoma, glioma, sarcoma, mesothelioma, and myelodisplastic syndromes. The administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumoral or parenteral (including subcutaneous, intramuscular, intravenous and/or intradermal). Preferably, the administration route is parental, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.
The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
Preferably, the treatment with the compound according to the invention or the pharmaceutical composition according to the invention start no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a most preferred embodiment, the treatment starts the day of the diagnosis. The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses.
Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.
The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient.
In a preferred embodiment, the total compound dose for each administration of the compound according to the invention or of the pharmaceutical composition according to the invention is comprised between 0.00001 and 1 g, preferably between 0.01 and 10 mg.
The form of the pharmaceutical compositions, the route of administration and the dose of administration of the compound according to the invention, or the pharmaceutical composition according to the invention can be adjusted by the man skilled in the art according to the type and severity of the disease, and to the patient, in particular its age, weight, sex, and general physical condition.
In one embodiment, the compound of the invention can be used in combination with another antitumoral drug or antineoplastic agent.
The additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor, and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions. Antimitotic agents include, but are not limited to, Paclitaxel, Docetaxel and analogs such as Larotaxel (also called XRP9881; Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer- Squibb), Ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131 ; Bristol-Meyer-Squibb), RPR 109881 A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT-287 (TAPESTRY), PG-Paclitaxel (also called CT-2103, PPX, Paclitaxel Poliglumex, Paclitaxel Polyglutamate or XyotaxTM), ABRAXANE® (also called Nab-Paclitaxel ; ABRAXIS BIOSCIENCE), Tesetaxel (also called DJ-927), IDN 5390 (INDENA), Taxoprexin (also called Docosahexanoic acid-Paclitaxel; PROTARGA), DHA-Paclitaxel (also called Taxoprexin®), and MAC-321 (WYETH). Preferably, antimitotic agents are Docetaxel, Paclitaxel, and is more preferably Docetaxel.
Inhibitors of topoisomerases I and/or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as Doxorubicin, Epirubicin, Daunorubicin, Idarubicin and Mitoxantrone. Inhibitors of Topoisomerase I and II include, but are not limited to Intoplicin.
The additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes. Non- exhaustive examples thereof include Uracil mustard, Chlormethine, Cyclophosphamide (CYTOXAN(R)), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Cisplatin, Carboplatin, Fotemustine, Oxaliplatin, Thiotepa, Streptozocin, Dacarbazine, and Temozolomide. In a preferred embodiment, the DNA alkylating agent is preferably Cisplatin, Fotemustine or Dacarbazine.
Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis. Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly Methotrexate, Floxuridine, Cytarabine, 6-Mercaptopurine, 6- Thioguanine, Fludarabine phosphate, Pentostatine, 5-Fluorouracil, Gemcitabine and Capecitabine.
The additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor. The kinase may be selected from the group consisting of intracellular tyrosine or serine/threonine kinases, receptors tyrosine or serine/theonine kinase. The kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR. For instance, the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases. In particular, the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec, which inhibits Abl, and Iressa and Tarceva, which both inhibit EGFR, Sorafenib (Nexavar, BAY 43-9006) which inhibits Raf, Dasatinib (BMS-354825) and Nilotinib (AMN-107, Tasigna) which also inhibits Abl, Lapatinib which also inhibits EGFR, Temsirolimus (Torisel, CCI-779) which targets the mTOR pathway, Sunitinib (Stuten, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin and Avastin. The anti-EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, preferably is Erlotinib or Cetuximab. The ALK inhibitor can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib. The B-raf inhibitor can be selected among Vemurafenib, dabrafenib, regorafenib, and PLX4720. The MEK inhibitor can be selected among Cobimetinib, Trametinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733.
The additional drug can also be a checkpoint inhibitor, for instance an antibody targeting PD- 1, PD-L1, CTLA-4 and the like.
Hyperthermia is a medical treatment in which is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anti cancer drugs. There are many techniques, well-known by the one skilled in the art, by which heat may be delivered. Some of the most common involve the use of focused ultrasound (FTiS or HIFTi), infrared sauna, microwave heating, induction heating, magnetic hyperthermia, infusion of warmed liquids, or direct application of heat such as through sitting in a hot room or wrapping a patient in hot blankets.
Further aspects and advantages of the invention will be disclosed in the following experimental section.
EXAMPLES
EXAMPLE A - CHEMTSTRY
Abbreviations
AcOH Acetic acid ACN Acetonitrile Aq Aqueous br s Broad singlet
Cs2C03 Cesium Carbonate CDCL Deuterated chloroform d Doublet
DAD Diode Array Detector
DCM Dichloromethane (methylene chloride) dd Doublet of doublets ddd Doublet of doublets of doublets
DIAD N, A-Di isopropyl azodi carb oxy 1 ate
DIEA N, A-Dii sopropy 1 ethyl amine
DMF A A-Di methyl form amide
DMSO Dimethyl sulfoxide dt Doublet of triplets eq Equivalent
EtOAc Ethyl acetate
Et20 Diethyl ether
EtOH Ethanol g Gram(s) h Hour(s)
H2SO4 Sulfuric acid
HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3 -oxide hexafluorophosphate or Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium
HC1 Hydrochloric acid
HCOOH Formic acid
HPLC High-pressure liquid chromatography
/-PrOH Isopropanol
K2CO3 Potassium carbonate
LC/MS Liquid chromatography/mass spectrometry
Li OH Lithium Hydroxide m Multiplet
M Molar w-CPBA 3-chloroperbenzoic acid
MeOH Methyl alcohol
MgS04 Magnesium sulfate min Minute(s)
MHz MegaHertz mg Milligram(s) mL Millilitre(s) mmol Millimole mol/L Mole(s)/L
M Molar
MS Mass spectrometry
MsCl Methanesulfonyl chloride
MW Microwave mp melting point
NH4CI Ammonium chloride
N Normal
NaH Sodium hydride NaHCCri Sodium bicarbonate NiCl2, 6H2O Nickel(II) chloride hexahydrate NMR Nuclear magnetic resonance
P para
Pd2(dba)3 Bis(dibenzylidenacetone)palladium(0)
Pd(OAc)2 Palladium acetate
PDA Photodiode Array
PPh Triphenylphosphine ppm Parts per million q Quadruplet quant Quantitative quint Quintuplet
RP-HPLC Reverse-phase high-pressure liquid chromatography
Rt Retention time rt Room temperature s Singlet
S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl t Triplet tBuOK Potassium ter-butoxide td Triplet of doublets
TEA Triethylamine
TFA Trifluoroacetic acid tert- Tertiary THF Tetrahydrofuran
General Synthetic Schemes
Compounds of the invention may be prepared using the synthetic transformations illustrated in Schemes II, III, IV, VIII, IX, X, XI, and XII. Starting materials are commercially available or may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one skilled in the art of organic chemistry. Unless stated, all aqueous solutions are saturated.
In Scheme II, the intermediate 3, can undergo a nucleophilic substitution reaction with various anilines 6 (Scheme I, step b) using similar conditions such as those described in Example #1 using an appropriate base and solvent such as K2CO3 in EtOH, or by methods known to one skilled in the art (for example European Journal of Medicinal Chemistry , 2012, 48, 231-243) to provide the 2-(anilinomethyl)-3H-quinazolin-4-one 7.
Scheme II:
Figure imgf000039_0001
Heterocyclic amines 9 can be be prepared according to Scheme III by nucleophilic substitution of R2 substituted heterocyclic amines 8 onto chloromethylquinazolinone 3 using similar conditions such as those described in Example #1 using an appropriate base and solvent such as K2CO3 in EtOH, or by methods known to one skilled in the art (for example, PCT Int. Appl. 2009, W02009086264).
Scheme III:
Figure imgf000039_0002
In Scheme IV, Heterocyclic amines 13 can also be prepared from nucleophilic substitution on haloheterocycle 12 by amimomethylquinazolinone 11. This aminomethylquinazolinone is prepared in 2 steps from chloromethylquinazolinone 3 by first nucleophilic substitution of chloride by azide using sodium azide using an appropriate solvent and temperature (Scheme IV, step a) or by methods known to one skilled in the art (for example A. Mohamed et al 2017, Monatshefte fiir Chemie, 148(8), 1513-1523) then transformation into the primary amine 11 (Scheme IV, step b) by Staudinger type reduction such as using triphenylphosphine in appropriate solvent and water or by methods known to one skilled in the art (for example A. Lindgren et al ; 2013, Journal of Medicinal Chemistry, 56(23), 9556-9568)
Scheme IV:
Figure imgf000040_0001
Substitution R1 on quinazolinone ring can be placed by functionalization of the anthranilic acid. If anthranilic acids 1 are commercially not available they can be prepared by methods known in the art and as described in literature, for example in Organic Preparations and Procedures International, 1981, 13(3-4), 189-96.
Substitution R1 on quinazolinone can also be placed by further functionalization of 2- (aminomethyl)-3H-quinazolin-4-one compounds 7, 9 and 13.
In scheme VIII, phenol ether derivatives 26 are prepared using conditions described in Example #28 by reacting phenol dervatives 25 with an appropriate base and solvent such as NaH in DMF or by methods known to one skilled in the art (for example, U.S. Pat. Appl. 2012, US20120094997) (Scheme VIII, step a). In a similar manner, thiophenol derivatives 28 are prepared using conditions described in Example #25 by reacting thiophenol dervatives 27 with an appropriate base and solvent such as NaH in DMF or by methods known to one skilled in the art (for example, K. Junwon et al 2014, Bioorganic & Medicinal Chemistry Letters, 24(23), 5473-5477) (Scheme VIII, step b). The thiophenol ether 28 can be further transformed into sulfone 29 by oxidation using m- CPBA in DCM or by methods known to one skilled in the art (for example, R.A. Devender et al, 1986, Indian Journal of Pharmaceutical Sciences, 48(1), 13-15) (Scheme VIII, step c).
Scheme VIII:
Figure imgf000041_0001
In scheme IX, preparation of heterocyclic ether 31 is performed by simple nucleophilic substitution of chloromethylquinazolinone 3 using conditions described in Example #28 by reacting heterocyclic phenol derivatives 30 with an appropriate base and solvent such as NaH in DMF or by methods known to one skilled in the art (for example, U.S. Pat. Appl. 2016, US20160122343) (Scheme IX, step a).
Scheme IX:
Figure imgf000041_0002
In Scheme X, Heterocyclic ether 31 can also be prepared from heteroaryloxy acetonitriles 32 using conditions described in Example #107 by reacting anthranilic acid derivatives 1 with an appropriate base and solvent such as K2CO3 in EtOH. The heteroaryloxy acetonitriles 32 are itself prepared by phenol alkylation of heterocyclic phenols 30 with chloroacetonitrile 2 with an appropriate base and solvent such as CS2CO3 in ACN, or by methods known to one skilled in the art (for example in PCT Int. Appl.2014, W02014012360).
Scheme X:
Figure imgf000042_0001
In Scheme XI, Heterocyclic ether 31 can also be prepared by Nucleophilic substitution reaction onto heterocyclic halide 12 using conditions described in Example #113 by reacting quinazolinone methylene alcohol 35 with an appropriate base and solvent such as NaH in 1,4-dioxane or by methods known to one skilled in the art (for example in PCT Int. Appl.2016, WO2016161176) (Scheme XI, step d). This synthetic route requires protection of the quinazolinone NH by a protecting group such as SEM. NH protected quinazolinone methylene alcohol 35 illustrated in Preparation #9 is then prepared in 3 steps from chloromethylquinazolinone 3 by first substitution of chloride by acetate group (Scheme XI, step a) with an appropriate base and solvent such as CS2CO3 in DMF, or by methods known to one skilled in the art (for example in GB Patent Appl. 1994, GB2271111). Quinazolinone NH is then protected by a protecting group such as SEM by reacting with 2- (trimethylsilyl) ethoxymethyl chloride and an appropriate base and solvent such as DIEA in DCM or by methods known to one skilled in the art (for example N. Kohyama, Y. Yamamoto, 2003, Synthesis, (17), 2639-2642) to provide protected alcohol and NH intermediate 34 (Scheme XI, step b). Depotection of alcohol from acetate 34 is performed (Scheme XI, step c) with an appropriate base and solvent such as K2CO3 in MeOH, or by methods known to one skilled in the art (for example X. Song et al, 2004, Journal of Organic Chemistry, 69(19), 6474-6477) to provide the desired NH protected quinazolinone methylene alcohol 35 Eventually the ether coupling product 36 illustrated with Example #113 is deprotected in acidic condition such as HC1 4N in 1,4-dioxane or by methods known to one skilled in the art (for example, U.S. Pat. Appl. 2010, US20100204226) to provide ether 31 (Scheme XI, step e).
Scheme XI:
Figure imgf000043_0001
In Scheme XII, Heterocyclic ether 31, providing they bear a chloro, bromo or iodo or any group allowing metal catalysed reactions such as triflate, mesilate group as example such as decribed for intermediate 37, can be further functionalized on the aromatic ring of quinazolinone bicyclic system. Hence, aniline 38 as illustrated in Example #111 is prepared by pallado-catalyzed reaction between the bromoaryl substrate 37 with cyclic amines 20 in presence of tBuOK as base, X-Phos and Pd2dba3 as source of palladium or by methods known to one skilled in the art (see for example PCT Int. Appl.2011, WO2011045258).
Scheme XII:
Figure imgf000043_0002
Analytical Methods Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all 'H NMR data were collected on a Bruker DPX 300MHz equiped with 5mm BB(0)F GRADZ probe, Bruker AVIII 400MHz equiped with 5mm BB(0)F GRADZ probe or Bruker AVIII 500MHz equiped with 5mm BBI GRADZ probe instruments and chemical shifts are quoted in parts per million (ppm). LC/MS was performed on HPLC Agilent 110 series instrument with a PDA detector from 1100 series coupled to Waters ZQ mass spectrometer, UPLC Acquity Waters with a PDA Acquity detector and a SQ Acquity mass spectrometer or a Shimadzu UFLC-XR system coupled to a LCMS-IT-TOF mass spectrometer. LC/MS data is referenced to LC/MS conditions using the method number provided in Table 1.
Table 1. LC/MS analysis methods
Figure imgf000044_0001
Purification Methods
For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include flash chromatography with a solid phase (i.e. silica gel, alumina, etc.) and a solvent (or combination of solvents, i.e. heptane, EtOAc, DCM, MeOH, ACN, water, etc.) that elutes the desired compounds; RP- HPLC purification performed on Waters system including a 2525 binary Pump, a ZQ Mass spectrometer, two 515 pumps, a PDA detector and a 2767 Autosampler, managed by MasslynX/fractionlynx (see Table 2 for some non-limiting conditions); recrystalization from an appropriate solvent (i.e. MeOH, EtOH, z-PrOH, EtOAc, toluene, etc.) or combination of solvents (i.e. EtOAc/heptane, EtOAc/MeOH, etc.); precipitation from a combination of solvents (i.e. DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with an appropriate solvent (i.e. EtOAc, DCM, ACN, MeOH, EtOH, z-PrOH, //-PrOH, etc.); extraction by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (i.e. DCM/water, EtOAc/water, DCM/saturated NaHC03, EtOAc/saturated NaHC03, DCM/10% aqueous HC1, EtOAc/10% aqueous HC1, etc.); distillation (i.e. simple, fractional, Kugelrohr, etc.). Descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist’s Companion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”, 2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 75, 2923; Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “Experimental Organic Chemistry: Standard and Microscale, 2nd Edition”, 1999. Table 2. RP-HPLC and Chiral purification methods
Figure imgf000045_0002
Preparation #8: 6-bromo-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000045_0001
2-(3-Pyridyloxy) acetonitrile (CAS RN 266348-17-8, 931 mg; 6.94 mmol; 3.00 eq.) was dissolved in MeOH (6.00 mL) under N2 atm and the solution was cooled in an ice bath at 10°C. Sodium methoxide (25 mg; 0.46 mmol; 0.20 eq.) was added and the solution was stirred for 40 min at 10°C. A solution of 2-amino-5-bromobenzoic acid (CAS RN 5794-88-7, 500 mg; 2.31 mmol; 1.00 eq.) in MeOH (6 mL) was quickly added. Ice bath was removed and the mixture was stirred at rt for 24h.The reaction mixture was diluted with 20 mL of H2O and filtered. The solid was washed with H2O three times, 4mL of ACN once and Et20 three times, dried under reduced pressure for 2 days to give 6-bromo-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (567 mg, 69%) as a beige solid. 1H MR (DMSO-d6) d: 12.71 (br s, 1H), 8.42 (d, J = 3.0 Hz, 1H), 8.22 (dd, J = 1.3, 4.6 Hz, 1H) 8.20 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 2.2, 8.8 Hz, 1H), 7.62 (dd, J = 0.4, 8.8 Hz, 1H), 7.50 (ddd, J = 1.3, 3.0, 8.6
Hz, 1H), 7.36 (ddd, J = 0.4, 4.6, 8.4 Hz, 1H), 5.10 (s, 2H). LC/MS (Table 1, Method A) Rt = 1.96 min; MS m/z: 332 [M+H]+.
Preparation #9: 2-(hydroxymethyl)-6-methoxy-3-(2-trimethylsilylethoxymethyl)quinazolin-4- one Step A: (6-methoxy-4-oxo-3H-quinazolin-2-yl)methyl acetate
Figure imgf000046_0001
2-(Chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 5 g; 22.3 mmol; 1.00 eq.) and CS2CO3 (15.85 g; 82.58 mmol; 3.71 eq.) were dissolved in DMF (140 mL). The resulting white suspension was stirred at 95°C for lh30. The mixture was poured into 100 mL of a saturated aqueous solution of NH4CI to give a white precipitate. It was filtered, washed three times with water, three times with Et20 and dried. Filtrate was extracted once with 100 mL and twice with 50 mL of EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated in vacuum to give: ( 6-methoxy-4-oxo-3H-quinazolin-2-yl)methyl acetate (4.67 g, 75 %) as a yellow amorphous powder. LC/MS (Table 1, Method A) Rt = 1.80 min; MS m/z: 249 [M+H]+.
Step B: [6-methoxy-4-oxo-3-(2-trimethylsilylethoxymethyl)quinazolin-2-yl] methyl acetate
Figure imgf000046_0002
(6-Methoxy-4-oxo-3H-quinazolin-2-yl)methyl acetate (Preparation #9, Step A, 4.67 g; 16.7 mmol; 1.00 eq.) was dissolved in DCM (134 mL). DIPEA (6.09 mL; 36.84 mmol; 2.20 eq.) and 2- (trimethylsilyl) ethoxymethyl chloride (CAS RN 76513-69-4, 3.56 mL; 20.09 mmol; 1.20 eq.) were added, then the cloudy white mixture was stirred at rt overnight. Mixture was washed with 100 mL of H2O. Aqueous layer was extracted twice with 100 mL of DCM. The combined organic layers were dried over MgSCL, filtered and concentrated. Acetic acid (0.96 mL; 0.02 mol; 1.00 eq.) was added and the reaction was stirred at rt for 2h30 to remove the O-SEM protecting group on the by product. Mixture was extracted with 100 ml of DCM (three times). The combined organic layers were dried over MgSCL, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 0 to 30% EtOAc in cyclohexane) to give [6-methoxy-4-oxo-3-(2- trimethylsilylethoxymethyl)quinazolin-2-yl]methyl acetate (2.25 g, 35.5 %) as a pale yellow oil. 'H NMR (DMSO-d6) d: 7.60 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 3.0 Hz, 1H), 7.45 (dd, J = 3.0, 8.9 Hz, 1H), 5.54 (s, 2H), 5.27 (s, 2H), 3.88 (s, 3H), 3.59-3.64 (m, 2H), 2.16 (s, 3H), 0.84-0.94 (m, 2H), -0.04 (s, 9H). LC/MS (Table 1, Method A) Rt= 2.93 min; MS m/z: 379 [M+H]+.
Step C : 2-(hydroxymethyl)-6-methoxy-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one
Figure imgf000047_0001
[6-Methoxy-4-oxo-3-(2-trimethylsilylethoxymethyl)quinazolin-2-yl]methyl acetate
(Preparation #9, Step B, 2.25 g; 5.93 mmol; 1.00 eq.) was dissolved in MeOH (27.5 mL) and K2CO3 (1.23 g; 8.92 mmol; 1.50 eq.) was added. The mixture was stirred at rt, under N2 atm, for 45 min. Mixture was diluted in 100 mL of H2O to give a white precipitate. It was filtered, washed three times with H2O and dried to give 2-(hydroxymethyl)-6-methoxy-3-(2- trimethylsilylethoxymethyl)quinazolin-4-one (1.95 g; 97.5 %) as a white amorphous powder. 1HNMR
(DMSO-d6) d: 7.64 (dd, J = 0.3, 9.2 Hz, 1H), 7.54 (d, J = 2.9 Hz, 1H), 7.45 (dd, J = 2.9, 8.9 Hz, 1H), 5.65 (s, 1H), 5.62 (s, 2H), 4.61 (s, 2H), 3.88 (s, 3H), 3.59-3.65 (m, 2H), 0.85-0.90 (m, 2H), -0.05 (s, 9H). LC/MS (Table 1, Method A) Rt = 2.71 min; MS m/z: 337 [M+H]+.
Preparation #10: 6-chloro-2-(chloromethyl)quinazolin-4(3H)-one
Figure imgf000047_0002
Sodium methoxide (30 wt% solution in MeOH) (1.513 ml, 8.17 mmol) was added dropwise to a solution of chloroacetonitrile (7.74 ml, 123 mmol) in MeOH (30 mL) cooled to 10 °C and the solution was stirred for 50 minutes at room temperature. A solution of 2-amino-5-chlorobenzoic acid (7.01 g, 40.9 mmol) in MeOH (100 mL) was then slowly added and the mixture was left to stir at room temperature for 3 h. The reaction mixture was then diluted with water 50 mL, and the resulting precipitate was filtered, washed with water (20 mL), cold MeOH (15 mL) and dried under reduced pressure to give 6-chloro-2-(chloromethyl)quinazolin-4(3H)-one (6.79 g, 72.6 %) as a colourless powder. MS (ES+): 229/331 (M+H)+
Example #1. 2-(indolin-l-ylmethyl)-6-methoxy-3H-quinazolin-4-one (illustrative) A mixture of 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 450 mg; 2.00 mmol; 1.00 eq.), indoline (CAS RN 496-15-1, 0.27 mL; 2.40 mmol; 1.20 eq.) and K2CO3 (415 mg; 3.00 mmol; 1.50 eq.) in EtOH (9 mL) was stirred at 80°C overnight. Reaction mixture was diluted with H2O and extracted with EtOAc three times. The combined organic layers were dried over MgS04, filtered and concentrated. The residue was purified by column chromatography (0 to 50% of EtOAc in cyclohexane) to give 2-(indolin-l-ylmethyl)-6-methoxy-3H- quinazolin-4-one (283 mg; 46 %) as a white amorphous powder. 'H NMR (400 MHz, DMSO-d6) d = 12.24 (br s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.40 (dd, J = 3.0, 8.9 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.98 (dt, J = 1.0, 7.7 Hz, 1H), 6.61 (dt, J = 1.0, 7.3 Hz) 6.59 (d, J = 7.7 Hz,
1H), 4.17 (s, 2H), 3.87 (s, 3H), 3.49 (t, J = 8.3 Hz, 2H), 2.93 (t, J = 8.3 Hz, 2H). LC/MS (Table 1, Method B) Rt = 1.43 min; MS m/ 308 [M+H]+.
Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one
Figure imgf000048_0001
The compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) and N-methylaniline (CAS RN 100-61-8, 53 pL; 0.49 mmol; 1.10 eq.). The residue was purified by column chromatography (0 to 30% of EtOAc in DCM) giving 6-methoxy-2-[(N- methylanilino)methyl]-2H-quinazolin-4-one (60 mg; 45 %) as a white amorphous powder. mp=206- 211°C. ¾ MR (400 MHz, DMSO-de) d = 12.15 (br s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.36 (dd, J = 3.0, 8.9 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.75 -6.72 (m, 2H), 6.67 - 6.60 (m, 1H), 4.46 (s, 2H), 3.85 (s, 3H), 3.11 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.39 min; MS m/r 296 [M+H]+. Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one
Figure imgf000048_0002
Thiophenol (CAS RN 108-98-5, 182 pL; 1.78 mmol; 2.00 eq.) was dissolved in DMF (2 mL), then the reaction mixture was cooled down to 0°C and NaH (60% in oil) (85 mg; 2.13 mmol; 2.40 eq.) was added. The reaction mixture was stirred at 0°C under N2 atm. After 30 min at 0°C, the temperature was raised to rt and 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 200 mg; 0.89 mmol; 1.00 eq.) was added. The mixture was stirred at rt overnight. The reaction was quenched by addition of H2O, and the solid was filtered, rinsed with Et20. The residue was purified by column chromatography (0 to 100% EtOAc in cyclohexane) to give 6-methoxy-2- (phenylsulfanylmethyl)-3H-quinazolin-4-one (120 mg; 44. %) as a white amorphous powder. 'H NMR (400 MHz, DMSO-de) d = 12.33 (br s, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 2.9 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.38 (dd, J = 3.0, 8.9 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 4.11 (s, 2H), 3.86 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.34 min; MS m/r 299 [M+H]+.
Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one
Figure imgf000049_0001
A solution of 3-chloroperbenzoic acid (90 mg; 0.52 mmol; 2.00 eq.) in DCM (2 mL) was added slowly to 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one, (Example #25), (80 mg; 0.26 mmol; 1.00 eq.) in DCM (3 mL) at 0°C and the mixture was stirred at rt for 18h. 3- chloroperbenzoic acid (223 mg; 0.13 mmol; 0.50 eq.) was added and stirring was maintained at rt for 4h. A saturated aqueous solution of NaHCC was added and stirring was maintained for 30 min. The layers were separated, the aqueous layer was extracted with EtOAc three times. The organic layer was washed with an aqueous solution of NaHC03, dried on MgS04, filtered and concentrated. The residue was purified by column chromatography (0 to 2% of MeOH in DCM) to give 2- (benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one (69 mg; 80%) as a white amorphous powder. mp= 201-226°C. ¾ NMR (400 MHz, DMSO-de) d = 12.34 (s, 1H), 7.84 - 7.80 (m, 2H), 7.79 - 7.74 (m, 1H), 7.66 - 7.60 (m, 2H), 7.48 (dd, J = 0.9, 2.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 4.66 (s, 2H), 3.87 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.13 min; MS m/ 331 [M+H]+.
Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one (CAS RN 387346-90-9) Example #28. 2- [(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one
Figure imgf000050_0001
2-Fluorophenol (CAS RN 367-12-4, 119 pL; 1.34 mmol; 2.00 eq.) was dissolved in DMF (4.50 mL). The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (67 mg; 1.67 mmol; 2.50 eq.) was added. The reaction mixture was stirred at 0°C for 45min. 2-(chloromethyl)-6- methoxy-3H-quinazolin-4-one (CAS n°1263413-60-0, 150 mg; 0.67 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt until completion. The reaction mixture was diluted in H2O and extracted with EtOAc three times. The organic layer was washed with water twice then with brine. The organic layer was dried over MgSCri, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (5 to 40% of EtOAc in cyclohexane) giving 2-/(2- fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (63 mg; 31 %) as a white amorphous powder. mp=204-208°C. ¾NMR (400 MHz, DMSO-de) d = 12.50 (s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.18 - 7.11 (m, 1H), 7.04 - 6.95 (m, 1H), 5.03 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.32 min; MS m/r. 301
[M+H]+.
Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one
Figure imgf000050_0002
3-phenoxyphenol (CAS RN 713-68-8, 215 pL; 1.34 mmol; 3.01 eq.) was dissolved in DMF
(1.00 mL). The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (53 mg; 1.33 mmol; 3.00 eq.) was added. The reaction mixture was stirred at 0°C for 30 min. 2-(chloromethyl)-6- methoxy-3H-quinazolin-4-one (CAS n°1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt until completion. The reaction mixture was diluted in H2O was added and mixture was stirred at rt for 30 min to give a white solid. It was filtered, washed three times with H2O and three times with Et20. The residue was purified by column chromatography (0 to 20% of EtOAc in DCM) giving 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one (98 mg; 59 %) as a white amorphous powder. mp=192-196°C. ¾ NMR (400 MHz, DMSO-d6) d = 12.44 (br s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.31 (t, J = 8.3 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.04 - 6.98 (m, 2H), 6.83 (ddd, J = 0.8, 2.4, 8.3 Hz, 1H), 6.71 (t, J = 2.4 Hz, 1H), 6.60 (ddd, J = 0.8, 2.4, 8.3 Hz, 1H), 4.97 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.67 min; MS m/r 375 [M+H]+.
Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one
Figure imgf000051_0001
The compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) and 3-chlorophenol (CAS RN 108-43-0, 0.34 mL; 3.35 mmol; 3.01 eq.). The residue was purified by column chromatography (0 to 25% of EtOAc in DCM) giving 2-[(3- chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (143 mg; 38.5 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-de) d = 12.47 (br s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.39 (dd, J = 3.0, 8.9 Hz, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.17 (t, J = 2.2 Hz, 1H), 7.06 - 7.01 (m, 2H), 4.99 (s, 2H), 3.87 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.48 min; MS m/ 317 [M+H]+.
Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one
Figure imgf000051_0002
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) and 3-fluorophenol (CAS RN 372-20-3, 80 pL; 0.88 mmol; 1.99 eq.). The residue was purified by column chromatography (0 to 20% of EtOAc in DCM) giving 2-[(3- fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (28 mg; 21 %) as a white amorphous powder. mp=204-210°C. ¾ NMR (400 MHz, DMSO-de) d = 12.44 (br s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.35 (dt, J = 7.1, 8.3 Hz, 1H), 6.97 (td, J
= 2.4, 11.2 Hz, 1H), 6.91 (ddd, J= 0.7, 2.4, 8.3 Hz, 1H), 6.86 - 6.78 (m, 1H), 5.00 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.36 min; MS m/z: 301 [M+H]+.
Example #32. 2- [(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one
Figure imgf000052_0001
The compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) and 3-bromophenol (CAS RN 591-20-8, 0.35 mL; 3.35 mmol; 3.01 eq.). The residue was purified by column chromatography (0 to 25% of EtOAc in cyclohexane) giving 2-[(3- bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one (188 mg; 43.5 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-de) d = 12.46 (br s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.32 (t, J = 2.2 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.21 - 7.15 (ddd, J = 0.9, 1.8, 8.1 Hz, 1H), 7.08 (ddd, J = 0.9, 2.2, 8.1 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.51 min; MS m/r. 362 [M+H]+.
Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one
Figure imgf000052_0002
The compound was synthesized using the same procedure detailed in Example #29 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 200 mg; 0.45 mmol; 1.00 eq.) and 3 -(trifluorom ethoxy )phenol (CAS RN 827-99-6, 0.17 mL; 1.32 mmol; 3.00 eq.). The residue was purified by column chromatography (0 to 20% of EtOAc in DCM) giving 6-methoxy- 2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one (77 mg; 47 %) as a white amorphous powder. mp=196-20PC. ¾ NMR (400 MHz, DMSO-de) d = 12.48 (br s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.14 - 7.09 (m, 2H), 6.99 (tdd, J = 1.0, 2.1, 8.2 Hz, 1H), 5.04 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.60 min; MS m/r. 367 [M+H]+.
Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one
Figure imgf000053_0001
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 200 mg; 0.45 mmol; 1.00 eq.) and 2-methyl-l,3-benzoxazol-4-ol (CAS RN 51110-60-2, 133 mg; 0.89 mmol; 2.00 eq.). The residue was purified by column chromatography (20 to 80% of EtOAc in DCM) giving 6- methoxy-2- [(2-methyl- l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one (18 mg; 12 %) as a beige amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.53 (br s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 8.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.01 (dd, J= 2.8,
6.3 Hz, 1H), 5.22 (s, 2H), 3.88 (s, 3H), 2.59 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.25 min; MS z: 338 [M+H]+.
Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one
Figure imgf000053_0002
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 500 mg; 2.23 mmol; 1.00 eq.) and 3-hydroxy-6-methylpyridine (CAS RN 1121-78-4, 486 mg; 4.45 mmol; 2.00 eq.). The residue was purified by preparative LC-MS (Table 2, conditions 3) (column: X Bridge C 18,30 x 150 mm 5 pm (Waters); flow rate: 42 mL/min; Mobile phase: H2O with 0.1% of AcOH /
ACN with 0.1% of AcOH; gradient : 15 to 20%; run 30min) giving 6-methoxy-2 -[(6-methyl- 3- pyridyljoxymethyl l-3H-quinazolin-4-ox\e (11 mg; 2 %) as a white amorphous powder. 'H NMR (400 MHz, DMSO-de) d = 12.45 (br s, 1H), 8.26 (d, J = 2.9 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 3.0, 8.9 Hz, 1H),7.39 (dd, J = 2.9, 8.6 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 5.02 (s, 2H), 3.87 (s, 3H), 2.39 (s, 3H). LC/MS (Table 1, Method B) Rt = 0.81 min; MS m/r. 298 [M+H]+.
Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one
Figure imgf000054_0001
1H NMR (DMSO-d6, 500 MHz) d 12.40 (1H, s), 8.03 (1H, d), 7.79 (1H, dd), 7.58 (1H, d), 7.22 - 7.11 (2H, m), 6.78 - 6.71 (2H, m), 6.65 (1H, t), 4.50 (2H, s), 3.12 (3H, s). MS (ES+): 300/302 (M+H)+
Example #66. 6-chloro-2- [(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one
Figure imgf000054_0002
The compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.) and N,3-dimethylaniline (CAS RN 696-44-6, 90 pL; 0.72 mmol; 1.10 eq.). The residue was purified by column chromatography (5 to 40% of EtOAc in cyclohexane) giving 6-chloro-2-[(N,3- dimethylanilino)methyl]-3H-quinazolin-4-one (114 mg; 55 %) as a white amorphous powder. 'H NMR (400 MHz, DMSO-de) d = 12.37 (br s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.78 (dd, J = 2.5, 8.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.58 (s, 1H), 6.52 (dd, J = 2.4, 8.3 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 4.47 (s, 2H), 3.09 (s, 3H), 2.21 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.67 min; MS m/z: 314 [M+H]+.
Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one
Figure imgf000054_0003
1H NMR (500 MHz, DMSO-d6) d 8.22 - 8.19 (m, 1H), 8.19 - 8.15 (m, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.75 (dd, 1H), 7.61 (dd, 1H), 7.43 (dd, 1H), 7.29 (d, 1H), 7.21 - 7.16 (m, 1H), 5.45 (s, 2H), 2.79 (d, 3H). MS (ES+): 301/303 (M+H)+
Example #68. 6-chloro-2- [(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one
Figure imgf000055_0001
The compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.) and N-methyl-p-toluidine (CAS RN 623-08-5, 90 pL; 0.72 mmol; 1.10 eq.). The residue was purified by column chromatography (0 to 30% of EtOAc in cyclohexane) giving 6-chloro-2-[(N,4- dimethylanilino)methyl]-3H-quinazolin-4-one (51 mg; 25 %) as a white amorphous powder. 1H MR (400 MHz, DMSO-de) d = 12.35 (br s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.78 (dd, J = 2.5, 8.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 8.7 Hz, 2H), 4.44 (s, 2H), 3.07 (s, 3H), 2.15 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.68 min; MS m/r. 314 [M+H]+.
Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one
Figure imgf000055_0002
2-(phenylamino)ethanol (0.083 ml, 0.668 mmol) was added to a mixture of 6-chloro-2- (chloromethyl)quinazolin-4(3H)-one (0.102 g, 0.445 mmol) and potassium carbonate (0.185 g, 1.336 mmol) in EtOH (10 mL). The mixture was stirred at 50 °C overnight, then flushed with nitrogen and stirred at 70 °C for a futher 48 h. The mixture was cooled to room temperature, diluted with methanol (4 mL), and filtered. The filtrate was concentrated and the residue was dissolved in DMSO (3 mL). The crude product was purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 pm, 19x50 mm column, 20-50% MeCN in Water) to afford 6- chloro-2-(((2-hydroxyethyl)(phenyl)amino)methyl)quinazolin-4(3H)-one (0.028 g, 19.1 %) as a tan solid. 1HNMR (DMSO, 500 MHz) d 12.64 (1H, s), 8.03 (1H, d), 7.83 (1H, dd), 7.65 (1H, d), 7.19 - 6.95 (2H, m), 6.70 (2H, d), 6.64 (1H, t), 5.70 (1H, s), 4.55 (2H, s), 3.74 (2H, t), 3.68 (2H, t). MS (ES+): 330/332 (M+H)+ Example #70. 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one (CAS RN 900467-55-2)
Figure imgf000056_0001
Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one
Figure imgf000056_0002
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 200 mg; 0.87 mmol; 1.00 eq.) and m-cresol (CAS RN 108-39-4, 183 pL; 1.75 mmol; 2.00 eq.) to give 6-chloro-2-[(3- methylphenoxy)methyl]-3H-quinazolin-4-one (68 mg; 25.5 %) as a white amorphous powder. mp=237-240°C. ¾ NMR (400 MHz, DMSO-de) d = 12.78 (br s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 2.5, 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.84 (dd, J = 2.6, 8.1 Hz, 1H), 6.82 - 6.78 (m, 1H), 4.98 (s, 2H), 2.28 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.59 min; MS m/z: 301 [M+H]+.
Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one
Figure imgf000056_0003
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN2856-54-4, 200 mg; 0.87 mmol; 1.00 eq.) and p-cresol (CAS RN 106-44-5, 0.18 mL; 1.75 mmol; 2.00 eq.). The residue was triturated in Et20 giving 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one (208 mg; 77 %) as a white amorphous powder. mp=233-254°C. ¾NMR (400 MHz, DMSO-de) d = 12.70 (br s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.85 (dd, J= 2.5, 8.7 Hz, 1H), 7.69 (d, J= 8.7 Hz, 1H), 7.11 (d, J= 8.3 Hz, 2H), 6.94 (d, J= 8.7 Hz, 2H), 4.96 (s, 2H), 2.23 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.61 min; MS m/z: 301 [M+H]+. Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000057_0001
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-(dimethylamino)-3H-quinazolin-4-one (CAS RN 1690569-78-8, 200 mg; 0.84 mmol; 1.00 eq.) and 3-hydroxypyridine (CAS RN 109-00-2, 160 mg; 1.68 mmol; 2.00 eq.). The residue was purified by column chromatography (0 to 5% of MeOH in DCM) then recrystallized in ACN giving 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (12 mg; 5 %) as a yellow amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.25 (br s, 1H), 8.41 (d, J = 2.9 Hz, 1H), 8.21 (dd, J = 1.2, 4.6 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.50 (ddd, J = 1.2, 3.0, 8.5 Hz, 1H), 7.36 (ddd, J = 0.6, 4.6, 8.5 Hz, 1H), 7.32 (dd, J = 3.0, 9.0 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 5.02 (s, 2H), 3.01 (s, 6H). LC/MS (Table 1, Method B) Rt = 0.92 min; MS m/r. 297 [M+H]+.
Example #98. 6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000057_0002
The compound was synthesized using the same procedure detailed in Example #28 starting from 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 400 mg; 1.78 mmol; 1.00 eq.) and 3-hydroxypyridine (CAS RN 109-00-2, 339 mg, 3.56 mmol, 2.00 eq;). The reaction mixture was purified by column chromatography (0 to 30% of EtOAc in DCM) preparative chromatography (Table 2, condition 3) (column: X BRIDGE C18, 30 x 100mm 5pm (WATERS); Flow rate: 42 mL/min; Mobile phase: EEO + 0.1% AcOH / ACN + 0.1% AcOH; Gradient: 20-35%; run 30min) giving 6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (9 mg; 2 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-de) d = 11.9-12.8 (br s, 1H), 8.41 (d, J = 2.9 Hz, 1H), 8.21 (dd, J= 1.2, 4.6 Hz, 1H), 7.59 (d, J= 8.9 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.40 (dd, J= 3.1, 8.9 Hz, 1H), 7.35 (dd, 7= 4.6, 8.5 Hz, 1H), 5.05 (s, 2H), 3.87 (s, 3H). LC/MS (Table 1, Method B) Rt = 0.87 min; MS m/z: 284 [M+H]+.
Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one 2-(3-Pyridyloxy) acetonitrile (CAS RN 266348-17-8, 305 mg; 2.27 mmol; 3.00 eq.) was dissolved in MeOH (2 mL) and the solution was cooled in an ice bath at 10°C under N2 atm. Sodium methoxide (8 mg; 0.15 mmol; 0.20 eq.) was added and the solution was stirred for 45 min at 10°C. A solution of 2-amino-5-(dimethylamino)-4-fluoro-benzoic acid (CAS RN 1247552-18-6,150 mg; 0.76 mmol; 1.00 eq.) in MeOH (2 mL) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 3 days. The reaction was poured in 15 mL of H2O and filtered. The solid was washed with H2O three times, ACN one time, Et20 three times and dried under reduced pressure at 50°C for 3h providing 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H- quinazolin-4-one (127 mg; 53 %) as a beige amorphous powder. mp=245-260°C. 'H NMR (400 MHz, DMSO-de) d = 12.47 (br s, 1H), 8.41 (d, J= 2.8 Hz, 1H), 8.22 (dd, J= 1.3, 4.6 Hz, 1H), 7.50 (ddd, J = 1.3, 3.1, 8.5 Hz, 1H), 7.49 (d, J = 9.8 Hz, 1H), 7.42 (d, J= 14.1 Hz, 1H), 7.36 (ddd, J= 0.6, 4.7, 8.5 Hz, 1H), 5.06 (s, 2H), 2.88 (d, J= 0.9 Hz, 6H). LC/MS (Table 1, Method B) Rt = 1.02 min; MS in z: 315 [M+H]+.
Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000058_0001
The compound was synthesized using the same procedure detailed in Example #107 starting from 2-amino-5-isopropyl-benzoic acid (CAS RN 68701-22-4, 111.34 mg; 0.62 mmol; 1.00 eq.) and 2-(3-pyridyloxy)acetonitrile (CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.) providing after stirring only for 3h at rt 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (80 mg; 43 %) as a beige amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.45 (br s, 1H), 8.42 (d, J= 2.8 Hz, 1H), 8.21 (dd, 7= 1.2, 4.6 Hz, 1H), 7.96 (d, 7= 2.1 Hz, 1H), 7.74 (dd, 7= 2.1, 8.4 Hz, 1H), 7.60 (d, 7 = 8.4 Hz, 1H), 7.50 (ddd, 7 = 1.3, 3.0, 8.5 Hz, 1H), 7.36 (ddd, 7= 0.6, 4.6, 8.5 Hz, 1H), 5.09 (s, 2H), 3.06 (quin, 7 = 6.9 Hz, 1H), 1.26 (d, 7 = 6.8 Hz, 6H). LC/MS (Table 1, Method B) Rt = 1.18 min; MS m/z: 296 [M+H]+.
Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one The compound was synthesized using the same procedure detailed in Example #107 starting from 2-amino-4-fluoro-5-methoxybenzoic acid (CAS RN 637347-90-1, 115.03 mg; 0.62 mmol; 1.00 eq.) and 2-(3-pyridyloxy)acetonitrile (CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.) providing 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (41 mg; 22 %) after stirring 2 days at rt and 24h at 40°C as a beige amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.59 (br s, 1H), 8.41 (d, J= 2.9 Hz, 1H), 8.22 (dd, 7= 1.3, 4.6 Hz, 1H), 7.69 (d, J= 9.2 Hz, 1H), 7.54 (d, J = 12.0 Hz, 1H), 7.50 (ddd, J= 1.3, 3.0, 8.5 Hz, 1H), 7.36 (ddd, J= 0.6, 4.6, 8.5 Hz, 1H), 5.08 (s, 2H), 3.97 (s, 3H). LC/MS (Table 1, Method B) Rt = 0.95 min; MS m/z: 302 [M+H]+.
Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one
Figure imgf000059_0001
The compound was synthesized using the same procedure detailed in Example #107 starting from 5-amino-2-methoxy-pyridine-4-carboxylic acid (CAS RN 183741-91-5, 104.47 mg; 0.62 mmol; 1.00 eq.) and 2-(3-pyridyloxy)acetonitrile (CAS RN 266348-17-8, 250 mg; 1.86 mmol; 3.00 eq.) after stirring for lh at rt providing 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one (135 mg; 76 %) as a white amorphous powder. mp=239-259°C. ¾ NMR (400 MHz, DMSO-d6) d = 12.65 (br s, 1H), 8.75 (d, J= 0.7 Hz, 1H), 8.42 (d, J= 2.9 Hz, 1H), 8.22 (dd, J= 1.2, 4.6 Hz, 1H), 7.51 (ddd, J= 1.3, 3.0, 8.5 Hz, 1H), 7.37 (dd, J= 4.6, 8.5 Hz, 1H), 7.30 (d, J= 0.8 Hz, 1H), 5.08 (s, 2H), 3.95 (s, 3H). LC/MS (Table 1, Method B) Rt = 0.80 min; MS m/z: 285 [M+H]+.
Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000059_0002
In a 5mL microwave tube, 6-bromo-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (Preparation #8, 186 mg; 0.56 mmol; 1.00 eq.) was dissolved in anhydrous THF (5.6 mL), and the mixture was degazed with Ar bubbling during 10 min. Then azetidine hydrochloride (CAS RN 36520- 39-5, 68 mg; 0.73 mmol; 1.30 eq.), tBuOK (189 mg; 1.68 mmol; 3.00 eq.), 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (26.7 mg; 0.056 mmol; 0.10 eq.) and tris(dibenzylideneacetone)dipalladium (0) (51.3 mg; 0.056 mmol; 0.10 eq.) were successively added under Ar. The mixture was heated under microwave for 2h30 at 120°C. Extra 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (26.7 mg; 0.056 mmol; 0.10 eq.), tris(dibenzylideneacetone)dipalladium (0) (51.3 mg; 0.056 mmol; 0.10 eq.), azetidine hydrochloride (CAS RN 36520-39-5, 68 mg; 0.73 mmol; 1.30 eq.) and tBuOK (189 mg; 1.68 mmol; 3.00 eq.) were added under Ar bubbling. The mixture was heated again under microwave for 2h at 120°C. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (0 to 5% of MeOH with 0.1% of NH3 in DCM) then purified by column chromatography with amino silica gel (0 to 5% of MeOH in DCM) giving 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H- quinazolin-4-one (29 mg; 17 %) as a white amorphous powder. 'H NMR (500 MHz, DMSO-d6) d = 12.26 (s, 1H), 8.40 (d, J= 2.9 Hz, 1H), 8.21 (dd, J= 1.1, 4.7 Hz, 1H), 7.51 (d, J= 8.7 Hz, 1H), 7.49 (ddd, J = 1.2, 3.0, 8.5 Hz, 1H), 7.36 (dd, J= 4.6, 8.5 Hz, 1H), 6.95 (dd, J= 2.8, 8.7 Hz, 1H), 6.92 (d, J= 2.6 Hz, 1H), 5.02 (s, 2H), 3.92 (t, J= 7.3 Hz, 4H), 2.35 (quin, J= 7.3 Hz, 2H). LC/MS (Table 1, Method B) Rt = 0.97 min; MS m/z: 309 [M+H]+.
Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one
Figure imgf000060_0001
The compound was synthesized using the same procedure detailed in Example #111 starting from 6-bromo-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one (preparation #8, 186 mg; 0.56 mmol; 1.00 eq.) and pyrrolidine (CAS RN 123-75-1, 60 pL; 0.73 mmol; 1.30 eq.) after reaction 2 x 3h at 120°C under microwave. The residue was purified by column chromatography (0 to 5% of MeOH with 0.1% of ME in DCM) then purified by column chromatography with amino silica gel (0 to 5% of MeOH in DCM) giving 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one (50 mg; 27 %) as a white amorphous powder. ¾ NMR (500 MHz, DMSO-d6) d = 12.21 (s, 1H), 8.40 (d, J= 3.0 Hz, 1H), 8.21 (dd, J= 1.2, 4.5 Hz, 1H), 7.52 (d, J = 8.9, 1H) 7.50 (ddd, J = 1.2, 3.0, 8.5 Hz, 1H), 7.36 (ddd, J= 0.6, 4.7, 8.4 Hz, 1H), 7.12 (dd, J= 2.9, 8.9 Hz, 1H), 7.02 (d, J= 2.9 Hz, 1H), 5.01 (s, 2H), 3.30-3.35 (m, 4H), 2.00 (td, J = 3.4, 6.4 Hz, 4H). LC/MS (Table 1, Method B) Rt = 1.13 min; MS in z: 323 [M+H]+.
Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one Step A: 6-methoxy-2-(thiazol-5-yloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4- one
Figure imgf000061_0001
2-(Hydroxymethyl)-6-methoxy-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (Preparation #9, 250 mg; 0.74 mmol; 1.00 eq.) was dissolved in dry 1,4-dioxane (5 mL). NaH (60% in oil) (37 mg; 0.93 mmol; 1.25 eq.) was added and the mixture was stirred at rt for 30 min. 5-Bromo- 1,3-thiazole (CAS RN 3034-55-7, 133 pL; 1.49 mmol; 2.00 eq.) was added and the mixture was stirred at 100°C overnight. Reaction was cooled to rt and 25 mL of H2O were added. The mixture was extracted three times with 25 mL of EtOAc. The combined organic layers were washed with 20 ml of brine, dried over MgSCL, filtered and concentrated. The residue was purified by column chromatography ( 0 to 30% of EtOAc in DCM) giving 6-methoxy-2-(thiazol-5-yloxymethyl)-3-(2- trimethylsilylethoxymethyl)quinazolin-4-one (72 mg; 20 %) as a brown oil. 'H NMR (300 MHz, DMSO-de) 5 = 8.51 (d, J= 1.0 Hz, 1H), 7.66 (d, J= 8.9 Hz, 1H), 7.56 (d, J= 2.8 Hz, 1H), 7.50 - 7.43 (m, 2H), 5.58 (s, 2H), 5.34 (s, 2H), 3.89 (s, 3H), 3.63 (dd, J= 7.7, 8.5 Hz, 2H), 0.93 - 0.84 (m, 2H), -0.05 (s, 9H). LC/MS (Table 1, Method A) Rt = 2.93 min; MS m/z: 420 [M+H]+.
Step B: 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one
Figure imgf000061_0002
6-Methoxy-2-(thiazol-5-yloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (Example #113, Step A, 67 mg; 0.16 mmol; 1.00 eq.) was dissolved in HC14N in 1,4-dioxane (3 mL). The reaction mixture was stirred at 50°C for 2h. Mixture was poured slowly in 20 mL of a saturated aqueous solution of NaHCC . Mixture was filtered, solid was washed three times with LEO, once with ACN and three times with Et20 to give 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4- one (26 mg; 56 %) as a brown amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.50 (br s, 1H), 8.50 (s, 1H), 7.64 (br d , J= 8.7 Hz, 1H), 7.52 (br d, J= 2.2 Hz, 1H), 7.48 - 7.39 (m, 2H), 5.05 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 0.99 min; MS m/z: 290 [M+H]+.
Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000062_0001
Step A: 6-methoxy-2-(2-pyridyloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one
Figure imgf000062_0002
2-(Hydroxymethyl)-6-methoxy-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (preparation #9, 150 mg; 0.45 mmol; 1.00 eq.) was dissolved in dry 1,4-dioxane (3 mL). NaH (60% in oil) (23 mg; 0.58 mmol; 1.3 eq.) was added and mixture was stirred at rt for 10 min. 2-
Chloropyridine (63 pL; 0.67 mmol; 1.50 eq.) was added and the reaction mixture was refluxed overnight. The mixture was diluted with 15 mL of water and extracted three times with 15 mL of EtOAc. The combined organic layers were washed with 15 ml of brine, dried over MgSCL, filtered and concentrated in vacuo. The residue was purified by column chromatography (0 to 20% of EtOAc in cyclohexane) giving 6-methoxy-2-(2-pyridyloxymethyl)-3-(2- trimethylsilylethoxymethyl)quinazolin-4-one (77 mg; 42 %) as a colourless oil. 1H NMR (300 MHz, DMSO-de) d = 8.16 - 8.12 (m, 1H), 7.82 (ddd, J = 2.0, 7.1, 8.4 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H) 7.60 (d, J = 2.2 Hz, 1H), 7.48 (dd, J= 3.0, 8.8 Hz, 1H), 7.03 (ddd, J= 1.0, 5.1, 7.1 Hz, 1H), 6.96 (td, J = 0.9, 8.3 Hz, 1H), 5.61 (s, 2H), 5.51 (s, 2H), 3.88 (s, 3H), 3.71 - 3.64 (dd, J= 7.6, 8.4 Hz, 2H), 0.93 - 0.82 (m, 2H), -0.05 (s, 9H). LC/MS (Table 1, Method A) Rt = 3.16 min; MS m/z: 414 [M+H]+.
Step B: 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one
Figure imgf000062_0003
6-Methoxy-2-(2-pyridyloxymethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (Example #114, Step A, 72 mg; 0.17 mmol; 1.00 eq.) was dissolved in HC1 4N in 1,4-dioxane (1.1 mL). The reaction mixture was stirred at rt for 15h then at 50°C for 2h. The mixture was poured slowly in 25 mL of a saturated aqueous solution of NaHCC to give a white precipitate. Solid was filtered, washed three times with water and three times with Et20 then two times with ACN to provide 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one (40 mg; 78 %) as a beige amorphous powder. mp=195-203°C. ¾ NMR (400 MHz, DMSO-de) d = 12.41 (br s, 1H), 8.15 (ddd, J = 0.8,
2.0, 5.0 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.58 (d, J= 8.9 Hz, 1H), 7.51 (d, J= 3.0 Hz, 1H), 7.40 (dd, J = 3.1, 8.9 Hz, 1H), 7.02 (ddd, J= 0.9, 5.1, 7.1 Hz, 1H), 6.97 (td, J= 0.8, 8.4 Hz, 1H), 5.20 (s, 2H),
3.87 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.15 min; MS m/z: 284 [M+H]+. Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one
Figure imgf000063_0001
To a solution of 2-chlorobenzothiazole (CAS RN 615-20-3, 45 pL; 0.37 mmol; 1.00 eq.) and 2-(aminomethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1781075-04-4, 100 mg; 0.48 mmol; 1.30 eq.) inEtOH (1.51 mL) was added K2CO3 (76.15 mg; 0.55 mmol; 1.50 eq.). The reaction mixture was stirred at 70°C overnight. 10 mL of H2O were added and the solution was acidified until pH=6 then filtered. The solid was washed with water three times then Et20. The organic filtrate was concentrated. The residue was purified by column chromatography (0 to 5% of MeOH in DCM) giving 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one (41 mg; 31 %) as a yellow amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d = 12.30 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 7.69 (dd, J= 0.8, 7.8 Hz, 1H), 7.58 (d, J= 8.9 Hz, 1H), 7.50 (d, J= 3.0 Hz, 1H), 7.39 (dd, J =
3.0, 8.9 Hz, 1H) 7.38 (br d, J = 8.3 Hz, 1H), 7.22 (ddd, J= 1.3, 7.2, 8.2 Hz, 1H), 7.04 (dt, J= 1.2, 7.5 Hz, 1H), 4.57 (d, J= 5.6 Hz, 2H), 3.86 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.29 min; MS m/z: 339 [M+H]+.
Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one
Figure imgf000063_0002
In a Q-tube, to a solution of 2-chloro-5-phenyl-thiazole (CAS RN 329794-40-3, 350 mg; 1.79 mmol; 1.00 eq.) and 2-(aminomethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1781075-04-4, 477.19 mg; 2.33 mmol; 1.30 eq.) in EtOH (7 mL) was added K2CO3 (370.82 mg; 2.68 mmol; 1.50 eq.) at rt. The reaction mixture was stirred under N2 atm, at 70°C overnight. Heating was gradually raised up to 120°C for 4 days. The reaction mixture was concentrated then 20 mL of H2O were added and the solution was filtered. The solid was washed with water three times. The residue was purified by washing with ACN/H2O giving 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H- quinazolin-4-one (7 mg; 1 %) as an orange amorphous powder. 'H NMR (400 MHz, DMSO-d6) d = 12.25 (s, 1H), 8.26 (t, 7 = 5.8 Hz, 1H), 7.58 (d, 7 = 8.8 Hz, 1H), 7.49 (d, 7= 3.0 Hz, 1H), 7.46 (s, 1H), 7.45 - 7.41 (m, 2H), 7.39 (dd, 7 = 3.1, 8.9 Hz, 1H), 7.34 (t, 7 = 7.8 Hz, 2H), 7.22 - 7.17 (m, 1H), 4.45
(d, 7 = 5.8 Hz, 2H), 3.86 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.42 min; MS m/r 365 [M+H]+.
Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one (CAS RN 2130021-45-1)
Figure imgf000064_0001
Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one
Figure imgf000064_0002
3-Trifhioromethylphenol (CAS RN 98-17-9, 270 pL; 2.23 mmol; 2.00 eq.) was dissolved in DMF (2.50 mL) under N2. The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (107 mg; 2.67 mmol; 2.40 eq.) was added. The reaction mixture was stirred at 0°C for 30min. The temperature was raised to rt and 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt for 48h until completion. The reaction mixture was diluted in H2O and the formed white precipitate was filtered and washed with water (3x) and Et20 (6x). The residue was purified by column chromatography (0 to 10% of EtOAc in DCM) giving 6-methoxy-2-[[3- (trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one (34 mg; 8 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-de) d 12.49 (br s, 1H), 7.62 (d, 7=8.9 Hz, 1H), 7.56 (t, 7=7.3 Hz, 1H), 7.52 (d, 7=2.9 Hz, 1H), 7.41-7.46 (m, 2H), 7.32-7.40 (m, 2H), 5.09 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.55 min; MS m/ 351 [M+H]+. Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one 3-Nitrophenol (CAS RN 554-84-7, 186 mg; 1.34 mmol; 3.00 eq.) was dissolved in DMF (1.00 mL) under N2. The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (53 mg; 1.33 mmol; 2.98 eq.) was added. The reaction mixture was stirred at 0°C for 30min. The temperature was raised to rt and 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 100 mg; 0.45 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt for 3 days. The reaction mixture was diluted in H2O and after 10 minutes the formed precipitate was filtered and washed with water (3x) and Et20 (3x). The beige residue was purified by column chromatography (0 to 100% of EtOAc in DCM) followed by trituration in Et20 giving 6-methoxy-2-[[3-nitrophenoxy]methyl]-3H- quinazolin-4-one (11 mg; 7 %) as a white amorphous powder. 'H NMR (400 MHz, DMSO-d6) d 12.52 (br s, 1H), 7.92 (t, J= 2.3 Hz, 1H), 7.87 (ddd, =1.0, 2.2, 8.0 Hz, 1H), 7.59-7.65 (m, 2H), 7.53- 7.58 (m, 1H), 7.52 (d, J= 2.9 Hz, 1H), 7.43 (dd, J= 3.0, 8.8 Hz, 1H), 5.15 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.34 min; MS m/z: 328 [M+H]+.
Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile
Figure imgf000065_0001
3-Hydroxybenzonitrile (CAS RN 873-62-1, 265 mg; 2.23 mmol; 2.00 eq.) was dissolved in DMF (2.50 mL) under N2. The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (107 mg; 2.67 mmol; 2.40 eq.) was added. The reaction mixture was stirred at 0°C for 30 min. The temperature was raised to rt and 2-(chloromethyl)-6-methoxy-3H-quinazolin-4-one (CAS RN 1263413-60-0, 250 mg; 1.11 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water and the formed precipitate was filtered and washed with water (3x) and Et20 (3x). The residue was purified by column chromatography (0 to 10% of EtOAc in DCM) providing 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile (33 mg; 10 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d 12.48 (br s, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.58 (dd, J=1.3, 2.3 Hz, 1H), 7.51-7.54 (m, 2H), 7.45-7.48 (m, 1H), 7.41-7.45 (m, 2H), 5.06 (s, 2H), 3.88 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.26 min; MS m/z: 308 [M+H]+.
Example #137. 6-chloro-2- [(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one
Figure imgf000066_0001
3-Methoxyphenol (CAS RN 150-19-6, 217 mg; 1.75 mmol; 2.00 eq.) was dissolved in DMF (2.00 mL) under N2. The reaction mixture was cooled at 0°C, under N2 atm, NaH (60% in oil) (84 mg; 2.10 mmol; 2.40 eq.) was added. The reaction mixture was stirred at 0°C for 30 min. The temperature was raised to rt and 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54- 4, 200 mg; 0.87 mmol; 1.00 eq.) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water and the formed precipitate was filtered and washed with water (3x) and Et20 (3x) providing 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one (147 mg; 51 %) as a white amorphous powder. ¾ NMR (400 MHz, DMSO-d6) d 12.67 (br s, 1H), 8.06 (d, J= 2.5 Hz, 1H), 7.86 (dd, J= 2.5, 8.7 Hz, 1H), 7.70 (d, =8.7 Hz, 1H), 7.21 (t, =8.4 Hz, 1H), 6.61-6.68 (m, 2H), 6.53-6.59 (m, 1H), 4.99 (s, 2H), 3.73 (s, 3H). LC/MS (Table 1, Method B) Rt = 1.49 min; MS m/z: 317 [M+H]+.
Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one
Figure imgf000066_0002
The compound was synthesized using the same procedure detailed in Example #1 starting from 2-(chloromethyl)-6-chloro-3H-quinazolin-4-one (CAS RN 2856-54-4, 150 mg; 0.65 mmol; 1.00 eq.), N-methylcyclohexylamine (CAS RN 100-60-7, 95 pL; 0.72 mmol; 1.10 eq.) and K2CO3 (136 mg; 0.98 mmol; 1.50 eq.) in EtOH (3 mL) was stirred at 80°C overnight. Reaction mixture was diluted with H2O and filtered. The residue was washed with water (2x) and Et20 then dried to provide 6- chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one (95 mg; 45 %) as a white amorphous powder. mp=183-197°C. ¾ NMR (400 MHz, DMSO-de) d 8.04 (d, J= 2.6 Hz, 1H), 7.82 (dd, J= 2.5, 8.7 Hz, 1H), 7.66 (d, =8.7 Hz, 1H), 3.55 (s, 2H), 2.43-2.49 (m, 1H), 2.21 (s, 3H), 1.69- 1.86 (m, 4H), 1.52-1.63 (m, 1H), 1.13-1.31 (m, 4H), 0.99-1.12 (m, 1H). LC/MS (Table 1, Method B) Rt = 0.93 min; MS m/r. 306 [M+H]+.
Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one
Figure imgf000067_0001
Step A: tert-butyl (2-(phenylamino)ethyl)carbamate (0.134g, 0.568 mmol) was added to a mixture of 6-chloro-2-(chloromethyl)quinazolin-4(3H)-one (0.1 g, 0.437 mmol) and potassium carbonate (0.181 g, 1.310 mmol) in ethanol (2 ml, 0.437 mmol) and the mixture was stirred at 75 °C for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtred and concentrated. The residue was dissolved in DMSO (2 mL) and the crude product was purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep- C18, 5 pm, 19x50 mm column, 35-65% MeCN in Water) to afford tert-butyl (2-(((6-chloro-4-oxo- 3,4-dihydroquinazolin-2-yl)methyl)(phenyl)amino)ethyl)carbamate (0.031 g, 0.072 mmol, 16.56 % yield) as a tan solid. MS (ES+): 329/331 (M-C02tBu+H)+
Step B: HC1 (4M solution in Dioxane) (0.175 ml, 0.699 mmol) was added to a solution of tert-butyl (2-(((6-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(phenyl)amino)ethyl)carbamate (0.030 g, 0.070 mmol) in DCM/Dioxane (1:1, 2 mL) and the mixture was left to stir at room temperature overnight. The mixture was concentrated and the residue was dissolved in methanol then loaded on a column packed with SCX. The column was washed with methanol and the compound eluted with 1% MLMeOH. The product was further purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 pm, 19x50 mm column, 20-50% MeCN in Water) to afford 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one (0.013 g, 53.7) as a colourless solid. 1H NMR (DMSO-d6, 500 MHz) d 7.93 (1H, d), 7.67 (1H, dd), 7.58 (1H, d), 7.16 - 7.09 (2H, m), 6.69 (2H, d), 6.61 (1H, t), 4.41 (2H, s), 3.73 (2H, t), 3.03 (2H, s) (exchangeable protons not observed). MS (ES+): 329/331 (M+H)+
Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one
Figure imgf000067_0002
1HNMR (500 MHz, DMSO-d6) d 11.75 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.82 (dd, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.99 - 6.91 (m, 2H), 6.88 (ddd, 1H), 4.15 (s, 2H), 3.76 (s, 3H), 2.83 (s, 3H). MS (ES+): 330/332 (M+H)+
EXAMPLE B - BIOLOGY
Material and Method
• HMGB1
Construction of pBiT3.1-HMGBl plasmid
HMGBl derived from pCMV6-AC-GFP plasmid (ref. RG205918, Origene) was amplified by PCR using the following set of primers: Seq ID No 1: forward, 5’- GATATCGAATTCATGGGC AAAGGAGATCCTAAGAAGCCGAGAGGC-3 ’ ; Seq ID No 2: reverse, 5’- TATC AGCTCGAGACTTCATCATCATCATCTTCTTCTTC ATCTTC-3 ’ . The PCR fragment was subsequently digested by EcoRI and Xhol (R3101S and R0146S respectively, New England Biolabs) and inserted between the EcoRI and Xhol sites in the plasmid pBiT3.1-C (ref. N237A, Promega). The resulting plasmid (pBiT3.1 -HMGBl) was grown in NEBlO-beta competent E. coli (ref. C3019I, New England Biolabs) and purified using the NucleoBond Xtra Midi Kit (ref. 740410, Macherey -Nagel).
Construction of HMGBl reporter cell line pBiT3.1 -HMGBl was transfected in MDA-MB-231 cells (ref. ATCC HTB-2) using Lipofectamine 2000 reagent (ref. 11668, Invitrogen). Transfected cells were selected for blasticidin resistance (15pg/ml, ref. Al l 13903 Gibco) in medium containing DMEM IX (ref. 1995065, Gibco) with 1% penicillin and streptomycin, and 10% fetal bovine serum.
Screen for HMGBl-releasing drugs
MDA-MB-23 1 cells stably expressing HMGBl-HiBiT (104 cells/well) were seeded into white 96-well plates (ref.3917, Coming) and allowed to recover for 24h. Following this, serial 2-fold dilutions of compounds (between ImM and lnM) were added. Mitoxantrone dihydrochloride (ref. M6545, Sigma-Aldrich) was used as a positive control. Extracellular translocation of HMGBl was measured using the Nano-Glo HiBiT extracellular detection system (ref. N2422, Promega). Nano- Glo HiBiT Extracellular Reagent was prepared in advance, added to the well and incubated lOmin. Luminescence of the extracellular HMGBl-HiBiT was quantified using the Spark 20M spectrofluorimeter (TEC AN).
• Calreticulin Construction of pBiT3.1-Calreticulin plasmid
Calreticulin derived from pCMV6-AC plasmid (ref. SC320287, Origene) was amplified by PCR using the following set of primers: Seq ID No 3: forward, 5’- GATATCGAATTCATGCTGCTATCCGTGCCGCTGCTGCTCGGCCTCCTCG-3 ’ ; Seq ID No 4: reverse, 5 ’ - T ATC AGCTCGAGACC AGCTCGTCCTTGGCCTGGCCGGGGAC ATCTTCC-3 ’ . The PCR fragment was subsequently digested by EcoRI and Xhol (R3101 S and R0146S respectively, New England Biolabs) and inserted between the EcoRI and Xhol sites in the plasmid pBiT3.1-C (ref. N237A, Promega). The resulting plasmid (pBiT3.1 -Calreticulin) was grown in NEBlO-beta competent A. coli (ref. C3019I, New England Biolabs) and purified using the NucleoBond Xtra Midi Kit (ref. 740410, Macherey -Nagel).
Construction of Calreticulin reporter cell line pBiT3.1 -Calreticulin was transfected in MDA-MB-231 cells (ref. ATCC HTB-2) using Lipofectamine 2000 reagent (ref. 11668, Invitrogen). Transfected cells were selected for blasticidin resistance (15pg/ml, ref. Al l 13903 Gibco) in medium containing DMEM IX (ref. 1995065, Gibco) with 1% penicillin and streptomycin, and 10% fetal bovine serum.
Screen for calreticulin-ER to plasma membrane translocating drugs
MDA-MB-231 cells stably expressing Calreticulin-HiBiT (104 cells/well) were seeded into white 96-well plates (ref 3917, Corning) and allowed to recover for 24h. Following serial 2-fold dilutions, compounds (between ImM and InM) were added. Mitoxantrone dihydrochloride (ref. M6545, Sigma-Aldrich) was used as a positive control. Extracellular translocation of Calreticulin was measured using the Nano-Glo HiBiT extracellular detection system (ref. N2422, Promega). Nano- Glo HiBiT Extracellular Reagent was prepared in advance, added to the well and incubated lOmin. Luminescence of the extracellular Calreticulin-HiBiT was quantified using the Spark 20M spectrofluorimeter (TEC AN).
Results
The results on Calreticulin release (EC50) and HMGBl release (High-mobility group box 1) (EC50) are represented in the Table 3 below. Particularly, the results show that the compounds of formula (I) induce calreticulin and HMGBl release. More particularly, EC50 for Calreticulin release are in mM ranges, preferably lower than 12 pM, and more preferably lower than 1 pM, demonstrating thereby an efficicient anticancer effect for the compounds of the present invention. Table 3:
Figure imgf000070_0001
ND: Not Determined

Claims

1. A compound for use for treating a cancer having the following formula (I):
Figure imgf000071_0001
wherein:
> X represents:
• an oxygen atom,
• a methylene group,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or - a -CHI group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, and a (Ci- Ce)alkyloxy optionally substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyl or a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a -NH-CCk-Rs with Rs being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen or a (Ci-C6)alkyloxy; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
2. A compound for use according to claim 1, wherein Y represents a nitrogen or a -CR2 group, preferably a -CR2 group, in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, preferably a fluorine or a chlorine, a (Ci-C6)alkyloxy optionally substituted by a halogen, preferably a methoxy or a trifluoromethoxy, a (Ci-C6)alkyl optionally substituted by a halogen, preferably a methyl or a trifluorom ethyl, more preferably R2 is a hydrogen or a halogen, preferably a fluorine, and even more preferably R2 is a hydrogen.
3. A compound for use according to claim 1 or 2, wherein R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a (Ci-C6)alkyloxy, preferably a methoxy, a (Ci-C6)alkyl, preferably an isopropyl, a -NR6R7 with 5 and R7 being a methyl, and a halogen, preferably a chlorine.
4. A compound for use according to any one of claims 1 to 3, wherein n is 0.
5. A compound for use according to any one of claims 1 to 4, wherein X represents an oxygen atom.
6. A compound for use according to claim 5, wherein: Ri represents a 5-10 membered ring selected in a group consisting of a pyridinyl and a phenyl, said 5-10 membered ring is optionally substituted by at least one radical selected in the group consisting of: a phenyloxy, a halogen, preferably a florine or a chlorine, and a (Ci-C6)alkyl, preferably a methyl;
> n is 0;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of: an azetidinyl, a pyrrolidinyl, a methoxy, an isopropyl, and a -NR6R7 with 5 and R7 being a methyl; and R4 represents a hydrogen.
7. A compound for use according to any one of claims 1 to 4, wherein X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group, preferably a methyl.
8. A compound for use according to claim 7, wherein: Ri represents an unsubstituted phenyl, a phenyl substituted by a methyl, a methyloxy, a pyridinyl, a benzothiazolyl, a thiazolyl substituted by a phenyl, and a cyclohexyl;
> n is 0;
> Y represents a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen and a halogen; R3 represents a radical selected in the group consisting of a methoxy and a halogen, preferably a chlorine; and R4 represents a hydrogen.
9. A compound for use according to any one of claims 1 to 3, wherein said compound is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #70. 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #26. 2-(benzenesulfonylmethyl)-6-methoxy-3H-quinazolin-4-one;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one; - Example #137. 6-chloro-2-[(3-methoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one; - Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
10. A compound for use according to any one of claims 1 to 4, wherein said compound is selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one - Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #27. 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #121. 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one; - Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one; - Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one; and
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one.
11. A compound having the following formula (I):
Figure imgf000075_0001
wherein:
> X represents: • an oxygen atom,
• a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group,
• a sulfur atom or a sulfone group; n is an integer equal to 0 or 1, preferably equal to 0; Ri represents a 5-10 membered ring selected in a group consisting of:
• a pyridinyl,
• a phenyl, and
• a thiazolyl, a benzothiazolyl, a benzoxazole, an isoxazolyl, and a cyclohexyl, said 5-10 membred ring is optionally substituted by at least one radical selected in the group consisting of: a halogen, a (Ci-C6)alkyl optionally substituted by at least one halogen, a (Ci-C6)alkyloxy optionally substituted by at least one halogen, a phenyloxy, a phenyl, a pyridinyl, a nitro, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, and a cyano;
> Y represents:
- a nitrogen, or
- a -CR2 group in which R2 is a radical selected in the group consisting of a hydrogen, a halogen, a (Ci-C6)alkyl substituted by at least one halogen, a (Ci-C6)alkyloxy substituted by at least one halogen; R3 represents a radical selected in the group consisting of: a 3-10 membered ring selected in the group consisting of a cycloalkyl, a heterocycloalkyl, and an aryl, said 3-10 membered ring is optionally substituted by a radical selected in a group consisting of: o a (Ci-C6)alkyl optionally substituted by a (Ci-C6)alkyloxy, a hydroxy or a halogen, o a (Ci-C6)alkyloxy optionally substituted by a a halogen, o a halogen, and o a hydroxy a (Ci-C6)alkyloxy optionally substituted by a halogen, a (Ci-C6)alkyloxy, or a - NH-CO2-R8 with R.8 being a (Ci-C6)alkyl, a -NR6R7 with 5 and R7 being independently a hydrogen or a (Ci-C6)alkyl, a halogen, a hydrogen, and a cyano, or
R3 may form with R2 a dioxolanyl; and R4 represents a hydrogen; with the proviso that the compound of formula (I) is not a compound selected in the group consisting of:
- 2-(4-chloro-phenoxymethyl)-6-methoxy-3H-quinazolin-4-one;
- 7-fluoro-2-(phenoxymethyl)-3H-quinazolin-4-one;
- 6-chloro-2-(phenoxymethyl)-3H-quinazolin-4-one; and
- 6-methoxy-2-(phenoxymethyl)-3H-quinazolin-4-one; and the stereoisomers, the tautomers, and the pharmaceutical salts thereof.
12. A compound according to claim 11, wherein Y represents a -CR2 group in which R2 is a hydrogen.
13. A compound according to claim 11 or 12, wherein R3 represents a (Ci-C6)alkyloxy or a halogen, preferably a methoxy or a chlorine, more preferably a methoxy.
14. A compound according to any one of claims 11 to 13, wherein:
> X represents an oxygen atom; and Ri represents a pyridinyl optionally substituted by at least a (Ci-C6)alkyl, preferably a methyl.
15. A compound according to any one of claims 11 to 13, wherein:
> X represents a -NR5 group with R5 being a hydrogen or a (Ci-C6)alkyl optionally substituted by a hydroxy or an amino group; and Ri represents a phenyl optionally substituted by at least a halogen, a (Ci-C6)alkyl, preferably a methyl, or a (Ci-C6)alkyloxy, preferably a methoxy.
16. A compound selected in the group consisting of:
- Example #75. 6-(dimethylamino)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #111. 6-(azetidin-l-yl)-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #107. 6-(dimethylamino)-7-fluoro-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one; - Example #29. 6-methoxy-2-[(3-phenoxyphenoxy)methyl]-3H-quinazolin-4-one;
- Example #108. 6-isopropyl-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #98. 6-m ethoxy -2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #28. 2-[(2-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #35. 6-methoxy-2-[(6-methyl-3-pyridyl)oxymethyl]-3H-quinazolin-4-one;
- Example #109. 7-fluoro-6-methoxy-2-(3-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #24. 6-methoxy-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #112. 2-(3-pyridyloxymethyl)-6-pyrrolidin-l-yl-3H-quinazolin-4-one ;
- Example #30. 2-[(3-chlorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example#25. 6-methoxy-2-(phenylsulfanylmethyl)-3H-quinazolin-4-one;
- Example #113. 6-methoxy-2-(thiazol-5-yloxymethyl)-3H-quinazolin-4-one;
- Example #65: 6-chloro-2-[(N-methylanilino)methyl]-3H-quinazolin-4-one;
- Example #31. 2-[(3-fluorophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #32. 2-[(3-bromophenoxy)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #110. 6-methoxy-2-(3-pyridyloxymethyl)-3H-pyrido[3,4-d]pyrimidin-4-one;
- Example #71. 6-chloro-2-[(3-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #115. 2-[(l,3-benzothiazol-2-ylamino)methyl]-6-methoxy-3H-quinazolin-4-one;
- Example #116. 6-methoxy-2-[[(5-phenylthiazol-2-yl)amino]methyl]-3H-quinazolin-4-one;
- Example #114. 6-methoxy-2-(2-pyridyloxymethyl)-3H-quinazolin-4-one;
- Example #72. 6-chloro-2-[(4-methylphenoxy)methyl]-3H-quinazolin-4-one;
- Example #33. 6-methoxy-2-[[3-(trifluoromethoxy)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #34. 6-methoxy-2-[(2-methyl-l,3-benzoxazol-4-yl)oxymethyl]-3H-quinazolin-4-one;
- Example #66. 6-chloro-2-[(N,3-dimethylanilino)methyl]-3H-quinazolin-4-one;- dEF13564;
- Example #67. 6-chloro-2-[[methyl(3-pyridyl)amino]methyl]-3H-quinazolin-4-one;
- Example #68. 6-chloro-2-[(N,4-dimethylanilino)methyl]-3H-quinazolin-4-one;
- Example #69. 6-chloro-2-[[N-(2-hydroxyethyl)anilino]methyl]-3H-quinazolin-4-one;- dEF13361;
- Example #134. 6-methoxy-2-[[3-(trifluoromethyl)phenoxy]methyl]-3H-quinazolin-4-one;
- Example #141. 6-chloro-2-[[cyclohexyl(methyl)amino]methyl]-3H-quinazolin-4-one;
- Example #135. 6-methoxy-2-[(3-nitrophenoxy)methyl]-3H-quinazolin-4-one;
- Example #143. 6-chloro-2-(((2-methoxyphenyl)(methyl)amino)methyl)quinazolin-4(3H)-one;
- Example #142. 2-(((2-aminoethyl)(phenyl)amino)methyl)-6-chloroquinazolin-4(3H)-one; and
- Example #136. 3-[(6-methoxy-4-oxo-3H-quinazolin-2-yl)methoxy]benzonitrile.
17. A compound according to any one of claims 11 to 16, for use as a drug.
18. A pharmaceutical composition comprising a compound according to any one of claims 11 to 16.
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